The Canadian Association for Neuroscience presents 8th Annual Canadian Neuroscience Meeting 2014

Place des Arts

Old Montréal

Place Jacques-Cartier Place Jacques-Cartier

© Tourisme Montréal, Stéphan Poulin May 25–28, 2014 CAN-ACN The Hilton Bonaventure Hotel Abstract Booklet Montréal, Québec www.can-acn.org TABLE OF CONTENTS

Invited Speaker Abstracts page 4

Parallel symposia Abstracts pages 5 - 19

Poster Session 1, May 26 pages 20 – 94

Poster Session 2, May 27 pages 95 – 169

Poster Session 3, May 28 pages 170 - 244 CAN-ACN 2014: Abstract Booklet Montreal, May 25-28

Invited Speakers Huntington Disease Initiative, and Michael Smith Foundation for Health Research. Presidential Lecture: Lynn Raymond, University of British Featured Plenary Speaker: Columbia Edward S. Boyden, MIT Mechanisms and neuroprotective strategies Tools for Mapping Brain Computations in neurodegeneration: Huntington disease The brain is a densely and precisely wired circuit can lead the way made of heterogeneous cells, which themselves Evidence indicates that NMDA-type glutamate are complex computational devices made of an receptor (NMDAR)-induced synaptic loss and incredible repertoire of molecules. Our group neuronal dysfunction/death contributes to develops tools for mapping, recording from, mechanisms underlying certain controlling, and building brain circuits, in order to neurodegenerative diseases and acute reveal how they work, as well as to open up new neurological insults. Yet, cell signaling therapeutic avenues. We have developed downstream of NMDARs can promote cell genetically-encoded reagents that, when survival and plasticity as well as excitotoxicity, expressed in specific neurons, enable their which may help explain why general NMDAR electrical activities to be precisely driven or inhibitors have failed in clinical trials. A new silenced in response to millisecond timescale paradigm developed over the past decade pulses of light. I will give an overview of these suggests that over-stimulation of extrasynaptic optogenetic tools, adapted from natural NMDARs triggers stress/death pathways photosensory and photosynthetic proteins, and whereas physiological activation of those inside discuss new tools we are developing, including the synapse contributes to cell survival, raising molecules that enable multiplexed, noninvasive, the possibility of neuroprotection based on and ultraprecise optical neural control. We are subcellular localization. This idea has been also developing optogenetic tools that enable tested in the inherited, predominantly adult activation of endogenous protein and signaling onset, neurodegenerative disorder Huntington pathways (e.g., lumitoxins). Often working in disease (HD), which manifests as progressive interdisciplinary collaborations, we are motor, mood and cognitive impairment. Caused developing microfabricated hardware to enable by a polymorphic CAG repeat expansion in the complex and distributed neural circuits to be HD gene that encodes an enlarged controlled and recorded in a fully 3-D fashion, polyglutamine tract in the protein huntingtin, HD new kinds of microscopes capable of whole- is associated with selective neurodegeneration, nervous system neural activity imaging, robots principally of striatal GABAergic spiny projection that can automatically record neurons neurons (SPN) and cortical pyramidal neurons. intracellularly and integratively in live brain, and Genetically accurate mouse models have strategies for building 3-D brain circuits in facilitated understanding of HD pathogenesis. In vitro. We aim to provide these tools to the one HD mouse model (YAC128), we have neuroscience community in order to open up shown an increase in number, activity, and new fundamental as well as clinically relevant downstream signaling of extrasynaptic NMDARs explorations of how to observe and repair brain on SPN beginning in the early postnatal period; circuits. selective inhibition of these receptors from an early age ameliorates later stage cell death Plenary Symposium: Development and signaling and also improves motor learning and application of optogenetic tools coordination. Moreover, we and others have identified additional synaptic alterations that Timothy H Murphy, University of British occur prior to overt motor manifestations. In Columbia particular, we have characterized morphological In vivo optogenetic assessment and control and electrophysiological changes in cortical- of mouse cortical circuits striatal co-cultures from HD mice, a simple Optogenetics employs light to measure brain model system that can serve as a platform for activity by assessing the effect of membrane testing therapeutics. Since HD gene mutation voltage, intracellular calcium, or even carriers can be identified decades before clinical extracellular neurotransmitter concentration on diagnosis, targeting early changes in cortical- recombinant protein sensors. A second class of striatal synaptic transmission may significantly recombinant proteins-light-activated actuators, delay onset of manifest disease. Supported by alter circuit function by activating excitatory or the CIHR, Huntington Society of Canada, Cure inhibitory ion channels or pumps. Relatively non-invasive through-skull in vivo imaging and 1

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 optical manipulation of cortex will be discussed. of this and other targets of interest to To assess changes in functional connectivity neuroscientists will be discussed. after stroke, we have developed an automated approach to monitor intrahemispheric and Featured Plenary Speaker: interhemispheric relationships by the activation Eric Neslter, Mt Sinai, NYC of ChR2-expressing cortical neurons. To monitor Transcriptional and Epigenetic Mechanisms regional cortical activity we employ organic of Drug Addiction voltage sensitive dyes or genetically encoded Drug addiction can be viewed as a stable form sensors. In vivo imaging of functional of drug-induced neural plasticity, whereby long- connectivity is extended genetically-encoded lasting changes in gene expression mediate indicators of intracellular calcium using some of the stable behavioral abnormalities that GCAMPs, glutamate iGluSNFR, and voltage define an addicted state. Our laboratory has sensitive fluorescent protein butterfly (VSPF- focused on two main transcriptional pathways in butterfly). We apply network analysis to addiction. Chronic exposure to cocaine or connection matrices derived from functional opiates causes the prolonged activation of the maps to elucidate reciprocal connections transcription factor CREB within the brain’s between primary and secondary sensory areas, reward circuits and several other brain regions, identify network hubs, and determine and this adaptation mediates aspects of drug symmetries within intracortical connectivity. tolerance and dependence. In contrast, Comparisons of functional connectivity maps to induction of another transcription factor, the cortical structural connectome (Allen DeltaFosB, in brain reward regions by virtually Institute) indicate that intracortical monosynaptic all drugs of abuse exerts the opposite effect and structural connections predict hemisphere-wide contributes to sensitized responses to drug patterns of spontaneous and sensory-evoked exposure. Studies are underway to explore the depolarization. A new approach to stroke detailed molecular mechanisms by which CREB damage is to treat it as a disorder of connectivity and DeltaFosB regulate target genes and and loss of function. The talk will provide an thereby contribute to the complex state of introduction into circuit-level optogenetic addiction. One way to approach such molecular actuators and sensors, circuitry database such mechanisms of drug action in vivo is through the as the Allen Institute Mouse Brain Connectivity study of chromatin remodeling, that is, changes Atlas, and how these approaches can be in the acetylation or methylation of histones that applied to stroke damage. bind to certain drug-regulated gene promoters, or changes in methylation of the genes Andrew Woolley, University of Toronto themselves, as revealed by chromatin Optogenetic control using photoactive immunoprecipitation (ChIP). We are utilizing yellow protein ChIP to examine chromatin changes at specific Numerous processes, in addition to the firing of candidate genes for CREB and DeltaFosB, as action potentials, that are of interest to well as genome-wide measures to gain a more neuroscientists exhibit complex spatiotemporal global view of target genes for these patterns of activity. Optogenetic tools for transcription factors. Prominent among these manipulation of these processes could offer new targets are those that regulate synaptic function ways to probe the function in vivo. In addition to and plasticity as well as the morphology of drug- channelrhodopsins, a number of other regulated neurons. We have also demonstrated photoswitchable domains exist that may be drug regulation of some of the enzymes that harnessed to control function. Strategies for catalyze chromatin modifications, which achieving this have thus far relied mainly on indicates that chromatin remodeling control of protein localization. Photoactive yellow mechanisms are themselves important targets protein, a small, cytosolic domain, undergoes a of drug action. These findings establish particularly large change in conformation and chromatin remodeling as an important regulatory dynamics upon exposure to blue light. This mechanism underlying drug-induced neural and feature has allowed us to develop strategies to behavioral plasticity, and provide fundamentally couple to PYP isomerization to changes in new insight into how CREB and DeltaFosB, and target protein function with affecting protein several other drug-regulated transcription localization. In particular we have developed an factors, contribute to addiction by regulating the approach to the optogenetic control of CREB expression of specific target genes in the brain’s activity by linking PYP to a dominant negative reward circuitry. These advances can now be CREB inhibitor. Approaches to the photo-control mined to develop improved diagnostic tests and treatments for addictive disorders. 2

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visceral bias towards larger, uncertain rewards, Plenary Symposium: Mechanisms in learning whereas prefrontal regions serve to temper reward value these urges when riskier options become less

Jonathan Britt, McGill University profitable via top-down control over the Dissecting the Neural Circuits Underlying amygdala. Dopamine D1/D2 transmission within Motivated Behaviours Relevant to Reward these regions also makes dissociable, yet Learning and Drug Addiction complementary, contributions to risk/reward The nucleus accumbens plays a major role in judgments, promoting either exploitation of the generation of motivated behaviour. It current favorable circumstances or exploration integrates dopaminergic reinforcement signals of more profitable ones when conditions with glutamate-encoded environmental change. Dynamic fluctuations in prefrontal and stimuli. Prominent glutamate afferents to the accumbens tonic dopamine transmission appear nucleus accumbens come from the to encode distinct types of information related to hippocampus, amygdala, thalamus, and decision making related to changes in reward prefrontal cortex. Pathway-specific activation of availability, uncertainty and choice biases. On these inputs is known to produce distinct the other hand, phasic increases and decreases behavioral responses, but mechanistic in dopamine activity, regulated in part by the explanations for these pathway-specific effects lateral habenula, appear to play a key role in are lacking. This talk examines the pathway- providing short-term information about recent specific differences in synaptic properties and outcomes that bias subsequent choice. These innervation patterns between these findings provide insight into the dynamic glutamatergic inputs to the nucleus competition between cortical/subcortical circuits accumbens. While there are important that shape decision biases and underlie distinctions between these afferent connections, conflicting urges when evaluating options that optogenetic stimulations targeted to any of them vary in terms of potential risks and rewards. can reinforce instrumental behaviour. This finding challenges the idea that these inputs Keynote Lecture: encode motivationally-neutral information. Mice Michael E. Greenberg, Harvard Medical will also work to obtain optical manipulations to School projections neurons throughout the striatum as Signaling Networks that Regulate Synapse well as downstream structures, but, regardless Development and Cognitive Function of which basal ganglia nuclei are targeted for Our interactions with the outside world trigger self-stimulation, the behaviour is always changes at synapses that are critical for proper sensitive to dopamine receptor blockade. This brain development and higher cognitive function. work characterizes some of the fundamental Research in the Greenberg laboratory has organizing principles of basal ganglia focused on the identification of a genetic information processing. program that is activated by neuronal activity, the mechanisms of signal transduction that carry Stan Floresco, University of British Columbia the neuronal activity-dependent signal from the Dopaminergic circuits mediating risk/reward membrane to the nucleus, and the identification decision biases of regulators of this experience-dependent Choosing between smaller, assured rewards or process that affect synapse development and larger, uncertain ones requires reconciliation of plasticity. Our recent studies using global competing biases towards more certain or riskier screening techniques have identified activity- options. These conflicting urges reflect an dependent genes that control 1) the complexity interplay between distributed neural circuits of the dendritic arbor, 2) the formation and linking the frontal lobes to subcortical regions maturation of excitatory and inhibitory synapses, processing emotional and reward-related 3) the composition of protein complexes at the information that in turn influence response pre- and post-synaptic sites, and 4) the selection. Each of these regions is production and secretion of neuropeptides that interconnected with the dopamine system. Our control neural circuit development. These studies have used a probabilistic discounting activity-regulated processes are critical for task to probe the interactions between these normal brain development and function, and systems in regulating risk/reward decision defects in the activity-dependent gene program making. Data will be reviewed showing that contribute to disorders of human cognition such subcortical circuitry linking the amygdala and the as Rett Syndrome (RTT) and Angelman ventral striatum appears to promote a more Syndrome (AS), two neurological disorders associated with syndromic autism. 3

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Understanding how the neuronal activity- navigation in humans and rats will be presented dependent gene program functions may provide to examine this proposal. The results will show insight into how the dysregulation of this process that the hippocampus is needed to retain and leads to neurological diseases and, ultimately, retrieve detailed memories of spatial layouts may suggest therapies for treatment of disorders (scenes) for as long as the memories exist. With of cognitive function. time, however, some of these memories are transformed, shedding contextual details, but Featured Plenary Speaker: retaining schematic cognitive maps that can Jay Gottfried, Northwestern University represent space allocentrically. In the process, All Roads Lead to Smell: What Odors Can these transformed memories lose their Teach Us About Brain Function hippocampal signature, and are represented in extra-hippocampal structures where they can be An essential function of the brain is to encode retained and from where they can be retrieved and interpret the behavioral salience of stimuli without hippocampal involvement. A multiple encountered in the environment. Throughout trace theory of hippocampal-neocortical much of the animal kingdom, odors are essential interaction, and a transformation hypothesis, are for directing animals toward a wide array of proposed to account for the data. salient stimuli, including foods, friends, and friends with benefits (mates) -- it follows that the Ingrid Johnsrude, Queen’s University: The olfactory system should share intimate role of prediction and attention in speech anatomical overlap with limbic brain regions perception involved in the control of emotion, decision Abstract: When speech is heard in the presence making, and goal-directed behavior. Research of background sound, or when hearing is in our lab combines sensory psychophysics with impaired, the sensory information at the ear is functional MRI, multivariate pattern-based often too ambiguous to support speech analysis, and intracranial EEG recordings to recognition by itself. In order to disambiguate investigate olfactory functional organization in and interpret the incoming sounds, the brain the human animal, whose ability to talk and must integrate the auditory information with provide ratings of their experiences offers a other sensory information and with prior highly tractable way to relate brain activity knowledge to facilitate understanding. Prior patterns directly to perception. This presentation information can enhance speech perception in will include an overview of recent studies different ways. For example, intelligibility and examining the impact of attentional states on segregability of familiar voices is greater than for olfactory predictive coding, and the interactions unfamiliar voices in the presence of competing of smells and sleep in modulating fear memory. I speech; and coherent, predictive, semantic will also focus on new data that address the context appears to reduce processing load. A mechanisms by which olfactory perceptual recent series of experiments exploit behavioural experience and associative learning drive the de and imaging methods to explore the novo formation of object categories in entorhinal mechanisms underlying the integrative cortex and orbitofrontal cortex. Finally, I will processes that permit knowledge and discuss how the mere act of odor sampling, i.e., experience to enhance understanding of sniffing, can profoundly shape network degraded speech, and to examine how dynamics and oscillations in the human brain, recruitment of such mechanisms is gated by with relevance for memory and behavior. attentional state. The field of visual perception

has long recognized the important role played Plenary symposium: The Cognitive by feedback connections to early visual cortices Neuroscience of the Senses in shaping perception; an emerging literature in Morris Moscovitch, University of Toronto: the auditory domain is consistent with the idea Spatial (and event) memory in humans and that early auditory processing (in primary rodents auditory cortex) is modulated by higher-level Since the discovery of place cells, it has been (linguistic) knowledge. This work adds to a believed the hippocampus in both rodents and growing literature indicating that primarily humans is needed for representing spacial feedforward accounts of perceptual processing layouts (environments) allocentrically. That are incomplete, and that frontally mediated representation, in turn, is needed for navigation, control processes are essential to accurate regardless of whether the environment was speech comprehension in the noisy and variable encountered and learned recently or long ago. listening conditions that are characteristic of Evidence from studies on spatial memory and everyday life. 4

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Parallel Symposia Abstracts cerebral artery trees. These collaterals represent a potential, under-recognized, Symposium 1: Functional and dysfunctional emergency “backdoor” to maintain blood flow to regulation of brain blood flow brain that would otherwise die during an acute stroke. There is wide variability in the presence New roles for astrocyte Ca2+ in relation to of these collaterals in humans. There are, brain blood flow however, very few studies that have sought to Grant Gordon, University of Calgary, Hotchkiss understand why this variability exists in the first Brain Institute place, although experimental studies in animals have identified large contributions from Neurovascular coupling is an essential process environmental factors and genes for differences ensuring blood flow is matched to the metabolic in the density and diameter of these vessels. needs of the brain. The current model stipulates Knowledge of this nature in humans can that increases in neuronal activity lead to a rapid potentially be used to identify therapeutic targets elevation in astrocyte endfoot Ca2+, which capable of modulating native collateral status, triggers the release of diffusible messengers thereby achieving better clinical outcomes in that initiate changes to arteriole diameter to patients with ischemic stroke. This presentation control blood flow. While much in vitro data describes the challenges we face when trying to demonstrates the sufficiency of astrocyte Ca2+ image pial collaterals in humans. It then goes on in controlling arteriole diameter, recent in vivo to describe what we have learned until now studies call the current model into question. about pial collaterals, their physiology and their Using two-photon imaging in acute brain slices, determinants from such studies. It also we tested the causal role of synaptically evoked describes the vital role that measuring pial astrocyte Ca2+ transients in neurovascular collaterals plays in determining treatment coupling under conditions in which astrocytes decisions and prognosis in patients with acute were functionally silenced by the intracellular ischemic stroke. Finally, the presentation seeks delivery of BAPTA. Surprisingly, we found that to give an overview of exciting new research in synaptically triggered astrocyte Ca2+ transients this field in humans that is informed by current were not necessary for vasodilation. However, research in animal labs. we found that Ca2+ chelation itself in astrocytes caused a prominent vasoconstriction of Imaging and augmenting collateral blood arterioles, suggesting that astrocytes provide flow in the brain during acute ischemic steady-state vasodilation. Next, using two- stroke photon imaging in awake mice, we found that Ian Winship, University of Alberta endfoot Ca2+ transients followed, rather than preceded, sensory evoked vasodilation of Blockage of a cerebral artery induces focal arterioles. Furthermore, similar astrocyte ischemia downstream of the occlusion. While endfoot Ca2+ transients could be evoked by severe blood flow reduction in the core of the intraluminal acetylcholine delivered IV, ischemic territory results in rapid cell death, suggesting arteriole diameter/blood flow surrounding “penumbral” regions have partially changes per se can drive endfoot Ca2+ maintained circulation and delayed cell death. transients. Our data redefine the potential role Maintained blood flow is primarily due to of astrocyte Ca2+ in relation to brain blood flow, “collateral circulation.” Collateral circulation in which basal astrocyte Ca2+ controls resting refers to alternative circulatory pathways for arteriole tone, and in which endfeet Ca2+ blood that allow blood to reach ishemic transients are mostly observed in response to territories when primary routes are blocked, and increases in blood flow, rather than to initiate is a critical predictor of clinical prognosis after rapid changes caused by neural activity. stroke and response to recanalization. Here, I will discuss my lab’s work imaging and Pial Collaterals in humans: Imaging, augmenting collateral blood flow in clinically hemodynamics, determinants and effect on relevant models of ischemic stroke. Our studies clinical outcomes in patients with acute use high-resolution, wide field laser speckle ischemic stroke contrast imaging to create maps of collateral Bijoy Menon, University of Calgary circulation in the ischemic cortex, and two photon microscopy to quantitatively assess Pial collaterals are native (pre-existing) blood flow velocity and direction in ischemic anastomoses that cross-connect a small number tissue. Our data shows that anastomatic of distal-most arterioles within the crowns of the connections between the distal branches of the 5

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 arterial cerebral artery (ACA) and the middle Rosemary Bagot, Icahn School of Medicine at cerebral artery (MCA) can partially compensate Mt Sinai for ischemia induced by proximal or distal MCA occlusion. Additionally, we demonstrate that Alterations in nucleus accumbens are implicated transiently diverting blood flow from peripheral in the pathophysiology of depression. Chronic circulation towards the brain via intra-aortic social defeat stress (CSDS) produces a catheter and balloon induces persistent depression-like phenotype in mice associated increases in blood flow through these with robust transcriptional alterations in NAC. anastomoses. New methods for systemic or The NAC receives major excitatory inputs from targeted collateral blood flow augmentation will the medial prefrontal cortex (mPFC), ventral also be discussed. Given the importance of hippocampus (vHIP), and basolateral amygdala these collateral pathways in predicting stroke (BLA) and alterations in this circuitry regulate outcome and response to treatment, our work depression-like behavior. To examine the highlights the potential of collateral therapeutics mechanistic basis of CSDS effects on this as an adjuvant or stand-alone therapy for acute network, we performed next-generation RNA- ischemic stroke. sequencing on NAC, mPFC, vHIP, and BLA tissue from control animals and mice determined Seizures Induce a Severe Ischemic/Hypoxic to be either susceptible or resilient to CSDS. We Episode employed both differential expression analyses G. Campbell Teskey, University of Calgary as well as co-expression network analyses to further characterize circuit-wide transcriptional Seizures often result in negative neurological profiles. Inter-region comparisons of global gene outcomes as well as post-seizure sensory, expression patterns across the circuit indicate cognitive and behavioural dysfunction similar to enhanced synchrony of differential expression ischemic/hypoxic attacks. Given that seizures between NAC and mPFC in mice resilient to also disrupt ion homeostasis and neurovascular CSDS and increased synchrony between mPFC control of blood flow, we hypothesized that and vHIP in susceptible mice. We constructed seizures would lead to a subsequent weighted gene co-expression networks in ischemic/hypoxic event culminating in post- control, susceptible and resilient mice and seizure behavioural impairment. We discovered identified modules of genes exhibiting a severe hypoxic event (pO2 < 10mmHg) that differential connectivity between conditions. begins after the termination of a seizure in both Several of these modules also showed experimental animal models and a person significant enrichment of differentially expressed exhibiting spontaneous epileptic seizures. We genes. To identify transcriptional “master also observed post-seizure hypoxia regulators” of resilient-specific gene expression accompanied by reduced hippocampal perfusion profiles, we focused on genes with high intra- in awake, freely moving rats. Nifedipine, utilized module connectivity. Viral-mediated over- as a tool that promotes vasodilation and expression of one potential master regulator, prevents vasoconstriction (ischemia), inhibited sdk1, in mPFC increased resilience to CSDS the severe ischemia/hypoxia after experimental while the same manipulation in vHIP increased seizures and prevented ensuing behavioural susceptibility. Our findings suggest that deficits. This novel finding identifies susceptibility and resilience to CSDS associate ischemia/hypoxia as a new mechanism by which with distinct circuit-wide transcriptional profiles. seizures may negatively impact brain function Susceptibility may arise from a general and suggests pharmacological treatments that dysregulation of transcriptional programs in this target attenuation of the post-seizure circuit. ischemic/hypoxic event could prevent the neurological and behavioural consequences of A novel role for the 6th base: how DNA seizures. hydroxymethylation governs adaptive behavior Symposium 2: Genetic and environmental Timothy Bredy, University of California, Irvine regulation of gene expression and development of vulnerability to psychiatric 5-hydroxymethylcytosine (5-hmC) is a novel disorders DNA modification that is highly enriched in the adult brain and dynamically regulated by neural Circuit-wide transcriptional profiling in a activity. 5-hmC accumulates across the lifespan; mouse model of depression however, the functional relevance of this change in 5-hmC and whether it is necessary for 6

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 behavioral adaptation have not been fully data suggest that epigenetic mechanisms may, elucidated. Moreover, although the ten-eleven at least in part, mediate treatment effects translocation (Tet) family of enzymes is known associated with early intervention programmes to be essential for converting methylated DNA to such as the NFP. 5-hmC, the role of individual Tet proteins in the adult cortex remains unclear. Using 5-hmC Genomic Embedding of Early Life capture together with high-throughput DNA Experiences sequencing on individual mice, we show that Michael Kobor, University of British Columbia fear extinction, an important form of reversal learning, leads to a dramatic genome-wide Symposium 3: Synaptic Adhesion redistribution of 5-hmC within the infralimbic Molecules: From Synapse Development to prefrontal cortex. Moreover, extinction learning- Complex Behavior induced Tet3-mediated accumulation of 5-hmC is associated with the establishment of Synaptogenic adhesion complexes for epigenetic states that promote gene expression excitatory and inhibitory synapse and rapid behavioral adaptation. development Hideto Takahashi, Institut de recherches Epigenetics and Early Intervention: a study cliniques de Montreal of DNA methylation in the Nurse Family Partnership Synapse development requires not only physical Kieran O'Donnell, Douglas Research Institute contact between axons and target neurons but also chemically matched pre- and post-synaptic The persisting influence of childhood adversity assembly. Thus, synaptic organizing complexes, on vulnerability for mental disorder is well trans-neuronal adhesion complexes with the established. Both animal models and clinical ability to induce pre- and/or post-synaptic studies identify epigenetic regulation of genomic assembly, have been suggested to function as function as a plausible mediating mechanism. It essential molecular signals for synapse is unknown if early intervention programs, which development. The neuroligin-neurexin complex buffer the effects of early adversity, mediate has been the most notable synaptic organizing their treatment effects via epigenetic complex and a genetic determinant predisposing mechanisms. We have carried out the first to autism. However, synapse diversity suggests epigenetic analysis in the Nurse Family many other synaptic organizing complexes for Partnership (NFP), a randomised control trial of excitatory (glutamatergic) and/or inhibitory a perinatal parenting intervention targeting high- (GABAergic) synapses. To identify novel risk women and their infants. We assessed synaptic organizers that induce presynaptic genome-wide DNA methylation (Illumina 450k) assembly, we performed a functional expression in whole blood samples from adult participants screen based on a neuron-fibroblast coculture (n=69) born to women from treatment and assay combined with full-length cDNA library or control groups. Methylation data were corrected candidate prediction. Further, to identify their for cellular heterogeneity and batch effects. presynaptic receptor, we performed candidate Principal component analysis, variance and cDNA screen based on a cell-surface binding regression analyses determined associations assay using soluble Fc-fusion extracellular between DNA methylation, early intervention proteins of the synaptic organizers. Using these and current psychiatric symptoms. The NFP two screening approaches, we demonstrated program was significantly associated DNA that TrkC-PTPσ trans-synaptic complex acts as methylation 27 years post-intervention (F = 5.28, a bidirectional synaptic organizing complex that p=0.03). Barlett tests of variance revealed selectively regulates excitatory synapse markedly increased variance in methylation development. We also identified Slitrk3-PTPδ profiles in the treatment group. Both early trans-synaptic complex as an inhibitory intervention and current symptoms of substance synapse-specific synaptic organizing complex. abuse associated a principal component Given genetic linkages of our identified accounting for 8.1% of the variance in DNA molecules with neuropsychiatric disorders, our methylation. Candidate genes identified from data suggest that aberrant synaptic organization these analyses include PAX8 and CACNA1D could be a common pathogenesis of many implicated in development and risk of psychiatric neuropsychiatric disorders. disorder, respectively. We provide some of the first clinical evidence that early intervention is Variable effects on brain and behaviour in associated with DNA methylation. These novel mouse models featuring loss of function 7

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 mutations in Neuroligin3, Neurexin1, and Translational control of autism and Fragile-X Cntnap2 syndrome Jason Lerch, SickKids Nahum Sonenberg, McGill University

Advances in the genetics of Symposium 4: Moving toward an neurodevelopmental disorders, in particular understanding of brain functioning using autism, have identified a series of causative computational approaches mutations in synapse adhesion genes. We have, over the last years, set out to phenotype multiple Variability, homeostasis and modulation in mouse models related to autism spectrum neural circuits disorders in order to understand commonalities Eve Marder, Brandeis University and differences amongst these models. To that end we've been using high-resolution Magnetic Multi-scale in silico modeling of personal ion Resonance Imaging and assessing subtle channel gene mutations as a cause of alterations in neuroanatomy across the brain. epilepsy and brain mediated sudden death Included in this effort have been several mouse lines with mutations affecting synapse adhesion, Tara Klassen, University of British Columbia including neurexins, neuroligins, and Cntnap2. Intriguingly, the phenotype of each of these One of the central challenges of personalized mutations is drastically different, with Neurexin1- medicine is to solve a model where risk is a non- alpha showing brain overgrowth, Neuroligin3 linear summation of contributions from many reduced brain volume, and Cntnap2 no gene variants. The fourth most prevalent differences. This talk will explore these neurological disorder, epilepsy, affects 65 million differences in phenotype between related people worldwide and ~1% of the Canadian synapse adhesion mutation mouse models in population. Epilepsy is a multifactorial spectrum greater detail. of clinical disorders characterized by unpredictable seizures that vary in type and Synaptic Adhesion Molecules: From severity resulting from an imbalance of Synapse Development to Complex Behavior excitation and inhibition in neural networks. Ion Valerie Mongrain, Université de Montréal channels regulate and respond to changes in membrane voltage such that mutations in >60 of Current hypotheses support that sleep these genes cause a plethora of neurological regulation depends on mechanisms controlling and somatic excitability disorders including synaptic plasticity. Indeed, modifications in epilepsy, cardiac arrhythmias and sudden neuronal synchrony and firing occurring as a unexpected death in epilepsy (SUDEP). Genetic function of vigilance state changes across the background has an essential role on variant 24-h day involve profound alterations in synaptic penetrance and complicates risk prediction transmission. Moreover, sleep loss, achieved for because inheritance of identical ion channel instance using sleep deprivation, impairs mutations can be both dominant and recessive, mechanisms underlying synaptic plasticity in and causative mutations are found in several brain areas. Therefore, we anticipated asymptomatic individuals. Regardless of that synaptic adhesion molecules, which control disease status, genetic variation in a personal synaptic strength by regulating both pre- and channotype is extensive, forming a highly post-synaptic mechanisms, will be involved in complex pattern of common and rare alleles. To sleep regulation. Results supporting this evaluate the contribution of common population hypothesis and concerning two different polymorphisms to risk in epilepsy and SUDEP synaptic adhesion systems will be presented. we have inverted the classical experimental The first findings will focus on the role of paradigm employing computational models of Neuroligin 1 in the regulation of wakefulness proteins, cells and neural networks to evaluate duration and of sleep intensity. Then, recent the theoretical (dys)functional contributions from data showing an implication of EphA4 in the combinations of ion channel mutations. These control of sleep consolidation and of paradoxical combinatorial models of voltage and ligand- sleep duration will be highlighted. Lastly, two gated channels have identified compound different molecular mechanisms targeting mutations which result in overt cellular transcription that likely contribute to sleep/wake- hyperexcitability or quiescence. Cross- dependent changes in the expression of these comparison with pre-existing channotypes is synaptic adhesion elements will be discussed. guiding mutation profile analysis for in vitro experimentation and validation. 8

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learning of such networks can reproduce acute Gene networks for understanding brain and acquired symptoms of posterior parietal function and dysfunction cortex lesions due to stroke. We hope that Jesse Gillis, Cold Spring Harbor Lab findings from these neural network studies will help understanding stroke symptoms and A central challenge to understanding ameliorate treatment options. neuropsychiatric disorders is determining how candidate variants interact with one another and Symposium 5: Large-scale brain dynamics: the environment to produce a disease combining insights from intracranial EEG phenotype. In response to this challenge, gene and fMRI networks have become a common resource for integrating potentially diffuse functional effects Thalamic control of cortical dynamics into a single common framework. Ideally, Yuri Saalmann, University of Wisconsin – candidate variants not only converge on Madison consistent pathways or interact within a network, but also do so in a way that is perturbed in Brain networks are commonly defined using response to disease or factors relevant to correlations between blood oxygen level- disease. While gene network analyses can be dependent (BOLD) signals in different brain extremely opaque, they are grounded in a few areas. Although evidence suggests that gamma- straightforward principles. The central top-down band (30–100 Hz) neural activity contributes to principle in the interpretation of gene networks is local BOLD signals, the neural basis of inter- ‘Guilt by Association’ (GBA) and it simply states areal BOLD correlations is unclear. We first that genes which share functions are more likely defined a visual network in monkeys based on to be associated. Many, perhaps most, analyses inter-areal BOLD correlations, and then of ‘novel’ sets of candidate disease genes rely simultaneously recorded local field potentials on GBA to claim that the genes have some (LFPs) from the same four network areas. Low- known shared function determinable through frequency oscillations (<20 Hz), and not gamma their associations. In a recent series of papers, activity, predominantly contributed to inter-areal we laid out grounds for treating previous gene BOLD correlations. Specifically, the degree of network analyses related to function with synchrony between low-frequency oscillations in skepticism. We showed that gene networks different network areas best predicted BOLD (protein interactions, genetic interactions and connectivity. The low-frequency oscillations also co-expression) tend to encode very generic influenced local processing by modulating information about gene function without gamma activity within individual areas. We learnable specificity, leading to highly suggest that such cross-frequency coupling links multifunctional genes dominating analyses to local BOLD signals to BOLD correlations across the point that details of network structure have a distributed networks. How are these cortical surprisingly small impact. We suggest that this oscillations and the inter-areal synchrony property plays a dominant role in most controlled? Based on its anatomical connectivity previously reported network analyses. We focus with the cortex, we hypothesized that the on potential corrections in an analysis of pulvinar, a thalamic nucleus, regulates cortical schizophrenia co-expression and disease- synchrony. We mapped pulvino-cortical associated variant data. networks within the visual system, using diffusion magnetic resonance imaging, and Understanding sensory-to-motor simultaneously recorded spikes and LFPs from transformations through network models these interconnected network sites in monkeys Gunnar Blohm, Queen’s University performing a visuospatial attention task. The pulvinar synchronized activity between Artificial neural network models provide a interconnected cortical areas according to mechanistic link between behaviour, neuronal attentional allocation, suggesting a vital role for recordings and disease that cannot be achieved the thalamus in regulating information otherwise. Here, I exploit neural networks to transmission across the cortex according to gain insight about the brain’s sensory to motor behavioral demands. transformation for planning reaching movements. Emergent properties of neural Large-scale patterns of rhythmic networks learning this complex transformation suppression in human cerebral cortex are in tight accordance with electrophysiological Christopher Honey, University of Toronto observations. I will show how damage and re- 9

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28

Rhythmic activity in populations of neurons is players of attentional control. These findings believed to coordinate neural activity within and identify burst synchronization as a possible across regions of the mammalian brain. mechanism to enable the formation of large- However, we lack a framework for scale attention networks based on ‘top-down’ understanding which rhythms operate in each information in dorsal anterior cingulate and region and what their distinct roles are. Here, lateral prefrontal cortex. using intracranial recordings from humans and macaques, we show that, almost all regions of The neurophysiological basis of the default- the primate neocortex contain at least one mode network suppressive oscillatory process within the 4-30 Karim Jerbi, University of Montreal Hz range. Population activity is decreased on average when the suppressive rhythm is strong, Resting-state networks are predominantly and this effect is strongest at particular phases investigated by measuring the brain's of the local oscillation. The frequency of haemodynamic responses during rest. However, suppressive rhythms varies across regions, and our understanding of its fnctional role will not be with a similar topography across individuals. complete without elucidating their Moreover, increases in the activity of the electrophysiological underpinnings. We report suppressive rhythm occur at the same time as an extensive intracerebral EEG (iEEG) decreases in the BOLD signal, and changes in exploration of the neural correlates of intrinsic suppressive rhythms are also coordinated correlation patterns. To this end, we acquired across regions. We consider whether sets of data directly from core default-mode network regions with shared suppressive rhythms (DMN) areas, including the posterior cingulate correspond to the large-scale brain networks cortex (PCC) and the medial prefrontal cortex that are ubiquitously observed in neuroimaging. (MPFC) in stereotactically implanted epilepsy Overall, the concept of suppressive rhythms patients. We investigated spontaneous long- provides a framework for understanding how range coupling between nodes of the DMN rhythmic activity modulates function within and using a combination of time and frequency across a wide range of mammalian cortical domain correlation measures. The observed networks. iEEG resting-state correlation dynamics were compared to the functional connectivity patterns How single cell activity in prefrontal and obtained in the same subjects with fMRI. Our anterior cingulate cortex contributes to results reveal a combination of sustained and large-scale network dynamics: State specific transient patterns of long-distance neuronal burst synchronization at beta and gamma correlations between DMN nodes at various band activity spatial, spectral and temporal scales. In T. Womelsdorf, York University particular, sustained broadband gamma amplitude envelopes in DMN areas reveal slow Attention is realized in the brain by the rapid correlated fluctuations, similar to those observed formation of a coalition of brain cells into a large- with fMRI. Our findings help bridge the gap scale attention network. Cells in medial and between fMRI and human electrophysiological lateral prefrontal cortex control this formation of studies of the brain's large-scale functional attention networks, but how the activity of single architecture at rest. cells exerts network control is unknown. This talk will discuss possible mechanisms on how Symposium 6: Novel cellular and molecular cell activation dynamics link to large scale mechanisms in the pathophysiology of network dynamics and suggest that burst- parkinsonism synchronization could serve as potent candidate mechanism to achieve network control during The function of PINK1 and parkin in attentional states. We find in single cell activity mitochondrial quality-control of macaque prefrontal cortex an increase in the Edward Fon, McGill University firing of brief 200 Hz burst events when subjects shifted attention and engaged in selective Parkinson’s disease (PD) is a common, sensory processing. In contrast to non-burst devastating neurodegenerative disorder. Both spikes, burst spikes synchronized at narrow genetic and environmental models strongly beta and gamma frequencies. Burst implicate mitochondrial dysfunction in PD. In synchronization is anatomically specific, particular, PINK1 and Parkin, two recessive PD functionally connecting the anterior cingulate genes, function in a common pathway regulating cortex with the lateral prefrontal cortex, both key mitochondrial quality-control. In healthy 10

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 mitochondria, PINK1, a mitochondrial kinase, is disease (PD). Graft of dopaminergic neurons rapidly degraded in a process involving both newly generated from stem cells represents a mitochondrial proteases and the cytosolic promising therapeutic avenue. However, a major proteasome. This process is highly dependent factor limiting success in transplantation studies upon the membrane potential across the is the inappropriate re-innervation of the grafted mitochondrial inner membrane (ΔΨm), which neurons. Thus it is primordial to identify factors drives PINK1 import into mitochondria. Indeed, regulating axon projection and connectivity of mitochondrial damage that dissipates ΔΨm mDA neurons. Here we demonstrate the role of blocks PINK1 import and leads to its two transcription factors, Lmx1a and Lmx1b, in accumulation on the surface of mitochondria. the regulation of mDA neurons circuit formation. PINK1 accumulation triggers the translocation of We then reveal Lmx1a/b target genes and parkin, an E3 ubiquitin ligase, from the cytosol to identify PlexinC1 as a crucial axon guidance mitochondria, where it mediates the elimination receptor allowing segregation of dopaminergic of dysfunctional mitochondria by autophagy pathways. Our results show new mechanisms (mitophagy). From these studies, a concept of regulating dopamine neurons connectivity and PD pathogenesis is emerging whereby defects should help in the effort to understand the in PINK1 or parkin function reduce the efficiency molecular factors contributing to the efficiency of with which damaged mitochondria, a major cell replacement therapies for PD. In addition to source of toxic reactive oxygen species, are their role during development, we demonstrate eliminated. We will present recent work, based the requirement of Lmx1a/b in the maintenance on the crystal structure of parkin and on genetic of dopaminergic neurons. Inactivation of screens to identify regulators of parkin function, Lmx1a/b in mDA neurons induces metabolic exploring how parkin is activated upon its changes and leads to dopaminergic axon recruitment to damaged mitochondria. degeneration, alpha-synuclein accumulation, microglia activation and progressive Axonal arborization and energetic degeneration of mDA neurons. Gene profiling metabolism of nigral dopamine neurons: a experiments also reveal that Lmx1a/b regulate window into selective vulnerability genes of the mitochondrial respiratory chain. Louis-Eric Trudeau, Université de Montréal Our results show that the maintenance of dopaminergic systems is underpinned by the Parkinson’s disease (PD) is associated with continued action of Lmx1a/b beyond the stages severe locomotor deficits accompanied by the of development. These findings also suggest selective and progressive loss of a small subset that Lmx1a/b could be promising therapeutic of neuronal populations including dopamine targets to prevent the degeneration of mDA (DA) neurons of the substantia nigra pars neurons in patients suffering from PD. Finally, compacta (SNc). Why SNc neurons are mutant mice for Lmx1a/b represent a valuable particularly vulnerable and degenerate in PD is new model that reproduces cellular poorly understood. However, mitochondrial characteristics of PD. dysfunction and oxidative stress have been proposed as key contributors. This presentation Multiple Parkinson’s disease-linked proteins will discuss recent data testing the hypothesis regulate synaptic transmission and that the selective vulnerability of SNc DA neurotransmitter receptor trafficking neurons, in comparison to other less vulnerable Austen Milnerwood, University of British DA neurons including those of the ventral Columbia tegmental area (VTA), is due to the fact that these neurons have a higher basal rate of The etiology of Parkinson’s disease (PD) is mitochondrial oxidative phosphorylation related unknown, symptoms are progressive and to their considerably larger axonal arborization. patients suffer inexorable decline of cognitive Work funded by Brain Canada and the Krembil and motor functions then death. Contemporary Foundation. treatments have limited efficacy, troubling side effects and do not modify progression. Studies Multiple roles of Lmx1a and Lmx1b in of familial parkinsonism have linked pathogenic dopaminergic axonal connectivity and mutations in several genes, providing the maintenance potential for mechanistic insights and novel Martin Levesque, Université Laval therapeutic targets. Furthermore, tracking of ‘asymptomatic’ mutation carriers enables Degeneration of midbrain dopaminergic neurons investigation of early disease processes. (mDA) is the principal cause of Parkinson’s Mutations in alpha-synuclein (aSyn) and 11

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 leucine-rich repeat kinase-2 (LRRK2) are the network. Disruption of calpain activity results in major genetic risk factors for sporadic and exuberant growth and sprouting along axons in familial PD. Recently, mutations in Vacuolar vitro and our most recent data provides Protein Sorting 35 (VPS35) and Receptor evidence that this active stabilization model Mediated Endocytosis 8 (RME8) have also been operates in vivo. Calpain activity is robust in linked to autosomal dominant, late-onset neurons of the developing nerve cord in parkisonism. As multiple mutations in several Drosophila melanogaster. After manipulating proteins produce a similar disease, studying calpain activity and cortactin expression in their physiological and pathophysiological specific identified neurons in the developing activity may uncover a common neuronal nerve cord we find that neurons show exuberant dysfunction important to the etiology of many growth and branching. We will test whether forms of parkinsonism. Longitudinal similar mechanisms regulate neuronal plasticity investigations of transgenic cells and mice, in the mature nervous system. alongside emerging evidence from asymptomatic mutation carriers, are redefining Conditional disruption of calpain in the CNS the classical understanding of PD pathogenesis. alters dendrite morphology, impairs LTP, We demonstrate that LRRK2, VPS35 and RME8 and promotes neuronal survival following physically interact and, when mutated, alter injury neuronal connectivity and synaptic function. Mandana Amini, University of Ottawa Furthermore, neurotransmitter receptor function and trafficking are altered by PD mutations in Ubiquitous classical (typical) calpains, calpain-1 these proteins, and we are beginning to define and -2, are Ca+2-dependent cysteine proteases the links with aSyn function / pathology. We which have been associated with numerous posit that perturbed endosomal and vesicle physiological and pathological cellular functions. sorting is a common feature of genetic, and However, clear understanding of the role of potentially idiopathic, parkinsonism. An calpains in the CNS has been hampered by the improved knowledge of the underlying lack of appropriate deletion paradigms in the pathophysiology is vital to define biomarkers brain. In this study, we describe a unique model and design neuroprotective strategies for PD of conditional deletion of both calpain-1 and -2 and related disorders. which more definitively assesses the role of these ubiquitous proteases in brain Symposium 7: New cuts by calpain to development/function and pathology. remodel the nervous system Surprisingly, we show that these calpains are not critical for gross CNS development. Calpain activity maintains the stability of However, our study reveals that calpain-1/2 loss neurite morphology in Vivo leads to reduced dendritic branching complexity Tim O'Connor, University of British Columbia and spine density deficits associated with major deterioration in hippocampal long-term An essential feature of the nervous system is its potentiation and spatial memory. Moreover, long-term stability. After development a neuron’s calpain-1/2 deficient neurons were significantly capacity for plasticity is restricted. This stability resistant to injury induced by excitotoxic stress is essential for the maintenance of neuronal or mitochondrial toxicity. Examination of identity, morphology, appropriate connectivity, downstream target showed that the conversion and ultimately network properties. This has of the Cdk5 activator, p35, to pathogenic p25 engendered a belief that with age, neurons form, occurred only in the presence of calpain settle into a ‘locked-in’ default state. However, and it played a major role in calpain-mediated our recent work leads us to propose a markedly neuronal death. These findings unequivocally different hypothesis from this long-standing establish two central roles of calpain-1/2 in CNS view. Our data uncovers a novel principal for the function in plasticity and degeneration. stable maintenance of neuronal morphology. We have found that maintenance of stable neuronal A tail to memorize: cleavage of synaptic processes is not a passive default mechanism GluN2B by calpain to support synaptic but instead requires ongoing active repression plasticity of sprouting. This stability is established by an Paul De Koninck, Université Laval antagonistic interaction between the calcium- activated cysteine protease, calpain, and At excitatory synapses, the mechanisms that specific proteins including cortactin, that support learning may be initiated by long-term regulate the assembly of the actin cytoskeletal alterations in the content of specific dendritic 12

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 spines to modify synaptic strength and to prime live cells, we generated PKC FRET connections for further activity-dependent (Fluorescence Resonance Energy Transfer) modifications. Synaptic potentiation is triggered reporters in which Cyan Fluorescent Protein by NMDA receptor activation and downstream (CFP) was added to the N-terminal and Yellow signaling processes that involve Ca2+ Fluorescent Protein (YFP) added to the C- responsive enzymes, such as CaMKII and ERK. terminal. Our results show that different PKC A particular feature of the NMDA receptor is the isoforms are cleaved by distinct calpains in long cytoplasmic tails of its GluN2 subunits, diverse cellular plasticity paradigms. The which are believed to engage in subunit-specific calcium-dependent PKC Apl I is cleaved by interactions with signaling enzymes for synaptic classical calpain during associative potentiation. The interaction between CaMKII intermediate-term facilitation (ITF). In contrast, and GluN2B is particularly recognized as the SOL calpain is important for cleaving PKC important for the induction of synaptic Apl III downstream of PKC Apl III activation in a potentiation. Meanwhile, calpain is capable of positive feedback mechanism that may be cleaving the cytoplasmic tail of GluN2 subunits, important for persistent formation of PKM Apl III particularly GluN2B, raising the question of during long-term memory. whether such cleavage can participate in GluN2B-dependent synaptic signaling. We will Symposium 8: Linking neural circuit discuss the hypothesis that strong synaptic dynamics to cognition and behaviour activity can trigger calpain-mediated cleavage of the c-tail of GluN2B, releasing a signaling Role of sleep for motor skill learning complex to which CaMKII is associated and Masami Tatsuno, University of Lethbridge which participates in signaling for synaptic potentiation. We will examine this process with Increasing evidence suggests that sleep plays the combination of biochemical and molecular an active role in our cognitive and motor methods, advanced optical imaging and functions. One suggestion is that memory is electrophysiology in rat hippocampal and consolidated during sleep or quiet wakefulness, cortical cultures and slices. Results from our possibly by reactivating neural activity that experiments might reveal a novel view of how occurs during waking and driving synaptic NMDA receptors modify synaptic contents for changes that strengthen a memory trace. With modifying strength in transmission and/or for respect to spatial memory, studies have priming specific synapses for further suggested that reactivation during non-REM modifications. sleep and quite wakefulness is particularly important. With respect to motor skill memory, Role of typical and atypical calpains in even though there is substantial behavioural cleavage of PKCs into PKMs for memory evidence showing the importance of sleep, formation relatively little is known about the underlying Carole Abi Farah, McGill University neural activity. We have performed high-density multi-electrode recordings from rats as they are Protein kinase Ms (PKMs) are truncated trained with the single-pellet reaching task. Daily persistently active forms of protein kinase Cs recordings (a 3 hr pre-task sleep, a 30 min task, (PKCs) that play an important role in memory and a 3 hr post-task sleep) were performed 3-4 formation both in vertebrates and invertebrates weeks to cover the entire learning period. By but may be generated differently in these analyzing spike-sorted unit activity, we obtained systems. In rodents, the atypical PKM Zeta can preliminary evidence that reactivation of the be transcribed from an internal promoter in the single pellet reaching task occurred during both PKC Zeta gene whereas this transcript is not non-REM and REM sleep. Analysis of multi-unit present outside of chordates. In Aplysia, the activity (MUA) during cortical spindles also atypical PKM Apl III, the orthologue of PKM demonstrated that the modulation of MUA zeta, is generated by calpain-dependent decreases in the post-task sleep and that the cleavage of PKC Apl III. To investigate the role decrease of modulation was related to learning. of calpains in the formation of PKMs and In summary, our experiments have provided the memory, we have cloned Aplysia calpains and evidence of reactivation for motor skill learning generated constructs and dominant negative during both non-REM and REM sleep. forms for the classical, SOL and PalB calpains Additional MUA analysis also demonstrates that which we found to be enriched in sensory and the neural dynamics of sleep spindles change motor neurons. To monitor cleavage of the with motor skill learning. different PKC isoforms and PKM formation in 13

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28

Processing objects and space in the during off-line “replay” and during theta states hippocampus associated with attentive spatial behavior. Jennie Young, Massachusetts Institute of Specifically, it becomes possible to determine if Technology the hippocampus represents a trajectory corresponding to one (left) or another (right) The hippocampus plays a key role in the spatial choice -- or to an experienced past or acquisition of new memories for places and imagined future. Historically, hippocampal events. In rodents, it is believed to provide a sequences have been interpreted as a short- spatial framework within which items and events term memory buffer that repeats recent can be integrated to form a coherent experience to facilitate systems consolidation representation of the animal's on-going into other brain structures. However, recent experience. Sensory information arrives in the results suggest that the content of these hippocampus through two parallel processing hippocampal sequences can dissociate from streams: place-related information from medial literal experience. In particular, theta sequences entorhinal cortex (MEC) and object-related do not represent the environment uniformly, but information from lateral entorhinal cortex (LEC). tend to avoid crossing turns and decision points, The unique anatomical arrangement of inputs to resulting in a “chunking” of spatial experience CA1 suggests that it may receive both into segments. Awake replay can favor remote, integrated and segregated space/object rather than more recent experiences, as well as information - from upstream hippocampal contain never-experienced trajectories. Thus, subregions and directly from MEC/LEC, the rodent hippocampus appears to broadcasts respectively. We carried out large-scale a selective and highly processed record of ensemble recordings in area CA1 of mice as experience. These observations invite questions they performed novel object-location of what factors control the content of recognition, a one-trial contextual learning task hippocampal sequences, and how they are that occurs in a familiarized environment. We interpreted by downstream structures that may present physiological data that reflects the be involved in the evaluation of alternatives anatomical segregation of parallel processing during decision making and in the formation of streams to the hippocampus, and we find that semantic-like knowledge structures. the formation of new object-place representations requires CA3 input to CA1. Hippocampal oscillations in monkey and Distal CA1 cells, which receive predominantly humans during memory-guided visual LEC input, fire selectively at locations relative to search objects in both controls and in mice with blocked Kari Hoffman, York University CA3 transmission. However, only control animals show changes in object-related firing Symposium 9: An unexpected roundtrip that are specifically associated with object journey through the hippocampal trisynaptic displacement. Our ensemble data support the excitatory network idea that CA3 inputs provide a more stable representation of the familiarized context to Synaptic vesicle dynamics and the timing CA1; Meanwhile information on new features in and efficacy of glutamate release at the environment arrives concurrently through the hippocampal mossy fibre terminals direct entorhinal inputs, where it can be quickly Katalin Toth, Université Laval incorporated to reflect the animal's present experience. Hippocampal mossy fibres play a key role in translating dense cortical information into sparse Segmentation of spatial experience by theta hippocampal code. How do mossy fibres shape oscillations the fidelity of neurotransmission? How do the Matthijs van der Meer, University of Waterloo unique features of this presynaptic terminal such as the presence of multiple release sites, a very “Place cells” in the rodent hippocampus are large vesicle pool and a profound short-term tuned to specific locations within an facilitation contribute to information processing? environment, such that the animal’s location can Calcium-dependent neurotransmitter release be inferred on a moment-to-moment basis from involves a fast synchronous component and a the ensemble activity of many such cells when slower asynchronous phase. We investigated recorded simultaneously. This decoding how asynchronous release influences procedure enables access to the content of postsynaptic action potential coding. hippocampal sequential firing patterns that occur Asynchronous release is expected to decrease 14

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 temporal fidelity, surprisingly our results show efficacy of transmission in CA1 pyramidal cells that in the presence of asynchronous release through activation of presynaptic adenosine A2A the precision of action potential firing is receptors. This work provides a new increased in an activity-dependent manner. perspective of fundamental brain function since Synaptic short-term plasticity is a key regulator astrocytes are now intimately involved with of neuronal communication. We found that two neurons in the regulation of elementary synaptic distinct presynaptic mechanisms are involved in communication in the brain. We will discuss how short-term facilitation, with their relative astrocyte can integrate synaptic activity in time contribution dependent on extracellular calcium and space, providing a unique feedback to the concentration: multivesicular release and the neuronal network. recruitment of additional release sites. Multivesicular release was dominant at lower Developmentally-regulated spatiotemporal release probabilities and the recruitment of features of calcium signaling at CA1 additional release sites played a key role at glutamatergic synapses higher p. The increase in N could be promoted Jean-Claude Béïque, University of Ottawa by calcium microdomains of heterogeneous amplitudes observed in single mossy fiber New mechanisms for bidirectional boutons. Our findings suggest that the communication in the trisynaptic combination of multivesicular release and the glutamatergic circuit of the hippocampus recruitment of additional release sites act Sylvain Williams, McGill University together to increase glutamate release during bursts of activity. This is supported by the The hippocampus plays a central role in compartmentalized spatial profile of calcium memory processing. The seminal work of elevations in boutons and helps to expand the neuroanatomists Ramon Y Cajal and Lorente de dynamic range of mossy fibers information No, and physiologist Per Andersen, proposed transfer. that information travels unidirectionally across the tri-synaptic circuit from the CA3, CA1 and Astrocytes detect and regulate basal subiculum. This canonical unidirectional flow of synaptic transmission at single CA1 information through feed-forward glutamatergic synapses synapses across the hippocampus remains Richard Robitaille, Université de Montréal central to our understanding of how this structure operates. The objective of this Basal synaptic transmission is fundamental for presentation is to revisit this paradigm and information processing in the brain. It occurs at determine the direction of information flow in a individual synapses and involves the release of complete hippocampus in vitro and in freely neurotransmitters evoked by single action behaving mice in vivo. The predominant state of potentials. Over the past two decades, evidence the hippocampus is theta rhythm, a 4-8 Hz has shown that astrocytes actively regulate frequency oscillation found both in the complete synaptic transmission. Classically, it was hippocampus in vitro as well as during considered that these glial cells detect and in exploration or REM sleep in vivo. By measuring turn modulate synaptic transmission during theta rhythm and cell spiking across the CA3, intense and sustained neuronal network activity. CA1 and subiculum transverse axis in the However, the ability of astrocytes to detect and complete hippocampus, we found that the regulate basal synaptic transmission remained hippocampus is made-up of two separate unclear and controversial. We monitored basal, networks located in CA3 and subiculum. minimal synaptic transmission at CA3-CA1 Surprisingly, we found that theta flows synapses of rat hippocampus using whole-cell predominantly backward from subiculum to CA3 patch-clamp recordings. Simultaneously, we and that spikes in subiculum most often monitored local Ca2+ activity in small preceded those in the CA3. Moreover, compartments along astrocytic processes using optogenetic activation of GABAergic the line-scan mode of a confocal microscope. interneurons in the subiculum generated CA3 We show that astrocytes in CA1 region of theta activity and modulated the intrinsic CA3 hippocampus detect synaptic activity induced by network. Finally, in vivo recordings suggest that single synaptic stimulation at functional this reversed theta influence of subiculum compartments along the astrocytic process. This operates in the majority of theta epochs to detection is mediated by metabotropic glutamate govern the timing of the CA3. Thus, intra- receptors subtype 5. Moreover, we uncovered hippocampal communication between sub- that astrocytes release purines to increase the 15

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 regions is bidirectional and suggests a new form their etiology and thus intervention for affected of communication in hippocampus. individuals is lacking. Recently it has become evident that in many forms of severe autism are Symposium 10: Novel Pharmacology of Ion- caused by mutations in the X-linked genes Channels & Transporters NHE6 and NHE9. NHE6 and NHE9 function to regulate the acidification of endosomes the Allosteric potentiation of synaptic inhibition compartments within the cell that mark a protein by excitatory neurotransmitters for degradation or recycling. In this talk the Yu-Tian Wang, University of British Columbia localization of these NHEs in the brain and mechanisms how these mutations can lead to Neuronal excitability in the central nervous the neuronal defects will be explored. system (CNS) is fundamental to neuronal function, and is primarily controlled by a fine Chloride dysregulation; a culprit for several balance between synaptic excitation and brain diseases inhibition. In the mammalian central nervous Yves De Koninck, Université Laval system, synaptic excitation and inhibition are mediated by the excitatory transmitter Sodium ion On/Off switch for ionotropic glutamate, which acts on ionotropic glutamate glutamate receptors receptor-gated cationic channels, and the Brent Dawe, McGill University inhibitory transmitter glycine acting on glycine receptor (GlyR)-gated chloride channels in the A major challenge for modern medicine is to brainstem and spinal cord and by GABA acting develop better therapeutic approaches to treat on A type of GABA receptor (GABAAR)-gated the many disease states of the human brain. chloride channels in the brain. Here we report Although significant progress has been made in that glutamate and several of its analog ligands the last decades, a perennial problem has been potentiate GlyR- or GABAAR-gated chloride developing drugs that lack side-effects. This currents in cultured neurons. The potentiation is issue has been particularly pertinent to the not dependent on activation of any known development of drugs targeted to ionotropic ionotropic or metabotropic glutamate receptors, glutamate receptors (iGluRs). Although iGluRs and manifests as an increase in single-channel are implicated in many CNS disorders from early open probability in single-channel recordings. childhood development (e.g. autism) to the Moreover, this glutamate potentiation could be aging brain (e.g. Alzheimer's disease, demonstrated in HEK293 cells transiently Parkinsonism), therapeutic compounds targeted expressing human GlyRs or GABAARs. Using to them have met with limited success. I will ligand-binding assay and site-directed present recent data from our lab uncovering the mutations, we identified the glutamate binding importance of an allosteric cation-binding pocket sites at these inhibitory receptors. Our data in the extracellular ligand-binding domain of strongly indicate that glutamate may kainate-type receptors that is absent from all allosterically potentiate GlyR- or GABAAR-gated other iGluRs. Ongoing work in the lab is aimed chloride channels, thereby blurring the at exploiting the cation binding pocket to traditional distinction between excitatory and develop therapeutically-relevant compounds that inhibitory transmitters. Such a rapid will either inhibit or potentiate KAR activity homeostatic regulatory mechanism may have a without little or no off-target effects. significant role in tuning functional balance between synaptic excitation and inhibition in the Symposium 11: Alzheimer’s disease CNS. molecular mechanisms and therapeutics

Na+/H+ exchanger NHE6, X-linked The role of BACE1 in Alzheimer’s Disease intellectual disability and autism Pathogenesis Anne McKinney, McGill University Weihing Song, University of British Columbia

Neurodevelopmental disorder encompasses a Alzheimer’s Disease (AD) is the most common wide range of diseases, including rare but neurodegenerative disorder leading to dementia. recognizably distinct syndromes and also much Deposition of amyloid β protein (Aβ) to form more common disorders such as autism neuritic plaques in the brains is the pathological spectrum disorders, idiopathic epilepsy and hallmark of Alzheimer’s disease (AD). Aβ is mental retardation. Despite the high prevalence generated from sequential cleavages of the of such disorders, relatively little is known about amyloid β precursor protein (APP) by the β- and 16

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28

γ-secretases. Beta-site APP cleaving enzyme 1 levels of STI1 have increased sensitivity to (BACE1) is the β-secretase essential for Aβ amyloid beta peptide, whereas increased STI1 generation. Increased Aβ levels could facilitate levels decreased amyloid beta toxicity. AD pathogenesis and inhibition of Aβ generation Recombinant STI1 prevented amyloid toxicity by may have therapeutic implications for AD inhibiting the binding of Amyloid-beta peptide to treatment. Our studies showed that regulation of PrPC and by activating alpha 7 nicotinic BACE1 expression plays an important role in AD receptors. Our results demonstrate novel pathogenesis and is a valid target for AD drug mechanisms by which neuronal dysfunction can development. We found that BACE1 tightly trigger behavioural alterations in Alzheimer’s controlled APP processing and Aβ production in disease and provide a new pathway to interfere normal condition, and selection of APP β- with Amyloid beta-induced neuronal toxicity. cleavage site by BACE1 had a dramatic effect on Aβ production in the pathological condition. Role of beta oligomers in triggering Upregulating BACE1 expression by hypoxia Alzheimer’s like pathology and the role of facilitated neuritic plaque formation and insulin receptor signalling in potentiated behavioral deficits in AD neuroprotection pathogenesis. Alteration of BACE1 trafficking Doug Munoz, Queen’s University and maturation contributes to increased Aβ production in Down Syndrome. Furthermore, we Recent evidence shows that the neurotoxins in found that GSK3β signaling regulated BACE1 Alzheimer’s disease (AD) comprise soluble gene expression and AD pathogenesis and that AβOs that accumulate in the brain. These AβOs inhibition of GSK3 signaling reduced Aβ instigate synapse damage, promote neuronal neuropathology and alleviate memory deficits in dysfunction, and impair brain insulin signaling. AD model mice. Our hypothesis is that decreased insulin sensitivity triggered by AβOs contributes to Chaperoning neurotoxicity in Alzheimer’s neuronal dysfunction and represents a novel risk disease factor for diseases like AD. Therapeutics Marco Prado, University of Western Ontario designed to boost neuronal insulin signaling could protect neurons against AβOs and open Alzheimer’s disease is triggered when the up new avenues for the prevention and balance between production and elimination of treatment of AD. Currently, there is no effective Amyloid-beta peptides increase above a treatment for AD, and the pursuit of new threshold. Cholinergic neurons are particularly disease-modifying therapeutics is the object of vulnerable to Amyloid-beta toxicity, but the long- intense investigation. A major impediment lies in term consequences of cholinergic dysfunction the difficulty of translating the mechanisms, for brain activity is still not fully understood. We behavioural indicators and therapies that work in have found that cholinergic dysfunction in the animals (usually rodents), to the specific human hippocampus changes alternative splicing of disease condition. To reduce the translational pre-mRNAs by regulating the expression of the gap, we have developed a non-human primate mRNA chaperone and transcriptor regulators (NHP) model of AD. Intraventricular (icv) hnRNP A2/B1 and A1. Mice genetically altered injection of AβOs (100μg, 4-6 injections over 2-3 to model cholinergic dysfunction reproduced weeks) leads to pathology in the macaque brain most of the key alterations in alternative splicing that is strikingly similar to that observed in observed in Alzheimer’s disease. Moreover, we humans with AD. While AβOs may not be the found that these mice present several cognitive root cause of sporadic AD in humans, they alterations in executive function and seem to be critical for the disease development. hippocampal learning, which resemble those in Therefore, reversing the effect of AβO injection Alzheimer’s disease. In order to understand the into the NHP model may lead to future AD basis of neuronal vulnerability in Alzheimer’s therapies in humans. We have initiated one disease, we investigated mechanisms of approach by using the anti-diabetic drug, amyloid beta toxicity. Recent work has liraglutide. Pretreatment with liraglutide, starting implicated the prion protein (PrPC) in 1 week before the first AβO injections, produced Alzheimer’s disease and suggested PrPC as a reduction in pathology induced by AβO possible receptor for amyloid peptides. Stress injection, providing one example of how the Inducible phosphoprotein 1 (STI1) is well- NHP model can be used. conserved protein thought to regulate cellular function by interacting with Hsp70/Hsp90 or with Multiple roles of cholinergic neurons in the PrPC. We found that neurons with decreased modulation of amyloid production 17

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28

R. Jane Rylett, University of Western Ontario Obesity is among the most pressing health issues facing Western societies. It is evident that Alzheimer disease (AD) is associated with stress is a factor leading to metabolic changes increased amyloidogenic processing of amyloid that can lead to obesity. In particular, continuous precursor protein (APP) to β-amyloid peptides social stressors can result in increased body (Aβ), cholinergic neuron loss with decreased weight and abdominal fat deposition, insulin choline acetyltransferase (ChAT) activity, and resistance, and cardiovascular disease. These cognitive dysfunction. Both 69- and 82-kDa changes, however, do not occur in all ChAT are expressed in cholinergic neurons in individuals, suggesting that there may be traits human brain and spinal cord with 82-kDa ChAT that make some individuals more likely to localized predominantly to neuronal nuclei, develop metabolic alterations when stressed suggesting potential alternative functional roles. than others. Ghrelin, a peptide hormone The presence of 82-kDa ChAT in nuclei of produced by the stomach, could be a critical cholinergic neurons decreases with increasing factor mediating the development of obesity age and is lost in mild cognitive impairment and following social stressors. In contrast to other early AD. By gene microarray analysis, we peripheral signals regulating food intake, ghrelin found that 82-kDa ChAT-expressing neural cells stimulates feeding and increases adiposity in have altered expression of genes involved in laboratory animals and in humans. Interestingly, diverse cellular functions. Genes for several chronic social defeat in mice results in increased proteins regulating APP processing are caloric intake and promotes adiposity, and this is differentially expressed in 82-kD ChAT- mediated by stress induced ghrelin secretion. containing cells, and the predicted effect is We have also determined that ghrelin produces decreased amyloidogenic APP processing with these effects acting at central sites. decreased Aβ production. This was verified as a Interestingly, social stressors also generate significant decrease in BACE1 levels and increases in the secretion of ghrelin in human activity and a concomitant reduction in release subjects. In subjects that have high emotional of endogenous Aβ1-42 from neurons cultured eating scores, ghrelin are lower than those that from brains of AD-model APP/PS1 transgenic have low emotional eating scores, but the post- mice. Expression of 82-kDa ChAT in neurons prandial decrease in ghrelin concentrations was increased levels of GGA3, which is involved in absent in high emotional eaters. These results trafficking BACE1 to lysosomes for degradation. point to ghrelin as a hormone that secreted in shRNA-induced decreases in GGA3 protein the face of social stressors, and one that levels attenuated 82-kDa ChAT-mediated increases appetite and weight gain. Overtime, decreases in BACE1 protein and activity and increased ghrelin secretion may lead to obesity. Aβ1-42 release. 82-kDa ChAT can enhance In humans, susceptibility to overeat following GGA3 gene expression shown by enhanced social stress may be determined by abnormal GGA3 gene promoter activity in neural cells post-prandial ghrelin responses. expressing this ChAT protein. These studies indicate a novel relationship between cholinergic Glucocorticoid hormones recruit neurons and APP processing, with 82-kDa endocannabinoid signaling to promote ChAT acting as a negative regulator of Aβ obesity and metabolic syndrome production. This decreased formation of Aβ Matthew Hill, University of Calgary could result in protection for cholinergic neurons, as well as protection of other cells in the vicinity Obesity, and associated cardiometabolic that are sensitive to increased levels of Aβ. diseases such as type 2 diabetes, are Decreasing levels of 82-kDa ChAT due to increasing in modern society and represent a increasing age or neurodegeneration could alter major contributor to morbidity and mortality. the balance towards increasing Aβ production, Persistent exposure to environmental and with this potentiating decline in cholinergic psychological stress, and the concomitant neuron function. increase in circulating glucocorticoids (the primary stress hormones), are believed to Symposium 12: Comfort Feeding: Functional contribute to the ever-growing epidemic of Interplay Between Feeding Behaviour, Stress obesity and metabolic syndrome. The and Emotionality mechanisms by which glucocorticoids produce these changes in weight regulation and Stress and Obesity: The Ghrelin Connection metabolism remains unclear. Multiple studies Alfonso Abizaid, Carleton University have shown that glucocorticoids mobilize the endocannabinoid (eCB) system and that this 18

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 process is essential for the effects of to HF during the postnatal period only has long glucocorticoids to exert feedback regulation, for lasting consequences on the offspring. Initially, example. It is also clear that the eCB system HF exposure might be protective to the has effects on feeding and metabolism that developing brain by limiting stress responses, mirror those of glucocorticoids. These but in adolescence and adulthood, such dietary observations lead to the hypothesis that stress- changes might reduce functional plasticity and induced increases in glucocorticoids result in a adaptation to environmental stressors, thus hyperactive eCB system, which contributes to enhancing vulnerability to disease. Supported by metabolic syndrome and obesity. Using a CIHR. combination of genetic and pharmacological tools to ablate the eCB system, we demonstrate Nutritional, metabolic and neural signals that eCB signalling through the CB1 receptor connecting obesity and depression (CB1R) contributes to the development of Stephanie Fulton, Université de Montreal obesity and metabolic syndrome in a mouse model of excess glucocorticoid exposure, Obesity and diabetes are significant risks factors independent of central feeding effects. These for mood disorders. Excessive consumption of data further substantiate the role of the eCB high-fat foods not only contribute to the system in obesity and metabolic syndrome and development of obesity but can also promote indicate that the eCB system contributes to emotional impairments and heightened hormonally mediated forms of obesity, in responses to stress that can exacerbate intake addition to diet-induced obesity. of palatable, high-calorie foods as a means to offset a negative mood state. Our findings show Early life exposure to high fat diet modulates that long-term consumption of diets enriched the development and maturation of stress with saturated but not unsaturated fat in rodents responses leads to depressive-like behaviour, decreased Claire-Dominique Walker, McGill University behavioural sensitivity to rewards (reward deficiency) and impaired HPA responses. The Environmental influences during early life are behavioural and metabolic impairments elicited important determinants of adult responsiveness by saturated fat intake are tied to to stress, in particular by altering regulation in neuroinflammation and neuroplastic adaptations the hypothalamic-pituitary-adrenal axis and in the nucleus accumbens, a limbic brain region mesocorticolimbic dopamine (DA) system. strongly tied to hedonic and motivational deficits During this critical period, maternal dietary in depression. Our results suggest that dietary changes signal available resources to the derived free fatty acids and the metabolic offspring and alter the nutritional and hormonal consequences associated with saturated fat environment of the young, which is important for intake impact limbic and midbrain circuitry to brain maturation. Maternal high-fat (HF) feeding affect feeding, emotions and reward function. (30% vs 5%) increases the lipid content of the maternal milk and plasma concentrations of leptin and corticosterone in the offspring. While perinatal HF feeding reduces acute stress responses in neonates through the action of increased leptin, after weaning to a control diet (CD), adolescent HF rats display higher ACTH and corticosterone responses to stress compared to CD controls. As adults, HF offspring display higher accumbens DA responses to an acute stress even though the neuroendocrine response is comparable to that of CD offspring. The effect of the HF perinatal exposure is revealed after repeated exposure to stress where HF adult offspring fail to show the normal neuroendocrine adaptation to a homotypic stressor and exhibit exaggerated responses to a novel stressor. High DA responses in the nucleus accumbens are maintained in HF offspring after repeated stress. These studies demonstrate that early exposure 19

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28

POSTER SESSION 1 The secreted protein netrin-1 is sequestered at paranodes and is required for their A – Development maintenance. Both neurons and oligodendrocytes express netrin-1, but it has not 1-A-1 Perinatal environmental been determined whether paranode enrichment alters the trajectory of mouse maintenance requires netrin-1 made by the brain development oligodendrocytes, the axon, or both. To address whether cell-autonomous expression of netrin-1 Rylan Allemang-Grand¹, Jan Scholz¹, Ellen by oligodendrocytes is required for myelin Langille², Jason Lerch² maintenance, we transplanted oligodendrocyte ¹Mouse Imaging Centre, ²University of Toronto precursor cells (OPCs) from netrin-1 knockout pups into organotypic cerebellar slices from In a preliminary study, we found that 3 weeks of shiverer mice. In slices transplanted with netrin- housing in an enriched enrichment lead to 1-/- OPCs there was a delay in the sequestering volumetric increases in brain areas associated of sodium channels compared to slices with explorative behaviour and spatial memory. transplanted with OPCs from control littermates. In this study, we wanted to determine how In addition, in long term, but not short term, perinatal exposure to an enrichment netrin-1-/- OPC transplanted cultures the environment alters brain development and adult paranodal caspr immunoreactive domain was neuroanatomy. Pregnant CD-1 dams were extended and the juxtaparanodal kv1.2 channel housed in enriched environments (multi-level domains were closer together resulting in a loss maze and running wheel in a large rat cage) or of the juxtaparanode-paranode boundary. This standard housing (no maze or wheel) leakage of proteins into neighbouring domains conditions. Pups lived in the cage until weaning, could be explained by the loss of contact at which point they were assigned into the same between the oligodendroglial loops and the environment they grew up in. Pups were axon, as observed by electron microscopy. longitudinally scanned at 2.5, 3.5 and 5 weeks Together these results indicate a role for netrin- of age with a manganese-enhanced MRI 1 expressed by oligodendrocytes in paranode protocol to acquire high-resolution images of the maintenance. Uncovering the fundamental brain. Images acquired at each time point were mechanisms that regulate myelin maintenance registered and deformed to generate a is an important step in identifying novel consensus average. A mixed effects model was therapeutic targets to protect and repair myelin computed at each voxel relating the Jacobian- in patients with demyelinating diseases. determinant, a value related to volume, to the fixed effects of Age and Cage. At 2.5 weeks of 1-A-3 Ten-m regulates precise synaptic age, enriched pups had volume increases in targeting in Drosophila mechanosensory regions of the hippocampus and cerebellum as neurons well as volume reductions in the cortex (10% FDR corrected). Interestingly, the trajectory of Vedrana Cvetkovska¹, Brian Chen¹ these differences between enriched and control ¹Research Institute of the McGill University mice did not change over the time course of the Health Centre study, suggesting an alteration in early-life brain development. We are currently studying pups Teneurins are a highly conserved family of cell (P7) that have not yet opened their eyes or surface receptors that have important roles started moving to determine whether the during nervous system development for axon neuroanatomical changes are caused by early guidance, cell adhesion, and synaptic specificity. life exploration in the enriched cage, or via a Drosophila Teneurins have been shown to maternal epigenetic mechanism. regulate synaptic partner matching between classes of olfactory neurons and at the larval 1-A-2 Paranode Maintenance Requires neuromuscular junction. However, it is not clear Netrin-1 Expression by Oligodendrocytes how Teneurins regulate axonal targeting decisions at the level of single neurons and its Jenea Bin¹, Timothy Kennedy¹ effect on circuit function. To address this issue, ¹McGill University we use the Drosophila hard-wired mechanosensory circuit for identification and Myelinated axons are divided into several quantitative analysis of axonal targeting errors, specialized domains: the node of Ranvier, the with a functional assessment of synaptic paranode, the juxtaparanode, and the internode. connectivity through behaviour. We found that 20

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28

RNAi knockdown of Ten-m solely within specific P18, Tsc1fl/fl::Nkx2.1Cre mice showed both mechanosensory neurons produced stereotyped mTORC1 hyperactivation in BC and an axonal targeting errors, including mis-routing of increased expression of perisomatic VGAT, a axonal branches, inappropriate midline crossing, presynaptic GABAergic marker. Behavioral and premature branch termination or studies are currently underway to investigate extensions. We assessed mechanosensory possible deficits in working memory and social circuit function by stimulating mechanosensory behavior. bristles to elicit a cleaning reflex in Ten-m RNAi mosaic animals. We found that loss of Ten-m 1-A-5 Mcl-1 and Bcl-x survival signaling within neurons reduced the ability of the animal through neurogenesis to perceive a mechanical stimulus. Our results demonstrate that Ten-m is required for precise Lauren Fogarty¹, Hiliary Martin¹, Beibei synaptic targeting in single sensory neurons and Song¹, Allison Parrill¹, S. M. Mahmudul for proper circuit function. In humans, the TEN- Hasan¹, Jieying Xiong¹, Joseph Opferman², M1 gene is located in a region associated with Lothar Hennighausen³, Jacqueline X-linked mental retardation; thus, further Vanderluit¹ examination of the roles of Teneurins in the ¹Memorial University of Newfoundland, ²St. Jude developing brain may provide insight into the Children's Research Hospital, ³NIDDK mechanisms of miswiring in disease. During development of the murine embryonic 1-A-4 Role of mTOR pathway in nervous system cells progress through different GABAergic maturation in the mouse stages from neural stem cells to progenitors to neocortex neuroblasts and finally differentiated neurons. Cell survival signaling changes during Mayukh Choudhury¹, Josianne Nunes neurogenesis however, are still poorly Carrico², Martin Berrier², Graziella Di Cristo² understood. Here we have examined the role of ¹CHU Ste-Justine, ²Université de Montréal the anti-apoptotic Bcl-2 proteins Mcl-1 and Bcl-x in promoting survival as cells progress through mTOR pathway has been implicated in the stages of neurogenesis. Nestin-mediated controlling several aspects of neurodevelopment conditional deletion of Mcl-1(Mcl-1 CKO) or Bcl- by regulating the rate of protein-synthesis. x (Bcl-x CKO) results in extensive cell death Mutations in the regulatory components Tsc1 within specific neural populations in the and Tsc2 of mTOR-Complex1 (mTORC1) cause forebrain, hindbrain and spinal cord at different Tuberous Sclerosis (TSC) in humans. The time points during development. In the Mcl-1 majority of TSC patients develop neurological CKO, apoptosis begins at embryonic day 10 problems like seizures, mental retardation and (E10), the start of neurogenesis and is seen autism. The role of mTORC pathway in the initially within the proliferating cell populations. development of neocortical GABAergic In the Bcl-x CKO, apoptosis begins in post interneurons and the specific contribution of mitotic cells at E11 in the spinal cord and altered GABAergic cells in disease hindbrain, but not until E17 in the cortex as manifestation remain largely unknown. Here, we neurogenesis is concluding. To determine investigated whether and how Tsc1 knockdown whether changes in the expression of Bcl-2 pro- perturbs GABAergic circuit development, both in apoptotic proteins coincide with the stages of vitro and in vivo. In particular, we focused on neurogenesis, qPCR and in situ hybridization parvalbumin basket cells (BC), a major were used to examine the expression profiles of GABAergic cell subtype. To investigate the role Bcl-2 family members. Differences in cell death of mTORC1 activation in BC development, we in the CKO models suggest Mcl-1 and Bcl-x are knocked down Tsc1 expression, by transfecting critical for cell survival during neurogenesis, CRE-GFP driven by a promoter specific for BC however further investigation into the specific in cortical organotypic cultures prepared from cell populations affected will clarify their distinct Tsc1-lox mice. Tsc1 knockdown in vitro caused and overlapping roles. This work was supported a precocious increase in bouton density and by an operating grant from the CIHR, RDC-NL terminal branching in BC, which was reversed to JV. LF is supported by an NSERC Canada by Rapamycin treatment. These data suggest Graduate Scholarship. that mTOR pathway hyperactivation might affect the timing of basket cell synapse maturation. To 1-A-6 Autism-Associated Ankrd11 is a investigate the role of mTORC1 in BC in vivo, Novel Epigenetic Regulator of Neurogenesis we bred Tsc1-lox mice with Nkx2.1-CRE mice At 21

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28

Denis Gallagher¹, Anastassia Voronova¹, lasting synaptic plasticity in the mature brain, Sarah Burns¹, Alexa Bramall¹, Annie Paquin¹, little is known about its role during development. Gordon Keller², David Kaplan¹, Freda Miller¹ Using electrophysiological recordings and time- ¹The Hospital for Sick Children, ²McEwen lapse two-photon imaging techniques, we Centre for Regenerative Medicine investigated the role of TORC1-dependent translation in synapse stabilization and Increasing evidence suggests that perturbations maturation in vivo in the retinotectal system of in stem cell differentiation during the the albino Xenopus laevis tadpole. We show development of the nervous system may that TORC1 inhibition, by either raising tadpoles underlie cognitive dysfunction associated with in rapamycin or electroporating tectal neurons neurodevelopmental disorders. We have with a Raptor Morpholino oligonucleotide, identified a novel role for a recently identified, significantly reduced AMPA mEPSC amplitudes autism-associated gene, ankyrin repeat domain- and frequencies, as well as AMPA/NMDA ratios, containing protein 11 (Ankrd11), in the compared to neurons in control tadpoles. On the development of the cerebral cortex. Ankrd11 is a other hand, neurons that were electroporated to nuclear protein capable of regulating overexpress Rheb, an upstream activator of transcription through recruitment of histone- TORC1, exhibited greatly enhanced AMPA modifying enzymes such as histone mEPSC amplitudes and frequencies, as well as deacetylases (HDACs), but its physiological role greater AMPA/NMDA ratios. Interestingly, is still unknown. Here, we show that Ankrd11 is mIPSCs were not affected by TORC1 activation, expressed in both embryonic cortical precursors resulting in a significant imbalance in the and in newly-born cortical neurons. Embryonic excitatory-inhibitory (E/I) ratio. Moreover, we cortical precursor proliferation and differentiation showed that TORC1 inhibition significantly were perturbed after acute shRNA-mediated reduced dendritic arbor size and complexity, knockdown of Ankrd11 in vivo using in utero whereas TORC1 activation dramatically electroporation. Furthermore, "Yoda" mice, increased dendritic arbor size and complexity. which are heterozygous for a point mutation in These experiments therefore suggest that the C-terminal, HDAC-binding domain of TORC1 activity is critical for regulating the Ankrd11 display defects in both embryonic and number and maturity of excitatory synapses and adult neurogenesis reminiscent of human may also contribute to setting the E/I balance in patients carrying similar mutations. the developing brain. Overexpression of HDAC3 rescues the effects of Ankrd11 knockdown on neural precursor 1-A-8 Response of Medullary proliferation, suggesting that Ankrd11 mediates Catecholaminergic Heme-Oxygenase-2 its effects in cortical precursors by recruiting and Coexpressing Neurons to Hypoxia in Chick regulating HDACs. To ask whether Ankrd11 is Embryos similarly important in human cortical precursors, we developed a method for generating forebrain Connor Hawkins¹, Aaron Lee¹, Jeremy neural precursors from human embryonic stem Landry¹, Maria Pompeiano¹ cells (hESCs) and human induced pluripotent ¹McGill University stem cells (hiPSCs). Knockdown of Ankrd11 in human precursors causes the same deficits Monitoring O2 availability is of critical importance for vertebrate embryos as they 1-A-7 TORC1 regulates excitatory prepare for transitioning to air-breathing. A brain synaptic maturation and dendritic area believed to be a primary O2 sensing site is development in vivo in the retinotectal the volume of tissue which includes the A1/C1 system of Xenopus laevis region in the ventrolateral medulla. This region contains A1/C1 catecholaminergic (CA) neurons Delphine Gobert¹, Anne Schohl¹, Edward which are thought to sense oxygen through the Ruthazer¹ action of heme-oxygenase-2 (HMOX2), an ¹Montreal Neurological Institute - McGill enzyme involved also in peripheral oxygen University sensing. However, it is possible that non-CA neurons in this region may also be oxygen During early brain development, neurons sensitive, in addition to the CA ones. In order to undergo extensive growth and rearrangement of better study the neuronal populations their connections, contributing to the formation expressing HMOX2 and their roles in the brain of functional circuits. While TORC1-dependent response to hypoxia, we used triple-labelling protein synthesis has been implicated in long- immunofluorescence for tyrosine hydroxylase (a 22

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 marker of CA neurons), HMOX2 and c-fos function. Together, these experiments suggest (indicating neuronal activation) on embryonic the DISC1-Dixdc1 pathway is important for day 18 chick medullary tissue sections. Embryos neural connectivity development, revealing a were kept in either normoxic (21% O2) or signaling pathway that may underlie the disease hypoxic (10% O2) conditions for 4 hours before pathology of neurodevelopmental and perfusion. A population of A1/C1 CA neurons psychiatric disorders. co-expressed HMOX2, and significantly increased their activity in response to hypoxia. A 1-A-10 The distribution of cFos- population of interdigitating HMOX2- expressing immunoreactive neurons in the brainstem non-CA neurons was also present but these did and hypothalamus of late gestation chicken not significantly increase their activity in embryos in response to acute hypoxia response to hypoxia. This suggests that in late gestation chick embryos, the A1/C1 CA neurons Jeremy Landry¹, Aaron Lee¹, Maria are the dominant cell population driving brain Pompeiano¹ responses to changes in oxygen availability. ¹McGill University Non-CA HMOX2 producing cells are present within the A1/C1 region, but do not appear to Research into the effects of prenatal hypoxia participate in O2 sensing in late gestation chick has benefited in recent years from the study of embryos. avian embryos, as they lack the confounding effects of maternal and placental adaptation 1-A-9 Regulation of Neural Connectivity during hypoxia exposure. Both bird and mammal by DISC1 through a novel Dixdc1-Actin embryos display comparable subcortical brain Cytoskeleton Pathway anatomy and similar physiological responses to hypoxia; however it has yet to be determined Vickie Kwan¹, Karun Singh¹ whether similar CNS structures are involved. ¹McMaster University Therefore, in concordance with previous studies of late gestation mammalian embryos, this study Gene mutations associated with uses cFos (a measure of neuronal activation) to schizophrenia(SZ) are shared among map the pattern of subcortical activation in late neuropsychiatric diseases, such as autism gestation chicken embryos (embryonic age 18 spectrum disorder(ASD). While the out of 21) after acute exposure to normoxia pathophysiology of these disorders remains (21% oxygen), modest hypoxia (15% oxygen), unknown, they are hypothesized to be a and medium hypoxia (10% oxygen). Results neurodevelopment disorder, arising from largely confirmed a similar pattern of hypoxia- abnormalities in neural connectivity at different related cFos activation to that of mammalian stages of development. To better understand embryos: greater cFos labeling in areas of the the disruptions in neural connectivity, we are brainstem (nucleus of the solitary tract, dorsal studying the role of a well-established SZ risk motor nucleus of vagus, ventral lateral medulla, gene, disrupted in schizophrenia-1(DISC1). lateral parabrachial nucleus, and periaqueductal DISC1 plays an important role in the regulation grey) and hypothalamus (arcuate nucleus, of neural connectivity, however the molecular ventral zone, and median preoptic nucleus). and cellular mechanisms by which this occurs However, unlike mammalian embryos, reduced remain unknown. Using mouse in vitro and in cFos activity in hypoxic groups was found in the vivo models, we are testing the hypothesis that caudal medullary raphe and its lateral a DISC1-binding partner, DIX domain extensions. As this area drives thermogenesis in containing-1 (Dixdc1), a key regulator of neural mammals, the moderate normoxic activation connectivity, plays a role in dendrite outgrowth, (absent in mammals) may reflect the unique dendritic spine and synapse formation. Our tendency for bird embryos to maintain their body results show that decreasing expression of temperature above of incubation temperature; DISC1 or Dixdc1 reduces dendritic outgrowth, hypoxic deactivation here would act to reduce branching, and spine formation. Interestingly, thermogenesis and therefor oxygen expenditure. overexpression of DISC1 or Dixdc1 increases dendritic outgrowth. Finally, we have evidence 1-A-11 Activity Induced Plasticity in to suggest that Dixdc1 may mediate its effects AMPAR composition at the Developing Calyx through regulation of the actin cytoskeleton. We of Held/MNTB Synapse will determine if the newly discovered genetic variants in Dixdc1, associated with ASD, have Stephen Lesperance¹, Lu Yang Wang¹ an impact on dendritic spine and synapse ¹The Hospital for Sick Children 23

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28

= 14). Migrating neuroblasts immunostained for The development of high fidelity synaptic DCX in the olfactory tract were quantified and transmission at the calyx of Held synapse reconstructed in 3 dimensions using the requires a postsynaptic shift of slow-gating Neurolucida software, and cell densities in the GluA1 dominant too fast-gating GluA4 dominant granule cell layer were estimated in Nissl- AMPARs, but the initiating signal remains stained OB sections. Results: Compared to unknown. The onset of sound evoked neural controls, suicides displayed a greater responses coincides with the beginning of this expression of DCX and Sox2 (stem cell marker) gating switch, suggesting activity dependent in the SVZ, and higher DCX levels in the OB. processes may drive the GluA subunit shift. To Antidepressant treatment appeared to normalize test this, pre-hearing synapses were subjected SVZ protein expression, but had no effect on OB to burst stimulation imitating acoustically evoked DCX levels. Although suicides showed no activity followed by a >30 min expression phase change in OB cell densities, they displayed before membrane rupture to establish whole-cell increased DCX multipolar cells and processes in recording. In these neurons we observed the olfactory tract, which in turn correlated acceleration of the fast decay time constant positively with OB DCX expression. DCX cells (tau-f) of evoked EPSCs. Distribution histograms varied considerably in size, tended to be aligned of miniature EPSC (mEPSC) tau-f values for rostro-caudally along the tract, and were naive and tetanized cells showed two mEPSC structurally similar in suicides and controls, with populations with tau-f being 0.4 and 0.7ms, the exception of process volume, which was respectively, with the relative weight of the fast significantly higher in suicides. Conclusions: population increasing in tetanized synapses. These data suggest that the migration and Such changes are blocked by NMDAR or differentiation of SVZ-derived neuroblasts may mGluR antagonism and inhibitors of CamK or be impaired in suicides. PKC signalling implicated in post-translational AMPAR regulation. These kinetic changes are 1-A-13 Patterned activity instructs axon absent in GluA4-/- synapses, suggesting GluA4 refinement: a revision of Hebb's rules is a key substrate underlying this gating switch. Interference of an interaction between the Martin Munz¹, Delphine Gobert¹, Anne immediate early gene product, Neuronal Activity Schohl¹, Jessie Poquérusse², Kaspar Regulated Pentraxin (Narp), and AMPARs, Podgorski³, Perry Spratt¹, Edward Ruthazer¹ blocks this switch, substantiating a role for Narp ¹McGill University , ²Geisel School of Medicine, in excitatory synapse remodeling. These results ³University of British Columbia show that activity works through NMDAR/mGluR signalling mechanisms to facilitate high fidelity Hebbian plasticity posits that temporal transmission at the calyx of Held synapse in correlation in pre- and postsynaptic cell firing vitro. instructs circuit refinement. In Xenopus tadpoles, retinal ganglion cell (RGC) axons 1-A-12 Evidence for impaired migration mainly innervate the contralateral optic tectum, of SVZ-derived neuroblasts in suicide but we found in about 40% of tadpoles that a few axons are misguided to the ipsilateral Marissa Maheu¹, Julia Devorak¹, Alexander tectum. We used visual stimuli designed to Freibauer¹, Maria Antonietta Davoli¹, Gustavo synchronously or asynchronously activate single Turecki¹, Naguib Mechawar¹ ipsilateral RGC axons relative to the ¹McGill Group for Suicide Studies, Douglas contralateral inputs to see how correlated firing Mental Health University Institute instructs circuit formation and plasticity. Using perforated patch recordings of tectal neurons, Background: Alterations in adult hippocampal we found that asynchronous visual stimulation neurogenesis have been implicated in reduced the strength of ipsilateral eye input depressed mood and antidepressant efficacy. relative to the contralateral eye. Synchronous This study investigated neurogenesis in the stimulation maintained the ipsi-to-contralateral subventricular zone (SVZ)-olfactory bulb (OB) input ratio at baseline levels. Live imaging of pathway of medicated and unmedicated suicide ipsilateral RGC axons revealed that completers. Methods: Neurogenic markers in asynchronous, but not synchronous stimulation, OB and SVZ were assessed by immunoblotting upregulated branch additions. However, axonal in postmortem tissue samples from subjects branches formed during synchronous having died by suicide (n = 21) and stimulation were more stable. To see how psychiatrically healthy sudden-death controls (n synaptic transmission contributes to axonal 24

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 branch formation and stability, we transfected 1-A-15 Maternal care influences ipsilateral RGCs to express tetanus toxin light susceptibility to anxiety-type behaviours chain to prevent synaptic transmission. RGC mediated by neurogenesis-dependent firing still promotes axonal branching in these mechanisms. cells but, the stabilization of newly formed branches by synchronous stimulation was lost. Naghmeh Rastegar¹, Josie Diorio¹, Michael Blocking NMDARs gave a similar outcome, Meaney¹ consistent with their putative role as synaptic ¹Douglas Mental Health University Institute, correlation detectors. Thus, presynaptic activity McGill University, promotes axonal branch motility, but correlated firing suppresses both branch addition and Variations in maternal care during the first week stabilization. of life influence the offspring's susceptibility to depression and anxiety in adulthood. We have 1-A-14 Development of melanin- previously shown that offspring of low licking concentrating hormone neurons in the and grooming (LG) dams display increased chicken hypothalamus depression and anxiety-type behaviours. In an analysis of adult neurogenesis, high LG Alissa Yip¹, John Pidakala¹, Bong Seok¹, offspring displayed increased proliferation and Jaimie Bird¹, Maria Pompeiano¹ survival of adult-born neurons in the dentate ¹McGill University gyrus (DG). Given the strong correlation of decreased adult neurogenesis with anxiety, we Melanin-concentrating hormone (MCH) acts as propose that low maternal care in early life leads a neurotransmitter/neuromodulator in the to an increase in anxious behaviour in adulthood vertebrate brain. MCH neurons are found in the through a neurogenesis dependent pathway. dorsal and lateral hypothalamus in both rodents The anti-depressant fluoxetine hydrochloride and birds, and send diffuse projections has been shown to ameliorate anxiety-type throughout the brain that regulate a variety of behaviour in correlation with an increase in DG physiological and behavioral functions, including neurogenesis. In order to establish whether this the sleep-waking cycle. The developmental effect is varied in high and low LG offspring, a expression of MCH has been studied in rodents, chronic treatment regiment was undertaken in but no previous information is available for birds. adult rats. Anxiety and depressive behaviours In order to better understand the possible role(s) were subsequently assessed. Fluoxetine-treated of MCH neurons in the developing avian brain, low LG offspring displayed significantly we studied MCH expression using standard decreased levels of anxious behaviour. The immunohistochemistry on tissue sections decrease in anxiety was correlated with obtained from the hypothalamus of chickens at decreased expression ratio of pro/anti-apoptotic different embryonic (E6-E20) and postnatal (P1 factors as well as an increase in neurogenic and P21) ages. We occasionally detected marker expression in the ventral DG. There is labelled neurons lying along the 3rd ventricle at clear evidence that maternal care affects E8. A good number of lightly labeled MCH depression and anxiety-type behaviour in adult neurons were seen at E10. The number of male rat. We hypothesize that anti-depressant labeled neurons and the intensity of staining treatment leads to an increase in neurogenesis increased at E12 and older ages. MCH neurons in the ventral DG, rescuing the effects of low LG were generally seen in medial locations at on anxiety through an apoptosis-dependent anterior levels (retromammillary area, posterior mechanism. hypothalamic nucleus). More posteriorly, they extended from the hypothalamic periventricular 1-A-16 Precipitated cannabinoid organ laterally into the lateral hypothalamic withdrawal in the rat brain: Mapping c-fos area. These results suggest that the distribution gene expression in adolescent and adult of MCH neurons in chickens is more complex rats. than originally described. The presence of a substantial number of MCH neurons in the Gehan Senthinathan¹, Gabrielle Willems¹, second half of embryonic development suggests Sylvia Skrzypczak¹, Carolyn Leckie¹, Paul that these neurons may play a functional role in Mallet¹ developmental processes, and possibly also in ¹Wilfrid Laurier University regulating brain states in chick embryos. The immediate early gene c-fos is a biological marker of recent cellular activity. Using 25

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 immunohistochemistry, we quantified Fos (the number of hippocampal newborn neurons was protein product of c-fos) in several brain regions increased in p300G422S mutants at the age of of adult and adolescent rats undergoing drug 3-month. More interestingly, we found that the withdrawal precipitated by the selective CB1 percentage of double labeled BrdU/NeuN receptor antagonist SR141716 (SR). Rats were positive neurons over total BrdU positive cells in first chronically treated with Ä9- the dentate gyrus was reduced in CBPS436A tetrahydrocannabinol (THC, 10 mg/kg, IP, twice mutants at 6-month, whereas the percentage of daily for 6 days), or its vehicle, and then were double labeled BrdU/Sox2 positive neural stem injected with SR (3 mg/kg, IP) or its vehicle 2 h cells (NSCs) in the same dentate gyrus was after the final THC or vehicle treatment, and 2 h surged. However, total number of immature later were perfused transcardially. The doublecortin positive neurons was not changed. anatomical distribution of cannabinoid- These data suggest that aPKC-mediated CBP responsive brain structures was analyzed by phosphorylation is important for normal adult localization of Fos-immunoreactivity (Fos-IR) in neurogenesis, and it modulates rate of response to 1) acute SR, 2) chronic THC, and 3) differentiation of NSCs and maturation of newly- SR-precipitated withdrawal in rats treated born neurons in the hippocampus in an age- chronically with THC. SR-precipitated dependent fashion. withdrawal was associated with increased Fos- IR in reward related and stress responsive brain 1-A-18 Functional connectivity changes areas including the nucleus accumbens and the induced by monocular deprivation during the central nucleus of the amygdala. Preliminary critical period analysis suggests that in some brain areas of THC-naive animals, SR alone was associated Kaiyun Yang¹, Allen Chan¹, Jeffrey LeDue¹, with age-dependent c-fos expression. SR- Matthieu Vanni¹, David McVea¹, Majid precipitated cannabinoid withdrawal was Mohajerani¹, Timothy Murphy¹, Max Cynader¹ associated with age mediated differences in ¹Brain Research Centre Fos-IR in response to the SR challenge in areas including the lateral septum and the Monocular deprivation is a well-characterized ventromedial hypothalamus. example of how early sensory experience effectively modifies neuronal circuits during 1-A-17 Atypical PKC-CBP Pathway development. During the critical period, brief Regulates Murine Adult Neurogenesis monocular deprivation causes weakening of input from the deprived eye to the contralateral Jing Wang¹, Karolynn Hsu¹, Ling He², Fredric binocular zone. Here we examined functional Wondisford², Freda Miller³ connectivity changes induced by monocular ¹Ottawa Hospital Research Institute , ²Johns deprivation across the brain using intrinsic Hopkins Hospital, ³Hospital for Sick Children optical signal (IOS) imaging. IOS imaging was performed in C57BL/6 mice anesthetized with Our previous study has shown that isoflurane. We studied functional connectivity by phosphorylation of serine 436 (S436) in CBP by examining spontaneous metabolic activity, using aPKC is important for CBP to promote data collected in the absence of stimuli. Studies embryonic neural precursor differentiation in have indicated that functionally related areas culture. Recently, intriguing findings that CBP have correlated neural and hemodynamic level and/or its activity is also required to activity in the resting state. To guide the regulate adult neurogenesis led us to ask further interpretation of spontaneous data, primary whether CBP aPKC phosphorylation at S436 is sensory areas were mapped with peripheral a key modulator of adult neurogenesis. We used stimulation. Centers of maps calculated from two knock-in mouse models to target the aPKC- sensory-evoked response were assigned as CBP pathway, CBPS436A and p300G422S, seed pixels in the analysis of spontaneous where an aPKC phosphorylation site was activity. Seed pixel correlation was performed modified in CBP and p300 allelles in order to and correlation coefficients were used as an generate phosphorylation-defective indicator of strength of functional connectivity. (CBPS436A) and phosphorylation-competent Using this method, we observed robust (p300G422S) mouse models. By using BrdU in functional connectivity changes in the mouse vivo labeling technique, we showed that total brain after monocular deprivation during the number of hippocampal and olfactory bulb critical period. Within the primary visual cortex, newborn neurons (BrdU/NeuN positive) was the monocular zone contralateral to the deprived decreased in CBPS436A mutants, while total eye became less correlated with the rest of the 26

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 visual cortex, the binocular zone became more 1-B-20 Targeting the TRPV1 assembly correlated with the ipsilateral visual cortex. domain attenuates inflammation-induced Global asymmetry in functional connectivity was hypersensitivity also observed in monocularly deprived mice. Robyn Flynn¹, Reem Aboushousha¹, Kevin B - Neural Excitability, Synapses, and Glia: Chapman¹, Diego Varela², Christophe Altier¹ Cellular Mechanisms ¹University of Calgary, ²CEMC & ICBM, Facultad de Medicina, Universidad de Chile 1-B-19 Control of vesicle release by cortical presynaptic NMDA receptors Transient receptor potential vanilloid 1 (TRPV1) ion channels are major contributors of Therese Abrahamsson¹, Rui Costa², Kate inflammatory pain. They are composed of four Buchanan³, Dale Elgar³, Arne Blackman³, subunits surrounding a central pore. To function Julia Oyrer³, Adam Tudor-Jones³, Mark van as noxious sensors in primary afferent dorsal Rossum², Jesper Sjostrom¹ root ganglion (DRG) neurons, TRPV1 subunits ¹The Research Institute of the McGill University must assemble into tetramers, a process Health Centre, ²Institute for Adaptive and Neural dependent on the C-terminal domain, as well as Computation, ³University College London be exported to the plasma membrane. Using biochemical assay, imaging in live cells as well Traditionally, postsynaptic NMDARs act as as electrophysiological recordings of coincidence detectors. Recently, presynaptic recombinant TRPV1 channel mutants, we NMDARs (preNMDARs) have been found at identified the TRPV1 assembly domain in the C- several synapse types, although their functional terminal region of the channel. We tested role remains debated. Cortical preNMDARs are whether preventing TRPV1 assembly with a known to upregulate probability of release (Pr) membrane-tethered disrupting peptide during high frequency firing, but it is unclear how mimicking this domain may block channel Using whole-cell recordings, we compared function and thus inflammatory pain. Results: evoked and spontaneous release onto layer-5 TRPV1 subunit association was disrupted by pyramidal cells (PCs) in acute slices of juvenile truncating the protein shorter than residue mouse visual cortex. AP5 blockade of G734. Peptides comprised of residues 734-751 preNMDARs resulted in a characteristic and 752-772 both bound the C-terminus of downregulation of evoked Pr, but only at high TRPV1 in co-immunoprecipitation and presynaptic firing rates (>8 Hz). In apparent membrane translocation assays. Using mutant contradiction, the frequency of spontaneous TRPV1 channels combined with release (2.4±0.5 Hz) was reduced by AP5. Two- bioluminescence resonance energy transfer photon imaging indicated that in PC boutons assay (BRET), we found that 734-751 motif AP5 reduced basal calcium level, which is governs channel assembly. Finally, we show known to control spontaneous Pr directly. We that interfering with TRPV1 subunit association next asked whether preNMDARs regulate in vivo attenuated mechanical and thermal evoked Pr directly or indirectly, e.g. by hypersensitivity in mice models of inflammatory controlling the readily releasable pool (RRP) hyperalgesia. Conclusions: We have identified size. With Schneggenburger-Neher's approach, residues 734-751 of the TRPV1 C-terminus to we found that preNMDAR blockade decreased be critical in TRPV1 subunit assembly. both RRP size and replenishment rate. In Disrupting TRPV1 channel tetramerization may agreement, fitting a modified Tsodyks-Markram represent a novel therapeutic way of reducing short-term plasticity model to evoked responses hypersensitivity in inflammatory pain. before and after AP5 showed that preNMDARs upregulate vesicle replenishment rates and Pr 1-B-21 Pharmacological characterization during high but not low frequency firing. To of electrical coupling between identified conclude, preNMDARs control evoked Pr peptidergic neurons indirectly by upregulating RRP replenishment rates in the face of high-frequency firing. Christopher Beekharry¹, Neil Magoski¹ However, preNMDARs control spontaneous Pr ¹Queen's University directly by increasing bouton basal calcium levels, presumably by flickering open at resting Electrically coupled neurons communicate potentials. through an assembly of channels called gap junctions, which connect one cell to another and mediate the transfer of metabolites and current. 27

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28

Electrical coupling is involved in the central nervous system site at which circulating synchronization of spiking and rapid melanocortins may act to influence energy transmission of action potentials within circuits. homeostasis. Supported by the Canadian In turn, this influences the coordination, bursting Institutes for Health Research pattern, and firing frequency of coupled neurons. The present study concerns an electrically 1-B-23 Pore properties of heteromeric coupled two-neuron system within the CNS of kainate receptors the gastropod mollusc, Lymnaea stagnalis. The two neurons, designated Visceral Dorsal 1 Patricia Brown¹, Mark Aurousseau¹, Hugo (VD1) and Right Parietal Dorsal 2 (RPD2) are McGuire², Rikard Blunck², Derek Bowie¹ readily identifiable, peptidergic, strongly-coupled ¹McGill University, ²Université de Montréal and, given their role in cardio-respiratory function, crucial for survival. In isolated brain Kainate receptors (KARs) are ionotropic preparations, under dual sharp-electrode glutamate receptors that modulate synaptic current-clamp recording, neurons were exposed transmission. Intracellular polyamines block to gap junction blockers to disrupt electrical KARs in a voltage-dependent manner; this can coupling. Hyperpolarizing current was injected be abolished by RNA editing of a Q/R site at the into either VD1 or RPD2 to determine the apex of the channel pore. Not all KAR subunits coupling coefficient before and after drug are edited, suggesting that many native KARs application. Niflumic acid and 5-nitro-2-(3- are formed from unedited subunits. Native KARs phenylpropylamino) benzoic acid significantly are heteromeric; the most widely-expressed are decreased the coupling coefficient, whereas composed of GluK2 and GluK5. The extent to meclofenamic acid, quinine, and carbenoxolone which heteromerization imparts functional had no effect. Moreover, uncoupling revealed a changes to the properties of the channel block is distinct firing pattern and frequency in RPD2, currently unknown, largely owing to the suggesting that gap junctions are key to the challenges of studying heteromers in regulation of synchronous rhythmic control. recombinant systems. We used a single- molecule fluorescent subunit counting approach 1-B-22 The Subfornical Organ: A new to determine, for the first time in mammalian target for melanocortins cells, that the stoichiometry of GluK2/K5 is fixed at 2:2. This finding enabled the identification of Emily Black¹, Alastair Ferguson¹ outside-out patches from HEK293T cells ¹Queen's University containing high levels of GluK2/K5. Electrophysiological analysis of unedited Alpha -Melanocyte Stimulating Hormone (α- GluK2/K5 receptors revealed that MSH) is a peptide that has demonstrated heteromerization reduces channel block by involvement in the maintenance of energy spermine without affecting calcium permeability. homeostasis. Specifically, α-MSH has been This is in contrast to the conventional shown to have profound inhibitory effects on understanding of polyamine block and provides feeding through actions at the melanocortin 4 new evidence that it can be uncoupled from receptor (MC4R). Systemic administration of calcium permeability in KARs. Here, we show MT-II (an MC4R agonist) has been suggested to that a proline located in the pore of GluK5 is similarly inhibit feeding through actions at one of responsible for the reduction in polyamine block two circumventricular organs the subfornical in GluK2/K5. We propose that the fixed organ (SFO) or the area postrema (AP) (Trivedi stoichiometry imparted by KAR heteromerization et al 2003), both of which have been shown to provides neurons with an additional mechanism express MC4R mRNA (Kishi et al 2003). The by which to control the apparent affinity of current study was therefore undertaken in order polyamines, and thus the shape of native KAR to determine the effects of α-MSH on the responses. excitability of SFO neurons. We used the whole- cell patch clamp technique to determine the 1-B-24 Electrical coupling in Aplysia: influence of α-MSH on the membrane potential identification of innexin genes. of dissociated SFO neurons. We found that 50% of neurons responded when treated with α-MSH Christopher Carter¹, Neil Magoski¹ (250 nM-500 nM). Of the cells that responded, ¹Queen's University 25% showed a depolarization (mean 33 mV) and 75% a hyperpolarization (mean-11.9 mV). Electrical synapses are employed throughout This study suggests the SFO as a potential the animal kingdom as a means to achieve rapid 28

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 and synchronous neuronal communication. In 20ºC, this temperature is known to block the the snail, Aplysia californica, a group of transport in the late endosome and the receptor electrically-coupled neuroendocrine cells, known is no longer able to go upstream. The receptor as the bag cell neurons, initiate reproductive co-localizes with the M6PR (marker of trans- behaviour via the release of hormone during a Golgi network (TGN) and late endosome (LE)) lengthy afterdischarge. This burst of action and depends on Rab9 and TIP47 (two proteins potentials is synchronized across essentially all involved in LE to TGN transport) to be recycled bag cell neurons due to extensive gap junctional to the membrane. This recycling was dependent coupling. For invertebrates, gap junctions are on the kinase PKD which is involved in the mediated by cell-to-cell channels comprised of transport of the cargo from the TGN to the innexin proteins. We used a bioinformatic membrane. We can conclude that DOR recycle approach to search for innexin homologues from the LE to the membrane via the TGN. Our utilizing both the University of California, Santa outlook is to study recycling mechanisms for all Cruz (UCSC) Aplysia Genome Browser and the the drugs cited and to correlate these properties University of Maryland Aplysia transcriptome with drugs tolerance potential. These results will assembly. Following in silico identification of enable the development of ligands with a longer putative genes, standard PCR was used to analgesic activity. obtain 18 full-length Aplysia innexins. All putative Aplysia innexins showed intracellular 1-B-26 Involvement of spinal nuclear amino and carboxy termini, four transmembrane metabotropic glutamate 5 receptors domains, and two extracellular loops containing (mGluR5) in persistent pain: anatomical and conserved cysteines required for channel-to- biochemical evidence channel association between cells. Real time PCR indicated that most of the Aplysia innexins Virginia Cornea¹, Yuh-Jiin Jong², Alfredo were expressed in nervous tissue as well as foot Ribeiro-da-Silva¹, Karen O'Malley², Terence muscle and salivary glands. However, Aplysia Coderre¹ innexins 7, 8, and 10 were the most abundant in ¹McGill University, ²Washington University both the bag cell clusters and the abdominal and buccal ganglia. Identification of Aplysia innexins mGluR5 play a key role in the modulation and will provide the molecular tools needed to study plasticity of pain especially in dorsal horn spinal how electrical coupling contributes to the bag cord. mGluR5's are GPCR's that have been cell neuron afterdischarge and the control of shown to be expressed on cell surface and reproductive behaviour. nuclear membranes of striatal neurons in culture. While it has been shown in neuronal 1-B-25 Molecular determinants of cultures that the activation of plasma membrane recycling of delta-opioid receptor versus nuclear membrane mGluR5 stimulates different signalling pathways leading to the Iness Charfi¹, Graciela Pineyro¹ activation of different genes, the physiological ¹Université de Montréal role of the nuclear-located receptors of the GPCR family remains unknown. Electron Opioids are the most potent analgesics for the microscopy was used to show that mGluR5s are treatment of severe pain. The delta opioid localized on the nuclear membrane of neurons receptor (DOR) agonists induce fewer side in rat spinal cord dorsal horn. Moreover, we effects than those of mu receptor, making them found that mGluR5s on the nuclear membrane a target of interest for chronic pain treatment. are increased in dorsal horn neurons from However, they induce tolerance to analgesia. neuropathic rats, without changes in the plasma Recent hypotheses suggest that drugs tolerance membrane compartment. Western blots, potential is the result of stabilization of different demonstrate that mGluR5 is increased in the ligand-specific conformations of the receptor, nuclear fraction from neuropathic rats, while no each having different trafficking profiles. We will changes are detected in the plasma membrane determine whether DOR ligands display different fraction. EAAT3 protein level remained post-endocytic trafficking (recycling) properties. unchanged after SNI. Downstream signalling The experiments were done in cortical neurons molecules induced by intracellular mGluR5 transfected with the DOR. Our results indicate activation, such as pERK and Arc, showed an that only DPDPE, UFP-512 and TIPP were able increase in the nuclear fraction from neuropathic to induce DOR recycling (SNC-80 and morphine rats. Intrathecal glutamate-induced activation of did not). Recycling of neuronal DOR stimulated spinal dorsal horn mGluR5s led to an increase by DPDPE was reduced when conducted at in Fos immunolabelling which was prevented by 29

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 previous injection of an inhibitor of neuronal Distinct axoglial domains - the node, paranode, glutamate transporters. First evidence that juxtaparanode and internode - are assembled nuclear mGluR5s in dorsal horn are functionally along myelinated axons to enable saltatory active during neuropathic pain. Moreover, this is conduction of the action potential. We have the first model which shows the physiological previously shown that stability of paranodal function of a nuclear GPCR junctions requires netrin-1 and its receptor DCC, however it is currently unknown if unc5 netrin 1-B-27 Glial cells govern synaptic receptors also play a role in myelin plasticity of competing nerve terminals at the maintenance. To address this question, we have mammalian neuromuscular junction crossed Olig2-CRE and Unc5b flox mouse lines to ablate Unc5B specifically from Houssam Darabid¹, Richard Robitaille¹ oligodendrocytes. Surprisingly, when compared ¹Université de Montréal to wild-type littermate controls, Olig2CRE/Unc5Bflox mice exhibit enhanced The precise wiring of synaptic connections is motor function, including balance, strength and shaped by elimination of supernumerary inputs exploratory activity, suggesting that overall competing for the innervation of the same target motor function is modulated by netrin-1 and its cell. At the neuromuscular junction (NMJ), this receptors at paranodes. Further characterization competition depends on the synaptic efficacy of of this transgenic line will contribute to competing terminals which strengthens one elucidating the mechanisms regulating paranode input and weakens the others, leading to their stability and motor function in the adult CNS. elimination. However, mechanisms responsible for the strengthening and weakening of inputs 1-B-29 Chondroitin Sulfate Proteoglycan remain ill defined. Here, we propose that negatively regulate the properties of Adult perisynaptic Schwann cells (PSCs), glial cells at Spinal Cord Neural Precursor Cells through NMJs, play a key role in synapse competition LAR and PTPσ receptors and activation of since they are known to modulate synaptic the Rho/ROCK pathway efficacy at mature NMJs, decode synaptic strength of competing terminals and eliminate Scott Dyck¹, Arsalon Alizadeh¹, Evan Proulx¹, the losing ones. Here, we performed intracellular Soheila Karimi-Abdolrezaee¹ recordings from dually innervated P7-8 mouse ¹University of Manitoba Soleus muscle fibres and monitored PSC activity using confocal Ca2 imaging. In addition, Multipotent neural stem/progenitor cells (NPCs) we specifically activated or blocked PSCs by reside in the spinal cord and are capable of photoactivation of NP-EGTA (caged Ca2 replacing lost oligodendrocytes following spinal molecule) or Diazo-2 (photoactivable BAPTA) cord injury (SCI). Despite this intrinsic capacity, respectively. First, we confirmed that PSCs spinal NPCs mainly differentiate into astrocytes, decode synaptic competition as revealed by with only a limited number becoming tight relationship between the size of Ca2 oligodendrocytes. We recently reported that responses and the synaptic efficacy of injury-induced upregulation of chondroitin sulfate competing inputs. Second, at the same NMJ, proteoglycans (CSPGs) restrict the survival, the strong input showed a long-lasting integration, and oligodendrocytes differentiation potentiation of neurotransmission while the of resident and transplanted NPCs in their post- weak one displayed only a small transient SCI milieu. Given the long-lasting upregulation potentiation. Finally, this plasticity was mimicked of CSPGs in NPCs niche after SCI, it is by direct induction of PSCs Ca2 responses and important to unravel the potential mechanisms prevented by PSCs Ca2 chelation. Altogether, by which CSPGs influence the properties of these data indicate that glial cells regulate NPCs. Using an in vitro model of the synaptic efficacy which may influence the extracellular matrix of SCI, we investigated the outcome of synaptic competition. direct role of CSPGs on NPCs. In primary cultures of adult spinal NPCs, using cell viability, 1-B-28 Myelin-specific ablation of UNC5B western blotting and immunocytochemistry improves motor function in mice assays, we show that CSPGs significantly decrease NPC growth and attachment, survival, Omar de Faria Jr.¹, Jenea Bin¹, Timothy proliferation and oligodendrocytes Kennedy¹ differentiation. Genetic down-regulation of ¹Montreal Neurological Institute CSPG receptors protein tyrosine phosphate receptor sigma (PTPσ) and leukocyte common 30

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 antigen-related phosphatase (LAR) in NPCs attenuated the inhibitory effects of CSPGs on 1-B-31 Accessory beta subunits for NPCs. CSPGs inhibitory effects were mediated molluscan Nav1 sodium channels are through activation of the Rho/ROCK pathway members of a novel CUB domain containing and inhibition of Akt and Erk phosphorylation. protein family Our data suggest the impact of CSPGs and its signaling receptors in governing the response of Julia Fux¹, Neil Hsueh¹, J.David Spafford¹ NPCs in their post-SCI niche, and identify new ¹University of Waterloo therapeutic targets for enhancing NPC-based therapies following SCI. Voltage-gated sodium channels are responsible for the action potentials upstroke and form a 1-B-30 Anatomical characterization of complex with accessory beta subunits (Navβ), VGLUT3-POSITIVE gabaergic basket cell which in vertebrates are related to the neural terminals in the hippocampus cell adhesion molecules (CAMs) with a V-set Ig extracellular loop. We have identified the Caroline Fasano¹, Maya Marcus-Sells¹, molluscan equivalent of Navβ subunits, using Veronique Bernard², Erika Vigneault¹, Sylvain mass spectrometry analyses of a ~40 kDa William¹, Salah El Mestikawy¹ protein bound to the Nav channel complex ¹McGill UNiversity, ²Université Pierre et Marie isolated in snail (Lymnaea stagnalis) brain Curie UM CR18 homogenate by high affinity, Nav α subunit antibody. LNavβ subunits are members of a Glutamate is the most prevalent excitatory novel CUB domain containing protein family, neurotransmitter in the central nervous system. which has no structural kinship to thev ertebrate It plays an important role in hippocampal CAM-like, Navβ subunits or the insect TipE and functions such as learning and memory. The Teh Navβ subunits which have a likeness to hippocampus consists mostly of large (Slo/BK) Kvβ subunits (eg. KCNMB4), with EGF- ensembles of glutamatergic neurons (namely like domains. There are four molluscan LNavβ pyramidal and granular cells). A small candidate genes, three of which contain a string population of GABAergic interneurons finely of (>10) repeat sequences in addition to the tunes the activity of these excitatory neurons. It CUB domain in the extracellular C-terminus and has been recently shown that a subpopulation of a putative N-terminal transmembrane helix. CUB these interneurons (CCK-positive basket cells) domains are found in cell adhesion molecules expresses the vesicular glutamate transporter 3 like the neuropilins, and accessory subunits to (VGLUT3). VGLUTs are considered as ligand gated channels such as NETO (kainite anatomical and functional markers of receptors) and LEV-10 (acetylcholine receptors). glutamatergic transmission. Therefore, We are presently characterizing the effect of the paradoxically, some basket cells in the structurally dissimilar molluscan, insect and hippocampus have the ability to co-release mammalian Navβ subunits on expressed snail GABA and glutamate from the same terminals. (LNav1) and mammalian (Nav1.2 and Nav1.4) In this study we investigated the anatomical sodium channels in transfected HEK-293T cells. characteristics of these basket cell terminals Our hypothesis is that the Navβ subunits are an expressing VGLUT3 in the CA1 pyramidal layer example of convergence, which evolved of the mouse hippocampus. Using double independently in different invertebrates and fluorescent in situ hybridization (FISH), we found vertebrate groups to serve similar functions. that 8.7 ± 0.3 % of all GABAergic neurons express VGLUT3. In the pyramidal layer of CA1, 1-B-32 Transmembrane Protein 3D quantification of terminals showed that 98 ± Coxsackievirus and Adenovirus Receptor 1 % of VGLUT3-positive terminals were (CAR) Promotes Neurite Outgrowth: Role of GABAergic but only 13 ± 2 % of GABAergic Translation Regulation terminals contained VGLUT3. Electron microscopy revealed that VGLUT3-positive Songsong Geng¹, Patrick Fok¹, Josephine synapses are forming axo-somatic symmetric Nalbantoglu¹ contacts, supporting their role as inhibitory ¹McGill University synapses. Our anatomical data support the hypothesis that basket cells expressing VGLUT3 Coxsackievirus and Adenovirus Receptor might co-release GABA and glutamate in the (CAR), a transmembrane receptor for pyramidal layer, a strategic location for adenovirus and coxsackie B virus, is a cell regulation of hippocampal functions. adhesion molecule that may play a role in brain 31

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 development. Although its mechanism of action possible roles of the RNA binding protein is unknown, it does promote neurite outgrowth Staufen 2 in regulating granules. We found that when triggered by ligands. To explore which knockdown of Staufen 2 reduces the number of pathways signal downstream of CAR, we stalled polyribosomes in distal neurites of performed pulldown and proteomic analysis with primary hippocampal neurons. We also report a GST protein fused to CAR's cytoplasmic that the number of dendritic map1b transcripts, a domain. Surprisingly, we identified many Staufen 2 target mRNA, decreases in neurons proteins which function in translation, such as expressing Staufen 2 RNAi. These data indicate ribosomal proteins S6 & L4, translation factors that Staufen 2 is critical for somato-dendritic eIF4G1 & eEF1A1, and RNA-binding proteins transport of stalled polyribosomes. Intriguingly, hnRNPU & LRPPRC. Therefore, we Staufen 2 was found to interact with Upf1, a hypothesized that CAR may promote neurite protein well-known for its role in nonsense- outgrowth through regulating translation. Using mediated RNA decay. We found that knockdown GST-pulldown, ribosome centrifugation, and of Upf1 in primary hippocampal neurons also confocal microscopy, we showed that CAR leads to a decrease in the number of distal interacts with translational proteins. By in vitro stalled polyribosomes. These data highlight a and in vivo translation assays, we demonstrated new role for Staufen 2 and Upf1 in regulating that CAR affects translation level. We then mRNA targets at the level of translation in the asked whether CAR promotes neurite outgrowth neuron. through its regulation of translation. We first verified that CAR's ligands, FN40 (a 40-kDa 1-B-34 Cysteine substitutions in the fragment of fibronectin) and collagen (CL), Domain II turret of T-type channels can promote significant neurite outgrowth. We uncouple ion conductances and alter cation further confirmed that this effect is mediated by block CAR as CAR-knockdown reduced FN40- and CL-stimulated neurite outgrowth to control Wendy Guan¹, Robert Stephens¹, Adriano levels. Finally, we showed that FN40- and CL- Senatore¹, David Spafford¹ stimulated neurite outgrowth can be blocked by ¹University of Waterloo inhibiting translation using cycloheximide. We are now determining whether CAR directly The pore of voltage-gated channels consists of affects neuronal protein synthesis through a wide outer vestibule formed by an extracellular transmembrane signaling. turret. Pore helices lead into and out of a narrow selectivity filter and an inner water-filled 1-B-33 Investigating the role of Staufen 2 compartment is formed between the selectivity and the nonsense-mediated decay factor filter and a bundle crossing of S6 helices that Upf1 in regulating stalled neuronal form an inverted teepee and inner channel gate. polyribosomes. Our research focus is on understanding how the extracellular turret in the outermost vestibule, Tyson Graber¹, Wayne Sossin¹ contributes to ion selectivity and drug block in T- ¹Montreal Neurological Institute type channels. We discovered that the extracellular turret in Domain II can be In neurons, where there is a pronounced alternatively-spliced in invertebrates to generate distance between the cell body and sites of highly sodium permeant T-type channels (with protein synthesis, messenger RNA (mRNA) exon 12a) or a more calcium selective T-type transport and localized translation are important channel (with exon 12b). A notable feature of mediators of synaptic plasticity. Some neuronal the Domain II turret is a conserved pattern of mRNAs are packaged in translationally-silenced cysteine residues, which consists of a tricysteine ribonucleoprotein complexes, which we have and pentacysteine pattern for exon 12a and recently shown to consist of polyribosomes exon 12b in invertebrates respectively, and a reversibly stalled at the level of translation unicysteine framework for vertebrate T-type elongation and/or termination. Stimulation of channels. Creation of unicysteine turrets that metabotropic glutamate receptors reactivates resemble the vertebrate condition in the translation on these mRNAs, a phenomenon invertebrate LCav3 channel, caused an: 1) an exhibited during mGluR-LTD. This form of increase in sodium permeability; 2) an enhanced plasticity is deregulated in diseases such as divalent cation block; and 3) a decoupling of Fragile X Syndrome and understanding the mixed ionic currents, so that the multi-ion pore mechanism could reveal new approaches to mostly passes monovalent ions or divalent ions therapies. To this end, we are now exploring the at one time, but not both at once. This research 32

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 has given insight to the structural elements in the extracellular turret of Domain II that Pentameric ligand-gated ion channels (pLGICs) contribute to ion selectivity and drug block. play a central role in rapid communication between neurons in the central and peripheral 1-B-35 Investigating Formation and nervous systems. pLGICs are also the sites of Substrates of Protein Kinase M During action of numerous pharmaceuticals, which alter Synaptic Plasticity in Aplysia channel gating to influence synaptic communication. The prototypic pLGIC, the Margaret Hastings¹, Katrina Gong¹, Cherry nicotinic acetylcholine receptor (nAChR), is Gao¹, Xiaotang Fan¹, Joanna Bougie¹, Danay influenced by endogenous and exogenous Baker-Andresen¹, Wayne Sossin¹ compounds that interact with the ¹McGill University transmembrane domain. M4, the most lipid- exposed of the transmembrane α‐helices, likely Ongoing activity of Protein Kinase Ms (PKM), plays a key role in lipid sensing, protein folding, truncated, persistently active forms of PKC has and the action of many transmembrane domain been proposed as a mechanism for memory allosteric modulators. Surprisingly, M4 exhibits a maintenance. Most research has focused on the high degree of variability from one nAChR rat atypical PKM zeta. Using the simple mollusc subunit to another. Here, we use two prokaryotic Aplysia californica, in which the PKM form of the homologs of the nAChR, GLIC and ELIC, to zeta homolog, PKC Apl III, is implicated in explore the functional consequences of M4 synaptic plasticity, we sought to 1) confirm sequence variability. We show that mutations in endogenous PKM formation during plasticity, 2) GLIC M4 invariably lead to a reduction in identify upstream events required for PKM channel gating, suggesting that interactions with formation and 3) identify a candidate substrate the adjacent transmembrane α-helices, M1 & for memory maintenance. To probe for M3, are optimized to promote channel gating. In endogenous PKM formation, ganglia were contrast, ELIC retains function even in the treated with a protocol that induces long-term absence of M4, while mutations in ELIC M4 synaptic facilitation. Immunoblotting revealed typically result in a gain of function, suggesting increased PKM in ganglia homogenized 1h after that interactions are poorly optimized, with treatment, confirming PKM formation during intrinsically weak coupling of agonist binding to plasticity. Upstream, we followed up on existing gating. Our data suggest that the importance of evidence that PKM Apl III formation in Aplysia M4 as an allosteric regulatory element may vary results from calpain cleavage of PKC Apl III that from one nAChR subunit type to another. This can be monitored by over-expression dependent variability may influence the susceptibility of cleavage. To identify the calpain isoform different nAChRs to allosteric modulation by involved, we overexpressed dominant-negative compounds that interact with the (DN) forms of specific Aplysia calpains and transmembrane domain. tested for PKM formation. DN Small optic lobes (Sol) calpain blocked cleavage of PKC Apl III, 1-B-37 Electrophysiological properties of suggesting Sol calpain mediates PKM formation. rat subfornical organ neurons expressing Downstream, as PKMs are thought to act on calbindin d28K glutamate receptor trafficking, we investigated Numb, an endocytic protein regulated by Shuo Huang¹, Mark Fry¹ atypical PKC phosphorylation, as a PKM Apl III ¹University of Manitoba substrate. PKM Apl III phosphorylated Numb in vitro and in neurons, making it a candidate The subfornical organ (SFO) is a sensory substrate. These results suggest new elements circumventricular organ, an area of the central for a model of events surrounding PKMs in nervous system characterized by lack of a plasticity. blood-brain-barrier. The SFO is well-known to play key roles in regulation of thirst, water 1-B-36 Sequence variability leads to balance, cardiac output and energy balance. distinct roles for M4 as an allosteric Several subtypes of neurons underlie the regulator of pentameric ligand-gated ion various roles of SFO: most neurons of SFO are channels either calbindin-positive (CalB ) or calretinin- positive (CalR ). CalB neurons project axons to Camille Hénault¹, Peter Juranka¹, Julian the magnocellular neurons of the paraventricular Surujballi¹, John Baenziger¹ nucleus (PVN), stimulating vasopressin and ¹University of Ottawa oxytocin release, while CalR neurons project 33

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 axons to the parvocellular PVN and regulate chromophore-assisted light inactivation (CALI) pre-autonomic output. In this study, we used a rescued the block of structural plasticity. CalB mRNA-specific fluorescent probe Furthermore, the dissociation of CaMKIIâ from (SmartflareTM) to enable identification of CalB the actin cytoskeleton was followed by an influx neurons. Patch clamp recording was carried out into the spine of cofilin1, a potent actin binding and intrinsic electrophysiological properties were and regulating protein. These results suggest compared between CalB and non-CalB neurons. that CaMKIIâ plays an important role in The CalB SFO neurons demonstrated regulating the activity-dependent structural significantly lower spontaneous action potential modification of synaptic structure. frequency and higher coefficient variation compared to non-CalB SFO neurons. While 1-B-39 Altered neuron-glia interactions CalB neurons exhibited lower Na current at the neuromuscular synapse during normal density, there was no difference in activation or aging inactivation of Na currents. Consistent with a previous study demonstrating that SFO neurons Noam Krief¹, Alexandre Saint-Amour¹, projecting to the PVN of the hypothalamus have Joanne Vallée¹, Richard Robitaille¹ unique electrical properties, this study indicated ¹University of Montreal that SFO neurons exhibit unique electrophysiological fingerprints. Our results Whether it is for memory loss, difficulties in demonstrate the validity of the Smartflare voluntary movement executions and reduced reagent to identify biochemically defined muscle strength, age-induced alterations could subpopulations of neurons in culture for use in be related to an altered synaptic transmission. A patch clamp studies. growing body of evidence revealed the role of glial cells as a modulator of synaptic 1-B-38 The role of CaMKII beta in transmission at adult synapses, however little is regulating structural plasticity of dendritic known about their contribution to synaptic spines activity during normal aging. In this study, we characterized glial cell activation at the old Mustafa Khan¹, Gurpreet Lakhanpal¹, Karam neuromuscular junction (NMJ). We recorded Kim², Yasanori Hayashi², Kenichi Okamoto¹ synaptic transmission of old NMJ (620 days) ¹Lunenfeld-Tanenbaum Research Institute, following high frequency electrical (HFS) ²RIKEN Brain Institute stimulation of the levator auris longus nerve since it has been demonstrated that perisynaptic Structural plasticity involves activity-dependent Schwann cells (PSC), glial cells at the NMJ, modification of synaptic structure and is regulate synaptic plasticity at adult NMJ. As a essential for reorganization of synaptic function sign of weakness, old NMJs were less likely to and structure. Here, we study how CaMKIIâ potentiate compared to adult NMJ during both (calcium/calmodulin-dependent protein kinase short and long-term plasticity. We then type II beta), an abundant F-actin binding measured PSC activity during HFS by calcium Ser/Thr kinase, regulates structural plasticity of imaging at the old NMJ since PSCs ability to dendritic spines. Actin is the major cytoskeletal detect and modulate synaptic transmission is protein in dendritic spines and the mechanism based on their calcium activity. We observed for its regulation is a key locus in spine structural that PSCs detect synaptic activity but with a plasticity. Previously, we found that CaMKIIâ reduced contribution of muscarinic receptors. bundled F-actin and stabilized actin dynamics to Since these are very important for synaptic maintain dendritic spine structure. Moreover, maintenance, we studied the morphological when CaMKIIâ was activated, it unbundled actin integrity of the three synaptic elements of the old filaments in vitro. These results suggest that NMJ by immunohistochemistry. Regardless of CaMKIIâ kinase activation status may regulate the changes at the presynaptic and the activity-dependent reorganization of the actin postsynaptic element, PSCs were abnormally cytoskeleton in dendritic spines during structural quiescent. Together these results suggest that plasticity. In this study, we found that novel PSCs interactions with pre and postsynaptic autophosphorylation sites in the F-actin binding elements at the synapse is inadequate at NMJ domain of CaMKIIâ are crucial for unbundling F- from old animals. actin. Expressing a CaMKIIâ phosphoblock- mutant resulted in the blocking of structural 1-B-40 Synaptic inputs to somatostatin plasticity. Whereas, mimicking the dissociation interneurons display transcription- and of CaMKIIâ from the actin cytoskeleton by 34

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 translation-dependent long-term synaptic plasticity at pyramidal cell (PC) synapses onto plasticity basket (BCs) and Martinotti cells (MCs) in layer 5 of acute mouse visual cortex slices. With 50- Alexandre La Fontaine¹, Isabel Laplante¹, Hz induction, which potentiates PC-PC Jean-Claude Lacaille¹ synapses, we observed non-Hebbian ¹Université de Montréal depression of both PC-BC and PC-MC connections. In hippocampus, calcium- The hippocampus contains a heterogeneous permeable (cp) AMPARs underlie non-Hebbian population of inhibitory interneurons (INs). The plasticity, so we looked for cpAMPARs in PCs, role that subtypes of INs play in hippocampal MCs, and BCs. With internal spermine, both learning and memory remains largely unknown spontaneous and evoked currents onto BCs but likely relies on cell type-specific plasticity rectified, suggesting the presence of mechanisms at IN synapses. Previously, we cpAMPARs. Controls showed that rectification uncovered a persistent long-term potentiation at required internal spermine. In agreement, the excitatory synapses onto CA1 oriens/alveus cp-AMPAR blocker Naspm reduced both interneurons induced by chemical activation of spontaneous and evoked release in BCs. In mGluR1 [mGluR1-mediated chemical late LTP contrast, PC-MC connections did not rectify with (cL-LTPmGluR1)]. Oriens/ alveus neurons internal spermine, suggesting excitatory inputs showing cL-LTPmGluR1 are potentially onto MCs may not have cp-AMPARs. To ensure somatostatin-positive interneurons (SOM-INs). Naspm acts post-synaptically, we uncaged Our hypothesis is that cL-LTPmGluR1 is specific NPEC-AMPA with a 405-nm laser while to SOM-INs and defines cell type-specific roles washing-in the drug, which still reduced in network plasticity underlying learning and responses in BCs but not MCs or PCs. We memory. First we showed that repetitive tuned a network model to our data, which mGluR1 stimulation activates, in an ERK showed that cp-AMPARs differentially impact dependent fashion, the CREB transcriptional fast BC but not slow MC feedback inhibition onto and mTOR translational pathways required for PCs. To conclude, both PC-MC and PC-BC persistent plasticity. Next we determined if cL- synapses show non-Hebbian long-term LTPmGluR1 is present at excitatory synapses depression, yet cp-AMPARs are specifically onto SOM-INs. EPSCs recorded in SOM-INs expressed at PC-BC but not PC-MC were potentiated after mGluR1 activation, connections. Such synapse-specific plasticity compared to sham-treated slices. Application of may critically influence information processing in U0126 (MEK inhibitor) or PP242 (mTOR cortical networks. inhibitor) during induction blocked this cL- LTPmGluR1, consistent with a requirement for 1-B-42 The role of PAK signaling in ERK and mTOR activation. cL-LTPmGluR1 was synaptic transmission and plasticity using a prevented by the mGluR1 antagonist LY367385. tetracycline inducible system in mice These data indicate that transcription- and translation-dependent plasticity (cL- Celeste Leung¹, Shouping Zhang², LTPmGluR1) is present at excitatory synapses Zhengping Jia² onto CA1 SOM-INs and requires mGluR1- ¹University of Toronto, ²Hospital for Sick dependent activation of the mTOR and ERK Children pathways. Funded by CIHR, CRC and FRQS. Neurodevelopmental disorders including autism, 1-B-41 Synapse-specific plasticity in the Alzheimer's disease and intellectual disability neocortical layer 5 microcircuit are among the most devastating deficits of mental and neurological diseases. These brain Txomin Lalanne¹, Julia Oyrer², Rui Costa³, diseases are associated with a diversity of Andrew Chung¹, You Chien Chou¹, Mark potential causes, including single gene Farrant², Jesper Sjöström¹ mutations. PAKs (p21-activated kinases) 1-3 are ¹McGill University, ²University College London, a family of serine/ threonine protein kinases that ³University of Edinburgh are target enzymes of Rho small family GTPases and central regulators of actin Long-term plasticity is cell-type specific and cytoskeleton and neuronal morphology. In vivo depends on differences in synaptic molecular studies reveal that PAKs are involved in machinery. Little is known about neocortical synaptic and behavioural plasticity. Mutations in inhibitory neuron (IN) plasticity, in part because the PAK gene are implicated in various brain INs are difficult to classify. We examined diseases however we do not understand how 35

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 these mutations cause synaptic and behavioural Furthermore, western blot analysis of Khc-73 deficit. We employ a tetracycline inducible mutants show an increase in BMP receptor system where the dominant negative PAK3 protein levels. We propose Khc-73 is required mutation can be spatiotemporally modulated. for retrograde routing of receptor containing We found that mutant PAK3 mice had profound endocytic vesicles during the expression of impairments in spatial and associative memory. synaptic homeostasis. Furthermore, the learning deficit in the mutant mice can be rescued with a tetracycline analog 1-B-44 Two-photon optogenetic control that blocks the expression of the mutant PAK3 of cAMP dynamics in dendritic spines for transgene, which suggests that the memory studying synaptic plasticity impairments are not perturbed at development and are caused by deficits in mature synapses. Thomas Luyben¹, Mustafa Khan¹, Kenichi We showed that mutant mice had reduced basal Okamoto¹ synaptic strength and plasticity that were not ¹Samuel Lunenfeld Research Institute due to alterations in presynaptic function. Our data indicate that the molecular pathways Understanding how synaptic function is through which PAK3 may mediate the Rho modulated by neural activity is essential for signalling process through cofilin dependent elucidating the mechanisms of learning and actin regulation in the cortex and hippocampus memory. Here we study the role of cyclic AMP has a central role in the regulation of cognitive (cAMP) in the structural plasticity of dendritic and synaptic function. spines by developing two-photon optogenetics and live imaging techniques. cAMP is a 1-B-43 The Kinesin Khc-73 regulates ubiquitous second messenger involved in a BMP signaling and Synaptic Homeostasis at variety of cellular events, particularly synaptic the Neuromuscular Junction plasticity such as the late-phase of long-term potentiation (L-LTP). However, the precise Edward Liao¹, Kazuya Tsurudome¹, Wassim dynamics and role of cAMP in dendritic spines El Mounzer¹, Fatima Elazzouzi¹, Pejmun remains elusive. We have therefore prepared a Haghighi¹ genetically-encoded cAMP sensor utilizing ¹McGill University Fӧrster resonance energy transfer (FRET), and visualized the spatiotemporal dynamics of cAMP At Drosophila larval neuromuscular junctions, in dendritic spines during synaptic plasticity by reduction in postsynaptic receptor activity two-photon FRET microscopy. In addition, we triggers a compensatory increase in presynaptic have developed a two-photon optogenetic neurotransmitter release. Loss of function in approach to non-invasively manipulate local Khc-73, a kinesin motor protein suppresses this cAMP levels with light by a combination of two- effect, indicating a role for Khc-73 in the photon microscopy and photoactivatable synaptic homeostasis pathway. The Bone adenylyl cyclase (PAC). Using this two-photon Morphogenetic Protein (BMP) pathway is optogenetic tool, we found that light-dependent required in synaptic homeostasis and relies on postsynaptic cAMP production enhanced endocytic pathways to shuttle activated dendritic spine enlargement after LTP induction receptors to the cell body in a retrograde by caged-glutamate uncaging. This suggests a direction. Activated BMP signaling increases role for postsynaptic cAMP in the maintenance synaptic transmission and nuclear accumulation of reorganized dendritic spine structure during of phosphorylated Mad (Mothers against structural plasticity in dendritic spines. Thus, this decapentaplegic). Loss of Khc-73 suppresses two-photon optogenetic approach provides a both these effects of enhanced BMP signalling. powerful tool to elucidate intracellular signaling Accordingly, overexpression of Khc-73 mechanisms, such as synaptic plasticity in living enhances synaptic transmission. neurons. Electrophysiological recordings ruled out Khc-73 effects on synaptic vesicle turnover, thus 1-B-45 eEF2 acts as a biochemical pointing to receptor containing endosomes. sensor during synaptic plasticity, coupling Consistent with a role in endosome sorting, Khc- diverse activity patterns to translational 73 synaptic termini exhibit large vesicles and control multivesicular bodies. Khc-73 likely functions during late endosomal stages since Khc-73 Patrick McCamphill¹, Carole Abi Farah¹, mutants lack the synaptic overgrowth phenotype Wayne Sossin¹ found in mutants of early endosome formation. ¹McGill University 36

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28

movement initiation. The amplitude and Activity-dependent regulation of protein frequency of extracellular lactate and glucose synthesis is important for enduring changes in changes associated with movement were synaptic function. Distinct activity patterns can dramatically increased in fasted animals and be transduced by the neuronal translation after receiving a 0.4IU/kg insulin ip injection. machinery into different outputs. At the sensory- However insulin led to only a small decrease in motor neuron synapse of Aplysia both spaced or extracellular glucose while there was a modest continuous (massed) applications of serotonin rise in extracellular lactate. When the animals (5-HT) induce increases in synaptic strength that received a 2g/kg glucose injection, the requires new protein synthesis but not gene extracellular glucose levels rose and the transcription, a form of intermediate-term amplitude of movement-elicited lactate facilitation (ITF). However, these two forms of increases were blunted. Running on a running ITF (spaced vs massed) are expressed by wheel was associated with a steady and different pathways. Here, we demonstrate that sustained increase in lactate and glucose levels. eukaryotic elongation factor 2 (eEF2), a GTP- Usually, the animals stopped running after the dependent translocase which catalyzes nascent extracellular glucose and lactate reached a peptide translocation through the ribosome, acts plateau for a few seconds. These results as a biochemical sensor that is specifically support the idea that lactate and glucose levels tuned to the pattern of neuronal stimulation. follow closely neuronal activity in the motor Phosphorylation of eEF2, a modification known cortex and that systemic glucose levels to inhibit translational elongation, is increased by modulate both glucose and lactate levels. massed training but decreased by spaced training. Consistent with eEF2 as a downstream 1-B-47 Unlearning: NMDA receptor effector for differentiating patterns of stimulation, mediated metaplasticity in the anterior the increase in eEF2 phosphorylation observed piriform cortex following early odor after massed 5-HT was blocked with inhibitors of preference training in rats PKC and the decrease in eEF2 phosphorylation by spaced 5-HT was blocked by inhibitors of Bandhan Mukherjee¹, Gillian Morrison¹, PKA. An inhibitor of eEF2 Kinase, or expressing Christine Fontaine², Qinlong Hou¹, Qi Yuan¹, a form of eEF2 kinase that could not be Carolyn Harley¹ activated by 5-HT, blocked ITF after massed ¹Memorial University Of Newfoundland & 5HT. In contrast, the inhibitor of eEF2K did not Labrador, ²University Of Victoria block ITF induced by spaced training and indeed it was sufficient to induce ITF. These results The NMDAR undergoes activity-dependent suggest that eEF2 is a sensor integrating plasticity, which likely influences the threshold neuronal activity patterns. of, and capacity for, future plasticity - a phenomenon termed metaplasticity. The 1-B-46 Extracellular glucose and lactate functional significance of NMDAR-mediated rapidly increase in the motor cortex after metaplasticity for learning is not understood. initiation of movement Here we investigated NMDAR plasticity and metaplasticity in early odor preference learning Jeremy Larcher¹, Tina Yuan¹, Claude in the anterior piriform cortex (aPC) in rat pups. Messier¹ Western blots of synaptoneurosomes showed ¹University of Ottawa that the NMDA NR1 subunit was down- regulated 3 h following odor training and up- We measured extracellular concentrations of regulated at 24 h. Ex vivo fEPSP recordings glucose and lactate using fixed-potential revealed the same patterns of NMDAR plasticity amperometry in freely moving CD-1 mice. Mice at the afferent synapse in the aPC. were implanted with bilateral guide cannulas in Concomitantly, 3 h following training, AMPAR the limb area of the primary motor cortex. A LTP was excluded while LTD became inducible. lactate electrode was inserted on one side and a Behaviorally, one trial, 10 min peppermint-odor glucose electrode on the other side. stroking conditioning produces a peppermint Simultaneous measures were obtained during a preference memory lasting 24 h. Pups lost the period of several hours. Locomotion were normally acquired peppermint preference 24 h associated with a 50% simultaneous increase in later if they were re-exposed to peppermint glucose and lactate followed by a progressive stroking 3 h following initial peppermint stroking decline once movement stopped. Glucose and training. This unlearning is pathway-specific lactate increases occurred within 1 second of since pre-training with another odor did not 37

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 affect the later peppermint preference memory. Down-regulating NR1 with SiRNA prevented 1-B-49 Investigating the Role of the odor preference memory. Finally, blocking mRNA Binding Protein FXR1P in Brain NMDAR with MK-801 abolished LTD induction Plasticity ex vivo 3 h following odor learning, and eliminated the loss of peppermint odor Erin Nuro¹, Denise Cook², Emma V. Jones³, preference when MK-801 was injected before Edith Hanna¹, Haider Altimimii¹, W.Todd the 2nd peppermint stroking training at 3 h. Farmer¹, David Nelson⁴, Joseph Rochford⁵, These results demonstrate an NMDAR- David Stellwagen³, Keith Murai¹ mediated metaplastic effect in a cortical ¹Centre for Research in Neuroscience , structure that has broad implications for learning ²University of Ottawa, ³Centre for Research in optimization. Neuroscience, ⁴Department of Molecular and Human Genetics, Baylor College of Medicine, 1-B-48 Variations in Early Life Maternal ⁵Douglas Institute Research Centre Care Program Molecular Determinants of Hippocampal Plasticity and Intrinsic Fragile X Related Protein 1 (FXR1P) is one of Excitability two autosomal homologues of the Fragile X Mental Retardation Protein (FMRP), a protein Huy-Binh Nguyen¹, Michael Meaney¹, Tak whose expression is significantly reduced in Pan Wong¹ Fragile-X Syndrome. Like FMRP, FXR1P is an ¹Douglas Mental Health University Institute mRNA binding protein that is implicated in regulating the synthesis of specific target Naturally occurring variations in early life proteins. However, in comparison to FMRP, little maternal care modulate hippocampal is known about the function of FXR1P in brain development and function to program distinct function. Our lab has recently discovered that cognitive phenotypes which persist into FXR1P co-localizes with translational machinery adulthood. Adult rat offspring which received low near synapses suggesting that it could play a maternal licking and grooming (low LG offspring) role in locally controlling the levels of proteins show reduced long term potentiation (LTP), and involved in synaptic plasticity and learning and impairment in hippocampal-dependent spatial memory. In order to test this, we have generated memory tasks. However, previous studies an FXR1 conditional knockout mouse model focused uniquely on the dorsal hippocampus where the FXR1 gene is conditionally ablated (DH). Emerging evidence suggests a distinct from neurons in the forebrain, including the role of the ventral hippocampus (VH) in hippocampus (a brain region important for mediating fearfulness and fear memory learning and memory). Interestingly, after formation, behaviours in which low LG offspring screening for potential synaptic proteins whose are increased. We have presently found that the expression may be altered in the knockout mice, early life environment differentially programs we found that FXR1P is critical for regulating the hippocampal function along the dorsal-ventral expression of the AMPA-type glutamate axis. Low LG offspring were suppressed in DH- receptor subunit GluA2; a protein known to have LTP, but enhanced in VH-LTP. CA1 pyramidal a profound role in synaptic plasticity, learning neurons in the VH of low LG offspring fired and memory, and autism spectrum disorders. action potentials at lower threshold voltages, Moreover, we have also found that FXR1P which were larger in amplitude and faster in rise conditional knock-out mice have significant rate than those recorded in high LG offspring. changes in synaptic plasticity, synaptic Furthermore, we found a specific enhancement morphology, and cognitive function. We are of synaptic potential-to-spike coupling (E-S currently investigating the mechanism through coupling) in VH of low LG offspring. Expression which FXR1P regulates GluA2 expression, and of the voltage-gated sodium channel NaV1.2- in turn understand the implications of this coding mRNA SCN2A is specifically enhanced mechanism in learning and memory. in the VH of low LG offspring, providing a candidate molecular mechanism. Taken 1-B-50 Immature phenotype in together, these findings suggest that low Perisynaptic Schwann cells after denervation maternal care in early life programs intrinsic and during reinnervation excitability specifically in VH, which in turn associates with enhanced synaptic plasticity and Anna Perez¹, Isabelle Rousse¹, Houssam the capacity for fear-associated hippocampal Darabid¹, Benoit Lamoureux¹, Richard cognition in these offspring. Robitaille¹ 38

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28

¹Université de Montréal interacts with the kainate receptor subunit GluK2 and can positively regulate KCC2 function at the Synaptic contacts in the neuromuscular membrane. Here we demonstrate the role of junctions (NMJs) can be re-established following GluK2 in regulating normal KCC2 trafficking and nerve injury. Some events during synapse stability at the neuronal membrane surface reformation, like synaptic competition prior to the using life cell imaging, immunohistochemistry, establishment of the NMJ, recapitulate events electrophysiology, and surface biotinylation taking place during development. We assays. Using these approaches we hypothesize that PSCs should change following demonstrate the dynamic regulation of KCC2 denervation reverting to a more immature state, stability by GluK2 to maintain normal Cl- compatible with synapse plasticity during regulation in hippocampal neurons. synaptogenesis. To evaluate this hypothesis we compared the excitability of PSCs at NMJs from 1-B-52 Age-dependant plasticity of chronically denervated mouse soleus muscles to cortical GABAergic innervation lessens PSCs excitability at different development seizure severity in Cacna1a mutants. postnatal ages. PSCs excitability is based on the variations in intracellular Ca2 visualized Elena Samarova¹, Alexis Lupien-Meilleur¹, using a calcium indicator and elicited either by Xiao Jiang¹, Jean-Claude Lacaille², Elsa endogenous transmitter release induced by Rossignol¹ motor nerve stimulation or by local application of ¹CHU Ste-Justine, Université de Montréal, agonists (muscarine or ATP). Muscarine ²Université de Montréal application revealed that muscarinic receptors were functional during development but their Background. CACNA1A deletions result in contribution to synaptic-induced activity in PSCs ataxia and epilepsy in humans. We showed that was marginal as shown by minimal effects of a prenatal Cacna1a deletion in forebrain muscarinic receptor antagonist. Synaptic- GABAergic interneurons (IN) results in synaptic induced responses in PSCs were driven by impairment of parvalbumin (PV) fast-spiking purinergic receptors, confirmed by their basket cells and induces epilepsy in mice. As blockade with RB2, a P2 receptor antagonist. In CACNA1A-associated epilepsy improves with denervated NMJs, PSCs excitability to age, we propose that specific compensatory muscarine application was significantly smaller mechanisms occur in the face of cortical in comparison to innervated NMJs. This disinhibition to re-establish inhibition/excitation decrease in PSC sensibility to muscarine was balance with time. Methods. We generated maintained during reinnervation. These results conditional mutant mice carrying a post-natal indicate that PSCs at denervated mature deletion of Cacna1a in telencephalic PV synapses revert their phenotype to an immature neurons (PVCre;Cacna1ac/c). Results. one providing the required plasticity to complete PVCre;Cacna1ac/c mutants develop ataxia and the reformation of the NMJ. a mild epileptic phenotype with spike-wave seizures and behavioral arrests after P45. 1-B-51 The role of KCC2 interacting Surprisingly, these mutants display a two-fold partners in maintaining stability and function increase in the frequency of miniature inhibitory at the membrane synaptic currents (mIPSC) in cortical pyramidal cells (PC) at P60, whereas Nkx2.1Cre; Jessica Pressey¹, Vivek Mahadevan¹, Brooke Cacna1ac/c mutants display a significant Acton¹, Melanie Woodin¹ decrease of mIPSC frequency in cortical PC at ¹University of Toronto P20 suggesting a compensatory age-dependent plasticity of GABAergic circuits. We show a GABAergic transmission is critically dependent comparable reduction of GABAergic perisomatic on neuronal Cl- regulation. The neuronal Cl- boutons on cortical PC and a similar impairment gradient is largely established by the neuron- of synaptic release from PV INs in both pre-natal specific K -Cl- cotransporter KCC2, which (Nkx2.1Cre) and post-natal (PVCre) mutants. maintains a low intracellular concentration of However, we demonstrate a significant increase neuronal Cl- ([Cl-]i). The molecular regulation of of functional dendrite-targeting GABAergic KCC2 trafficking and stability at the membrane projections from somatostatin (SOM) INs in is of utmost importance for understanding post-natal mutants. Interpretation. neurological disorders such as neuropathic pain Reorganization of dendritic inhibition by SOM and for developing therapeutic treatments for INs restricts cortical excitability and lessens epilepsy. Recently, our lab discovered KCC2 seizure severity in PVCre; Cacna1ac/c mutants. 39

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28

¹Georgia State University, ²University of 1-B-53 The role of Disrupted-in- Waterloo, ³Institut de Génomique Fonctionnelle Schizophrenia 1 (DISC1) in synaptic CNRS plasticity T-type channels (or Cav3 channels) are Ner Mu Nar Saw¹, Shouping Zhang¹, ubiquitous in animals, where they help regulate Yanghong Meng¹, Xinuo Gao¹, Zhengping membrane excitability by amplifying sub- Jia¹ threshold depolarization. Key to this are their ¹Hospital for Sick Children relatively fast kinetics and low voltages of activation, which functionally distinguishes them Schizophrenia is a severe psychological from high voltage-activated calcium channels disorder that affects about 1% of the population. classically associated with excitation-contraction One of the key characteristics of this disorder is coupling in myocytes (i.e. L-type channels), and a deficit in cognitive function such as learning excitation-secretion coupling at the synapse (N- and memory. Synaptic plasticity is a feature of and P-/Q-type channels). Molecular cloning and the brain that is believed to be the basis for expression of a T-type calcium channel learning and memory and is represented by homologue from eumetazoan Trichoplax changes in synaptic strengths between adhaerens, a basal animal that lacks neurons presynaptic and postsynaptic neurons. and muscle, suggests that the key distinguishing Increases in postsynaptic response, termed features of T-type channels existed before the 'potentiation', or decreases in this response, nervous system, and that in turn that these termed 'depression', underlie the mechanisms of features were exploited by the evolving nervous synaptic plasticity and are correlated with system to regulate cellular excitability. dendritic spine regulation. Disrupted-in- Schizophrenia 1 (DISC1) has emerged as a 1-B-55 Population bursts in large strong genetic risk factor for psychological excitatory network models of hippocampus disorders such as schizophrenia, bipolar with biological constraints disorder, and major depression. DISC1 has been shown to be important in Felix Njap¹, Wilten Nicola², Katie Ferguson¹, neurodevelopment through its involvement in Sue Ann Campbell², Frances Skinner¹ neuronal proliferation and migration. In this ¹Toronto Western Research Institute, University study we find that this protein may also play a Health Network, ²University of Waterloo role in the regulation of synaptic plasticity. Using DISC1 mutant mice L100P and Q31L we find Previous modeling and theoretical studies have that hippocampal long-term depression and clearly shown that it is possible to obtain robust potentiation are altered in these mutant mice. network bursting in excitatory networks in which We also found changes in the Rac1 signalling the individual cells exhibit spike frequency pathway, a well-established signaling pathway adaptation. The mechanism involves a balance involved in the regulation of actin cytoskeleton between the amount of adaptation and the and dendritic spines, which may mediate the excitatory synaptic strengths and drive. What is observed changes in synaptic plasticity. We less clear is whether such a mechanism hypothesize that DISC1 play a role in contributes to the generation of population hippocampal synaptic plasticity by regulating the bursts in biological networks. To examine this, Rac1 signaling pathway. To test this hypothesis we have used: (i) excitatory cell models that are we will use a combination of based on pyramidal, excitatory cells in electrophysiological, imaging and biochemical hippocampus, (ii) theoretical insights from mean techniques. field theory to determine whether and in what parameter regimes population bursts could 1-B-54 The T-type calcium channel from occur, and (iii) high performance computing. Our basal eumetazoan Trichoplax adhaerens simulation results show that networks with tens highlights the evolutionary history and of thousands of cells can robustly produce fundamental features of the Cav3 channel population bursts when connection strengths are family within physiological ranges, and this could occur even for sparse connectivity as is present in Adriano Senatore¹, Wendy Guan², Arnaud hippocampus CA1. We find that burst frequency Monteil³, Arainna Tamvacakis¹, Liana increases with increasing excitatory drive mainly Artinian¹, Vincent Rehder¹, Paul Katz¹, J. due to a decreasing inter-burst interval, whereas David Spafford² the burst frequency decreases with increasing 40

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 excitatory synaptic strength, and the number of ¹Queen's University excitatory cells involved in population bursts can vary considerably. We conclude that cellular Reproduction in Aplysia californica is initiated by adaptation mechanisms are in play in a prolonged period of enhanced excitability, hippocampal network bursts and that our known as the afterdischarge, in the bag cell models can provide insight into the conditions neurons. During this period, several 2nd underlying their generation. messengers control a calcium-dependent, voltage-gated, non-selective cation channel to 1-B-56 Cholinergic effects on temporal provide depolarizing drive required for summation of theta and gamma-frequency maintaining the afterdischarge. Using single- synaptic inputs in the parasubiculo- channel recording in excised, inside-out entorhinal pathway patches, the calcium-activation of the cation channel and its response to 2nd messengers Daniel Sparks¹, C. Andrew Chapman¹ was investigated. In addition to confirming that ¹Concordia University the channel is calcium-dependent, we now find that it also desensitizes in the presence of high Neurons in the superficial layers of the calcium. We investigated if diacylglycerol (DAG), entorhinal cortex provide the hippocampus with a lipid produced during the afterdischarge, the majority of its cortical sensory input, and modulates the cation channel, similarly to also receive the single major output projection transient receptor potential (TRP) channels. Like from the parasubiculum. This puts the TRPC6, DAG transiently increased the activity parasubiculum in a position to modulate the of the channel followed by a decrease below the activity of entorhinal cortex neurons that project initial level. The Aplysia channel exhibits other to the hippocampus. These brain areas receive TRP channel properties, and is blocked by the cholinergic projections that are active during general TRP channel blockers flufenamic acid periods of theta and gamma-frequency EEG and SKF-96365, as well as the TRPM4/5- activities which are expressed when an animal specific inhibitor, 9-phenanthrol. In an effort to navigates its environment. The purpose of this functionally compare the Aplysia cation channel study was to investigate how cholinergic activity to TRP channels, we have cloned and are affects the strength of repetitive synaptic expressing Aplysia TRP-M, -C and -V responses at these frequencies in the rat homologues in HEK293 cells. Characterizing the parasubiculo-entorhinal pathway and to assess native Aplysia cation channel, and comparing its the cellular mechanisms involved. Whole-cell properties to the Aplysia TRP channels, will patch clamp recordings of layer II medial provide a molecular foothold towards entorhinal neurons were conducted in acute determining the specific role for TRP channels in slices, and responses to 5-pulse trains of regulating long term changes in excitability like stimulation delivered to the parasubiculum were the afterdischarge. recorded. The cholinergic agonist carbachol suppressed the amplitude of single synaptic 1-B-58 Hippocampal development and responses, but also enhanced temporal neural excitation modulate H2A histone summation of responses recorded during theta variant epigenetic responses and gamma-frequency stimulation. The Ih channel blocker ZD7288 mimicked the Anita Thambirajah¹, Josie Diorio¹, Michael enhanced temporal summation of synaptic Meaney¹ responses induced by carbachol, indicating that ¹Ludmer Centre for Neuroinformatics and Mental carbachol may produce these effects by Health, Douglas Mental Health University inhibiting Ih. Cholinergic input to the entorhinal Institute (Mc cortex may enhance synaptic responses during theta and gamma frequency EEG activities due The profound morphological and functional to enhanced summation of EPSPs induced by changes that mark early brain development are an increase in input resistance associated with rooted in dynamic gene activation. It is closure of Ih channels. imperative that variations in gene expression are precisely coordinated temporally and spatially. 1-B-57 Fine-tuning of cation channel Otherwise, deleterious neuropathologies can function by TRP channel modulators in ensue. DNA encodes genetic information and is Aplysia bag cell neurons packaged with histone proteins to form chromatin. Chromatin controls genomic Raymond Sturgeon¹, Neil Magoski¹ information through the complex interplay 41

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 between the DNA, histone proteins and other fluctuations could be evoked by intraluminal chromatin proteins. Chromatin structural acetylcholine delivered IV, suggesting arteriole variability mediates changes to gene diameter/blood flow changes per se can drive accessibility in many ways. Some involve the astrocyte Ca2 transients. Our data redefine the inclusion of specialized histone variants within potential role of astrocytes as responders to chromatin or histone post-translational blood flow, rather than rapid initiators of flow modification (PTM). This work explores the control. dynamic regulation of histone variants and their PTMs during rat hippocampal development and 1-B-60 Fructose feeding increases neural activation. The protein and mRNA of H2A catecholamine release from rat adrenal variants, H2A.Z and H2AX, and their PTMs chromaffin cells decrease significantly as perinatal development progresses. The reduced levels are sustained Frederick Tse¹, Michael Simpson¹, Weixiao into adulthood. To assess a relation between Zhao¹, Amy Tse¹ these development-dependent changes and ¹University of Alberta neuron activation, primary hippocampal cultures were treated with KCl. H2A.Z and H2AX An increased consumption of fructose has been displayed variable responses to excitation, linked to the development of metabolic which may reflect their unique roles regulating syndrome. Male Sprague Dawley rats fed with chromatin metabolism. Glutamate treatment 10% fructose in their drinking water for 6 weeks recapitulated these results. Genomic regions developed hypertension. Since an augmentation developmentally controlled by H2A variants are of the sympatho-adrenal outflow has been linked being defined by chromatin-immunoprecipitation to both the genetic and dietary components of sequencing. These novel findings suggest that essential hypertension, we examined whether H2A variants modulate genomic responses fructose feeding affects the secretion of during early postnatal development and neural catecholamine (CA) from chromaffin cells of the activity. adrenal medulla. Using carbon fiber amperometry, we found that the amount of 1-B-59 Astrocyte Ca2+ transients cholinergic agonist-evoked CA release from respond to changes in blood flow: Revealed individual chromaffin cells, which were acutely by two-photon imaging in awake mice isolated from the hypertensive fructose-fed rats, was larger than that released from the Cam Ha Tran¹, Grant Gordon¹ normotensive age-matched controls. This ¹University of Calgary augmentation of CA release involves an increase in the number of release events during Neurovascular coupling is an essential process the "sustained phase" of secretion. In addition, ensuring blood flow is matched to the metabolic fructose feeding increased the amount of CA needs of the brain. The current model stipulates released per granule (quantal size) and altered that abrupt increases in neuronal activity lead to the release kinetics of individual amperometric rapid elevation in astrocyte and endfoot free signals. However, fructose feeding did not Ca2 , which triggers the release of diffusible change the amplitude of the cholinergic agonist- messengers that initiate either vasodilation or evoked calcium signal or the voltage-gated vasoconstriction to change blood flow. However, calcium current. These data suggest that the recent in vivo studies call this model into development of hypertension with high fructose question. Our objective was to uncover the consumption involves an adaptation of the spatiotemporal basis of the communication stimulus-secretion coupling in chromaffin cells to between astrocytes and the vasculature using metabolic stress which in turn leads to an two-photon imaging in awake, behaving mice. augmentation of CA release. The vasculature was filled with FITC-dextran and astrocyte activity was captured using Rhod- 2/AM Ca2 indicator or transgenic mice in which only astrocytes express the genetically encoded 1-B-61 δGABAA receptors facilitate long- Ca2 indicator GCaMP3. We found that endfoot term potentiation in the CA3 subfield of the Ca2 transients and cell-wide Ca2 transients hippocampus followed, rather than preceded, sensory evoked vasodilation of arterioles as well as sensory Paul Whissell¹, Sinziana Avramescu¹, Irene evoked increases in red blood cell flux in Lecker¹, Beverley Orser¹ capillaries. Furthermore, similar astrocyte Ca2 ¹University of Toronto 42

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28

anesthesia. Wild-type (WT) and α5GABAAR Introduction: γ-Aminobutyric acid type A null-mutant (Gabra5-/-) mice were treated with receptors (GABAARs) are novel targets for the anesthetic etomidate (8 mg/kg i.p.) and memory-enhancing drugs. Recently, we showed memory was assessed 24 h, 72 h and 1 week that a drug selective for δ subunit-containing later with the object recognition task. The activity GABAARs (δGABAARs) receptors enhanced of GABAARs was studied 24 h - 2 weeks after hippocampus-dependent memory and anesthesia by measuring miniature inhibitory neurogenesis. Long-term potentiation (LTP) of postsynaptic currents (mIPSCs) and the tonic synaptic transmission, a cellular correlate of inhibitory current in CA1 pyramidal neurons. memory, is modulated by GABAARs. In the Additionally, surface biotinylation and Western hippocampus, LTP at Mossy fiber-CA3 blot were used to detect changes in surface pyramidal cell synapses (MF-CA3 LTP) is expression of GABAAR subunits. WT but not facilitated by presynaptic GABAARs. Gabra5‒/‒ mice exhibit impaired memory for 72 δGABAARs may be expressed at presynaptic h. mIPSCs are not affected by etomidate MF terminals and could have an excitatory treatment. However, the amplitude of the tonic action that facilitates MF-CA3 LTP. Here, we current is increased 24 h (P < 0.001) to 1 week tested this hypothesis. Method: Extracellular after anesthesia (P < 0.01). Lastly, the surface field postsynaptic potentials (fPSPs) were expression of α5GABAARs is increased 24 h recorded from the CA3 subfield in hippocampal after etomidate treatment. These results show slices from wild-type (WT) and δ subunit null that post-anesthetic memory deficits may be (Gabrd-/-) mice. Basal neurotransmission and caused by a long-term increase in the presynaptic plasticity were measured using expression and function of α5GABAARs. These input-output plots and paired pulse responses, results provide the first evidence that a general respectively. MF-CA3 LTP was induced using a anesthetic causes an increase in the expression tetanic stimulation. fPSPs recorded in the first of its target receptors after it has been minute after stimulation were used to measure eliminated. post-tetanic potentiation (PTP) while fPSPs recorded from 55-60 minutes after stimulation C - Disorders of the Nervous System were used to measure LTP. Results: A pronounced PTP and LTP was observed in both 1-C-63 Involvement of autophagy in the genotypes. However, PTP and LTP were neuroprotective properties of Oleuropein reduced in Gabrd-/- slices. The input-output against 6-hydroxydopamine-induced plots and paired pulse ratios were similar neuronal death between genotypes. Conclusions: δGABAARs facilitate MF-CA3 LTP. It is possible that Imene Achour¹, Manon Legrand¹, Anne-Marie pharmacologically enhancing δGABAAR activity Arel-Dubeau¹, Marc Germain¹, Everaldo could improve memory functions regulated by Attard², Maria-Grazia Martinoli¹ the CA3 subfield, including working memory. ¹Université du Québec à Trois-Rivières, ²University of Malta 1-B-62 General anesthetics cause memory deficits after drug elimination by Parkinson's disease (PD) is a progressive increasing a tonic inhibitory current in the neurodegenerative disorder associated with the hippocampus destruction of dopaminergic neurons in the substantia nigra. The goal of this study was to Agnieszka Zurek¹, Jieying Yu¹, Erica investigate whether Oleuropein (Ole), a phenolic Bridgwater¹, Beverley Orser¹ compound found in olive leaf, may prevent ¹University of Toronto neuronal cell death observed in dopaminergic neurons. For this purpose, we used a cellular General anesthetics cause memory deficits that model of PD, neuronal PC12 cells differentiated persist after the anesthetic has been eliminated. in dopaminergic neurons by nerve growth factor We previously showed that pharmacologically (NGF), and exposed them to the potent inhibiting γ-aminobutyric acid type A receptors neurotoxin 6-hydroxydopamine (6-OHDA). that contain the α5 subunit (α5GABAAR) Cytotoxicity as well as measures of specific reversed memory deficits after anesthesia (Anes apoptotic DNA fragmentation demonstrate that Analg 2012: 114 (4): 843-55). Here, we tested Ole significantly decreases 6-OHDA-induced the hypothesis that α5GABAARs are necessary neuronal death and apoptosis. Besides, the for the postanesthetic memory deficits and that antioxydant effect of Ole against 6-OHDA- the activity of these receptors is enhanced after induced production of radical oxygen species 43

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28

(ROS) was evaluated by MitoSOX red and spiking brain levels of drug promote compulsive dihydrorhodamine. Currently, a growing body of drug use. evidence shows that autophagy plays a key role in the pathogenesis of PD. Indeed, we also 1-C-65 Cucurbitacin E is a novel observed autophagic vacuoles in the cytoplasm neuroprotective phytosterol with autophagy- of neuronal cells treated with Ole and we modulating activities on dopaminergic identified them by labeling with Cyto-ID and by neurons measuring reliable markers of autophagy-related processes such as LC3, HDAC6, LAMP2, Anne-Marie Arel-Dubeau¹, Fanny Longpre¹, mtHSP70, and P62 expression by Marc Germain¹, Everaldo Attard², Maria- immunofluorescence and Western blots. These Grazia Martinoli¹ preliminary results suggest that Ole may act on ¹Universite du Quebec a Trois-Rivieres, the delicate balance between pro-survival and ²University of Malta anti-survival parameters to regulate neuroprotection against 6-OHDA-induced Neuroprotective therapies may have the neurotoxicity. potential to reduce the incidence of neurodegenerative disorders such as 1-C-64 How fast cocaine is delivered to Parkinson's disease (PD). Natural the brain is decisive in determining the neuroprotective molecules are currently under motivation to take the drug study to protect cells from a variety of toxic effects often linked to neuronal death, oxidative Florence Allain¹, Anne-Noël Samaha¹ stress, organelle dysfunction and protein ¹UdeM aggregation. In this study, we analyzed the neuroprotective potential of Cucurbitacin E The faster drugs reach the brain, the more (CuE), a triterpene phytosterol extracted from addictive they are. Indeed, drug users who the Cucurbitaceae Ecballium elaterium, on an in favour rapid routes of consumption (e.g., vitro model of PD consisting of PC12 cells smoking or i.v. injection versus intranasal use) differentiated in dopaminergic neurons using show a greater likelihood and severity of nerve growth factor (NGF). We exposed these addiction. Those who smoke or inject drugs also neurons to 1-methyl-4-phenylpyridinium (MPP ), consume more. As such, 'how fast' is a well known neurotoxin provoking a PD-like confounded with 'how much'. The question syndrome. Even if cytotoxicity and apoptosis addressed here is, is a more abrupt rise in brain assays have proven the neuroprotective effects drug levels sufficient to promote excessive of CuE, its mechanism of action remains motivation for drug? Rats self-administered unknown and does not seem to involve rapidly rising (delivered i.v. over 5 s) or more antioxidative properties, as demonstrated by sustained (90 s) cocaine infusions during daily oxidative stress measurements. Cellular 6-h sessions. We then measured the motivation macroautophagy, a complex degradation and for cocaine using a progressive ratio schedule of recycling pathway for old and damaged cell reinforcement (PR). Experienced human components, has been studied as a potential cocaine users achieve spiking rather than target of CuE. Epifluorescent autophagic flux continuously high brain levels of drug during a assays have shown enhanced autophagy binge. To mimic this during the 6-h sessions, following CuE treatment. Further studies have cocaine was available intermittently (12 x 6-min illustrated that CuE modulates the expression of cocaine bins, separated by 26-min drug-free HDAC6, a key regulator of the degradation bins; Zimmer et al., 2012). To ensure that the 5- process, as well as its colocalization with LC3, a and 90-s groups would take the same amount of common marker of autophagy. These interesting cocaine, infusions were limited to 2 per 6-min properties of CuE point to an autophagy-related bin. Cocaine intake did not differ between the mechanism of neuroprotection in parkinsonian groups. In spite of this, the 5-s rats were more dopaminergic neurons and open the way to motivated to take cocaine under PR than the 90- neuroprotectives strategies. s rats. Thus, even when cocaine intake is held constant, increasing the rate of rise of brain 1-C-66 ¬¬¬ Neurons Regulate the Cell cocaine levels promotes increased motivation Surface Proteome of Central Nervous for the drug. Thus, drugs, formulations, and System Glia routes of administration that result in rapid drug uptake might be more addictive because rapidly Anshul Awasthi¹, Gregoire Morisse¹, Amit Bar-Or¹ 44

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28

¹Montreal Neurological Institute sites of injury rapidly express IL-1α, and that infiltrating Ly6G 7/4 neutrophils and Ly6C high The objective of this study is to investigate how 7/4 monocyte-derived M1 macrophages the signals from soluble factors of neurons are subsequently produce IL-1β. While infiltration of transduced into glial specific functional these two cell types was equally reduced in IL- responses. To identify molecules on glial cells 1α-/- and IL-1β-/- mice compared to wild-type modulated by neuronal signals, a proteome (WT), IL-1α-/- mice exhibited better locomotor screen was performed on cell surface enriched recovery as early as day 1 post-SCI. This early proteins of glial cells following exposure to recovery seen in IL-1α-/- mice persisted over neuronal conditioned media (NCM). While time and correlated with reduced lesion volume. protein levels in total cell lysates remained the Transcriptome analysis of SCI tissue at day 1 same, NCM caused reciprocal regulation of identified 18 transcripts differentially regulated in adhesion molecules (N-cadherin and β-catenin) IL-1α-/- mice compared with IL-1β-/- and WT. along with neurotrophin receptors on the surface Notably, the list includes the survival factor of astrocytes compared to oligodendrocytes TOX3. IL-1α -/- mice have markedly increased (OLs). Secreted neurotrophins (BDNF) and the levels of TOX3 in their neurons and shed ecto domain of N-cadherin (NCED) were oligodendrocytes, beginning early in found to be present in NCM. Using function development and persisting through adulthood. blocking antibodies and recombinant proteins, Accordingly, neuronal and oligodendrocyte we show that the astrocytic surface expression survival was significantly increased in IL-1α-/- of Trk-B and N-cadherin are modulated by mice compared to IL-1β-/- and WT at 1 day secreted BDNF and NCED respectively. post-SCI. Thus, we show for the first time that Furthermore, neuronal factors also modulated IL-1α represses expression of survival factors the cell-substrate adhesion of astrocytes and such as TOX3 in neurons and oligodendrocytes, OLs in a reciprocal manner. While there was no suggesting that inhibiting IL-1α may help reduce effect of neuronal factors on migration of OLs, neurodegeneration during CNS insult. NCM exposure led to increased migration and polarisation of astrocytes. Our data show that 1-C-68 The phosphodiesterase inhibitor short exposure to neuronal factors modulate cell Ibudilast attenuates glial cell reactivity, surface proteins and function of glial cells, a production of proinflammatory cytokines system that may be useful for examining neuro- and neuronal loss in experimental glaucoma glial cross-talk. Our ongoing studies focus on elucidating how inflammatory mediators present Nicolas Belforte¹, Jorge Cueva-Vargas¹, in the inflamed MS CNS may impact such cross- Adriana Di Polo¹ talk and how therapies known to access the ¹University of Montreal Hospital Research CNS (eg FTY720; BAF) that signal through Center neurons and glial cells may impact the repair process. Ibudilast, a phosphodiesterase inhibitor with glial cell modulation, anti-inflammatory and 1-C-67 Deletion of the IL-1α gene vasodilator properties, has been used for the upregulates expression of the survival factor treatment of asthma and stroke. Here, we TOX3 in neurons and oligodendrocytes and characterized the role of Ibudilast on the protects these cells from death after spinal response of glia and retinal ganglion cells cord injury (RGCs) in experimental glaucoma. Ocular hypertension (OHT) was induced by injection of Dominic Bastien¹, Martine Lessard¹, Steve hypertonic saline solution into an episcleral vein Lacroix¹ in rats. Ibudilast or vehicle were administered by ¹Université Laval-CRCHUL intravitreal injection. Animals were euthanized at 3 weeks after OHT induction. Tumor necrosis Spinal cord injury (SCI) causes the release of factor α, (TNFα), interleukin 1 (IL-1β), interleukin danger signals by stressed and dying cells, a 6 (IL-6), macrophage migration inhibitory factor process that leads to neuroinflammation. (MIF), glial fibrillary acidic protein (GFAP) and Evidence suggests that inflammation plays a ionized calcium binding adaptor molecule 1 role in both damage and repair of injured neural (Iba1) expression were evaluated by tissue. Here, we have analyzed the synthesis, immunohistochemistry and western blots. RGC release mechanisms and function of IL-1α and soma and axon densities were quantified on IL-1β in neuroinflammation, tissue damage and retinal whole mounts or optic nerve cross recovery after SCI. We found that microglia at sections, respectively. Our data demonstrate a 45

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 decrease in the number of GFAP-positive induced oxidative stress and neuronal cell astrocytes and Iba1-labeled microglia in death. Ibudilast-treated glaucomatous retinas and optic nerves compared to vehicle-treated controls. 1-C-70 Excitatory and inhibitory Ibudilast treatment also led to marked reduction contributions to seizure like events in in vitro of pro-inflammatory cytokines TNFα, IL-1β, IL-6, human neocortical tissue and MIF in ocular hypertensive eyes. Ibudilast promoted robust RGC soma and axonal Vanessa Breton¹, Joshua Dian¹, Peter protection, while not affecting intraocular Carlen¹, Taufik Valiante¹ pressure. Our data demonstrate that Ibudilast ¹Toronto Western Hospital, University of Toronto attenuates glial cell reactivity, reduces production of pro-inflammatory cytokines, and Intractable epilepsy remains a burden on a great promotes RGC soma and axon protection in number of individuals supporting the necessity experimental glaucoma. for continued research initiatives into its potential underlying cause and novel treatment 1-C-69 Evaluation of wild partridgeberry plans. The present study exploits the unique polyphenols as potential natural health opportunity to record from human neocortex and product to reduce the risk of Alzheimer's to assess the contributions of GABAergic and disease glutamatergic synaptic activity to seizure activity in the human brain. Human cortical slices were Khushwant Singh Bhullar¹, H.P.Vasantha isolated from patients with medically refractory Rupasinghe¹, George Robertson¹ Medial Temporal Lobe Epilepsy, from which ¹Dalhousie University recordings of spontaneous seizure like events were made in vitro after drug treatment with Alzheimer's disease (AD) is characterized by the kainate, then carbachol (Florez et al., 2013). excessive production of amyloid-β1-42 (Aβ1-42) Local field recordings were used to isolate these that promotes oxidative stress and neuronal cell spontaneous events, while whole cell activities death. Diets abundant in polyphenols are known were recorded using patch clamp techniques. to decrease Aβ1-42-induced neurotoxicity, Excitatory and inhibitory synaptic currents were reduces the risk of developing AD. Using rat then observed in voltage clamp, holding cells at primary cortical and hippocampal neurons, we the reversal potentials for either GABA or have examined the inhibitory effects of four glutamate. At least two types of seizure like polyphenol preparations of wild partridgeberry events were obtained and could be categorized (crude extract, anthocyanin-, flavan-3-ol- and based on whether or not they have long preictal flavonol-rich fractions) on Aβ1-42-induced oscillations. The ratios of excitatory and oxidative stress and cell death. The flavan-3-ol- inhibitory synaptic conductances were analyzed rich fraction exhibited the highest antioxidant at different points during seizure initiation, as activity (p<0.05) as indicated by multiple well as spike field coherence done to reveal antioxidant assays. The flavonol- and flavan-3- possible mechanisms for the underlying ol-rich fractions (EC50<9 µg/mL) protected rat dynamics of the transition to seizure in human primary cortical neurons and rat primary cortex. CM Florez, RJ McGinn, V Lukankin, I hippocampal neurons from Aβ1-42-induced cell Marwa, S Sugumar, J Dian, L-N Hazrati, PL death as measured by MTS cell viability assay. Carlen, L Zhang, and TA Valiante. In Vitro The flavan-3-ol-rich fraction profoundly Recordings of Human Neocortical Oscillations. attenuated neural membrane damage produced 2013. Cerebral Cortex by Aβ1-42 in primary cortical and hippocampal neurons with EC50 values of 0.03 and 0.01 1-C-71 Intracerebral thrombin infusion µg/mL, respectively. All four polyphenol causes acute neuronal atrophy and cell preparations also inhibited the production of death, but does not lead to chronic reactive oxygen species (ROS) by Aβ1-42. The degeneration: implications for hemorrhagic flavan-3-ol-rich fraction exhibited the greater stroke ability to maintain neural redox balance that was associated with elevated cellular concentrations Jayalakshmi Caliaperumal¹, Sonia Brodie¹, of superoxide dismutase and catalase relative to Yonglie Ma¹, Frederick Colbourne¹ the control (p<0.05). These findings indicate that ¹University of Alberta at brain concentrations readily achieved by dietary supplementation (50-100 nM), wild Intracerebral hemorrhage (ICH) is a devastating partridgeberry polyphenols reduce Aβ1-42- type of stroke, causing significant mortality rate 46

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 and long-term disability. Brain injury after ICH using repeated trains of 445-nm laser pulses. arises from blood vessel rupture leading to We collected EEG data several minutes before, primary (mechanical) and secondary (delayed) during, and after each stimulation sessions and damage. Notably, thrombin production, needed scored behaviour using modified Racine criteria. to stop bleeding, also causes early cell death Sessions were repeated at least 20 times. and edema. In some rodent models of ICH, peri- Repeated stimulation progressively led to hematoma neurons die over weeks. Hence we seizures in 6 out of 6 animals. Epileptogenesis evaluated whether thrombin could be correlated with significant EEG changes, such responsible for this chronic degeneration as well as altered dynamics of evoked responses, and as sub-lethal changes known to contribute to increased delta band power. Next, we will functional impairment. Adult rats had an intra- investigate in acute slices the local circuit striatal infusion of thrombin (1 U) or saline changes that are associated with disease followed by behavioral assessment using the progression in epileptic animals. With our novel corner turn test 7 days later. After this they were model, it may be possible to identify candidate euthanized and tissue stained with Golgi-Cox to circuit changes that underlie epileptogenesis in assess dendritic morphology. In a second otherwise healthy animals. experiment, rats survived 7 or 60 days after thrombin infusion in order to histologically 1-C-73 HPRT Deficiency in Human Neural determine lesion volume. Thrombin caused Progenitor Cells early cell death and considerable atrophy in surviving peri-lesion neurons. However, total Liam Crapper¹, Gilles Maussion¹, Carolina tissue loss was comparable at 7 and 60 days. Gigek², Alpha Diallo¹, Gustavo Turecki¹, Carl Acute thrombin infusion, a reductionist model of Ernst¹ ICH, causes early cell death and neuronal ¹Douglas Mental Health University Institute , atrophy in nearby surviving striatal neurons, but ²Universidade Federal de São Paulo not on-going tissue loss. Thus, the chronic degeneration found after ICH in rats is not Lesch-Nyhan disease (LND) is a rare genetic simply and solely due to acute thrombin disorder caused by the disruption of the gene production. Nonetheless, thrombin likely HRPT1, which plays a key role in purine contributes to behavioral dysfunction owing to metabolism. LND causes a variety of metabolic causing cell death and marked dendritic injury. and neurological symptoms including crystals in the urine, gout, dystonia, intellectual disability, 1-C-72 A novel optogenetic kindling and chronic self-injury. While the metabolic model of epilepsy symptoms are easily treated with allopurinol this has no effect on the neurological symptoms, the Elvis Cela¹, Andrew Chung², Taiji Wang², Li- causes of which remain unknown. We have Yuan Chen², Jesper Sjöström³ created a novel model of LND by knocking down ¹Integrated Program in Neuroscience, McGill HPRT1 expression in human ventral midbrain University , ²Montreal General Hospital, ³McGill derived neural precursor cells. Using University transcriptome sequencing and western blots we demonstrated substantial alterations in the Epilepsy is a devastating neurological disease, expression of genes related to protein yet the microcircuit changes that underlie it translation and metabolism. remain unclear. Many epilepsy models rely on chemical or electrical induction in rodents. In 1-C-74 The role of leptin in the these models, however, brain injury and augmentation of heroin seeking induced by nonspecific targeting of cell subtypes make it chronic food restriction. difficult to study the microcircuit changes that accompany epileptogenesis. To overcome these Tracey D'Cunha¹, Melissa Russo¹, Emilie limitations, we developed a novel optogenetic Daoud¹, Uri Shalev¹ kindling model of epilepsy. To target ¹Concordia University glutamatergic neurons, we injected AAV- CaMKIIa-hChR2 (E123T/T159C)-p2A-EYFP into Dietary manipulations during drug abstinence primary motor cortex (M1) of male C57BL/6J can increase the risk of relapse. We have mice. After 21 days, we confirmed expression of demonstrated that chronic food restriction ChR2 in L2/3 and L5 of M1 by acute slice augments heroin seeking following a period of electrophysiology and 2-photon microscopy. We abstinence. The precise mechanisms mediating then stimulated M1 of awake behaving animals this effect remain unknown. Leptin, a hormone 47

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 involved in the regulation of energy balance and could be detected in the brain and was food intake, attenuates acute food-deprivation maintained for 3.5 months. Animals were then induced reinstatement of heroin seeking. tested on behavioral tasks before the brains However, the metabolic consequences of acute were harvested for molecular and biochemical food deprivation and chronic food restriction are analyses. Here we demonstrate that SAM distinct. Therefore, we examined the effect of administration prevented the behavior deficits in exogenous leptin on heroin seeking in abstinent, the novel object recognition and Morris water chronically food restricted rats. Rats self- maze tasks. It also led to the modulation of administered heroin for 10 days. Next, rats were proteins involved in the amyloidogenic cascade moved to the animal colony for 14 days, and and its resulting products such as Amyloid- given either free access to food or underwent beta42 and BACE levels and activity. Effects on chronic food restriction to maintain them at 90% DNA methylation were also examined. Our of their original body weight. In experiment 1, results indicate that SAM supplementation can rats were injected with leptin (0.0 or 2.0 μg; impact and delay the progression of AD i.c.v.) immediately prior to a heroin seeking test neuropathology. under extinction conditions. In Experiment 2, rats were administered two injections of leptin 1-C-76 Chronic haloperidol enhances (2.0 μg; i.c.v.) or vehicle, 24 hours before and amphetamine-induced conditioned reward: immediately prior to the heroin seeking test. altered reward circuits? Chronic food restriction augmented heroin seeking during abstinence. A single leptin Cynthia El Hage¹, Anne-Noel Samaha¹ injection did not affect the augmentation of ¹Université de Montréal heroin seeking induced by chronic food restriction; however, two injections may Drug addiction is common in schizophrenia. attenuate heroin seeking. Leptin might modulate Chronic antipsychotic treatment might contribute the augmentation of heroin seeking induced by to this co-morbidity by altering the reward chronic food restriction. system. We have shown that rats withdrawn from continuous haloperidol (HAL) treatment 1-C-75 S-adenosylmethionine reduces (via minipump) pursue reward cues more amyloid pathology severity in the McGill- vigorously than HAL-naive rats following Thy1-APP mouse model of Alzheimers systemic amphetamine (AMPH). AMPH-induced disease potentiation of conditioned reward is mediated by the nucleus accumbens (NAc). Here we Sonia Do Carmo¹, Marie Jacobs¹, Marc evaluate the hypothesis that the NAc is both Danik¹, M Florencia Iulita¹, Lionel Breuillaud¹, necessary and sufficient for enhancement of Moshe Szyf¹, A Claudio Cuello¹ AMPH-evoked potentiation of conditioned ¹McGill University reward in HAL-treated rats. Rats were trained to associate a light-tone cue with water, and then Late onset Alzheimer's disease (AD) is a given continuous HAL via minipump. Following complex multi-faceted disorder likely brought treatment cessation, we assessed lever about by the interaction of genetic, social and pressing for the light-tone cue (now a environmental factors. Increasing evidence conditioned reward) after intra-NAc AMPH suggests epigenetic involvement, resulting in the injections or inhibition of the NAc with deregulation of genes that participate in AD muscimol/baclofen. Surprisingly, intra-NAc development and progression. As such, it is now AMPH enhanced operant responding for the well known that AD is accompanied by DNA conditioned reward only in control rats. hypomethylation and decreased S- Furthermore, in HAL-treated rats, inhibiting the adenosylmethionine (SAM) levels. Data from our NAc did not alter potentiation of conditioned lab demonstrates that strong DNA reward by systemic AMPH. The NAc is a brain hypomethylation is present in our McGill-Thy1- region that normally subserves AMPH-induced APP mouse model of AD-like amyloid pathology potentiation of conditioned reward. However, at 5 months of age, one month after the continuous HAL treatment modifies reward accumulation of the first amyloid plaques. In this circuitry such that the NAc becomes neither study, we examined if the administration of SAM necessary nor sufficient to evoke this response. could revert the general DNA hypomethylation The challenge now is to identify the neural and ameliorate or delay the amyloid pathology circuits that underlie the ability of HAL to and related deficits in the McGill mouse model. augment the pursuit of reward cues. This could SAM administration started before plaques shed new light on the neurobiological substrates 48

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 by which antipsychotic treatment alters reward deficits accompanied by the selective and function. progressive loss of dopamine (DA) neurons of the substantia nigra pars compacta (SNc). The 1-C-77 Granulocyte macrophage-colony exact mechanism by which SNc neurons stimulating factor and erythropoietin degenerate in PD is poorly understood. influence striatal regeneration in a prodromal However, mitochondrial dysfunction has been model of Parkinson's disease. proposed as a key contributor. We tested the hypothesis that the selective vulnerability of SNc Kyle Farmer¹, Christopher Rudyk¹, Natalie DA neurons, in comparison to those from the Prowse¹, Shawn Hayley¹ closely located VTA, is due to higher ¹Carleton University mitochondrial metabolism related to their larger axonal arborization. In the present study we Parkinson's disease (PD) is believed to have a quantified basal and activity-dependent protracted prodromal state, wherein the mitochondrial energy metabolism in primary degeneration of midbrain dopamine neurons is cultures of postnatal mesencephalic mouse DA ongoing and by the time the cardinal motor neurons, grown on an astrocyte monolayer, signs of the disease manifest, upwards of 50- using a Seahorse XF24 analyzer. Using 80% of these neurons have been lost. Hence, it confocal imaging, we also quantified the extend is critical to find methods of interfering with the of the neurons' axonal arborization and the progression of this prodromal state or inducing density of mitochondria after lentivirus-mediated compensatory recovery processes. To this end, overexpression of Mito-DsRed. Our data show we presently utilized a 6-OHDA partial lesion that the more vulnerable SNc DA neurons differ model to model the PD prodromal state, in from VTA DA neurons in that they show higher which a modest but significant loss of striatal basal mitochondrial respiration, higher axonal dopamine terminals was observed (~10%). mitochondrial density, a larger axonal Importantly, intervention with two cytokines that arborization and an increased susceptibility to possess trophic properties, namely the neurotoxin MPP+. Our data are compatible erythropoietin (EPO) and granulocyte with the hypothesis that SNc DA neurons are macrophage-colony stimulating factor (GM- more vulnerable because their elevated CSF), administered systemically following the 6- mitochondrial function leads to more extensive OHDA lesion provoked a time-dependent re- oxidative stress. innervation of the striatum. Moreover, enhanced GAP43 and Tau-1 staining in the striatum 1-C-79 Activation of caspase-6 and indicated that local GABA neurons might have cleavage of STK3 in an early event in an in also responded to the cytokine administration. vitro model of stroke. Curiously, however, subventricular zone and hippocampal neurogenesis was not increased Marie-Josee Demers¹, Kim Girling², Shu but actually decreased by the EPO and GM- Zhang², Yu Tian Wang², Rona Graham¹ CSF treatments. Hence, these neurogenic ¹Univerity of Sherbrooke, ²Univerity of British niches were likely not directly linked to the re- Columbia innervation of the striatum. Taken together, these data hint at the possibility of using certain In Canada, the US and Europe, stroke is the immune modulator molecules that have trophic leading cause of long term adult disability and properties to "rescue" nigrostriatal pathology the 3rd leading cause of death. Activated during the early stages of PD. caspase-6 (casp6) has been observed in post- mortem tissue from brains of patients who died 1-C-78 Axonal arborization and following stroke and casp6-/- mice demonstrate mitochondrial metabolism as key reduced stroke injury and improved contributors to the selective vulnerability of sensorimotor abilities. These data provide substantia nigra dopamine neurons. important validation for the activation of casp6 as key step in the pathogenesis of stroke. There Consiglia Pacelli¹, Nicolas Giguère¹, Ruth is strong evidence to support a critical role for Slack², Louis-Éric Trudeau¹ NMDAR-mediated excitotoxicity as a ¹Université de Montréal, ²University of Ottawa mechanism underlying stroke injury. Inappropriate caspase activation in stroke could Parkinson's disease (PD) is the second most result from increases in calcium levels due to common neurodegenerative disorder. The excitotoxic stress and lead to generation of disease is associated with severe locomotor proteolytic fragments as a result of caspase 49

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 substrate proteolysis. Using rat primary cortical remaining viable. Later, macrophages of neurons ± NMDA we demonstrate that at early peripheral origin contribute predominantly to time points post NMDA no increase in cell death phagocytosis but are less efficient at processing is observed. However at 24h a significant CNS debris, and their death, in situ, may increase in cell death is detected (ANOVA contribute to the secondary damage after CNS p<0.0001). Assessment of caspase mRNA injury. levels demonstrates that increased casp6 mRNA is observed at 1, 4 and 24hrs post NMDA 1-C-81 Recombinant IL-4 injection into (ANOVA p=0.016). No differences in casp8 or the brain alters the inflammatory response casp9 levels were observed. Increased casp6 and grey matter injury in a rat model of activity post NMDA was also detected (p<0.05). ischemic stroke Preliminary data also shows that a significant decrease in full-length levels (ANOVA p=0.03) of Sarah Hutchings¹, Lyanne Schlichter¹ the novel casp6 substrate STK3, and increase in ¹University Health Network STK3 fragments (ANOVA p=0.009) occurs prior to cell death. These data provide a clear link Following a stroke, there is a CNS inflammatory between excitotoxicity and proteolysis and response involving activation of resident suggest that activation of casp6 is an early microglia, and infiltration of peripheral innate event in the pathogenesis of stroke. immune cells (mainly macrophages and neutrophils). This response can last for hours to 1-C-80 Differences in the phagocytic days, making it more amenable to treatment response of microglia and peripheral than acute neurotoxicity. Microglia can exist in macrophages after spinal cord injury and its several activation states, and in vitro, their effects on cell death alternative activation is readily evoked by the cytokine, IL-4. Here, we modeled transient focal Andrew Greenhalgh¹, Sam David¹ ischemia by injecting the vasoconstrictor ¹McGill University peptide, endothelin-1 (ET-1), into the rat striatum, either alone (untreated) or with 500 ng Macrophages in the injured spinal cord arise of rat recombinant IL-4 (treated) to enhance from resident microglia and infiltrating, alternative activation. Gene expression analysis peripherally derived monocytes. The aims of this revealed an increase in the alternative activation study were to investigate the phagocytic markers, CD163 and CCL22 at 24 hr after response and clearance of damaged axons and ischemia onset, ARG1 at 3 days, and molecules tissue debris by these distinct subsets of related to IL-4 signaling (IL-4rα, STAT6) at 7 macrophages and assess their viability after days. Immunohistochemistry was used to spinal cord injury (SCI). The lysozyme M EGFP- quantify inflammation, neuronal, and glial knock in (lys-EGFP-ki) mouse tags responses in the ischemic core. Surprisingly, hematogenous macrophages, but not microglia. early IL-4 treatment increased the number of Using neuronal tracing techniques we show that degenerating neurons (FluoroJade B labeled), microglia contact damaged axons early (24 h) and apparently phagocytic neutrophils (labeled after SCI and are the main type of macrophage with anti-PMN to identify neutrophils, and anti- to contain phagocytic material at 3 days. ED1 for activated lysosomes) at 24 hr. Thereafter, infiltrating macrophages become the Moreover, early IL-4 treatment did not alter the predominant cell in contact with degenerating number of activated microglia/macrophages or axons and contain more phagocytic material, the extent of white matter injury at 1, 3 or 7 days which in contrast to microglia, persists for up to post-ischemia. Thus, IL-4 treatment delivered at 42 days. The proliferation marker Ki67 was ischemia onset might be harmful. Future studies found predominantly to the nuclei of resident are needed to evaluate whether IL-4 microglia, suggesting a mechanism by which administration at later times is beneficial. microglial division contributes to phagocytic load management. Furthermore, after phagocytosis 1-C-82 Dissociating dopamine functions of myelin in vitro, macrophages are much more with new models of dopamine depletion susceptible to apoptotic and necrotic cell death, specific to the mesocorticolimbic or which is mirrored in vivo with apoptotic TUNEL- nigrostriatal pathways positive cells of infiltrating macrophage origin. This work suggests that microglia play a major Elsa Isingrini¹, Lea Perret¹, Marie-Eve role in the early response to SCI, by Desaulniers¹, Luc Moquin¹, Alain Gratton¹, phagocytosing injured tissue efficiently and Bruno Giros¹ 50

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28

¹McGill university, Douglas Institut Retinitis Pigmentosa (RP). The GDNF/GDNF-R axis is a validated target for the treatment of The dopamine (DA) system has been involved many conditions, and it has been applied in a large number of neuropsychiatric disorders. successfully in multiple animal models. However, the exact implication of DA involved in Moreover, GDNF has been used in human the two different pathways remains difficult to clinical trials. Nonetheless, its clinical explore with the current animal models. The development faces major obstacles inherent to goal of this proposal is to create new models of proteins, such as high cost, poor delivering to dopamine depletion. We generated a conditional the target tissue, poor stability, and poor VMAT2 KO (vesicular monoamine transporter, selectivity. Our laboratory has promoted a knockout) using the Cre recombinase to splice conventional pharmacological approach by out the VMAT2 floxed gene specifically in DAT- designing drug-like small molecule GDNF positive neurons. This model was validated by mimetics with agonistic activity, and high an absence of VMAT2 mRNA in the ventral receptor selectivity. By using small, non-peptide tegmental area (VTA) and substantia nigra (SN) molecules with improved stability and relatively and a complete DA depletion in the whole brain. easy delivery, it may be possible to sustain However, the VMAT2DATcre KO mice die at neuronal function beyond previous postnatal week 3. Therefore, we generated a achievements. We will present data from in vitro, VMAT2 KO model which enabled us to ex vivo and in vivo studies on the development, dissociate the mesocorticolimbic and nigrostrital the selectivity, the efficacy, the potency, and the pathways. An adeno-associated virus encoding mechanism of action of our novel drug-like the Cre recombinase (AAV2-Cre) was injected GDNF mimetics. Our ongoing trials with these either in the VTA or in the SN of VMAT2lox mimetics have yielded evidence of therapeutic homozygous adult mice. The VMAT2AAVcre KO merit. Further development or optimization of mice were validated by a lack of VMAT2 mRNA the lead compounds is likely to yield clinical expression in the site of injection, and by candidates for treatment of progressive specific DA depletion in the nucleus accumbens neurodegenerative disorders. and prefrontal cortex (VTA projections) or in the dorsal striatum (SN projections). Despite 1-C-84 Identifying microRNA regulators conservation of DA neurons, all VMAT2AAVcre of neuronal viability and repair in multiple KO mice died after 16 weeks post-injection due sclerosis to a drastic weight loss. In parallel, mice injected in the SN demonstrated motor alterations Camille Juzwik¹, Amit Bar-Or¹, Alyson appearing from postnatal week 8 onwards. In Fournier¹ conclusion, the VMAT2AAVcre KO models of ¹McGill University dopamine depletion will allow to unravel DA functions in the etiology of psychiatric or Multiple sclerosis (MS) is an autoimmune neurological pathologies. disease characterized by the infiltration of peripherally activated immune cells into the 1-C-83 GDNF Mimetics for central nervous system. Current MS therapies Neuroprotection in the Retina are immunomodulatory rather than neuroregenerative, making neural repair and Sean Jmaeff¹, Pablo Barcelona¹, Sylvia viability an ideal direction for future work. Josephy¹, Alba Galan², Lukas Merhi³, Lukasz Previously we have identified neurite outgrowth Szczygiel³, Marinko Sarunic³, Yulia inhibition by immune cells and their conditioned Sidorova⁴, Mart Saarma⁴, Uri Saragovi¹ media (CM). Our lab is interested in how ¹McGill University, ²Pharmacology, ³Simon immune cells and their products affect neuronal Fraser University, ⁴University of Helsinki viability and repair. MiRNA are short RNA sequences, a single miRNA is able to target Glial cell-line derived neurotrophic factor several different mRNA. Altered miRNA (GDNF) and its receptors (GDNF-R) are expression has been identified in blood cells of expressed in the developing and the adult MS patients, as well as active and inactive MS nervous system. GDNF yields pro-survival lesions. An investigation of neuronal miRNA signals by activating AKT and related pathways expression can provide further insight into in cells expressing GDNF-R. GDNF signalling immune-neural interactions in MS. We has shown promise in degenerative diseases developed a list of candidate miRNAs to including Parkinson's disease, Huntington's investigate during neurite outgrowth inhibition in disease, Amyotrophic Lateral Sclerosis and mouse cortical neurons following treatment with 51

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 peripheral blood mononuclear cell CM (PBMC- Traumatic Brain Injury. Abbreviations: TBI; CM). Specifically, levels of miR-27a-3p increase Traumatic Brain in response to stimulation with PBMC-CM raising the possibility that it may be involved in 1-C-86 Pathological sharp waves and neurite outgrowth inhibition. Preliminary data hyperexcitability in a mouse model of fetal however shows that treatment of neurons with alcohol spectrum disorder (FASD) miR-27a mimic during control conditions promotes outgrowth and process formation, Michal Krawczyk¹, Meera Ramani ¹, Shanthini suggesting that the up-regulation of miR-27a Mylvaganam¹, Peter Carlen² during PBMC-CM treatment functions as a ¹Toronto Western Hospital, ²Toronto Western neuroprotective response. Probing for different Hospital and University of Toronto mRNA targets of miR-27a can unravel its function in neuronal viability and repair. Fetal Alcohol Spectrum Disorder (FASD) refers to the wide variety of physiological and 1-C-85 The Frequency of Coagulopathy behavioral postnatal pathologies induced by in And Its Significance In An Emergency utero exposure to alcohol, which includes an Neurotrauma Facility. increased prevalence of seizures. However, to date, there exists limited information regarding Salman Khan¹, Muhammad Waqas¹, Mohsin the underlying pathophysiological mechanisms. Qadeer¹, Shahan Waheed¹, Iqra Patoli¹, The hippocampus is strongly implicated in Muhammad Bari¹ FASD, and is a source of seizure activity in ¹Aga Khan University various epileptic conditions. The hippocampal CA3 region generates population activities Background: Most data on coagulopathy are called sharp waves (SPWs), and emerging from the West. We sought to determine evidence suggests that dysregulation of SPWs frequency of coagulopathy in our population and induces epileptiform activity. We therefore determine the relationship of coagulation hypothesize that mice prenatally exposed to parameters and other clinical variables with alcohol will have increased hyperexcitability in unfavorable outcomes of patients with TBI. the CA3 hippocampal region and dysregulated Methods: This was an observational cohort SPWs. Pregnant mice received 10% v/v ethanol study conducted in a tertiary care facility from for the first trimester-equivalent of gestation by 1st January 2010 to 31st December 2012. All voluntary consumption. Spontaneous in vitro patients with isolated traumatic brain injury SPW were recorded from the CA3 hippocampal presenting within 24 hours of injury were region using acute brain slices prepared from included in the study. Coagulation parameters at ethanol-exposed pups and controls of ages PD presentation were recorded and Glasgow 15-21. Prenatal ethanol exposure significantly Outcome Scale calculated on the last follow up. altered in vitro SPW waveforms, with a 50% Outcomes were dichotomized into favorable and increased duration and amplitude, when unfavorable outcomes. Relationship of compared to controls. Application of the GABA- coagulopathy with GCS, GOS, RTS and A receptor antagonist bicuculline (BMI) led to unfavorable outcomes was calculated using the transition of SPWs into a longer duration and Pearson`s correlation and Receiver Operator amplitude in both ethanol-exposed mice and Curve analysis. Results: 121 patients were controls. Interestingly, the percent change included in the study. Mean age was 38.86 induced by BMI was significantly lower in years (± 16.71). Overall frequency of ethanol-exposed mice, indicative of a loss of coagulopathy was found to be 6 %. In severe inhibition. These results may account for the head injury group it was 14%. Area under curve increased seizure susceptibility observed in (AUC) for aPTT was found to be 0.702 (95%CI individuals with FASD. =0.602-0.802, p < 0.001) indicating its strong predictive value. Predictive value of platelets 1-C-87 The genetic landscape of infantile and INR was not found to be significant. APTT, spasms INR, RCTS, Age, GCS and RTS were found to be significantly correlated with GOS. Jacques Michaud¹, Mathieu Lachance¹, Fadi Conclusion: Overall incidence of coagulopathy Hamdan¹, Patrick Cossette¹, Lionel Carmant¹, in our population was 6 %. APTT, INR, RCTS, Anne Lortie¹, Emmanuelle Lemyre¹, Guy Age, GCS and RTS in emergency are correlated Rouleau2, Elsa Rossignol¹ with outcomes of patients with TBI. Keywords: ¹CHU Ste-Justine Research Center, 2Montreal aPTT, Coagulopathy, Unfavorable outcomes, Neurological Institute 52

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28

investigate the neurochemical basis of TD, we Background. Infantile spasms (IS) is an early- exposed adult capuchin (Cebus apella) onset epileptic encephalopathy of unknown monkeys to prolonged treatments with etiology in 40% of cases. We hypothesised that haloperidol (N=11) or clozapine (N=6). Six unexplained IS cases represent a large untreated animals were used as controls. Five collection of rare single-gene disorders. haloperidol-treated animals developed mild TD Methods. We investigated 44 children with movements similar to those found in humans. unexplained IS using comparative genomic No TD was observed in the clozapine group. hybridisation arrays (aCGH) (n=44) followed by Using receptor autoradiography, we measured targeted sequencing of 48 epilepsy genes (n=8) dopamine D1, D2 and D3 receptors, as well as or whole-exome sequencing (WES) of familial glutamate mGluR5, adenosine A2A and trios (n=18) to search for rare inherited or de serotonin 5-HT2A receptor levels. Haloperidol, novo mutations. Results. aCGH revealed de but not clozapine, strongly induced D3 receptors novo variants in 7% of patients (n=3/44), in monkey putamen, but spared D2 receptor including a 16p11.2 duplication, a 15q11.1q13.1 binding sites. Interestingly, dopamine D3 tetrasomy and a 2q21.3-q22.2 deletion. receptor mRNA levels were upregulated in Furthermore, it identified a pathogenic substance P positive striatal cells. In addition, maternally inherited DupXp11.2. Targeted dopamine D3, but not D2, receptor levels sequencing was informative for ARX (n=1/14) correlated with TD intensity. These results and STXBP1 (n=1/8). By contrast, sequencing indicate that D3 receptor upregulation in the of a panel of 48 known epilepsy genes (n=8) did direct pathway is associated with TD in this non- not identify further mutations. Finally, WES human primate model, as opposed to rodent (n=18) was very informative, with an excess of data, which have rather suggested D2 receptor de novo mutations identified in genes involved in involvement. Thus, the D3 receptor could neurodevelopmental processes and intolerant to provide a novel target for drug intervention in functional variations. Several pathogenic human TD. Supported by CIHR (MOP-300152). mutations were identified, including de novo SM and OP hold fellowships from FRQS and mutations in STXBP1, CASK, and ALG13, and GRUM/Hydro-Québec, respectively. recessive mutations in PNPO and ADSL, together explaining 28% of cases (5/18). 1-C-89 The hemisphere-specific effect of Furthermore, WES identified 1-3 de novo chronic stress on the dendritic morphology variants in 64% of remaining probands, of rat prefrontal cortical callosal neurons revealing several interesting candidate genes. Our results indicate that IS are genetically Pauline Luczynski¹, Luc Moquin¹, Alain heterogeneous with a major contribution of de Gratton¹ novo mutations and that aCGH with WES is ¹McGill University highly effective in achieving a molecular diagnosis in IS. Exposure to chronic stress induces dendritic atrophy of pyramidal neurons in the rat medial 1-C-88 Haloperidol-induced dopamine D3 prefrontal cortex (PFC). Importantly, these receptor upregulation in the direct pathway morphological alterations appear to be correlates with tardive dyskinesia in non- lateralized in nature. The PFC regulation of human primates stress responses is also lateralized, suggesting that in order to mount an appropriate stress Souha Mahmoudi¹, Olivier Perreault¹, Pierre response, the hemispheres must somehow J. Blanchet², Daniel Levesque¹ communicate. PFC callosal neurons project to ¹University of Montreal, ²University of Montreal, the contralateral hemisphere and are thought to Faculty of Dentistry be involved in the interhemispheric communication of stress-relevant information. Tardive dyskinesia (TD) is a delayed and We tested the hypothesis that callosal neurons potentially irreversible motor complication would have a lateralized pattern of remodelling arising in patients chronically exposed to in response to chronic stress. A retrograde dopamine receptor antagonists. Typical tracer was injected into rats' PFC prior to 21 antipsychotic drugs, metoclopramide and days of restraint stress. After completion of the several modern (so-called atypical) stress regimen, labelled callosal neurons in the antipsychotic drugs are associated with PFC were loaded with Lucifer Yellow dye to generation of TD. But, the pathophysiology of visualize their dendrites. We observed a TD remains elusive and difficult to treat. To reduction in the total dendritic length and 53

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 branching of callosal neurons in both the right and the left hemispheres. However, the 1-C-91 Overlap in transcriptional and distribution of these stress-induced alterations in epigenetic signatures between sleep dendritic morphology differed between deprivation and epilepsy hemispheres: both proximal and distal dendrites underwent stress-induced changes in dendritic Renaud Massart¹, Ziv Machnes¹, Marlene morphology in the right hemisphere, while in the Freyburger², Anne McKinney¹, Valerie left hemisphere, only distal dendrites were Mongrain², Moshe Szyf¹ affected. Such hemisphere-specific alterations in ¹McGill University, ²Montreal University morphology of callosal neurons could affect the inter-hemispheric exchange of stress-relevant Relationships between sleep and epilepsy have information, and ultimately contribute to the been described since antiquity. Notably, prefrontal cognitive deficits associated with epileptic seizures interfere with normal sleep chronic stress. Funded by the CIHR. patterns whereas specific sleep-wake stages have been associated with the occurrence of 1-C-90 Characterizing upregulated epileptic seizures (ES) and of interictal miRNAs during preclinical prion disease: epileptiform discharges (IEDs). Moreover, sleep possible roles in neuroprotection deprivation (SD) facilitates the onset of ES. However, the molecular basis of the Anna Majer¹, Yulian Niu¹, Stephanie Booth¹ development and predisposition for seizures ¹Public Health Agency of Canada caused by sleep loss are poorly understood. Therefore, we compared mRNA expression Prion diseases are caused by the conversion of profiles obtained by RNASeq of mouse cortex normal prion protein (PrPC) into the infectious after an acute SD and of mouse hippocampal form (PrPSc) leading to neuronal dysfunction, slices exposed to kainate, a model of degeneration and death. However, how this epileptogenesis. We observed a significant conversion affects neuronal mechanisms which overlap (p=3.9E-265, hypergeometric test) of leads to neuronal dysfunction remains unknown. 1702 genes that are enriched in biological To address this gap in knowledge we performed pathways such as cell death, neurotransmission global high-throughput transcriptomic and or mRNA processing. Moreover, the comparison miRNomic temporal screens on a neuronal-rich of the genome-wide epigenetic alterations region (CA1 hippocampus) to obtain profiles of associated with SD with the ones induced by the transcripts and their regulatory small RNAs, kainate treatment, reveal 1115 and 41 common respectively. We identified the presence of a genes differentially hydroxymethylated (p=3.6E- neuroprotective response that occurs in these 65) and methylated (p=0.04), respectively. The neurons only during preclinical disease. We epigenetic affected genes scarcely overlap with validated 7 miRNAs to be upregulated during the genes differentially expressed and are early disease of which 3 had known related to the morphology of the nervous neuroprotective function. Using prediction system, metabolism and apoptosis. These programs we confirmed that the remaining 4 common transcriptional and epigenetic miRNAs were also potential regulators of signatures may provide insight into the numerous neuronal-specific genes, many of immediate and long-lasting adaptive or which affect neuronal morphology. Post-mitotic maladaptive processes involved in the mouse hippocampal primary neuronal cultures relationship between SD and epilepsy. were employed to further study possible effects of these 4 miRNAs on neuronal morphology; a 1-C-92 Atrophy and cortical characteristic that highlights relative fitness of demyelination predict the severity of neurons and was previously shown to be depressive symptoms among people with affected by neuroprotective miRNAs. Over- relapsing-remitting multiple sclerosis expressing of miR-26a-5p showed increased arborization and spine density in hippocampal Julia Nantes ¹, Lisa Koski ¹ neurons suggesting a possible neuroprotective ¹McGill University role. We are currently characterizing the molecular pathway regulated by miR-26a-5p. Background: Although people with relapsing- Since miRNAs are global gene regulators, better remitting multiple sclerosis (RRMS) can live for understanding of their contribution to years without motor or sensory symptom neuroprotective pathways may reveal possible exacerbations, the prevalence of depression avenues for therapy development. among people with this disease is very high. 54

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28

Past research has identified a link between brain the activation of ERK1/2 by hyperthermia but not volume and depression experienced by such hyperthermia-induced Tau dephosphorylation. patients. However, these studies did not control Finally, immunoblots indicated that Tau for some important factors (e.g. motor disability), phosphorylation is not altered in Mek1-/- mice nor has magnetization transfer (MT) imaging, a compared to wild-type mice. In conclusion, method sensitive to demyelination within normal these results do not support the notion that appearing brain tissue, been used. Objective: ERK1/2 are involved in Tau phosphorylation in Among RRMS patients in clinical remission, we intact cells. sought to estimate the extent to which global white and grey matter damage predicts 1-C-94 Unraveling the function of depressive symptoms. Methods: Sixteen people norepinephrine in anxiety and depression with RRMS participated. Neuroimaging data with a new NE depletion model: the (conventional; MT) and clinical data (Hospital conditional VMAT2 knockout mouse Anxiety and Depression Scale; Self-reported Fatigue Scale; Multiple Sclerosis Functional Lea Perret¹, Elsa Isingrini¹, Marie-Eve Composite (MSFC)) were collected. Brain Desaulniers¹, Luc Moquin¹, Alain Gratton¹, volumes (normalized to skull size) were Bruno Giros¹ measured using SienaX. Mean regional MT ¹Douglas Hospital Research Center - McGill ratios (MTR) were computed. Results: When University adjusting for fatigue and MSFC score, more severe depressive symptoms were predicted by The noradrenergic (NE) neurons, mainly located lower normal appearing white matter volume (β in the locus coeruleus (LC), have been linked to = -0.87, p<0.01), normal appearing grey matter psychiatric disorders involving anxiety and (cortical deep) volume (β = -0.75, p<0.001), and depression. Previous studies have shown that cortical grey matter MTR (β = -0.47, p=0.05). changes in NE transmission from the LC MTR within deep grey matter and white matter influence anxio/depressive-related behaviors. did not predict depressive symptoms (p>0.05). The purpose of this study was to develop a Conclusion: Atrophy and cortical demyelination viable model of NE depletion in the central may contribute to depressive symptoms of nervous system without affecting the periphery RRMS patients, irrespective of fatigue and to investigate NE functions. The NE depletion motor/cognitive disability. model was developed using the cre recombinase expressed by the dopamine β- 1-C-93 Involvement of ERK1/2 in Tau hydroxylase (DBH) genes, which splices out the phosphorylation floxed VMAT2 gene (Vesicular Monoaminergic Transporter). The VMAT2DBHcre KO mice were Anastasia Noel¹, Isabelle Poitras¹, Jacinthe validated by a lack of VMAT2 mRNA expression Julien¹, Françoise Morin¹, Emmanuel Planel¹ specifically in the LC, and NE depletion in the ¹Centre de Recherche du Centre Hospitalier de entire brain. The assessment of development l'Université de Laval and motor abilities confirmed VMAT2DBHcre KO as viable subjects for further testing. Alzheimer disease is characterized by the VMAT2DBHcre KO mice demonstrated less deposition of intracellular aggregates of anxiety- and depression-related behaviors. hyperphosphorylated Tau protein. This Moreover, tissue level of DA and 5HT were phenomenon has been attributed in part to the altered in different brain structures associated increase of kinases and/or the decrease of with mood and motivational behavior. While phosphatases activities. ERK1/2 are activated in basal corticosterone levels were not affected in the first stages of AD and they are proposed as the VMAT2DBHcre KO mice, acute stress therapeutic target for the treatment of this through physical restraint revealed a faster pathology. However, although the return to basal corticosterone levels in phosphorylation of Tau by ERK1/2 has been VMAT2DBHcre KO mice. In addition, prior to the demonstrated for a long time in cell-free system, restraint, dexamethasone injections yielded this capacity remains controversial in vivo. Here, further differences between wildtype and KO we showed that pharmacological ERK1/2 mice. All together, these observations showed a inhibition in mice and in SH-SY5Y cells did not predisposition for VMAT2DBHcre KO mice to reduce basal levels of phospho-Tau or exhibit an altered susceptibility to developing hypothermia-induced Tau hyperphosphorylation. anxiety and depression related psychiatric We also found that treating cells with the disorders. specific MEK1/2 inhibitor PD0325901 prevented 55

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28

1-C-95 Calretinin striatal interneurons: sustain neuronal health. Disrupted mitochondrial characterization and distribution in a murine trafficking may play a role in neurodegenerative model of Parkinson's disease diseases. In our study we investigated the impact of changing mitochondrial motility on Sarah Petryszyn¹, Dave Gagnon¹, Jean- mitochondrial form and function using disruptors Martin Beaulieu¹, André Parent¹, Martin of kinesin and dynein mediated transport in Parent¹ cultured neurons. The elongated morphology of ¹Centre de recherche de l’Institut universitaire a mitochondrion is maintained by a balance en santé mentale de Québec between fission and fusion. Following disruption of molecular motors, mitochondrial motility, Despite their small number, interneurons play a morphology, ROS and ATP production were crucial role in the organization of the striatum, a examined by fluorescence microscopy. In major basal ganglia integrator that is severely addition to the expected disruption of transport, affected in Parkinson's disease (PD). Here we we found that mitochondrial morphology was compare the state of striatal interneurons profoundly affected, displaying a punctate form. expressing the calcium binding protein calretinin We also found that punctate mitochondria (CR) in both normal and PD (6-OHDA) produced differing levels of ROS and ATP. conditions in mice. Immunostaining for CR Interestingly, neurons with disrupted kinesin revealed the presence of two morphological transport exhibited greater survival than controls distinct types of CR striatal interneurons (CR1 after excitotoxic treatment. Our results suggest a and CR2), whose distribution and density were novel role for molecular motors. In addition to determined stereologically in normal, sham and mediating mitochondrial transport, motors may 6-OHDA-injected mice. The CR1 cells were play a role in the mechanism of regulating small (9-12 µm), round and intensely mitochondrial morphology. Furthermore our fluorescent, they had beaded processes and results suggest that molecular motor mediated abounded in the rostral striatum, whereas CR2 mitochondrial dynamics may play an important neurons were larger (15-20 µm), less intensely role in regulating various mitochondrial functions fluorescent, had poorly branched dendrites and and in turn cellular health. were more uniformly distributed than CR1 cells. Immunostaining for CR in BAC double 1-C-97 Synaptic Transmission is transgenic mice expressing tdTomato protein Depressed in Sympathetic but not under the control of dopamine D1 receptor Parasympathetic Ganglia of Diabetic Mice promoter and GFP under the control of D2 due to Different Susceptibility to Oxidative promoter showed that CR1 and CR2 cells are Stress devoid of D1 or D2 receptors. In PD mice, no major difference in the density of CR1 cells was Alona Rudchenko¹, Eli Akude¹, Ellis Cooper¹ detected between intact and 6-OHDA-lesioned ¹McGill University sides, or between sham and lesioned animals. In contrast, the CR2 cell density was decreased Excitatory cholinergic-nicotinic synapses in in both intact and lesioned sides in 6-OHDA- autonomic ganglia form a vital link between the injected mice, as compared to shams. The integrative activities of the CNS and peripheral present study has provided the first detailed autonomic effector mechanisms. Normally, description in mouse of a unique population of these synapses produce large suprathreshold striatal interneurons that might play a crucial role EPSPs; however, recently, we reported that in in the functional organization of the basal diabetic mice, synaptic transmission in ganglia. sympathetic ganglia is depressed. We showed that hyperglycemia elevates reactive oxygen 1-C-96 Impact of molecular motor species (ROS) in sympathetic neurons, causing disruption on mitochondrial dynamics and the postsynaptic α3-containing nicotinic function receptors to inactivate. The question is: how widespread is this mechanism in the autonomic Diepiriye Iworima¹, Justin Lardizabal¹, nervous system? To address these issues we Gordon Rintoul¹ have studied synaptic transmission in three ¹Simon Fraser University branches of the autonomic nervous system: a prevertebral sympathetic ganglion, the superior Due to the unique architecture of neurons, mesenteric; a parasympathetic ganglion, the trafficking of mitochondria throughout processes submandibular; and the adrenal medulla. In all to regions of high energetic demand is critical to three, we find that the nerve-evoked EPSPs are 56

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 mediated by α3-containing nAChRs. Synaptic to chronic phase. These changes may represent transmission is markedly depressed in the biomarkers of epileptogenicity in MTLE. superior mesenteric ganglia and in the adrenal medulla within 1 week of diabetes. 1-C-99 The Parkinson disease gene Unexpectedly, however, synaptic transmission LRRK2 works in concert with clathrin-light in the parasympathetic submandibular ganglion chains to limit activation of Rac1 is only marginally affected by diabetes, even after 4 months. Using combined ROS imaging Andrea Schreij¹, Mathilde Chaineau¹, Edward and electrophysiology, we show that this Fon¹, Peter McPherson¹ differential effect on synaptic transmission ¹McGill University occurs because sympathetic neurons are more vulnerable to hyperglycemia-induced oxidative Mutations in leucine-rich repeat kinase 2 stress than parasympathetic neurons. (LRRK2) are the most common cause of Supported by JDRF, CIHR, NSERC. dominant-inherited and sporadic Parkinson disease yet our understanding of the 1-C-98 Dynamics of interictal spikes and physiological function(s) of LRRK2 remains high-frequency oscillations during incomplete. LRRK2 is a large molecular weight epileptogenesis in temporal lobe epilepsy protein composed of multiple modules including a Ras of complex proteins (ROC) domain, a Pariya Salami¹, Maxime Lévesque¹, Ruba functional GTPase. Using affinity-selection Benini¹, Charels Behr¹, Jean Gotman¹, assays with the isolated ROC domain we Massimo Avoli¹ identified clathrin-light chains (CLCs) as novel ¹McGill University LRRK2-binding partners and mapped LRRK2 binding to a 10-residue stretch in the C-terminal Mesial temporal lobe epilepsy (MTLE) is region of CLCs. We previously demonstrated characterized in humans and in animal models that CLCs, through an unknown mechanism by a seizure-free latent phase that follows an function as inhibitors of actin polymerization. We initial insult and is associated to plastic changes now demonstrate that knock down of CLCs in temporal lobe excitability. Here, Sprague- and/or LRRK2 enhance activation of Rac1, but Dawley rats were implanted with electrodes in not Cdc42 and lead to alterations in cell the hippocampus CA3 region and entorhinal morphology. LRRK2 expression rescues Rac1 cortex (EC), after a pilocarpine-induced status activation and cell morphology changes epilepticus. EEG recordings and video- resulting from CLC knock down, placing LRRK2 monitoring were then performed to study the downstream of CLCs. Our data reveal a novel occurrence of interictal spikes and high pathway in which CLCs function upstream of frequency oscillations (HFOs; ripples: 80-200 LRRK2 to control Rac1 activation. Hz, fast ripples: 250-500 Hz) from 48 h before to 96 h after the first seizure. Interictal spikes were 1-C-100 Characterization of cognitive classified as type 1 (characterized by a spike function in the 3xTg-AD mouse model of followed by a wave) or type 2 (characterized by Alzheimer's disease at 6 months of age a spike with no wave). We found a switch in the distribution of both types of interictal spikes Kurt Stover¹, Mackenzie Campbell¹, Christine before and after the first seizure: during the Van Winssen¹, Richard Brown¹ latent phase both types of interictal spikes ¹Dalhousie University predominated in EC whereas during the chronic phase they predominated in CA3. In addition, The 3xTg-AD strain is a commonly used mouse type 2 spike duration decreased in both areas model of Alzheimer's disease (AD). These mice from latent to chronic phase. HFO analysis have three transgenes, two associated with showed that type 2 spikes associated to fast familiar AD, APPswe and PS1M1461, and one ripples occurred during the latent phase at associated with tau pathology, Tau301L. higher rates in EC than in CA3 but at similar Currently, there are conflicting reports about rates in both areas in the chronic phase. Finally, when this strain develops cognitive deficits, and rates of fast ripples outside of spikes were the nature of these deficits. Therefore, we tested higher in EC than in CA3 during the latent male and female 3xTg-AD mice and their phase. Our findings demonstrate dynamic wildtype (WT) controls (B6129S/F2) at six changes in interictal spike and HFO expression months of age on a battery of tests to determine in EC and CA3 during the transition from latent which cognitive deficits are present in these mice at this age and to determine which 57

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 behavioural tests are the most sensitive for Thus it is possible to use FRET to monitor detecting these deficits. Our preliminary results conformational changes in parkin. indicate that there were no differences between the 3xTg-AD and WT control mice in 1-C-102 Longitudinal imaging of spontaneous alternation behaviour in the Y- thalamocortical projections after stroke maze, a test of spatial memory, or in a novel object recognition task with a 15-minute delay, Kelly Tennant¹, Craig Brown¹ which is a task that measures short-term ¹University of Victoria memory. Interestingly, the 3xTg-AD mice spent more time freezing than WT control mice in cued The large majority of stroke survivors must cope fear conditioning, which may indicate they have with chronic disability, often affecting the upper enhanced fear learning. However this could also limbs. Improved use of the stroke-affected limb be a result of a higher level of anxiety in 3xTg- is accompanied by neuroplasticity in peri-infarct AD mice. In the Barnes maze, 3xTg-AD made areas. Modulating this plasticity should promote more errors than the control mice at the end of further gains in recovery. One largely unknown the acquisition phase, which indicates that they issue in stroke research involves the role of the have a deficit in spatial learning. Overall our thalamus, the brain's relay center for sensory preliminary findings indicate that there are information en route to the cortex, in recovery of modest deficits in spatial learning in the 3xTg- function and cortical remapping after stroke in AD at six months of age, and that the Barnes the forelimb area of the somatosensory cortex maze is most sensitive task for measuring this (FLS1). Thus, the aim of the current study was deficit. to elucidate the role of thalamocortical projections in recovery of function. We 1-C-101 Deciphering the mechanisms of hypothesized that rewiring of thalamocortical action of parkin during mitophagy using a projections to peri-infarct cortex occurs after structure-based FRET-reporter system FLS1 stroke and may be crucial for stroke recovery. Adult C57BL/6 mice underwent a Matthew Tang¹, Jean-Francois Trempe¹, surgical procedure to inject a green fluorescent Edward Fon¹ protein tagged adeno-associated virus (AAV- ¹Montreal Neurological Institute GFP) into the ventroposteriolateral nucleus of the thalamus, which sends projections to FLS1. To understand the structural basis of parkin's Immediately following virus injection, an imaging function and to gain insight its mechanism of window was implanted over forelimb and activation, Gehring and coworkers have hindlimb S1. Axon terminals and cerebral determined the structure of parkin using X-ray vasculature were imaged in vivo using two- crystallography in collaboration with our group. photon microscopy before and at various times The structure reveals that parkin exists in an after stroke to assess acute and long-term auto-inhibited state and its activation must be changes in vascular and neuronal structure and associated with conformational changes at the function. Preliminary data indicate that stroke C-terminal domain. We investigated the causes an acute loss of axonal density followed structural changes of parkin during the activation by increases in axon branching, axon length, of parkin using fluorescent probes, and set out and turnover of varicosities early after the stroke to characterize the activity of parkin in followed by later stabilization as recovery mitochondrial autophagy (mitophagy) based on progresses. insights obtained from the structure of parkin. Time-lapse fluorescent microscopy was used to 1-C-103 Increased microglial priming and examine the kinetics of wild-type and mutant perivascular macrophage density in the parkin recruitment to the mitochondria after their dorsal anterior cingulate white matter of depolarization with carbonyl cyanide m- depressed suicides chlorophenyl hydrazone (CCCP). We use a Förster Resonance Energy Transfer (FRET) - Susana Torres-Platas¹, Cristiana Cruceanu¹, reporter to monitor conformational changes in Gary Chen¹, Gustavo Turecki¹, Naguib parkin during the course of mitophagy. Mechawar¹ Preliminary experiments with the FRET reporter ¹McGill University - Douglas Hospital constructs show that labelling at specific positions does not interfere with parkin's Despite increasing evidence supporting the function, and that a FRET signal is detected. neuroinflammatory theory of depression, little is known about the distribution of microglia in 58

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 individuals suffering from major depression. In associated with compulsive drug seeking. this study, we investigated the morphology and Despite these findings, little is known about the distribution of microglia and perivascular epigenetic factors associated with cocaine macrophages in postmortem samples of dorsal dependency in humans. Of particular interest is anterior cingulate cortex (dACC) white matter. DNA methylation as it represents a mitotically Fixed dACC samples from depressed suicides stable epigenetic mark. Methods: We used (n=14) and matched sudden-death controls Reduced Representation Bisulfite Sequencing (n=8) were obtained from the Dougla-Bell (RRBS), on nucleus accumbens and caudate Canada Brain Bank. Tissue sections were tissue from dependent cocaine users and immunostained for the macrophage-specific controls, to detect differences in DNA marker IBA1, and immunoreactive (-IR) methylation. RRBS is a high throughput microglial phenotypes were assessed using a sequencing technique that enriches DNA combination of stereology and cell fragments for CpG dinucleotides, capturing morphometry, and blood vessels were promoter regions at relatively high coverage. characterized as being associated with either a Results: Our preliminary findings suggest that high or a low density of IBA1-IR perivascular DNA methylation in the striatum is lower, in macrophages. The ratio of primed over ramified some genetic regions, in cocaine dependent ("resting") microglia was significantly increased abusers than in controls. Further investigations in depressed suicides. The ratios of reactive and will determine the cell-type specific pattern of amoeboid microglia over ramified microglia, these changes. however, remained statistically similar between groups. Strikingly, the proportion blood vessels 1-C-105 Betacellulin regulates the that were surrounded by a high density of formation of myelin incisures and perivascular macrophages was more than twice conduction of nerve impulses in the as high in depressed suicides than in controls regenerating peripheral nerve (87% vs 42%, respectively), and this difference was strongly significant. These results suggest a Linda Xiang Wang¹, Nicolas Vallières¹, Erik higher incidence of microglial priming and Bélanger², Louise Thiry¹, Daniel Côté², increased densities of perivascular Frédéric Bretzner¹, Steve Lacroix¹ macrophages around blood-vessels in dACC ¹Centre de recherche du CHU de Québec - white matter of depressed suicides, and support CHUL, ²Institut universitaire de santé mentale the notion of central neuroinflammatory de Québec processes in depression and suicide. When a nerve fiber is cut or crushed, the axon 1-C-104 DNA Methylation in the Striatum segment that is separated from the soma of Dependent Cocaine Abusers degenerates distal from the injury in a process termed Wallerian degeneration (WD). Ola/WldS Kathryn Vaillancourt¹, Gang Chen¹, Alpha mutant mice exhibit delays in WD, resulting in Diallo¹, Carl Ernst¹, Deborah Mash², Gustavo considerable lags in clearance of inhibitors of Turecki¹ axonal regeneration that are associated with ¹McGill Group for Suicide Studies, McGill myelin debris, thereby delaying nerve University, ²University of Miami School of regeneration. In our previous work, thousands of Medicine genes were screened by DNA microarrays and >500 transcripts were found differentially Background: Cocaine dependency, like many expressed in Ola/WldS compared with wild-type psychiatric conditions, is characterized by mice (WT). One of these genes, betacellulin phenotypic heterogeneity and variable response (Btc), was selected as it was yet to treatment. While genome-wide association uncharacterized in the nervous system, despite studies have identified common variants being known as a ligand of the ErbB receptor associated with addiction, they fail to explain all family, which play a key role in remyelination. the biological variation associated with these The goal of our study was therefore to disorders. Epigenetics, chemical modifications investigate the role of Btc in WD, nerve to the structure of DNA without changing the regeneration and remyelination. First, we genetic sequence, may explain some of the compared recovery of locomotor function in variability. Animal studies describe numerous mice deficient in Btc, transgenic mice epigenetic alterations in response to chronic overexpressing Btc (Tg-Btc) and their respective cocaine administration. Importantly, these WT littermates after a sciatic nerve crush injury. modifications relate to behavioral changes We found that Btc overexpression improved 59

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 recovery 7, 14 and 21 days post-injury. Using Coherent anti-Stokes Raman spectroscopy to 1-C-107 Impact of Bronchopulmonary visualize Schmidt-Lanterman clefts and nodes of Dysplasia on Brain Development Ranvier, we showed that Tg-Btc have increased numbers of myelin incisures compared to WT. Laurel Stephens¹, Zehra Khoja¹, Megan Ex vivo electrophysiology analysis further O'Reilly², Farah Eaton², Bernard Thebaud³, revealed significant differences in nerve Pia Wintermark¹ conduction velocity and excitability threshold ¹McGill University, ²University of Alberta, values between Tg-Btc and WT mice. Taken ³University of Ottawa together, these results suggest a novel regulatory role of Btc in myelin formation and Background: Many premature newborns repair. develop bronchopulmonary dysplasia (BPD), a chronic lung disease resulting from prolonged 1-C-106 The quest for early reversible mechanical ventilation and oxygen exposure. changes in Alzheimer's disease: mass BPD survivors typically suffer long-term injury to spectrometric imaging of gangliosides in a the lungs, but also to the brain. However, it is novel transgenic rat model of prodromal AD currently not clear if the brain injury in these newborns is related only to their prematurity, or Nina Weishaupt¹, David Cechetto¹, Vladimir also to BPD. Objective: We investigated whether Hachinski², Shawn Whitehead¹ BPD has an effect on brain injury. Methods: A ¹University of Western Ontario, ²London Health rat model of BPD was used to examine the Sciences Centre, University of Western Ontario direct effect of hyperoxia on the developing brain. Rat pups were exposed to hyperoxia Identifying the earliest cellular changes that lead (95% O2) from postnatal day 4-14 (P4-14); at to Alzheimer's disease (AD) is an important step P14, rats were then housed in room air until two towards preventing the disease. In search of months of age. Controls were only exposed to such changes, we investigate membrane lipids room air. At two months of age, rats were called gangliosides that are essential for cell sacrificed and their brains extracted. signaling and survival. The expression pattern of Hematoxylin & Eosin staining was performed on ganglioside species can change in response to brain sections. Areas of different brain structures stress, and in turn, altered membrane lipid were measured and compared between the two composition can increase a cell's vulnerability. groups. Results: Hyperoxia exposure resulted in We hypothesize that changes in membrane lipid a significantly smaller corpus callosum, anterior composition, including gangliosides, may be commissure, and optic tract, compared to room evident in prodromal AD. To model the air controls. The optic chiasma also tended to be prodromal stage of AD in the elderly brain, we smaller in the hyperoxia group. Discussion: use a novel transgenic rat strain. APP21 Hyperoxia exposure seems to have a direct transgenic (tg) rats express human APPSwe/Ind impact on brain development. The rat model of in high quantities but do not develop histological BPD may be used to further study brain injuries hallmarks of AD spontaneously as they age. related to hyperoxia. Yet, these animals are susceptible to developing pathological hallmarks of AD when challenged, 1-C-108 The effects of intra-hippocampal for example with AD brain extracts. In rat brain histamine on dorsal and ventral hippocampal sections, we can image and profile gangliosides theta rhythm based on their chemical structure using matrix- associated-laser-desorption/ionization imaging Michelle Yeung¹, Emma Frieser¹, Clayton mass spectrometry (MALDI-IMS). This Dickson¹, Dallas Treit¹ innovative technology allows us to visualize ¹University of Alberta changes in ganglioside expression profiles within a neuroanatomical context, and to relate Recently it has been suggested that the these profiles to neuropathological events. A suppression of evoked hippocampal theta comparison of brain ganglioside expression frequency is a reliable neurophysiological between APP21 tg rats and wildtype rats will be signature of anxiolytic drug action. This is based presented. If our hypothesis is confirmed, an on the observation that all clinically proven intervention aimed at stabilizing membrane lipid anxiolytic drugs tested so far (benzodiazepines, composition in individuals at risk of developing 5-HT1A agonists, and SSRIs) reduce the AD may make the aging brain more resistant to frequency of reticularly-elicited dorsal neurodegenerative challenges. hippocampal theta brain rhythm, while drugs 60

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 that do not selectively affect anxiety (e.g. of TRPC3 in both store- and GqPCR-operated antipsychotics and procognitive drugs) do not channels in recombinant preparations as well as modulate theta frequency in this way. While in rat DRG neurons. Overexpression of TRPC3 considerable pharmacological evidence in rat DRG neurons resulted in a strong increase supports this model, there is emerging evidence of calcium influx upon endoplasmic reticulum that drugs belonging to different therapeutic (ER) store depletion, implicating the channel's classes (e.g. the anticonvulsant drug phenytoin, role in SOCE. This was complemented with see Yeung et al., 2012a; the bradycardic agent shRNA-mediated knockdown, where we ZD7288, see Yeung et al., 2012b), can also measured a significant decrease in calcium suppress hippocampal theta and produce robust entry following ER store depletion. Furthermore, anxiolytic effects in behavioral models of anxiety we observed a functional link between TRPC3 (e.g., the plus-maze; Yeung et al, 2012a). Here and the inflammatory metabotropic receptors we investigate the effects of intra-hippocampal P2Y2 and PAR2. Our results suggest that histamine on both dorsal and ventral elicited TRPC3 contributes to inflammatory sensitization theta rhythm. Dorsal hippocampal through both store- as well as receptor-operated microinfusions of histamine had no significant mechanisms. effect on evoked hippocampal theta frequency, but did produce behavioral anxiolysis in the 1-D-110 Cortical mechanisms for plus-maze. In contrast, ventral hippocampal transaccadic feature integration in infusions strongly increased the frequency of spatiotopic vs. Retinotopic coordinates: an evoked hippocampal theta at both the dorsal fMRIa study. and ventral level, but did not produce behavioral anxiolysis. Taken together with previous results Bianca-Ruxandra Baltaretu¹, Ben Dunkley¹, (Chee el al., 2014), our results directly challenge Simona Monaco¹, J. Douglas Crawford¹ the theta suppression model of anxiolytic drug ¹York University action. The neural substrates underlying visual D - Sensory and Motor Systems processing of object features across eye movements remain unclear. In 2013, Dunkley & 1-D-109 Contribution of TRPC3 to Crawford (SfN Abst. 2013) found that the calcium homeostasis and inflammatory bilateral supramarginal gyrus (SMG) is involved nociceptive pathways in DRG sensory in orientation discrimination of 2D images across neurons eye movements. Here, we aimed to further explore the frames of reference of orientation Hazim Alkhani¹, Ariel Ase¹, Rebecca Grant², processing. In particular, we tested whether the Dajan O'Donnell², Philippe Séguéla¹ adaptation effect to orientation in SMG is ¹McGill University, ²AstraZeneca R&D Montreal maintained also across different spatial locations. We used an fMRI adaptation Pathologically abnormal calcium levels in DRG paradigm in which participants performed an neurons are linked to sensory hyperexcitability orientation-discrimination task while fixating on and chronic pain. Tight regulation of one of two possible fixation crosses. An extracellular calcium entry is key to calcium obliquely oriented stimulus was presented in homeostasis and STIM1-dependent SOCE either the same or different orientation in two (store-operated calcium entry) has been successive events of a trial. Therefore, we implicated as a major mechanism for regulating manipulated the orientation of the stimulus in 3 intracellular calcium levels. The TRPC (transient conditions: 1) same retinotopic, different receptor potential, canonical) channel family has spatiotopic position; 2) same spatiotopic, a documented role in both store- and receptor- different retinotopic position; or 3) different operated responses linked to phospholipase C, retinotopic and spatiotopic position. Results a key pathway in inflammatory sensitization of (n=7) show adaptation to stimulus orientation in DRG neurons. Our in situ hybridization data on bilateral pre-supplementary eye fields (SEF), the distribution of the entire TRPC family right SMG and left intraparietal sulcus for showed that TRPC3 is strongly expressed in condition 1. Adaptation in condition 2 is adult rat DRG sensory neurons, particularly in observed in left SEF, hand motor area (HMA), small and medium diameter nociceptors. Using superior parietal lobe (SPL) and SMG. For ratiometric calcium imaging, pharmacology, condition 3, adaptation is seen in right pre-SEF, gene knockdown and overexpression, we left frontal eye fields, HMA, precentral gyrus, gathered evidence for a significant involvement superior frontal gyrus, SMG, SPL and inferior 61

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 parietal lobe. These results suggest a critical the cortical mechanisms underlying the role of the SMG in orientation discrimination in representation of target location and movement different frames of reference. planning have not been disentangled yet. Here we investigated the neural circuits involved in 1-D-111 A simplified up-down (SUDO) these two mechanisms by separating the method for measuring mechanical representation of target location from reach nociception in rodents using von Frey planning in a pro-/anti-reaching event-related filaments fMRI design. Subjects are shown a target location, then after a delay (target Robert Bonin¹, Cyril Bories¹, Yves De representation period) are instructed with an Koninck¹ auditory cue to perform a pro- or anti-reach. ¹CR-IUSMQ Following a 2nd delay (movement planning period), subjects perform the instructed The measurement of mechanosensitivity is a movement by reaching-to-touch a touchscreen key tool for the study of pain in animal models. with their right hand. In a control condition, This is often accomplished with the use of von subjects indicate the colour of the initial target. Frey filaments in an up-down testing paradigm. Preliminary analysis (n=3) indicates that bilateral The up-down testing method described by Dixon dorsal premotor (PMd) and extrastriate cortex as (1965) and adapted by Chaplan et al. (1994) for well as the superior parieto-occipital cortex mechanosensitivity testing in rodents remains (SPOC) and midposterior intraparietal sulcus in one of the most widely used methods for the left hemisphere show higher activation measuring pain in animals. However, this during the target representation period than the method results in animals receiving a varying colour report condition. During the movement number of stimulations, which may lead to planning period, bilateral PMd and superior animals in different groups receiving different parietal cortex, as well as SPOC and lateral testing experiences and influence their later occipital cortex (LO) in the left hemisphere, responses. To standardize this approach we show higher activity for the pro-reach condition propose a simplified up-down (SUDO) method when compared to the colour report condition. for determining PWT with von Frey filaments This suggests that although target memory and that uses a constant number of five stimuli per motor planning recruit similar parieto-frontal test. We further refined the PWT calculation to networks, parietal and occipito-temporal regions allow estimation of PWT directly from are selectively involved in one of the two behavioural response to the fifth stimulus, mechanisms. omitting the need for look-up tables. The PWT estimates derived using SUDO strongly 1-D-113 Expression of endocannabinoid correlate (r > 0.96) with the PWT estimates enzymes diacylglycerol lipase alpha determined with the conventional up-down (DAGLα) and monoacylglycerol lipase (MGL) method of Chaplan et al., and this correlation during postnatal retinal development remained very strong across different levels of tester experience, different experimental Bruno Cecyre¹, Marjorie Monette¹, Liza conditions, and in tests from both mice and rats. Beudjekian¹, Sebastien Thomas¹, Christian Finally, the use of either testing methods Casanova¹, Jean-Francois Bouchard¹ produced similar PWT estimates in behavioural ¹Université de Montréal tests with mice. SUDO thus offers an accurate, fast and user-friendly replacement for the widely In the last decades, there has been an used up-down method of Chaplan et al. increased interest in the physiological roles of the endocannabinoid (eCB) system and its 1-D-112 Cortical mechanisms for receptors, cannabinoid receptor types 1 (CB1R) reaching to a remembered visual location and 2 (CB2R). Some constituents of the eCB during target memory and motor planning system were found in the retina of several periods: an fMRI study species. To our best knowledge, no studies were conducted on the developmental David Cappadocia¹, Simona Monaco¹, Ying expression of the synthesizing and catabolic Chen¹, J. Douglas Crawford¹ enzymes of the cannabinoid endogenous ligand ¹York University 2-arachidonoylglycerol (2-AG). Due to their lipophilic nature, eCBs are synthetized on Although the human brain areas involved in demand and are not stored in vesicles. reach planning have been extensively studied, Consequently, the enzymes responsible for their 62

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 synthesis and degradation are key regulators of the physiological actions of the eCBs. Therefore, 1-D-115 Optogenetic modulation of knowing their expression pattern during GABAergic activity in mouse primary visual development is crucial for a better cortex affects contrast adaptation understanding of the role played by eCBs during the formation of the retina. We investigated the Kurt Stover¹, Jillian King¹, Kaitlyn Gordon¹, expression pattern of the enzymes responsible Nathan Crowder¹ for the synthesis (DAGLα) and the degradation ¹Dalhousie University (MGL) of the principal eCB of the retina, 2-AG, in young and adult rats. The specific aim of this Prolonged viewing of high contrast gratings study was to determine the profile of DAGLα alters perceived stimulus contrast, and produces and MGL expression for each retinal cell types, characteristic changes in the contrast response from birth to adulthood. Our results indicate that functions of neurons in the primary visual cortex DAGLα is expressed early in postnatal (V1). This phenomenon is referred to as contrast development. It is also largely expressed in the adaptation. Contrast adaptation has been retina, including in the photoreceptors, associated with membrane hyperpolarization, horizontal, amacrine, and ganglion cells. MGL although the underlying cellular and network appears later during retinal development and is mechanisms mediating this change are expressed in limited number of retinal cells. unknown. Having previously established broad Overall, these results suggest that the eCB similarities in V1 contrast adaptation between system could play a key role in the development mice and higher mammals, we sought to use a and function of the retina. mouse model of optogenetic perturbation to study a possible role for GABAergic 1-D-114 Proprioceptive Precision is interneurons in this adaptation associated Impaired in Ehlers-Danlos Syndrome hyperpolarization. We performed extracellular recordings from V1 neurons in transgenic mice Holly Clayton¹, Stephanie Jones², Denise that express channelrhodopsin-2 (ChR2) in Henriques¹ GABAergic neurons, and coupled contrast ¹York University, ²Dalhousie University adaptation stimulus protocols with V1 photostimulation. We found that optogenetic Ehlers-Danlos Syndrome (EDS) is a group of activation of GABAergic neurons when the genetic connective tissue disorders associated adapting grating was present caused a decline with collagen malformation, which is proposed to in activity during this period that altered the include Hypermobility Syndrome (HMS) and amount of adaptation observed to the test Benign Joint Hypermobility Syndrome (BJHS). stimulus. These preliminary results indicate that One of the main clinical features present in EDS the hyperpolarization produced by GABAergic is generalized joint hypermobility and it has neurons may play a role in controlling the been suggested by Rombaut (2010) that EDS magnitude of contrast adaptation in V1 neurons. patients may have proprioceptive impairments; perhaps because there is mutated collagen in 1-D-116 Loss of alpha-9 nAChR in the proprioceptors which may be providing efferent vestibular pathway affects vestibulo- suboptimal signals. Recently Clayton et al. ocular reflex responses to horizontal rotation (2013) found that EDS patients were less in mice precise in estimating their felt hand position in the peripheral workspace compared to healthy Yi Shan Wong¹, Kathleen Cullen¹ controls, and that patients who were the most ¹McGill University hypermobile were also the least precise. Here we investigated this further by testing patients Little is understood about the exact mechanism on a greater number of locations across a larger and function of the efferent vestibular system workspace. While EDS participants were just as but many parallels have been drawn from the accurate as healthy controls (as shown by efferent auditory system given their anatomical similar absolute errors), they were not as similarities. In particular, its role in modifying the precise as healthy controls. Precision of these development of the vestibular hair cells has reaches, measured by computing the areas and been proposed through cholinergic efferent axes of the elliptic fits, were all significantly innervations, much like the alpha-9 nicotinic larger for EDS than healthy controls. This acetylcholine receptor (nAChR) has been suggests a possible proprioceptive impairment implicated to do so for the inner hair cells via the in EDS. efferent auditory pathway. In order to determine 63

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 that the alpha-9 subunit of the nAChR is indeed affects the firing of SAI fibers, decreased by half functionally relevant to proper vestibular the triceps responses. AM1-43 entering cells via function, as it has been shown for auditory purinergic-2X receptors, we tested the effect of function, the vestibular-ocular reflex (VOR) in bath applications of the antagonist PPADS and mutant knock-out strains of mice was saw a decreased response to 24% of the characterized. Analysis of VOR gains in control. These results support that touch response to horizontal sinusoidal rotation sensitivity of the snout is functional in newborn demonstrated a significant decrease of opossums and may influence forelimb approximately 40% across all frequencies locomotion, possibly contributing to guiding the greater than 0.2Hz within alpha-9 knock-out animal to the nipple. mice with no consequent effects on the phase of the response. Main sequence analysis of fast- 1-D-118 SK channels convert burst phase eye movements for these mice also NMDAR-dependent LTD to LTP in showed no significant difference from wild type, communication sensory neurons thus excluding the possibility of defective eye muscle development affecting the VOR in alpha- Len Maler¹ 9 mutants. Given these results, it is evident that ¹University of Ottawa the alpha-9 subunit - found in the hair cells of the vestibular end organ as targets for vestibular Feedback and descending projections from efferent signaling - does not play a crucial role in higher brain centers play a prominent role in all proper VOR signaling and poses a likely target vertebrate sensory systems. Feedback might be for investigating the developmental role of the optimized for the specific sensory processing efferent vestibular pathway. tasks in their target brain centers, but it has been difficult to connect the properties of 1-D-117 Snout mechanosensory feedback synapses to sensory tasks. We used influence on arm extensor response in the electrosensory system of a gymnotiform fish newborn opossums, Monodelphis domestica to address this problem. Cerebellar feedback to pyramidal cells in the first central electrosensory Marie-Josee Desmarais¹, Therese Cabana¹, processing region, the electrosensory lateral line Jean-Francois Pflieger¹ lobe (ELL), is critical for canceling spatially and ¹Université de Montréal temporally redundant electrosensory input. The ELL contains four electrosensory maps and we The opossum is born very immature but crawls, have previously analyzed the synaptic and unaided, with its forelimbs from the mother's network bases of the redundancy reduction birth canal to a nipple where it attaches to mechanism in a map (CLS) involved in pursue its development. Sensory clues are electrolocation behavior. In the CLS only long- needed to guide it and trigger its attachment to term depression was induced by pairing the nipple. We have shown that stimulations of feedback presynaptic and pyramidal cell post- the trigeminal ganglion induce forelimb synaptic bursts. Here we turn to an ELL map movement, trigeminal ganglion fibers distribute (LS) known to encode electrocommunication to the facial skin and slowly adapting signals. We find remarkable differences in mechanosensory receptors Merkel cells (AM1- synaptic plasticity of the morphologically 43 positive) are present in the face epidermis. identical cerebellar feedback input to the LS. To determine the involvement of Merkel cells in Pyramidal cell SK channels permit LTP of locomotion of newborn opossums, we have feedback synapses when pre- and post-synaptic applied calibrated forces to the snout and bursts occur at the same time. We hypothesize recorded the bursts of the triceps brachii as an that LTP in this map is required for enhancing indicator of forelimb responses in in vitro the encoding of weak communication signals. preparations. Pressure applied to the face We conclude that feedback inputs that appear induced bilateral triceps responses in proportion morphologically identical in sensory maps to stimulation intensity. During consecutive dedicated to different tasks, nevertheless every 1-2 min. stimulations for 1h, the display different synaptic plasticity rules responses showed a trend toward decrease. contributing to differential sensory processing in Removing the facial skin nearly abolished the these maps. responses, indicating that the previous effects were specific to skin stimulation. Bath 1-D-119 Primary motor cortical neurons applications of the glutamate metabotropic reflect torque-related activity from ipsilateral receptor antagonist YM298198, which strongly limb 64

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28

from the pyramidal cells (PC) of three Ethan Heming¹, Stephen Scott¹ Electrosensory lateral line lobe (ELL) segments ¹Queen's University of the weakly-electric fish using well-established techniques. Simultaneously, we presented It is commonly accepted that the primary motor mimics of the envelope stimuli that occur cortex (M1) is involved in controlling naturally ranging from 0.05Hz to 10Hz. We contralateral limbs. However recent work has hypothesized that pyramidal neurons in different shown that many M1 cells respond during ELL segments will be tuned differently for lower ipsilateral as well as contralateral movement. As envelope frequencies (<1Hz) corresponding to feedback plays an important role in voluntary movement and for higher envelope frequencies motor actions, we were interested in exploring (>1Hz) corresponding instead to social whether neural activity was also related to interaction. We used quantitative data analysis mechanical perturbations applied to the techniques such as information theory in order ipsilateral and contralateral arm. For our tasks, to determine how much information about we recorded the activity of M1 cells from a envelope stimuli is transmitted by individual and micro-electrode array in a non-human primate populations of pyramidal neurons. Our results (NHP). During the task, the NHP stabilized a therefore provide new results elucidating how cursor representing its right hand at a target. envelopes are processed in the brain. After 1000ms, flexor or extensor step torques were applied to the shoulder, the elbow, or both 1-D-121 MEG gamma oscillations in (9 load conditions). The NHP had 1000ms to primary visual cortex are correlated with return and stabilize at the target for another resting GABA-A receptor density 1500ms hold period. This paradigm was repeated for the left arm, and then for both limbs Jan Kujala¹, Julien Jung², Sandrine simultaneously. We found that a large proportion Bouvard³, Carolina Ciumas², Françoise of M1 cells produce perturbation responses and Lecaignard², Romain Bouet², Philippe modulate their activity to static torque for either Ryvlin², Jerbi Karim⁴ limb. Cells often displayed preferred torque ¹O.V. Lounasmaa Lab, Aalto University, , ²Lyon directions (PTD) that were different for each Neuroscience Research Center, INSERM- arm, such as increasing firing for shoulder CNRS-University of Lyon I, ³CERMEP imaging flexion in the left arm, but increasing firing for center Lyon, ⁴Université de Montréal elbow flexion in the right arm. When torques where applied to both arms, cell PTDs tended to The mechanisms that underly cortical gamma- reflect an average of the PTDs for each arm band oscillations remain poorly understood. alone. Our results indicate that M1 represents Previous reports point to a key role of GABA- perturbation and torque-related activity from mediated inhibition (Buzsaki & Wang, 2012). both limbs. Recent studies combining magnetoencephalography (MEG) with magnetic 1-D-120 Differential neural responses to resonance spectroscopy (MRS) GABA- naturally occurring envelopes in the concentration measures suggest that the electrosensory system dominant frequency of cortical gamma- oscillations is correlated with the concentration Chengjie Huang¹, Maurice Chacron¹ of GABA at rest (Muthukumaraswamy et al., ¹McGill University 2009; Gaetz et al., 2011). To investigate the relationship between gamma oscillations and Natural sensory stimuli frequently consist of a GABA-A receptor density we recorded MEG and fine structure whose amplitude (i.e. envelope) positron emission tomography ([11C] varies more slowly. Previous studies have Flumazenil-PET) data from a population of 10 demonstrated that envelope signals are involved healthy participants. The flumazenil uptake in several sensory systems and are necessary recordings were conducted during rest, and the for perception. However, the neural mechanisms MEG data were collected during an N-back underlying the encoding of envelope signals are visual working memory task. We investigated poorly understood in general. Gymnotiform task-related modulations of gamma power and wave-type weakly electric fish constitute an performed correlation analyses between GABA- attractive model system for studying how A receptor density and both the peak frequency envelopes are processed in the brain because and amplitude of gamma power in V1. We of well-characterized anatomy and physiology. detected memory-load dependent task-induced In our study, we recorded extracellularly in vivo increases in gamma-band (60-90 Hz) power 65

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 across a widely distributed network and a 1-D-123 TRPV1 sensitization is essential notable increase in V1 gamma power. Across for the development of chronic, but not acute subjects, measures of GABA-A at rest pain following colonic inflammation correlated positively with the peak gamma frequency and negatively with gamma amplitude Tamia Lapointe¹, Robyn Flynn¹, Kevin in V1. These results extend previous MEG-MRS Chapman¹, Christophe Altier¹ findings by providing the the first direct link ¹University of Calgary between GABA-A receptor density and task- related gamma oscillations and allow us to fine- Inflammatory bowel disease (IBD) is associated tune our understanding of the link between with debilitating abdominal pain, which can GABAergic inhibition and gamma-band persist throughout quiescent phases of the oscillations. disease. While a growing body of evidence suggests a role for the transient receptor 1-D-122 Effects of transcr‚nial direct potential vanilloid 1 (TRPV1) in neurogenic current stimulation, tDCS, of primary inflammation and visceral hypersensitivity, somatosensory cortex, S1, on tactile functional studies have yet to assess its function detection. in post-inflammatory pain. This study aimed at establishing the role of TRPV1 in peripheral Sara Labbé¹, El Mehdi Meftah¹, Elaine sensitization and pain during the acute and Chapman¹ remission phases of colitis. Methods: Male ¹Université de Montréal C57BL/6 mice were separated into controls, acute DSS (2.5% DSS, 7 days), and recovery tDCS is a non-invasive technique whereby (acute DSS, followed by a five-week recovery weak, direct current stimulation is applied to period) groups. Results: Mice treated with DSS cortex. This is reported to enhance, anodal (a), showed signs of visceral pain five weeks post- or decrease, cathodal(c), cortical excitability. DSS discontinuation, at which point Few studies have tested the effects of S1 tDCS inflammation had resolved. This effect appears on tactile perception, and the results to date are to be TRPV1-dependent, as deletion of the mixed. We tested the effects of tDCS (a-, c- and channel prevented the development of visceral sham) applied to the right S1 hand pain in the remission phase of the disease. representation, 2 cm posterior to C4, on tactile Importantly, the deletion of TRPV1 failed to detection of vibration (0.5 s duration, 20Hz, alleviate both inflammation and pain in the acute amplitudes of 2, 6 and 10μm) applied to the phase of colitis. In vitro experiments revealed distal pad of the left middle finger. Tactile that prolonged exposure to substance P detection was measured before, during and after potentiates capsaicin-evoked responses by 20 min of tDCS (1mA). A bias-free signal mediating TRPV1 channel accumulation at the detection theory approach was used: half of the plasma membrane. Conclusion: Our results trials contained a stimulus; 50% had no demonstrate that although TRPV1 is not stimulus. Subjects indicated whether a stimulus required for acute inflammation and visceral was present or not and rated their degree of hypersensitivity, it plays a pivotal role in the confidence in this using a 5-point scale. These development of persistent visceral pain during data were used to generate ROC (receiver the resolution phase of colitis, and could operating characteristic) curves. The area under therefore represent an attractive therapeutic the ROC curves was calculated for each target in the management of IBD-related pain. vibrotactile intensity. From this we interpolated detection threshold (0.75). Mean baseline 1-D-124 Role of residual dorsolateral detection threshold was 4.2 μm (n=13). To date, pathways in locomotor recovery after spinal the results are variable. With a-tDCS, 4 subjects hemisection in cats showed the predicted decrease in threshold (to 61% of control), but 4 others showed an Marina Martinez¹, Eleonore Serrano², Paul increase (144% of control). With c-tDCS, the Xing², Hugo Delivet-Mongrain², Serge results were general negative (no change, 4/6). Rossignol² It is expected that the results will lead to a better ¹University of Calgary, ²University of Montreal understanding of the neuronal mechanisms underlying the effects of tDCS on tactile After an incomplete spinal cord injury (iSCI), perception. Supported by CIHR, GRSNC. locomotor recovery is achieved through changes at both supraspinal and spinal levels. However, the relative importance of these mechanisms on 66

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 locomotor recovery has never been elucidated. responses to current injection. We further show In this study, we evaluated the role of intact that ketanserin applied in vivo can block the pathways coursing in the dorsolateral funiculus effects of 5-HT on behavioral responses. Thus, (DLF) of the spinal cord which mainly contains our results show that the previously observed the cross components of the cortico- and effects of 5-HT on sensory processing within rubrospinal tracts. Our choice was based on the ELL and their consequences on behavior are fact that, in intact conditions, DLF pathways are mediated by 5-HT2 receptors. not crucial for treadmill locomotion but are known to modulate the basic locomotor rhythm 1-D-126 Training induced dynamic suggesting that they could play a compensatory filtering of auditory distractors in the rat role after iSCI through its interactions with the primary auditory cortex spinal circuitry. Four adult cats were submitted to a dual spinal lesion protocol consisting in a Kim Mirédin¹, Étienne De Villers-Sidani¹ left hemisection at T10 level followed, 3 weeks ¹McGill University later, by a lesion of the right DLF at the same spinal level. Locomotion was evaluated on a Ignoring distracting sounds becomes treadmill and overground in the intact state and increasingly difficult with aging even without then 3 weeks after each spinal lesion. We significant hearing loss. We previously showed showed that the DLF lesion abolished for at in aging rats that a reduced active inhibition of least 3 weeks (time of experiment) bilateral repetitive background sounds could explain this hindlimb locomotion that had previously impairment. However, the cortical mechanisms recovered from the hemisection. Such a involved in this dynamic contextual filtering of disruption of bilateral hindlimb locomotion sound and the experiences that alter their suggests that, after hemisection, DLF pathways specificity for complex sounds are still largely had gain the capacity to activate the muscles of unknown. Here we tested the hypothesis that both hindlimbs, probably through their filtering spectrally complex sounds would be interactions with the spinal circuitry. more robust and specific after training on an adaptive auditory task aiming to differentiate fine 1-D-125 Serotonin modulates spectral features of complex sounds. We trained electrosensory processing and behavior via young adult (6-12 months old) and aging (20-24) 5-HT2 receptors rats on such a task until performance reached plateau and then densely mapped their primary Erik Larson¹, Michael Metzen¹, Maurice auditory cortical (A1) responses to simple and Chacron¹ complex trained and untrained sounds in the ¹McGill University presence of background distractors. Similar recordings were performed in naïve untrained Efficient sensory processing of the environment rats. Our results confirmed that aging associates is a critical function for any organism to survive with poorer A1 extraction of complex sounds in and is accomplished by having neurons adapt the presence of background distractors. We also their responses to stimuli based on behavioral found in both young and aged rats that context in part through neuromodulators such as expecting to hear a specific sound made A1 serotonin (5-HT). We have recently shown that momentarily more sensitive to that sound and one critical function of the serotonergic system less sensitive to non-behaviourally relevant in weakly electric fish is to enhance sensory ones. This rapid expectation based shift in A1 pyramidal neuron responses within the tuning appeared to be mediated by increased electrosensory lateral line lobe (ELL) to a cooperativity between A1 neurons sharing initial specific stimulus class: those caused by same selectivity for the trained sound. Our findings sex conspecifics. This enhancement is indicate that distractor sensitivity in the aged accomplished by making pyramidal neurons brain can be improved by simple but targeted more excitable through downregulation of auditory training strategies. potassium channels. However, the nature of the 5-HT receptors that mediate this effect is not 1-D-127 Neural substrates involved in known. Here we show that the 5-HT2 receptor the integration of object properties and antagonist ketanserin can effectively block the intended actions effects of 5-HT on pyramidal neuron excitability in vitro. Indeed, 5-HT application subsequent to Simona Monaco¹, Ying Chen¹, Noura ketanserin application did not cause any AlOmawi¹, John Crawford¹ significant changes in neuron excitability and ¹York University 67

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28

that this reduction reflects the increasing We tested seven right-handed subjects in an influence of transcortical feedback through fMRI experiment to investigate the neural primary motor cortex (M1), which possesses substrates involved in the integration of object knowledge of the inherent properties of properties and hand actions. Subjects viewed an motorneurons. Thus, we predict that neurons in object (visual cue: VC) and received auditory primary motor cortex are responsible for the information about the action to be performed on reductions in gain scaling observed in the the object (action cue: AC) in two successive periphery. We examined this issue by phases. We manipulated the order of cue quantifying the response of muscle activity and presentation (VC:AC and AC:VC), the action M1 neurons in monkeys to similar mechanical type (Grasp or Align) and the orientation of the perturbations during a postural control task, with object (two orientations). In the VC:AC and without background loads. Similar to conditions, an object was presented for 250ms previous reports, we found that muscle activity followed by a delay of 8s. The audio cue was exhibited gain scaling in the short latency then provided and followed by a delay of 8s, response, but observed a rapid decrease in this after which a sound cued subjects to act on the scaling in the long latency epoch. Similarly, the object that was no longer visible. In the AC:VC perturbation response of M1 neurons initially conditions, the order of the cues was inverted. scaled with the size of pre-perturbation neural We hypothesized that areas involved in activity. However, we found that the initial integrating object properties and action type scaling was rapidly reversed at ~50ms post- would show higher response during the delay perturbation. Critically, this reversal following the second cue because of the added compensates for early gain scaling and integrative process of visual information into highlights the sophistication of feedback control. action planning. The posterior intraparietal sulcus (pIPS) and dorsal premotor area (dPM) in 1-D-129 Retinotopic maps and functional the left hemisphere showed higher response in properties of V1 in D2 dopamine receptor the delay following object presentation when the knockout mice action type had already been specified as opposed to when it had not. The pIPS also Bruno Oliveira Ferreira de Souza¹, Sebastien showed higher response in the delay following Thomas¹, Jean Martin Beaulieu², Christian the audio cue about action type when the object Casanova¹ had already been presented as opposed to ¹Université de Montréal, ²Institut Universitaire de when it had not. These results suggest that the Sante Mentale de Quebec fronto-parietal network is strongly involved in incorporating object properties, such as In the retina, dopamine plays a critical role in the orientation, into context cues, such as action modulation of visual information through the type. activation of D1 and D2-like receptors. Interestingly, D2 receptors are also found in the 1-D-128 The sensitivity of primary motor primary visual cortex (V1) where their function is cortex to pre-perturbation muscle activity unknown. In this study, we evaluate the impact suggests knowledge of the inherent of D2 receptor deletion (D2r-KO) on the properties of motorneurons structure and visual processing of mouse V1 using optical imaging of intrinsic signals. Data Joseph Nashed¹, Mohsen Omrani¹, J. Andrew from adult D2r-KO mice (n=12) and their wild- Pruszynski², Stephen Scott¹ type (WT) littermates (n=9) were compared. ¹Queen's University, ²University of Umea Continuous visual stimulation and frequency- based analysis were used to obtain retinotopic Following a mechanical perturbation, short- maps and to calculate V1 shape, surface, ocular latency responses (25-45 ms) will increase dominance and scatter. Sinusoidal gratings of proportional to the level of background muscle varying spatial frequency (SF) and contrast activity. This 'gain scaling' is thought to be due values were used to evaluate population SF to the properties of motoneurons. Counteracting selectivity and contrast response function. No this property poses a challenge for the nervous abnormalities were observed in D2r-KO system, which must ultimately counter the retinotopic maps and no difference was absolute change in load regardless of the initial observed between the various parameters muscle activity. We recently showed that this calculated from the maps. Furthermore, no gain scaling diminishes throughout the long difference in the contrast response function was latency response (50-105 ms). Our hypothesis is observed between the 2 groups. However, the 68

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 optimal SF was higher for D2r-KO mice when compared to the WT group (0.031 cpd ± 0.002 1-D-131 Investigating the transformation vs. 0.023 cpd ± 0.002, p<0.05, Student's t-test), from a dense to a sparse neural code consistent with a rightward shift of the SF selectivity curve and higher SF selectivity cut-off Michael Sproule¹, Maurice Chacron¹ (0.138 cpd ± 0.010 in D2r-KO vs. 0.094 cpd ± ¹McGill University 0.010 WT, p<0.01, Student's t-test). Our results suggest that D2 receptors do not contribute to A fundamental operation performed by sensory the structure and connectivity of V1 but may systems is the transformation from a dense modulate response properties such as spatial neural code in the periphery to a sparse code frequency selectivity of the comprising neurons. more centrally such that populations of 'dense coding' neurons which, encode a broad range of 1-D-130 Properties of synaptic inputs stimulus features project to populations of from hair cells and efferents onto the 'sparse coding' neurons that respond selectively vestibular afferent calyx terminals to particular stimulus features. Previous investigations have established that such a Soroush Sadeghi¹, Zhou Yu², Sonja Pyott³, transformation occurs at the level of the Elisabeth Glowatzki² midbrain in the well characterized ¹University at Buffalo, ²Johns Hopkins School of electrosensory system of the weakly electric fish Medicine, ³University of North Carolina Apteronotus leptorhynchus. Here we aimed to Wilmington uncover the mechanisms underlying this transformation. Patch clamp recordings were Calyx afferent terminals completely cover the made from neurons within the midbrain Torus basolateral walls of hair cells and receive inputs Semicircularis (TS) in response to natural from multiple hair cell ribbons as well as efferent electrosensory stimuli and were filled with fibers (mainly cholinergic). To investigate the biocytin for post hoc identification of previously synaptic properties of these inputs, in vitro established cell types. We found that toral whole-cell patch-clamp recordings were neurons form different classes based on their performed from calyces in cristae of 2-4 week responses, some classes distinctly sparse and old rats. AMPA-mediated postsynaptic currents others dense. Additionally, we found that these showed an unusually wide range of decay time classes correspond to distinct cell types. Cluster constants (< 5 to > 500 ms). Decay time analysis revealed several groups of sparse constants increased (or decreased) in the coding and dense coding neurons based on presence of a glutamate transporter blocker (or response profiles to an ensemble of a competitive glutamate receptor blocker), behaviourally relevant stimuli. Our results reveal suggesting glutamate accumulation and that dense coding and sparse coding neurons spillover. Glutamate accumulation increased correspond to different cell types within the TS. firing rates of calyces by slowly depolarizing them. To investigate acetylcholine (ACh) 1-D-132 Modulation of stimulus saliency receptors mediating efferent inputs, 1 mM ACh on human pupil orienting response was applied. About 56% of calyces (n = 75) showed an inward current at a negative holding Chin-An Wang¹, Douglas Munoz¹ potential, which reversed at ~0 mV (n = 7). ¹Queens University Presence of 10 µM tubocurarine, 10 µM strychnine, 400 nM α-BTX (n = 3 for each) or The sudden appearance of a salient stimulus 600 nM α-RgIA (n = 5) resulted in an ~80% initiates a series of responses to orient the body block. Thus, excitatory efferent inputs to the for appropriate actions, including not only shifts calyx are most likely mediated by α9-containing of gaze and attention, but also transient pupil receptors. Together, these findings suggests dilation. Modulation of pupil dynamics by glutamate accumulation/spillover and cholinergic stimulus saliency is less understood, although inputs function as gain control mechanisms in its effects on other components of orienting the majority of the calyces. Further studies are have been extensively explored. required to investigate whether other efferent Microstimulation of the superior colliculus (SC) fibers (e.g., glycinergic) also play a role in these evoked transient pupil dilation, and the initial and the calyces without any ACh response. This component of pupil dilation evoked by work was supported by NIDCD grants microstimulation was similar to that elicited by R01DC006476 and R01DC012957 to EG and a the presentation of salient sensory stimuli, NOHR grant to SGS. suggesting a coordinated role of the SC on this 69

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 behavior, although evidence in humans is yet to show evidence for anxiety or depressive-like be established. To examine pupil orienting behaviors, as measured by social interaction responses in humans, we presented visual and open field test. Thus, we propose a novel stimuli while participants fixated on a central compound to be further investigated for the visual spot. Transient pupil dilation in humans potential treatment of metabolic disorders was elicited after presentation of a salient visual associated with body weight gain and adiposity. stimulus in the periphery. The evoked pupil responses were modulated systematically by 1-E-134 Role of Acyl-CoA Binding stimulus contrast, with faster and larger pupil Protein (ACBP) in Hypothalamic Control of responses triggered by higher contrast stimuli. Energy Homeostasis The saliency modulation was pronounced under different levels of baseline pupil size. The pupil Lionel Budry¹, Khalil Bouyakdan¹, Bouchra response onset latencies for high contrast Taib¹, Nusrat Dewan¹, Ann-Britt Marcher², stimuli were comparable to those produced by Maria Bloksgaard², Susanne Mandrup², Luc the light reflex and much faster than the Pénicaud³, Xavier Fioramonti³, Thierry darkness reflex, suggesting that the initial Alquier¹ component of pupil dilation is more likely ¹CHUM research center, ²Syddansk Universitet, mediated by inhibition of the parasympathetic ³Université de Bourgogne pathway. Together, our results suggest that the orienting pupil response in humans is modulated The control of energy balance mainly relies on by stimulus saliency. the hypothalamus and its capacity to detect nutritional signals including glucose and fatty E - Homeostatic and Neuroendocrine acids (FA). FA act in the mediobasal Systems hypothalamus (MBH) to inhibit food intake and glucose production, but the mechanisms and 1-E-133 Novel putative GOAT Inhibitor, cell types involved have not been identified. CF801, Reduces Acylated Ghrelin & Body ACBP binds fatty acyl-CoA with high affinity and Weight in C57/BL6J Male Mice regulates their metabolism in the periphery. In the central nervous system (CNS), ACBP is Zack Patterson¹, Martin Wellman¹, Alfonso secreted by astrocytes and central Abizaid¹ administration of ACBP has anorectic effects ¹Carleton University and increases glucose tolerance. Our preliminary results suggest that ACBP Ghrelin is a 28 amino-acid peptide implicated in modulates intracellular FA metabolism in the regulation of food intake and body weight. cultured astrocytes. Altogether this suggests a Ghrelin serves a wide range of physiological role for ACBP in central FA action and control of roles including the promotion of food intake and energy homeostasis. First, we show that ACBP adiposity. Once secreted, ghrelin binds to the is mainly expressed in astrocytes and tanycytes groth hormone secretagogue receptor (GHSR), in the MBH. Second, we generated an to increase food intake and body weight. The astrocyte-specific ACBP KO using the Cre-Lox ability of ghrelin to bind to the GHSR is strategy, ACBP-GFAP KO mice, and assessed dependent on a post-translation modification of their metabolic status and feeding behavior. Our the mature ghrelin protein, wherein an n- results show that astrocyte-specific deletion of octanoic acid is added to the third serine residue ACBP does not affect food intake, satiety, on the ghrelin molecule through the activity of weight gain or glucose tolerance in male mice the ghrelin-O-acyl-transferase (GOAT) enzyme. fed with a regular chow or high fat diet (HFD). Here we present a novel peptide, CF801 (patent Female mice however have a tendency for pending), that decreases acylated ghrelin increased weight gain and fat mass when fed concentrations in vivo potentially through the HFD without changes in food intake. Additional inhibition of GOAT. Intraperitoneal behavioral and metabolic phenotyping is administration of CF801 reduced circulating ongoing to assess the impact of ACBP deletion plasma acylated ghrelin levels, body mass and in astrocytes on glucose and energy total adipose tissue mass in mice, relative to homeostasis. Our results suggest that ACBP animals receiving vehicle-injections. deficiency in astrocytes increases the Furthermore, CF801 administration reduced susceptibility to diet-induced obesity in a caloric intake following an overnight fast in a gender-specific manner. dose dependent fashion, relative to vehicle- injected controls. CF801 treated animals did not 70

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28

1-E-135 Transgenerational transmission increase their electrical activity in response to of maternal care via the regulation of increased glucose level. Despite their suggested estrogen receptor alpha role in the control of glucose homeostasis, molecular mechanisms involved in HGE neuron Sabine Dhir¹, Tie Yuan Zhang¹, Josie Diorio¹, glucose response are unknown. Reactive Michael Meaney¹ Oxygen Species (ROS) are produced into the ¹Douglas Mental Health University Institute MBH in response to increased blood glucose level and necessary for glucose detection. Variations in maternal behavior influence the Interestingly, some transient receptor potential development of multiple biological systems in canonical (TRPC) channels are ROS-sensitive. the offspring and such traits are transmitted from Thus, we hypothesized that HGE neuron detect one generation to the next through genomic as glucose through a ROS-TRPC signaling well as nongenomic processes. Female rats will pathway. Activity of freshly dissociated rat MBH exhibit high levels of maternal behaviors cells was monitored by Fura-2 calcium imaging towards their offspring when reared by mothers in response to increased extracellular glucose who display high levels of maternal licking and level from 2.5 to 10 mM. We found that ~100% grooming (i.e. High LG). High LG offspring have of MBH HGE neurons responses to increased increased mRNA and protein levels of estrogen glucose are inhibited by antioxidants or the non- receptor alpha (Esr1) in the medial preoptic area selective TRPC channel inhibitor (SKF96365). (mPOA) when compared to Low LG offspring. Interestingly, ~70% of HGE glucose responses We aimed to assess the functional role of Esr1 are inhibited by the TRPC3 channel inhibitor expression in the mPOA on maternal behavior. Pyr3 or activated by the TRPC3 activator OAG, Lentiviral shRNAs targeting Esr1 were injected suggesting that this specific channel is involved into the mPOA of High and Low LG dams. After in the majority of MBH HGE neurons glucose reducing protein and mRNA Esr1 expression in response. TRPC channel expression in HGE the mPOA of High LG dams, there was a neurons is being explored by single-cell RT- significant decrease in maternal behavior such PCR. Finally, pharmacological inhibition of that their maternal LG resembled the levels TRPC3 channel into the MBH in vivo decreases seen in Low LG reared dams. Offspring of both insulin secretion in response to increased brain groups had decreases in Esr1 expression in the glucose level. Altogether, these data suggest mPOA and a decreased pup LG. Thus, we were that ROS-TRPC3 signaling is implicated in MBH able to disrupt the transgenerational HGE glucose sensitivity and cerebral control of transmission of both Esr1 expression and pup glucose homeostasis. LG. We then analyzed histone modifications and histone binding proteins in the mPOA, and found 1-E-137 A novel circuit for stress significant differences in the Esr1 promoter termination region of High and Low LG offspring in acetylation and methylation determining histone Tamás Füzesi¹, Jaclyn Wamsteeker Cusulin¹, marks. These studies demonstrate that Amy Li¹, Jaideep Bains¹ expression of Esr1 in the mPOA in female ¹University of Calgary offspring of High LG dams is critical for the transgenerational transmission of individual Responding appropriately to a stressor is differences in LG and is epigenetically necessary for survival; it requires rapid regulated. recruitment of neural and endocrine systems to meet an impending challenge. This response is 1-E-136 Involvement of Reactive Oxygen well understood, but represents only the Species (ROS) and Transient Receptor engagement component of the stress response. Potential Canonical (TRPC) in glucose By contrast, very little is known about the neural sensitivity of hypothalamic neuron. circuits responsible for terminating the stress response. The termination is usually associated Chloé Chrétien¹, Claire Fenech¹, Sylvie Grall¹, with a series of behaviours, such as grooming in Luc Pénicaud¹, Corinne Leloup¹, Xavier rodents that serve a de-arousal function Fioramonti¹ following stress. We hypothesized that the ¹UMR 6265 CNRS, 1324 INRA-uB principal drivers of the visceral stress response, the corticotrophin-releasing hormone (CRH) The mediobasal hypothalamus (MBH) houses neurons in the paraventricular nucleus of the specific glucose-sensitive neurons known as hypothalamus (PVN) may also contribute to dis- high-glucose excited (HGE) neurons which engagement following stress. We utilized a 71

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 transgenic CRH-Cre mouse strain and targeted - an effect blocked by phloretin, and reduced the PVN CRH neurons with recombinant adeno- amplitude but not the frequency of mEPSCs. associated virus carrying channelrhodopsin 2. In Together, the findings suggest that oleate in the vivo stimulation of PVN CRH neurons with blue VTA has anorectic actions that may involve light induced rapid and robust grooming. There intracellular transport of FA and inhibition of DA was an inverse relation between grooming and neurotransmission and offer a means whereby the anxiety state of the animal. In order to dietary FA may directly modulate brain reward elucidate the neural circuit(s) responsible for circuitry. Supported by CIHR stimulated grooming, we traced CRH fibers and identified neurons in the perifornical area/lateral 1-E-139 Optogenetic dissection of the hypothalamus. Using whole-cell patch clamp MCH system: implications for sleep-state recordings, we determined that these cells modulation. receive glutamatergic input from PVN CRH neurons. Our data provide evidence that PVN Sonia Jego¹, Stephen Glasgow¹, Carolina CRH neurons, serve a dual function, Gutierrez Herrera¹, Richard Boyce¹, Sean contributing to both the launch of the visceral Reed¹, Antoine Adamantidis¹ response to stress and driving behaviours that ¹McGill University contribute to the termination of the stress response. The hypothalamus consists of intermingled inhibitory and excitatory neural circuits. Their 1-E-138 The monounsaturated fatty acid activity correlates with one or more vigilance oleate in the ventral tegmental area inhibits states, including wakefulness, non-Rapid Eye food intake and dopamine Movement (REM) sleep and REM sleep. Recent neurotransmission evidence suggests that neurons expressing Melanin-Concentrating Hormone (MCH) have a Cecile Hryhorczuk¹, Zhenyu Sheng², Vanessa sleep-promoting action; however, their selective Routh², Thierry Alquier¹, Stephanie Fulton¹ modulation of sleep states remains unclear. To ¹University of Montreal, ²Rutgers New Jersey investigate the specific role of MCH neurons, we Medical School genetically targeted the expression of activatory (ChETA, SSFO) and inhibitory (eNpHR3.0) Dopamine (DA) neurons of the ventral tegmental optogenetic tools to MCH neurons to reliably area (VTA) are critical for the control of control their activity in vitro and in vivo. Using motivation and reward-relevant behaviors. real-time EEG/EMG detection of vigilance Evidence that DA neurons respond to hormones states, we found that optical activation of MCH like leptin, ghrelin and insulin to modulate neurons during NREM sleep increased the feeding, reward-relevant behavior and DA tone probability of NREM-to-REM sleep transitions, raises the possibility that, as in the while MCH neuron activation during REM sleep hypothalamus, cells of the VTA act as metabolic extended its duration in ChETA animals sensors that integrate both hormonal and compared to EYFP-expressing controls. These nutrient signals. The aim of the present work results were confirmed by SSFO activation of was to evaluate the impact of long-chain fatty MCH neurons in vivo. In contrast, we showed acids (FA) in the VTA on feeding and DA that optogenetic silencing of MCH neurons neurotransmission. Methods: Following during REM sleep significantly reduced theta stereotaxic implantation of a double cannula into rhythm amplitude concomitant to an increase of the VTA, male Wistar rats (n=12-15/group) slow theta range amplitude (3-5 Hz). Finally, we received either vehicle (2-HydroxyPropyl-β- demonstrated that optical activation of MCH cyclodextrin (HPB) in ACSF; 500nl), oleate terminals induced fast GABAA-mediated (12mM; monounsaturated FA) or palmitate inhibitory currents in local wake-promoting (12mM; saturated FA). Patch clamp recordings histaminergic neurons, an effect that is partly were made in rat VTA slices preparations mediated by the release of MCH peptide. perifused with oleate (6µM, 2.5mM glucose; Collectively, these results support a causal role n=15) or oleate+phloretin (6µM; 2.5mM glucose; for MCH neurons in the onset and maintenance 100µM phloretin; n=6), to block fatty acid of cortical REM sleep in the mammalian brain. transport. Results and conclusion: Behavioral results show that a single injection of oleate, but 1-E-140 Alterations in Hypothalamic not palmitate, in the VTA significantly decreased Feeding Circuitry and Leptin Response in dark cycle chow intake. Oleate significantly CD-1 Mice Perinatally Exposed to the inhibited firing in ~50% of DA neurons recorded Endocrine Disruptor Bisphenol-A (BPA) 72

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effects on hippocampal dendrites, suggesting a Harry MacKay¹, Zachary Patterson¹, Rim possible species difference. To test this Khazall¹, Alfonso Abizaid¹ hypothesis, we examined the effects of GDX on ¹Carleton University dendritic branching patterns and dendritic spine density in CA1 and CA3 pyramidal neurons of Bisphenol-A (BPA) is a component of adult male mice. The brains of CD-1 mice were polycarbonate plastic, and is commonly found in removed and stained using the Golgi-Cox food and drink containers. BPA has been method 21 days after either GDX or sham- characterized as an endocrine disruptor capable operation. Sholl analysis was used to assess of acting as a xenoestrogen and an obesogen in dendritic branching of 3-dimensionally traced a variety of experimental models. Given the pyramidal neurons in 300um thick coronal sensitivity of the developing hypothalamus to the sections. These same sections were used to organizational effects of sex steroids, we measure dendritic spine density in the proximal, hypothesized that early-life BPA exposure medial, and distal regions of the apical dendrites adversely affects the development of of CA1 and CA3. Results show a small overall hypothalamic feeding circuitry in order to bring decline in dendritic spine density in CA1 and about an obesity-prone phenotype. To test this, CA3 following GDX, similar to what has been we used male and female CD-1 mice exposed observed in the rat. However, Sholl analysis via maternal diet to either a control diet, a diet revealed a decline in dendritic branching in both containing BPA (appx. 13.5 µg/kg/day), or the CA1 and CA3, without an effect on dendritic estrogenic diethylstilbestrol (DES) as a positive length. This result is consistent with previously control (appx. 3 µg/kg/day) during pregnancy observed effects of manipulating androgen and lactation. Adult male BPA-exposed offspring levels in mice, supporting the view that mice and weaned onto a control diet had impaired glucose rats may show very different hippocampal tolerance and reduced pro-opiomelanocortin responses to changes in circulating androgen (POMC) innervation into the hypothalamic levels. [Supported by NSERC 197293-2007 and paraventricular nucleus (PVN) relative to control CFI 30381] animals. Adult BPA exposed females became hyperphagic and obese when exposed to a 1-E-142 Infusions of ghrelin into the high-fat diet, and showed no evidence of POMC medial preoptic area inhibits appetitive up-regulation in the hypothalamus, nor a drop in sexual behaviour and shortens copulatory body weight in response to exogenous leptin. behaviours in the male rat Serum from pups was collected on PND2, 8, 10, 12, 16, and 21 for analysis of circulating leptin. Stephanie Rosenbaum¹, Daniel Palacios², Results from this study show that BPA and DES Matthew Graham², James Pfaus², Alfonso exposed pups have respectively delayed and Abizaid¹ blunted postnatal leptin surges - a state of ¹Carleton University, ²Concordia University affairs that points to a role for leptin in the organizational effects of early-life xenoestrogen Ghrelin, an orexigenic peptide, has been shown exposure. to play an inhibitory role on the hypothalamic pituitary gonadal axis as well as overall 1-E-141 The effects of gonadectomy on reproductive physiology. The role of ghrelin on hippocampal dendritic spine density and rodent sexual behaviour, however, has not been branching in adult male mice investigated. The medial preoptic area (mPOA) has been shown to be an important region in Dallan McMahon¹, Sarah Atwi¹, Craig Bailey¹, mediating male sexual behaviour by integrating Neil MacLusky¹ environmental and internal physiological stimuli ¹University of Guelph and has been shown to contain receptors for ghrelin. Interestingly, no definitive role for ghrelin The effects of androgens on hippocampal in the mPOA has been elucidated. Here we morphology and function are poorly understood. investigated the role of mPOA ghrelin receptors Gonadectomy (GDX) induces a small decline in in mediating male rat sexual behaviours, both dendritic spine density in CA1 and CA3 in adult appetitive and consummatory. Sexually- male rats, accompanied by an outgrowth and experienced male Long-Evans rats were increase in branching of apical dendrites of implanted with bilateral cannulae aimed at the neurons located in the CA3 pyramidal cell layer. mPOA and a week later received micro- In mice, by contrast, previous work has infusions of ghrelin (1μg/ul) or saline (1μl) into suggested that androgen may have trophic the mPOA, prior to access to a sexually 73

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 receptive female. We observed that ghrelin- pro-cognitive effect. The results of this study infused animals displayed less activity in clarify the comorbidity between anticipation to a receptive female, as measured cannabis/tobacco use and the expression of by level changes in the bi-level chamber psychotic symptoms as well as the possible role apparatus (p < .05). Further, males receiving of cannabinoid-nicotinic receptor interactions in ghrelin displayed shorter latencies to their first schizophrenia-like CIs. ejaculation compared to saline animals(p < .05). Finally, no significant difference in food intake 1-F-144 Investigation of the role of was seen 1-, 2-, or 24-hours post-testing across insulin deficiency and loss of PI3K-AKT all groups, suggesting that ghrelin in the mPOA downstream regulators GSK3fl-CREB has no effect on food consumption. Results from signaling in the pathogenesis of diabetic the current study suggest that ghrelin acts on brain the mPOA to inhibit sexual appetitive behaviours and shorten copulatory behaviours without Tazrina Alrazi¹, Alma Rosales¹, Cory Toth¹ influencing food consumption. ¹University of calgary

F - Cognition and Behavior Canadians are subject to an epidemic of diabetes mellitus (DM). Our lab has developed a 1-F-143 Acute Effects of Nabilone on robust streptozotocin (STZ)-induced murine Sensory Gating in Healthy Participants: A model with changes analogous to human Brain Event-Related Potential Study diabetic brain, with evidence of brain atrophy, white matter disease, and cognitive decline and Robert Aidelbaum¹, Dylan Smith¹, Joelle we have shown that replacement of insulin in Choueiry¹, Sara de la Salle¹, Danielle Impey¹, the brain via intranasal delivery prevents DM- Jasmit Heera¹, Renee Nelson¹, Lawrence mediated neurodegeneration. Insulin is Inyang¹, Ashley Beaudoin¹, Vadim Ilivitsky¹, speculated to act through activation of PI3K-Akt Jakov Shlik¹, Verner Knott¹ signaling. In our proposed work, we examined ¹Royal Ottawa Mental Health Centre downstream of PI3K-Akt, looking at phosphorylation of cAMP response element- Chronic cannabis use has been shown to binding protein (CREB)/ glycogen synthase produce schizophrenia (SZ)-like cognitive kinase 3 beta (GSK3ß), critical neuronal signals impairments (CI) in predisposed individuals. in the insulin pathway. Intranasal insulin delivery Evidence has shown that cannabis use avoids conventional subcutaneous routes to suppresses sensory gating, a neuronal level prevent hypoglycaemia at high dose. We also cognitive process which facilitates the pre- used transgenic models with downregulation of attentive filtering out of unimportant/redundant CREB to complement interventions to attempt to sensory information. Though the precise rescue the diabetic brain in the murine model of mechanisms remain unclear, it has been type1 DM. GSK3ß was inhibited by intranasal hypothesized that neuroadaptive alterations in delivery of TDZD-8. Our model was used to cannabinoid receptors, specifically increases in study cognitive behavioral testing (Morris water cannabinoid-1 (CB1) receptors, may be maze, hole board, radial arm, object precipitated by cannabis use, facilitating the recognition), magnetic resonance imaging (MRI) expression of sensory gating related CIs and and molecular testing (Western blot) to examine possibly contributing to the pathology of SZ. An insulin-mediated pathways including CREB and obstacle in clarifying the effects of chronic GSK3ß. Knockout of CREB in forebrain blocked cannabis consumption is its frequent use in insulin's beneficial effect upon previously combination with tobacco, thus limiting our detected cognitive and MRI measures. Blocking ability to relate CIs to the specific use of one GSK3ß activation had beneficial effects on drug. The primary goal of this study was to cognition. Our results suggest that the beneficial examine the independent effects and effect of insulin on brain cognition and structure interactions between nicotine and the CB1 results from CREB activation and GSK3ß receptor agonist nabilone. Using the auditory inactivation.(Supported by CIHR) P50 paired-clicks paradigm, sensory gating was analyzed in 20 male non-tobacco/cannabis 1-F-145 The Neurobiology of Adult users using a randomized, double-blind, placebo Attachment controlled design. Based on previous findings, nabilone was predicted to show P50 Martha Bailey¹, Mark Sabbagh¹ impairments while the nicotine dose produces a ¹Queen's University 74

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consolidation processes. In fact, Akt3 knockout Attachment style comprises behaviors, affects mice still learned the rotarod task, but to a much and cognitions that developed in response to slower degree than the WT mice. On the other variations of the caregiver's sensitivity to a hand, notably, genetic deletion of Akt3 did not child's biologically embedded signals for affect the capacity of mice to execute the wire proximity. Adults who are comfortable and suspension, the pole test as well as the stepping confident in close relationships are described as test. We hypothesized that the observed having a "secure" attachment style. Those who exclusive impairment in rotarod learning could fear rejection and yearn for intimacy have an be attributed to a reduction of Akt downstream insecure "anxious" attachment style. Those who targets activation. Our results proposed that are uncomfortable with closeness and prefer Akt3 activity in mice was mainly controlling self-sufficiency have an insecure "avoidant" motor learning rather than motor abilities. attachment style. Adult attachment style has long been associated with many aspects of 1-F-147 Changes in rat inhibitory control health, behavior and disease, but its and response adjustment with aging and neurobiological underpinnings remain poorly time-out penalty understood. In this study I will record resting electroencephalogram (EEG) in adults aged 18- Jonathan Beuk¹, Richard Beninger¹, Elysia 25. Growing evidence shows an association Mechefske¹, Martin Paré¹ between left frontal asymmetry measured at rest ¹Queen's University and approach motivation, whereas right frontal asymmetry is associated with withdrawal The stop task measures inhibitory control by motivation. I will identify associations between examining the ability to withhold a response to a asymmetry level and the attachment style of go stimulus when a stop signal is presented participants as measured by the Attachment occasionally (Logan & Cowan, 1984). Human Style Questionnaire. I will use sLORETA to responding is slower relative to go trial-only estimate intracerebral electrical sources tasks (Akerfelt et al., 2006) and task underlying alpha1 and alpha2 activity recorded performance declines with age (Van de Laar et at the scalp. I predict that those who are al., 2011). We investigated these aspects of the insecurely attached will have neural circuitry that stop task in rats. We also explored whether is different from those who are securely post-error slowing observed for rats (Beuk et al., attached. Specifically, I predict that relatively low 2014) but not humans (Emeric et al., 2007) resting-state activity in the left prefrontal cortex could be attributed to the 10-s post-error timeout will predict avoidant attachment, while relatively that only rats received. Male Wistar rats were high resting-state activity in the left prefrontal trained to respond to a visual stimulus by cortex will predict anxious attachment. pressing a lever below an illuminated light for food reward, but to countermand the lever press 1-F-146 Genetic deletion of Akt3 in mice (25% of trials) subsequent to a tone (stop signal) altered motor learning presented after a variable delay. Experiment 1: Rats (N=13) were tested at approximately 6 and Yan Bergeron¹, Amélie Pelletier¹, François 12 mo. of age with intermittent training between Fabi¹, Eric Asselin¹, Michel Cyr¹ tests. Experiment 2: Rats (N=12) were tested for ¹Université du Québec à Trois-Rivières 3 consecutive sessions (counterbalanced) in a stop task with a 10- or 1-s timeout following The serine/threonine protein kinase B (Akt) is errors or a go trial-only task. Rats at 12 mo. of suspected to be engaged in the molecular age demonstrated slower responding and events leading to synaptic plasticity. However, stopping and less post-error slowing than at 6 whether it plays a role in motor learning and mo. Responses were slower for the stop task in control is unknown. Here, we investigated the comparison to the go trial-only task. Post-error effect of a genetic deletion of Akt3 in the slowing was observed in sessions with a 10-s, memorization processes associated with a but not a 1-s timeout period; response speeding variety of motor behavior tests in mice, such as following consecutive go trials was also no the accelerating rotarod test for the acquisition longer observed. Thus, rat performance in the of skilled behavior, a pole and stepping tests for stop task declines with age and response times sensorimotor functions, and a wire suspension can be adjusted depending on task parameters. test for motor abilities. We observed a significant (Funded by NSERC) reduction in the rotarod performances of Akt3 knockout mice that was reminiscent of impaired 75

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1-F-148 Neural correlates of temporally measures to extract meaningful information from and spatially predictive saccades electroencephalographic (EEG) data. Although a number of methods have been devised to Benedict Chang¹, Donald Brien¹, Brian Coe¹, measure CFC, no gold standard has been Douglas Munoz¹ established--each measure provides its ¹Queen's University strengths and limitations, and must be carefully investigated before valid conclusions about the Prediction is the process of using information data can be drawn. In the present study, we from either the past or present to guide future evaluate the performance of one common behaviour, and is important for compensating for measure of CFC, the modulation index (MI). neural delays between sensory and motor Using artificial signals, we assess the measure's outputs. We investigated the behavioural control ability to correctly identify CFC and to and the neural correlates involved in temporal discriminate between different strengths of CFC. and spatial prediction by administering a task in We then assess the measure's performance on the Magnetic Resonance Imaging scanner that several signal-specific factors and offer involved both temporally and spatially theoretical insights into their influence on (un)predictive saccades with 4 conditions: (a) results. Finally, we relate our findings from spatially/temporally predictive (STP), (b) artificial signals to resting-state EEG data and temporally predictive/spatially unpredictive (TP), discuss the scope of conclusions that can be (c) spatially predictive/ temporally unpredictive made between CFC and underlying cognitive (SP), and (d) spatially/temporally unpredictive processes, given the measure's computational (NON). Participants (n=24; ages=19-25) constraints. displayed distinct behavioural differences between conditions. All participants showed 1-F-150 Premotor cortical activity primarily predictive saccades (saccadic reaction reflects value and effort biases during reach time (SRT) <100ms) in the STP condition, and decisions elicited primarily reactive saccades (SRT>100ms) in the NON conditions. For the Alexandre Pastor-Bernier¹, Marie-Claude SP condition, SRTs fell between the average Labonté², Paul Cisek² SRTs of the STP and the NON conditions. ¹Cambridge University, ²University of Montreal However, no significant difference in SRT was observed between the NON and TP conditions. The "affordance competition hypothesis" Functional contrasts of predictive conditions suggests that when the brain decides between isolating both spatially and temporally predictive actions, they are represented simultaneously areas show bilateral activation of the DLPFC and compete against each other within and the PEF, while contrasts that isolate sensorimotor circuits, biased by any factors spatially predictive areas show activation of the relevant to the choice. Consistent with this, we pre-SMA and insular cortex. Overall, there were have shown that primate dorsal premotor cortex clear behavioural changes between select (PMd) can simultaneously represent multiple predictive conditions which allowed for the potential actions modulated by their relative identification of neural correlates of spatial expected value. However, the hypothesis further prediction as well as both spatial and temporal predicts that neural activity in sensorimotor prediction. regions will integrate all factors that influence choices, including the expected costs of actions. 1-F-149 Validity and application of the We tested this prediction by recording single- modulation index in assessing cross- unit activity in PMd while monkeys performed frequency coupling delayed center-out reaching tasks with one or two potential targets whose stimulus features Anna Choutova¹, Jean-Philippe Thivierge¹ indicated the associated reward or the effort that ¹University of Ottawa would be needed to obtain that reward. Consistent with our hypothesis, we found that Increasing attention has been directed at neural activity in PMd increased with value and investigating the functional role of oscillatory decreased with effort associated with a cell's synchronisation between different frequency preferred target. The interactions between two bands, a phenomenon termed cross-frequency simultaneous targets were stronger when the coupling (CFC). Studies in this area rely upon targets were further apart, consistent with the accurate quantification of CFC, and require hypothesis that the biased competition takes robust, sensitive, and statistically powerful place within a sensorimotor map of action 76

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 space. These results support the hypothesis that 1-F-152 Neural response to social when deciding between actions, the factors evaluation in previously depressed relevant to the choice (reward, effort, estimates compared to healthy young women: of success probability, subjective preferences) Differential engagement of dorsal anterior all converge to bias a competition evolving cingulate over time within the fronto-parietal sensorimotor circuits that guide the movements themselves. Katarina Dedovic¹, George Slavich², Keely Muscatell³, Michael Irwin², Naomi 1-F-151 Metabolic Imbalance, Default Eisenberger² Mode Network Activity, White Matter Integrity ¹UCLA/Douglas Mental Health University and Cognitive Outcome in Stroke Patients Institute, ²UCLA, ³UCSF

Rosalia Dacosta-Aguayo¹, Manuel Graña², Studies have shown that activation of dorsal Carles Falcon¹, Marina Fernández-Andújar¹, anterior cingulate (dACC) to negative feedback Elena López-Cancio³, Cynthia Caceres³, is associated with feelings of distress and poor Nuria Bargallo⁴, Maite Barrios¹, Imma health outcomes. However, it remains unclear Clemente¹, Pere Toran Monserrat⁵, Rosa whether the recruitment of dACC dynamically Fores Sas⁵, Antoni Davalos³, Maria Mataró¹ changes over the course of being exposed to ¹University of Barcelona, ²University of the social evaluation in both healthy participants and Basque Country, ³Hospital Germans Trias i those at-risk for mental health disorders. Here, Pujol, ⁴Hospital Clínic, ⁵Institut Universitari de healthy controls (HC) and previously depressed Investigació en Atenció Primària (-IDIAP) Jordi (PD) young women received socially evaluative Gol feedback, in two bouts, from a confederate, regarding participants' pre-recorded interview; After acute stroke, diaschisis leads to changes we examined participants' mood and neural in cerebral blood flow, white matter integrity and responses. At the beginning, and at a halfway metabolism in areas connected to the ischemic point, of the social evaluative session, lesion. Our goal was to investigate whether participants saw short clips of their interview to certain metabolites in the contralesional remind them of what the confederate is watching hemisphere are altered and if these alterations and evaluating. Following this session, everyone are correlated with resting-state activity, white reported increased feelings of being evaluated matter integrity and cognitive outcome. 11 (p<.001); however, only PDs reported increased survivors of a single right ischemic stroke and negative mood (p=.05). We ran a flexible 17 healthy controls were included. At three factorial analysis of group x time (first- vs months after stroke, principal metabolites, second-half) for negative > positive feedback. fractional anisotropy and resting-state activity We observed that, in the first half of the values were extracted in the anterior cingulate. evaluation, in response to negative > positive Stroke group showed lower levels of Myoinositol feedback, the HC group recruited dACC (mI), Glycerolphosphocholine Phosphocholine bilaterally, which then decreased in the second (Cho compounds), and Glutamate Glutamine half; the PD group showed the opposite pattern (Glx) when compared to controls. Levels of mI over time (p=.006, 111 voxels, FDR small- and Glx were associated with the Rhythms volume corrected). Impact of the differential subtest; Cho levels were related with timing of recruitment of the dACC between the percentage of line cancelation, with Mini mental groups with respect to dACC connections to State Examination (MMSE), and with the Barthel emotional regulatory neural networks are being Scale. Functional activity at rest was greater for assessed; these results will be presented at the the stroke group when compared to controls. conference. This greater activity was associated with levels of mI, N-Acetylaspartate (NAAG) and Glx and 1-F-153 The effect of memory with the MMSE, TMT-part A and GPT for the reconsolidation blockade on functional stroke group. Stroke group showed less white connectivity matter integrity when compared to controls and it was associated with the GPT. Our preliminary Philip Dickinson¹, Pierre Bellec², Lars data demonstrated persistent neurometabolic, Schwabe³, Jens Pruessner¹ resting-state activity and white matter alterations ¹McGill University, ²Université de Montréal, in the contralesional hemisphere of stroke ³Ruhr-Universität Bochum survivors.

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CAN-ACN 2014: Abstract Booklet Montreal, May 25-28

Memory reconsolidation is a process where lateral septum (LS) of rats decreased anxiety- retrieved memories are re-stabilized. like responses in two models of anxiety, the Conversely, propranolol, a ß-adrenergic elevated plus maze and novelty-induced receptor antagonist drug, can attenuate the suppression of feeding test. Surprisingly, these reconsolidation of emotional memory. Little data; same infusions significantly increased however, is available on this effect in humans. hippocampal theta frequency elicited by reticular Resting state functional magnetic resonance stimulation in urethane-anesthetized rats. In imaging (rs-fMRI) studies assess inter-regional contrast to these findings, additional correlations of brain activity (functional experiments showed that the clinically effective connectivity) and are ideal for studying anxiolytic buspirone (40 mg/kg, i.p.) reduced phenomena across distributed brain regions. theta frequency, confirming previous Hence, the objective of this study was to exploit observations. Taken together, the dissociation of novel multivariate functional connectivity behavioural anxiolysis and theta frequency methods to explore the distributed effects of reduction noted here suggest that hippocampal propranolol on emotional memory consolidation. theta frequency is not a direct index of anxiety Fifty-two healthy individuals were assigned to levels in rodents. Further, the mechanisms one of four groups in a two-by-two design. underlying the behavioural and physiological Participants underwent two ten-minute rs-fMRI effects elicited by histamine in the lateral septum scans: propranolol vs placebo preceding the first require further study. scan and reactivation vs no reactivation was initiated during the second scan. A bootstrap 1-F-155 Dopamine "Plasticity" genes- A analysis was applied to the data to identify review of the theory and its potential group brain networks that formed the basis of relevance for understanding overeating and the connectivity analysis. Under propranolol, in obesity contrast with placebo, the cuneus and precuneus showed increased connectivity with Laurette Dube¹, Hajar Fatemi², Patricia the parahippocampal gyrus (PHG), while the Silveira³, Robert Levitan⁴ precuneus also showed an increase with the ¹McGill University, McGill Centre for superior frontal gyrus and the fusiform gyrus. Convergence of Health and Economics Reduced connectivity was found between (MCCHE), ²McGill University, ³Faculdade de portions of the PHG-amygdala network and the Medicina, Hospital de Clínicas de Porto Alegre, inferior parietal lobule during memory Universidade Federal do Rio Grande do S, reactivation under propranolol. The interaction ⁴University of Toronto between propranolol and reactivation in these regions suggest an important role in mediating The vast majority of genetic association studies, emotional memory reconsolidation. including those focused on obesity, are based on the classic notion that "risk alleles" lead to 1-F-154 Behavioral anxiolysis without pathology by altering key biological pathways reduction of hippocampal theta frequency underlying a given disease state. An alternative after histamine application in the lateral approach, informed by Belsky's differential septum of rats susceptibility hypothesis and the biological sensitivity to context model developed by San-San Chee¹, Janet Menard¹, Hans (Boyce and Ellis, 2005), considers how genetic Dringenberg¹ variation might contribute to one or more ¹Queen's University disease states by promoting individual differences in environmental susceptibility and Hippocampal theta activity is linked to various developmental plasticity. In this scenario, a processes, including locomotion, learning and given genetic variant would be associated with memory, and defense and affect (i.e., fear and an increased risk of pathology in negative anxiety). Interestingly, all classes of clinically environments but resilience in enriched ones. effective anxiolytics, as well as experimental The goal of the current paper is to systematically compounds that decrease anxiety in pre-clinical review recent evidence in support of these animal models of anxiety, reduce the frequency genetic developmental plasticity models, with a of hippocampal theta activity elicited by particular emphasis on dopamine system gene stimulation of the reticular formation in freely variants such as the 7-repeat allele of DRD4 behaving or anesthetized animals. In the and the DRD2 Taq1 polymorphism. These present experiments, we found that bilateral variants have been associated with both an histamine infusions (0.5 µg/hemisphere) into the increased risk for psychopathology in the 78

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 presence of early adversity and with resilience in more nurturing environments. After having Peter Finnie¹, Maria Protopoulos¹, Karim systematically reviewed the literature on the Nader¹ effect of DRD4 and DRD2 Taq1 polymorphism ¹McGill University on eating and obesity that has had thus far an exclusive "risk allele" focus, the paper discusses Although it is well-established that the peptide how these particular gene variants might amyloid beta (Aβ) plays a role in the influence eating related phenotypes and obesity pathogenesis of Alzheimer's disease (AD), there through one or more developmental plasticity is accumulating evidence of its involvement in effects. normal physiological function, neuronal plasticity, and memory. For instance, Aβ can be 1-F-156 Loss of Stat3 signalling in released during neuronal stimulation (Kamenetz midbrain dopamine neurons enhances et al., 2003, Cirrito et al., 2005) and acute stress anxiety-like behaviour in female mice (Kang et al., 2007), and may facilitate memory encoding at normal physiological levels (Garcia- Maria Fernanda Fernandes¹, Sandeep Osta & Alberini, 2009). Elevated Aβ has been Sharma¹, Shizuo Akira², Stephanie Fulton¹ observed to enhance both the induction of ¹Université de Montréal, ²Osaka University synaptic depression via NMDA-receptors containing NR2B subunits, and the synaptic The adipocyte-derived hormone leptin targets exchange of NR2B for NR2A (Kessels et al., the long form of its receptor (LepRb) in the CNS 2013). Based on these findings we posited dual to produce several behavioural actions functions for endogenous Aβ in learning and compatible with the maintenance of energy memory. First, it may promote the induction of balance. Leptin activates a number of LepRb plasticity after a behavioural experience. Then it signalling pathways including janus-activated may facilitate the subsequent stabilization of this kinase 2 - signal transducer and activator of memory during the consolidation process. We transcription-3 (Jak2-Stat3), MAPK, PI3-K and report here that several Aβ-inhibiting treatments AMPK pathways. Jak2-Stat3 constitutes a key had effects on auditory fear memory pathway by which leptin modulates gene reconsolidation that were largely consistent with expression. Leptin has anxiolytic effects which these predictions. Molecular mechanisms have been tied to LepRb signaling on mediating these effects (including alteration of mesolimbic dopamine (DA) neurons that project NMDA-receptor expression and composition) to the central nucleus of the amygdala (CeA), will be discussed based on the results of several however, it remains to be resolved which LepRb biochemical assays. Together our findings signalling pathways are involved. To assess the suggest that this process implicated in the onset contribution of Stat3 signalling in DA neurons on of AD may initially serve to promote the adaptive anxiety-related behaviour we generated a DA- stabilization and updating of memories. This specific Stat3 knockout by crossing dopamine may provide one explanation for why several transporter (DAT)Cre mice with Stat3lox/lox clinical trials of Aβ-inhibiting drugs have caused mice. Female knockout (KO) mice exhibited worsening AD symptomatology. normal feeding, locomotion, body weight and behavioural despair (forced swim test) relative to 1-F-158 Behavioral adverse effect profile littermate controls. However, KO mice showed of Brivaracetam versus Levetiracetam in the increased anxiety-like behaviour in both the rat kainic acid (KA) model of temporal lobe elevated plus maze and open field tests as well epilepsy (TLE). as increased plasma corticosterone levels. Blocking D1 DA receptors in the CeA by local Jonathan Gagné¹, Nathalie Sanon², microinjection of the D1 antagonist SCH23390 Sébastien Desgent², Lionel Carmant¹ reversed the anxiogenic phenotype of KO mice. ¹University of Montreal, ²Centre de recherche du These results suggest that activation of Stat3 in CHU Sainte-Justine midbrain DA neurons that project to the CeA mediates the anxiolytic effects of leptin. Background Adverse effects of anticonvulsants Supported by a CIHR grant to SF and doctoral in patients are among the main reasons for non- awards to MFF from the Canadian Diabetes observance of medication. Levetiracetam (LEV), Association and UdeM used since the year 2000,targets the synaptic vesicle SV2A in the brain and inhibits voltage- 1-F-157 Amyloid-beta regulates memory gated Na channels. Some studies report stability adverse effects such as aggressiveness, 79

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 drowsiness and loss of appetite. Brivaracetam attended]. Event-related potential markers of (BRV) is a newly developed drug with the same attentional control - i.e., the P3a and P3b - could target, but its affinity for the SV2A vesicle is be reliably detected across participants. about 10x greater. Methods Our current study Crucially for communication purposes, a characterises the adverse effects of LEV and machine-learning algorithm could reliably predict BRV on rat behavior, using the kainic acid (KA) which wrist was being attended with high model of temporal lobe epilepsy (TLE). At P60, accuracy (Trials: M=70.43%; SE=±2.76%; rats are injected with either KA (12mg/kg) or a Blocks: M=93.30%, SE=±0.031%). These saline solution intraperitonneally (i.p.). At P90, results are promising for future work with DOC they receive an injection of LEV (300mg/kg), patients in that this BCI will allow for the BRV (30mg/kg) or saline i.p., one hour before identification of prognostic brain markers of testing. Behavioral tests include: Open Field attentional control, while simultaneously (OP), Elevated Plus Maze (EPM), Fear providing a communication device for those Conditioning (FC), Forced Swim Test (FST), patients with top-down attention. Morris Water Maze (MWM) and Resident- Intruder (RI) test allowing us to measure anxiety, 1-F-160 Local Morphology Predicts mobility, depression, spatial memory, social Functional Organization for the Cognitive interaction and aggressiveness. Results: Our Map Task within Parahippocampal Cortex in results indicate an increase of aggressiveness in the Human Brain control rats receiving LEV (N=10). We also see a rescue of exploration behavior in the OF of KA Sonja Huntgeburth¹, Jen-Kai Chen¹, Alain rats who receive LEV (N=9) or BRV (n=10) and Ptito¹, Michael Petrides¹ a rescue of time spent in closed arms in EPM of ¹Montreal Neurological Institute; McGill KA rats who receive LEV (N=9) or BRV (N=10). University Our findings confirm the aggressiveness caused by LEV, as seen in previous studies, and The relationship between local morphological suggest that both anti-convulsants modify the features defining the parahippocampal region of anxiety behaviour in epileptic rat the human brain and functional activation in this region measured during a navigation task with 1-F-159 Detection of bottom-up and top- functional magnetic resonance imaging was down attentional control mechanisms using examined on a subject-by-subject basis in 14 a vibro-tactile Brain-Computer Interface (BCI) healthy participants. The location of the peaks of functional activation was examined in relation to Raechelle Gibson¹, Kyle Goldberger¹, Srivas the morphology of the collateral sulcus as Chennu², Adrian Owen¹, Damian Cruse¹ described by Huntgeburth & Petrides (2012). ¹Western University, ²University of Cambridge There were three main clusters of activation in the parahippocampal cortex: two posterior and Brain-computer interfaces (BCI) refer to a one middle parahippocampal cluster. One of the category of devices that use electrophysiological posterior parahippocampal peaks was located signals to modulate the activity of a computer. within the posterior portion of the collateral Non-communicative individuals, e.g., those with sulcus proper where it merges with the Disorders of Consciousness (DOC), can benefit parahippocampal extension of the collateral from BCIs because these devices may provide a sulcus. The second posterior peak was located means to communicate without overt movement. within the parahippocampal extension of the BCIs can also provide an assessment of covert collateral sulcus. The middle parahippocampal cognition not available with traditional activation peak was located where the anterior behavioural tests. The current work focused on segment of the collateral sulcus makes way for the development of a BCI that can detect its posterior segment, when two segments are bottom-up and top-down attentional control present. These results illustrate the importance mechanisms. Healthy participants (n=16) of local morphology and how it may clarify the directed their attention to infrequent vibrations location of functional activity in the human brain. on their wrists (10% of all stimuli per wrist) while Functional neuroimaging studies using regular vibrations occurred more frequently navigation tasks should take into consideration (80% of all stimuli) on their upper back. In blocks this differentiation in activation patterns within of about 60 s duration, participants counted the the parahippocampal cortex. number of vibrations on one wrist of interest [explicitly attended] and ignored the infrequent vibrations on their other wrist [implicitly 80

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28

1-F-161 The effects of beta-amyloid may be involved in SWM maintenance, but administration in an animal model of whether and how these units interact with each diabetes other remains poorly understood. In order to investigate this issue, we recorded responses of Robin Keeley¹, Nhung Hong¹, Robert Balog¹, multiple single units in dlPFC area 8r of two Cameron Bye¹, Robert McDonald¹ macaca fascicularis using microelectrode ¹University of Lethbridge arrays. The task consisted of fixation on a central spot for 494-800ms, presentation of a Alzheimer's disease (AD) is a progressive circular sine wave grating at one of 16 randomly neurodegenerative disease affecting primarily selected locations for 507ms, then offset of the the elderly. Although AD research primarily grating followed by a delay period that could last examines the contributions of beta-amlyoid between 494-1500ms, and ended with the offset accumulation and tau hyperphosphorylation, an of the central fixation point, cuing the animals to additional theory concerning the etiology of AD make a saccade to the remembered stimulus has been postulated - namely the co-factor location. We recorded the activity of neurons in model of AD. This theory suggests that multiple blocks of 32 channels and sorted spikes using combinations of factors, such as stroke, Plexon software (Plexon Inc, TX). We isolated circadian rhythm disruption, stress and diabetes, responses of 199 single units for a total of 1375 lead to the development of AD. Indeed, there neuronal pairs. Neurons were classified as are many links between diabetes and AD, such being selective (one-way ANOVA, p<.05) for the that diabetics are more likely to develop AD, and spatial location of the stimulus during the have a worse disease prognosis. There is a stimulus presentation period (visually-selective, complex interplay between diabetes and n = 128, or 64%) and the delay period (memory- vascular events as well, such that diabetics are selective, n = 145, or 73%). We then computed more likely to experience a cerebrovascular spike-rate correlations and found that event, such as stroke. Stroke itself also acts as interactions between neurons in the dlPFC vary a risk factor for AD, as AD patients are at a based on task epoch and neurons' selectivity. higher risk for stroke as well as suffer a worse disease prognosis following a cerebrovascular 1-F-163 The loss of a generation: the accident. With these risk factors in mind, we accelerating decline of hearing acuity among used an animal model of obesity and type 2 healthy adults diabetes, the Zucker obese rat either alone or in combination with an intracerebral infusion of Catherine Lortie¹, Mylène Bilodeau-Mercure¹, beta-amyloid. Following surgery recovery, all Claudie Ouellet¹, Pascale Tremblay¹, rats were exposed to a stimulus-response Matthieu Guitton¹ version of radial arm maze, Morris water task ¹Laval University and discriminative fear-conditioning to context. In addition to these behavioural tasks, fasting According to the Canadian Association of blood glucose and blood glucose in response to Speech-Language Pathologists and Audiologists a glucose challenge were measured. The 20-40% of adults over 65 have a significant present study highlights the importance of hearing problem. However, little is known about diabetes in the etiology of AD. the manner in which hearing evolves throughout adulthood. Is hearing loss gradual or sudden? 1-F-162 Correlated spiking during spatial Does the rate of change accelerate after a working memory in macaque prefrontal area certain age? This study aims to establish a 8r detailed audiometric portrait of healthy adults. One hundred forty two healthy adults ranging in Matthew Leavitt¹, Florian Pieper², Adam age from 19 to 93 years old participated in the Sachs³, Julio Martinez-Trujillo¹ study. Their pure tone hearing thresholds, ¹McGill University, ²University of Hamburg- speech reception threshold (SRT) and distortion Eppendorf, ³Ottawa Hospital Research Institute, product otoacoustic emissions (DPOAEs) were University of Ottawa measured. Mean hearing losses across frequencies were compared to normative values Neurons in the primate dorsolateral prefrontal for each age group. Hearing thresholds are cortex (dlPFC) are known to exhibit selective significantly affected by age when controlling for activity during the delay period of spatial working gender and educational level (F(6,133) = 53.54, memory (SWM) tasks. It has been hypothesized p < .001), as are DPOAEs amplitudes (F(6,133) that functional interactions between these units = 13.32, p < .001). SRT increases with age (r = 81

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28

.63, F(1,140) = 93.71, p < .001). Hearing loss not develop memory deficits with aging. begins around 50 to 59 years old and worsens Therefore, we investigated the status of with age. While higher frequencies are affected glutamatergic receptors and VGLUTs in aging first, lower frequencies (including the LOU rats. No differences were observed conversational range) progressively weaken. between 24-month-old LOU rats and their young Adults between 19-29 years old have a mean counterparts. Correlation of spatial memory hearing loss of 18 dB, which is 17 dB worse capacities with VGLUTs and postsynaptic GluR than normative values published in 1949. In in these two rat strains suggests that intact contrast, older adults (60 to 93 years old) exhibit coordination of the glutamatergic neuronal only a 5 dB decline compared to the 1949 data. networks appears to be a prerequisite to healthy These results suggest that normal age-related cognitive aging. hearing decline has changed over the past fifty years occurring earlier and being more 1-F-165 Increasing the speed of cocaine extensive. delivery augments the motivation to take the drug and promotes regulation of 1-F-164 Glutamate presynaptic vesicular corticostriatal BDNF and TrkB mRNA transporter and postsynaptic receptor levels correlate with spatial memory in aging rat Ellie-Anna Minogianis¹, Daniel Levesque¹, models Anne-Noel Samaha¹ ¹Université de Montréal Caroline Ménard¹, Erika Vigneault², Guylaine Ferland³, Pierrette Gaudreau⁴, Salah El The rapid delivery of drugs to the brain Mestikawy⁵, Remi Quirion⁵ increases the risk and severity of addiction. We ¹Université de Montréal, Centre hospitalier have shown that rats with a history of self- Université de Montreal Research Center, McGill administering rapid cocaine infusions (delivered University, ²Douglas Mental Health University i.v. over 5 vs. 90 s) later show increased Institute, ³Université de Montréal, Hôpital du motivation to take the drug. BDNF-mediated Sacré-Coeur de Montréal Research Center, signalling in corticostriatal regions mediates the ⁴Université de Montréal, Centre hospitalier development and expression of addiction- Université de Montreal Research Center, relevant patterns of drug taking. Thus, we ⁵McGill University, Douglas Mental Health hypothesized that the intake of rapid cocaine University Institute infusions involves increased regulation of brain- derived neurotrophic factor (BDNF) and TrkB In human, memory capacities are generally mRNA in corticostriatal nuclei. Rats self- affected in aging even in the absence of administered cocaine or saline delivered i.v. neurological disorders. Mechanisms underlying over 5 or 90 s under a fixed ratio schedule (FR) cognitive decline are still not well understood. during nine 6-hour (h) sessions. Next, motivation Glutamate is the major excitatory transmitter in for cocaine was assessed using a progressive the brain and numerous data from the literature ratio (PR) schedule. Finally, rats were tested suggest major alteration of glutamatergic under FR for 1h and decapitated 15 minutes transmission during normal and pathological later. BDNF and TrkB mRNAs were measured aging. Here, we examine whether or not post- using in situ hybridization. Compared to 90-s synaptic glutamate receptor (GluR) levels and rats, 5-s rats consumed more cocaine during FR pre-synaptic vesicular glutamate transporters sessions and showed greater motivation to (VGLUTs) expression are affected by aging in obtain the drug during PR sessions. In parallel, 24-month-old Long-Evans rats, with intact only 5-s rats showed altered BDNF and TrkB (aged-unimpaired, AU) or impaired (AI) spatial mRNA levels. Relative to 90-s and control rats, memory. AU rats maintained similar levels of 5-s rats had increased BDNF mRNA levels in hippocampal ionotropic post-synaptic GluR several cortical regions coupled with decreased levels as young animals. On the other hand, TrkB mRNA levels in both cortex and dorsal receptor expression was significantly reduced in striatum. Thus, the intake of cocaine under AI animals. Conversely, VGLUT1 and VGLUT2 conditions that lead to a rapid rise in brain drug levels were enhanced in AI rats and inversely levels facilitates the brain changes that promote correlated with individual GluR levels. These excessive motivation to take the drug. The data suggest that unbalanced expression of pre- present data suggest that these neural changes and postsynaptic components is involved in age- could involve increased regulation of related cognitive deficits. The obesity-resistant BDNF/TrkB. healthy aging Lou/C/Jall (LOU) rat strain does 82

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28

1-F-166 Linking memory-related firing of exploitation from opponents. We have prefrontal neurons to the strength of their previously shown that mixed-strategy decision- entrainment to theta oscillations in the rhinal making (DM) recruits a distributed brain network cortex and ventral hippocampus in humans; however, the role of motor structures remains unknown. The current study used fMRI Mark Morrissey¹, Kaori Takehara-Nishiuchi¹ to dissociate key regions of a strategic network ¹University of Toronto from those involved in controlling specific motor effectors; the eye and hand. A colour-based The lateral entorhinal cortex (LEC) and medial version of Matching Pennies was played against prefrontal cortex (mPFC) are necessary for the a dynamic computer opponent that exploited expression of consolidated memory (Takehara- biases in player's responses. Players chose one Nishiuchi et al., 2006; Morrissey et al., 2012), of two different coloured visual targets, and were and they closely communicate with one another rewarded if their choice matched the opponent's. as detected by synchronized theta oscillations Using a block design, we contrasted brain (Takehara-Nishiuchi et al., 2011). However, activation underlying choices made using a precisely what information is transferred saccade with choices made using a button- between these regions remains unclear. By press; differences in brain patterns should examining the phase-locking to afferent highlight effector-specific processes. Strategic oscillations of single neurons encoding specific DM, regardless of the effector, was associated information, we may reveal the source of this with activation of the caudate nucleus (head), encoding. To this end, we simultaneously dorsolateral prefrontal, anterior cingulate, recorded single neuron activity in the prelimbic parietal, insular and orbitofrontal cortices, (PrL) mPFC and local field potentials in several comprising the core elements of a strategic afferent cortical regions, including the LEC, network. Conversely, we observed effector- perirhinal, secondary visual, and ventral specific activation of the frontal eye fields during hippocampus while rats formed an association saccade blocks, and the supplementary motor between two different conditioned stimuli (CS) area (SMA) and pre-SMA during button press and a single aversive outcome (US). Roughly blocks. Results suggest that strategic DM 25% of PrL neurons exhibited significant phase- activates a common brain network, distinct from locking to theta oscillations in all cortical regions regions involved in controlling specific effectors. examined, but individual neurons preferentially phase-locked to one of the afferent regions. 1-F-168 Analysis of the sleep - wake Neurons that were selective for the CS-US cycle in EphA4 knockout mice association were more numerously and robustly phase-locked to afferent theta oscillations than Audrey Pierre¹, Marléne Freyburger¹, neurons that either did not respond to the CS or Gabrielle Paquette¹, Erika Bélanger-Nelson¹, unselectively responded to the two CS. Valérie Mongrain¹ However, the degree of phase-locking of ¹Hopital sacré coeur de Montréal association selective neurons to the LEC was comparable to the other regions. Thus, the Introduction: Sleep is a vital function that can be association-selective activity of prefrontal disrupted by external and internal factors. Sleep neurons may be shaped by converging inputs regulation, and regulation of sleep intensity in from the rhinal, sensory cortex and ventral particular, has been linked to changes in hippocampus. synaptic functioning. Epha4 is a receptor involved in synaptic plasticity that was shown to 1-F-167 A brain network for strategic regulate glutamatergic transmission. Here we decision-making investigated the impact of its absence on sleep architecture. Methodology: Vigilance states Ashley Parr¹, Brian Coe¹, Douglas Munoz¹, (wakefulness, non-rapid eye movement [NREM] Michael Dorris² sleep and REM sleep) duration was quantified ¹Queen's University, ²Institute of Neuroscience, using continuous electrocorticography [ECoG] in Chinese Academy of Sciences mice lacking EphA4 (provided by K. Murai and bred on site). Male mice (ten-week-old) from During competitive interactions, one's actions three genotypes (15 wild-type [WT], 16 and their outcomes change dynamically based heterozygous [HET] and 13 homozygous on the actions of other agents. A mixed-strategy mutants [KO]) were used. ECoG was recorded is often used, choosing among actions during 4 days: 2 baseline [BL] days, a 6h sleep unpredictably and stochastically, to avoid deprivation and 42h of recovery. Preliminary 83

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 analyses have been performed on the second belief that a modulation of DAT activity triggers BL day. Results: We observed a significantly important DA related changes in the mice HP shorter REM sleep duration in KO mice than in and it should help us to better understand the WT mice during the 24h period. This role of endogenous DA levels in learning and observation was also specific to the 12h light memory processes. period. KO showed significantly longer wake bouts duration compared to WT, which 1-F-170 The Role of Cholinergic Tone in occurred, for the most part, in the 12h light. The Depression duration of NREM sleep bouts was also significantly higher during the 12h light in KO Kaie Rosborough¹, Monica Guzman¹, mice. Discussion: These results suggest that Mohammed Al-Onaizi¹, Vania Prado¹, Marco EphA4 may regulate sleep as its absence Prado¹ seems to consolidate wake and NREM sleep ¹University of Western Ontario occurrence, and lessen the duration of REM sleep. Current analyses are evaluating the Major depression is one of the most prevalent impact of sleep deprivation and the spectral psychiatric disorders worldwide. The cholinergic profile of vigilance states. hypothesis of depression suggests that dysregulation of the cholinergic system may 1-F-169 Hyperdopaminergia induced by contribute to the etiology of major depression. In DAT blockade alters synaptic plasticity, support of this hypothesis, antagonists of learning and memory in the temporal acetylcholine receptors (nAChR) have an hippocampus. antidepressive effect on animals as well as on humans. However, it is not clear which Jill Rocchetti¹, Caroline Fasano¹, Elisa cholinergic nuclei in the brain control Guma¹, Tak Pan Wong¹, Bruno Giros¹ depression-like behaviour. We generated three ¹Douglas Research Center novel mouse lines where the vesicular acetylcholine transporter (VAChT), a protein Endogenous levels of dopamine (DA) have been responsible for synaptic storage and release of shown to modulate activity-dependent synaptic ACh, was specifically deleted from the plasticity in the rodent hippocampus (HP). In pedunculopontine tegmental nucleus (PPT), the dopamine transporter (DAT) knock-out mice, a basal forebrain, or the striatum. We model of persistent hyperdopaminergia, long- hypothesized that decreased cholinergic term depression (LTD) was impaired at signaling from one or more of these cholinergic Schaffer's collateral (SC) - CA1 synapses and nuclei will cause an antidepressive-like mice exhibited impaired behavioral flexibility in phenotype, as measured by the tail suspension the Morris water maze (MWM). To investigate test (TST) and forced swimming test (FST). further the effect of DA elevation on HP synaptic Interestingly, mice with a VAChT knockout in the plasticity, we first tested the effect of the DAT basal forebrain are not different from controls in blocker GBR12935 on SC-CA1 synapse LTP both the TST or the FST, but shown a resilient and LTD in vitro. Field recordings in CA1 of phenotype in these tasks after stress. Striatal adult C57BL/6J mice in presence of GBR VAChT knockout mice showed antidepressive- (30nM) resulted in no impairment of LTP after like phenotype in the FST but not in the TST. high frequency stimulation. Conversely, GBR Consistent with the cholinergic hypothesis of application suppressed paired-pulse low depression, mice with a VAChT knockout in the frequency-induced LTD. Then we clarified how PPT showed a significant antidepressive-like high DA levels affect HP dependent memory phenotype in both the FST and the TST, processes by implanting bilateral canulae in suggesting a role for the PPT cholinergic system either septal or temporal HP of C57 mice and in depression. Our experiments provide new testing their performance in the MWM following insight regarding the role of altered cholinergic chronic administration of GBR. Infusion of GBR signaling in psychiatric disorders. (300nM) in the septal CA1 resulted in no significant impairment in the spatial MWM. 1-F-171 Role of dopamine signaling in Conversely, GBR infusion in the temporal CA1 electrotactic swimming behavior of the resulted in a deficit in escape latency and nematode Caenorhabditis elegans success rate compared to controls. Mice treated with GBR in the temporal HP also exhibited a Sangeena Salam¹, Ram Mishra¹, P Ravi total deficit in the novel object recognition task. Selvaganapathy¹, Bhagwati Gupta¹ Altogether, this ongoing study reinforces the ¹McMaster University 84

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female mice displayed difficulty learning the C. elegans (worm) is an established model reversal, making a greater numbers of errors organism for the study of the neuronal basis of during the reversal than the discrimination task. behavior. The nervous system of worm consists These results of sex differences on a simple of just 302 neurons and utilizes conserved olfactory discrimination task show the neurotransmitter signaling such as dopamine importance of testing both sexes of mice when (DA). DA modulates a range of behavior in C. conducting experiments. elegans such as feeding and locomotion. We have recently shown that DA signaling is 1-F-173 Trace eyeblink conditioning involved in the electric field-induced swimming depends on neural activity, but not NMDA or behavior (termed "electrotaxis") of worms. In muscarinic acetylcholine receptors, in the electrotaxis, C. elegans moves toward cathode lateral entorhinal cortex in the presence of a DC electric field. To investigate the role of DA signaling in Xiao Yu¹, Stephanie Tanninen¹, Lina Tran¹, electrotactic behavior, we used a novel Rami Bakir¹, Mark Morrissey¹, Kaori microfluidic device set-up wherein the worm Takehara-Nishiuchi¹ movement is controlled by the electric field. The ¹University of Toronto DA transporter mutant, dat-1, exhibits a slow electrotactic swimming speed. However, The entorhinal cortex is necessary for Pavlovian mutations in AADC and VMAT genes, bas-1 and trace conditioning, which requires animals to cat-1, respectively, cause worms to have faster associate a neutral conditioned stimulus with a speed. Furthermore, bas-1 mutant phenotype is salient unconditioned stimulus across a partially rescued by exogenous DA treatment. temporal gap. Yet, it remains unknown what Similar to mammals, C. elegans DA mediates neurotransmitter receptor mechanism supports extrasynaptic signaling through DA receptors memory acquisition in the entorhinal cortex. that are present in different cells including Here, we examined whether NMDA receptors or cholinergic motor neurons and muscle cells. Of muscarinic acetylcholine (mACh) receptors in the two D2-like receptors in worms (DOP-2 and the lateral entorhinal cortex are involved in DOP-3), dop-3 mutants have a faster speed memory acquisition in trace eyeblink whereas dop-2 are normal. Thus, DOP-3 conditioning. We first confirmed that the lateral appears to be the primary receptor through entorhinal cortex is necessary for acquisition by which DA acts to inhibit the electrotactic inactivating this region during acquisition movement. The D1-like receptor mutants, dop-1 sessions with microinfusions of a GABAA and dop-4, exhibit a normal electrotactic receptor agonist, muscimol. Subsequent response. These results provide first evidence experiments kept the same infusion volume and for the role of DA signaling in modulating the location as the first experiment with muscimol, electrotactic swimming behavior in worms. but infused a NMDA receptor antagonist, APV or mACh receptor antagonist, scopolamine. 1-F-172 Sex differences in olfactory Contrary to expectations, pharmacological discrimination learning in mice blockade of NMDA or mACh receptors did not have a significant effect on the acquisition or Andra Sterea¹, Kyle Roddick¹, Heather expression of the conditioned response. Thus, Schellinck¹ trace eyeblink conditioning requires normal ¹Dalhousie University activity of the lateral entorhinal cortex; however, it does not depend on local NMDA or mACh Mice have been shown to perform olfactory receptors. These results highlight a unique role based tasks better than tasks requiring the use of the lateral entorhinal cortex in trace eyeblink of other sensory modalities. We assessed sex conditioning that does not include NMDA differences in CD-1 mice using automated receptor-dependent synaptic plasticity or olfactometers. Male and female mice were cholinergic-dependent persistent activity. tested on two-odour discrimination and reversal tasks. During the initial training phase male mice 1-F-174 The hormone replacement learned the task faster than female mice. The therapy Premarin differentially affects spatial males also displayed greater performance than memory and hippocampal plasticity the females on the two-odour discrimination dependent on reproductive experience in task. No sex differences were seen on the middle age female rats. reversal task. Although the mice easily learned the initial discrimination task, both male and 85

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28

Christina van den Brink*¹, Meighen Roes*¹, stress alone could reduce hippocampal volume Stephanie Lieblich¹, Carmen Chow¹, Dwayne in animal studies, vulnerability to mood Hamson¹, Liisa A.M. Galea¹ disorders may be related to a susceptibility to ¹University of British Columbia stress-induced hippocampal shrinkage. However, a smaller hippocampal volume before Hormonal replacement therapies are commonly stress exposure has also been suggested to prescribed during menopause and have been confer vulnerability of stressed individuals to found to affect cognition, dependent on estrogen PTSD or depression. In this study, we examined type (estradiol v. estrone) and subject age. the contribution of either innate hippocampal Reproductive experience has persisting effects volume differences or hippocampal susceptibility on the aging hippocampus, increasing cell to stress-induced shrinkage to the formation of proliferation in response to estrogens, altering stress-related psychopathology using performance on hippocampus-dependent tasks longitudinal MRI measurements of hippocampal and varying the sensitivity of the female brain to volume in inbred C57 mice before and after estrogens long after offspring are weaned. chronic social defeat stress. We found that only Estrogen treatments may therefore affect brain half of the stressed mice were susceptible to health in aging females differently depending on stress and developed psychopathological reproductive experience and hormonal milieu. behaviors such as social avoidance and the The current study aimed to elucidate the effects other half were resilient to stress. Before of reproductive experience and ovarian status exposure to stress, we observed a positive on the cognitive and neuroplastic effects of correlation between hippocampal volume and Premarin, an estrone-based therapy, in middle- social avoidance. Exposure to chronic social aged female rats. Primiparous (one time defeat associated with an increase in the left pregnant and mothering) or nulliparous (no hippocampal volume in resilient and reproductive experience) rats underwent nonstressed control mice. Intriguingly, this ovariectomy or sham ovariectomy at 8 months. increase in hippocampal volume was not found Seven months later rats received daily in susceptible mice. Our findings suggest that subcutaneous doses of Premarin or vehicle for both a larger hippocampus before stress 21 days. In the final week of hormone exposure and a susceptibility to stress-induced administration, rats were tested for hippocampal volume changes confer hippocampus-dependent learning in the Morris vulnerability to psychopathology after chronic Water Maze. Chronic Premarin administration stress. enhanced performance in nulliparous rats but impaired performance in primiparous rats. 1-F-176 Infusions of Neuropeptide Y into Brains are being processed for immediate early the ventral hippocampus decrease rats' gene and neurogenesis markers. Our findings defensive behaviour in the shock-probe suggest that Premarin has differential effects on burying test of anxiety the aging primiparous brain which has potential clinical implications for treatment during aging Samuel Yoon¹, Geoffrey Harrison¹, Janet and for neurodegenerative disease. Funded by Menard¹ AD Society of Canada to LAMG. ¹Queen's University

1-F-175 A longitudinal study of stress- The current study investigated whether induced hippocampal volume changes in Neuropeptide Y (NPY) in the ventral mice that are susceptible or resilient to hippocampus contributes to anxiety regulation. chronic social defeat Prior research implicates NPY in the regulation of rats' anxiety-related behaviors. The Yiu Chung Tse¹, Ixchel Montoya¹, Alice hippocampus is similarly implicated in anxiety Wong¹, Axel Mathieu¹, Jennifer Lissemore¹, and defensive behaviors - specifically, the Diane Lagace², Tak Pan Wong¹ ventral hippocampus regulates innate defensive ¹Douglas Mental Health University Institute, behaviors, and contains a high concentration of ²University of Ottawa NPY receptors as well as cells that produce NPY. I explored the role of ventral hippocampal Hippocampal shrinkage is a commonly found NPY in anxiety by bilaterally implanting cannula neuroanatomical change in stress-related mood guides and infusing either 1.5µg/side of NPY or disorders such as depression and PTSD. Since physiological saline into the rat ventral the onset and severity of these disorders are hippocampus. This was followed by behavioural closely related to stressful life events, and as testing in animal models of anxiety - i.e., the 86

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 elevated plus-maze (nNPY = 13 nsal = 17) and 1-G-178 A simple procedure to improve the shock-probe burying task (nNPY = 12, nsal immunohistochemistry co-labelings with = 10). Although NPY-treated rats did not BrdU significantly differ in percentage of open arm entries, rats that received an NPY infusion Jenna Boulanger¹, Claude Messier¹ displayed a significant reduction in burying ¹University of Ottawa without any drug-related changes in the duration of time spent immobile, the number of contact- 5-bromo-2'-deoxyuridine (BrdU) is an analog of induced probe shocks and mean shock the nucleoside thymidine widely used in the reactivity scores. These results underscore the study of cell proliferation as dividing cells selective actions of intra-ventral hippocampal incorporate BrdU into their DNA during the S- NPY infusions on defensive burying and support phase of the cellular cycle. the role of NPY in the ventral hippocampus in Immunohistochemistry (IHC) is then used to regulation of anxiety-like behaviors. label the cells, thereby providing visual evidence of cell division. Binding of the BrdU antibody G - Novel Methods and Technology requires denaturation of the DNA by heat or Development acid, which can considerably damage the tissue. We found that incubation for 30 minutes in 2N 1-G-177 A bright genetically-encoded HCl at 37°C was optimal for both DNA sensor to determine protein expression at denaturation and tissue preservation. However the cell surface in live cells this protocol was not optimal for every antigen we wished to co-localize with BrdU. For Mark Aurousseau¹, Patricia Brown¹, Derek example, the EYFP antigen found in Bowie¹ NG2Cre/Rosa26S-EYFP transgenic mice, while ¹McGill University incorporated into cells, appeared to be degraded by the acid treatment, thus preventing visual The process of signal transduction from the optimization with an anti-GFP antibody. While extracellular environment is largely mediated by alternatives to BrdU do exist, such methods also membrane-bound proteins expressed at the cell present pitfalls which limit their usefulness in the surface. This important class of proteins context of proliferation and lineage tracing includes ionotropic and metabotropic receptors studies. Sample fixation is believed to greatly including the glutamate and cys-loop family of condition the denaturation step. We found that ion channels as well as G-protein coupled incorporating a second post-fixation step receptors (GPCRs). Changes to the extent of (overnight at 4°C in 4% paraformaldehyde-picric surface expression are the basis for a multitude acid mixture) following the anti-GFP IHC but of physiological regulatory mechanisms prior to HCl treatment and BrdU IHC conserved including synaptic plasticity as well as GPCR the fluorescent labellings even after DNA desensitization. Here we describe a simple denaturation. This IHC protocol also improved method of quantifying the extent of protein visualization of doublecortin and other antigens expression at the plasma membrane of of interest in the study of glio- and individual live cells using a pH-sensitive neurogenesis. superfolder GFP. The increased brightness of this genetically-encoded fluorophore coupled 1-G-179 In vivo inhibition of with total internal reflection fluorescence (TIRF) subcutaneous glioma progression by oral microscopy permits for improved detection 2,5-dihydroxyphenyl sulfonate in rats sensitivity compared with existing biochemical through reduction of tumoral angiogenesis methods. Additionally, this method avoids the and apoptosis induction pitfalls of inadvertent permeabilization due to fixation when employing immunohistochemical Mohamad El Youssef¹, Pedro Cuevas¹, methods. To demonstrate its practicality, we Begoña Cuevas¹, Eduardo Martínez- have used this technique to examine differences Salamanca¹, Fernando Carceller², Javier in surface expression of heteromeric kainate Angulo¹ receptor subtypes containing the GluK4 or ¹Departamento Investigación - Hospital GluK5 subunits. Additionally, we show how this Universitario Ramón y Cajal, ²Servicio de technique can be used to quickly assess the Neurocirugía - Hospital Universitario La Paz surface expression profile of various iGluR mutants. Despite the use of multimodal therapies which includes surgery, radio and chemotherapy, 87

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 glioblastoma prognosis is very poor. with eyes open/closed, 90° left/right rotation, Pathological angiogenesis combined with the and tilt up/down/left/right. Graphical aggressive invasion and rapid diffusion into the representation was used to display angular brain are characteristics of glioblastoma, The deviation from neutral position in lateral, considerable evidences pointing to fibroblast rotational and vertical degrees of freedom growth factor (FGF) as promoter of tumor (DOF). These objective measures showed the angiogenesis and progression, awake the unique positional composition of each patient's scientists interest to look for an effective inhibitor torticollis. At natural position, angular tremor to abolish the pro-angiogenic and anti-apoptotic amplitudes were plotted in all DOF. Range of activities of the FGF in vivo. Recently, the motion was captured in all DOF at caput and capacity to inhibit FGF-mediated biological collis positions. Kinematic measures actions by 2,5-dihydroxyphenyl sulfonate distinguished dystonic posture, superimposed (DHPS) has been described. The aim of the tremors and dynamic range of motion. present study was to evaluate the in vivo Kinematics can quantitatively measure the efficacy of a derivative of DHPS, 2,5- biomechanics of neck movements in lateral, diacetyloxyphenyl sulfonate (DAPS) to inhibit rotational and up/downward degrees of freedom. tumor progression in a rat model of Since dystonic posturing, range of motion and subcutaneous glioma induced by C6 cell superimposed tremor may all contribute to the implantation in immunocompetent rats. Oral abnormal neck movement, BoNT-A injections DAPS (200 mg/kg/day) for 10 days resulted in can be better tailored if these movements are inhibited progression of glioma as demonstrated separated. Kinematics is able to do this, as by the reduction of size (235±48 vs. 111±27 visual assessment cannot. mm3, p < 0.05) and weight (346±49 vs. 129±29 mg, p < 0.01) of subcutaneous gliomas obtained 1-G-181 Characterization of a new red from DAPS-treated rats. This effect was genetically encoded calcium indicator accompanied by significant inhibition of optimized for 2-photon imaging angiogenesis (73.2±16.5 vs. 39.6±6.3 vessels/mm2, p < 0.05) and increase of Loïs Miraucourt¹, Elena Kutsarova¹, Jiahui apoptosis (5.5±1.1 vs. 24.4±3.3%, p < 0.001) in Wu², Robert Campbell², Edward Ruthazer¹ DAPS-treated tumors. These findings suggest ¹Montreal Neurological Institute, McGill that DAPS displays efficacy in inhibiting glioma University, ²Department of Chemistry, University progression by reducing angiogenesis and of Alberta promoting apoptosis. DAPS represents a promising candidate for treatment of In recent years, there has been intensive glioblastoma and other similar malignancies development of calcium ion indicators that can be used to study the activity of neuronal 1-G-180 Objective kinematic assessment populations in vivo. Much progress has been of torticollis using motion sensors made in improving the sensitivity of green- emitting Genetically Encoded Calcium Indicators Olivia Samotus¹, Fariborz Rahimi¹, Jack Lee¹, (GECIs) based on the jellyfish green fluorescent Mallory Jackman¹, Mandar Jog¹ protein (GFP), allowing the measurement of ¹Western University calcium transients in specific cell types and even within subcellular compartments. A larger color Visual assessment of cervical dystonia (CD) is palette of GECIs to facilitate the study of challenging due to complex abnormal posturing multiple intermingled and potentially interacting and superimposed hyperkinetic movements like cells would greatly expand the potential tremors. Sensor-based kinematic technology applications for GECIs. In the current study, can measure multiple movements using high-speed multiphoton imaging, we simultaneously, providing an objective, characterize the sensitivity of REX-GECO, a quantitative measure of dystonic movement. 11 novel red coral-derived GECI with a long Stokes patients were assessed at weeks 0, 6, 16, 22 shift that we expressed in the brains of Xenopus and 32, receiving BoNT-A injections at week 0, laevis tadpoles. The 2-photon excitation peak for 16 and 32. TWSTRS and UDRS were REX-GECO is 910 nm, coinciding with the administered at each visit. Sensors were maximum excitation of EGFP, making it well attached to the surface of the skin over spinal suited for simultaneous imaging of both REX- segments C2 and T2, above the right ear and on GECO either EGFP or GCaMP. Using each shoulder. Sensors measured kinematic GCaMP6s as a gold standard, we movements. Recorded positions included: rest electroporated GCaMP6s and REX-GECO 88

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 plasmids in tectal neurons and compared their 1-G-183 Whole-brain mapping of direct responses to various stimulation intensities. We inputs to serotonergic neurons of the dorsal measured responses to visual stimuli in vivo and and median raphe nucleus to pharmacological and electrical stimulation in an isolated brain preparation. Our results show Iskra Pollak Dorocic¹, Daniel Furth¹, Yang that although this first variant of REX-GECO has Xuan¹, Victor Salander¹, Marie Carlén¹, properties that make it a promising red GECI for Konstantinos Meletis¹ 2-photon imaging, there are still improvements ¹Karolinska Institute to be made, regarding its sensitivity and toxicity to neurons. Funded by a CIHR grant to REC. The serotonin system is proposed to regulate physiology, behaviour and to underlie mood 1-G-182 Neurointensivist as the main disorders; nevertheless, circuits controlling providers of care for Tele-stroke transfers: serotonergic neurons remain uncharacterized. Our 4-year experience. We therefore generated a comprehensive whole-brain atlas defining the monosynaptic Raisa Martinez¹, Vivek Sabharwal², Gabriel inputs onto forebrain-projecting serotonergic Vidal², Aaron Bridges ², Kenneth Gaines² neurons of dorsal versus median raphe based ¹Louisiana State University Health Sciences on a genetically-restricted transsynaptic Center, ²Ochsner Medical Center retrograde tracing strategy. Using a genetically modified rabies virus in transgenic mice we have Introduction Telestroke networks are crucial to selectively mapped the monosynaptic inputs to providing early and effective care in areas that serotonin transporter (SERT) expressing lack access to acute specialized stroke care neurons. We identified discrete forebrain, services. Numerous studies have shown midbrain and hindbrain neurons targeting variable transfer rates from spoke to the hub serotonergic neurons and found specific inputs facility, but little has been described about the from hypothalamus, cortex, midbrain and basal disposition of the telestroke patients once ganglia, displaying a greater than anticipated admitted to the hub. Objective To complexity and diversity of the cell-type specific restrospectively analyze all the Tele-stroke connectivity. Our results reinforce the patients requiring transfer from the peripheral importance of direct inputs to serotonergic hospitals (spoke) to Oschner Medical Center neurons from prefrontal cortex and lateral (hub) from 2009 to 2013 and to determine the habenula, while uncovering a prominent role for proportion of transferred patients requiring basal ganglia circuits, including inputs from Neurocritical Care services based on admitting striatum, globus pallidus as well as diagnosis. Methods We analyzed the Telestroke dopaminergic and non-dopaminergic substantia program database at Oschner Medical Center nigra neurons. Furthermore, we functionally from the year 2009 to 2013. The patients were probed selected input circuits by using rabies classified into the following diagnosis: ischemic virus containing channelrhodopsin, thus stroke (IS), hemorrhagic stroke (HS), transient selectively stimulating input populations to the ischemic attack (TIA). Results The spoke dorsal raphe nucleus. Our data provide a whole- hospitals requested 2060 Oschner Telestroke brain view of the diversity of circuits that directly Program consults with 652 patients (31.65%) control the activity of the serotonin system. transferred to the hub. Of the patients transferred 523 (80.21%) required Neurocritical 1-G-184 Lipid nanoparticle delivery of Care services. Out of these Neurocritical Care RNA for loss- and gain-of-function studies in patients 425 (81.26%) were diagnosed with IS, neurons in vitro and in vivo. 60 (11.47%) with ICH, and 38 (7.27%) were non-stroke diagnosis. Conclusion David Zwaenepoel¹, Aysha Ansari¹, Colin Neurointensivists provided the care to the Walsh¹, James Taylor¹, Euan Ramsey¹, Pieter majority of patients transferred to our facility due Cullis¹, Brian MacVicar², Hyun Beom Choi², to their complexity. With the rapid expansion of Yu Tian Wang², Yuping Li² tele-stroke centers, the expertise of ¹Precision NanoSystems Inc., ²Brain Research neurointensivists will be increasingly needed Center UBC Hospital University of British and will translate to a need for more Columbia Neurocritical Care beds and trained Neurocritical Care intensivists. A lipid nanoparticle (LNP) technology was developed to deliver mRNA and siRNA into neurons in vitro and in vivo with high efficiency 89

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 and low toxicity: LNPs encapsulating RNA were understanding can impact public policy, prepared using the NanoAssemblr. LNPs mimic comprehensive public communication is low-density-lipoproteins (LDL) which are taken necessary. In order to identify and address up by cells though the LDL-receptor in presence informational gaps or contradictions in media of Apolipoprotein E4 (ApoE4). In vitro - More discourse, we have conducted a content than 98% of primary neurons (PN) grown +/- analysis of 189 Canadian news articles astrocyte feeder layer incubated 1h with siRNA- published between 2003 and 2011 found using LNP (3.3 µg/mL) showed LNP uptake in the Factiva database. Major themes that presence of ApoE4. PN incubated with 100 emerged included 1) descriptions of FASD (e.g., ng/mL of PTEN siRNA-LNP (siPTEN-LNP) for primary and secondary disabilities, severity); 2) 72h showed > 90% knockdown (qPCR, WB). systemic concerns (e.g., inadequate social The knockdown sustained for 21 days after services, inadequate criminal justice treatment (qPCR). Incubation of PN with 100 accommodation); 3) medical concerns (e.g., ng/mL siPTEN-LNP on DIV 6, 9, 13 and 16 access to - and efficacy of - diagnoses, showed > 80% knockdown 72h post-treatment preventions, treatments); and 4) social concerns (qPCR). PN incubated with 500 ng/mL GFP (e.g., criminality, stigma, race and class myths). mRNA-LNP for 72h showed GFP expression Preliminary results indicate a wide variability in (WB). Comparison of Neuro9Kit to reported safe amounts of alcohol while pregnant contemporary transfection kits showed and descriptions of FASD. This likely reflects significantly higher transfection efficiency of 100 disagreements in the literature itself, where ng/mL siPTEN (qPCR). Neuro9Kit showed no these questions remain heavily debated. Our toxicity (LDH). In vivo - An intracranial injection final results will quantify the kind of information of siPTEN-LNP (500 nL at 5 mg/mL) showed > presented to the Canadian public so that we can 85% knockdown of in cortical slices 5 days post- better gauge public discourse about FASD. injection (WB). Solid-core LNP manufactured using the NanoAssemblr demonstrated rapid 1-H-186 For shame! Stigma against fetal uptake by neurons which mediated effective and alcohol spectrum disorder: Examining the sustained silencing/expression of a target gene ethical implications for healthcare practices in vitro and in vivo with no detectable toxicity. and policies This technology offers a simple and flexible alternative to viral vectors, electroporation and Emily Bell¹, Gail Andrew², Albert Chudley³, lipofection for loss- and gain-of-function studies Nina DiPietro⁴, Courtney Green⁵, Judy Illes⁴, in neural development, injury and degeneration. Eric Racine¹ ¹Insitut de recherches cliniques de Montreal, H - History, Teaching , Public Awareness and ²University of Alberta, ³University of Manitoba, Societal Impacts in Neuroscience ⁴University of British Columbia, ⁵Canadian FASD Research Network 1-H-185 Canadian Media Discourse about Fetal Alcohol Spectrum Disorder Fetal alcohol spectrum disorder (FASD) is the leading, non-genetic cause of developmental John Aspler¹, Natalie Zizzo¹, Emily Bell¹, Nina disability in North America. Although stigma is Di Pietro², Courtney Green³, Eric Racine¹ presumed to be an important factor of the ¹Institut de recherches cliniques de Montréal, experiences of individuals with FASD, we lack ²University of British Columbia, ³Canadian FASD specific reflections about stigma or stigma Research Network process in this context. We conducted a review of social sciences and biomedical literatures Fetal Alcohol Spectrum Disorder (FASD), a about stigma and mental health, range of neurodevelopmental disabilities caused neurodevelopmental disorders, and disability as by exposure to alcohol in utero, could affect as well as qualitative research about the many as 1 in 100 Canadians. Its actual experiences of individuals with FASD. A prevalence remains unknown due to confounds deliberative working group of experts (the such as inaccessible diagnostic services, the authors) in the fields of FASD and neuroethics effects of stigma on willingness to report was convened. The following questions were drinking during pregnancy, and uncertainty used to guide discussion by the working group about subtle alcohol-related about stigma and FASD: Are there elements of neurodevelopmental effects. The Canadian stigma associated with FASD that are unique news media has explored some of these from other illnesses? What elements of stigma challenges; however, given that public deserve special attention from an ethical 90

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 standpoint? What ways could stigma be ¹University of Toronto impacted by healthcare or public policy decision- making? The individual with FASD faces Several senior level neuroscience courses in the complex sources of stigma due to the wide neuroscience program have undergone range of disabilities and deficits related to the significant content and curriculum re-design to disorder and the negative associations with their enhance transparent, active, student-centered prenatal exposure to alcohol. Stigma learning. Specifically, the re-design sought to experienced by other members of the family, align undergraduate learning outcomes to match especially the biological mother may also post-graduate expectations in neuroscience. influence and impact the individual with FASD's These outcomes included independent literature own experience with stigma. From an ethical research and critical review, experimental perspective, stigma not only undermines respect design, enhancing presentation skills and peer for the person and their equal access to evaluation through a variety of online and in- opportunities, but also leads to important class activities. Purpose: Course and curriculum compromises in distributive justice across re-design were intended to enhance the various health and social systems traditional classroom approach to learning. internationally. Elements of the re-design included technology- enhanced, extended classrooms and authentic, 1-H-187 The rising tide of transcranial online assignments. Methodology: Students direct current stimulation (tDCS) in the enrolled in two 3rd and 4th year courses were media and peer review literature given different methods of learning outcomes assessments including several online Veljko Dubljevic¹, Victoria Saigle¹, Eric publications, in-class peer reviews of Racine¹ presentations, in addition to classroom teaching. ¹Insitut de recherches cliniques de Montreal Results: Anonymous post-course surveys (IRCM) showed that students felt that online assignments have a beneficial impact and that TDCS has caused excitement in the lay public peer review of assignments have the potential to and academia as a "portable, painless, become a useful pedagogical method. inexpensive and safe" therapeutic and enhancement device. This paper reports the 1-H-189 The impact of a landmark paper results of a content analysis of print media on the concept of free will: Reconsidering coverage and academic papers on tDCS. Four the legacy of the Libet EEG experiments broad areas of focus were identified: therapeutic, enhancement, investigative and Victoria Saigle¹, Veljko Dubljevic¹, Eric technical aspects of tDCS use. The academic Racine¹ literature focused primarily on therapeutic uses ¹Institut de recherches cliniques de Montreal of tDCS (N=427; 45%), with less emphasis on investigative uses (N=294; 31%), enhancement Neuroscientific findings impact the way in which uses (N=120; 13%), and technical aspects individuals perceive themselves and others, (N=104; 11%). In contrast, the focus of the print especially when it comes to morality, media was on enhancement and therapeutic responsibility, and self-control. Results applications (N=92; 42% each), followed by generated by social and cognitive neuroscience investigative uses (N=23; 11%) and technical often appear to generate fundamental insights aspects (N=11; 5%). Print media articles into the workings of our own minds and, thus, focusing on tDCS for enhancement neglected their interpretations garner both academic and reporting side effects. The headlines in print public attention. One landmark contribution are media were enthusiastic. The rising tide of the EEG studies conducted by Benjamin Libet. academic and print media coverage of non- In 1983, Libet reported the results of an investigative uses of tDCS calls for urgent experiment in which he was able to measure regulation. brain activity (or "readiness potentials") several seconds before participants reported being 1-H-188 Extending the neuroscience aware of their intention to act. This result was classroom: Approaches to enhance student interpreted as limiting free will. We report the learning and specific learning outcomes results of a historical meta-analysis of neuroscientific experiments using a Libet-like Pavel Tselichtchev¹, Olivia Dell'Unto¹, Joel paradigm (N=40) in which we investigated (1) Tan¹, Bill Ju¹ available scientific evidence that tries to confirm 91

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 or refute these claims, and (2) the authors' self- 1-IBRO-191 Duchenne Muscular reported metaphysical and societal implications Dystrophy in Probable Monozygotic Twins: of this work. We found a large degree of Seventh Report Worldwide. variance within this body of literature both in 1 2 terms of the methodology used and the purpose Nalaka Wijekoon , Pyara Ratnayake , Vindika 1 1 for conducting the work. Furthermore, despite Suriyakumara , Beneeta Hettiarachchi , 1 3 the fact that the judgments that were measured Lakmal Gonawala , Ashwin Dalal , 4 5 vary from paper to paper, the results are often Sebahattin Cirak , Javad Nazarian , Eric 5 1 combined indiscriminately to refute the Hoffman , Ranil de Silva existence of free will. We recommend caution in 1 making metaphysical claims based on Faculty of Medical Sciences, University of Sri Jayewardenepura, 2Lady Ridgway Children's neuroscience research given their societal 3 impact. Hospital, Center for DNA Fingerprinting and Diagnostics, 4Children's National Medical 5 1-H-190 "Everyday ethics" in Center, George Washington University School neurodegenerative conditions: Examining of Medicine and Health Sciences salient challenges in Parkinson's disease research and health care Duchenne muscular dystrophy (DMD), an X- linked inherited disorder, is a rare incidence in Natalie Zizzo¹, Emily Bell¹, Eric Racine¹ monozygotic twins. We report a sporadic case of ¹Institut de recherches cliniques de Montréal probable monozygotic twin boys (7yrs) clinically diagnosed with DMD. Sociodemographic & Parkinson's disease (PD) is a common clinical data were documented using a standard neurodegenerative condition that affects questionnaire. The delivery of twin 1 and twin 2 approximately 100,000 Canadians and involves was a normal vaginal & Emergency Lower progressive impairments in motor movement as Segment Caesarean Section with birth weights well as psychiatric and cognitive co-morbidities. of 2.0 kg and 2.1 kg respectively where as twin The majority of the ethics literature on PD has 2 was in the special care baby unit for 3 days. been focused on issues related to specific Patients were having difficulties in walking & research and innovative interventions such as climbing stairs from the age of 4.5 years. Both fetal tissue transplantation, gene transfer, and demonstrated bilateral calf muscle hypertrophy deep brain stimulation. While important topics, with weakness of proximal muscles of lower & they do not reflect many of the ethical and social upper limbs, positive Gower's sign, elevated challenges that most PD patients will face in Serum creatinine kinase levels (>9500 U/L), research and health care. Given the lack of myopathic EMG findings & no literature on the "everyday" clinical and research echocardiographic evidence of cardiomyopathy. experiences of PD patients, a review of such Vignos & Brook scales scored 5 & 1 for challenges is warranted. An expanded search of functional status of lower & upper extremities the available ethics and social science literature respectively. Barthel Index demonstrated on the related challenges neurodegenerative variation in the item "climbing stairs" scoring 0 populations experience can enable us to identify and 5 by twin 1 and twin 2 respectively. Mutation issues that are of particular relevance to PD. We detection in the dystrophin gene by multiplex undertake such a review by examining the PCR revealed deletion of exons 08,17 & 19 in current ethics-related literature discussing key twins. We are in the process of zygosity challenges neurodegenerative populations and confirmation at the genetic level & analyzing the related healthcare providers and researchers dystrophin gene mutations by Multiple Ligation face, and discuss how these issues relate to PD. Dependent Probe Amplification technique where We expect challenges are potentially related to the results will be discussed in the poster. The autonomy, capacity, decision-making, rare incidence of DMD in monozygotic twins communication of information, and obligations of provides an opportunity to study the extent of researchers and healthcare providers, and are environmental, genetic & epigenetic factors that relevant for responsible conduct of research and control the different manifestations of the the delivery of ethical care to PD patients. By disease calling attention to these everyday ethical 1-IBRO-192 Characterization of Wnt/b- issues, awareness can be enhanced and may catenin and BMP/Smad signaling pathways contribute to a more patient-centered approach in an in vitro model of amyotrophic lateral to research and health care. sclerosis

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Cristina Pinto1, Pilar Cardenas2, Nelson gather more information on the age-related Osses2, Juan Pablo Henriquez1 changes in very old rats, we undertook a study in 28 month-old female rats. A set of senile rats 1 2 Universidad de ConcepciÛn, Pontificia received an icv stereotaxic injection of either the Universidad Catolica de Valparaiso therapeutic adenovector RAd-IGF-I, expressing the gene for IGF-I (experimental group) or the Different pathways activated by morphogens of control adenovector RAd-DsRed2, expressing the early embryonic development, such as the the gene for the red fluorescent protein. Both Wnt and the Bone Morphogenetic Protein (BMP) groups were tested in the Barnes Maze. ligands, are involved in diverse physiological Interestingly, the experimental group showed and pathological conditions of the nervous some improvement in spatial memory, whereas system, including neurodegeneration. In this the control group displayed a poorer work, we have analyzed the endogenous activity performance. Also, immunohistochemistry of the canonical Wnt/β-catenin and BMP/Smad- studies showed that the experimental group had dependent pathways in an in vitro model of a higher rate of neurogenesis in the Dentate amyotrophic lateral sclerosis (ALS), given by Gyrus than the control counterparts. Also, the motor neuron-like NSC34 cells stably experimental animals showed less astrogliosis expressing wild-type or G93A mutated forms of in the stratum radiatum of the hippocampus than human Cu/Zn superoxide dismutase-1 (SOD1). the control group. These results suggest that As ALS-derived motor neurons, NSC34 cells short-term IGF-I gene therapy can ameliorate expressing mutated hSOD1 show a decreased some age-associated functional and proliferation rate, are more susceptible to morphological deficits in rats and encourage us oxidation-induced cell death and display Golgi to undertake a long-term study, in order to fragmentation. In addition, they display an assess the preventive capability of IGF-I gene impaired ability to induce the expression of the therapy when the treatment is started at an motor neuronal marker Hb9 and, consistently, to earlier age morphologically differentiate into a motor neuronal phenotype. Regarding signaling, our 1-IBRO-194 Tectal EphA3 guides nasal data show that the transcriptional activity retinal ganglion cells axons during associated to the Wnt/β-catenin pathway is retinotectal mapping by competing with decreased, a finding possibly associated to the axonal EphA4 for axonal ephrin-As binding. cytosolic aggregation of β-catenin. In turn, the BMP-dependent phosphorylation of Smad1 and Luciano Fiore1, Mara Medori2, Nicolas Di the transcriptional activation of the BMP/Smad siervi2, Lisandro Anton2, Luisa Teruel2, pathway is increased in the pathologic model. Melina Rapacioli3, Viviana Sanchez2, Nestor Together, these findings suggest that Wnt/β- Carri4, Gabriel Scicolone2 catenin and the BMP-dependent pathways could 1 play relevant roles in the neurodegeneration of Instituto de BiologÌa Celular y Neurociencias, motor neurons in the context of ALS Prof.Eduardo De Robertis (IBCN-UBA- CONICET). Facultad de Medicina. Universidad 1-IBRO-193 Intracerebroventricular IGF-I de Buenos Aires, 2Instituto de BiologÌa Celular y gene therapy for cognitive deficit in the Neurociencias, Prof.Eduardo De Robertis senile rat (IBCN-UBA-CONICET). Faculta, 3Grupo Interdisciplinario de BiologÌa TeÛrica, 1 1 Joaquin Pardo , Gustavo Morel , Paula Universidad Favaloro. , 4Instituto 1 1 1 Reggiani , Claudia HereÒ˙ , Rodolfo Goya Multidisciplinario de BiologÌa Celular, (IMBICE- CIC-CONICET). 1INIBIOLP We demonstrated that tectal EphA3 stimulates Ageing plays a key role in the development of axon growth of nasal retinal ganglion cells neurodegenerative disorders. Although there is (RGC) toward the caudal tectum preventing a substantial number of studies addressing the them from branching in the rostral tectum. Now changes in the brain of old rats (24 mo), there is we postulated that activation of axonal EphA4 scarce information about neurological deficits in decreases axon growth and tectal EphA3 very old rats (28 mo or older). The use of increases axon growth by reducing EphA4 neurotrophic factors, such as IGF-I, is emerging activation throughout competing with axonal as a promising therapeutic tool to prevent neural EphA4 for axonal ephrin-As binding. We used damage and restore the function of the retinal explants treated with EphA3, PIPLC remaining population of neurons. In order to 93

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(sheds ephrin-As) or KYL (EphA4 inhibitor). We electroporated retinas in vivo/in vitro with EphA4, KiEphA4 (dominant negative) or GFP. We showed that: -Nasal RGC axons present higher levels of ephrin-As, colocalization of ephrin-A2/EphA4, and EphA4P than temporal RGC axons. -Axonal response to EphA3 is associated to ephrin-A expression and EphA4- P. -The EphA3 and ephrin-A shedding both decrease the degree of EphA4-P. -Removal of axonal ephrin-As and inhibition of ephrin-As- mediated EphA4 signaling recapitulate the effects of EphA3 on RGC axon growth and branching. -In vitro overexpression of EphA4 produces neurons with shorter axons whereas neurons expressing KiEphA4 have longer axons than the control. In vivo overexpression of EphA4 produces nasal RGC axons with terminal zones closer to the rostral tectum than the control. Nasal RCGs expressing KiEphA4 form terminal zones closer to the caudal tectum. These results support the idea of a new molecular mechanism whereby tectal EphA3 increases axon growth toward the caudal tectum and collaborate to inhibit axon branching in the rostral tectum by decreasing ephrin-As- mediated EphA4 forward signaling.

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POSTER SESSION 2 Julie Boucher¹, Hayley R. Forbes¹, Sai Priya Anand¹, Alison C. Holloway², Anne TM. A - Development Konkle¹ ¹University of Ottawa, ²McMaster University 2-A-1 Status epilepticus-induced precocious expression of KCC2 impairs The teratogenic effects of smoking during excitatory synapse formation pregnancy have been discussed at length in the literature. For this reason, clinicians have been Patricia Awad¹, Bidisha Chattopadhyaya¹, advocating the use of nicotine replacement Nathalie Sanon¹, Joanna Szczurkowska ², therapy (NRT) as a safer alternative, despite Elie Baho¹, Sandra Duss¹, Sébastien animal and human studies questioning both its Desgent¹, Laura Cancedda², Lionel Carmant¹, safety and efficacy. The mechanism and long- Graziella Di Cristo¹ term impacts of nicotine treatment at doses ¹Université de Montréal/CHU Sainte-Justine, mimicking NRT remain elusive. Therefore I ²Istituto Italiano di Tecnologia propose a mechanism involving neuronal-glial interaction dependant upon estradiol Febrile seizures affect 5% of children. About 2% homeostasis. By altering estradiol synthesis, this will develop atypical febrile seizures with an neurosteroid cannot act upon glial cell estrogen increased risk of developing epilepsy later in life. receptors, thus negating its ability to protect the The presence of a cerebral malformation brain from reactive astrocytes' proinflammatory predisposes to the development of both atypical response to nicotine, resulting in neuronal febrile seizures and temporal lobe epilepsy. We damage. Randomly assigned nulliparous female have established a rat model of dual pathology Wistar rats were injected subcutaneously with 1 by combining a cortical freeze Lesion at post- mg/kg/day of nicotine bitartrate or saline for 2 natal day 1 (P1) and Hyperthermia-induced weeks before mating until weaning (postnatal seizure at P10 (LH rats). 86% of LH males day 21). One cohort of pups (saline, n=6 and develop epilepsy and learning and memory nicotine, n=6) was sacrificed at 26 weeks of age deficits in adulthood. The cotransporter KCC2 is and GFAP (glial fibrillary acidic protein), NeuN crucial for inhibitory GABA function and its (neuronal nuclei) and ERα (estrogen receptor α) dysregulation has been associated with several immunohistochemistry were performed. Results diseases. Whether alterations in KCC2 suggest that low-level nicotine replacement expression before the onset of spontaneous during pregnancy alters programming of later life seizures are involved in neural circuit alterations brain immunoreactivity in the offspring. in LH model is unknown. We found increased However, further studies must be performed to KCC2 expression exclusively in LH rats, as well further substantiate these findings throughout as hyperpolarization of the reversal potential of the lifespan. GABA. We also found a significant reduction in spine density and mEPSC amplitude and 2-A-3 Role of GPR55 in the development frequency in CA1 pyramidal neurons. of the central nervous system. Interestingly, KCC2 has been implicated in spine development; we therefore mimicked KCC2 Hosni Cherif¹, Anteneh Argaw¹, Bruno overexpression in hippocampal slice culture by Cécyre¹, Sebastien Desgent², Alex biolistic transfection and in vivo by in utero Bouchard¹, Jonathan Gagnon³, Ken Mckie³, electroporation. Both manipulations decreased Jean-Francois Bouchard¹ spine density and maturity. In parallel, we found ¹University of Montreal, ²St. Justine Hospital that shRNA-mediated KCC2 reduction in vivo research center, ³University of Indianna reduced the time of seizure onset during hyperthermia in LH rats. Determining the role of Guidance molecules, through their receptors KCC2 in spine development and seizure onset expressed at growth cones (GCs), regulate the may help us understand the mechanisms navigation of retinal ganglion cell (RGC) underlying circuit alterations caused by atypical projections toward the visual thalamic nuclei. In febrile seizure. this study, we demonstrate that GPR55 is expressed by the retinothalamic system during 2-A-2 ERα immunoreactivity in the rat development and it regulates GC morphology brain as a consequence of developmental and axon growth via the MAPK pathway. We exposure to nicotine observe that the GPR55 agonists LPI and O1602 induce a chemo-attractive effect on the GC, an increase of its size and the number of 95

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 filopodia present on the GC. Conversely, the exogenous expression of Hsc70 potentiated Trio GPR55 antagonist cannabidiol decreases these Rac-GEF activity in cultured fibroblasts, while endpoints and induces chemo-repulsion. When expression of ATPase-deficient Hsc70 (D10N) these agents are added to neuronal cultures abolished both Trio Rac1 GEF activity, and obtained from GPR55 knockout (GPR55-/ -) netrin-1-induced Rac1 activation. Furthermore, mouse embryos, no effects on growth cone depletion of Hsc70 abolished netrin-1-mediated morphology or on axon growth are observed. cortical axon growth and turning responsiveness Hence, the effects of these pharmacological to a netrin-1 gradient. Taken together, we agents are mediated by GPR55. The MAPK implicate the chaperone activity of Hsc70 in the pathway inhibitor CI1040 induces a decrease in regulation of Trio-dependent Rac1 activation in the effects of the GPR55 ligands on the axon cortical neurons during netrin-1/DCC-mediated growth, the GC area and the number of axon outgrowth. filopodia. In vivo, a single intraocular injection of a GPR55 agonist (LPI) increases branching in 2-A-5 The effects of reducing early life the lateral terminal nucleus (LTN) in hamsters. estradiol on Morris water maze performance Axon branching was decreased following in rats treatment with cannabidiol. These results suggest that GPR55 modulates the navigation of Valeria Fomitcheva¹, Anne Konkle¹ retinal projections and may play an important ¹University of Ottawa role in the development of the neurovisual system. These findings highlight, for the first Estradiol (E2) is important for the development time, the important role played by the GPR55 in of the brain, specifically in areas that exhibit the formation of the central nervous system. A estrogen receptors (ER) such as the better understanding of the brain wiring telencephalon, frontal cortex, amygdala, and mechanisms will lead to potentials new hypothalamus. The cortical regions of the limbic therapies. area are imperative in development of cognitive skills such as memory and learning. The current 2-A-4 The molecular chaperone Hsc70 is study is interested in investigating the effects of a modulator of Trio Rac1 GEF activity, reduced E2 levels on behaviour in rats with critical for netrin-1/DCC-dependent cortical regard to specific tasks such as the Morris water axon outgrowth and guidance maze (MWM). The model developed for diminishing E2 levels in the rats is through Jonathan DeGeer¹, Andrew Kaplan¹, Morgane subcutaneous injections of the aromatase Morabito¹, Ursula Stochaj¹, Fiona Bedford¹, inhibitor formestane (FORM); aromatase is the Anne Debant², Alyson Fournier¹, Nathalie enzyme responsible for converting androgens to Lamarche-Vane¹ estrogens. Prenatal administration was done ¹McGill University, ²CNRS through the pregnant dams, with either sesame oil (vehicle) or FORM given for the last 4-5 days During development, neurons extend axons of pregnancy. During the first four days of life, towards their associated targets in a mechanism neonatal days, pups were treated with either mediated by extracellular guidance cues. Netrin- vehicle or FORM, to construct the following 1 is one such cue that mediates attractive axon treatment groups: prenatal/neonatal: oil/oil, guidance through the receptor Deleted in oil/form, form/form form/oil. Analysis of 12 trials Colorectal Cancer (DCC). Reorganization of the of the MWM task revealed a significant four-way actin cytoskeleton, which underlies axon growth interaction between sex, testing block (a block induced by netrin-1, requires the activity of Rho consists of 4 consecutive trials), prenatal and GTPases. The Rac1 guanine nucleotide neonatal treatment on the latency to find the exchange factor (GEF) Trio is essential for submerged platform - females neonatally treated netrin-induced axon outgrowth, but the with FORM showed elevated latency scores in molecular mechanisms governing Trio activity the second testing block of the MWM. Probe trial have remained elusive. Here, we identify the analysis is ongoing for time spent in each molecular chaperone heat shock cognate quadrant and thigmotaxis (swimming near the protein 70 (Hsc70) as a novel Trio regulator. border). Hsc70 dynamically co-associated with both Trio and DCC in cortical neuron growth cones. The 2-A-6 Calcium imaging in the neural association of Hsc70 with Trio is accommodated stem cell of the adult brain by the N-terminal Sec14-containing and Rac1 GEF domain regions of Trio. Intriguingly, 96

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Archana Gengatharan¹, Magdalena Götz², repressive protein:mRNA complex involving the Armen Saghatelyan¹ translational regulator eIF4E and its binding ¹CRIUSMQ - Universite Laval, ²Institute for Stem partner eIF4ET that is essential to maintain Cell Research Helmholtz Zentrum München - neural stem cells in an undifferentiated state. National Research Center for Environment This complex is localized to granules, and perturbations of eIF4E, eIF4ET, or the P-body Neural stem cell (NSC) persists in the proteins Lsm1 and Rck all cause premature subventricular zone during adulthood. These neurogenesis and deplete stem cells. Analysis NSC transit from the quiescent to the of the eIF4E-T complex shows that it is highly proliferative states to produce new neurons for enriched in mRNAs encoding transcription the olfactory bulb. The mechanisms regulating factors, including many known to drive the transition from quiescence state to neurogenesis. Thus, embryonic neural proliferation states remains unclear. To address precursors are primed to differentiate by this issue we performed calcium imaging in the expression of proneurogenic mRNAs, but an adult NSC at their different states. To distinguish eIF4E/eIF4E-T complex sequesters these different cellular populations, we used BrdU mRNAs in a repressive granule, thereby label-retaining protocol in GFAP-GFP mice and inhibiting their translation and maintaining the a proliferative marker Ki67 post hoc stem cell state until an appropriate immunostaining to differentiate stem cells at developmental time point. their quiescent and proliferative states. Our data reveal that quiescent stem cells display a 2-fold 2-A-8 Anatomical study of the higher frequency of calcium signal compared to relationship between neurons releasing proliferative NSC. Next, we aim to elucidate gonadotrophin hormone and the terminal cellular and molecular mechanisms in the NSC nerve in neonatal opossum (Monodelphis leading to the changes in the calcium dynamic. domestica) To label NSC, we electroporated CAG-GFP plasmid into the postnatal brain and analyzed Naussicca Hour¹, Jean - Francois Pflieger¹, GFP-retaining cells in the adult brain. Therese Cabana¹ Characterisation of electroporated population in ¹Université de Montréal the adult brain reveals that a majority of GFP cells are also immunopositive for GFAP The newborn opossum is quite immature but (expressed by NSC and astrocytes) and that crawls, unassisted, from the birth canal to a among GFP /GFAP cells a substantial mother's nipple where it attaches for several proportion is Ki67 and labels with BrdU-retaining weeks. The forebrain of the newborn is very protocol. We currently employ the immature; fibers which are probably the terminal pharmacological approach to dissect the nerve are the only ones expressing the 200kDA mechanisms underlying different calcium neurofilament NF200, an indicator of maturation signalling in NSC during their different states. of neuronal fibers. They form a thin fascicle from Altogether, our data suggest that the the olfactory bulbs to the lamina terminalis. It mechanisms regulating the transition from was shown in neonatal opossums that neurons quiescent to proliferative state are calcium expressing the gonadotropin luteinizing dependant. hormone releasing hormone (LHRH) migrate from the olfactory placode to the brain using an 2-A-7 The translational regulators eIF4E unidentified neural pathway. To determine if the and eIF4E-T form a repressive protein:mRNA NF200 fascicle is associated with the migration complex that determines neural stem cell of gonadotrophin releasing hormone (GnRH) self-renewal versus differentiation neurons, we have used NF200 and GnRH1 immunochemistry on forebrain slices from Guang Yang¹, David Kaplan¹, Freda Miller¹ neonatal opossums. Our results reveal NF200 ¹Hospital for Sick Children and University of labeled fibers coursing from the nasal septum, Toronto along the olfactory bulb near the midline and reaching the hypothalamus. GnRH1 labeled eIF4E is genetically-perturbed in autism, raising cells were seen along the nasal septum but the possibility that eIF4E-dependent were more numerous in the olfactory bulbs. The translational regulation plays a key role in NF200 fascicle clearly overlapped GnRH1 fibers mammalian brain development. Here, we have as well as GnRH1 cells between the nasal asked if this is so, focusing upon stem cells of septum and the olfactory bulbs. At 15 days, the the embryonic murine cortex. We identify a NF200 fascicle is no longer detected and 97

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GnRH1 fibers were observed in the Baptiste Lacoste¹, Cesar Comin², Ayal Ben- hypothalamus down to the nucleus of the Zvi¹, Pascal Kaeser¹, Xiaoyin Xu³, Luciano diagonal band. These results suggest that Costa², Chenghua Gu¹ NF200 labeled fibers observed in the forebrain ¹Harvard Medical School, ²IFSC, University of of neonatal opossums are the terminal nerve Sao Paulo, ³Brigham and Women's Hospital which serves as substrate for the migration of GnRH1 cells at least to the olfactory bulbs and In the central nervous system, the substrate for of GnRH1 fibers to the hypothalamus. interactions between vascular and neuronal modules is known as the "neurovascular unit". 2-A-9 14-3-3 proteins regulate However, the basic principles orchestrating the commissural neuron responses to netrin development and plasticity of the neurovascular unit remain to be elucidated. To address this, we Andrew Kaplan¹, Ricardo Alchini¹, developed an approach integrating mouse Christopher Kent¹, Timothy Kennedy¹, genetics, 3D imaging and computational Alyson Fournier¹ analysis. First, we characterized the formation of ¹McGill University vascular networks in the developing somatosensory (S1) cortex. We constructed a The ability of neurons to interpret a wide array of compound transgenic mouse to simultaneously environmental cues as they project axons to visualize both neuronal and vascular their targets is critical to establish correct components and identified two phases of neuronal connections during development. We vascular maturation in layer IV of the S1 cortex: previously identified 14-3-3 proteins, a family of i) an early growth period starting at birth with a phospho-serine and -threonine binding adaptor peak of complexity at postnatal day 14 (P14), ii) proteins, as major constituents of the growth a subsequent remodeling period where vascular cone that are important for axon guidance in complexity decreases and then stabilizes. Then, vitro and in vivo, in part through regulation of using a loss of function approach, we protein kinase A (PKA). Here, we show that investigated whether the vascular maturation inhibition of 14-3-3s with the R18 peptide observed in the S1 cortex is driven by neuronal abolishes netrin-dependent attraction of pre- activity. We tested the effects of various sensory crossing spinal commissural axons in the Dunn deprivation paradigms, including follicular Chamber turning assay and blocks netrin- lesions and whiskers removal, which all resulted induced growth cone expansion. Analysis of cell in a reduction of vascular complexity in layer IV signaling reveals that R18 blocks netrin-induced of the barrel cortex, thus identifying a direct role engagement of pathways that are crucial for of neuronal activity in vascular development. axon attraction. Evaluation of DCC dimerization Finally, using a mutant mouse in which reveals that R18 impairs netrin-induced receptor neurotransmitter release is dramatically reduced dimerization, suggesting that 14-3-3 proteins at thalamocortical synapses, we further may function to facilitate DCC dimerization, demonstrated genetically that neuronal activity thereby allowing for appropriate signal drives vascular maturation. These results transduction. In a co-immunoprecipitation deepen our understanding of neurovascular screen for 14-3-3 isoforms that interact with development and plasticity. DCC, we show that 14-3-3zeta, specifically co- precipitates with DCC in a netrin-dependent 2-A-11 Spinal Neuron Identity and manner. Using a GST pull-down assay, we Survival in the Absence of Neurosecretion further show that this interaction is direct. We therefore suggest a novel role for 14-3-3 Chris Law¹, Michel Paquet¹, Matthijs proteins in modulating signal transduction by Verhage², Artur Kania¹ regulating receptor dimerization. Future work will ¹Institut de recherches cliniques de Montréal, continue to address the role of 14-3-3zeta ²Center for Neurogenomics and Cognitive association with DCC in promoting attractive Research responses to netrin. Spinal cord development is critically dependent 2-A-10 Neuronal activity drives vascular upon intercellular communication via the network formation in layer IV of the mouse regulated secretion of morphogens, somatosensory cortex neurotrophins and neurotransmitters. Electrical activity influences neural circuit development by affecting gene transcription, neural tube patterning and axon guidance, though 98

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 understanding of these effects has been Cited2 regulates two distinct stages of precise hampered by the imprecise nature of CPN development in mouse: Cited2 first pharmacologically-induced electrical activity functions broadly in embryonic basal progenitors manipulations. The Munc18-1 protein is critical of the SVZ to regulate generation of superficial to neurosecretion and regulates docking of layer CPN throughout the neocortex; and, next, vesicles containing neurotrophins or functions in an areally-restricted manner neurotransmitters. We examined development postnatally to refine the distinct identity and of the spinal cord of mice lacking Munc18-1 to development of somatosensory CPN. This probe the role of patterned activity and neurally- identification of a postnatal disruption in a derived neurotrophin secretion in spinal neuron specific areal subpopulation of CPN with distinct patterning and survival. Mice lacking Munc18-1 connectivity and function, following a global lack patterned activity, though numbers of reduction in progenitors, highlights not only the molecularly-defined motor- and interneurons are diversity of CPN, but also the fine precision and normal, demonstrating that patterned electrical refinement necessary for the functional activity is not critical for neuronal specification. development of this population of neurons that However, in Munc18-1 mutants there is an are centrally-implicated in high-level cognition. increase in cell death both in vivo and in vitro. As we also observe a dysregulation of 2-A-13 High-Fat Diet-Induced Obesity neurotrophin receptor localisation, we Disrupts Hippocampal Synaptic Plasticity in hypothesise that the observed apoptosis is due both Female Rats and their Offspring to inhibited neurotrophin signalling. When Munc18 is ablated only in motor neurons, they Isabelle Messa¹, John Mielke¹ are spared from apoptosis at E13.5, suggesting ¹University of Waterloo that it is a non-cell autonomous phenotype. Given that Munc18 mutants have a normal The notable increase in obesity prevalence has response to peripheral limb-derived been accompanied by a rise in the number of neurotrophins, our hypothesis is that there is a women of reproductive age who are either remarkable dependence of motor neurons and overweight, or obese. Maternal obesity can interneurons on central neurotrophic signals. place offspring at a higher risk of developing metabolic disease, and mounting evidence 2-A-12 The Transcriptional Co-Regulator suggests that brain development may also be Cited2 functions at Two Distinct Stages of disrupted. As a result, the current study sought Precise Neocortical Callosal Projection to investigate the effects of diet-induced Neuron Development maternal obesity on development of the hippocampus (an area important for learning Jessica MacDonald¹, Ryann Fame¹, Jeffrey and memory). Female rats were fed either a Macklis¹ control-diet (CD), or a high-fat diet (HFD) for 16 ¹Harvard University weeks, and various biometric measures were taken to establish an obese phenotype. Synaptic The neocortex contains thousands of distinct plasticity (long-term potentiation; LTP) was types of precisely connected neurons, allowing it examined in the hippocampal CA1 subfield by to perform remarkably complex tasks of high- recording field potentials from acutely prepared level cognition. The broad population of slices. In addition, a subset of animals were interhemispheric callosal projection neurons bred, and kept on their respective diets (CPN) plays a key role in complex associative throughout gestation and lactation. Pups were cognition, connecting the cerebral hemispheres weaned onto the CD, and sacrificed at young- via the corpus callosum (CC), and integrating adulthood to permit biometric and cortical information. Disruptions in CPN / CC electrophysiological analyses. The HFD induced development are correlated with cognitive and an obese phenotype in the maternal generation, behavioural deficits in multiple but did not affect offspring body weight, or neurodevelopmental disorders, including glucose metabolism. In each generation, agenesis of the CC, autism spectrum disorders, baseline synaptic transmission was unaffected, and schizophrenia. Currently, however, little is but a reduction in the magnitude of LTP was known about the molecular development and observed in the HFD-fed dams, as well as in heterogeneity of CPN, and even less is known both male and female offspring. Taken together, about subpopulations of CPN with distinct, and our data confirm that a high-fat diet can affect likely important associative functions. We have plasticity within the maternal generation, and identified that the transcriptional co-regulator illustrate that maternal obesity can alter the 99

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 development of cellular processes responsible The cerebellum functions in motor coordination for hippocampal plasticity. and also implicated in non-motor behaviors including emotion and cognition. The basic 2-A-14 The effects of environmental circuitry of the cerebellum is well understood. enrichment on transcriptional regulation in Purkinje cells (Pcs) are the sole output of the the hippocampus are associated with early cerebellar cortex and they project to the life maternal care in rats. cerebellar nuclei (CN). The CN provide the main output of the cerebellum. During cerebellar Carine Parent¹, Xianglan Wen¹, Josie Diorio¹, development the CN neurons and Pcs are the Michael Meaney¹, Tieyuan Zhang¹ earliest born among the different neuronal ¹Douglas Mental Health University Institute subtypes. However, they are generated from two distinct germinal zones: the ventrally located Maternal care leads to individual differences in ventricular zone, which produces Pcs and the physiology and behavior within rat offspring. The dorsally located rhombic lip, which produces offspring of High-licking/Grooming (High-LG) large CN neurons. This study utilized whole mothers show increased learning in the Morris mount/section IHC, and primary dissociated Water Maze (MWM) and decreased cerebellar and embryonic cultures to examine corticosterone responses to acute stress. the origin and organization of a new subset of Environmental enrichment (EE) rescues learning CN neurons. The results showed that a subset abilities on the MWM in low-LG offspring but of CN neurons, which are immunopositive for does not ameliorate performance in High-LG SNCA, originate from the mesencephalon and offspring. We used a genome-wide array to migrate to the rostral end of nuclear transitory characterize the transcriptional changes zone. SNCA and p75 neurotrophin receptor associated with EE in the hippocampus of High- double immunostaining suggests that these cells and Low-LG offspring. We performed microarray are derived from the neural crest and they form analyses using Affymetrix Gene 1.0 ST to a combination of neurons and nerve fibers that examine whole genome hippocampal terminate near the pial surface of lobules VI/VII. transcriptional regulation in adult High- and Low- Interestingly, the SNCA /p75 cells divide the LG offspring exposed to standard housing or cerebellar primordium into rostrodorsal and EE. Ingenuity IPA software analysis revealed caudoventral compartments, which correspond that variations in maternal care differentially to the mature anterior and posterior cerebellum. regulated gene expression. In High-LG The position and direction of mesencephalic offspring, EE regulated genes related to derived early CN neurons suggest an important endocrine system disorders, cell-to-cell signaling role as an intrinsic organizer that divides the and hematological system development. In Low- cerebellum into anterior and posterior regions. LG offspring, EE regulated genes related to metabolic disease, cell signaling and connective 2-A-16 Medial preoptic morphology in tissue development. Variations in maternal care the lactating rat and the effects of pCREB regulated gene expression within the central nervous system of offspring. In high-LG Richard Ryan¹, Carine Parent¹, Sabine Dhir¹, offspring, EE influenced inflammatory and Xianglan Wen¹, Josie Diorio¹, Tie Yuan immune functions and affected the expression of Zhang¹, Michael Meaney¹ genes in a network regulated by NFκB. In Low- ¹Douglas Mental Health University Institute LG offspring, EE influenced metabolic and endocrine function and affected the expression The medial preoptic area (mPOA) is an of genes in a network regulated by TNF. Thus, important brain region involved in mediating the effects of EE are differentially influenced by maternal behavior. In this study, we examined variations in early life maternal care. the expression of phosphorylated cyclic adenosine monophosphate responsive element- 2-A-15 Defining a novel subset of binding protein (pCREB) in the mPOA of mesencephalic derived cerebellar nuclei lactating rat dams at 5 days post parturition and neurons mPOA neuronal morphology at 10 days post parturition. We found significantly higher levels Maryam Rahimi Balaei¹, Karen Bailey¹, of pCREB immunoreactive cells in the mPOA of Hassan Marzban¹ high-licking/grooming (LG) mothers compared to ¹University of Manitoba low-LG mothers after an LG bout on post parturition day 5. Morphological analysis using Golgi staining also revealed significant 100

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 differences in the mPOA between high-LG and to the nAcc and an area rich in oxytocin low-LG dams at 10 days post parturition. Low- receptors, and found that OTA infusions LG mothers displayed a significant increase in significantly reduce maternal LG. Finally, we number of neurons with greater dendritic used hippocampal cell cultures to show that complexity in the mPOA compared to high-LG oxytocin increases BDNF expression through mothers. A significant negative correlation was MAP kinase signaling. We suggest that found between the number of neurons with oxytocin-induced regulation of BDNF provides a greater dendritic complexity, and dam's LG and neuroendocrine basis for individual differences arched-back nursing scores. We also found that in maternal behavior. over-expressing CREB in mPOA cell cultures significantly reduced the number of more 2-A-18 Exposure to water immersion dendritically complex neurons present. These stress in mid-adolescence increases risk- findings suggest that the pruning of neurons in taking behaviour and sensitivity to the mPOA through CREB expression may be amphetamine in adult rats. associated with the morphological differences we observed in the mPOA and may in part Meaghan Wilkin¹, Matthew Lam¹, Janet account for individual differences observed in Menard¹ the maternal behavior of these dams. ¹Queen's University

2-A-17 Brain-derived neurotrophic factor We previously found that exposing rats to (BDNF) in the nucleus accumbens mediates intermittent physical stress (IPS) during mid- individual differences in behavioral adolescence increased their exploration of the responses to a natural, social reward normally avoided open-arms of the elevated plus-maze (Wilkin et al., 2012). Others have Dara K. Shahrokh¹, Tie Yuan Zhang¹, Richard linked individual differences in rats' open-arm Ryan¹, Xianglan Wen¹, Josie Diorio¹, Michael exploration with individual differences in J Meaney¹ sensitivity to drugs of abuse, such as ¹Douglas Mental Health University Institute - amphetamine (e.g., Watt et al., 2009). Thus, the McGill University primary goal of the current study was to determine whether mid-adolescent stress- BDNF regulates behavioral responses to induced increases in open-arm exploration are psychostimulants as well as natural rewards. associated with increases in sensitivity to Oxytocin is critical for maternal behavior and amphetamine in adulthood. The secondary goal facilitates behavioral sensitization to was to examine the generality of our prior psychostimulants. Since the neural systems that findings by using a modified stress regimen. In mediate the expression of maternal behavior in the current experiment, male rats were randomly mammals overlap considerably with the reward exposed to a 45 min water immersion, 6 times circuitry, we wondered whether oxytocin might randomly, across the mid-adolescent (PD35-46) act to regulate BDNF expression, and whether period. The rats were later tested in adulthood such effects would in turn mediate the (~PD72), using the EPM and amphetamine- expression of maternal behavior. In situ induced locomotion tests. In line with our hybridization and qRT PCR results revealed previous work, we observed trend-like increases increased BDNF mRNA in the medial prefontal in open-arm activity in adult rats, previously cortex (mPFC), hippocampus, and ventral exposed to water immersion stress in mid- tegmental area (VTA) of high LG mothers adolescence, relative to age-matched no-stress compared to low LG mothers on post partum controls. Additionally, the mid-adolescent stress day 4 (PP4). ELISA and western blot results rats also displayed increases in locomotor revealed increased BDNF and phospho-TrkB activity, in response to low dose (1mg/kg) expression in the nAcc of high LG dams amphetamine, in adulthood. Together these compared to low LG dams on PP4. In order to results suggest that stress during the mid- examine the effect of mesolimbic BDNF on adolescent period might increase an organism's maternal behavior, we immunoneutralized propensity to engage in risk-taking behaviour as BDNF using bilateral anti-BDNF infusions in the well as increase their sensitivity to nAcc and were able to eliminate the differences psychostimulants in adulthood. in pup LG between high and low LG mothers. In addition, we bilaterally infused an oxytocin 2-A-19 Nemo kinase modulates bmp antagonist (OTA) into the ventral subiculum of signaling in synaptic growth PP4 dams, the major input of the hippocampus 101

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28

Kimberly Young¹, Mario Calderon¹ synapses in cerebellar stellate cells. However, it ¹McGill University remains unclear whether this regulation is specific to all GABAergic synapses. Thus, we Retrograde Bone Morphogenic Protein signaling set out to address whether mROS can influence is essential for the coordinated growth of GABAergic neurotransmission in another cell neuromuscular junction synapses during type, specifically, cerebellar granule cells. To do Drosophila larval development: postsynaptic this we used whole cell patch-clamp release of a BMP ligand triggers a retrograde electrophysiology and a mitochondrial poison cascade, which culminates in the (e.g. antimycin-A) to elevate mROS. Similar to phosphorylation and nuclear translocation of the stellate cells, mROS increased the frequency of transcription factor Mad in presynaptic motor miniature inhibitory postsynaptic currents neurons. Previously, we reported that Nemo (mIPSCs) in granule cells in a time dependent (Nmo) kinase phosphorylates Mad at a site manner which was attenuated in the presence of distinct from that phosphorylated by BMP an antioxidant, N-acetylcysteine. Interestingly, receptors, thereby modulating the ability of Mad there was a gradual reduction in tonic current to accumulate in the nucleus. This modulation over time in the presence of antimycin-A. The influences synaptic structural growth but not presence of the δ-subunit was essential for the function and neurotransmitter release. We find increase in mIPSC frequency since δ-KO mice that overactivation of Nmo affects synaptic did not possess an mROS-induced time- function but not structure. Combining fly dependent mIPSC frequency increase. Taken genetics, electrophysiology and imaging, we set together, our data indicates that mROS plays a out to investigate how these two regulatory more global regulatory role at several actions of BMP signaling are alternatively GABAergic synapses since, like stellate cells, regulated by Nmo. Our live imaging analysis granule cells possess GABAergic synapses suggest that activation of Nmo reduces the which are modulated in a subunit-specific residency of nuclear Mad, most likely through an manner via mROS. increase in the rate of nuclear export of Mad. This accelerated nuclear export is correlated 2-B-21 EphA7 in adult rodent brain: with a significant reduction in synaptic release, regional distribution and ultrastructural which can be restored when a non- localization in hippocampus and cerebellum phosphorylatable Mad transgene is expressed in motor neurons. Interestingly, quantitative PCR Akofa Amegandjin¹, Wafaa Jammow¹, Sylvie as well as in vivo reporter assays suggest that Laforest², Mustapha Riad¹, Moogeh transcription of Nmo mRNA is regulated by BMP Baharnoori¹, Frédérique Badeaux¹, Luc signaling in motor neurons. We propose a model DesGroseillers¹, Elena Pasquale³, Guy in which BMP signaling self-regulates its action Drolet², Guy Doucet¹ in motor neurons through transcriptional ¹Université de Montréal, ²Centre de recherche regulation of its own modulator, ensuring normal du CHU de Québec, Université Laval, ³Sanford synaptic growth and function. Burnham Medical Research Institute

B - Neural Excitability, Synapses, and Glia: EphA7 is widely expressed in CNS during Cellular Mechanisms embryogenesis. We mapped its distribution in adult rat and mouse CNS using in situ 2-B-20 GABAergic transmission in hybridization (ISH), immunohistochemistry (IHC) cerebellar granule cells is regulated through and electron microscopy (EM). By ISH, the mitochondrial metabolism strongest signal was observed in the hippocampal pyramidal and granule cell layers. Michael Accardi¹, Beverley Orser², Derek Moderate levels were detected in the habenula, Bowie¹ striatum, amygdala, the cingulate, piriform and ¹McGill University, ²University of Toronto entorhinal cortex, and in the cerebellum, notably Purkinje cells. By IHC, the general distribution Reactive oxygen species (ROS) are important was consistent with ISH results, considering the signaling molecules in the CNS found to play transport of the EphA7 protein to neuronal both physiological and pathophysiological roles. processes, as exemplified in the strongly labeled ROS are particularly important in the context of neuropil layers and weakly stained pyramidal synaptic function since recent evidence has layers of hippocampus. In contrast, in demonstrated that mitochondrial-derived ROS cerebellum, the protein remained in the Purkinje (mROS) can regulate the strength of GABAergic cell bodies. In EM, EphA7 was localized 102

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 essentially in dendritic spines and astrocyte the somatosensory cortex but no genotype processes, often perisynaptic, in hippocampus. differences existed for the response to fourfold- Immunopositive axon terminals were rarely threshold. Preliminary analyses revealed that observed. In the cerebellum, EphA7 KO mice tend to show a reduced contralateral immunoreactivity was prominent in Purkinje cell oxyhemoglobin increase after stimulation somata, with much weaker staining in the compared to WT and HET, but no differences granule cell layer. Ultrastructural examination for deoxyhemoglobin were observed. showed EphA7 mostly intracellularly, associated Discussion: These preliminary results may with vesicles, within Purkinje cell somata. In the suggest that NLG1 is involved in the granule cell layer, the immunolabel was cerebrovascular response to neuronal activity. detected in mainly axons, some axon terminals, Current analyses are being performed on and in dendrites. The preferential localization of specific response parameters (e.g., amplitude, EphA7 in dendritic spines and perisynaptic peak time, response duration). astrocytic processes of the hippocampus is consistent with a role in synaptic plasticity. 2-B-23 GABAA receptor antagonist Further examination of cerebellar deep nuclei promotes oligodendrocyte precursor cell should help clarify its potential roles in this proliferation in adult mice region. Jenna Boulanger¹, Claude Messier¹ 2-B-22 Brain hemodynamic response to ¹University of Ottawa somatosensory stimulation in Neuroligin-1 knockout mice Oligodendrocyte progenitor cells (OPCs) give rise to myelinating oligodendrocytes during Erika Bélanger-Nelson¹, Marlène Freyburger², embryogenesis and early stages of post-natal Éric Beaumont³, Phillippe Pouliot⁴, Frédéric life. A large number of OPCs maintain their Lesage⁴, Valérie Mongrain⁵ undifferentiated state after these initial ¹Center for Advanced Research in Sleep developmental stages making them abundant in Medicine and Research Center, Hôpital du the adult brain. While their proliferative activity Sacré-Coeur de Montré, ²Université de does decline with age, they continue to undergo Montreal, ³East Tennessee State University, cell division throughout adulthood, representing ⁴École Polytechnique de Montréal and Research the most active population of cycling cells within Center, Montreal Heart Institute, ⁵Université de the adult brain. Some studies have also shown Montreal that they may be pluripotent in later stages of life but little is known about the conditions Introduction: Neuroligin 1 (NLG1) is a promoting OPC proliferation and differentiation postsynaptic adhesion molecule that determines in the healthy adult brain. OPCs contain N-methyl-D-aspartate receptor (NMDAR) receptors for both glutamate and GABA which, function and localization. Our recent work when activated, induce depolarization of their showed that Nlg1 knockout (KO) mice cannot membrane. We examined if activity-induced sustain neuronal activity occurring during changes in OPC dynamics could be modulated wakefulness for a prolonged period. Since through synaptic transmission. We measured neuronal activity (and NMDAR activity) drives a the effects of GABAergic agonists and vascular response, we used multispectral optical antagonists on OPC proliferation and imaging to determine if the observed sleep/wake differentiation in vivo. Muscimol (GABAA modifications were associated with changes in receptor agonist), baclofen (GABAB receptor the cerebrovascular response to neuronal agonist), picrotoxin (GABAA receptor stimulation in Nlg1 mutant mice. Methodology: antagonist), and saclofen (GABAB receptor Wild-type (WT), heterozygous (HET) and antagonist) were administered acutely to homozygous Nlg1 KO male mice (B6; 129- NG2Cre/R26S-EYFP mice to study OPC Nlgn1tm1Bros/J) were studied. The brain proliferation and also over 6 days to study OPC hemodynamic response was recorded (12 bit differentiation. Preliminary results suggest that CCD camera), under deep ketamine/xylazine GABAA receptor antagonist picrotoxin promotes anesthesia following stimulation of the left OPC proliferation in healthy adult rodents. forepaw with two different intensities (twofold- Supported by NSERC and fourfold-threshold). Results: Nlg1 KO mice showed a 10% lower response rate to twofold- 2-B-24 Ion channel regulation and threshold stimulation compared to both WT and internal calcium flux of retinal horizontal HET on both the ipsi- and contralateral sides of 103

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 cells under hypoxic conditions in the facilitation they demonstrate during high goldfish (Carassius auratus) frequency bursts. We addressed the mechanisms governing facilitation using whole- Benjamin Campbell¹, Michael Jonz¹ cell electrophysiological recordings, minimal ¹University of Ottawa stimulation and two-photon microscopy in acute hippocampal slices. Two presynaptic Mammals are intolerant to prolonged periods of mechanisms were involved in short-term hypoxia or oxygen-glucose deprivation (OGD) facilitation, with their relative contribution whereas some ectotherms like goldfish dependent on extracellular calcium (Carassius auratus), can survive weeks under concentration. First, synchronization of anoxic conditions. Neurons are especially multivesicular release was observed during susceptible to anoxic damage from trains of EPSCs recorded in 1.2 mM Ca2 . pathologically disrupted ion regulation due to Indeed, covariance analysis revealed an reduced energy availability; Therefore protective augmentation in quantal size during trains of strategies that minimise anaerobic energy EPSCs and a low-affinity glutamate receptor demand are key. Of these, "channel arrest", or antagonist showed an increase in cleft the down-regulation of ion channel abundance glutamate concentration during paired-pulsed or function is critical to anoxic survival. stimulation. Whereas synchronization of Glutamate receptors (GluRs), major contributors multivesicular release contributed to the to excitotoxicity, undergo channel arrest in the facilitation in 1.2 mM Ca2 , variance-mean anoxic turtle brain, and channel arrest has also analysis showed that recruitment of more been demonstrated in the goldfish brain. release sites (N) was likely to account for the Recently, hemichannels too have been facilitation observed in 2.5 mM Ca2 . implicated in the generation of OGD-mediated Furthermore, this increase in N could be damage in mammals. The retina serves as a promoted by calcium microdomains of model of sensory physiology as well as of heterogeneous sizes observed in single MF central nervous system circuitry. Horizontal cells boutons. Overall, our findings reveal that the (HCs) are second order neurons of the retina combination of multivesicular release which are chronically depolarised by synchronization and the recruitment of additional photoreceptor-released glutamate under light release sites supported by the spatial profile of conditions, and utilise GluRs and hemichannels calcium elevations in boutons expands the to mediate formation of the visual field. Patch- dynamic range over which MF reliably transmit clamp electrophysiology and calcium imaging information. techniques can be used to examine the activity of HC ion channels and induced changes in 2-B-26 Imaging synaptic vesicle tethers intracellular calcium. Preliminary results indicate at the presynaptic terminal that glutamate-elicited increases in intracellular calcium are reduced under conditions of OGD. Robert Chen¹, Arup Nath¹, Elise Stanley¹ Further study will elucidate if goldfish HCs retain ¹Toronto Western Research Institute a neuroprotective mechanism to preserve retinal function during low oxygen conditions. Neurotransmitter is released from presynaptic terminals by calcium-gated fusion and discharge 2-B-25 Interplay between of synaptic vesicles (SVs) at the active zone synchronization of multivesicular release (AZ). Based on single-channel gated fusion we and recruitment of additional release sites predicted that SVs are attached to the calcium support short-term facilitation at channels by a molecular tether (Stanley 1993). hippocampal mossy fiber to CA3 pyramidal Recent studies have implicated a link via the cells synapses channel C terminal (Kaeser et al 2011, Wong et al. 2013). Previous studies have imaged Simon Chamberland¹, Alesya Evstratova¹, structures that link SVs to the AZ but these Katalin Tóth¹ methods required complex or analysis-intensive ¹Universite Laval processing. We reasoned that tethered SVs might be visible if unrelated contents of the Synaptic short-term plasticity is a key regulator terminal could be removed. CNS synaptosomes of neuronal communication and is controlled via (isolated presynaptic terminals) were ruptured various mechanisms. A well-demonstrated by osmotic shock; a standard step used to property of mossy fiber (MF) to CA3 pyramidal separate cytoplasm and SVs from the nerve cell synapses is the extensive short-term terminal membranes. When imaged by EM, 104

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 most of the resulting "synaptosomal ghosts" (SSMg) were empty of contents but some Zahra Dargaei¹, Neil Magoski¹ retained a few SVs either attached directly to the ¹Queen's University AZ surface membrane or within the SSMg interior. Fibrous projections that linked SVs to The bag cell neurons of Aplysia initiate egg- the AZ were identified as tethers. SVs within laying behavior by secreting egg-laying hormone <~45 nm of the surface membrane often during a prolonged period of synchronous and exhibited multiple tethers whereas more distant repetitive firing known as the afterdischarge. SVs exhibited only single tethers, with a These neurons function as an electrical maximum length (99% percentile) of 175 nm. syncytium, which is the result of gap junctions. Based on structural predictions, we estimate The generation of an afterdischarge is that channel C-termini could extend as far as accompanied by an increase in intracellular ~200 nm into the presynaptic interior and hence, calcium and upregulation of protein kinase C may correspond to the observed long single (PKC). Here, dual whole-cell recording of paired tethers. Biochemical analysis supports this cultured bag cell neurons shows that electrical interpretation (see: Gardezi et al. CAN 2014 coupling is modulated by calcium and PKC. poster). Elevating calcium with a train of voltage steps which mimics the onset of the afterdischarge 2-B-27 Mechanisms of septin 5-mediated decreased junctional conductance for up to 30 inhibition of neurotransmitter release min. The inhibition was most effective when calcium entry occurred in both electrically Ceilidh Cunningham¹, William Reginold¹, coupled neurons. Depletion of calcium from the Carol Froese¹, Lu-Yang Wang¹, William mitochondria, but not the endoplasmic reticulum, Trimble¹ also attenuated junctional communication. ¹The Hospital for Sick Children Buffering calcium with high intracellular EGTA prevented uncoupling, as did inhibition of Neurons communicate at chemical synapses via calmodulin kinase. Application of PMA, a PKC exocytosis of synaptic vesicles containing activator, to coupled bag cell neurons slightly neurotransmitter. Exocytosis occurs when decreased junctional current, while elevation of vesicle and plasma membranes fuse, a process intracellular calcium in PMA-treated neurons mediated by the bundling of the SNARE proteins inhibited electrical synapses to an even greater syntaxin 1A (STX1A), SNAP25, and VAMP2. extent. Our results demonstrate that calcium- Protein interactions with SNAREs can therefore dependent activation of calmodulin kinase and influence exocytosis. Septin 5 (Sept5), a PKC inhibit electrical signaling. This may synaptic vesicle-associated protein, inhibits contribute to an increase in bursting frequency exocytosis and also binds to the SNARE and enhancement of neuronal excitability which STX1A. Sept5 is a member of the septin family results in the secretion of reproductive hormone. of filamentous cytoskeletal proteins and is expressed predominantly in the brain, where it 2-B-29 PKA-GluA1 coupling via AKAP5 also prevents close docking of synaptic vesicles controls AMPA receptor phosphorylation at the plasma membrane. However, the specific and cell-surface targeting during mechanism underlying the inhibition of bidirectional homeostatic plasticity exocytosis by Sept5 is unknown. Intriguingly, two sequences found within Sept5 contain Graham Diering¹, Ahleah Gustina¹, Richard residues found in the STX1A-binding region of Huganir¹ VAMP2. Thus, Sept5 could compete with ¹Johns Hopkins University VAMP2 for STX1A binding. Using GST pull- down and yeast two-hybrid assays, the current Bidirectional synaptic plasticity occurs locally at study maps the region of Sept5 responsible for individual synapses during LTP or LTD, or STX1A binding and aims to determine if globally during homeostatic scaling. LTP, LTD, mutating the VAMP2-like regions affects STX1A and homeostatic scaling alter synaptic strength binding. This study thereby aims to advance our through changes in post-synaptic AMPARs, understanding of the mechanisms regulating suggesting the existence of overlapping exocytosis and neurotransmitter release. molecular mechanisms. Phosphorylation is critical for controlling AMPAR trafficking during 2-B-28 PKC and Ca2+ suppress electrical LTP/LTD. Here we addressed the role of signaling between neuroendocrine cells of AMPAR phosphorylation during homeostatic Aplysia scaling. We observed bidirectional changes in 105

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28

PKA phosphorylation of GluA1 S845, during calpain to generate a signaling complex scaling, resulting from a loss of PKA from the containing CaMKII and GluN2B Ctail supporting synapse during scaling-down and enhanced synaptic potentiation activity of PKA in the synapse during scaling-up. Altered synaptic PKA signaling, requiring the 2-B-31 Characterization of drg sandwich scaffold AKAP5, alters the effectiveness of synapse neuron pairs: involvement of neuromodulators and NMDAR activation. TRPV1-POSITIVE sensory neuron types Increased phosphorylation of S845 could drive scaling-up while loss of S845 blocked scaling- Brittany Elliott¹, Gabriela Rozanski¹, Elise up. Finally we show that AMPARs scale Stanley¹ differentially based on their phosphorylation ¹University of Toronto/Toronto Western status at S845. These results show that Research Institute rearrangement in PKA signaling controls AMPAR phosphorylation and surface targeting The dorsal root ganglion (DRG) encases the during homeostatic plasticity. neuronal somata (NS) of the peripheral somatic sensory system, which projects a short 2-B-30 Role of calpain-mediated bifurcating axon that branches to the sense cleavage of NMDA receptor GluN2B subunit organ and the spinal cord. Most of the NS are on synaptic potentiation enveloped by a satellite glial cell (SGC) and isolated from each other and there is no Farida El Gaamouch¹, Mado Lemieux¹, Nancy evidence to suggest that direct synaptic Cote¹, Veronique Hamel¹, Paul De Koninck¹ connections occur between DRG NS. However, ¹CRIUSMQ a subset of NS are enclosed in a common SGC capsule separated only by a thin SGC Long-term potentiation (LTP) of excitatory membrane, forming an NS-glial cell-NS (NGlN) synaptic transmission involves Ca2 influx trimer, termed "Sandwich Synapse" (SS) through NMDA receptors (NMDAR), followed by (Rozanski et al., 2012). Our laboratory has a multitude of signaling processes in spines. shown, through the use of electrophysiology and The cytoplasmic tail (Ctail) of NMDAR subunit immunocytochemistry, interneuronal GluN2B acts as a central hub for several protein transmission between NS pairs via transglial- interactions in synaptic plasticity. Previous work signaling pathway (Rozanski et al., 2013a,b). indicated that CaMKII interaction with GluN2B However, it is not known if SS contacts form Ctail plays a central role in LTP. We found that randomly or involve specific DRG soma types. this interaction is required for activation of the In this study we test whether SS neurons belong ERK/MAPK pathway, critical in LTP. Another to the subtypes characterized by the presence enzyme activated by Ca2 influx through the of TRPV1 family of channels which include pain- NMDAR is calpain, which cleaves several sensing neurons. DRGs were dissociated by our substrates including the Ctails of GluN2 standard gentle enzymatic method and were subunits. However, it is unknown whether the immunostained with an antibody against cleavage of NMDAR subunits occurs at TRPV1. Approximately 60% of the dissociated synapses during synaptic transmission and neurons were TRPV1 sensitive. However, our whether it plays a role in synaptic signaling and initial results indicate that staining for this remodeling. By blocking calpain marker is random for the subset of neurons that activation,genetically or pharmacologically, we form SS pairs. Thus, SS contacts are not formed found that it prevented NMDAR-dependent ERK preferentially between this class of sensory activation. We showed by immunoblotting from neurons in the normal ganglion. cortical synaptic fractions that GluN2B is cleaved upon NMDAR activation, releasing a 2-B-32 The role of CAV2.2 DISTAL C- Ctail fragment, still bound to CaMKII. Also, over- Terminus in synaptic vesicle tethering expression of a GluN2B Ctail fragment,not mutated in the CaMKII binding site, could Sabiha Gardezi¹, Fiona Wong², Qi Li², Elise support NMDAR-dependent ERK Stanley² phosphorylation in presence of calpain inhibitor. ¹Krembil Discovery Tower at Toronto Western We also mutated a putative calpain cleavage Research institute, ²Toronto Western Research site on GluN2B and found that the over- Institute expression of this molecular construct could block ERK phosphorylation. Our experiments Voltage gated neuronal calcium channels suggest that NMDAR synaptic activation leads (Cav2.2) gate synaptic vesicle (SVs) fusion and 106

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 discharge at transmitter release sites. Findings that the concentration of carbachol required to that a single Ca2 channel can gate transmitter elicit persistent activity was significantly less in release (Stanley, 1993) suggested that the SVs slices from p75NTR-/- animals. To determine if are 'tethered' within 25 nm of the channel. this effect reflected a loss of neuronal or glial Recent studies (Kaeser et al, 2011; Wong et al, p75NTR, we used a Talpha1:cre driver line to 2013) have proposed that SVs interact with the selectively ablate p75NTR in neurons of channel distal C-terminus. Kaeser et al p75NTRfl/fl animals. To further determine if this proposed that the SV is tethered to the C- effect reflected a developmental defect in terminus by RIM via two links. The first, a direct p75NTR null mice, we generated link to a 4 amino acid PDZ ligand domain within p75NTRfl/fl:CMV-ERcre animals. In both cases, the C-terminus, and the second, an indirect link deletion of p75NTR reduced the threshold for to a PxxP motif. We tested these hypotheses persistent activity in the EC, indicating that using a novel in vitro SV- binding assay termed p75NTR expressed within adult neurons SV-PD (Wong et al, 2013) and Cav2.2 distal C- negatively regulates this property. Bathing EC terminus (C3 region) fusion proteins. SVs were slices with a p75NTR-blocking antibody also captured by the normal C3 fusion protein. reduced the threshold for persistent activity However, SV-PD was not observed with a whereas application of the p75NTR ligand truncated C3 fusion protein (C3prox) comprising proBDNF rapidly and reversibly blocked the PxxP motif, narrowing down the SV persistent firing induced by carbachol. Together, attachment site to the last 58 amino acids. these results showed that the p75NTR controls However, data that SV-PD persisted with C3 neuronal excitability, acting as a negative mutant fusion proteins with a defective PDZ regulator of persistent firing in pyramidal ligand domain or in the presence of a mimetic neurons of EC. peptide blocker argues against a PDZ- dependent mechanism. We conclude that the 2-B-34 The characterization and role of unidentified SV tethering site is within the mitochondrial Ca2+ dynamics in Aplysia terminal 49 amino acid residues proximal to the neuroendocrine cells PDZ-ligand domain. Further, we predict that the channel C-terminal could extend as far as 200 Neil Magoski¹ nm from the surface membrane (see: Chen et ¹Queen's University al. CAN 2014 poster) and, therefore tethering may involve additional short range molecular In many types of neurons, mitochondria regulate links to bring the SV within gating range of the intracellular Ca2 . As such, these organelles can calcium channel. modulate Ca2 -dependent processes. To study this, we characterized mitochondrial Ca2 2-B-33 ProBDNF and p75NTR regulate dynamics in the bag cell neurons of the mollusc, excitability and firing of pyramidal neurons Aplysia californica. Upon stimulation, these neuroendocrine cells undergo an afterdischarge Julien GIBON¹, Nicolas Unsain¹, Shannon during which elevated intracellular Ca2 Buckley¹, Vesa Kaartinen², Philip Barker¹, increases excitability and hormone secretion to Philippe Séguéla¹ initiate reproduction. Cultured neurons were ¹McGill University, Montreal Neurological fura-loaded with whole-cell recording, to monitor Institute, ²The Saban Research institute of intracellular Ca2 under voltage-clamp in Children's hospital Los angeles response to a train stimulus. Secretory output and endocytosis were determined by measuring Persistent activity of entorhinal cortex (EC) changes in membrane capacitance post-train. pyramidal neurons, regulated by cholinergic Stimulation increased cytosolic Ca2 , followed inputs from basal forebrain through activation of by clearance and mitochondrial Ca2 -induced muscarinic receptors, has emerged as a key Ca2 -release (CICR). Ca2 recovery was slowed element in working memory. We are examining by the protonophore, FCCP, or double stranded the role of neurotrophins and their receptors in RNA interference of the mitochondrial Ca2 modulating persistent activity within the EC. uniporter or H /Ca2 exchanger, LetM1. Here, we report on the role of p75NTR and Conversely, CICR was sensitive to intracellular proBDNF in this function. Electrophysiological Na , EGTA, or TPP (an inhibitor of mitochondrial recordings were performed on layer V pyramidal Ca2 exchangers). Furthermore, CICR was neurons in acute EC slices. In this preparation, regulated by the plasma membrane Ca2 ATP- persistent firing is induced by addition of ase, which, when inhibited by carboxyeosin, carbachol, a cholinergic agonist. We observed potentiated CICR. Lastly, while CICR did not 107

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 alter secretion magnitude, it did promote Neural circuits consist of highly dynamic membrane endocytosis, as shown by the networks of excitatory and inhibitory neurons. acceleration of membrane capacitance While synaptic plasticity at excitatory synapses recovery. Thus, we find a contribution of throughout the brain is well-established, mitochondria to both bag cell neuron Ca2 synaptic plasticity of inhibitory synapses is a far dynamics and endocytosis. These results less characterized phenomenon. The bed expand the known physiological roles for nucleus of the stria terminalis (BNST) is a mitochondria and reinforce their importance for structure known to be an interface between fundamental processes of the nervous system. homeostatic neuro-regulation and circuits mediating higher cognitive processes. We have 2-B-35 Effects of a KCC2 blocker on recently shown that changes in synaptic network activity in piriform and entorhinal plasticity in the oval nucleus (ovBNST) is cortices significantly correlated with drug taking behaviors. Thus, the ovBNST serves as a region Shabnam Hamidi¹, Massimo Avoli¹ of interest for studying the role of plasticity, ¹McGill University specifically, that of plasticity at inhibitory synapses. Using whole-cell patch clamping in The efficacy of inhibitory transmission mediated the slice, low frequency stimulation (LFS; 1 Hz by GABAA relies on low levels of [Cl-]i that is 900 pulses) at inhibitory synapses in the controlled by cation-chloride co-transporters ovBNST produced long-term potentiation (LTP) such as KCC2. Here, we investigated the effects of GABAa inhibitory post-synaptic currents induced by blocking KCC2 activity with either (IPSC). Twenty-minutes following LFS, IPSCs VU0240551 (10 µM) or bumetanide (50 µM) on increased on average 173% ± 77% (SE) above the epileptiform activity generated by piriform baseline values and was sustained and and entorhinal cortices during 4AP (50 µM) sometimes continued to increase for up to 60 application in an in vitro brain slice preparation. minutes post-induction (n=9/8). This effect Field potential recordings revealed interictal- appears to be post-synaptically mediated as and ictal- like discharges along with high- there was no change in paired-pulse ratios (0.9± frequency oscillations (HFOs, ripples: 80-200 0.04:1.1 ± 0.09, pre ± SE:post ± SE) and no Hz, fast ripples: 250-500 Hz) in these two significant change in the coefficient of variation regions during 4AP application. In addition, ictal (1/CV2 pre ± SE:post ± SE, 26.8 ± 8.2: 24.3 ± discharges in piriform and entorhinal cortices 6.4). The ubiquity of this phenomenon in the occurred either synchronously or independently brain has yet to be determined. of each other; duration and interval of occurrence of independent ictal discharges was 2-B-37 Neurosteroids modulate interictal longer when compared to synchronized ictal activity and high frequency oscillations in discharges. We also found that ictal discharges the CA3 subfield were abolished in both areas during VU0240551 or bumetanide application; these Rochelle Herrington¹, Maxime Levesque¹, pharmacological procedures decreased interictal Massimo Avoli¹ discharge duration and their interval of ¹Montreal Neurological Institute occurrence. Finally, blocking KCC2 activity increased HFOs occurring in the piriform cortex Two types of spontaneous interictal discharges, during interictal activity. Our data demonstrate identified as fast or slow events, are recorded that ictogenesis can be abolished by inhibiting from the hippocampal CA3 subfield in rodent KCC2 activity. We propose that these effects brain slices during application of 4- result from the reduction of GABAA receptor- aminopyridine (4AP, 50µM). Here, we dependent increases in [K ]o that are known to addressed how neurosteroids modulate the rest on KCC2 function. occurrence of these interictal events and their associated high frequency oscillations (HFOs, 2-B-36 Post-synaptic Long-Term ripples: 80-200 Hz, fast ripples: 250-500 Hz). Potentiation of GABA Synapses in the Oval Allotetrahydrodeoxycorticosterone (THDOC; 100 Bed Nucleus Stria Terminalis nM and 5 µM) was applied during continuous 4AP application. Local field potentials were Emily Hawken¹, Eric Dumont¹ recorded from CA3 with glass micropipettes. ¹Queen's University Under control conditions (i.e., during 4AP application), ripples and fast ripples occurred with 12.3 % and 17.5 % of fast interictal 108

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 discharges, respectively. In contrast, ripples and Key Terms: NCKX, SLC24A gene family, fast ripples co-occurred with less than 1% of calcium homeostasis, sodium-calcium slow interictal discharges. Application of 0.1 to 5 exchange, fluorescent based assay, crystal µM THDOC to 4AP-treated slices caused a structure of NCX_Mj. dose-dependent decrease in the duration of the fast events while that of slow events increased. 2-B-39 Cholinergic regulation of THDOC also led to an increase in the proportion cognitive function and underlying molecular of fast interictal events coinciding with ripples mechanisms (15%) but there was no change in fast ripples co-occurrence. Finally, blocking glutamatergic Benjamin Kolisnyk¹, Mohammed Al-Onaizi¹, transmission abolished the occurrence of ripples Gustavo Parfitt¹, Maxine Kish¹, Jason Xu¹, and fast ripples while blocking GABAA receptor Geula Hanin², Hermona Soreq², Marco signaling increased the occurrence of fast Prado¹, Vania Prado¹ ripples associated with robust interictal activity. ¹University of Western Ontario/Robarts Our data show that neurosteroids differentially Research Institute, ²The Hebrew University of modulate fast and slow interictal discharges, Jerusalem and HFOs occurrence in the CA3 subfield. These effects are presumably due to the Cholinergic vulnerability, characterized by loss potentiation of GABAA receptor mediated of acetylcholine (ACh), is one of the hallmarks of activity. Alzheimer's disease (AD). Recent work has suggested that decreased ACh activity in AD 2-B-38 Residues Important for Ca2+ may contribute to pathological changes through Transport in the Neuronal Na+ /Ca2+ and K+ global alterations in alternative splicing. This Exchanger (NCKX2) occurs via the regulation of the expression of a critical protein family in RNA processing, hnRNP Ali Jalloul¹, Guohong Liu¹, Paul Schnetkamp¹ A/B proteins. Changes in pre-mRNA processing ¹University of Calgary may underlie dysfunction of neurons; impairing plasticity, metabolism, the inflammatory Na /Ca2 K Exchangers (NCKX) belong to the response and promoting neurodegeneration. To SLC24 Solute Carrier gene family of membrane assess the role of ACh in cognitive function we transporters. NCKXs play an important role in targeted the expression of the Vesicular calcium homeostasis in excitable tissues. Five Acetylcholine Transporter (VAChT), the rate different gene products (NCKX1-5) of the limiting step in ACh release. To test the exchanger have been identified in humans and hypothesis that cholinergic tone regulates they play a role in many biological processes alternative splicing in neurons by controlling the including vision in cone and rod photoreceptors, fate of hnRNPA2/B1 expression, thereby olfaction and skin pigmentation. NCKXs are also influencing cognition, we employed a widely expressed throughout the brain. NCKXs combination of genetic in vivo and in vitro are bi-directional plasma membrane Ca2 techniques to alter cholinergic tone and evaluate transporters which utilize the inward Na and expression of hnRNPA2/B1. Decreasing outward K gradients to extrude Ca2 from the cholinergic tone reduced levels hnRNPA2/B1 cytosol (4Na :1Ca2 1K ). Here, we examined and alternative splicing patterns mirroring those residues important for Ca2 transport using a seen in Alzheimer's disease, while increasing fluo4-based assay. Scanning mutagenesis was cholinergic signalling in vivo increased carried out in the two regions with the highest expression of hnRNPA2/B1. This effect is not degree of homology between different NCKX due to decreased hnRNP mRNA expression or isoforms (the α1 and α2 repeats). 13 residues increased degradation of the protein. Cell were found to be important as their substitution culture experiments demonstrated that in the human NCKX2 gene decreased the muscarinic signalling may underlie cholinergic affinity of NCKX2 for Ca2 . Interestingly, most of control of hnRNPA2/B1 expression. Finally we these 13 residues are conserved in the distantly evaluated long term changes in APP processing related archaebacterial exchanger NCX_Mj for and other key AD related transcripts in aged which a crystal structure was recently obtained. forebrain VAChT deficient mice. Location of these residues within the crystal structure of the NCX_Mj revealed that they are 2-B-40 Hydrogen sulfide influences either in direct contact with the Ca2 ion or lining sodium channels in subfornical organ a Ca2 transport pathway at the center of the neurons exchanger. Supported by CIHR MOP-81327. 109

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Markus Kuksis¹, Alastair Ferguson¹ quantum-dot-labelled GluA1 to monitor both the ¹Queen's University exocytosis and lateral mobility of AMPARs in the plasma membrane. To assess the roles of α or Hydrogen Sulfide (H2S) has been shown to act β-CaMKII, we knocked down their expression as a gasotransmitter in the central nervous with specific shRNAs (with or without rescue system to control cardiovascular function. Our transfections) or overexpression of CaMKII previous microarray analyses and RT-PCR have natural inhibitor (CKIIN). Our experiments show shown that enzymes responsible for production that knocking down either subunits lower the of H2S are expressed in the subfornical organ frequency, the amplitude and accelerate the (SFO), and our previous intracerebroventricular decay of exocytosis events of AMPAR- (ICV) injections of H2S into SFO resulted in containing vesicles. Meanwhile, genetic knock increases in blood pressure. This led us to down of either α or β-CaMKII increased AMPAR hypothesize that H2S may alter the excitability synaptic diffusion. However, upon chemical LTP of SFO neurons. We used RT-PCR to confirm induction, we found that the isoforms had the presence of the voltage gated sodium distinct impacts on AMPAR diffusion at channels Nav1.1, Nav1.2, Nav1.3, and Nav1.6, synapses. Our results suggest that both major which are responsible for producing the isoforms of CaMKII in the brain promote the transient and resurgent Na currents. We then accumulation of AMPARs at synapses via a used whole cell patch clamp recordings in combined increase in their exocytosis and voltage clamp to investigate the influence of diffusional trapping, albeit through different H2S on these Na currents. We first used a mechanisms. We are currently examining the voltage step protocol and observed a roles of AMPAR phosphorylation in these depolarizing shift in the activation curve of the processes. transient Na current. We next used a voltage step protocol designed to isolate the resurgent 2-B-42 hERG and hEAG1 K+ channels sodium current. 60% of neurons tested passed a are regulated by Src kinase and by SHP-1 resurgent sodium current measuring on average tyrosine phosphatase via an active ITIM 23.0 ± 13.0% of the peak transient sodium region in the cyclic nucleotide binding current. The current decreased by an average of domain 97.4 ± 8.7 pA in response to H2S in all neurons passing the current. This study has therefore Lyanne Schlichter¹, Jiahua Jiang¹, John identified a potential mechanism whereby H2S Wang¹, Evan Newell², Florence Tsui³, Doris alters the excitability of SFO neurons by Lam⁴ influencing the transient and resurgent voltage ¹Krembil Discovery Tower, Toronto Western gated sodium currents. Supported by the Hospital, ²Singapore Immunology Network Canadian Institutes for Health Research (SIgN) , ³University of Toronto, ⁴Krembil Discovery Tower, Toronto Western Hospital/ 2-B-41 Roles of alpha and betaCaMKII in University of Toronto exocytosis and synaptic trapping of AMPA receptors Members of the EAG superfamily of K channels (EAG/Kv10.x, ERG/Kv11.x, ELK/Kv12.x Simon Labrecque¹, Benoit Audet¹, Christian subfamilies) are expressed in many cells and Tardif¹, Paul De Koninck¹ tissues. In microglia, innate immune cells of the ¹Universite Laval CNS, we published the first studies demonstrating that endogenous ERG-like AMPA receptors (AMPAR) and Ca2 /calmodulin- currents were regulated by Src, a protein dependent protein kinase II (CaMKII) are tyrosine kinase. While the native current was important mediators of synaptic plasticity. The very similar to ERG1, we could not rule out the synaptic delivery of AMPAR in the postsynaptic possibility that it was produced by sites results from interplay between rates of heteromultimeric channels; e.g., ERG1 and exocytosis at extra/peri-synaptic sites and ERG2. Given the importance of EAG and ERG diffusional trapping at synapses. Little is known channels to human pathology, it is crucial to about the specific roles that α/βCaMKII isoforms address regulation of the identified human play in these mechanisms. In this study, we are channels, hERG and hEAG1 by tyrosine using cultured hippocampal neurons, gene phosphorylation. In the present study, we transfer of recombinant SEP-GluA1 (AMPAR demonstrate that tyrosine kinase inhibitor, PP1, receptor subunit fused to pH-sensitive GFP), and the selective Src inhibitory peptide, Src40- TIRF microscopy and single particle tracking of 58, reduce the hERG current amplitude, without 110

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 altering its voltage dependence or kinetics. PP1 the "Groupe de Recherche Universitaire sur le similarly reduces the hEAG1 current. Médicament" (GRUM) and "bourse d'excellence Surprisingly, we discovered an 'immuno- Hydro-Québec de la Faculté des études receptor tyrosine inhibitory motif' (ITIM) within supérieures et post-doctorales de l'Université de the cyclic nucleotide binding domain of all EAG- Montréal". superfamily members, which is conserved in the human, rat and mouse sequences. We found 2-B-44 Developmental regulation of that when tyrosine phosphorylated, this ITIM can synaptic function by hydrogen peroxide at directly bind to and transactivate SHP-1, a developing Xenopus neuromuscular tyrosine phosphatase predominantly expressed synapse. in hematopoietic cells. We show that hERG and hEAG1 currents are regulated by activated Jau-Cheng Liou¹ SHP-1, in a manner opposite to their regulation ¹National Sun Yat-Sen University by Src. Given the widespread distribution of these channels, Src and SHP-1, this work has Successful synaptic transmission at the broad implications in ERG and EAG functions in neuromuscular junction depends on the precise many cell types, including microglia. alignment of the nerve terminals with the postsynaptic specialization of the muscle fiber. 2-B-43 Identification of gene targets for We have previously demonstrated that muscle- Nur77, a transcription factor associated with derived IGF-1 is important in the development of dopamine-related neuroadaptation neuromuscular synapse and hydrogen peroxide (H2O2) plays an important role in the release of Olivier Perreault¹, David Voyer¹, Daniel IGF-1. Here we further test the role of H2O2 in Levesque¹ the development of neuromuscular synapse of ¹University of Montreal Xenopus laevis by using the recording of whole- cell patch clamp. Bath application of H2O2 Nur77 (NGFI-B, Nr4a1) is an orphan nuclear dose-dependently potentiates the frequency of receptor of the transcription factor family spontaneous ACh release in Day-1 Xenopus expressed in brain structures innervated by neuromuscular junction. The dose-response dopamine neurons. Nur77 has been linked to L- curve shift to left while the facilitation effect of dopa and antipsychotic drug-induced H2O2 on SSC frequency was test in Day-3 dyskinesias in animal models and Nur77 cultures, suggesting the sensitivity of H2O2- knockout (KO) mice and rats showed changes in induced facilitating effect reduced as synapse these dopamine-related behaviors. These data matured. Pretreatment of the culture with H2O2 converge to an implication of Nur77 in regulation scavengers both N-Acetylcysteine or sodium and homeostasis of dopamine pyruvate for 1 day significantly hampered the neurotransmission in the striatal complex. development of synapse as the SSC frequency However, Nur77 gene targets implicated in and amplitude both significant reduced in these processes have not been identified yet. treated Day-1 synapses. We next test the effect Using in situ hybridization, we compared basal of H2O2 on Day-1 N-Acetylcysteine/sodium and haloperidol-induced mRNA expression of pyruvate-pretreated synapse was test after several genes associated with striatal plasticity extensively washed the culture to removed N- and functions, including neurotrophic tyrosine Acetylcysteine/sodium pyruvate. The SSC kinase receptor 2, glutamic acid decarboxylase frequency facilitating effect induced by H2O2 1, neurotensin and proenkephalin in wild type was significantly enhanced in treated synapse, and Nur77 KO mice. We then proceed to a which supports the notion that H2O2 in involved bioinformatic analysis to identify putative Nur77 in the development of synapse. Furthermore, response element in those gene promoters co-pretreatment the culture with insulin in N- using MEME Suite platform. The NBRE Acetylcysteine/sodium pyruvate group reversed consensus AAAGGTCA was used to find N-Acetylcysteine/sodium putative binding site for Nur77. Gene reporter assay, electromobility shift assay and chromatin 2-B-45 Sex differences in the spinal immunoprecipitation were performed to confirm mechanisms underlying neuropathic pain in Nur77 regulatory action on these genes. mice Altogether, these results support Nur77 regulatory role of gene related to striatal Josiane Mapplebeck¹, Robert Sorge², Loren adaptation and plasticity. Supported by the Martin³, Jessica Alexander¹, Simon Beggs¹, CIHR (MOP-300152). OP holds fellowships from 111

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Sarah Rosen³, Ji Zhang³, Jeffrey Mogil³, identified in different families with Michael Salter¹ neurodevelopmental disorders, including a 6 ¹University of Toronto, ²University of Alabama at base-pair deletion that results in the loss of Birmingham, ³McGill University amino acids E287 and S288 (ΔES) located near predicted membrane-spanning segment 7. To Chronic neuropathic pain is characterized by better understand the nature of this defect,ΔES mild to severe pain and results in significant as well as single (E287Q, E287A and S288A) human suffering and economic burden. The and double (E287Q-S288A) mutations were spinal mechanisms underlying neuropathic pain engineered in wild-type (WT) NHE6, and the have been extensively investigated in male effects on its biosynthesis, post-translational rodents, indicating an integral role for spinal oligosaccharide processing, membrane microglia-released brain-derived neurotrophic trafficking and function were assessed in factor (BDNF) in the maintenance of pain transfected AP-1 cells as well as cultured hypersensitivity. However, investigation of these hippocampal neurons. We found that only mechanisms in female rodents is nearly constructs containing mutations of E287 nonexistent. Consequently, we examined the displayed impaired glycosylation and decreased spinal mechanisms underlying neuropathic pain half-life compared to WT. The mutants were still in mice of both sexes. First, we demonstrated able to traffic to the plasma membrane, though that mechanical pain hypersensitivity resulting their cell surface levels and rates of endocytosis from Spared Nerve Injury (SNI) was reversed were significantly diminished. Further after inhibiting (via intrathecal minocycline) or examination of the ΔES mutant revealed a lesioning (via intrathecal MAC-1-saporin) pronounced impairment of recycling endosomal microglia in male but not female mice. These pH and cargo trafficking. Transient expression of findings indicate that pain hypersensitivity in the WT and ΔES mutant in cultured female mice is mediated by a microglia- hippocampal neurons also revealed aberrant independent mechanism. Second, we trafficking of NHE6ΔES-containing vesicles that demonstrated that pain hypersensitivity post-SNI accumulated within the soma, were poorly reverts to a microglia-dependent system in sorted along the dendritic processes and lead to immune deficient female mice. Furthermore, a reduction in synapses. adoptive transfer of T-cells rescued the microglia-independent system in immune 2-B-47 Endocannabinoid signaling deficient female mice. Finally, we demonstrated enhances visual responses through a role for BDNF in mediating pain modulation of intracellular chloride levels in hypersensitivity post SNI in both sexes. Our retinal ganglion cells. experiments indicate that female and male mice use distinct spinal mechanisms in the mediation Loïs Miraucourt¹, Jennifer Tsui², Jean- of neuropathic pain hypersensitivity. Taking into François Desjardins¹, Delphine Gobert¹, consideration sex differences in the spinal Perry Spratt¹, Annie Castonguay³, Nicholas mediation of chronic pain may greatly improve Marsh-Amstrong⁴, Anne Scholtz¹, Yves future treatment development. DeKoninck³, Paul Wiseman¹, Edward Ruthazer¹ 2-B-46 Christianson Syndrome-Linked ¹McGill University, ²Marygrove College, ³Institut Mutation in the Na+/H+ Exchanger SLC9A6 Universitaire en Santé Mentale de Québec, Disrupts Recycling Endosomes and Synaptic ⁴John Hopkins University Structures Type I cannabinoid receptors (CB1R) are found Rebecca McKinney¹, Johnathan Reid¹, Alina throughout the retinae of all vertebrates, from Ilie¹, Gergely Lukacs¹, John Orlowski¹ human to fish, but the functional role of ¹McGill University endocannabinoids in vision is not clear. Here we demonstrate that CB1R activation markedly The Na /H exchanger SLC9A6/NHE6 is a improves contrast sensitivity, using a dot recycling endosomal pH-regulating transporter avoidance assay in freely swimming Xenopus that is abundant in the CNS. Within hippocampal tadpoles. We examined multiple levels of the CA1 pyramidal neurons, NHE6-containing visual system from the outer retina to the optic vesicles are distributed throughout the soma tectum, and identified a CB1R-mediated and dendrites, with noticeable accumulation at increase in the intrinsic excitability of retinal dendritic spines and presynaptic terminals. A ganglion cells (RGCs) that paradoxically number of mutations in NHE6 have been requires tonic inhibition through glycine 112

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 receptors. CB1R activation reduced intracellular unit, causing simultaneous internalization of the chloride and negatively shifted the chloride receptor and the effector. equilibrium potential, an effect that could be mimicked and occluded by NKCC1 inhibition. 2-B-49 Examination of TrkB-receptor Consistent with this, hyperpolarizing current signalling and accumbal dendritic spine injections increased RGC excitability, density in the sensitization response to suggesting that tonic inhibition may enhance ethanol RGC responsiveness by de-inactivating voltage- gated channels. These results highlight a critical Christina Nona¹ role for endocannabinoids in modulating vision, ¹University of Toronto and present a novel mechanism for endocannabinoid regulation of neuronal activity. Repeated exposure to ethanol (EtOH) in mice produces behavioural sensitization. We have 2-B-48 Beta-Arrestin2 modulates the recently found that mice resistant to developing signalling complexes formed by the inward EtOH sensitization have decreased levels of rectifying potassium channels KIR3 and trkB mRNA throughout the brain, suggesting a delta opioid receptors critical involvement for TrkB receptor signaling in this behavior. We have also found that Karim Nagi¹, Iness Charfi¹, Terence Hebert², sensitized mice show greater levels of pCREB in Graciela Pineyro¹ the nucleus accumbens (NAc) compared to ¹University of Montreal and Sainte-Justine resistant mice and saline controls. Given that Hospital Research Center, ²McGill University pCREB changes in the NAc induced by other sensitization-producing drugs has been Monitoring of G-protein coupled receptor associated with structural changes in accumbal (GPCRs) interactions has revealed that medium spiny neurons (MSNs), our finding receptors, G proteins and downstream effectors raises the possibility that EtOH sensitization reach the membrane as a signalling unit. These may also involve structural changes in this signalling complexes maintain their integrity neuronal population. Therefore, the overall goal during early stages of receptor activation of the present study was to determine whether implying that proteins responsible for receptor sensitization to EtOH is like that of other drugs, regulation are most probably recruited to the requiring TrkB signalling and involving NAc MSN complex rather than to isolated receptors. Here spine density changes. To this end, male DBA we were interested in the regulation of DOR-Kir3 mice received 5 biweekly EtOH (2.2g/kg, i.p.) or signalling complexes. In a first series of saline injections, after pretreatment with the experiments, we used BRET and co- TrkB receptor antagonist ANA-12 (0 and immunopurification assays, to establish if Kir3 0.5mg/kg, i.p.). In a separate experiment, brains channels constitutively associate with were removed for the analysis NAc MSN spine heterotrimeric G protein subunits and delta density using diolistic labeling. Results showed opioid receptors (DORs). We then showed that that ANA-12 did not block the development of all complex components remained associated EtOH sensitization. Furthermore, sensitization to after sustained activation (30 min) of the EtOH was not associated with changes in NAc receptor with SNC-80 (1 uM). We further MSN dendritic spine density. These results observed that DOR stimulation (SNC-80 1 uM; suggest that the neurobiology underlying EtOH 30 min) induced Barr2 recruitment towards sensitization is distinct from that of other DORs, Gbg subunits and Kir3 channels, and sensitization-inducing drugs. established that receptors and channels expressed in primary neuronal culture were both 2-B-50 Activity-dependent localization internalized by SNC-80 and morphine. and turnover of Argonaute proteins in Moreover, receptors and Kir3 channels hippocampal neurons. colocalized with each other after stimulation with SNC-80 and morphine agonists but only SNC- Nicolas Paradis-Isler¹, Jannic Boehm¹ 80 induced colocalization of Barr2 with DORs ¹Université de Montréal and Kir3 channel subunits. Taken together, these data show that DORs and Kir3 channels Localized protein synthesis in the dendrites of form constitutive complexes that remain neurons is a cellular process critical for synaptic associated during late stages of receptor plasticity. This process is modulated by the activation and indicate that regulatory proteins selective transport of specific messenger such as Barr2 recognize these complexes as a ribonucleic acids (RNAs) to synapses and the 113

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 activity-dependent regulation of their translation and suggests a constant synaptic activity, into proteins. Argonaute (AGO) proteins loaded whereas the second fit is staircase-like and with microRNAs (miRNAs), a class of small non- suggests a burst-like activity. These markers of coding RNAs, target messenger RNAs for synaptic activity enable us to better characterize storage, silencing and/or degradation. As such, the integration of somatosensory information in AGO proteins are important actors in the control the dorsal horn. of local protein synthesis. However, the cellular pathways that direct AGO proteins function in 2-B-52 Homeostatic synaptic plasticity at neurons during synaptic plasticity remain poorly GABAergic synapses requires dystroglycan defined. We are observing by confocal microscopy the distribution of AGO proteins in Horia Pribiag¹, Huashan Peng¹, Waris Shah¹, hippocampal neurons. More specifically, we David Stellwagen¹, Sal Carbonetto¹ monitor the localization of AGO proteins in ¹McGill University dendrites and their spines and changes following selective activation or inhibition of Dystroglycan (DG), a cell adhesion molecule different membrane receptors involved in well known to be essential for skeletal muscle excitatory neurotransmission and synaptic integrity and formation of neuromuscular plasticity. Using immunofluorescence labelling, synapses, is also localized to inhibitory we analyze the occurrence of endogenous AGO synapses in the central nervous system. proteins alongside dendritic and synaptic Mutations that affect DG function not only result structures. We also express ectopically different in muscular dystrophies, but also in severe forms of AGO, some of which have mutations cognitive deficits and epilepsy. Here we altering their affinity for RNA and their tendency investigate the role of DG during activity- to aggregate. We find that AGO proteins are dependent homeostatic regulation of degraded in an activity-dependent manner and hippocampal inhibitory synapses. Prolonged that their ability to bind RNA and their targeting elevation of neuronal activity increases DG to RNA granules affects their localization and expression as well as clustering of DG their turnover in the dendrites of hippocampal colocalized with GABA(A)Rs. In contrast, neurons. inhibition of protein synthesis prevents this activity-dependent accumulation of synaptic DG 2-B-51 Quantification of the frequency of and GABA(A)Rs, and blocks scaling up of spontaneous synaptic currents in the dorsal inhibitory neurotransmission. RNAi-mediated horn of the spinal cord using non stationary knockdown of DG also blocks scaling up of analyses. inhibitory synapses, as does knockdown of LARGE - a glycosyltransferase critical for DG Hugues Petitjean¹, Reza Sharif Naeini¹ function. The DG ligand agrin rapidly increases ¹McGill University GABA(A)R clustering and mimics inhibitory scaling up induced by prolonged increased Primary afferent fibers carry somatosensory activity, indicating that activation of this pathway information from the periphery to the central alone is sufficient to regulate GABA(A)R nervous system. The complex network of trafficking. These data demonstrate for the first interneurons in the dorsal horn of the spinal cord time that DG is regulated in a physiologically serves as the first integrator of sensory relevant manner in neurons, and that DG and its information before transmitting it to projection glycosylation are essential for homeostatic neurons. The temporal integration of inhibitory synaptic plasticity at inhibitory synapses. synaptic inputs (IPSCs) is central to the processing of somatosensory information in the 2-B-53 Optogenetic activation of dorsal horn. Using a voltage-clamp recording of glutamatergic neurons in the medial septum spontaneous IPSCs (sIPSCs) from rodent dorsal drive activity within the septum and across horn neurons, we present a method of sIPSC the hippocampal network. time-frequency analysis based on non-stationary variance. The sIPSC sequence is represented Jennifer Robinson¹, Frederic Manseau ¹, as a time function. Using multi-linear Sylvain Williams² regressions, we observed significant ¹McGill University, Douglas Mental Health distributions that correlated with different states University Institute , ²McGill University, Douglas of synaptic activity. Based on the shape of the Research Center distribution, two types of sIPSCs synaptic activities were extracted. The first fit is linear 114

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Neurons in the medial septum diagonal band of Transmission was, however, blocked by a Broca (MS-DBB) are well known to provide moderate depolarization (-50 mV) or low- important connections to the hippocampus, and concentration Ni2 (0.1 mM). Transmission critical for spatial learning and memory. Three persisted using low voltage pulses to -40 mV main neuronal populations have been identified (holding potential -80 mV) and in the presence in this region: cholinergic, GABAergic and of the HVA current blocker ω-Agatoxin IIIA, glutamatergic. Glutamate neurons were shown confirming the involvement of a low voltage- (by Williams's lab) to project to hippocampus, activated (LVA) channel. This result limited the release glutamate and to discharge rhythmically candidate channel type to either Cav3.2 or an at theta frequency. To further explore the role of inactivation- and Ni2 -sensitive Cav2.3 channel MS-DBB glutamatergic neurons we have used subtype. SNX482 had no significant effect on optogenetics to target these neurons. We have the NS Ca2 current or SS transmission, arguing targeted glutamatergic VGLUT2 neurons of the against the latter. We conclude that inter- MS-DBB with the light-sensitive protein, ChETA. somatic transmission at the DRG SS is gated by The VGLUT2 CRE-mouse line are injected with Cav3.2 type channels. DRG neurons exhibit a ChETA Cre-recombinase adeno-associated sub-threshold membrane potential oscillations virus to specifically target glutamate neurons of (Amir et al. J.Neurosci 1999) that are enhanced the MS-DBB. Using this model we aim to after nerve injury (Liu et al. J.Physiol 2000). determine how the activation of glutamatergic Hence, gating of ATP release by LVA channels neurons from MS-DBB modulate postsynaptic may serve a trophic or homeostatic function in targets both within the septum and across the the normal DRG or play a role in the etiology of hippocampal network. By selectively activating neuropathic pain. these neurons, we have obtained postsynaptic excitatory potentials onto both neurons within 2-B-55 Identifying the interacting regions the septum and to interneurons in the between GluN1 & ND2 in the Src-NMDAR hippocampus. We will further determine how pathway. glutamatergic MS-DBB neurons can modulate hippocampal theta rhythm in the whole septo- David Scanlon¹, Heather Leduc-Pessah¹, hippocampal network in vitro and how this Michael Salter¹ population affects hippocampal theta rhythms in ¹SickKids vivo. These experiments will help to understand how MS-DBB glutamatergic neurons contribute Upregulation of NMDA receptors (NMDARs) by to learning and memory in freely behaving mice. the tyrosine kinase Src is critical for chronic pain hypersensitivity in the spinal cord & 2-B-54 Low voltage-activated calcium hippocampal LTP. Src is anchored in the channels gate transmitter release at the NMDAR complex by an adaptor protein, ND2, dorsal root ganglion Sandwich Synapse (NADH dehydrogenase subunit 2). The primary sequence requirements for the interaction Gabriela Rozanski¹, Arup Nath¹, Michael between Src & ND2 have been determined, but Adams², Elise Stanley³ the interacting regions between ND2 & the ¹Toronto Western Research Institute/University NMDAR complex have remained elusive until of Toronto, ²University of California Riverside, the present study. To elucidate the basis for this ³Toronto Western Research Institute interaction, we transfected HEK293 cells with GFP-tagged ND2 or with one of a systematically The dorsal root ganglion (DRG) contains a generated series of GFP-tagged fragments of subset of closely-apposed neuronal somata ND2, with NMDAR subunits or receptor controls. (NS) that are separated solely by a thin glial cell The NMDAR subunits/controls were membrane septum. Stimulation of one NS leads fluorescently labeled & confocal images to transglial activation of its neighbour via a captured. Thresholded Pearson's Correlation bisynaptic purinergic/glutamatergic pathway, a Coefficient (PCC) was used as measure of signaling mechanism that we term Sandwich colocalization. GFP-ND2 differentially Synapse (SS) transmission. ATP release from a colocalized with both GluN1 alone (0.61 ± 0.03) stimulated NS can be attributed to classical & a GluN1-C-terminal & Amino Terminal Domain calcium (Ca2 )-dependent exocytosis but (ATD) deletion mutant (0.61 ± 0.03), but the involves an undetermined voltage-gated Ca2 additional deletion of the TM4 region led to a channel (Cav) type. Specific blockers and toxins loss of colocalization (0.09±0.04). Swapping in a ruled out gating by the more typical high GluN2A TM4 region into GluN1 recapitulated voltage-activated (HVA) Cav1, 2.1 and 2.2. this colocalization (0.78±0.06), but neither the 115

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GluN1 nor the GluN2A TM4 alone colocalized Sara Soltani¹, Josée Seigneur¹, Sylvain with ND2, illustrating that TM4 is necessary but Chauvette¹, Igor Timofeev¹ not sufficient for this interaction. The ND2 ¹Institut universitaire en santé mentale de fragment 151-223 (0.71±0.02), also colocalized Québec (IUSMQ) with GluN1 alone, but smaller ND2 fragments did not. Thus, we have determined the minimal Traumatic brain injury is a major risk factor for interacting region of ND2 required in the ND2- epileptogenesis. Understanding and preventing NMDAR complex, & identified GluN1 TM4 as a trauma-induced epileptogenesis (TIE) will critical GluN1-ND2 interacting region. prevent epilepsy and therefore significantly increase the quality of life of patients. We aimed 2-B-56 Neurosteroid modulation of to test the age-dependency of TIE in a mouse synchronous activity in the piriform and model of cortical undercut. Because the efficacy entorhinal cortices of pilocarpine-treated and of homeostatic plasticity processes decreases non-epileptic control rats with age, we hypothesized that cortical trauma will induce epilepsy in adult, but not young Zahra Shiri¹, Rochelle Herrington¹, Massimo animals. We performed undercut in the Avoli¹ somatosensory area in C57/BL6 young (3 ¹McGill University months) and adult (12-14 months) mice and implanted LFP electrodes in diverse cortical We employed field potential recordings in brain areas and EMG electrodes for chronic slices obtained from pilocarpine-treated and recordings. The electrographic activities were from age-matched, non-epileptic control (NEC) recorded continuously for at least two months. rats to examine the effects of the neurosteroid Almost all animals generated acute seizures of allotetrahydrodeoxycorticosterone (THDOC) on variable morphology within the first 10 hours the epileptiform activity induced by 4- from lesion. In young animals only isolated aminopyridine (4AP) in the piriform (PC) and interictal spikes were recorded afterwards. In the entorhinal (EC) cortices. Both structures are following weeks, all but one old mouse revealed highly susceptible to generate seizures and may recurrent seizure activities of different types. also be involved in epileptogenesis. Status The most common type was 8-16 Hz spindle- epilepticus (SE) was induced by i.p. injections of like oscillation in frontal cortex accompanied pilocarpine (380 mg/kg) in adult Sprague with an increase in the muscle tone and either Dawley rats. SE was terminated after one hour body freezing or rhythmic contractions. The using diazepam (5 mg/kg) and ketamine (50 lower frequency (3-6Hz) seizures were mg/kg). The in vitro electrophysiology generalized and accompanied by behavioral experiments were carried out four-five weeks freezing and low muscle tone or by rhythmic following SE. Transverse brain slices were muscle and body contractions. The low obtained and bathed in 4AP (50 µM) to induce frequency (1.5-3Hz) seizures were accompanied epileptiform activity. THDOC (5 μM) was bath with rhythmic muscle contractions. We conclude applied and local field potential (LFP) recordings that TIE is age-dependent and is likely due to an were obtained from the PC and EC networks. uncontrolled homeostatic up-regulation of We found that THDOC: (i) decreased interictal excitation in adult animals. discharge frequency in PC of pilocarpine-treated and NEC brain slices while increasing it in EC of 2-B-58 Spreading depression in the brain pilocarpine-treated rats; (ii) reduced the duration of Drosophila melanogaster of ictal discharges in NEC PC as well as in pilocarpine-treated EC; (iii) increased the Kristin Spong¹, Esteban Rodríguez¹, R. occurrence of ripples and fast ripples during Meldrum Robertson¹ interictal events in pilocarpine-treated PC and ¹Queen's University EC; (iv) changed the timing of HFO occurrence during ictal discharges in pilocarpine-treated PC Spreading depression (SD) is characterized by a and EC. Our results demonstrate that massive redistribution of ions which is neurosteroids maintain their ability to control accompanied with an arrest in electrical activity epileptiform synchronization in pilocarpine- that propagates through neural tissue. It is treated epileptic rats. important to understand the cellular mechanisms underlying SD due to its 2-B-57 Seizure patterns induced by association with human pathologies such as cortical deafferentation in adult mice stroke, migraine, and traumatic brain injury. We have recently designed an experimental protocol 116

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 where repetitive SD can be reliably triggered in investigate the hypothesis that the nAChR the fly brain by inhibition of the channel pore collapses in the uncoupled sodium/potassium-ATPase with ouabain. Small conformation by characterizing the pore binding volumes (~5nL) of ouabain were administered of several non-competitive antagonists. Binding directly into the head using a pressure injection of several of these compounds was system and SD was monitored by recording the characterized for both the resting and extracellular potassium concentration in the desensitized conformations, but no (or only very brain with potassium-sensitive microelectrodes. weak) binding was observed to the uncoupled We administered increasing concentrations of nAChR. These studies shed light on the ouabain (10-4M, 2×10-4M, and 5×10-4M) to structural changes that underlie the uncoupling individual preparations and found that ouabain of binding and gating in a eukaryotic nAChR. exerts its effect in a concentration-dependent manner. Additionally, we show that hypotonic 2-B-60 Selective post-synaptic deletion saline exacerbated ouabain-induced SD of DCC from CA1 pyramidal neurons alters suggesting an effect of cell swelling. dendritic spine morphology and impairs Furthermore, we found that flies lacking the spatial memory in aging mice white gene (w1118 mutants), which encodes for an ATP-binding cassette transporter, were more Greta Thompson-Steckel¹, Stephen susceptible to ouabain-induced SD compared to Glasgow¹, Abbas Sadikot¹, Edward wild-type flies (Canton S strain). Lastly, by Ruthazer¹, Timothy Kennedy¹ measuring direct current (DC) potential with two ¹McGill University microelectrodes placed at increased distances from the ouabain injection site we have Little is known regarding the contribution of the demonstrated that these events propagated netrin-1 receptor DCC to synapse function in throughout the fly brain at rates similar to that adulthood. We have recently demonstrated that observed in mammalian cortex. DCC is expressed by neurons in the adult brain and regulates synapse function and plasticity in 2-B-59 Structural Insight into the the mature nervous system. DCC is enriched Uncoupled Conformation of the Nicotinic along both axons and dendrites during Acetylcholine Receptor development, however the precise pre- and post-synaptic functions of DCC at synapses in Jiayin Sun¹, John Baenziger¹ the adult brain remain unclear. We therefore ¹University of Ottawa generated R4ag11::Cre/DCCf/f mice in which DCC expression is selectively eliminated from Nicotinic acetylcholine receptors (nAChRs) are CA1 pyramidal neurons but not in neurons in the members of the superfamily of pentameric adjacent CA3 region of the hippocampus. This ligand-gated cation channels (pLGICs). They conditional loss of DCC from the CA3-CA1 post- are ubiquitous in mammalian nervous systems synaptic neuron resulted in aberrant spine and are implicated in a range of neurological morphology in CA1 neurons in aged mice, while diseases, including Alzheimer's disease, etc. maintaining overall topographical organization. nAChR activity is regulated by its lipid We have also shown that the loss of DCC in microenvironment, which can differentially these transgenic animals results in significant stabilize activatable resting versus non- deficits in spatial memory and novel location activatable desensitized or uncoupled recognition tasks, but fails to disrupt novel object conformations. Interestingly, neuronal nAChRs recognition memory, suggesting that selective expressed in heterologous systems often adopt deletion of DCC in CA1 neurons results in an uncoupled state, leading to the hypothesis disturbances in the neural circuits underlying that uncoupled nAChRs serve as a reserve contextual spatial memory. Together, these population that can be "awakened" to potentiate findings provide evidence for a critical post- the post-synaptic response. Our working model synaptic role for DCC in adult mice and that proposes that uncoupling results from a tilting- DCC contributes to memory consolidation during away of the lipid-facing transmembrane α-helix spatial navigation. M4 from the body of the receptor, leading to weakened interactions between the agonist- 2-B-61 Predicting brain-wide binding domain and channel gating domains, electrophysiological diversity of mammalian and a collapsing of the channel pore. However, neurons from genome-wide expression little direct structural insight into this atlases conformation has been obtained. Here, we 117

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Shreejoy Tripathy¹, Emily Hindalong¹, Garvin saturated under physiological conditions in vivo. Pang¹, Paul Pavlidis¹ Rearing tadpoles in elevated D-serine (100µM) ¹University of British Columbia for 2 days greatly increased the frequency of miniature excitatory postsynaptic AMPAR Brains achieve efficient function through currents and resulted in higher retinotectal implementing a division of labor, in which synaptic AMPA/NMDA ratios compared to different neurons serve distinct computational control animals. To investigate pathways roles. Neuronal computations are established involved in modulating the release of through the expression of combinations of ion endogenous D-serine we used D-serine- channels and associated proteins which define sensitive amperometric biosensors and found neuronal electrophysiological properties. that glutamate receptor activation results in an Despite numerous studies characterizing increase in D-serine release. To examine the neuronal physiological properties and gene effects of D-serine on axonal development, expression patterns, linking neuron genomics to retinal ganglion cells were electroporated to neuron function has been challenging due to the express EGFP and 2-photon images were complexity of these heterogeneous data. Here, collected daily over 4 days. We find that employing data integration and machine- increasing available D-serine during early learning approaches, we combine published developmental periods results in less complex reports of neuronal physiological properties with retinal axons arbors consistent with the public genome-wide expression atlases. hypothesis that D-serine promotes synaptic Specifically, we integrate NeuroElectro maturation and leads to stabilization of axonal (www.neuroelectro.org), a database of literature- branches. These results suggest that D-serine mined neuron-type physiological diversity, with levels are modulated by glutamatergic the Allen Brain Atlas. We demonstrate that neurotransmission in vivo and can influence the relative differences among the genes that maturation of retinotectal synapses and axonal neurons express are significantly predictive of refinement. Supported by a CIHR grant to ESR neuronal biophysical parameters (such as and a Banting Fellowship to MVH. resting potential and input resistance; R² = .65, .41). Our approach allows us to ask which 2-B-63 δGABAA receptors: A novel genes, of the 20,000 in the genome, are most target for gabapentin actions predictive of electrophysiological diversity. In addition to ion channel genes (such as inward Jieying Yu¹, Robert Bonin², Beverley Orser¹ rectifying K channels, e.g. Kcnj4), genes related ¹University of Toronto, ²Centre de Recherche to synaptic plasticity and neuronal differentiation Université (e.g. Slit3) were also surprisingly correlated with neuronal physiology. Moreover, cross- Gabapentin (GBP) is a ɣ-aminobutyric acid referencing these gene lists with those (GABA) analogue that is widely used to treat implicated in mental disorders, we find that neuropathic pain and epilepsy. GBP has these genes are also disrupted in epilepsy, multiple side-effects including anxiolysis, schizophrenia, and autism. sedation and ataxia. The mechanisms underlying the varied effects of GBP are poorly 2-B-62 The importance of D-serine in understood. The α2δ subunit of Ca2 channels is circuit refinement in the developing visual a known target of GBP; however, the interaction system of the Xenopus tadpole at this site fails to fully account for the multiple effects of GBP. We previously showed that GBP Marion Van Horn¹, Edward Ruthazer¹ increased a tonic inhibitory conductance ¹Montreal Neurological Institute generated by extrasynaptic GABA type A (GABAA) receptors in hippocampal neurons D-serine is an endogenous co-agonist for (Cheng et al 2006). GABAA receptors that synaptic N-methyl-D-aspartate receptors contain the δ subunit (δGABAA) generate tonic (NMDAR). Here we examined the inhibitory currents in the CNS. We test the neurophysiological significance of D-serine, a hypothesis that an increase in the activity of known gliotransmitter, in regulating neuronal δGABAA receptors contributes to the activity and axonal remodeling in the developing behavioural properties of GBP. To test this visual system of the Xenopus tadpole. Acute D- postulate, wild-type (WT) and δGABAA receptor serine (100µM) wash-on significantly enhanced null mutant (Gabrd-/-) mice were treated with the NMDAR currents of optic tectal neurons GBP or vehicle (i.p.) 2 hours before testing. The indicating that the NMDAR glycine site is not antinociceptive, anxiolytic and ataxic effects 118

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 were studied with the formalin assay, elevated activation promotes dendritic regeneration in plus maze and rotarod, respectively. The results injured neurons. showed GBP had no effect on phase 1 of the formalin assay but inhibited responses in phase 2-C-65 Persistent individual differences 2 to a similar extent in both genotypes. GBP in stress susceptibility and antidepressant treated WT mice, but not Gabrd-/- mice spent treatment response following chronic social more time in the open arms. GBP decreased stress in mice time on the rotarod in a dose-dependent manner in WT but not Gabrd-/- mice. The expression of Christoph Anacker¹, Michael Kmeid¹, Dara δGABAA receptors is necessary for the Shahrokh¹, Richard Ryan¹, Josie Diorio¹, anxiolytic and ataxic, but not the anti-nociceptive Michael Meaney¹ effects of GBP. Thus, δGABAA receptors ¹McGill University appear to be a novel target for GBP. Identifying the determinants of individual C - Disorders of the Nervous System differences in stress susceptibility and antidepressant treatment response will be 2-C-64 Activation of the mammalian crucial for our understanding of depression target of rapamycin promotes dendritic pathogenesis and for the development of novel regeneration after axonal injury. antidepressant therapies. Here we used social defeat stress, followed by chronic Jessica Agostinone¹, Adriana Di Polo¹ antidepressant treatment, to model stress ¹Université de Montréal susceptibility and antidepressant treatment response in mice. Adult C57/Bl6 mice were Loss of vision in glaucoma is caused by the physically defeated by a new CD1 aggressor death of retinal ganglion cells (RGCs). Emerging mouse for 5 min every day, and subsequently data indicate that early retraction of RGC housed across a partition in the same cage with dendrites plays a prominent role in the aggressor for 24 hours. After 10 days, mice neurodegeneration. Our recent data were segregated into 'susceptible' or 'resilient' demonstrate that: 1) the activity of the phenotypes depending on their social interaction mammalian target of rapamycin (mTOR), a key (SI) score. Susceptible mice were socially regulator of cell growth and protein synthesis, is avoidant (SI score < 1) and showed decreased markedly reduced soon after axonal injury; and sucrose preference, while resilient mice were 2) that mTOR is a key mediator of dendritic not socially avoidant (SI score > 1) and showed stability in adult RGCs. Here, we sought to similar sucrose preference as controls. determine whether mTOR upregulation Fluoxetine treatment (10 mg/kg/day, ad libitum) promotes dendrite regeneration. Acute axonal for 28 days reversed social avoidance behavior injury was induced by optic nerve axotomy in in 53% of susceptible mice, while 47% of mice transgenic mice that express yellow fluorescent did not respond to fluoxetine treatment. protein (YFP) in RGCs under Thy1 promoter Fluoxetine had no effects on social avoidance control. In this strain, only ~1% of RGCs are behavior in control mice. We show that social YFP-labeled, allowing visualization of individual defeat stress, followed by chronic fluoxetine dendritic trees. Two approaches were used to treatment, allows segregation of stress activate mTOR: intraocular injection of a short susceptible and resilient phenotypes, as well as interference RNA (siRNA) against the mTOR of responders and non-responders to inhibitor Redd2 (siRedd2), or systemic antidepressant treatment. This model therefore administration of insulin. Treatment with provides a powerful paradigm to investigate siRedd2 or insulin was performed three days persistent neurobiological mechanisms that are after axotomy, a time when there is substantial crucial for the pathogenesis and treatment of dendritic retraction, and analysis of dendritic depression. length and field area was assessed at one week post-injury. Our data show that mTOR activation 2-C-66 Aberrant glutamatergic synaptic promotes robust dendrite regeneration and connectivity with motoneurons in the spinal restores dendritic length and field area to values cord of zebrafish expressing mutant human similar to those found in intact RGCs. TARDBP (TDP-43) with a mutation causing Rapamycin administration abrogated the ALS and FTLD. regenerative effect of mTOR activation, confirming that dendritic regrowth was mTOR- Gary Armstrong¹, Pierre Drapeau¹ dependent. Our data demonstrate that mTOR ¹Université de Montréal 119

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sensitive dye SBFI. In acute slices hippocampal Mutations in the TARDBP gene encoding TDP- neurons had significantly higher [Na ]i than has 43 have been found in patients with been reported in undamaged neurons, Amyotrophic Lateral Sclerosis (ALS) and particularly near the cut surface of the slice. In Frontotemporal Lobar Degeneration (FTLD). organotypic slice cultures, [Na ]i returned to low Although several animal models have been levels ~2 days after slice trauma. At longer developed to studying pathologies associated incubation times, during which slices become with mutant TDP-43 expression very few have epileptic, [Na ]i increased to levels seen characterized the pathophysiological immediately post-trauma. By 20 days after abnormalities that arise following their trauma, [Na ]i returned to low levels. The Na /K expression. To advance our understanding of ATPase inhibitor ouabain and the KCC2/NKCC1 the pathogenicity of these mutations we used a antagonist furosemide increased [Na ]i. The zebrafish model previously described by our lab NKCC1 antagonist bumetanide increased [Na ]i in which we transiently expressed mutant during the first ~10 days after trauma, and human TARDBPG348C as well as wild type thereafter decreased [Na ]i; thus, in the days TARDBPWT mRNA in zebrafish larvae. We after trauma NKCC1 operates in reverse by examined glutamatergic interneuron synaptic exporting Na . There was a correlation between connectivity with primary motoneurons by [Na ]i and propidium iodide staining, suggesting performing paired recordings by evoking action that [Na ]i may serve as an early biomarker of potentials (APs) while monitoring excitatory neuronal death. Increases in intracellular [Na ]i post-synaptic currents (EPSCs). We observed could engender cerebral edema, cause that glutamatergic EPSCs in larvae over- depolarizing shifts in the reversal potential for expressing mutant TARDBPG348C but not wild GABA, and thus promote early epileptic type TARDBPWT mRNA were significantly seizures. larger in amplitude when compared to controls. We next examined glutamatergic miniature 2-C-68 Beta-amyloid inhibits PDGFbeta excitatory post-synaptic currents (mEPSCs) in receptor activation and prevents PDGF-BB- CaP motoneurons. Two striking features were induced neuroprotection observed: the amplitude of mEPSCs were significantly larger and occurred at a higher Michael Beazely¹, Hui (Lucy) Liu¹, Golam frequency in fish expressing mutant (but not Saffi¹, Maryam Vasefi¹, Nawaz Ahmed¹, WT) TARDBPG348C. These data represent the Nyasha Gondora¹ first electrophysiological description of abnormal ¹University of Waterloo synaptic connectivity in the spinal cord following expression of a mutant TDP-43 and suggests When applied exogenously, PDGF-BB is that a significant excitotoxic component may neuroprotective against ischemia, excitotoxicity, occur in individuals harbouring mutations in and HIV proteins. Given its ability to protect TDP-43. neurons against such a wide variety of insults, we wished to determine if PDGF-BB is 2-C-67 Acute and chronic increases in neuroprotective against beta-amyloid (1-42), neuronal sodium concentrations during one of the putative pathological agents in post-traumatic epileptogenesis Alzheimer's disease. In both primary hippocampal neurons and the human-derived Trevor Balena¹, Kevin Staley¹ neuroblastoma cell line SH-SY5Y, beta-amyloid ¹Massachusetts General Hospital treatment for 24 h dose-dependently decreased cell viability. Pretreatment with PDGF-BB did not Post-traumatic accumulation of intracellular Cl- provide any neuroprotection against beta- results in GABA becoming depolarizing, which amyloid in primary neurons. In SH-SY5Y cells, reduces inhibition, enhances propagation of PDGF-BB pretreatment significantly, but only neuronal firing, and may contribute to early post- partially, prevented beta-amyloid-induced cell traumatic seizures. Charge balance dictates that death. PDGF promotes cell growth and division increases in [Cl-]i may be accompanied by in several systems, and the application of increases in cations, which could underlie PDGF-BB to SH-SY5Y cells resulted in an cytotoxic edema and accompany epilepsy. We increase in cell number. Beta-amyloid tested for changes in intracellular Na attenuated the trophic effects of PDGF-BB. concentration using acute hippocampal slices Upon closer examination, we determined that and organotypic hippocampal slice cultures from beta-amyloid decreased PDGF-BB-induced wild-type C57BL/6J mice, imaged with the Na - PDGFbeta receptor phosphorylation. Despite 120

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 the ability of beta-amyloid to inhibit PDGFbeta for slowing, preventing, or reversing AD receptor activation, immunoprecipitation progression. experiments failed to identify a physical between beta-amyloid and the PDGF-BB ligand or the 2-C-70 It's time to move: a dopaminergic PDGFbeta receptor. The ability of beta-amyloid oscillator driving rhythms of arousal. to block ligand activation of the PDGFbeta receptor may explain the lack of neuroprotective Ian Blum¹, Lei Zhu², Luc Moquin², Maia effects of PDGF-BB. Furthermore, as the PDGF Kokoeva³, Alain Gratton¹, Bruno Giros¹, Kai- system is upregulated upon neuronal damage, Florian Storch¹ the ability of beta-amyloid to inhibit this ¹Douglas Mental Health University Institute - endogenous neuroprotective system may McGill University, ²Douglas Mental Health contribute to the pathology of Alzheimer's University Institute, ³McGill University disease. Ultradian (~4hrs) rhythms of locomotor activity 2-C-69 Characterization of aldehyde that do not depend on the master circadian dehydrogenase 2 (ALDH2) null mice as a pacemaker in the suprachiasmatic nucleus model of age-related cognitive impairment (SCN) have been observed across mammalian with Alzheimer's Disease-like pathologies species, including humans, yet not a single study has attempted to identified the neural Yohan D'Souza¹, Ahmed Elharram¹, David substrate driving these rhythms. We observed Andrew¹, Brian Bennett¹ that distinct alteration of the dopaminergic ¹Queen's University system - by either genetic ablation of the dopamine transporter gene or pharmacological Most animal models of AD rely on the manipulation with psychostimulants - leads to overexpression of genes related to familial AD. ultradian locomotor rhythm lengthening from However, there is a paucity of animal models approximately 4h to greater than 24 hours. that mirror late-onset/age-related AD (95% of Importantly, the antipsychotic haloperidol had AD patients). Oxidative stress is considered a the opposite effect; shortening periodicity in causative factor in age-related AD, and ALDH2 naïve, methamphetamine-treated, and DAT-/- is important for the catabolism of toxic animals. Finally, we observed that striatal aldehydes associated with oxidative stress, For dopamine levels fluctuate in synchrony with example, 4-hydroxynonenal (HNE) adducts ultradian activity rhythms and that the period of accumulate in AD brain and are associated with these ultradian rhythms strongly predicts AD pathology. Given this linkage, we followed dopaminergic tone in both naïve and changes in relevant AD markers in Aldh2 null methamphetamine treated mice. Our data mice and their wild type littermates over a 1 year support the existence of a dopaminergic period. Marked increases in HNE adducts arise ultradian oscillator (DUO) operating in the in hippocampi from Aldh2 null mice, as well as mammalian brain that controls arousal in age-related increases in A-beta, p-tau, p-cofilin concert with the circadian clock. The striking and activated caspases. Also observed are age- similarity between the aberrant sleep/wake related decreases in PSD95, synaptophysin, patterns observed here and in human subjects CREB and pCREB. Age-related memory deficits afflicted with either bipolar disorder or begin at 3 months. These mice exhibit schizophrenia suggests that this clock is endothelial dysfunction, A-beta deposition in similarly perturbed in psychiatric conditions cerebral microvessels, decreases in carbachol- associated with hyperdopaminergia and that induced pCREB formation, and also dystrophic locomotor activity patterns may provide a new neurites, dendritic spine loss, and brain atrophy. biomarker for altered dopaminergic tone and These AD-associated pathological changes are associated mental illnesses. rarely observed as a constellation in current AD animal models. Chronic administration of 2-C-71 Systems Neurobiology of Autism GT1061, a neuroprotectant that targets synaptic Spectrum Disorders (ASD) failure via activation of NO/cGMP/pCREB signaling, reverses the progressive memory James Cairns¹, Daniel Goldowitz ¹, Timothy deficits and biochemical changes that occur in Murphy¹, Allen Chan¹, Price Dickson², Guy these mice, suggesting that this new model will Mittleman², Anna Sinova¹, Ronny Chan¹, prove useful for assessing the efficacy of Praneetha Potluri¹ therapeutic agents for improving memory and ¹University of British Columbia, ²University of Memphis 121

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wildtype mice on the Rotarod. Conversely, ASDs are a heterogeneous group of disorders wildtype mice had better performance than characterized by symptoms such as impaired 3xTg-AD mice on both the grid suspension and and disordered language, decreased social wire hang tasks of grip strength. On the balance interactions, extreme fixation on certain objects beam, wildtype mice had significantly fewer foot or activities and impaired fine and gross motor slips, indicating better performance than movements. We used Lurcher (Lc) mutants and transgenic mice but no significant difference was Lc chimeras as mouse models of autism-like found between genotypes in speed or number of phenotypes to investigate the relationship turns. These findings suggest that the between cerebellar pathology, behavioural mechanisms underlying the improved motor deficits and differences in functional cortical performance of 3xTg-AD mice on the Rotarod activity at rest or following sensory-evoked may not be due to improved grip, balance, or cortical activation. We predict that cerebellar speed but rather may be due to cognitive pathology in phenotypically autistic-like mouse differences in endurance, motivation or anxiety. models (including Purkinje cell (PC) and The improved Rotarod performance, deficits in Granule cell (GC) death) causes a shift in the grip strength and balance of 3xTg-AD mice excitability of surviving cerebellar neurons and should be considered when performing leads to changes in the activity of structurally behavioural tasks on this strain. We are and functionally connected brain regions. Using currently examining motivation and endurance cFos as a marker of recent neuronal activity, we using a voluntary wheel running task and found that there is an inverse relationship performing gait analysis to identify any other between the number of surviving PCs and the motor abnormalities in these mice. density of cFos expression in surviving GCs. In addition, we tested our Lc chimeras on a higher 2-C-73 Increased expression of retinal order form of behavioural flexibility to study the Tau in experimental glaucoma is neurotoxic relationship between PCs and attentional set shifting. If PCs are involved in attentional set Marius Chiasseu¹ shifting then we would expect to see a negative ¹CR-CHUM/University of Montreal relationship between PC number and performance on learning measures. Finally, Retinal ganglion cell (RGC) death is the primary since the cerebellum has many connections with cause of vision loss in most optic neuropathies, the cortex we used Voltage-sensitive Dye (VSD) including glaucoma. There is a high occurrence imaging to look at differences in cortical activity of glaucoma amongst Alzheimer's disease (AD) between Lc mutants and wildtype mice to patients. Indeed, preferential loss of large explore the relationship between the loss of PCs diameter RGCs has been documented in AD and changes in cortical activation. patients. Moreover, AD and glaucoma share a number of pathological features such as the 2-C-72 Characterizing Motor presence of amyloid beta plaques and Tau Performance in the 3xTg-AD Mouse Model of aggregates. In this study, we examined changes Alzheimer's Disease in retinal Tau expression and the effect of Tau on RGC survival using an experimental rat Mackenzie Campbell¹, Kurt Stover¹, Christine glaucoma model. Ocular hypertension (OHT) Van Winssen¹, Richard Brown¹ was induced in rats by injection of hypertonic ¹Dalhousie University saline into an episcleral vein. Retinal Tau expression and phosphorylation were assessed The 3xTg-AD mouse model of Alzheimer's by western blot analysis using antibodies disease has three transgenes including a against phosphorylated and total Tau. The mutated mouse presenilin-1 gene (PS1M1461), cellular localization of Tau was investigated by a human amyloid precursor protein gene retinal and optic nerve immunohistochemistry (APPswe), and a gene associated with human using cell-specific markers. Our data tau pathologies (Tau301L). We examined the demonstrate that OHT leads to a rapid motor performance of 3xTg-AD mice (15M, 15F) accumulation of retinal Tau characterized by a and their wildtype controls (B6129SF2; 15M, complex phosphorylation profile. Both 15F) using a behavioural motor test battery at 6 hyperphosphorylated and hypophosphorylated months of age. Mice were tested on the Tau were detected in glaucomatous retinas Rotarod, wire hang test, grid suspension test compared to intact controls. We show that soon and balance beam. 3xTg-AD transgenic mice after OHT induction, Tau accumulates within had significantly better performance than RGCs, primarily in their dendritic compartment. 122

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Importantly, Tau deletion using siRNA led to Mitochondrial dysfunction has emerged in recent substantial protection of RGC soma and axons years as an important factor contributing to the from glaucomatous damage compared to retinas aetiology of neurodegenerative diseases. To treated with control siRNA. In conclusion, OHT study the impact of mitochondrial activity on glaucoma displays features of a taupathy neuronal function, we deleted the essential namely compartmental redistribution of Tau, mitochondrial protein AIF in the mouse altered phosphorylation and neurotoxicity. forebrain. The loss of mitochondrial function caused by AIF deletion activated several 2-C-74 Translocation breakpoint compensatory mechanisms and triggered the sequencing for the identification of appearance of dysfunctional lysosomes and the pathogenic genes in psychiatry accumulation of ubiquitinated protein aggregates, indicating that mitochondrial activity Cristiana Cruceanu¹, Fabrice Jollant¹, regulates the appearance of these important Gustavo Turecki¹, Carl Ernst¹ features of neurodegenerative diseases. ¹McGill University Furthermore, similar dysfunctional lysosomes were also observed in a cellular model of Numerous studies show high heritability of mitochondrial dysfunction where OPA1, a key psychiatric disorders such as schizophrenia or regulator of mitochondrial cristae structure, is bipolar disorder, but revealing the genes deleted. This cross talk between mitochondria involved has proven difficult due to a was dependent on the presence of LKB1, a combination of study cohort heterogeneity and kinase regulating changes in cellular metabolism imprecise phenotypic boundaries. One way to following a decrease in cellular energy. complement and support large cohort Importantly, the changes in lysosomal function association or linkage studies is to identify exact caused by the loss of mitochondrial function breakpoint boundaries of balanced were independent of autophagy, but required chromosomal rearrangements in subjects with reactive oxygen species. Since loss of psychopathology, thereby pointing to directly mitochondrial function is a central mechanism disrupted genes that may be associated with implicated in neurodegenerative diseases, disease. To 151with unipolar depression, modulation of LKB1-dependent pathways may anorexia nervosa, panic disorder, or autism therefore represent an important strategy to spectrum disorders. High-throughput whole- preserve neuronal survival and function. genome sequencing localized the translocation breakpoint to intron 3 of LRRC4C, encoding the 2-C-76 Neurophysiological traces of L- Netrin-G1 ligand (NGL1), a gene important in DOPA-induced dyskinesia in the bed nucleus axon guidance during brain development. We of the stria terminalis of 6-OHDA-lesioned then assessed 24,277 schizophrenia and rats neurodevelopmental disorder cases and 27,896 controls with Copy Number Variation (CNV) Cynthia Di Prospero¹, Matthieu Bastide², calls; as well as exome sequencing from 41 Emily Hawken¹, Michael Naughton¹, unrelated families (N=189) with a history of Catherine Normandeau ¹, Nikola episodic mood disorders for supporting evidence Misljencevic¹, Erwan Bezard², Eric Dumont¹ of pathogenic variation in this gene. These ¹Queen's University, ²University de Bordeaux results highlight the utility of studying balanced chromosomal rearrangements in families with The most used treatment for Parkinson's high rates of psychiatric disorders and support disease (PD), L-3,4-dihydroxyphenylalanine (L- the need for multi-disciplinary approaches to DOPA), results in involuntary movements build the case for genetic risk factors in complex referred to as L-DOPA-induced dyskinesia (LID). traits. The mechanisms of LIDs are largely unknown and there is no current strategy to prevent or 2-C-75 LKB1-regulated adaptive control LIDs. Recent evidence has found that mechanisms are essential for clearance of the expression of several immediate early genes protein aggregates and neuronal survival is positively correlated with LID severity in a following mitochondrial dysfunction basal forebrain structure, the bed nucleus of the stria terminalis (BNST). Thus, this study aims to Julie Demers-Lamarche¹, Martine Grondin¹, identify potential neurophysiological traces of Marc Germain², Marc Germain¹ LIDs in the BNST of 6-OHDA-lesioned rats. ¹UQTR, ²Ottawa university Male Sprague Dawley rats (N=25) surgically received unilateral 6-OHDA lesions (2.5 µl at 123

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3µg/µl). Three weeks post-op if the lesions rest of the session. Lastly, central administration produce PD symptoms measured by a stepping of OXT occasionally resulted in severe seizures. test, rats received daily injections of the vehicle Benserazide (15mg/kg, i.p.) or L-DOPA 2-C-78 Clustering autism - using (6mg/kg, i.p.) in Benserazide. On the 10th neuroanatomical differences in 27 mouse injection day, rats were assessed for the models to gain insight into the severity of three subtypes of dyskinesia. Rats heterogeneity. were then euthanized one hour post injection and whole cell patch clamping was done in both Jacob Ellegood¹, Evdokia Anagnostou², the juxtacapsular (jx) and oval (ov) areas of the Brooke Babineau³, Jacqueline Crawley⁴, Lulu BNST. L-DOPA treatment was not found to alter Lin⁵, Matthieu Genestine⁵, Emanuel DiCicco- strength at excitatory synapses in the BNSTov Bloom⁵, Jonathan Lai⁶, Jane Foster⁶, Olga or jx as measured by AMPA/NMDA ratios, nor Penagarikano⁷, Daniel Geschwind⁷, Laura was it found to alter DAergic modulations of Pacey⁸, David Hampson⁸, Christine glutamate transmission in these two areas. Laliberte¹, Guy Horev⁹, Alea Mills⁹, Elaine However, preliminary results suggest an Tam⁸, Lucy Osborne⁸, Mehreen Kouser¹⁰, alteration of GABA transmission in ov and Felipe Espinosa-Becerra¹⁰, Zhong Xuan¹⁰, jxBNST. If further investigation confirms this, we Craig Powell¹⁰, Armin Raznahan¹¹, Diane would have a non-striatal mechanism Robins¹², Nobuhiro Nakai¹³, Jin Nakatani¹³, associated with LID that could be a target for Toru Takumi¹³, Matthijs van Eede¹, Travis treatment in the future. Kerr¹⁴, Chris Muller¹⁴, Randy Blakely¹⁴, Jeremy Veenstra-VanderWeele¹⁴, Mark 2-C-77 Role of exogenous oxytocin on Henkelman¹, Jason Lerch¹ heroin self-administration in male Long- ¹Hospital for Sick Children, ²Bloorview Research Evans rats: A time factor effect Institute, ³UCSF School of Medicine, ⁴UC Davis MIND Institute, ⁵UMDNJ - Robert Wood Janie Duchesneau¹, Loïc Welch¹, Cristina Johnson Medical School, ⁶McMaster University, Casola¹, Leon Mayers¹, Uri Shalev¹ ⁷UCLA, ⁸University of Toronto, ⁹Cold Spring ¹Concordia University Harbor Laboratory, ¹⁰UT Southwestern, ¹¹NIH, ¹²University of Michigan, ¹³RIKEN, ¹⁴Vanderbilt Recent studies reported that exogenous University oxytocin (OXT) has some potential for treating individuals suffering from substance use Autism is heritable, with 250+ associated genes disorders. To date, the involvement of OXT has (Banerjee-Basu and Packer, 2010), yet no been mostly reported in relation to single gene accounts for more than 1-2% of psychostimulant drugs. However, earlier studies autistic cases (Abrahams and Geschwind, reported that OXT attenuated the development 2010). The clinical presentation, behavioural of tolerance to the analgesic effects of opiates symptoms, imaging, and histopathology findings and opiate withdrawal, and inhibited heroin self- are strikingly heterogeneous. We propose that administration (SA). Thus, we examined the examining 27 different mouse models related to effects of OXT on heroin SA in male rats and autism using MRI based neuroanatomical hypothesized that central administration of OXT phenotyping can provide a better understanding will be effective in reducing heroin SA. of autism. Imaging was performed ex-vivo using Moreover, considering the very short half-life of an optimized anatomical sequence. In total, 553 exogenous OXT, we analyzed the effects of individual brains were scanned and analyzed OXT on SA over time, under different types of with previously described methods (Lerch et al. injection and training conditions. Male Long- 2012). The volumes of 62 different regions (Dorr Evans rats were trained to SA heroin for 66 days et al. 2008) were calculated. Group differences under fixed and progressive ratio schedules of across the models were then used to cluster reinforcement to assess their motivation for both regions and the models together. The heroin taking. Once heroin SA stabilized, rats clustering of models revealed 3 large groups were administered OXT (0.0, 0.5 and 2.5 ug/rat; (Figure 1). Group 1 (En2, Fmr1, Nrxn1α, and i.c.v. or 1 mg/ml; i.p.; counterbalanced), before Shank3) had increases in the cortex and white the SA session. The results suggest a strong matter structures and decreases in the initial sedative effect of OXT at the beginning of cerebellar cortex. Conversely, in group 2 (AndR, the SA session. However, a clear augmentation BTBR, Gtf2i (+/-), Itgβ3, and Nlgn3 KI) white of responses for heroin was observed for the matter structures were found to be smaller.

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Group 3 (15q11-13, 16p11, BALB/c, Cntnap2 (- 2-C-80 Optimization of Deep Brain /-), Gtf2i (dp/dp), Mecp2, Nf1, Slc6A4 KI (129), Stimulation Parameters for PD Patients and XO) had a mixture of increases and Using Objective Measures decreases (Figure 1). This all suggests that the autistic phenotype not only recapitulates the Greydon Gilmore¹, Kristina Ognjanovic¹, heterogeneity seen in human autism, but also Mehdi Delrobaei¹, Mandar Jog² affects key brain regions, and divides into ¹Western University, ²Western University clusters based on directionality and localization Hosptial of the differences. This work can lead to an increased diagnostic specificity and targeted Background: Deep Brain Stimulation (DBS) is a treatment. complex surgical therapy that seeks to reduce the symptoms of advanced, L-DOPA responsive 2-C-79 Sustained Ischemia/Hypoxia PD patients who are not adequately controlled Follows Cessation of Seizures and Results in by medication. DBS is a relatively new Todd's Paralysis technique and as such its full potential remains elusive. The programming of the device is still a Jordan Farrell¹, Rachel Wang¹, Jeff Dunn¹, trial and error process. Methods: 24 DBS Michael Antle¹, G. Campbell Teskey¹ patients will be monitored during programming ¹Hotchkiss Brain Institute/University of Calgary sessions for 6 months. Whole-body mobility, gait and speech are assessed. We use a gait Seizures are frequently accompanied by analysis system (PKMAS) to measure a variety behavioural impairments that occur after the of gait parameters including: walking speed, seizure terminates and can last for several stride length, cadence and functional ambulation minutes to hours. Todd's Paralysis, for example, profile. We also use a motion capture body suit is specific to seizures that affect motor cortex (Animazoo) to measure mobility parameters and is marked by severe muscle weakness on such as: rest and action tremor, bradykinesia, the contralateral side. Although recognized first arm swing, range of motion, balance and in 1849, we still do not have an explanation for postural stability. Once the data has been its occurrence. Given the strikingly similarities to collected and analyzed, we will establish a stroke, we hypothesized that there is a severe standardized DBS stimulation program for future ischemic/hypoxic event that follows seizures and DBS patients. Pre-operation assessments of gives rise to specific behavioural impairments. future patients will be carried out. These will We first approached this by recording local then be entered into the program and the tissue oxygenation in the hippocampus of patient's optimal DBS set-point will be awake, freely moving rats. Following brief computed. Results: Preliminary data has shown seizures, we discovered that hippocampal tissue fluctuations in various programming parameters. oxygenation dropped below 10mmHg (severe We have documented that some programming hypoxia) and remained below this level for over parameters are more efficacious than others. an hour. Hypoxia was also confirmed with an Conclusion: Future clinicians will be able to use immunohistochemical marker of hypoxic cells the system as a set point for their patients DBS (HypoxyprobeTM-1). We then showed that device. As a result of this study DBS patients hippocampal blood flow was reduced during the will have a significantly reduced DBS entire duration of hypoxia and pretreatment with programming time, optimal personalized DBS nifedipine, a potent anti-vasoconstrictor, settings and an overall improved quality of life. restored blood perfusion and tissue oxygenation to the hippocampus. Lastly, we employed 2-C-81 Age-related changes in brain nifedipine as a tool to determine the effect of region weights are associated with caspase hypoxia on forelimb motor weakness following activation in wild type C57Bl6 mice. neocortical seizures. Forelimb weakness was observed at 40 minutes post-seizure only in rats Melissa Lessard-Beaudoin¹, Marie-Josee that experienced hypoxia after a seizure Demers¹, Melissa Laroche¹, Guillaume (vehicle). In sum, we have discovered a novel Grenier¹, Rona Graham¹ phenomenon, which we have termed, Seizure- ¹Univerity of Sherbrooke Induced Severe Ischemic/Hypoxic Episode (SISIHE), which is responsible for Todd's The prevalence of neurodegenerative disorders Paralysis. is increasing dramatically as people are living longer and now affects millions of people. Activation of caspases is a key event in the 125

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 pathogenesis of several neurodegenerative Disrupting ΔΨm with CCCP blocks import and diseases. Caspase-6 (casp6) in particular has stabilizes PINK1 on the mitochondrial outer emerged as an important player in the neuronal membrane, which in turn promotes Parkin degeneration in Alzheimer and Huntington recruitment. We previously identified a key step disease where it is activated early in the in PINK1 turnover, mediated by the disease. We undertook a study to assess the mitochondrial processing peptidase (MPP). MPP effects of aging on organ size in wild type knockdown stabilizes PINK1 at the C57Bl6 mice and to determine the role of mitochondrial surface, induces Parkin apoptotic mechanisms in the pathophysiology of recruitment, and leads to mitochondrial aging. Peripheral organs, body and brain region clearance, much like CCCP. Here we show that weights were collected from young (3-4m), mid MPPβ silencing-induce PINK accumulation is (12m) and old (>23m) mice. Significant dependent on the presence of MPPα. We alterations in peripheral organ and brain weights suggest that free monomers of MPPα binds are observed with aging (body (p<0.0001), liver PINK1's MTS in a unique way, preventing it from (p<0.0001), kidney (p<0.0001), spleen being extruded to the inner membrane and (p=0.0004), heart (p=0.0004), testes (p=0.0002) promoting its accumulation at the outer and brain (p<0.05). Within the brain, hippocampi membrane. (p=0.03), striata (p=0.02) and olfactory bulbs (p=0.04) weight decreases with age. A 2-C-83 The role of the NOD-like receptor, significant increase in casp6 activity is detected NLRX1, in neuronal cell death in C57Bl6 cortex corresponding with the time point where brain weight is starting to trend Emilie Imbeault¹, Salah Rahmani¹, Tara M. downwards with age. Furthermore, there is an Mahvelati¹, Denis Gris¹ increase in full-length (p=0.004) and fragment ¹CRC Université de Sherbrooke levels (p<0.0001) of the casp6 substrate, STK3, in the aging cortex. Increases in cortical casp8 Neuronal cell death is a phenomenon that expression were also detected. These data occurs in normal conditions such as in brain further our understanding of the anatomical and development and in pathological conditions like biological changes that occur with aging and in Multiple Sclerosis (MS). Although the exact suggest that caspase activation may be an cause of MS is unclear, neurons undergo cell important event in the neurodegeneration death early in the disease. Apoptosis and observed in the aging autophagy are two processes that are implicated in neuronal cell death. A recently discovered 2-C-82 Mitochondrial Processing protein, NLRX1, is a NOD-like receptor that is Peptidase Regulates PINK1 Processing, implicated in innate immunity by attenuating an Import and Parkin Recruitment : Insights into inflammatory response. Also, NLRX1 plays a mechanism role in autophagy by interacting with Atg proteins. Using ShRNA against NLRX1 and Edward Fon¹, Karl Grenier¹ True ORF cDNA clone in N2A cells, we ¹Montreal Neurological Institute evaluated the expression of apoptotic (caspase- 3, caspase-8, caspase-9, and PARP) and Several lines of evidence implicate autophagic (LC3 and Beclin-1) proteins after mitochondrial dysfunction in PD, including the different stimuli. Using Western Blotting, NLRX1 role of two recessive PD genes, Parkin and knock-down (KD) cells showed a decrease in PTEN-induced putative kinase 1 (PINK1), in a LC3 cleaved protein and Beclin-1, suggesting an novel mitochondrial quality control pathway. overall reduction in autophagy. Additionally, Upon disruption of the electrochemical potential these cells showed a higher expression of (ΔΨm) across the inner mitochondrial cleaved PARP and cleaved caspase-3 membrane with the protonophore carbonyl compared to wild-type cells after TNF-α cyanide m-chlorophenyl hydrazone (CCCP), the treatment. Furthermore, NLRX1 KD cells are E3 ubiquitin ligase Parkin translocates from the more prone to cell death in normal conditions cytosol to mitochondria. Parkin subsequently and NLRX1 knock-in (KI) cells are more mediates the destruction of such defective resistant to cell death compare to wild-type cells mitochondria by autophagy (termed mitophagy) as observed by flow cytometry using Annexin V- in a PINK1-dependent manner. Under basal PI staining. These results suggest that NLRX1 conditions PINK1 is rapidly degraded in a has a neuroprotective role and plays an process involving ΔΨm-driven mitochondrial important function in neuronal cell death. By import and cleavage by mitochondrial proteases. understanding the mechanism of action of 126

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NLRX1 in the process of autophagy and Infantile Spasms (IS) is a catastrophic childhood apoptosis, it could help develop novel seizure disorder. It is characterized by extension treatments for MS. and/or flexion jerking movements, cognitive deterioration and Electrodecremental events 2-C-84 Regulation of ischemic neuronal (EDR) which refers to the flattening of the EEG death by E2F4/p130 complexes. waveform. The mechanism/circuitry contributing to the disorder is unknown. We hypothesize that Grace Iyirhiaro¹, Yi Zhang¹, Carmen Estey¹, the overexpression of GIRK2 (G protein inward Michael O’Hare¹, Farzaneh Safarpour ¹, rectifying potassium channel) is necessary and Mohammad Parsanejad ¹, Suzi Wang¹, sufficient for the GABAb-GIRK2 agonist-induced Elizabeth Abdel-Messih¹, Steve Callaghan ¹, Infantile Spasms phenotype in the Ts65Dn Matthew During², Ruth Slack¹, David Park¹ mouse model of Down's Syndrome. We reduced ¹University of Ottawa, ²The Ohio State the GIRK2 channel activity in the Ts65Dn mice University pharmacologically using a GIRK antagonist tertiapin Q (TPQ) and observed a significant Inappropriate activation of cell cycle proteins, in reduction in EDR activity. To further validate the particular cyclin D/Cdk4, is implicated in role of GIRK2, we engineered the segmentally neuronal death induced by various pathologic trisomic Ts65Dn mouse to be disomic for the stress including DNA damage and ischemia. GIRK2 gene. We then measured the difference Key targets of Cdk4 in proliferating cells include in behavioural spasm number and EDR duration members of the E2F transcription factors which between the Ts65Dn mice, Ts65Dn disomic mediate the expression of cell cycle proteins as mice and Wild Type controls. We found a well as death inducing genes. However, the significant reduction in both behavioural spasms presence of multiple E2F family members and EDR duration in the Ts65Dn disomic mice complicates our understanding of their role in compared to the Ts65Dn mice. The data death. Presently, we focussed on whether E2F4, suggest that over expression of GIRK2 leading an E2F member believed to exhibit crucial to excess hyperpolarization is the reason for this control over the maintenance of a differentiated inhibitory epilepsy disorder. Our next aim is to state of neurons, may be critical in ischemic create a transgenic GIRK2 over expressing neuronal death. We observed that in contrast to mouse line to further strengthen our hypothesis. E2F1 and 3 which sensitizes to death, E2F4 This study has important implications for future plays a crucial protective role in neuronal death therapies for IS, Down's syndrome and other evoke by DNA damage, hypoxia and global inhibitory seizure disorders. ischemic insult both in vitro and in vivo. E2F4 occupies promoter regions of pro-apoptotic 2-C-86 FTY720 induces transcription of factors such as B-Myb under basal conditions. neuroprotective genes to regulate Ca2+ Following stress exposure, E2F4/p130 homeostasis in human astrocytes complexes are rapidly lost along with the presence of E2F4 at E2F containing B-Myb Pavel Gris¹, Jack Antel¹, Timothy Kennedy¹ promoter sites. In contrast, E2F1 presence at B- ¹McGill University Myb sites increases with stress. Furthermore, B- Myb and C-Myb expression increases with FTY720 is an S1P receptor (S1Pr) modulator ischemic insult. Taken together, we propose a approved for treatment of multiple sclerosis model by which E2F4 plays a protective role in (MS). It prevents lymphocytes from leaving the neurons from ischemic insult by forming lympnodes and entering the CNS; however, repressive complexes which prevent pro-death FTY720 injections into the CNS reduce neuro- factors such as B-Myb from being expressed. inflammation in mice in the absence of peripheral lymphopenia. Effects within the CNS 2-C-85 Delineating the role of the GIRK2 were initially attributed to FTY720 inhibiting the channel in the generation of Behavioral actions of S1P. In contrast, we and others Spasms and Electrodecremental events in demonstrated that FTY720 continues to signal Infantile Spasms even while inhibiting S1Pr. When bound by S1P, S1Pr is recycled to the cell membrane. When Krutika Joshi¹, Lily Shen¹, Miguel Cortez¹, FTY720 binds to S1Pr, the receptor-ligand O.Carter Snead¹ complex is targeted to an endosomal ¹The Hospital for Sick Children compartment. FTY720 inhibits IL-1 beta induced calcium release from intracellular stores in human astrocytes. On the basis of microarray 127

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 analysis and studies of functional Ca2 efflux, we 2-C-88 Macrophage polarization after propose that during MS progression or spinal cord injury is influenced by TNF-α and inflammatory challenge, ER stress in astrocytes iron leads to increased ER Ca2 release, resulting in activation of store operated Ca2 entry (SOCE) Antje Kroner-Milsch¹, Andrew Greenhalgh¹, and further build-up of intracellular Ca2 altering Juan Zarruk¹, Rosmarini Passos dos cell signaling. By studying the transcriptome Santos¹, Samuel David¹ signature of FTY720, we obtained evidence that ¹McGill University FTY720 increases expression of Ca2 regulating proteins, which reduce ER Ca2 efflux and inhibit Macrophages/microglia appear to have both SOCE. We predict that this in turn will prevent detrimental and beneficial effects in the injured the reversal of glutamate re-uptake and limit NO CNS, which may be due to their polarization production, thereby reducing neuronal excito- state. M1 polarization includes production of toxicity and mitochondrial damage in axons. We nitric oxide and pro-inflammatory cytokines, propose that on this basis, the application of while M2 polarized macrophages are anti- FTY720 protects astrocytes from Ca2 induced inflammatory and pro- tissue repair. We have excito-toxicity to facilitate neuroprotection. extended earlier work to show that myelin phagocytosis by bone marrow derived 2-C-87 Pharmacogenetic inhibition of macrophages and microglia stimulated with M1 eIF4E-dependent Mmp9 mRNA translation polarizing factors cause a shift in polarization to reverses Fragile-X syndrome-like an M2 state. This is based on the expression of phenotypes various cell surface and intracellular M1 and M2 makers assessed by flow cytometry. Arkady Khoutorsky¹, Christos Gkogkas¹, Interestingly, although myelin phagocytosis Ruifeng Cao¹, Argel Aguilar-Valles¹, Karim occurs in the first 2 weeks after spinal cord Nader¹, Jean-Claude Lacaille², Nahum injury (SCI), macrophages/microglial are Sonenberg¹ predominantly M1 polarized as assessed at the ¹McGill University, ²Université de Montréal single cell level by FACS. We therefore assessed why these cells fail to switch to a M2 Fragile-X syndrome (FXS) is the leading genetic phenotype in the injured CNS. In vitro studies cause of intellectual disability and autism. revealed that TNF-a can abrogate the effects of Mutations in Fmr1 (Fragile-X mental retardation myelin phagocytosis on polarization. gene) engender exaggerated protein synthesis Furthermore, we show that TNF-a null mice resulting in dendritic spine dysmorphogenesis, have increased numbers of M2 macrophages synaptic plasticity alterations and behavioral after SCI. As hemorrhage and dying cells are a deficits in mice, reflecting a significant part of the feature of SCI, we assessed the role of iron in FXS phenotype diagnosed in patients. In FXS polarization. We found that heme and non-heme postmortem brains and Fmr1 knockout mice iron induce M2 polarized cells in vitro to switch (Fmr1-/y), phosphorylation of the 5' mRNA cap to proinflammatory M1 cells. In addition, iron binding protein, eukaryotic initiation factor 4E loaded M2 macrophages transplanted into the (eIF4E) at Ser209 is elevated concomitant with injured cord transform into M1 polarized cells. increased expression of Matrix Metallopeptidase This indicates that TNF-a and intracellular iron 9 (MMP-9). Here we show that genetic or loading play a key role in modulating pharmacological reduction of eIF4E macrophage/microglia polarization to a phosphorylation rescued core behavioral detrimental proinflammatory M1 state. deficits, synaptic plasticity alterations and dendritic spine morphology defects via reducing 2-C-89 Robust stress response does not exaggerated translation of Mmp9 mRNA in alter adult hippocampal neurogenesis after Fmr1-/y mice. Furthermore, MMP-9 acute predator stress overexpression produced several FXS-like phenotypes. These results uncover a novel Catherine Lau¹, Mark Hebert¹, Susan mechanism of regulation of synaptic function by Walling¹, Diane Lagace², Jacqueline Blundell¹ translational control of MMP-9 in FXS, which ¹Memorial University, ²University of Ottawa opens new treatment avenues for the diverse neurological and psychiatric aspects of FXS. Traumatic, stressful life events are thought to trigger a variety of neuropsychiatric disorders including post-traumatic stress disorder (PTSD), generalized anxiety disorder and depression. 128

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28

Identifying the mechanisms underlying the TMS. We find peptide trimerization to depend on stress response may aid in understanding the (i) the presence of copper ions and (ii) the development or improving treatment options for sulfhydryl group of Cys466. For the full-length these debilitating disorders. Neurogenesis, the protein, FLIM-FRET experiments revealed that production of new neurons, is known to occur in BACE1 oligomers are naturally present in living the subgranular zone (SGZ) of the adult cells. We determined a stable trimeric assembly mammalian hippocampus. While the reduction of BACE1 in the plasma membrane by accurate in adult neurogenesis following chronic stress is single-molecule fluorescence counting. Although largely supported, acute stress models, the oligomeric state of full-length BACE1 was particularly predator stress, have yielded not altered by the addition of copper in living inconsistent results. Thus, the goal of the cells, the addition of monovalent metal-ions was current study is to help elucidate the effects of required to visualize di- and oligomers by predator stress on adult hippocampal Western blot analysis. Additionally, our results neurogenesis. Our study is unique as it demonstrate a novel metal-ion controlled implements a single, unprotected cat exposure stabilization mediated by the TMS of the (10 minutes) which produces anxiety-like BACE1. We propose that BACE1 acts as a bona behaviors and hyperarousal in rats for up to fide metalloprotein in an oligomeric form in vivo. three weeks. We investigated the effect of predator stress on both proliferating and 2-C-91 Changes in functional surviving cells in the adult hippocampus. Rats connectivity correlate with attentional were injected with 5-bromine-2-deoxyuridine deficits in Alzheimer’s disease (BrdU) immediately following treatment (predator stress or handling) and brains were Angela Luedke¹, Carlos Hernandez-Castillo², harvested 2 hours or 4 weeks later. Despite a Juan Fernandez-Ruiz², Angeles Garcia¹ robust stress response detected by ¹Queen's University, ²Universidad Nacional corticosterone (CORT) in predator stressed rats, Autonoma de Mexico predator stress had no effect on the total number of proliferating or surviving cells in the Default mode network (DMN) task-induced SGZ at 2 hours or 4 weeks post-stressor. deactivation may contribute to selective Further investigation of overall neuronal activity attention (SA) errors. We assessed functional in the hippocampus following predator stress is connectivity (FC) of DMN areas in Alzheimer's currently underway. disease (AD) and healthy controls (HC). 11 AD (mean age 77.3) and age-matched HC 2-C-90 Determining the oligomeric state participants underwent Stroop fMRI. Verbal of the beta-site APP-cleaving enzyme 1 responses identifying the ink colour in (BACE1) in natural membranes and congruent, incongruent and neutral colour words detergents were recorded. We contrasted neural activity preceding an incongruent error between HC and Filip Liebsch¹, Gerhard Multhaup¹ AD. Four regions of interest that showed group ¹McGill University differences served as seeds for FC analyses. AD and HC connectivity maps were compared The beta-site APP-cleaving enzyme 1 (BACE1) by t-test. Results were correlated with Stroop has a transmembrane sequence (TMS), which is scores. The AD group had slower reaction times necessary for effective BACE1 cleavage of the and more errors for incongruent trials than HC. amyloid precursor protein (APP). An uncommon There was decreased activation in numerous sulfur-rich motif, MxxxCxxxMxxxCxMxC, spans Stroop related areas in HC, including the left the entire TMS of BACE1. The sequence is anterior cingulated cortex (ACC) and precuneus highly conserved among homologues and is (PCu). AD participants had greater activity in reminiscent of a high-affinity binding site for parietal and posterior areas, including the right Cu(I) found in other copper-transporting lingual gyrus and superior/inferior parietal proteins. We designed model peptides of the lobules, as well as right lateralized ACC and BACE1-TMS to investigate metal-ion binding PCu activity. FC increases in AD were between and oligomerization uncoupled from the the left ACC and the right precentral gyrus and cytoplasmic and the ectodomain. We found that the left PCu and bilateral middle occipital gyrus. the sulfur-rich core motif MxxxCxxxM is involved Decreases were found between the left PCu and in metal-ion coordination and oligomerization of parahippocampal gyrus. We found correlations BACE1. Addition of Cu(II) facilitated the between FC and Stroop scores. AD results in formation of dimers and trimers of the BACE1 altered activity preceding an error on the Stroop 129

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 task. Precuneus task-related changes are Proper mitochondrial function is essential for related with FC changes and correlate with poor neuronal health. Whereas mitochondrial Stroop performance. These findings help identify dysfunction has long been associated with neural correlates underlying SA deficits in AD. Parkinson's disease (PD), we have only recently begun to understand the molecular mechanisms 2-C-92 Glial cells at the NMJ are underlying this process. Notably, studies maladapted for reinnervation in the concerning the cellular functions of PARKIN and SOD1G37R ALS mouse model. PINK1, two genes linked to familial PD, have indicated that a loss of mitochondrial quality Éric Martineau¹, Elsa Tremblay¹, Danielle control (MQC) mechanisms may underlie PD Arbour¹, Richard Robitaille¹ pathogenesis. In cells, parkin and PINK1 have ¹Université de Montréal been shown to target entire, dysfunctional mitochondria for degradation through the Amyotrophic lateral sclerosis (ALS) is a autophagy-lysosome system. Additionally, we neurodegenerative disease characterized by the have recently reported that, in response to loss of motoneurons. Glial cells are known to oxidative stress, parkin and PINK1 are also play a major role in the disease progression required for the selective removal of damaged which can be either beneficial or detrimental to mitochondrial proteins from the organelle via motoneurons. However, the contribution of mitochondria-derived vesicles (MDVs), which Perisynaptic Schwann cells (PSCs), glial cells at target to lysosomes independently of autophagy. the neuromuscular junction (NMJ), is still ill- Thus, PINK1/parkin MQC functions at two defined. PSCs regulate both the synaptic and distinct, yet complimentary, levels. Our recent structural plasticity of the NMJ and should data indicate that, following induction of MDV therefore contribute to the compensatory formation, parkin accumulates on multivesicular reinnervation observed in ALS. However, we bodies (MVBs), suggesting turnover of vesicles previously reported that PSC properties are through the MVB-lysosome pathway - a altered in the partially resistant Soleus muscle at targeting mechanism typically associated with a presymptomatic stage (P120) of the disease. cell surface receptor endocytosis and We first tested whether PSCs' ability to detect degradation. Moreover, an siRNA-based screen synaptic activity would also be changed in has identified components of the endocytic/MVB vulnerable fast-twitch muscles. Using Ca2 pathway required for turnover of parkin/PINK1 imaging, we found that glial responses evoked MDVs. We hypothesize that interactions by motor nerve stimulation were unaltered at between parkin and the endocytic system P120 but greatly diminished at P180 in the facilitate the targeting of MDVs to lysosomes, Sternomastoid muscle. PSCs also displayed a and that disruption of these delivery reduced response to purines. Since decoding of mechanisms contributes to the pathogenesis of synaptic activity by PSCs is essential for the PD. maintenance of the NMJ, these results suggest that PSCs may not respond adequately to 2-C-94 GABA Neuron Inhibition in the denervation and injury in ALS. Consistent with Ventral Hippocampus Induces Behavioural this possibility, PSCs at denervated NMJs of Models of Schizophrenia end-stage animals failed to upregulate Mac-2, a marker for axonal debris phagocytosis, while Robin Nguyen¹, Vivek Mahadevan¹, Janine PSCs at innervated NMJs upregulated it. Cajanding¹, Melanie Woodin¹, John Together, these results suggest that synapse- Yeomans¹, Junchul Kim¹ glia communication is altered early in ALS ¹University of Toronto leading to a maladaptive and disorganised glial response to denervation. Hyperactivity in the ventral hippocampus (vHPC) has been implicated in the pathophysiology of 2-C-93 Lysosomal targeting of schizophrenia. A proposed mechanism mitochondrial vesicles requires components underlying this hyperactivity is dysregulation in of the endocytic system: implications for the GABA system. Studies on postmortem Parkinson's disease brains and animal models have provided indirect evidence of reduced activity in GABA neurons, Gian-Luca McLelland¹, Adrianna Tsang¹, specifically parvalbumin neurons. However, the Edward Fon¹ role of vHPC GABA neurons in schizophrenia- ¹McGill University associated behaviours has not been directly examined. Here, we tested the effect of 130

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 selective GABA or parvalbumin neuron inhibition maturation or activation state. In contrast, in the vHPC on behavioural assays of lymphocytes were present in higher numbers in schizophrenia. The DREADD (Designer the bone marrow and blood of IL-1ß-KO mice Receptors Activated by Designer Drugs) after immunization, perhaps a sign that they receptor hM4D was expressed in vHPC GABA were locked outside of the CNS. Together, or parvalbumin neurons by infusing a Cre- these results add more weight to the implication dependent viral vector (AAV-FLEX-hM4D) into of neutrophils in EAE. Further work is needed to the vHPC of Gad65:cre or Parvalbumin:cre mice study the impact of neutrophils and IL-1ß in respectively. In hippocampal slice recordings, antigen presentation and T cell activation and bath application of clozapine-N-oxide (CNO) polarization. reduced the firing rate of parvalbumin neurons expressing hM4D. GABA neuron inhibition with 2-C-96 Familial Prion protein mutants CNO increased both spontaneous and inhibit HRD1-mediated retrotranslocation of amphetamine-induced locomotor activity while misfolded proteins parvalbumin neuron inhibition did not significantly change locomotor activity. The Sarah Peters¹, Andrea LeBlanc¹ effects of GABA or parvalbumin neuron ¹Lady Davis Institute, McGill University inhibition on prepulse inhibition and social interaction were also examined. These findings Prion diseases are neurodegenerative disorders provide support for the role of reduced ventral caused by a misfolded isomer of the hippocampal GABA neuron activity in symptoms ubiquitously expressed prion protein (PrP) of schizophrenia. (Prusiner, 1982). Mostly expressed at the cell surface, a small proportion of PrP is found in the 2-C-95 EARLY EFFECTS OF cytosol (CyPrP) arising from the endoplasmic NEUTROPHILS AND IL-1fl IN reticulum associated degradation (ERAD) EXPERIMENTAL AUTOIMMUNE pathway (Yedida, 2001, Roucou, 2003). This ENCEPHALOMYELITIS. CyPrP has been shown to prevent Bax- mediated apoptosis in both human primary Alexandre Paré¹, Sébastien Lévesque¹, neurons (HPN) and MCF7 cells (Lin, 2008). Benoit Aubé¹, Martine Lessard¹, Steve Familial PrP mutants fail to undergo Lacroix¹ retrotranslocation, and this correlates with a loss ¹Université Laval of PrP's anti-Bax function (Jodoin, 2007, 2009). HPNs contain a considerable amount of Increasing evidence suggests that neutrophils endogenous PrP suggesting that mutant PrP are key players in experimental autoimmune may generally inhibit the retrotranslocation of encephalomyelitis (EAE), an animal model of proteins to the cytosol. To investigate this effect, multiple sclerosis. In vitro and in vivo studies we first identified that the E3 ubiquitin ligase, have revealed that neutrophils participate in Hrd1, was involved in PrP's retrotranslocation in dendritic cell recruitment, activation as well as human CR7 cells submitted to Brefeldin A and immune activity in lymph nodes. Accordingly, proteasome inhibitor, epoxomicin. our group and others found that neutrophil Overexpression of eYFP-Hrd1 increased levels depletion delayed the onset and reduced the of CyPrP, while siRNA against Hrd1 significantly severity of EAE. Another key factor for EAE decreased levels of CyPrP. The expression of development is interleukin-1ß (IL-1ß). The PrP mutants V210I and M232R both decreased effects of IL-1ß have been reported to be CyPrP levels and concomitantly prevented widespread and diverse, and include endothelial retrotranslocation of model Hrd1-mediated cell activation, leukocyte activation and ERAD substrates, transthyretin mutant recruitment and Th17 cell differentiation. Here, TTRD18G and α1-anti-trypsin variant, A1AT- we show that neutrophils are important NHKKKK. These results indicate an inhibition of producers of IL-1ß in the blood and spinal cord Hrd1-dependent retrotranslocation by familial of EAE mice. Flow cytometric analysis revealed PrP mutants. The accumulation of ERAD- that neutrophil counts are normal in the bone substrate proteins, combined with a loss of anti- marrow of IL-1ß-knockout (KO) mice, but greatly Bax protection, could explain the age-dependant reduced in the blood, both before and at disease neurodegeneration seen in familial prion onset (7 and 10 dpi, respectively). Furthermore, disease. we found that neutrophils of IL-1ß-KO mice are significantly smaller than those of wild-type 2-C-97 Regional role of D1 receptor in controls, a phenomenon that may reflect their responses to psychostimulants in new 131

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 conditional D1 dopamine receptor knockout cortex (mPFC) is postulated to underlie mice cognitive symptoms of schizophrenia. In order to improve our understanding of schizophrenia it is Quentin Rainer¹, Merouane Messekher¹, important to develop and further characterize Bruno Giros¹ neurodevelopmental animal models with ¹Douglas hospital research centre relevance to the human condition. Previous research has demonstrated that rodents There is considerable evidence that drugs of exposed to neonatal treatment with domoic acid abuse converge on a common circuitry, the (DOM) (20 μg/kg), a kainate receptor agonist, mesolimbic dopamine pathway, involving the during a critical period of brain development (i.e. ventral tegmental area (VTA) the nucleus post-natal day 8-14) produces animals that accumbens (Nac). Nac is part of the striatum, exhibit several behavioural, neurochemical, and involved in motor control and motivational neuroanatomical abnormalities that are processes, altered in drug addiction and characteristic of schizophrenia. The current schizophrenia. Its neuronal population is mostly study assessed whether DOM treatment composed of medium spiny neurons (MSNs). produces alterations in developmental apoptosis Dopaminergic signaling within the basal ganglia as evidenced by altered capase-3 staining and has been thought to occur in the striatonigral DA system integrity as evidenced by altered DA MSNs which contains the dopamine D1 receptor transporter (DAT), D1R, and D2R in the mPFC. (D1R) and the striatopallidal MSNs which It was hypothesized that DOM administration expresses dopamine D2 receptor (D2R). While would produce alterations in there is still no clear concensus, increasing neurodevelopmental apoptosis with consequent evidence indicate that D1R and D2R can be co- alterations in the DA system. Results expressed in a subpopulation of striatal MSNs. demonstrated increased DAT staining in the A number of studies have shown that D1R and right prelimbic cortex (PRL) of DOM-treated D2R are involved in cocaine-induced molecular females and decreased caspase-3 staining in and behavioral changes but required their co- the right PRL of both DOM-treated females and activation. Therefore more selective approaches males. These results serve to strengthen the are needed, including cell-type-specific, region- construct and etiological validity of the model as specific manipulations of the dopamine they demonstrate neurochemical alterations receptors to better elucidate their functional which are associated with behavioural roles in drug addiction. To target specific symptomatology. neuronal populations, we generated a novel strain of mice allowing a conditional deletion of 2-C-99 Transcriptional Deficits in an the D1R gene, the D1loxP mice. This strain is Isogenic Stem Cell Model of Parkinson's under characterization using AAVcre virus injections in striatal regions. D1loxP mice will be Tammy Ryan¹, Scott Ryan¹ bred with either D1Cre or D2Cre mice, which ¹The University of Guelph express Cre recombinase under the D1 or D2 promoters, respectively. This tool will allow a Neuronal loss in Parkinson's Disease (PD) is better understanding of the D1R involvement in associated with both aberrant mitochondrial drug of abuse mechanisms according to its function as well as impaired proteostasis in expression in the brain. dopaminergic neurons (DA) of the substantia nigra pars compacta. A strong association has 2-C-98 Altered Dopamine Transporter been reported between PD and exposure to and Caspase-3 Staining in the Prefrontal mitochondrial toxins such as the environmental Cortex in Rats Following Neonatal Treatment pesticides paraquat, maneb, and rotenone. With Domoic Acid These toxins are associated with increased oxidative stress that may link mitochondrial Mark Robbins¹, Catherine Ryan¹, Tracy dysfunction with aberrant proteostasis. Using a Doucette¹ robust, patient-derived human induced ¹University of Prince Edward Island pluripotent stem cell model (hiPSC) of PD that allows for comparison of A53T-SNCA mutant Schizophrenia is a debilitating cells against isogenic mutation-corrected neurodevelopmental disorder which is controls, in addition to a human embryonic stem characterized by positive, negative, and cell (hESC) model with the A53T-SNCA cognitive symptoms. Decreased glutamate and mutation introduced, we generated A9-type DA dopamine (DA) signaling in the medial prefrontal neurons (hNs). An analysis of mitochondrial 132

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 function in these neurons identified complex and variable neuro-glia interactions perturbations in mitochondrial respiration regulate healthy and injured states in the adult specific to A53T mutant hNs. A decrease in mammalian retina. maximal respiratory capacity was observed in A53T hNs following mitochondrial toxin 2-C-101 Effects of Task-Irrelevant exposure. Furthermore, we report a novel Emotional Face Processing on Bipolar molecular pathway whereby basal as well as Disorder and Attention-Deficit Hyperactivity toxin-induced stress inhibited the MEF2C- Disorder Patients on an Antisaccade Task PGC1α-NRF2 transcription network in A53T hNs, leading to mitochondrial dysfunction and Stephen Soncin¹, Don Brien¹, Victoria Yang¹, cell death. This occurred, in part, through redox- Edwin Ho¹, Alina Marin², Doug Munoz¹ based modification of MEF2C that prevented the ¹Queen's University, ²Hotel Dieu Hospital transcription factor from binding to the PGC1α promoter. Our data provide mechanistic insight Differentiating symptoms between Attention- into gene by environment interactions in the Deficit Hyperactivity Disorder (ADHD) and pathogenesis of PD, and identify NRF2 as a Bipolar Disorder (BD) is difficult because the promising target for therapeutic development. core features of ADHD are quite similar to the symptoms of BD. Antisaccade tasks, which 2-C-100 Injury to distant neuronal fibers require inhibiting a prepotent visual response, activates retinal glia, followed by neuronal probes differences between these groups which cell cycle re-entry and DNA hyperploidy, and may differentiate diagnoses based on each neuronal death. group's distinct reaction profile. Performance deficits would represent the underlying Alba Galan¹, Pauline Dergham¹, Philippe neuropathology of these disorders, specifically D'Onofrio ², Mark Magharious², Paulo for deficits of executive control. 20 ADHD, 20 Koeberle², José Frade³, Uri Saragovi¹ BD, and 25 Control subjects performed an ¹McGill University, ²University of Toronto, ³Cajal interleaved pro and antisaccade task (look Institute toward vs away from visual target, respectively). In order to further differentiate between subject Retinal ganglion cells (RGCs) are neurons that groups, standardized emotional faces (fear, relay visual signals from the retina to the brain. happy, sad, neutral) were used as task- The RGC cell bodies reside in the retina and irrelevant stimuli, which are expected to their fibers form the optic nerve. Full transection influence emotion-processing deficits in BD, with (axotomy) of the optic nerve is an extra-retinal control images (object, no picture). In all injury model of RGC degeneration. Optic nerve conditions, Controls had faster mean saccadic transection permits time-kinetic studies of reaction times and reduced variability compared neurodegenerative mechanisms in neurons and to ADHD and BD groups while the ADHD group resident glia of the retina, the early events of was faster than the BD group. Controls also which are reported here. One day after injury, made less antisaccade direction errors and before atrophy of RGC cell bodies was (prosaccade on antisaccade trial). Emotion apparent, glia had increased levels of phospho- effects were group dependent: fear increased Akt, phospho-S6, and phospho-ERK1/2; direction errors for ADHD subjects while neutral however, these signals were not detected in had the same effect on BD subjects. In injured RGCs. Three days after injury there were conclusion, there is a clear pattern separating increased levels of phospho-Rb and cyclin A Controls from ADHD and BD groups and these proteins detected in RGCs, whereas these patient groups from each other, demonstrating signals were not detected in glia. DNA emotion-processing deficits that are disorder- hyperploidy was also detected in RGCs, specific as well as the usefulness of eye indicative of cell cycle re-entry by these post- movements as a biomarker. mitotic neurons. These events culminated in RGC death, which is delayed by 2-C-102 The Neuroprotective Role of Gap pharmacological inhibition of the MAPK/ERK Junctions in Brain Glucose Deprivation pathway. Our data show that a remote injury to RGC axons rapidly conveys a signal that Sonia Sugumar¹, Carlos Florez¹, George activates retinal glia, followed by RGC cell cycle Zoidl², Peter Carlen¹ re-entry, DNA hyperploidy, and neuronal death ¹Toronto Western Research Institute, ²York that is delayed by preventing glial MAPK/ERK University activation. These results demonstrate that 133

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28

Severe brain hypoglycemia, as the result of an were filled with hyper-phosphorylated tau and insulin overdose in diabetic patients, can cause the area adjacent to the injection sites showed serious neurological complications such as signs of astrogliosis and neurofibrillary tangles. seizures and coma, resulting in brain death. When tested in trace eyeblink conditioning, the However, the mechanisms underlying Tau rats formed the association between a tone hypoglycemic seizure generation and and eyelid stimulation in a comparable manner propagation remain unclear. Gap junctions not to the GFP rats; however, the hippocampus of only play a role in neural synchrony, promoting the Tau rats had relatively smaller amplitude of seizure activity, but are also known to be theta oscillations upon tone presentation in involved in cell death mechanisms during comparison to GFP rats. Thus, minor entorhinal metabolic inhibition. We found that mouse brain tau pathology attenuates the transfer of stimulus slices perfused with low-glucose (0.5 mM) information to the hippocampus, which is artificial cerebral spinal fluid (aCSF) typically detectable at the level of neuronal activity even experienced several repetitive seizure-like before memory impairments become apparent. events (SLEs), after which there is an irreversible loss of evoked potentials within 30 2-C-104 Deletion of C9ORF72 results in minutes unless immediately rescued by normal motor neuron degeneration and stress glucose aCSF. When gap junction blockers sensitivity in C. elegans were added to the hypoglycemic perfusate, SLEs were blocked and neuronal death was Martine Therrien¹, Guy Rouleau², Patrick prevented. Blockade of pannexins using a Dion¹, J. Alex Parker¹ selective blocker, however, prevented neither ¹Université de Montréal-CHUM, ²Montréal the hypoglycemic SLEs nor the subsequent loss Neurological Institute of field response. These data suggest that blockade of gap junctional communication plays An expansion of the hexanucleotide GGGGCC a neuroprotective role during brain glucose repeat in the first intron of C9ORF72 gene was deprivation. Supported by JDRF and CIHR recently linked to amyotrophic lateral sclerosis. It is not known if the mutation results in a gain of 2-C-103 The overexpression of mutated function, a loss of function or if, perhaps both tau in the entorhinal cortex: its effects on mechanisms are linked to pathogenesis. We local neurons, cortical theta oscillations, and generated a genetic model of ALS to explore the memory biological consequences of a null mutation of the Caenorhabditis elegans C9ORF72 Stephanie Tanninen¹, Mark Morrissey¹, orthologue, F18A1.6, also called alfa-1. alfa-1 Ronald Klein², Kaori Takehara-Nishiuchi¹ mutants displayed age-dependent motility ¹University of Toronto, ²Louisiana State defects leading to paralysis and the specific University Health Sciences Center degeneration of GABAergic motor neurons. alfa- 1 mutants showed differential susceptibility to The accumulation of hyper-phosphorylated tau environmental stress where osmotic stress protein in the entorhinal cortex is one of the first provoked neurodegeneration. Finally, we abnormalities observed in Alzheimer's disease observed that the motor defects caused by loss (AD). The entorhinal cortex is reciprocally of alfa-1 were additive with the toxicity caused connected with many cortical regions critical for by mutant TDP-43 proteins, but not by the memory formation and expression. Entorhinal mutant FUS proteins. These data suggest that a tau pathology would therefore disrupt the loss of alfa-1/C9ORF72 expression may transfer of information with the cortical memory contribute to motor neuron degeneration in a network, resulting in memory impairments in AD. pathway associated with other known ALS To test this hypothesis, we expressed, through genes. transfection with a viral vector, an excess of human tau with the P301L mutation (Tau rats) or 2-C-105 Differential changes in green fluorescent protein as a control (GFP microglial ultrastructure in the APPswe-PS1 rats), specifically in the entorhinal cortex of adult mouse model of amyloid-β deposition rats. We then tested the rats' ability to acquire an associative memory in trace eyeblink Maria Gabriela Sánchez¹, Marie-Eve conditioning while monitoring local field Tremblay¹ potentials in the hippocampus, a major efferent ¹Axe Neurosciences, CHU de Québec and target of the entorhinal cortex. One month after Département de médecine moléculaire, transfection, approximately 20% of neurons Université Laval 134

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fluid of ALS patients. To better understand the Microglial activation is well-documented in innate IS role in this pathology, we have turned Alzheimer's disease (AD), especially near the to the model organism C. elegans. We have plaques of amyloid-β (Aβ), but their implication created novel models of ALS in C. elegans remains undetermined. In this study, we based on the expression of ALS-associated examined microglial ultrastructure in the human mutations in the worms motor neurons. APPswe-PS1 mouse model of Aβ deposition, at We have focused on genes encoding TAR-DNA 6 months of age where the impairment of binding protein 43 (TDP-43) and fused in synaptic plasticity, learning and memory is first sarcoma (FUS). Mutations in these genes are observed, using immunocytochemical electron found in 5-10% of familial ALS cases. Worms microscopy. To visualize microglial cell bodies expressing mutant TDP-43 or FUS proteins and processes, immunohistochemistry staining show progressive motility defects accompanied for Iba1 (ionized calcium binding adaptor by motor neuron degeneration. Our preliminary molecule 1) was performed with data suggests that genes encoding components diaminobenzidine. Our analysis in the of the innate IS, including TLR, promote hippocampus CA1 reveals that diseased neurodegeneration associated with mutant TDP- microglia present distinct morphologies, 43 and FUS proteins. Genetically disabling the ultrastructural features and interacting partners, TLR signalling pathway improves movement depending on their proximity to the plaques. For and decreases neurodegeneration in our C. example, microglia displayed various signs of elegans ALS models. Our data suggest that TLR cellular stress including darkening of their immune pathway genes may be new targets for cytoplasm and nucleoplasm, mitochondrial therapeutic development. An update of our dysfunction, dilation of the endoplasmic findings will be presented. reticulum, and overall shrinkage, especially in the vicinity of the plaques and blood vessels. In 2-C-107 Overexpression of the insulin- regions of cellular dystrophy, microglia with like growth factor-II receptor increases β- enlarged cell bodies and processes containing amyloid production in fibroblast various types of inclusions were also encountered. Nevertheless, in regions distanced Yanlin Wang¹, Satyabrata Kar¹ from the plaques, healthier-looking microglia ¹University of Alberta frequently juxtaposed axon terminals, dendrites and dendritic spines as during normal The insulin-like growth factor-II (IGF-II) receptor physiological conditions, but their phagocytosis involves in the transport of newly synthesized was significantly reduced. These results suggest lysosomal enzymes from the trans-Golgi distinct microglial phenotypes which could be network to endosomes. The endosomal- involved in the complex mechanism of AD lysosomal system, the major site of IGF-II pathogenesis. receptor expression, plays a critical role in the processing of amyloid precursor protein (APP) 2-C-106 The role of the innate immune leading to the generation of β-amyloid (Aβ) system in neuronal toxicity in C. elegans peptide - a key player in the development of models of ALS Alzheimer's disease pathology. However, the role of IGF-II receptor in APP processing Julie Vérièpe¹, Alex Parker¹ remains unclear. To address this issue we used ¹Univerité de Montréal IGF-II receptor overexpressing and deficient fibroblasts to study the influence of the receptor Amyotrophic lateral sclerosis (ALS) is the most on APP processing and Aβ metabolism. A common age-related neurodegenerative disease variety of biochemical assays were used to affecting motor neurons. Symptoms are measure mRNA or protein levels of APP, its characterized by progressive paralysis leading processing enzymes and Aβ in these cells. to respiratory deficiency. 90-95% of the cases Confocal microscopy and lipid raft isolation were are sporadic and 5-10% are inherited. Many of used to detect the distribution of the IGF-II the genetic causes are now known but no receptor, APP and its processing enzymes. Our curative treatments are available. Recent data revealed higher mRNA levels of APP as studies have shown there may be an abnormal well as β- and γ-secretases in IGF-II receptor contribution of the immune system (IS) in ALS. overexpressing cells. Accordingly, we observed The Toll-Like Receptor (TLR) is one of the main increased levels of APP, precursors of Aβ and components of the innate IS, and TLR mRNA activities of β- and γ-secretases in these cells. expression is increased in the cerebrospinal Secreted APP and Aβ1-40/Aβ1-42 were also 135

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 higher in their conditioned media. These ASPP family in CNS neuronal survival after changes were reversed by knocking down IGF-II axonal injury. receptor levels. Additionally, higher levels of APP and its processing enzymes were localized 2-C-109 5HT receptor neurons with IGF-II receptors on lipid raft, an active APP differentially modulate locomotor recovery processing site. Our results suggest that from anoxia in Drosophila overexpression of IGF-II receptors can increase APP level/processing leading to enhanced Chengfeng Xiao¹, R Meldrum Robertson¹ production of Aβ. ¹Queen's University

2-C-108 Inhibitor of Apoptosis Locomotor recovery from an anoxic coma is Stimulating Protein of p53 (iASPP) is dependent on a rapid restoration of ion required for retinal ganglion cell survival distribution in neural tissue followed by recovery after axonal injury of neuronal circuit function. The cellular and molecular mechanisms underlying the complete Ariel Wilson¹, Vince Chiodo², Sanford Boye², recovery of locomotor coordination are largely Nicholas Brecha³, William Hauswirth², unknown. Preliminary data showed that Adriana Di Polo¹ knockdown of the Drosophila white gene ¹Université de Montréal, ²University of Florida, (encoding an ABC transporter) in serotonergic ³University of California Los Angeles neurons was sufficient to delay locomotor recovery. We aimed to identify the roles of Purpose: p53 apoptotic activity is regulated by different serotonin (5HT) receptor neurons in the apoptosis-stimulating proteins of p53 locomotor recovery from anoxia. 5HT1A, (ASPP) family members ASPP1/2 and iASPP. 5HT1B, 5HT2A and 5HT7 receptor neurons We previously showed that pro-apoptotic were targeted by (1) overexpressing the pro- members ASPP1/2 contribute to p53-dependent apoptotic factor Grim and (2) white knockdown. death of retinal ganglion cells (RGC), yet the We characterized locomotor recovery in a role of the p53 inhibitor iASPP in the CNS is behavioural assay. We found that genetic unknown. Here, we addressed the role of iASPP ablation through Grim expression in 5HT on RGC survival in a model of acute optic nerve receptor neurons was lethal when combined injury. Methods: iASPP knockdown was carried with some Gal4 lines, or caused severe delay of out by intravitreal injection of small interference locomotor recovery with others. white RNA (si-iASPP). Overexpression of iASPP in knockdown in all 5HT receptor neurons caused RGCs was achieved by intraocular delivery of significant delays of locomotor recovery. White adeno-associated virus (AAV.iASPP). transports small molecules, including cyclic Phosphoserine immunoprecipitation was guanosine monophosphate (cGMP) and performed on retinal lysates of intact, biogenic amines, and may improve signaling axotomized, and iASPP overexpressing retinas. efficacy. We expressed a cGMP-specific bovine iASPP, Fas/CD95, PUMA, Noxa and Bax phosphodiesterase (bPDE5) in 5HT receptor protein levels were examined by retinal neurons and found that bPDE5 expression in immunohistochemistry and western blot 5HT1A neurons but not 5HT1B, 5HT2A or 5HT7 analysis. RGC densities were assessed by neurons caused a severe delay of locomotor quantification of Brn3a-positive cells on retinal recovery. Therefore, 5HT receptor neurons whole mounts. Results: Our data show that differentially modulate locomotor recovery, iASPP is expressed by intact and injured RGCs, although normal White expression is also and that iASPP phosphoserine levels are important during recovery from anoxia. significantly reduced following axotomy. We show that iASPP downregulation by siRNA 2-C-110 Role of ceruloplasmin on iron exacerbates RGC death, whereas selective accumulation after permanent experimental AAV-mediated overexpression of iASPP brain ischemia. promotes robust RGC survival. iASPP overexpression following axotomy results in an Juan G. Zarruk¹, Rosmarini Pasos dos increase of iASPP phosphoserine levels and Santos¹, Samuel David¹ downregulation of PUMA and Fas/CD95. ¹McGill University Health Centre Conclusions: Our study demonstrates a novel role for iASPP in the death of RGCs, and Several studies have shown the relation provides further evidence of the importance of between iron and ferritin levels on clinical outcome in stroke patients. However, the 136

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 understanding of the mechanisms underlying utilized rectangular 'virtual' targets presented at iron accumulation after brain ischemia is still 3 orientations, 3 locations, and with 3 gaze lacking. Ceruloplasmin (Cp) is a multicopper fixation positions. Here we used the same enzyme that oxidizes the ferrous form of iron paradigm to investigate the influence of online (Fe2 ) to its ferric form (Fe3 ). We induced visual feedback (VF) on the grip components. 7 permanent cerebral ischemia in Cp knock-out subjects reached to grasp a target during 4 VF (CpKO) and C57BL/6 wild type (WT) male mice conditions: brief target presentation with no of 8-10 weeks of age by permanently occluding online VF (NVF), vision of the target (TVF), hand the middle cerebral artery (pMCAO) with a 9-0 (HVF), and both target and hand (BVF). We suture. Infarct volume and the adhesive removal found that reach location errors related to gaze test (ART) were done at different time points and target location were highly correlated and tissue from pMCAO and sham control between NVF and TVF, whereas, BVF errors animals was collected to determine protein correlated to HVF errors. However, the expression. CpKO mice had an increased infarct modulation of HVF and TVF was dependent on volume at 24h compared with WT animals. We both of the stimulus and gaze directions. HVF also observed an asymmetry in the ART in the increased the reach location errors for the WT group 24h and 7 days post-MCAO with an central target and reduced these errors when spontaneous recovery 14 days after the targets were located to the left and right relative occlusion. However, in CpKO animals the to the body midline. In addition, looking directly asymmetry kept progressing with time, being to viewed target led to accurate grip size, while significantly different from the WT group 14 days HVF increased the grip size. The results after pMCAO. Western blot data on WT animals suggest that processing hand visual information shows that ceruloplasmin is upregulated 24h adds more complexity to the system and may post-pMCAO, peaks at 72h and starts rely on different mechanisms as compared to no decreasing 14 days after pMCAO. Ferritin VF task. expression is upregulated 24h after pMCAO and increases with time presenting the highest 2-D-112 Involvement of foot afferents in expression 14 days after pMCAO; the iron influx corrective postural reactions transporter, DMT1, reaches peak expression 72h post-pMCAO. These data suggests that Cp Annie Pham¹, Zoe Miranda¹, Dorothy plays an important role in infarct evolution and is Barthélemy¹ accompanied by changes in the expression of ¹Université de Montréal other iron homeostasis proteins after brain ischemia. Several studies suggest that corrective reactions to perturbations are mediated by plantar muscle D - Sensory and Motor Systems afferents projecting to leg muscles, but their precise role is not fully understood. The goal of 2-D-111 Influence of Visual Feedback on this study was to assess the contribution of foot Gaze-Dependent and Location-Dependent afferents in corrective postural reactions. Errors in Grasping Movements METHODS: Electrical stimulation to the right posterior tibial nerve (PTN) below the internal Noura AlOmawi¹, Joost Dessing², Simona malleolus was applied at different delays during Monaco¹, Xiaogang Yan ¹, J. Douglas unexpected forward or backward tilts in 8 Crawford ¹ healthy subjects. EMG activity of right flexor ¹Centre for Vision Research, York University, digitorum brevis and soleus (SOL) were ²Queen's University recorded. PTN stimulation (2-2.5 x motor threshold) was applied during quiet standing, Previous studies have shown that visual prior to and during the perturbations. RESULTS: feedback from the target and the hand is 1) Quiet standing: PTN stimulation induced a important to enhance the accuracy of reaching short-latency suppression (53±6 ms), a medium- movement. A recent study found that online latency facilitation (67±6 ms) and a long-latency visual feedback from the hand suppresses gaze facilitation (92±5 ms) in SOL. 2) Standing dependent errors (Dessing et al, 2012). In a between perturbations: the short-latency previous experiment (AlOmawi et al, 2013) we suppression appeared more rapidly (difference = investigated the influence of gaze and target -9.1 ms, Student's t test, p<0.01) and amplitude positions on the transport, final grip size, and of suppression was increased compared to quiet orientation components in a reach to grasp task standing (35%, p<0.01). 3) Backward tilt: the during open loop condition. This paradigm short latency suppression observed during 137

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 standing reversed to a facilitation at 150 ms Almost 15 years ago, Botvinik and Cohen after tilt onset (185% vs 64% during standing; discovered that when subjects watched their p<0.001) and the facilitation observed at long- own hand being brushed synchronously with a latency became an inhibition (57% vs 141% fake hand, they felt like the fake hand was their during standing; p<0.01). 4) Forward tilt: the real hand. This illusion, called Rubber Hand short-latency suppression increased but Illusion (RHI), has since been studied by many insignificantly. DISCUSSION: PTN stimulation researchers who found that a key aspect is the induces responses in SOL that are modulated in visual similarity between the fake hand and the a task-specific way and may contribute to subjects' hand. Indeed, the RHI arises only in induction of postural reactions. NSERC, REPAR presence of a fake hand and not other objects, as for example wooden blocks (even when they 2-D-113 Expression of CB1, CB2, and are shaped as a human hand). Here we tested GPR55 in the monkey retina whether functional similarity (instead of anatomical similarity) is sufficient for the illusion Joseph Bouskila¹, Pasha Javadi¹, Christian of ownership to extend to non-hand-shaped Casanova¹, Maurice Ptito¹, Jean-François tools. In particular, we wanted to test whether it Bouchard¹ is possible to induce the illusion by stroking a ¹University of Montreal grabber that shares the same functionality of a human hand (to grasp), despite its different The endocannabinoid system is present in the visual appearance. We hypothesized that motor mammalian central nervous system including experience with the tool would be necessary to the retina, and is responsible for the regulation induce the illusion. We tested subjects in a of many physiological processes. Recent modified version of the classical RHI paradigm. anatomical and functional data collected in the Subjects were asked to observe a grabber being rodent retina indicate that cannabinoid receptors stroked synchronously (test) or asynchronously are important mediators of retinal functions. (control) with their own (hidden) right hand, While the expression pattern of cannabinoid before and after a short period of tool-use receptors has been well established in the consisting in grasping and lifting objects with the rodent retina, little data is available for the grabber. We used three different measures: primate. Using confocal microscopy, we show proprioceptive drift, questionnaire and GSR here the differential expression of CB1R, CB2R, (Galvanic Skin Response) to threat. Crucially, and GPR55 in the vervet monkey retina subjects had no previous experience with the (Chlorocebus sabaeus). We found that CB1R is tool prior to the experiment. Results from this present mainly in cone photoreceptors and other study showed that it is possible to experience an retinal components. Indeed, higher CB1R illusory sen expression was detected in the glutamatergic vertical signal pathway, namely bipolar and 2-D-115 The effect of training and ganglion cells. Moderate to low expression of cholinergic stimulation on visual capacities CB1R was also found in horizontal and in healthy rats. amacrine cells. CB2R was exclusively located in the retinal glia, the Müller cells. Expression of Mira Chamoun¹, Jun-Il Kang¹, Frédéric GPR55, a recently de-orphanized receptor and Huppé-Gourgues ¹, Elvire Vaucher¹ a putative cannabinoid receptor, was restricted ¹University of Montreal to rod photoreceptors. These results show that these receptors are differentially expressed in Electrical stimulation of the cholinergic system the retinal mosaic of monkeys and might have a paired with visual stimulation to a specific functional role in visual perception. pattern induces long-term enhancement of visual acuity for this pattern in rats. We 2-D-114 The Toolish Hand Illusion: Motor evaluated whether repeated visual exposure of experience facilitates incorporation of a tool. a specific stimulus paired with pharmacologically induced build-up of acetylcholine (Donepezil Lucilla Cardinali¹, Alice Roy², Jody Culham¹, administration) would change the cortical activity Alessandro Farnè³ and visual acuity of the rats for the trained ¹The Brain and Mind Institute, Western stimulus. Donepezil, a specific inhibitor of University, ²L2C2 - Institut des Sciences, UMR acetylcholine esterase, is used for the treatment 5230 CNRS/UCBL, ³Lyon Neuroscience of Alzheimer's patients. We recorded visual Research Center, ImpAct Team evoked potentials (VEPs) in rat's primary visual cortex before and after a 2 weeks visual 138

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 exposure of a sinusoidal grating pattern phase motion patterns, but this transfer was non- converting, shown in a pseudo-random manner existent when joint motion patterns differed from for 30° and 120°orientations and spatial the training task. We propose that a common frequency. During the 2 weeks of visual learning mechanism governs the adaptation of exposure (10min/day, 0.12CPD training feedback control and voluntary action, and frequency), the cholinergic system was produces learning that is localized and sensitive stimulated through an electrode implanted in the to the training conditions. basal forebrain or by injecting Donepezil (i.p., 0.5mg/kg daily) 30min prior to visual exposure. 2-D-117 Direct conversion of Pharmacological and electrical stimulation of the endogenous cells into functional neurons in cholinergic system during the visual training the mammalian inner ear using defined induced similar enhancement (70% increase) of transcription factors the cortical response to visual stimulation. VEPs were enhanced in the electrically stimulated Alain Dabdoub¹, Koji Nishimura² group (p=0.046) and in Donepezil-injected group ¹University of Toronto / Sunnybrook Research at the trained frequency 0.12 cpd (p=0.043). Our Institute, ²Sunnybrook Research Institute study suggests that pharmacological stimulation of the cholinergic system via Donepezil Hearing loss is the fastest growing and one of administration is a potential method for the most prevalent chronic conditions today improving visual capacities if coupled with visual affecting 600 million people worldwide. Primary training. auditory neurons (spiral ganglion neurons) are crucial in hearing as they transmit sound 2-D-116 Local Adaptation of Feedback information from the inner ear to the brain. Responses and Voluntary Reaching Auditory neurons are lost due to disease, Movements excessive noise and aging; and like most neurons, once lost they do not regenerate. Tyler Cluff¹, Stephen Scott¹ Hence, they are a primary target for ¹Queen's University regeneration since the induction of even a small number of neurons in a damaged ear could A hallmark of voluntary motor control is the have significant impact on hearing restoration. ability to adapt our motor patterns to physical One approach to hearing loss treatment is the loads applied to the limb. This adaptation use of gene therapy for the induction of generalizes to movements that differ in endogenous cells. Two target cell populations in amplitude, direction, and speed, with the amount the mouse cochlea for induction are non- of learning decaying rapidly with the distance sensory epithelial cells and spiral ganglion glial from the training conditions. In parallel, recent cells. We have used neurogenic transcription studies have highlighted feedback responses factors known to directly reprogram cells and that mirror the adaptation of voluntary induce neurons in several systems as well as behaviour, leading to the hypothesis that transcription factors required for the generation feedback responses should exhibit the same and survival of auditory neurons. learning patterns expressed during voluntary Overexpression of these factors in vitro induced actions. Here we investigate whether feedback neurons at high efficiency at embryonic, responses compensate for novel interaction postnatal and juvenile stages. The induced loads, and then measure how these adapted neurons expressed neuronal markers and were responses transfer across conditions requiring electrophysiologically functional producing identical or different joint motion patterns. action potentials. Thus, overexpression of Participants reached to two targets while transcription factors is sufficient to convert adapting to loads that altered the relationship endogenous cochlear cells into functional between elbow and shoulder motion. On neuron-like cells. We will investigate random trials, we applied elbow perturbations combinatorial factors that induce phenotypes while subjects reached to a probe target that that most closely resemble auditory neurons, required only shoulder motion. We found that, and examine connectivity to the inner ear in the as subjects adapted their reaching patterns, periphery and the cochlear nucleus in the CNS. shoulder muscle responses compensated for the novel interaction loads. Importantly, these 2-D-118 Optical inhibition of peripheral adapted feedback responses generalized when pain pathways in freely moving optogenetic subjects reached from different workspace mice locations to targets requiring identical joint 139

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28

Ihab Daou¹, Ariel R. Ase¹, Jeffrey S. ChAT+ axon varicosities reveal that the total Wieskopf¹, Jeffrey S. Mogil¹, Philippe density of innervation is significantly lower in Séguéla¹ GPi (0.26 ± 0.03 million axon varicosities / mm³) ¹McGill University than in GPe (0.47 ± 0.07 million), with an anteroposterior decreasing gradient and a The nerve endings of peripheral nociceptors are dorsoventral increasing gradient in both pallidal the initiation sites of nociceptive transduction, segments. Unbiased neuronal counts on Nissl- therefore their selective activation and/or stained adjacent sections indicate that the silencing can control pain perception. Using a number of ChAT+ axon varicosities per pallidal conditional genetic strategy, we sought to neurons is not statistically different in GPi generate an analgesic model in which the compared to GPe (74 ± 9 and 127 ± 29 activity of nociceptors is optically silenced using varicosities / neuron, respectively). At the light-gated inhibitory opsins. This approach electron microscopic level, ChAT+ axon consisted of expressing the proton pump varicosities in GPi and GPe are comparable in Archeorhodopsin (Arch) or the chloride pump size and shape. Only 20% of ChAT+ axon Halorhodopsin-3 (eNpHR3.0) in the Nav1.8- varicosities establish a synaptic contact, positive nociceptors, using the Nav1.8-Cre indicating that ACh neurotransmission occurs recombinase driver line. Cellular distribution of predominantly through volume transmission in the Arch-EGFP and eNpHR3.0-EYFP constructs both pallidal segments. The absence of axo- was assessed in fluorescence in dorsal root axonic contacts suggests that presynaptic ACh ganglia (DRG), trigeminal ganglia, sciatic nerve, modulation of pallidal afferents is mainly glabrous skin and dorsal horn of the spinal cord, asynaptic. Altogether, these results indicate that and showed a strong and selective expression the PPN exerts a potent influence on the GPi of these opsins in nociceptive soma and fibers. and the GPi, mainly through volume Electrophysiological recordings on cultured DRG transmission of ACh. neurons revealed significant outward photocurrents and hyperpolarizations in 2-D-120 White Noise Visual Motion response to yellow light (589 nm) stimulation. Reconstruction From MEG These light-evoked hyperpolarizations were sufficiently large to block electrically- as well as Alireza Hashemi¹, Erik Cook¹ chemically (αβmeATP)-induced action potentials ¹McGill University in Arch-expressing neurons. Strong expression of Arch in the periphery translated into Decoding time-varying stimuli from human brain significant reduction in mechanical allodynia activity by means of functional neuroimaging under inflammatory conditions, providing has been difficult in part due to poor signal evidence for a novel promising analgesic model quality. Here we derived the relationship in which nociception is optically silenced in between randomly time-varying motion stimuli awake, behaving mice. and MEG signals at both the sensor and source level. Subjects fixated on a cross hair between 2-D-119 Pallidal neurons and their two circular random dot patches located in afferent projections are influenced by opposite visual fields for the full duration of the volume transmission of acetylcholine in trial. Our stimuli consisted of pulses of coherent primates motion made from white random dot patterns on a grey background. The pulse sequence was Lara Eid¹, André Parent¹, Martin Parent¹ random on every trial. Our approach to ¹Universite Laval reconstructing the motion stimulus was derived from electrophysiology, where the latency at The primate basal ganglia receive a highly which neurons increase their firing rate to fast heterogeneous cholinergic (ACh) innervation random stimuli ("white noise input") is assessed arising chiefly from the pedunculopontine by means of an optimal reconstruction filter. Our tegmental nucleus (PPN) of the brainstem. The model was a standard linear filter followed by a present light and electron microscopic study static nonlinearity (LN model), which was characterizes and compares the ACh physiologically plausible and allowed innervation of the internal (GPi) and external comparison to single cell electrophysiological (GPe) segments of the globus pallidus in responses in visual cortex. Our analysis squirrel monkeys (Saimiri sciureus) following accounted for up to 3% of the variance in the labeling with an antibody against choline stimuli. We observed filters in occipital and acetyltransferase (ChAT). Unbiased counts of occipital-parietal areas with properties similar to 140

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 filters estimated with single cell to motor control. Here, we compare the electrophysiology. influence of the STN on goal-directed, and non- goal directed eye movements in two monkeys, 2-D-121 TMS-induced plasticity causes in order to resolve whether STN output can vary changes in cerebral blood flow between inhibitory and facilitatory effects according to behavioral condition. In the same Robert Hermosillo¹, Tanis Burnett¹, Krista monkeys, we compared the STN to the Fjeld¹, Francisco Colino¹, Darian Cheng¹, downstream SNr. We found that: (1) electrical Gordon Binsted¹, Paul van Donkelaar¹ stimulation of the STN inhibited and facilitated ¹University of British Columbia saccades in goal directed and non-goal directed tasks respectively, while SNr stimulation Plasticity in the human brain represents the inhibited saccades across tasks; and (2) STN intrinsic property of neurons to alter their activity and SNr local field potential was correlated at in response to physiological changes and beta frequencies in goal directed tasks, but in experiences, such as reorganization due to the non-goal directed task was correlated at adaptation, training, or repair after injury. gamma frequencies only. We suggest that when However, it is unclear if plasticity induced by a rewarding goal exists, the STN increases repetitive transcranial magnetic stimulation inhibition from BG output to decrease (rTMS) and the resulting altered cortical unnecessary movements in favor of goal- excitability is coupled with changes in cerebral directed movements. Alternatively, when no blood flow (CBF) delivery. In the present explicit goal exists, the STN reduces inhibition experiment, we sought to answer this question from BG output to facilitate automatic by monitoring CBF changes and cortical movements toward unexpected stimuli. excitability using a combination transcranial doppler (TCD) ultrasound and TMS. In 2-D-123 The influence of remembered particular, we used single-pulse TMS to map out sensory information on sensory integration motor-evoked potentials (MEP) in the right primary motor cortex before and after 30 Sajida Khanafer¹, Erin Cressman¹ minutes of either real or sham rTMS at 1Hz. At ¹University of Ottawa the same time as the mapping process we monitored CBF. Results showed that cortical To plan a reach, one must identify the location excitability and right hemispheric CBF increased of the target in space. When the target is one's following 30 minutes of real, but not sham, hand, vision and proprioception can provide the rTMS. Taken together, this suggests that brain with information regarding the target's cerebral blood flow can be modulated spatial location. It has been proposed that these temporarily by altering the activity of neurons in sensory signals are optimally integrated to the motor cortex using rTMS. estimate the object's location. In particular, according to the maximum-likelihood estimation 2-D-122 Functional connectivity of the (MLE) model, more reliable sensory inputs are subthalamic nucleus and substantia nigra assigned a greater weight (Ernst & Banks, pars reticulata depends on behavior 2002). In this study, we investigated whether the brain is able to adjust which sensory cue it Jay Jantz¹, Masayuki Watanabe¹, Ron Levy¹, weights the most. Specifically, we examined if Douglas Munoz¹ the brain changes how it weights sensory ¹Queen's University information when the availability of sensory inputs was manipulated. Subjects reached to The subthalamic nucleus (STN) is a common visual (V), proprioceptive (P), or visual hub for the two major basal ganglia (BG) proprioceptive (VP) targets under different delay inhibitory pathways (hyperdirect and indirect). conditions (i.e. subjects reached when the target Consequently, current models of BG voluntary was available or to a remembered target), using motor control predict that STN efferent signals their right or left hand. Results indicated that inhibit movement or incorrect motor plans. subjects' reaches differed based on the hand However, STN output can also facilitate used. Specifically, reaching movements movement, via opposing pathways to the performed with the left hand were less accurate substantia nigra pars reticulata (SNr, BG output and more biased to the right of the target in the oculomotor loop) through the external compared reaches completed with the right segment of the globus pallidus. It is unclear how hand regardless of target modality. However, these conflicting signals from the STN contribute subjects weighted sensory cues in accordance 141

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 with the MLE model across all delay conditions Postural adjustments precede reaching and these weights were similar regardless of the movements of the arm by ~100ms and can delay condition. Thus, manipulating the precede corrections to arm trajectory by 80- availability of the target did not cause sensory 85ms after visuomotor perturbations. Such reweighting. anticipatory postural adjustments appear implausible following mechanical perturbations 2-D-124 Changes in contrast responses to the arm given the rapid nature of corrective of cells in the primary visual cortex after responses (muscle activity changes within deactivation of the pulvinar 60ms). We hypothesized that in standing, the postural system is updated at the same latency Jimmy Lai¹, Sébastien Thomas¹, Christian as the arm, and postural responses are Casanova¹ modulated by the behavioural goal, as observed ¹Université de Montréal for arm responses. Standing subjects held a robotic handle and reached to a target. Step The pulvinar establishes reciprocal connections torque perturbations were interleaved with with nearly all visual cortical areas and is thus in unperturbed reaches. In order to probe the a strategic position to influence their stimulus flexibility of the responses, targets were decoding processes. Projections from the presented as a dot or rectangular bar. Following pulvinar to the primary visual cortex (V1) are perturbation onset, arm muscle activity considered to be modulatory, altering the increased as early as 45-75ms. Leg muscle response of neurons without changing their activity increased ~75-100ms post-perturbation, basic receptive field properties. Results from our leading to deviations in center of pressure laboratory, based on optical imaging, had lent (COP) ~25-50ms later. Subjects corrected the support to this assumption (Soc. Neurosci. Abst. hand back to the dot target but corrected to off- 2011. Vanni et al.). Here, we investigate further center locations on the bar. Task-related this issue by studying V1 single unit responses differences were observed as increased arm during the reversible deactivation of the lateral muscle activity (~60-75ms post-pert) and posterior (LP) - pulvinar complex in the cat increased hand trajectory and velocity (~150- through microinjections of gamma-aminobutyric 200ms post-pert) for the dot vs. the bar. As acid. Recording and injection electrodes were predicted, task-related differences were positioned to obtain overlapping thalamic and observed at similar latency in leg muscles (~75- cortical receptive fields. Results are as follows: 120ms post-pert) and COP trajectory and no change in the preferred orientation or velocity (~150-200ms post-pert). These findings direction selectivity of V1 neurons was observed suggest that the postural system is rapidly during pulvinar deactivation. However, for 67% updated with feedback from the arm to elicit of the cells tested (n=39/58), the response appropriate postural responses with changing amplitude to the optimal stimulus was reduced task demands. by a mean of 65%. The contrast response function of neurons was modeled with the Naka- 2-D-126 The Debate Is Over: Action and Rushton function and analysis of the effects of Perception Dissociate Using a 3D Variant of pulvinar deactivation revealed at least three the Sanders Parallelogram Illusion While types of modulation based on the function Controlling for Visual and Haptic Feedback parameter predominantly affected: 24% of cells had a decrease in Rmax, 13% had an increase Kate Merritt¹, Robert Whitwell¹, Gavin in the exponential factor and 11% had a C50 Buckingham², Philippe Chouinard¹, Melvyn increase. Our results suggest that the pulvinar Goodale¹ modulates activity of V1 neurons in a contrast- ¹The University of Western Ontario, ²Heriot-Watt dependent manner. Supported by CIHR grant University #MOP231122 to CC. According to the two visual systems hypothesis 2-D-125 Rapid whole-body postural (TVSH), 'vision-for-action' and 'vision-for- responses following mechanical perception' are mediated by two distinct cortical perturbations to the upper limb. pathways. Supporting evidence for the TVSH has come from neuropsychological, Catherine Lowrey¹, Joseph Nashed¹, Stephen neurophysiological, and neuroimaging studies of Scott¹ humans and non-human primates. One ¹Queen's University contentious line of evidence, however, comes from studies that find weaker effects of pictorial 142

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 illusions on action than on perception. Re- well as alive mice presented similar results. In appraisals of these studies have rendered the each condition, 5 different IVD patterns were perception-action dissociation interpretation identified (normal, lost of signal, black, bulged or problematic, noting confounding task-differences herniated) that corresponded to different in attention, stimulus-response functions, histopathologies (normal, desiccated, internal obstacle avoidance, and visual and haptic disc disruption, bulged and herniated, feedback. Here, participants either reached out respectively). Conclusion: T2-MRI scan adds a to pick up (length-wise) target bars embedded in new dimension to classical histology. It allows the Sanders illusion or perceptually estimate screening for abnormal and potentially pain their lengths. We removed visual feedback by generator discs in alive mice. Future studies will suppressing the participants' vision throughout compare biochemical content of normal vs. their grasps. We controlled for haptic feedback degenerative discs and time-course of IVD by allowing the participants the same degeneration intra-subject. opportunity to touch the targets in the perceptual estimation task as they had in the grasping task. 2-D-128 Investigating the neural In line with the TVSH, the illusory effect was encoding of linear self-motion significantly weaker on grasps than on perceptual estimates when the tasks was Mohsen Jamali¹, Jerome Carriot¹, Kathleen blocked separately and when the perceptual Cullen¹ estimation and grasping tasks were alternated ¹McGill University from trial to trial. In addition, an analysis of the illusory effects 'corrected' for any biases in Understanding how sensory neurons transmit response-functions supported our key findings. information about relevant stimuli is a major These results provide positive evidence for challenge in neuroscience. Accordingly, we took separate visual-perceptual and visuomotor advantage of the otolith system which is well- systems in neurologically-intact individuals. defined anatomically and physiologically and benefits from easily characterized sensory 2-D-127 Moderate to Severe stimuli (i.e., head acceleration). Moreover, Degenerative Intervertebral Discs identified otolith afferents have a broad diversity in their by T2-RARE MRI in alive SPARC-null mice. spontaneous discharge regularity. Here, we employed multiple measures (i.e., gain, Magali Millecamps¹, Axel Mathieu², Scott information theoretic, and spike timing precision) Thompson¹, Laura Stone¹ to probe the impact of background discharge ¹McGill University, ²Douglas Mental Health regularity on the encoding of linear acceleration University Institute by otolith afferents. Specifically, we investigated how sensory information is processed in Introduction: Chronic low back pain (cLBP) macaques' otolith afferents during translations affects 12-35% of the global population and with broad band (0-15 Hz) noise linear intervertebral disc (IVD) degeneration is accelerations. We found an increase in gain for considered to be its primary source in 40-45% of both regular and irregular afferents as a function the cases. SPARC-null mice are a clinically of the stimulus frequency; however, the gain relevant model cLBP with signs of IVD enhancement was more prominent for irregular degeneration. The objective of the present study units. Irregular units conveyed more information is to use Magnetic Resonance Imaging (MRI) in at higher frequencies (e.g., >7Hz), whereas SPARC-null mice to identify degenerative and regular afferents transmitted slightly greater possible pain generator discs. Method: T1 to S4 information at low acceleration frequencies spines were dissected from fixed (PFA4%, intra- (≤2Hz). Finally, our preliminary analysis shows cardiac) or fresh (exsanguination) mice (2-20 that irregular units display more spike time mth old) and embedded in 15ml tubes with 10% precision in response to the same stimuli agarose. Alive mice (3 or 18 mth old) were suggesting a role for spike timing in the anesthetized with 2.5% Isofluorane. T2-RARE encoding of linear motion. Taken together our weighted MRI scan were collected with a 7T results suggest that while highly sensitive magnet with volumetric coil. After scanning, ex- irregular afferents are more advantageous for vivo samples were processed for histological transient and dynamic stimuli, the regular units analysis using the FAST protocol. Alive animals can provide accurate information when the were euthanized and spines were collected for stimulus is less dynamic (e.g. static tilt). further biochemical analysis. Results: Sagittal images of ex-vivo fixed and fresh samples as 143

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28

2-D-129 Neural Correlations in the change during a saccade, converging towards Electrosensory Lateral Line Lobe of the the saccade target (Tolias et. al., 2001). Our Weakly Electric Fish, Apteronotus goal was to solve this confound by studying the leptorhynchus: Analysis of Multi-Channel peri-saccadic RFs of V4 neurons using 10x10 Recordings electrode arrays. The peri-saccadic spike RFs showed classical shift parallel to the saccade Teerawat Monnor¹, Michael Metzen¹, Maurice vector, but did not show convergence towards Chacron¹ the saccade target. Such a shift in LFP RFs was ¹McGill University accompanied by a subsequent shift towards the saccade target. When the flashed probe was It is recognized that perception and behavior replaced with the static probe, used by Tolias et result from the activities of large neural al (2001), both the spike and LFP RFs shrunk ensembles. As such, it is key to understand the and shifted towards the saccade target. The mechanisms that give rise to correlated activity manifestation of predictive remapping is in the brain. However, correlated activity is therefore paradigm-dependent. The dynamics of highly plastic as it is regulated during specific peri-saccadic LFP RFs implies sub-threshold behavioral contexts. In this work, we aim to activities competing for one of the two scenarios understand how activation of neural circuits can of remapping. Flashed probes, generating shape correlated activity by using the weakly strong bottom-up attention, cause the neurons electric fish, Apteronotus leptorhynchus. We to shift their RFs parallel to the saccade vector. performed multi-channel recordings in the For static probe, the only salient feature on the electrosensory lateral line lobe, which benefits screen during a saccade is the recently from well-characterized neural architecture. appeared saccade target. Hence, the RFs shift First, a spike-sorting algorithm was applied on and compress towards the saccade target. By the recorded signals to extract neural units. thus keeping track of momentary attentional loci Then, correlated activity can be examined from on the visual field, our visual system is able to pairwise population-averaged cross- attain, what appears to us as stable vision. correlograms calculated from all pairs of the extracted units. We found that the activities are 2-D-131 Interhemispheric modulation of positively correlated for neurons of the same primary motor cortex outputs by the ventral type (ON-ON, OFF-OFF), but negatively premotor cortex in Capuchin monkeys correlated for neurons of opposite type (i.e. ON- (Cebus apella) OFF). Also, the effect of different stimulus characteristics on the correlation is observed. Stephan Quessy¹, Joan Deffeyes¹, Adjia While the correlation is decreased by Hamadjida¹, Melvin Dea¹, Numa Dancause¹ conspecific-like stimuli, it is increased by prey- ¹Université de Montréal like stimuli. Furthermore, some neurons tend to fire synchronously at particular portions of In primates, the primary motor cortex (M1) stimulus, e.g. at specific phases of sinusoidal receives numerous inputs from several premotor stimuli. Thus, this work will give important areas. These connections may allow premotor insights in how correlated activity contributes to areas to modulate the corticospinal outputs of the processing of natural stimuli. M1. To date, only the effects of the ipsilateral PMv (iPMv) on M1 outputs have been studied in 2-D-130 Dynamics of peri-saccadic detail. Here, we studied the interhemispheric receptive fields in monkey area V4 influence of PMv on M1 outputs. We used paired-pulse stimulation protocols while Sujaya Neupane¹, Daniel Guitton¹, recording electromyographic (EMG) activity from Christopher Pack¹ up to 8 forelimb muscles in each arm. Under ¹McGill University ketamine anesthesia, we first used intracortical microstimulation (ICMS) techniques to identify Predictive remapping of receptive field (RF) has the M1 hand area and iPMv in one hemisphere given some insight on the mechanisms that and PMv in the contralateral hemisphere underlie stable vision during eye movements. (cPMv). Then, a stimulating electrode was Neurons transiently respond to stimuli flashed, placed in the hand representation of M1 to be prior to the eye movement, in their future RF used as our test electrode (T). We only used parallel to the impending saccade vector sites where a single pulse shock could elicit a (Sommer and Wurtz, 2006). Other findings clear motor evoked potential (MEP) in at least suggest that RF dynamics of V4 neurons one of the EMG recorded signals. A second, 144

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 conditioning electrode (C) was placed in the hand representation of the cPMv. The intensity 2-D-133 TrkB receptor activity in the of the C stimulus was subthreshold. In total, we olfactory bulb is needed for long-term recorded 11 pairs of cPMv-M1 sites in 4 memory of odour-reward learning monkeys and compared the results to 11 pairs of iPMv-M1 in the same animals. Our results Michelle Tong¹, Thomas Cleland¹ indicate that subthreshold stimulations of cPMv ¹Cornell University are more likely to produce facilitation of M1 outputs when C and T are separated by Understanding the molecular mechanisms moderate latencies (5-10 ms). Longer latencies underlying long-term memory (LTM) has been a between C and T are more likely to have an long-standing goal in neuroscience. It is well inhibitory effect. Our results thus support that established that LTM requires protein synthesis interhemispheric interactions between PMv and whereas short-term memory (STM) does not. M1 are complex and strongly temporally While specific proteins have been identified as modulated. -- crucial for LTM consolidation, what remains unclear is the specific timecourse of their 2-D-132 Statistics of natural vestibular involvement, particularly in multi-trial appetitive stimuli in primates: Implications for learning. To further explore this idea, we nonlinear coding. examine the time course of brain-derived neurotrophic factor (BDNF) activity in an Adam Schneider¹, Jerome Carriot¹, Mohsen olfactory bulb (OB)-dependent incremental Jamali¹, Maurice Chacron¹, Kathleen Cullen¹ learning task. BDNF is a strong candidate due to ¹McGill University its established involvement in promoting neuron survival, the activity-dependent nature of its Understanding how neurons process sensory secretion, and its established effect on OB- information requires not only a characterization dependent learning mechanisms (Bath et al., of the neuronal responses, but also the natural 2008, J Neurosci). It has been shown to be stimuli encountered in an organisms sensory necessary for LTM consolidation, but not for environment. The vestibular system has two STM (Alonso et al., 2005, Learn Mem). In the kinds of afferents, canals afferents (sensitive to present study, animals were trained over several angular velocity) have been characterized by trials to learn an odour-reward association and stimuli with standard deviations (std) around 40 memory was probed 48 hours later. We found deg/sec, and otolith afferents (sensitive to linear that, compared to controls, mice infused with the acceleration) with stimuli of std around 0.2G, BDNF receptor antagonist K252a into the OB and frequencies from 0-20Hz. We thus prior to training showed normal learning, but measured the head movements of monkeys impaired memory at 48 hours. This finding during natural behaviours, using a micro- suggests that early activation of the BDNF-TrkB electromechanical systems module sensitive to pathway is necessary for the consolidation of linear acceleration and angular velocity in 3D. OB-dependent LTM. We compared the probability distributions of the head movement signals to Gaussians, and 2-D-134 DF's Visual Brain in Action: The found that the former have significantly longer Role of Tactile and Visual Feedback tails as quantified by the kurtosis, as seen for other modalities of natural stimuli. We found that R Whitwell¹, A Milner², C Cavina-Pratesi², M head movement signals could reach values up Barat¹, M Goodale¹ to 500-1500 deg/sec and 2-6G, respectively, but ¹The University of Western Ontario, ²Durham had frequency content from 0-20 Hz, peaked University around 2Hz. Based on current afferent models, we predict that natural stimuli will elicit cut-off Patient DF, who developed visual form agnosia and saturation in single afferent responses. We following ventral stream damage, configures her also predict that such nonlinear responses will hand in flight to match the geometric properties synchronize the afferent population, in which of novel objects when picking them up, despite case precise spike timing would carry essential her inability to use these same properties to stimulus information. These results challenge explicitly differentiate amongst these objects. the traditional wisdom that early vestibular We have proposed that her spared grasping is pathways use a linear rate code, thus motivating mediated by a feedforward visuomotor system a comprehensive rethinking of sensory coding in housed within the posterior parietal cortex. the vestibular system. Alternatively, DF might use haptic feedback from 145

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 grasping the objects to calibrate egocentric KO. To test whether the deficiency in TNFá KO visual cues to the object's surface, or she might is limited to the prolonged phase following use visual feedback during the grasp to stress, we compared the AMPA/NMDA ratio of appropriately scale her in-flight hand aperture to WT and TNFá KO shortly (1 -3 h) after stress, the target's size. To test these alternatives, we and found that TNFá KO mice lack the response devised a grasping task that disrupted visual- to stress even at these early time points, haptic calibration by varying the visual size of suggesting an altogether absent the target from trial to trial while keeping its felt neurophysiological stress response. Plasma size constant. In a second condition, we corticosterone was similar between WT and removed visual feedback by suppressing her TNFá KO at baseline, and following stress, vision throughout her grasping movement. If the suggesting an intact hormonal response in alternative accounts were true, DF's grasps TNFá KO. Future experiments are aimed at should no longer reflect the visual size of the delineating which component of the synaptic goal objects. Contrary to their predictions, response is altered in response to stress at however, DF continued to scale her grip Schaffer collateral to CA1 synapses of adult aperture to the visual sizes of the targets. mice. Furthermore, providing haptic feedback about perceptual judgments of visual size did not 2-E-136 Chronic intracerebroventricular improve her chance performance. Together, administration of relaxin-3 induces sex- these findings strengthen the proposal that DF's specific effects on food intake and body spared grasps are driven by visual feedforward weight in rats processing. They also suggest that tactile contact with an object keeps DF's residual Juliane Calvez¹, Christophe Lenglos¹, visuomotor system engaged, preventing the Geneviève Guèvremont¹, Arojit Mitra¹, Elena grasps from defaulting to pantomimes. Timofeeva¹ ¹Laval University E - Homeostatic and Neuroendocrine Systems Relaxin-3 (RLN3) is a neuropeptide that is thought to play a role in modulating 2-E-135 The Involvement Of Tumor physiological functions such as food intake and Necrosis Factor Alpha In The stress. Recent results suggest a sex-specific Neurophysiological Response Of CA1 regulation of the central RLN3 system. While Synapses To Acute Stress acute and chronic central administration of RLN3 has been shown to increase feeding and Haider Altimimi¹, Nicole Bailey¹, David body weight in male rats, it has never been Stellwagen¹ tested in female rats. Our goal was thus to ¹McGill University examine the role of RLN3 on food intake regulation and body weight in both male and Stress is disruptive to immune function, but the female rats by using chronic reverse relationship - how the immune system intracerebroventricular (icv) administration of can influence the animal's response to stress - is RLN3. Two groups of male and female rats not clear. Here we investigate the received vehicle or human RLN3 (400 pmol/d) neurophysiological response of adult mice to during 14 days. During all the experiment, the acute stress, and the potential involvement of RLN3 rats displayed persistently higher body Tumor Necrosis Factor Alpha (TNFá) - an weight than control rats and this increase was immune factor that has been shown to modulate significantly greater in female than male rats. In homeostasis of neuronal synaptic plasticity. To both sex, the percentage of body fat of RLN3 this end, we subjected adult wild-type (WT) male rats was significantly increased. Accordingly, the mice to a forced swim as a stressor, and found RLN3 rats demonstrated higher intake of chow that the AMPA/NMDA ratio (a readout of compared to the vehicle-treated rats. This synaptic strength) at hippocampal Schaffer hyperphagia persisted in female rats during all collateral to CA1 synapses is altered one day the infusion period whereas male rats showed following stress. However, when TNFá knockout an increase of food intake only during the first (KO) mice were subjected to the same stressor, week of treatment. Furthermore, RLN3 female we found no alteration from baseline in the but not male rats had a greater mean feed AMPA/NMDA ratio one day following stress, efficiency compared to their respective vehicle- indicating a deficiency in the sustained treated groups. In conclusion, female rats neurophysiological response to stress in TNFá exhibited greater hyperphagia and overweight 146

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 than male rats when chronically icv infused with plasma osmolality by increasing their firing rate RLN3.These results confirm that RLN3 up- and the release of vasopressin (VP). VP regulates food intake, body weight and adipose suppresses diuresis and thereby plays a critical tissues and suggest, for the first time, that these role in maintaining the osmolality of body fluids effects are sex-specific. near a "set point", which is 295 mosmol/kg in the rat. The mechanisms of osmosensitivity in the 2-E-137 Rimonabant peripheral MNCs are incompletely understood, but could injections attenuate the orexigenic effect of include osmotically-evoked changes in second ghrelin infused into the VTA messenger systems. We used immunocytochemistry to monitor Alexander Edwards¹, Stephanie phosphatidylinositol 4, 5-bisphosphate (PIP2) in Rosenbaum¹, Samantha Chin¹, Alfonso the plasma membrane of acutely isolated rat Abizaid¹ MNCs. A 5 minute exposure to hypertonic ¹Carleton University solution (325 mosmol/kg) caused a marked decrease (~25%) in immunoreactivity to PIP2. Ghrelin is an endogenous signal that targets the This decrease was reversible and was brain to increase food intake and energy prevented by the phospholipase C inhibitor balance. Recent evidence suggests that ghrelin U73122 (1 ìM). The muscarinic agonist increases appetite by acting on receptors in the oxotremorine (10 µM) also decreased PIP2 ventral tegmental area (VTA), a brain region immunoreactivity and this effect was also associated with reward seeking behaviors. The blocked by U73122. The osmotically-evoked ability of ghrelin to induce appetite is reminiscent decrease in PIP2 was prevented by minimizing of the appetite inducing effects of endogenous the Ca2+ concentration in the external solution cannabinoids (CBs). Interestingly, recent studies and by the L-type Ca2+ channel antagonist suggest that ghrelin's ability to stimulate feeding nifedipine (30 ΜM), suggesting that Ca2+ influx is dependent on a functional CB system in the is necessary for this effect. PLC converts hypothalamus. Here we hypothesize that a plasma membrane PIP2 to the second similar interaction between ghrelin and the CB messengers diacylglycerol (DAG) and inositol system exists in the VTA to modulate feeding. 1,4,5-trisphosphate (IP3) and all three of these To test this hypothesis, Long-Evans rats were signaling molecules regulate the activity of ion subjected to VTA cannulation procedures and channels. The osmotically-induced activation of placed in one of the following 4 treatment PLC may therefore make an important groups (IP/intra-VTA): vehicle/saline, contribution to the osmosensitivity of the MNCs rimonabant (1.5 mg/kg)/saline, vehicle/ghrelin (1 and therefore to the neural regulation of body µg /0.5 µl), rimonabant (1.5 mg/kg)/ghrelin (1 µg fluid balance. /0.5 µl) to determine if global pharmacological inhibition of the cannabinoid system would 2-E-139 Feeding and Hormonal attenuate the ability of ghrelin within the VTA to abnormalities in 5xFAD mice acutely increase food intake (measured 1, 2, 4, 6 hours post-microinjection). Results show that William Gendron ¹, Stephanie Pelletier¹, ghrelin administered into the VTA significantly Younes Anini¹, Richard Brown¹ increased food intake (p<0.05) and that this ¹Dalhousie University effect was attenuated to control levels when animals were pre-treated with rimonabant 30 The 5xFAD mouse is a double transgenic model minutes prior to ghrelin microinjections. This of Alzheimer's disease (AD), which carries an suggests that ghrelin targets the VTA to amyloid precursor protein transgene with three increase food intake through an interaction with mutations (Sweden, London, Florida), and a the CB system. presenilin-1 transgene with 2 mutations (M146L and L286V). These mutant transgenes act 2-E-138 Osmotic activation of additively to produce massive increases in AB- phospholipase C in osmosensitive peptides, and the development of AB-plaques supraoptic neurons by 2 months of age. Previously, we have observed age-related weight-loss in the 5xFAD Vimal Bansal¹, Thomas Fisher¹ mouse. Weight-loss is a common problem in ¹University of Saskatchewan human AD patients. Therefore, we investigated feeding behaviour and insulin levels in 5xFAD The magnocellular neurosecretory cells of the mice and their wildtype (B6SJLF2) controls. We hypothalamus (MNCs) respond to increases in measured food intake and body weight at 3, 6, 9 147

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 and 12 months of age and activity (grooming, effects of ghrelin on morphological and electrical climbing, stillness, and jumping), muscle mass, properties were abolished by pretreatment with fat tissue, and insulin concentrations at 12 100 uM of the ghrelin receptor antagonist, D- months of age. To investigate if weight loss was Lys-GHRP-6. Together these data indicate that due to age-related motor impairments that made ARC dopaminergic neurons are subject to the retrieval of food difficult, we measured food plasticity induced by ghrelin. intake at 12 months of age for 21 days when food was placed on the hopper (7 days), when 2-E-141 Methyl-CpG-binding domain food was placed on the floor of the cage (7 protein 2 (MBD2) is associated with levels of days), and when food was mashed with water (7 maternal care in C57/BL6 mice days). There were no significant differences between 5xFAD and WT mice in insulin levels, Sabine Dhir¹, Michael Kmeid¹, Michael muscle mass, activity, or overall feeding, except Meaney¹ for when food was placed on the hopper. ¹Douglas Mental Health University Institute However, fat mass and weight were significantly lower in the 5xFAD mice compared to WT The methyl-CpG-binding domain (MBD) family controls. These results indicate that weight loss of proteins is known to interact with regions of 5xFAD mice is not likely due to immobility or methylated DNA in the genome. Recent work feeding impairments but rather to an impaired has begun to elucidate the specific molecular metabolic system. function of each of the MBDs. However, little is known regarding the role of MBDs on 2-E-140 Morphological and phenotypic outcomes. Therefore, the aim of this electrophysiological plasticity of tyrosine project was to characterize the role of MBD2 on hydroxylase neurons in mouse arcuate maternal care. To address this question, we nucleus developed a novel protocol for characterizing and quantifying maternal behaviours in a line of Shuo Huang¹, Mark Fry¹, Karen Oswald¹ MBD2 null, heterozygous and wild type C57/BL6 ¹University of Manitoba mice during the early postnatal period. Our results from maternal observations across The orexigenic peptide ghrelin has previously multiple cohorts show that MBD2 null dams been demonstrated to induce changes in displayed lower levels of licking and grooming synaptic connectivity of NPY and POMC towards their offspring over the first six days of neurons within the arcuate nucleus of the life when compared to heterozygous and wild hypothalamus (ARC). Yet the long-term effects type litter mates. MBD2 null dams also showed of ghrelin on ARC tyrosine hydroxylase (TH) deficiencies in the level of active maternal neurons, another ARC population which behaviours when assayed in retrieval and nest contributes to regulation of energy balance, building performance tests on postnatal day 7. have not been investigated. We carried out Moreover, we found estrogen receptor alpha experiments using dissociated neuronal cultures (Esr1) mRNA expression in the medial preoptic from mice expressing EGFP under the control of area (mPOA) of MBD2 null dams is significantly the TH promoter to investigate whether ghrelin decreased when compared to heterozygous and treatment could cause alterations in wildtype litter mates, and that Esr1 expression is morphological and electrical properties of positively correlated with licking and grooming putative ARC dopaminergic neurons. Ghrelin levels. These studies demonstrate the administration for 5 days to dissociated ARC association of MBD2 with levels of Esr1 and the neurons significantly increased the number and role of MBD2 in maternal behaviour. This work length of neurites on TH-EGFP neurons. Using was funded by the Canadian Institutes of Health electrophysiology, we next examines whether Research ghrelin caused changes in intrinsic electrical properties of ARC TH-EGFP neurons. While 2-E-142 Chronic social stress influences resting membrane potential and spontaneous maternal behavior in rats action potential frequency remained unchanged after ghrelin treatment, ghrelin did cause a Rachel Massicotte¹, Michael Meaney¹ significant 4 mV hyperpolarization of the action ¹Douglas Mental Health University Institute potential threshold. This increased excitability is correlated with a significantly increased input Environmental epigenetics has attracted resistance and 6 mV hyperpolarizing shift in the considerable attention but little is known about activation of voltage-gated Na channels. The the mechanisms implicated in environmentally 148

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 induced phenotypic variation in adulthood. In subset of neurons is simultaneously directly mammals, parent-offspring interactions are depolarized and indirectly hyperpolarized by influenced by the quality of the environment. αMSH, resulting in a net lack of effect on There are highly stable individual differences in membrane potential. The inhibitory inputs maternal behavior among lactating rats, influenced by αMSH were identified as especially in the frequency of pup licking and GABAergic, as αMSH increased the frequency, grooming (LG). However, adult female offspring but not amplitude, of inhibitory post synaptic of High LG mothers reared under conditions of currents (IPSCs) in 50% of cells. social isolation early in development show a Pharmacological blockade of GABAA and decreased frequency of pup LG. The objective GABAB receptors, and physical removal of of this study is to investigate the cause-effect synaptic inputs via cellular dissociation, relationship between impoverished housing abolished αMSH induced hyperpolarizations. conditions and variations in maternal care. We conclude αMSH exerts direct, postsynaptic Female offspring of High and Low LG mothers excitatory effects on some NTS neurons. By were socially isolated or standard housed at presynaptically enhancing GABAergic signaling, post-natal day (PND) 70 for 35 days. At PND αMSH indirectly inhibits other NTS cells. These 105, tissues and blood were collected or the findings provide critical insight into the cellular females were bred and the maternal behavior mediators of medullary melanocortin was observed. Results show that socially- anorexigenic effects, and expand knowledge of isolated virgin females are more fearful, have the circuitries involved in melanocortin signaling. elevated levels of plasma corticosterone and Funding: NSERC,HSFO,FQRNT significant alterations in gene expression in the paraventricular nucleus of the hypothalamus 2-E-144 Modulation of corticotropin- and medial preoptic area. Importantly, the releasing factor (CRF)-mediated stress and frequency of LG is significantly reduced in anxiety-related behaviours by teneurin C- socially-isolated dams. Altogether, these terminal associated peptide (TCAP)-1 experiments indicate that chronic stress in adulthood leads to significant alterations in gene Rebecca Woelfle¹, Yani Chen¹, Dhan Chand¹, expression, which have a profound influence on Laura Tan¹, Suzanne Erb², David Lovejoy¹ the maternal behavior. Ongoing experiments are ¹University of Toronto, ²University of Toronto- focusing on the epigenetic regulation of the Scarborough genes associated with stress and maternal care. The neuropeptide, teneurin C-terminal 2-E-143 alpha-MSH exerts direct associated peptide (TCAP), exists in four postsynaptic excitatory effects on NTS isoforms, each of which is encoded by the neurons and enhances GABAergic signaling terminal exon of the teneurin transmembrane in the NTS protein. However, TCAP-1 is expressed as a separate mRNA distinct from teneurin-1 and its Andrea Mimee¹, Markus Kuksis¹, Alastair mature peptide acts as a ligand to β- Ferguson¹ dystroglycan (β-DG), thereby inducing a MEK- ¹Queen's University ERK1/2 signal transduction cascade in neurons to stimulate cytoskeletal reorganization and The melanocortin system plays a critical role in glucose transport. At the onset of stress, the control of feeding. While anorexigenic corticotropin-releasing factor (CRF) is released, effects of α-melanocyte stimulating hormone stimulating the HPA axis and stress-associated (αMSH) acting in the medullary nucleus of the behaviours. Previous studies show that TCAP-1 solitary tract (NTS) have been shown, the inhibits the CRF-mediated stress response in cellular events underlying these effects are less mice and rats. Intracerebroventricular (ICV), well known. We thus used whole cell patch intravenous (IV) or subcutaneous administration clamp electrophysiology to examine the effects of synthetic TCAP-1 can attenuate anxiety- of αMSH on rat NTS neurons in slice related behaviours, and inhibit CRF-induced preparation. In normal aCSF, αMSH (500 nM) cocaine reinstatement at picomole and depolarized 39% of cells (n=16, mean: nanomole concentrations. Also, rats with ICV- 6.14±0.54mV) and hyperpolarized 22% of cells administered TCAP-1 and acute CRF injections (n=9, mean: -6.79±1.02mV). The use of show altered behavioural responses in the tetrodotoxin revealed αMSH exerts direct elevated plus maze, open field test, and depolarizing effects on some NTS neurons and acoustic startle test. However, TCAP-1 has no indirect inhibitory effects on others. A third effect on the HPA axis or on CRF receptor- 149

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 binding activation. Interestingly, neuronal cells GPR120 is a g-protein coupled receptor that is treated with TCAP-1 show enhanced neurite activated by polyunsaturated fatty acids (FA) formation, axon growth, and dendritic spines, and reported to mediate the anti-inflammatory suggesting that TCAP-1's effects are associated and insulin-sensitizing effects of omega-3 FA. with neuronal circuitry and synaptic plasticity. Omega-3 FA have been linked to central Thus, TCAP-1 is a novel regulator of CRF- anorectic and anxiolytic actions. The objective of dependant behaviours, and may function by our study was to test the effects of acute targeting downstream components of the pharmacological GPR120 stimulation in CNS on extrahypothalamic CRF pathway. We suggest a feeding, the rewarding effects of high-fat and - plausible model on the regulatory actions of sugar food, energy expenditure and anxiety-like TCAP-1 on CRF. behavior. Methods: Intraventricular (ICV) cannulas were stereotaxically implanted in adult F - Cognition and Behavior male C57Bl6 mice. Mice (N=11) received vehicle injection (saline+1%DMSO/1ìl), a 0.1ìM 2-F-145 Effects of housing conditions on and a 1ìM dose of GPR120 agonist. Mice (n=7) neurogenesis in black-capped chickadees were also placed in metabolic chambers for (Poecile atricapillus) assessment of locomotor activity and indirect calorimetry. Operant responding on a Sean Aitken¹, Leslie Phillmore¹ progressive ratio schedule was used to evaluate ¹Dalhousie University food reward. Elevated plus maze and open field tests were employed to assess anxiety-like In captive black-capped chickadees, behavior. Results and conclusion: GPR120 neurogenesis in the hippocampal complex is agonist produced a significant reduction in chow suppressed compared to free-flying birds. intake at 1,2 and 4 hours post-injection (up to However, it is not known whether varying 80% reduction), an effect not observed with housing condition influences the degree to GPR40 agonist. GPR120 (1ìM) also produced a which neurogenesis is suppressed. We captured brief increase in locomotor activity, a decrease groups of chickadees during winter, spring, and in respiratory exchange (suggesting increased fall, and housed them in four different utilization of fat), reduced breakpoint responding conditions: Outdoor aviary, indoor aviary, and for high-fat/sugar food and produced a modest outdoor cage, and indoor cage. Birds were decrease in anxiety-like behavior. Together, injected with BrdU within two days of capture these findings suggest that GPR120 stimulation and behaviour was observed for six weeks, after in the brain has catabolic and anxiolytic actions which time their brains were assessed for and that it may mediate the central effects of neuronal proliferation and survival. Preliminary omega-3 FA. Funded by NSERC results from behavioural data seem to show that enclosure size did not affect behaviour as much 2-F-147 Pre-ischemia CRH receptor 1 as being housed indoors. Results from this blockade attenuates hippocampal cell death study will allow us to determine whether being and prevents spatial memory impairments in housed outdoors and/or in a larger enclosure rats. relieves effects of captivity on both behaviour and neurogenesis. These results will provide Patricia B. de la Tremblaye¹, Marika insight to what factors underly differences in Bonneville¹, Hélène Plamondon¹ neurogenesis between captive and free-flying ¹University of Ottawa birds. Further, results will aid in understanding the influence of environmental context in field Recently, findings from our laboratory and laboratory studies using songbirds. demonstrated that Corticotropin releasing hormone receptor 1 (CRHR1) blockade, prior to 2-F-146 Central GPR120 activation ischemia, significantly attenuated elevations of inhibits food intake, food reward and basal and stress-induced corticosterone anxiety-like behavior secretion post ischemia. CRHR1 is known to mediate the rapid effects of stress on learning Stéphanie Auguste¹, Maria Fernandes¹, and memory through changes in neuroplasticity, Vincent Poitout¹, Thierry Alquier¹, Stephanie thus providing a potential molecular basis for Fulton¹ impaired spatial memory by cerebral ischemia. ¹University of Montreal Thus, the current study investigated whether ischemic hippocampal cell death, and impaired spatial memory ability may be improved by 150

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 pretreatment of Antalarmin, a selective CRHR1 3β in the striatum, anterior cortex and antagonist. Forty-eight male Wistar rats (n=12 hippocampus. Altogether, our results per group) were subjected to sham surgery or demonstrate that lithium affects early encoding global cerebral ischemia using the four vessel processes of motor learning, but whether this occlusion (4VO) model. ICV injection of effect is due to GSK-3 activity remains Antalarmin (2µg/2µl) or saline was administered uncertain. 30 min prior to ischemia. Spatial learning and memory ability was measured using the Barnes 2-F-149 Optogenetic investigation of Maze task. Results show prevention of septal GABAergic modulation of ischemia-induced spatial impairment in hippocampal theta rhythm. Antalarmin-pretreated rats, achieving comparable memory performance to that of Richard Boyce¹, Stephen Glasgow¹, Sylvain sham groups. Hippocampal cell death, assessed Williams¹, Antoine Adamantidis¹ thirty days following ischemia, indicated ¹McGill University increased neuronal survival in Antatarmin pretreated rats, as compared to the saline- Hippocampal neurons oscillate in synchrony at treated ischemic group. These results suggest theta (4-10 Hz) frequencies during periods of neuroprotective effects of CRHR1 blockade wakefulness and rapid-eye-movement (REM) associated with improved spatial learning and sleep, and evidence suggests that these theta memory after global cerebral ischemia. rhythms are required for cognitive processing. The hippocampus receives cholinergic, 2-F-148 Early memory processes are glutamatergic and inhibitory GABAergic inputs altered by Lithium administration from the medial septum (MS), a brain region required for normal theta rhythm generation in Laure Chagniel¹, Mélanie Brien¹, Yan vivo. Previous work using lesional, Bergeron¹, Geneviève Bureau¹, Michel Cyr¹ pharmacological or electrical modulation of MS ¹Université du Québec à Trois-Rivières cell activity suggested that septal GABAergic neurons may be important for theta rhythm Recently, lithium has been proposed as a generation. However, due to the difficulty in treatment for neurodegenerative conditions, but achieving both temporal precision in clinical trials have been hampered by its combination with cell-type specificity using these prominent side effects in the elderly. The methods, the causality of this neural pathway on mechanisms underlying both the positive and hippocampal theta rhythms remains to be negative effects of lithium are not fully known. clarified. Here, we genetically targeted We have investigated the effect of lithium archaerhodopsin (ArchT), a silencing opsin to treatment on the memorization processes GABAergic neurons of the MS. We found that associated with motor learning. Lithium was yellow light pulses reliably hyperpolarized administered in drinking water for two weeks ArchT-expressing cells in the MS in brain slices prior testing mice motor behaviors. Lithium did in vitro. Using a combination of optogenetic and not alter the general motor capacity of mice on electrophysiological (field potential and unit three motor execution tests, the wire recording) techniques in freely-moving mice, we suspension, the pole and the stepping tests. On further found that theta power was significantly the other hand, lithium-treated mice displayed a and reversibly attenuated when septal delay in the early phase of rotarod learning GABAergic neurons were optically inhibited compared to vehicle-treated mice. As lithium during periods of active wakefulness or REM inhibits glycogen synthase kinase-3 (GSK-3) in sleep. These results demonstrate that septal vivo, we have investigated the role of GSK-3 in GABAergic neurons are critical for normal motor learning. We performed intracranial hippocampal theta rhythm in vivo and may injections of the selective GSK-3 inhibitor implicate this neuronal population as an SB216763 directly into the dorsal striatum prior important component of cognitive processing each rotarod training sessions. This inhibitor did mechanisms during wakefulness or REM sleep. not alter any of the motor behavior tested. At the biochemical level, we have investigated the 2-F-150 Utilization Behaviour after temporal changes of GSK-3α and GSK-3β Lesions Restricted to the Prefrontal Cortex activities after the rotarod learning in different brain regions. Learning the rotarod task did not Catherine Chapados Noreau¹, Michael affect levels of total GSK-3α and β, but induced Petrides¹ a selective modulation of p-GSK-3α and p-GSK- ¹Montreal Neurological Hospital and Institute 151

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28

amnestic MCI (PD naMCI)(n=10), PD noMCI Utilization behaviour refers to the tendency of (n=11) and age-matched healthy controls (HC) patients to pick up and use objects presented to (n=15) Patients were classified according to the them, in the absence of instructions to do so Level 2 MDS task force criteria, and were (Lhermitte, 1983). It has been ascribed to considered PD aMCI if 2 memory tests were damage to the frontal lobe, with the assumption impaired (≥1.5 std below normative mean) on a of critical involvement of the frontal cortex. neuropsychological test battery. They were However, careful examination of studies of scanned with [¹¹C] DTBZ to examine striatal DA patients presenting with utilization behaviour depletion, and [¹¹C] FLB 457 to measure D2 shows that these patients had sustained receptor availability in the cortex. The PD aMCI widespread cerebral lesions extending beyond group had significantly more striatal DA the frontal cortex and involving subcortical depletion compared to HC, PD noMCI and PD neural structures. The present study examined naMCI in the associative striatum. D2 receptor utilization behaviour in patients with lesions levels were also significantly reduced compared restricted to the prefrontal cortex, and no more to HC, PD noMCI and PD naMCI in the bilateral than the immediately subjacent white matter. insula, anterior cingulate cortex (salience There was no difference in the presence of network) and the parahippocampal gyrus (PHG). utilization behaviour between patients with This PET imaging study showed that lesions restricted to the prefrontal cortex, dopaminergic changes in the salience network patients with temporal lobe lesions and carefully and PHG underlie PD aMCI. These findings also matched neurologically intact participants. The demonstrated the first evidence of the results suggest that the exhibition of utilization contribution of dopamine to memory impairment behaviour in patients with large damage to the in PD. anterior part of the hemisphere reported in previous studies may have been due to the 2-F-152 Interacting with bots online: extensive damage to subcortical structures. The users reactions to actions of automated present results emphasize the need to base programs in the virtual community of claims about frontal cortex functions on damage Wikipedia limited to the frontal cortex. Lhermitte F. 'Utilization Behavior' and its relation to lesions of Maxime Clément¹, Matthieu Guitton¹ the frontal lobes. Brain 1983; 106: 237-255. ¹Université Laval

2-F-151 Aberrant dopamine in the With the drastic rise of social media, large-scale salience network and parahippocampal collaborative online projects such as Wikipedia gyrus contributes to memory impairment in are now dealing with incredible large amount of Parkinson's disease data. This growth forces the community to provide tremendous efforts in order to maintain Leigh Christopher¹, Connie Marras², Sarah the accuracy and structure of the database. To Duff-Canning², Yuko Koshimori¹, Anthony deal with such amounts of data, Wikipedia users Lang², Sylvain Houle¹, Antonio Strafella² have developed automated programs - bots - to ¹Research Imaging Centre, Centre for Addiction help them to do some of the maintenance tasks. and Mental Health, University of Toronto, However, it is unclear how human users react to ²Toronto Western Hospital (Movement Disorders the actions of these bots. Based on a corpus of Centre) & Research Institute (Division of Brain, 6,528 interventions (2,353 different discussions) Imaging) of users on talk pages of 50 bots active on English-language Wikipedia pages between Patients with Parkinson's disease (PD) and mild January 4, 2012 and January 2, 2013, we cognitive impairment (PD-MCI) represent a analysed the reactions of users depending of vulnerable group for the development of the characteristics of the bots' actions. Bot dementia. Many patients experience memory activity was strongly associated with the impairment, however its neurochemical basis in functioning Wikipedia internal community. Bots PD-MCI is unknown. Large-scale brain networks whose activity was mostly related to the work of interact to facilitate memory, and are known to other users (e.g. high degree of constraint or be dysfunctional in PD. The objective was to visibility) elicited more reactions. By combining investigate dopamine (DA) changes in the the different characteristics of the bots, we were salience, central executive and default mode able to define two opposite "ideal types" of bots networks in patients with amnestic PD-MCI (PD with distinct behavior: "servant bots" which aMCI) using PET. PD aMCI (n=8), PD non- mainly do repetitive and laborious work instead 152

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 of human users, and policing proactively enforcing Wikipedia's guidelines and norms, Isabelle Deschamps¹, Uri Hasson², Pascale which elicited more polarized reactions from Tremblay¹ users (either negative or positive rather than ¹Université Laval, ²University of Trento neutral). Our results demonstrated differential reactions of humans in fonction of the behevior The processing of a complex auditory signal of bots, and unveiled a surprising dichotomy in relies, in part, on the ability to decipher the the level of acceptance of control by automated statistical structure of the incoming sounds. programs. Here we studied inter-individual differences in statistical processing to identify regions in which 2-F-153 Slow oscillations augmentation cortical thickness (CT), and/or surface area (SA) during sleep increases object recognition correlate with sensitivity to statistical structure. performance in mice Participants heard short auditory sequences consisting of either syllables or bird songs and Bibiana Maria de Franca¹, Sylvain completed two behavioral tasks: estimation of Chauvette¹, Josée Seigneur¹, Igor Timofeev¹ the number of discrete elements (numerosity ¹University Laval ratings targeting grouping of sounds) and estimation of the degree of statistical order The slow oscillation of slow-wave sleep induces (regularity ratings targeting sensitivity to (long-term potentiation) LTP and it is also structure). We then correlated measures of CT associated with cortical memory consolidation. and SA taken from supratemporal cortices We hypothesized that an experimental increase against (1) sensitivity to regularity and (2) the of the slow wave activities during the natural impact of regularity on perceptual grouping. sleep would improve memory. The memory was Results from the supratemporal plane analysis tested using the novel object recognition test demonstrate that CT and SA correlate (NOR) in mice as a well-accepted memory test significantly with both regularity-induced in rodents. This test does not use fear perceptual grouping and sensitivity to structure, (amygdala-dependent) or space (hippocampal- but in markedly different regions, and that the dependent) task and appears to depend on the areas implicated differ partially depending on frontal cortex. We used Thy1-COP4/EYFP mice, whether the input consists of speech or non- which express channelrhodopsyn 2 channels in speech sounds. We conclude that inter- a large number of cortical neurons. A fiber-optic individual differences in the influence of microcannula and an LFP electrode were regularity on the perception of statistical implanted in the frontal cortex. After a recovery structure and numerosity in the auditory domain period, mice performed the NOR and LFPs were can be detected using thickness and surface recorded continuously. Blue light stimulations at based morphometry. In addition, examining 0.8 Hz induced slow waves (Stim group) during brain/behavior correlations to uncover the neural the first 4 hours of the light cycle and the sham underpinning of statistical information group had the same surgery but did not receive processing can provide novel insights into the stimulation. We performed intracellular biological basis of human cognition and recordings in vivo and in vitro to characterize the behavior. pattern of neuronal activity using the same stimuli. The stimulation induced neuronal 2-F-155 Memory or attention? The effect excitatory responses in vitro and in vivo. In of early auditory experience on neural implanted mice it induced a slow-wave type of immediate-early gene expression in female responses and an overall increased delta power zebra finch (Taeniopygia guttata) auditory in the LFP. The NOR test showed that mice forebrain areas. from the Stim group spent much less time exploring the old object, suggesting that they Beatriz Diez¹, Scott MacDougall-Shackleton¹ remembered more the old object than the sham ¹University of Western Ontario group of mice. These experiments showed an improvement in memory after an optogenetic The auditory forebrain regions caudo-medial increase in slow-wave activity in the frontal nidopallium (NCM) and caudo-medial cortex. mesopallium (CMM) of songbirds are associated with auditory perception and complex auditory 2-F-154 Correlations between brain and processing. Neural activation measure through behavior: insights into the processing of the expression of the immediate-early gene statistical information. ZENK in these areas varies in response to 153

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 different sounds. Two hypotheses are proposed assigned to E3DA or EDA based on initial 24h for this variation. First, ZENK may reflect access consumption. Q solutions were consumed in to a representation of song memories created lower quantities than their non-Q counterparts, early in life. Second, ZENK may reflect and an E3DA/EDA difference emerged in the attentional processes. We tested these 8%+Q rats but not the 8% sucrose rats. This hypotheses by measuring ZENK in response to suggests that access-induced consumption tutored heterospecific or isolate songs differences are acquired across sucrose compared to non-tutored wild-type song. Young concentrations but are masked as rats approach zebra finch females were exposed during an intake-limit with higher sucrose development to one of three different tutoring concentrations. conditions; 1. Conspecifics that sang an isolate song, 2. Heterospecific, Bengalese finches 2-F-157 The effect of JDTic on stress- (Lonchura striata domestica), 3. Conspecifics induced reinstatement of sugar seeking that sang a wild-type song. After maturity females were exposed to one of five different Justin Ferdinand¹, Paul Marshall¹, Francesco playback types; wild type song, isolate song, Leri¹ their own tutor song, heterospecific song ¹University of Guelph (Bengalese finch song), or white noise. Subsequently, the expression of ZENK in CMM It is known that food restriction acts as a and NCM was measured. We found that ZENK stressor in rats, and stressors tend to increase responses varied across playback stimuli in consumption of palatable food in rats and CMM and NCM, and this variation seemed to humans. The kappa opioid (KOR) receptor interact with early auditory tutoring conditions. modulate stress responses, and controls Females tutored by wild type conspecifics or consumption of palatable foods in both rats and heterospecific showed more activation in rhesus monkeys. Interestingly, the KOR response to conspecific or isolated song, but antagonist JDTic attenuated stress-induced isolate females did not. In conclusion, these reinstatement of cocaine and alcohol seeking, results do not support the hypothesis that ZENK suggesting that JDTic may also be effective in activation reflects early auditory memories. reducing seeking of palatable food produced by food restriction stress. We recently developed a 2-F-156 Quinine adulteration allows for novel method to test self-administration of an access-induced consumption difference sugar, and reinstatement of sugar seeking, in an to emerge with higher sucrose automated radial arm maze. Twenty-four free- concentrations fed Sprague Dawley rats were trained for 14 days to nose poke for sugar pellets. Rats then Milan Valyear¹, Roelof Eikelboom¹ received 3 extinction sessions, and they were ¹Wilfrid Laurier University subsequently either free fed (FF) or food restricted (FR) to 85% of their ad-lib body Rats with ad lib access to food and water will weight. When rats were tested for reinstatement consume significantly more 4% sucrose solution of nose poking behaviour 4 days later, it was when it is available for 24h every 3rd day found that only FR significantly elevated (E3DA) as opposed to every day access (EDA). responding over extinction. We are currently This difference is maintained when all rats are evaluating the effect of JDTic (0, 3 and 10 switched to every 2nd day access (E2DA). The mg/kg) on reinstatement produced by FR. These E3DA/EDA difference becomes smaller and, at studies are supported by NSERC. times, unnoticeable with more concentrated (8% and 16%) sucrose solutions. When rats with a 2-F-158 The relationship between history of E3DA or EDA to 16% sucrose are schizotypy and willingness to play social given E2DA to 4% sucrose a significant roles consumption difference emerges immediately. The lack of an initial consumption difference Ana Fernandez Cruz¹, Ola Mohamed Ali¹, J. may be attributed to the higher caloric Bruno Debruille¹ consumption with 16% sucrose. In the current ¹McGill University study quinine (Q) was added to an 8% sucrose solution to reduce intake and allow an Studies investigating the varying degrees of E3DA/EDA difference to emerge. Sprague- schizotypy in healthy volunteers provide a Dawley rats (n=64) were given 4% or 8% valuable method for assessing symptoms sucrose with or without added Q and then observed in schizophrenia, such as delusions, 154

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 jumping to conclusion bias and disorganization. submitted to SD followed by qPCR In addition they allow for studying how these measurements of markers of sleep need in the symptoms could influence social functioning. forebrain. Results: 1) The expression of EphA4 Emerging research has explored the and its partners was not changed by SD in the performance of individuals with different degrees CTX or HP. However, SD significantly increased of schizotypy in tasks evaluating social related EphA4 mRNA in the TH/H region. 2) SD did not skills such as empathy, facial expression and significantly affect synaptic and total protein emotion recognition and Theory of Mind. Thus level of EPHA4 in the 3 brain regions studied. 3) far, their results suggest that healthy non-clinical The absence of EphA4 did not significantly individuals with higher schizotypy perform impact on SD-dependent increase in Bdnf, Per2, significantly worse than individuals with lower Homer1A, Fos and Arc. Discussion: These schizotypy. The present study aims to further preliminary results suggest that sleep loss may contribute to this area of research by increase EphA4 expression in the thalamus or investigating the performance of low and high hypothalamus. Current experiments are schizotypy but healthy volunteers in a novel assessing the genome-wide response to SD in decision task with large ecological validity, i.e., EphA4 KO mice. decide whether or not social roles were suitable for them. Four categories of names of social 2-F-160 Effects of chronic prenatal MK- roles were randomly presented and participants 801 treatment on cognitive flexibility in the had to decide whether they could consider adult rat offspring themselves playing each role. This task was done to test if participant´s (n=120) selection of Stephanie Gallant¹, Loic Welch¹, Patricia unsuitable or inappropriate roles correlated with Martone¹, Uri Shalev¹ their degree of schizotypy (measured with the ¹Concordia University Schizotypal Personality Questionnaire (SPQ) and the Peter´s Delusions Inventory (PDI)). The Patients with schizophrenia exhibit impairments total SPQ and PDI scores significantly in executive functions. The neurodevelopmental correlated with the percentage of acceptance of hypothesis of schizophrenia posits that unsuitable and inappropriate roles, further disruption of the developing brain predisposes contributing to the relationship between neural networks to lasting structural and schizotypy and social functioning. functional abnormalities resulting in the emergence of such cognitive symptoms in 2-F-159 Effect of sleep deprivation on adulthood. Given the critical role of the EphA4 and response to sleep deprivation in glutamatergic system in cognitive performance, EphA4 knockout mice we investigated whether chronic prenatal exposure to the glutamate NMDA receptor Marlene Freyburger¹, Janine El Helou¹, Erika antagonist, MK-801, would induce impairments Belanger-Nelson¹, Valérie Mongrain¹ in cognitive flexibility in adult male offspring. ¹Université de Montreal Pregnant Long-Evans rats were administered saline or MK-801 (0.1 mg/kg; s.c.) at gestation Introduction: Sleep is required in mammals and day 7 through 19. Cognitive flexibility was its recovery aspect was hypothesized to depend assessed using a maze-based set-shifting on mechanisms controlling synaptic strength. procedure. We tested the effects of prenatal EphA4 is an adhesion molecule implicated in the MK-801 on (1) acquisition of response or visual- regulation of synaptic function. The aim of the cue discrimination and (2) acquisition of the shift study is to understand the impact of sleep from a response to visual-cue discrimination deprivation [SD] on the expression of EphA4 task and vice versa. The shift procedure and on gene expression in EphA4 knockout required rats to suppress the use of the [KO] mice. Methodology: 1) The expression of previously relevant strategy. Prenatal MK-801- EphA4 and its partners was measured by treated rats showed impaired acquisition when quantitative PCR [qPCR] after a 6h SD in 3 shifting to a new strategy compared to saline- different mouse brain regions (cortex [CTX], treated rats, though this difference was not hippocampus [HP], and a thalamic/hypothalamic statistically significant. Analysis of the errors [TH/H] region). 2) EPHA4 synaptic and total revealed that the deficit was due to regression to protein level was measured by Western blot the previously learned behaviour. These findings after a 6h SD in the same 3 brain regions. 3) suggest that glutamate dysfunction during early Mice from 3 genotypes (wild-type, heterozygous development may mediate cognitive deficits in and homozygous EphA4 KO mice) were 155

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 adulthood and therefore may shed light into the object properties, respectively, the current study cognitive symptoms observed in schizophrenia. was conducted to better establish the precise contributions of OFC to crossmodal object 2-F-161 Decision-related eye movement recognition (CMOR). We began by examining patterns during virtual navigation in non- the temporal involvement of OFC during the human primates (Macaca mulatta) tactile sample and visual choice phases of CMOR. Transient lesions induced by intra-OFC Roberto Gulli¹, Guillaume Doucet¹, Julio infusions of lidocaine produced a delay- Martinez-Trujillo¹ dependent impairment when given prior to the ¹McGill University sample but not the choice phase, suggesting a role in information encoding. We next tested the Virtual reality can be used as a tool to study the hypothesis that this putative function may help neurobiology of cognition and behaviour, to prevent interference effects during extended including processes such as decision-making delay periods. When rats were exposed to a and memory. To this end, we have used an sensory restriction procedure in order to reduce open-source video game engine (Unreal Engine potential interfering stimulation during the 3) to create immersive virtual reality retention delay, the impairment produced by environments that can be modified in real-time pre-sample intra-OFC lidocaine was reversed. through a custom-built Matlab interface. We Finally, we further explored the circuitry have trained rhesus monkeys (Macaca mulatta) underlying CMOR by transiently disconnecting to freely navigate through these environments communication between the OFC and other using a two-axis joystick. In one paradigm, regions previously implicated in the task. Thus monkeys were presented with a two-alternative far, we have established that CMOR forced choice paradigm (similar to a Y-maze) performance relies on communication between and learned an arbitrary object/reward value OFC and PPC but not between OFC and PRh. hierarchy through trial and error. Analysis of We are currently examining the possibility that navigational and eye-movement patterns at the OFC interacts with areas located caudal to PRh point of decision-making yielded patterns of along the ventral visual stream to facilitate visual fixation that correlate with object choice. crossmodal encoding of object representations. That is, when faced with differentially-rewarded and choice-exclusive objects, non-human 2-F-163 Oscillatory responses to primates will rapidly saccade between them; the sentence embedded semantic and syntactic proportion of time fixating on each object is violations: Effect of bilingualism predictive of the object choice. Further, the proportion of time fixating on the object of higher Aneta Kielar¹, Jed Meltzer¹, Sylvain Moreno¹, reward value increases as the monkeys learn Claude Alain¹, Ellen Bialystok ² the object/reward value association. These ¹Baycrest Hospital, ²York University findings are congruent with human and animal models of decision-making. Importantly, they EEG studies employing time-frequency analysis support the utility of dynamically controlled have revealed modulations of theta and alpha virtual environments in understanding the power in a variety of language and memory neurobiology of complex cognitive behaviours in tasks. Semantic and syntactic violations non-human primates. embedded in sentences evoke well-known event-related potentials, but little is known about 2-F-162 Investigating the role of the oscillatory responses to these violations. We orbitofrontal cortex in crossmodal object investigated oscillatory responses to both kinds recognition in rats of violations, while monolingual and bilingual participants performed an acceptability Derek Jacklin¹, Emily Boughner¹, Michelle judgement task. Both violations elicited power Moon¹, Boyer Winters¹ decreases (event-related desynchronization, ¹University of Guelph ERD) in the 8-30 Hz frequency range, but with different scalp topographies. In addition, We have previously shown that rats rely on the semantic anomalies elicited power increases interaction between posterior parietal (PPC), (event-related synchronization, ERS) in the 1-5 perirhinal (PRh) and orbitofrontal (OFC) cortices Hz frequency band. The 1-5 Hz ERS was to recognize objects across the tactile and visual strongly phase-locked to stimulus onset and sensory domains. Whereas past studies suggest highly correlated with time-domain averages, that PPC and PRh process tactile and visual whereas the 8-30 Hz ERD response varied 156

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 independently of these. In addition, the results 2-F-165 Differences of fructose/glucose showed that language expertise modulated 8-30 ratios on operant self-administration and c- Hz ERD for syntactic violations as a function of fos expression in the hypothalamus and the executive demands of the task. When the nucleus accumbens executive function demands were increased using a grammaticality judgment task, bilinguals Paul Marshall¹, Katrina Kent¹, Stephen but not monolinguals demonstrated reduced 8- Daniels ¹, Ari Shore ¹, Tiana Downs¹, 30 Hz ERD for syntactic violations. These Francesco Leri¹ findings suggest a putative role of the 8-30 Hz ¹University of Guelph ERD response as a marker of linguistic processing that likely represents a separate One potential contributor to obesity is over- neural process from those underlying event- consumption of sugars. More specifically, it is related potentials. believed that foods containing high levels fructose (instead of glucose) are more likely to 2-F-164 Intraoral self-administration of be "abused" and hence promote overeating. The sweeteners in laboratory rats current study explored the hypothesis that ratio of fructose/glucose influences reward-related AnneMarie Levy¹, Gabrielle Colangelo¹, behaviors and neuronal activity in areas of the Mazen El-Baba¹, Cheryl Limebeer¹, Linda brain involved in reward and energy balance. Parker¹, Francesco Leri¹ Using a radial arm maze, male Sprague-Dawley ¹University of Guelph rats self-administered high ratio (HR; 55%F- 45%G, typical ratio used in the food industry) or The food addiction hypothesis predicts that low ratio (LR ; 30%F-70%G, typical commercial some foods may share with drugs of abuse the sucrose pellets ratio, Bio-Serv, Frenchtown, NJ) ability to reinforce behaviors leading to their fructose-glucose pellets for 10 minutes daily, consumption. The current study in male over 14 days. Control rats received the same Sprague-Dawley rats was designed to compare treatment but did not receive pellets after nose the reinforcing effect of sucrose (S) and high pokes. On day 14, rats were sacrificed 90 fructose corn syrup (HFCS) using procedures minutes after the session, and brains were commonly used to study the reinforcing extracted and processed for Fos-like properties of drugs. To assess the palatability of immunoreactivity in the hypothalamus and these sweeteners, rats implanted with intraoral nucleus accumbens. Initial results indicated no cannulas received taste reactivity (TR) tests with significant differences between HR and LR in isocaloric solutions of S (20%) or HFCS (25%). consumption of pellets, or c-fos density Then, rats self-administered the same solutions (count/um2) within the nucleus accumbens. (one 3 hour session/day) for 40 days. To this However, within the perifornical area of the end, rats pressed a lever to receive an intraoral lateral hypothalamus, there was a significant infusion (90µl/inf) of either S or HFCS on trend for the HR group to display lower c-fos continuous and progressive ratio (PR) density. In light of these preliminary findings, it is schedules of reinforcement. Preliminary data concluded that 5%-30% differences in ratio of indicate that HFCS engendered greater hedonic fructose/glucose may not be large enough to reactions in tests of TR; however, palatability induce significant changes in rewarded behavior was not related to intake when lever pressing on and underlying neural substrates. a continuous schedule in self-administration (SA) as rats maintained higher intake of S while 2-F-166 Lack of sex differences but binge-like behavior only emerged in rats that menstrual cycle phase dependent self-administered HFCS. Finally, group modulation of craving for cigarettes in differences did not emerge when lever pressing female smokers : An fMRI study on a PR schedule. Taken together, these data suggest that isocaloric solutions of S and HFCS Adrianna MENDREK¹, Laurence DINH- do not have the same effect on mechanisms of WILLIAMS², Josiane BOURQUE², Stéphane reward and reinforcement as these sweeteners POTVIN³ engendered differences in palatability, overall ¹Bishop's University, ²Université de Montreal, ³1. intake, and binge-like behavior. Future studies Centre de recherche de l'Institut universitaire en will focus on replicating these results as well as santé mentale de Montréal identifying features of S and HFCS that may contribute to these notable effects. While overall more men than women smoke cigarettes, women and girls take less time to 157

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 become dependent after initial use and have (i.e., the N400). We investigated the immediate more difficulties quitting the habit, than men and effect of a single dose of risperidone (n=45) and boys. One of the factors contributing to these a placebo (n=25) on this N400 in healthy, drug- differences may be that women crave cigarettes naïve individuals, as they performed a semantic more than men and that their desire to smoke is categorization task. An increase in the frontal influenced by hormonal fluctuations across the N400 amplitudes was observed in both the menstrual cycle. Therefore, the purpose of the medication and placebo groups in the 300-500 present study was two-fold: a) examine potential ms time window, while an increase of this ERP sex differences in functional neuroanatomy of in the medication group only was seen in the craving; b) delineate neural correlates of 200-300 ms time window. We conclude that cigarette cravings in women across their risperidone has an immediate impact on the menstrual cycle. Fifteen tobacco-smoking men early part of the N400, while practice to task and 19 women underwent a functional MRI augments the later part of this ERP. during presentation of neutral and smoking- related images, known to elicit craving. Women 2-F-168 Profile differences in 50 kHz were tested twice; once during early follicular vocalizations induced by systemic or (low levels of estradiol and progesterone) and intraaccumbens application of amphetamine once during mid-luteal (high levels of estradiol and progesterone) phase of their menstrual Kevin Mulvihill¹, Stefan Brudzynski¹ cycle. The analysis did not revealed any ¹Brock University significant sex differences in the cerebral activations associated with craving. Ultrasonic vocalizations in rats serve as a Nevertheless, the pattern of activations in behavioural index of their affective states. It has women varied across their menstrual cycle; been established that production of 50 kHz calls, significant activations in the precuneus, anterior associated with appetitive states, involves and posterior cingulate, medial frontal, inferior activity of the ascending mesolimbic dopamine temporal and angular gyrus during follicular (DA) pathway from the VTA to the nucleus phase, and only limited activations in the right accumbens. The 50 kHz call category can be hippocampus and precuneus during the luteal further subdivided into flat and frequency phase. Present findings may provide some modulated subtypes based on sonographic preliminary clues to design better programs to characteristics. Little is known about the role of quit smoking for women. these subtypes and how they are generated. The purpose of the current study was to 2-F-167 The effect of atypical investigate whether the route of DA agonist antipsychotics on an index of semantic application can have effect on parameters and processing subtypes of elicited 50 kHz calls. Injections of saline or the indirect DA agonist, amphetamine Ola Mohamed Ali¹, Ana Lucia Fernandez (AMPH) were made both systemically (1.5-2.0 Cruz¹, Bruno Debruille¹ mg/kg, subcutaneous) and directly to the brain ¹McGill University (7 μg, intraaccumbens) with the resultant call profiles analyzed (N = 24). Systemically-induced Semantic processing relates to the access of AMPH calls were found to differ significantly in meanings about incoming information from total number of generated calls, acoustic semantic memory. Deficits in this process have parameters, and subtype proportions when been proposed to account for the symptomology compared with those after saline (n = 12), as of schizophrenia as well as the schizotypal well as compared to intraaccumbens AMPH tendencies seen in the general population. For microinjections (n = 12). These results support instance, an abnormal spread of activations the hypothesis that different routes of drug within semantic memory networks could underlie application differentially elicit 50 kHz call disorganization while inefficient use of context to subtypes and modulate their acoustic inhibit incongruent activations could underlie parameters. Systemic application appears to delusional ideation. Antipsychotic medications more effectively induce affective signaling could thus alleviate these symptoms by acting presumably by more complete activation of the on the neural networks underlying semantic mesolimbic DA system than local processing. To test this hypothesis, we intraaccumbens injection. examined a well-known index of semantic processing: the event-related potential (ERP) peaking negatively 400 ms post stimulus onset 158

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28

2-F-169 Haloperidol-Environment extreme sex differences in these nuclei and in Interaction Mediates Expression of c-Fos singing behaviour, making songbirds an Proteins in the Ventral Pallidum of Rats excellent model to study sex differences in the brain. Myelination of the SCS, while potentially Lexy Pezarro Schimmel¹, Emily Hawken¹, vital to its function, has not been extensively Eric Dumont¹, Tomek Banasikowski², examined. The current study used male and Richard Beninger¹ female adult zebra finches to examine sex ¹Queen's University, ²University of Pittsburgh differences in myelination of the SCS. Male zebra finches sing but females do not. Enhanced ventral pallidum (VP) activity has Immunohistochemical labeling of myelin basic been shown to mediate dopamine (DA) neuronal protein (MBP) was used to measure myelination activity and facilitate the strength of within the SCS. Regions of interest included motivationally salient environmental stimuli. HVC, RA, and LMAN. Fibre tracts analyzed Repeated treatment with antipsychotic drugs included the HVC to RA tract and the HVC to reduces the salience of biologically significant Area X tract contained within lamina stimuli and gradually produces motivational mesopallium ventralis (LMV). Results show a impairments observed as a loss of motor significant male-biased sex difference in MBP engagement with the environment. We immunoreactivity within HVC and the HVC to RA examined the neural mechanisms of context- tract, but not within RA, LMAN, or LMV. These dependent catalepsy sensitization in rats with an results suggest that the myelination of HVC and immunohistochemical assay for c-Fos, a marker the HVC to RA tract is important to adult singing of recent neuronal activity. During the training behaviour, as the males sing and females do phase (15 daily sessions), the paired group not. Furthermore, the non-significant findings in received haloperidol (0.25 mg/kg; n=9), a DAD2 other areas of the SCS suggest that these receptor-preferring antagonist, 1 h prior to a regions are still important for females, potentially catalepsy test carried out in a specific for the perception of song, and/or the production environment by placing the rats with their of other vocalizations. Determining how sex forepaws resting on a horizontal bar. The differences in myelination of the SCS are unpaired group (n=9) was treated with saline regulated will provide an important advance in before catalepsy test and then injected with basic neurobiology. haloperidol 1 h later; a third group (n=9) was treated with saline before and after catalepsy 2-F-171 Set, reversal, and long-term test. On a test day when all groups were treated olfactory learning in the 3xTG-AD mouse with haloperidol prior to the catalepsy test, the model of Alzheimer’s disease. paired group showed significantly longer descent latency from the bar compared to the Kyle Roddick¹, Heather Schellinck¹, Richard unpaired and saline control groups. Brown¹ Immunohistochemical results found that ¹Dalhousie University haloperidol paired animals (n = 5) had significantly attenuated c-Fos expression in the The 3xTG-AD transgenic mouse model of AD VP compared to both the unpaired (n = 6) and develops both amyloid-β plaques and tau saline controls (n = 3). No differences were tangles between 3 and 6 months of age. We found in the parietal cortex. Results implicate tested female 3xTG-AD mice (n=14), and their the VP in the integration of contextual and wildtype controls (B6129S/F2) (n=13), at 6 to 18 motivational information. (Funded by NSERC) months old on a series of 18 olfactory discrimination and reversal tasks in an operant 2-F-170 Sex Differences In Myelination olfactometer. Mice were trained to discriminate Of The Song Control System between two odour stimulus, an S and an S-, on a go, no-go task. The mice were then presented Adam Piraino¹, David Sherry¹, Scott with a reversal task in which the S and S- MacDougall-Shackleton¹ odours were switched. Following the reversal ¹Western University task, the mice were given a new pair of odours to discriminate, followed by a reversal, and this The song control system (SCS) is an intensively was repeated until the mice had completed a studied network in the songbird brain. Nuclei series of 18 discriminations and reversals. Mice within this network are responsible for learning, were retested on the final odour pair 1, 2, or 3 production, and maintenance of song, and months later. Mice made more errors learning furthermore adult singing behavior. There are the reversal tasks than the discrimination tasks. 159

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This difference was most pronounced on the hyperactivity, cognitive rigidity and reduced earliest odour pairs and decreased as the mice spatial memory in mice. Conclusions. Our advanced through the series. Many of the mice results demonstrate the critical role of CaV2.1 in showed near errorless learning, making only 1 regulating perisomatic inhibition during cognitive or 2, in the final stages of the series. During the processes. retest phase performance returned to levels comparable to the start of the series. Transgenic 2-F-173 Dorso lateral corticoid area and mice reached their maximum performance its neuronal classes: possible role in vocal earlier in the series than the wildtype mice, but learning and cognition in Indian Ring Neck with the wildtype mice reached a higher level of parrot (Psittacula krameri) performance in the later odour pairs. This high level of performance suggests that the mice Sudhi Shrivastava¹, Shubha Srivastava² were able to develop a strategy during the ¹Barkatullaha University Bhopal, ²KNPG college earlier stages of the experiment and apply this , Sant ravidas nagar to the later stages. Detailed study of avian pallium provides 2-F-172 Synaptic impairment of cortical apprehension, how birds are able to carry out and hippocampal fast-spiking basket cells higher order cognitive functions without a induces cognitive deficits in Cacna1a laminated cerebral cortex. However, birds are mutants. able to do so as major part of avian telencephalon contributes to pallium and is Alexis Lupien-Meilleur¹, Ilse Ribe², Elena comparable to mammalian cortex, Parrots Samarova¹, Lena Damaj³, Jean-Claude possess quite sophisticated cognitive abilities Lacaille², Elsa Rossignol¹ and vocal abilities carried out by nuclear pallial ¹CHU Ste-Justine, Université de Montréal, areas. Most of the telencephalic vocal control ²Université de Montréal, ³CHRU Rennes nuclei are in the pallium with one vocal nucleus in the striatum. Dorsolateral corticoid area (CDL) Background. CACNA1A encodes the α1 sub- in aves is a part of corticoid complex and is unit of Cav2.1 channels. CACNA1A deletions located as a thin narrow part at dorsolateral result in episodic ataxia (EA2) and epilepsy in surface of telencephalic pallium. The present humans. We recently demonstrated that a study was designed to explore the targeted deletion of Cacna1a in forebrain neuroarchitecture of parrot telencephalon with GABAergic interneurons (IN) leads to selective CDL in particular. Using Nissl stain and Golgi synaptic impairment of parvalbumin-positive impregnation techniques, the types of neuronal (PV) fast-spiking basket cells and is sufficient to sub-classes in parrot CDL were identified and induce epilepsy in mice. Altered function or studied in detail. Neurons of this area are maturation of cortical PV INs have been distinguished in two prominent cell types, reported to impair cognition in mice. We propose spinous projection neurons and local circuit that impaired perisomatic inhibition resulting neurons. Detailed morphology and the possible from PV INs synaptic dysfunction in neocortical roles of these cell types in regulating cognitive and hippocampal circuits leads to cognitive and emotional processing including vocal deficits in Cacna1a mutants. Method. We abilities are also discussed. We also conclude assessed the cognitive abilities of 12 patients about how the CDL interact with other pallial from 3 different families carrying CACNA1A regions as a part of circuits involved in the deletions. Furthermore, we generated mutant regulation of cognitive functions. The CDL of mice carrying a targeted Cacna1a deletion birds is most recently proposed as homologous restricted to telencephalic PV populations to mammalian cingulate cortex, suggests that (PVcre;Cacna1ac/ ). We assessed their complex cognitive function of birds are due to cognitive abilities and behaviour in the Open similar neuronal components of homologous Field, T-maze and Morris Water Maze. We also regions of brain. investigated cortical and hippocampal perisomatic inhibition in vitro. Results. Patients 2-F-174 Muscarinic cholinergic receptor carrying CACNA1A deletions displayed a activation destabilizes object memories, spectrum of neurocognitive deficits including possibly via proteasome-mediated protein inattention, impulsivity and/or intellectual degradation disability. We show that Cacna1a haploinsufficiency in PV populations alters perisomatic inhibition and is sufficient to cause 160

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Mikaela Stiver¹, Derek Jacklin¹, Nevena single trial based on the activity of many Vicic¹, Justine Carlin¹, Matthew O'Hara¹, neurons. Thus, whether and how the activity of Boyer Winters¹ simultaneously active LPFC neurons can ¹University of Guelph effectively filter relevant targets in the presence of distractors remains unclear. Here we Consolidated memories can become chronically implanted multielectrode arrays in destabilized and open to modification upon area 8r of the LPFC of two non-human primates retrieval. Destabilization is most reliably and showed that the activity of small assemblies prompted when novel information is present of ~50 simultaneously recorded neurons can be during memory reactivation. We hypothesized reliably decoded to determine the location of an that acetylcholine (ACh) plays an important role attended target among distractors. The in novelty-induced memory destabilization due decoding was robust to unexpected transient to its established involvement in new learning. changes in the distractors' features, predictive of Accordingly, we investigated the effects of behavioral errors, and stable across a timespan cholinergic manipulations in rats using an object of multiple weeks, suggesting that it can be of recognition paradigm that requires reactivation potential use in the implementation of cognitive novelty to destabilize object memories. The brain machine interfaces. muscarinic receptor antagonist scopolamine, systemically or infused directly into the perirhinal 2-F-176 Muscarinic Control of cortex (PRh), a brain region strongly implicated Rostromedial Tegmental Nucleus GABA in object memory, blocked this novelty-induced Neurons and Morphine-induced Locomotion memory destabilization. Conversely, systemic injection or PRh infusion of a muscarinic David Wasserman¹, Joel Tan¹, Junchul Kim¹, receptor agonist (oxotremorine or carbachol) John Yeomans¹ mimicked the destabilizing effect of novel ¹University of Toronto information during reactivation. Furthermore, preliminary data suggest that carbachol-induced Opioids induce rewarding and locomotor effects destabilization requires proteasome-regulated mainly via rostromedial tegmental (RMTg) protein degradation in the PRh. The bidirectional GABA neurons that express μ-opioid and cholinergic effects suggest a crucial influence of nociceptin receptors. These GABA neurons then ACh on memory destabilization and the strongly inhibit midbrain dopamine neurons. updating functions of reconsolidation. This is a Opioid rewards and locomotion also depend on hitherto unappreciated mnemonic role for ACh dorsal tegmental cholinergic and glutamate with implications for its potential involvement in neurons that project to and activate VTA cognitive flexibility and the dynamic process of dopamine neurons. Here we show that many long-term memory storage. A connection pedunculopontine and lateral tegmental between muscarinic receptor activation and cholinergic neurons project to both RMTg and proteasome activity provides a basis for VTA, and that M4 muscarinic receptors are co- investigation into the intracellular pathways localized with μ-opioid receptors on RMTg involved in object memory destabilization. GABA neurons. To inhibit or excite RMTg GABA neurons, we bilaterally transfected designed 2-F-175 Decoding the focus of visual muscarinic receptors (M4D or M3D) in GAD2- attention from prefrontal ensemble activity Cre mice with AAV. In M4D-expressing mice, clozapine-N-oxide (CNO) increased morphine- Sebastien Tremblay¹, Florian Pieper², Adam induced, but not saline-induced locomotion. In Sachs³, Julio Martinez-Trujillo¹ M3D-expressing mice, CNO blocked morphine- ¹McGill University, ²University Medical Center induced locomotion, but not saline-induced Hamburg-Eppendorf (UKE), ³University of locomotion. We propose a disinhibitory model of Ottawa opioid-induced locomotion in which cholinergic inhibition of RMTg GABA neurons via M4 The lateral prefrontal cortex (LPFC) is thought to muscarinic receptors facilitates opioid inhibition play an important role in visual selective of the same neurons. Collateral cholinergic attention. Traditional single cell studies in non- activation of VTA dopamine neurons via M5 human primates have revealed that the activity muscarinic receptors activates dopamine of individual LPFC neurons pooled over many neurons and facilitates dopamine-dependent trials can filter behaviourally relevant from locomotion. irrelevant visual information. However, in real situations the brain must filter information in a 161

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2-F-177 Sensitization of the Activity- rodent dorsal hippocampus (dHC) prior to Decreasing Effects of Haloperidol in Rats: training, we show that first object location Preliminary Results learning acquisition requires NMDA receptors, while subsequent learning of the same task Kathleen Xu¹, Richard Beninger¹ does not. We used this difference in a second ¹Queen's University learning protocol to determine whether amnesia for first learning induced by ZIP infusions in the Increases in brain dopamine (DA) produced by dHC would affect second learning. Rats were repeated administration of cocaine or taught first learning of a novel object location amphetamine in a particular environment result task in context A and then infused with ZIP or in sensitization of locomotor activity in rats, scrambled ZIP (SCR) 24 hours after the end of activity increasing over sessions. This effect is training. The following day both groups specific to the drug-paired environment. We underwent AP5- or vehicle-infusions investigated whether decreased activity could be immediately prior to second learning training in sensitized using a similar sensitization Context B. We show that only ZIP-infused paradigm. In previous work in rats, low doses of amnesic rats required NMDA receptors to the D2 receptor-preferring antagonist acquire second learning memory of object haloperidol (HAL; 0.25 mg/kg, i.p.) led to location, as if there was no previous memory of context-dependent increases in catalepsy, a first training. These data are consistent with the phenomenon marked by immobility on a interpretation that the amnesia induced by ZIP- suspended horizontal bar. We hypothesized that infusions does not impair retrieval, but erases decreases in brain DA neurotransmission memory. produced by repeated administration of HAL would lead to context-dependent sensitization of G - Novel Methods and Technology decreased activity. The paired group (n = 10) Development received HAL (0.1 mg/kg, i.p.) 1 h before placement in the test chamber, where activity 2-G-179 Examining astrocyte was measured for 3 min daily during 13 morphology using DiOlistic labeling with the sessions. The unpaired group (n = 10) received PDS-1000/He Particle Delivery System haloperidol 1 h after the daily activity test, serving as a drug-history control, but without the Lindsay Alvis¹, Kristin Milloy¹, Adrienne drug-environment pairing. A third group (n = 10) Benediktsson¹ received saline instead of HAL. The groups did ¹Mount Royal University not differ during the early test sessions but the paired group showed less activity than the Morphological changes in astrocytes have unpaired and saline groups on days 12 and 13, profound effects on nervous system function, yet revealing sensitization to the activity-decreasing detailed characterization of their 3-D effects of HAL. Results suggest that DA D2 morphology is not complete. Astrocytic neurotransmission plays an important role in morphology is highly complex; numerous producing context-dependent sensitization of spines, lamellae and filopodia radiate along the decreases in activity. (Funded by NSERC) lengths of astrocyte processes. To visualize these morphological structures it is necessary to 2-F-178 The Nature of Forgetting: use a membrane associated dye or membrane Storage or Retrieval Impairment in targeted fluorescent protein. Typically, Experimental Amnesia transgenic mouse lines have been used to express fluorescent proteins within individual Jie Jane Zhang¹, Oliver Hardt², Karim Nader¹ cells; however, these are costly and difficult to ¹McGill University, ²University of Edinburgh maintain. DiOlistics, a less costly method, has been used to label cells with membrane- Experimental amnesia can reflect impaired targeted dyes. DiOlistics involves coating 1.0 µm storage (memory erasure), or impaired retrieval tungsten particles with lipophilic dyes and (inaccessible memory). We have previously delivering them into tissues using a blast of proposed a novel paradigm to test this helium. When these particles come in contact unresolved issue. We proposed that exploiting with a cell, the entire membrane is labelled with the differences in brain mechanisms which are the fluorescent dye, enabling an examination of selective to first versus second learning is a its structure in its native environment. The constructive approach to dissociate these two labeling also occurs quickly and persists for long theories. Specifically, by infusing AP5 into the periods of time (at least 9 months). Finally, 162

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DiOlistic labeling can also be combined with immunocytochemistry to examine the 2-G-181 A novel method of electrical subcellular distribution of proteins within stimulation to reduce tibialis anterior individual cells. Where DiOlistic labeling contraction fatigue normally requires a BioRad Helios gene gun, we have adapted this methodology to the PDS- Jenny Lou¹, Abdulaziz Aldayel¹, Jennifer 1000; this permits a larger number of brain Czitron¹, David Collins¹ sections to be bombarded at one time, ¹University of Alberta increasing the number of labelled cells. We are currently combining confocal microscopy and 3- Neuromuscular electrical stimulation (NMES) D reconstruction using Imaris to localize proteins can be used to produce contractions for people within labelled astrocytes. who have had a stroke or a spinal cord injury. Traditionally, NMES is applied either over a 2-G-180 Focused ultrasound-mediated muscle belly (mNMES) or nerve trunk (nNMES). blood-brain barrier opening in a mouse Unfortunately, NMES is limited by rapid model of Alzheimer’s disease contraction fatigue, due in part to abnormally high discharge rates of recruited motor units. To Alison Burgess¹, Tam Nhan¹, Sonam Dubey¹, overcome this problem, we developed Isabelle Aubert¹, Kullervo Hynynen¹ interleaved NMES (iNMES), in which stimulus ¹Sunnybrook Research Institute pulses are alternated between the muscle and nerve sites. Since mNMES and nNMES recruit Focused ultrasound (FUS) can temporarily open different motor unit populations, we propose that the blood-brain barrier (BBB) to permit access of iNMES will halve motor unit discharge rates therapeutic agents into localized brain regions. compared to mNMES or NNMES delivered FUS-mediated BBB opening has reduced alone. Presently, we compare contraction amyloid plaque load in the cortex of a mouse fatigue during mNMES, nNMES and iNMES. We model of Alzheimer's disease (AD). Here, we hypothesized that iNMES will generate the most correlate reduced plaque pathology with fatigue-resistant contractions, followed by changes in cognition. Further, we use two- mNMES and nNMES respectively. Able-bodied photon microscopy to evaluate the changes in subjects participated in 3 experimental sessions BBB permeability in the presence of plaque on separate days. The fatigue protocol pathology. 8 month old transgenic (Tg) mice consisted of 250 trains of NMES (50 µs pulse exhibiting advanced pathology and duration, 40 Hz, 2 s "on", 1 s "off"). At the start compromised vasculature, were treated with of the protocol, contraction amplitudes were 10- weekly MRI-guided FUS treatments in the 15% of a maximum voluntary contraction. hippocampus. In the Y maze, untreated Tg mice Contraction fatigue was quantified as the fatigue spent significantly less time in the novel arm index: the average torque for the last 5 compared to their non-Tg littermates but contractions divided by the average torque for following FUS, Tg mice performance was the first 5 contractions, multiplied by 100. Data restored to levels of non-Tg mice. Increases in collected from 6 subjects thus far show that the number and complexity of doublecortin- iNMES generated the most fatigue-resistant expressing cells in the dentate gyrus suggest contractions (75±61), followed by nNMES that FUS promotes neuronal plasticity and (67±75) and mNMES (51 ± 25) respectively. improves cognitive behaviour even in Tg mice iNMES demonstrates potential to reduce with advanced pathology. Further, using two- contraction fatigue for rehabilitation. photon microscopy and fluorescent intravascular dye, we demonstrated that dye leakage 2-G-182 A new standalone software for following FUS-induced BBB permeability was interactive filtering of movement artifacts significantly less in Tg compared to non-Tg generated during multiphoton intravital mice. Changes in vessel diameter after FUS imaging of neuroinflammation treatment were diminished in plaque-coated vessels suggesting that the mechanisms of BBB Catherine Fontaine-Lavallée¹, Benoît Aubé¹, opening may be different in Tg mice. These Mélissa Côté¹, Alexandre Paré¹, Steve studies further the understanding of FUS- Lacroix¹, Denis Soulet¹ induced BBB permeability in presence of ¹CRCHUL (Laval university) amyloid pathology, and they contribute to evaluating the potential of FUS in the Two-photon intravital microscopy is a powerful development of treatments for AD. and versatile tool to investigate with high spatial 163

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 and temporal resolution biological samples in identified so far and drugs acting at RXR remain their unaltered environments. Notably, it allows poorly characterized. Furthermore, presently the live visualization of neuro-immunological available assays cannot recapitulate the events taking place in the central and peripheral complexity of NR activities and generate indirect nervous systems both in physiological and measures of drug activities. For this purpose, we pathological contexts, which is of the utmost have developed and optimized luciferase protein interest for studying animal models of complementation-based Bioluminescence neurological disorders. The acquisition of high Resonance Energy Transfer (BRET) assays for quality intravital time-lapse data is however the recruitment of a YFP-tagged co-activator by hampered by movement artifacts generated by specific NR species. We validated the assays cardiac and respiratory cycles as well as with available compounds using dose-response peristaltism, which even deep anesthesia and curves. EC50 obtained were very similar to animal stabilization cannot eliminate. This is a previously reported values. Our results indicate major obstacle to studying dynamic that these BRET assays can be used as morphological changes in living tissue at the biosensors to monitor selective drug activities at cellular level. To overcome these caveats, we RXR/RXR and Nur77/RXR complexes. Thus, recently developed a post-acquisition software this technology can be used to identify new that allows to minimize the impact of movement compounds showing specificity profiles to artifacts through image treatment, filtering and individual dimeric species formed by one NR. alignment techniques (Soulet et al, PLoS ONE, Supported by the GRUM. 2013). In this communication, we present a new, standalone multiplatform version of our 2-G-184 Kinematic Assessment algorithm that was completely rewritten with Effectively Guide Botulinum Neurotoxin Type MathWorks® MATLAB. Among the new A Injections for Essential Tremor Treatment functions available, we have developed a user- friendly graphical interface that greatly facilitates Fariborz Rahimi¹, Olivia Samotus¹, Jack Lee¹, the navigation through the different features of Mallory Jackman¹, Mandar Jog¹ the software. Of importance, execution time has ¹Western University been optimized to allow more efficient multidimensional image processing in 4 Efficacy of botulinum neurotoxin type A (BoNT- channels in the Z-axis over time. This results in A) injection in treating essential tremor (ET) has a dramatic increase in image quality and better been poor due to the difficulty of visual interpretation of dynamic biological events. assessment in arm tremor. 24 ET patients were assessed over 48 weeks using kinematic 2-G-183 Development of BRET-based sensors placed on the wrist, elbow and shoulder biosensors for nuclear receptors associated joints. Recordings were taken with the patient's with dopamine neurotransmission arm in rest, posture, load and kinetic states. Measurements were processed and kinematic Xavier Giner¹, David Cotnoir-White¹, Sylvie results were provided to the physician. Based on Mader¹, Daniel Lévesque¹ the physician's own clinical experience, BoNT-A ¹University of Montreal dose and injection sites were determined. Kinematic assessment and clinical tremor rating The Nur (Nr4a) subgroup includes 3 members scales were completed at each visit. Injection (Nur77, Nurr1 and Nor-1). They are transcription cycles were 4 months apart. Following the first factors of the orphan nuclear receptor (NR) injection, kinematic measurements showed a family. Nurr1 is expressed in dopamine (DA) significant tremor reduction at the shoulder, neurons, whereas Nur77 and Nor-1 are normally elbow and wrist. The Quality of Life scale expressed in brain structures innervated by DA showed a significant improvement, dropping neurons. Previous works from our laboratory from an average of 40 to 31 by week 22. indicated that Nur77, along with its cognate Similarly, the Fahn, Tolosa, Marin Tremor partner retinoid X receptor (RXR), is involved in Rating Scale showed significant improvement by antipsychotic and anti-parkinsonian drug week 6 with a reduction in total score of 47 to activities. However, Nur-dependent 36. The Unified Parkinson Disease Rating Scale transcriptional activity in the brain remains action tremor assessment declined from 2.6 to elusive. Nurs can interact with distinct gene 1.6 by week 16. Maximal grip strength was promoter response elements through monomer, reduced by 25% following the first injection; homodimer, or heterodimer forms with RXR. patients perceived mild weakness with limited to Very few drugs targeting Nurs have been no loss of function. Using this kinematic 164

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 assessment technique, overall arm tremor post BoNT-A injection showed remarkable reduction. To understand the heterogeneous properties of The kinematic device and software were able to single neurons, real time quantitative deconstruct the complex movements of tremors polymerase chain reaction (qPCR) is a sensitive and thus increase BoNT-A injection accuracy, technique to measure gene expression. Using an outcome not possible by visual assessment SYBR Green in qPCR experiments can be cost- alone. effective compared to the taqman approach. However, the sensitivity of this technique for 2-G-185 BrainDir: A Public Online quantification of genes expressed at low number Repository for Healthy Control of copies is typically lower than with taqman. In Neuroimaging Data the present study, we tested the hypothesis that the use of nested qPCR, in which two different Jeremy Moreau¹, Chris Lepage¹ pairs of primers are designed for each gene of ¹University of Ottawa interest, could allow to overcome the lower sensitivity of SYBR Green qPCR. Using single A matched control group is often a requirement mouse dopamine neurons, we optimized nested of well-designed imaging studies; however, the qPCR for 2 genes: the vesicular glutamate elevated costs associated with scanning can transporter 2 (VGLUT2) and tyrosine prohibit the recruitment of adequately large hydroxylase (TH). Specific primers for VGLUT2, samples of healthy controls. A sufficiently large TH and a house keeping gene (GAPDH) were pool of publicly available healthy control imaging designed. The technique was performed in three data would allow researchers to reduce their steps: the reverse transcriptase reaction, an imaging costs by searching for and reusing outer round of PCR and finally qPCR. For a low healthy control data shared by other copy gene such as VGLUT2, a higher number of researchers. Previous attempts at creating cycles were needed in the outer round. The online repositories of neuroimaging data have specificity of the primers used was confirmed by been undertaken, but there is a lack of options analyzing the melt curves and by performing for cross-laboratory sharing of healthy control regular nested RT-PCR. We also performed for imaging data. Here we propose a freely each gene a linear standard curve from a available web application and companion cross- dilution of a pool of cells in order to confirm an platform desktop application to facilitate the efficiency between 90-110 % of the qPCR exchange of neuroimaging data between reaction. Our results show that such a three research groups. Our application consists of an steps single-cell reverse transcriptase nested online repository of anonymised imaging qPCR using SYBR Green is a sensitive and datasets stored in the DICOM image format reproducible technique to quantify low searchable by criteria such as participant age, abundance mRNA in single neurons. sex, handedness, and years of education. The web application also provides facilities for easily 2-G-187 Whole-brain mapping of neural importing author information into popular activation in mice reference managers. The companion desktop application provides a simple interface allowing Dulcie Vousden¹, Jonathan Epp², Hiroyuki for the anonymisation of DICOM metadata. As Okuno³, Brian Nieman², Matthijs van Eede², well, it provides functionality for reliably Jun Dazai², Tim Ragan4, Haruhiko Bito5, Paul uploading and downloading large neuroimaging Frankland², Jason Lerch², Mark Henkelman² datasets to and from BrainDir's centralised ¹University of Toronto, ²Hospital for Sick online repository. Finally, in accord with ethical Children, ³Kyoto University, 4TissueVision, Inc., principles and Canadian regulation, we provide 5University of Tokyo a set of standardised consent forms for researchers to include in their studies to obtain The ability to visualize behaviourally-induced participant consent for secondary use of their neural activity patterns across the rodent brain is imaging data. critical for understanding the distributed brain networks mediating particular behaviours. 2-G-186 Optimization of SYBR Green real However, current imaging methods are limited in time quantitative PCR for single neurons their spatial resolution and/or ability to efficiently image the entire brain. Here we describe a new Zahra Saneei¹, Guillaume Fortin¹, Louis Eric automated method for mapping behaviourally- Trudeau¹ evoked neural activity over the whole mouse ¹ Université de Montréal brain at cellular resolution. This method 165

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 combines the use of transgenic immediate-early the first demonstration of a reconsolidation-like gene reporter mice to visualize recent neural phenomenon in a sensory system, suggesting activity; serial two-photon tomography for high- that reconsolidation may exist more broadly resolution whole-brain imaging; image throughout the CNS than previously known. processing algorithms to count the activated These findings may further provide a novel neurons and align the datasets to the Allen therapeutic strategy for the treatment and Mouse Brain Atlas; and statistical analysis to erasure of persistent pain. identify the network of activated brain regions evoked by behaviour. To validate our approach, 2-I-189 In Vivo 2-Photon calcium imaging we used this method to determine the whole- of the brain : active neurons revealed by brain networks activated during the retrieval of spatio-temporal correlation analysis and fear memories. Consistent with previous studies, region-growing segmentation. we identified a large network of amygdalar, hippocampal, and neocortical brain regions Jean-Francois Desjardins¹, Lois Miraucourt², implicated in fear memory retrieval. This imaging Edward Ruthazer2, Paul Wiseman¹ pipeline can thus be used to map the networks ¹Mcgill University, 2Montreal Neurological mediating the expression of normal behaviours, Institute, McGill University as well as to investigate circuit dysfunction in mouse models of neurobiological disease. Two-photon calcium imaging in the nervous system has proven to be a key tool to I - Neuroengineering characterize single neuron activity in intact brains. However, the low signal-to-noise ratio in 2-I-188 A spinal analogue of memory an in vivo system and the high concentration of reconsolidation enables the reversal of neurons makes the distinction of single neurons hyperalgesia challenging. So far, no image-processing algorithm has been reported for calcium imaging Robert Bonin¹, Yves De Koninck¹ that provides effective and tangible identification ¹CR-IUSMQ of neuronal cells. We present a new image segmentation technique using the calcium The development of persistent pain through the activity as the base for cell identification. The sensitization of pain relays in the spinal cord spatio-temporal correlation of the pixel calcium dorsal horn shares many mechanistic and signaling and the method of region growing are phenotypic parallels with memory formation. employed to identify single calcium-active cells. Memory reconsolidation, in which the On simulated calcium imaging data of neurons reactivation of memories renders them labile with irregular morphologies, the algorithm and susceptible to erasure by inhibition of correctly assigns the ROIs within the attributed protein synthesis, may thus be of particular cell boundaries of all active neurons. The relevance to the treatment of persistent pain. algorithm was tested on images of Oregon Yet, it is unknown if the reactivation of sensitized Green BAPTA-1 taken in vivo in tectum pain pathways initiates a process similar to Xenopus laevis tadpole, revealing ROIs within memory recall and reconsolidation and renders the boundaries of neuronal cells. These results hyperalgesia labile. We discover that both acute demonstrate that the combination of correlation and long-lasting mechanical hyperalgesia can analysis with region growing method is a be reversed after reactivation of the sensitized promising image segmentation tool with the pain pathway and the concomitant inhibition of potential to identify and isolate active neurons spinal protein synthesis. This process was consistently, opening the possibility of the dependent on the activation of spinal AMPA, automatic analysis of neuronal activity in vivo via NMDA, and NK1 receptors, and on the calcium imaging. activation of CaMKII and ERK. Additionally, the activation of spinal AMPA or NMDA receptors 2-I-190 Creating Artificial Neuronal was sufficient to render hyperalgesia labile, Connections suggesting this process is mediated by post- synaptic activation of dorsal horn neurons. G Monserratt Lopez Ayon¹, Margaret Synaptic long-term potentiation (LTP) in the Magdesian¹, Megumi Mori¹, Xue Ying Chua¹, superficial dorsal horn, a cellular model of Alexis Goulet Hanssens¹, David Oliver¹, hyperalgesia, was similarly reversed by William Paul¹, Dominic Boudreau², Delphine reapplying the LTP induction stimulus in the Gobert¹, Ricardo Sanz¹, Yoichi Miyahara¹, presence of anisomycin. These findings provide 166

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Alyson Fournier¹, Edward Ruthazer¹, Chris GlyRα1 SU and their anchoring protein, Barrett¹, Yves DeKoninck¹, Peter Grutter¹ gephyrin on terminals of primary afferents ¹McGill University, ²Laval University identified by CGRP/IB4 labeling. An algorithm was designed to recognize structures with Many forms of brain and spinal cord (CNS) dimensions similar to those of the microscope injuries cut axons. When axons can regenerate, resolution. To avoid detecting false co- as in peripheral nerves, they can bring back localization, the latter was considered significant function. However in the CNS axon regeneration only if the degree of pixel overlap exceeded that fails. This is the main reason why paralysis and expected from randomly overlapping pixels loss of sensation is permanent in conditions given a hypergeometric distribution. We found such as spinal cord injury. First because the that both CGRP( )/IB4( ) terminals were devoid environment surrounding CNS lesions is of GlyRα1 SU and gephyrin. The α1 GABAAR inhibitory to axonal growth, and second because was also absent from these terminals. In most CNS axons only mount a feeble contrast, the GABAARα2/α3/α5/β3 SU were regeneration response after they are cut. Here significantly expressed in both terminal types, as we show that we can manipulate the growth of well as other GABAAR-associated-proteins (α- CNS axons using Atomic Force Microscopy Dystroglycan/Neuroligin-2/Collybistin-2). (AFM) and optical microscopy. Axons adhere to Ultrastructural immunocytochemistry confirmed functionalized beads precisely positioned at the the presence of GABAARβ3 SU in small afferent tip of an AFM cantilever. Once the adhesion is terminals. RT qPCR confirmed the results of created we can pull the beads, thereby light microscopy immunochemical analysis. extending a new neurite for several hundreds of These results indicate that dorsal horn inhibitory microns. When in contact with another neuron synapses follow different rules of organization at the newly formed neurite forms a stable pre vs. postsynaptic sites (i.e. in nociceptive connection. To test the functionality and the type afferent terminals vs. inhibitory synapses on of connection, we put together an dorsal horn neurons). As a consequence, electrophysiology setup which enables paired presynaptic GABAAR-mediated inhibition may recordings. We faced several instrumental and be more diffuse than at dorsal horn neuron biological challenges to keep neurons healthy synapses. and responsive to perform paired recordings after artificially connecting the cells. From 2-I-192 Interfacing synthetic and native connection to recording, the pieces of the puzzle membranes: model lipid membrane domains are finally together. Now we have for evaluating specific cellular responses instrumentation reliability allowing experiments to be carried out routinely. We will discuss Carolin Madwar¹, Gopakumar potential biological factors that may lead to a Gopalakrishnan², R. Bruce Lennox¹ strong, mature and stable artificial connection. ¹Mcgill University, ²Université Paris-Sud

2-I-191 Gephyrin clusters are absent Lipid membrane domains (also known as lipid from small diameter primary afferent rafts) are dynamic assemblies of membrane terminals despite the presence of GABA(A) components (phospholipids, cholesterol, receptors proteins, etc.) that provide a platform for many cellular functions including signaling, protein Louis-Etienne Lorenzo¹, Antoine Godin², transport, lipid sorting and membrane fusion. In Feng Wang¹, Manon Saint-Louis³, Salvatore this study, co-existing lipid microdomains, Carbonetto⁴, Paul Wiseman³, Alfredo Ribeiro- supported on spherical substrates (SS-BLMs), da-Silva³, Yves De Koninck¹ are utilized to interact with living cells (primary ¹CRIUSMQ/Laval University, ²CRIUSMQ, hippocampal neurons) in order to evaluate their ³McGill University, ⁴Montreal General Hospital responses with different cellular entities and Research Institute/McGill University processes. Spherical solid substrates (silica beads) combine the convenience of a While both GABAA receptors and glycine mechanically stable platform for performing receptors play a role in control of dorsal horn experiments while providing an environment that neuron excitability, their relative contribution to closely resembles the biological system being inhibition of small primary afferent terminals modeled. In addition, they provide a new way to remains controversial. To address this, we observe relationships between curvature, lipid designed an approach for quantitative analyses organization, and phase behaviour in lipid of the distribution of GABAAR subunits (SU), mixtures. Confocal fluorescence microscopy and 167

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 cryo-EM are used to characterize the SS-BLM 2-I-194 Quantification of Cellular formation and the co-existence of Mechanotransduction Force with Micropillar microdomains. The interactions of these model Array Detectors membrane domains with living cells as well as the cellular membrane organization in relation to Liangcheng Xu¹, Sebastien Ricoult¹, Timothy the co-existing microdomains are examined Kennedy¹, David Juncker¹ using immunofluorescence confocal microscopy. ¹McGill University The SS-BLM approach is now extended to geometries such as silica fibers in order to better Cells sense molecular cues in the ECM and mimic the axonal surface shape in a neural cell mediate force through focal adhesions in a culture. process termed mechanotransduction, relaying information from the cell's surroundings to the 2-I-193 Digital Nanodot Gradients with cytoskeleton. Even though the emergence of Adjustable Reference Surfaces to Explore micro and nanotechnologies has allowed the Growth Cone Navigation on Gradients of role of mechanotransduction in defining cellular Nanopatterned Protein Cues motility and differentiation to be addressed, the role of mechanotransduction in neurons is still Greta Thompson-Steckel¹, Grant Ongo¹, poorly understood owing to the lack of adequate James Correia¹, Timothy Kennedy¹, David tools to measure these fragile cells. We Juncker¹ measure discrete traction forces in neuronal ¹McGill University growth cones by adopting micropillar array detectors (mPADs). Cells are seeded on top of Cell navigation operates in response to an the mPAD pillars and the force matrix exerted by inhomogeneous distribution of extracellular a cell is visualized and quantified as the cues. There is therefore an incentive to create magnitude of pillar tip displacement. A novel deterministic protein patterns in vitro to address printing technique was used to pattern the pillar how the density and distribution of these cues with a desired protein, as well as specific protein directs cell migration. Although many patterns to investigate growth cone traction experimental results were reported, (i) the force. C2C12 myoblast traction force was gradients are often limited in range, produced as assayed on mPADs with 6 µm high pillars and a continuous patterns, and difficult to quantify; variety of surfaces with low and high affinity for moreover (ii) the reference surface (RS) - the the cells. Average force measurements ranged area surrounding the patterns - is often not well from 4.89 nN on low affinity surfaces (high % controlled nor characterized, and in fact PEG) to 7.11 nN on high affinity surfaces (RGD methods to adjust it had not been developed. or high % PLL). We fabricated 12 µm long (and Here, we address these two points by 2 µm wide) pillars that are 8 times softer than introducing digital nanodot gradients (DNGs) any previously reported and can respond to the and a RS with tunable affinity. We present new weak forces of neurons down to pN resolution. DNG algorithms that fit monotonic and non- Studies focusing on neuronal growth cone monotonic functions, composed of 200 nm dots traction forces are in progress. that follow ordered or random arrangements. An Mechanotransduction information will be array of 100 distinct DNGs was then designed particularly valuable in the areas of tissue and printed using lift-off nanocontact printing to engineering and nerve regeneration. pattern the 57 million protein dots. Cell-surface affinity was then identified to critically influence 2-I-195 A novel Fluorescence Lifetime cell response to a patterned cue. We therefore Nanoscopy approach to resolve protein developed means to easily adjust the RS to the interactions inside dendritic spines. experiment to maximize specific cell response. Substrate-bound protein gradients with Christian Tardif¹, Daniel Côté¹, Paul De adjustable RSs will facilitate the study of axonal Koninck¹ migration by enabling the attribution of ¹CRIUSMQ movement to patterned protein. Gradient geometries that most readily promote axonal Having the ability to localize protein interactions migration will enhance our understanding of the inside the synaptic area is important for mechanisms that underlie development and may deciphering the signaling cascades implicated in facilitate the design of efficient therapies for learning and memory. Fluorescence Lifetime regeneration. Imaging (FLIM) to quantify Foster Resonant Energy Transfer (FRET) is useful to study 168

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 protein interactions. However, FRET-FLIM the ionotropic P2X7 purinergic receptor. Patch approaches provide limited spatial resolution clamp whole-cell recordings in SC slices due to the diffraction of light (~250nm), revealed that BzATP, a P2X7 receptors agonist, particularly for studying interactions in synaptic generated inward currents in most RG and domains. Super resolution methods have been ependymocytes. Inward currents were larger developed to beat this resolution limit. We than currents induced by equimolar combined STimulated Emission Depletion concentrations of ATP, had a reversal near 0mV (STED) with FRET-FLIM technique to study and were reduced by bath application of the molecular interactions within spines at P2X7 receptor antagonist brilliant blue G. Ca 2 nanoscale. We built a STED microscope that imaging (Fluo-4) revealed that BzATP generated currently achieves an x/y resolution of 60 nm. To Ca2 waves in RG that propagate along the measure protein interactions, we used an entire cell. We conclude that progenitor-like cells immuno-FRET technique, which we validated by in the ependyma of the rat SC have functional measuring a known, activity-regulated, ionotropic P2X7 receptors. The intracellular Ca2 interaction between the Calcium/Calmodulin- signaling triggered by P2X7 receptor activation dependent protein kinase β (β CaMKII) and may be an epigenetic mechanism that regulates actin filaments (F-actin) inside the spines of their biology in response to ATP released after cultured hippocampal neurons. We are now tissue damage. investigating the interaction of αCaMKII with the N-methyl-D-aspartate receptor (NMDAR), which is believed to be critical for long term potentiation. Our preliminary results indicate that we can resolve which specific clusters of NMDARs interact with CaMKII inside a dendritic spine. Since the specific location of NMDARs with respect to the post-synaptic density is thought to critically impact on their functions, our Fluorescence Lifetime Nanoscopy (FLIN) approach should help us understanding NMDAR-dependent signaling and remodeling.

2-IBRO-196 Purinergic receptor activation induces Ca2+ waves in a stem cell niche of the rat spinal cord.

Nicolas Marichal1, Gabriela Fabbiani1, Omar Trujillo-CenÛz1, Ra˙l Russo1

1 Instituto de Investigaciones BiolÛgicas Clemente Estable

The ependyma of the spinal cord (SC) harbors stem cells which are activated and recruited by traumatic SC injury. Progenitor-like cells are organized in spatial domains around the central canal (CC). On the lateral aspects, cells combine characteristics of ependymocytes and radial glia (RG). On the poles of the CC, RG cells display complex electrophysiological phenotypes. The mechanisms regulating the behavior of these progenitors -in particular their reaction to injury- remain unknown. During development, purinergic signaling regulates progenitor cell proliferation, migration and differentiation. Thus, we explored the effects of adenosine triphosphate (ATP) on ependymal progenitor-like cells in the neonatal (P1-P6) rat SC. Cells in midline and lateral domains express 169

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28

POSTER SESSION 3 The accessory olfactory system controls social A - Development and sexual interactions in mice that are crucial for survival. Vomeronasal sensory neuron (VSN) axons form synapses with dendrites of second 3-A-1 Role of the precursor form of the order neurons in glomeruli of the accessory brain-derived neurotrophic factor, proBDNF, olfactory bulb (AOB). Axon guidance molecules and its receptor p75NTR on GABAergic control the anterior-posterior segregation of VSN synapse maturation in neocortex axons in the AOB, however less is known about the mechanisms regulating the coalescence of Elie Baho¹, Bidisha Chattopadhyaya¹, Marisol axons into specific glomeruli. We have Lavertu Jolin¹, Graziella Di Cristo¹ previously shown that Kirrel-2 and Kirrel-3 of the ¹Université de Montréal/CHU Ste-Justine Kirrel family of cell adhesion molecules are differentially expressed in subpopulations of Basket cells innervate hundreds of postsynaptic VSNs, thereby defining a molecular code of targets with synapses clustered around the axonal recognition. Also, germline ablation of soma and proximal dendrites. They are Kirrel-3 expression led to a loss of male-male important for gamma oscillation generation and aggression in mice. Here, we show that for the regulation of developmental cortical germline ablation of either Kirrel-2 or Kirrel-3 plasticity. Although the function of basket cells expression results in the formation of fewer yet within cortical networks is being explored, the larger glomeruli in the posterior AOB while mechanisms that control the development of removal of both prevents the formation of their extensive arborisation and synaptic distinct glomeruli altogether. In addition, the contacts have not been entirely resolved. BDNF coalescence of specific tau-lacZ-labeled has been shown to be a strong modulator of populations of VSN axons is severely disrupted activity-dependent maturation of GABAergic in kirrel-2-/-; kirrel-3-/- mice. More precisely, synapses. BDNF is initially synthesized as a Kirrel function is required in VSN axons as its precursor, proBDNF, which is cleaved to specific ablation in VSNs (kirrel-2lox/lox; OMP- produce mature BDNF. Whether proBDNF per Cre) leads to defects in glomeruli formation that se plays a role in the development of basket cell phenocopy kirrel-2-/- mice. We are currently synaptic territory is unknown. Our results show assessing whether the wiring defects observed that treating organotypic cultures prepared from in kirrel-2lox/lox; OMP-Cre mice cause changes mouse cortex during the synaptic proliferation in VNO-mediated behavior. Altogether, our phase with exogenous cleavage-resistant results show that differential expression of proBDNF (proBDNFmut) strongly reduces the Kirrels on VSN axons dictates their proper synaptic territory of basket cells. To increase coalescence into glomeruli in the AOB. endogenous levels of proBDNF, we treated cultures with a tPA-inactivating peptide, PPACK, 3-A-3 Early changes in the offspring which also reduced basket cell synaptic mesolimbic dopaminergic system induced innervation. We further showed that proBDNF by perinatal maternal high-fat diet acts through p75NTR, by knocking down p75NTR specifically in basket cells and treating MinGi Cho¹, Greg Dal-Bo², Hong Long², them with proBDNFmut. p75NTR-/- basket cells Claire-Dominique Walker² form exuberant innervations compared to control ¹McGill university, ²Douglas Mental Health cells, an effect that is not rescued by University Institute proBDNFmut. All together, these results suggest that proBDNF negatively regulates the synaptic Recent evidence demonstrates that maternal territory of basket cells through direct activation high-fat consumption during pregnancy and of p75NTR. In vivo studies are underway. lactation increases the risk of metabolic disorders and obesity in the offspring, although 3-A-2 Expression of Kirrels in the mechanisms remain unknown. We vomeronasal sensory neuron axons controls previously showed that adult offspring of their coalescence into glomeruli of the AOB mothers exposed to a high-fat (HF) diet during the last week of gestation and lactation have Alexandra Brignall¹, Janet Prince¹, Jean- altered mesolimbic dopamine (DA) activity, a Francois Cloutier¹ system that regulates the hedonic value of food. ¹Montreal Neurological Institute, McGill In particular, adult HF male rats display University increased tyrosine hydroxylase (TH) activity and 170

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 reduced D2 receptor expression in the VTA, but currently investigating whether the presence of the time of onset of these changes is unknown. microglia is necessary to mediate the effect of Here we examined when these changes first an inflammatory stimulus on developing axons. appear and whether they are dependent of the This research was funded by a CIHR grant to post weaning diet. In contrast to the adult ESR and a CIHR Vanier Canada Graduate offspring, pre-weaning HF pups on PND 10, 16 Scholarship to NF. or 25 did not show significant differences in the concentration of TH, but showed a trend 3-A-5 Effects of prenatal and neonatal towards increased D2 receptor expression in the nicotine exposure on the 3beta- VTA. These data suggest that changes induced hydroxysteroid dehydrogenases (3β-HSD) by the maternal diet in the mesolimbic DA enzymes of steroidogenesis in the rat system observed in adult HF offspring do not hippocampus appear before weaning and might be dependent upon the post-weaning diet. We are currently Hayley Forbes¹, Julie Boucher¹, Allison testing offspring during puberty (PND 45) after Holloway², Anne TM. Konkle¹ weaning on either a HF or CD diet. Together ¹University of Ottawa, ²McMaster University with the onset of molecular changes in the DA system, we are also examining whether the Early life exposure to nicotine is known to have expression of Nurr-1, a transcription factor deleterious effects on development. While required for the development of DA cells and smoking during pregnancy has decreased, upregulation of DA synthesis, is increased in HF nicotine replacement therapy is abundant. NRT rats concomitantly to TH activity in the VTA. is commonly used in order to aid individuals in Supported by CIHR to CDW. quitting smoking. Our recent characterization of de novo steroidogenesis in the developing brain 3-A-4 Inflammation elevates the rate of has shed new light on the role of these sex axonal structural remodeling in a developing hormones in brain development. 3β-HSD is one neural circuit key enzyme in the steroidogenic pathway, of particular interest to us is the synthesis of Nasr Farooqi¹, Edward Ruthazer¹ androgens (And) and estrogens (E). This ¹McGill University steroidegenic enzyme has been found to be expressed in brain regions not necessarily Exposure to infection and inflammation in early involved in reproduction, specifically the hipp, development is associated with an increased cortex, cerebel, among others. Given the incidence of subsequent neuropsychiatric diversity of developmental effects associated disease. To investigate the effects of with maternal smoking, the aim of the current inflammation on a developing neural circuit in project is to assess the effects of early life vivo, we exposed larval zebrafish to bacterial nicotine exposure on expression of 3β-HSD in lipopolysaccharide (LPS) to induce an rat hipp tissue via quantitative PCR. Dams were inflammatory response. We demonstrate that injected subcutaneously with 1mg/kg of nicotine exposure to this stimulus results in bitartrate or a saline vehicle once daily for two morphological activation of microglia, confirming weeks prior to mating until the time of weaning. an active immune response. We expressed Male pups were selected for this experiment and EGFP under a retinal ganglion cell (RGC) were housed in sibling pairs until sacrifice at promoter to sparsely label axons arborising in post natal weeks 15 or 26. Brains were carefully the tectum and imaged them at high spatio- extracted and flash frozen, dissected and kept at temporal resolution with in vivo two-photon -80°C until processed for qPCR assays. While microscopy. Morphometric analyses of RGC the exact role of And and E synthesized in the axons arborising in the tectum before and after telencephalon during development is still not acute immersive exposure to LPS or a control well understood, results from this experiment will solution demonstrate that exposure to an provide a glimpse as to the influence of the inflammatory stimulus increases arbor motility environment on this steriodogenic pathway in as measured by rates of axonal branch addition the developing brain. and retraction. Increased structural plasticity in early development may reflect a failure to 3-A-6 Pre-pubertal rats behaving badly: stabilize synaptic contacts, leading to aberrant Assessing behaviour in the Morris water circuit formation. Microglia have been implicated maze as regulators of normal neural development and of inflammatory responses in the CNS. We are Nitasha Gill¹, Karen Mezher¹, Anne Konkle² 171

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28

¹Carleton University, ²University of Ottawa postnatal life. Using viral injections, transgenic mice, confocal imaging and whole-cell patch- When sex specific behaviours are being clamp recordings we analyzed the structural and assessed in animal models, the tests are either functional properties of different sub-populations conducted in pre-pubertal animals or in of GCs at different maturational stages with gonadectomized adults, in order to control for particular emphasis on calretinin-expressing circulating gonadal hormones. Given that rats newborn cells (CR ). Our morphological analysis are not seasonal breeders we would expect performed at 1, 3 and 5 weeks after generation similar latencies in finding the submerged of newborn GCs revealed that CR GCs display platform in the Morris water maze, regardless of similar maturational pattern as compared to CR- the time of year when these animals are tested. cells. Patch-clamp recordings from early Early confusing results prompted us to assess postnatal and adult-born CR GCs showed the performance of separate cohorts of pre- similar frequency and amplitude of spontaneous pubertal animals in this task. Shockingly, we inhibitory currents. In contrast, our preliminary found that grouping the behavioural results of results suggest that adult-born CR GCs may multiple cohorts of animals in a seasonal receive less frequent excitatory inputs as fashion, or in a long versus short day one, compared to early-born CR neurons. These data revealed that learning to use the spatial cues to are essential to better understand the integration locate the hidden platform did not occur at the and the specific role in the neuronal network same rate across the "seasons" and sexes. Is functioning and odor behavior of diverse sub- this effect truly a seasonal one? One populations of newborn cells. explanation for this finding is related to season, but not the season when the rats were born or 3-A-8 Controlling postsynaptic receptors when behavioural tests were conducted. Rather, expression as a model to investigate it may be related to seasonal variations in the synaptic refinement phytoestrogen content of the rat feed. Other potential explanations will also be discussed. Emily Irvine¹, Yumaine Chong¹, Brigitte Pie¹, These findings have obvious consequences and Ellis Cooper¹ implications for those conducting behavioural ¹McGill University studies using this and potentially other paradigms. Confounding factors appear to be As neural circuits become established, synaptic playing a significant role in altering behaviour, connections undergo considerable thus, any comparison to a treatment group may rearrangement. It is commonly believed that be seriously impacted. only functional synapses are maintained, whereas non-functional synapses are 3-A-7 Integration and functional role of eliminated; this suggests that postsynaptic different sub-populations of newborn activity plays an important role in synaptic granule cells in the adult olfactory bulb. refinement. Yet, the underlying mechanisms are poorly understood. To learn more, we are Delphine Hardy¹, Vincent Breton- developing a new model to control postsynaptic Provencher¹, Armen Saghatelyan¹ receptor expression. Our experiments focus on ¹Le Centre de recherche de l'Institut universitaire cholinergic-nicotinic synapses in mouse en santé mentale de Québec, Université Laval. sympathetic ganglia. The postsynaptic receptors at these synapses are α3-containing nicotinic In the adult brain, the olfactory bulb is receptors. In our model, the α3 gene is deleted continuously supplied with new neurons from its normal location on chromosome 9 and differentiating into granule and periglomerular its cDNA is expressed elsewhere in the genome cells. Newborn granule cells (GCs) have usually under the control of the human ubiquitin been considered as a homogenous population promoter. To ensure functional α3 expression in of neurons, but growing evidence suggests that this model, we are using intracellular recordings they can be differentiated into several sub- to measure synaptic transmission in intact populations. It is still not clear what is the pattern sympathetic ganglia, as well as whole-cell of maturation and integration of distinct sub- recordings from isolated sympathetic neurons in populations of newborn GCs, as well as their culture. We find that nerve-evoked EPSPs are role in the bulbar network functioning and odor present as early as P7 and persist throughout behavior. It is also unknown if structural and postnatal development; however, interestingly, functional differences exist in the same sub- synaptic refinement seems to be impaired. In population of GCs born during early and late addition, we find that whole-cell acetylcholine- 172

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 evoked inward currents from mutant neurons are considerably smaller than those from Netrin-1 is a secreted chemotropic guidance wildtype neurons. Our results suggest that molecule that attracts extending spinal controlling postsynaptic receptors expression is commissural neurons towards the ventral a useful approach to investigate how synaptic midline of the developing spinal cord. Through activity refines connections. Funding: CIHR (EC) its receptor Deleted in colorectal cancer (DCC), netrin-1 promotes cytoskeletal rearrangement 3-A-9 Prenatal paternal stress and and changes in growth cone morphology postnatal enhanced home cage affect necessary for commissural axon extension. The maternal care and anxiety like behaviour in exact mechanisms by which this occurs are juvenile rats however not fully understood. We have previously demonstrated that netrin-1 Austin Korgan¹, Tara Perrot¹ chemoattraction in commissural neurons ¹Dalhousie University requires the activation and recruitment of the rho GTPases rac1 and cdc42, as well as the serine- Paternal effects have recently drawn interest threonine kinase Pak1 to the intracellular from neuroscientists, within the context of domain of DCC (Shekarabi et al., 2005). To epigenetic transmission, largely following further our understanding of the mechanisms evidence from behavioural ecology and that regulate rac1 and cdc42 downstream of epidemiology. Recent studies have DCC, we have now demonstrated that the rho demonstrated offspring effects of paternal age, guanine nucleotide exchange factor (rhoGEF) obesity, enrichment, and psychological stress. beta-Pix, along with the adaptor protein Git2, These outcomes may be partially manifested associate with DCC in commissural neurons through differences in maternal care. For the following netrin-1 stimulation. We also report current study, we used predator odour exposure that the dimerization of beta-Pix and the to stress male Long-Evans rats for 7 days, association with its downstream effector Pak1 immediately preceding a partner preference test, are essential for filopodial formation and growth followed by breeding. On the day of parturition, cone expansion induced by netrin-1. dams were transferred to enhanced home cages Additionally, we provide evidence that beta-Pix (EHC), which are approximately twice the size of function is required for proper guidance of a standard cage (SC) and contain a burrow, or commissural axons to the ventral midline in the SC. Maternal care was observed for 10 days in embryonic spinal cord. Together, these findings both the EHC and SC conditions. Offspring were provide evidence that beta-Pix plays a key role weighed at birth and at weaning, postnatal day in netrin-1 dependent commissural axon 22 (P22). Following weaning, two male and two chemoattraction. female pups were pair-housed while the rest of the litter was sacrificed. At P25, offspring were 3-A-11 mTOR signaling in observed for social play behaviour for 5 days. oligodendrocytes Anxiety-like behaviour was examined using the elevated plus maze and open-field test on P32- Ueli Suter¹ 35. Then, between P35-40 offspring were ¹ETH Zürich exposed to a predator odour for 30-minutes and post-fixed in PFA for immunohistochemical Mammalian target of rapamycin (mTOR) is a detection of GH and/or NPY. Females spent central regulator of multiple cellular functions less time with stressed males, compared to including cell growth, protein synthesis and control males in the partner preference test. metabolism. The mTOR pathway exists as two Further, maternal care was affected by both distinct signaling complexes: mTORC1 (mTOR- paternal stress and EHC rearing. Anxiety raptor) and mTORC2 (mTORC-rictor). Both behaviour and immunohistochemistry results complexes are intimately linked with the PI3K- have yet to be analyzed. Supported by an Akt signaling network, which is a major player in NSERC Discovery Grant to TP. CNS myelination. Previous studies showed that Akt/mTOR signaling is essential for 3-A-10 The Rho guanine nucleotide oligodendrocytes precursors differentiation and exchange factor beta-Pix is required for for the expression of myelin proteins during netrin-1 mediated chemoattraction active myelination (Narayanan et al, 2009; Tyler et al, 2009). However, very little is known about Karen Lai Wing Sun¹, Timothy Kennedy¹ the specific role of mTORC1 or mTORC2 in ¹Montreal Neurological Institute regulating oligodendrocytes myelination during 173

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 development and for the myelin maintenance in the adult. Our research aims is to determine the The correct wiring of many neural circuits in the specific role of the two mTOR complexes during nervous system depends on the myelination of the CNS. spatiotemporally-controlled binding of contact- mediated axon guidance molecules, but also on 3-A-12 Effects of exogenous neuregulin- the adequate detachment of axons following 1 on maturing adultborn neurons in the contact in order to continue growing. Ephrins hippocampus and their Eph receptors, cleaved by metalloproteases after binding to each other, Ian Mahar¹, Angus MacIsaac¹, Adeline mediate the guidance of motor neuron axons in Rachalski¹, Naguib Mechawar¹ the developing limb mesenchyme by being ¹McGill University expressed in both tissues and signaling to the Eph-expressing cell (forward) and to the ephrin- Introduction Neuregulin-1 (NRG1) is a expressing cell (reverse). To investigate the role neurotrophic factor implicated in schizophrenia that Eph receptor cleavage plays in its signaling, and depressive disorders. We have shown that we created a mutant version of EphA4 that is peripheral NRG1 administration increases cell unable to be cleaved, but whose signaling proliferation and neurogenesis in the dentate properties are otherwise unaffected. A knock-in gyrus (DG) of the hippocampus, and these mouse mutant in which cleavage was abolished effects are associated with antidepressant-like in both neurons and limb exhibited axon behaviour. However, effects of NRG1 on guidance errors, raising the question of whether maturing adultborn DG neuronal growth and cleavage is important in forward or reverse survival have not been characterized. Methods signaling, or both. To specifically ask whether Adult male C57BL/6 mice were injected with forward ephrin:Eph signaling requires receptor BrdU (3x50mg/kg) and implanted 15 days later cleavage, we unilaterally overexpressed the with s.c. minipumps delivering either saline mutant, its wild type form, or GFP alone in the (n=9) or NRG1 (n=10; 10µg/day) for 3 days spinal cord of chick embryos. We found that the before perfusion. Sections underwent BrdU ability of ectopic EphA4 expression to reroute immunohistochemistry (IHC) and BrdU DG cells axons in this choice point was similar in the were counted. To analyze dendritic extension cleavage-resistant mutant compared to the wild BrdU/DCX IHC was performed and neurons type receptor, suggesting that cleavage is not were reconstructed. Results NRG1 critical for forward signaling and arguing that the administration did not affect adultborn cell misrouting seen in the mutant mouse is due to survival overall (p=0.26) or in the dorsal impaired reverse signaling alone. (p=0.19) or ventral (p=0.41) DG. Cytogenesis was higher in the ventral DG than in the dorsal 3-A-14 Hypocretin/Orexin receptors in DG (p=0.0061). Dorsal and ventral cytogenesis the chick embryo brain were correlated (r=0.5, p=0.03). Preliminary analyses suggest that NRG1 did not affect Tom Cerazy¹, Nazanin Saadat¹, Gillian overall cell body perimeter, area, feret min or Fuchs¹, Maria Pompeiano¹ max, aspect ratio, form factor, or roundness ¹McGill University (ps>0.22), and did not affect overall dendritic nodes, length, surface area, or volume Hypocretin/Orexin (H/O) neurons in the posterior (ps>0.51). Conclusions NRG1 does not affect hypothalamus of adult mammals and birds survival or morphology of immature cells in the regulate the sleep-waking cycle, among other adult DG, suggesting that neurogenic effects of physiological functions. H/O receptors (2 types) NRG1 administration are restricted to increased are widespread in the adult rodent brain. H/O proliferation. We are currently assessing neurons first become detectable in rats at day synapse formation to further test this hypothesis. 18 out of a 21-day gestation period. However, H/O neurons are detectable in chick embryos as 3-A-13 Characterization of a cleavage- early as embryonic day (E) 3 of a 21-day fetal resistant EphA4 receptor in spinal motor period, and their number progressively neurons increases and reaches a plateau in the second half of embryonic development (Godden et al, Graziana Gatto¹, Daniel Morales², Artur submitted). In order to better understand the Kania², Ruediger Klein¹ possible roles of H/O neurons in the developing ¹Max Planck Institute of Neurobiology, ²McGill chick, expression of the single H/O receptor type University expressed in birds was surveyed in embryo 174

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 brains of different ages using standard region but do not display defects in MOR174-9- immunohistochemistry. At E12, labelling was positive axon targeting to the dorsal region of very low in the forebrain while high levels of the OB. Furthermore, MOR28 glomeruli, formed expression were seen in some brainstem areas in the ventral region of the OB, are significantly (cranial nerve sensory and motor nuclei, smaller in size in these mice. These findings cerebellum). At E16 and E20, H/O receptors identify Amigo-1 as a key regulator of OSN were seen at high levels in analogous brain axonal targeting in the mouse OB. areas to those that contain H/O receptors in adult rodents (pallium, medial septum, 3-A-16 Proteolytic cleavage of IgLON hippocampus, amygdala, paraventricular adhesion proteins by MMPs promotes hypothalamic nucleus, cranial nerve sensory neurite outgrowth and motor nuclei, locus coeruleus). Strong signals were also seen in the cerebellar Purkinje Ricardo Sanz¹, Alyson Fournier¹ cells and nuclei. These observations suggest ¹McGill University that H/O could exert an early effect on the development of sensory and motor brainstem Matrix metalloproteinases (MMPs) are a family circuits. At later ages, the widespread of zinc-peptidases capable of cleaving expression of H/O receptors including forebrain extracellular matrix and cell surface proteins areas suggests that H/O could be involved in resulting in degradation or release of biologically regulating brain state changes. active fragments. MMPs process ligands and receptors that regulate neuronal plasticity and 3-A-15 AMIGO-1 regulates the targeting neurite growth following injury in the Central of olfactory sensory neuron axons Nervous System. In the present study, we evaluated the role of MMPs in regulating neurite Reesha Raja¹, Emilie Dumontier², Jean- growth. We find that pan-MMP inhibitors inhibit Francois Cloutier² outgrowth of cortical neurons and dorsal root ¹Montreal Neurological Institute, McGill ganglion neurons (DRGs) and that this effect is University, ²McGill University dependent on the stage of neuronal maturity. Through tandem mass spectrometry we Proper sensory system functioning relies on the identified the IgLON family of glycosyl- development of precise connections between phosphatidyl inositol (GPI)-anchored cell sensory and second order neurons in a adhesion molecules as proteins that are shed in topographic manner. Sensory axons are guided an MMP-dependent manner. IgLONs are the toward their correct synaptic partners by various earliest and most abundant GPI-anchored axon guidance and cell adhesion molecules proteins expressed in the nervous system and (CAMs). In the olfactory system, olfactory are implicated in the process of neuronal sensory neurons (OSNs) expressing the same outgrowth and cell adhesion. Using reverse- olfactory receptor (OR) innervate specific transcription PCR and cell surface biotinylations, stereotypically located glomeruli in the olfactory we observed a correlation between the bulb (OB). While several guidance molecules expression of IgLON family members in vitro help segregate OSN axons into broad zones of and our outgrowth phenotype with MMP the OB, less is known about molecules inhibitors. Our findings suggest that a near full regulating their coalescence into individual length fragment of the IgLON ectodomain is glomeruli. The few families of CAMs implicated cleaved from the surface of cortical neurons in in local axon sorting are unlikely to be sufficient an MMP-dependent manner. Outgrowth to coordinate the sorting of axons expressing experiments on immobilized full-length IgLON over 1000 different OR types into their proteins identified NTM and LSAMP as IgLON appropriate glomeruli. Aiming to identify other family members that promote neurite extension CAMs in this process, we have found one in cortical neurons. Together our findings member of the 'amphoterin-induced gene and support a role for MMP-dependent shedding of ORF' (AMIGO) family of transmembrane IgLON family members in regulating neurite proteins as a regulator of axonal coalescence in extension. the OB. AMIGO-1 expression is confined to the ventrolateral regions of the olfactory epithelium, 3-A-17 Investigating the role of Disrupted and AMIGO-1-expressing OSN axons project to in Schizophrenia 1 (DISC1) in cortical the ventral region of the OB. AMIGO-1 null inhibitory interneuron development mutant mice show improper targeting of MOR28-positive OSN axons within this ventral Brianna Unda¹, Vickie Kwan¹, Karun Singh¹ 175

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¹McMaster University and female rats to a cat odour cue or a control cue on five half-hour occasions during the Aberrant development of cortical inhibitory adolescent period (between postnatal days 38- interneurons is hypothesized to play a role in 48) and sacrificed the animals after the final Schizophrenia etiology. This hypothesis has exposure. We then measured levels of α2, γ2, been supported by post-mortem studies, which and δ GABAA receptor subunits in hippocampus show reduced inhibitory markers, as well as using western immunoblotting. We found patient studies which show disruptions in GABA- significantly decreased levels of the γ2 GABAA ergic interneuron-driven gamma oscillations. receptor subunit (p=0.028) in stress-exposed However, the molecular mechanisms underlying animals relative to control but no changes in the interneuron development remain largely α2 and δ GABAA receptor subunits. There were unknown. The schizophrenia risk gene no sex differences observed. These findings Disrupted in Schizophrenia 1 (DISC1) works suggest that more work should be conducted in through its many interacting partners to regulate determining the timeline of juvenile stress- various aspects of neuronal development. induced changes in GABAA receptor subunits in However, studies on DISC1 have been largely brain regions important for regulating the stress confined to excitatory neurons, and therefore, response, as well as in determining the the role of DISC1 in interneuron development functional consequences of these changes. has not been clearly defined. Using a mouse in vitro model, we are examining the effects of B - Neural Excitability, Synapses, and Glia: shRNA-induced knockdown of DISC1 on Cellular Mechanisms dendrite growth and synapse formation in cortical inhibitory neurons. Preliminary results 3-B-19 Emotional and cognitive show that DISC1 knockdown causes a decrease behaviour changes are associated with in dendritic complexity in inhibitory neurons. We increased glutamatergic transmission in the are also investigating the possibility that the early stages of experimental allergic Schizophrenia risk genes Neuregulin 1 (NRG1) encephalomyelitis (EAE) and its receptor ErbB4 function through DISC1 to regulate inhibitory interneuron development. Shaona Acharjee¹, Quentin Pittman¹ Preliminary results show that application of ¹University of Calgary NRG1 to cortical cultures increases DISC1 levels in the primary dendrites of inhibitory Multiple sclerosis (MS) is often associated with neurons. These results suggest that DISC1 is an co-morbid behavioural and cognitive important regulator of dendritic growth in cortical impairments, affecting around 50% of MS interneurons and that its expression may be patients. We have identified similar behaviour regulated by NRG1-ErbB4 signaling. co-morbidities, many of which are reflective of amygdalar abnormalities, in a mouse model of 3-A-18 Repeated predator odour stress MS, Experimental Autoimmune across the adolescent period alters γ2 Encephalomyelitis (EAE). These include GABAA receptor subunit levels in anxiety- and depression-like behaviour even hippocampus of male and female rats prior to the onset of motor deficits. The aim of the current study was to investigate Lisa Wright¹, Tara Perrot¹ mechanisms underlying these behaviour ¹Dalhousie University changes. We hypothesized that inflammation results in alteration of neuronal excitability and Prior work has demonstrated that juvenile stress neurotransmission in the amygdala. EAE was in rats can alter adult levels of gamma amino induced in C57/BL/6 mice with MOG35-55 /CFA butyric acid (GABA)A receptor subunit levels in and pertussis toxin (PTX). Control mice received the hippocampus and amygdala, and this has CFA and PTX only. Whole-cell recording was functional consequences with respect to the role carried out in the principal neurons of the of the receptor in controlling physiological basolateral amygdala (BLA), a key region responses to stress and anxiety. In particular, involved in emotional behaviour regulation. changes in adult levels of the α2 GABAA Hyperpolarization activated current (Ih) was receptor subunit have been observed following increased in the EAE mice. Investigation into stressor exposure during the juvenile period; glutamatergic synaptic transmission revealed however, it is unknown at what point between increased frequency, but not amplitude of mini- the juvenile period and adulthood these changes excitatory postsynaptic currents; this is arise. In the present study, we exposed male indicative of increased glutamate release. 176

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AMPA:NMDA ratio was also increased in the 3-B-21 Microglia respond to brain anoxia EAE animals. No changes in the GABAergic with rapid morphological changes transmission were observed at this stage. In conclusion, emotional and cognitive deficits Louis-Philippe Bernier¹, Lasse Dissing- observed in EAE (and possibly MS) were Olesen¹, Brian MacVicar¹ associated with alteration in the ¹University of British Columbia hyperpolarization activated current (Ih) and glutamatergic transmission in the BLA. Future Microglia are highly motile cells that play a studies will explore the possible involvement of pivotal role in monitoring brain homeostasis by inflammatory mediators in these changes. constantly probing the environment and responding to extracellular cues. They are 3-B-20 The distribution of cytoplasmic involved in stroke-related pathologies, mediating and membrane-associated TrkB in the a nonspecific neuroinflammatory reaction that dendrites of adult spinal motoneurons could lead to long-term deleterious effects following transient anoxia. However, the acute Farin B. Bourojeni¹, Ethan Zhao², Monica functional response of microglia during anoxic Neuber-Hess², P Ken Rose² periods remains unclear. Here, we used real- ¹Institut de recherches cliniques de Montréal, time two-photon imaging in acute brain slices to ²Queen's University monitor the initial effect of anoxic insults on the morphological phenotype and dynamic The majority of synapses in motoneurons are properties of microglia. Microglia in resting positioned on the dendrites. The strength of conditions display a highly branched these synapses is regulated by several morphology with motile processes, however neuromodulators. The neurotrophin BDNF is oxygen depletion induces a rapid, actin- conventionally associated with the growth, dependent retraction of processes that is fully guidance, and survival of developing reversible upon reoxygenation. This finding motoneurons. There is however emerging indicates that microglia sense decreased evidence that activation of TrkB receptor by oxygen levels in brain tissue within minutes. The BDNF is vital in the maintenance and rapid loss of major processes, normally needed strengthening of different classes of synapses in by microglia to probe the environment, adult motoneurons. While previous studies have translates into a significant change in microglia shown that TrkB is present in the soma and function. Under normal conditions, microglia proximal dendrites of motoneurons, it remains quickly extend their major processes towards unclear whether its regulatory role is restricted focal injury, however this mechanism is inhibited to these regions or if it also involves synapses in during anoxia. We show that this phenotype is other dendritic regions. We used mimicked by multiple signaling molecules immunohistochemical, microscopy, and 3D hypothesized to be released during brain image analysis techniques to examine the anoxia, indicating a common intracellular proximal to distal dendritic distribution of TrkB pathway is activated to induce microglial on the membranes and in the cytoplasm of adult process retraction. Characterizing the molecular spinal motoneurons. We found that in cues responsible for this functional switch of intracellularly stained motoneurons, TrkB microglial behaviour will likely provide valid immunoreactivity is arranged in punctae and is targets for stroke treatment. widely distributed in all regions of the dendrite tree. The density of TrkB immunoreactivity on 3-B-22 Dual Role of Acyl-CoA Binding the membranes and in the cytoplasm of Protein (ACBP) in the Hypothalamus: dendrites was the same regardless of distance Regulator of Astrocytes Fatty Acid (FA) from the soma and the diameter of the dendrite. Metabolism and Gliotransmitter Targeting Additionally, via Western blotting, we detected Pro-opiomelanocortin (POMC) Neurons. several immature TrkB isoforms; a number of which are reported to be involved in the Khalil Bouyakdan¹, Bouchra Taib¹, Lionel strengthening of synapses. Together, these Budry¹, Chloé Chrétien², Susanne Mandrup³, results suggest that TrkB may be involved in the Luc Pénicaud², Xavier Fioramonti², Thierry maintenance and regulation of synapses that Alquier¹ are located throughout the dendritic tree of ¹CRCHUM, ²Université de Bourgogne, motoneurons. ³University of South Denmark

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The arcuate nucleus (ARC) of the hypothalamus [K ] of ~-70mV) and cessation of spontaneous detects changes in circulating nutrients levels firing, without evidence of spreading depression (glucose, FA) via two antagonist neuronal in the extracellular recordings. Concomitantly populations, orexigenic neuropeptide Y and the input resistance decreased. Addition of anorexigenic POMC neurons to in turn regulate 100uM 4-aminopyridine (4AP) generated energy balance. However, little is known seizure like events (SLEs) in slices in control [K ] regarding the cellular mechanisms involved in of 3.5mM. Moderately raised [K ] up to 9mM FA regulation of feeding and glucose increased the frequency of SLEs. In contrast, homeostasis. In the periphery, ACBP binds and 12mM [K ] blocked or diminished the SLEs and creates an intracellular pool of Acyl-CoA's that is left only inter-ictal bursts. When [K ] was pushed important for their metabolism. In the brain, to 15mM, no local field activities could be ACBP is secreted by astrocytes and inhibits the recorded. SLEs and single cell action potentials GABAA receptor. We show here that ACBP is reappeared within seconds after changing mainly localized in hypothalamic astrocytes and perfusate back to regular aCSF from any raised its central administration inhibits food intake (FI). [K ]. Focal cortical seizures, generated in vivo by Thus, we propose that ACBP plays a dual role in application of 4AP onto mouse somatosensory the hypothalamus as a regulator of FA cortex, were also blocked by local application of metabolism in astrocytes and a gliotransmitter raised [K ]. These results show a concentration targeting ARC neurons to inhibit FI. Using in dependent bidirectional regulation of cortical vitro and ex vivo models generated from ACBP seizure activity by raised [K ]. Supported by KO and WT mice, we show that ACBP CIHR deficiency reduces FA oxidation without affecting esterification into complex lipids in 3-B-24 Omega-3 fatty acid prevents pro- hypothalamic astrocytes. Our inflammatory induced dendritic spine loss electrophysiological data show that ACBP and synaptic deficits in the mature reduces the frequency of inhibitory postsynaptic hippocampus currents in anorectic POMC neurons leading to increased action potential frequency. These Philip Chang¹, Dusica Maysinger¹, Rebecca findings suggest that the anorectic effect of McKinney¹ ACBP in the brain may be dependent on POMC ¹McGill university neurons activation and that ACBP may be part of FA-sensing mechanisms by regulating their It is widely accepted that the soluble oligomeric oxidation in hypothalamic astrocytes. Targeted β-amyloid (Aβ) peptide accumulation ablation of ACBP in brain astrocytes is ongoing exacerbates brain microcircuitry defects in to determine its role in the hypothalamic control Alzheimer's disease (AD). This may occur of energy balance. through an inflammatory-mediated response. Here, we investigated the initial effects of Aβ 3-B-23 Increasing extracellular exposure prior to plaque and tangle formations. potassium excites and then depresses We compared synaptic structure and function of cortical seizure activity in vitro and in vivo CA1 pyramidal neurons in the mature hippocampus using lipopolysaccharide (LPS), Lihua Wang¹, Suzie Dufour¹, Simon Stern¹, an inflammatory agent, to gain insight to AD Peter Carlen¹ pathophysiology. Our study focuses on ¹University of Toronto emerging evidence that lipid abnormalities are crucial in AD. We applied oligomeric Aβ peptide Elevated extracellular potassium ([K ]) causes to mature organotypic hippocampal slices to seizures and also is increased by seizure model the initial AD insults and compared that to activity. Whole cell recordings were made in LPS. We report an abnormality in neuronal and vitro from layer II/III pyramidal cells with local microglial lipid components by finding field potentials recorded from within 150um. observable changes in lipid droplets (LDs) Membrane properties, measured in control [K ] formation following Aβ treatment. The size of 3.5mM, were subsequently compared with distribution of LDs was altered after Aβ higher [K ] of 6mM, 9mM, 12mM and 15mM. As treatment, where an increase in large (> 1.0 μm) the [K ] increased from 3.5mM to 12mM, cells LDs was found. Similar alteration in lipid depolarized and changed their firing from silent compartmentalization was observed with LPS- to bursting and/or irregular firing, and in 15mM elicited inflammatory response. Furthermore, [K ] there was further depolarization (20-25mV dendritic spine densities were decreased while from the resting membrane potential in control AMPA-mediated mEPSC frequency was 178

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 increased after both Aβ and LPS treatments. 3-B-26 Functional consequences of When the omega-3 fatty acid, docosahexanoic cysteine mutations at the kainate receptor acid (DHA), was supplemented during Aβ or dimer interface LPS treatments, abnormal LD distribution, morphological, and electrophysiological Bryan Daniels¹, Mark Aurousseau¹, George phenotypes were restored to that of control Dawe¹, Derek Bowie¹ slices. Our findings suggest that DHA could ¹McGill University reduce functional impairments in neuroinflammation and may provide an Glutamate is the principle excitatory innovative approach to AD therapies. neurotransmitter in the central nervous system. It acts at three ionotropic receptor-types 3-B-25 Importance of astrocytic coupling (iGluRs): AMPA, NMDA and kainate receptors, for rhythmogenesis in neurons of the which have similar gating processes. Glutamate masticatory central pattern generator. binds to the ligand binding domain (LBD) causing conformational changes leading to Steven Condamine¹, Raphaël Lavoie², Arlette channel activation. These structural changes are Kolta¹ highlighted by the relative positions of adjacent ¹Université de Montréal, ²Douglas Mental Health pairs of LBDs to one another in an area called Research Institute the LBD dimer interface. Previously we reported that restricting movement of the LBDs by In the trigeminal main sensory nucleus crosslinking the dimer interface with the (NVsnpr), a key component of the trigeminal Y521C/L783C GluK2 mutation severely circuit thought to be involved in mastication, hampered single channel activity. For this study rhythmic neuronal bursting can be induced by we investigated the equivalent mutation in repetitive stimulation of glutamatergic afferent AMPA receptors (L504C/L772C GluA2) in order fibers or local applications of NMDA. This to determine if its activation process was bursting is mediated by a sodium persistent similarly disrupted. Macroscopic current current (INaP) and is promoted when the responses of the double cysteine and each extracellular concentration of calcium ([Ca2 ]e) single cysteine mutations were similar for AMPA decreases. Our previous work has shown that a and kainate receptors. The double cysteine Ca2 -binding protein released from astrocytes receptors produced currents that did not decay can lower [Ca2 ]e and that integrity of the in the continued presence of agonist, the L504 astrocytic syncytium is required for bursting to GluA2 and Y521 GluK2 single cysteine occur in NVsnpr. Here we examine the potential mutations had long decay kinetics (decay ~50 role of astrocytic coupling through gap junctions ms) compared to wild-type receptors (~5 ms) in determining the firing pattern of NVsnpr and the L772 GluA2 and L783 GluK2 single neurons. We postulate that burst inducing cysteine mutations were both non-functional. stimuli activate astrocytes, increase their Discrete channel openings were recorded from coupling and by doing this induce bursting. To cross-linked AMPA receptors and, like kainate assess this hypothesis, we measured the size of receptors, displayed many brief channel astrocytic syncytia revealed by injections of openings and closures, with apparently low biocytine in a single astrocyte in whole-cell conductance. Together these data suggest that patch clamp recordings in different conditions. this location in the dimer interface is a Local NMDA applications and [Ca2 ]e decreases conserved functional domain of AMPA and increased coupling between astrocytes, while kainate receptors. NMDA-induced neuronal bursting was abolished by Carbenoxolone (20µM), a blocker of gap 3-B-27 Glutamate receptor activation junctions. Once blocked, this bursting could be involves stabilization at the apex of the rescued by local application of the astrocytic ligand-binding domain Ca2 -binding protein. This work suggests that in addition to regulating the extracellular ions Brent Dawe¹, Maria Musgaard², Bryan concentrations which determine the neuronal Daniels¹, Mark Aurousseau¹, Philip Biggin², firing pattern of NVsnpr neurons, astrocytes may Derek Bowie¹ also play an important role in synchronizing ¹McGill University, ²University of Oxford entire assemblies of neurons in this nucleus. Fast excitatory neurotransmission in the central nervous system involves the transient activation of AMPA and kainate-type (AMPAR and KAR) 179

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 glutamate receptors (iGluRs), which desensitize theta. Thus, we investigated the influence of the within milliseconds of glutamate binding. Crystal septo-hippocampal GABAergic projections on structures of AMPAR ligand-binding domain theta rhythm. To do so, we used the isolated (LBD) dimers have been used to propose a septo-hippocampal preparation developed in our mechanism whereby separation between laboratory together with optogenetics to subunits at the LBD underlies desensitization. specifically control GABAergic projections from We identify the importance of an electronegative the MS. We found that rhythmic stimulation of pocket at the apex of the LBD dimer interface in the MS GABAergic fibers increased both theta facilitating KAR activation. Using a combination power and oscillation strength. In addition, we of outside-out patch clamp electrophysiology found that such stimulation synchronized and molecular dynamics simulations, we show separate theta generators within the that occupancy of this pocket by a positive hippocampus. However, these stimulations only charge correlates with receptor activation and influenced theta when the stimulation frequency prevents subunit separation (i.e. was close to the natural frequency of the desensitization). For the KAR subunit GluK2, ongoing oscillation. Importantly, when the sodium fulfills this charge requirement, and is stimulation was given at specific phases of the therefore necessary to achieve activation once oscillation (to mimic the normal activity pattern glutamate is bound. Interestingly, the occupancy observed in vivo) we found that stimulation of of the pocket by a mutant lysine residue the septo-hippocampal GABAergic fiber tethered between subunits permits continuous increased or decreased theta power in a phase- receptor activation. In contrast, disulfide dependent manner. crosslinking of both KARs and AMPARs at a lower position in the LBD prevents stable 3-B-29 Sleep deprivation impacts on activation, despite yielding nondecaying Neuroligin-2 and -3 protein levels in the population responses. An intermediate mouse brain phenotype occurs following binding of the allosteric modulator cyclothiazide (CTZ) to the Janine El Helou¹, Valérie Mongrain¹ LBD of the AMPAR subunit GluA2, as channels ¹Hôpital du Sacré-Coeur de Montréal alternate between periods of high and low activity. Our data indicate that the arrangement Sleep loss affects brain functioning and the of subunits at the apex of the iGluR LBD molecular mechanisms underlying these regulates the transduction of ligand binding into changes remain mostly unclear. We previously channel opening. showed that sleep deprivation (SD) changes the forebrain expression of Neuroligin 1 (NLGN1), a 3-B-28 Weakly coupled oscillators synaptic adhesion molecule involved in synaptic interactions between the medial septum and plasticity. In this study, we assess the impact of the hippocampus mediated by the septum SD on other members of the NLGN family, long-range GABAergic projections. NLGN2 and NLGN3, in different brain regions. C57BL/6J mice were subjected to a 6-h SD Guillaume Ducharme¹, Bénédicte Amilhon¹, starting at light onset and achieved by gentle Stephen Glasgow¹, Antoine Adamantidis¹, handling. Mice were then sacrificed along with a Sylvain Williams¹ non-SD control group and the cortex, striatum, ¹McGill University hippocampus and a region covering the thalamus/hypothalamus were extracted. The rodent hippocampus displays oscillations at Synaptoneurosomal and total protein extractions various frequencies including those in the theta were performed, and NLGN2 and NLGN3 range (3 to 10 Hz). During theta, the activity of protein levels were quantified by Western blots. neurons is tightly coordinated by the ongoing SD altered the level of NLGN2 in the cortex, rhythm such that synchronous interactions increasing its synaptic protein level and between neurons are governed by the local decreasing its total protein level. SD also rhythm, thus promoting synaptic plasticity and decreased NLGN2 synaptic level in the striatum. memory formation. Lesion studies have These changes altered the synaptic/total protein suggested that the medial septum (MS) is ratio, with a SD-dependent increase in ratio in responsible for hippocampal theta rhythm the cortex and a decreased ratio in the striatum. generation. However, work in our laboratory has Total NLGN3 levels tended to decrease after SD shown that the isolated hippocampus can in the hippocampus and the generate theta oscillations intrinsically, which thalamus/hypothalamus region, which was prompted us to revise the role of the MS in accompanied by a significant increase of 180

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 synaptic/total protein ratio at the hippocampus. 3-B-31 Functional Dissection of These results suggest that the levels and Descending Medial Prefrontal Cortex Inputs trafficking of NLGN2 and NLGN3 are affected by to the Dorsal Raphe Nucleus SD in a brain-dependent manner, therefore providing a mechanism by which excitatory and Sean Geddes¹, Saleha Assadzada¹, inhibitory synaptic transmissions in the brain are Alexandra Sokolovski¹, Richard Bergeron¹, modulated by elevated sleep pressure. Samir Haj-Dahmane², Jean-Claude Beique¹ ¹University of Ottawa, ²University of New York at 3-B-30 Network models provide insight Buffalo into how oriens-lacunosum-moleculare (OLM) and bistratified cell (BSC) interactions The serotonin (5-HT) system has been widely influence local CA1 theta oscillations studied in part because of its involvement in mood regulation and major depressive Katie Ferguson¹, Carey Huh², Bénédicte disorders. Anatomical and functional studies Amilhon², Sylvain Williams², Frances have described a number of descending cortical Skinner¹ inputs that regulate 5-HT neuron activity, ¹Toronto Western Research Institute and including those from the medial prefrontal cortex University of Toronto, ²Douglas Mental Health (mPFC). Activation of the mPFC has been University Institute, McGill University shown to markedly improve depressive moods in humans and reverse depression phenotypes Although hippocampal theta, a 4-12 Hz rhythm induced in animals. Whereas such associated with episodic memory, has been "antidepressant-like" effects may be due to studied extensively, the cellular mechanisms direct modulation of 5-HT neuron function by underlying its generation are unclear. OLM cells these descending inputs, our limited have been considered pacemakers of local CA1 understanding of the synaptic architecture of the theta, but recent experimental work has mPFC innervation onto 5-HT neurons in the disputed this role (Kispersky et al. 2012). The dorsal raphe nucleus (DRN) complicates the complex interactions that OLM cells have with elaboration of a satisfactory framework to other cell types, such as BSCs (Leão et al. explain these findings. Here, we sought to 2012), make their contribution to network dissect out the functional properties of the rhythms difficult to determine experimentally. mPFC-DRN circuit using a combination of Thus, we created a network model that is tied to immunohistochemistry, optogenetics and whole- experimental work on multiple levels, and cell recordings. We show that the mPFC inputs explored how cell interactions affect the power to the DRN are: 1) glutamatergic; 2) modulated of local oscillations. We derived cellular by 5-HT and; 3) mono-synaptically activate both properties from patch clamp recordings of fast- 5-HT neurons and local GABA neurons located spiking paravalbumin-positive interneurons primarily in the lateral wings of the DRN. (comprising basket cells, BSCs, and axo-axonic Activation of the mPFC innervation onto local cells) and of somatostatin-positive putative OLM GABA neurons triggers a di-synaptic inhibition cells in the CA1 region of an intact hippocampus not only of 5-HT neurons, but as well as other in vitro, and used them to constrain Izhikevich- local GABA neurons. Future work will be type models. Our network model size, required to fully grasp the dynamical nature and connectivity, and synaptic properties were also functional implication of this complex array of experimentally constrained. We examined direct activation and feed-forward inhibition in various synaptic strengths and connectivities the DRN triggered by activation of descending between OLM and BSCs to determine their cortical inputs implicated in affective disorders. influence on network power. Spike characteristics and firing behaviors in our 3-B-32 D1-receptor activation facilitates network models approximated those determined synaptic transmission in the lateral experimentally. Our models distinguish between entorhinal cortex via activation of the cAMP- regimes in which OLM cells minimally or PKA pathway and elevation of intracellular strongly affect the power of network oscillations, calcium and predict that the dis-inhibitory effect of OLM cells on BSC to pyramidal cell interactions plays Iulia Glovaci¹, C. Andrew Chapman¹ a critical role in the power of network theta ¹Concordia University oscillations. Dopamine modulates synaptic transmission in the lateral entorhinal cortex in a reversible, 181

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 concentration-dependent manner. We used low dose Bicuculline (2µM) reduced the theta voltage-clamp recordings from layer II entorhinal power by 68±5%, low gamma power by 91±3% cortex neurons to investigate the intracellular and high gamma power by 51±9%. The mechanisms mediating dopamine-induced Modulation index (a measurement of how facilitation of EPSCs. Results show that gamma amplitude is modulated by theta phase) dopamine (1 µM) activates D1 receptors and the of low and high gamma were reduced by 88±4% cAMP-PKA pathway to enhance AMPA, but not and 84±4 % respectively (t-test, n=4, p<0.01). NMDA, glutamate receptor-mediated currents. However, it is still remains to be determined how Elevations in PKA can lead to direct theta gamma coupling are related to theta power phosphorylation of AMPA-receptors, and may and frequency change. Here, using optogenetic also enhance synaptic responses by increasing techniques, we further examined the properties the activity of protein phosphatase 1 (PP-1) of theta and gamma oscillations as well as their inhibitors. The synaptic facilitation was blocked interactions (Modulation index) in the by intracellular application of PKA inhibitors, and CA1/subiculum area. By injecting a CRE- was also blocked by inhibition of PP-1, dependent AAV2-Cheta-eYFP virus in CamKII- suggesting that dopamine facilitates AMPA CRE and PV-CRE mice line to selectively currents via PKA-induced inhibition of PP-1. In activate pyramidal cells or GABAergic PV- addition, we found that application of the Ca2 positive interneurons, we reliably elicited theta chelator BAPTA blocked the facilitation of and gamma oscillations with blue light. By EPSCs, indicating that the facilitation is varying protocols of stimulus frequency (ZAP) dependent on elevated intracellular calcium. and light intensity (RAMP), we are exploring the Calcium release from internal stores can be coupling properties between theta and low/high triggered by IP3 or ryanodine receptor (RyR) gamma oscillations. activation. Application of either heparin, an IP3 antagonist, or dantrolene, a RyR blocker, 3-B-34 Action Potential Induced blocked the facilitation of EPSCs, suggesting Dendritic Calcium Responses in Spinal Cord that Ca2 release from internal stores is Lamina I Neurons essential. Overall, the present results suggest that the dopamine-induced facilitation of AMPA Erika Harding¹, Michael Salter¹ receptor-mediated currents in the entorhinal ¹The Hospital for Sick Children cortex is mediated via a D1-receptor-dependent activation of the cAMP-PKA pathway, inhibition Lamina I neurons of the spinal cord, which are of PP-1, and elevated intracellular calcium responsible for integrating pain information from released from internal stores. the periphery and projecting this to the brain, are hyperexcitable in chronic pain conditions. 3-B-33 Intrinsic theta-gamma coupling Despite the role of calcium as a second properties in the mouse CA1/subiculum area messenger in many cellular processes, calcium in the complete hippocampus in vitro dynamics of spinal lamina I neurons have been largely neglected. Here, we develop an Ning Gu¹, Bénédicte Amilhon¹, Jesse approach to measure calcium dynamics in Jackson¹, Guillaume Ducharme¹, Sylvain lamina I neurons, and use this to characterize Williams¹ calcium responses evoked by action potential ¹Douglas Mental Health University Institute, firing. We made whole-cell patch recordings Mcgill University from the soma of visualized lamina I neurons in adult rat spinal cord slices. The neurons were Fast neuronal network oscillations in the gamma loaded with the calcium indicator Oregon Green range have been involved in a variety of brain Bapta-1 and we performed simultaneous functions. Many cognitive operations require current-clamp recording and two-photon dynamic coordination of activity across different imaging. Action potentials were induced through groups of neurons. Gamma oscillations are 200-300pA current injections via the patch known to synchronize the activity of selected pipette. Single action potentials induced ensembles of cells during hippocampal function. fluorescence increases in the soma (ΔF/F = 0.07 Our group recently reported that theta (4-12Hz) ± 0.03, n= 4 somata), dendrites (ΔF/F = 0.17 ± oscillations were elicited concomitantly with low 0.02, n= 5 dendrites), and dendritic spines (ΔF/F (25-50Hz) and high (150-250Hz) gamma = 0.12 ± 0.02, n= 2 spines). The presence of oscillations in the subiculum area in an isolated tetrodotoxin abolished both the action potentials hippocampal preparation in vitro (Jackson et al., and their subsequent calcium responses. 2011). Blockade of GABAergic receptors using Increasing frequency of a burst of four action 182

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 potentials within a range of 0.2Hz to 5Hz led to a non-linear rise in fluorescence. These findings Derek Howard¹, Lu-Yang Wang¹ suggest that somatically generated action ¹The Hospital for Sick Children potentials elicit calcium responses in the soma and propagate into the dendritic arbour of The development of high fidelity synaptic lamina I neurons. Additionally, calcium transmission at the calyx of Held-MNTB responses to action potentials in lamina I synapse requires the complex regulation of neurons integrate in a non-linear process. synaptic glutamate receptors and active intrinsic membrane properties. Previous studies have 3-B-35 Translational control downstream shown that patterned activity can concurrently of initiation during mGluR LTD in cultured activate NMDARs and mGluRs and increase the hippocampal neurons fidelity of neurotransmission at high rates by translational and post-translational modifications Sarah Hebert-Seropian¹, Tyson Graber², of glutamate receptors. It is however unknown Wayne Sossin², Jean-Claude Lacaille¹ whether or how activity drives the development ¹Université de Montréal, ²Montreal Neurological and maturation in the intrinsic excitability of Institute, McGill University MNTB principal neurons. We used NMDA and DHPG (100 µM each) to selectively co-activate Some forms of synaptic plasticity require rapid, postsynaptic glutamate receptors of developing local activation of protein synthesis. It is MNTB neurons from the auditory brainstem of believed that mRNAs are translationally prehearing mice. We show that co-activation of repressed during transport to synaptic NMDAR and mGluR have time-dependent compartments, but the mechanisms underlying alteration of the action potential (AP) waveform this translational silencing, and its de-repression and of the maximum AP frequency during a during plasticity, remain largely unknown. We 100ms current step stimulus. Given that AP recently showed using field potential recording waveform is dependent on the biophysical in hippocampal slices that translational properties of a number of voltage-gated ion regulation in metabotropic glutamate receptor- channels, we performed whole cell voltage- mediated long-term depression (mGluR LTD) clamp recordings to determine potential occurs downstream of initiation, likely via the mechanisms underlying observed changes in reactivation of stalled polysomes. Here, we use AP waveform. We observed an increase in a cell culture model to study mGluR LTD at the current density and an acceleration of kinetic single synapse/cell level to further investigate properties of TEA-sensitive potassium current these mechanisms. Using whole cell recording 30 minutes after application of NMDAR and from hippocampal neurons in dissociated mGluR agonists. These results suggest that cultures, we show that application of the group I selective co-activation of NMDAR and mGluR mGluR agonist DHPG produces a significant can regulate intrinsic membrane properties and decrease in the frequency of miniature play a role in shaping action potential waveform excitatory postsynaptic currents (mEPSCs) and the ability to spike at high-frequencies. lasting 30 minutes, indicative of mGluR LTD. Application of the translation elongation inhibitor 3-B-37 Role of synaptically-induced emetine during induction blocks the decrease in intracellular acidification on synaptic mEPSC frequency while homoharringtonine, an plasticity initiation inhibitor, does not affect depression of mEPSC frequency. Our results indicate that Tushare Jinadasa¹, Mado Lemieux¹, Paul De translational control during mGluR LTD in Koninck¹ cultured hippocampal neurons occurs ¹University of Laval downstream of initiation, consistent with a de- repression of stalled polysomes. Having Synaptic plasticity involves activity-dependent established a cell culture model of mGluR LTD, recruitment of proteins to the synapse. This we will next use gene knockdown and protein results in a strengthening of the synapse rescue studies to determine the molecular through electro-chemical and local structural mechanisms underlying translational control in changes. Stimuli that evoke synaptic long term this synaptic plasticity. potentiation (LTP) at excitatory synapses result in the insertion of glutamate receptors and 3-B-36 Activity induced changes in recruitment of Ca2 /calmodulin dependent neuronal excitability in a developing central kinase II (CaMKII) into spines, which can be synapse measured optically as metrics of LTP induction. 183

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28

These processes are known to depend on TNFα signaling antagonizes cocaine-induced NMDA receptor activity and Ca2 influx. changes in behavior and synaptic strength. We However, other ions such as Na and H also conclude that TNFα may be an adaptive increase transiently during glutamatergic mechanism to reduce synaptic changes induced transmission. It has been shown that in the nucleus accumbens by chronic cocaine. intracellular acidification occurs during neuronal firing and that the accumulated H is extruded 3-B-39 Active zone proteins RIM1ab are from the neuron in a regulated manner with required for normal corticostriatal slower kinetics when compared to Ca2 transmission and striatal-dependent sequestering. Little is known however on the behaviours dynamics of pH fluctuations in spines and their potential impact on synaptic plasticity. We set David Kupferschmidt¹, David Lovinger¹ out to measure pH fluctuations, using pH- ¹National Institutes of Alcohol Abuse & sensitive fluorescent proteins, in dendritic spines Alcoholism of cultured hippocampal neurons, in conjunction with measurements of either Ca2 fluctuations The presynaptic scaffolding proteins RIM1αβ (GCaMP5) or GFP-aCaMKII translocation. To (RIM1) coordinate key active zone processes evoke plastic changes in the cultures, we used a involved in fast neurotransmitter release and chemical LTP (cLTP) induction protocol, which mediate various forms of presynaptic plasticity. triggered a global and local transient Genetic deletion of RIM1 results in several acidification. Interestingly, disruption of this behavioural abnormalities and learning deficits. acidification associated with cLTP induction Given the near ubiquitous neuronal expression resulted in a loss of CaMKII clustering of RIM1, the specific cell types and projections suggesting a possible role for protons during contributing to the altered transmission and synaptic potentiation. behaviour seen following RIM1 deletion are unknown. Using offspring of Cre-conditional 3-B-38 Adaptive role for TNFa-mediated RIM1 knockout mice and Emx1-Cre mice plasticity in cocaine addiction (Emx1:RIM1 KO), we report that loss of RIM1 in cortical pyramidal neurons alters corticostriatal Sarah Konefal¹, Gil Lewitus¹, Sabrina transmission and select striatal-dependent Chierzi¹, Keith Murai¹, David Stellwagen¹ behaviours. Whole-cell recordings of excitatory ¹McGill University transmission in medium spiny neurons of the dorsolateral striatum reveal that Emx1:RIM1 KO Drug addiction is a maladaptive form of learning mice show enhanced paired-pulse facilitation and memory that is regulated by glutamatergic and reduced synaptic depression during 10-Hz synaptic plasticity. Tumor Necrosis Factor‐α trains, indicating impaired release probability at (TNFα) is a pleiotropic cytokine that modulates these synapses. Consistent with global RIM1α glutamatergic synaptic plasticity via the KO mice, Emx1:RIM1 KO mice show normal trafficking of AMPA‐type glutamate receptors motor learning on the accelerating rotarod, but (AMPARs) and is a key mediator of homeostatic elevated basal and novelty-induced locomotion. synaptic plasticity. The contribution of TNFα to Emx1:RIM1 KO mice also display dramatically drug addiction has never been thoroughly enhanced responding for food pellets when investigated. We examined the role of TNFα on trained on random interval schedules. Our the behavioral and synaptic changes occurring results implicate cortical pyramidal cells as in mice after cocaine administration. First, we important mediators of the behavioural observed that chronic cocaine administration impairments seen in RIM1α KO mice, and reveal increases TNFα levels in the nucleus novel physiological roles for cortical RIM1 in accumbens, a key brain region that regulates normal corticostriatal transmission and striatal- drug addiction. Blocking TNFα signaling both dependent learning. genetically and pharmacologically in mice increased behavioral sensitization to cocaine. 3-B-40 Cacnb4 regulates cortical fast- This increased behavioral response to cocaine spiking basket cells synaptic efficiency: was correlated with an increased synaptic implications for epilepsy and cognitive response to cocaine in the nucleus accumbens impairment. of TNFα KO mice. Following chronic cocaine treatment, TNFα KO mice also displayed an Lydia Marcoux¹, Illya Kruglikov², Alexis elevated dendritic spine density in the nucleus Lupien-Meilleur¹, Mathieu Lachance¹, Elsa accumbens. Overall, these results suggest that Rossignol¹ 184

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28

¹CHU Ste-Justine Research Center, ²NYUMC observed a robust increase in the number of sites per neuron exhibiting MSCTs, as well as Background. Mutations in Cacnb4, encoding the their frequency and amplitude, following a β4 subunit of voltage-gated Ca2 channels, are chemical LTP stimulation (0Mg2 /Glycine). Even associated with epilepsy and ataxia in humans though the amplitudes of MSCTs and mEPSCs and mice. A similar phenotype results from at the same synapse should be correlated deletions of Cacna1a, encoding the a1 subunit (Murphy TH et al, 1995), the observed of CaV2.1 channels. We recently demonstrated potentiation of mEPSCs was subtle, that the targeted deletion of Cacna1a in emphasizing the need to identify the specifically forebrain GABAergic interneurons (INs) results potentiated synapses over the non-potentiated in a selective synaptic impairment of ones. Moreover, the whole-cell configuration parvalbumin-positive fast-spiking basket cells decreased basal frequency of MSCTs, (PV) and causes epilepsy and cognitive deficits suggesting a possible effect of cytosolic in mice. Hypothesis. We propose that Cacnb4 washout on the recordings. We observed two mutations lead to a similar synaptic impairment types of MSCTs: the Ca2 transients were either of PV INs and that this is sufficient to induce restrained to spines or spreading also in short behavioral deficits in mice. . Results. Using in segments of the dendritic shaft. Mg2 or APV vitro whole-cell patch-clamp recordings and application confirmed the NMDAR-dependent paired recordings between genetically-labeled nature of MSCTs. We are now using dual-color PV INs and pyramidal cells, we show a striking imaging to assess if the potentiation of MSCTs reduction of cortical mIPSCs frequency from 33 is correlated with other synaptic events to 23Hz and an enhancement of synaptic failure associated with plasticity such as CaMKII rates at PV-mediated perisomatic synapses in translocation, AMPARs insertion and changes in Cacnb4lh/lh;G42EGFP mutants. We also show spine size. that CaV2.1 channels mediate the residual synaptic release at PV synapses.. Finally, we 3-B-42 Dynamic regulation of TREK-1 show that this impairment of cortical perisomatic gating by polycystin-2 via a Filamin A- inhibition is clinically relevant as mutants mediated cytoskeletal mechanism. carrying targeted repression of Cacnb4 in forebrain GABAergic INs (Lhx6-Cacnb4kd) Steven Li Fraine¹, Reza Sharif-Naeini¹ display behavioral abnormalities reminiscent of ¹McGill University those of Cacnb4lh/lh mutants. Perspectives. Our results illustrate the critical role of Cacnb4 in TREK-1 is a mechanosensitive potassium regulating cortical PV INs synaptic function and channel that is widely expressed throughout the it's relevance to cognitive dysfunctions in mammalian nervous system and implicated in epilepsy. several mechanosensory functions. Our understanding of the mechanisms responsible 3-B-41 Imaging of miniature synaptic for TREK-1 mechanosensitivity and the Ca2+-transients as a readout of synaptic regulation of its gating by accessory proteins is potentiation incomplete. In heterologous systems expressing TREK-1 channels, mechanical stimuli induce an Mado Lemieux¹, Theresa Wiesner¹, Gabriel outward current. In basal conditions, this current Nadeau¹, Paul De Koninck¹ is under a partial inhibition by the F-actin ¹Université Laval/CRIUSMQ cytoskeleton. Interestingly, in the presence of polycystin-2 (PC2), the inhibitory effect of the F- Classical measurements of synaptic plasticity actin cytoskeleton is enhanced through the involve electrophysiological recordings which recruitment of the actin binding protein Filamin A lack information about the location of the (FLNa). However, the characteristics of this synapses that undergo plastic changes. Since inhibition are poorly understood. Our hypothesis synaptic plasticity can be synapse-specific, it is is that this inhibition is highly dynamic and is necessary to directly correlate changes in mediated by a FLNa-dependent increase in F- synaptic transmission with local molecular actin cross-linking at the cell membrane. Our mechanisms. We thus combined imaging of a preliminary results show that the gradual and genetically-encoded Ca2 sensor GCaMP5 and reversible removal of the F-actin reversibly whole-cell patch clamping to record both relieves PC2-mediated TREK-1 inhibition. miniature synaptic Ca2 -transients (MSCTs) and Interestingly, the rate at which the cytoskeletal miniature excitatory postsynaptic currents inhibition recovers is faster in cells expressing (mEPSCs) in cultured hippocampal neurons. We TREK-1 with PC2 than TREK-1 alone. These 185

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 results indicate that PC2 recruits FLNa to the McPherson¹, Liang-Wei Gong², Wayne membrane, where it cross-links F-actin filaments Sossin¹ into a 3D framework that rigidifies the cortical ¹McGill University, ²University of Illinois at cytoskeleton and inhibits TREK-1 activity. This Chicago suggests that conditions that involve a change in cytoskeletal stiffness may affect Synaptic vesicle protein Synaptotagmin I (Syt I) mechanosensory processes via a modulation of is a well-studied calcium sensor critical for mechanosensitive channel gating. synchronized neurotransmitter release. Syt I contains a conserved juxtamembrane domain of 3-B-43 The microglial activation state unknown function. Using pulldown assays with regulates migration and invasion fusion proteins, we have shown that the Syt I juxtamembrane region directly interacts with the Starlee Lively¹, Lyanne Schlichter¹ endocytic protein Dynamin. The interaction is ¹Toronto Western Research Institute specific to the Dynamin I isoform and is localized to its membrane-interacting pleckstrin In response to damage or disease, microglial homology domain. This interaction is blocked in cells undergo complex activation processes. vitro using a Syt I phosphomimetic mutation. We Recently, there is considerable interest in hypothesize that this interaction mediates comparing their pro-inflammatory (e.g., activity-dependent retrieval of synaptic vesicles, 'classical') and resolving (e.g., 'alternative') and thus may influence short-term synaptic activation states. Almost nothing is known about plasticity. To determine if disrupting the how these activation states affect the ability of interaction affects vesicle retrieval, we are microglia to migrate and degrade ECM in order expressing a mutant Syt I that does not interact to reach their target sites. In the present study, with Dynamin in hippocampal neurons and we exposed primary rat microglia to LPS to neuroendocrine chromaffin cells. In neurons, evoke classical activation or IL4 to evoke live-imaging of exogenous membrane tracer FM alternative activation. We monitored changes in 4-64 during a pulse-chase assay will determine cell morphology and analyzed their ability to if compensatory endocytosis is affected. In migrate and invade. A panel of inhibitors was chromaffin cells, electrophysiological recordings used to analyze the contributions of different of membrane capacitance will determine how matrix-degrading enzymes to microglial vesicle fission pore kinetics of large dense-core migration and invasion, and qRT-PCR was used vesicles may be affected. Findings from this to assess changes in their expression. IL4 work have implications in uncovering a increased the migratory capacity of microglia but molecular link between synaptic vesicle eliminated the preferential anterior nuclear- exocytosis and endocytosis. centrosomal axis polarity. Microglia degraded fibronectin regardless of treatment, but LPS- 3-B-45 Activation of the ERK/MAPK treated cells were relatively immobile and IL4- pathway by dimethyl sulfoxide is ameliorated treated cells invaded much more effectively by the 5α-reduced testosterone metabolite through Matrigel?. For invasion, untreated 3α-androstanediol via GABAergic microglia primarily used cysteine proteases, but modulation in SH-SY5Y neuroblastoma cells. IL4-treated cells used a wider range of enzymes. In addition, each activation condition Ari Mendell¹, Bettina Kalisch¹, Neil up-regulated a different set of enzymes. MacLusky¹ Microglia migrate during CNS development and ¹University of Guelph after CNS damage or disease. Thus, there are broad implications of the finding that classically The mechanisms by which androgens regulate and alternatively activated microglia differ in synaptic plasticity in the brain are largely their migratory and invasive capacity, and their uncharacterized. It has recently been usage of ECM-degrading enzymes. demonstrated that hippocampal synaptic responses to fluctuating androgen levels are 3-B-44 Role of the Synaptotagmin- more complicated than previously believed, and Dynamin interaction in synaptic vesicle it is becoming increasingly important to recycling understand the signaling pathways involved. Additionally, it has been suggested that the Robyn McAdam¹, Fiona Young¹, Vanessa cognitive effects of testosterone may be largely Blandford¹, Sebastien Thomas¹, Peter mediated by conversion to its 5α-reduced metabolites. Therefore, we investigated the 186

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 effects of the testosterone metabolites inhibition increased sucrose intake and dihydrotestosterone (DHT) and 5α-androstane- decreased anorectic stress effects. Food 3α,17β-diol (3α-diol) on extracellular signal- restriction and chronic stress induced LS regulated/mitogen-activated protein kinase inhibition leads to compulsivity and increased (ERK/MAPK) activation in SH-SY5Y human incentive value of palatable food, eventually neuroblastoma cells. During our investigation, switching rats to a stable sucrose-seeking and - we found a substantial activation of ERK/MAPK consuming phenotype. This shifted preference by the dimethyl sulfoxide (DMSO) vehicle, towards high palatable food to counteract stress which, even at a final concentration of 0.001%, effects comes at a cost of maladaptive feeding interfered with any observable androgenic behavior and harmful metabolic consequences effects of DHT. However, the reduced including diet-induced obesity. metabolite of DHT, 3α-diol, significantly reduced this activation via modulation of gamma- 3-B-47 Functional Analysis of Calcium aminobutyric acid (GABA)A receptor signaling. Channel-Synaptic Vesicle Tethering in Live The importance of these findings is two-fold. Cryoloaded Synaptosomes. First, it appears that the commonly used vehicle DMSO induces activation of ERK Arup Nath¹, Robert Chen¹, Elise Stanley¹ phosphorylation, which may interfere with ¹Toronto Western Hospital studies of rapid steroid signaling responses. Second, 3α-diol has the ability to inhibit Temporal synchronization between quantal ERK/MAPK activation through GABAergic release and Ca2 influx through a single CaV led modulation. The interaction between GABA to the prediction that SVs must be attached by a signaling and ERK/MAPK activation may have a molecular tether to the channel (Stanley, 1993). role in synaptic remodelling. A recent biochemical report proposes that tethering is mediated by RIM binding to 3-B-46 Decreased activity of the lateral vesicular Rab3a and its simultaneous domain- septum in sucrose-overeating rats with a specific interactions with the channel C-terminal. history of repeated food restriction and Two binding sites were proposed: first, directly stress via the C terminal tip 'PDZ ligand domain', and indirectly via a more proximal proline-rich Arojit Mitra¹, Christophe Lenglos¹, Geneviève domain (Kaeser et al., 2011). We hypothesized Guevrèmont¹, Elena Timofeeva¹ that if SV binding to the channel C terminal was ¹University Laval blocked by competing peptides then SV recycling should be compromised. However, The Lateral septum (LS) is interconnected to the due to the small size of typical presynaptic limbic, hypothalamic and reward centers of the terminals, there was no simple method to brain to regulate coordinated behaviors such as introduce the peptide blockers. We therefore stress response, feeding behavior and developed a novel method, termed cryoloading, motivational states. LS lesion escalates sweet to introduce any large alien compounds into taste preference. LS activity is enhanced by isolated CNS presynaptic terminals stress and attenuated by access to sucrose. (synaptosomes; SSM). PDZ-ligand domain and Stress responses elicit essential behavioral and proline-rich domain mimetic peptides were physiological changes to ensure survival but cryoloaded into the SSMs and SV turnover was chronic stress may become maladaptive. Role assayed using the standard FM, styryl dye and mechanisms by which the LS regulate method. Cryoloaded botulinum light chain was chronic stress-induced changes in dietary used as a positive control and blocked FM preference are largely unknown. We subjected uptake, as predicted. However neither mimetic rats to chronic food restriction with intermittent peptide blocker, used alone or in combination, access to sucrose and weekly foot shock stress had any effect on SV turnover. This lack of session to evaluate the ingestive behavior along functional deficit together with complementary with molecular and electrophysiological effects biochemical SV binding studies (see Gardezi et on LS. Treatment leads to increased al. CAN 2014 Poster) lead us to conclude that consumption of sucrose with enhanced lick SVs tether to CaV C terminals by an alternative numbers, lick-cluster number and its duration. It but unidentified mechanism. also amplified GAD-67 mRNA expression, decreased firing rate of LS neurons, 3-B-48 Neurotensin And Anxiety In The consequently reducing c-fos mRNA expression Oval Bed Nucleus Of The Stria Terminalis in the LS. Additionally, baclofen-induced LS 187

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28

Ana Paula entura-Silva , Emily Haw en , (°OH) through interaction of H2O2 with ferrous Cynthia Di Prospero , Jos Miguel P go¹, irons (Fe2 ). The aim of the current study is to Éric Dumont², Catherine Normandeau² determine whether H2O2 similarly regulates ¹University of Minho, ²Queen's University GABAA receptor-mediated tonic current. Methods: Whole-cell voltage clamp recordings Anxiety is both an adaptive and pathological were performed from cultured mouse behavioural state that is coordinated by hippocampal neurons. The antioxidants neuronal pathways. Previous evidence, has glutathione (GSH, 1 mM), dithiothreitol (DTT, 1 implicated the Bed Nucleus of the Stria mM), or the iron chelator deferoxamine (DFO, Terminalis (BNST) in anxiety behaviour and 100 μM) were used to prevent the oxidative responses to contextual stimuli. More recently, a reaction and Fenton reaction, respectively. An study demonstrated optogenetic stimulation of oxygen glucose deprivation (OGD) protocol was the oval nucleus (ovBNST), a subregion of the used to stimulate the endogenous release of BNST, enhanced anxiety-like behavior. reactive oxygen species, including H2O2. However, the underlying cellular mechanism Results: The addition of GSH to the pipette remains unknown. Neurotensin (NT) is a solution failed to modify the H2O2-induced neuropeptide found both in NT-positive neurons increase in tonic current. In contrast, the and synaptic terminals of the ovBNST and plays addition of GSH, DTT or DFO to the a role in anxiety behaviour. Yet, the extracellular solution completely abolished the neurophysiological role of NT in the ovBNST increase. GSH also completely abolished the and its involvement in anxiety remains largely increase in tonic current produced by OGD. unclear. Our electrophysiology experiments Conclusion: These results suggest that the were conducted in male Long-Evans rats using increase in tonic GABA current by H2O2 results whole cell patch clamping. Our observations from an extracellular oxidative reaction and the show that endogenous and exogenous release Fenton reaction. of NT potentiates GABAergic inhibitory synaptic transmission in the ovBNST. NT mostly acted 3-B-50 Unique interweaved microtubule pre-synaptically to increase the probability of scaffold mediates osmosensory GABA release since the paired-pulse ratio transduction via physical interaction with (PPR) significantly decreased (p=0.001). These TRPV1 results suggest NT is a modulator of inhibitory synaptic transmission in the ovBNST. We then Masha Prager-Khoutorsky¹, Arkady investigated whether selective NT-antagonist in Khoutorsky², Charles Bourque¹ the ovBNST had an effect on anxiety-like ¹Research Institute of the McGill University behaviour. Our preliminary results suggest NT Health Centre, ²McGill University has an anxiogenic effect in the ovBNST. The electrical activity of mammalian 3-B-49 Hydrogen peroxide potentiation osmosensory neurons (ONs) is increased by of a tonic GABA current in hippocampal plasma hypertonicity to command thirst, neurons requires extracellular oxidation and antidiuretic hormone release and increased the Fenton reaction sympathetic tone during dehydration. Osmosensory transduction is a mechanical Antonello Penna¹, Dian-Shi Wang¹, Jieying process whereby decreases in cell volume lead Yu¹, Irene Lecker¹, Beverley Orser¹ to the activation of transient receptor potential ¹University of Toronto vanilloid type-1 (TRPV1) channels to cause depolarization and increase spiking activity in Background: Hydrogen peroxide (H2O2), a key ONs. However it is not known how cell shrinking reactive oxygen species, contributes to is mechanically coupled to channel activation. pathological disorders such as ischemia- Using super-resolution imaging we found that reperfusion injury and neurodegenerative ONs are endowed with a unique interweaved disease. We recently showed that H2O2 scaffold of microtubules in their soma. robustly increases a tonic GABA current in Microtubules physically interact with the C- hippocampal neurons that might contribute to terminus of TRPV1 at the membrane surface H2O2-induced brain dysfunction. The and this interaction is necessary for channel mechanisms underlying such H2O2 effects are activation during cell shrinking. Moreover, unclear. H2O2 can regulate the function of ion changes in microtubule stability can bi- channels via oxidative reaction, as well as directionally modulate osmosensory gain. Fenton reaction that produces hydroxyl radical Microtubules are thus an essential component of 188

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 the vital neuronal mechanotransduction indicate that synaptically evoked astrocyte Ca2 apparatus that allows the brain to monitor and transients are not necessary to change arteriole correct body hydration. diameter in response to a burst of afferent activity, suggesting neural signalling alone is 3-B-51 TRPM2 regulates migration of sufficient. Further we propose a novel role for primary microglia cells the resting Ca2 concentration in astrocytes in controlling the steady-state tone of vessels Melanie Ratnam¹, Michelle Aarts¹ when neural activity is quiesce ¹University of Toronto Scarborough 3-B-53 The cellular mechanisms of TRPM2 is a calcium permeable non-selective neuronal swelling underlying cytotoxic brain cation channel that is highly expressed in edema immunocytes throughout the periphery and in the primary immune cell of the central nervous Ravi Rungta¹, Hyun Choi¹, John Tyson¹, system: microglia. We hypothesized that Terrance Snutch¹, Brian MacVicar¹ TRPM2 may play a role in migration since ¹University of British Columbia calcium regulation is important for cell migration. Our results revealed a significant decrease in Cytotoxic brain edema is the principal cause of TRPM2 knockout (-/-) microglia in scratch- mortality following brain trauma, cerebral infarct wound assays when compared to WT microglia. and infection yet the mechanisms underlying This work will contribute significantly to our neuronal swelling are poorly understood. We understanding of the role of TRPM2 in examined the ionic basis for neuronal swelling, neuroinflammatory diseases. and quantified the intracellular sodium and chloride concentration of individual cortical 3-B-52 Astrocytes provide steady-state, neurons as they swelled using fluorescence activity independent control of cerebral lifetime imaging. We show that sodium entry, blood vessel diameter triggers a secondary transmembrane chloride influx via a yet unidentified pathway and that this David Rosenegger¹, Grant Gordon¹ chloride influx is required for neuronal swelling ¹University of Calgary and calcium independent cell death. To identify the novel chloride influx pathway that caused Neuro-vascular coupling encompasses all the neuronal swelling we first took a signalling events utilized by neurons and pharmacological approach to narrow down a list astrocytes that instruct the micro-vasculature to of candidates followed by siRNA knockdown of change diameter, thereby controlling local blood these targets using lipid nanoparticle delivery. flow. In the prevailing model, synaptic glutamate The identification of cellular targets necessary release activates glutamate receptors on both for neuronal swelling could conceivably lead to neurons and astrocytes, which initiate Ca2 therapies to reduce cytotoxic edema by dependent pathways that ultimately signal to inhibiting the transporter or process required for contractile vascular smooth muscle cells. swelling and subsequent cell death. Astrocytes, therefore, are believed to be an essential relay cell that communicate to 3-B-54 Non-uniform dendritic arterioles on behalf of neural activity. This model distributions of Ih channels in however, has not been systematically dissected. experimentally-derived multi-compartment Studying activity-dependent neuro-vascular models of oriens-lacunosum/moleculare coupling in acute brain slices of the neocortex hippocampal interneurons using two-photon microscopy, we observed robust vasodilations and vasoconstrictions that Vladislav Sekulic¹, Tse-Chiang Chen², John follow increases in neural and astrocytic free Lawrence³, Frances Skinner¹ Ca2 that initiated rapidly in response to brief ¹Toronto Western Reseach Institute/University electrical stimulation. Interestingly, effective of Toronto, ²University of Toronto, ³University of reduction of free astrocytic Ca2 by the Montana intracellular delivery of BAPTA into the astrocyte network, failed to affect activity-dependent Inhibitory interneurons are crucial for generating diameter changes. However, when BAPTA itself prominent network rhythms and coordinating invaded the astrocyte endfeet that were directly information flow in hippocampal microcircuits. apposed to the arteriole, a prominent The oriens-lacunosum/moleculare (O-LM) cell is vasoconstriction was observed. Our data an interneuron type in the hippocampal CA1 189

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 region that mediates feedback inhibition onto amplitude and frequency of the miniature pyramidal cells and gates information flow excitatory postsynaptic currents measured in between sensory input from entorhinal cortex nearby tectal neurons were diminished, and previously stored associations from the CA3 suggesting reduced synaptic maturation when area. O-LM cells are known to express the glia cannot fully participate. We have also hyperpolarization-activated cation current (Ih), observed that the rates of glial process motility but due to experimental constraints it is not vary with the age of the tadpoles, being highest known whether these channels are present in during the period of greatest synaptogenesis. dendrites. In previous work, we used ensemble modeling techniques in conjunction with 3-B-56 Role of Early Acoustic Experience experimental data to show that physiologically in Development of the Rat Primary Auditory realistic multi-compartment O-LM cell models Cortex may possess dendritic Ih, but only uniform distributions across the dendritic tree were Chloe Soutar¹, Simon Rodier ¹, Meaghan examined. Here, we tuned the Ih model's Wilkin¹, Janet Menard¹, Hans Dringenberg¹ kinetics in addition to examining the influence of ¹Queen's University non-uniform dendritic distributions on the model cells' outputs. We found that different Ih kinetics Cortical architecture is established by both as well as non-uniform distributions were better genetic and experience-dependent factors. able to reproduce experimental O-LM cell Postnatal sensory experience plays a significant responses. Interestingly, this occurred for role in the maturation and refinement of cortical decreasing conductance densities away from sensory fields, such as the primary auditory the soma. This is in contrast to pyramidal cells cortex (A1). Long-term potentiation (LTP) which have higher Ih conductance densities in mediates synaptic strengthening in sensory more distal dendrites. cortices with postnatal sensory exposure. We assessed levels of LTP and short-term plasticity 3-B-55 Radial glia filopodial motility is (paired-pulse facilitation/depression; PPF/PPD) required for the normal development of in vivo (under urethane anesthesia) in A1 of excitatory synapses in the optic tectum of normally reared rats and rats reared in the Xenopus laevis absence of patterned acoustic input through continuous white noise exposure (cWN). Rats Mari Sild¹, Marion Van Horn¹, Dantong Jia¹, reared under cWN showed greater LTP of field Edward Ruthazer¹ postsynaptic potentials in A1 compared to ¹McGill University controls, indicative of immature, more plastic synaptic connectivity. Both groups showed Radial glia serve as a migratory scaffold for the similar, moderate levels of PPD (25-1000 ms neuroblasts in the developing mammalian brain. intervals) prior to LTP induction. Importantly, However, glia, especially astrocytes, are also PPD was significantly enhanced after LTP known to be actively involved in synapse induction, indicative of a presynaptic component development and maintenance. In the Xenopus of thalamocortical LTP in A1. Ongoing laevis tadpole, which lacks classical astrocytes, morphological analyses (Golgi-Cox staining) the radial glia extend many fine filopodial currently do not show clear differences in processes within the neuropil where they appear dendritic complexity of A1 pyramidal neurons to interact with developing synapses, as has (layers II/III) between control and cWN groups. been described for astrocytic processes in the These data indicate that patterned sensory mammalian brain. Earlier findings in our experience results in a reduction of plasticity in laboratory revealed that neural activity induces A1, indicative of more mature, hard-wired an increase in glial process motility, dependent synaptic connectivity. Further, we propose that on the activation of neuronal N-methy-D- LTP in A1 in vivo is mediated in part by aspartate (NMDA) receptors and the production presynaptic mechanisms, such as increases in of nitric oxide. We have further determined that transmitter release probability at thalamocortical the increase in motility of these filopodia synapses (supported by NSERC and The requires the activation of cGMP dependent Hearing Foundation of Canada). protein kinase I (PKGI), known to phosphorylate the small GTPase RhoA. Using genetic 3-B-57 Calcium-dependent calcium manipulations of small GTPase activity to either decay explains STDP in a dynamic model of eliminate the fine glial processes altogether or to hippocampal synapses "freeze" their movement, we found that both the 190

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28

Dominic Standage¹, Thomas Trappenberg², by manipulations like altered extracellular Gunnar Blohm¹ potassium concentration and application of ¹Queen's University, ²Dalhousie University inflammatory mediators. Here we describe a novel methodology in which virtual It is widely accepted that the direction and conductances are applied via dynamic clamp, magnitude of synaptic plasticity depends on and the effect of various manipulations on post-synaptic calcium flux, where high levels of excitability are quantified by the change in the calcium lead to long-term potentiation and minimal virtual sodium conductance needed to moderate levels lead to long-term depression. At switch the spiking pattern. In other words, we synapses onto neurons in region CA1 of the use dynamic clamp to measure the distance of hippocampus (and many other synapses), the neuron from its tipping point before and after NMDA receptors provide the relevant source of manipulations that mimic various factors calcium. In this regard, post-synaptic calcium contributing to neuropathic pain. By establishing captures the coincidence of pre- and post- a novel methodology by which the distance to synaptic activity, due to the blockage of these the tipping point can be assessed, effects of receptors at low voltage. Previous studies show inflammatory mediators and other factors on that under spike timing dependent plasticity excitability can be rigorously quantified. (STDP) protocols, potentiation at CA1 synapses Moreover, the susceptibility of different cell requires post-synaptic bursting and an inter- types to qualitatively altered excitability can be pairing frequency in the range of the compared. hippocampal theta rhythm. We hypothesize that these requirements reflect the saturation of the 3-B-59 Synapse-specific expression of mechanisms of calcium extrusion from the post- the alpha5 GABAA receptor subunit in synaptic spine. We test this hypothesis with a hippocampal interneurons and its rapid minimal model of NMDA receptor-dependent decline in the pilocarpine model of temporal plasticity, simulating slow extrusion with a lobe epilepsy calcium-dependent calcium time constant. In simulations of STDP experiments, the model Elise Magnin¹, Lisa Topolnik¹ accounts for latency-dependent depression with ¹Université Laval either post-synaptic bursting or theta-frequency pairing (or neither) and accounts for latency- Synaptic expression of the alpha 5 GABAA dependent potentiation when both of these receptor subunit (a5-GABAAR) has been requirements are met. The model makes reported in hippocampal CA1 inhibitory testable predictions for STDP experiments and interneurons (INs). However, the types of our simple implementation is tractable at the synapses that express a5-GABAAR and its network level, demonstrating associative functional role have not been investigated. learning in a biophysical network model with Using a combination of whole-cell patch-clamp realistic synaptic dynamics. recordings, optogenetics and immunohistochemistry, we examined the 3-B-58 Using dynamic clamp to quantify synapse-specific expression of the a5-GABAAR changes in somatosensory afferent and its modifications in the animal model of excitability associated with neuropathic pain temporal lobe epilepsy (TLE). Our data showed that both the a5-GABAAR and its anchoring Petri Takkala¹, Steven Prescott¹ protein radixin exhibit a strong colocalisation ¹University of Toronto with a vesicular GABA transporter in hippocampal CA1 oriens-alveus (O/A) INs. Hyperexcitability in cutaneous primary afferent Moreover, inhibitory postsynaptic currents neurons is a feature of the pathophysiology evoked in O/A INs by selective activation of underlying neuropathic pain. Qualitative calretinin-positive (CR+) interneuron-specific changes in excitability, such as a change in cells in CR-Cre mice were decreased in the spiking pattern, are obvious whereas subtler presence of the a5-GABAAR inverse agonist L- changes can be difficult to quantify. The switch 655,508 (to 65 +/- 5.7 % of control; n = 8). in spiking pattern occurs abruptly at a tipping Synaptic expression of the a5-GABAAR was point that depends on the relative proportion of revealed in different IN types, including oriens- sodium and potassium conductances (gNa and lacunosum moleculare cells, bistratified cells, gK, respectively). Using acutely dissociated basket cells and oriens-oriens interneurons. dorsal root ganglion (DRG) neurons, we sought Finally, a rapid decrease in the a5-GABAAR and to measure subtle changes in excitability caused radixin expression was observed in pilocarpine 191

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 model of TLE, pointing to a significant 3-B-61 Non-canonical signaling of disinhibition of O/A INs. Our data showed that NMDARs to pannexin-1 in ischemia the a5-GABAAR is expressed at inhibitory synapses formed at different types of INs by the Nicholas Weilinger¹, Jennifer Bialecki¹, local inhibitory input from CR+ cells. Moreover, Brooke Rakai¹, Nathan Ikuta², Ian Winship², the rapid decline of the a5-GABAAR in G. Campbell Teskey¹, Roger Thompson¹ hippocampal INs during TLE may contribute to ¹University of Calgary, ²University of Alberta IN disinhibition and hyperexcitability with consequences for network activity. N-methyl-D-aspartate receptors (NMDAR) are critical mediators of excitoxicity and neuronal 3-B-60 The adrenocorticotrophin (ACTH) death. As such, NMDARs have been the focus secretagogue, arginine vasopressin (AVP) of neuroprotection studies for ischemic stroke. reduces the background TREK-1 current in Despite over a decade of success in animal mouse pituitary corticotropes models, pharmacologically targeting NMDARs during / post stroke failed clinical trials due to Amy Tse¹, Andy Lee¹ lack of efficacy and / or were poorly tolerated ¹University of Alberta due to side effects. However, important mechanistic insights were gleaned because of Upon stress, the hypothalamic hormones, the differential efficacy of antagonists with corticotropin-releasing hormone (CRH) and AVP distinct modes of action. Here, we hypothesized stimulate ACTH secretion from corticotropes. that NMDARs can signal to the large-pore We showed previously that the resting potential channel pannexin-1 (Panx1) without opening as of corticotropes is set by the basal activities of ion channels. To approach this, we performed TREK-1 channels. The suppression of TREK-1 whole-cell patch clamp recordings, as well as current by CRH causes depolarization and fluorescent calcium imaging to measure activation of voltage-gated calcium channels. excitotoxic events while NMDARs were pore- AVP acts synergistically with CRH to stimulate blocked with either magnesium or MK-801. ACTH secretion but the underlying mechanism Pore-blocked NMDARs activated Panx1 is unclear. We tested the hypothesis that TREK- channels to induce ionic dysregulation, leading 1 current can be reduced by AVP and this to mitochondrial dysfunction and neuronal death inhibition is additive to that mediated by CRH. during ischemia. Furthermore, Panx1 Using the green fluorescent corticotropes antagonism with a Src family kinase (SFK) isolated from POMC-eGFP mice, we found that interfering peptide blocked neuronal death AVP (200 nM) reduced the amplitude of the during ischemia / stroke both in vitro and in vivo. TREK-1 current at -70 mV by ~28%; and the We conclude that NMDAR signaling during addition of CRH (20 nM) in the continued stroke involves a novel, ionotropic-independent presence of AVP, further reduced the current by mechanism. 45%. For cells exposed first to CRH, the TREK- 1 current was reduced by ~38%; and the 3-B-62 Regulation of NMDA receptors by addition of AVP in the continued presence of tyrosine-protein kinase Fyn in human CRH, further reduced the current by ~47%. induced pluripotent stem cell-derived These results show that the AVP and CRH- neurons mediated inhibition on TREK-1 current are additive. We also examined the effect of AVP Wenbo Zhang¹, P. Joel Ross¹, Yongqian and CRH on membrane potential. The co- Wang¹, James Ellis¹, Michael Salter¹ application of AVP and CRH depolarized the ¹The Hospital for Sick children corticotropes by ~33 mV, larger than that evoked by AVP (~11 mV) or CRH alone (~24 NMDA receptor (NMDAR)-mediated fast mV). Overall, our results suggest that in the excitatory neurotransmission is implicated in a presence of CRH, AVP can further suppress the broad range of physiological and pathological TREK-1 current, resulting in a more robust processes in the mammalian central nervous depolarization. This mechanism may contribute system. The functions and regulation of to the synergistic actions of these two NMDARs have been extensively studied in hypothalamic hormones on ACTH secretion. neurons from rodents and other non-human species, and in recombinant expression systems. Here, we investigated human NMDARs in situ by using neurons produced by directed differentiation of human induced 192

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 pluripotent stem cells (hiPSCs). The resultant transforming growth factor-beta and then Nrg-1 cells showed morphological, biochemical and was added to the cultures. Using electrophysiological characteristics immunocytochemistry, spectrophotometry, demonstrating that they are bona fide neurons. Western and slot blotting on astrocyte In particular, the hiPSC-derived neurons conditioned media and cell lysate, we show that expressed functional ligand-gated ion channels, Nrg-1 treatment significantly attenuates several including glycine receptors, GABAA receptors, inhibitory aspects of reactive astrogliosis AMPA receptors, and NMDARs. The including CSPG production and the release of pharmacological and electrophysiological TNF-α and IL-1β. Moreover, Nrg-1 activation properties of the NMDAR currents indicated that attenuated cell proliferation and nestin these were dominated by receptors containing upregulation, two cellular characteristics of GluN2B subunits. The NMDAR currents were astrogliosis. Intrathecal Nrg-1 infusion in SCI suppressed by genistein, a broad-spectrum also resulted in mitigation of astrogliosis in vivo. tyrosine kinase inhibitor, or by PP2, a selective Evidence in this work and our previous reports inhibitor of Src family tyrosine kinases. suggest the therapeutic potential of Nrg-1 for the Furthermore, we found that the currents were treatment of SCI. suppressed by a Fyn-interfering peptide, Fyn(39-57), but not a Src-interfering peptide, 3-C-64 Altered muscarinic activation in Src(40-58), and normalized currents after Perisynaptic Schwann Cells of SOD1G37R treated by scrambled Fyn(39-57) or Fyn(39-57) mice; implication for the fate of the were 88.4 ± 4.5% and 60.2 ± 5.1% (P<0.01), neuromuscular junction. respectively. In addition, RT-PCR revealed that the hiPSC-derived neurons expressed mRNA Danielle Arbour¹, Éric Martineau¹, Elsa for Fyn. Together, these findings are the first Tremblay¹, Richard Robitaille¹ evidence that Fyn kinase regulates the function ¹Université de Montréal of NMDARs in the hiPSC-derived neurons. Amyotrophic Lateral Sclerosis (ALS) is a C - Disorders of the Nervous System devastating neurodegenerative disease characterized by a progressive loss of 3-C-63 Neuregulin-1 Attenuates motoneurons and consequent skeletal muscle Astrogliosis and Glial Scar Formation after denervation and neuromuscular junction (NMJ) Spinal Cord Injury destruction. Furthermore, ALS is a non-cell autonomous disease. Perisynaptic Schwann Arsalan Alizadeh¹, Scott Dyck¹, Dung cells (PSCs), specialized glial cells at the NMJ, Nguyen¹, Santhosh Kallivalappil¹, Evan regulate morphological stability and integrity and Proulx¹, Soheila Karimi-Abdolrezaee¹ actively participate in the re-innervation of the ¹University of Manitoba NMJ, events under the influence of synaptic communication by muscarinic receptors Reactive astrogliosis is a key pathophysiological (mAChRs) activation. Hence, we postulate that event after Spinal Cord Injury (SCI). Activated PSCs muscarinic activation is altered in ALS. astrocytes secrete pro-inflammatory cytokines NMJs fom soleus nerve-muscle preparations of and chondroitin sulphate proteoglycans presymptomatic (120 days) and symptomatic (CSPGs) that impede spinal cord repair and (370 - 500 days) SOD1G37R mice and their regeneration. Our recent evidence shows that litter mates were used. We labelled the three dysregulation of Nrg-1 signaling after SCI may synaptic elements (pre-, postsynaptic and underlie the astrocytes reactivity following injury. PSCs) as an indicator of the integrity of the Here we elucidated the impact of Nrg-1 on NMJ. Also, PSCs decoding ability was astrocyte activation after SCI. Using an in vivo investigated using calcium imaging of PSCs rat model of incomplete compressive SCI and elicited by endogenous neurotransmitter release two in vitro models of reactive astrogliosis, we and local agonist application. Our data suggest found that availability of Nrg-1 can mitigate that alteration of PSC mAChRs functions are astrocyte reactivity. In SCI rats, recombinant detectable at presymptomatic stage of ALS human Nrg-1ß1 (rhNrg-1β1) was delivered (P120), independently of motor unit vulnerability intrathecally and spinal cord tissue was and persist at a symptomatic stage (P363) in a analyzed by immunohistochemistry and specific motor unit matter. Taken together, these stereological techniques 2 weeks post-SCI. For results suggest that the inadequate muscarinic in vitro astrogliosis, primary astrocytes were regulation of PSCs could lead to an improper activated using lipopolysaccharide or 193

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 maintenance and repair of NMJs structure and ischemic insult by proliferating and migrating to functions during the course of the disease. the site of injury where they have the capacity to differentiate. The majority of these cells however 3-C-65 Adeno-Associated Virus Gene undergo apoptosis before differentiating and Delivery of Fmr1 in Fragile X Knockout Mice affecting neural recovery. My goal is to promote the survival of NPCs by manipulating the Jason Arsenault¹, Shervin Gholizadeh¹, expression of anti-apoptotic proteins. To do this, Ingrid Yang Xuan¹, Laura Pacey¹, David I am examining the NPC and glial response to Hampson¹ an ET-1 focal ischemic injury to identify the ¹University of Toronto optimal time point in which to manipulate the NPCs. BrdU/Dcx double labelling at 1, 3, 5, 7 Fragile X syndrome is caused by a pathological and 10 days post ischemia revealed a significant trinucleotide repeat expansion in the FMR1 increase in neuroblast proliferation at 7 days. gene; the expanded repeat causes a reduction Next, immunohistochemistry was performed with or elimination of the gene product, Fragile X antibodies to CD-68, a marker of activated mental Retardation Protein (FMRP). Current microglia and macrophages and to GFAP, a pharmacological treatments for fragile X marker of activated astrocytes to examine the syndrome partially ameliorate certain symptoms glial response. Microglial and macrophage yet do not address the underlying etiologies. In activation started at 3 days and continued to 14 order to attempt to up-regulate FMRP days post-ischemia. Astrocyte activation spread expression in the central nervous system of the across the ipsilateral cortex and into the Fmr1-knockout (Fmr1-KO) mouse model of contralateral cortex by 7 days post-ischemia. fragile X syndrome, we used single-stranded Currently we are manipulating the expression of adeno-associated viral vector (AAV) that anti-apoptotic proteins in NPCs in the first week expresses the major isoform of FMRP, driven by post-ischemia to identify the optimum time point a neuron-specific promoter. The vector was that would have the maximum effect on delivered into the brain via bilateral intra- neuroblast survival. Acknowledgements: This cerebroventricular injections in neonatal Fmr1- work was supported by an operating grant from KO mice. FMRP transgene expression and the CIHR, RDC-NL, HSF-Partnership for Stroke behavioral assessments were conducted at Recovery Catalyst grant to JV. RFB is supported different time points post-injection. Western by a HSF-Partnership for Stroke Recovery blotting and immunocytochemical analyses of Studentship, and RBR was funded by a Keith AAV-FMRP injected KO mice revealed FMRP Griffiths HSF Student Award. transgene expression in the striatum, hippocampus, retrosplenial cortex and cingulate 3-C-67 Temporal evolution of different cortex. FMRP expression was almost limbic seizure onset types in the pilocarpine exclusively restricted to neuronal cells and rat model of mesial temporal lobe epilepsy reached approximately 50% of wild-type levels in the hippocampus, striatum and cerebral Charles Behr¹, Maxime Levesque¹, Massimo cortex. The elevated repetitive behavior and Avoli¹ deficit in social dominance behavior seen in ¹McGill University PBS-injected Fmr1 KO mice were normalized to wild-type values following AAV-FMRP injection. Depth electrode EEG studies in patients with These results provide the first proof-of-principle mesial temporal lobe epilepsy have identified for gene therapy for reversing specific two types of seizure onset: the low-voltage-fast behavioral abnormalities in the mouse model of onset (LVF) and the hypersynchronous onset fragile X syndrome. (HYP). LVF onset consists of a pre-ictal spike preceding low-voltage beta activity, whereas the 3-C-66 Identification of the optimal time HYP onset refers to an early, repetitive pre-ictal window to enhance NPC survival after a spiking activity. It has also been suggested that focal ischemic injury. LVF and HYP seizures originate from extra- hippocampal regions and from the hippocampus Robert Bartlett¹, R. Brian Roome¹, Jieying proper, respectively. Finally, HYP seizures may Xiong¹, Jacqueline Vanderluit¹ correlate with hippocampal sclerosis. In this ¹Memorial University of Newfoundland study, we have analyzed the temporal evolution of HYP and LVF seizures in pilocarpine-treated Neural precursor cells (NPC) within the animals. We performed depth EEG recordings in subventricular zone (SVZ) respond to an the CA3 region of the hippocampus, entorhinal 194

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 cortex, dentate gyrus and subiculum in higher DA concentrations and DA turnover in the pilocarpine-treated rats from 4 days to 2 weeks GP compared to AAV-GFP MPTP. These (n = 8 rats, 419 seizures) after status epilepticus results suggest that upregulation of striatal (SE) and from 4 to 6 weeks (n = 7 rats, 140 pENK could enhance locomotor activity, seizures) after SE. Results showed that 63% of increase DAergic tone in GP, and may exert LVF started outside of CA3, compared to 12% of protective effect against the MPTP insults at HYP. In contrast 88% of HYP involved the CA3 nigrostriatal nerve terminals. at onset compared to 37% of LVF. HYP seizures predominated during the 2 first weeks following 3-C-69 The interplay between astrocytes SE but decreased in favor of LVF onset type 5 and microglia shapes the progression of weeks after (2.3 HYP seizure per days Alzheimer's disease. compared to 0.5 LVF seizure per day during the first 2 weeks following SE (p<0.05), 1.3 LVF Bouvier David¹, Emma Jones¹, Rémi seizures per days after 2 weeks compared to Quirion², Naguib Mechawar¹, Keith Murai¹ 0.4 HYP seizure per days (p<0.05)) . We are ¹McGill University, ²Douglas Mental Health currently evaluating respective neuronal loss in University Institute each of the recorded structures using a stereological method. A. Alzheimer was the first to describe dysmorphic microglia and astrocytes aggregated 3-C-68 The effect of striatal pre- around amyloid plaques. However, exactly how enkephalin overexpression in MPTP mouse these cells contribute to the onset or model of Parkinson's disease progression of AD still remains an open question. Using a new method for high- François Bezeau¹, Stéphanie Bissonnette¹, resolution confocal microscopic analysis on Nathalie Vernoux¹, Sophie Muratot¹, Frédéric human tissue, we investigated the Calon¹, Sébastien Hébert S.¹, Pershia characteristics of glial organization around Samadi¹ amyloid plaques and paired-helical filaments ¹CHUL (Université Laval) (PHF) aggregates. We observed that glial cells have a remarkable spatial organization around Midbrain dopamine (DA) cell death in amyloid plaques, with an inner shell of activated Parkinson's disease (PD) is associated with an microglia and an outer shell of reactive upregulation of striatal pre-enkephalin (pENK). astrocytes. We named this structure "the Our previous results using the parkinsonian reactive glial net" (RGN). Using the CRND8 AD monkeys suggest that increased expression of mouse model, we monitored the temporal pENK mRNA in the striatum is a compensatory characteristic of RGNs. Their assembly starts response to alleviate PD motor symptoms. To with the appearance of amyloid deposits, is determine the role of striatal pENK in motor dynamic and sequential. RGNs are behavior, and to define whether striatal pENK progressively disrupted in late stages. may have a protective effect against the Furthermore, RGNs form a toxic environment for neurotoxin insults in the MPTP mouse model of neurons as neurites trapped within this structure PD, viral vector was used to overexpress striatal become dystrophic and produce pENK before DA depletion. One group received hyperphophorylated Tau granules in CRND8Tg. saline, and two other groups received striatal This is correlated with high concentrations of injection of AAV2-GFP or AAV2-GFP-pENK two PHF within RGNs in human AD brains. We weeks before MPTP injection. Overexpression screened for the expression of the cytokines of striatal pENK associated with an increased IL1β and IL6, biomarkers of inflammation in AD level of opioid peptide ENK in striatum, globus and potential promoters of Tau pathology. pallidus (GP) and substantia nigra. Moreover, Astrocytes of RGNs, but not microglia, were mice overexpressing pENK displayed enhanced found as a main source of IL-1β and IL6 in locomotor activity. Higher density of striatal mouse and human tissue. Interestingly, their tyrosine hydroxylase (TH) positive fibers also upregulation is gradated and first restricted to detected in mice overexpressing pENK in the astrocytes of RGNs but spreads locally at different regions of the striatum compared to late stages. We conclude that RGNs are key control groups. High performance liquid structures that shape the progression of AD. chromatography showed a marked reduction of DA level in the striatum and GP of MPTP- 3-C-70 Characterizing the effect of treated groups compared to saline. Remarkably, maternal immune activation on perisomatic striatal overexpression of pENK led to two folds 195

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GABA neurons using a dual recombinase- upregulated in both humans with AD and mediated gene activation strategy. transgenic models of the disease. Although TNFα is a well-known immune mediator, it is Janine Cajanding¹, Junchul Kim¹ recognized as a modulator of learning, memory, ¹University of Toronto and synaptic function. The role of TNFα in synaptic function is thought to be regulatory or The GABAergic system encompasses a neuroprotective at physiological levels, but functionally diverse network of neurons defined neurotoxic when found in excess. Since proper by their structural, electrophysiological and synaptic function underlies healthy cognitive molecular expression profiles. Disruptions to this processing, it is critical to understand the effect system have been implicated in animal models of TNFα on synaptic function in AD. of neuropsychiatric disorders, such as maternal Consequently, the early intervention of TNFα immune activation (MIA); however, previous signaling may help prevent the detrimental experiments often lack the spatial resolution effects of excess TNFα on synaptic function. We necessary for defining this relationship to the hypothesize that increased levels of TNFα at specific subtypes of GABA cells. We attempt to early stages of AD-like pathology may become circumvent these technical limitations by pathogenic and lead to deficiencies in synaptic employing a dual-recombinase system (Cre/loxP function. We use the TgCRND8 mouse model of and Flp/FRT) to drive the expression of a AD, which overexpresses a double human reporter molecule at the intersection of Dlx5/6 mutation of the precursor to amyloid-β (Aβ), the and parvalbumin (PV) or cholecystokinin (CCK) amyloid precursor protein, to show that 1-month- driver genes. For subsequent experiments, we old mice display both a significant increase in achieved the selective labelling of PV- or CCK- TNFα and alterations in synaptic function before positive GABA neurons with GFP and the the overproduction of Aβ or cognitive deficits. remaining subtractive GABA neurons with Our findings may provide insight on TNFα as a mCherry. Here, pregnant mice received an i.p. potential therapeutic target in the prodromal injection of saline or the viral mimetic stages of AD and will help elucidate the effects polyinosinic:polycytidylic acid (poly I:C) at of TNFα on synaptic function. gestational day 9 or 17. Neural tissue was harvested at post-pubertal stage for cell 3-C-72 Depletion in pro-inflammatory counting and morphological analyses, monocytes/macrophages is neuroprotective specifically in the hippocampus and medial in the myenteric plexus but not in the basal prefrontal cortex. Future aims of this study will ganglia in a mptp mouse model of attempt to characterize the epigenetic profile in Par inson’s disease these region-specific, genetically labelled populations using fluorescent activated cell Melissa Cote¹, Catherine Lavallée¹, Benoit sorting (FACS). By combining this intersectional Aube¹, Denis Soulet¹ strategy to analyses at both the cellular and ¹CHUQ Research Center (CHUL), Québec epigenetic level, we hope to elucidate the relationship between specific interneuronal A growing body of evidence supports a critical classes and the pathophysiological changes in role for inflammation in the dysfunction of MIA. neurons in the central nervous system (CNS) and the enteric nervous systems (ENS) during 3-C-71 Investigation of TNFalpha acute and chronic insults. We investigated the signaling before amyloid overproduction in a role of inflammation in dopaminergic central and mouse model of Alzheimer's disease myenteric neuronal alterations secondary to 1- methyl-4-phenyl-1,2,3,6-tetrahydropyridine Chelsea Cavanagh¹, Remi Quirion¹, Tak Pan (MPTP) lesioning. Our results show that mice Wong¹ depleted in pro-inflammatory Ly6Chi monocytes ¹Douglas Hospital Research Center by clodronate liposome treatments were protected against the MPTP-induced loss of Alzheimer's disease (AD) develops decades tyrosine hydroxylase (TH) expression in the before clinical symptoms arise and can remain ENS. Furthermore, a strong immune response undiagnosed for years. For this reason, there is was observed in undepleted mice 5 days a need to intervene before the development of following the first MPTP injection, as cognitive symptoms. One possible culprit in the demonstrated by the prominent presence of pro- development of AD is tumor necrosis factor-α inflammatory monocytes and the production of (TNFα), a pro-inflammatory cytokine. TNFα is IL-1β and IL-6 in all the segments of the gut. 196

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However, in the CNS, both mice depleted and confirmed that RGCs in hypertensive eyes are undepleted in pro-inflammatory monocytes were more sensitive to PhTX than those in control still subjected to 25% of striatal TH loss eyes, indicative of CP-AMPA upregulation. following MPTP administration. Moreover, the Robust protection of RGC soma and axons was MPTP treatment elicited strong microglial observed using inhibitors of TNFα or CP- activation in the striatum in both depleted and AMPAR. Our data support a model in which undepleted animals. Taken together, our results TNFα-induced upregulation of CP-AMPAR plays demonstrate a critical role for pro-inflammatory a key role in RGC damage in experimental monocytes/macrophages in the gastrointestinal glaucoma. dopaminergic dysfunction in the MPTP model of Parkinson's disease. At the contrary, in the 3-C-74 The effects of focal ischemic CNS, the immune response was not impaired by lesions of the prefrontal cortex on attentional the clodronate liposome treatment, suggesting set-shifting behaviour in the rat that circulating monocytes do not reach the brain parenchyma and do not contribute to the Robert Déziel¹, R. Tasker¹ MPTP-induced toxicity. ¹University of Prince Edward Island

3-C-73 Glia-derived tumor necrosis Stroke is one of the leading causes of disability factor alpha promotes retinal ganglion cell in adults, and has been estimated to cost the death through overexpression of Canadian economy 2.8 billion dollars annually. philantotoxin-sensitive calcium permeable Further, studies examining patients three AMPA receptors. months post-stroke have found that approximately 25% of stroke survivors suffer Jorge Cueva-Vargas¹, Joseph Nemargut², from cognitive deficits. Cognitive deficits in Ingrid Osswald², Mark Aurousseau², Nicolas stroke survivors may occur because of damage Unsain², Phil Barker², Derek Bowie², Adriana to the prefrontal cortex (PFC), which has been Di Polo¹ heavily implicated in the control of higher-order ¹Research Centre of the University of Montreal cognitive functions in the brain. Therefore, an Hospital Centre (CRCHUM), ²McGill University improved understanding of the role of the PFC in cognitive dysfunction post-stroke is Tumor Necrosis Factor-α (TNFα) has been necessary. Utilizing bilateral microinjections (2 x proposed to mediate retinal ganglion cell (RGC) 1 μl) of the vasoconstricting peptide endothelin-1 death in glaucoma, but its mechanism of action (ET-1) (400 pmol) into the medial PFC in adult is unknown. Here we tested whether TNFα male SD rats (N=12/group) we produced enhances cell surface expression of calcium localized ischemic lesions in the PFC (or sham) permeable AMPA receptors (CP-AMPAR) thus and the effects of these lesions on cognition increasing the vulnerability of RGCs to were assessed using a colour-texture glaucomatous damage. Ocular hypertension discrimination attentional set-shifting task. (OHT) was induced in rats by injecting Following testing, rats were euthanized and hypertonic saline into an ocular episcleral vein. lesion location and volume was confirmed via TNFα, TNFR1/2, and AMPAR GluA2 subunit cresyl violet stain. During the set shifting aspect expression was examined by RT-PCR, western of the test, animals shifting attention to colour blot and immunohistochemistry. Expression of from texture reached criterion faster than CP-AMPAR was assessed by cobalt staining animals shifting attention to texture from colour. assays. Electrophysiological responses were Further analysis revealed a difference in the rate examined by whole-cell patch-clamping. RGC of learning between stroke and sham animals soma and axon density were assessed on flat- for this aspect of the test. This model shows mounted retinas or optic nerve cross sections, potential in examining post-ischemic cognitive respectively. Our data demonstrate that TNFα deficits in rats, and future experiments are and TNFR1/2 levels increase early after OHT required to further refine the model and to test induction and remain elevated with disease other aspects of higher order cognitive progression. TNFα was detected in microglia functioning post-stroke. and Müller cells of glaucomatous retinas. Cobalt uptake through CP-AMPAR, observed in RGCs 3-C-75 Spatial characterization of subjected to OHT, was blocked by philantotoxin optogenetically induced seizures (PhTX). While the GluA2 subunit was edited at the Q/R site, the level of GluA2 in RGCs was Joshua Dian¹, Peter Carlen¹, Taufik Valiante¹ markedly reduced. Electrophysiological data ¹University of Toronto 197

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previously implicated in mitochondrial quality Synchrony of the local field potential (LFP) in control, is critical for parkin-mediated mitophagy. addition to single unit - LFP synchrony are USP8 preferentially removes non-canonical K6- characteristic features of epileptic seizures in linked ubiquitin chains from parkin, a process rodent seizure models and in clinical epilepsy. required for the efficient recruitment of parkin to The role synchronization plays in the initiation depolarized mitochondria and for their and termination of seizures remains unresolved. subsequent elimination by mitophagy. This work Here we exploit mouse lines expressing uncovers a novel role for USP8-mediated channelrhodopsin-2 (ChR2) in cortical deubiquitination of K6-linked ubiquitin interneurons under the control of the vesicular conjugates from parkin in mitochondrial quality gamma-aminobutyric acid transporter (VGAT) to control. induce interneuronal synchrony in the network and investigate the critical transitions that 3-C-77 Peptide-mediated degradation of underlie ictogenesis. Cortical brain slices from a death-inducing kinase as a therapy for VGAT-ChR2 mice were stimulated using a 470 stroke nm fiber coupled light emitting diode (LED) and the LFPs recorded using a 60-channel multi Xuelai Fan¹, Wu Yang Jin¹, Jie Lu¹, Yu Tian electrode array. Seizure like events (SLEs) were Wang¹ reliably initiated with optical stimulation while the ¹University of British Columbia slice was perfused with 4-Aminopyridine (4-AP) containing artificial cerebrospinal fluid (ACSF). Despite the massive socioeconomic toll of the We show putative pyramidal cells synchronously ischemic stroke, there is currently no effective fire at the onset of both light induced and neuroprotectant available for clinical use. spontaneous SLEs and their firing patterns Recent efforts have identified death-associated appears to be a characteristic feature of seizure kinase 1 (DAPK1) as a key mediator of ischemic initiation. In accordance with seizures observed cell death. Following an ischemic insult, DAPK1 in humans and rodents, pyramidal cell firing was activates and binds to the GluN2B subunit of the synchronous with the low frequency LFP. We NMDA Receptor (NMDAR) and enhances further demonstrate layer specific activation NMDAR-mediated currents and excitotoxicity. patterns which rapidly diverge after light induced DAPK1 is also involved in mediating cell-death synchronization. Finally we use of focal 470nm through non NMDAR-mediated oxidative stress. light stimulation to generate SLEs and explore In an effort to reduce ischemic brain injury, we the propagation dynamics of these SLEs within fashioned a blood brain barrier and cell the slices. membrane permeant peptide TAT-GluN2BCTM which, when systemically administered in the 3-C-76 USP8 Regulates Mitophagy by MCAo rat model of ischemia, efficiently knocks Removing K6-linked Ubiquitin Conjugates down active (but not inactive) DAPK1 through from Parkin chaperone-mediated autophagy. A single intravenous injection of 10mg/kg TAT- Thomas Durcan¹, Matthew Tang¹, Edward GluN2BCTM (but not control TAT-GluN2B) 1h Fon¹ post reperfusion specifically knocked down ¹Montreal Neurological Institute, McGill DAPK1 only in brain areas affected by the insult, University including the ipsilateral striatum and nearby cortex as visualized with hematoxylin and eosin Mutations in the Park2 gene, encoding the E3 staining. Most significantly, the specific ubiquitin-ligase parkin, are responsible for a knockdown of DAPK1 by TAT-GluN2BCTM was familial form of Parkinson´s disease (PD). associated with a much more substantial Parkin-mediated ubiquitination is critical for the reduction of the infarct area and fewer number efficient elimination of depolarized dysfunctional of degenerating neurons in comparison with that mitochondria by autophagy (mitophagy). As provided by uncoupling DAPK1 from the damaged mitochondria are a major source of GluN2B receptor signaling complex with TAT- toxic reactive oxygen species within the cell, this GluN2B. Together, these data point to DAPK1 pathway is believed to be highly relevant to the as a key target for the intervention of pathogenesis of PD. Little is known about how neurotoxicity and illustrate peptide-mediated parkin-mediated ubiquitination is regulated degradation of death-promoting proteins as a during mitophagy or about the nature of the new avenue to develop therapeutics for stroke. ubiquitin conjugates involved. We report here that USP8/UBPY, a deubiquitinating enzyme not 198

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3-C-78 Age-Related Changes in Working remodeling through activation of the RhoA Memory in the Hebb-Williams Maze in the GTPase. RhoA plays a central role in blocking Triple Transgenic Mouse Model of axon regeneration and has been targeted in Alzheimer's Disease clinical trials for spinal cord injury. We have found that RhoA is processed through Emre Fertan¹, Richard Brown¹ proteolytic cleavage to generate a stable 10kDa ¹Dalhousie University amino terminal fragment. We are studying this process to understand how this may affect RhoA The 3xTG-AD mouse model of Alzheimer's activity. Our studies revealed that RhoA disease (AD) has three mutations, two proteolysis occurs preferentially for active RhoA associated with AD, APPSwe, PS1M146V, and and that this process is dependent on one with tau pathology, tauP301L. 3xTG mice prenylation and phosphorylation. Further, develop intracellular plaques at 3 months of age, inhibitors of Calpains and Caspases stabilize the followed by extracellular plaques at six months, amino terminal RhoA fragment. We have and tau tangles by 12 months of age. Previous mapped the RhoA cleavage site and generated research using 3xTG mice demonstrated a cleavage-resistant RhoA construct. impairments in spatial learning at six months of Overexpression of wild type or cleavage age. However, there has not been any reported resistant RhoA is sufficient to induce stress fiber progression of deficits from six to twelve months formation in serum-starved fibroblasts. of age in these mice. We used the Hebb- Overexpression of the amino terminal RhoA Williams (H-W) maze to assess spatial learning fragment induces mild stress fiber formation and memory in 3xTG mice at 7 months of age. while overexpression of the carboxy terminal The H-W maze is an open field with start and RhoA fragment leads to the formation of nuclear goal boxes located at opposite corners. Barriers actin rods, a hallmark of cellular stress observed of various lengths are arranged to design in conditions of neurodegeneration. Our findings different mazes that the mouse has to solve in describe a novel mechanism for processing order to find food reward. The H-W maze has RhoA, which affects actin cytoskeletal multiple levels of difficulty, with 12 maze designs remodelling. Future work will focus on the role of in total, four in each group of easy, intermediate RhoA cleavage in neurons. and hard mazes. In previous studies using the H-W maze, mice with limbic lesions performed 3-C-80 Age-dependent tau worse than control mice (Meunier at al., 1986). hyperphosphorylation and deregulation of We found that the 3xTG mice made significantly PP2B in Huntington mice models more errors than wild type mice in only the hard mazes. Our results support the previously Maud GRATUZE¹, Anastasia Noel¹, Philippe reported spatial memory deficit in 3xTG mice at Millot-Rousseau², Françoise Morin¹, François seven months of age compared to their wild type Bezeau¹, Pershia Samadi¹, Emmanuel Planel¹ controls. However this difference may be ¹CHUL (Université Laval), ²Université Laval smaller than previously reported. Our results emphasize the value of behavioural tests with Background:Huntington disease (HD) is an multiple levels of difficulty such as the H-W autosomal dominant neurodegenerative disorder maze, which are more sensitive at detecting caused by a polyglutamine expansion in the N- smaller cognitive deficits. terminal region of the huntingtin protein. HD is characterized by proteolytic cleavage, misfolding 3-C-79 RhoA proteolysis: A novel and aggregation of huntingtin, leading to mechanism for RhoA regulation and its neuronal death, primarily in the spiny neurons of possible applications for CNS regeneration the striatum, but also in structures involved in cognition. Aggregates of hyperphosphorylated Marie-Pier Girouard¹, Alyson Fournier¹ tau proteins are characteristic of a class of ¹Montreal Neurological Institute neurodegenerative disease called tauopathies, including Alzheimer's disease. HD is not a Traumatic injuries to the central nervous system tauopathy, but there are several articles have devastating and persistent clinical reporting limited tau pathology in HD patients. consequences as a result of the failure of injured These observations prompted us to axons to spontaneously repair themselves. Axon hypothesized that HD pathology might promote repair is impeded by inhibitory molecules at the tau hyperphosphorylation. Methods:To test this injury site, which bind to receptors on axonal hypothesis, we used two well-characterized surface and signal inappropriate cytoskeletal models of HD (R6/2, Q175), and analyzed tau 199

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 phosphorylation. Results:We found that before brain volume is due to the activity of D2-like the onset of HD symptoms, mice present a slight receptors, commonly targeted by typical APs, or elevation of tau phosphorylation compared to whether these changes might involve alternate controls. After the onset of symptoms, mice mechanisms. To understand the cellular basis of displayed tau hyperphosphorylation at multiple volume changes, stereological analysis of epitopes. There was no activation of tau kinases neuronal and glial populations will be performed examined that could explain this in the brain areas showing significant variations. hyperphosphorylation. However, when we examined tau phosphatases, we found that 3-C-82 Reduction of 2-4 Hz coherence PP2B was extremely downregulated. Moreover, between the hippocampus and prefrontal inhibition of PP2B in cells promoted tau cortex following chronic prefrontal cortex hyperphosphorylation. Conclusion:Our data stimulation suggest that, in R6/2 and Q175 mice, mutant huntingtin lead to deregulation of PP2B and Maryna Pilkiw¹, Nathan Insel², Jose consequent tau hyperphosphorylation, and that Nobrega², Kaori Takehara-Nishiuchi¹, the mild tau pathology seen in HD might, to Clement Hamani² some extent, stem from impaired PP2B ¹University of Toronto, ²Centre for Addiction and regulation. Mental Health

3-C-81 Effects of chronic typical and Many psychiatric disorders likely result from a atypical antipsychotic treatment on mouse breakdown of communication in particular brain brain volume: a longitudinal magnetic pathways, but others may stem from resonance imaging study pathologically high communication levels. Hyperactivity of the ventral medial prefrontal Elisa Guma¹, Jill Rocchetti¹, Axel Mathieu², cortex (vmPFC) has been observed in patients Blandine Courcot², Pinkal Patel¹, Bruno suffering from depression. This can be treated, Giros¹ with associated depression symptoms, by focal ¹Douglas Research Center, ²Douglas Brain electrical stimulation ("deep brain stimulation", Imaging Center or DBS). The effects of DBS on communication between the vmPFC and other brain regions Longitudinal MRI studies have consistently remain unknown. The present study examined shown that patients suffering from schizophrenia the effect of DBS on communication between exhibit decreases in brain volume over the the rat ventral hippocampus and vmPFC by course of the illness. However, these patients measuring coherence of local field potentials are often treated with antipsychotic (AP) (LFPs). Rats received daily treatments of medication. Thus, it is difficult to determine vmPFC DBS (100 µA pulsed at 130 Hz) or sham whether the changes are related to the disorder, stimulation. Recordings were conducted in to the effects of the medication or both. Using unrestrained, behaving animals on the day animal models allows for a more ethical before treatment, 1 to 10 days of treatment, and assessment of the effect of AP treatment on 10 days after stimulation ended. Coherence brain volume, without interference of the between the two regions was high in the 6 to 10 pathology. Naïve C57BL/6J mice received daily Hz (theta) range, which could be further evoked intraperitoneal injections of saline or haloperidol by auditory stimulation; however, this was not (HAL) (0.5mg/kg/day) for 9 weeks. Animals were affected by DBS. In contrast, coherence in the 2 scanned using a Brücker 7T small MRI scanner to 4 Hz band was reduced following 10 days of before starting treatment, then at 3, 6 and 9 DBS (p = 0.009). Coherence at 2-4 Hz was not weeks to assess volumetric changes in the related to rats' movement speed, suggesting whole brain and predefined subregions. In that the physiological changes took place accordance with previous studies done in rats, independent of behavior. Physiological patterns this treatment lead to a decrease in pre-frontal in the 2 to 4 Hz band have been previously cortex volume. With access to D2 and D3 associated with dopamine activity; the data may dopamine (DA) receptor knockout transgenic therefore have implications for how frontal strains, we aim to assess the role that D2-like cortex DBS affects the dopaminergic system DA receptors may play in the brain volume and its feedback on hippocampal-prefrontal changes associated with AP use. The effect of a processing. typical - HAL - and a D2-independant atypical AP - clozapine - in D2KO and D3KO mice will 3-C-83 Abnormal Myelination during allow us to better understand if the decrease in Brain Development in Fragile X Mice 200

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neurodegenerative phenotypes associated with David Jiang¹, Laura Pacey¹, David Hampson¹ Huntington's disease allow identifying ¹University of Toronto mechanisms involved in this disease. Methodology: Genetic models of polyglutamine Myelination in the mammalian brain is mainly a (polyQ) toxicity and lines having mutations in postnatal process. It begins in the brainstem and orthologous genes for TDP-43, FUS and cerebellum and then proceeds rostrally over progranulin in C. elegans, polyQ striatal cell several weeks in rodents, and over years in lines with 111 repeats and the polyQ Q175 humans. Fully intact and mature myelin sheaths mouse model were used. Results: In C. elegans, are obligatory the normal firing and we observed that mutations leading to loss of differentiation of neurons. Thus, myelination, function for orthologous genes TDP-43 and FUS neuronal firing, and neuronal differentiation are reduced behavioural deficits and intimately linked to each other, and impaired neurodegeneration caused by polyQ toxicity. myelination may impact negatively on neuronal Moreover, we found that TDP-43 and development. We have reported that FMRP co- progranulin genetically interact for regulating localizes with oligodendrocyte precursor cells in polyQ toxicity and that progranulin protects from the immature CNS, and that myelination in the toxicity associated with mutant huntingtin in C. Fmr1 fragile X knockout mouse cerebellum is elegans. Furthermore, in the Q175 mice, we delayed compared to wild-type mice (Pacey et observed an increase of TDP-43 levels and al., 2013). Markers for myelination eventually decreases of FUS and progranulin levels. Also, reach normal (wild-type) levels around 3-4 quantitative PCR revealed changes in weeks after birth in the Fmr1 mouse. The expression of genes involved in the endoplasmic consequences of this delay in brain maturation reticulum stress response. are not understood. Our recent studies have Discussion/conclusion: TDP-43 and FUS seem focussed on assessing which brains regions (in to be key actors in polyQ toxicity and addition to the cerebellum) are affected by progranulin could act play a crucial role, abnormal myelination, whether other types of enabling a potential therapeutical target of glia show abnormalities during maturation, and Huntington's disease. Funding: CIHR (AP, CJ), whether Fmr1 mouse myelination responds CIHR-Huntington Society of Canada (AT), differentially to stress compared to control mice. CHUM Foundation, ALS Canada. We have observed that astrocytes are "activated" in the immature brain, and that this 3-C-85 Ceramidase Activity is Required appears to be a permanent feature of the Fmr1 for the Neurotoxic Effects of a Lipid Second mouse brain. Further studies are being Messenger Molecule Elevated in Alzheimer's conducted to examine the relationship between Disease these parameters (oligodendrocytes, astrocytes, and stress) in the mouse model of fragile X Michael Kennedy¹, Yun Wang¹, Hongbin Xu¹, syndrome. Kenneth Gable², Teresa Dunn², Kristin Baetz¹, Steffany Bennett¹ 3-C-84 Endoplasmic reticulum stress, ¹University of Ottawa, ²Uniformed Services TDP-43, FUS and progranulin involvement in University of the Health Sciences models of Huntington’s disease Alzheimer´s disease (AD) is associated with Carl Julien¹, Arnaud Tauffenberger¹, Julie distinct changes to the lipid profile of the brain. Veriepe¹, Sarah Peyrard¹, Babykumari The consequence of these apparent alterations Chitramuthu², Andrew Bateman², Hugh in lipid metabolism upon neuronal cell function Bennett², Alex Parker¹ and viability are not well understood. Previously ¹CRCHUM; Université de Montréal, ²Endocrine we have reported that elevating intraneuronal Research Laboratory, Royal Victoria Hospital concentrations of the AD-associated and Department of Medicine, McGill University glycerophosphocholine second messenger, PC(O-16:0/2:0) or C16 platelet activating factor Introduction: Cytoplasmic accumulations of (C16 PAF), is sufficient to induce endoplasmic TDP-43 and FUS are observed in multiple late- reticulum stress and neurotoxicity. Subsequent onset pathologies including Huntington's studies in Saccharomyces cerevisiae have disease. However, how these pathological suggested that the toxic effects of PC(O- accumulations occur remains poorly known. 16:0/2:0) are, in part, due to a disruption in Objective: The study of TDP-43 and FUS ceramide metabolism. Utilizing the genetic contribution and the impact of progranulin on tractability of S. cerevisiae we have now 201

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 identified the alkaline ceramidase orthologues, group. In the HAB group, the elevated Vt YPC1 and YDC1, as critical mediators of the occurred in the striatum, putamen, thalamus, as PC(O-16:0/2:0)-induced changes in ceramide well as left frontal, left temporal, and occipital metabolism and toxicity in yeast which led us to cortices. This is the first study to demonstrate examine whether similar changes may occur in that only PD patients expressing the genotype neurons. Profiling of the ceramide lipid species for high affinity binding for [18F]-FEPPA by mass spectrometry revealed a significant presented elevated microglial activation increased in most species following a 24 h compared to HCs. Our preliminary data suggest treatment of terminally differentiated hNT cells. that this radioligand may provide new evidence Furthermore, a small molecule inhibitor of of an interaction between TSPO genotype and ceramidase (Ceranib-2), but not ceramide microglial expression in PD pathology. synthase activity (Fumonsin B1), protected neurons from the neurotoxic effects of PC(O- 3-C-87 Investigation of 16:0/2:0) over a 24 h period. In conclusion, our neurotransmission and synapse data support an unappreciated role for maintenance in cultures from G2019S knock- ceramidase activity in mediating neuronal in mice toxicity associated with pathological levels of PC(O-16:0/2:0). Naila Kuhlmann¹, Igor Tatarnikov¹, Dayne Beccano-Kelly¹, Patrick Chou¹, Daisy Cao¹, 3-C-86 Elevated microglial activation in Katherine Yu¹, Matthew Farrer¹, Austen PD patients expressing a polymorphism for Milnerwood¹ high- affinity binding for [18F]-FEPPA in ¹University of British Columbia striatal and extra-striatal regions: A PET study Parkinson's disease (PD) is the second most common neurodegenerative disease, with Yuko Koshimori¹, Ji Hyun Ko², Rostom mutations in the Leucine-rich repeat kinase 2 Mabrouk¹, Leigh Christopher¹, Romina (LRRK2) protein being the most common known Mizrahi¹, Pablo Rusjan¹, Anthony Lang³, Alan cause. The LRRK2 G2019S mutation alone Wilson¹, Sylvain Houle¹, Antonio Strafella¹ accounts for up to 30% of all cases in some ¹Centre for Addiction and Mental Health, populations. Whilst the physiology of LRRK2 is University of Toronto, ²Feinstein Institute for poorly understood, it has been implicated in Medical Research, ³Toronto Western Hospital, synaptic transmission and dendritic morphology. UHN, University of Toronto Previous findings suggest that LRRK2 mediates glutamate release in simple model systems, but Microglial activation has been implicated as a this has yet to be examined in a LRRK2 mutant potential mechanism for the disease progression mouse model. We investigated synaptic and producing non-motor symptoms of PD. It transmission in primary cortical cultures from can be quantified in vivo using PET radioligands non-transgenic and G2019S knock-in (KI) mice. targeting for 18kDa translocator protein (TSPO). Patch clamp recordings were conducted in Second-generation TSPO radioligands including mature neuronal cultures. We measured [18F]-FEPPA may present three binding affinity miniature excitatory/inhibitory currents to phenotypes: High affinity binders (HABs), low estimate receptor numbers/responsiveness affinity binders (LABs) and mixed-affinity binders (amplitude) and release probability (frequency). (MABs). These phenotypes can be predicted by Staining for pre- and postsynaptic markers was genotyping one polymorphism (rs6971) in the used to determine synaptic density. Western TSPO gene. Here, we have investigated the role blotting was also performed to identify changes of microglial activation in PD pathology using in levels of neurotransmitter receptors, synaptic [18F]-FEPPA. Forty subjects were included in markers, and LRRK2 itself. We observed the study. Total distribution volume (VT) values, alterations to both excitatory and inhibitory obtained using an unconstrained two- transmission in the presence of the G2019S compartment kinetic model were compared mutation. Our results suggest that mutant between PD and healthy controls (HCs) LRRK2 disrupts neural transmission within matched for the binding affinity phenotypes. cortical networks, highlighting the benefit of There were 25 HABs (13 PD and 12 HCs), 12 further characterization of this model. We hope MABs (6 PD and 6 HCs) and 3 LABs (3 PD). PD to determine the mechanistic defect conveyed patients showed significantly elevated VT values upon LRRK2 by this mutation, and the potential compared with HCs in the HAB group while no consequences for PD. Subsequent research will difference in VT value was observed in the MAB 202

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 focus on LRRK2 in synaptic connectivity and Autism spectrum disorders (ASD) are a class of plasticity in corticostriatal co-cultures. life-long neurodevelopmental disorders. Their diagnostic criteria consist of impaired social 3-C-88 Elevated NKG2D and NKG2D interactions, restricted interests, and repetitive ligands expression in a mouse model of behaviours. In addition to the diagnostic multiple sclerosis (EAE) features, patients with ASD are found to have increased risk for seizure. For example, while Laurine Legroux¹, Camille Pittet¹, Chanel 30% of ASD cases are reported to develop Cadieux-Dion¹, Alma Nazlie Mohebiany¹, seizure, epileptiform activity is reported in 60% Diane Beauseigle², Nathalie Arbour¹ of patients with ASD during sleep. Despite the ¹Université de Montréal CRCHUM high risk of seizure development in ASD, its molecular basis remain elusive. Alterations in Multiple sclerosis (MS) is an inflammatory the excitability of neuronal networks has been disease of the central nervous system. proposed as a key contributor to ASD as well as Hallmarks of MS lesions include injury to seizure. Neuroligins (NL), which are a family of oligodendrocytes and axonal loss. NKG2D is an postsynaptic cell adhesion proteins, were shown activating (co)receptor expressed by numerous to be important for the proper maintenance of immune effector cells. Our laboratory has neuronal excitation/inhibition balance, and their previously shown that: 1) oligodendrocytes mutations have been linked with ASD. The express ligands of NKG2D (NKG2DL) in MS present study aims to examine the role of lesions but not in controls; 2) CD8 T cells in MS neuroligins in seizure development. We lesions are detected in close proximity to observed that deletion of NL2 is linked with an NKG2DL expressing cells. We have also occurrence of abnormal rhythmic theta previously established that disruption of the discharge that resembles electrographic NKG2D-NKG2DL interaction inhibits killing of seizures. human oligodendrocytes by immune cells. These results imply that NKG2D-NKG2DL 3-C-90 The role of NOD-like Receptor interaction can contribute to cytotoxic response Nlrp12 in Multiple Sclerosis mediated by immune effector cells in the inflamed CNS, as observed in MS. Our goals Tara M. Mahvelati¹, Emilie Imbeault¹, Salah are to characterize the in vivo role of NKG2D Rahmani¹, Denis Gris¹ and its ligands in experimental autoimmune ¹Sherbrooke University encephalitis (EAE) mice. To determine qualitatively and quantitatively NKG2D/NKG2DL Multiple Sclerosis (MS) is a disease that affects expression during the development of EAE we the central nervous system as well as the spinal use flow cytometry, qPCR and cord resulting in the presence of demyelinating immunohistochemistry. We observed that plaques. Several molecular pathways have been NKG2D ligands are upregulated in the CNS identified as potential targets for therapeutic during the development of EAE. Microglia and interventions in MS such as NF-κβ and neurons from EAE animals express elevated nucleotide‐binding leucine‐rich repeat‐containing levels of NKG2DL compared to controls. proteins (Nlrs). Nlrs are regulatory proteins of Moreover, a greater proportion of T cells that the immune system. Once activated, these have infiltrated the CNS express NKG2D proteins trigger pro‐inflammatory pathways for compared with cells from other organs. Our example activation of NF‐κβ pathways. Newly results suggest that NKG2D and its ligands discovered Nlrp12 has been shown to inhibit could play a role in the development of EAE. We inflammation by suppressing NF‐κβ activity. To will use different strategies to block NKG2D at evaluate the hypothesis that Nlrp12 plays an different disease states to clearly establish anti-inflammatory role in MS, we used a well‐ whether NKG2D is a relevant therapeutic target. characterized mouse model of MS, Experimental Autoimmune Encephalomyelitis. 3-C-89 The role of neuroligins in the Immunization of C57BL/6 female mice with generation of abnormal rhythmic theta MOG35-55:CFA, demonstrated Nlrp12 knockout discharges in EEG recordings (KO) mice to have an aggravated form of the disease. Also, the disease started earlier in KO Jackie Liu¹, Miguel Cortez², Zhengping Jia² and was characterized by higher clinical scores ¹University of Toronto, ²Hospital for Sick compared to Wild-Type (WT) mice. An increase Children in the expression of pro‐inflammatory genes (mip3α, Cox2, IL‐1β Ccr5) were seen in KO 203

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 compared to WT mice. In vitro stimulation of ¹University of Toronto primary microglial cells with LPS demonstrated an increase in the expression of iNOS in KO Introduction: Patients with injuries to the mice. Griess reagent assay showed more thoracolumbar region of the spinal cord often nitrates secreted in the media from KO mice. lose neurons essential for locomotion. Our focus Additionally, purified microglia from KO mice is on replacing lost circuitry by transplanting treated with LPS for 12 hours demonstrated adult spinal-derived neural stem/progenitor cells significantly more pro-inflammatory cytokines (NSPCs) that have been differentiated into TNF‐α and IL‐6. Moreover, photomicrograph of neurons in vitro. We hypothesize that optimal spinal cord showed enhanced astrogliosis in KO differentiation of NSPCs in vitro towards a compared to WT mice. neuronal lineage will promote transplant survival and functional recovery after transplantation in 3-C-91 Nucleus accumbens DNA the injured lumbar spinal cord. Methods: NSPCs methylation states determine cocaine were treated with 1mM dibutyryl-cyclic AMP craving (dbcAMP) to enhance neuronal differentiation and stained with BIII tubulin to confirm neuronal Renaud Massart¹, Royi Barnea², Yahav character. 40 (Wi) rats were injured with a 26g Dikshtein², Matthew Suderman¹, Oren Meier², clip and split into 4 treatment groups: (1) Moshe Szyf¹, Gal Yadid¹ dbcAMP treated cells + Rolipram injection (RI) ¹McGill University, ²Bar-Ilan University post-op, (2) dbcAMP treated cells + saline injection (SI), (3) untreated cells + RI ,(4) media Cocaine addiction is characterized by a pattern injection control + SI. Four hundred thousand of cyclic binges. Indeed, a withdrawal period cells were transplanted 1mm rostral and caudal following a cocaine abuse phase, progressively to the injury site in the subacute phase of injury. leads to high craving and resumption of the Results: DbcAMP robustly differentiated NSPCs drug. Usually, relapse, which is the major clinical towards BIII positive neurons: 72%±6.3. In the problem in the treatment of cocaine addiction, is transplant study, rats in the double treatment elicited during this incubation period by re- group (dbcAMP cells + RI) improved to a exposure to a cue previously associated with statistically significant (p<0.05) average of cocaine intake. Mechanisms underlying 5.16(±3.2) compared to dbcAMP + saline = progression to high craving during the 2.2(±1.5), untreated cells + RI = 1.1(±1.07) or withdrawal period are poorly understood. We control = 2.2(±1.3). Conclusion: We have show using a rat model that genome-wide DNA generated a novel pre-clinical lumbar spinal cord methylation modifications in the nucleus injury model and displayed that transplant of accumbens are associated with cocaine self- neuronally differentiated stem cells is associated administration. DNA methylation changes with an increase in functional recovery. increase over time during a withdrawal period in the absence of any exposure to cocaine, 3-C-93 Decreased mTOR signaling via paralleling the increase in craving. Interestingly, p70S6K/eIF4B is associated with loss of the application of an environmental cue, paired with excitatory postsynaptic marker PSD-95 in cocaine self-administration, reverses the DNA autism methylation changes associated with the withdrawal period. Moreover, we found that Chiara Nicolini¹, Margaret Fahnestock¹ intra-cerebral injections of DNA methylation ¹McMaster University modifying drugs modulate cocaine craving. These results suggest that DNA methylation Defects in the establishment of neuronal modifications define progression to cocaine networks are believed to be responsible for the addiction and that it might be possible to reverse clinical symptomatology of autism. However, the craving in humans using epigenetic modulators molecular mechanisms underlying the abnormal following long withdrawal periods. cortical circuitry seen in autistic brains remain to be elucidated. We previously found imbalances 3-C-92 Development of a Novel Lumbar in TrkB isoforms and decreased upstream Spinal Cord Injury Model to Examine the components of the mTOR pathway in Therapeutic Potential of Transplanting postmortem brains of autism versus control Neuronally Induced Neural Stem/Progenitor subjects. mTOR downstream signaling Cells. pathways p70S6K/eIF4B and 4E-BP1/eIF4E are involved in regulation of dendritic spines which Gray Moonen¹, Charles Tator¹ form excitatory postsynapses. Thus, we now 204

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 aimed to examine whether mTOR-mediated the cellular stress response. The transgenic signaling pathways are disrupted in autism and models allowed us to isolate chemical whether their disruption is associated with suppressors of motor defects. In particular, changes in PSD-95, a marker of excitatory several neuroleptics protected against synapses. Phospho-mTOR, mTOR, p70S6K, development of the motor phenotype and one is eIF4B, 4E-BP1, eIF4E and PSD-95 were currently in clinical trial.Together these data measured by Western blotting in postmortem provide clues to help unravel the mechanism for fusiform gyrus of 11 autism and 13 control TDP-43 toxicity that should also provide leads subjects. Significantly decreased phospho- for early drug discovery. mTOR, mTOR, p70S6K, eIF4B and PSD-95 protein levels were observed in autism versus 3-C-95 Alteration of Spreading control fusiform gyrus. Surprisingly, no Depolarization During Infarct Maturation significant changes in 4E-BP1 and eIF4E protein expression were found. Our findings show Dylan Petrin¹, David Andrew¹, Nichole decreased mTOR expression and activation and Peterson¹, Albert Jin¹ down-regulation of mTOR downstream pathway ¹Queen's University p70S6K/eIF4B in autism which might result in reduced protein translation at spines. Spine Introduction: We studied the influence of protein translation deficits are likely to adversely initiators of spreading depolarization (SD) in affect spine density as suggested by decreased mouse brain slices taken immediately and 12- PSD-95 in autistic fusiform gyrus. Changes in hours after 30-min middle cerebral artery spine density might perturb cortical circuitry and occlusion (MCAO). Method: Coronal slices (350 thus contribute to autism's cognitive and µm, C57BL6/J, n=107) were harvested behavioural deficits. immediately or 12-hr after 30-minute MCAO and superfused with oxygenated aCSF at 34C. 3-C-94 Chemical genetic screens of Oxygen-glucose deprivation (OGD), 9.7mM [K ] TARDBP modifiers in C. elegans and and 500 µM glutamate solutions replaced zebrafish control aCSF during imaging and SD events were detected as light transmittance changes. Shunmoogum Patten¹, Gary Armstrong¹, Synaptic communication was assessed with Claudia Maios¹, Dina Aggad¹, Alexandra field recordings evoked with a bipolar stimulating Vaccaro¹, Edor Kabashi², J Alex Parker¹, electrode (1 Hz, 0.25 ms) in Layer VI and Pierre Drapeau¹ recorded with a micropipette in Layer II/III in ¹Université de Montréal, ² L'Institut du Cerveau overlying cortex. Results: Immediately after et de la Moelle Épinière MCAO, OGD-initiated SD in the ischemic hemisphere in 29/29 slices, [K ] (3.2 mM and Mutations in the TARDBP gene (coding for TDP- 9.7mM) initiated SD in 12/20 slices and 43) have been reported to cause Amyotrophic glutamate initiated SD in 0/11 slices. In contrast, Lateral Sclerosis (ALS) and related dementia, 12-hr following 30-min MCAO, OGD-initiated SD but little is known about the neurotoxic in the ischemic hemisphere in 5/12 brain slices, mechanisms. We have generated C. elegans [K ] (3.2 mM and 9.7 mM) initiated SD in 3/9 and zebrafish models expressing wild-type or slices and glutamate initiated SD in 0/10 slices. mutant human TDP-43[G348C] that reflect All 12 slices harvested immediately after MCAO aspects of ALS. To explore the potential of our displayed evoked field potentials in the ischemic models in identifying chemical suppressors of brain territory, whereas only 3/8 slices displayed mutant TDP-43 neuronal toxicity, we tested a evoked responses following 12-hr of reperfusion set of compounds with potential neuroprotective (Mann Whitney U, p < 0.05). Conclusion: Both properties. We performed motility assays in SD susceptibility to OGD or elevated [K ] and zebrafish and lifespan and stress response synaptic communication are intact immediately assays in worms. We observed that TARDBP following MCAO but diminish following 12 hr of have roles in the response to oxidative and infarct maturation. Elevating glutamate does not osmotic stress. The expression of mutant TDP- promote SD at either timepoint. 43 in worm motor neurons produces robust, adult onset motility defects and in both models 3-C-96 Effect of 6-hydroxydopamine and this was caused by motor neuron deficits. We resveratrol on Nur77 nuclear to cytoplasmic isolated a number of chemical suppressors of translocation in PC12 cells mutant TARDBP toxicity. Under normal conditions TDP-43 regulates specific aspects of 205

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28

Justine Renaud¹, Mélodie Plourde¹, Cindy to form insoluble neurofibrillary tangles. The Tremblay¹, Aparna Singh¹, Maria-Grazia toxic mechanism of tau is not well understood. Martinoli¹ We hypothesize that tau's neurotoxicity is due to ¹Université of Québec in Trois-Rivières its ability to decrease trophic support for affected neurons. Brain-derived neurotrophic factor Nur77, a member of the nuclear receptors (BDNF) supports the survival of neurons that are superfamily, plays an important role in dopamine vulnerable in aging and in AD. Here we have neurotransmission and in mediating the effects used 8c-het and hTau transgenic mice to of antiparkinsonian and neuroleptic drugs. As examine the effect of excess tau on BDNF well, Nur77 survival and apoptotic roles depend expression. 8c-het mice over-express wild-type largely on its subcellular localization. human tau on a wild-type mouse tau Resveratrol (RESV), a natural polyphenol, is background, and while they exhibit increased known for its neuroprotective properties, as tau phosphorylation and more abundant 3- demonstrated in vitro and in vivo. However, its repeat tau compared to normal human brain, action on Nur77 translocation pertaining to they do not develop neurofibrillary tangles. On neuroprotection has not been investigated yet. the other hand, hTau mice which over-express The aim of our study was to perform a kinetic wild-type human tau on a null mouse tau study on the effect of neurotoxic 6- background exhibit neurofibrillary tangles similar hydroxydopamine (6-OHDA) and RESV on the to those found in AD. We have found that 8c-het subcellular localization of Nur77 with reference mice but not hTau mice show significant down- to the modulation of apoptosis in PC12 cells. regulation of BDNF mRNA compared to non- PC12 cells, a well-known catecholaminergic transgenic mice, as quantified by qRT-PCR. paradigm, were pre-treated with or without This BDNF down-regulation in 8c-het mice is RESV for 3 hours, then treated with or without 6- specific for transcript IV, the same transcript that OHDA for 0, 3, 6, 9, 12 or 24 hours. Leptomycin is decreased in AD. Our results demonstrate B, a specific inhibitor of CRM1-mediated nuclear that excess tau alone is capable of down- export, was used to confirm the effect on Nur77 regulating BDNF, show that a mutation in tau is cytoplasmic translocation. Our results not required, and suggest that soluble tau may demonstrate that 6-OHDA significantly be the toxic form. enhances cytoplasmic translocation of Nur77 after merely 3 hours while concomitantly 3-C-98 Effect of mild traumatic brain precipitating apoptosis. Interestingly, pre- injury on sleep structure and sleep treatment with RESV delays Nur77 molecular markers in mice accumulation in the cytoplasm and postpones apoptosis induced by 6-OHDA. Our findings Meriem Sabir¹, Pierre-Olivier Gaudreault¹, demonstrate an important role for Nur77 Michèle Houde¹, Valérie Mongrain¹ subcellular localization in 6-OHDA-mediated ¹University of Montreal apoptosis. Our data also highlight a novel mechanism for RESV neuroprotection in this Introduction: Subjects who experience mild catecholaminergic paradigm, relevant to the traumatic brain injury (mTBI) often complain development of new therapeutic avenues in about sleep-wake disturbances. However, sleep Parkinson's disease. serves brain recovery, and sleep disturbances may thus be deleterious to recovery after brain 3-C-97 TAU-INDUCED DOWN- injury. This study aims to evaluate the impact of REGULATION OF BDNF IN TRANSGENIC mTBI on sleep architecture and to verify that MOUSE MODELS OF TAUOPATHY sleep loss is detrimental to brain recovery following mTBI. Methods: Adult male C57BL/6J Elyse Rosa¹, Nick Déry¹, Sujeivan mice were submitted to mTBI or sham surgery. Mahendram¹, Margaret Fahnestock¹ EXP 1: Sleep was recorded by ¹McMaster University electroencephalography starting 14-16 hours post-mTBI and vigilance states were analyzed Tau is a microtubule binding protein that can be for a first 24 hours. EXP 2: Mice were submitted altered by various post-translational to 2 consecutive 6 hours sleep deprivation (SD) modifications to result in the primary toxic during the light period, and their brain was then species of neurodegenerative diseases known sampled for quantification of mRNA levels of as tauopathies. In one such tauopathy, genes associated to sleep regulation or plasticity Alzheimer's disease (AD), soluble tau is (Arc, Homer1a, Hif1A, Bdnf, Fos, EfnA3, EfnB3, hyperphosphorylated and eventually aggregates EfnB2, Dnajb5, Fgf1, EphA4, EphB2) in the 206

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 hippocampus and a region covering the mutation on Kif1a/25b isoform, from both a thalamus and hypothalamus. Results: Mild TBI fundamental and pathological perspective. increased slow wave sleep and decreased Furthermore, the mouse model generated in this wakefulness in the first 24 after mTBI. In the project will serve as a paradigm for testing future thalamus/hypothalamus, SD decreased the HSANII therapeutics treatment. expression of Fos in both mTBI and sham mice, and of Homer1a only in mTBI mice. In the 3-C-100 The Effects of Sepsis on the hippocampus, SD decreased the expression of Neurons of the Osmoregulatory Pathway EfnB3 in all animals but decreased the expression of Arc and EfnA3 only in mTBI mice. Jerneja Stare¹, Shidasp Siami², Eric Trudel¹, Conclusion: The results suggest that mTBI Masha Prager-Khoutorsky³, Tarek Sharshar⁴, affects the duration of sleep without having a Charles Bourque³ major effect on gene expression in the ¹McGill University , ²Sud Essonne Hospital, thalamus/hypothalamus. Gene expression will ³McGill University Health Center, ⁴Raymond next be quantified in the cerebral cortex. Poincaré teaching Hospital and University of Versailles Saint-Quentin en Yvelines 3-C-99 Generation of a novel mouse model of the neuronal isoform Kif1a/25b to The osmoregulatory pathway of the study hereditary sensory & autonomic hypothalamus is a vital system for the neuropathy type II maintenance of plasma osmolality. Hyperosmolality stimulates the osmosensor Jean-Francois Schmouth¹, Daniel Rochefort², organum vasculosum of the lamina terminalis Pascale Hince², Jeffrey Mogil2, Patrick Dion¹, (OVLT), which in turn stimulates the supraoptic Guy Rouleau² and paraventricular nuclei (SON; PVN) to induce ¹Université de Montréal, 2McGill University release of vasopressin (antidiuretic hormone) into the bloodstream. In sepsis (a systemic Problematic: Hereditary sensory & and immune response to a severe bacterial autonomic neuropathy II (HSANII) is an early- infection), this pathway is severely disturbed by onset, autosomal recessive disorder hypovolemia and hypotension which leads to characterized by a loss of perception to pain, organ failure and death. Several studies have touch, and heat that results in severe debilitating shown that vasopressin levels do no complications. Our group reported truncating appropriately adjust in septic shock despite mutations in HSANII patients of a KIF1A severe hypotension or hyperosmolality, and that nervous-system specific isoform; KIF1A/25B osmotic thirst sensation is defunct. We (Kinesin Family member 1A/Isoform 25B). This hypothesized that septic shock irreversibly report was the first identifying a pathology impairs the osmosensory activity of OVLT associated with truncating mutations of neurons, thereby disrupting the osmotic KIF1A/25B, from which the functional information pathway. We used an acute model mechanism leading to HSANII remains of the cecal ligation and puncture (CLP) surgery unknown. We hypothesized that truncating to induce sepsis in male rats. Extracellular mutations in KIF1A/25B trigger degeneration of single unit recordings from hypothalamic myelinated axons in the peripheral nervous explants indicate a prominent loss of system, leading to nociception defects in spontaneously active neurons (p<0.005) and affected patients. Methods: To investigate the response to hyperosmotic stimulation in the effect of KIF1A/25B truncating mutations in septic OVLT (p<0.05). Whole cell patch clamp HSANII development, we will generate a mouse recordings indicate that a change in the model harbouring the equivalent human excitability of these neurons is responsible for truncating deletion. The model will be generated this outcome, and not a loss of the neurons by insertion of a single T deletion at the themselves. We show that despite a deficit in conserved position in the mouse genome the OVLT, SON neurons are more (Kif1a/25bdelT/delT). Standardized nociception spontaneously active (p<0.01), and are more tests will be performed to evaluate the excitable. Understanding the mechanisms of this development of a sensory phenotype on 20 paradox has great implications for the treatment animals of different age (1, 3, 6, and 12 months) of severe sepsis. for each genotype (wild-type and Kif1a/25bdelT/delT). Significance: The mouse 3-C-101 Role of the lipid transcription model generated in this project has the potential factor SBP-1 and its down-stream genes in to inform us on the biology of a truncating 207

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 dopaminergic neurons degeneration in C. metabolism, like dietary restriction, have elegans become active areas of investigation. Work from yeast to primates has demonstrated that dietary Siavash Khalaj¹, Kunal Baxi¹, James restriction may not only increase lifespan, but MacPherson¹, Carlos Carvalho¹, Catherin also more importantly, maintain healthspan. Rankin², Changiz Taghibiglou¹ Aging societies are also burdened by the ¹University of Saskatchewan, ²University of increasing incidences of age-related diseases British Columbia including late onset neurological disorders including Alzheimer's disease, Huntington's The human transcription factor srebp-1 disease (HD) and amyotrophic lateral sclerosis regulates lipid levels within cells, partially by (ALS). Metabolic dysfunction in controlling the expression of desaturase neurodegeneration, and in particular the role of enzymes. Defects in the regulation of this gene glucose metabolism is not completely network have been linked to Parkinson's understood. To investigate the role of glucose disease and it may represent one of the factors metabolism in aging and proteotoxicity, we used leading to the degeneration of dopaminergic C. elegans transgenic models expressing neurons within the brain. The nematode C. human protein TDP-43 in the motor neurons. elegans has a homologous gene network Mutations in TDP-43 are causative for ALS consisting of sbp-1 (srebp-1) and three leading to the loss of motor neurons in patients. desaturases: fat-5, fat-6 and fat-7 whose Our transgenic TDP-43 worms display motility expression is regulated by SBP-1. To study the defects leading to age-dependent paralysis and effects of the sbp-1 regulatory network on the degeneration of GABAergic motor neurons. dopaminergic neurons (DA), transgenic strains Surprisingly, we have observed that glucose has of C. elegans were produced. Each transgenic the capacity to rescue age-dependent line overexpressed either SBP-1 itself or one of proteotoxicity and perhaps global protein its different transcriptional targets, specifically in homeostasis DA neurons that were visualized using a GFP reporter (Pdat-1::GFP). Overexpression of sbp- 3-C-103 Changes in the histone code - a 1, the regulatory gene of the network, caused loss of function mechanism resulting from degeneration in a significant number of the cytoplasmic redistribution and aggregation worms. Two of the genes whose transcription is of FUS upregulated by SBP-1: fat-5 and fat-6 did not cause significant neuronal degeneration. Michael Tibshirani¹, Katie Mattina¹, Heather Conversely, fat-7, another target of SBP-1- Durham¹ mediated transcription, was found to cause ¹Montreal Neurological Institute neurodegeneration in every worm which overexpressed it. Previous examination of the Fused in sarcoma/translated in liposarcoma fat genes in the context of lipid metabolism and (FUS/TLS) is a heterogenous nuclear embryonic development has suggested that they ribonuclear protein (hnRNP) with major roles in have overlapping functions in C. elegans. Our RNA metabolism. FUS mutations have been results indicate a difference in function not linked to ALS (ALS6) and FTLD. FUS traffics previously described for these enzymes. between the nucleus and cytoplasm, but normally appears concentrated in nuclei and at 3-C-102 Glucose influences aging, synapses; however, in ALS6, as well as in many proteotoxicity and stress response in C. other familial forms and sporadic ALS, FUS can elegans accumulate in cytoplasmic inclusions. Protein Arginine Methyltransferase 1 (PRMT1) is Arnaud Tauffenberger¹, J. Alex Parker¹ responsible for 85% of asymmetric dimethylation ¹Université de Montréal of arginine residues. This post-translational modification modulates various cellular functions In developed countries, it is believed that over such as gene transcription, signal transduction consumption of carbohydrates and fat is and nucleocytoplasmic shuttling of RNA-binding responsible for many metabolic disorders, proteins, including FUS. Using cultured motor including obesity, type 2 diabetes and coronary neurons, we have shown that PRMT1 interacts diseases. These disorders exact enormous with and methylates FUS, and influences its costs on health systems and research into intracellular localization (Tradewell et al., 2012). mechanisms and therapeutic approaches are of In those studies we noted that PRMT1 obvious importance. Conditions that reprogram redistributes with FUS. This study investigated 208

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 the consequences of PRMT1 nuclear depletion segregation and for a role in serotonin on methylation of its nuclear substrates, neurons survival specifically Arginine 3 on Histone 4, and downstream effects on transcription. In cultured Aurore Voisin¹, Nicolas Giguère¹, Guillaume motor neurons , nuclear depletion of PRMT1 Fortin¹, Salah El Mestikawy², Louis-Éric was accompanied by decreased H4R3 Trudeau¹ methylation and H3 acetylation, a downstream ¹Université de Montréal, ² Douglas Institut consequence, and decreased RNA synthesis. universitaire en santé mentale, McGill University

3-C-104 Motor unit specific synaptic A subset of serotonin (5-HT) neurons has been changes at the neuromuscular junction in an shown to release glutamate as a cotransmitter ALS mouse model due to specific expression of the vesicular glutamate transporter 3 (VGLUT3). VGLUT3 Elsa Tremblay¹, Éric Martineau¹, Danielle enhances 5-HT vesicular loading through a Arbour¹, Richard Robitaille¹ functional synergy with VMAT2, the vesicular ¹Université de Montréal monoamine transporter, in a common pool of vesicles. A recent study suggested a functional Amyotrophic lateral sclerosis is a late-onset role of glutamate corelease by dopamine neurodegenerative disease that leads to neurons in promoting their growth and survival. paralysis and eventually death in 2 to 5 years Whether VGLUT3 plays a similar role in 5-HT after the diagnosis. The loss of the neurons is undetermined. It is also unclear if neuromuscular junction (NMJ) is the first event glutamate is released by all or only a subset of in the disease process. NMJs show temporal 5-HT terminals. Using primary mouse Raphe patterns of denervation in ALS depending on the cultures, in which 5-HT neurons develop highly motor unit (MU) type: NMJs from fast-fatigable arborized axonal processes, we first tested the (FF) MUs are the first to denervate, followed by hypothesis of partial axon terminal segregation. the fast resistant and finally the slow MUs. Using immunostaining and confocal microscopy, However, no study has taken into account the we first found that contrary to 5-HT, the 5-HT different MU types when investigating reuptake transporter (SERT) was only present in neurotransmission at the NMJ in ALS. We a subset of axonal terminals; while 25 % of therefore hypothesized that NMJ function would terminals were SERT-positive at day 1 in vitro, be altered in a MU type specific manner. We 48% expressed SERT at day 7. Moreover, only used electrophysiology and a subset of SERT- and 5-HT-positive axonal immunohistochemistry to study synaptic varicosities expressed VGLUT3, with SERT and properties in two nerve-muscle preparations of VGLUT3 being mostly segregated in different SOD1G37R mice and their wild-type (WT) axonal domains. Finally, using a VGLUT3 littermates: the slow-twitch Soleus and the fast- knockout mouse, we found that VGLUT3 gene twitch extensor digitorum longus (EDL). At a deletion did not impair the axonal and dendritic presymptomatic stage (P140), synaptic strength growth of cultured 5-HT neurons but reduced was already altered in SOD1 mice where FF their survival by approximately 15%. We NMJs of the EDL and slow NMJs of the Soleus conclude that Raphe 5-HT neurons express had respectively a lower and a higher quantal SERT and VGLUT3 in segregated axonal content compared to WT. Long-term synaptic terminals and that VGLUT3 may regulate the plasticity was also reduced in the EDL. At a vulnerability of these neurons. symptomatic age (P380), differences in quantal content were still present in innervated NMJs of 3-C-106 Developmental abnormalities in both muscles. Taken together, these results the cerebellum of spinocerebellar ataxia type reveal that NMJ physiology is altered in ALS 6 mice according to MU selective vulnerabilities. This study provides insights for a better Sriram Jayabal¹, Alanna Watt¹ understanding of NMJ function during the ¹McGill University disease that is essential for the development of a proper NMJ-targeted treatment in ALS. Spinocerebellar ataxia type 6 (SCA6) is a neurodegenerative disorder caused by a 3-C-105 Vesicular glutamate transporter polyglutamine tract expansion in the P/Q-type 3 expression in Raphe serotonin neurons: calcium channel that eventually causes evidence for transmitter phenotype degeneration of cerebellar Purkinje cells. Although P/Q channels are required for the 209

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 proper refinement of climbing fiber synapses on significantly smaller, compared to controls. In Purkinje cells in the developing cerebellum the pilocarpine rats treated with sunitinib, the (Miyazaki et al., 2004), disease onset occurs in hippocampi sizes were not anymore significantly adulthood in SCA6. To determine if cerebellar different, compared to controls. Of note, the development is altered in SCA6, we used a control animals treated with sunitinib had recently described SCA6 mouse model significantly smaller hippocampus areas, containing a hyperexpanded polyglutamine tract compared to controls. Ratios to the whole in P/Q channels (SCA684Q; Watase et al., hemisphere follow the same trends. Blocking 2008). We made whole-cell patch clamp angiogenesis immediately following the initial recordings from Purkinje cells in acute sagittal insult may prevent the development of slices from cerebellar vermis from juvenile hippocampal atrophy in this animal model. SCA684Q and litter-matched wildtype (WT) However, using this medication in normal mice, and evoked excitatory post-synaptic animals may have deleterious effects. currents (EPSCs) in Purkinje cells by stimulating climbing fibers extracellularly. At a 3-C-108 A new animal model of developmental stage when the majority of WT spontaneous autoimmune peripheral Purkinje cells normally receive input from only polyneuropathy: implications for Guillain- one or two climbing fibers (P10-13; 15% of WT BarrÈ syndrome cells innervated by > 2 climbing fibers, N = 19), significantly more Purkinje cells from SCA684Q Mu Yang¹, Anthony Rainone¹, Xiang Qun mice were multiply innervated by climbing fibers Shi¹, Sylvie Fournier¹, Ji Zhang¹ (47% innervated by > 2 climbing fibers, N = 17; ¹McGill Univeristy P<0.005, Wilcoxon rank sum test). Our findings show that circuit alterations occur in the Background: Spontaneous autoimmune cerebellum during development in SCA6 mice peripheral neuropathy including Guillain-Barré long before the pathophysiology is observed. Syndrome (GBS) represents as one of the serious emergencies in neurology. Although 3-C-107 Role of angiogenesis in the pathological changes have been well development of hippocampal atrophy in the documented, molecular and cellular pilocarpine rat model of temporal lobe mechanisms of GBS are still under-explored, epilepsy partially due to short of spontaneous and translatable models. Results: We demonstrated Raquel Roth¹, Ruba Benini¹, Zehra Khoja¹, that B7.2 Tg/CD4-/- (L31/CD4-/-) mice exhibited Massimo Avoli¹, Pia Wintermark¹ both motor and sensory deficits, including ¹McGill University weakness and paresis of limbs, numbness to mechanical stimuli and hypersensitivity to Temporal lobe epilepsy (TLE) is a form of focal thermal stimulation. Pathological changes were epilepsy often resistant to treatment. It is known characterized by massive infiltration of to be associated with hippocampal sclerosis. We macrophages and CD8 T cells, demyelination are investigating whether blocking angiogenesis and axonal damage in peripheral nerves, while immediately following the initial insult alters the changes in spinal cords could be secondary to temporal pattern that leads to the initiation of the PNS damage. In symptomatic L31/CD4-/- chronic epilepsy and hippocampus atrophy. A mice, the disruption of the blood neural barriers rat model of chronic TLE (i.e., the pilocarpine was observed mainly in peripheral nerves. model) was used. A 60-minute status epilepticus Interestingly, the infiltration of immune cells was (SE) (initial brain injury) was induced by initiated in pre-symptomatic L31/CD4-/- mice, intraperitoneal injection of pilocarpine in adult prior to the disease onset, in the DRG and Sprague-Dawley rats. Angiogenesis was spinal roots where the blood nerve barrier is blocked pharmacologically by sunitinib for a total virtually absent. Conclusions: L31/CD4-/- mice of 14 days in some pilocarpine animals. Control mimic most parts of clinical and pathological animals were included; some of them were also signatures of GBS in human; thus providing an treated with sunitinib. Animals were sacrificed 3 unconventional opportunity to experimentally weeks after SE, and their brains were extracted. explore the critical events that lead to Hematoxyline & Eosin staining was performed spontaneous, autoimmune demyelinating on the brain sections; areas of bilateral disease of the peripheral nervous system. hippocampi and ratios to the whole hemisphere were measured for each animal. Rats with D - Sensory and Motor Systems pilocarpine-induced seizures had hippocampi 210

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28

3-D-109 The role of intrinsic contextual targets. We recently reported on the design, cues and extended training in facilitating synthesis and analgesic properties of a novel T- concurrent reach adaptation to opposing type channel inhibitor (NMP-7) that also shows visuomotor rotations mixed agonist activity on CB1 and CB2 receptors in vitro. Here, we analyzed the Maria Ayala¹, Denise Henriques¹ analgesic effect of systemically delivered NMP-7 ¹York University (i.p. or i.g. routes) on mechanical hypersensitivity induced by Complete Freund's When reaching towards objects, the human Adjuvant (CFA). NMP-7 produced dose- central nervous system (CNS) can actively dependent inhibition of mechanical hyperalgesia compensate and adapt to two different of mice treated either by i.p. or i.g. routes in the perturbations simultaneously, though this does CFA model without altering spontaneous not simply occur upon presentation. In fact, the locomotor activity in the open-field test at the CNS requires distinctive contextual cues to active dose. Neither i.p. or i.g. treatment differentiate between adaptive states. reduced peripheral inflammation per se, as Furthermore, not all contextual cues are evaluated by examining paw edema and effective in facilitating dual adaptation. Here, we myeloperoxidase activity. The analgesia investigated the efficacy of contextual cues produced by NMP-7 in the CFA test was which are intrinsic to the CNS including hand abolished in CaV3.2 null mice, confirming and body posture, and extended training in CaV3.2 as a key target. The analgesic action of adapting to two opposing visuomotor rotations intraperitoneally delivered NMP-7 was not concurrently. Using a virtual reality paradigm, affected by treatment of mice with CB1 participants manipulated a projected hand- antagonist AM-281, suggesting CB1 receptors cursor using a digitizing tablet. A 30° CW and are not involved in NMP-7 mechanism of action CCW rotation was associated with 2 distinct in vivo even though this compound acts on hand postures respectively in the first these receptors in vitro. Overall, our work shows experiment and 2 distinct body postures that NMP-7 mediates a significant analgesic respectively in the second experiment. Also, effect in a model of persistent inflammatory pain. because the learning rate in dual adaptation is This effect is dependent on T-type channels, but not as steep as that of single adaptation, we not CB1 receptors. Our approach provides a implemented an extended training set in the first novel therapeutic approach for chronic experiment to examine the effect of greater inflammatory pain treatment via a novel class of practice. We found that how people held the tool compounds. or oriented their body while reaching is sufficient for recalling an adaptive state such that over 3-D-111 Frequency Response Of time, reach errors decrease despite being Correlated Motion Discrimination In Humans presented both perturbations in a randomized, concurrent manner. Extended practice did not Hayeden Bye¹, Philippe Nguyen¹, Alireza provide additional benefits suggesting that dual Hashemi¹, Erik Cook¹ adaptation training reaches a saturation point. ¹McGill University Our results suggest that intrinsic cues which produce distinct muscle synergies are effective Humans effortlessly perceive visual inputs that at facilitating dual adaptation. move together in a correlated fashion. Previous work has shown that there are limits over which 3-D-110 Analgesic effect of NMP-7, a these temporal correlations cannot be novel mixed T-type calcium perceived. For example, the temporal frequency channel/cannabinoid receptor ligand limit of visual motion correlation is ~10 Hz (Maruya, et. al 2013, Holcombe 2009). Our goal N. Daniel Berger¹, Kevin Chapman², Ravil was to describe more than just the temporal Petrov³, Philippe Diaz³, Vinicius Gadotti¹, limit, but to measure the full frequency response Gerald Zamponi¹ of human motion correlation perception. ¹Hotchkiss Brain Institute, University of Calgary, Subjects (N=9) were shown two non-overlapping ²Snyder Institute for Chronic Diseases, patches of randomly moving dots. The University of Calgary, ³University of Montana correlation between these patches was varied from 100% correlated to 100% anti-correlated. T-type calcium channels and cannabinoid With gaze fixed on a central point, subjects receptors are known to play important roles in viewed a 500 ms presentation of the stimulus chronic pain, making them attractive therapeutic and then reported if the motion was correlated 211

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 or anti-correlated. Stochastic stimulus motion important implications for understanding the patterns allowed the application of signal brain's ability to ensure accurate postural and processing techniques to elucidate the motor control, as well as perceptual stability, frequencies linked to the behavioural choice during active self-motion. using second order interactions of the stimulus patterns. Results show that there was a steady 3-D-113 Neural substrates for allocentric- reduction in the correlation between stimulus to-egocentric conversion of remembered frequency and behavioural report, with the limit target location for reach at ~10 Hz. Additionally, the initial portion of the stimulus was more correlated with perception Ying Chen¹, John Crawford¹ than the latter portion. A model, which low ¹York University passed filtered the motion pulses before computing the correlation of the motion time Allocentric cues can be used to encode target series, emulated both the psychometric and location in visuo-spatial memory and the frequency characteristics of our human subjects. allocentric representation is converted into Our results suggest a steady roll-off with lower egocentric representation at the first possible frequencies contributing more to the perception opportunity for reach (Chen et al., 2011). of temporal correlation than higher frequencies. However, neural substrates for allocentric-to- egocentric conversion have not been explored 3-D-112 Differential encoding of self- yet. We used fMRI to investigate brain areas generated and externally produced head tilt involved in this conversion for memory-guided by the vestibular and fastigial nuclei reach. Ten participants reached toward a remembered target location represented in Jerome Carriot¹, Kathleen Cullen¹ allocentric coordinates. Participants fixated a ¹McGill University central point while a target was presented along with an allocentric cue. This was followed by a The ability to distinguish sensory inputs that are delay phase (6s), after which an auditory a consequence of our own actions from those instruction ("Same cue" or "Different cue") that result from changes in the external world is instructed participants that the allocentric cue essential for perceptual stability and accurate would re-appear at the same location, allowing motor control. We have previously shown that for a conversion of target location from neurons at the first central stage of the allocentric to egocentric, or at a different vestibular processing and in the cerebellum location, requiring participants to wait for the re- robustly encode passively applied head appearance of the cue for reach. A second rotation/translation in the horizontal plane while delay phase (10s) followed the auditory their responses are attenuated during instruction. Next, the allocentric cue re-appeared comparable self-generated head motion. and was followed by reaching toward the However, natural head movements are not remembered target relative to the location of the restricted to one plane and create more complex re-displayed allocentric cue. We found that vestibular stimuli because of the presence of the during the second delay the "Same cue" gravity. Therefore, we hypothesized that the condition elicited higher activation as compared brain uses an internal model that includes to the "Different cue" condition in bilateral gravity to distinguish between self- versus precuneus, left angular gyrus and bilateral externally- generated head motion. Here we inferior frontal gyrus. Our results suggest that tested this proposal by performing single unit posterior parietal cortex and frontal areas play a recording experiments in alert macaques during critical role in allocentric-to-egocentric passive and active 1) head-on-body tilts and 2) conversion of target representation for reach head-on-body translations. Interestingly, planning. responses related to actively-generated tilts were significantly attenuated relative to 3-D-114 Multi-Sensory Integration passively applied tilts. Moreover, this attenuation following Mechanical Perturbations was comparable to that observed for active versus passive head translations (67 vs 74%, Frederic Crevecoeur¹, Douglas Munoz¹, p>0.05). Thus, our findings show that the Stephen Scott¹ neuronal coding of natural self-motion ¹Queen's University comprises an elegant computation of an internal model of active head motion that accounts for An important challenge for the brain is to gravity. Taken together our results have combine information from distinct sensory 212

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 modalities into a single percept. Previous work We then computed noise correlations between emphasizes that the nervous system integrates each pair's activities for the two conditions. We different sensory signals by weighting them found that the magnitude of resting rate noise according to their reliability, such that the correlations for all pairs was not significant. This resulting estimate is more reliable than each revealed that in the absence of stimulation, source taken independently. Although this afferent inputs did not synchronize neurons in model captures many features of decision- the vestibular nuclei. We then discovered that making and motor planning in static conditions, pairs of afferents exhibited increased synchrony it remains unclear how multi-sensory integration during motion. Their noise correlations, is performed in real-time given differences in however, were not significantly different sensorimotor delays associated with distinct between the resting and driven conditions. The sensory modalities. We address this problem by same was true for the vestibular nuclei. Thus, asking participants to track their fingertips while while common afferent input increases mechanical loads were applied on their arm. We synchrony between vestibular nuclei neurons also used visual perturbations in which the during motion, their outputs remain largely cursor followed a trajectory similar to their hand independent. These results provide evidence motion, without any load applied on their limb. that the brain pools signals from many neurons We used the first saccade following the to achieve accurate computation of self-motion. perturbation as a proxy of participants' estimation of their fingertip motion. We show 3-D-116 The characterization of that saccade latencies are substantially faster Calretinin expressing V3 interneurons in the following mechanical perturbation than following mouse spinal cord visual perturbations. In addition, tracking performances following mechanical Dylan Deska-Gauthier¹, Ying Zhang¹ perturbations were similar regardless of whether ¹Dalhousie University the fingertip was lit or not. These results indicate that state estimation following perturbations is V3 interneurons (INs) in the spinal cord are a rapidly performed based on limb afferent major group of excitatory commissural INs that feedback. We suggest that multi-sensory are essential in establishing a robust and integration during online movement control may balanced locomotor rhythm during walking. be more heavily driven by proprioception, which, During development V3 INs, as marked by the although less accurate, presents the advantage expression of the transcription factor Sim1, exit to be affected by shorter sensorimotor delays. from the most ventral progenitor domain, p3, at embryonic day (E) 9.5 in the mouse spinal cord. 3-D-115 Vestibular neuronal ensemble In order to better understand the embryonic coding during self-motion development of V3 INs, the expression of calretinin (CR) in V3 INs has been investigated. Alexis Dale¹, Jerome Carriot¹, Kathleen CR is a calcium binding protein that has been Cullen¹ implicated as a neuronal sub-population marker ¹McGill University in specific areas of the developing nervous system. V3 INs were identified by their Neurons in the vestibular nuclei that receive expression of tdTomato fluorescent protein in direct afferent input mediate postural reflexes Sim1Cre/+; Rosafoxstop26TdTom mice. and contribute to the perception and Approximately 20-30% of V3 INs begin to computation of motion. Behavioral studies have express CR at E14.5 in the lumbar and sacral shown, however, that single neurons' motion spinal cord. Of these cells two subpopulations of detection thresholds are not as good as those CR expressing V3 INs are identified. The first is observed for perception. Thus, we have a group of ventral and intermediate V3 INs that hypothesized that pooling the activity of many transiently express CR from E14.5 to P0. The neurons better matches the output of the second is a cluster of V3 INs forming a vestibular nuclei with behavior. To accurately subpopulation at the intermediate region of the model this ensemble output, it is important first L6-S2 spinal cord. Their expression of CR lasts to determine whether the responses of individual into adulthood. We further studied the effect of neurons are independent. Accordingly, we sim1 on CR expressing V3 INs during recorded from pairs of semicircular canal or development. We found that in Sim1 null mutant otolith afferents and pairs of neurons in the mice, CR positive V3 INs significantly decreased vestibular nuclei 1) in the absence of stimulation in the transient-expressing group, although the (resting rate) and 2) during self-motion (driven). total number of V3 INs didn't change. Sim1 did 213

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 not affect the V3 subgroup that persistently citizens. Though there are many well expressed CR. Further investigation of these characterized symptoms of OA, the pain cells function in spinal neural networks is associated with its progression is poorly needed. understood. The pain usually manifests as hypersensitivity to mechanical stimuli (i.e. joint 3-D-117 Topographic analysis of cortical palpation, movement) and is linked to connections of the primary motor cortex dysfunction in pain-sensing neurons innervating (M1) in a New World monkey (Cebus apella). the joint (nociceptors). This dysfunction can be the result of modulation of mechanosensitive ion Adjia Hamadjida¹, Melvin Dea¹, Audree channels (MSCs) and/or voltage-gated ion Lachance¹, Stephan Quessy¹, Numa channels, responsible for the transduction and Dancause¹ transmission of peripheral stimuli, respectively. ¹University of Montreal Importantly, direct evidence for sensitization of the transduction process has not yet been Premotor areas have extensive cortical reported. We hypothesize that an important connections with the primary motor cortex (M1). contributor to the mechanical hypersensitivity in To date, the precise topographic location of OA pain is sensitization of MSCs found in these connections within M1 has only been nociceptors. Using the monoiodoacetate (MIA) studied for the ventral premotor cortex (PMv). mouse model of knee OA pain, we performed PMv is specifically interconnected with the hand single channel electrophysiological recordings and proximal representations in the rostrolateral from MSCs in knee-innervating nociceptors from portion of M1. These data suggest that premotor naïve and OA mice. Our preliminary data shows areas are not uniformly interconnected with M1 that in OA nociceptors, the mechanical but instead are preferentially connected with activation threshold of MSCs is reduced, and the specific subregions in M1. In the present study, current generated by these channels tends to be we examined the topographic specificity of M1's greater than those from the contralateral knee or connections with PMv as well as the dorsal mice injected with control solution. Our data premotor cortex (PMd), supplementary motor indicates that MSCs sensitization may underlie area (SMA) and primary somatosensory cortex mechanical hypersensitivity in OA patients. We (S1). Intracortical microstimulations and intend to explore the functional relevance of this multiunit recordings techniques were used to sensitization and whether blockade of MSCs will define the forearm and hand area in M1, PMd, attenuate mechanical hypersensitivity. PMv, SMA and S1. Neuronal tracers were injected within the hand representation of PMd, 3-D-119 Repetitive Transcranial Magnetic PMv, SMA and S1. Following incubation and Stimulation Disrupts Prediction of Spatial perfusion, the cortex was flattened and cut Location of the Limb tangentially. The distribution of labeled cell bodies in the ipsilateral hemisphere was Robert Hermosillo¹, Paul van Donkelaar¹ reconstructed and coregistered with the ¹University of British Columbia electrophysiological data. We found that PMd has more connections with the rostromedial part Limb movement prediction has been previously of M1; SMA has connections distributed hypothesized to allow differentiation between throughout the medial part of M1; and S1 is self-induced sensory information arising from more intensely interconnected with the caudal limb from external somatic information. This part of M1. Our results indicate that subregions process of forward modeling has been used to in M1 have different patterns of cortical explain many sensory cancellation processes in connections. This anatomical specificity may the body, however the cortical regions allow areas within M1 to play different roles for responsible for this process in human limb the control of hand movements. movements are still unclear. In our current experiment, we applied repetitive transcranial 3-D-118 Role of Mechanosensitive magnetic stimulation (rTMS) to 3 different Channels in Osteoarthritis Pain cortical locations (posterior parietal cortex (PPC), dorsal premotor cortex (dPMC), and Haitian He¹, Reza Sharif-Naeini¹ visual area V4) while subjects performed a ¹McGill University vibrotactile temporal order judgement task (TOJ) under moving or stationary conditions. Under Osteoarthritis (OA) is a chronic debilitating moving conditions, participants were instructed disease that affects millions of Canadian and US to cross their arms as soon as they heard a 214

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 tone. Previous work has shown that under stationary conditions, error rates increase when 3-D-121 Orientation Plasticity in Mouse participants have their arms crossed or are Primary Visual Cortex about to cross his or her arms. Under stationary conditions, we observed an increase in TOJ Jillian King¹, Nathan Crowder¹ error after rTMS was applied to the PPC, but not ¹Dalhousie University when it was applied to the dPMC compared to pretesting or to control. However under moving Information processing in the visual system is conditions, after rTMS to the dPMC, error rates shaped by recent stimulus history, such that were decreased relative to pre-testing. This prolonged viewing of an adaptor can alter the trend was not observed after area V4 was perception of subsequently presented stimuli stimulated, and TOJs increased slightly after and modify the visual response properties of PPC stimulation. This pattern of results neurons in multiple brain areas. In the tilt- suggests that the brain generates predictions aftereffect, the perceived orientation of a grating about spatial state of the limb using dorsal is often repelled away from the orientation of a premotor cortex in concert with spatial previously viewed adaptor grating. A potential information from the parietal cortex. neural correlate for this tilt-aftereffect has been described in cat and macaque primary visual 3-D-120 The role of cannabinoid cortex (V1), where adaptation produces receptors in monkey retina repulsive shifts in the orientation tuning curves of V1 neurons. In these animals, columns of V1 Pasha Javadi¹, Joseph Bouskila¹, Christian neurons are clustered into iso-orientation Casanova¹, Jean-François Bouchard¹, domains and pinwheel centers, and there is Maurice Ptito¹ evidence that orientation adaptation is more ¹Université de Montréal prevalent near pinwheel centers. We investigated orientation adaptation in mouse V1 The expression patterns of cannabinoid with the aim of establishing a genetically receptors CB1 and CB2, and GPR55 are well tractable model to study this form of plasticity. described in the vervet monkey retina. Yet, there We were also curious about how orientation are no reports on the exact role of these adaptation might differ in a species known to receptors in retinal function. Therefore, in order lack pinwheel columnar organization and have a to study the neural correlates that accompany lower proportion of orientation tuned neurons. the disruption of endogenous endocannabinoid We used stimulus protocols that were readily signaling in the retina, we recorded the neural comparable with previous studies, and found activity by electroretinographic (ERG) that orientation adaptation caused repulsive recordings. We evaluated ERG changes after shifts in the majority of orientation tuned administration of specific antagonists or agonist neurons, and a general decrease in firing in of these receptors. Photopic or scotopic ERGs neurons that were not selective for orientation. were recorded in 15 normal adult vervet monkeys before and shortly after intravitreal 3-D-122 C-fos study of vestibular activity injections of CB1 antagonist (AM251), CB2 in neonatal opossums, Monodelphis antagonist (AM630) and GPR55 agonist (LPI). domestica, a marsupial model for Pre- and post-injection ERG waves were sensorimotor development compared. The intravitreal injection of AM251 and AM630 resulted in a significant increase of Frederic Lanthier¹, Therese Cabana¹, Jean- the b-wave component of the ERG in photopic Francois Pflieger¹ conditions. Since GPR55 is exclusively ¹Université de Montréal expressed in rod photoreceptors, we evaluated the effects of the natural agonist (LPI) of GPR55 The opossum is born very immature. It on the scotopic ERG. Twenty minutes following nonetheless crawls, unaided, from the mother's the LPI injection, the scotopic b-wave was birth canal to a nipple where it attaches to increased in amplitude in all treated eyes. There pursue its development. Of the senses proposed was no statistical difference in the latency of the to guide the newborn to a nipple and trigger its ERG waves and the intraocular pressure before attachment, audition, vision and olfaction are and after injections. These results indicate that insufficiently developed, but the vestibular and CB1 and CB2 receptors in primates are involved trigeminal systems are good candidates. in retinal function under photopic conditions, Anatomical studies in newborn opossums have whereas GPR55 is involved in scotopic vision. shown that the utricule is the least immature 215

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 component of the labyrinth, it is innervated by (0.5 Hz, /-9 cm, /-0.09G) with the head upright, vestibular afferents projecting to vestibular after vertical plane head reorientation (in nuclei, and the latter to the cervical spinal cord. pitch/roll) and, whenever possible, after It has also been shown that low intensity horizontal plane reorientation. Tuning shifts electrical stimulations of the vestibulospinal area were observed in the rFN after both vertical induce forelimb movements in in vitro plane and horizontal plane head reorientations, preparations. To further test the functionality of consistent with the requirements for a distributed the vestibular system, conscious neonatal 3D transformation towards body-centered opossums were subjected to sinusoidal coordinates. In contrast, rostral VN cells showed acceleration along the three planes for 60 no evidence for such shifts, consistent with an minutes. Control animals were left in the same encoding of vestibular signals in head-centered condition but without stimulation. The animals coordinates. were then anesthetized by hypothermia, decapitated and the heads fixed by immersion in 3-D-124 Changes in stimulus envelope paraformaldehyde to be sectioned and reveal two classes of peripheral processed immunochemically to reveal c-fos. electrosensory neurons This protein is used as a marker of activity as it is expressed following stimulation in neurons. Michael Metzen¹, Maurice Chacron¹ We did not observe c-fos labeling in the ¹McGill University vestibular ganglion and nuclei before P15. These results do not support an influence of the Natural sensory stimuli are characterized by vestibular system in the locomotion of newborn time varying moments such as mean (first-order) opossums. Instead, the vestibular system shows and variance (second-order). While activity before the opossum starts to detach psychophysical studies have shown that second from the nipple, around 21 days after birth. order attributes (the envelope) are critical for perception, how they are encoded in the brain 3-D-123 Comparison of the reference remains largely unknown. Here we focused on frames for encoding translational self-motion envelope coding by peripheral electrosensory in the vestibular and rostral fastigial nuclei neurons (P-type afferents) in the weakly electric fish, Apteronotus leptorhynchus, using Christophe Martin¹, Jessica Brooks¹, Andrea narrowband noise stimuli that where modulated Green¹ by sinusoids in the frequency range between ¹Université de Montréal 0.05 and 10Hz. Envelopes are an essential feature of natural electrosensory stimuli. When The vestibular sensors provide self-motion two fish come within close proximity of one information in a head-centered reference frame. another, each animal will experience an Thus, to contribute appropriately to estimates of amplitude modulation of its own electric signal body or spatial motion, vestibular signals must that oscillates at the difference between the be transformed from a head- to a body- or individual EOD frequencies. The envelope world-centered reference frame. Previous varies in time as the distance between two fish studies provided evidence for such a changes, and recent studies have shown that it transformation toward body-centered primarily contains low temporal frequencies (<1 coordinates in the rostral fastigial nucleus (rFN) Hz). While primary afferents always increase by showing shifts in the spatial tuning properties their firing rates in response to an increase in of rFN cells when the head was statically EOD amplitude, we show that they can either repositioned relative to the body in the horizontal increase or decrease their firing rates in plane. In contrast, rostral vestibular nucleus response to an increase in the envelope (VN) neurons remained head-centered. provided that this increase is greater than their However, because these studies were limited to threshold. However, the gain and phase of the horizontal plane they could neither confirm a afferent responses are independent of envelope full three-dimensional (3D) transformation frequency. Therefore, this study gives important towards body-centered coordinates in the rFN, insights as to how neural heterogeneities can nor examine the evidence for a gravity- influence responses to envelopes and might dependent transformation towards world- provide an answer as to why primary afferent centered coordinates in the VN. To address baseline firing rates vary over such a large these questions we characterized the 3D spatial range. tuning of rFN and VN neurons in two rhesus monkeys during sinusoidal translational motion 216

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3-D-125 Contribution of presynaptic canal, which stimulate the vestibular nerve to inhibition to balance control reactions in send head motion information to the brainstem. healthy subjects Behavioral studies have shown that vestibular prosthetic stimulation produces vestibulo-ocular Zoe Miranda¹, Dorothy Barthélemy¹ reflex eye movements although these responses ¹Université de Montréal remain smaller than what would be expected from normal vestibular function. To optimize Background: During unexpected perturbations, stimulation parameters and improve behavioral sensory inputs are integrated in the central performance it is imperative to discover how the nervous system to generate appropriate postural brain responds to this type of stimulation. Thus, responses. Presynaptic inhibition is thought to to better understand the effect of prosthetic play an important role in modulating such stimulation protocols on vestibular processing, sensory transmission. Here, we assessed the we recorded the responses of neurons in the modulation of presynaptic inhibition during vestibular nuclei receiving direct input from the postural perturbations. Methods: Subjects (n=9, vestibular nerve in alert rhesus monkeys while 27±7 yrs) stood upon a platform that was delivering prosthetic stimulation. We found that randomly tilted forward/backward. 1) Modulation each neuron's spiking activity was time locked to of SOL H reflex was assessed by stimulating the pulses delivered through the prosthesis tibial nerve at the popliteal fossa at different suggesting that the vestibular afferent delays prior and during the perturbations. 2) To population was synchronously activated by estimate presynaptic inhibition, we quantified: A) prosthetic stimulation, which in turn drove the facilitation of SOL H-reflex induced by synchronous central responses. We hypothesize femoral nerve (FN) and B) the depression of that this synchronicity is in part the cause for the SOL H-reflex (D2 inhibition) by common low behavioral performance obtained using the peroneal nerve (CPN). Results: 1) During vestibular prosthesis thus far, and predict that backward tilt, decreased H-reflex amplitude was desynchronizing afferent inputs will enhance the observed from 75ms after tilt onset, which response of central vestibular neurons to preceded SOL EMG decrease (149 ±20 ms). prosthetic stimulation thereby improving During forward tilt, facilitation was first observed behavioral performance. at 100ms and preceded SOL EMG facilitation (162±18 ms). 2) During standing, SOL H-reflex 3-D-127 Generalization of Reach depression by CPN was 81+/-9% of the test Adaptation and Proprioceptive Recalibration reflex value, and the SOL H reflex facilitation by to Different Distances of the Workspace FN was 105+/-8%. During forward tilt, H-reflex depression from CPN is decreased (103±6%) Ahmed Mostafa¹, Rozbeh Kamran-Disfani¹, and H-reflex facilitation from FN is increased Golsa Bahari-Kashani¹, Erin Cressman¹, (118±8%), suggesting a decrease in presynaptic Denise Henriques¹ inhibition. Similar changes were observed during ¹York University backward tilt at 75 ms (120±16% for CPN and 196±37% for FEM). Conclusions: Preliminary Studies have shown that adapting one's reaches results suggest that presynaptic inhibition is in one location in the workspace generalizes to modulated during balance control reactions. other novel locations. Generalization of this visuomotor adaptation is influenced by the 3-D-126 Characterization of central location of novel targets relative to the trained vestibular neuron activity during electrical location. Reaches made to novel targets that are stimulation delivered by a vestibular located far from the trained target (i.e. ~22.5°; prosthesis Krakauer et al. 2000) show very little generalization compared to those closer to the Diana Mitchell¹, Charles Della Santina², trained direction. However, the generalization is Kathleen Cullen¹ much broader when reaching to novel targets in ¹McGill University, ²Johns Hopkins the same direction but at different distance from the trained target. Reach training with a Ongoing research is focused on developing a misaligned cursor not only leads to changes in vestibular prosthesis as a treatment option for movements, but also to changes in hand these patients suffering from bilateral vestibular proprioception (i.e., proprioceptive recalibration deficiency. This device consists of a gyroscope, (Henriques & Cressman, 2012). In this study, we which senses the movement of the head, and investigated whether proprioceptive electrode arrays implanted in each semicircular recalibration, like motor adaptation, generalizes 217

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 to different distances of the work space. V1 but this function is not supported by HDB Subjects adapted their reaches with a rotated cholinergic neurons. cursor to two-target locations. We then compared changes in open-loop reaches and 3-D-129 Visual remapping is more felt hand position to novel targets located in the impaired in patients with unilateral parietal same direction as the trained targets but either lesion than in hemidecorticate patients as at a closer or farther distance, with those to the revealed by novel version of the double step trained targets. We found motor changes task generalized to novel, closer and farther targets to the same extent as they did to the trained Kate Rath-Wilson¹, Daniel Guitton¹ distance. In contrast, the changes in hand ¹McGill University proprioception was significantly smaller for far- novel compared to trained location. From these Studies of remapping abilities in human patients and earlier results from our lab, we can infer that with distinct cortical lesions are inconclusive. proprioceptive recalibration may arise Patients with parietal lobe lesions, primarily of independently of motor changes. the right side, tested on the classical double- step task have a particular deficit in generating 3-D-128 Activation pattern of the primary an ipsilesional saccade if it follows a visual cortex elicited by electrical stimulation contralesional saccade (Duhamel et al, 1992 & of the prefrontal cortex in mice Heide et al, 1995). This deficit has been explained as an inability to generate/ interpret Hoang Nam Nguyen¹, Frédéric Huppé- corollary discharge for saccades elicited by the Gourgues¹, Elvire Vaucher¹ lesioned hemisphere. Recent studies, however, ¹Université de Montréal have called this finding into question. A review has re-interpreted the data from these earlier The prefrontal cortex (PFC) is involved in visual publications, suggesting that these results are attention which results in enhancement of the actually evidence of right-hemisphere neurons response to the attended stimulus in dominance in human visual remapping (Pisella the primary visual cortex (V1). The objective of et al, 2011). Several studies of patients with this study was to determine the pattern of V1 right parietal lesions have determined that activation following electrical stimulation of ipsilesional but not contralesional eye different subregions of the PFC. The movements can result in a deficiency in contribution to V1 activation of the basal remembering spatial information from previous forebrain (BF) cholinergic neurons, which are fixations (Vuilleumier et al, 2007 & Russel et al, also involved in visual attention, was tested, to 2010). We tested hemidecorticate subjects on a evaluate whether they could be a relay in the novel version of the double-step task, adapted PFC-V1 interaction. Three PFC subregions because our patients are hemianopic. We found stimulation sites were selected; the anterior that they do not have any impairment in cingulate (Cg1), the prelimbic (PrL) and the remapping in either direction. We have tested a infralimbic (IL) cortices. Electrical stimulation right parietal patient with this novel double-step (100 Hz bursts for 0.3 s every 2 seconds at 50 task and found that he is unable to generate a μA) was performed during 15 or 30 mins to contralesional saccade when it follows an quantify neuronal activity in V1 and BF by ipsilesional saccade, in opposition to the thallium autometallography (staining of findings of Duhamel et al, 1992. We are in the potassium reuptake) or c-Fos immunoreactivity, process of testing more patients with our novel respectively. Neuronal activation of layers II/III paradigm to provide further insight into the and V following PrL and IL stimulation was saccadic remapping system in humans. significantly increased in the stimulated hemisphere compared to the non-stimulated one 3-D-130 The effects of fatty acid amide as shown by c-Fos immunoreactive neurons (p hydrolase (FAAH) and monoacylglyercol ˂ 0.01) or thallium optical density values (p ˂ lipase (MAGL) inhibition on motor map 0.05). Cg1 did not elicit neuronal activation in expression in rats V1. BF was not activated by any of the stimulated PFC sites as shown by both Kathleen Scullion¹, Nadine Mahgoub¹, techniques. Moreover, lesions of BF cholinergic Matthew Hill¹, G. Campbell Teskey¹ neurons using mu-p75 saporin did not eliminate ¹University of Calgary - Hotchkiss Brain Institute the induced c-Fos expression in V1. This suggests a functional link between the PFC and 218

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Motor maps are the topographical fast process could be particularly affected in representation of movements in the motor cortex later adulthood. However, aging is also and are derived by stimulating pools of layer 5 associated with increased rates of forgetting that pyramidal neurons that give rise to the cortical could translate to changes in retention for either spinal tract. Previously it has been shown that the fast or slow process. To investigate changes motor map expression can be altered by the in these parameters in aging, we compared the quantity and type of neurotransmitters present in performance of healthy younger (M = 23 years) the neocortex. The balance between cortical and older (M = 70 years) adults when adapting excitation and inhibition determines motor map their reaching movements to novel loads, or expression. Endocannabinoids are retrograde force fields, applied by a grasped handle. We neurotransmitters that regulate neurotransmitter found that retention of the slow process was release at many different types of synapses and most altered in the older adults. However, for may therefore modulate cortical excitability. older adults who performed poorly on an Endocannabinoids and the cannabinoid (CB) independent explicit memory task the retention receptors are found in layer 5 of the neocortex, of the fast process was also diminished. These the source of the cortical spinal tract. Previously findings demonstrate that aging results in we examined the role of CB1 receptors on the impaired retention of procedural aspects of expression of cortical forelimb motor maps. It adapted motor responses, and that declines in was discovered that activation of CB1 receptors the retention of the fast, declarative component in the motor cortex causes a reduction in are limited to older adults with poor explicit forelimb map size. We now determined which memory. endocannabinoid (anandamide or 2- arachidonoyl glycerol) is responsible for this 3-D-132 Stereological analysis of spinal effect. We made the following 2 predictions: 1) cord neurons involved in primate forelimb inhibition of fatty acid amide hydrolase (FAAH) motor control and monoacylglycerol lipase (MAGL) will increase movement thresholds and decrease Nolan Wilson¹, Stephen Scott¹ map size 2) inhibition of MAGL will have a ¹Queen's University greater effect than inhibition of FAAH. Adult rats underwent high-resolution ICMS to map forelimb Neurons within the spinal cord grey matter of (digit, wrist, elbow, shoulder) movement non-human primates were quantified to provide representation areas. Once the initial map was a more robust anatomical framework for derived a FAAH or MAGL inhibitor was placed modelling upper limb motor control. Transverse on the cortex and 15 minutes later all forelimb sections from spinal cords of three rhesus responsive sites were re-visited. monkeys (Macaca mulatta) were examined from segments C5 to T1. Three areas of interest were 3-D-131 Modelling Altered Adaptive identified within each section using laminar Processes for Motor Learning in Aging boundaries in order to compare regions with varying populations of motor neurons and Kevin Trewartha¹, Daniel Wolpert², Angela interneurons. The first of the areas contained Garcia¹, Randall Flanagan¹ lamina IX while the remaining two areas ¹Queen's University, ²University of Cambridge contained groups of laminae (V-VI and VII-VIII). Stereological methods were used to estimate Motor learning is often studied by examining neuron density and the total number of neurons how people adapt their motor output when in these specific areas of the grey matter. moving grasped objects with novel dynamics. Segments C3 and C4 were also examined using Such adaptation involves a fast process that the same criteria in one primate in order to adapts and decays quickly and a slower process further study the changing populations between that adapts and decays more gradually. The fast segments. Neuron density (neurons per mm³) process is thought to involve declarative from C5-T1 was determined to be 6610 ± 80 memory whereas the slow process is linked to (IX), 11770 ± 50 (VII-VIII) and 28030 ± 180 (V- procedural memory. Importantly, each VI) while total number of neurons was calculated component is characterized by a learning rate to be 36800 ± 800 (IX), 84400 ± 1700 (VII-VIII) that specifies the rate at which motor output is and 88800 ± 500 (V-VI). The increase in both updated based on previous errors, and a density as well as overall number of neurons in retention factor determining the rate of trial-to- laminae V through VIII suggests that a high trial memory decay. Declarative memory degree of motor processing can occur in processes decline with age suggesting that the numerous interneurons before activation of a 219

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 comparatively smaller population of neurons 3-E-134 A novel peptide-based within lamina IX. These results provide a mechanism for the regulation of glucose numerical baseline which can be used to further homeostasis in hypothalamic neurons understand and model the processing that takes place within a system of neurons in order to Yani Chen¹, Mei Xu¹, Autumn Otchengco¹, generate a motor command. Lifang Song¹, Dhan Chand¹, Claudio Casatti², David Lovejoy¹ E - Homeostatic and Neuroendocrine ¹University of Toronto, ²Sao Paulo State Systems University

3-E-133 Effects of the cannabinoid The regulation of glucose homeostasis is receptor 1 antagonist, AM251, on vGluT2 and achieved primarily in the hypothalamic arcuate CRH expression, neuronal injury and anxiety nucleus. While several peptides such as insulin, following global cerebral ischemia GLP-1, etc... are described to be involved in this function, they are not evolutionarily conserved. Idu Azogu¹, Megan Dunbar¹, Patricia Barra de Recently, the Teneurin C-terminal Associated la Tremblaye¹, Helene Plamondon¹ Peptide family consisting of TCAP-1 to -4 have ¹University of Ottawa been discovered to be ubiquitously expressed in metazoans. TCAP-1 administration in vitro Endocannabinoids can play a modulatory role in results in increased ATP production, decreased emotional brain circuitry and neuroendocrine lactate accumulation and increased glucose stress activation. In the current study, we transporter relocation to the plasma membrane assessed the neuroprotective actions of type 1 of hypothalamic neurons. These findings cannabinoid receptor (CB1) antagonist, AM251, indicate that the primary role of TCAP may be to on neuronal injury, dopaminergic transmission regulate metabolic optimization in the brain by changes, excitotoxicity and stress response, and increasing the efficiency of glucose transport behavioral deficits post ischemia. 4 groups of and energy utilization. I hypothesize that TCAP- male Wistar rats (n=10 per group) were 1 plays a significant role in regulating energy pretreated with AM251 (2mg/kg, i.p.) or saline metabolism of the organism. Preliminary results 30 minutes prior to sham or global cerebral in vivo indicate that TCAP-1 results in a 15-20% ischemia. After 5 days of recovery, animals were decrease in plasma glucose levels in rats one exposed to the open field and the elevated plus week after administration. TCAP-1 also induced maze tests. Rats were killed 7 days post 3H-deoxyglucose transport into hypothalamic ischemia and immunohistochemical detection neurons via an insulin-independent manner. We was performed. Our findings support a partial or used a previously deduced pathway by which full reversal by AM251 of ischemia-induced TCAP-1 signals in vitro to establish a link reduction in dopamine transmission (tyrosine between the MEK-ERK1/2 pathway and glucose hydroxylase and dopamine D1 receptor uptake as well as a connection between the expression) in mesolimbic brain regions MEK-ERK1/2 and AMPK pathways. We including the ventral tegmental area and speculate that the role of TCAP-1 in regulating basolateral amygdala (BLA). Interestingly, glucose metabolism could be useful in AM251 significantly reduced vesicular glutamate neuroprotection. TCAP-1 may represent an transporter 2 expressions in the BLA and ancient and conserved mechanism for glucose paraventricular nucleus, independent of the homeostasis in animals. ischemic/sham condition. Compared to all sham groups, elevated corticotropin-releasing 3-E-135 Loss of STAT-3 Signaling in hormone (CRH) expression in the ischemic Dopamine Neurons Enhances Locomotor condition was reduced by AM251. Finally, Activity and Running Reward AM251 reduced CA1 neuronal injury, and prevented ischemia-induced changes in anxiety. Maria Fernanda Fernandes¹, Sandeep AM251 pretreatment prior to global cerebral Sharma¹, Shizuo Akira², Stephanie Fulton¹ ischemia has beneficial effects on neuronal ¹Université de Montréal, ²Osaka University survival and behavior, alleviates reduced dopaminergic transmission, and regulates CRH Leptin modulates neural circuits regulating expression in brain areas related to anxiety and appetite, locomotion, reward and emotion stress. through the long-form of its receptor (LepRb) via signaling pathways including Jak-Stat3, -PI3K and -Erk. Signal Transducer and Activator of 220

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Transcription 3 (Stat3) is the predominant signal transcript, we carried out patch clamp whereby leptin regulates gene expression and experiments on acutely dissociated SFO LepRb-Stat3 signaling plays an important role in neurons from 48h fasted rats and sated controls the control of food intake and body weight. and quantified action potential and Na+ channel Dopaminergic (DA) neurons of the midbrain are properties. After 48h fast, the threshold, height part of a neural circuit involved in reward and and duration of action potentials showed a motivation. To determine the role of Stat3 in this significant change. We also observed a circuitry, we inactivated this signaling molecule concomitant decrease in Na+ current density in DA neurons of mice (DA-specific Stat3 KO and a depolarized shift in voltage dependence of mice). Lack of Stat3 in DA neurons resulted in Na+ current activation and inactivation. The 48h no changes in feeding, increased locomotion, fast-induced change in excitability was running-wheel exercise and running reward. consistent with altered Na+ currents. These data Moreover, KO mice exhibited impairments in demonstrate food restriction alters Nav1.3 learning an appetitive operant conditioning task expression level and also electrical properties of accompanied by reduced DA biosynthesis and SFO neurons, reflecting the notion that SFO is a DA receptor protein expression in the striatum. dynamic sensor for energy balance. Taken together, these results suggest that Stat3 mediates the action of leptin in the midbrain to 3-E-137 Developmental responses of the decrease locomotion and exercise and to lateral hypothalamus to leptin and ghrelin in increase DA availability, but not to decrease rat pups. feeding behavior, implying that different LepRb signaling molecules regulate distinct behavioral Eva Gjerde¹, Hong Long¹, Claire-Dominique and biochemical actions of midbrain leptin. Walker¹ Additionally, Stat3 signaling in DA neurons ¹McGill University, Douglas Mental Health modulates the rewarding aftereffects of running University Institute and leptin facilitation of learning. Supported by CIHR and doctoral awards to MFF from Food intake is regulated by a close Université de Montréal and Canadian Diabetes communication between the homeostatic Association (CDA). system in the hypothalamus and the hedonic system (including the mesocorticolimbic 3-E-136 Na+ channel expression in rat pathway). A key region for this communication is subfornical organ is regulated by fasting and the lateral hypothalamus (LH), also known as AMP kinase the "feeding center" of the brain. Both systems are still developing during the late fetal and early Huang Shuo¹, Suman Lakhi¹, Samantha Lee¹, post-natal periods in the rat, and they are known Sylvia Wong², Darcy Childs¹, Mark Fry¹ targets for peripheral metabolic hormones such ¹University of Manitoba, ²University of Toronto as leptin and ghrelin. Here we examined the onset of leptin and ghrelin responsiveness in the The subfornical organ (SFO) is a sensory LH, and the activation of cellular signaling circumventricular organ that plays a key role in molecules in identified neurons on postnatal day detection of circulating satiety signals and (PND) 10 and 16. Leptin significantly activated regulation of energy balance. Previous work pERK and pSTAT3 in the LH on PND16, while using Affymetrix microarrays revealed patterns on PND10, only sparse pSTAT3 cells were of gene expression in rat SFO and identified a identified and the activation of pERK did not twofold change in over 600 transcripts after a reach significance. Double-immunofluorescence 48h fast. Included in the expressed and staining showed that the majority of pERK- downregulated transcripts was the Nav1.3 activated neurons are orexin-positive neurons. voltage-gated Na+ channel, a major contributor However, leptin-induced pSTAT3 was clearly to electrical excitability of SFO neurons. observed in another population of neurons, Quantitative PCR confirmed that following a 48h possibly neurotensin-positive. The development fast, Nav1.3 levels in SFO were reduced by of ghrelin responsiveness in the LH is currently 54%, compared to sated controls, a result which being investigated using immunostaining for Fos was paralled by application of the AMPK activation. Our results suggest that the activator AICAR to SFO explants. development of metabolic hormone Immunohistochemistry revealed the pattern of responsiveness in the LH is only partially expression of Nav1.3 within the SFO. In order to achieved prior to the onset of independent investigate changes in electrical properties feeding on PND16, and that the maturation of associated with the reduction of Nav1.3 functional connections between the LH and the 221

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 ventral tegmental area (VTA - a major center of ¹CRIUCPQ the hedonic system) might play a crucial role in independent feeding initiation. Supported by Relaxin-3 is a newly discovered neuropeptide CIHR to CDW. which is notably known to produce an orexigenic effect in rats. Previous studies have shown that 3-E-138 Brainstem noradrenergic relaxin-3 intracerebroventricular (ICV) injection afferents excite hypothalamic neurons increases feeding in male rats but its effect in through glutamate co-release females remains unknown. Moreover, our previous study shows that chronic stress and Wataru Inoue¹, Tamás Füzesi¹, Diana food restriction sex-specifically regulates relaxin- Baimoukhametova¹, Quentin Pittman¹, 3 expression in rats and this neuropeptide could Jaideep Bains¹ thus have a different effect in female versus ¹Hotchkiss Brain Institute male rats. The aim of the present study is to investigate relaxin-3 effects on food intake after The paraventricular nucleus of the its ICV injection at different doses in male and hypothalamus (PVN) integrates inputs from female rats. Twenty male and female Sprague- diverse stress-sensitive brain areas to regulate Dawley rats received once a week, over three the hypothalamus-pituitary-adrenal axis. weeks, 50, 200 and 800 pmol of relaxin-3 or Tyrosine hydroxylase (TH)-expressing neurons vehicle in within-subject counterbalanced in the caudal medulla densely innervate the design. Food intake (standard chow) was PVN, release noradrenaline (NA), and increase measured every 30 minutes during two hours the excitability of PVN neurons. Interestingly, after injection. Results show that post injection subpopulations of caudal medulla TH neurons food intake significantly increased by low (200 co-express vesicular glutamate transporter 2, pmol) and high (800 pmol) doses of relaxin-3 in raising a possibility that the excitatory effects of female and male rats, respectively. Moreover, these inputs may also rely on glutamate this feeding response appeared earlier in female transmission. To address this question, we used (30 minutes post injection) than in male rats (60 an optogenetic approach. Cre-dependent AAV minutes post injection) and gradually increased vector carrying channelrhodopsin 2-enhanced during two hours of post-injection in female rats yellow fluorescent protein (eYFP) was while it reached a plateau in male rats after 90 stereotaxically injected into the caudal medulla minutes post injection. In conclusion, because of mice that express Cre under the control of TH females demonstrated earlier feeding response promoter. We observed that eYFP axons to a lower dose that persisted longer than in innervating the PVN were TH immunopositive, males, this study shows that acute ICV verifying targeted expression. Using whole-cell administration of relaxin-3 induces sex-specific voltage clamp recordings from PVN neurons, effects on food intake in rats. blue light illumination (473 nm, 5 ms) evoked inward postsynaptic currents (PSCs), with short 3-E-140 Repeated Maternal Separation latency (4.3 ± 0.2 ms) and large amplitude (-93 and Fragmented Maternal Care Differentially ± 11 pA). In current-clamp mode, the light Modulate Neonatal Neuroendocrine stimulation evoked a rapid postsynaptic Activation in Response to a Novel depolarization, which occasionally generated Psychological Stressor action potentials. The light-evoked PSCs were still evident in the presence of adrenergic Ryan McLaughlin¹, Claire-Dominique Walker¹ receptor antagonists. They were also unaffected ¹McGill University by a GABAA receptor antagonist but were completely abolished by ionotropic glutamate Early-life stress exerts profound effects on the receptor blockade. These results are consistent maturation of the neuroendocrine stress axis. with the hypothesis that NAergic terminals in the However, the effects of early-life stress on the PVN co-release glutamate. neuroendocrine response to novel psychological stressors during the neonatal stage are 3-E-139 Acute intracerebroventricular unknown. We sought to determine whether two administration of relaxin-3 induces sex- commonly employed paradigms of early-life specific effects on food intake in rats stress (daily 3-hr maternal separation [MS] or limited access to nesting/bedding material [LB]) Christophe Lenglos¹, Juliane Calvez¹, would facilitate or dampen the neuroendocrine Geneviève Guèvremont¹, Arojit Mitra¹, Elena response to a novel psychological stressor. In Timofeeva¹ the first study, pups exposed to repeated 3-hr 222

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MS from postnatal day (PND) 2-9 were significant reduction of organ's weight on subjected to either a familiar stressor (60 min ischemic rats and a protective effect of MS) or a novel stressor (60 min immobilization) Antalamin on seminal vesicles for ischemic rat. on PND10 and corticosterone (CORT) and The findings support that overactivation of CRH- adrenocorticotropin hormone (ACTH) were 1 receptors associated with global cerebral measured either 0 or 60 min post-stress. Pups ischemia plays a significant role in immediate exposed to daily MS displayed enhanced ACTH and remote HPA reactivity and/or CORT and CORT secretion in response to secretion. The finding that regulation of immobilization (but not in response to MS) endogenous regulators of the stress response compared to non-stressed pups. No significant can exert delayed effects on physiological differences were observed with respect to basal responses is important to consider when ACTH and CORT secretion. Next, separate determining therapeutic approaches to stress litters were given restricted access to nesting related disorders. materials (which engenders fragmented maternal care) from PND2-9 and challenged on 3-E-142 Conservation of dN- PND10 with a 60-min immobilization stressor. TRPV1osmosensitive channel in Preliminary analyses indicate that pups reared osmoregulating animals. in LB conditions exhibited higher baseline CORT secretion and a lack of response to Cristian A Zaelzer¹, Charles Bourque¹ immobilization stress, contrary to what was ¹McGill University Health Centre observed in study 1. Thus, repeated MS and fragmented maternal care exert fundamentally Transient receptor potential (TRP) channels different effects on neuroendocrine responses to have been involved with the complex ways in a novel stressor during the neonatal period. which metazoans sense stimuli around them. They are implicated in vision, thermosensation, 3-E-141 Central blockade of type 1 CRH olfaction, hearing and mechanosensation receptors prior to transient forebrain among many others. Several are activated by ischemia attenuate delayed basal and stress- more than one different stimulus, which is then induced corticosterone secretion in male integrated in the gating step that allows the ions rats. to pass through the channel's pore. The superfamily is divided in 6 subcategories, and Julie Raymond¹, Patricia Barra de la even though one member has been described in Tremblaye¹, Hélène Plamondon¹ yeasts, the majority of them appear in more ¹University of Ottawa complex multicellular organisms, such as nematodes, insects and all kind of vertebrates. We have previously demonstrated that transient Recently, we have cloned and described a global cerebral ischemia is associated with variant form of TRPV1, a member of the dysregulation of the hypothalamic-pituitary- Vanilloid subfamily, from rat Supraoptic Nucleus adrenal axis (HPA) activity leading to important (SON). This variant lacks part of the N-terminus changes corticotropin-releasing hormone (CRH), (ΔN-TRPV1). The transcript forms a channel glucocorticoid receptor and CRH type 1 receptor that allows the non-selective permeation of (CRH-R1) expression in distinct brain regions cations when the cells are stimulated with post ischemia. The current study aimed to hypertonic fluids or negative pressure. Based in examine time-dependent changes in basal and multiple alignments of TRPV1 sequences, we stress-induced corticosterone secretion have predicted the conservation through following 10 min global cerebral ischemia in rats vertebrates of ΔN-TRPV1. This hypothesis has and the effect of pre-treatment with the CRH-R1 been corroborated by the detection and cloning antagonist Antalarmin (2μg/2μl; icv). Our of five variant homologs, introduced in this work, findings demonstrate significant inhibition of in fish, amphibians, birds and mammals ischemia-induced CORT morning secretion up including human. The high conservation of ΔN- to 7 days post ischemia. Effects of Antalarmin TRPV1 on osmoregulating animals and the pre-treatment on attenuation of CORT levels evidence pointing for this specific role detecting were maintained in ischemic animals exposed to extracellular fluid osmolality changes, suggests a 15 min restraint stress 27 days following that this variant is a key piece in the machinery reperfusion. On the 30th day post ischemia that has allowed animals to adapt to and stress-sensitive organs including the seminal conquest dry land. vesicles, thymus and adrenal glands were collected and weighted. Analyses show a F - Cognition and Behavior 223

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between neurons. We examined such 3-F-143 Saccadic eye movements in interactions in simultaneously recorded pairs of children with and without dyslexia neurons in the dorsolateral prefrontal cortex performing a letter naming speed task (dlPFC) of a macaque monkey while it performed an attentional task. While fixating the Noor Al Dahhan¹, Donald Brien¹, John Kirby¹, center, the animal had to indicate a change in Douglas Munoz¹ one of two peripherally presented stimuli, ¹Queen's University ignoring the other. The target was determined by the stimulus color. ~20% of the neurons Naming speed (NS) deficits, impaired timing showed a preference for the target's location mechanisms that affect reading fluency, are (ipsi- versus contralateral hemifield). We characteristic of reading difficulty from the early analyzed noise correlations (rnoise) during the stages of reading into adulthood. NS tasks allocation and maintenance of attention. We measure how quickly and accurately subjects found differences in rnoise based on spatial can name a set of highly familiar stimuli (e.g., preferences with positive correlations between letters) randomly presented in a visual array. We similarly tuned neurons and negative used a letter NS task and three variants that correlations between neurons of opposite were either phonologically and/or visually similar tuning. Interestingly, the size of rnoise varied while participants' eye movements and between epochs for contralateral neurons but articulations were recorded. We examined how not for ipsilateral neurons. Correlations also these manipulations influenced performance depended on task difficulty: Similarly selective and whether there were differences with neurons were more positively correlated for increased reading acquisition from ages 6-10 easier trials than more difficult ones. Likewise, and between dyslexic and average readers. rnoise between pairs of neurons with opposite Participants were in three groups (n=15/group): preferences were more negative for easier dyslexics (age 9-10), chronological-age (CA) stimulus pairs. Finally, we used different controls (age 9-10), and reading-level (RL) classification tools to explore the importance of controls (age 6-7). For all groups NS noise correlations on stimulus decoding. manipulations were associated with specific Together, these results suggest that neuronal patterns of behavior and saccade performance interactions contribute to the amount of which were influenced by visual rather than information carried by neuronal populations phonological similarity. When the task was both within dlPFC areas 46/8a. visually and phonologically similar all groups made longer naming times and fixation 3-F-145 The Effects of Acute Nabilone durations, more naming errors, more frequent Administration on Resting State EEG in and shorter saccades, and had shorter eye- Healthy Participants voice spans. Compared to CA controls, dyslexics performed more like RL controls and Ashley Beaudoin¹, Sara de la Salle¹, Joelle were less efficient, had longer articulation times, Choueiry¹, Dylan Smith¹, Danielle Impey¹, pause times, and fixation durations, shorter eye- Renee Nelson¹, Jasmit Heera¹, Lawrence voice spans, and made more errors, saccades, Inyang¹, Vadim Ilivitsky¹, Jakov Shlik¹, Verner and regressions. Overall there were Knott¹ developmental changes in performance in ¹University of Ottawa Institute of Mental Health normally achieving children from ages 6-10 that Research appear to occur more slowly for dyslexics. Long-term use of cannabis, the most widely 3-F-144 Noise correlations in macaque used illicit drug, has been associated with the areas 46/8a reflect target selection and appearance of psychotic symptoms and strength of distractors cognitive impairments, similar to those found in schizophrenia (SZ). Although the exact Theda Backen¹, Stefan Treue², Julio mechanisms are unclear, CB1 receptors in the Martinez-Trujillo¹ dorsolateral prefrontal and anterior cingulate ¹McGill University, ²German Primate Center cortices are often increased in SZ patients, which may suggest that CB1 receptors play a Visual attention selectively enhances neuronal role in cannabis precipitated psychosis and responses to behaviorally relevant stimuli while associated neurobiological dysfunction. In SZ, suppressing irrelevant ones. However, it is cerebral dysfunction is evidenced by disturbed unclear how attention modulates interactions patterns of electroencephalographic (EEG) 224

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 activity, which is also modulated by acute and strategy was previously successfully used to long-term cannabis use. The main objective of reverse the learning deficits in mice caused by this study was to examine the EEG correlates of the heterozygous knockout of another Ras-GAP acute selective CB1 agonist treatment in a gene, neurofibromin 1 (Nf1). healthy population. EEG power spectrum measures were acquired during resting state in 3-F-147 Response selection to emotional 20 healthy, non-smoking, non-cannabis using stimuli in adults with ADHD: a fMRI study males in a randomized, double-blind procedure, using the Affective Spatial Compatibility with participants receiving the selective CB1 task. agonist nabilone (0.5 mg) in one session and placebo in the other. Single dose administration Mikael Cavallet¹, Claudinei Biazoli Junior¹, of nabilone is expected to mimic the effects of Paulo Bazán¹, Tiffany Chaim¹, Maria da cannabis in EEG and possibly result in transient Silva¹, Mário Louzã¹, Luiz Gawryszewski², frequency changes similar to those seen in SZ. Geraldo Filho¹ The findings of this study may lead to a clearer ¹University of São Paulo, ²Universidade Federal depiction of the role of the CB1 receptor in the Fluminense regulation of electrocerebral activity and may help to elucidate the contributing role of The response selection to stimuli with different cannabis use in the etiology of schizophrenia emotional valences was investigated in symptoms. Attention-Deficit/Hyperactivity disorder (ADHD). The stimulus-response compatibility effects and 3-F-146 Strategies to rescue cognitive inhibitory mechanisms involved with response deficits due to SYNGAP1 haploinsufficiency selection were assessed using fMRI and manual responses. Method: 20 ADHD male adults Martin Berryer¹, Fadi Hamdan¹, Graziella Di underwent the task while been scanned (3-T, Cristo¹, Jacques Michaud¹ TR/TE=2s/30ms). Stimuli were figures of the ¹Université de Montréal/Hôpital Sainte-Justine most popular soccer teams of São Paulo, Brazil presented to the left/right of fixation. Participants We have previously shown that heterozygous informed his Favorite and Rival teams, and for loss-of-function mutations in SYNGAP1 cause the task, they were instructed to press in one nonsyndromic intellectual disability (NSID) with block of trials the key which is ipsilateral to or without epilepsy and autism. SYNGAP1, Favorite team hemifield (compatible) and the which codes for a Ras GTPase-activating contralateral key for Rival team (incompatible) protein (GAP), is a component of the NMDA and the reverse arrangement in the other block. receptor complex. Knockdown of SYNGAP1 Blocks were counterbalanced across results in hyperactivation of Ras, an increase of participants. Results: The behavioral data ERK phosphorylation, and an excess number of showed that Favorite-Compatible(FC)/Rival- GluR1 at the surface of post-synaptic Incompatible(RI) block were faster than Rival- membrane, which correlate with altered spine Compatible(RC)/Favorite-Incompatible(FI) and morphologies and impaired long term that FC were faster than RC and FI while RI was potentiation. We propose to use Syngap1 /- faster than FC. fMRI findings are summarized in mice to test strategies to rescue the cognitive Fig 1. An ANOVA reveals an interaction deficit phenotype. Specifically, since SYNGAP1 between right dorsal-lateral prefrontal cortex exerts its synaptic function through inhibiting (DLPFC) and left posterior parietal cortex (PPC) Ras, we propose to test whether using Ras activations (A). Similar areas were found for the inhibitors in Syngap1 mutant mice could rescue contrasts between RI-RC (B) and RI-FI (C). The the associated behavioral and learning deficits. bilateral DLPFC, left PPC, thalamus and left First, we subjected Syngap1 /- mice to a battery basal ganglia areas were found for the RI-FC of behavioral tests. We showed that they contrast. Conclusion: RI condition in ADHD exhibited hyperactivity, appeared less anxious, recruited areas of the attentional network displayed deficits in working memory, had slight involved with negative emotional processing. impairments in long term spatial memory and Grants: 2011/19179-5; 2011/09946-9 displayed deficit in social recognition, consistent FAPESP/CNPq/NARSAD with previously reported observations. Currently, we are testing whether the administration of the 3-F-148 Acute Effects of Nabilone on well-characterized Ras inhibitor, lovastatin, is Attentional Processing in Healthy able to rescue the behavioral and cognitive Participants: A Brain Event-Related Potential defects of Syngap1 /- mice. This Ras inhibition Study 225

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Exposing animals to an enriched environment Joëlle Choueiry¹, Renee Nelson¹, Jasmit (EE) increases adult hippocampal neurogenesis Heera¹, Lawrence Inyang², Sara de la Salle¹, and improves spatial learning and memory. Dylan Smith¹, Danielle Impey³, Ashley Synaptic zinc is highly concentrated in the Beaudoin⁴, Vadim Ilivitsky⁵, Jakov Shlik⁵, neurogenic region of the hippocampus, the Verner Knott⁴ dentate gyrus, yet its role in hippocampal ¹University of Ottawa , ²Carleton University, neurogenesis and behaviour remain unclear. ³University of Ottawa, ⁴University of Ottawa The aim of the current study was to determine Institute of Mental Health Research, ⁵The Royal whether synaptic zinc is important for Ottawa Mental Health Centre modulating adult neurogenesis and, consequently, hippocampal-dependent Cognitive impairments are prominent in behavior. By comparing neurogenesis in adult schizophrenia (SZ) and are a strong predictor of zinc transporter 3 (ZnT3) wild-type (WT) and the patient's functional status. While knockout (KO) mice, which lack synaptic zinc, antipsychotics efficiently relieve positive we found that synaptic zinc is necessary for EE- symptoms (i.e. hallucinations), they exert no induced neuronal proliferation and survival in the significant benefits over cognitive impairments. hippocampus. Further, utilizing two tests of A strong association has been shown between spatial memory, the Spatial Object Recognition long-term cannabis use and emergence of SZ- and Morris Water tasks, we show that mice like cognitive impairments in healthy individuals. lacking synaptic zinc show no improvement in In addition, increased levels of cannabinoid spatial memory following EE. The neurogenic receptors (CB1) have been observed in the and cognitive effects of EE can be mediated, at dorsolateral pre-frontal and anterior cingulate least in part, by increased levels of brain-derived cortices of SZ patients. Objective: To examine neurotrophic factor (BDNF). We demonstrate the implication of the CB1 receptor in cognitive that EE-dependent increases in BDNF require processing by applying an acute dose of the synaptic zinc signaling, as hippocampal levels of selective CB1 agonist nabilone. Methods: Brain BDNF in ZnT3-KO mice in standard housing even-related (ERP) potential indices of pre- were not significantly different from KO animals attentive (P3a) and attention-dependent (P3b) placed in EE. These experiments show that processing were assessed in 20 non-smoking synaptic zinc is essential for the modulation of males during an auditory odd-ball paradigm adult hippocampal neurogenesis, and within a randomized, double-blind, placebo hippocampus-dependent behaviour, supporting controlled design involving the administration of a role for zincergic neurons in modulating 0.5 mg of nabilone. Compared to placebo, experience-dependent plasticity in the nabilone is expected to mediate: 1) lower P3a hippocampus. Acknowledgments: Funded by amplitudes (poorer pre-attentional novelty NSERC detection capacity) and, 2) lower P3b amplitudes (poorer attention-dependent 3-F-150 GABAA receptor blockade performance). Implications: Enhancing our prevents nicotinic reversal of crossmodal understanding of the CB1 receptor involvement object recognition impairment in ketamine- in attentional processing is important for both treated rats: implications for cognitive clinical and scientific aspects, as greater deficits in schizophrenia cannabis use is observed in SZ patients compared to healthy individuals and acute Jacob Cloke¹, Boyer Winters¹ cannabis effects on P3a indexed novelty ¹University of Guelph detection/attentional switching has not yet been examined. The neural bases of multisensory integration impairments in schizophrenia are not well 3-F-149 The Benefits of Environmental understood. Rats treated sub-chronically with Enrichment on Hippocampal Neurogenesis NMDA receptor antagonists (e.g., ketamine), and Behavior Require Synaptic Zinc which model symptoms of schizophrenia, are Signaling. impaired on a tactile-to-visual crossmodal object recognition (CMOR) task; this deficit is reversed Michael Chrusch¹, Simon Spanswick¹, Payal by systemic nicotine. Furthermore, cortical Patel¹, Haley Vecchiarelli¹, Matthew Hill¹, gamma oscillations mediated by parvalbumin- Richard Dyck¹ containing GABAergic interneurons (PV-INs) ¹University of Calgary may be deficient in schizophrenia, potentially contributing to aberrant multisensory 226

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 processing. PV-INs contain nicotinic administration of a CB-1 receptor agonist acetylcholine receptors (nAChR). The current decreased MMN amplitudes in healthy controls, study assessed the receptor specificity of and that MMN amplitudes are reduced in long- nicotine's ameliorative effect in the CMOR task term and heavy cannabis users. Studies have and the interaction between nAChRs and also consistently shown marked MMN amplitude GABA. Male Long-Evans rats were treated sub- reductions in SZ. 20 male non-smokers and chronically for 10 days with ketamine or saline non-cannabis-users were examined within a and then tested on the CMOR task after a 10- randomized, double-blind, placebo controlled day washout. Systemic nicotine given prior to design. MMN amplitudes were expected to the sample phase of the CMOR task reversed decrease (vs. placebo) with an acute dose of the ketamine-induced impairment, but this effect nabilone (0.5 mg). The implications for these was blocked by co-administration of the GABAA findings may be a better understanding of the receptor antagonist bicuculline at a dosage that role of the CB-1 receptor in cognitive otherwise did not induce impairment. Selective impairments and may help to further elucidate α7 and α4β2 nAChR agonists were also tested, the process by which cannabis use leads to with only the latter reversing the ketamine- psychosis and cognitive impairments. induced impairment. These results suggest that nicotine, likely through stimulation of the α4β2 3-F-152 Rewards and movement-related subtype of nAChR, ameliorates CMOR deficits costs shape fast decision-making in a in ketamine-treated rats via stimulation of the human target foraging task GABAergic system. These findings may have important implications for understanding the Jonathan Diamond¹, Michael Dorris², Daniel nature and potential treatment of cognitive Wolpert³, J Flanagan¹ impairment in schizophrenia. ¹Queen's University, ²Institute of Neuroscience, Shanghai Institutes for Biological Sciences, 3-F-151 Acute Effects of Nabilone on ³University of Cambridge Sensory Memory in Healthy Participants: A Brain Event-Related Potential Study Real-world tasks typically consist of a series of target-directed actions and often require choices Sara de la Salle¹, Lawrence Inyang¹, Danielle about which targets to act on and in what order. Impey¹, Dylan Smith¹, Joëlle Choueiry¹, Such choice behaviour can be assessed from Renee Nelson¹, Jasmit Heera¹, Ashley an optimal foraging perspective whereby target Beaudoin¹, Jakov Shlik², Vadim Ilivitsky², selection is shaped by a balance between Verner Knott³ rewards and costs. Here we evaluated such ¹University of Ottawa, ²The Royal Ottawa Mental decision-making in a rapid movement foraging Health Care Centre, ³Institute of Mental Health task. In a given trial, participants were presented Research with 15 targets of varying size and value and were instructed to harvest as much reward as Long-term cannabis use has been associated possible by either moving a handle to the targets with the expression of psychotic symptoms and (hand task) or by briefly fixating them (eye task). cognitive impairments in vulnerable individuals. The trial duration (3.25 s) enabled participants to However, the mechanisms by which cannabis harvest about half the targets, ensuring that total use precipitates these effects is unclear. It has reward was due to choice behavior. We been suggested that certain neuroadaptive developed a probabilistic model to predict changes, such as an increase in cannabinoid-1 target-by-target harvesting choices that (CB1) receptors in the dorsolateral prefrontal considered rate of reward and costs associated and anterior cingulate cortices, may be with target distance and size for up to five future associated with the pathology of schizophrenia harvests in succession. Because the time and (SZ). Additionally, cannabis use in SZ can energy costs are greater for hand than eye exacerbate symptoms and trigger relapses. It movements, we predicted that in the hand task, has also been demonstrated that in healthy in comparison to the eye task, target choice individuals, cannabis use can induce a full-range would be more strongly influenced by of transient SZ-like positive, negative, and movement-related costs and would take into cognitive symptoms. The objective of this study account a greater number of future targets. The was to assess the acute effects of the selective model results confirmed both predictions. In a CB-1 receptor agonist nabilone on the mismatch version of the hand task in which choices could negativity (MMN) even-related potential. only be based on target positions, participants Previous studies have shown that an acute consistently chose among the shortest 227

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 movement paths. Our results demonstrate that 4% sucrose solution, whereas with continuous, optimal foraging theory offers a useful every day access (EDA), the same solution is framework for understanding choice behaviour consumed at lower, stable levels. If sucrose in target-directed movements. solution access is then switched to a common E2DA schedule, rats with E3DA experience 3-F-153 Decline in Cognitive Function continue to consume more solution than rats and Risk of Elder Self-Neglect: Finding from with EDA experience over an extended period of the Chicago Health Aging Project time. Here, we ask if the E3DA/EDA difference reflects a change in sucrose solution value. Rats Melissa Simon¹ were first provided with a 4% sucrose solution ¹Northwestern University paired with one flavour (counterbalanced), for 12 E3DA exposures or 36 days of EDA. Rats with Background: This study aimed to examine the E3DA escalated their intake to consume almost longitudinal association between decline in twice as much sucrose solution as EDA rats cognitive function and risk of elder self-neglect (326 vs. 173 grams). Next, a series 24h, 2 bottle in a community-dwelling population. Methods: preferences tests were performed on an E2DA Prospective population-based study of those schedule. On each test day, preference was participated in the Chicago Health Aging Project measured for the standard solution against (CHAP). Of the 5,519 participants, 1,017 were ascending concentrations (2-32%) of a second reported to social services agency for suspected sucrose flavour (the alternate). The point at elder self-neglect from 1993-2005. which standard and alternate solutions were Measurements: The primary predictor was isohedonic occurred at a higher alternate decline in cognitive function assessed using the concentration (rightward shift) for rats with E3DA MMSE, the Symbol Digit Modalities Test relative to EDA experience. Furthermore, both (Executive Function), and both immediate and preference for the standard, as well as overall delayed recall of the East Boston Memory Test consumption of standard and alternate (Episodic Memory). An index of global cognitive combined, were always higher after E3DA function scores was derived by averaging z- experience. Preference testing was followed by scores of all tests. Outcome was elder self- 12 E2DA exposures to the standard only. Again, neglect as confirmed by social services rats with E3DA experience consumed more than agencies. Logistic and linear regression models rats with EDA experience. These findings were used to assess these longitudinal suggest that E3DA relative to EDA can increase associations. Results: After adjusting for the value of a sucrose solution over a longer potential confounding factors, decline in global term. cognitive function, MMSE or episodic memory was not independently associated with 3-F-155 The action of vitamin K in brain increased risk of reported and confirmed elder during aging is linked to the pAKT/AKT and self-neglect. Decline in executive function was apoptotic caspases-3, -8, -12 signaling associated with increased risk of reported and pathways. confirmed elder self-neglect. Decline in global cognitive function was associated with increased Guylaine Ferland¹, Alexandra Mabit¹, Chantal risk of greater self-neglect severity Fournier¹ (PE=0.76,SE=0.31,p=0.014). Conclusion: ¹Hopital du Sacré-Coeur de Montréal Decline in executive function was associated with increased risk of reported and confirmed Vitamin K (VK) participates in brain function elder self-neglect. Decline in global cognitive through sphingolipid metabolism and activation function was associated with increased risk of of proteins S and Gas6. We have previously greater self-neglect severity provided evidence that long-term low VK intake leads to cognitive deficits in aging rats and to a 3-F-154 Escalated sucrose intake is concurrent accumulation of ceramides in certain accompanied by increased value brain regions. To gain further insight on the mechanisms of action of VK in brain, we Adam Celejewski¹, Milan Valyear¹, Roelof investigated the phosphatidil-inositol-3- Eikelboom¹ kinase/Akt and apoptotic caspases-3, -8, -12 cell ¹Wilfrid Laurier University signaling pathways, as well as DNA damage, in the brains of 21-mo female Sprague Dawley rats With 24 h periods of every 3rd day access which had been fed either a low (L: 80 μg K1/Kg (E3DA), rats markedly escalate their intake of a diet) or an enriched (E: 2000 μg K1/Kg diet) VK 228

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 diet since weaning, or a L (ages 2-13.9 months) than WT females in the probe trial. This followed by an E diet (ages 14-21 months). experiment indicates that the standard MWM Lifetime intake of an enriched VK diet was may be more sensitive than the 2-day MWM associated with a significant increase in cell because it detected modest deficits in spatial survival based on the pAKT/AKT ratio and learning in female mice that were not detected in significant decrease in DNA damage as the 2-day version. assessed by transcription protein p53. Strong trends were also observed for decreased 3-F-157 The supraoptic nucleus neuron- apoptosis. The systematically higher pro-form of glia structural plasticity and the social caspases-3, -8, -12 suggests that less of these behavior responses to salt loading in proteins were being activated, an assumption rodents are regulated by EphA4 that was verified with caspase-12 where both the pro and active forms were assessed. In Daniella Isacu¹, Marlene Freyburger¹, Sylvie conclusion, long-term consumption of a VK rich Laforest², Akofa Clara Amegandjin¹, Diane diet appears to offer cellular protection in brain Gingras¹, Janine El Helou¹, Moogeh and could contribute to the maintenance of Banarnoori¹, Wafaa Jammow¹, Michel cognitive functions during aging. Supported by Lauzon¹, Luc DesGrosseillers¹, Sabrina CIHR. Chierzi³, Keith Murai³, Elena Pasquale⁴, Guy Drolet², Valerie Mongrain¹, Guy Doucet¹ 3-F-156 Validation and comparison of 2- ¹Université de Montreal, ²Université de Laval, day and standard-length MWM protocols: ³McGill University, ⁴Sanford-Burnham Medical Analysis of procedural sensitivity to detect Research Institute visuo-spatial learning and memory in the 5XFAD mouse model of Alzheimer's disease. The hypothalamic supraoptic nuclei (SON) display marked structural changes after salt Maximillian Fiander¹, Richard Brown¹ loading (2% NaCl in drinking water): astrocytic ¹Dalhousie University leaflets enveloping oxytocin (OT) neurons retract and are replaced by new synapses. We The Morris Water Maze (MWM) is one of the here examined whether EphA4, which regulates most popular measures of visuo-spatial learning cell motility and adhesion, is involved in this and memory in mice. Standard MWM protocols neuronal-glial structural plasticity (NGSP). Using take 6-8 days to complete. Gulinello et al. (2009, in situ hybridization (ISH), Behav Brain Res 196(2)) attempted to validate a immunohistochemistry and electron microscopy 2-day MWM protocol that used one day of (EM), we assessed the expression and visible platform trials, followed by one day of localization of EphA4 in the SON of naïve and hidden platform trials. Although they were able salt-loaded rodents. We also used EM to to detect a deficit in the 3xTG mouse model of quantify the effect of salt loading on NGSP in Alzheimer's Disease (AD) at 18-19 months of the SON of wild type (WT) and EphA4 KO mice. age, two questions arise: (1) is the task as ISH showed selective expression of EphA4 in sensitive as standard protocols, and (2) are the the SON and other hypothalamic nuclei mice using spatial strategies to locate the exhibiting NGSP. Counting silver grains showed platform. Therefore, we compared the standard a significant increase in EphA4 mRNA in the and 2-day MWM protocols with a hybrid 2-day SON of salt loaded vs. naïve WT rats. By EM, and conventional protocol in the 5xFAD mouse there was a significant increase in the number of model of AD (10M, 10F) and their wild-type EphA4-labeled dendrites in salt loaded vs. WT (WT) controls (10M, 10F) at 4-6 months of age. mice, but no change was detected by Western All mice showed improvement across days in blotting of EphA4 from rat SON. In addition, latency and swim distance in all phases of the NGSP did not occur in salt loaded KO mice. experiment but there were no significant Since OT influences social behavior, we tested genotype effects in latency or distance in either KO and WT mice in the 3-chamber social protocol. In the 2-day phase, 5xFAD mice had interaction test after salt loading. Compared to more thigmotaxis than WT mice, with females untreated KO mice, salt loaded KO mice exhibiting more thigmotaxis than males. Female exhibited a significant decrease in the total mice swam significantly longer distances and duration of their interactions with all targets swam faster in the acquisition stage of the combined. In contrast, salt loading in WT mice standard MWM. Lastly, female 5xFAD mice tended to increase the total duration of spent significantly less time in the target interactions. These results support a role for quadrant and made fewer annulus crossings 229

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EphA4 in mediating NGSP of OT neurons in the ¹Universiti Sains Malaysia, ²Queen's University, SON, and thereby influencing social behaviour. ³Friedrich-Alexander-University Of Erlangen- Nuremberg

3-F-158 Acquisition of schedule-induced Introduction: Cerebral ischemia is one of the polydipsia: hippocampal and striatal leading causes of death and long-term disability dissociation in the Y maze in aging populations. Chronic cerebral ischemia can induce the accumulation of reactive oxygen James Gardner Gregory¹, Emily Hawken¹, species (ROS) and nitric oxide (NO), which lead Eric Dumont¹, Richard Beninger¹ to neuronal injury in selective, vulnerable ¹Queen's University regions of the brain, especially the hippocampus and cerebral cortex, leading to cognitive In rodents, excessive non-physiological drinking impairment and some motor dysfunction. Aims: can be induced by intermittent presentation of In the present study, the effect of chronic food in the presence of a drinking spout to a cerebral ischemia induced by permanent, hungry animal (schedule-induced polydipsia; bilateral occlusion of the common carotid SIP). Acquisition of SIP can be modified by arteries (2VO) on locomotor activity and learning lesions to the hippocampus and by drugs and memory processes were evaluated at targeting the dopamine (DA) systems of the different time points following the occlusion. striatum. We previously observed that repeated Method: Male Sprague Dawley rats (200-300g) amphetamine exposure shifted rats' learning were subjected to 2VO or sham-operated strategies from the hippocampus to the striatum surgery and tested 1, 2, 3 and 4 weeks following and also significantly increased water-drinking the ischemic insult. Results: The results showed (SIP). It is currently unknown whether the that 2VO significantly reduced step-through animals that develop SIP have impaired latency in a passive avoidance task at all time hippocampal functioning, augmented DA points when compared to the sham-operated functioning in the striatum or other neurological group. Further, 2VO rats showed significant changes that predispose them to compulsive increases in escape latencies during training in drinking behaviors (SIP). We attempted to the Morris water maze, as well as a reduction of elucidate some of the neurological the percentage of times spend in target underpinnings of SIP development. We quadrant of the maze at all time points following examined each rat's learning strategy in the Y- the occlusion. Importantly, there were no maze: animals were food-restricted and trained significant changes in locomotor activity in a Y maze to find food pellets placed in a between 2VO and sham-operated group. baited arm to determine if the animals were Conclusion: The present data suggest that the response learners or place learners. Following 2VO procedure effectively induces behavioral, this, all animals were exposed to the SIP cognitive symptoms associated with cerebral paradigm for a period of 21 days to determine if ischemia and, consequently, provides a valuable rats that went on to develop SIP had a learning- model to study ischemia and related strategy preference. Following SIP acquisition, neurodegenerative disorder. histological staining for FosB & c-fos examined neuronal activation elicited by SIP. Rats 3-F-160 Identifying TrkA receptor characterized as response learners on the Y- mediated mechanisms affecting maze demonstrated greater SIP than rats hippocampal-dependent memory characterized as place learners. Immunohistochemical data in the caudate Sylvia Josephy-Hernández¹, Tahar putamen, prefrontal cortex & Ca1 area of the Aboulkassim², Mario Maira², Iulia Pirvulescu¹, hippocampus will be reported. Caroline Menard³, Rémi Quirion¹, Horacio Uri Saragovi¹ 3-F-159 The development of a rat model ¹McGill University, ²Lady Davis Institute for of chronic cerebral ischemia: effects on Medical Research, ³Université de Montréal motor and cognitive functions The molecular and cellular mechanisms by Zurina Hassan¹, Thenmoly Damodaran¹, which memories are formed, stored and Visweswaran Navaratnam¹, Hans retrieved are poorly understood. Also, no Dringenberg², Christian Muller³ effective medications exist to halt the neurodegenerative process leading to cognitive impairment in Alzheimer's disease (AD) and 230

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 ageing. Here, we present an in vivo than the accepted roles. This prediction has pharmacological model where memory can be been confirmed by our recent works. Here, we manipulated; and through which we hope to gain test whether this additional fN400 activity insights into the mechanisms of memory actually indexes the inhibition of self-unfit formation. We also might validate a therapeutic behaviors. Participants were shown 216 names target to relieve memory-impairing pathologies. of social roles in three tasks. First, they The in vivo model involves manipulation of the performed the self-fit task. Then, they named all activity of the receptor for nerve growth factor the behaviors associated with the role. Finally, (NGF), called TrkA. TrkA activation by NGF they named only the first behavior that came to promotes neurogenesis, neuronal differentiation mind. In accordance with the hypothesis, fewer and survival and plays a role in hippocampal behaviors were named for the social roles that dependent memory. Reduced TrkA receptor were rejected and the dampening effect of density and function correlates with progression stimulus repetition on the N400 amplitude was in AD, ageing, and Down syndrome patients and eliminated between the 2nd and 3rd task, as rodent models. Our laboratory designed D3, a should be the case given a greater need of specific peptidomimetic partial agonist of TrkA. behavior repression in the third task. D3 improved learning and long-term memory (LTM) in aged rats with memory impairment. D3 3-F-162 Systems consolidation and also improved short-term memory (STM) in the reconsolidation in the thalamus amyloid precursor protein AD mouse model. Paradoxically, D3 impaired LTM in wild-type Joëlle Lopez¹, Karine Gamache¹, Carmelo young mice, without effects on STM or evidence Milo¹, Karim Nader¹ of toxicity. Our preliminary results in vitro and in ¹McGill University vivo suggest that this LTM impairment was due to D3 increasing hippocampal neurogenesis, The anterior thalamic nuclei (ATN) and the and a corresponding change of several signaling intralaminar/lateral thalamic nuclei (ILN/LT) play proteins in the hippocampus. This work may different roles in memory processes. The ATN validate TrkA as a therapeutic target for are believed to be part of an extended memory-impairing pathologies. hippocampal system, and the ILN/LT have strong connections with the medial prefrontal 3-F-161 What prevents us from engaging cortex. Recently, it was shown that the ILN/LT in self-unfit behaviors: the putative role of were involved in systems consolidation. the frontal N400 event-related potential in However, it could not be determined clearly their preconscious inhibition whether the ILN/LT were necessary only for the process of systems consolidation, or for retrieval Katherine L'Abbée Lacas¹, Ana Fernandez as well. The role of the ATN in retrieval was also Cruz¹, J. Bruno Debruille¹ left unclear. We therefore used an immediate- ¹McGill University early gene imaging approach and reversible inactivations to further investigate the role of Across a lifespan, one can embody various these nuclei in recent and remote memory social roles. The mechanisms by which one retrieval, in a contextual fear conditioning task in decides which are conceivable with respect to rats. As the ATN are believed to be part of an oneself still remains largely unknown. The extended hippocampal system, we also present research aims at exploring one assessed whether the ATN were involved in possibility as to these mechanisms. This reconsolidation and systems reconsolidation. possibility is based on extrapolations of results Results confirmed a differential role of the ATN of grounded semantics and affordance studies. and ILN/LT in systems consolidation, and It rests on the idea that names of social roles pinpoint for the first time which specific nuclei automatically and preconsciously activate the are involved in this process: the anterodorsal behaviors associated with them. In a self-fit task nucleus (AD), and the mediodorsal nucleus in which participants have to decide whether or (MDL). The results also show for the first time not they would endorse the role, the behaviors the involvement of the ATN in recent but not that are deemed unfit to the self could then be remote memory retrieval. In addition, we show inhibited. Roles that are rejected should thus that the ATN is not involved in reconsolidation or induce more inhibition. According to the idea systems reconsolidation, suggesting that these that the N400 event-related brain potential nuclei do not store memory but provide essential indexes a preconscious inhibition, these rejected feedback to the hippocampus during recent roles should elicit a larger frontal N400 (fN400) memory retrieval. 231

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yohimbine (YOH) on goal-directed and reflexive 3-F-163 Developmental high fat diet behaviors. Male Sprague-Dawley rats self- exposure induces long-term changes in administered 0.05 mg/kg/inf heroin for 10 anxiety behaviour and glucocorticoid sessions (1 session x day, 3h each). Four hours signaling in the brain after each session, rats received 3 injections (SC) of vehicle or heroin, 2h apart. The dose of Wilfred de Vega¹, Aya Sasaki¹, Shathveekan these injections escalated from 3 to 24 Sivanathan¹, Patrick McGowan¹ mg/kg/day. Withdrawal precipitated by naloxone ¹University of Toronto Scarborough (NAL; 0.1 mg/kg, SC) was measured after the last session of self-administration (SA) on a Maternal obesity and a diet high in saturated fat progressive ratio schedule. After 9 sessions of during pregnancy carry significant risks for extinction, rats were pre-treated with 0 or 0.5 health problems in offspring that manifest later mg/kg injection (IV) YOH and tested for in life. For example, maternal high fat diet reinstatement. In a separate study, rats received consumption is a risk factor for heart disease, SC injections of heroin as described above. type 2 diabetes and the metabolic syndrome in Following a 13-day drug-free period, rats offspring, in addition to less obvious effects on received two tests of startle separated by 24 h: the risk for affective disorders. A high fat diet one test following an injection of vehicle, and the also increases systemic inflammation and recent other after 0 or 2.5 mg/kg YOH (IP). It was found studies show that it directly influences local that rats injected with heroin during SA inflammatory expression in the brain. However, displayed greater signs of NAL-precipitated few studies have examined the effect of withdrawal, and greater YOH-induced maternal high fat diet on brain areas linked to reinstatement. YOH also amplified startle anxiety behaviour. We investigated the influence reactivity, but this was not affected by previous of maternal high fat diet in male and female heroin dependence.These data suggest a offspring in Long-Evans rats. We measured possible dissociation between the actions of anxiety behaviour in the open field, elevated heroin dependence on stress-induced plus maze and light dark transition tasks in behaviors. Specifically, with chemical stressors adolescent and adult offspring. In addition, we i.e., YOH, dependence may amplify the effect of examined levels of corticosterone, a major stress on goal-directed behavior, without altering stress hormone, by radioimmunoassay and reflexive stress responses. gene expression by quantitative PCR in the brains of adolescent and adult offspring. High fat 3-F-165 Optogenetic modulation of diet-exposed offspring show age-specific cholinergic neurons in the medial septum- alterations in anxiety behaviour and vertical limb of the diagonal band of Broca corticosterone levels. High fat diet-exposed (MSvDB) and its effect on hippocampal offspring also show sex-specific alterations in activity the expression of corticosterone receptors and inflammatory genes in the hippocampus and Siddhartha Mondragon-Rodriguez¹, Sylvain amygdala, brain areas known to regulate anxiety Williams¹ behaviour and the response to stress. The data ¹McGill suggest that developmental high fat diet exposure alters anxiety and the response to Cholinergic neurons in the medial septum- stress at least in part by long-term changes in vertical limb of the diagonal band of Broca glucocorticoid signaling pathways in the brain. (MSvDB) are known to have an important role during normal hippocampal functions and theta 3-F-164 Effects of heroin dependence on oscillations. Although previous studies have yohimbine-induced reinstatement of heroin focused on understanding how cholinergic seeking and startle reflex in rats neurons from the MSvDB neurons fire to pace hippocampal theta oscillations, a significant Meenu Minhas¹ Francesco Leri¹ portion of MSvDB neurons are slow-firing and ¹University of Guelph thus may not have the capacity to pace theta oscillations. The function of these neurons, Heroin dependence alters responses to especially their role in modulating hippocampal stressors, but it is not clear if these effects can activity, remains unknown. Here, we combined be observed after dissipation of withdrawal optogenetics with our recently developed septo- symptoms. The current study explored whether hippocampal preparation in vitro to answer this heroin dependence alters the action of question. For this study, we used ChAT- 232

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 mhChR2-YFP BAC transgenic mice expressing endocannabinoids in problem gambling-related channelrhodopsin-2/EYFP fusion protein decision making. (mhChR2:YFP) targeted selectively to cholinergic neuronal populations. 3-F-167 Effects of parent removal on Characterization of septo-hippocampal neurons parents and offspring in a typically showed photocurrents of 190 /- 50 pA (steady biparental songbird, Taeniopygia guttata state: 160 /- 50 pA) and depolarizations of 25 /- 3 mV. Cholinergic neurons followed light Leslie Phillmore¹, Jordan Fisk¹, Jill Squires¹, stimulation of 1 to 20 ms pulse duration, firing Sean Aitken¹, Tara Perrot¹ efficiency increased with pulse size and ¹Dalhousie University stimulation response ratio reached value of 1 - 5, 10 and 20 ms, suggesting that ACh neurons Stressful events during childhood, such as could be finely activated with light. Surprisingly, having a single parent, shape brain and optogenetic activation of cholinergic neurons behaviour later in life. Previous work modelling caused a scopolamine sensitive reduction in the effects of developmental stress have theta power in the CA1 area in the intermediate primarily used a rodent model, however hippocampus. Together, these results suggest because only mothers provide care for the that the role of slow firing septo-hippocampal young, meaning the potential contribution of neurons contribute to oscillation power fathers to offspring rearing, and the effects of modulation in the hippocampus. single vs. biparental care cannot be examined. Our model uses a typically biparental songbird, 3-F-166 Endocannabinoid System the zebra finch, so we can examine how Involvement in Impulsivity and Decision- removal of one parent affects both the remaining Making parent and the offspring in terms of feeding behaviours, begging behaviours, and Christopher Norris¹, Paul Mallet¹ corticosterone levels. In addition, we compared ¹Wilfrid Laurier University song learning in males reared by single fathers to those reared by both parents to see if song Recent studies suggest that dysregulation of the learning was compromised. Preliminary results endocannabinoid system may lead to impaired show that offspring reared by single parents did decision making. For example, chronic cannabis not weigh less than offspring reared by both use is associated with impaired learning of the parents, however, males reared by a single optimal strategy in the Iowa Gambling Task. The father had lower similarity scores (when present study sought to elucidate the role of comparing their own song to their fathers) endocannabinoids in impulsivity and decision- compared to males reared by both parents, making in laboratory rats. Food-deprived adult indicating that having a mother present during male CD IGS rats (n=10) were trained in a food- song development is beneficial, even when she reinforced 5-choice serial reaction time task (5- does not contribute to song learning directly. CSRTT) until accuracy exceeded 80%. In subsequent drugged test sessions, 3-F-168 Mesocortical dopamine administration of cocaine (15 mg/kg, i.p.) depletion reverses blunted responses to significantly decreased choice accuracy relative amphetamine in dcc haploinsufficient mice to saline control treatments, primarily by increasing the number of premature responses. Matthew Pokinko¹, Luc Moquin², Alain The fatty acid amide hydrolase (FAAH) inhibitor Gratton¹, Cecilia Flores¹ URB597 (0.03, 0.3 or 1.0 mg/kg, i.p.), which ¹McGill University, ²Douglas Mental Health leads to an accumulation of the endogenous University Institute cannabinoid anandamide, had no significant effects on choice accuracy or premature The netrin-1 receptor, dcc, determines a) the responding. Experiments in progress are extent of dopamine (DA) innervation to the examining the ability of the CB1 cannabinoid medial prefrontal cortex (mPFC), b) the receptor antagonist/inverse agonist rimonabant organization of local circuitry, and c) individual to attenuate cocaine-induced premature vulnerability to effects of drugs of abuse. Adult responding. Future experiments using a rat dcc haploinsufficient mice have a selective analog of the Iowa Gambling Task (the rGT), increase in mPFC DA fiber innervation and DA and a newly developed operant slot machine release in comparison to wild-type littermates. task will be used to further examine the role of Furthermore, adult dcc haploinsufficient mice show blunted DA release in the nucleus 233

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 accumbens (NAcc) and reduced locomotor correlated positively with the left postcentral activity when challenged with drugs of abuse sulcus SF and VOL, and the right frontomarginal such as amphetamine (AMPH). Because mPFC sulcus TH, SF and VOL; and negatively with the DA transmission in the mPFC can negatively left supramarginal gyrus TH. No correlations regulate DA release in the NAcc in response to were found with the subcortical regions. drugs of abuse or stressors, we hypothesized Conclusion: The structure of several frontal and that the blunted effects of AMPH in dcc parietal regions was associated with language haploinsufficient result from increased mPFC performance, mainly in the left hemisphere. The DA innervation. We therefore examined the presence of both negative and positive effects of selective mPFC DA depletion on correlations highlights the complex relation AMPH-induced locomotion in dcc between language and its anatomical correlates. haploinsufficient and wild-type mice. Adult mice received bilateral mPFC injections of 6- 3-F-170 Attentional oscillation as a hydroxydopamine (lesion) or vehicle (sham) 10 clocking mechanism for timing rhythm days before an i.p. AMPH challenge. In wild type intervals mice, AMPH-induced locomotion was similar between lesion and sham groups. Remarkably, Navid Sadeghi¹, Erik Cook¹ mPFC DA lesions in dcc haploinsufficient mice ¹McGill University reversed their blunted response to AMPH. These findings demonstrate that the protective An important goal in neuroscience is to phenotype of adult dcc haploinsufficient results understand how the brain computes the from the effects of DCC on the organization of passage of time. We wanted to understand the mPFC DA connectivity. neural mechanisms responsible for predicting the time of future events based on observed 3-F-169 Structural correlates of language stimulus periodicities. We used a visual rhythmic abilities: surface-based region-of interest motion pulse stimulus (200ms coherent random morphometry study dot motion pulses, separated by 350ms random motion), and trained two Macaque monkeys to Didier Roehrich-Gascon¹, Steven L. Small², detect a dysrhythmia created by omitting a pulse Pascale Tremblay¹ and presenting it slightly later. After the last ¹Centre de recherche de l'institut universitaire en motion pulse and around omission time, the santé mentale de Québec, ²University of animals viewed only 0% coherent motion. We California recorded 64 multiunits from the Middle Temporal area (MT) of the visual cortex while the monkeys Intro: Examination of the relation between brain performed the task. In randomly interleaved structure and behaviour offers novel insights into trials, we matched the direction of the pulses to the neural underpinning of language and either the preferred or the null direction of an cognitive processes. Objective: Explore the isolated unit. Peri-omission neural activity was relation between cerebral morphometry and informative of the animals' speed of response performance on language tasks. Method: MRI and detection performance in a manner images were acquired from 21 healthy adults consistent with top-down attention. These (25±4.4 yrs, 10 men) who also underwent 2 neural-behavioral correlations increased in time language tasks: 1) verbal fluency and 2) in expectation of the omitted pulse, suggesting sentence generation. Using Freesurfer, MRI that attention was entrained to the regular images were edited to segment gray matter into motion pulses. Our results therefore imply that multiple regions. For each cortical region, the brain may use attentional oscillation for cortical thickness (CT), surface (SF) and volume clocking intervals in subsecond rhythms. This in (VOL) were calculated; for subcortical regions, turn suggests that perception of time does not the VOL was calculated. Analyses of correlation arise from the activity of a specialized module in were conducted between morphometric data the brain, but is derived from actively-generated and the scores on the 2 language tasks (number internal dynamics. of words produced and percent of correct sentences). Results: Fluency scores correlated 3-F-171 Von Economo neurons may be positively with the triangular part of the left responsible for vocal acquisition and inferior frontal gyrus SF and right frontomarginal language gyrus TH; and negatively with the orbital part of the left inferior frontal gyrus and inferior frontal Shubha Srivastava ¹, Sudhi Shrivastava² sulcus THs. Sentence generation scores 234

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¹K N Government Post Graduate College drastically change their firing rate to a sensory Gyanpur S R N Bhadohi, ²Barkat Ulla University stimulus (CS) when paired with a salient Bhopal outcome, such as an eyelid shock (US). This results in a neural ensemble pattern unique to Von Economo neurons (VENs) can be good the CS-US association. Here, we examined targets for research to solve the mystery of whether this association-related ensemble origin of language. Vocal learning is a substrate pattern was reactivated during periods of quiet for spoken language, the ability to modify wakefulness. Rats received daily pairings of an acoustic or syntactic sounds, or ability to acquire auditory CS and US (100 trials, TEBC) followed vocalizations through imitation rather than by pairings of a visual CS and US (100 trials, instinct. It is a rare trait, and has only been VEBC). The trials were separated by an interval detected in a few groups of mammals- humans, ranging from 20 to 40 seconds. Prefrontal bats, cetaceans, pinipedes (seals and sea neuron ensemble formed two distinct ensemble lions), elephants, macaques monkey, goats and patterns for the auditory CS and visual CS. zebras and three distantly related bird groups These ensemble patterns were reactivated including songbirds, parrots, and hummingbirds. during the inter-trial intervals at an apparently Surprisingly almost all vocal learner groups of random timing. The reactivation of two patterns mammals have VENS. The emergence of VENs was equally robust during both TEBC and VEBC in great apes coincides with the evolution of the and was observed from the first day of planum temporale, a region that is important for conditioning. Thus, prefrontal neurons are language comprehension considering the spontaneously organized into groups whose language comprehension abilities of great apes. synchrony is driven by an internal mechanism, VENs are reported to be altered in patients with rather than an immediate experience. The distinct symptoms affecting language such as internal dynamics during off-line periods may frontotemporal dementia, autism and influence which group of neurons participates in schizophrenia which also associated with the the encoding of external stimuli. role of VENs in origin of language; But these cells have not been noticed to date in any bird 3-F-173 Unilateral cerebellar taxa of equivalent behavioral correlates. Here haemorrhage combined with early systemic we first report the localization and inflammation alters neonatal mouse neuroarchitecture of VENs by Nissl and Golgi sensorimotor reflex development method in vocal counterparts of parrot (Psittacula krameri) brain and discuss the role of Sophie Tremblay¹, Gloria Mak¹, Daniel VENs in vocal learning and origin of language. Goldowitz¹ we also compare VENs and brain areas of ¹University of British Columbia parrots and other vocally imitative animals to reveal how evolution shapes neural Background: Extreme preterm infants are mechanisms for complex social communication exposed to multiple stressors during their which provide new insight into role of VENs in postnatal development including perinatal evolution of language. cerebellar haemorrhage (CBH) and postnatal infection, two major risk factors for 3-F-172 Awake reactivation of neurodevelopmental impairments. In order to association-related neuronal ensemble understand how cerebellar development is patterns in rat medial prefrontal cortex altered by those insults, we developed an animal model using a cerebellar haemorrhagic Kaori Takehara-Nishiuchi¹, Mark Morrissey¹ insult combined with an early or late ¹University of Toronto inflammatory event in mice pups. Methods: Unilateral intraparenchymal CBH was induced During periods of rest or immobility, by using local injection of bacterial collagenase hippocampal neurons are reactivated in a (0.15U) at postnatal day 1 (P1) combined with sequence corresponding to a specific spatial intraperitoneal lipopolysaccharide (LPS) trajectory regardless of whether it was injection (300µg/kg) concomitantly (early experienced or not (Foster and Wilson, 2006; inflammatory state, EIS) or at P5 (late Gupta et al., 2011; Pfeiffer and Foster, 2013). It inflammatory state, LIS). Mice were remains unknown whether a similar behaviourally tested on a daily basis and phenomenon is observed during the processing cerebellar tissues were collected at P2, P7 and of non-spatial information in other brain regions. P15. Results: Sensorimotor reflexes were Neurons in the medial prefrontal cortex altered in the treated mice. There was a 24hr 235

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 delay in forelimb grasp acquisition in the cognition as well as related risk for collagenase-treated group compare to vehicle. neuropsychiatric disease. At P15, grip strength in the CBH EIS group was lower compared to vehicle (0.055±0.002 vs 3-F-175 Neurons are recruited to a 0.033±0.002, p=0.0013). However, no significant memory trace based on relative neuronal difference in the forelimb strength was excitability at the time of training measured in the LIS groups at P15. P2 preliminary histological data shows an increase Adelaide Yiu¹, Valentina Mercaldo¹, Chen in microglial cells surrounding the haemorrhagic Yan¹, Blake Richards², Asim Rashid¹, Hwa- site along with a massive ipsilateral inflamed Lin (Liz) Hsiang¹, Jessica Pressey², Vivek subarachnoidal space. Conclusions: Unilateral Mahadevan², Matthew Tran², Steven cerebellar haemorrhage combined with early Kushner³, Melanie Woodin², Paul Frankland¹, systemic inflammation delayed grasping reflex Sheena Josselyn¹ acquisition and altered forelimb strength in ¹Hospital for Sick Children, ²University of neonatal mice pups. Toronto, ³Erasmus Medical Center

3-F-174 Maternal care effects on ATRX Memories are thought to be sparsely encoded expression and long-term neurobehavioural over a distributed memory network. How are development neurons that become integrated into the memory trace chosen? We, and others, showed Austin Korgan¹, Amos Hundert¹, Ian Weaver¹ that it was possible to bias the subpopulation of ¹Dalhousie University neurons selected to participate in a memory trace by manipulating levels of the transcription Mounting evidence indicates that the factor CREB (cAMP/Ca2 responsive element maintenance of chromatin architecture is binding protein) in individual LA neurons, essential for normal human development and although the underlying mechanism is unknown. cognitive function. The ATRX gene, which is Neurons overexpressing CREB are highly essential for normal growth and cognitive excitable. We used 3 ways to examine if development, encodes a chromatin-remodeling increasing intrinsic excitability in a small protein that is expressed in developing neural population of LA neurons is sufficient to bias structures, including newly-born cortical and their inclusion in a memory trace. First, we hippocampal neurons. We have shown that manipulated KCNQ2, a voltage-dependent K maternal care influences gene programmes, channel which mediates afterhyperpolarization including forebrain ATRX gene expression, and currents. A dominant negative dnKCNQ2 (hQ2- is associated with stable individual differences in G279S) co-assembles with native KCNQ2/3 learning and memory and anxiety- related and subunits, suppresses their activity and increases social behaviour, as well as cortical and neuronal excitability. Second, to gain temporal hippocampal function in adult rodents. These control of neuronal excitability, we virally results suggest the possible involvement of expressed the DREADDs (designer receptors ATRX in somatic behaviour in response to exclusively activated by designer drug) hM3Dq. maternal care. Since disruption of ATRX impairs Activation of hM3Dq receptors by the synthetic cognition and motor functions, inhibits learning ligand clozapine-N-oxide (CNO) leads to in mouse pups, and contributes to depolarization and increased action potential developmental silencing of imprinted genes that firing. Increasing intrinsic excitability minutes shape somatic growth and brain, we before training enhanced memory and these hypothesize that the effects of mother-offspring neurons were more likely to be included in the interactions during the first week of postnatal life memory trace. Finally, we used optogenetics to on ATRX expression influences epigenetic show that increasing excitability seconds before programmes that underlie cognitive and training similarly enhanced memory formation. emotional development. The elucidation of the Together, these data suggest that neurons are mechanisms involved in the effects of maternal recruited based on their relative excitability at behaviour addresses perhaps the most the time of training. challenging question in development: How are experiences occurring in early life rendered 3-F-176 Morphology and patterns of the permanent? In the case of sustained changes in anterior intermediate parietal sulcus of gene expression in brain cells, we can begin to Jensen in the human brain understand the neurobiological basis for individual differences in personality and Veronika Zlatkina¹, Michael Petrides¹ 236

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¹Montreal Neurological Institute, McGill plasticity. Optogenetics is a powerful tool to non- University invasively manipulate cellular functions by light. We utilized Blgc, a mutant photoactivatable The anterior intermediate parietal sulcus of adenylyl cyclase (PAC) that produces cGMP by Jensen (aipsJ), also called the sulcus of Jensen, binding GTP instead of ATP. We demonstrated emerges out of the inferior bank of the cGMP production by activating Blgc by various intraparietal sulcus in the human brain between light sources in vitro. To apply this optogenetic the first and second caudal terminations of the approach to target subcellular regions, we superior temporal sulcus and runs for some optimized two-photon laser excitation light in distance at the posterior end of the vitro. For visualization of cGMP dynamics at the supramarginal gyrus (Petrides, 2012). Because single synapse level in living hippocampal the aipsJ often approaches the first caudal neurons, we evaluated and optimized superior temporal sulcus and may appear to genetically encoded cGMP sensors utilizing two- merge with it, there has been considerable photon FRET (Fӧrster resonance energy confusion in its identification. The aipsJ was transfer) both in vitro and in vivo. To avoid examined in forty magnetic resonance images of photobleaching of the cGMP sensors during the human brains in order to define its relations to optogenetic light stimulation, we modified the the intraparietal sulcal complex and the caudal cGMP sensors for FRET/FLIM (fluorescence terminations of the superior temporal sulcus. lifetime imaging microscopy), and demonstrated The results demonstrate that the aipsJ forms a that Blgc produced cGMP in response to light number of patterns with the nearby sulci. In the activation in living hippocampal neurons. This majority of cases, the aipsJ emerges out of the combination of two-photon optogenetics and live main stem of the intraparietal sulcus as an imaging techniques will provide new tools for inferiorly directed side-branch. In a smaller studying the cGMP signaling pathway in living number of cases, the aipsJ is a small shallow tissues. sulcus attached to the main stem of the intraparietal sulcus and the connection between 3-G-178 A Dynamic Model of the the two sulci is observed only in a few horizontal Potassium Chloride Co-transporter KCC2 in sections. When the aipsJ is underdeveloped, it Regulating Efficacy of Inhibitory appears as a notch on the surface of the brain. Neurotransmission The aipsJ appears to mark the boundary between an anterior section of the intraparietal Annik Yalnizyan-Carson¹, Jordan Guerguiev¹, sulcus related to the supramarginal gyrus (areas Nicolas Doyon², Jessica Pressey¹, Vivek PF and PFG) and a more posterior part related Mahadevan¹, Blake Richards³, Melanie to the angular gyrus (area PG). Woodin¹ ¹University of Toronto, ²Laval University, G - Novel Methods and Technology ³University of Toronto Scarborough Development The potassium-chloride co-transporter KCC2 3-G-177 Two-photon optogenetics and plays a critical role in neuronal chloride (Cl-) FRET sensors for studying the role of cGMP homeostasis, and therefore regulation of in living neurons inhibitory neurotransmission. Post-translational modifications of KCC2 such as phosphorylation Jelena Borovac¹, Thomas Luyben¹, Mustafa and oligomerization in the membrane may have Khan¹, Kenichi Okamoto¹ significant effects on KCC2 transport function, ¹University of Toronto which modifies the strength of GABAergic inhibitory synaptic transmission. Cyclic GMP (cGMP) is a second messenger Phosphorylation of specific residues in the with a variety of physiological functions, intracellular domain have been shown to play an including synaptic plasticity in the nervous important role in KCC2 membrane stabilization, system. However, its role in activity-dependent and implicated in the recruitment of additional dynamics at the synapse is poorly understood KCC2 molecules for oligomerization, which has due to a lack of visualization and manipulation been suggested to be critical to proper transport techniques. Here we report the development of function. In this study we hypothesized that genetically encoded cGMP sensors, in phosphorylated KCC2 is a more efficacious combination with an optogenetic approach using transporter than its unphosphorylated two-photon microscopy, to study the role of equivalent, in part because this phosphorylation cGMP in dendritic spines during synaptic promotes oligomerization. We test this 237

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 hypothesis using experimentally-constrained single living cells, to relate cellular phenotypes computational modeling, first creating a single as a function of protein concentrations. compartment model to simulate event probability of KCC2 transport based on phosphorylation 3-G-180 Efficient gene delivery into the state. We compared simulation data to both mouse hindbrain using in utero biochemical and electrophysiological data electroporation obtained from hippocampal neurons to verify the model. We then expanded our model to include Laurence David¹, Jamila Aitoubah¹, Lu-Yang morphometric data from a CA1 pyramidal Wang¹ neuron, allowing us to assess the effects of ¹The Hospital for Sick Children KCC2 phosphorylation on transport function in distal dendrites. This model allows us to observe Manipulation of gene expression via these effects in real time, and draw conclusions recombinant viral vectors and creating about Cl- regulation in distal dendrites, which transgenic knock-out/in animals has have been previously experimentally intractable. revolutionized our understanding of genes that play critical roles during neuronal development 3-G-179 Quantification of Protein Levels and the pathophysiology of neurological in Single Cells disorders. Target-specific genetic manipulations are made possible in Cre-lines, albeit costly, Chiu-An Lo¹, Ibrahim Kays¹, Farida Emran¹, labor-intensive and time consuming. Thus, Tsung-Jung Lin¹, Vedrana Cvetkovska¹, alternative methods of gene manipulations have Brian Chen¹ been adapted to address important biological ¹Research Institute of the McGill University questions. In this study, we utilized an in utero Health Centre electroporation technique which involves efficient delivery of a hindbrain-specific Accurate measurement of the amount of specific enhancer/promoter construct into the 3rd protein a cell produces is important for ventricle of live mouse embryos to investigate investigating basic molecular processes of the GFP expression pattern in the mouse hindbrain. cell. The current methods for determining We created a GFP DNA construct containing a protein amounts have poor cellular resolution Krox20 B enhancer and β-globin promoter to and are inherently destructive to cells, limiting drive GFP expression in the hindbrain and the accuracy and relevance of the subsequently introduced it into the lateral measurements. We have developed a technique ventricles of mouse E12 to E13.5 embryo that allows for quantitation of protein levels in allowing it to flow to the 3rd ventricle. Electrical single living cells. This Protein Quantitation currents were applied to allow DNA uptake into Ratioing (PQR) technique uses a genetic tag the cell and confocal images from fixed brain that produces a stoichiometric ratio of a slices were analyzed for GFP expression. By fluorescent protein reporter and the protein of using a cell-type specific enhancer as well as interest during protein translation. The region specific injection and electroporation, fluorescence intensity (i.e., brightness of the robust expression of GFP was observed. Our cell) is directly proportional to the number of long-term goal is to establish the utility of this molecules produced of the protein of interest, technique for performing specific genetic and thus is used to determine the relative manipulations to unravel critical molecular protein amount within the cell. Using quantitative substrates underpinning functional and imaging and electrophysiology, we demonstrate morphological remodeling of synapses as well that PQR can produce stoichiometric as understanding the pathophysiology of certain separations and linear relationships between disorders targeting hindbrain. different genes. Using the circadian system, we demonstrate cyclical changes in fluorescence in 3-G-181 Excross: a tool multigene small lateral ventral neurons in the Drosophila expression mapping in the mouse brain brain. We use genome editing techniques to insert Protein Quantitation Reporters into Leon French¹, Paul Pavlidis² endogenous genomic loci in three different ¹University of Toronto, ²University of British genomes for quantitation of endogenous protein Columbia levels. The Protein Quantitation Ratioing technique allows for measurements of Most mental disorders are complex, caused by endogenous or exogenous protein amounts in many genes possibly interacting with various environmental factors. Compounding this 238

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 etiological complexity is the heterogeneity of the task or are affected by a certain type of gene expression in the brain, with the majority of distractor. Further applications are required, genes differentially expressed across brain especially with clinical populations. regions or time. Excross helps understand these expression pattern by providing genome and 3-G-183 Effective Long-term Upper-Limb brain wide views of gene expression. Excross Tremor Treatment in Parkinson Disease combines data across user provided gene sets Patients to show heatmaps of developmental expression and voxelwise 3D views of adult mouse brain Jack Lee¹, Fariborz Rahimi², Olivia Samotus², expression ( http://excross.chibi.ubc.ca/ ). We Mallory Jackman², Mandar Jog² use large and expensive public gene expression ¹Lawson Research Institute, ²Western University atlases (Allen Brain atlases) which are underused for the study of polygenic brain Tremor is the most visible symptom of diseases because the data is not easily Parkinson Disease (PD), which significantly accessible for study beyond the single gene impacts the patient's quality of life. Two major scope. In contrast, we provide a fast tool that aspects that prevent physicians from treating only requires a list of mouse genes. A similar tremor are inadequate objective assessments tool for exploring human brain gene expression for tremor and lack of tremor-specific therapy. is under construction and available for 23 PD patients underwent kinematic demonstration. assessment over 64 weeks, receiving Botulinum neurotoxin type A (BoNT-A) injections every 4 3-G-182 The Virtual Reality Stroop: months. Recordings were taken with patients in Impulsivity and Attention Assessment rest, posture, and kinetic states. Degrees of freedom (DOF) at each joint were: flexion- Mylene Henry¹, Pierre Nolin¹, Christian Joyal¹ extension, pronation-supination, radial-ulnar at ¹Université du Québec à Trois-Rivières wrist, flexion-extension at elbow, and flexion- extension, abduction-adduction at shoulder. Impulsivity is a multifactorial construct Based on kinematic data and the physician's (Evenden, 1999) and no single task can assess clinical experience, BoNT-A injection sites and all its component. The Stroop is known to dose parameters were determined. An average assess impulsivity and attention (Lezak, et al. decrease of 75% in tremor amplitude at the 2012).The VR-Stroop assess impulsivity (both wrist, 65% in the elbow and 50% in the shoulder motor and cognitive) and elicit a "stroop-effect" was seen following the first treatment cycle. (Henry, Joyal, & Nolin, 2012). For this study, Maximal grip strength was reduced by 20% but performances on the virtual task were combined did not impact function. The UPDRS rest tremor with eye-tracking data to determine if it would score (item 20) decreased from 2.75 to1.81 and further improve sensitivity. Volunteers were action tremor (item 21) decreased from 1.67 to recruited among the general population (39 0.77 by week 16. The Fahn-Tolosa-Marin tremor females and 13 males, mean age: 26.92 ± rating scale showed significant improvement 10.63, 20-63). The VR-Stroop consists of color over 8 months. Tremor did not improve for 6 of words presented on the screen of a virtual the 27 patients who had noticeable advances in apartment. Concomitantly, color words are other PD symptoms. Tremor treatment in PD spoken. Correct answers required participants to patients using kinematic guided BoNT-A identify matching auditory and visual stimuli (i.e. injections improved tremor scores. The use of when the participant hears blue and the color objective kinematic assessment allows word is written with a blue ink). Distractors also physicians to pinpoint tremor sources in the arm, appeared throughout the task. Eye-tracking data increasing efficacy of BoNT-A treatment. were collected via FaceLAB (Seeing Machines). Eye-tracking data was not associated with 3-G-184 Functional optical imaging of commission errors (p > 0.05) but with omissions the retina through intrinsic signals errors. Omissions errors were inversely associated with the time spent on the TV (r = - Azadeh Naderian¹, Laurent Bussieres¹, 0.501, p < 0.0001) and associated with the Sebastien Thomas¹, Frederic Lesage², number of deviations (r= 0.413, p= 0.004). Christian Casanova¹ These results suggest that the VR-Stroop alone ¹University of Montreal, ²Ecole polytechnique is sufficient. Eye-tracking data do not improve Montreal significantly the sensitivity of this task. It should be explore if eye movements differ throughout 239

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28

Optical imaging of retinal intrinsic signals (RIS) the phase shift measured by holographic is a method that measures changes in light microscopy. In order to achieve such reflectance of the retina that occur following computations, we build a computer model to visual stimulation. The aim of this study is to describe a neuron response to synaptic and examine the characteristics of RIS as a function spiking activity in terms of changes in volume of stimulation conditions and to determine the and refractory index. The reverse use of our cellular origin of these signals. Experiments model allows computation of magnitude of were performed on anesthetized rabbits in synaptic events from phase shifts and refractory scotopic condition. RIS imaging was performed index. Water fluxes in our model are controlled using a fundus camera, illuminated by near by passive and active mechanisms of water infrared light. Retinal stimulation consisted of a transport such as cation-chloride-cotransporters diffuse flash of green light. Electroretinograms and aquaporines. Our model pinpoints some were concurrently recorded. The activity- inconsistencies in our current state of dependency of RIS was evaluated by observing knowledge that could be due to unknown the effects of stimulus intensity on RIS volume regulating mechanisms or to poorly amplitude and by comparing the RIS with the described biomechanical properties of ERG waves. The cellular origin of RIS was membrane, suggesting further experimental studied by blocking different retinal cell types by investigation. Moreover, we show that a train of injections of various pharmacological agents. synaptic events should be well measured while Strong correlations were found between RIS only large individual synaptic events could be amplitude and stimulus intensity as well as with detected but not precisely quantified. the ERG b-wave. No RIS were obtained when the photoreceptors' activity was isolated with 3-G-186 Gene Delivery to the Spinal Cord aspartate, suggesting that photoreceptors using MRI-guided Focused Ultrasound activity is not at the source of RIS. A small but significant decrease in RIS amplitude was Danielle Weber-Adrian¹, Emmanuel observed using TTX, suggesting a partial role Thevenot¹, Meaghan O'Reilly², Wendy for ganglion cells activity in RIS. The Oakden¹, Margarete Akens³, Nicholas Ellens¹, administration of bipolar cells blockers (PDA and Kelly Markham², Joel Finkelstein², Albert APB) affected the RIS amplitude in a dose- Yee², Cari Whyne², Kevin Foust⁴, Brian dependent manner. Our results indicate that RIS Kaspar⁴, Rajiv Chopra⁵, Kullervo Hynynen², are dynamic signals that can reflect the various Isabelle Aubert² levels of retinal activity. RIS originate from the ¹University of Toronto, ²Sunnybrook Research inner retina cellular activity with a strong Institute, ³University Health Network, ⁴Ohio contribution of bipolar cells. State University and Center for Gene Therapy, ⁵University of Texas Southwestern Medical 3-G-185 A Computer model of neuron Center swelling and shrinkage under synaptic activity. How much can we expect from Gene therapy shows promise in preclinical holographic microscopy? animal models for the treatment of spinal cord injury (SCI) and spinal muscular atrophy (SMA). Marie Annie Saucier¹, Nicolas Doyon¹, Yves For SCI, intraparenchymal injections allow for De Koninck¹ targeted gene transfer, but this delivery method ¹Centre de recherche de l'institut universitaire en is invasive and impractical to cover large areas santé mentale de Québec of the cord. Intrathecal injections are also invasive, and although they allow for delivery to Water fluxes through neuron membranes are a larger area, gene transfer throughout the essential in regulating homeostasis while entire spinal cord and brain may result in osmolarity is challenged by heavy synaptic detrimental side effects. Here, we demonstrate activity or high frequency spiking. The that MRI-guided focused ultrasound (MRgFUS) membrane displacement caused by the volume can be used to transiently permeabilize the change in response to such activity may be only blood-spinal cord barrier and allow for targeted, of a few tens of nanometres. The technique of non-invasive delivery of an adeno-associated holographic microscopy, a novel measurement virus (AAV) expressing a reporter gene, from the method, enables us to assess these small blood to the rat spinal cord. volume changes using interferometry. However, Immunohistochemistry, histology, and confocal indirect computations are necessary to infer microscopy were used to determine the location, magnitude and duration of synaptic current from efficacy and cell-specificity of gene delivery 13 240

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 days post treatment. The results show successful transduction of spinal cord neurons 3-IBRO-188 NMDA-R Affects Cellular and oligodendrocytes. Overall, this Process Formation in Tilapia Melanocytes; a demonstrates that MRgFUS-mediated delivery Model for Pigmented Adrenergic Neurons in of AAV is an effective method of non-invasive, Process Formation and Retraction targeted gene delivery to the spinal cord. 1 1 Olalekan Ogundele , Philip Adeniyi

IBRO – International Brain Research 1 Association Afe Babalola University

3-IBRO-187 Absence of endosomal NMDA-R is an important glutamate receptor SNAREs vti1a and vti1b led to significant implicated in neurogenesis, neuronal migration, neuronal degeneration in central as well as maturation and cell death, thus we investigated peripheral nervous system. the role of NMDA-R potentiation by glutamate/KCN and its inhibition by ketamine in Ajaya Kunwar¹, Micheal Rickmann², Gabriele the behavior of fish scale melanocytes in vitro. Fischer Von Mollard³, Kerstin Krieglstein⁴ This is aimed at establishing the regulatory role ¹Nepalese Army Institute of Health Sciences - of NMDA-R in this cell type (melanocytes College of Medicine, ²Georg August University isolated form Tilapia) in a similar manner to what of Goettingen, ³University of Bielefeld, is observable in the mammalian neurons. Glutamate treatment caused formation of short ⁴University of Freiburg cellular processes localized directly on the cell SNARE (Soluble NSF attachment protein body while ketamine treatment (inhibition of receptor) proteins play vital role in membrane NMDA-R) facilitated elongation of secondary trafficking events. SNAREs vti1a and vti1b share cellular processes (highly branched) from primary major processes (Less branched); co- 30% similarity in their amino acid sequences and have a distinct but overlapping subcellular incubation of glutamate and ketamine induced localization. Vti1a has role in trans-Golgi short and highly branched process formation. network/early endosomal fusion whereas vti1b is Cyanide toxicity induced degeneration and linked with late endosomal fusion/lysosomal reduction of cell size while co-treatment of degradation events. Mice deficient of both cyanide and ketamine gave changes similar to that observed in glutamate-ketamine co- endosomal SNARE proteins, vti1a and vti1b, die during intrauterine life just before birth, whereas incubation. NMDA-R is present in the single knockouts and triallelic mice survive and melanocytes. Activation of the receptor reduced reach normal age without difficulty. These KO elongation process, while inhibition of the mice have various deficits in central (CNS) and receptor facilitated cell process elongation and branching. This confirms that like pigmented peripheral nervous system (PNS). In CNS, they adrenergic cells of the nervous system, this cell show wide ventricles and lack several fibre tracts including anterior commisure. Corpus contains NMDA-R and this receptor also callosum thickness is greatly reduced and regulates cell process elongation. The study thalamocortical axons cannot cross pallio- also showed that inhibition of NMDA-R in subpallial border. On the other hand, only a few melanocytes gave opposite outcomes to the role of the receptor in developing neurons; a function corticothalamic fibres can reach to thalamus. In case of PNS, KO mice show various degrees of that is protective in adult neurons. neurodegeneration in number of ganglia. 3-IBRO-189 Microbats appear to have Trigeminal (TG), dorsal root (DRG) and nodose- adult hippocampal neurogenesis, but post- petrosal ganglia show severe capture stress causes a rapid decline in the neurodegeneration (98%) whereas vestibular number of neurons expressing doublecortin and cochlear ganglia show only 15-25% degeneration. This neurodegeneration was due Richard Chawana1 to the lack of delivering efficient plasma membrane required during axonal growth cone 1University of the Witwatersrand formation. Disparity in neurodegeneration among these ganglia could be due to the A previous study investigating potential adult distance between the ganglia and their target. hippocampal neurogenesis in microchiropteran Overall phenotype suggests that neuronal cell bats failed to reveal a strong presence of this require adequate endosomal traffic events to neural trait. As microchiropterans have a high produce their normal axonal growth. field metabolic rate and a small body mass, it is 241

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 possible that capture/handling stress may lead to E12 rat embryos notably reduced VM to a decrease in the detectable presence of Tyrosine Hydroxylase (TH) staining 2 days later, adult hippocampal neurogenesis. Here we without affecting GABA or serotonin neurons. looked for evidence of adult hippocampal qRT-PCR and Western blot analyses confirmed neurogenesis using immunohistochemical that several markers important for the techniques for the endogenous marker generation and maintenance of DA lineage were doublecortin in 10 species of microchiropterans significantly diminished. We injected H1R or euthanized and perfusion fixed at specific time H2R antagonists to identify the receptor points following capture. Our results reveal that responsible for the detrimental effect of HA on when euthanized and perfused within 15 DA lineage and found that activation of H1R was minutes of capture, abundant putative adult required. To identify the cell type susceptible to hippocampal neurogenesis could be detected HA action, we injected embryos of different using doublecortin immunhistochemistry. developmental stages, and found that neural Between 15 and 30 minutes post-capture, the progenitors (E10 and E12) were responsive, detectable levels of doublecortin dropped whereas differentiated DA neurons (E14 and dramatically and after 30 minutes post-capture, E16) were not susceptible to HA actions. immunohistochemistry for doublecortin could not Accordingly, the expression of H1R is co- reveal any significant evidence of putative adult localized with the neural precursor marker hippocampal neurogenesis. Thus, as with all Nestin at E12, but not at E14. These results other mammals studied to date, bats, including reveal a novel action of HA affecting both microchiropterans and megachiropterans, dopaminergic lineage during VM development. appear to exhibit substantial levels of adult hippocampal neurogenesis. The present study 3-IBRO-191 A novel role for medial underscores the concept that, as with laboratory prefrontal cortex in taste aversion memory experiments, studies conducted on wild-caught Carolina Gonzalez1, Maria Villar1, Micol animals need to be cognizant of the fact that 1 1 1 stress (capture/handling) may induce major Tomaiuolo , Haydee Viola , Jorge Medina changes in the appearance of specific neural 1 traits. IBCN - School of Medicine - University of Buenos Aires 3-IBRO-190 Histamine impairs midbrain dopaminergic development in vivo by The role of the medial prefrontal cortex (mPFC) activating histamine type 1 receptors in taste aversion memory processing has been scarcely investigated. Few works have studied Itzel Escobedo Avila1, Fernanda Vargas- its participation in conditioned taste aversion Romero1, Anayansi Molina-Hern·ndez2, (CTA) extinction memory and only one work Rodrigo LÛpez-Gonz·lez3, Daniel CortÈs1, described a prefrontal b-adrenergic receptors Juan De Carlos4, Iv·n Velasco1 requirement in CTA memory formation. Nevertheless, it has recently been described 1Instituto de FisiologÌa Celular-Neurociencias, that mPFC neurons can encode aspects of UNAM, 2Instituto Nacional de PerinatologÌa, gustatory stimuli suggesting that this cortex 3University of Massachusetts, 4Instituto Cajal could be part of the encoding taste network. In this work, we studied the involvement of the Histamine (HA) regulates sleep-wake cycle, mPFC in taste memory processing using the synaptic plasticity and memory in adult CTA task in rats. We microinfused the protein organisms. Dopaminergic specification in the synthesis inhibitor emetine, the GABAa receptor embryonic ventral midbrain (VM) coincides with agonist muscimol or the N-methyl-d-asparate increased HA brain levels. To study the effect of (NMDA) receptors antagonist AP-V into the HA receptor stimulation on dopamine (DA) mPFC before CTA training. We found that all neuron generation, we administered HA to DA these treatments impaired the formation of CTA progenitors, both in vitro and in vivo. Embryonic long-term memory, but not its acquisition. day 12 (E12) VM expressed HA receptors H1R, Furthermore, we infused muscimol before a H2R and H3R. These undifferentiated 72h-retention test session and observed progenitors increased intracellular calcium upon impairment in CTA long-term-memory retention. HA addition. In HA-treated cultures, DA neuron These results indicate that neural activity, numbers significantly decreased. We performed protein synthesis and NMDA receptors in the intrauterine injections in the developing VM to mPFC are necessary during traning or early investigate HA effects in vivo. HA administration after for CTA memory consolidation and that this

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CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 cortex is required for normal CTA memory glomeruli is conserved across species, their retrieval. Altogether, our findings suggest that particular role in olfactory processing is not fully the mPFC is an essential structure taking part in understood. Also, it remains unclear whether the CTA memory processing network. sensory experience actively participate in the formation of glomeruli as in the further process 3-IBRO-192 Enriched environment and of refinement and remodelling. We studied the neuronal plasticity in the hippocampus of composition, formation and maintenance of adolescent and adult mice glomeruli in knock-in mice whose I7 and M72

1 2 primary afferents express GFP and betta-gal, Salma Hamed , Alice Guyon correspondingly. Animals were continuously 1 2 exposed to heptaldehyde and acetophenone, Alexandria university, Institut de cognate ligands of these olfactory circuits during PharmacologieMolÈculaire etCellulaire CNRS, different stages of postnatal development. Our Valbonne, France results revealed that exposure from postnatal day (PD) 0 to 20 led to the formation of Enriched environment (EE) on rodents positively permanent supernumerary I7 and M72 glomeruli regulate the remodeling of neural circuits, in a dose and time dependent manner. promoting memory consolidation, hippocampal Glomeruli in exposed mice were formed within long-term changes in the strength of synaptic the same regions of olfactory bulb and occupy weight and neurogenesis. However, the fine small space volumes compared to non-exposed mechanisms by which environment shapes the mice. When exposed from PD 5 to 10 glomeruli brain at different development stages and the were high in number, had an irregular shape, duration required to induce such changes are and were interconnected, nonetheless if odorant still a matter of debate. In this study, weaned exposure is interrupted until PD 20, glomeruli mice were housed in EE for 4, 6 or 8 weeks and morphology is recovered and their number compared with matched control mice raised in slightly decreased. We suggest that local standard environment (SE). To investigate the reorganization of the primary afferents caused differential effects of EE on immature by odorant exposure could participate in the developmental and mature brains, we also process of formation of supernumerary glomeruli housed adult mice (8 weeks old) for 4 weeks in and that the developing olfactory system EE. We studied the influence of onset and through sensory experience actively maintains duration of EE housing upon the structure and glomerular morphology and number. function of hippocampal neurons. We found that 1) EE enhances neurogenesis in the 3-IBRO-194 Memory reactivation and hippocampus at youth but not at adulthood gene expression in striatum, hippocampus stage, 2) EE increases the number of synaptic and amygdala contacts at every stage, 3) EE modifies differentially long-term potentiation as well as Sofia Gonzalez-Salinas1, Eduardo Alvarado spontaneous and miniature activity at the Ortiz1, Andrea Cristina Medina1, Anaid glutamatergic synapses depending on the onset Antaramian1, Gina Lorena Quirarte1, Roberto and duration of EE. Our study emphasizes the Agustin Prado-Alcala1 importance of environment of life, particularly cognitive, sensory and motor stimulations, on 1Universidad Nacional Autonoma de Mexico brain plasticity during postnatal maturation. The course of a memory continues after 3-IBRO-193 Supernumerary formation of consolidation as this can be modified by olfactory glomeruli and morphological retrieval. Extinction or reconsolidation can take recovery following continuous exposure to place after a memory is retrieved; those ligands of specific olfactory receptors processes can attenuate or strengthen that

1 2 memory, respectively. Pharmacological studies Valle-Leija Pablo , René Drucker-ColÌn have found elements needed to retrieve a memory; nevertheless different approaches 1Instituto de Investigaciones BiomÈdicas, 2 might be used to identify new ones that could UNAM, Instituto de FisiologÌa Celular, UNAM play a role after retrieval. In this study we investigated the temporal and regional Olfactory glomeruli are formed by the expression of genes that code for proteins in the convergence of axons of the same type of MAPK pathway following memory retrieval. We sensory neurons onto the olfactory bulb. evaluated mRNA levels of chrm1, erk1, arc and Although the anatomical organization of 243

CAN-ACN 2014: Abstract Booklet Montreal, May 25-28 zif268 that code for the cholinergic muscarinic GLAST signalosome includes among other receptor M1, a MAPK, a cytoskeleton protein proteins, the Na /K ATPase, the Na /Ca2 and a transcription factor, respectively. Gene exchanger (NCX), mTOR, p60Src and expression was analyzed in striatum, amygdala, Glutamine Synthetase (GS). Interestingly, the and dorsal hippocampus using Real-Time PCR. use of specific inhibitors for the proteins At 30 min after memory retrieval of an inhibitory mentioned reduces GLAST activity, suggesting avoidance task, an increase in arc associated to that signalosome integrity is needed for the retrieval was observed only in striatum. On the proper Glu removal. Our results add new other hand, zif268 increased at 30 min in mediators of Glu effects and strengthen the striatum and hippocampus. The increase of critical role of Bergmann glia in cerebellar zif268 was maintained in striatum and glutamatergic neurotransmission. hippocampus up to 90 and 180 minutes, respectively. We show for the first time that arc 3-IBRO-196 Regulation of the glutathione and zif268 mRNAs were increased in striatum and reactive oxygen species during after memory retrieval and we propose that cerebellar granule neurons development these changes could be related to processes Mauricio Olguin-Albuerne1, Mauricio Olguin- taking place following memory reactivation. 1 1 These findings provide insights for manipulating Albuerne , Julio Moran zif268 to change the fate of a memory after 1 retrieval. National Autonomous University of Mexico / Institute of Cellular Physiology 3-IBRO-195 Na+-dependent glutamate/aspartate transporter Reactive oxygen species (ROS) are highly (GLAST/EAAT-1) signalosome in Bergmann reactive molecules derived from molecular glia oxygen, these molecules could act as signaling molecules, regulating numerous physiological Zila Martinez-Lozada1, Alain Guillem1, Luisa processes. In this study we aim to determine the Clara Hernandez-Kelly1, Jose Aguilera2, relevance of ROS during cerebellar granule Arturo Ortega1 neurons (CGN) development. For this porpoise we evaluated the levels of ROS and glutathione 1Cinvestav del IPN, 2Universitat Autonoma de content in CGN cultures from 0 to 8 days in vitro Barcelona (DIV). We found that during the first 2 DIV, CGN gradually increase the levels of ROS measured Glutamate, the main excitatory amino acid by dihydroethidium oxidation. The highest levels transmitter in the vertebrate brain triggers a wide were founded at 2 DIV, this increment was variety of signal transduction cascades that sustained until 3 DIV. After 3 DIV, the levels of regulate protein synthesis at the transcriptional ROS return to the basal levels founded at 1 DIV. and translational levels. Activity-dependent In addition, the levels of reduced glutathione differential gene expression has been attributed (GSH) increased two fold from 0 to 1 DIV, to the activation of ionotropic and metabotropic preceding the peak of ROS founded at 2 and 3 glutamate receptors, however recent findings DIV. The high levels of GSH were sustained had shown that the electrogenic Na -dependent until 5 DIV, and at 8 DIV the levels of GSH glutamate transporters, responsible of its returned until the basal levels founded at 0 DIV. removal from the synaptic cleft participate in To determine the relevance of this increase in glutamate-induced signaling. Although these GSH levels during CGN development, we transporter proteins are present in neurons and inhibited the synthesis of GSH with BSO during glia cells, the vast majority of the transport takes different periods. When GSH synthesis was place in glial cells. Within the cerebellum, inhibited with 48 h treatments from 0 to 2 DIV, Bergmann glia cells are responsible for most of the totality of CGN died, which was completely glutamate uptake activity through the Na - rescued by the antioxidant Euk-134. However, dependent glutamate/aspartate transporter these treatments did not alter the cell viability (GLAST/EAAT-1). With this in mind we decide to from 5 DIV onwards. These results suggest that investigate GLAST/EAAT1 signaling partners, the balance between the antioxidant and pro- using cultured Bergmann glial cells, oxidant systems are essential for normal CGN immunoprecipitation assays coupled to Western development. blot and we measured GLAST activity through radioligand transport assays. Though this approach we were able to demonstrate that the

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