The Canadian Association for Neuroscience presents 9th Annual Canadian Neuroscience Meeting 2015 ABSTRACT BOOKLET ABSTRACT

May 24–27, 2015 Westin Bayshore Hotel www.can-acn.org Vancouver, BC CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

INVITED SPEAKERS restrained, orienting of the line of sight can be brought about by coordinated movements of the Presidential Lecture: eyes, head, and body, and may also incorporate subtle changes in pupil diameter. A key oculomotor Melvyn Goodale, University of Western Ontario area is the superior colliculus (SC), which coordinates an ancient orienting reflex via outputs that distribute How We See and Hear Stuff: Visual and Auditory widely within the brainstem and spinal cord to Routes to Understanding the Material Properties of saccadic and other premotor and autonomic circuits. Objects There are key differences in the response properties Almost all studies of object recognition, particularly of such downstream circuits, with saccadic circuits in in brain imaging, have focused on the geometric particular having the highest threshold for structure of objects (i.e. ‘things’). Until recently, engagement. Because of such differences, non- little attention has been paid to the recognition of saccadic circuits are, somewhat paradoxically, more the materials from which objects are made (i.e. responsive to subtle changes in upstream SC ‘stuff’), information that is often signalled by signaling. In my talk, I will illustrate how this surface-based visual cues (the sheen of polished framework provides a unifying explanation to a metal) as well as auditory cues (the sound of water variety of curious findings, including short-latency being poured into a glass). But knowledge about neck and limb muscle recruitment time-locked to the stuff (the material properties of objects) has onset of visual stimuli, the modulation of such profound implications, not only for understanding responses with cognitive state, and the elaboration what an object is, but also for the planning of of non-saccadic responses following sub-threshold actions, such as the setting of initial grip and load stimulation of the frontal cortex. forces during grasping. In recent years, our lab has Christopher Pack, McGill University made some headway in delineating the neural systems that mediate the recognition of stuff (as A sensorimotor role for oscillations in the visual opposed to things), not only in sighted people but cortex also in blind individuals who use echoes from tongue clicks to recognize the material properties of objects Brain activity is often observed to be oscillatory, they encounter. I will discuss evidence from both meaning that it increases and decreases in strength neuropsychological and fMRI studies demonstrating at regular intervals. Oscillations at particular that lateral occipital regions in the ventral stream frequencies often vary in strength depending on a play a critical role in processing the 3-D structure and sensory stimulus or the cognitive state of the geometry of objects, whereas more anteromedial subject. As a result, oscillations have figured regions (particularly areas in the parahippocampal prominently into many models of brain function, gyrus and collateral sulcus) are engaged in particularly the hypothesis that oscillations provide a processing visual and auditory cues that signal the way to synchronize the timing of long-range material properties of objects. communication across neural ensembles. In this presentation I will focus on the spatial Plenary Symposium: structure of oscillations measured via the local field potentials (LFP) in primate visual cortex. In particular Seeing and moving: how the brain controls vision I will discuss recent recordings from area V4 of and gaze monkeys implanted with chronic multi-electrode Brian Corneil, Robarts Research Institute recording arrays. Our results show that there is a spatial pattern of oscillatory activity across Through the looking glass: reflections of sensory retinotopic maps of visual space, and that this and cognitive processing in the motor periphery pattern is reorganized by the execution of saccadic eye movements. Saccade-related LFP patterns in The oculomotor system, which rapidly moves or turn seem to regulate the timing of single-neuron stabilizes the line of sight, is one of the best- spiking activity, providing a possible basis for understood motor systems in the human brain. optimizing perisaccadic visual perception. I will While this system is often studied via discrete suggest that well-known phenomena such as saccadic eye movements made with the head perisaccadic remapping, saccadic suppression, and CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

saccadic momentum are consistent with a role for Plenary Symposium: oscillations in linking oculomotor commands with visual processing. Mike Salter, Sick Kids

Featured Plenary Speaker: From Receptors to Pain: The Molecular Dynamics of Pain Mayank Mehta, UCLA Neuron-microglial interactions are increasingly From Virtual Reality to Reality: How Neurons Make recognized as being key for physiological and Maps pathological processes in the central nervous system. Microglia have been found to play a causal All animals move through space. What are the role in neuropathic pain behaviours resulting from sensory and biophysical mechanisms that generate peripheral nerve injury, and a core neuron-microglia- mental maps of space? How do these maps neuron signaling pathway has been elucidated. contribute to behavior? Despite tremendous Within the dorsal horn, microglia suppress neuronal progress these questions have not been fully inhibition by a cascade involving activation of resolved, partly because it is difficult to precisely microglial P2X4 receptors causing the release of measure, let alone manipulate, the wide range of brain derived neurotrophic factor (BDNF). BDNF acts sensory and motor variables that change when on trkB receptors which leads to a rise in subjects move in space. Hence, we have developed a intracellular chloride concentration in dorsal horn noninvasive, immersive and multisensory virtual nociceptive output neurons, transforming the reality system where precisely controlled stimuli response properties of these neurons. In addition determine the surrounding virtual space, and to suppressing inhibition, peripheral nerve injury nonspecific stimuli are spatially uninformative. We causes activity-dependent facilitation at dorsal horn simultaneously measured rats’ behavioral glutamatergic synapses which enhances nociceptive performance and the activities of thousands of transmission. This enhancement is mediated by neurons from the hippocampal circuit while rats intracellular signaling networks involving performed complex tasks, including the Virtual serine/threonine and tyrosine kinases within Morris Water Maze task. We also developed nociceptive transmission neurons. Key for this computational techniques to decipher the emergent enhancement is facilitation of NMDA receptor neural dynamics. This integrative, experiment-theory function by Src family tyrosine kinases. Recently we approach provided many surprising results. For have discovered that microglia-to-neuron signaling is example, when only the visual landmarks provide not only critical for pain hypersensitivity after spatial information, more than half of hippocampal peripheral nerve injury but also for the paradoxical neurons shut down and the remaining active hyperalgesic effect of morphine and other opioids. neurons are unable to form robust spatial maps, We anticipate that by targeting microglia-neuron contrary to commonly held theories. Instead, signaling pathways new therapeutic strategies for additional multisensory cues are required to chronic pain as well as its comorbid sequelae may be generate spatially selective activity. Indeed, inclusion developed. of consistent locomotion cues generates spatial maps, but they encode relative distance traveled, Lisa Topolnik, Universite Laval not an allocentric representation of space. Theta rhythm too is significantly altered in virtual reality. Synaptic integration and plasticity gradients in We propose a “multisensory-pairing” hypothesis for dendrites of hippocampal inhibitory interneurons hippocampal function where the entorhinal- hippocampal circuit forms rapid associations Hippocampal interneurons play a critical role in the between multisensory stimuli using both cooperative spatiotemporal organization of principal cell and competitive mechanisms. This can explain the assemblies and formation of memory fields. The formation of diverse representations of space under synaptic mechanisms responsible for recruitment of different conditions. distinct subtypes of interneurons in governing network activity are a matter of intense investigation, as it is still largely unknown how do interneurons integrate multiple inputs during CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

specific brain states. In addition, understanding the The current decade is emerging as golden age of mechanisms of multiple forms of synaptic plasticity neuroanatomy. Connectomics began was defined a experienced by interneurons and providing for decade ago, mostly as an aspiration for the future, functional segregation of GABAergic inputs but is likely to emerge as a mature field in this converging onto principal cells remain an open decade. In the first published use of the term question. Using two-photon microscopy and whole- (Sporns, Tononi, and Kotter, 2005 PLos Comp Biol), it cell patch-clamp recordings in combination with was recognized that connectomics should be computational simulations, we have examined the considered on multiple scales, from the macroscale mechanisms of synaptic integration and plasticity of entire brains to the microscale of individual along a somatodendritic axis of hippocampal basket synaptic connections between neurons. At the Allen cells (BCs). Significant fluctuations in the summation Institute, we have begun a ten-year program to of excitatory inputs through a variable contribution study the cerebral cortex of mice and humans. The of GluA2-lacking AMPA vs NMDA receptors have mouse program, called MindScope, concentrates on been detected in dendritic branches of parvalbumin- the cortico-thalamic visual system and seeks to positive BCs, with a direct impact on the synapse- examine the computations that lead from visual specific integration and direction of long-term input to behavioral responses. In this program, there plasticity. In contrast, cholecystokinin-positive BCs is a strong emphasis on neuroanatomy, or have shown a variable gain function for excitatory connectomics at a macro- and microscale. Already a inputs but also a somatodendritic gradient in the large-scale study of mesoscale connectivity in the expression of Cav3.1 Ca2+ channels, which mouse brain has been completed (Oh et al., 2014 controlled LTP induction at inhibitory synapses. The Nature). Future work will include further mesoscale lifetime of Ca2+ elevations in dendrites of BCs was connectivity atlases that concentrate on the mouse critical in pacing down their activity through the cell visual system, as well as microscale connectivity of type-specific induction of depression at excitatory or local cortical circuits. At a microscale, we have potentiation at inhibitory synapses. These data demonstrated that the relationship between indicate that afferent inputs can differentially structure and synaptic connectivity can be studied in activate the two subtypes of BCs through the cell local cortical circuits by combining in vivo physiology type- and input-specific dendritic mechanisms, with subsequent network anatomy with electron providing for flexible recruitment of BCs during microscopy (Bock et al., Nature, 2011; and network activity. subsequent studies), leading towards a functional connectome (Reid, 2012, Neuron). I will examine the Featured Plenary Speaker: near-term and long-term prospects for microscale connectomics and argue that connectomics at all Karel Svoboda, HHMI Janelia Farm Research Campus scales must be combined with functional studies to fully exploit its great promise. Illuminating the neural circuits underlying tactile decisions Plenary Symposium:

Optical methods are revolutionizing our Mei Zen, University of Toronto understanding of neural circuits. Cellular imaging allows measurements of cording of information in The Development and Operation of the C. elegans populations of defined cell types and subcellular Motor System structures. Optogenetic manipulations permit testing for causality of patterns of neural activity and Animals sense environments and respond with behavior. We use these tools to dissect the circuit changes in motility. These sensorimotor behaviors mechanisms underlying tactile decision making in are fundamental to life, and governed by nervous behaving mice. systems. All nervous systems undergo postnatal development, predicting changes in circuit Keynote Lecture: connections. There is however surprisingly little understanding of how synaptic wiring changes, and Clay Reid, Allen Institute for Brain Science how they affect behaviors during development. In C. elegans, the 302 neuron adult nervous system was Functional Connectomics at the Allen Institute reconstructed by serial section electron microscopy CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

(EM), yielding the first connectome for an entire The ability to identify food that is nutrient-rich and animal. Yet the adult nervous system starts from 220 avoid toxic substances is essential for an animal's neurons at birth; the animal also grows fourfold in survival. Although olfaction and vision contribute to size, adding new glia, muscles and epidermis. food detection, the gustatory system acts as a final Throughout postnatal development, the nervous checkpoint control for food acceptance or rejection. system remains functional, even as new neurons, The fruit fly Drosophila melanogaster tastes many of glia and non-neuronal partners integrate into the same stimuli as mammals and provides an existing circuits. Combining EM, calcium imaging, excellent model system for comparative studies of optogenetics and molecular genetics, we are taste detection. The relative simplicity of the fly addressing how the growing nervous system brain and behaviors, along with the molecular remodels and regulates motor behaviors across genetic and functional approaches available in development. Applying acquired insights on motor Drosophila, allow the examination of gustatory circuit function, we have further established relevant neural circuits from sensory input to motor output. C. elegans models for human disorders, and applying We have utilized a combination of molecular, them to address underlying physiological defects. behavioral, and calcium imaging studies to determine the taste ligands that different gustatory Douglas Altshuler, University of British Columbia neurons detect and how taste information is processed in the higher brain. More recently, we Visual motion perception in avian flight have begun to examine how hunger, satiety and learning influence activity in taste circuits and Flying birds use diverse sensory information to guide regulate feeding decisions. These studies provide their flight, and the available evidence suggests that insight into how taste compounds are detected and visual information plays a prominent role in flight processed by the brain. control. For example, the avian midbrain in general, and the optic tectum in particular, are relatively Parallel Symposia: much larger than homologous regions in other vertebrates. Although there is considerable Symposium 1: Glial handling of neuronal functions: information available about the neural circuitry for from synapses to blood flow sensing and processing visual motion in birds, there is a major gap in our understanding of how motion Overview: perception is used during flight. Our research aims to Glia are very dynamic cells that regulate a large unify electrophysiological and immunohistochemical variety of neuronal functions. This workshop will investigations of neural circuitry with behavioural highlight some recent aspect of the dynamic and studies of visual guidance. We work with pluripotent roles that glial cells play in the regulation hummingbirds and zebra finches, which differ in of various neuronal functions. This will span from the flight behaviour and neuroanatomy but have fast fine regulation of molecular organisation at synapses wingbeat frequencies and similar muscle physiology. to the whole in vivo brain activity and functions. Our most recent work has demonstrated that Stéphane Oliet will discuss the dynamic regulation of hummingbirds are extraordinarily sensitive to global glutamate transporters in processes of astrocytes visual motion during hovering flight, even when the while Keith Murai will discuss the role of glial motion is small and displayed in the presence of interactions in shaping dendritic spines. Marie-Eve prominent stationary features. Current research is Tremblay will discuss the interplay between focused on how visual motion processing guides astrocytes and microglial cells in the regulation of other flight modes and flight mode transitions, and synapse elimination and Hélène Girouard will then how cellular responses to visual motion differ across discuss the regulation of blood flow by astrocytes as flight behaviours and species. a function of neuronal activity. This would represent an opportunity to have a workshop regrouping Featured Plenary Speaker: young Canadian investigators (Girouard and Kristin Scott, UC Berkeley Tremblay) with more senior researchers (Oliet and Murai). Taste processing in Drosophila Speakers: Stéphane H. R. Oliet | Université de Bordeaux CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

Surface dynamics of the astrocytic glutamate Stephen G. Lomber | University of Western Ontario transporter GLT-1 Vocalization Processing Along a “What” Processing Pathway in Auditory Cortex Marie-Ève Tremblay | Université Laval Microglial remodeling of neuronal circuits in the Sarah M.N. Woolley | Columbia University healthy brain Neural Basis and Behavior of Social Communication

Keith Muray | McGill University Susan A. Graham | University of Calgary, Hotchkiss Neurons actively sustain the unique molecular and Brain Institute physiological properties of astrocytes in the adult Preschoolers’ Real-Time Processing of Vocal brain through morphogen signaling pathways Emotional Information

Hélène Girouard | Université de Montréal The astrocytic contribution to neurovascular Symposium 3: Shaping inhibition: new insights into coupling in health and disease the development and function of GABAergic inhibitory interneurons in the cortex

Symposium 2: Development and Processing of Overview: Vocal and Social Communication In the mammalian cortex, GABAergic inhibitory interneurons are remarkably diverse in terms of Overview: morphology, connectivity, and physiological There is tremendous information carried in all properties. In addition to their recognized roles in vocalizations. For instance, we are very sensitive to maintaining the E/I balances, recent studies have human voices and can readily recognize others by suggested that different subtypes of inhibitory listening to their voice. Our vocal inflections also interneurons can be involved in sensory processing, have emotional content which relay how we feel, learning and memory, and cognitive behavior. In this and what we hope to elicit in others. This means that symposium, speakers will present data using a our communication system is fundamentally a social variety of approaches, including genetic one, and many other social animals share the basic manipulations, electrophysiology, optogenetics, and properties of human vocal communication. This in vivo two-photon imaging to provide new insights conceptual link allows us to study the into the development and function of GABAergic communication systems in humans and other inhibitory interneurons. Dr. Graziella Di Cristo will species. Recently, much progress has been made in discuss how neural activity regulates the understanding the neural mechanisms underlying innervations of cortical basket cells. Dr. Melanie various components of communication in both Woodin will address the molecular mechanisms of humans and non-human animals. These studies synaptic plasticity of inhibitory synapses in the reveal how the brain extracts, represents, and hippocampus. Dr. Mingshan Xue will move into in encodes not only the physical features of a vivo system and show how different subtypes of communication signal but also their perceptual interneurons equalize E/I ratios during visual representations and other abstract quantities (eg, processing. Dr. Simon Chen will focus on the role of semantic meaning). In this symposium, we will subtype-specific reorganization of inhibitory circuits discuss new and exciting data that identify these during motor learning in awake and behaving mice. important relationships across a variety of animals (songbirds, cats, monkeys, and humans) using an Speakers: integrative approach of psychophysical, Graziella Di Cristo | Université de Montréal electrophysiological, and functional imaging Mechanisms regulating GABAergic cell innervation techniques. fields in the adolescent brain

Speakers: Melanie Woodin | University of Toronto Yale E. Cohen | University of Pennsylvania Inhibitory Synaptic Plasticity and Chloride Regulation Mechanisms Underlying Auditory Decision-Making in the Hippocampus

CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

Mingshan Xue | Baylor College of Medicine Symposium 5: Imaging brain complexity Inhibitory synapses equalize excitation-inhibition ratios across cortical neurons Overview: The brain is a complex organ, containing billions of Simon Chen | University of California, San Diego neurons, each connected through synapses to Cell-type specific reorganization of inhibitory circuits several thousand other neurons. Therefore an during motor learning appreciation of how the brain works necessarily involves understanding how information is Symposium 4: Neural stem cells in cognitive repair integrated both in individual neurons, as well as and aging across brain regions. This symposium brings together 4 Canadian researchers tackling this complexity at Overview: both the micro- and macroscales. Using new tools to An evolving body of work indicates that resident image dendritic activity at high speed in vivo, stem cells function to maintain and in some cases Podgorski will show how sensory inputs are repair tissues. These findings have led to the idea integrated in a single neuron in the developing that if we could recruit these stem cells, then we Xenopus. Frankland has developed whole brain could enhance repair or regeneration. For example activity dependent mapping approaches in mice, and in rodents, exercise, learning, and enriched used graph theoretical approaches to define environment enhance, and stress and aging suppress functional networks engaged by fear memory. neurogenesis or oligodendrogenesis. Here, Liisa Mohajerani has developed voltage-sensitive dye Galea will present data on how estrogens affect wide-field imaging approaches to investigate hippocampus-dependent neuroplasticity and hippocampal-cortical interactions during sleep. Ko cognition and how reproductive experience uses FDG-PET in patients with movement disorders, moderates those effects in aging. Cindi Morshead and will present graph theoretical analyses to will present on how metformin repairs stroke understand the underlying cause of aberrant damage in postnatal mice by enhancing network activity. neurogenesis. Don Mabbott will talk about his recent findings (in review in New Eng J Med) on how Speakers: exercise greatly improves cognition and increases Kasper Podgorski | Howard Hughes Medical hippocampal volume and white matter in children Institute with brain injuries. David Kaplan will provide a short Comprehensive 3D imaging of synaptic activity in the overview and short talk on maternal influences on awake brain adult neurogenesis in progeny. Majid Mohajerani | University of Lethbridge Speakers: In vivo optical imaging assessment of mouse cortical- David Kaplan | The Hospital for Sick Children hippocampal dialogue during sleep Introduction, and Long-term effects of maternal infection and diabetes on neural stem cell pools Paul Frankland | The Hospital for Sick Children Pharmacogenetic interrogation of a fear memory Lisa Galea | University of British Columbia network Estrogens, memory, neuroplasticity and aging: the good, the bad and the ugly Ji Hyun Ko | University of Manitoba Network analysis approach with metabolic PET Cindi Morshead | University of Toronto imaging in neurodegenerative movement disorders Activating endogenous stem cells to promote brain repair and cognitive recovery Symposium 6: Are you what you eat? Impact of diet on mesocorticolimbic circuit Donald Mabbott | The Hospital for Sick Children Training the brain to repair itself Overview: Obesity can be viewed as a disorder of decision- making. Feeding is not only governed by homeostatic energy signals, but also by stress, CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

variety and availability of low cost calorically dense systems. Dr. Cayouette will present a novel foods, habitual factors and even previous diet that transcriptional cascade controlling temporal identity govern our decisions of what and when to consume. progression in retinal progenitor cells and how it This symposium will explore the neurobiological might improve strategies for cell replacement mechanisms of how diet can influence our feeding therapy. Dr. Wallace will discuss the importance of behavior. Dr. Fulton will demonstrate that lipid type maintaining morphogen responsiveness for the can influence signaling and behavior within the production of neurons in the retina. Dr. Deppmann mesolimbic system. Dr. Winstanley will demonstrate will discuss the function of TNF receptor family that impulse control is affected in rats consuming a members in the formation of somatosensory high fat diet. Dr. Borgland will demonstrate that a neurons and their importance for proprioception cafeteria diet promotes compulsive eating and and touch sensation. Dr. Cloutier will describe how dysfunction in the orbitofrontal cortex. Finally, Dr. cell-cell interactions influence both the generation Dagher will show functional imaging data on and survival of sensory neurons in the olfactory decision-making, food valuation, and appetite epithelium. control as they relate to weight gain in humans. Together, this symposium will implicate diet-induced Speakers: alterations in the mesocorticolimbic system resulting Valerie Wallace | Toronto Western in changes in ingestive behaviour. Notch and Hedgehog cross talk in neural progenitors converges on Gli2 activity Speakers: Thierry Alquier | University of Montreal Michel Cayouette | Institut de recherches cliniques Regulation of mesolimbic function, reward and de Montréal feeding by lipids A Conserved Regulatory Logic Controls Temporal Identity in Mouse Neural Progenitors Catharine Winstanley | University of British Columbia Christopher Deppmann | University of Virginia Steady-state consumption of a high-fat diet can Molecular Rheostats Governing Sensory Perception decrease impulse control even in the absence of excessive weight gain Jean-François Cloutier | McGill University Cellular interactions in the control of neural Stephanie Borgland | Hotchkiss Brain Institute progenitor cell differentiation Compulsive eating reduces inhibitory control of pyramidal neurons of the lateral OFC Symposium 8: Homeostatic plasticity: molecular mechanisms and physiological function Alain Dagher | McGill University Brain Endophenotypes of Obesity Overview: Synapses have the capacity to alter their strength in Symposium 7: Establishment and maintenance of a process called synaptic plasticity. Plasticity can cell diversity in sensory system function occur at individual synapses in the form of LTP and LTD, forming the cellular basis of learning and Overview: memory, or more globally during homeostatic The degeneration of neurons in sensory systems and plasticity in order to regulate neuronal firing rates their associated pathologies, such as loss of vision and network activity. Homeostatic plasticity was and olfaction, represent a growing problem in our originally described as a scaling of excitatory aging population. The development of stem cell synapses. Recent investigations have shown that based regenerative therapies in sensory systems homeostatic plasticity involves different synapse requires a fundamental understanding of the types, occurs over different spatial scales and in molecular mechanisms underlying the generation multiple brain regions. Despite advances in and function of these neurons. This symposium will understanding the molecular mechanisms underlying describe how both intrinsic and environmental homeostatic plasticity, its impact on information factors impinge on the generation and function of processing or on learning and memory through neurons in the visual, olfactory, and somatosensory interaction with LTP/LTD remain largely unknown. CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

This symposium will highlight the various forms and Cortical lineages are primed by the competing functions of homeostatic plasticity, including lineage determinants Neurog2 and Ascl1 plasticity of excitatory and inhibitory synapses, the involvement of glia, and the role of this plasticity Stefano Stifani | McGill University type in different physiological states such as Regulation of neurogenic and anti-neurogenic inflammation, stress and sleep. transcription factors during murine cortical neurogenesis Speakers: David Stellwagen | McGill University Ruth Slack | University of Ottawa TNF-mediated suppression of striatal reward Mitochondrial -mediated regulation of stem cell dysfunction maintenance and cell fate decisions

Jaideep S. Bains | Hotchkiss Brain Institute David Picketts | Ottawa Hospital Research State-dependent plasticity in stress circuits Institute Defining the role of chromatin remodeling proteins Salvatore Carbonetto | McGill University in balancing progenitor expansion with Dystroglycan Mediates Homeostatic Plasticity at differentiation during cortical neurogenesis GABAergic Synapses Symposium 10: New insights into classical memory Graham Diering | John Hopkins University issues. Homeostatic scaling-down of excitatory synapses during sleep Overview: This symposium brings together a group of Symposium 9: Regulatory mechanisms in cortical internationally renowned researchers who study neurogenesis cutting edge issues in memory processing. The talks will discuss issues involved from simple to complex Overview: systems. Specifically, using wild-type and mutant The regulation of neurogenesis in the developing strains of c. elegans, Prof. Rankin explores nuanced cerebral cortex is highly dynamic and complex, being issues on the molecular neurobiology of memory influenced by gene regulatory programs interacting consolidation mechanisms. Using a technique that with epigenetic mechanisms to establish cell fates. enables single cell resolution over brain areas, Prof The symposium with open with a lecture from Dr. Sauvage will discuss the specific areas implicated Carol Schuurmans (University of Calgary) on her within the medial temporal lobe mediating memory recent findings concerning the role of the proneural tasks. Prof Bolshakov will discuss a completely new factors Neurog2 and Ascl1 in priming cell lineage finding in neuroplasticity. All previous work has selection in the neocortex. This will be followed by a shown that the molecular and cellular correlates lecture by Dr. Stefano Stifani (McGill University) on induced by learning are reversed when amnesia is mechanisms that antagonize the functions of induced. Prof Bolshakov found that learning induced proneural factors during cortical neurogenesis and changes in pre-synaptic efficacy. Surprisingly, he regulate the transition from neurogenesis to found that reconsolidation blockade led to a gliogenesis. The third lecture by Dr. Ruth Slack reduction in the post-synaptic mechanisms but (University of Ottawa) will highlight recent findings spared the pre- synaptic changes induced by that mitochondrial function impinges on cortical cell learning. The pioneering work in forgetting byProf fate decisions. The final talk of the session by Dr. Kida shows that forgetting is a neurobiologically David Picketts (Ottawa Hospital Research Institute) conserved phenomenon and not brain dysfunction will discuss the crucial role of chromatin remodelling as commonly believed. in balancing cortical progenitor proliferation with differentiation. Speakers: Catharine Rankin | University of British Columbia Speakers: Rethinking habituation: New Insights into the Carol Schuurmans | University of Calgary Complexity of the Simplest Form of Learning

CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

Magdalena Sauvage | Ruhr University Bochum Genetic mechanisms underlying sexually dimorphic New evidence for a segregation of spatial and non- development of female-specific neural populations spatial memory subnetworks along the proximodistal in Drosophila axis of the hippocampus Edward Ruthazer | McGill University Vadim Bolshakov | McLean Hospital, Harvard How sensory experience controls circuit wiring in the Medical School developing visual system Diminishing fear by disrupting retrieval-induced synaptic restabilization Symposium 12: Dysregulated synaptic plasticity in models of brain disorders Satoshi Kida | Tokyo University of Agriculture Erasure of recent and remote fear memory by Overview: enhancing forgetting through increase in adult Synaptic plasticity is a fundamental neural process hippocampal neurogenesis critical for brain development and function. Symposium 11: Linking nervous system Dysregulations in synaptic plasticity are closely development with function associated with many neurological and mental disorders, including Alzheimer's disease (AD), Overview: Huntington's disease (HD), Neuropathic pain and Nervous system developmental mechanisms have drug abuse, which represent a major burden to our been studied for many years now, but their precise society. Therefore, investigating synaptic plasticity link to specific neural circuit functions remains and how it is altered in these brain disorders is a key unclear. Considering the high number of neurological to the understanding and treatment of these disorders that arise because of developmental diseases. In this symposium, we will bring together defects, this symposium seeks to link specific leading researchers working on synaptic plasticity in developmental events and aspects of neural circuit various animal models of brain disorders; Dr. function. We will present evidence tying the Dumont will present studies on compulsive molecular specification of spinal interneuron behaviors in rats including compulsive drug intake, subclasses to locomotor circuits. We will discuss the Dr. Min on neuropathic pain, Dr. Sepers on impact of developmental sensory experience on the transgenic models of HD, and Professor Collingridge connectivity and function of the vertebrate visual on current state of synaptic plasticity and system. We will discuss the dimorphic cellular and mechanisms underlying synaptic degeneration that genetic mechanisms that direct the formation of a is a core feature of AD. Therefore, the proposed sex-specific neuronal circuit required in females for symposium will be timely and of interest to a wide reproduction. Finally, we will explore how molecular range of audience. mechanisms controlling neuronal stem cell development contribute to the function of cognitive Speakers: neural circuits. The emergent theme of this Éric C. Dumont | Queen’s University symposium is that linking developmental processes Altered plasticity at glutamate and GABA synapses in with circuit function is essential to understanding compulsive behaviours in rats neurodevelopmental disorders. Min Zhuo | University of Toronto Speakers: Aberrant synaptic plasticity and treatment in animal Freda Miller | Hospital for Sick Children models of neuropathic pain and anxiety Understanding cognitive disorders: from neural stem cells to neurons Marja D. Sepers | University of British Columbia Endocannabinoid-mediated synaptic plasticity at Ying Zhang | Dalhousie University cortico-striatal synapses in the YAC128 model of Distinctive developmental pathways of functional Huntington’s disease subpopulations of V3 interneurons in the mouse spinal cord Graham L Collingridge | University of Bristol Dysregulated synaptic plasticity in models of Douglas Allan | University of British Columbia Alzheimer’s disease CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

We used data from the Allen Spinal Cord Atlas (ASCA) to mine for cell-specific gene expression to POSTER SESSION 1 enhance our understanding of the identity of spinal cord progenitors. The ependymal cell layer (ECL) of A – Development the central canal (CC) of the spinal cord is considered to be a neural stem cell niche, as cells isolated from 1-A-1 Lipid mediator prostaglandin E2 alters it possess the potential to differentiate into calcium homeostasis during neuronal astrocytes, oligodendrocytes, and neurons in vitro differentiation in neuroectodermal stem cells and when transplanted into brain neurogenic zones. Using in-situ hybridization (ISH) data from the ASCA, Jennilee Davidson¹, Hongyan Li¹, Dorota Crawford¹ we discovered temporal and spatial segmentation of ¹York University CC cells expressing distinct groups of genes. We categorized each gene as exhibiting expression at Lipid mediator prostaglandin E2 (PGE2) is an either postnatal day 4 (P4), postnatal day 56 (P56) or endogenous molecule that plays an important role both. These ages are relevant to understanding the during early development of the nervous system mechanisms of neurogenesis and gliogenesis, as the (NS). Abnormal PGE2 signaling due to environmental P4 spinal cord is capable of regenerating impacts can result in the pathology of the NS and has functionality following spinal cord injury, whereas been implicated in neurodevelopmental disorders the P56 spinal cord is not. Gene ontology analysis like Autism Spectrum. We previously showed PGE2 suggests that these different regions of the CC may influences gene expression, migration, proliferation contribute in different ways to spinal cord and differentiation of neuroectodermal stem cells regeneration and repair. We show here that many of (NE-4C). In this study, we aimed to elucidate if PGE2 the gene expression patterns seen in ISH from the can alter calcium homeostasis in neuronal ASCA are maintained by the corresponding proteins differentiation of NE-4C cells. Using ratiometric fura- in the ECL: this differential protein expression 2AM calcium imaging we assessed cytosolic and suggests the existence of subpopulations of growth cone calcium dynamics of differentiated NE- ependymal cells. Furthermore, we find that the CC 4C cells. We have found PGE2 alters calcium ependymal cell niche experiences altered protein homeostasis in a time- and dose-dependent expression after different types of injury or insult, response. We found 3 and 24 hours of 0.1, 1 and 10 such as spinal cord injury or demyelinating lesion. µM PGE2 exposure on day 12 significantly increased These results have potential applications for spinal both cytosolic and growth cone mean intracellular cord regeneration and repair. calcium level ([Ca2+]i) as well as the amplitude and minimum (min)/maximum (max) levels of fluctuation 1-A-3 The Role of Activator E2Fs in Stem Cell in the growth cones. When PGE2 was continuously Maintenance during Neurogenesis present during differentiation, cytosolic [Ca2+]i Raghda Gemae¹, Mireille Khacho¹, Alysen Clark¹, significantly changed depending on the Kristen Stevens¹, David Park¹, Ruth Slack¹ concentration, whereas growth cone mean, amplitude and min [Ca2+]i did not change, but max ¹University of Ottawa [Ca2+]i increased significantly. Our results show that PGE2 can disrupt calcium homeostasis during The recent discovery of adult neural precursor cells neuronal differentiation in a time- and dose- (NPCs) holds much hope for the potential dependent manner. Our data suggests that prenatal regeneration of damaged brain tissue. However, increase in PGE2 may adversely impact calcium their use has been limited by their low numbers and signaling in differentiating neurons and result in relatively quiescent state, particularly in the aging pathologies of the NS. brain. Previous studies from our laboratory have demonstrated a crucial role for the Rb/E2F pathway 1-A-2 Spatio-Temporal Heterogeneity of the in NPCs regulation and proliferation, in addition to Spinal Cord Central Canal the importance of E2F3 in the regulation of the pluripotency factor, Sox2, in NPCs. As activating E2Fs Kathryn Douglas¹, Dongho Lee¹, Jane Roskams¹ (1-3) are regulators of gene transcription, it is ¹University of British Columbia important to understand how they function to CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

maintain the NPCs population during embryogenesis mice show a loss of a subpopulation of glutamatergic and in the adult brain. Knowing that E2F2 expression dorsal horn neurons, abnormal sensory afferent has not been previously demonstrated in the brain, innervation and reduced spinofugal innervation of we have investigated the role of E2F1 and E2F3 in the parabrachial nucleus and the periaqueductal neurogenesis embryonically by knocking both these gray, important nociceptive structures. Altogether, genes out using an Emx1Cre and a NestinCreERT2 to our results demonstrate an important role for the specifically delete E2F3 in the cerebral cortex. To intersection of Lmx1b and Hoxb8::cre expression in eliminate possibilities that E2F2 may be playing a the development of nociceptive dorsal horn circuits role in the E2F1/3 double knockout, these results will critical for mechanical and thermal pain processing. be compared to an E2F1/2/3 triple knockout Emx1Cre model. Our results show a decrease in 1-A-5 Docosahexaenoic acid status and NPCs proliferation, suggesting that E2F1 and E2F3 neurodevelopment at birth are comparable in are essential for the maintenance of stem cells and controls and neonates born to well-controlled neurogenesis from embryogenesis to adulthood, and gestational diabetes mellitus that they regulate multiple genes required for stem cell self renewal. This will be beneficial in the Pauline Léveillé¹², Jean-Luc Ardlouze³, Jean-Charles development of therapeutics to enhance Pasquier², Charles Deacon², Kevin Whittingstall², neurogenesis in the context of brain damage or Mélanie Plourde² neurodegenerative disease. ¹Centre de recherche sur le vieillissement, This research is supported by a CIHR grant to RSS ²Université de Sherbrooke, ³Université de Sherbrooke, département de médecine 1-A-4 Hoxb8 intersection defines a role for Lmx1b in excitatory dorsal horn neuron Background/aims: Docosahexaenoic acid (DHA) is a development, spinofugal connectivity and key fatty acid for neurodevelopment. Non-esterified nociception DHA seems to be the preferred form for building-up brain membranes. Lower DHA levels are reported in Nora Szabo¹, Ronan V. da Silva¹, Susana G. blood of fetus born to gestational diabetes mellitus Sotocinal², Hanns Ulrich Zeilhofer³, Jeffrey S. Mogil², (GDM). The aims of this study were to evaluate at Artur Kania¹ birth whether non-esterified DHA in cord blood is 1) modified by GDM and, 2) associated with ¹IRCM (Institut de recherches cliniques de Montreal), neurodevelopment of the offspring. ²McGill University, ³University of Zurich Methods: Offspring of 46 pregnant women (21 Spinal cord neurons respond to peripheral noxious controls, 25 with diet- or insulin-controlled GDM) stimuli and relay this information to higher brain were recruited. Cord blood was collected for centers but the molecules controlling the assembly measuring DHA in the non-esterified fatty acids of such pathways are poorly known. In this study, we (NEFA), the phospholipids (PL), the cholesteryl esters use the intersection of Lmx1b and Hoxb8::Cre (CE) and the triacylglycerols (TAG). An EEG was expression in the spinal cord to genetically define performed to the newborns 48 hours post-delivery. nociceptive circuits. Specifically, we show that EEG data were recorded using a 15-channel bi-polar Lmx1b, previously shown to be expressed in montage. Data were sampled at 200 Hz and acquired glutamatergic dorsal horn neurons and critical for for 10 minutes. We developed a new method dorsal horn development, is expressed in nociceptive allowing identification of artifact-free periods and dorsal horn neurons and that its deletion results in then computing the mean spectral power. the specific loss of excitatory dorsal horn neurons by apoptosis, without any effect on inhibitory neuron Results: In GDM vs. controls, maternal A1C was 5.3 ± numbers. To assess the behavioral consequences of 0.5% vs 5.4 ± 0.3% (P = 0.803), respectively; in cord Lmx1b deletion in the spinal cord, we used the brain- plasma, DHA levels in the NEFA, the PL, the CE and sparing driver Hoxb8::Cre. We show that such a the TAG were similar in both groups. The mean deletion of Lmxb1 leads to a robust reduction in signal of the 15 EEG electrodes was -0.986 ± 0.005 sensitivity to mechanical and thermal noxious dB in GDM vs. -0.985 ± 0.005 dB in controls (P = ns). stimulation. Furthermore, such conditional mutant CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

Conclusion: Our novel electrophysiological method Despite important advances in our understanding of allows for reliable recording of brain activity in the mechanisms of axon guidance, the location and newborns. Neurodevelopment was similar in timing of the intracellular events leading to growth neonates with comparable cord esterified and non- cone behavior in relation to guidance cue detection esterified DHA, under tight-controlled GDM or remain obscure. One emerging approach is the physiologic conditions. imaging of intracellular signaling in situ, which has the powerful advantage of linking biochemical-level 1-A-7 The Effect of Microglia on Progenitor Cells events with specific cellular structures. We are using During Tuberal Hypothalamic Development this approach to investigate the molecular cascade downstream of ephrin:Eph signaling in the context of Candace Marsters¹ spinal motor axons, where it plays a significant role in their guidance. Specifically, we characterized ¹University of Calgary antibodies raised against the phosphorylated forms Microglia influence during central nervous system of candidate effector proteins in cultured motor (CNS) inflammation and injury is an active area of neuron growth cones. Using immunohistochemistry, research. However, new research has shown we show robust, localized, and ephrin dose- microglia begin to invade the embryo brain around dependent phosphorylation of known Eph effectors, embryonic (e) day 10.5 in mouse, suggesting a the Src family kinases. The guanine nucleotide unique role microglia in CNS development. My exchange factor and Eph effector ephexin, is overall research is focused on asking three similarly phosphorylated in growth cones after questions: (1) what are the microglia populations exposure to ligand. These phosphorylation events present during development; (2) what mechanisms occur in dense puncta that co-localize with EphB direct and attract microglia towards the developing receptors and ephrin ligands, suggesting that fetal brain; (3) determine what functional role signaling occurs in small, contained environments microglia plays in the developing hypothalamus. within the growth cone. By imaging signaling events downstream of axon guidance signals, we may begin I have systematically identified the timing of to link the known biochemistry with the emergent microglia invasion into the developing hypothalamus behavior of growth cones. The multiple overlapping and microglia activation state using fluorescent signals presented to growth cones during imaging approaches. I have defined the development suggest that molecular convergence spatiotemporal timing of microglia invasion in the events mediating their integration may be localized developing embryonic tuberal hypothalamus and am in time and in space. now determining the influence of microglia on developing cell populations by using pharmacological 1-A-9 Neuronal activity of surrounding axons knock down models. Specifically, pregnant CD1 mice instructs retinal ganglion cell axon growth in the were sacrificed and embryonic brain tissue was Xenopus laevis visual system harvested on e11.5, e13.5, e15.5 and e17.5. Martin Munz¹, Tasnia Rahman¹, Edward Ruthazer¹ Cryosectioned brains were labeled with microglia and hypothalamic markers for fluorescent imaging ¹McGill University followed by stereological analyses employed to quantify the hypothalamic microglia population. My Competing presynaptic inputs use neuronal activity data suggest a possible role for microglia in to select their appropriate postsynaptic partners maintaining hypothalamic progenitor populations during the development of neuronal circuits. We given their pivotal position during development, have previously shown that in Xenopus tadpoles, an where they can interact with progenitors. occasional stray retinal ganglion cell (RGC) axon is misdirected to the ipsilateral tectum where the 1-A-8 In Situ Imaging of Intracellular Axon other retinal inputs originate from the contralateral Guidance Signaling eye. Two-photon imaging of ipsilateral RGC axons revealed that asynchronously stimulating the two Daniel Morales¹, Artur Kania¹ eyes upregulated branch additions in the ipsilateral ¹McGill University axon. In contrast, synchronous stimulation stabilized the arbor. Synaptic transmission is required for the CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

axon to be stabilized by synchronous stimulation, as amygdala, which is known to be larger in males, does both tetanus toxin light chain (TeNT-LC) expression not show any difference until postnatal day 10 when to prevent synaptic transmission and MK801 the sex difference emerges, and then remains stable treatment to block NMDA receptors prevented the until the last time point at postnatal day 65 (fig1b). stabilization. The enhancement of branch dynamics Longitudinal in vivo MEMRI effectively captures under asynchronous stimulation conditions was not developmental changes that occur in the male and prevented by these manipulations. Thus, we sought female brain, and will allow us to further explore to determine whether it was primarily mediated by more detailed development of sex differences in the unpaired firing activity in the lone axon or by activity brain longitudinally. in its neighbors. We found that stimulation of the ipsilateral eye alone is not sufficient to upregulate 1-A-11 AF1Q Interacts with TCF7 to Facilitate axonal branch motility, but stimulation of the Neural Stem Cell Proliferation contralateral eye alone can enhance axonal branch motility by the ipsilateral axon. Thus, firing of Xiulian Sun¹ surrounding contralateral axons non-cell- ¹Shandong University autonomously promotes branch motility in the non- coactive ipsilateral axon. ALL1-fused from chromosome 1q (AF1q), originally considered as an oncogenic factor, has been 1-A-10 Imaging the longitudinal development of implicated in the pathogenesis of structural sex differences in the mouse brain using neurodegeneration. AF1q is highly expressed during in vivo manganese enhanced magnetic resonance neurodevelopment, but its specific functions and imaging molecular mechanisms in neural system remained Lily Qiu¹, Kamila Szulc², Brian Nieman², Sharon elusive. Our study here demonstrated that AF1q Portnoy¹, Daniel Turnbull³, Mark Palmert¹, Jason facilitated neural stem cell proliferation. Since Lerch² previous studies have shown WNT signaling being involved in neural stem cell proliferation, we ¹University of Toronto, ²The Hospital for Sick examined whether AF1q could induce cell Children , ³New York University proliferation by activating Wnt signaling pathway. Reporter assay showed AF1Q could activate WNT Previous research has demonstrated that the signaling. And coimmunoprecipitation (CO-IP) development of the brain differs in males and analysis demonstrated that AF1q bound specifically females, and some areas show sexual dimorphisms to T-cell factor/lymphoid enhancer binding factor-7 beginning in neonatal life, a critical period where (TCF/LEF7), which stabilized TCF7 and facilitated many sex differences are thought to emerge. TCF7 translocation into nucleus. Additionally, we However, a comprehensive, whole brain assessment identified the amino acid 11-20 on AF1Q is sufficient of where and when sex differences emerge in the for the binding of TCF7. Furthermore, the brain is not yet available. This project aims to phosphorylation of Serine 11 on AF1Q is required for characterize the development of male-female the binding of TCF7. The AF1Q-S11F mutant differences in the whole mouse brain and establish decreased the activation of WNT signaling and was the trajectory of these sex differences in the brain. unable to induce cell proliferation. Our study here Ten male and ten female C57Bl/6 mice were identified AF1Q as an important factor in longitudinally imaged with manganese enhanced neurodevelopment by interacting with TCF7 and magnetic resonance imaging (MEMRI) at 90 micron regulating WNT signaling pathway. resolution (imaging protocol from Szulc et al, 2015, in press). Up to seven mice were imaged 1-A-12 Identification of a novel interaction simultaneously, in vivo, at postnatal days 3, 5, 7, 10, between Pannexin 1 and Collapsin response 17, 23, 29, 36 and 65 (fig1a). Image registration mediator protein 2 that regulates neuronal techniques were used for analysis. Preliminary development results show that all sex differences in the brain are present by postnatal day 23, while different sexual Esther Carmona-Wagner¹, Leigh Anne Swayne¹ dimorphisms in the brain emerge at different times ¹University of Victoria between birth and day 23. For example, the medial CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

Pannexin 1 (Panx1) is highly expressed in the brain themselves (or their progeny) and influence these and forms channels permeable to ions and processes in an autocrine/paracrine manner. In a metabolites of up to 1 kDa, including ATP. Panx1 was recent example, we have shown that interleukin-6 originally detected in mature neurons. We (IL-6) can act in an autocrine/paracrine manner to discovered that Panx1 is also expressed in influence radial glial cell proliferation. Spurred by developing neurons of the ventricular zone and this result, we have devised an integrated proteomic positively regulate their proliferation and migration, and transcriptomic approach to identify the diversity while negatively regulating neurite outgrowth. To of secreted factors which influence radial glial cell understand the specific molecular players involved in proliferation and differentiation. Here, we report the Panx1 signaling in developing neurons, we use of this approach to define the cortical precursor performed the first unbiased proteomics screen for growth factor milieu, and demonstrate the general Panx1 protein interactions partners. Here we importance of autocrine/paracrine mechanisms on present data for a direct interaction with collapsin radial glial cell proliferation and differentiation. response mediator protein 2 (Crmp2), a protein that plays a key role in neuronal maturation by positively B - Neural Excitability, Synapses, and Glia: Cellular regulating neurite outgrowth. We demonstrate that Mechanisms Panx1 and Crmp2 associate both in vitro and in vivo, in developing and mature neurons, and identify the 1-B-14 Acute Actions of Gabapentinoids on specific region of Panx1 interacting with Crmp2. Next Neuropathic Spinal Cord Slices: Preferential Actions we investigate the hypothesis that Panx1 negatively on Excitatory Neurons regulates neurite outgrowth by sequestering Crmp2 using a cell-permeable (TAT) peptide to disrupt the Sascha Alles¹, Nataliya Bukhanova¹, Peter Smith¹ Panx1/Crmp2 interaction. Consistent with this ¹University of Alberta hypothesis, neural precursor cells treated with this interfering peptide show increased neurite The α2δ ligands, gabapentin and outgrowth. Overall, we present several novel pregabalin, are treatments for neuropathic pain. findings that expand our understanding of the However, their mechanism of action is poorly cellular role of Panx1 in the brain, and the molecular understood. We propose an acute mechanism of mechanisms underlying its function in neural cells. action based on data showing that clinically relevant doses of gabapentin significantly decrease overall 1-A-13 Autocrine/paracrine control of neural dorsal horn excitability in approximately 30 min as precursors: an integrated proteomic and measured using confocal Ca2+ imaging and patch- transcriptomic approach for defining the cortical clamp electrophysiology of ex vivo spinal cord slice precursor niche preparations. In addition, we have shown that the Scott Yuzwa¹, Geoff Clarke², Peter Zandstra², David acute actions of the gabapentinoids in ex vivo slices Kaplan¹, Freda Miller¹ correlates with their ability to supress chronic neuropathic pain in animal models using rats subject ¹The Hospital for Sick Children, ²University of to sciatic chronic constriction injury (CCI). We Toronto characterized excitatory delay firing neurons and inhibitory tonic firing neurons based on firing The development of the mammalian brain is a finely pattern. Our results indicate that gabapentin tuned process that integrates a precise genetic decreases excitatory drive to excitatory neurons and program with information from the cell environment increases excitatory drive to inhibitory neurons. to generate the three cell lineages required to build Furthermore, by examining postsynaptic firing the brain: neurons, astrocytes and oligodendrocytes. frequency in response to current ramps, we have Radial glial precursor cells are thought to be established that the effect of gabapentin depends on responsible for the production of these cell types in modification of synaptic transmission as opposed to the cerebral cortex. While a host of different changes in postsynaptic ion channels. Previous secreted factors (for example the neurotrophins) studies of the gabapentinoids in in vitro models have have been shown to play roles in the proliferation or failed to identify any major acute effect since these differentiation process of radial glial cells, very few studies have been mainly carried out on naïve have been shown to be made by the radial glia animals or with no reference to effects on specific CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

cell types. Mechanisms of these acute, cell-type Phosphodiesterases (PDEs) degrade cAMP and specific actions of gabapentinoids remain to be cGMP, which are essential for synaptic plasticity and elucidated. memory, providing important regulatory control. However the exact function of PDEs in synaptic 1-B-15 Projection-target dependent effects of plasticity is unclear due to the lack of techniques to orexin and dynorphin on VTA dopamine neurons locally monitor and control their activity. Here we report the development of two-photon optogenetic Corey Baimel¹, Stephanie Borgland², Jennifer tools to manipulate PDEs in a spatiotemporally Thompson³ precise manner, to study their synaptic function. Mammalian PDEs are divided into 3 types: cAMP ¹University of British Columbia, ²University of specific (PDE4,7,8), cGMP specific (PDE5,6,9) and Calgary, ³Medical University of South Carolina PDEs that hydrolyze both (PDE1-3,10,11). To activate Ventral tegmental area (VTA) dopamine neurons are PDE by two-photon illumination, we utilized the a critical part of the neural circuits that underlie recently described light sensitive domain PAS-GAF- reward and motivation. Dopamine neurons send PHY from Deinococcus radiodurans linked to the dense projections to many brain areas and recent conserved catalytic domain of Homo sapiens PDE2A observations suggest that the properties and forming light activated phosphodiesterase (LAPD) functional output of dopamine neurons can be (Moglich et al, 2014). To validate LAPD, we first segregated on the basis of projection target. The examined the LED light-dependent PDE activity in output of dopamine neurons is regulated by lateral vitro by measuring cGMP/cAMP degradation with an hypothalamic (LH) orexin (also known as hypocretin) ELISA. The level of applied cGMP/cAMP decreased neuronal input. These neurons are critically involved within seconds of illumination, indicating strong in mediating both arousal and reward and can photoactivation. To achieve necessary precision to release both excitatory orexin peptides and the target PDEs at a single synapse we used two-photon inhibitory kappa opioid agonist dynorphin. We have laser excitation in vitro. At 1000nm, cGMP/cAMP previously demonstrated that orexin and dynorphin concentrations decreased rapidly within minutes, exert balanced but opposing effects on VTA DA indicating LAPD photoactivation. The neurons, but circuit specific effects of these peptides photoactivation for cGMP was less than half has been largely overlooked. Here we are compared to cAMP, reflecting the natural affinities investigating the effect of orexin and dynorphin on of PDE2A. We will discuss other photoactivatable projection-target specific VTA dopamine neurons. To PDEs as two-photon optogenetic tools, for use in in do this, we inject retrograde beads into either the vivo studies of second messengers in synaptic nucleus accumbens (NAc) or the basolateral plasticity during learning and memory. amygdala (BLA) of adult Pitx3-enhanced green 1-B-17 Microglia rapidly adopt a filopodia-rich fluorescent protein (Pitx3-eGFP) mice. We then use phenotype upon oxygen depletion by sensing tissue whole-cell patch clamp electrophysiology to acidosis determine the effects of bath application of orexin and dynorphin on the firing rate of fluorescently Louis-Philippe Bernier¹, Lasse Dissing-Olesen¹, Jasmin labeled dopamine neurons. The probability of Hefendehl¹, Jeffrey LeDue¹, Brian MacVicar¹ nucleus accumbens shell-projecting dopamine neurons responding to both orexin and dynorphin is ¹University of British Columbia greater than of the VTA-BLA projection neurons. These preliminary results suggest that there may be Microglia are highly motile cells that play a pivotal projection-dependent effects of the LH role in monitoring brain homeostasis by constantly orexin/dynorphin input to the VTA. probing the environment and responding to extracellular cues. They are involved in long-term 1-B-16 Two-photon optogenetics for controlling stroke recovery, however the acute responses of PDE activity in living neurons microglia to the metabolic stresses of ischemia remain unclear. Here, we used two-photon imaging Fiona Bergin¹, Kenichi Okamoto¹ in vivo and in acute brain slices to monitor the initial effect of anoxia on the morphological phenotype ¹University of Toronto and dynamic properties of microglia. The highly CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

ramified morphology of resting microglia is rapidly how palmitoyl acyl-transferases regulate synapse transformed during oxygen depletion with extension plasticity in response to activity. of fine actin-dependent filopodia followed by retraction of microtubule-dependent ramifications. 1-B-20 Mitochondria regulation of neuronal This rapidly reversible switch in morphology drives structural and functional plasticity significant changes in microglial sensing behavior, affecting microglial cells capacity to respond to Janaina Brusco¹, Serhiy Opushnyev¹, Kurt Haas¹ tissue damage. Several observations indicate that ¹University of British Columbia increased intracellular cyclic AMP is a key trigger of both filopodia extension and retraction of The classical view of mitochondria as housekeeping ramifications. Our data suggests that during short organelles acting in the background to simply anoxia insults, this phenotypic switch is induced by maintain cellular energy demands has been shaken the accompanying acidic shift in the extracellular by mounting evidence of their direct and active environment. This pH drop causes microglia to adopt participation in synaptic plasticity in neurons. Time- a filopodia-rich phenotype through an increase in lapse imaging has revealed that mitochondria are cyclic AMP induced by activation of the Gs-coupled motile in dendrites, with their localization and fusion proton-sensing receptor TDAG8. Characterizing the and fission events regulated by synaptic activity. highly specialized sensing structures of microglia and Recent studies have also shown that mitochondrial defining the molecular cues responsible for the protein cascades classically associated with functional switch of microglial behaviour observed apoptosis are involved in neural plasticity and upon oxygen depletion will likely provide promising metaplasticity in healthy cells. To investigate the role targets for stroke treatment. of mitochondria on plasticity modulation we performed in vivo imaging of neuronal morphology 1-B-19 Activity-Regulated Trafficking of the and activity, and real-time mitochondria tracking in Palmitoyl-Acyl Transferase DHHC5 the awake visual system of Xenopus laevis tadpoles. Stefano Brigidi¹, Brendan Santyr¹, Jordan Shimell¹, The tri-dimensional analysis of each individual Blair Jovellar¹, Shernaz Bamji¹ mitochondrion in the entire neuronal dendritic tree show that mitochondria are faster, smaller, and ¹University of British Columbia translocate towards motile and stable filopodia 30 min after LTD induction, but no mitochondrial Neuronal activity can regulate the palmitoylation of changes were observed in LTP neurons. Our data proteins, which in turn controls the dynamic supports evidence of mitochondria as central localization of proteins to and from synaptic organelles controlling the spatiotemporal expression compartments. Here we report that DHHC5's ability of LTD. A complex model is emerging of an intimate to palmitoylate substrates in an activity-dependent and dynamic relationship between mitochondrial manner is dependent on changes in its subcellular function and neuronal plasticity. More refined localization. Under basal conditions DHHC5 is bound measures of the spatiotemporal dynamics of to PSD-95 and Fyn kinase and is stabilized at the mitochondrial proteins, and their correlation to local synaptic membrane through Fyn-mediated functional and structural plasticity are required to phosphorylation of a tyrosine residue within the decipher precise pathways regulating plasticity and endocytic motif of DHHC5. In contrast, DHHC5's metaplasticity. substrate, δ-catenin, is highly localized to dendritic shafts, resulting in the segregation of the 1-B-21 Scavenging reactive oxygen species enzyme/substrate pair. Neuronal activity disrupts initiates GABA A receptor-mediated electrical the DHHC5/PSD-95/Fyn kinase complex, resulting in suppression in anoxia-tolerant turtle neurons DHHC5 endocytosis, translocation to dendritic shafts, and association with δ-catenin. Leslie Buck¹, David Hogg¹ Following DHHC5-mediated palmitoylation of ¹University of Toronto δ-catenin, DHHC5 and δ-catenin are trafficked together back into spines where δ- Anoxia induces hyper-excitability and cell death in catenin enhances cadherin stabilization and AMPA mammalian brain but in the anoxia-tolerant western receptor surface insertion. This study demonstrates painted turtle (Chrysemys picta bellii) neuronal CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

electrical activity is suppressed (i.e., spike arrest), investigate the regulation of KCC2 and NKCC1 by adenosine triphosphate (ATP) consumption is another class of ionotropic glutamate receptors: N- reduced, and cell death does not occur. Electrical methyl-D-aspartate receptors (NMDARs). In vivo suppression is primarily the result of enhanced and in heterologous expression systems, co- γ-aminobutyric acid (GABA) transmission; immunoprecipitation assays revealed that NMDAR however, the underlying mechanism responsible for subunits GluN2A and GluN2B interact with KCC2 and initiating oxygen-sensitive GABAergic spike arrest is NKCC1. Previously, the Ca2+-dependent protease unknown. In turtle pyramidal neurons there are calpain was found to cleave KCC2 upon Ca2+ influx three types of GABAA receptor-mediated currents: due to NMDAR activation, thereby disrupting KCC2 spontaneous inhibitory postsynaptic currents function and EGABA. Interestingly, GluN2A and (sIPSCs), giant IPSCs and tonic currents. The aim of GluN2B were found to interact with the non- this study was to assess the effects of reactive functional KCC2 cleavage product as well as with full oxygen species (ROS) scavenging on these three length KCC2 monomers and oligomers. These currents since ROS levels naturally decrease with unexpected interactions between excitatory anoxia and may serve as a redox signal to initiate ionotropic glutamate receptors and inhibitory spike arrest. We found that anoxia, pharmacological cation-chloride cotransporters suggest the existence ROS scavenging, or inhibition of mitochondrial ROS of a functional glutamate-dependent complex generation enhanced all three types of GABA capable of regulating neuronal chloride homeostasis. currents, with tonic currents comprising ~ 50% of the total current. Application of hydrogen peroxide 1-B-23 Heterogeneous populations of neural stem inhibited all three GABA currents, demonstrating a progenitor cells and astrocytes express brain lipid reversible redox-sensitive signaling mechanism. We binding protein in aged human neurogenic niches conclude that anoxia-mediated decreases in mitochondrial ROS production are sufficient to Athena Chou¹, Jane Roskams¹ initiate a redox-sensitive inhibitory GABA signaling ¹University of British Columbia cascade that suppresses electrical activity when oxygen is limited. This unique strategy for reducing New neurons are continuously generated in two neuronal ATP consumption during anoxia represents main regions of the adult human brain: the a natural mechanism in which to explore therapies subventricular zone (SVZ) of the lateral ventricle and to protect mammal the dentate gyrus (DG) of the hippocampus. Data on the dynamics of adult neurogenesis in humans have 1-B-22 Regulation of Chloride Homeostasis by demonstrated moderate decline during aging. NMDA Receptors However, the cellular organization of the neural Jonah Chevrier¹, Vivek Mahadevan¹, Melanie stem progenitor cells (NSPCs) and the niche- Woodin¹ maintaining cells as well as their proliferation activities in aged humans have yet to be fully ¹University of Toronto explored. In this study, we reveal the cellular heterogeneity of the neurogenic niches and show Within the family of electroneutral cation-chloride brain lipid binding protein (BLBP) expression in cotransporters (CCCs), there are two members subpopulations of NSPCs using triple primarily responsible for setting the reversal immunofluorescence on formalin-fixed brain potential for GABA (EGABA): NKCC1 and KCC2. In samples from aged humans. We find spatial immature neurons, NKCC1 predominates and heterogeneity along the lateral ventricles, as mediates the influx of chloride, resulting in high evidenced by variable thickness of the progenitor- intracellular chloride ([Cl-]i) and depolarizing GABA rich astrocytic ribbon and cell-scarce hypocellular currents. In mature neurons, KCC2 is robustly gap, which appear to correlate positively with upregulated and maintains low [Cl-]i, which is proliferative activity. The integrity of the ependymal required for hyperpolarizing GABAergic inhibition. cells is also highly variable between different regions Recently, kainate receptors (KARs) have been of the SVZ. In addition, we demonstrate BLBP observed to post-translationally regulate KCC2 expression in the proliferative Sox2+/Nestin+ NSPCs expression and function. In this study, we use of the astrocytic ribbon, and in GFAP+ astrocytes of biochemical and electrophysiological techniques to the hypocellular gap. In the aged hippocampus, we CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

identify multiple subtypes of BLBP+ cells: the radial 1-B-25 Inhibitory Synaptic Transmission and KCC2 glia and putative NSPCs in the DG and the Function in the Brain of Huntington's Disease protoplasmic astrocytes in the molecular layer, both of which exhibit mitotic activities. Thus, our data Zahra Dargaei¹, Melanie Woodin¹ provide a comprehensive spatial map of the aged human subventricular zone and the expression ¹University of Toronto pattern of BLBP in both neurogenic niches Proper GABAA-mediated synaptic inhibition requires 1-B-24 Nicotinic receptor signaling in principal low levels of neuronal Cl- that is mainly achieved by neurons of the mouse hippocampal formation the K+-Cl- cotransporter, KCC2. When there is a during postnatal development decrease in KCC2 expression or when KCC2's ability to efficiently extrude Cl- decreases, it results in Beryl Chung¹, Derek Jacklin¹, Warren Bignell¹, Boyer reduced synaptic inhibition contributing toward the Winters¹, Craig Bailey¹ pathophysiology of numerous neurological disorders. Huntington's disease (HD) is a progressive ¹Unviersity of Guelph neurodegenerative disorder that is caused by mutations in the Huntington protein (Htt). Previous The normal development and function of the proteomic analysis using mass spectrometry has hippocampal formation depends on afferent revealed that the KCC2 encoding gene, Slc12a5, is acetylcholine (ACh) neurotransmission that is highly enriched in the Htt proteome, and this mediated by nicotinic acetylcholine receptors interaction decreases when Htt is mutated (mHtt). (nAChRs). Although the α4β2* isoform Based on the critical role of KCC2 in constitutes a major class of nAChR in the neurophysiological function, and the reported hippocampus, the ability of these receptors to decease in KCC2 interaction with Htt in the mediate nicotinic signaling in glutamatergic Huntington brain, we propose that KCC2 function is pyramidal neurons of the hippocampus is not well compromised in neurons with mHtt. Using co- understood. We first sought to determine whether immunoprecipitation from COS7 cells co-transfected functional α4β2* nAChRs are present on with full length KCC2 and wild type Htt, we found pyramidal neurons located within the cornu that KCC2 is capable of precipitating Htt. We also ammonus (CA) area 1 of the hippocampus in male performed the experiment in reverse direction and CD1 strain mice during postnatal development. observed that Htt also precipitates KCC2. We are Whole-cell electrophysiological responses to ACh in currently determining whether the KCC2: mHtt CA1 pyramidal neurons were measured within acute interaction is reduced or absent compared with the brain slices in the presence of antagonists to both KCC2: Htt interaction. We are also evaluating the α7 nAChRs and muscarinic receptors. We physiological and pathological relevance of the found that ACh elicited postsynaptic inward currents interaction. The identification of the KCC2: Htt and facilitated neuronal excitation, and that the interaction and its fundamental molecular pathways magnitude for both of these nicotinic responses was could represent novel insights into the pathogenesis greatest in CA1 pyramidal neurons during the first of HD. and second postnatal weeks of life compared with later developmental ages examined. Since the 1-B-26 Homeostatic scaling of excitatory synapses hippocampal formation also comprises the during sleep additional CA areas, dentate gyrus, subiculum and entorhinal cortex, we are now continuing to Graham Diering¹, Raja Nirujogi¹, Paul Worely¹, characterize α4β2* nAChR function Akhilesh Pandey¹, Richard Huganir¹ within the principal neurons of these regions. Our findings demonstrate that α4β2* nAChRs ¹Johns Hopkins University mediate nicotinic signaling in principal neurons of Homeostatic scaling is believed to regulate neuronal the developing hippocampus, and suggest a role for firing through global, non-Hebbian, adjustments to these receptors in the formation and maturation of synaptic weights while maintaining the information hippocampal learning and memory networks. stored through Hebbian plasticity mechanisms. While scaling has clearly been demonstrated in neurons in culture, true physiological functions of CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

homeostatic scaling in vivo are not known. Sleep (NHE1) truncated the acid load compared to the plays an essential role in normal cognitive functions. control pre-pulse, maintaining pHi values more basic Evidence suggests that the benefits of sleep may than controls. Since NHE-1 participates in the occur via synaptic mechanisms, including a global regulation of early neurite morphogenesis, we also weakening of synapses to restore synaptic studied the effect of Bact-2 on axon extension, using homeostasis which is perturbed by synaptic embryonic hippocampal neurons. We observed that strengthening during waking life. Using sub-cellular cariporide increased the total axon length. fractionation, biochemistry and quantitative Unfortunately, we were unable to detect significant proteomics, we characterized the changes that occur differences with Bact-2 at the concentration used. in forebrain excitatory post-synaptic densities (PSD) These results, suggest that Bact-2 affect the during sleep. We observed reduced levels of synaptic regulation of cellular pH, probably by modulating AMPA receptors and reduced AMPA receptor some NHE isoforms. Finally, in the case of NHE-1, it is phosphorylation consistent with global synaptic possible that we need to test higher concentrations weakening during sleep. Further, our data suggest of Bact-2, or that Bact-2 acts on isoforms different that multiple signaling pathways become down- from NHE-1. regulated during sleep suggesting possible mechanisms to drive sleep-dependent synaptic 1-B-28 Altered TORC1-dependent protein weakening. Sleep-dependent removal of AMPA synthesis dysregulates the excitatory-inhibitory receptors requires the immediate early gene balance and dendritic branching in vivo Homer1a, a protein known to drive homeostatic down-scaling and to regulate sleep. These findings Delphine Gobert², Anne Schohl², Edward Ruthazer² reveal part of the molecular mechanisms at play ¹McGill University, ²Montreal Neurological Institute during sleep and suggest that the physiological function of homeostatic scaling-down may be to During early development, neurons undergo renormalize synaptic strength during sleep. extensive growth and rearrangement of their connections, which ultimately leads to the formation 1-B-27 Identification of Na+/H+ exchanger as a of functional circuits. While TORC1-dependent possible second target for Bactridine 2 protein synthesis has been implicated in dendritic Lisbeth Garcia¹, Pedro Royero², Gina D?Suze³, growth and branching, its role in synapse formation Arnaldo Rosales³, Marianela Tirado¹, Cecilia Castillo¹ is less clear. Using electrophysiological recordings and two-photon imaging, we therefore investigated ¹Instituto de Estudios Avanzados, ²Universidad Simon the role of TORC1-dependent translation in synapse Bolivar, ³Instituto Venezolano de Investigaciones stabilization and maturation in vivo in the Científicas retinotectal system of Xenopus laevis tadpoles. We show that tectal neurons that were electroporated Bactridine 2 (Bact-2) is an antibacterial toxin from with Rheb, an upstream activator of TORC1, Tityus discrepans venom which modifies the function exhibited enhanced AMPA mEPSC amplitudes and of isoforms 1.2, 1.4 and 1.6 voltage dependent frequencies, as well as larger AMPA/NMDA ratios. sodium (Nav) channels. In previous works, we had Interestingly, GABA mIPSC amplitudes or frequencies determined that Bact-2 induced Na+ outward were not affected, resulting in a significant rectifying currents in DRG neurons. We found that imbalance in the excitatory-inhibitory (E/I) ratio. To these currents, were amiloride sensitives and could further investigate how a TORC1-mediated E/I correspond to the Na+/H+ exchanger (NHE) coupled imbalance could affect the cell's integration into the to an H+ conductance. To corroborate the effect of circuit, we performed receptive field mapping of Bact-2 as NHE modulator, we characterized the excitatory and inhibitory inputs onto Rheb- effect of Bact-2 in the regulation of pHi in DRG expressing neurons and observed that TORC1 neurons, using the NH4+ prepulse technique and the activation selectively results in larger excitatory pH indicator BCECF-AM. Bact-2 inhibited the pH receptive fields, suggesting that the developmental recovery mediated by NHE, after an acid load of refinement of retinotopic inputs to tectal neurons cells, but to a lesser extent than amiloride, a known may be dysregulated. Moreover, neurons expressing NHE inhibitor. On the other hand, unexpectedly, Rheb have significantly larger and more complex cariporide a specific inhibitor for NHE isoform 1 dendritic arbors. These experiments therefore CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

suggest that TORC1 activity is critical for regulating The anoxia-tolerant western painted turtle the number and maturity of excitatory synapses and (Chrysemys picta bellii) has uniquely adapted to also contributes to setting the E/I balance in the surviving extended periods of low O2 by reducing developing brain. the activity of energy-consuming pathways. The largest such pathway is the re-establishment of ionic 1-B-29 Calcium Responses to Single Action gradients following excitatory transmission. We Potentials in Spinal Cord Lamina I Neurons are hypothesize that the mitochondria serve as the Mediated by T-Type VGCCs nexuses of glutamatergic receptor down-regulation and GABAergic receptor up-regulation with the goal Erika Harding¹, Michael Salter¹ of reducing energetic demand. Here, we show that a mild depolarization of the mitochondrial membrane ¹The Hospital for Sick Children potential (MMP) during anoxia results in the release Lamina I neurons of the spinal cord are critical for of Ca2+, which reduces glutamate receptor activity the integration of nociceptive information from the in pyramidal neurons. MPP collapse is prevented by periphery and relay this information to the brain. action of the F1F0-ATPase, which maintains the MPP Lamina I neurons exhibit hyperexcitability and by pumping H+ out of the matrix. This activity decreased inhibition in chronic pain models. Voltage- functions in a pH-sensitive manner, as analysis of gated calcium channels (VGCCs) have been matrix pH by confocal microscopy using the pH- implicated in the development of chronic pain sensitive dye SNARF-1 indicates a mild acidification symptoms, however their functionality in lamina I of the mitochondrial matrix during anoxia. The neurons is poorly understood. Here, we develop an reduction in mitochondrial O2 consumption during approach to measure calcium responses evoked by anoxia limits the production of ROS, which we have individual action potentials (APs) in lamina I neurons. found to increase both tonic and phasic GABAergic We made current-clamp recordings from the soma signaling. We have observed inter-neurons in the of lamina I neurons, loaded via the patch pipette turtle cortex identified as stellate neurons that burst with the calcium indicator Oregon Green Bapta-1 fire (0.09 ± 0.01 Hz) at the same frequency as (OGB1). APs were induced by current injection. GABAergic phasic currents and number of action Simultaneous two-photon imaging of OGB1 potentials per burst doubles during anoxia, fluorescence in the somata, dendrites, and dendritic suggesting that mitochondrial signaling in these spines of lamina I neurons allowed for analysis of neurons controls widespread GABAergic signaling in calcium responses. Single APs induced robust the turtle cortex. ΔG/R increases in the soma (peak ΔG/R = 1-B-31 Serine 863 regulates surface expression of 0.06, n= 20 cells), nucleus (peak ΔG/R = 0.03, GluA1 and is Phosphorylated by PAK3 n= 6 nuclei), dendrites (peak ΔG/R = 0.2, n=20 dendrites) and dendritic spines (peak ΔG/R = Natasha Hussain¹, Gareth Thomas², Richard Huganir¹ 0.07, n=5 spines). We found that calcium responses were prevented by the addition of tetrodotoxin. The ¹Johns Hopkins University, ²Temple University School effects of cadmium, nickel, and TTA-P2 of Medicine demonstrated that calcium responses were mediated by T-Type VGCCs. These findings suggest PAK kinases are highly expressed in the brain, and that single APs are capable of opening T-Type VGCCs, are known to play a critical role in actin and eliciting calcium entry into the entire dendritic polymerization and dendritic spine morphogenesis. arbour and nucleus. Calcium influx caused by AP Disruption of PAK kinases activity or expression has firing could aid integration of inputs and alter gene been linked to abnormal synapse formation, transcription to upregulate excitability. dysfunctional plasticity, and diseases affecting cognition. Several studies demonstrate that aberrant 1-B-30 Anoxic regulation of mitochondrial AMPAR trafficking impairs memory and cognition. membrane potential and ROS production leads to Dynamic control of AMPAR recycling to and from electrical suppression in turtle cerebral cortex synapses is regulated by posttranslational modifications and interactions with accessory Peter Hawrysh¹, David Hogg¹, Les Buck¹ proteins. We identified a novel site in AMPAR subunit GluA1 (serine 863) that is rapidly ¹University of Toronto CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

phosphorylated following brief TTX-mediated excitatory synapse proteins have on KCC2, disruption of neuronal activity, and can regulate suggesting a potential role for this interaction in the surface expression of AMPARs. Activation of PAK3 regulation of excitation-inhibition balance in the through the small GTPases Cdc42 and Rac1 enhances CNS. phosphorylation of S863. In contrast, targeted loss of PAK3 expression disrupts activity-dependent 1-B-33 Modulation of PTEN/mTOR pathway phosphorylation of S863 in neurons. The receptor through Ndfip1 over-expression promotes neuronal tyrosine kinase EphB2 has been shown to regulate survival and regeneration following injury Cdc42 and Rac GTPase activity, in addition to modulating synaptic recruitment of AMPAR. In this Mohamad Khazaei¹, Michaeil Fehlings² study we demonstrate that activation of EphB2 ¹Toronto Western Research Institute, ²University of enhances GluA1 phosphorylation at S863. Toronto Furthermore, we identify EphB2 as a novel interactor of the guanine-nucleotide exchange factor Zizimin1. Spinal cord injury involves a mechanical injury to the In vivo activation of either Cdc42 or Rac1 by Zizimin1 axons which results in progressive degeneration of is sufficient to stimulate GluA1 phosphorylation at the axons and subsequent neuronal cell death. PTEN S863. Collectively, our findings outline a novel plays as a negative regulator of axon outgrowth and signaling cascade that includes EphB2, Zizimin1 and regeneration. Pharmacological inhibition or genetic PAK3 in the regulation of S863 phosphorylation and ablation of PTEN increases neurite outgrowth and AMPAR trafficking in neurons. axon regeneration after injury. However, the nuclear form of PTEN is crucial for neuronal survival. Ndfip1 1-B-32 Interactions between excitatory synapse is an adaptor protein which regulates PTEN proteins and KCC2 influence KCC2 function and trafficking to the nucleus causing its reduction in the GABAergic inhibition cytosol and increasing its pro-survival nuclear pool. Sahara Khademullah¹, Vivek Mahadevan¹, Melanie This mechanism has not been previously shown in Woodin¹ neurons, making Ndfip1 a potential factor for down- regulating PTEN in the neuronal cytosol, while ¹University of Toronto maintaining its role in their survival.

A balance between synaptic excitation and inhibition Here we have shown that Ndfip1 expression in is essential for normal brain function. When this cultured neurons resulted in the reduction of PTEN delicate balance is disrupted, it can lead to neuronal level in the cytosol leading to the activation of mTOR hyperexcitability, resulting in alterations in neuronal pathway. Moreover, nuclear trafficking of PTEN was network activity and the onset of various stimulated by overexpression of Ndfip1 and neurological disorders. KCC2 is the neuron-specific overexpression of Ndfip1 increased neuronal survival K+-Cl- co-transporter that extrudes Cl- from neurons after mechanical injury. Stretching of axon in an in and thus maintains intracellular Cl- levels low, which vitro model for mechanical injury resulted in an is critical for GABAergic inhibition in the mature increase in apoptotic death of cultured cells. nervous system. In addition to its role in regulating However, neurons overexpressing Ndfip1 showed an inhibitory transmission, KCC2 also plays an important increased survival compared to control neurons role at the excitatory synapse. Here, KCC2 functions expressing GFP. Furthermore, we have shown that as structural support essential for dendritic spine Ndfip1 expression could reduce cleavage of caspase- formation and maintenance, and contributes to the 3 and could also inhibit the degradation of structural organization of AMPA receptors at the dephosphorylated NF200. Additionally our results excitatory synapse. We sought to investigate the indicate that Ndfip1 can promote axonal outgrowth interaction between proteins expressed at excitatory formation of longer axons in injured neurons. synapses and KCC2. We hypothesize that these interactions may form the basis of a protein complex 1-B-34 Activity-dependent and bi-directional important for the excitation-inhibition balance. To plasticity of glutamate synapses on striatal investigate these interactions, we used co- projection neurons in cortico-striatal co-cultures. immunoprecipitation assays in heterologous systems Naila Kuhlmann¹, Li-Ping Cao¹, Austen Milnerwood¹ and in vivo. Our work sheds light on the effects that CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

¹Centre for Applied Neurogenetics, UBC in acute hippocampal slices, we found that synaptic NMDA receptor activation during a narrow Striatal synaptic plasticity and dendritic spine developmental epoch triggered ryanodine receptor- morphology are implicated in numerous psychiatric dependent calcium-induced calcium release (CICR) at and neurodegenerative disorders, including CA1 pyramidal cell dendrites. This NMDAR-mediated Parkinson's Disease (PD). However, few studies have CICR was a major determinant of spine calcium explored the molecular mechanisms underlying this kinetics, and drove local calcium signal propagation plasticity, especially within the context of PD-linked to nearby spines. Moreover, NMDAR-CICR coupling gene mutations. We recently reported that enabled dendrites to biochemically encode a range mutations in the protein leucine rich repeat kinase 2 of distinct spatiotemporal features of synaptic input. (LRRK2; the most common genetic risk factor for PD) We hypothesized that this mechanism may spatially alter synaptic activity of cortical neurons in cultures regulate the development of synaptic ensembles in from LRRK2 G2019S knock-in mice: glutamatergic vivo. To test this prediction, we mapped synapse transmission was increased, and the phosphorylation maturation by probing the functional AMPAR and status of presynaptic proteins was reduced. Here, we NMDAR content of neighbouring spines and found explored the effects of synaptic silencing, NMDAR- unequivocal evidence for clustered synapse dependent long-term potentiation (LTP) and development along individual dendritic segments. mGluR1/5 dependent long-term depression (LTD) in Our results reveal novel developmental features of cortico-striatal co-cultures. We quantified striatal NMDAR-dependent calcium dynamics suited to spiny projection neuron (SPN) spine morphology and instruct the assembly of synaptic microcircuit motifs density by confocal microscopy to examine the apt to exploit the nonlinear regimes of dendritic activity-dependence of structural plasticity, and information processing. Dysregulation of these measured changes in synaptic proteins, including mechanisms may be involved the genesis of subtle surface expression of glutamate receptors. microcircuit disturbances underlying Manipulating cortical glutamatergic activity neurodevelopmental disorders. significantly altered spine structure and synaptic proteins, particularly after chronic treatment. LTP 1-B-36 Short-term consumption of high fat food increased spine density and AMPA-type glutamate increases long lasting excitatory synaptic receptor subunit density/intensity; the reverse was transmission onto VTA dopamine neurons observed for LTD. This study provides a useful assay to explore the mechanisms regulating SPN synaptic Shuai Liu¹, Andrea Globa², Fergil Mills², Shernaz transmission and plasticity, and is now being Bamji², Stephanie Borgland¹ extended to investigate PD-linked mutations and how altered synaptic activity may contribute to PD ¹University of Calgary, ²University of British Columbia pathology. Dopamine neurons of the ventral tegmental area 1-B-35 Spatiotemporal transformations of local (VTA) are part of a critical circuit for reward seeking calcium dynamics during clustered synapse and hedonic feeding. Consumption of energy dense, development palatable food activates the mesolimbic dopaminergic circuit to reinforce food intake. It is Kevin Lee¹, Cary Soares¹, Jean-Philippe Thivierge¹, well known that the sensory properties, such as the Jean-Claude Béïque¹ perceived palatability, can drive food intake. However, it is unknown if consumption of palatable ¹University of Ottawa food can have lasting effects on future food intake or food seeking behaviours. Here, we test the Pyramidal neurons establish thousands of synaptic hypothesis that short-term consumption of palatable connections during early postnatal brain food can drive future feeding behavior and development, marking a key period in neural circuit consumption. Mice given 24 h access to a sweetened assembly. Despite the eminent role of calcium in high fat diet (SHF) had increased anticipatory and synapse regulation, remarkably little is known about food approach behaviors as well as consumption 2 intracellular calcium dynamics during days later compared to mice given only 1 h access or synaptogenesis. Using whole-cell electrophysiology, chow. Immediately after 24 h SHF intake, increased two-photon calcium imaging and glutamate uncaging endocannabinoid tone onto excitatory inputs to CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

dopamine neurons was offset by increased signalling and suggests a possible involvement of glutamatergic synaptic density onto dopamine, but ciliary proteins in epileptogenesis. not non-dopamine neurons. This was followed days later by an increase in glutamatergic synaptic 1-B-38 Optogenetic control of second messenger strength that lasted at least a week. Finally, dynamics in dendritic spines during synaptic increased food approach behaviour and plasticity using a two-photon approach consumption two days after short-term access to SHF was reversed with intra-VTA administration of Thomas Luyben¹, Jelena Borovac¹, Fiona Bergin¹, insulin, known to selectively induce a synaptic Megan Valencia¹, Mustafa Khan¹, Kenichi Okamoto¹ depression at glutamatergic inputs to the VTA. In ¹The Lunenfeld-Tanenbaum Research Institute conclusion, the short-term consumption of SHF induces a long lasting strengthening of excitatory Cyclic adenosine monophosphate (cAMP) is a synaptic transmission onto VTA dopamine neurons, ubiquitous second messenger involved in synaptic indicating a potential mechanism underlying plasticity, such as LTP (long-term potentiation). Here increased food approach behaviors and we study the role of postsynaptic cAMP in the consumption. structural plasticity of dendritic spines by developing two-photon optogenetics and live imaging 1-B-37 The ciliary gene, EFHC1, implicated in techniques in cultured hippocampal slices. Dendritic human epilepsy, modulates dopamine signalling in spines are thought to change their shape and C. elegans properties during LTP. To understand cAMP's role in Catrina Loucks¹, Andrea McEwan², Chunmei Li¹, this process, we prepared a genetically-encoded Jacque-Lynne Johnson¹, Catharine Rankin², Michel optical cAMP sensor and used two-photon FRET Leroux¹ (Fӧrster resonance energy transfer) microscopy to image neurons during LTP. Time-lapse ¹Simon Fraser University, ²University of British imaging of two-photon FRET in living neurons Columbia allowed us to detect a transient increase in cAMP after inducing LTP via strong tetanus, but we did not Aberrant dopamine signalling is associated with detect a change after caged-glutamate uncaging various forms of epilepsy. An important question is (early LTP induction), suggesting a role of cAMP in whether alterations in dopamine signalling late LTP. We have also established a two-photon contribute to epileptogenesis or are merely a optogenetic technique to activate PAC consequence of increased neuronal excitability. In (photoactivatable adenylyl cyclase) at targeted this work, we provide evidence for a direct link dendritic spines to locally produce cAMP. We found between the ciliary protein, EFHC1, commonly that postsynaptic cAMP enhanced dendritic spine mutated in juvenile myoclonic epilepsy, and enlargement during the plasticity, and it was dopamine signalling. C. elegans EFHC1 localizes to a required within the first minute after induction of subset of ciliated dopaminergic neurons responsible spine structural plasticity, suggesting the for modulating specific behaviors based on food intracellular signaling critical for the structural availability. In the presence of food, cilia are plasticity last for less than one minute. The rapid mechanically activated, leading to synaptic release of effect of cAMP is requires PKA, but not HCN dopamine that is then able to modulate neuronal (hyperpolarization-activated cyclic nucleotide) activity. Interestingly, while EFHC1 is enriched at channels or protein synthesis. We will discuss a role cilia, it also localizes to synapses. Mutations in EFHC1 for postsynaptic cAMP in the dendritic spine cause phenotypes consistent with increased structure reorganization during synaptic plasticity. dopamine signalling due to spontaneous dopamine release. Overactivity of a pre-synaptic voltage-gated 1-B-39 Sex differences in the involvement of calcium channel in overlapping cells has the same spinal P2X4 receptors and BDNF in pain effect, suggesting that EFHC1 may negatively hypersensitivity induced by peripheral nerve injury regulate this voltage-gated calcium channel at the synapse to prevent spontaneous dopamine release. Josiane Mapplebeck², Simon Beggs², Michael Salter² This represents the first evidence that a gene ¹Hospital for Sick Children, ²The Hospital for Sick implicated in epilepsy directly influences dopamine Children CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

Chronic neuropathic pain is characterized by mild to electrocortical activity that resemble those elicited severe pain and results in significant human suffering by etomidate, such as increased 8-12Hz and 12-30Hz and economic burden. The spinal mechanisms activity, decreased 1-4Hz activity, and increased underlying neuropathic pain have been extensively spindle-like oscillations; and 2) thalamic T-type Ca2+ investigated in male rodents, indicating an essential channels, which promote 1-4Hz activity, do not role for P2X4 receptor-driven release of brain- mediate these changes. Microperfusion of the derived neurotrophic factor (BDNF) from spinal extrasynaptic δGABAAR positive allosteric microglia in the maintenance of pain modulator DS2 (100μM), which promotes spill- hypersensitivity. However, we recently over inhibition, into the thalamus effected demonstrated that microglia do not mediate pain electrocortical activity in wild-type mice, but not in hypersensitivity in female mice. The role of BDNF in mice lacking δGABAARs. Specifically, during mediating pain hypersensitivity in females remains non-REM sleep DS2: (i) increased 8-12Hz and 12- unknown. Consequently, we investigated the role of 30Hz power (both p<0.032), (ii) decreased 1-4Hz spinal BDNF in neuropathic pain in female and male power (p<0.001), and (iii) increased spindle-like mice. Neuropathic pain was modeled in mice via oscillations (p=0.034). The electrocortical effects of spared nerve injury. Mechanical sensitivity was DS2 were unaffected by blocking T-type Ca2+ measured using von Frey fibers. First, we found that channels with TTAP2 (300μM). These results intrathecal application of BDNF (0.5µg/mouse) in indicate that enhanced thalamic spill-over inhibition naïve mice induces pain hypersensitivity in either elicits changes in electrocortical activity that sex. Second, we determined that pain resemble those elicited by etomidate at the hypersensitivity after spared nerve injury was thalamus and do not require activation of T-type reversed in males but not females through inhibition Ca2+ channels. of TrkB functioning via spinal application of TrkB-Fc (0.5µg x3 days) and y1036 (5.0µg). Furthermore, we 1-B-41 cAMP-dependent protein kinase inhibits a7 found that inhibiting P2X4 receptors with TNP-ATP nicotinic receptor activity in layer 1 cortical (5.0µg) reversed pain hypersensitivity in males but interneurons through activation of D1/D5 not in females. Our experiments provide evidence dopamine receptors indicating that female mice do not use P2X4 receptors or BDNF to mediate neuropathic pain Raad Nashmi¹, Pragya Komal¹, Anthony Renda¹, Raad hypersensitivity. Taking into consideration sex Nashmi¹ differences in the spinal mediation of chronic pain ¹University of Victoria may greatly improve future treatment development. Phosphorylation of ion channels, including nicotinic 1-B-40 Enhanced thalamic GABAAR-mediated acetylcholine receptors (nAChRs), by protein kinases spill-over inhibition elicits anesthetic-like changes plays a key role in the modification of synaptic in electrocortical activity that do not require T-type transmission and neuronal excitability. α7 Ca2+ channel activation nAChRs are a major subtype of nAChRs in the CNS. Lia Mesbah-Oskui¹, Richard Horner¹ Serine 365 in the M3-M4 loop of α7 is a phosphorylation site for protein kinase A (PKA). We ¹University of Toronto used pharmacological and molecular approaches to target PKA and monitor alterations in α7 Increased thalamic GABAA receptor (GABAAR)- nAChR activity. In layer 1 interneurons of mouse mediated inhibition can trigger changes in prefrontal cortex, α7 nAChR currents were electrocortical activity indicative of sedation. decreased upon stimulation with 8-Br-cAMP, a PKA GABAAR-mediated inhibition can be either tonic (i.e. activator. In HEK293T cells, dominant negative PKA extrasynaptic), phasic (i.e. synaptic), or spill-over (i.e. abolished 8-Br-cAMP's effect of diminishing α7 requiring both synaptic and extrasynaptic GABAARs). nAChR currents, while a constitutively active PKA Importantly, the alterations in thalamic activity catalytic subunit decreased α7 currents. In elicited by the general anesthetic etomidate require brain slices, the PKA inhibitor KT-5720 nullified 8-Br- both synaptic and extrasynaptic GABAARs in vitro. cAMP's effect of attenuating α7 nAChR Here we test 2 hypotheses in vivo: 1) enhanced responses, while applying a purified PKA catalytic thalamic spill-over inhibition elicits changes in subunit in the pipette significantly decreased CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

α7 currents. There was no effect of 8-Br-cAMP potentiated synapses from activity-induced on the function of mutant α7 receptors, in weakening. (Funded by CIHR) which serine 365 was mutated to alanine. The reduced α7 current was due to a decrease in 1-B-43 IKCa channels are a critical determinant of surface expression of α7 nAChRs. The D1/D5 the slow AHP in hippocampus dopamine receptor agonist SKF83822 attenuated α7 nAChR currents from interneurons and this Brian King¹, Arsalan Rizwan¹, Hadhimulya Asmara¹, N. attenuation of nAChR current was prevented with Colin Heath¹, Jordan Engbers¹, Steven Dykstra ¹, KT-5720. These results demonstrate that dopamine Theodore Bartoletti¹, Shahid Hameed¹, Gerald receptor mediated activation of PKA attenuates Zamponi¹, Ray Turner¹ nicotinic neurotransmission in prefrontal cortical ¹The University of Calgary interneurons, which may be a contributing mechanism of dopamine modulation of cognitive Of the many classes of potassium channels behaviors such as attention or working memory. recognized in central neurons, few have as key a role in regulating the frequency and pattern of spike 1-B-42 Norepinephrine Protects Synapses from discharge as calcium-gated potassium channels. Depotentiation by Priming Translation-Dependent However, an unidentified class of calcium-gated LTP. potassium channel that generates a slow AHP (sAHP) Sean Rah¹, Saby Maity¹, Peter Nguyen¹ that can last seconds exerts a far greater influence on the excitability of almost all neurons. We recently ¹University of Alberta found that a sAHP in cerebellar Purkinje cells is generated by a third class of "intermediate Norepinephrine (NE) is a key neuromodulator that conductance calcium-gated potassium channel" controls the longevity of distinct forms of synaptic (IKCa) that was not believed to be expressed in plasticity such as LTP. Activation of beta-adrenergic central neurons. We used patch recordings in rat or receptors (b-ARs) is known to boost persistence of mouse in vitro tissue slices to test the hypothesis LTP in area CA1 of mouse hippocampal slices. We that CA1 pyramidal cells express IKCa channels. tested the hypotheses that: 1) NE primes synapses Under conditions of BK, SK and Kv7 channel block we for subsequent long-lasting LTP (an effect known as recorded a potassium current derived from calcium- "metaplasticity"); 2) NE-induced metaplasticity activated channels of intermediate conductance that requires activation of specific subtypes of b-ARs; 3) is sensitive to IKCa channel blockers (ie TRAM-34) This metaplasticity serves to protect potentiated and enhanced by IKCa agonists. The sAHP is known synapses from activity-induced weakening to exert significant control over pyramidal cell (depotentiation, DPT). Using population EPSP excitability by restricting EPSP summation and recordings from CA1 of mouse hippocampal slices, mediating spike accommodation. Internal infusion of we show that NE (10uM) applied well before weak 1 µM TRAM-34 blocked the sAHP evoked by tetanic stimulation (1 x 100-Hz, 1s) induces repetitive stratum radiatum stimulation (5-30 pulses, metaplasticity of LTP by engaging beta-1 adrenergic 50 Hz). TRAM-34 further blocked spike receptors. LTP persistence was enhanced by prior NE accommodation during synaptic trains or direct application. Interestingly, 5-Hz stimulation induced current injection in wild type but not IKCa knockout DPT in control potentiated neurons, but not in animals. These data reveal the expression of IKCa neurons pre-treated with NE before LTP induction. channels in CA1 hippocampal pyramidal cells that The NE-induced metaplasticity of LTP required exert a significant contribution to the calcium- protein synthesis, as evidenced by a significant dependent component of the sAHP. *Shared first reduction of LTP persistence when slices were authorship. Funded through CIHR. acutely treated with a translational inhibitor, cycloheximide, during NE application. Thus, NE 1-B-44 Effects of wild-type and mutant huntingtin primes synapses to undergo long-lasting on the in vitro corticostriatal synapse potentiation when a stimulus that is otherwise sub- threshold for induction of persistent LTP is later Mandi Schmidt¹, Matthew Parsons¹, Caodu Buren¹, applied. One function of NE may be to prime Shaun Sanders¹, Lynn Raymond¹, Michael Hayden¹ intracellular mechanisms that protect, or immunize, ¹University of British Columbia CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

Huntington disease (HD) is caused by a CAG synapses in order to tune cellular excitability within a expansion in huntingtin (HTT), leading to early defined range. Interestingly, homeostatic and corticostriatal dysfunction, progressive striatal death Hebbian synaptic plasticity operate through partially and motor, psychiatric and cognitive disturbances. overlapping mechanisms to modify synaptic Huntingtin-interacting protein 14 (HIP14) is a strength, including through postsynaptic regulation palmitoyl acyltransferase responsible for of excitatory glutamate receptors of the AMPA and palmitoylation and localization of HTT and synaptic NMDA subtypes. As such, homeostatic adaptions are proteins. HIP14 function is potentiated by wild-type well poised to exert strong control over Hebbian HTT (wtHTT) and impaired by mutant HTT (mHTT). synaptic plasticity rules, although this possibility has Thus, a hypothesis has emerged whereby HIP14 received little direct attention. Using an established dysfunction in the presence of mHTT results in model of HSP in organotypic hippocampal slices, we deficient palmitoylation and mislocalization of its investigated whether and how homeostatic substrates, contributing to early aberrant neuronal mechanisms influence Hebbian plasticity rules at transmission in HD. A corticostriatal co-culture CA1 synapses. We show that HSP mechanisms model was utilized to study the effects of wtHTT and powerfully influence the ability of CA1 neurons to mHTT on the distribution and palmitoylation of express subsequent synaptic plasticity through synaptic HIP14 substrates. Immunocytochemical Hebbian induction mechanisms. A complete analyses of YAC128 co-cultures expressing mHTT elucidation of the mechanistic interplays between indicate altered localization of the presynaptic HIP14 homeostatic and Hebbian synaptic plasticity will substrates cysteine string protein and contribute to a more comprehensive understanding synaptotagmin-1 compared to wild-type, HTT of how information is processed and stored in the heterozygous, or wtHTT-overexpressing YAC18 co- brain. cultures. These changes correspond with a 15-20% reduction in substrate palmitoylation. 1-B-46 Control of trauma-induced epileptogenesis Electrophysiological recordings reveal a dramatic in mice and its age dependency reduction in spontaneous excitatory events in YAC128 co-cultures as well as impaired transmitter Sara Soltani¹, Josée Seigneur¹, Sylvain Chauvette¹, replenishment following synaptic release. Igor Timofeev¹ Postsynaptic AMPA receptor distribution and ¹Institut universitaire en santé mentale de Québec glutamate response are largely unaffected by HTT expression level or mutation. Altogether, these Severe brain damage leads to epilepsy several findings suggest that early corticostriatal dysfunction months to years after the trauma. The mechanisms in HD may be mediated primarily through leading to epileptogenesis are unknown. We used a presynaptic mechanisms. model of cortical trauma epilepsy (TIE) in mice cutting the white matter underneath a cortical 1-B-45 Homeostatic influence on Hebbian region. We hypothesized that the reduction in plasticity rules at central synapses afferent excitatory inputs in the undercut region Cary Soares¹, Jean-Claude Béïque¹ leads to the upregulation of excitability and, this leads to epilepsy. This homeostatic process might be ¹University of Ottawa age-dependent. We performed undercut in the somatosensory area in young and adult C57/BL6 Changes in fine circuit architecture of the brain are mice and implanted LFP and EMG electrodes for believed to participate in neural computation and continuous electrographic recordings for at least two information storage. This malleability of neural months. In the following weeks, we found only circuits is dependent on the capacity of individual isolated interictal spikes in young animals, but all old synapses to express rapid structural and functional mice revealed recurrent seizure activities. We used modifications in response to incoming activity, the DREADD technology to test the hypothesis that through mechanisms collectively referred to as controlling the level of excitability will control the Hebbian synaptic plasticity. In the face of perpetual development of epilepsy. Target cortical regions changes in network excitability, slower-acting were injected with AAV-hM3D(Gq) or AAV-hM4D(Gi) homeostatic synaptic plasticity (HSP) mechanisms and infected neurons were continuously activated operate bidirectionally to regulate the strength of via an osmotic pump. We found that activation of CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

hM3D(Gq), which leads to depolarization and 1-B-48 A brain-wide analysis of neuronal increased firing in infected neurons, reduced the transcriptomic and electrophysiological diversity occurrence of seizures in chronic stages, while the activation of hM4D(Gi), which induces a Shreejoy Tripathy¹, Dmitrii Tebaykin¹, Ogan hyperpolarization of neurons, strongly increased the Mancarci¹, Lilah Toker¹, Paul Pavlidis¹ occurrence and severity of spontaneous seizures. We conclude that TIE is age-dependent and that ¹University of British Columbia recovering the normal level of activity in the Brains achieve efficient function through undercut region could lead to the prevention of implementing a division of labor, in which different epileptogenesis. neurons serve distinct computational roles. Neuronal Supported by CIHR, NSERC, and NIH computations are established through the expression of combinations of ion channels and 1-B-47 Identifying sources of study-to-study associated proteins which define neuronal variability in neuronal electrophysiology data electrophysiological properties. Despite numerous studies characterizing neuronal physiological Dmitrii Tebaikin¹, Dmitrii Tebaikin¹, Shreejoy properties and gene expression patterns, linking Tripathy¹, Paul Pavlidis¹ neuron genomics to neuron function has been challenging due to the complexity of these ¹University of British Columbia heterogeneous data. Here, employing data integration and statistical approaches, we combine Recently, there has been a major effort by published reports of neuronal physiological neuroscientists to systematically organize and properties with public genome-wide expression integrate vast quantities of brain data (Allen Brain atlases. Specifically, we integrate NeuroElectro Atlas, NeuroLex, NeuroMorpho, NeuroElectro). For (www.neuroelectro.org), a database of literature- example, meta-analysis of electrophysiological data mined neuron-type physiological diversity, with the using NeuroElectro.org has shown that various Allen Brain Atlas. We demonstrate that relative experimental conditions, or metadata (animal age, differences among the genes that neurons express recording temperature, electrode type) can in part are significantly predictive of neuronal biophysical explain study-to-study variance in neuronal parameters (such as resting potential and input electrophysiology values (resting membrane resistance; R2 = .65, .41). Our approach allows us to potential, input resistance, spike half-width). Here, ask which genes, of the 20,000 in the genome, are we employ a large scale text-mining approach, most predictive of electrophysiological diversity. In supplemented with manual curation, that provides addition to ion channel genes (such as inward us access to quantitative data from hundreds of rectifying K+ channels, e.g. Kcnj4), genes related to thousands of published neuroscience articles. synaptic plasticity and neuronal differentiation (e.g. Specifically, our goal is to identify additional Slit3) were also surprisingly correlated with neuronal metadata that may explain more of the physiology. Moreover, cross-referencing these gene electrophysiological variance and further reconcile lists with those implicated in mental disorders, we experiment-to-experiment differences. We are find that these genes are also disrupted in epilepsy, exploring how external (recording) and internal schizophrenia, and autism. (pipette) chemical compositions affect variance of intrinsic and synaptic measurements (i.e. long term 1-B-49 Mild traumatic brain injury produces more potentiation). Our literature-based approach serves immediate and prolonged LTP deficits in the to cover this gap in evidence by extracting metadata juvenile female brain from a large corpus of neuroscience articles. Ultimately, normalizing electrophysiology values Emily White¹, Jessica DeVries¹, Jennifer Graham¹, based on experimental conditions within each Sean Kennedy¹, Crystal Bostrom¹, Brian Christie¹ neuron type will allow us to link electrophysiological diversity to corresponding differences in gene ¹University of Victoria expression levels and disease phenotypes. Traumatic brain injury (TBI) is the leading cause of disability in individuals under 45 years of age, with mild TBI (mTBI) accounting for the majority of cases. CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

The juvenile brain is in a period of robust synaptic leading to inhibition of proteasomal degradation of reorganization and myelination, making adolescence RCAN1. Furthermore, knockdown of RCAN1 a particularly vulnerable time to incur a TBI. Learning expression attenuated APP-induced neuronal and memory deficits that involve the hippocampal apoptosis. Taken together, the results clearly formation are often observed following mTBI in showed that APP has a previously unknown function adults. To examine this issue we examined changes in regulating RCAN1-mediated neuronal apoptosis in electrophysiology following closed-head mTBI in through proteasome pathway. Our study male and female Long-Evans rats (25-28 days of age). demonstrates a novel mechanism by which Synaptic plasticity of field excitatory post-synaptic overexpression of APP and RCAN1 causes potentials (fEPSPs) was assessed at either one hour, neurodegeneration and AD pathogenesis in DS and it one day, seven days, or 28 days following mTBI in provides new insights into the potential of targeting either the dentate gyrus (DG) or cornu ammonis area APP-induced proteasomal impairments and RCAN1 1 (CA1) regions of the hippocampus. In female rats, accumulation for AD and DS treatment. the CA1 region ipsilateral to the impact showed a significant reduction in long-term synaptic plasticity 1-B-51 Cannabinoid receptor 1 and Somatostatin (LTP) as early as one hour following mTBI. Similar LTP receptor subtypes colocalization in rat brain deficits were apparent at one day in the DG, and persisted to 28 days following injury. In male rats, a Ujendra Kumar¹, Shenglong Zou¹, Rishi Somvanshi¹ deficit in both DG- and CA1-LTP was apparent in the ¹UBC Pharmaceutical Sciences ipsilateral hemisphere by seven days following injury, but these deficits did not persist until 28 days Somatostatin (SST) and cannabinoids exert many post-injury. These data suggest that the juvenile overlapping functions in central and peripheral brain is susceptible to mTBI-induced impairments in tissues via binding to their cognate receptors which plasticity, and sex and regional differences are belong to GPCR superfamily. Whether these receptor apparent in the expression and recovery of synaptic subtypes are expressed in same cell specifically in plasticity following mTBI. central nervous system is not well understood. Recently, we described that somatostatin (SST) is 1-B-50 APP facilitates the RCAN1-mediated colocalized with cannabinoid receptor 1 (CB1) in rat apoptosis brain hypothalamus and hippocampus. In the Yili Wu¹, Yu Deng¹, Shuting Zhang¹, fang cai¹, weihui present study, by using double-labeled zhou¹, tingyu li¹, weihong song¹ immunofluorescence, we determined the distribution and colocalization of SSTR1-5 and CB1 in ¹The University of British Columbia rat brain regions including cortex, striatum and hippocampus. Results presented revealed a receptor Individuals with Down syndrome (DS), caused by subtype-and brain region-specific colocalization trisomy of chromosome 21, inevitably develop between CB1 and SSTRs. In cortical brain regions, characteristic Alzheimer's disease (AD) CB1 and SSTRs colocalize in both cell bodies and neuropathology including neuritic plaques, apical dendrites in different layers with various neurofibrillary tangles and neuronal loss after middle intensities. In comparison, colocalization in striatum age. Amyloid β protein (Aβ), the major was less frequently seen among all SSTRs with component of neuritic plaques, is the proteolytic distinct patterns in projection neurons and product of amyloid β precursor protein (APP). interneurons. In hippocampus, colocalization in both APP and regulator of calcineurin 1 (RCAN1) gene on neuronal cell bodies and dendrites was observed in chromosome 21 play a pivotal role in promoting CA1-3 and dentate gyrus. In addition to the neuronal plaque formation and neuronal apoptosis. However, population showing colocalization, neurons the mechanism underlying AD pathogenesis in DS is displaying either CB1 or SSTRs were also seen in not well defined. In this study, we demonstrated different brain regions in receptor specific manner. that APP significantly increased RCAN1 level in cells Our results provide first comprehensive study on and transgenic mice. Overexpression of APP colocalization between CB1 and SSTR subtypes and significantly reduced the expression of two establish a close relationship between these two proteasome subunits, proteasome α subunit 5 receptor families which can be explored as possible (PSMA5) and proteasome β subunit 7 (PSMB7), CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

therapeutic intervention in certain pathological Clinically indistinguishable cases of amyotrophic conditions. lateral sclerosis (ALS) can be caused by either inheritable mutation in the genes encoding SOD1, C - Disorders of the Nervous System TDP-43, FUS, among others, or can occur sporadically. Misfolded SOD1 has been detected in 1-C-52 Dopamine terminals mediate vesicular both familial and sporadic ALS patients, despite release of L-DOPA-evoked enhancement of SOD1 mutations accounting for only ~2% of cases. dopamine in the 6-OHDA lesioned striatum. We previously reported that pathological FUS or TDP-43 kindles misfolding of human wtSOD1 in living Soyon Ahn¹, Bonita Ma¹, Anthony Phillips¹ cells. Here, we used human cell cultures and mouse primary neural cultures expressing human wtSOD1, ¹University of British Columbia to establish that FUS or TDP-43-induced misfolded Administration of L-DOPA (≥25 mg/kg) to rats SOD1 can traverse between cells through incubation with extensive nigrostriatal degeneration of untransfected cells with conditioned media, (≥90%) resulted in enhanced dopamine (DA) triggering conversion of endogenous SOD1. This efflux that was impulse-independent and/or spread is arrested by pre-incubating the conditioned unaffected by DA transporter inhibition media with SOD1 misfolding-specific antibodies, (Abercrombie & Zigmond, 1990). However, L-DOPA- demonstrating their therapeutic potential. We find derived DA is indeed sequestered into vesicles in that recipient cells pre-treated with SOD1-siRNA do striatal DA terminals (Omiatek et al, 2013). The not contain misfolded SOD1, implying that present study utilized microdialysis to determine endogenous SOD1 is required as substrate for active whether increased DA efflux evoked by L-DOPA in conversion. Furthermore, transfection of TDP-43 into the 6-OHDA-lesioned striatum is mediated by cells triggers its cleavage, mislocalization and vesicular release. Reverse-dialysis L-DOPA [1 uM] hyperphosphorylation; these properties are not resulted in a significant increase in DA efflux. observed in untransfected cells incubated with Changes in DA in response to further experimental conditioned media from TDP-43 transfected cells, manipulations were dependent on the severity of further confirming that the transmission of SOD1 the lesion (moderate [0.4-1.5 nM] or severe [<0.3 misfolding occurs independently of TDP-43. nM]) indicated by extracellular basal concentration 1-C-54 Rauwolfia vomitoria root extract improves of DA. In moderately lesioned rats, L-DOPA-evoked behaviour and provides region-specific reduction in DA response was attenuated significantly by Aβ plaque coverage in the 5xFAD mouse model of inhibition of vesicular transport or omission of Alzheimer's Disease. calcium from the perfusate. Further, the DA response was eliminated by the D2 agonist Katerina Allan¹, Sunday Agba Bisong Sultan quinpirole, and restored by the addition of the D2 Darvish¹, Richard Brown¹ antagonist eticlopride, suggesting a role for D2 autoreceptor regulation of DA release. In contrast, in ¹Dalhousie University severely lesioned rats, L-DOPA-evoked DA appeared to be from a cytosolic pool as it was unaltered by the Rauwolfia vomitoria (RV) root extract contains same treatments. The present findings suggest that medicinal alkaloids and is used to treat pain, anxiety, with moderate nigrostriatal degeneration, synaptic psychosis, hypertension and cancer in Africa release of newly synthesized DA involves (Fapojuwomi & Asinwa, 2013. Gr J Med Sci. 3, 37- sequestration into vesicles and calcium-dependent 41). We have shown that RV reduces anxiety-like exocytosis from surviving DA terminals. behaviour without altering motor activity of CD-1 mice (Bisong, et al., 2011. J Ethnopharm. 132, 334- 1-C-53 In ALS, misfolded wtSOD1 induced by 339). The present study investigated the effects of pathological FUS or TDP-43 transmits intercellularly RV on learning, memory and amyloid beta (Aβ) and is propagated misfolding-competent plaque formation in the brains of 6 month old 5xFAD mice. Nine female wild type (B6SJLF2) and nine Edward Pokrishevsky¹, Leslie Grad¹, Neil Cashman¹ female 5xFAD mice were dosed with RV (0, 4, or 8 mg/kg, i.p) for 51 days and given behavioural tests ¹Brain Research Centre for locomotion, anxiety, learning and memory. They CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

were then sacrificed and their brains removed, cut in brain, particularly the cortex, hippocampus, corpus 40μm coronal sections and analyzed by callosum and cerebellum (5% FDR). We are in the immunohistochemistry using polyclonal anti- process of performing a localized Golgi stain to the Aβ antibodies with diaminobenzidine as the regions that show FA changes. This study will be chromogen for brightfield microscopy. These used to determine whether FA can be used as a sections were imaged at 2.5x magnification and the biomarker of the organization of cellular percent of different brain areas covered by Aβ environment in the RTT brain. These tools can then plaques measured. Behavioural results for be used to evaluate treatment success in future locomotion, anxiety, novel object recognition and studies that aim to reverse the structural spatial learning will be presented. There was a impairments of neurons in the RTT brain. significant decrease in percent area covered by Aβ plaques in hippocampus as well as motor 1-C-56 Age-related changes in frailty in the and somatosensory cortex in RV treated mice. There 3xTgAD and 5xFAD mouse models of Alzheimer?s was no effect of RV on Aβ plaque load in the disease auditory cortex, visual cortex, or basolateral amygdala. These results indicate that RV affects Sooyoun Shin¹, Richard Brown¹ behaviour and reduces Aβ plaque load in ¹Dalhousie University certain brain areas in 5xFAD mice and should be investigated further as a potential therapy for Frailty is a measure of the accumulation of age- Alzheimer's disease. related physical deficits [Howlett SE, Rockwood K. 2013. Age Ageing. 42, 416-423]. Although the 1-C-55 Neuroanatomical and microstructural concept of frailty was developed for humans, the differences in the brain of a Mecp2 mouse model of Frailty Index (FI) can also be used to assess age- Rett syndrome related disabilities in mice. The mouse FI consists of Rylan Allemang-Grand², Jacob Ellegood², Jason 31 health-related variables (integument, digestive, Lerch² ocular, auditory, urogenital, respiratory systems, signs of sickness, abnormalities in body temperature ¹University of Toronto, ²Hospital for Sick Children and weight) [Whitehead J et al., 2014. J Gerontol A. 69, 621-632], with higher FI scores indicating Rett syndrome (RTT) is an X-linked increased frailty. We found significant differences in neurodevelopmental disorder associated with the lifespan of 3xTgAD and 5xFAD mouse models of mutations in Mecp2 which leads to an early-life AD compared to their wildtype controls. In order to regression in cognitive function and quality of life. have a measure of aging that was independent of These behavioural deficits have been attributed to a chronological age, we calculated the FI for all of the loss of dendritic complexity of neurons within the mice from 3-28 months of age in our animal brain. Although magnetic resonance imaging (MRI) colonies. FI score was positively correlated with age has demonstrated alterations in the RTT in both the 5xFAD and 3xTgAD mice and, in both neuroanatomy, a direct association between the genotypes, males had higher FI scores than females. mesoscopic neuroanatomy and the microscopic The 5xFAD mice had higher FI scores than their cellular environment has not been established. Thus, wildtype (C57BL6xSJL) controls, but there was no the objecitve of this study was to determine whether difference in their rate of deficit accumulation. The the reduced neuronal complexity can be detected 3xTgAD mice had a higher rate of deficit with diffusion weighted MRI; reduced dendritic accumulation than their wildtype (B6129S/F2) complex in RTT brain leads to increased measures of controls, indicating that they have a faster rate of water diffusion. Hemizygous and wild type Mecp2- age-related frailty than their wildtype controls. tm.1Hzo brains were: a) imaged ex vivo with a These results indicate that both 3xTgAD and 5xFAD diffusion-weighted MRI sequence, b) aligned with an mice show more age-related indices of frailty than image registration algorithm and c) compared based their wildtype controls, which may explain the on a whole-brain, voxel wise analysis of fractional shortened lifespan of these mice. anisotropy (FA), a measure of water diffusion used to infer the order of the cellular environment. Differences in FA were found in many regions of the CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

1-C-57 Effects of uncoupling 2B-NMDA receptors present which may offer a window for therapeutic from PSD-95 by Tat-NR2B9c in Huntington?s intervention. Studies on a mouse model of prion disease corticostriatal co-culture disease in our lab uncovered an alteration in expression of microRNA (miRNA) in the Caodu Buren¹, Lynn Raymond¹ hippocampus during this period. MiRNA are small, non-coding RNA molecules that bind to ¹The University of British Columbia complementary regions in the 3'untranslated region of target mRNA, inhibiting protein synthesis. We Huntington's disease (HD) is a neurodegenerative hypothesize that one specific miRNA, miR-16-5p, disorder caused by expansion in the CAG repeat targets mRNA involved in neurodegeneration, and region of the Huntingtin (Htt) gene. Numerous thereby acts as a neuroprotective miRNA. Methods: studies suggest that mutant Htt (mHtt) expression Primary hippocampal neurons are dissected from causes deficiency in the major astroglial glutamate mice at embryonic day 18 and treated with a transporter and elevation in extrasynaptic NMDA lentiviral vector at maturity. This vector either receptor (NMDAR) expression, especially those encodes miR-16 or miR-ZIP, causing overexpression containing GluN2B subunit, in striatum. These or knockdown of miR-16, respectively. Evaluation of changes may contribute to NMDAR overactivation cellular morphology is performed via confocal and cell death. Uncoupling of PSD-95 from GluN2B microscopy. In order to determine which mRNA are with a disrupting peptide, NR2B9c, can rescue the targets of miR-16 in hippocampal cells, Argonaute increased vulnerability of HD striatal neurons to immunoprecipitation (Ago-IP) coupled to microarray NMDA-induced apoptosis, suggesting the peptide analysis is utilized. Validation of targets is carried out has therapeutic potential in HD. However, little is by real-time PCR and western blot. known about its effects on synaptic function. Here, Results/Conclusion: MiR-16 has been successfully we investigated whether TatNR2B9c treatment to overexpressed and knocked down in hippocampal weaken the PSD-95/GluN2B interaction can cell cultures. Ago-IP is underway, and targets were ameliorate synaptic signaling changes in striatal predicted using a variety of software programs. neurons in corticostriatal co-culture from the Many predicted target genes are involved in YAC128 HD mouse, a model that expresses human hippocampal neuron excitotoxicity such as NOS1, Htt of 128 repeats. Surprisingly, the peptide reduced GRIN1, GRIN2B and AKT3. This supports the rather than improved pro-survival signaling. hypothesis that miR-16 is involved in preventing Moreover, 1 hour treatment with TatNR2B9c neurodegeneration. decreased synaptic GluN2B-NMDAR, which may result in diminished synaptic NMDAR activity and 1-C-59 Two unique activities in the brain of contribute to impaired survival signaling. Currently, Parkinson's disease model rats: High-Voltage- we are testing whether NR2B9c peptide impairs Spindles and Beta-Oscillation NMDAR synaptic function permanently. In addition, we will assess whether this peptide rescues other Chi-Fen Chuang¹ changes, such as enhanced extrasynaptic NMDAR and impaired synaptic vesicle release in co-culture. ¹National Tsing Hua University Together, these studies will lay the foundation for a preclinical trial of Tat-NR2B9c peptide in HD mice. Exaggerated beta oscillations in the cortical-basal ganglia-thalamic loop are currently believed was 1-C-58 The Small RNA Molecule miR-16-5p is an related to the motor symptoms of patients with Early Biomarker of Neurodegeneration and a Parkinson's disease (PD), as well as to the movement Potential Target for Therapy in Prion Disease abnormalities observed in PD-model animals. In our studies, we have found exaggerated beta oscillations Kristyn Campbell¹,Yulian Niu², Stephanie Booth¹ and High-Voltage- Spindle (HVSs) episodes increases in the M1 of PD rats. Interestingly, exaggerated beta ¹University of Manitoba & Public Health Agency of oscillations was only occurred in 6-OHDA injection Canada, ²Public Health Agency of Canada side but HVS appear bilaterally. Reports have indicated that are related to an awake, idling state of Introduction: Prion disease is a uniquely infectious, animals and disappear right after the latter start to fatal neurodegenerative disease. Interestingly, the move. Similarly, excessive beta oscillations are clinical stage of this disease can take years to CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

attenuated during voluntary movements. Our increase in excitability of the NLH (C). Our studies further reveal that both HVSs and beta preliminary results suggest that bilateral therapy oscillations are suppressed by stimulating the may invoke an adaptive rather than inhibitory subthalamic nucleus (STN) with electric shocks influence of the NLH with greater motor impairment, similar to those used in clinical applications of DBS. where excitation of the NLH may influence the Beta-frequency oscillations could be suppressed and degree TCI is reduced. Future work will test whether other oscillations at higher frequencies (40-50 Hz behavioral outcomes following bilateral therapy is and 85 Hz) were formed in ipsilateral M1-LFP by superior to unilateral for patients with greater motor administration of apomorphine but couldn't be impairment. influenced by treatment with amphetamine. Additionally, we couldn't find significant coherence 1-C-61 Parkinson's disease targets intrinsic brain between M1-upper layer (layer I, II/III of primary networks motor cortex) and M1-deepper layer (layer V) in intact side of hemi-PD model and in normal rats Yashar Zeighami¹, Yashar Zeighami¹, Miguel Ulla², from the results. However, LFP from ipsi. M1-upper Yasser Iturria-Medina¹, Mahsa Dadar¹, Kevin Larcher¹, layerand ispi. M1-deeper layer coherence emerged Douglas Collins¹, Alan Evan¹, Alain Dagher¹ in the 30-40 Hz with a strong anti-phase relationship ¹Montreal Neurological Institute, McGill University, hemi-PD model rats. ²Centre Hospitalier Universitaire de Clermont- 1-C-60 Neurophysiologic response to bilateral vs. Ferrand unilateral therapy for chronic stroke patients with Network propagation hypothesis of varying degrees of motor impairment neurodegenerative diseases (e.g. Alzheimer's David Cunningham¹, Jayme Knutson², Kelsey Potter- disease) proposes that degeneration spreads Baker¹, Vishwanath Sankarasubramanian¹, Nicole through brain via intrinsic brain networks. Here we Varnerin¹, Corin Bonnett¹, Andre Machado¹, Ela Plow¹ test this hypothesis in Parkinson's Disease (PD). We used Parkinson's Progression Markers Initiative data ¹Cleveland Clinic, ²MetroHealth Medical Center including T1 MRI, Unified Parkinson's Disease Rating Scale motor score (UPDRS3) and striatal binding ratio For patients with chronic stroke, it is believed (SBR) of 232 PD patients and 117 controls. Brain excitation of the primary cortex of the non-lesioned atrophy was calculated using deformation based hemisphere (NLH) exacerbates motor deficits by morphometry (DBM) and decomposed into spatially exaggerating transcallosal inhibition (TCI) upon the independent maps using independent component lesioned hemisphere (LH). However, recent evidence analysis (ICA). ICA maps were compared to seed suggests the NLH may play a compensatory role in based functional connectivity map with Substantia recovery for patients with greater motor Nigra (SN) as seed. We also investigated the relation impairment. If true, then therapies recruiting the between regional functional connectivity and NLH would elicit a more adaptive role of the NLH. structural deformation. ICA estimated 30 Therefore, we tested the hypothesis that therapy deformation maps. PD patients had higher involving the NLH (bilateral) would lower TCI exerted deformation values in only one map (p=.003) upon the LH compared to therapy only involving the including the entire basal ganglia, amygdala, LH (unilateral); an effect that would become more hippocampus, insula, anterior cingulate cortex, and pronounced with increasing impairment. In a premotor areas. PD-ICA deformations were crossover repeated-measures design, six patients correlated with SBR (r=-.22,p<.001) and UPDRS3 with varying degrees of motor impairment (Fugl- (r=-.26,p<.0001). PD-ICA network was spatially Meyer: 15 to 59) underwent a single session each of correlated with SN functional network (r=- unilateral and bilateral therapy. We measured .3,p<.0001). Regional functional connectivity was excitation of the NLH and TCI it exerts upon the LH significantly correlated with regional structural using transcranial magnetic stimulation. Overall, deformation (r=-.41,p<.10-6). Regions bilateral therapy resulted in a greater reduction of demonstrating disease-related atrophy in PD TCI (A), where the effect was more pronounced in correspond to an intrinsic network in healthy brain. the more impaired patients (B). However, greater Also, the deformation in a given region was inversely reduction in TCI was associated with less of an proportional to functional distance from the CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

presumed disease epicenter in SN. This supports During stroke recovery, pyramidal neurons in the network propagation hypothesis in PD. peri-infarct cortex undergo structural re- arrangements, at both the level of dendritic 1-C-62 Striking differences in the neuroanatomical branches and spines. In contrast, very little is known phenotype of the Neuroligin3 R451C knock-in and about how stroke affects the morphology of cortical the Neurexin1α knock-out. interneurons. This knowledge gap should be addressed because many of these interneurons Jacob Ellegood¹, Felipe Espinosa-Becerra², Mehreen release GABA, acetylcholine and regulate cortical Kouser², Zhong Xuan², Craig Powell², Jason Lerch¹ excitability, which is profoundly disrupted after stroke. Of note, interneurons expressing vasoactive ¹The Hospital for Sick Children, ²UT Southwestern intestinal peptide (VIP) specialize in inhibiting other Background - Neurexin and neuroligins are synaptic classes of inhibitory cortical neurons, such as those cell adhesion genes that have been associated with expressing parvalbumin (PV) and somatostatin autism (Jamain et al., 2003; Kim et al., 2008). (SOM). Further, VIP neurons have been shown to Neurexins are on the pre-synaptic side and bind to regulate cerebral blood flow. Using longitudinal in neuroligin on the post synaptic side. Alterations in vivo imaging and Cre-dependent transgenic mouse either neuroligins or neurexins could alter the lines, we are currently investigating how stroke excitatory/inhibitory balance (Etherton et al., 2009, alters the growth and stability of dendritic arbors, 2011). Objectives - To compare the volumetric spines and axons in VIP interneurons. Preliminary differences of the neuroligin3 R451C knock-in (NL3 data suggest that, like their pyramidal neuron KI) with the neurexin1α (NRXN1α) knock- counterparts, VIP neurons lose a significant number out mouse. Methods - In total, 48 fixed mouse brains of dendritic spines in the first few weeks after were examined (8 NL3 KI with 8 WT and 10 WT stroke. The dendritic arbors of these neurons are (B6/SV129), 13 NRXN1α (%2B/-), and 9 generally stable, although some branch tips clearly NRXN1α (-/-). A multi-channel 7T MRI using a retracted from week to week. Based on these T2-weighted, 3-D fast spin-echo sequence was used preliminary findings, we believe that peri-infarct VIP to acquire images at 56 μm isotropic resolution neurons lose afferent excitatory input which may (Lerch et al. 2011). To compare the groups the permit excessive inhibitory activity (in downstream images were registered together. Volume PV and SOM neurons) in the recovering cortex. The differences were calculated voxelwise and in 62 functional consequences of stroke related changes in regions. Results - 14 regional differences were found VIP interneuron structure and excitability will be in both the NL3 KI and the NRXN1α (-/-), but explored in future studies. the differences were in opposing directions, smaller 1-C-64 Novel motor cortical output pathways in NL3 and larger in NRXN1α. Several white following spinal cord injury despite extensive matter structures were affected indicative of corticospinal loss revealed by optogenetic mapping structural connectivity differences. One of the largest differences was the 12% decrease in the Brett Hilton¹, Eitan Anenberg¹, Thomas Harrison¹, hippocampus in NL3. The hippocampus was not Jamie Boyd¹, Timothy Murphy¹, Wolfram Tetzlaff¹ affected in the NRXN1α model (%2B3%, FDR of 16%). In addition to the neuroanatomical differences ¹University of British Columbia in the hippocampus, the electrophysiology and behaviour are quite different (Etherton et al., 2009, Regeneration of lesioned fibers is limited in the adult 2011). Therefore, care must be taken in assessing mammalian CNS, but many individuals that sustain genetic manipulations involving similar genes or spinal cord injuries (SCI) undergo some spontaneous genetic pathway functional recovery. Cortical plasticity is one mechanism thought to underlie this recovery, but 1-C-63 VIP interneuron re-modelling during stroke how the motor cortex responds to spinal cord injury recovery. (SCI) longitudinally is largely unresolved. We applied optogenetic motor mapping in Channelrhodopsin-2 Kimberly Gerrow¹, Craig Brown¹ expressing mice before and at multiple time points after a C3/C4 dorsal column SCI to map changes in ¹University of Victoria motor cortical topography and output within the CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

same animals following bilateral ablation of the memory deficit in the GAERS rats. These results dorsal corticospinal tract and dorsal column sensory suggest that the GAERS strain is useful for studying afferents. We find that cortical motor maps of the the comorbidities in absence epilepsy as well as the limbs are greatly diminished in area and magnitude cognitive symptoms of some psychiatric disorders. in the early stages of injury. However, by 2-3 weeks Experiments with Z944 reveal that altered T-type post-injury, pre-injury forelimb and hindlimb output, calcium channel activity may underlie certain map area, and short latency to movement are re- cognitive deficits in the GAERS strain. established. Thus, the adult mammalian motor cortex has the capacity to spontaneously re-route 1-C-66 Thioredoxin system modulates neural stem motor output following SCI. Optogenetic motor cell proliferation and differentiation: Implication on mapping provides a quantitative assessment of Neurotrauma treatment motor cortical output, can be performed repeatedly in individual animals from acute to chronic stages of Mohamed Ariff Iqbal¹, Alysa Almoujela¹, Eftekhar injury, and represents a novel longitudinal Eftekharpour¹ quantitative assay to assess treatment following SCI. ¹University of Manitoba 1-C-65 Behavioural comorbidities related to Thioredoxin(Trx) system is a major controller of psychiatric disorders in a rat model of absence cellular redox status which regulates epilepsy: effects of the T-type calcium channel oxidation/reduction of thiol groups in signaling blocker Z944 proteins involved in cell survival & proliferation. John Howland¹, Wendie Marks¹, Mary Cavanagh¹, Increased availability of Trx1 has been shown to Quentin Greba¹, Stuart Cain², Terrance Snutch³ enhance survival & proliferation in neural precursor cells(NPCs). Their contribution towards repair after ¹University of Saskatchewan, ²University of British CNS trauma remains limited. In this study, we Columbia, ³University of British Columba hypothesized that; availability of Trx will optimize NPC's contribution to repair after neurotrauma. To The Genetic Absence Epilepsy Rats from Strasbourg increase Trx tissue deposition we employed TAT (GAERS) strain of Wistar rats are commonly used as a peptide mediated delivery method to ensure rodent model of childhood absence epilepsy. In intracellular delivery of Trx(I-Trx). A noTAT protein addition to the occurrence of absence seizures in was used to compare the advantage of intracellular 100% of GAERS, research suggests that the animals delivery, identified as Extracellular Trx(E-Trx). The also display characteristics of psychiatric disorders effect of I-Trx and E-Trx on NPCs proliferation was including heightened anxiety and increased quantified in cultures after local delivery. Our in vitro sensitivity to dopamine agonists. However, a data indicates an increased cell proliferation in brain detailed behavioural assessment of the strain has yet and spinal cord-derived NPCs in response to Trx to be completed. Therefore, we tested GAERS and treatment. This effect was more pronounced when Non-Epileptic Control (NEC) rats on a battery of cells were treated with I-Trx. Additionally, I-Trx cognitive tests relevant to psychiatric disorders. We increased oligodendrocytes in NPC differentiation. found that GAERS rats performed similarly to NEC To test efficacy of Trx transduction in preclinical rats on a test of tactile recognition memory. neurotrauma models, we used focal permanent However, their performance was impaired on a cortical devascularization and clip compression visual recognition test at a one hour, but not five spinal cord injury in rats. Preliminary results from minute, delay. The GAERS strain also showed a focal devascularization showed an increased number profound disruption of crossmodal memory (tactile- of proliferating NPCs in subventricular zone. We are to-visual memory) when compared to the NECs. In a currently investigating effect of Trx transduction classical fear conditioning paradigm, GAERS rats after spinal cord injury. This study represents the showed normal learning and memory to a first application of intracellular Trx delivery for conditioned stimulus but impaired extinction and potential treatment of neurotrauma. reinstatement. Latent inhibition was also dramatically reduced in GAERS rats. Acute administration of the T-type calcium channel blocker Z944 (10 mg/kg; i.p.) reversed the crossmodal CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

1-C-67 The role of eukaryotic elongation factor-2 ¹University of British Columbia kinase (eEF2K) activity in Alzheimer?s disease pathogenesis and relevance for novel therapies. The pathogenic D620N (DN) mutation in vacuolar protein sorting 35 (VPS35) is linked to late-onset, Asad Jan², Gabriel Leprivier², Syam Prakash², Milene autosomal-dominant Parkinson's disease (PD). Vandal³, Frederic Calon³, Michael Hayden¹, Poul VPS35 is a core component of the retromer complex, Sorensen¹ involved in endosomal recycling and intracellular trafficking. Data from overexpression models ¹University of British Columbia, ²BC Cancer Research suggests that the mutation confers a loss of function Centre, ³University of Laval in AMPA-type glutamate receptor (AMPAR) recycling, resulting in aberrant synaptic connectivity. Defects in neuronal energy metabolism and synaptic Here we explore early synaptic dysfunction in a plasticity are thought to underlie cognitive novel D620N knock-in mouse model of PD. Western dysfunction and neuronal loss in Alzheimer's disease blot and co-immunoprecipitation were performed in (AD), and potentially other neurological diseases. tissue from wild-type and mutant mice to explore The AMP-responsive protein kinase (AMPK), and its differences in retromer subunit expression, and downstream target the eukaryotic elongation factor- binding of neurotransmitter receptors. Fluorescence 2 kinase (eEF2K) couple neuronal energy metabolism recovery after photobleaching was used to assay to neural activity. This mechanism allows for tight AMPAR surface recycling. Whole-cell patch clamp regulation of dendritic protein translation in register and immunocytochemistry were used to explore with synaptic activity, and plays a pivotal role in differences in synapse number and response modulating synaptic strength and plasticity. amplitude in cultured cortical cells. We found Previously, we have shown that tumor cells exploit alterations in VPS35 binding to multiple the AMPK-eEF2K axis in developing resistance to neurotransmitter receptors, including AMPARs. nutrient deprivation (Leprivier, G. et al, Cell, 2013), Cultured cortical cells showed alterations in surface and targeting this pathway represents a potential recycling of AMPARs, spontaneous glutamate treatment strategy in cancers. Our recent findings release, and synaptic strength. Here we conclude suggest that aberrant activation of the AMPK-eEF2K that the D620N mutation alters glutamatergic pathway may also be relevant to neurodegeneration synapse maintenance, and that VPS35 may be in AD. Previous studies show that eEF2K activity, involved in the recycling/maintenance of surface measured by the phosphorylation of its substrate populations of other neurotransmitter receptors. eEF2, is enhanced in AD brains. We have also carried Many genes linked to PD appear are involved in out detailed analysis in two AD transgenic mouse synaptic transmission; thus, understanding the role models (APPPS1 and 3x-Tg AD), and utilized of VPS35 is important for uncovering how pharmacological and gene silencing approaches in disruptions of neurotransmission lead to primary neuronal cultures to understand the neurodegeneration in PD. relevance of AMPK-eEF2K pathway activity on amyloid-β induced deficits in dendritogenesis 1-C-69 Alcohol tolerance & histone modifications: and oxidative stress. Our results suggest that the histone methylation plays a role in altered response AMPK-eEF2K axis may provide a link between to second alcohol exposure aberrant synaptic activity and neurodegeneration in AD, and represents a novel target for developing Conny Lin¹, James Shih¹, Ankie Hung¹, Ashvini mechanism based therapies in AD and related Sunthoram¹, Catharine Rankin¹ dementias. ¹University of British Columbia 1-C-68 Characterization of AMPAR surface recycling and synaptic transmission in a novel Chronic alcohol consumption produces gene D620N knock-in mouse model of Parkinson?s expression changes in the brain. A microarray study disease. found altered regulation of histone methylation might underlie altered gene expression in alcoholic Chelsie Kadgien¹, Lise Munsie¹, Igor Tatarnikov¹, Li brains. To investigate whether histone methylation Ping Cao¹, Austen Milnerwood¹, Matthew Farrer¹ also plays a role in behavioral changes associated with previous exposure to alcohol we developed a CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

model using C. elegans to measure a key behavioral sessions and then exhibited a greater rate of indicator of previous experience of alcohol exposure: omissions under challenging training conditions tolerance, defined in DSM-IV, as a "markedly when the light stimulus was presented for short time diminished effect with continued use of the same periods. Mice in the ethanol treatment group also amount of alcohol". We pre-exposed C. elegans to performed with greater impulsivity during the most 200mM ethanol for 24 hrs, and tested for behavioral challenging test conditions, and this effect was changes on 200mM ethanol after 2 hrs recovery. corrected by acute treatment with the Wildtype animals pre-exposed to ethanol showed acetylcholinesterase inhibitor galantamine. We are diminished responses to ethanol compared to those now continuing to assess neuronal physiology and without pre-exposure, suggesting that pre-exposure responses to cholinergic stimulation in the prefrontal increased wildtype's tolerance to ethanol. To see cortex of these same mice. This work confirms the whether histone methylation plays a role in our presence of attention deficits in this mouse model of model, we tested animals defective in regulating FASD, and suggests that dysregulation of the histone methyltransferases (HMTs), an enzyme cholinergic system underlies certain aspects of this required for methylation of lysine residues on behavioural outcome histones. We tested two mutants: one carrying a mutation in set-2, a HMT transcriptional activator, 1-C-71 Investigation of --alpha-synuclein and another carrying a mutation in set-11, a HMT phenotype in primary cortical cultures from LRRK2 transcriptional repressor. Neither mutant showed a knockout mice diminished response to ethanol following pre- exposure, suggesting that both activator and Sarah MacIsaac¹ depressor HMTs were involved in tolerance. Further ¹University of British Columbia studies using this model could reveal whether HMTs involve in altering the gene expression profile and Parkinson's disease (PD) is the second most common behavioral responses following previous exposure to neurodegenerative disorder with a prevalence of alcohol. between 2-5% in people over age 65 . Clinically, PD is characterized by rigidity, tremor, bradykinesia, and 1-C-70 Assessment of attention behaviour and postural instability , but is often accompanied by cholinergic signaling in male mice following non-motor symptoms including autonomic developmental ethanol exposure. dysfunction, anosmia, REM sleep behaviour disorder, Emma Louth¹, Warren Bignell¹, Christine Taylor¹, mood disorders, and dementia . PD is pathologically Craig Bailey¹ defined by the death of dopaminergic nigrostriatal neurons with Lewy bodies composed primarily of ¹University of Guelph misfolded α-synuclein (α-syn) in surviving neurons . The most common genetic cause Chronic prenatal exposure to ethanol can produce a of PD is mutation of the gene that encodes leucine- spectrum of adverse effects known collectively in rich repeat kinase 2 (LRRK2), a large, multi-domain humans as Fetal Alcohol Spectrum Disorder (FASD). protein with functions in vesicular recycling and Although deficits in attention rank among the most neurotransmitter release. We are currently common and persistent behavioural components of investigating α-syn pathology in primary FASD, the mechanisms underlying this outcome are cortical neurons and whether LRRK2 modulates this not known. The objective of this study was to phenotype. Addition of synthetic α-syn pre- determine effects of developmental ethanol formed fibrils (PFFs) to primary neuronal cultures exposure on attention behaviour and on has been previously shown to induce aggregation of acetylcholine signaling in adult male C57BL/6 mice. α-syn, neuronal network dysfunction, and We measured attention performance in adult male eventual neuronal death . Examining differences in mice that were exposed via oral gavage to either the response of wild type and LRRK2 knockout ethanol or sucrose during prenatal and postnatal primary cortical neurons to PFFs will elucidate if development using the five-choice serial reaction LRRK2 is involved in the harmful effects of PFFs. This time test for sustained visual attention. In these information could be crucial in the characterization experiments, mice in the ethanol treatment group of early molecular correlates of the disease and in performed with lower accuracy during initial training CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

the design of therapeutic and neuroprotective Otávio Augustin¹, Gabriela Salvalaggio¹, Simone strategies for PD. Marcuzzo¹

1-C-72 Assembly of the mammalian palmitoylome ¹Federal University of Rio Grande do Sul indicates a pivotal role for palmitoylation in diseases and disorders of the nervous system Cerebral palsy (CP) is a disorder attributed to non- progressive lesions in the immature brain. The Dale Martin¹, Shaun Sanders¹, Stefanie Butland¹, treatment of CP is focused on enhance general Mathieu Lavallée-Adam², Diego Calzolari³, Chris abilities, physical strength, prevent complications Kay¹, John Yates³, Michael Hayden¹ and improve quality of life. However, scientific evidence of the treatments are scarce and the ¹University of British Columbia, ²The Scripps biological mechanisms have not been elucidated. Research Intstitute, ³The Scripps Research Institute The aim of this research was to evaluate the effects of the early-enriched environment (EE), the treadmill Palmitoylation involves the reversible addition of the walking (TW) and the association of both (EETW), in fatty acid palmitate to cysteine residues. The fatty order to simulate the reality of clinical rehabilitation. acid moiety promotes membrane binding as well as CP model was induced by maternal exposure of low protein-protein interactions and regulates protein doses of bacterial endotoxin (lipopolysaccharide), function and activity, through direct palmitoylation perinatal anoxia and hindlimb sensorimotor of catalytically active cysteines. Like restriction of male offspring. Pups were divided in 8 phosphorylation, palmitoylation is regulated by groups: (CP), (CP+EE), (CP+TW), (CP+EETW) and its many palmitoylating and depalmitoylating enzymes. respectively control groups (Figure 1). At 31 and 52 Alterations in palmitoylation of various proteins have days of life (P31 and P52), the ladder walking test been implicated in many diseases including obesity, (LWT) and barrow narrow test (BNT) were cancer and neurodegenerative diseases, such as performed. Data were analyzed by ANOVA for Alzheimer disease and Huntington disease. We have repeated measures followed by Tukey test. At P31 compiled a non-redundant list of palmitoylated the CPEE decreased the error score, evaluated in the proteins from 15 palmitoylation proteomic studies LWT, and the error steps, in BNT when compared from various mouse, rat and human tissues. This list with the CP (p<0.001) and CPTW groups was subjected to an unbiased systems biology (p<0.01). The groups CPTW and CPEETW were approach for biomarker-based disease enrichment able to reverse the error score and error step when and, for the first time, demonstrates that compared the day P31 with P52 (p<0.01). Factors palmitoylation plays a crucial role in diseases and such as novelty, motivation and social integration disorders of the nervous system. In particular, found in EE seem to be crucial in helping to motor Schizophrenia, Heredodegenerative disorders, recovery. This research joins others in order to Chorea and HD were among the top 5 diseases. elucidate the effects of the treatments used in Indeed, not only was palmitoylation found to be clinical rehabilitation of CP. enriched in 'synaptic vesicle fusion and recycling in nerve terminals,' but a significant amount of the 1-C-74 Restoring ability to form new, and recover synaptic proteome was found to be palmitoylated old "lost", memories in mice that model (~41%). Ultimately, this suggests that aberrant Alzheimer's disease palmitoylation may play a key role in many nervous system diseases. This may provide a myriad of novel Valentina Mercaldo¹, Adelaide Yiu¹, Asim Rashid¹, targets for the treatment of HD and diseases of the Derya Sargin², Jeimmy Marcela Cerón González², nervous system. Daniel Morrison¹, Paul Frankland¹, Sheena Josselyn¹

1-C-73 Isolated and combined effects of early- ¹Hospital for Sick Children, ²University of Toronto enriched environment and treadmill walking in a model of cerebral palsy in rats: motor behavior The clinical hallmark of Alzheimer's disease (AD) is a aspects progressive decline in cognitive function. Increasing evidence indicates that b-amyloid (Ab) disrupts André Meireles¹, Marília Marques¹, Chistiano neurotransmission and synaptic function, possibly by Spindler¹, Ethiane Segabinazi¹, Francele Piazza¹, promoting excessive internalization of postsynaptic CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

AMPA-type glutamate receptors (AMPARs). These animals received normal saline while a separate findings suggest that the memory deficits described group of control animals received the combined both in patients affected by early AD and mouse intervention of VDRA agonist and NMDAR inhibitor models of AD may be due to high levels of Ab without prior treatment with haloperidol. promoting the loss of postsynaptic AMPAR. Here we Behavioural tests for motor and cognitive functions tested the hypothesis that excessive AMPAR were carried out at the end of the treatment and internalization could account for the memory deficits intervention periods. Subsequently, neural activity in seen in AD mouse models. We found that increasing the motor cortex was recorded in vivo using Ab either acutely or chronically in mouse model of unilateral wire electrodes. We also, employed AD (TgCRND8, 5xFAD, HSV viral injection of mutated immunohistochemistry to demonstrate neuron, glia, APP) disrupts both consolidation and reconsolidation neurofilament and proliferation in the motor cortex of memory measured in hippocampal dependent after haloperidol treatment and the intervention. tasks (Context fear conditioning and Water Maze). Conclusion: Our findings suggests that calcium Preventing AMPAR endocytosis during memory mediated toxicity is primary to the cause and encoding restored the ability of both acute and progression of Parkinsonism and targeting receptors chronic mouse models to form new memories that primarily modulates calcium reduces the (consolidation) and to make these memories more morphological and behavioural deficits in drug persistent. Remarkably, preventing AMPAR induced Parkins. endocytosis during a memory reminder enabled the recovery of an otherwise inaccessible old memory 1-C-76 Patterns of APP fragments suggest that (reconsolidation) in AD mouse models. These Alzheimer disease is the end-point of distinct findings elucidate the disruptive role of Ab in processes in men and women synaptic function and raise the possibility that restoring plasticity during memory encoding and/or Paul Pennington¹, Jennifer Nyarko¹, Darrell retrieval by targeting the loss of postsynaptic AMPAR Mousseau¹ may help support the ability to form new memories ¹University of Saskatchewan as well as enable recovery of lost past memories in AD patients. Alzheimer's disease (AD) is identified by overt symptomatology, at a stage when there is evidence 1-C-75 -NMDA R/+VDR Pharmacological of extensive aggregation (as plaques) of the â- Phenotype as a Novel Therapeutic target in amyloid (Aâ) peptide. However, this late-stage in Relieving Motor-Cognitive Impairments in disease progression precludes effective disease Parkinsonism management and underscores the crucial need to Olalekan Ogundele¹, Tarebi Nanakumo¹, Azeez Ishola¹ identify AD in earlier stages. Risk of AD is influenced by factors such as advancing age and genetics, ¹Afe Babalola University including APOE å4 status. Several studies have reported that a single e4 allele increases the risk This study sets to investigate the effect of targeting four-fold in women, but exerts little risk in men. calcium controlling receptors, specifically activation Even so, clinical AD research continues to view male of Vitamin D3 receptor (VDR) and inhibition of N- and female APOE å4 carriers as having equal risk. We Methyl-D-Aspartate Receptor (NMDAR) in the motor examined autopsied control and AD brain samples cortex of mice model of drug induced Parkinsonism. for fragments of the Amyloid Protein Precursor Also we demonstrated how these interventions (APP), including the Aâ peptide, and observed improved neural activity, cytoskeleton, glia/neuron changes that clearly align with APOE å4 status in a count and motor-cognitive functions in vivo. sex-dependent manner. The increased detection of Methods: Adult mice were separated into six groups Aâ42 and Aâ40 in the guanidine extracted of n=5 animals each. 5mg/Kg body weight of (insoluble/plaque) fraction are matched by haloperidol was administered Intraperitoneally for 7 decreases in the TBS-extracted (soluble) fraction. days to block dopaminergic D2 receptors and induce These changes were not consistent between cortical degeneration in the motor cortex following which an and hippocampal samples from the same donor. intervention of VDR agonist (VDRA), and (or) NMDAR Furthermore, changes in expression of the receptor inhibitor was administered for 7days. A set of control for advanced glycation end-products (RAGE) and for CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

the low density lipoprotein receptor-related protein 1-C-78 Role of Thioredoxin Reductase in (LRP) suggest that the changes in Aâ levels are due to regulation of autophagic cell death in Neurons. disruption in clearance from the brain. This knowledge provides an understanding of how Nagakannan Pandian¹, Eftekhar Eftekharpour¹ relative risk factors, e.g. sex and APOE å4 status, can interact to increase a given individual's absolute risk ¹University of Manitoba of developing AD. Autophagy is an intracellular degradation process 1-C-77 Distribution of Somatostatin and under the stress conditions. Lack of energy supply Somatostatin Receptors in Human brain triggers the self-digestion process which delivers microvascular endothelial cell in β-amyloid induced cytoplasmic constituents to the lysosome to Toxicity maintain cellular homeostasis. Reactive oxygen species (ROS) regulate autophagy in several ways Seungil Paik¹, Rishi Somvanshi¹, Ujendra Kumar¹ and are implicated in cell survival, development and death. ROS mediate their effects by oxidation of key ¹UBC Pharmaceutical Sciences proteins and a sophisticated set of thiols must constantly maintain the balance between the We recently described the role of somatostatin (SST) reduced and oxidized proteins. Thioredoxin (Trx) and in lipopolysacchride (LPS) and cytokines induced its reducing enzyme TR is a major player in cell inflammation using human brain microvascular growth and survival but is dysregulated after endothelial cell line (hCMEC/D3) as model of blood trauma/neural diseases. While role of Trx1 in brain barriers. Previous studies have indicated the regulation of autophagy has been shown, we aimed pro-inflammatory role of amyloid in onset and to identify the impact of TR1 remains unidentified. progression of Alzheimer's disease (AD) via induction Manipulation of TR1 by using Auranofin, a specific of IL-1β. Since the biological effect of SST is inhibitor of TR1, caused dose dependent cell death mediated by five different receptor subtypes, in the in SH-SY5Y neuronal cell lines. This was blocked by 3- present study we determined the role of SSTR methyladenine, an inhibitor of autophagy, but not subtypes in BBB cells using β-amyloid. Rapamycin, an inducer of autophagy. Inhibition of hCMEC/D3, grown in DMEM, were treated with TR1 caused the cells to follow classical Type II 5μM of Aβ25-35 for 12-36 hr at 37ºC (autophagic) cell death pathway evidenced by and processed for MTT assay for cell viability. In accumulation of LC3-II and activation of caspases (3 addition, SST and SSTR mRNA expression was and 9) and PARP-1. Our data indicate an association determined using quantitative real time PCR and between autophagy and endoplasmic reticulum (ER) subcellular receptor expression using stress markers IRE1 and ATF6. These results suggest immunofluorescence staining. We also determined that the availability/level of TR1 may be a regulatory the expression of IL-1β mRNA upon treatment control in regulation of endoplasmic reticulum of A. hCMEC/D3 cells treated with stress. Using molecular tools such as gene/protein Aβ25-35 exhibit time dependent changes in transfection, we are currently investigating the lack mRNA expression for SST and SSTR subtypes. We /gain of function studies. also found significant changes in subcellular expression of SSTR subtypes in hCMEC/D3. 1-C-79 Eye movements reveal sexually dimorphic Furthermore, the expression of IL-1β mRNA in deficits in children with fetal alcohol spectrum response to A was increased at 12 and 24 disorder hr and decreases at 36 hr upon treatment. Collectively, our results indicate positive correlation Angelina Paolozza¹, Rebecca Munn¹, Douglas Munoz¹, between Aβ mediated changes in SST and SSTR James Reynolds¹ subtypes in a receptor specific manner. These findings might shed new insight for the role of SSTR ¹Queen's University subtypes as potential therapeutic intervention in AD. We examined the accuracy and characteristics of This work was supported by grant from CIHR and saccadic eye movements in children with fetal NSERC and Seungil Paik is a recipient of CIHR alcohol spectrum disorder (FASD) compared with fellowship. typically developing control children. Previous studies have found that children with FASD produce CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

saccades that are quantifiably different. Additionally, animals, but lacks some of the problematic adverse animal studies have found sex-based differences for effects of classic opioids, like morphine. The behavioral effects after prenatal alcohol exposure. discovery of additional DORs could reveal receptor Therefore, we hypothesized that eye movement isoform specific effects and help in harnessing the measures will show sexually dimorphic results. receptor as a therapeutic drug target. By combining Children (5-18 yrs) with FASD (n=71) and typically rapid amplification of 5' ends PCR with deep developing controls (n=113) performed a visually- sequencing of long transcripts, we identified novel guided saccade task. Saccade metrics and behavior OPRD1 transcripts, all including previously were analyzed for sex and group differences. unannotated exons. We are currently characterizing Accuracy was significantly poorer in the FASD group, a transcript that produces a truncated 6TM DOR. We especially in males, which introduced significantly have determined its expression levels by greater variability. Therefore, we conducted quantitative PCR from a library of human central additional analyses including only those trials in nervous system RNAs and BE(2)-C neuroblastoma which the first saccade successfully reached the cell line. The transcript was originally found from target within a ±1˚ window. In this restricted BE(2)-C cells, but we confirmed the expression in amplitude dataset, the females with FASD made RNA derived from human brain. Studies are ongoing saccades with significantly lower velocity and longer to reveal the mouse analogues of the novel human duration, whereas the males with FASD did not differ receptors. from the control group. Additionally, the mean and peak deceleration were decreased in the females 1-C-81 The effect of ASD-associated mutations on with FASD. These data support the hypothesis that neuronal development children with FASD exhibit specific deficits in eye movement control and sensory-motor integration Kathryn Post¹, Kurt Haas¹ associated with cerebellar and/or brain stem circuits. ¹University of British Columbia Moreover, prenatal alcohol exposure may have a sexually dimorphic impact on eye movements, with Over the last decade, the rate of children diagnosed males and females exhibiting differential patterns of with autism spectrum disorder (ASD) has risen deficit steadily. Given the early onset of the disease, one hypothesis is that impairment of normal neuron 1-C-80 Expression of a novel delta-opioid receptor growth and neural circuit connectivity during isoform in human brain and a neuroblastoma cell development contributes significantly to ASD line pathogenesis. However, the mechanisms of these Marjo Piltonen¹, Anne-Julie Chabot-Doré¹, Marc dysfunctions have yet to be elucidated. Although Parisien¹, Luda Diatchenko¹ numerous genes have been identified as mutated in cases of ASD, with a model emerging of a ¹McGill University combination of mutations whereby each contributes incremental susceptibility for disease expression, a Delta-opioid receptor (DOR) is one of four opioid few gene mutations appear to have strong and receptors. It has a role in pain, regulation of mood possibly monogenic action. To investigate the role of and neuroprotection, but there are no clinically used these mutations on neuronal morphological selective drugs acting on this receptor. There is only development and connectivity we employed in vivo one known gene transcript encoding for the classic imaging of the retinotectal system of the awake 7-transmembrane (7TM) domain G-protein coupled Xenopus laevis tadpole. Single-cell electroporation DOR. This simplicity is striking as the mu-opioid was used to transfect individual growing neurons for receptor (MOR) is diverse with dozens of transcripts expression of ASD-associated mutations of encoding for truncated 6-transmembrane (6TM) neuroligin 3 (NLGN3) followed by two-photon rapid domain receptors and single-TM domain chaperones time-lapse imaging to capture full 3D dendritic arbor in addition to the major 7TM isoform. 6TM MORs growth calcium transients in response to experience- are an intriguing target, because they induce driven plasticity training. Results elucidate the excitatory cellular responses in contrast to the relationship between the environment and gene inhibitory effects of 7TM isoforms. Additionally, a expression on functional and structural brain circuit 6TM MOR selective ligand is a potent analgesic in development. CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

1-C-82 Differential expression of connexins in a diabetes affects blood brain barrier (BBB) function mouse model of fetal alcohol syndrome after stroke. Since the BBB can be compromised for days after stroke and thus further exacerbate Meera Ramani¹, Meera Ramani¹, Shanthini ischemic injury, manipulating its function presents a Mylvaganam¹, Michal KrawczyK², James Brien³, unique opportunity for enhancing stroke recovery James Reynolds³, Bhushan Kapur⁴, Michael Poulter⁵, long after the window for thrombolytics has passed. Georg Zoidl⁶, Peter Carlen¹ Using a mouse model of type 1 diabetes, we discovered that ischemic stroke leads to an ¹Toronto Western Research Institute, ²Toronto abnormal and persistent increase in vascular Western Research Institute , ³Queen's University, endothelial growth factor receptor 2 (VEGF-R2) ⁴The Hospital for Sick Children, ⁵Western University, expression in peri-infarct vascular networks. ⁶York University Correlating with this, BBB permeability was markedly increased in diabetic mice which could not be Maternal alcohol exposure during gestation can prevented with insulin treatment after stroke. cause serious injury to the fetus, resulting in the fetal Imaging of capillary ultrastructure revealed that BBB alcohol syndrome (FAS) or the fetal alcohol spectrum permeability was associated with an increase in disorder (FASD). FASD is associated with a range of endothelial transcytosis rather than a loss of tight physiological and neurobehavioral impairments, junctions. Pharmacological inhibition (initiated 2.5 including increased seizure susceptibility. We days post-stroke) or vascular-specific knockdown of developed a mouse model of FAS to study the VEGF-R2 after stroke attenuated BBB permeability, expression pattern of connexins in the FAS brain. loss of synaptic structure in peri-infarct regions, and Prenatal alcohol exposure for the first trimester improved recovery of forepaw function. However, resulted in significant upregulation of Cx30 mRNA the beneficial effects of VEGF-R2 inhibition on stroke and Cx30 total protein in the hippocampus of FAS recovery were restricted to diabetic mice, and animals compared to age matched controls. appeared to worsen BBB permeability in non- Furthermore, surface level expression of both diabetic mice. Collectively, these results suggest that dimeric and monomeric Cx30 was found to be aberrant VEGF signaling and BBB dysfunction after significantly upregulated in both hippocampus and stroke plays a crucial role in limiting functional cortex of the animals that were prenatally exposed recover to alcohol compared to age matched controls. On the surface levels, the fast migrating form and the C 1-C-84 Leucine-rich repeat kinase 2 knockout tail fragment of Cx43 were found to be upregulated prevents behavioral deficits and promotes survival in the hippocampus of mice that were prenatally in Parkinson's disease model exposed to alcohol. These results indicate that the expression of astrocytic connexins (Cx30, Cx43) is Christopher Rudyk¹, Darcy Litteljohn¹, Zach Dwyer¹, altered in the FAS model, and these changes could Shawn Hayley¹ play a role in the alterations observed cerebral excitability of these animals. Supported by CIHR and ¹Carleton University CFFAR. Parkinson's disease (PD) is a neurodegenerative 1-C-83 Delayed inhibition of VEGF signaling after disorder characterized by motor and non-motor stroke attenuates blood brain barrier breakdown behavioral deficits. While the vast majority of PD and improves functional recovery in a co-morbidity cases arise from unknown origins, it is now well dependent manner established that chronic neuroinflammation and oxidative stress contribute to disease etiology. Much Patrick Reeson¹, Kelly Tennant¹, Kim Gerrow¹, attention has been afforded to the commonly used Sammy Novak¹, Patrick Nahirney¹, Craig Brown¹ pesticide, paraquat (PQ), as an environmental risk factor for the development of PD. Indeed, animal ¹University of Victoria models using PQ have shown to recapitulate many of the hallmark features of the disease. The leucine rich Diabetes is a common comorbidity in stroke patients repeat kinase 2 (LRRK2), a kinase mutated in both and a strong predictor of poor functional outcome. autosomal-dominantly inherited and sporadic PD To provide a more mechanistic understanding of this cases, has been shown to modulate inflammation in clinically relevant problem, we focused on how CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

response to different stimuli. However, whether or the developing neuron population at the time of not LRRK2 plays a role in PQ-induced brain and stroke. Within the ventricular zone 2 days after behavioral changes has not been determined. stroke, there were appreciable numbers of Panx1- Accordingly, we investigated the effect of PQ null cells. At 10 days, Panx1 null developing neurons exposure in male LRRK2 knockout (KO) and wild-type were absent suggesting its presence is critical for (WT) mice on behavioral functioning. Mice were maintaining these cells. Conversely, in the peri- given 6 injections of PQ (10 mg/kg; 3X/week) and infarct cortex at 10 days, Panx1-null cells were sacrificed 1 hour following the final injection. selectively spared in comparison with Panx1- Consistent with previous findings, PQ induced signs expressing cells, suggesting that the presence of of sickness and decreased motor and affiliative Panx1 is deleterious to developing neurons in this behavior in WT but not KO mice. Additionally, we region. assessed striatal levels of the neuroplastic cytokine, brain-derived neurotrophic factor (BDNF). We found 1-C-86 Generation of a novel mouse model of the that, irrespective of genotype, PQ decreased BDNF neuronal isoform Kif1a/25b to study hereditary levels. Taken together, these data suggest that sensory & autonomic neuropathy type II LRRK2 may play a role in select aspects of PQ induced pathology and may be relevant for primary Jean-Francois Schmouth¹, Daniel Rochefort¹, Pascale motor PD pathology, as well as other comorbid Hince¹, Jeffrey Mogil¹, Patrick Dion¹, Guy Rouleau¹ aspects of the disease. ¹McGill University 1-C-85 Investigation of Pannexin 1 in the response Problematic: Hereditary sensory & and autonomic of developing neurons to stroke neuropathy II (HSANII) is an early-onset, autosomal Juan Sánchez-Arias¹, Leigh Wicki-Stordeur¹, Esther recessive disorder characterized by a loss of Carmona-Wagner¹, Jagroop Dhaliwal², Adrianna perception to pain, touch, and heat that results in Gunton¹, Michelle Kim¹, Andrew Boyce¹, Valery severe debilitating complications. Our group Shestopalov³, Diane Lagace², Leigh Swayne¹ reported truncating mutations in HSANII patients of a KIF1A nervous-system specific isoform; KIF1A/25B ¹University of Victoria, ²University of Ottawa, (Kinesin Family member 1A/Isoform 25B). This ³University of Miami report was the first identifying a pathology associated with truncating mutations of KIF1A/25B, After stroke, developing neurons traveling along the from which the functional mechanism leading to rostral migratory stream are activated and diverted HSANII remains unknown. We hypothesized that to the peri-infarct cortex. The factors involved in truncating mutations in KIF1A/25B trigger their activation are poorly understood, but their degeneration of myelinated axons in the peripheral ablation worsens stroke outcomes. Here we nervous system, leading to nociception defects in investigated the hypothesis that a protein called affected patients. Methods: To investigate the effect pannexin 1 (Panx1) plays a role in their activation. of KIF1A/25B truncating mutations in HSANII Our data suggest that Panx1 has location-specific development, we will generate a mouse model effects on developing neurons following stroke. harbouring the equivalent human truncating Panx1 is a non-selective ion and metabolite deletion. The model will be generated by insertion of permeable channel enriched in the brain. It was a single T deletion at the conserved position in the originally detected in mature neurons and has been mouse genome (Kif1a/25bdelT/delT). Standardized implicated in their anoxic depolarization in stroke. nociception tests will be performed to evaluate the We recently detected Panx1 in developing neurons development of a sensory phenotype on 20 animals where it promotes proliferation and migration and of different age (1, 3, 6, and 12 months) for each negatively regulates neurite outgrowth. Using the genotype (wild-type and Kif1a/25bdelT/delT). photothrombotic focal cortical stroke model, we Significance: The mouse model generated in this investigated the role of Panx1 in developing neuron project has the potential to inform us on the biology activation. Stroke increased Panx1 expression in of a truncating mutation on Kif1a/25b isoform, from developing neurons within 4 hours. Treatment with both a fundamental and pathological perspective. the Panx1 blocker probenecid reduced their Furthermore, the mouse model generated in this proliferation. We next selectively ablated Panx1 in CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

project will serve as a paradigm for testing future Dysregulation of the ubiquitin proteasome pathway HSANII therapeutics treatment. has been implicated in the pathogenesis of neurodegenerative diseases and Down Syndrome. 1-C-87 Concurrent assessment of forelimb The ubiquitin-specific proteases 25 (USP25) gene function and mesoscopic cortical networks in spans over 150kb and located in Chr21q11.2. To mouse stroke models define the molecular mechanism of USP25 gene transcriptional regulation, we isolated a 2.2-kb 5'UTR Gergely Silasi¹, Matthieu Vanni¹, Federico Bolanos¹, of USP25 gene. A series of nested deletions of the Jamie Boyd¹, Stephen Scott², Timothy Murphy¹ 5'UTR fragments were subcloned into a luciferase reporter plasmid pGL3-Basic. HEK293 cells were ¹UBC, ²Queen's University transfected with the USP25 promoter constructs and We developed an automated forelimb motor task luciferase activity was measured to assay its that allows simultaneous imaging of brain activity promoter activity. We identified a 104-bp fragment using the GCaMP6s calcium indicator, and containing the transcription initiation site as the behavioural assessment during stroke recovery. The minimal region necessary for USP25 gene promoter task requires head-fixed mice to pull and hold a lever activity. Several putative cis-acting element including mounted on a rotary encoder, thus allowing limb SP1 are found in the 5' flanking region of USP25 gene position to be tracked throughout each trial. The and it regulates the promoter activity of the human apparatus is compatible with wide-field imaging, USP25 gene. enabling longitudinal assessment of cortical activity 1-C-89 VEGF protects against blood brain barrier and forelimb function during stroke recovery. disruption, dendritic spine loss and spatial memory Imaging was performed transcranially through a impairment in an experimental model of diabetes chronic window that did not require removal or thinning of the skull. Transgenic mice (Ai94; Jackson Stephanie Taylor¹, Dustin Trudeau¹, Brendan Arnold¹, Labs) expressing the GCaMP6s calcium indicator Joshua Wang¹, Kim Gerrow¹, Kieran Summerfeldt¹, completed an average of 128±27 successful trials per Andrew Holmes¹, Akram Zamini¹, Patricia Brocardo¹ 20-minute session (n=7 mice). Ca2%2B imaging revealed a time-locked increase in activity of the ¹University of Victoria forelimb sensorimotor region (8.5% ∆F/F) while barrel cortex and other unrelated sensory Clinical and experimental studies have shown a clear areas showed less activity (1.8% ∆F/F) during association between diabetes, vascular dysfunction pulling. After a photothrombotic stroke in motor and cognitive impairment. However, the molecular cortex, successful pulls decreased significantly during underpinnings of this association remain unclear. the first week (48% of baseline, p=0.022), indicating Since vascular endothelial growth factor (VEGF) that motor cortex at least in part contributes to task signaling is important for maintaining vascular performance. The Ca2%2B activity within the integrity and function, we hypothesized that forelimb region was also substantially diminished cognitive impairment and vascular dysfunction in the during the first week (1.5% ∆F/F), however diabetic brain could be caused by a primary peri-infarct motor regions such as the rostral deficiency in VEGF signaling. Here we show that forelimb area maintained their baseline level of chronic hyperglycemia in the streptozotocin model activity (5% ∆F/F). Our results demonstrate of type 1 diabetes leads to a selective reduction in the feasibility to monitor post-stroke cortical the expression of VEGF and its cognate receptor reorganization with optogenetic tools in awake mice (VEGF-R2) in the hippocampus. Correlating with engaged in a forelimb motor task. these changes, diabetic mice showed selective deficits in spatial memory in the Morris water maze, 1-C-88 Transcription regulation of the human increased vessel density, width and permeability in USP25 gene the dentate gyrus/CA1 region of the hippocampus and reduced spine densities in the apical dendrites Beibei Song¹, Odysseus Zis¹, Fang Cai¹, Weihong Song¹ of CA1 neurons. Chronic intracerebroventricular infusion of VEGF in diabetic mice was sufficient to ¹University of British Columbia protect them from memory deficits, as well as vascular and synaptic abnormalities in the CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

hippocampus. These findings suggest that a 1-C-91 Effect of chronic minocycline treatment on hippocampal specific reduction in VEGF signaling and restoring dendritic atrophy in a Murine Fragile X resultant vascular/neuronal defects may underlie Model early manifestations of cognitive impairment commonly associated with diabetes. Furthermore, Aaron Truesdell¹, Christine Chiu¹, Jason Chiu¹, restoring VEGF signaling may be a useful strategy for Mariana Vetrici¹, Suk-yu Yau¹, Brian Christie¹ preserving hippocampal-related brain circuitry and functions in degenerative vascular diseases. ¹University of Victoria

1-C-90 Transcriptomic approach to cellular Fragile X Syndrome (FXS) is the most common single composition changes in psychiatric disorders gene cause of inherited intellectual disability. FXS occurs when the CGG trinucleotide sequence Lilah Toker¹, Ogan Mancarci¹, Shreejoy Tripathy¹, expands to >200 repeats in the Fmr1 gene on the X Paul Pavlidis¹ chromosome. This leads to gene silencing and a loss of its protein product, Fragile X Mental Retardation ¹University of British Columbia Protein (FMRP). The Fmr1 knockout (Fmr1-/y) mouse also lacks FMRP, and displays mental impairments Increasing evidence has accumulated regarding the similar to those in humans. It also shows an involvement of cellular death and increased proportion of immature dendritic spines, neuroinflammation in neuropsychiatric disorders similar to that reported in humans. Recent clinical (e.g., bipolar disorder and schizophrenia). Identifying trials indicate that the tetracycline derivative the affected cell-types is crucial for understanding minocycline may be a promising treatment for FXS the pathophysiology of a disorder, providing new patients; however, its underlying mechanism directions for future studies, and assisting in the remains unclear. We investigated the effect of analyses and interpretation of the gene expression chronic minocycline treatment on dendritic data. Since different cell-types express distinct sets morphology in the dentate granule neurons of the of genes, it plausible that changes in cellular hippocampus of wildtype (WT) and Fmr1-/y mice. populations would result in observed transcriptional Minocycline (30mg/kg/day) was administered in alterations in the bulk tissue. For example, loss of drinking water to newborn mice until they were two- dopaminergic neurons in substantia nigra would months old. Biocytin-filled dentate neurons were result in decreased transcript levels of tyrosine obtained using whole cell patch technique and hydroxylase in that region. Thus, given that the cell- visualized by immunostaining. Sholl analysis revealed type specific transcripts are known, changes in that Fmr1-/y mice exhibited a decrease in both specific cellular populations could potentially be dendritic length and intersections with Sholl radii in inferred from the bulk tissue expression data. the dentate gyrus when compared to WT mice. Publicly available brain expression datasets of Chronic minocycline treatment restored such patients and healthy subjects provide the structural deficits in the dentate region of Fmr1-/y opportunity to accomplish this task without the need mice. Our results suggest that this beneficial effect for additional experiments. of minocycline in rescuing dendritic atrophy in the dentate region of the hippocampus of FXS mice may We used a cell-type enriched marker gene database partially underlie its therapeutic effect on cognitive compiled by our group to infer changes in different improvement in FXS. neuronal and glial populations in four expression datasets of dorsolateral prefrontal cortex from a 1-C-92 Amyloid-β oligomers induce similar cohort of psychiatric patients and healthy autophagy and inhibit axonal transport of subjects. Using statistical methods, we infered autophagosomes in cultured hippocampal neurons changes in several cell types , some of which were shown by others using direct cell counting methods Kresimir Ukalovic¹, Michael Silverman¹ (e.g. pyramidal cells). The inferred changes were similar across the datasets, supporting the ¹Simon Fraser University robustness of our approach. Autophagy, a lysosomal degradative process used to recycle cellular constituents and eliminate damaged organelles and proteins, plays a vital role in cellular CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

quality control. Mounting evidence has implicated regulation were also downregulated >2 fold by the defective autophagy in the pathogenesis of Luman siRNA treatment of injury-conditioned numerous neurodegenerative diseases, including neurons. Further, the Luman siRNA-reduced Alzheimer's disease (AD). Indeed, AD brains, which outgrowth could be significantly rescued by either are characterized by increased amounts of amyloid- cholesterol supplementation or 2ng/ml tunicamycin- beta plaques and neurofibrillary tangles, show a induced elevation of the depressed UPR gene buildup of faulty autophagosomes (APs) in expression to a level equivalent to that observed dystrophic neurites. Surprisingly, very little is known with crush injury, with outgrowth increasing to 74% about how amyloid-beta oligomers (AβOs) - or 69% that of injury-conditioned controls the main toxic species in AD - affect the autophagic respectively. The identification of Luman as an process. For example, although it is known that injury-induced UPR and cholesterol regulator at autophagy is responsible for the degradation of levels that benefit the intrinsic ability of axotomized intracellular AβOs, it is not known what effects adult rat sensory neurons to undergo axonal extracellular AβOs exert on autophagy. Here regeneration reveals new therapeutic targets for we show that application of AβOs to rat nerve repair. hippocampal neurons increases autophagic flux initially. However, as treatment time increases, 1-C-94 Altered precision of Purkinje cell firing in a AβOs induce transport defects, resulting in less mouse model of spinocerebellar ataxia type 6 AP movement from the distal axon (where APs form) to the cell body (where APs mature). These results Sriram Jayabal¹, Lovisa Ljungberg¹, Alanna Watt¹ suggest that extracellular AβOs play an ¹McGill University important role in altering autophagy dynamics in neurons, and this research will hopefully aid in the Spinocerebellar ataxia type 6 (SCA6) is a midlife- designing of AD therapeutics specifically targeting onset disease that affects motor control and gait. autophagy. SCA6 is caused by a poly-Q expansion in the Cacna1a gene that encodes the α1Α subunit of 1-C-93 The Unfolded Protein Response and the P/Q calcium channel and the α1ΑCT cholesterol biosynthesis link Luman/CREB3 to transcriptional regulator that are enriched in regenerative axon growth in sensory neurons cerebellar Purkinje cells. Since P/Q channels and the Zhengxin Ying¹, Vikram Misra¹, Valerie Verge¹ α1ΑCT transcriptional regulator are both implicated in neuronal development, we wondered if ¹University of Saskatchewan changes occur prior to disease onset in the developing cerebellum in a transgenic SCA6 knock-in Luman/CREB3 (herein called Luman) is an (SCA6 KI) mice. We found that firing rate and endoplasmic reticulum (ER) transmembrane basic precision is altered in Purkinje cells during postnatal leucine zipper transcription factor whose mRNA and development, and that these changes are protein localize to adult sensory neurons and axons, accompanied by alterations in excitatory, but not the latter with axonal ER along the axon length. We inhibitory input. Thus, there are changes in the SCA6 have recently shown that this axon ER brain well before disease symptoms are observed. transmembrane protein is a unique retrograde However, by the time cerebellar development is regeneration signal in axotomized sensory neurons complete in young adult mice, differences in Purkinje and that it plays a critical role in axon regrowth. cell firing and excitatory input can no longer be Here, we provide evidence that Luman contributes observed in SCA6 KI mice, suggesting that the SCA6 to axonal regeneration by regulating the Unfolded brain homeostatic recovers cerebellar function Protein Response (UPR) and cholesterol during development. These young adult SCA6 KI biosynthesis. siRNA knockdown of Luman expression mice also display no detectable motor deficits, in line in injury-conditioned neurons reduced axonal with the late age of onset observed in people. outgrowth to 48% of control injured neurons, and Finally, we found that in 7-month-old SCA6 KI mice was concomitant with reduced UPR- and cholesterol that display motor deficits on Rotarod, the precision biosynthesis-associated gene expression. UPR PCR- of cerebellar Purkinje cell firing is lost. These results array analysis coupled with qRT-PCR, identified and suggest that breakdown of Purkinje cell firing confirmed that 4 mRNAs involved in cholesterol CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

precision may contribute to the pathophysiology of Behavioural testing of disease models in rodents can SCA6. be useful in assessing the extent of cognitive and physical impairment, as well as evaluating the 1-C-95 Development of a primate model of efficacy of potential drug treatments. However, Alzheimer's Disease II: Characterization of many traditional behavioural paradigms involve behavioural phenotype putting the animal in stressful or unfamiliar environments, often during times of the day when Robert Wither¹, Susan Boehnke¹, Ann Lablans¹, Rob they would typically be sleeping, and this can cause Marino¹, Brian Coe¹, Fernanda De Felice², Douglas stress responses that introduce variability into the Munoz¹ data. To address this problem, we have adapted a new paradigm to identify behavioural phenotypes in ¹Queen's University, ²Federal university of Rio de models of chronic, progressive neurodegenerative Janeiro disease. This paradigm involves the incorporation of Alzheimer's disease (AD) is a devastating a lever pull task into the mouse home-cage neurodegenerative disease and there is an urgent environment, allowing continuous access to the task need to develop new therapeutics. Promising drugs and automated collection of data. Animals can be developed in rodents have failed to work in AD tested at different disease stages, and advancement patients in clinical trials. To bridge this translational through the levels of task difficulty can be gap, our laboratory has developed a non-human personalized to individual mice within the same primate (NHP) model of AD via cage. In addition, continuous testing over long intracerebroventricular injection of neurotoxic periods can be used to more accurately determine amyloid beta oligomers (AβOs). This model the change in behavioural phenotype over time in a recapitulates the molecular aspects of human AD particular animal model. So far, we have used this pathology, such as tau hyperphosphorylation paradigm to test procedural learning, cognitive coupled with tangle formation, synaptic loss, and flexibility, and fine motor ability in the YAC128 astrocytic activation (Forny-Germano et al., J. mouse model of Huntington's disease at 2 months Neurosci, 2014; Boehnke et al. at this meeting). To (presymptomatic) and 4 months (early symptomatic) characterize the behavioural deficits associated with of age. We plan to use this paradigm as a tool to these molecular pathologies, we have developed a screen therapies for efficacy in reversing the HD behavioural phenotyping platform for primates. behavioural phenotype in these mice. General home-cage activity levels including circadian 1-C-97 Effects of exercise on the basal ganglia rhythms are measured using activity monitors and morphology in schizophrenia. 24/7 video recording. Cognitive performance is measured using eye movement tasks (including step Melissa Woodward¹, Donna Lang¹ and memory-guided saccade tasks), as well as performance on classic CANTAB touchscreen-based ¹University of British Columbia tasks including self-ordered spatial search, delayed match to sample, and paired associate learning. Schizophrenia has been associated with Here, we present preliminary results of the changes morphological brain deficits, including alterations in in behavioural parameters from 3 male rhesus hippocampal and basal ganglia volume (McClure et macaques before and after AβO administration al., 2013). Abnormalities in these key regions are to provide behavioural validation of our primate thought to give rise to both neurocognitive deficits Alzheimer's disease model. and to the severity of psychosis. Psychotropic medications ameliorate psychosis, however they 1-C-96 Adaptation of a naturalistic motor learning adversely affect metabolism and cardiovascular task to assess behaviour and drug interventions in functioning and further increase changes in striatal the YAC128 model of Huntington's disease volume (Stassnig, Brar & Ganguli, 2011). In contrast, physical activity is also known to mediate some of Cameron Woodard¹, Federico Bolaños¹, Tim Murphy¹, the negative metabolic effects of antipsychotic Lynn Raymond¹ medication, including weight gain, hypertension and decreased vascular compliance in chronic patients ¹University of British Columbia (Bredin, Warburton & Lang, 2013). Of particular CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

interest, exercise may have ameliorative effects on 1-C-99 Using induced pluripotent stem cell- regional brain volumes, including the basal ganglia. derived neurons to uncover effects of autism-linked Using high resolution imaging, morphology, mutations on neuronal function. connectivity and local neurovascular integrity of psychosis patients may be examined. It is expected Kirill Zaslavsky¹, Wenbo Zhang², Eric Deneault², that physical activity would result in recuperation of Tadeo Thompson², Alina Piekna², Peter Joel Ross², basal ganglia volume and reduced symptom severity. Asli Dedeagac², Wei Wei², Peter Pasceri², Michael Better understanding of the beneficial effects of Salter², Stephen Scherer², James Ellis² exercise on basal ganglia volume, as well as clinical symptoms, would be critical in understanding the ¹University of Toronto, ²Hospital for Sick Children potential for physical activity as a non- De novo deletions and nonsense mutations of pharmaceutical intervention in these patients. SHANK2 have been implicated in several autism Further work would investigate whether these spectrum disorder (ASD) cases. To determine how effects are seen in other regions of the brain ASD-associated SHANK2 mutations affect human implicated in psychosis, including the frontal grey neuronal function, we have generated induced matter and the thalamus. pluripotent stem cells (iPSC) from two children with 1-C-98 Synaptic dysfunction by an Alzheimer- ASD, one with a nonsense mutation and the other associated mutation A713T in the APP gene with a deletion. We have also knocked out SHANK2 in iPSCs from neurotypic individuals using Qin Xu¹, Weihong Song¹ CRISPR/Cas9 technology. As controls, we are generating iPSCs from unaffected family members ¹University of British Columbia and unrelated individuals, as well as correcting the nonsense SHANK2 mutation in patient iPSCs. To Alzheimer's Disease (AD) is the most common obtain cortical neurons, we first generate neural neurodegenerative disease. A number of amyloid precursor cells with dorsal forebrain identity by β precursor protein (APP) mutations were inhibiting BMP, Nodal/Activin and Wnt signaling. To found in AD patients and studies of these mutations date, we have generated NPCs from the patient with profoundly improved the current understanding of the nonsense mutation, as well as two controls. To AD pathogensis and its drug development. The APP assess dendritic arborization, 6 week-old neurons A713T mutation was identified in two independent are transfected with a GFP plasmid and tracked on a families of AD and a strong genetic linkage between live-imaging platform. KCl stimulation causes neurite this mutation and AD pathology was confirmed by extension in control, but not patient-derived screening the gene sequence of the family members. neurons. To assess synaptogenesis, four week-old However, how this single mutation of APP causes AD neurons are re-seeded on mouse astrocytes to remains undefined. In the present study, we found promote synaptogenesis. Five weeks after re- that APP A713T mutation impaired APP protein's ER seeding, electrophysiological and imaging to Golgi transportation, its maturation, turnover and approaches are used in parallel to assess synaptic suppressed APP proteolytic processing by the connectivity. Specifically, we are currently recording secretases. Although the Aβ generation was miniature excitatory postsynaptic currents and reduced by A713T mutation, the Aβ harboring quantifying synapse number per cell. Using these this mutation exacerbated the neuronal toxicity phenotyping assays, we aim to determine how compared with the wildtype Aβ. More development and function are perturbed in neurons importantly, the A713T mutation significantly specific to children with ASD and SHANK2 mutations. impaired the synaptogenesis. Our study provides a new insight into the function of APP protein and 1-C-100 Electrophysiological investigation in suggests a novel effect of the APP mutation on AD neurons derived from human induced pluripotent pathogenesis. stem cells with deletions of PTCHD1 locus

Wenbo Zhang¹, P. Joel Ross¹, Kirill Zaslavsky¹, Wei Wei¹, Alina Piekna¹, Tadeo Thompson¹, Stephen Scherer¹, James Ellis¹, Michael Salter¹ CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

¹The Hospital for Sick Children minimum time course for emergence of the crossed effects. Therefore, the major purpose of this study Autism is an early onset neurodevelopmental was to characterize the time-course of strength disorder. The pathogenesis of autism remains changes in both the trained and untrained limbs unclear and genetic contributions are critically during unilateral handgrip training. Neurologically important in the occurrence of this disorder. The X- intact participants completed 6 weeks of unilateral linked PTCHD1 locus is one of the most frequently handgrip training 3 times/week. During each training disrupted loci in autism. However, the molecular session, participants performed 5 sets of 5 maximal mechanisms underlying autism due to the disruption isometric contractions (MVC) using a handgrip of PTCHD1 are poorly understood. To address dynamometer in their dominant right hand. Changes dysfunction of this gene in autism we utilized in strength and muscle function were evaluated by neurons derived from patient induced-pluripotent MVC force and electromyography (EMG) during stem (iPS) cells. We characterized handgrip in both trained and untrained limbs before electrophysiological function of neurons derived and after training. During training, handgrip force from iPS cells of an unaffected control and two was recorded for all handgrip repetitions while EMG probands with autism: proband 1 has a deletion of was measured weekly. For the untrained limb, PTCHD1 and proband 2 has a deletion disrupting the handgrip force and EMG were measured once a autism-associated long non-coding RNA PTCHD- week during a single contraction. After six weeks of antisense. Patch-clamp recordings showed that training, handgrip force significantly increased in neurons from the unaffected control, proband 1, or both trained and untrained limbs. Interestingly, the proband 2 displayed spontaneous and/or evoked increase in strength occurred at a similar rate action potentials and miniature excitatory between limbs. These results emphasize the postsynaptic currents, indicating that they have importance of establishing a "dose" for the time similar features to those neurons in the central course of functional and neurological adaptations in nervous system. Statistical analysis uncovered that strength for effective translation to rehabilitative there were not defects in the resting membrane interventions. potential, input resistance, or action potential waveform for iPS cell-derived neurons from proband 1-D-102 Repetitive transcranial direct current 1 or proband 2, compared with the unaffected stimulation (tDCS) of the primary visual cortex control. However, results from electrophysiology induces long-lasting enhancement of contrast revealed dysfunction of NMDA receptor-mediated perception currents in proband 2, compared with the unaffected control. These findings are the first Stephan Brandt¹, Janina Behrends¹, Antje Kraft¹, functional data characterizing the roles of PTCHD1 in Manuel Olma¹ neuronal activity in humans and its relevance to autism. ¹Charité University Hospital

D - Sensory and Motor Systems Background: The primary visual cortex (V1) plays a key role in humans' faculty to process contrasts that is crucial for almost all tasks of daily routine. 1-D-101 Time course 'dose' of cross-education of Understanding the type of processes performed by strength after handgrip training an intact visual cortex and developing methods that enhance visual perception are of great scientific Trevor Barss¹, Taryn Klarner¹, Yao Sun¹, E Paul Zehr¹ interest. Objective: In this study we tested whether contrast sensitivity can be enhanced in healthy ¹University of Victoria subjects via non-invasive, anodal transcranial direct current stimulation (tDCS) over V1. Methods: The Cross-education is a neural adaptation defined as the double-blind study comprised 24 healthy subjects increase in strength of the untrained contralateral (mean age 24.5 years, SD = 3.53), 12 subjects limb after unilateral training. It occurs in both received anodal tDCS, 12 received placebo neurologically intact and clinical (e.g. stroke, stimulation (sham). The polarization (P) electrode orthopedic injury) populations. Limitations for was placed over V1 for 20 minutes daily over five clinical translation include knowledge on the consecutive days. Contrast perception was tested CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

using threshold perimetry before and immediately type-specific synaptic changes of local excitatory and after stimulation, as well as at 2- and 4-week follow- inhibitory circuits in the motor cortex, which is up (days 19 and 33). Results: Compared to sham, the essential for acquiring a new motor skill tDCS group showed with 23% a significantly higher improvement of contrast perception (sham: 5%) (day 1-D-104 Cortical substrates for allocentric vs. 5 to baseline, p = 0.045). tDCS-effects lasted for 24 egocentric representation of remembered saccade hours (days 1-5, p = 0.020) within the tested visual targets in the human field (2-10°) and within the central 2-4° at follow-up dates (day 19 to baseline: p = 0.013, day 33 to Ying Chen¹, John Crawford¹ baseline, p = 0.021). Conclusion: Long-term effects ¹York University suggest that repeated anodal tDCS induces plasticity on the healthy human primary visual cortex. The The location of a remembered target can be defined effect-size was higher in the central visual field. in egocentric or allocentric reference frames, but the Regarding the retinotopic neuronal organization of neural mechanisms for allocentric saccade V1, this may indicate a stronger enhancement in the representation in humans are essentially unknown. brain region closer to P. Here we employed an event-related fMRI design same as our recent reach study (Chen et al. Journal 1-D-103 Cell-type specific reorganization of of Neuroscience 2014) to investigate the brain areas inhibitory circuits during motor learning supporting these two types of coding in twelve Simon Chen¹ participants. The target and the landmark were always presented briefly, but at the beginning of ¹University of California, San Diego each trial, participants were instructed to ignore the landmark and remember target location (Ego) or Motor learning is a basic form of learning that is remember target location relative to the landmark crucial for survival in all animals. However, our (Allo). During the delay phase participants had to understanding of precise microcircuit plasticity in remember the target location in the appropriate motor cortex during motor learning, especially with reference frame. In a non-spatial Control regards to different neuron types, is limited. To participants remembered and reported the target address this question, we utilized in vivo two-photon color. We found that during the delay phase Ego and imaging to chronically monitor synaptic structures of Allo elicited higher activation as compared to the excitatory neurons and two inhibitory neuron types Control in bilateral precuneus, midposterior in head-fixed awake mice as they learned a forelimb intraparietal sulcus, dorsal premotor cortex and left lever-press task over weeks. We found that, while extrastriate cortex. Inferior parietal lobes showed motor learning induces new dendritic spine higher activation for Ego vs. Allo, whereas temporal formation in the layer 2/3 excitatory neurons, it also and occipital cortex showed higher activation for Allo causes a reorganization of inhibitory circuits in a vs. Ego. Egocentric directional selectivity was neuron-type specific manner. Somatostatin (SOM) observed in superior and inferior occipital cortex inhibitory neurons that mainly inhibit the distal (IOG). Allocentric directional selectivity was dendrites of excitatory neurons showed a decrease observed in calcarine, IOG and precuneus. These in axonal boutons immediately after the training results confirm different cortical mechanisms for begins, whereas parvalbumin (PV) inhibitory neurons egocentric vs. allocentric target memory, but that mainly inhibit the perisomatic region of comparing this to our previous study, the detailed excitatory neurons exhibited a gradual increase in mechanisms also depend on the motor effector (eye the axonal boutons during training. Such structural vs. hand). reorganizations were restricted only to the learning phase and did not occur when the animals 1-D-105 Wii Balance Board and electromyography performed a previously learned task. Optogenetically to assess postural adjustment after perturbation manipulating SOM inhibition affected the stabilization of newly formed spines and thus Yao Sun¹, Hilary Cullen¹, Brian Christie¹, E.Paul Zehr¹ prohibited the animal from learning and forming ¹University of Victoria stereotyped lever-press movements. These findings demonstrate that motor learning induces neuron CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

The Nintendo Wii Balance Board (WBB) is reliable in Therefore, we employed a passive haptic vibratory measuring balance when compared to a force plate. prime in order to pre-engage the somatosensory As a cost effective and portable system, the WBB cortex, followed by a picture stimulus of either a may be used efficiently in clinical and research graspable (e.g., a spoon) or a non-graspable (e.g., an settings. Previous studies on balance assessment airplane) object. On half of the trials, presentation of tools measured ranges of center of pressure (COP) the picture stimulus was preceded by the vibratory and recovery time after perturbation. The current prime, whereas on the other half of the trials no study combined a customized WBB computer game vibration was received. Participants were then with electromyography (EMG) to determine required to report how they would interact with the feasibility to assess COP and recovery time in healthy presented object while visualizing themselves individuals. Participants' COP was presented as a dot performing that action. Results indicated that the on a laptop using a customized LabVIEW program. In graspable objects showed processing benefits on RT each trial (n=5), a target moved in random sequence when preceded by the passive vibratory prime as among eight cardinal and ordinal directions where N opposed when they received no prime, while there was to the front. Participants met the target with were no differences in RTs found in the vibration their COP by redistributing their weight on the WBB. versus no-vibration conditions for the non-graspable In each direction, time used to reach the target and objects. These results suggest that general return to centre was recorded along with bilateral somatosensory stimulation has the ability to impact EMG recordings of medial gastrocnemius (MG), motor representations for graspable objects. Pilot peroneus longus (PL) and tibialis anterior (TA). results from an fMRI variant will also be discussed. Preliminary results showed increased bilateral MG and PL activity when recovering from perturbation 1-D-107 Potentiation of phase II formalin responses signals to the N, NW and NE. When recovering from in zinc transporter-3 (ZnT-3) knockout mice the virtual perturbation to the S, SW and SE, an increase in bilateral TA activity was observed. This Churmy Fan¹, Brendan McAllister¹, Richard Dyck¹, study demonstrates that a simple device and Tuan Trang¹ computer software can be used as a tool to evaluate ¹University of Calgary muscle synergies in balance control. Future research aims to use this combined WBB and LabVIEW Zinc is abundant in the central nervous system, and program to assess balance deficits and recovery its activity is implicated in neuropathic and status in people with neurological disorders. inflammatory pain. Expression of zinc is high in synaptic vesicles, the localization of which is tightly 1-D-106 More than a feeling: Passive regulated by the vesicular zinc transporter 3 (ZnT-3). somatosensory priming facilitates processing of In the present study, we asked whether ZnT-3 is graspable objects critically involved in the sequelae of inflammatory Chelsea Ekstrand¹, Eric Lorentz¹, Layla Gould¹, Marla pain. To test this, we examined the behavioural Mickleborough¹, Ron Borowsky¹ response of ZnT-3 knockout mice to a single intraplantar injection of formalin, which evoked a ¹University of Saskatchewan biphasic nociceptive response characterized by licking and shaking of the injected paw. We found Cognitive embodiment refers to idea that cognitive that phase I of the formalin response (attributed to processes are rooted in perception and action c-fibre activation) was comparable in ZnT-3 knockout experience. Although much research has focused on and wild-type mice. By contrast, phase II nociceptive motor involvement in response to graspable object behaviours (associated with central sensitization) stimuli (e.g., Tucker & Ellis, 1998), somatosensory were significantly greater in the ZnT-3 knockout contributions to accessing motor knowledge have mice. We also determined that the deletion of ZnT-3 remained relatively unexplored. In the was associated with lower expression of the somatosensory domain, haptic object exploration microglial and astrocytic markers, ionized calcium- has been shown to facilitate object processing when binding adapter molecule 1 (Iba1) and glial fibrillary the prime object is congruent with the target object acidic protein (GFAP), respectively. Collectively, our (e.g., James et al., 2002), however, passive sensory findings suggest that zinc transport mediated by ZnT- contributions have received less attention. CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

3 plays a critical role in the central sensitization ¹Queen's University, ²Harvard Medical School, associated with phase 2 of the formalin response. ³Boston Children's Hospital, ⁴Université Laval

1-D-108 Central and peripheral afferent processing Inflammatory pain is a common medical condition of natural and artificial vestibular inputs characterized by pain hypersensitivity at the site of inflammation due to chronic immune diseases, Patrick Forbes¹, Gunter Siegmund², Alfred Schouten³, pathogenic infection and tissue injury. However, the Jean-Sébastien Blouin⁴ specific contributions of the innate and adaptive immune system to the generation of pain during ¹University of British Columbia/Delft University of inflammation have not been clearly or systematically Technology, ²MEA Forensic Engineers & Scientists, elucidated. We therefore set out to characterize the ³Delft University of Technology, ⁴University of British cellular and molecular immune response in two Columbia widely used preclinical models of inflammatory pain: 1) intraplantar injection of complete Freund's Electrical vestibular stimulation (EVS) is thought to adjuvant (CFA) as a model of adjuvant- and artificially modulate the firing rate of vestibular pathogen-based inflammation and 2) a plantar afferents, yielding a virtual sensation of head motion incisional wound as a model of tissue injury-based and reflexive responses in muscles throughout the inflammation. Our findings shed light on the body. The vestibulocollic reflex (VCR) provides differences in temporal patterns of immune cell robust control over neck muscles across a wide recruitment and activation states, cytokine bandwidth (0-70 Hz), even in the absence of head production, and pain in these two animal models, postural control. In this study, we explore how finding that CFA induced non-resolving vestibular inputs from electrical and kinematic granulomatous inflammation while tissue incision stimuli interact and affect the VCR. We applied induced resolving immune and pain responses. Using stochastic vestibular stimulation (0-75 Hz) to seated various cell-depletion strategies, we find that subjects who were rotated about a vertical axis at CD11b+Ly6G- monocytes/macrophages were various frequencies (0.4-4 Hz) and peak amplitudes necessary for mechanical hypersensitivity during (0-150 °/s). Bilateral EMG of the sternocleidomastoid incisional pain, and to a lesser extent CFA-induced was collected. The electrically-evoked VCR (i.e. inflammation. In contrast, CD11b+Ly6G+ neutrophils stimulus-EMG correlations) decreased with and TCRβ+ T cells do not contribute to the increasing angular velocity at all motion frequencies. development of thermal or mechanical pain This VCR attenuation occurred across the entire hypersensitivity in either model. This work bandwidth of electrical stimulation but varied within specifically identifies a population of CD11b+ Ly6G- the motion cycle: maximum attenuation led the myeloid cells as contributors to and potential targets input velocity signal by ~40-60°, irrespective of for the treatment of mechanical inflammatory pain. motion-induced muscle activity. Furthermore, the attenuation of the electrically-evoked VCR occurred 1-D-110 Cholinergic receptors expression in the in phase with the estimated natural motion-induced visual cortex following long-term enhancement of excitation of vestibular afferents (leading head visual cortical activity by cholinergic stimulation angular velocity by 10-60°). In other words, increased natural afferent activity due to motion Marianne Groleau¹, Mira Chamoun¹, Menakshi Bhat¹, decreases the relative contribution of electrical Frédéric Huppé-Gourgues¹, Réjean Couture¹, Elvire stimulation to the total vestibular input to neck Vaucher¹ muscles, an integration process that likely occurs peripherally, prior to central processing of vestibular ¹Universite de Montreal signals. The cholinergic transmission in the primary visual 1-D-109 CD11b+Ly6G- myeloid cells drive cortex (V1) is involved in the enhancement of mechanical inflammatory pain hypersensitivity specific visual stimuli as well as long-term modifications of the neuronal processing. We Nader Ghasemlou¹, Nader Ghasemlou¹, Isaac Chiu², investigated the involvement of cholinergic Sun Wook Hwang³, Jean-Pierre Julien⁴, Clifford receptors subtypes underlying this long-term Woolf³ functional plasticity. Perceptual learning-like test CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

was performed by exposing awaken rats to a visual 1-D-112 Primary motor cortical neurons reflect stimulation(VS) for 10min/day during 14days. This VS vector sum of ipsilateral and contralateral feedback was provided alone or coupled to an electrical modulation stimulation of the basal forebrain(HDB/VS) or paired with donepezil, a cholinesterase Ethan Heming¹, Stephen Scott¹ inhibitor(DONEP/VS). One week after the last training session, V1 were collected to determine the ¹Queen's University expression level of mRNA of muscarinic(M1-5) and It is commonly accepted that the primary motor nicotinic(á/â) receptors sub-units by RT-PCR. Two cortex (M1) is involved in controlling the weeks of VS treatment alone caused an increase of contralateral side of the body, but recent studies the expression of M3 and M5 mRNA suggesting an have noted some M1 neurons are active during increase of their production and activity during long- ipsilateral limb movements. We use mechanical term visual stimulation. In the HDB/VS group, á3 perturbations to quantify how M1 activity was sub-unit was decreased suggesting its involvement in related to ipsilateral and contralateral motor activity. phasic cholinergic stimulation. The DONEP/VS A non-human primate (NHP) stabilized a cursor treatment presented a decrease in the expression of representing the location of its right or left hand at a M2, suggesting a down regulation of mRNA central virtual target. After 1000-1500ms, flexor or synthesis. This could indicate an increased cortico- extensor step torques were applied to the shoulder, cortical inhibition, as M2 receptors are located the elbow, or both (9 load conditions). The NHP had massively on the GABAergic neurons. Therefore, 1000ms to return the cursor to, and stop at, the even with similar functional enhancement, the target. We recorded and examined the activity of cholinergic receptors regulation differs between an 167 M1 neurons using a micro-electrode array and electrical and a pharmacological treatment. These 29 neurons from single electrodes. We found that results are crucial for determining which receptors 73% of M1 neurons modulated their responses to are the most involved in the pharmacological contralateral perturbations, 40% modulated to cholinergic stimulation to enhance visual perception. ipsilateral perturbations and 34% modulated to 1-D-111 A computational approach to decipher the either. When torques were applied to both arms at network topology of the dorsal root ganglion once, the modulation of each neuron's activity corresponded to the vector sum of its modulation to Nicolas Doyon¹, Simon Hardy¹, Patrick Desrosiers¹, torques on either arm alone. When we considered Yves De Koninck¹ neural activity over time during perturbations, we found that the vector sum predicted modulation ¹Université Laval throughout the perturbation, even for neurons with very different response onsets to ipsi- and Understanding the network responsible for treating contralateral perturbations. Our results indicate that sensory inputs in the dorsal horn is necessary to M1 shows fast and substantial perturbation-related grasp how disinhibition in this network leads to activity from both limbs which interacts in a very allodynia and hyperalgesia. Despite reasonable lawful manner. hypotheses, the topology of the network connections linking afferent fibres to projection 1-D-113 Prediction of future sensory states requires neurons remains unresolved. We use computational self-generated motor commands modelling in order to investigate the vast space of possible networks and identify those compatible Robert Hermosillo¹, Paul van Donkelaar¹ with experimental findings. Our approach provides a rigorous way to rule out hypotheses as well as to ¹University of British Columbia identify possibilities that have been overlooked by Predicting the sensory consequences of limb experimentalists. movement has been thought to influence current decisions, however it is unclear whether these predictions are based on knowledge of upcoming movements or based directly on motor planning signals. The present experiment examines how forward modelling can influence limb localization. It CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

has been previously shown that crossing the arms stimuli. More importantly, presentation of induces a subjective reversal of spatially-defined audiovisual stimuli induced similar pupil responses cutaneous temporal order judgments. By applying with greater response magnitude. Together, the brief vibrations to the hands during the planning results demonstrated multisensory integration in stages of an arm-crossing movement, we observed pupil orienting responses, further arguing that the SC how forward modelling systematically influences is the likely neural substrate coordinating these pupil temporal order judgements. We tested this by orienting responses. having subjects either actively moving their arms into a crossed posture or having a robot passively 1-D-115 Reversible inactivation mapping of cortical move their arms into a crossed posture. In the sites required for voluntary forelimb movements in active condition, error rates increased as the VGAT-ChR2 transgenic mice. planning process evolved, mirroring the errors that were observed when the limbs were physically Raghu Ram Katreddi¹, Greg Silasi¹, Jamie Boyd¹, Jeff crossed. However, in the passive condition, error LeDue¹, Stephen Scott², Timothy Murphy¹ rates remained constant across the planning period. ¹University of British Columbia, ²Queen's University This data suggest that the brain uses motor planning signals to predict sensations from impending VGAT-ChR2 mice were used to induce reversible movements, and not necessarily the context of local loss of function (by activation of GABA neurons) future limb postures. while mice were engaged in a lever-pulling task to map cortical regions that were required for 1-D-114 Multisensory integration in human pupil voluntary forelimb movement. Awake water orienting response restricted mice with transcranial windows were Jeff Huang¹, Chin-An Wang¹, Douglas Munoz¹ head-fixed and trained to pull a robotic lever to get water rewards. Blue laser light was targeted to ¹Queen's University points within the contralateral and ipsilateral hemispheres to produce focal inhibition and probe The sudden appearance of a salient stimulus initiates their role in directed movements. Different a series of responses to orient the body for frequencies (10, 50, 100Hz) of the blue laser light appropriate actions, including not only shifts of gaze were targeted to the regions of interest for 1min and attention, but also transient pupil dilation. intervals. Our preliminary results show a 3mW train Recent studies have shown pupil dilation induced by of 5ms pulses delivered at 100Hz to the contralateral presentation of visual and auditory stimuli, and the primary motor cortex(M1) reduced the number of timing and size of the evoked responses are rewarded lever pulls by 95±9% relative to a control systematically modulated by stimulus salience. site located outside of the cranial window, 10 Hz was Moreover, microstimulation of the superior less effective. This extent of inhibition was not seen colliculus (SC), a midbrain structure involved in eye while photo-activating other contralateral points movements, attention, and multisensory integration, such as M2, visual cortex, and even ipsilateral M1, evokes similar transient pupil dilation, suggesting a showing (as expected) that contralateral M1 is coordinated role of the SC on the pupil orienting required for the execution of voluntary movement. response. Although pupil dilation is evoked by Putative hubs such as the retrosplenial cortex and presentation of single modality stimuli, stimuli in the parietal association area were not required to everyday life are often comprised of multisensory initiate pulling. M1 inhibition was fully reversible as inputs. Here, we examined how human pupil the mouse started pulling the lever within seconds dynamics are modulated by multisensory stimuli and once the laser was off the contralateral M1 site. hypothesized that sensory signals induced by salient Future experiments will require mice to correct for a stimuli presented from different modalities should perturbation in lever position after the initiation of a be integrated in the SC to produce coordinated trial, revealing sites of potential sensory-motor transient pupil responses. While requiring feedback. participants to maintain central fixation, we presented a visual, auditory, or combined audiovisual stimulus. Transient pupil dilation was elicited after presentation of visual or auditory CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

1-D-116 From chaos to control: Using oscillations to saccadic visual feature integration. In this study, we harness neuronal networks aim to model and integrate both of these phenomena. We developed a state space model for Eric Kuebler¹, Jean-Philippe Thivierge¹ updating gaze-centered spatial information. To explore spatial updating, we considered two kinds of ¹University of Ottawa eye movements, saccade and smooth pursuit. The inputs to our proposed model are: a corollary Synchronized (or zero time-lagged) activity carries discharge signal, an eye position signal and 2D visual functional benefits by dampening variability and topographic maps of visual stimuli. The state space is enhancing the reliability of neuronal responses to represented by a radial basis function neural stimuli. On the other hand, theoretical work has network and we can obtain a topographic map of the shown that neurons can generate asynchronous (or remembered visual target in its hidden layer. Finally, time-lagged) activity. Here, we employed numerical the decoded location of the remembered target is simulations to explore the benefits of synchronous the model output. Training this model revealed that versus asynchronous oscillations in balanced the receptive fields of state-space units are neuronal networks. Starting from a model of remapped predictively during saccades and updated sparsely connected integrate-and-fire neurons that continuously during smooth pursuit. Moreover, generates spontaneous spiking, we injected during saccades, receptive fields also expanded (to oscillations by adding a sine wave to the membrane our knowledge, this predicted expansion has not yet potential of all cells. We induced synchronized been reported in the published literature). spiking by tuning the waves such that the phase was Subsequently, we construct a computational model the same across all neurons; we elicited for integration of visual feature information across asynchronous activity by setting each neuron at a saccades using recent discoveries in hierarchical unique phase (Fig. 1A). We then examined the ability processing as well as different feature information of networks to respond reliably and discriminate channels of primate visual system. We believe that between large depolarizing events delivered to incorporating these two models can shed light on random subsets of the population. We show that the neural mechanism of Trans-saccadic perception. synchronized cells responded with greater reliability than asynchronous and hybrid (i.e., 50/50 mix of 1-D-118 Phosphatase 2B mediates NMDAR synchrony and asynchrony) networks to repeated plasticity and metaplasticity in early odor presentations of the same stimulus (Fig. 1B). preference learning in rats Asynchronous networks, however, responded with the highest degree of heterogeneity (i.e., distinct Bandhan Mukherjee¹, Bandhan Mukherjee², Qi Yuan² responses to different stimuli). These results highlight a functional trade-off between the ¹Memorial University, ²Memorial University of reliability and heterogeneity of neuronal responses Newfoundland that is dependent on the nature of upstream activity. Neuronal networks may utilize both synchronous Previously we have demonstrated NMDA receptor and asynchronous activity depending on the (NMDAR) plasticity in the anterior piriform cortex requisites of information processing. (aPC) of rat pups following early odor preference learning. Down-regulation of NMDAR at 3 hr post- 1-D-117 A Computational Model of Updating and training results in metaplasticity with decreased LTP Integration of Remembered Visual Stimuli across and inducible LTD at the aPC synapse. Re-training at Eye Movements 3 hr with the same odor abolishes preference memory. Here, we investigated the molecular Yalda Mohsenzadeh¹, Douglas Crawford¹ mechanisms of NMDAR plasticity and metaplasticity using quantitative immunoblot of synaptic fractions ¹York University of the aPC following training and pharmacological interventions. Intra-animal control was achieved Despite the ever-changing visual scene on the retina through unilateral drug infusion. NMDAR down- between eye movements, our perception of the regulation was prevented by aPC infusion of group visual world is constant and unified. It is generally I/II mGluR antagonist MCPG (100 mM), while neither believed that this space constancy is due to two NMDAR (D-APV, 500 µM or 5 mM) nor mGluR1 internal processes; spatial updating and trans- CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

(AIDA, 500 µM or 5 mM) blockage had such an analyses the motor recovery after a spinal cord effect. Down-regulation of NMDAR was also blocked injury (SCI). We find that brl mice show enhanced by FK-506 (5mM), a phosphatase 2B inhibitor. locomotor functions as assessed by the BMS (Basso Bilateral infusion of either MCGP or FK-506 during mouse scale) as early as 6h and up to 6 weeks after the initial training restored odor preference memory SCI, indicating a smaller responsiveness of brl mice when pups were re-trained at 3 hr. These results to SCI. It is therefore possible that developmental suggest mGluR (likely mGluR5) mediated effects on motor systems might decrease the phosphatase pathway leads to NMDAR down- locomotor effects consecutive to a SCI. This point is regulation at 3 hr and unlearning upon re-training. It particularly important with regards to the use of has been shown metaplasticity is mediated by transgenic animals for testing SCI recovery. NMDAR itself. Blocking NMDARs during the re- training prevents unlearning. Here we further 1-D-120 Spatiotemporal profiles of receptive fields demonstrated that unlearning was mediated by of area 21a neurons in the cat phosphatase 2B as FK-506 infusion during the re- training restored odor preference memory. Bruno Oliveira Ferreira de Souza¹, Christian Together, de-phosphorylation by phosphatase 2B Casanova¹ results in both NMDAR down-regulation and ¹Universite de Montreal NMDAR-mediated metaplasticity. In cats, cortical area 21a is considered a homolog of 1-D-119 Lack of adenylate cyclase 1 (AC1) affect primate's area V4 and is involved in high-level corticospinal tract development and locomotor cortical processing of visual information such as form recovery after spinal cord injury detection. Basic properties of 21a neuron receptive Hanane Nait Taleb Ali¹, Hanane Nait Taleb Ali ², fields (RFs) have been described in numerous studies Pierre marie Morel³, Sophie Scotto-Lomassese⁴, but their spatiotemporal dynamics has not yet been patricia Gaspar⁵, Isabelle Dusart⁶, Mohamed bennis⁷ described. In order to address this issue, extracellular recordings were undertaken in area 21a ¹Faculté des Sciences Semlalia, ²faculté des sciences of anesthetized adult cats. Visual stimulation Semlalia , ³UPMC, Univ paris06, ⁴Inserm, UMR-S839, consisted in a pseudo-randomized sequence of Inserm, UMR-S839, ⁵Inserm, UMR-S839, Institut bright and dark squares (4x4 deg) briefly presented duFeraMoulin, ⁶UPMC, UnivParis06, ⁷Lab (35 ms) against a gray background. To date, first- Pharmacology,Neurobiology&Behavior(URAC-37), order spatiotemporal profiles of 27 neurons were Faculté des Sciences obtained by reverse correlation analysis. Spatial analysis revealed that bright subfields were in Cyclic AMP(cAMP) signalling pathways are involved average larger than dark subfields (316.7 ± 42.9 vs in axonal growth and regeneration. The calcium- 168.8 ± 32.5 deg2) and, in most cells (25/27), calmodulin-stimulated adenylate cyclase1 (AC1),a subfields were overlapping (38 ± 7% overlap). regulator of cAMP levels,is strongly expressed in the Moreover, the average maximal spike probability of corticospinal motorneurons (CSMN) in cerebral bright subfields was greater than for dark subfields cortex layer V during development, but its role in the (0.04 ± 0.008 vs 0.02 ± 0.003). Temporal analysis development of the corticospinal tract (CST) is showed that subfields activity was highly concurrent unknown. In our study, we analyse the organization but also that bright subfield's activity peaked earlier of the CST pathway using anterograde and than their dark counterpart (58.3 ± 11.2 vs 87.5 ± retrograde tracers in the barrelless (brl) mouse that 16.9 ms). Our laboratory has previously carries an inactivating mutation of the AC1 gene. We characterized RF profiles of cells in regions providing show that in brl mice the general organization of the major input to area 21a. Thus far, the profiles CST is normal but there is an increase in the number obtained in area 21a differ substantially from the of axons in the ipsilateral contingent in the dorsal ones found in lateral suprasylvian areas and in and ventral medial funiculi of the cervical spinal pulvinar, supporting a distinct role of this cortical cord. The density of CSMN in layer V of the motor area in visual processing. Supp by CIHR grant to CC. cortex is increased in brl compared to wild-type mice. Thus,lack of AC1 likely perturbs late phases of CSMN and CST development. Moreover, our study CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

1-D-121 Precise coding of ankle rotation by lower- Neuromodulators, such as dopamine, have the limb muscle spindle afferents capacity to reconfigure neuronal networks creating diversity in the range of outputs that a fixed circuit Ryan Peters¹, Brian Dalton², Jean-Sébastien Blouin¹, can produce. However, evidence from invertebrate Tim Inglis¹ systems has demonstrated that the effect of neuromodulators is dependent on the pre-existing ¹University of British Columbia, ²University of Oregon state of the network on which it is acting. Work in our lab using the neonatal mouse isolated spinal Owing to the recent observation of paradoxical cord has demonstrated that spinal dopamine acts as muscle movements of the plantar flexors during a potent modulator of locomotor activity. Here we quiet stance, the contribution of calf muscle spindles present data demonstrating the capacity of during standing balance has recently been dopamine to evoke different patterns of motor questioned. To investigate whether calf muscle activity is not only concentration dependent, but spindles can provide useful feedback during the also dependent on the excitability state of motor small ankle movements associated with quiet stance, networks in the spinal cord. Specifically, we have we collected microneurographic recordings from found that low concentrations of dopamine inhibit human lower-limb muscle spindles. Muscle spindle motor activity by acting on D2 receptors where as afferents were recorded from the tibial (n=12) and higher concentrations of dopamine are capable of common peroneal (n=3) nerves in 9 healthy, young evoking patterns of rhythmic motor activity and are adults. Five muscle receptors from the lateral mediated by excitatory D1 receptors. At constant gastrocnemius, 1 from the medial gastrocnemius, 4 concentrations of dopamine, the different patterns from the soleus, 2 from the intrinsic foot muscles, of activity can be recapitulated by altering global and 3 from the tibialis anterior were sampled. When motor network excitability by manipulating the a muscle spindle was identified, the participant's extracellular potassium or NMDA concentration. foot was loaded into an actuated ankle platform Using dopamine as an example, this suggests that in instrumented with a load cell. Participants were vertebrate rhythmically-active motor systems, exposed to continuous ankle plantarflexion- excitability state may also play an important role in dorsiflexion movements with a power spectrum determining the influence of a neuromodulator on replicating that of quiet stance (peak-to-peak motor output. amplitude = 0.7°; bandwidth = 0 to 0.5 Hz; mean power frequency = 0.28 Hz). Three-quarters of the 1-D-123 Plasticity of Binocularity and Visual Acuity muscle spindles (9/12), particularly those located in are Differentially Limited by Nogo Receptor the soleus muscle (4/4), displayed instantaneous firing rates that correlated with ankle angle. Overall, Céleste-Élise Stephany¹, Leanne Chan², Sherveen the soleus exhibited the highest level and broadest Parivash¹, Hilary Dorton¹, Mariel Piechowicz³, bandwidth of significant coherence calculated ShenFeng Qiu³, Aaron McGee¹ between spike times and ankle angle. Thus, a sub- population of calf muscle spindles likely play an ¹The Saban Research Institute, Children's Hospital important role in the standing balance control loop. Los Angeles, ²Centre for Biosystems, Neuroscience, and Nanotechnology, City University of Hong Kong , 1-D-122 Dopamine exerts concentration-dependent ³University of Arizona, College of Medicine bidirectional modulation and evokes state- dependent rhythmicity in motor networks of the The closure of developmental critical periods neonatal mouse spinal cord consolidates neural circuitry but also limits recovery from early abnormal sensory experience. Degrading Simon Sharples², Patrick Whelan³ vision by one eye throughout a critical period both perturbs ocular dominance (OD) in primary visual ¹Hotchkiss Brain Institute, ²Hotchkiss Brain Institute, cortex and impairs visual acuity permanently. Yet University of Calgary, ³University of Calgary understanding how binocularity and visual acuity interrelate has proven elusive. Here we demonstrate Motor networks that produce rhythmic patterns of the plasticity of binocularity and acuity are motor activity in the hind limbs reside primarily in separable, and differentially regulated by the the spinal cord and are under the influence of a neuronal nogo receptor 1 (NgR1). Mice lacking NgR1 number of descending modulatory inputs. CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

display developmental OD plasticity as adults. areas S1 and M1. This study demonstrated that Furthermore, their visual acuity and OD several degrees of imbricated mesoscopic cortical spontaneously recover after prolonged monocular functional organization co-exist. We anticipate that deprivation throughout the critical period. calcium imaging of functional connections using Restricting deletion of NgR1 to either cortical spontaneous activity will enable longitudinal studies interneurons or a subclass of parvalbumin-positive during plasticity paradigms or after models of interneurons alters interlaminar synaptic disease such as stroke. connectivity in visual cortex and prevents closure of the critical period for OD plasticity. However, loss of 1-D-125 Decoding the encoding strategy of primary NgR1 in PV neurons does not rescue deficits in acuity sensory neurons by in vivo calcium imaging induced by chronic visual deprivation. Thus, NgR1 functions with PV interneurons to limit plasticity of Feng Wang¹, Erik Bélanger¹, Sylvain Côté¹, Daniel binocularity, but its expression is required more Côté¹, Yves De Koninck¹ extensively within brain circuitry to limit ¹Centre de Recherche de L'Institut Universitare en improvement of visual acuity following chronic Sante Mentale de Quebec deprivation. Dorsal root ganglion (DRG) neurons are the primary 1-D-124 Wide field calcium imaging of resting state sensory neurons in the somatosensory pathways. activity in mice reveals both motif level, as well The properties of individual DRG neuron have been larger sensory clusters thoroughly studied and many types of DRG neurons Matthieu Vanni¹, Allen Chan¹, Dongsheng Xiao¹, with distinct sensitivity have been identified. Gergely Silasi¹, Jeffrey Ledue¹, Mostafa Moshevand¹, However, the responsiveness of an isolated sensory Tim Murphy¹ fiber to a particular stimulus cannot predict the sensory modality it is associated with. Moreover, in ¹University of British Columbia vivo, how a specific stimulus is represented by different types of DRG neurons simultaneously Strong reciprocal connections exist between the remains poorly understood. Here, we used AAV9 primary (S1) and secondary somatosensory cortex virus to specifically label DRG neurons with (S2) and primary motor cortex (area M1). In this GCaMP6s, a genetically encoded calcium indicator, in study, the topology of functional connections wildtype mice. Then we conducted in vivo calcium between these areas was explored by using wide imaging from small populations of DRG neurons field calcium imaging in GCaMP3 or GCaMP6 mice using video rate laser scanning two-photon expressing genetically encoded calcium indicator in microscopy. The responsiveness of the neurons to cortical neurons. Wide field fluorescence imaging various thermal and mechanical stimuli were measured cortical calcium responses in anesthetized recorded and analyzed. Our results showed that the and awake mice. Spontaneous activity was recorded majority of DRG neurons were polymodal and to establish connectivity relations between cortical responded to multiple stimulations. The largest points using a "seed pixel" approach. During population is the DRG neurons which respond to hot sequences of spontaneous activity, calcium signals and noxious hot stimulations. The activation recorded of each location of the area S1 were patterns of different neurons by various thermal correlated with localized activity in region of stimuli were also studied to reveal the encoding of homotopic contralateral area S1, ipsilateral area S2 stimuli. Principle component analysis will be applied and bilateral areas of M1. Comparably, activity for further neuronal clustering and decoding within each location of area S2 was correlated with analysis. Our findings could help understand the activity localized in ipsilateral area S1 and M1. underlying coding principle for ambient information Activity within each location of area M1 was by DRGs and by sensory systems in general. correlated with localized activity in region of homotopic contralateral area M1, bilateral areas of 1-D-126 Unbiased estimate of the spinal cord S1, and ipsilateral area S2. The K-means clustering neuronal population involved in non-human revealed 3 mains clusters of brain areas primate motor control corresponding to locomotion, oro-facial activity and vision as well as the symmetries existing between Nolan Wilson¹, Stephen Scott¹ CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

¹Queen's University and pause for a variable delay period before resuming locomotion. Hindleg step height and The spinal cord plays an essential role in the sensory trajectory over the obstacle were measured to and motor functions that give rise to behaviours assess memory. While hindleg stepping was ranging from simple reflexes to complex goal unaffected when area 7 was bilaterally cooled, directed movements. The ratio between bilateral cooling of area 5 resulted in significantly motoneurons and interneurons in the spinal cord lower steps and altered trajectories, demonstrating a has been commonly computed to understand the disregard for the obstacle. When bilateral cooling relative computational capabilities of spinal motor was restricted to the delay phase during which networks (Walloe, 2011). Currently, there are few obstacle memory must be maintained, similar accurate estimates of the number of motoneurons stepping deficits were observed. Additionally, and interneurons within the non-human primate cooling of area 5 in one hemisphere produced spinal cord and this ratio is not well defined. stepping deficits in the contralateral hindleg only. Neurons within the spinal cord grey matter of non- Finally, when area 5 cooling was stopped human primates were quantified to provide a more immediately after the memory acquisition phase robust anatomical framework for modelling upper (approach and foreleg clearance), high hindleg steps limb motor control. The spinal cords of rhesus were restored, suggesting reactivation of obstacle monkeys (Macaca mulatta) were examined from memory. These results suggest that area 5 is critical segments C2 to T1 using stereological methods to for maintaining the memory of an obstacle estimate the total number of neurons in specific encountered in the contralateral hemispace. areas of the grey matter. These areas included both those containing motor neurons (Lamina IX) as well 1-D-128 Imbalance of Excitation and Inhibition at as those containing interneurons associated with Threshold Level In the Auditory Cortex motor pathways (Laminae V - VIII). A ratio of 1:25 in the rhesus monkey was calculated using Yan Zhao², Zizhen Zhang¹, Xiuping Liu¹, Colin Xiong¹, motoneuron and interneuron estimates. This ratio is Jun Yan¹ higher than that of other mammalian and non- mammalian vertebrates, indicating that a more ¹University of Calgary, ²Southern Medical University robust spinal network may underlie the ability of The interplay of cortical excitation and inhibition is a primates to generate complex upper limb fundamental feature of cortical information movements. processing. Excitation and inhibition in single 1-D-127 Dissociation of parietal cortex cortical neurons are balanced in their response to contributions to obstacle memory in walking cats optimal sensory stimulation due to thalamocortical feedforward microcircuitry. It is unclear whether the Carmen Wong¹, Keir Pearson², Stephen Lomber¹ balance between cortical excitation and inhibition is maintained at the threshold stimulus level. Using in ¹The University of Western Ontario, ²University of vivo whole-cell patch-clamp recording of Alberta thalamocortical recipient neurons in the primary auditory cortex of mice, we examined the tone- A working memory of environmental obstacles is evoked excitatory and inhibitory postsynaptic essential for avoidance in walking mammals. In currents at threshold levels. Similar to previous quadrupeds, vision is unavailable to guide hindleg reports, tone induced excitatory postsynaptic stepping over an obstacle previously cleared by its currents when the membrane potentials were held forelegs. Instead, visual information about an at - 70 mV and inhibitory postsynaptic currents when obstacle and motor information about foreleg the membrane potentials were held at 0 mV on clearance are held in memory to modify hindleg single cortical neurons. This coupled excitation and movements. Previous studies suggest that this inhibition is not demonstrated when threshold-level memory system relies on parietal areas associated tone stimuli are presented. In most cases, tone with sensorimotor integration. To examine parietal induced only excitatory postsynaptic potential. The contributions to obstacle memory, cortical cooling best frequencies of excitatory and inhibitory was used to reversibly deactivate areas 5 or 7 in cats responses were often different and thresholds of trained to step over an obstacle with their forelegs inhibitory responses were mostly higher than those CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

of excitatory responses. Our data suggest that the activation in the reward circuitry can negatively excitatory and inhibitory inputs to single cortical impact the emotional response. neurons are imbalanced at the threshold level. This imbalance may result from the inherent dynamics of 1-E-130 Dopamine acts directly on arcuate nucleus thalamocortical feedforward microcircuitry. Based neurons to alter expression of neuropeptide genes on our and other findings, a neural model is proposed to broaden our view of thalamocortical Samantha Lee¹, Lauren Shute¹, Mark Fry¹ feedforward circuitry (see attached figure). ¹University of Manitoba E - Homeostatic and Neuroendocrine Systems The arcuate nucleus (ARC) of the hypothalamus acts

as a central coordinator in the homeostatic 1-E-129 Effects of ANA-12, a selective tyrosine- regulation of energy balance. ARC neurons exhibit related kinase B (TrkB) antagonist, on anxiety, remarkable plasticity in response to changes in exploration, locomotion and fear avoidance peripheral and central energy balance signals. The learning following a repeated stress regimen in neurotransmitter dopamine (DA) appears to play a male Wistar rats role in the regulation of food intake through alteration of the ARC neuropeptide Y/melanocortin Idu Azogu¹, Helene Plamondon¹ circuit. Of particular interest is the D2 receptor, which has been implicated in mediating this effect. ¹University of Ottawa However, it is currently unclear what effects result from direct versus indirect action of DA on individual In both human and animal studies, repeated ARC neurons. In order to assess the direct effect of exposure to stressors can have negative impacts on DA on ARC neurons, we utilized a dissociated ARC brain health, cognition, and mood. Stress can neuron preparation that effectively isolates neurons promote the expression of brain-derived from interacting with one another. Cultures were neurotrophic factor (BDNF) and its primary receptor treated with the selective D2 agonist quinpirole (10 tyrosine-related kinase B (TrkB), and increased levels M), or selective D2 antagonist sulpiride (10 M) for 5- in the brain reward circuitry (e.g. nucleus accumbens 6 days and changes in morphology and gene (NAc)) can predict susceptibility to anxiety and expression examined. No significant difference in the depression. This study aims to assess the effects of total number of neurite branches, total branch repeated stress on the activity of BDNF/TrkB in the length or maximum branch length was found reward circuitry, and whether the inhibition of this between treatments and control. However, qPCR system can promote anxiolytic effects in dopamine- analysis revealed a robust increase in pro- related behaviors. 4 groups of male Wistar rats opiomelanocortin expression in agonist treated (n=10 /group) were implanted with guide cannulas in groups. These results indicate that DA acts directly the NAc shell and treated with ANA-12 or Vehicle 30 on ARC neurons to favour a decrease in food intake. minutes prior to undergoing a ten-day repeated stress/no stress regimen. A 5th group was added as 1-E-131 Intra-VTA insulin decreases nucleus non-treatment controls (n=6). Rats were subjected accumbens dopamine release in vivo to the open field test (OFT), elevated plus maze (EPM) and Y maze passive avoidance test (YM-PAT). Lindsay Naef¹, Jeff Huang², Calvin Lee², Dmitry Findings indicate that ANA-12 significantly reduced Mebel², Stephanie Borgland¹ anxiety-like behavior in the OFT and EPM in stressed rats. In contrast, ANA-12 increased anxiety-like ¹University of Calgary, ²University of British Columbia behavior in the no stress group, indicated by a higher Mesolimbic dopamine (DA) circuits, implicated in index of open arm avoidance in the EPM. Finally, in incentive motivation, are an important target for the YM-PAT, we observed an increased latency to re- metabolic hormones such as leptin, ghrelin and enter the aversive arm in the ANA-12 (stress) group insulin. We have previously demonstrated that compared to other groups. This study demonstrates insulin induces long-term depression of excitatory a beneficial effect of TrkB inhibition in stressed rats, synapses onto ventral tegmental area (VTA) DA and suggests that in a normal state, reduced TrkB neurons and reduces food reward behaviours, including food anticipatory behaviour and CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

conditioned place preference for food. Whether associated with OCM after PNEE in a manner that intra-VTA insulin reduces DA release in projection would elude to the point of OCM truncation, and aid areas of the VTA remains unknown. Using in vivo fast in the delivery of public understanding of the scan cyclic voltammetry in anesthetized rats, we detriments of PNEE. show that peripheral and intra-VTA administration of insulin reduces stimulated DA release in the NAc, an 1-E-133 4(5)-methylimidazole, found in caramel effect that is blocked by the insulin receptor colouring, alters gene expression in arcuate nucleus antagonist, S961. Furthermore, intra-VTA insulin neurons. reduces cocaine-evoked increases in NAc DA. Together, these results suggest that insulin action in Lauren Shute¹, Samantha Lee¹, Geemitha Ratnayake², the VTA decreases DA release in the NAc. Thor Halldorson¹, Lianna Bestvater¹, Gregg Tomy¹, Furthermore, because intra-VTA insulin decreases Mark Fry¹ cocaine-evoked DA in the NAc, CNS delivery of ¹University of Manitoba, ²Acadia Junior High School insulin may provide clinical utility for decreased drug-induced craving. Evidence indicates environmental and synthetic contaminants may contribute to the obesity 1-E-132 Alteration to one carbon metabolism may epidemic via endocrine disruption. Recent concern underlie glutathione deficiencies in the rat dentate has focused on 4(5)-methylimidazole (4-MEI), a gyrus after prenatal ethanol exposure chemical byproduct found in caramel colouring, with Scott Sawchuk¹, Anna Patten¹, Brian Christie¹ confirmed carcinogenic and suspected neuroendocrine disrupting activity; high levels of 4- ¹University of Victoria MEI are often found in foods despite stringent regulations. The goal of this study was to determine Fetal alcohol spectrum disorder (FASD) describes the levels of 4-MEI in various beverages and evaluate wide scope of symptoms that can arise in a child possible effects on morphological parameters and when a mother consumes alcohol during pregnancy, gene expression of arcuate nucleus neurons, and is one of the leading causes of preventable neurons that regulate energy balance. Levels of 4- mental disorder in Canada and the United States. MEI were determined using isotope-dilution reverse- Unfortunately, consensus is vague with regards to phase liquid chromatography tandem mass core cognitive defects and behavioural spectrometry. Of 19 beer and soda beverages temperaments associated with FASD, making containing caramel colouring tested, 10 exceeded diagnosis and treatment a considerable challenge. the maximum allowed dose of 29 μg per day; The varying degree symptoms that arise after notably Waterloo Original Dark Lager contained prenatal ethanol exposure (PNEE) points towards a 226.49 μg in a 355 mL serving. Based on these globally deleterious effect that fluctuates with observations, we investigated whether 4-MEI could timing, dosage, and pattern of exposure. For this influence morphology and gene expression of reason, a considerable amount of attention has been arcuate nucleus neurons maintained in culture for 5 invested into understanding the inhibitory effects of days in media that contained 0.3 μg/mL of 4- alcohol on one-carbon metabolism (OCM). OCM is a MEI or control media. Total neurite length, central pathway existing in all tissue types that maximum neurite length, total branch number, and regulates the metabolites necessary for epigenetic generalized morphological subtype were not altered modification of gene expression, and is very tightly by 4-MEI treatment. Interestingly however, qPCR associated with cellular signaling and homeostasis. analysis of RNA from treated cultures revealed that Furthermore, conditions of oxidative insult and 4-MEI reduced expression of TH, NPY and POMC damage are prevented when OCM metabolites are transcripts, which play a key role in the regulation of converted to cysteine and used in the synthesis of energy balance. These data indicate that 4-MEI has glutathione (GSH), an anti-oxidant molecule the capacity to act as a neuroendocrine disrupter. depleted in the brain after PNEE. Long-term deficits in OCM could alter cellular homeostasis and gene F - Cognition and Behavior expression, and affect GSH levels by restricting the limiting substrate for GSH synthesis. The aim of this study is to investigate the primary metabolites CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

1-F-134 Circuit principles of neuronal processing in ¹University of Saskatchewan, ²University of British larval Drosophila melanogaster thermotaxis Columbia

Bruno Afonso², Mason Klein³, Matthew Berck³, Ivan Absence epilepsy is a seizure disorder characterized Ilarderet⁴, Marc Gershow⁵, James Truman⁶, Simon by generalized spike-and-wave discharges (SWDs). Sprecher⁴, Albert Cardona⁶, Aravi Samuel³, Marta Although epidemiological studies report that Zlatic⁶ epilepsy syndromes with absence seizures are more likely to occur in females, potential sex differences in ¹HHMI Janelia / Harvard University, ²HHMI Janelia the comorbid cognitive functions are unknown. Research Center / Harvard University, ³Harvard Here, adult GAERS (Genetic Absence Epilepsy Rats University, ⁴University of Fribourg, ⁵New York from Strasbourg), a well-validated rat model with University, ⁶HHMI Janelia Research Center absence seizures, and their paired strain, non- epileptic control (NEC) rats, were tested on visual The goal of systems neuroscience is to understand discrimination learning using a paired-choice test in the computational process by which neural circuits touchscreen-equipped operant chambers. Results use sensory information to generate adaptive showed that GAERS males made more errors and behaviors. Drosophila larvae avoid excessively cool took more trials to reach criterion during visual temperatures using a small set of sensorimotor discrimination. In contrast, no statistical difference transformations regulating the frequency and was found between GAERS and NEC females, outcome of navigational decisions. During each although GAERS females tended to spend more days navigational decision, larvae sweep their head from in the pre-training stage. During the last two side to side, gathering thermal information that discrimination test days, reward latencies were informs the choice of a new direction for forward altered in both male and female GAERS rats. GAERS movement. Automated trajectory and posture males were slower to collect the reward, while analysis of individual animals navigating temperature GAERS females were faster. During the reversal gradients enables us to quantify navigational learning phase, male GAERS took significantly more decisions of each animal. Statistical analysis of an days and more trials to reach criterion than NECs. inactivation screen using the Gal4/UAS system with Our data suggest that a sex difference in visual Janelia collection allowed us to identify neurons in discrimination and reversal learning may exist in the the thermotactic circuit. We have identified two GAERS with males performing poorer on visual distinct groups of projection neurons that when discrimination and reversal learning than females. inactivated exclusively modulate individual Further studies are necessary to explore the navigational decisions, such as turn direction and mechanisms underlying these effects. acceptance of larval headsweep. We mapped all partners using EM and found they receive direct 1-F-136 Training experience affects the selectivity synaptic inputs from cold sensing neurons. We are of neurons and the pattern of noise correlations in currently characterizing the computational dynamics primate lateral prefrontal cortex of these neurons by measuring and manipulating neuronal activity in freely moving and/or restrained Theda Backen¹, Stefan Treue², Julio Martinez-Trujillo³ animals using novel methods in optical neurophysiology. Combining behavioral analysis, EM ¹McGill University, ²German Primate Center, reconstruction of behaviorally relevant neurons and ³University of Western Ontario functional imaging will allow the complete identification of circuits underlying thermotaxis from Recent studies have proposed that the primate sensory inputs to motor outputs. lateral prefrontal cortex (LPFC) plays an important role in attention. How neurons in this area interact 1-F-135 Cognitive impairments in a touchscreen- during attentional tasks and how that depends on based visual discrimination and reversal learning prior experiences remains unclear. We recorded procedure in a rat model of absence epilepsy responses of neurons in LPFC area 8a of two macaque monkeys using 96-channel microelectrode Lei An¹, Wendie Marks¹, Stuart Cain², Terrance arrays. The animals had to identify one of two Snutch², John Howland¹ moving random dot patterns as the target based on its color and indicate a change in its direction, while CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

ignoring the other stimulus. Monkey R was hippocampal damage localized to the dentate gyrus. exclusively trained in this task, while monkey S had B.L.'s performance was compared to that of age- previously been extensively trained on a pure matched controls on a widely used pattern motion discrimination task. In monkey R, ~1/3 of the separation task. Results of impaired pattern neurons were selective for the target location and separation provide the first evidence in humans of a few neurons were selective for motion direction. In selective role of the DG in creating and maintaining monkey S, ~1/3 of the neurons were tuned for distinct visual memories. motion direction and few neurons were tuned for the target location. We computed noise correlations 1-F-138 Simulation of embodied and the large- between pairs of neurons and found that similarly scale neuronal systems with the iqr software tuned neurons showed higher correlations than dissimilarly tuned ones. Using a linear classifier, we Ulysses Bernardet¹ further assessed if correlations influence the ¹Simon Fraser University neurons' ability to encode the stimulus features. In monkey S, removing noise correlations increased The notions that cognition is embodied, and that decoding performance. In monkey R, removing them function arises through the large-scale connectivity either decreased or increased performance. Our at least as much as the computational power of results suggest that training shapes the tuning of individual units, are now widely accepted as core to neurons in prefrontal area 8a. Moreover, noise understanding the human brain. Hence, neuronal correlations vary with the similarity between the simulations must incorporate these paradigms, and neurons coding preferences. The effect of noise to do so we have -- over the past more than 10 years correlations in information coding by LPFC -- developed the large-scale neuronal systems ensembles seems to be complex. simulator iqr. Embodiment of cognition is addressed in iqr by providing the means to interface neuronal 1-F-137 Pattern separation deficits in a patient simulations to "real-world" devices such as mobile with bilateral dentate gyrus lesions robots, cameras, microphones etc. While the need Stevenson Baker¹, R. Shayna Rosenbaum¹ for sophisticated connectivity is met by providing powerful, yet elegant ways of specifying the ¹York University connectivity between large groups of neurons. In iqr large-scale neuronal models are developed using a Neuroimaging and behavioural studies support graphical user interface, and the simulation can be various theories on the nature of hippocampal controlled on-line by changing parameters of the contributions to episodic memory, the ability to model at run-time. Built-in on-line tools allow to remember past personal events in one's life that are visualize, record, and analysis of data without the specific to time and place as well as items that have need for additional tools. iqr provides both, pre- been previously encountered in a laboratory setting. defined neuron and synapse types, and an open In order to represent episodic memories as distinct, architecture for new, user-defined neurons, a mechanism of pattern separation is needed to synapses, and hardware interfaces. The simulation reduce interference among similar neural inputs by software has been successfully used in research and using non-overlapping representations. In recent teaching in number of projects, is fully documented, years, computational models and animal studies and the source code of is publicly accessible under have prompted speculation that pattern separation the GNU General Public License (GPL). can be localized to the dentate gyrus (DG) and CA3 subfields at the core of the hippocampus. A 1-F-139 The Word on the Beat: Behaviour and challenge with studying pattern separation in Brain Interactions of Reading and Rhythm humans, however, is the fact that individuals with hippocampal damage typically have lesions that Layla Gould¹, Eric Lorentz¹, Chelsea Ekstrand¹, Tessa extend into and beyond the hippocampus, making it McKibben¹, Marla Mickleborough¹, Ron Borowsky¹ difficult to localize pattern separation to the DG. In ¹University of Saskatchewan the current study, we investigated pattern separation in a rare person, B.L., who, in relation to Like musical rhythm, speech rhythm involves electrocution and cardiac arrest, suffered bilateral organized acoustic sequences and complex cognitive CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

and motor processes. More specifically, speech reinstatement was assessed. In the first study male rhythm refers to the patterns of stressed and Wistar rats were trained to self-administer cocaine unstressed syllables that build up the meter of under a progressive ratio schedule of reinforcement spoken utterances. The current study used fMRI to and then pretreated with fendiline (vehicle, 1.78, identify common brain regions that are shared 3.16, or 5.62 mg/kg, IP). A separate group of rats during rhythm processing and reading aloud. A received baclofen (vehicle, 0.56, 1.78, 3.16, or 5.62 behavioral study revealed a connection between mg/kg, IP) 30 minutes before a 5.62 mg/kg dose of rhythm and reading, whereby reading was enhanced fendiline directly before their self-administration by the presentation of a rhythmic prime that was on- session. In the next study, the effect of fendiline beat compared to off-beat with the syllabic stress of pretreatment (vehicle, 3.16 or 5.62 mg/kg, IP) on the bisyllabic target letter string. We used words vs. cue-induced (light and tone) or drug-induced (10 pseudohomophones (PH; which must be mg/kg, cocaine, IP) reinstatement was assessed in phonetically decoded; eg praktis), to investigate separate groups of rats that underwent 10 days of whether sublexical reading would show a greater extinction training after cocaine self-administration effect of the rhythmic prime given recent findings had been established. Results indicated that (Cason & Schön, 2012). The results revealed a Beat fendiline only reduced breakpoints when it was by Stimulus Type interaction, indicating that reading combined with 3.16 or 5.62 mg/kg baclofen; sublexically (PHs) was more enhanced by preceding fendiline alone reduced both cue- and drug-induced the target with 'on-beat' primes than lexical reading reinstatement of lever pressing. Results suggest that (words). In an fMRI study, we examined overlap in fendiline, and other drugs that indirectly target the brain activation in regions such as the brain stem, GABAB receptor, warrant further investigation cerebellum, thalamus, basal ganglia, motor regions, prefrontal cortex and temporal cortex, as these 1-F-141 Younger age of onset of cannabis use is regions have been implicated as important for associated with thalamic dysconnectivity in youth speech rhythm (Fujii & Wan, 2014). Furthermore, at clinical high risk of psychosis the putamen was a region of interest given that it has recently been implicated in sublexical processing Lisa Buchy¹, Tyrone Cannon², Alan Anticevic², Kristina (Oberhuber et al. 2013), as well as rhythm Lyngberg¹, Kristin Cadenhead³, Barbara Cornblatt⁴, processing (Grahn, 2009). These regions of shared Thomas McGlashan², Diana Perkins⁵, Larry Seidman⁶, activation are discussed in terms of models of Ming Tsuang³, Elaine Walker⁷, Scott Woods⁸, Carrie reading and rhythm processing. Bearden⁹, Daniel Mathalon¹⁰⁹UCLA,

thalamic connectivity did not differentiate those 1-F-143 Effect of T-type calcium channel blockade with or without a lifetime history of cannabis use nor on the induction and reinstatement of morphine- significantly correlate with current use severity or induced conditioned place preference frequency in either group. In CHR cannabis users, attenuated thalamo-cerebellar connectivity Jonathan Cunningham¹, Carine Dias¹, Terry Snutch¹, significantly correlated with a younger age of onset Anthony Phillips¹ of cannabis use. CHR who used cannabis before age 15 did not differ on thalamic connectivity compared ¹University of British Columbia to CHR who used after age 15 or cannabis naive CHR. Z944 is a Ca2+ channel antagonist for the low- CHR converters and CHR non-converters separated voltage activated T-type channel. Rhythmic burst- according to positive/negative lifetime history of firing in the ventral tegmental area (VTA) is partially cannabis use did not differ on thalamic connectivity. driven by T-type channels. The VTA is responsible for These data indicate that although a younger age at dopamine (DA) release in the mesolimbic DA system, onset of cannabis use is associated with disrupted implicated in the rewarding properties of drugs of thalamo-cerebellar coupling, cannabis use does not abuse. Accordingly, pharmacological blockade of T- appear to be an identifying characteristic for type channels may attenuate the rewarding thalamic circuitry in CHR early-onset users or CHR properties of a drug by reducing DA efflux. We who convert to psychosis compared to non- evaluate the ability of a novel T-type Ca2+ converters. antagonist, Z944, to attenuate the rewarding 1-F-142 A novel Presenilin 1 mutation causes properties of morphine (MOR) in a conditioned place Alzheimer's Disease preference (CPP) paradigm. Rats were given injections of MOR (5mg/kg) or saline prior to being Fang Cai¹, Shuting Zhang¹, Weihong Song¹ placed in one of two contextually distinct chambers. Conditioning trials alternated between MOR or ¹UBC saline treatment for 4 days each. Z944 (5, 7.5mg/kg) or vehicle were administered 5 min. prior to each 45 Alzheimer's disease (AD) is the most common min. MOR conditioning session. Expression of MOR neurodegenerative disorder leading to dementia. A CPP was assessed after conditioning, and after at majority of AD cases are sporadic with late onset. least 12 days of extinction, MOR-induced (5mg/kg) Missense mutations in Presenilin 1 (PS1), Presenilin 2 reinstatement of CPP was assessed. We observed a (PS2) and Amyloid β Precursor Protein (APP) dose-dependent effect of Z944 on the induction of cause early onset familial AD (FAD). PS1 mutations MOR CPP. Both experimental groups extinguished account for the majority of early-onset FAD. PS1 is their preference for the 'MOR chamber' significantly the catalytic core of y-secretase complex to process faster (5 d) compared to vehicle controls (10 d). APP to generate amyloid β protein (Aβ), Reinstatement was blocked in the group that the central component of neuritic plaques in AD received 7.5mg/kg of Z944 during conditioning. brain. Pathogenic mutations in PS1 gene has been shown to contribute to AD pathogenesis via Induction and MOR-induced reinstatement of MOR impaired processing of APP. A novel PS1 mutation CPP is attenuated by the T-type Ca2+ channel has been identified in the AD patients with early antagonist Z944. Based on the findings, Z944 may onset in a Chinese family. We extensively provide a novel pharmacotherapy for modulating the characterized the function of the PS1 mutation in rewarding properties of MOR. mammalian cells and established a transgenic mouse strain carrying the mutation. We found that this PS1 1-F-144 Knowledge of haptic feedback availability mutation altered y-cleavage of APP to produce does not influence size information supporting Aβ and promoted AD pathogenesis in PS1/APP pantomime grasping double transgenic mouse model. Shirin Davarpanah Jazi¹, Stephanie Hosang¹, Matthew Heath¹

¹University of Western Ontario CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

Delayed grasp of a visual target entails the use of span using the odour span task (OST). The OST absolute size information. In addition, receiving requires rats to remember an increasing span of haptic feedback via target grasp plays an important odours to receive reward. Rats were cannulated role in the neural control of action. More specifically, bilaterally in mPFC and dmSTR and trained on a our previous work showed that pantomime grasp of delayed non-match to sample procedure with a target in delayed conditions (PH- condition) scented bowls containing food reward. Subsequent requires the use of relative size information. "span" tests involved adding bowls with novel However, when participants were given haptic odours one at a time until an error occurred. The feedback from the object following pantomime number of cups correctly chosen before an error was grasping to the target's empty location (PH+ the span. Infusions of the GABA receptor agonists condition) absolute size cues were used. Notably, in muscimol and baclofen (M/B) were used for this earlier work subjects were given instructions on inactivation or Ro25-6981 was used to block GluN2B how to perform the task prior to initiating the NMDARs. Bilateral inactivation of mPFC significantly experiment. As such, we wanted to investigate impaired span (span after inactivation = 2.7 odours; whether the knowledge of receiving haptic feedback vehicle = 7.8). Bilateral dmSTR inactivation or influences the distinct processing pathways blockade of GluN2B NMDARs significantly reduced supporting PH- and PH+ tasks. Participants grasped span (inactivation = 5.6; vehicle = 11.0; GluN2B differently sized objects in separate blocks of PH+ NMDAR blockade = 6.2; vehicle = 10.2). and PH- and instructions about the upcoming task Disconnection of mPFC and dmSTR significantly were given before the start of the each block. In a impaired span (inactivation = 1.7; vehicle = 6.8; third condition PH+ and PH- trials were randomly mPFC inactivation, dmSTR GluN2B NMDAR blockade presented (PR condition) meaning that participants = 2.4; vehicle = 9.0). The present results demonstrate did not know what trial type they were about to a critical role of the direct projection from the mPFC perform. To determine whether responses adhered to the dmSTR in performance of the OST in rats. to/or violated Weber's psychophysical law just noticeable difference scores (JNDs) were computed. 1-F-146 Moxifloxacin Induced Psychosis: A Case Comparable to the PH- trials, JNDs in the PR Report Study condition scaled to target size irrespective of the availability of haptic feedback. Our findings indicate Arman Fesharaki¹ that participant's anticipation about the upcoming ¹SUNY Downstate Medical Center task does not influence the nature of the processes controlling grip aperture formation in pantomime Background: Prior studies have demonstrated that conditions. the floroquinolones can cause drug induced mental status changes (Farrington et al. 1995). Discussion: 1-F-145 Functional interaction between medial The reported patient is a 91 year old lady with prior prefrontal cortex and dorsomedial striatum is medical history of chronic obstructive pulmonary necessary for odour memory span in rats: role of disease (COPD), hypertension, hypelipidemia , GluN2B-containing NMDA receptors coronary artery disease, peripheral artery disease Don Davies¹, Quentin Greba¹, Jantz Selk¹, Jillian and no prior psychiatric history. The patient was Catton¹, John Howland¹ admitted to the inpatient medical unit for COPD exacerbation , for which she was started on oxygen ¹University of Saskatchewan therapy, prednisone 40mg tab PO daily (the patient was on long term prednisone regimen), Working memory is a type of short-term memory for monteleukast 10mg tab PO every evening at 7pm, as storage and manipulation of information necessary well as Moxifloxacin 400mg tab PO daily. On the for higher order cognition. Working memory following evening after her admission, the patient capacity is often assessed using span tasks. Span became acutely agitated, displaying paranoid performance is linked to activation of medial delusions comprised of patient believing that the prefrontal cortex (mPFC). The present experiments inpatient nurses and staff members were trying to examined whether inactivation or GluN2B NMDA steal her belonging and kill her. Despite multiple receptor blockade in mPFC, dorsomedial striatum verbal redirection and reassurancefrom the inpatient (dmSTR), or disconnection of these areas reduced staff members, the patient remained acutely CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

agitated.Given the fact that this was the first time ¹York University, ²University of Toronto; Baycrest , that Moxifloxacin was administered for the patient ³University of Toronto , ⁴York University; Baycrest and there was no prior history of exposure to this regimen, and in light of prior clinical reports Recent research has challenged classic theories of regarding the possible psychiatric manifestations hippocampal function in spatial memory with regarding various floroquinolones, the CL team findings that the hippocampus may be necessary for recommended discontinuation of this medication. detailed representations of environments learned Conclusion:Given prior reports of floroquinolone long ago, but not for remembering the gist or induced mental status changes and with rate but schematic aspects that are sufficient for navigating possible psychiatric manifestations, due clinical within those environments (Rosenbaum et al., 2000; diligence is advised specially in the elderly 2012). We aimed to probe further distinctions population. between detailed and schematic representations of familiar environments with three medial temporal 1-F-147 Approach and Avoidance Processing: amnesic patients with hippocampal damage by Investigating a Rostrocaudal Gradient in the testing them on a route description task and mental Nucleus Accumbens Core navigation tasks that assess the identity and location of landmarks, and distances and directions between Laurie Hamel¹, Anett Schumacher¹, Rutsuko Ito¹ them. The amnesic cases could describe basic directions along known, imagined routes, estimate ¹University of Toronto distance and direction between well-known landmarks, and produce sketch maps with accurate The nucleus accumbens is a site of integration of layouts, suggestive of intact schematic positively and negatively valenced information and representations. However, findings that patients' action selection. While a rostrocaudal topographical route descriptions lack richness of detail, along with gradient in valence processing has been found in the impoverished sketch maps and poor landmark accumbens shell subregion primarily in terms of recognition, substantiates previous findings that unconditioned behaviours, a potential gradient has detailed representations are hippocampus- not fully been explored in the core in relation to its dependent. role in motivation in response to conditioned cues. In the current study, rats were trained to associate 1-F-149 Decoding Phenomenal Experience in visuo-tactile cues with appetitive sucrose, aversive Vegetative State Patients foot-shocks and neutral outcomes. In a test of motivational bias, the aversive and appetitive cues Austin Horn¹, Lorina Naci¹, Charles Weijer¹, Adrian were superimposed in a maze arm and rats' Owen¹ exploratory bias was measured for this arm vs. a neutral cued arm. Animals receiving GABA receptor ¹Western University agonists in the caudal core region displayed a bias in the direction of aversion, whereas those undergoing The objective of this project is to investigate the disruption of activity in the rostral core displayed an epistemological implications of recent neuroimaging ambivalence similar to controls, with an additional studies, which offer a "neural index" for conscious behavioural difference of augmented vacuous human experience. Neuroscientists have long chewing. The results suggest a rostrocaudal suspected that the network of brain regions involved differentiation in valence processing of conditioned in "executive function" may provide a window into cues in the accumbens core. conscious experience. However the numerous processes involved in conscious experience make it 1-F-148 Impoverished Descriptions of Familiar difficult to relate patterns of brain activity to specific Routes in Three Cases of Medial Temporal higher or lower-order functions. A recent study Lobe/Hippocampal Amnesia addressed this problem by having subjects watch an engaging and suspenseful movie, providing viewers Katherine Herdman¹, Navona Calarco¹, Morris with a shared conscious experience (Naci el al. Moscovitch², Marnie Hirshhorn³, R Shayna 2014). The results of initial investigations on healthy Rosenbaum⁴ controls showed that the timing of activity in the relevant regions of the brain was predicable based CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

on participants' highly similar qualitative experience discriminating environments in which place field of the movie's moment-to-moment executive repetition occurs. demands. The neural activity across participants was synchronized, indicating a similar conscious 1-F-151 Differential Effects of Dopamine and experience. Moreover, in a patient who was thought Selective Dopamine Agonists on Spatial Working to be in a vegetative state (VS), highly similar Memory, Attention, Learning and Reaction Time in moment-to-moment executive processes as healthy Healthy Controls individuals' were detected. This project aims to answer the following question: does Naci and Robert Marino¹, Alenka Bullen¹, Ron Levy¹ colleagues' "neural index" truly offer novel insight ¹Queen's University into the phenomenology of conscious experience? 
Answering this question will significantly Dopamine (DA) plays a critical role in working impact a number of areas of inquiry, including memory and cognitive control. However, DA has philosophy of mind and epistemology. been shown to both improve and/or impair cognitive performance across different subjects, tasks, and 1-F-150 Does place field repetition impair spatial studies. This complex relationship may be due to the learning? differential effects of dopamine at D1 and D2 Bryan Jenkins¹, Roddy Grieves¹, Bryan Jenkins¹, receptors in basal ganglia cognitive loop nuclei Emma Wood¹, Paul Dudchenko² (striatum and the dorsolateral prefrontal cortex). In order to address this question, we have investigated ¹University of Edinburgh , ²University of Stirling the effects of DA manipulation on cognitive performance in healthy monkeys using a touch Place cells are pyramidal neurons found in regions screen running the CAmbridge Neuropsychological CA1 and CA3 of the hippocampus. They fire in a Test Automated Battery (CANTAB). One of three DA particular area of an environment, referred to as a drugs or placebo were administered prior to each place field, and are generally thought to support daily CANTAB session: Sinemet spatial cognition. Recent research has shown that (Levadopa/Carbidopa), Dihydrexidine hydrochloride place cells exhibit repeating place fields in an (selective D1 like receptor agonist) or Sumanirole environment comprised of visually identical, parallel maleate (selective D2 agonist). Three CANTAB tasks compartments. Through two experiments, we set were tested at each session: (1) 'visually guided out to determine the significance of place cell reaching task', which tests reaction time and activity in supporting the discriminatory ability of reaching accuracy, (2) 'reversal learning task', which rats. In our first experiment, we tested whether a tests association learning, cognitive flexibility and group of rats (n=6) could learn a spatially-guided attention, and (3) 'spatial ordered sequential search odour discrimination task in an environment task' which tests spatial working memory. Metrics composed of 4 parallel compartments. A second from these tasks were compared between control group (n=6) was trained in the same 4 and each DA drug condition. Results demonstrated compartments arranged in a semi-circular (radial) that the D1 agonist most strongly impaired reversal formation; in which we would not predict place field learning whereby the D2 agonist most strongly repetition. Our results concluded that learning was impaired reaction time and spatial working memory. significantly impaired in the parallel environment. These results provide insight into the relationships Next, we performed single-unit recordings from CA1 between DA and cognition and provide baseline place cells as rats foraged in the parallel and radial behavioural data for future physiological recordings environments. We observed repeating place fields in the basal ganglia. across the parallel compartments. To quantify this we performed correlative analyses between 1-F-152 Increased spontaneous somatic-patterned compartments of each maze configuration and cortical activity in a mouse model of depression calculated a significantly higher correlation between place cell activity in the parallel compartments as Alexander McGirr¹, Allen Chan¹, Yicheng Xie¹, Jeffrey compared to activity in the radial compartments, LeDue¹, Diana Lim¹, Pumin Wang¹, Timothy Murphy¹ supporting the observation of place field repetition. ¹University of British Columbia Overall, these results suggest that rats have difficulty CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

Background: Individuals with depression commonly synaptic plasticity. Emerging evidence suggests that present with medically unexplained somatic cadherins and their intracellular binding partners, complaints. The neurobiology of somatisation, may be of importance in the study of addiction. however, is poorly understood. In mice, we have Indeed, several genome-wide allelic association shown that spontaneous cortical activity contains studies have reported a high incidence of mutations patterns resembling evoked sensory activity. We in cadherin genes in individuals with substance hypothesized that depression would induce abuse problems. We have demonstrated that alterations in spontaneous somatic-patterned cadherins are localized to excitatory and inhibitory activity. Method: Using the Chronic Social Defeat synapses being formed onto DA neurons within the (CSD) model, 8 week old C57/B6 males were VTA. We have used immunoelectron microscopy to exposed to 10 days of defeat. The depressive quantify cadherin localization at synapses within the phenotype was assessed using the Forced Swim Test VTA after wildtype mice develop preference for (FST) and the Sucrose Preference Test (SPT). A large cocaine in a conditioned place preference (CPP) craniotomy exposed both hemispheres and voltage- paradigm. With this method, we have shown that sensitive dye (VSD; Rh1692) was incubated over the cadherin localization is significantly increased at cortex. We imaged with 6.67ms temporal resolution excitatory synapses onto dopaminergic neurons of and 8.6*8.6mm field of view. We recorded 6 minutes the VTA after mice develop preference for cocaine. of spontaneous cortical activity after which we Moreover, inhibiting intercellular N-cadherin recorded somatic patterns of neuronal interactions abolishes spike-timing dependent depolarization using forelimb, hindlimb and whisker plasticity in the VTA, indicating that cadherin stimulation. These were used as templates to adhesion complexes play an important role in identify somatic-patterned activity in spontaneous synaptic plasticity in this region. brain activity. Results: Mice exposed to CSD had a depressive phenotype on the FST and SPT. Cortical 1-F-154 Synaptic Plasticity and Reversal Learning representation of sensory stimulation did not differ are Impaired following B-catenin Stabilization in between 'depressed' and control mice. Yet, Hippocampal Neurons 'depressed' mice had a higher frequency of somatic- patterned matches in spontaneous cortical activity, Fergil Mills¹, Thomas Bartlett¹, Lasse Dissing-Olesen¹, and the frequency of these was related to the FST Marta Wisniewska¹, Jacek Kuznicki¹, Brian Macvicar¹, and SPT. Discussion: A mouse model of depression is Yu Tian Wang¹, Shernaz Bamji¹ associated with increased frequency of spontaneous ¹University of British Columbia somatic-patterned cortical activity, a putative neurobiological underpinning of somatisation. The cadherin/β-catenin adhesion complex is a key mediator of the bidirectional changes in synapse 1-F-153 Cadherin adhesion complexes and cocaine- strength which are believed to underlie complex mediated synaptic plasticity learning and memory. In the present study, we Andrea Globa¹, Fergil Mills¹, Catherine Cowan¹, Shuai demonstrate that stabilization of β-catenin in Liu², Stephanie Borgland¹, Anthony Phillips¹, Shernaz the hippocampus of adult mice results in significant Bamji¹ impairments in cognitive flexibility and spatial reversal learning, including impaired extinction ¹University of British Columbia, ²University of Calgary during the reversal phase of the Morris Water maze and deficits in a delayed non-match to place T-maze Memory disorders are typically associated with the task. In accordance with this, β-catenin loss of memory, however pathological conditions can stabilization was found to abolish long-term also arise when the brain retains maladaptive depression (LTD) by stabilizing cadherin at the associations too powerfully. Exposure to addictive synaptic membrane and impairing AMPA receptor drugs elicits pathologic adaptations in many parts of endocytosis, while leaving basal synaptic the brain, specifically an LTP-like potentiation of transmission and long-term potentiation (LTP) excitatory synapses onto dopaminergic (DA) neurons unaffected. These results demonstrate that the in the ventral tegmental area (VTA). Cadherin cell β-catenin/cadherin adhesion complex plays an adhesion complexes are well suited to provide a link important role in learning and memory, and that between structural changes of the synapse and CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

aberrant increases in synaptic adhesion can have We present the case of a 31-year old patient who deleterious effects on cognitive function. perceived continuous simple hallucinations in a hemianopic field defect immediately following right 1-F-155 Disrupted docosahexaenoic acid occipital cortex stroke, which have remained metabolism in carriers of apolipoprotein E epsilon 4 unchanged over 2 years. We performed 1 Hz allele: is there a link with the risk of developing repetitive transcranial magnetic stimulation (TMS) to cognitive decline? the lesioned area for 30 minutes per day over 5 days in an attempt to suppress the perpetual Melanie Plourde¹ hallucinations. fMRI was performed prior to and after TMS treatment to assess plasticity changes. ¹Université de Sherbrooke Pre-TMS, the patient showed greater immediate Background: Over the last five years, our group activation at the boundary of the lesion compared to investigated imbalance in the metabolism of healthy controls; in the cuneus, lingual gyrus and docosahexaenoic acid (DHA) in humans and in surrounding areas. The associated "hyperactivity" transgenic mice carrying human apolipoprotein E corresponded to a reported perceptual increase in epsilon 4 (APOE4%2B) genotype. One of our visual hallucinations. During daily TMS sessions, the hypotheses is that rebalancing DHA metabolism perception of hallucinations was greatly reduced. could contribute to lower the risk of cognitive Post-TMS fMRI showed not only a suppression of decline in APOE4%2B. Objective: To overview activity in the previously associated regions of evidences collected from human and mice studies on "hyperactivity", but a redistribution of this activity to disturbed DHA metabolism in APOE4%2B compared surrounding regions, to a level similar to that of to APOE4-. Results: In APOE4%2B, DHA controls. A decrease in occipital activation with TMS concentration in plasma triglycerides was higher resulted in a decrease of frontal activity that is than APOE4-, but after a n-3 fatty acid consistent with our previous work, indicating supplementation, increase of DHA was lower than connections between ventral regions and the frontal APOE4-. Using 13C-DHA, APOE4%2B had 31% lower lobe. This case provides evidence of an infarct postprandial 13C-DHA compared to APOE4-. Our resulting in excitatory discharges at the border of the recent results in 4 and 13 month-old transgenic mice lesioned area which stimulate neighbouring areas, carrying human APOE4%2B showed that brain and thus result in abnormal visual perception. We uptake of 14C-DHA was 24% lower in APOE4%2B causally demonstrate that repetitive TMS provides a than APOE2 but cortex DHA was significantly lower valuable method of modulating hallucinations from in 13 month-old mice only. Plasma DHA was occipital injury or infarct. significantly higher in APOE4 mice than APOE2 1-F-157 Navigational strategies in young and older suggesting that lower brain uptake was not because adult Inuit hunters of lower availability of DHA in plasma. Recently, we prevented spatial and visual cognitive deficits in Devin Sodums¹ APOE4 mice by feeding a DHA diet compared to a control diet. Conclusion: Disturbed DHA metabolism ¹McGill University in APOE4%2B seems highly age-dependant. However, a diet rich in DHA seems to prevent Inuit hunters exhibit exceptional navigational skills. cognitive deficits in APOE4%2B mice. Therefore, Although researchers have described the ways in understanding why DHA metabolism if disturbed in which Inuit hunters navigate, such as by using the APOE4%2B will help in finding strategies for direction of winds, stars, landmarks, and snowdrifts, preventing or delaying onset of cognitive decline in we do not know the specific cognitive strategies this population. used. The use of these ever-changing features implies that they are constantly forming 1-F-156 Suppression of simple visual hallucinations relationships between their current location, from occipital stroke using TMS environmental features, and their destination. This process is the hallmark of the "spatial strategy". Sara Rafique¹, John Richards², Jennifer Steeves¹ Different strategies can be used to navigate, but we hypothesized that Inuit hunters use the spatial ¹York University, ²University of California, Davis, strategy to a greater extent. We also hypothesize Medical Center CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

that young Inuit hunters, because they rely more on aversion; and reaction times and reaching technology, use the spatial strategy to a lesser movements were primarily driven by reward and extent than older Inuit hunters. Nine healthy older expected value, respectively. In sum, our results Inuit men hunters and seven healthy young Inuit demonstrate that different measures within the men hunters, tested in Igloolik, Nunavut, took part in same economic decision making task can reveal the 4-on-8 virtual maze, an 8-arm radial maze. distinct behavioural biases. Our research sheds light Spatial learners use landmarks to learn the location on an often overlooked aspect of decision making of the objects in the maze, while response learners research-it is as important to consider how people use a sequence of right and left turns from a given physically make a choice as it is to measure what starting position or stimulus. As per our hypotheses, they chose. 87.5% of the elderly Inuit participants used a spatial strategy in contrast to only 39% of Southern 1-F-159 The role of parvalbumin-positive Canadians. Further, elderly Inuit participants used interneurons in memory consolidation spatial strategies to a greater extent than young adult Inuit hunters. Traditional occupations such as Frances Xia¹, Blake Richards², Sheena Josselyn¹, Kaori hunting seem to promote hippocampus-dependent Takehara-Nishiuchi², Paul Frankland¹ spatial memory in the Inuit, a strategy associated ¹Hospital for Sick Children, ²University of Toronto with healthy cognition. After a memory is initially encoded, it undergoes 1-F-158 Different measures of decisions yield consolidation, during which it becomes less reliant distinct information: Explicit and implicit measures on the hippocampus (HPC) and more dependent on reveal independent biases during economic the medial prefrontal cortex (mPFC). HPC decision making in a reaching task oscillations, called ripples, coincide with mPFC Nathan Wispinski¹, Christopher Madan², Craig oscillations, called spindles, and the spindle-ripple Chapman³ coupling is thought to facilitate memory consolidation. While parvalbumin-positive ¹University of British Columbia, ²Boston College, interneurons (PVNs) support spindles and ripples, ³University of Alberta whether they regulate the spindle-ripple coupling, and by doing so, modulate memory consolidation, is Decision making involves the neural accumulation unclear. Here, we combine the designer receptor and integration of evidence to make a choice approach with behavior experiments and in vivo between available options. Even the simplest recording in freely behaving mice, to manipulate decisions, such as deciding between an apple and an PVNs and investigate their role in memory orange, involve complex computations involving consolidation. PV-Cre mice were infused with Cre- sensory inputs, valuation, and memory; however, recombinase-dependent virus carrying the hM4Di real life decisions are often more complex and can receptor, allowing PVNs to be silenced by the involve additional factors, including risk and designer drug clozapine-N-oxide (CNO). Then mice ambiguity. That is, options that can have multiple were trained using contextual fear conditioning, and outcomes (risk) and the likelihood of outcomes can we silenced PVNs during the consolidation period. be uncertain (ambiguity). We investigated choice When mPFC PVNs were selectively silenced, mice biases during risky and ambiguous decision making showed memory deficits. To explore the using a simple reaching task, allowing us to collect electrophysiological mechanisms, we performed several behavioural measures. Participants reached simultaneous local field potential recordings in the to choose shapes that rewarded points with differing mPFC and HPC. Our preliminary data shows that probabilities (25%, 50%, and 75%), some of which inhibiting mPFC PVNs does not alter the density or they knew, and some they did not. Both explicit duration of spindles or ripples; however, spindle- (choices, questionnaires, and probability estimates) ripple coupling may be reduced. This suggests that and implicit (reaction times and reach trajectories) the mPFC PVNs are important in synchronizing the measures were recorded. Each measure revealed oscillations between HPC and mPFC, and interfering distinct results: probability estimates were relatively with their activity may disrupt the coherence accurate; early choices were biased by novelty- between the two regions, and impair memory seeking and later choices were sensitive to ambiguity consolidation. CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

resolution. To expand the toolbox of genetically encoded voltage indicators, we engineered two FP- 1-F-160 Prenatal Marginal Vitamin A Deficiency based voltage indicators: A bright Red fluorescent Facilitates Alzheimer's Disease Pathogenesis voltage indicator (FlicR1) and a green to red highlightable voltage indicator (FlicGR). We used Jiaying Zeng¹, Qian Chen¹, Zhen Fan¹, Li Chen¹, Tingyu directed protein evolution to screen libraries of Li¹, Weihong Song² thousands of variants to identify clones with sufficient brightness and response amplitude that ¹University of British Columbia, ²Children's Hospital would report membrane potential changes in of Chongqing Medical University mammalian cells. FlicR1 has voltage sensing Deposition of amyloid β protein (Aβ) to properties that are comparable to the best available form neuritic plaques in the brain is the pathological green indicators. It reports single action potentials in hallmark of Alzheimer's disease (AD). Mild or neurons in single trial recordings. Furthermore, marginal vitamin A deficiency (MVAD) is a serious FlicR1 can be imaged with wide field fluorescence and widespread public health problem in pregnant microscopy using a typical mercury arc lamp, and women and children in developing countries. There faithfully reports spontaneous activity in cultured has been increasing evidence for the involvement of hippocampal neurons and rat brain organotypic. We vitamin A in AD pathogenesis. However, the role of also demonstrate that FlicR1 can be used in vitamin A in the development of AD is not well conjunction with PsChR, a blue-shifted defined. Our studies in an elderly population have channelrhodopsin, for all-optical neuronal activation shown that vitamin A deficiency (VAD) could and activity recording. FlicGR is the first example of a enhance the risk to develop AD, and retinoic acid highlightable voltage indicator. A powerful receptors (RARs) plays an important role in the application of fluorescent proteins is their use as amyloid β precursor protein (APP) metabolic highlighters where they can be converted from one pathway. To further examine vitamin A's effect on color to another by light. Using blue light, we can AD pathogenesis, we established a prenatal MVAD photoconvert FlicGR from green to red. We model in APP/PS1 double-transgenic AD model mice. demonstrate that both the green and red forms are Our study showed that MVAD significantly increases sensitive to membrane potential changes in Aβ production by inhibiting ADAM10-mediated mammalian cells. α-secretase cleavage and increasing β- 1-G-162 RNA-Lipid Nanoparticles: A Robust and secretase (BACE1) cleavage of APP. MVAD Potent Tool for Gene Knockdown and Expression in significantly increased neuritic plaque formation and Primary Neurons aggravated spatial learning and memory deficits. Our findings provide a mechanistic explanation for the Aysha Ansari¹, David Zwaenepoel¹, Adam White², role of MVAD in AD pathogenesis and demonstrate Colin Walsh¹, Anitha Thomas¹, Timothy Leaver¹, the importance of retinoic acid signaling as a target Andre Wild¹, Yuping Li², Yu Tian Wang², James for AD therapy. Taylor¹, Euan Ramsay¹, Carl Hansen², Pieter Cullis²

G - Novel Methods and Technology Development ¹Precision NanoSystems Inc., ²University of British Columbia 1-G-161 Expanding the toolbox of genetically encoded voltage indicators The use of RNA to manipulate gene expression in neuroscience research is limited due to the lack of an Ahmed Abdelfattah¹, Samouil Farhi², Yongxin Zhao¹, effective delivery tool. Issues surrounding the use of Daan Brinks², Peng Zou², Araya Ruangkittisakul¹, viral vectors, electroporation, and lipofection Klaus Ballanyi¹, Adam Cohen², Robert Campbell¹ reinforce the demand for a more durable and less ¹University of Alberta, ²Harvard University toxic method to administer RNA into primary neurons. Here, we describe a solid-core lipid Optical imaging using voltage indicators based on nanoparticle (LNP) system, developed by employing green fluorescent proteins (FPs) has emerged as a the microfluidics-based NanoAssemblr platform, powerful approach for detecting the activity of many capable of delivering RNA into neurons in vitro and individual neurons with high spatial and temporal in vivo with high efficiency and low toxicity. CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

Treatment of primary neurons with siRNA-LNP expressing GABAergic interneurons in the lumbar results in > 85% gene knockdown which is sustained spinal cord induced mechanical but not thermal for 21 days after administration, even at a dose as hyperalgesia. Together, these results demonstrate low as 100 ng/ml of siRNA-LNP. This system affects the utility of our epidural optic fiber for the gene silencing even at DIV 2, providing flexibility optogenetic modulation of both sensory afferents over experimental design/setup. When exposed to and intrinsic spinal cord neurons, permitting studies mRNA-LNP, primary neurons exhibit >90% reporter of activity-dependent nociceptive sensitization and gene expression. The performance of these RNA-LNP the manipulation of sensory processing pathways systems is further characterized by looking at their within the spinal cord dorsal horn. effect on individual cells, by using a microfluidic device capable of conducting high-throughput single- 1-G-164 Optical Guidance for Deep Brain cell digital PCR. These single-cell studies are Stimulation Electrode Placement in the Treatment important to understand cell-to-cell heterogeneity in of Parkinson?s Disease terms of quantity of delivered RNA, and its correlation within a cell to changes in gene DePaoli Damon¹, Laurent Goetz¹, Martin Parent¹, Leo expression. The kinetics of LNP uptake and Cantin¹, Michel Prudhomme¹, Tigran Galstian¹, subsequent alterations in gene expression Younnes Messaddeq¹, Daniel Côté¹ demonstrate the potency of the developed RNA-LNP ¹University of Laval system. This technology, thereby, provides a simple and versatile solution to enable loss- and gain-of- Deep Brain Stimulation (DBS) surgery is a very function studies in difficult-to-transfect primary effective way to treat the motor symptoms of neurons. Parkinson's disease after standard medications, such as Levodopa, no longer have a positive effect. The 1-G-163 Epidural fiber optic implant for spinal surgery's effectiveness relies on the placing of a optogenetics in freely behaving animals stimulating electrode inside the brain with its tip Robert Bonin¹, Feng Wang¹, Mireille Desrochers- placed very precisely within a millimeter-sized region Couture¹, Yves De Koninck¹ called subthalamic nucleus (STN). Currently there is no onboard guidance for the stimulating electrode ¹Institut universitaire en santé mentale de Québec during the surgery, with only an x-ray projection as a means for navigation after the STN is located. Optogenetic tools enable the use of light to detect Onboard guidance would lead to decreased surgery and control neuronal activity with remarkable time, and increased accuracy. With this in mind, we temporal and cellular precision. Yet, the difficulty in have designed a cheap, optical fiber-based device delivering light to the spinal cord of awake, behaving that is small enough to be placed within animals has hampered the use of optogenetics in the commercially available DBS stimulating electrodes' study of spinal sensory processing. Accordingly, we hollow cores and is capable of sensing biological have developed an epidural optic fiber implant that information from the surrounding tissue using allows the delivery of light to the spinal cord dorsal diffuse reflectance spectroscopy. Using our device, horn and dorsal roots of sensory afferents. The we have shown the ability to sense the difference epidural optic fiber was implanted in adult mice that between white and grey matter both in vitro, in expressed the light-activated inhibitory opsin ArchT human and primate brain tissue, as well as in vivo, in in Nav1.8-expressing nociceptive afferents (Nav1.8- rats. With the current probe, we can already ArchT) and in wildtype C57Bl/6 mice. Amber light theoretically provide increased accuracy and (592 nm) inhibited acute thermal nociception in the efficiency during neurosurgery; however, there is a Nav1.8-ArchT mice, but did not affect nociception in high ceiling for increased utility using optical C57Bl/6 mice. The acute delivery of blue light (488 enhancements. We are currently designing probes nm) to the lumbar spinal cord of mice that with micro-optical components that can drastically selectively express channelrhodopsin (ChR2) in increase the axial resolution of our device and thus, Nav1.8+ afferents (Nav1.8-ChR2) produced will give it the ability to identify even smaller nocifensive behaviour, while repeated activation of structures within the brain, with increased precision. Nav1.8+ afferents in these mice induced long-lasting mechanical hyperalgesia. Finally, inhibition of ArchT- CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

1-G-165 Modeling by finite element method of ion axon numbers and diameters. We demonstrated this concentration fluctuations in dendritic spines and method with lesions in the animal model of multiple the extracellular space sclerosis, experimental autoimmune encephalomyelitis (EAE). Next, we analyzed the local Ibrahima Dione¹, Nicolas Doyon¹, Yves De Koninck¹ organization and structure of myelinated axons in the splenium of human corpus collosum. We ¹Universite Laval demonstrated that our method provides an accurate description of nerve fiber morphology and To understand the principles that govern the myelination. changes in electrical potential and ion concentrations in dendritic spines and the 1-G-167 AAV-compatible MiniPromoters Target extracellular space, we propose mathematical Specific Cell Types of the Central Nervous System modeling using the finite element method that provides outstanding spatial and temporal Andrea Korecki¹, Charles de Leeuw¹, Siu Ling Lam¹, resolution. We will consider the Poisson-Nernst- Garrett Berry², Jack Hickmott¹, Tess Lengyell¹, Russell Planck equations in order to understand how the Bonaguro¹, Lisa Borretta¹, Alice Chou¹, Olga phenomenon of 'crosstalk' comes regulate synaptic Kaspieva¹, Stephanie Laprise¹, Simone McInerny¹, spines and dendritic impact the integration of Elodie Portales-Casamar¹, Magdalena Swanson- signals. This model will also allow us to study the Newman¹, impact of the extracellular geometry on the accumulation of ions. ¹University of British Columbia,²University of North Carolina, ³Simon Fraser University 1-G-166 Label-free microscopy to infer nerve fibers morphology and myelination in structurally Purpose: Small promoters that drive cell-type complex samples restricted expression in the CNS are important tools for basic and clinical research, and may be critical for Alicja Gasecka¹, Steve Begin¹, Daniel Cote ¹ future gene therapies. Here, we have focused on the development of such promoters for use in ¹Quebec Mental Health Institute Research Centre recombinant adeno-associated virus (rAAV). We tested the hypothesis that CNS-restricted Pleiades Understanding mechanisms of neurodegenerative Promoters, which were developed using single-copy diseases, developing effective diagnostic strategies site-specific knock-in mice, would retain selectivity and comparing treatment methods often require the when used in rAAV. Methods: Promoters were investigation of nervous system cells morphology. typically cloned into a "plug and play" rAAV genome Widely used magnetic resonance imaging techniques plasmid driving: icre (improved), emGFP (emerald), constantly report new alterations of white matter in or MiniSOG; with or without WPRE (a transcript various brain regions. Although very successful, they stabilizer). 50 μL of rAAV2/9 at 10E13 genome lack the spatial resolution to infer myelin integrity at copies/mL was injected into the temporal vein of the cellular level. Recently demonstrated Coherent neonatal mice. For icre, the injected mice carried the anti-Stokes Raman Scattering (CARS) microscopy has Gt(ROSA)26Sortm1Sor allele, which responds to cre accomplished cellular level, label-free imaging of by rearranging the genome to express lacZ. myelin sheaths in the nervous system. However, a Expression was analysed in adults using whole quantitative morphometric analysis of nerve fibers mount or cryosections for lacZ, and cryosections for still remains a challenge especially in brain tissue immuno detection of emGFP or MiniSOG. Results: where fibers exhibit very small diameters (~1-3µm). We tested 29 experimental viruses carrying 19 In this work, we developed an automated myelin different MiniPromoters designed from 17 genes. identification and analysis method that is capable of Four MiniPromoters were tested with both icre and providing a complete picture of axonal myelination emGFP, and three with and without WPRE. Of the and morphology at the microscopic scale in experimental viruses, 24 (83%) showed specific CNS structurally complex samples. This method performs expression. Positive results were independent of three main procedures - extracts molecular reporter and WPRE, although the WPRE anisotropy of membrane phospholipids using CARS strengthened expression. Conclusions: The Pleiades images, identifies regions of different molecular MiniPromoters represent a rich resource of human- organization, and finally calculates myelin thickness, CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

DNA promoters, compatible with rAAV, able to 90% demonstrate evidence of cerebral small vessel express in the CNS, and useful for research and dysfunction including deposition of amyloid beta clinical applications. (Ab) within the vascular wall. This Aβ deposition is associated with cerebrovascular and 1-G-168 Hyperspectral imaging to track blood-brain barrier dysfunction. Little is known simultaneously the spatial dynamics of multiple about the mechanisms by which vascular risk factors subtypes of individual proteins on live neurons for AD lead to cerebral small vessel dysfunction. The potential magnitude of this knowledge gap is put Simon Labrecque¹, Jean-Philippe Sylvestre², into perspective when one considers that every Stéphane Marcet², Francesca Mangiarini², Marc neuron is partnered with its own capillary. The need Verhaegen², Sebastien Blais-Ouellette³, Paul De to better understand cerebral small vessel function Koninck¹ and dysfunction in dementia appears therefore of particular interest. ¹Universite Laval, ²Photon Etc., ³Photon Etc We recently developed a unique human based tissue The efficacy of existing therapies and the discovery engineering approach to develop a 3D functional of innovative treatments for Central Nervous System model of the cerebrovasculature, which is composed (CNS) diseases have been limited by the lack of of either vascular smooth muscle (SMC) and appropriate methods to investigate complex endothelial cells (EC) or astrocytes, SMC and EC molecular processes at the synaptic level. In order to culture under native like flow conditions in vitro. better understand the fundamental mechanisms Upon anteluminal injection, Aβ42 is that regulate synaptic signaling and remodeling, we accumulated within the tissue in a time and dose designed a fluorescence hyperspectral imaging dependent manner. A subsequent activation of the platform to track simultaneously different subtypes endothelium is measured by adherence of circulating of individual neurotransmitter receptors trafficking monocytes. In conclusion, the described tissue in and out of synapses. This new imaging platform engineered human vascular equivalent model allows fast simultaneous image acquisition of at least represents a significant step towards a relevant in five fluorescent markers in living neurons with a high vitro platform for the systematic assessment of spatial resolution. We used quantum dots of pathogenic processes in AD independently of any different emission wavelengths, functionalized to systemic factors. specifically bind single receptors on the membrane of living neurons, and quantified their mobility 1-G-170 Two-photon optogenetics with near- following treatments with various pharmacological infrared light-activated cyclases for studying the agents. This hyperspectral imaging platform enabled role of cAMP and cGMP in living neurons the simultaneous optical tracking of five different synaptic proteins, including subtypes of glutamate Megan Valencia¹, Thomas Luyben¹, Kenichi receptors (mGluR, NMDAR, AMPAR), postsynaptic Okamoto¹ density proteins, and signaling proteins. This technique provides an effective method to monitor ¹University of Toronto several synaptic proteins at the same time, which should accelerate the screening of effective Optogenetics provides powerful tools to non- compounds for treatment of CNS disorders. invasively manipulate neural activity by light. However, for studying intracellular signaling 1-G-169 Development of a novel tissue engineered mechanisms involved in synaptic function, these model of the cerebrovasculature tools are not yet well established. Here, we describe two-photon optogenetics with far-red light-activated Jerome Robert¹, Sophie Stukas¹, Cheryl Wellington¹ cyclases for elucidating the role of intracellular messengers cAMP and cGMP in the synapses of ¹UBC living neurons. To dissect the role of cAMP in synaptic plasticity, we utilized a bacterial The complex interrelationship between photoactivatable adenylate cyclase (PAC) which cerebrovascular dysfunction and Alzheimer's Disease produces cAMP in response to blue light. We (AD) is increasingly appreciated. Indeed 30% of AD demonstrated photoactivation of PAC at the single patients have cerebral infarcts at autopsy, and up to CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

synapse level by two-photon excitation light in the Allen Mouse Brain Connectivity Atlas and cultured hippocampal slices. We also examined a far- comparing these to the spike evoked maps, we red light-sensitive adenylate cyclase (NIR-PAC), a observed strong spatial co-localization. Within a fusion of the photosensory PAS-GAF-PHY domain functional domain, single neuron firing is linearly and the catalytic domain of adenylate cyclase (Ryu et correlated with regional calcium imaging, indicating al., 2014). By mutating the enzymatic pocket of NIR- how single neurons relate to large networks. Spike PAC, we engineered a far-red light-sensitive evoked maps should be useful for assessing the guanylate cyclase (NIR-PGC). We excited each functional relationship between single neurons and cyclase with LED light (660 nm peak) in vitro and wide-field activity in in vivo models of neurological measured cAMP or cGMP levels by ELISA. disease Intracellular messenger levels were raised within seconds after light stimulation, indicating rapid 1-G-172 High yield and purity of primary astrocyte photoactivation. We then examined enzymatic and microglia cultures from embryonic mouse and activity across the two-photon excitation spectra in rat cerebral cortex vitro. Longer wavelengths (1040 nm) activated both NIR-PAC and NIR-PGC, suggesting the possibility for Adam Yu¹, Sarah Neil¹, Jacqueline Quandt¹ co-application with PAC (750 nm peak). We will ¹University of British Columbia discuss how these two-photon optogenetic technologies serve as valuable tools for studying The study of disease-related processes and pathways cAMP and cGMP in the synapses of living neurons. is often done using primary cultures to best preserve characteristics seen in vivo. This study presents a 1-G-171 Point source networks: correlation cost-effective and simple protocol to culture both between local firing properties and regional cortical astrocytes and microglia from E18 primary cortical imaging in mouse cortex neural progenitor cells of rat or mouse origin with Dongsheng Xiao¹, Matthieu Vanni¹, Allen Chan¹, high yield and purity. Cortical cells are isolated Timothy Murphy¹ aseptically according to Aiga et al. (2011). Single cell suspensions were plated at 250,000 cells/cm2 on ¹Brain Research Centre, The University of British poly-L-lysine coated plates, and non-adherent cells Columbia removed 24h later. Astrocytes at days 14-21 in vitro (DIV) are enriched by media exchange every 3 days A more complete understanding of brain function and expanded until confluent and cells exhibit will require measurement techniques which monitor elongated/stellate morphology. For microglia, media large-scale neuronal activity across multiple brain exchange occurred DIV3 with or without addition of areas and relate this to single neuron properties. We granulocyte-macrophage colony stimulating factor. present a step towards achieving this aim: by Microglia appear by DIV14 and enrich to DIV21. simultaneous in vivo recording of cortical/subcortical Astrocytic layers show >95% purity with positivity for single unit activity and wide-field cortical imaging glial fibrillary acidic protein. Harvested microglia during spontaneous activity. We use glass pipettes to yield ~400,000 cells per 25 cm2 flask. Flow cytometry record single unit activity in target sites, and use shows >99% purity by OX42 (rat) and CD45/CD11b wide-field cortical imaging (GCaMP) to determine (mouse) staining. Murine microglia were further large-scale neuronal activity. By employing spike- characterized as CD45lo, CD80%2B, MHC I,IIlo, triggered averaging we established correlation CD40%2B, CD11b%2B, CD11clo and CD86%2B. between single neuron firing and regional cortical Lipopolysaccharide enhanced expression of OX42 in calcium imaging. We apply the method in cortex and rat, and CD80, CD40, CD11b, MHC I and CD86 in mice establish expected regional maps that are associated microglia, along with precise temporal with activity at single cortical points. Extension of the morphological changes. Experiments are ongoing to electrophysiological assessment to sub-cortical establish the relative activation states and structures permits the relations between these immunological profile of these cells. This method regions and maps of cortical activity to be provides a reliable, simple and cost-effective means determined. We find that wide-field regional calcium to obtain highly purified glial cultures in high yield. imaging is highly correlated with spiking activity from neurons. By examining axonal projections maps in CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

IBRO – International Brain Research Organisation encouraging potential for neurodegenerative and acute brain diseases treatment. NSC can migrate to CNS injury answering to chemotactic factors like 1-IBRO-173 Peer rescue of autism-related CXCL12. Despite the NSC capacity to generate behavior after prenatal exposure to valproic acid newborn neurons to different CNS areas, the most of neural stem cells undergo apoptosis after arrive at Marcos Campolongo¹, Nadia kazlauskas¹, Amaicha lesion site. CXCL12 or SDF-1 (stromal cell-derived Depino¹ factor 1) is a chemotactic cytokine and together with its CXCR4 receptor are constitutively and broadly ¹Institute of Phisiology, Molecular Biology and expressed in many tissues. Together with cytokines Neuroscience (IFIBYNE) and chemokines, matrix proteases are also released Autism is a severe neurodevelopmental disorder in brain injury states and activated to contribute for characterized by impediments in social interaction, a breakdown of the extracellular matrix and reduction in communicative skills and by consequent cell migration. Among those, matrix stereotyped behaviors. Symptoms appear in early metalloproteases 2 and 9 (MMP-2 and 9), gelatinase childhood and persist in adulthood. Currently there A and B, respectively, are secreted locally and could are no pharmacological treatments, but several cleave CXCL12 removing the first four N-terminal clinical studies suggest early social stimulation as the aminoacids generating CXCL12(5-67). We produced most effective treatment of autistic children, who CXCL12 and CXCL12(5-67) recombinant proteins, and show significant improvements in social behavior evaluated its effect on mice astrocytes and NSC in through these approaches. It was previously shown vitro. We identified that CXCL12(5-67) impairs neural that the mouse prenatal exposure to valproic acid stem cell migration, reduces astrocytes viability and (VPA) at gestational day 12.5 results in reduced induces apoptosis through caspases 9 and 3 social interaction in the adult offspring. In those activation in adult neural stem cell. A possible experiments VPA-treated mice were weaned with CXCL12(5-67) involvement in a low CNS regeneration other VPA mice. Here, we compared VPA mice capacity could became it a target for trauma and weaned with VPA mice (VPA-VPA mice) with VPA- neurodegenerative disease treatment. Saline groups (VPA-Sal), containing 2-3 VPA-exposed 1-IBRO-175 Acute stress increases FMRP levels mice per cage along with 2-3 Saline mice. This design in hippocampus and promotes Akt-mTOR and allowed VPA and Sal mice to interact in the home MAPK1/2 pathways activation in rats cage from postnatal day (P)21 to P60. At P60, VPA- Sal mice showed higher levels of sociability than Felipe Aguayo¹, Paulina Rojas², Aníbal Pacheco¹, VPA-VPA, showing that this treatment can rescue at Gonzalo Gracía-Rojo¹, Mauricio Muñoz-Llanoz¹, least some of the behavioral alterations observed in Alexandra García-Pérez¹, Ruth Márquez¹, Jenny our model. On the other hand, there are evidences Fiedler¹ to suggest that patients with autism have alterations in stress and inflammatory responses. We have ¹Facultad de Ciencias Químicas y Farmacéuticas, previously identified alterations in inflammatory and Universidad de Chile, ²Universidad Andrés Bello stress response after inflammatory stimuli in VPA mice. We therefore studied whether these Acute stress enhances learning and memory alterations are reversed in rescued animals. acquisition probably mediated by stress released corticoids. These hormones promote modifications 1-IBRO-174 Proteolytic processing of CXCL12 in morphology, cellular excitability and synaptic transforms CXCL12 into a death factor for neural efficacy in hippocampus. These processes involve stem cells mRNA transport to dendrites and local control of translation process. In line with this, the Fragile X Taís Adelita¹, Roberta Stilhano¹, San Han¹, Giselle Mental Retardation Protein (FMRP) acts suppressing Justo¹, Marimelia Porcionatto¹ translation of mRNAs encoding proteins involved in the regulation of synapsis. FMRP is phosphorylated ¹UNIFESP by S6K1 at Ser499 (p-FMRP), a modification required The neural stem cells (NSC) resident in mammalian for mRNA translational repression and its association adult central nervous system (CNS) represent an with stalled polyribosomes. In neuronal cultures, the CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

activation of mGluR1/5 type glutamatergic receptors regulatable promoter. This vector will be used to promote FMRP Ser499 phosphorylation by S6K1 implement direct cell reprogramming in a non- trough PI3K-AKT-mTORc1 and MAPK ERK1/2 integrative fashion. We describe the direct pathways in a different temporal pattern. We reprogramming protocol that we plan to use to proposed that acute restraint stress regulates FMRP convert fibroblasts into NPCs, which will be phosphorylation in rat hippocampus, event related subsequently used for experimental cell therapy in to activation of PI3K-AKT-mTORc1 and MAPK ERK1/2 the hippocampus of AR. pathways. Adult male rats were stressed by restraint during 0.5 or 2.5 h, and to evaluate the posterior 1-IBRO-177 Relative Expression of Odorant effects of stress another group was sacrificed after Binding Proteins in the Forest Tsetse fly Species 1.5; 6 and 24 h post stress. It was determined that Glossina brevipalpis restraint stress did not change p-FMRP levels. However at 0.5 hours of stress session there was an Mary Murithi¹, Rosaline Macharia², Esther Magiri¹, increase in FMRP protein levels, which was Steven Nyanjom¹, Daniel Masiga² coincident with the AKT activation. These findings ¹Jomo Kenyatta University of Agriculture and suggest that stress activates translational processes Technology, ²International Center Of Insect and FMRP acts as a negative modulator in Physiology and Ecology hippocampus. Glossina brevipalpis is a forest Tsetse fly species that 1-IBRO-176 Cognitive studies and a direct cell vectors Animal African Trypanosomiais. Olfaction is reprogramming protocol for the aging rat brain crucial for vital tsetse fly behaviours such as feeding, Micaela López-León¹, Gustavo Morel¹, Maia Uriarte¹, con specific mate selection and identification of Marianne Lehmann¹, Rodolfo Goya¹ larviposition sites. Odorant binding proteins (OBPs) are involved in the peri-receptor events in odour ¹National University of La Plata transmission. Identification of OBPs in various tsetse fly species has been achieved through annotation. We use the aging rat (AR) as a model of age-related However, little expression studies have been carried cognitive decline and plan to use cell reprogramming out.This study reports for the first time the as a restorative intervention in their hippocampus. expression profile of selected G. brevipalpis OBPs in We assessed the extent of spatial memory (SM) 3rd instar larvae, pupae and wild females starved at impairment in 26 (old), 31 (senile) and 5 (young) different periods; 2h, 24h,48h,72h and 96h post months female rats as well as the age-related blood meal. Expression profiles were analysed by changes in their dorsal hippocampus. Age changes in quantitative real time PCR. Anternnal OBP SM performance were assessed with the Barnes expression in the wild female G.brevipalpis was maze test. We employed two probe trials, 1 and 5 significantly high at 24h starvation period. Some days after training, in order to evaluate "short-term" OBPs were expressed in the larva and pupal stages and "middle-term" SM. The results revealed that old suggesting that they might be involved in the flys' rats perform better than senile rats in acquisition development. The findings from this study could give trials and young rats perform better than both aging insight on genes that could be targeted in the groups. Morphological analysis of the dorsal development of specific and environmentally hippocampus showed a marked decrease (94-97%) friendly approaches targeting the tsetse fly. in doublecortin neuron number in the dentate gyrus Keywords: Glossina brevipalpis, olfaction, odorant in both aging groups. It has been recently binding proteins, quantitative real time PCR demonstrated that transient induction of the four pluripotency genes oct4, sox2, klf4 and c-myc (the 1-IBRO-178 Impaired autophagy associated Yamanaka genes), followed by appropriate signalling with glucose deprivation induces neuronal death inputs, can efficiently transdifferentiate fibroblasts through subsequent autophagy activation. into neural stem/progenitor cells (NPCs). We report here the ongoing construction of a helper- Cristian Geronimo-Olvera¹, Teresa Montiel¹, Lourdes dependent recombinant adenovector for the Massieu¹ simultaneous expression of hGFP and the Yamanaka ¹Universidad Nacional Autonoma de Mexico genes all under the control of a bidirectional Tet-Off CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

Insufficient glucose supply to the brain results in the alterations in young adult rats and examined the impairment of neuronal function and neuronal hypothesis that the MD plays a role in the dendritic death. Hypoglycemia occurs as a complication of development of pyramidal cells in the PFC. Rat pups insulin treatment in diabetic patients, leading to at postnatal day four were randomized in 3 groups: brain glucose deprivation (GD). The cellular group 1 received bilateral electrolytic lesion of MD, mechanisms that ultimately lead to neuronal death group 2 with MD Sham lesion and group 3 without have not been completely elucidated and the role of any surgery Seven weeks later, all rats were tested autophagy remains unknown. Autophagy is a with the following behavioral and cognitive lysosome-mediated catabolic mechanism paradigms: open field test, elevated plus maze test, characterized by the appearance of double- social interactions test, passive avoidance test and membrane vesicles and the conversion of LC3-I to dorsal immobility. After the behavioral testing, then LC3-II. The role of autophagy is to maintain the we examined dendritic morphology, apical dendrite cellular homeostasis and supply energy in response number and spine density in several cortex areas, to starvation. However, excessive autophagy can which receive afferents from the MD by using Golgi lead to cell death. In this study we analyzed the technique. Our findings suggest a functional role for progress of autophagy along GD and glucose MD in the postnatal maturation of affective reperfusion periods (GR) and investigated its role on behavior. Further some of the behavioral and neuronal death. Cortical cultures exposed to GD and cognitive alterations observed in these young adult GR showed enhancement of LC3-II and accumulation rats after early MD lesion are reminiscent of those of autophagosomes during GD. When glucose is present in major psycho-affective disorders, such as reintroduced, LC3-II and p62 levels decrease at first schizophrenia in humans stages of GR, suggesting the completion of the autophagic flux, but during late stages of GR a 1-IBRO-180 Role of IL-10 in macrophage second peak of autophagosome accumulation polarization and recovery after peripheral nerve occurs. Results suggest that autophagy is impaired injury during GD, but the autophagic degradation occurs as soon as ATP recovers during GR. Partial inhibition of Bruno Mietto¹, Antje Kroner², Elizabeth Girolami², Ji autophagy by 3-MA or Atg7 siRNA reduces GD/GR Zhang³, Samuel David² damage. Moreover, inhibition of autophagic flux ¹Federal University of Rio de Janeiro, ²Montreal during GR increases cell survival. Results suggest that General Hospital, ³Alan Edwards Centre for Research autophagosome overload during GD triggers a on Pain subsequent degradation and autophagy induction during GR that contribute to neuronal damage. Wallerian degeneration (WD) is tightly regulated in injured axons and is crucial to provide a permissive 1-IBRO-179 Evidence for a decrease of microenvironment for axon regrowth. Macrophages pyramidal cells dendrites in neonatal thalamic enter the distal segment of injured nerve within lesioned rat?s prefrontal cortex: implication in about 2-3 days, remove tissue debris by 7-14 days, Schizophrenia and are cleared from the tissue by 3-4 weeks. An Zakaria Ouhaz¹, Saadia Ba-M’Hamed¹, Mohamed important feature of the peripheral nerve is the Bennis¹ rapid switching-off of the pro-inflammatory response, likely by anti-inflammatory cytokines in ¹Université Cadi Ayyad, Faculté des Sciences Semlalia the first 2 weeks after injury. However, the role of these "brakes" has not been fully studied after nerve Normal development of the cerebral cortex is injury. The aim of this study was to assess the dependent upon reciprocal connections with the expression profile of IL-10 after nerve injury and to thalamus. Therefore, understanding the role MD analyze how this cytokine affects the macrophage plays in the development of the PFC is important and responses and resolution of nerve inflammation. WT may help in understanding the progression of and IL-10 null mice underwent sciatic nerve crush psychiatric disorders that have their root in and the nerves were collected after varying lengths development. The present study assessed whether of time after injury. Macrophage polarization was early postnatal damage to mediodorsal nucleus of assessed by using a panel of M1 (CD16/32, CD86) the thalamus (MD) causes behavioral and cognitive and M2 markers (CD163, Arg1, CD206). We observed CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

that the lack of IL-10 resulted in higher number of provide detailed function of the robo3 gene in macrophages in the distal nerve segment at 3, 14 Xenopus and highlight functional differences and 21 dpi. Moreover, in the IL-10 null mice, there between lower vertebrate and mammalian ROBO3. was greater M1 and reduced M2 polarization in vitro and in vivo. A chemokine/cytokine PCR array of the 2-A-2 Survival and maturation of the nerves obtained from IL-10 null mice showed 2 to 4- developmentally-born cell population in the rat fold increase in the levels of ten pro-inflammatory dentate gyrus. mediators. Moreover, our data show that in the absence of IL-10, the increased pro-inflammatory Shaina Cahill¹, Ru Qi Yu¹, Dylan Green¹, Jason Snyder¹ milieu of the injured nerve leads to impairment of ¹University of British Columbia axon regeneration and loss of functional recovery. In the dentate gyrus, adult-born neurons have

enhanced plasticity and contribute to the mnemonic POSTER SESSION 2 and emotional functions of the hippocampus. While the stages of adult neurogenesis and the factors that A – Development regulate neuron addition in adulthood have been relatively well-characterized, less is known about 2-A-1 TALEN- and CRISPR/Cas9-mediated how developmentally born cells integrate and disruption of the robo3 gene in Xenopus tropicalis survive over time. Since the dentate gyrus is comprised of large numbers of adult-born and Anteneh Argaw¹, Dietmar Schmucker¹ developmentally-born cells, identifying the properties of these populations is essential for ¹VIB understanding how the dentate gyrus contributes to behavior. To address this question we used BrdU to Developing axons, tipped at their distal end by the label dentate gyrus neurons born on postnatal day 6 growth cone (GC), navigate through relatively long in rat pups, the peak of dentate gyrus development. distances in a highly directed manner to establish We quantified BrdU%2B cells in 2 and 6 month-old functional synapses with their targets. Intermediate rats and found 20% fewer BrdU%2B neurons at the 6 targets like the ventral midline play an important months, indicating substantial loss of mature, role by steering the GC by means of attractive developmentally-born cells throughout adulthood. and/or repulsive mechanisms. In mammals, netrin- This contrasts with adult-born cells, which show 1/DCC which attracts axons and slit/ROBO which stable survival after reaching maturity. We repels GCs play a major role by regulating additionally examined the survival and maturation of commissural axon midline crossing. Commissures fail developmentally-born cells at earlier timepoints, to develop in mice and humans in the absence of the similar to past work done in characterizing adult transmembrane receptor ROBO3 which appears to neurogenesis. We found that developmentally-born be the master regulator of midline crossing in cells are stable during development and have a mammals. To investigate in detail the function of prolonged period of loss into adulthood. Collectively, robo3 in lower vertebrates, we have generated the our findings indicate that the survival and turnover first Xenopus tropicalis mutant robo3 alleles using of developmentally-born cells influences the TALENs and CRISPR/Cas9 based genome engineering composition of the adult dentate gyrus. These techniques. After germline transmission multiple F1 findings are relevant for understanding the role of animals were obtained and are currently interbred. the dentate gyrus in learning and memory and in Phenotypic analysis will be performed in F2 diseases where neurons are lost. homozygous mutant animals where hindbrain and spinal commissural neurons will be sparsely labelled 2-A-3 Role of Cux factors in cerebellar by electroporating reporter transgenes. To compare development robo3 function in lower vertebrate and mammals, we will perform rescue experiments using ROBO3 Emily Capaldo¹, Angelo Iulianella¹ chimera with specific substitutions in the first immunoglobulin domain unique to mammalian ¹Dalhousie University ROBO3. Taken together these experiments will CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

The cerebellum has been known to be highly may affect the expression level of MR and GR involved in motor coordination, but more recently it proteins of control (C), pair-fed (PF), and PAE fetal has been implicated in various congenital and brains and placentae at gestational day 21. We acquired developmental conditions, including autism found that PAE resulted in differential expression of spectrum disorders. Although the anatomy and MR and GR proteins compared to that of C and PF connectivity of the adult cerebellum have been animals. PAE resulted in increased GR protein levels known for decades, the developmental origin of and an increased GR/MR ratio in the medial each cell type is only beginning to be understood. prefrontal cortex and amygdala, respectively. The numerous conditions associated with aberrant Furthermore, PAE induced a loss of sexually cerebellar development, such as the growth of dimorphic expression of MR in the amygdala, medulloblastomas, highlights the importance of hippocampus, and placenta, suggesting that PAE understanding the mechanisms controlling the may result in a decreased sensitivity to the development of this highly proliferative brain region. organizational effects of androgens. Our results The transcription factor Cux2 has been hypothesized indicated that PAE altered important regulatory to define a specific subset of neural progenitors in components of the HPA axis, setting the stage for various regions of the nervous system, including the increased risks for mental and behavioural issues cortex, hippocampus and spinal cord, but its role in later on in life. Funded by NIH/NIAAA R37 AA007789, the cerebellum is unknown. We used an inducible R01AA022460 and NeuroDevNet to JW; NSFC (China) transgenic mouse line that labels Cux2-expressing 31100793 and IMPART (CIHR) Fellowship to NL. progenitors to delineate the ontogeny of cerebellar precursors. We discovered that Cux2 activity was 2-A-5 Inflammation dysregulates neural circuit restricted to the developing rhombic lip region of the formation in vivo via microglial activation and IL-1β mid-hindbrain junction, and subsequently fate- mapped their descendants to the external granule Nasr Farooqi¹, Edward Ruthazer¹ layer and granule cells that radially migrate inwards ¹Montreal Neurological Institute during cerebellar development. These findings support the view that Cux2 expression delineates a Converging evidence implicates immune activation fate-restricted neural progenitor, and within the in the etiology of neuropsychiatric disease. Little is cerebellar primordia its activity is largely restricted known about the links between immune activation to granule cell formation. and neural circuit formation. We investigate these links by exposing larval zebrafish to bacterial 2-A-4 Prenatal Alcohol Exposure Alters lipopolysaccharide (LPS) to induce inflammation and Expression of Glucocorticoid and Mineralocorticoid subsequently observing neuronal development. LPS Receptor Levels in the Placenta and Fetal Brain at induces inflammatory cytokine (TNFα, IL- Gestational Day 21 1β, IL-6) transcription within two hours and Melissa Chiu¹, Ni Lan¹, Joanne Weinberg¹ induces an amoeboid microglial morphology suggesting microglial activation. In vivo two-photon ¹University of British Columbia microscopy of retinal ganglion cells (RGCs) demonstrates that two-hour LPS exposure acutely The hypothalamic-pituitary-adrenal (HPA) axis plays increases rates of axonal branch addition and a key role in the mediation of the stress response. retraction. This hyperdynamic remodelling may Prenatal alcohol exposure (PAE) can result in a reflect failure to stabilise synapses. Daily imaging of hyperresponsive HPA axis, which could leave an axons after LPS exposure reveals a shift in individual vulnerable to stress-related disorders such developmental trajectory with smaller, simpler as depression and anxiety later in life. The activation arbors and fewer presynaptic puncta. Microglia are of the HPA axis causes the secretion of key immune regulators of the CNS and we glucocorticoids, which feed back on the stress- hypothesised that they mediate inflammatory responsive neurocircuitry via mineralocorticoid effects on neurons. Morpholino knockdown of the receptors (MR) and glucocorticoid receptors (GR). SpI1/Pu.1 transcription factor depletes the myeloid Currently, the mechanism by which PAE results in lineage; morphant animals lack microglia and HPA hyperresponsiveness is not fully understood. macrophages. RGCs in Spi1/Pu.1 morphants exposed Utilizing an animal model, we investigated how PAE to LPS do not demonstrate the acute or lasting CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

perturbations seen in control animals. Morpholino Vickie Kwan¹, Susan Walker², Stephen Scherer², knockdown of IL-1β phenocopies the effect of Karun Singh¹ myeloid depletion. Microglial activation and/or IL- 1β may therefore mediate developmental ¹McMaster University, ²The Hospital for Sick Children effects of inflammation. We are currently analysing whether IL-1β acts upstream or downstream Emerging studies suggest that molecules in the Wnt of microglia in this process. Funding: CIHR Vanier signalling pathway are important for the CGS (NAIF); CIHR (ESR). development of neural connectivity and are associated with autism spectrum disorders (ASD). 2-A-6 The requirement for the Rb Family during We are studying a Wnt signalling molecule named Adult Neurogenesis DIX domain containing-1 (DIXDC1), a homolog of Disheveled. Using mouse in vitro and in vivo models, Bensun Fong¹, Renaud Vandenbosch², Devon preliminary results show that decreasing expression Svoboda¹, Alysen Clark¹, David Park¹, Ruth Slack¹ of DIXDC1 reduces dendritic outgrowth, and spine formation. We also found that MAP/microtubule ¹University of Ottawa, ²University of Liege affinity-regulating kinase 1 (MARK1), a kinase associated with ASD, phosphorylates DIXDC1 to During adult neurogenesis, the regulatory function mediate these effects. Preliminary data indicates of the Rb family - pRb, p107 and p130 - remains that the MARK1-DIXDC1 pathway regulates neural presently unclear. While p107 is required for neural connectivity by directly modulating actin dynamics. precursor cell (NPC) self-renewal and commitment, We found that the loss of DIXDC1 inhibits actin and Rb is required for neuronal quiescence and dynamics, and application of an actin polymerization survival, complications in data interpretation arise drug rescues abnormal dendritic spine phenotypes. from compensation between family members. In Furthermore, through exome sequencing, we order to address the function of the Rb family in discovered two rare inherited genetic variants in regulating NPC proliferation and differentiation, all DIXDC1 in patients with ASDs. Interestingly, three pocket proteins were inducibly deleted from expression of these variants in neurons causes the adult subgranular zone (SGZ) in the hippocampus impaired dendrite outgrowth and spine morphology. using the NestinCreERT2 mouse model. Four weeks This suggests the MARK1-DIXDC1 interaction is following protein deletion, brains were analyzed involved in a novel pathway for synaptic using immunohistochemistry. Triple knockout (TKO) development and its function may be disrupted in animals demonstrate a dramatic expansion of the ASDs. We are interested in identifying drugs and recombined cell population as marked using YFP. other compounds that target the actin cytoskeleton Within this recombined population, there is a network to rescue spine defects when the MARK1- significant increase in the number of cells expressing DIXDC1 pathway is inhibited. We are developing a markers for self-renewal and proliferation, high-throughput imaging assay to perform drug concomitant with a decreased in the number of cells screens to identify chemicals that modulate synaptic expressing markers for neuronal commitment and phenotypes for the development of novel maturation. This suggests that loss of the Rb family therapeutics for ASDs. leads to the development of an increased neural precursor pool, unable to commit to a mature neuronal fate: demonstrating a requirement for the Rb family in maintaining a balance between NPC 2-A-8 Inter-neuronal interaction defines proliferation and commitment. This study will define topographic synaptic innervation in C. elegans the mechanisms by which the Rb family pocket proteins regulate the NPC population. This Kota Mizumoto¹ understanding is crucially important in developing future therapeutic tools for regeneration therapies. ¹University of British Columbia This research is supported by a CIHR grant to RSS. Cellular interactions between neighboring axons are 2-A-7 Examining the Role of DIXDC1 in Neural essential for the stereotyped positioning of Connectivity and Autism Spectrum Disorders individual axons and topographic map formation. So far however, it is not known how axons communicate with each other at the level of synapse CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

formation. In other words, how do axons divide up dendritic spine density due to decreased spine the target area when they choose synaptic targets? stability, and translated into decreased synaptic To answer this question, we focus on two closely connectivity. While exploring mechanisms by which related cholinergic motor neurons, DA9 and DA8. TAO2 controls these processes, we found that TAO2 Both DA8 and DA9 neurons extend their axons mRNA is a target of the fragile x mental retardation through a commissure into the dorsal nerve cord, protein (FMRP). In this regard, TAO2 protein levels where they proceed anteriorly to form a series of en were higher in brains of FMR1 KO mice, suggesting passant synapses. Although those axons largely that elevated TAO2 plays a role in the abnormal overlap in the dorsal cord, they form synapses only synaptic phenotypes observed in the KO mice. By at the specific area. DA9 forms about 25 synapses overexpressing TAO2 to simulate the elevated onto the dorsal muscles in its axon in the posterior- protein levels, we found it resembled some aspects most domain (DA9 synaptic domain). Interestingly, of FMR1 KO spine/synapse pathology. This suggests DA8 axon has no synapses in DA9 synaptic domain, that reducing TAO2 levels in the FMR1 KO brain may and starts to form synapses just anterior to DA9 rescue its synaptic deficits. We then asked if TAO2 synaptic domain. Therefore, DA8 and DA9 form itself was genetically disrupted in patients with ASDs, "tiled" synaptic domains leaving no apparent gap or and discovered three genetic variants in TAO2. overlap between them. Recently, we developed a Overexpression of two TAO2 variants (a de novo genetic marker to visualize synaptic tiling between kinase dead mutant and a regulatory domain DA8 and DA9, and showed that Plexin-dependent mutant) resulted in impaired spine formation and axon-axon interaction as well as gradients of Wnt abnormal morphology. These results suggest a morphogens are critical for establishing stereotyped FMR1-TAO2 pathway regulates synaptic tiled synaptic innervation (Mizumoto and Shen, 2013 connectivity, which may be disrupted in ASDs. Neuron, Cell Reports). To fully understand the molecular mechanisms of synaptic tiling, we are 2-A-10 A FASD Mouse Model: Biochemically working on additional mutants that show synaptic Mimicking Alcohol Exposure using Gsc promoter tiling like plexin mutants. driven Cyp26A1 cDNA.

2-A-9 Regulation of synaptic connectivity by a Berardino Petrelli¹, Arzu Ozturk¹, Molly Pind¹, novel FMR1-TAO2 pathway and its disruption in Abraham Fainsod¹, Geoff Hicks¹ autism spectrum disorders. ¹University of Manitoba Nadeem Murtaza¹, Melanie Richter², Pritha Paul¹, Vickie Kwan¹, Emanuela Pasciuto³, Susan Walker⁴, Prenatal alcohol exposure resulting in Fetal Alcohol Stephen Scherer⁴, Claudia Bagni³, Froylan Calderon Spectrum Disorder (FASD) has an estimated de Anda², Karun Singh¹ prevalence of 1% in Canada. FASD is a spectrum of disorders, including Fetal Alcohol Syndrome (FAS), ¹Mcmaster University/Stem Cell and Cancer Research partial FAS, and alcohol related neurodevelopmental Center, ²University of Hamburg/Center for Molecular disorder (ARND). It is well established in FASD rodent Neurobiology Hamburg, ³University of and Xenopus models that even a single exposure to Leuven/Flanders Institute for Biotechnology, alcohol during the earliest stage of gastrulation is ⁴University of Toronto/Hospital for Sick Children sufficient to induce the developmental defects associated with FAS. We hypothesize that acute Abnormal neuronal communication is hypothesized ethanol exposure overwhelms the aldehyde to contribute to the pathogenesis of autism metabolic enzymes that also normally convert spectrum disorders (ASDs). Studies have discovered retinol (Vitamin A) to retinoic acid (RA); and numerous ASD-associated genes controlling synapse moreover, the reduction of RA levels during formation and function. One potential gene of gastrulation drives the cranio-facial defects significance is the thousand and one amino acid associated with FAS. To test our hypothesis, a kinase 2 (TAO2) located on 16p11.2, a common ASD- murine model was established to biochemically linked copy number variation. Initial studies have mimic the alcohol effect in vivo using a genetically shown a role for TAO2 in neuronal circuitry, but an engineered mouse expressing Cyp26A1-eGFP from underlying mechanism has not been elucidated. We the endogenous Goosecoid (Gsc) promoter. The Gsc found that loss of TAO2 resulted in decreased promoter is utilized to dictate spatio-temporal CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

expression of the Cyp26A1-eGFP cassette during interactive regulation of PGE2 and Wnt development. Cyp26A1, the normal down regulator neurodevelopmental pathways and for a potential of endogenous RA, mimics the reduced RA levels link between abnormal signalling of these pathways induced by acute alcohol exposure at early in ASDs. gastrulation. F1 mice were born with a normal Mendelian ratio of het:wt (0.95, n=127). Newborn F1 2-A-12 The ASD-associated gene Glyoxalase1 mice were phenotypically assessed (blinded) for integrates the fetal-maternal metabolism of the cranial-facial defects characteristic of FASD, diabetes risk factor methylglyoxal to regulate compared to normal pups. Pups were later embryonic neurogenesis genotyped at weaning and analysis shows 88% (15/17) of mutant mice assessed had a discernable Guang Yang¹, Freda Miller¹, David Kaplan¹ FAS phenotype. 100% of wild-type mice had been ¹The Hospital for Sick Children assessed as normal (14/14). Genetic perturbations and prenatal environmental 2-A-11 Collaborative regulation of Prostaglandin insults, such as maternal metabolic conditions, are E2 and Wnt signalling pathways in important sources of causality for ASD and other neuroectodermal stem cells: implication in autism mental illnesses. However, little is known about how Christine Wong¹, Eizaaz Ahmad¹, Hongyan Li¹, Dorota these two components interact at the molecular and Crawford¹ cellular levels to influence early brain development. Here, we report that the deregulation of a circulating ¹York University metabolite methylglyoxal (MG) that is elevated in maternal diabetic condition as well as a MG Prostaglandin E2 (PGE2) is an endogenous lipid- detoxification enzyme glyoxalase 1 (Glo1) that is derived signalling molecule important in early brain perturbed in ASD, synergistically disrupt neural development and function. We have previously precursor cells (NPCs) and embryonic neurogenesis shown that PGE2 is important for calcium regulation in the developing mouse cortex. We found in growth cones, and migration, proliferation, and Glo1expression is high in NPCs to keep the steady- differentiation in neural stem cells. Exogenous level of MG low. Acute knockdown of Glo1 in vivo factors, such as diet and exposure to infections, depletes NPCs as a result of premature inflammation, and chemicals, can disrupt the levels neurogenesis. Lateral ventricular injections of either of PGE2 and disturb its normal role in brain exogenous MG or a Glo1 inhibitor similarly increase development. Moreover, irregular PGE2 signalling neurogenesis. In contrast, ectopic expression of Glo1 has been associated with pathologies of the nervous promotes NPC maintenance. Mechanistically, system, including Autism Spectrum Disorders (ASDs). accumulation of MG causes NPC apical endfeet In this study, we examined the potential dose- detachment and basal-apical movement retardation, dependent interaction between two key leading to aberrant neurogenesis. Maternal developmental pathways, PGE2 and the crucial injections of MG, which mimic observed metabolic morphogen Wnt, in neuroectodermal (NE-4C) stem insults in diabetic patients, also increase cells. We report that concentration-dependent PGE2 neurogenesis at the expense of NPC maintenance. alters the expression of Wnt-target genes including These results highlight an important role of the Glo1- ligands, Wnt3, 3a, 5a, 8a, and downstream genes, MG metabolic pathway in embryonic cortical cyclooxygenase-2 (Ptgs2), cyclin d1 (Ccnd1), and development. Fetuses with genetic perturbations in matrix metalloproteinase 9 (Mmp9). Interestingly, this pathway may be particularly vulnerable to the Wnt pathway has also been previously maternal metabolic insults, and susceptible to implicated in ASDs, including Wnt-target genes neurogenesis deregulation, leading to the abnormal affected in this study. We also found that the development of cortical circuitry. expression of Wnt-target protein, Ccnd1, increased with higher concentrations of PGE2. Furthermore, 2-A-174 Effects of prenatal alcohol exposure and we found that Wnt agonist treatment elevates the early life stress on the immune response to expression of Ptgs2, which encodes the enzyme challenge: Profiling cytokine expression patterns in responsible for PGE2 production. Overall, our study multiple compartments provides novel molecular evidence for the CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

David Mak¹, Tamara Bodnar¹, Joanne Weinberg¹ to activate cannabinoid 1 (CB1) receptors. To regulate synaptic concentrations of AEA, an ¹The University of British Columbia unidentified protein transporter is hypothesized to shuttle AEA from the synapse to the post-synaptic Prenatal alcohol exposure (PAE) affects development cell to be degraded. Pannexin-1 is a large pore ion and function of many physiological systems resulting channel which is expressed post-synaptically in CA1 in a range of deficits, collectively known as Fetal hippocampal neurons and conducts large molecules. Alcohol Spectrum Disorders (FASD). Among these We hypothesized that Panx1 acts as an AEA deficits are changes in immune function, such as transporter. We tested this by blocking post-synaptic increased infections, as well as increased responses Panx1 with an intracellular Panx1 antibody and to stress. To investigate possible mechanisms observed an increase in the frequency of underlying altered immunity, pregnant rats were neurotransmitter release following stimulation. The assigned to: PAE, Pair-fed (control for reduced food same result was seen with bath application of AEA intake in PAE) or controls. At puberty, offspring were without Panx1 blocking. Application of AEA in the exposed to Chronic Mild Stress (CMS), a series of presence of a Panx1 block produced no further stressors (2/d for 10 d) to induce mild stress, or increase in neurotransmitter release. Since AEA is remained undisturbed. In adulthood, animals known to act at TRPV1 channels, we tested a TRPV1 received an adjuvant (inflammatory) challenge receptor antagonist, capsazepine, which prevented (adjuvant-induced arthritis; AA). Preliminary data any increase in neurotransmitter release seen with show that plasma cytokine levels are low and may exogenous AEA or during Panx1 block. Finally, not significantly change with AA. Interestingly, in the application of AM-404, an AEA transporter hind paw, while PAE CMS animals with AA show a antagonist, mimicked increased glutamate release blunted cytokine response, in the absence of AA, similar to that that seen with Panx1 block. We these animals show heightened cytokine expression, conclude that Panx1 is an important pathway for compared to controls. Overall, this suggests that AEA clearance from CA3-CA1 synapses. Furthermore, exposure to stress may alter the ability of PAE our data suggests that Panx1 may play a role in animals to mount appropriate immune responses to regulation of synaptic efficacy. challenge. Therefore, changes in cytokine expression may play a significant role in immune abnormalities 2-B-14 Two-photon FRET and optogenetics for seen in PAE offspring. Investigation into cytokine studying post-synaptic cGMP during plasticity responses in other tissues (brain and spleen) is currently underway to increase our understanding of Jelena Borovac¹, Tyler Luyben¹, Kenichi Okamoto¹ stress-immune interactions that may alter immune function in children with PAE. Support: NIH/NIAAA ¹University of Toronto RO1 AA022460, R37 AA007789, NeuroDevNet, & CFFAR to JW. Cyclic GMP (cGMP) is a crucial intracellular messenger which underlies synaptic plasticity. B - Neural Excitability, Synapses, and Glia: Cellular However, the role of post-synaptic cGMP is poorly Mechanisms understood due to a lack of established techniques for its spatiotemporal visualization and 2-B-13 Modulation of synaptic fidelity by post- manipulation. Here, we report two-photon live synaptic Pannexin-1 imaging and optogenetics to non-invasively monitor and manipulate cGMP at the level of the dendritic Jennifer Bialecki¹, Nicholas Weilinger ¹, Matthew spine. To monitor post-synaptic cGMP dynamics in Hill¹, Roger Thompson¹ living hippocampal neurons, we prepared genetically engineered cGMP sensors utilizing two-photon FRET ¹Hotchkiss Brain Institute (Fӧrster resonance energy transfer) and FLIM (fluorescence lifetime imaging microscopy). We Ananamide (AEA) is an endogenous fatty acid that expressed these sensors in pyramidal neurons of modulates synaptic activity though its activity as cultured organotypic hippocampal slices and both an endocannabinoid and endovanilloid. In observed post-synaptic cGMP dynamics during order for AEA to act as an endovanilloid, it must synaptic plasticity. We detected transient cGMP reach a concentration 10x greater than needed for it production in neurons during long-term depression CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

(LTD), but not long term potentiation (LTP), present evidence that implicates purinergic suggesting a role of postsynaptic cGMP in LTD. Since receptors and extracellular residues of Panx1 in the LTD is associated with dendritic spine shrinkage internalization mechanism. These results have (structural plasticity), we next examined the role of important implications for the regulation of Panx1 cGMP in structural changes at the dendritic spine. To signaling in the brain. mimic cGMP production in living hippocampal neurons, we characterized a mutant bacterial 2-B-16 Nemo kinase is a transcriptional target of photoactivatable adenylate cyclase (BlgC), which the BMP signaling cascade in motorneurons generates cGMP when exposed to light. We confirmed two-photon photoactivation of BlgC at Mario Calderon¹, Kimberly Young¹, Edward Liao¹, target dendritic spines by cGMP FRET/FLIM sensors, Pejmun Haghighi¹ and observed the effect of postsynaptic cGMP ¹McGill University production on structural plasticity. These two- photon optogenetics and live imaging techniques will Coordinated growth of synaptic structures and provide new tools for studying cGMP signaling synaptic strength are regulated by signaling cascades pathways. across pre- and post-synaptic terminals. Despite great progress, the molecular players that modulate 2-B-15 ATP-evoked internalization of Pannexin 1 signal transduction pathways remain largely channels unknown. We have used the genetic and molecular Andrew Boyce¹, Ross Prager¹, Leigh Wicki-Stordeur¹, tools in Drosophila to investigate how the retrograde Michelle Kim¹, Leigh Anne Swayne¹ bone morphogenic protein (BMP) cascade is regulated at the larval neuromuscular junction. BMP ¹University of Victoria signaling is initiated in the muscles by postsynaptic release of the ligand Gbb, and results in a cascade in Pannexin 1 (Panx1) is a large pore ion and the presynaptic motorneuron upon binding to a metabolite channel permeable to molecules up to receptor complex that includes the type II receptor 1kDa (including ATP), which is widely expressed in Wit and a combination of Type I receptors. This the brain, primarily in neurons. To date, exploration results in an increase in phosphorylation and nuclear of its function has focused on its role at the plasma translocation of the BMP transcription factor, Mad. membrane; however, populations of mature Panx1 Here we describe the identification of Nemo (Nmo) also localize to intracellular compartments. kinase as a transcriptional target of this pathway. Interestingly, recent evidence suggests that high Using an in vivo enhancer trap reporter for nmo, we levels of extracellular ATP inhibit Panx1 currents. found that nmo transcription responds to BMP This is physiologically relevant because ATP is signaling manipulation. Transgenic RNAi knockdown released as a signaling molecule in both regulated of Wit in motorneurons or Gbb in muscles led to a and constitutive contexts from multiple cell types in significant reduction in nmo mRNA expression. several brain regions, leading to transiently high Finally, chromatin immunoprecipitation and in vitro levels of extracellular ATP. Here we hypothesize that reporter gene assays of the nmo gene region ATP inhibition of Panx1 occurs by ligand-stimulated revealed a site that binds and responds to Mad. endocytosis of the Panx1 channel from the plasma Interestingly, our previous findings demonstrated membrane, akin to receptor-mediated endocytosis. that Nmo genetically and physically interacts with To explore the influence of ATP on Panx1 plasma Mad. Therefore, we propose a new model in which membrane localization, we transiently inhibited de BMP signaling self-regulates its action in novo protein synthesis (to stabilize the Panx1 motorneurons through transcriptional regulation of population) then stimulated with ATP and other its own modulator, ensuring normal synaptic growth stimuli known to modulate Panx1 activity and/or and function. cellular excitability as controls. Using both live and fixed cell confocal imaging, and cell surface 2-B-17 Distinct functional roles for P/Q- and N- luminometry, we show striking evidence for dose- types voltage-gated calcium channels in dependent ATP-induced internalization of Panx1 neurotransmitter release at mossy fiber to CA3 from the plasma membrane with concurrent pyramidal cell synapses increase in early endosome distribution. Further, we CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

Simon Chamberland¹, Alesya Evstratova¹, Katalin which constitute well over 60% of total synaptic Tóth¹ input onto corticotropin releasing hormone (CRH) PNCs in the PVN. Postsynaptic depolarization ¹Universite Laval induced suppression of inhibition (DSI) can regulate the efficacy of GABAergic transmission in the PVN, Neurotransmitter release from the presynaptic representing a mechanism by which PNCs may terminal is ensured by calcium entering through modulate their own afferent inputs. However, the several types of VGCCs. Although the spatial extent to which eCB signalling can regulate specific distribution of distinct VGCCs impacts calcium afferents is unclear. The fusiform nucleus of the bed dynamics and neurotransmitter release, the specific nucleus of the stria terminalis (BNSTfu) integrates contribution of individual types of VGCCs to specific stress- and anxiety-associated information neurotransmitter release remains poorly defined. To from a variety of nuclei, which it then relays to the dissect the roles of P/Q and N-types VGCCs, we used PVN through a dense GABAergic projection. random-access two-photon calcium imaging, Therefore, we assayed PNC DSI with pathway electrophysiology and electron microscopy. Our specificity by expressing ChR2 in VGAT positive results show that P/Q- and N-types VGCCs support BNSTfu neurons. PNCs in hypothalamic slices different calcium dynamics with specialized exhibited repeatable and robust DSI of light evoked functions in triggering glutamate release. First, currents that underwent a prolonged depression. bouton calcium imaging revealed that P/Q-type Both the DSI and the depression could be blocked by VGCCs contributed a larger but more spatially AM251, indicating a role for eCBs in self-regulating homogeneous fraction of calcium than N-type GABAergic tone. These results taken together show VGCCs. Consistent with a global calcium increase, that stress-associated signalling from the BNSTfu can blockade of P/Q-type VGCCs prevented the be silenced for a prolonged period, underlining the recruitment of additional release sites during trains plasticity present in this system. Understanding the of activity. This effect could be mimicked by EGTA- conditions in which eCBs regulate GABAergic AM, indicating that P/Q-type VGCCs can be loosely- signalling highlights how CRH PNCs can modulate coupled to the sensor. In contrast, antagonizing N- their own output along with that of the HPA axis. type VGCCs decreased the overall amplitude of EPSCs but had no effect on short-term facilitation. 2-B-19 Absence of MDGA1 Enhances Inhibitory Finally, the spatial distribution of P/Q- and N-type Drive and Confers Resistance to Increased VGCCs was investigated. Altogether, our results Excitation in Mouse Hippocampus demonstrate the highly specialized roles of P/Q- and N-type VGCCs in neurotransmitter release. While N- Steven Connor¹, Ina Ammendrup-Johnsen¹, Parisa type VGCCs are tightly-coupled to calcium sensor Karimi Tari¹, Tohru Yamamoto², Yu Tian Wang¹, Ann and provide local calcium elevations, P/Q-type Marie Craig¹ VGCCs are well-suited to support global calcium elevations and promote the recruitment of ¹University of British Columbia, ²Kagawa University additional release sites during trains of activity. Dysregulation of synapse development is emerging as a key cellular pathology underlying neurological disorders. MDGAs (MAM domain containing 2-B-18 Pathway specific depolarization-induced glycosylphosphatidylinositol anchor proteins) are suppression of inhibition in hypothalamic neuronal surface proteins that have been genetically parvocellular neuroendocrine neurons linked to schizophrenia and autism. Given that imbalance between inhibitory and excitatory Phillip Colmers¹, Jaideep Bains¹ synapses may contribute to these disorders, we sought to characterize the role of MDGAs in ¹University of Calgary mediating synaptic function and structure. Recently, we determined that MDGA1 acts as a rare negative Activation of parvocellular neurosecretory cells regulator of synapse development. We found that (PNCs) within the paraventricular nucleus of the MDGA1 directly binds neuroligin-2 to selectively hypothalamus (PVN) represents the final integrative repress inhibitory synapse formation. To further step in recruiting the stress axis. Output from these probe the role of MDGA1 in synapse dynamics, we neurons is constrained by GABAergic synapses, CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

studied MDGA1 knockout mice (MDGA1-/-). Whole- process of remodelling has been described in cell recordings taken from MDGA1-/- mouse previous reports, the regulation mechanisms and pyramidal cells in CA1 of the hippocampus showed functional significance are unclear. Through increased mIPSC frequency, whereas mEPSCs were membrane potential and cell viability experiments unaltered. Similarly, symmetric perisomatic synapse we show that remodelling may be a protective density and GAD-65 punctate immunofluorescence mechanism. Exploration of the mechanism and were increased in CA1, with no change in function of mito-remodelling will provide a greater asymmetric synapse density or VGlut1 puncta. To understanding into the role of mitochondria in cell determine if network excitability was altered, we maintenance and survival. measured the frequency of spontaneous excitatory events in MDGA1-/- slices in response to increased 2-B-21 Inducible Deletion of Myelin Regulatory extracellular potassium. Slices taken from MDGA1-/- Factor is a Cell Selective Mechanism to Impair mice showed resistance to excitation treatments Oligodendrocyte Remyelination consistent with enhanced inhibitory drive. Our results bolster our understanding of the molecular Greg Duncan¹, Jason Plemel², Jie Liu¹, Ryan Hirata¹, processes governing inhibitory synapse formation Yasmin Chaeichi¹, Matan Berson¹, Wolfram Tetzlaff¹ and function and provide the basis for more ¹ICORD/UBC, ²Hotchkiss Brain Institute, University of efficiently targeted therapeutics for brain-based Calagary diseases. During remyelination, oligodendrocyte precursor 2-B-20 Investigating the regulation and function of cells (OPCs) are recruited to the lesion epicenter mitochondrial remodelling in rat cortical astrocytes where they differentiate and mature into new Samineh Deheshi¹, Susu Fan¹, Bahram Dabiri¹, myelinating oligodendrocytes, a process requiring Michelle Tsang¹, Sarah Warda¹, Leili Atashkari¹, Yana intricate transcriptional regulation. Therapies that Saranchova¹, Gordon Rintoul¹ promote myelin repair hold enormous promise, but require a greater understanding of the key factors ¹Simon Fraser University regulating transcription during oligodendrocyte maturation and subsequent remyelination. One Mitochondria are dynamic organelles that drive gene, myelin regulatory factor (Myrf) is essential for cellular activity and maintenance in neurons and glial the maturation of oligodendrocytes and the cells. Investigation of mito-morphology has allowed formation of central nervous system (CNS) myelin for a greater understanding of their functional roles during development. However, its role in in eukaryotic cells and in neurodegeneration. To remyelination has not been elucidated. We crossed date, mito-morphological changes have mostly been Myrf floxed mice with PDGFRα Cre ERT2 mice attributed to fission and fusion. Mito- to remove Myrf from OPCs at the time of remodelling/rounding, however, is a process that demyelination. Mice were then injected with regulates mito-length without division or fusion of lysolecithin to induce a focal demyelinating lesion in the mito-membranes. We show that remodelling can the corpus callosum, and examined at different time occur concomitantly with fission and have provided points post lesion. Myrf was not required for evidence that the mechanism of mito-remodelling is recruitment of OPCs following demyelination, but distinct from fission. In our study, we used mito- there was a marked reduction in the total number of targeted yellow fluorescent protein, ROS-sensitive CC1-Olig2+ mature oligodendrocytes at ten days GFPs and live cell fluorescence microscopy to show post lesion (dpl). Recombined cells fail to robustly that ROS generating agents such as rotenone and express GST-π, oligodendrocytes by 14 dpl. Ca2+ caused mito-remodelling and fission. We used Recombined cells visualized with a membrane antioxidants to block mito-remodelling without tethered reporter reveal that when Myrf is deleted attenuating fission, indicating that remodelling is a in recombined cells, they rarely contributed to distinct process from fission and is regulated by ROS forming new myelin internodes. Thus, the inducible whereas fission is regulated by Ca2+. Furthermore, deletion of Myrf from OPCs prior to demyelination we provide evidence that glycogen synthase kinase mimics aspects of chronically demyelinated MS 3β (GSK3β) may be involved in the lesions: the inability of OPCs to mature and signaling mechanism of remodelling. Although the successfully remyelinate. CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

2-B-22 Reduced Hyperpolarization-Activated its ability to maintain a low intracellular chloride Current Contributes to an Enhanced Intrinsic level in the neuron. Surprisingly, KCC2 has also Excitability in Hippocampal Neurons from PrP-87-/- recently been found to interact with proteins Mice involved in excitatory neurotransmission, including the kainate receptor subunit GluK2. It is known that Jing Fan¹, Patrick Stemkowski ¹, Stefanie Black¹, Ivana independent of kainate receptor activity, the Souza¹, Gerald Zamponi¹ physical interaction between KCC2 and GluK2 is important for KCC2 surface expression and ¹University of Calgary oligomerization. However, it is unknown whether the activity of kainate receptors can directly Background: Hyperpolarization-activated cation influence KCC2 function. In this study we (HCN) channels are highly expressed in the hypothesized that the activation of GluK2-containing hippocampus where they act as key regulators of kainate receptors would increase KCC2s ability to firing properties. Recordings from hippocampal extrude chloride from the cell. We tested this neurons from prion protein (PrP) knockout mice hypothesis by performing slice electrophysiology reveal a variety of electrophysiological abnormalities experiments in the CA3 region of the hippocampus, including increased neuronal excitability. We thus recording EGABA as a measure of KCC2 function. wanted to determine whether PrP regulates Our findings demonstrate that activation of the neuronal firing properties via modulation of HCN kainate receptor is able to regulate KCC2 function, channels. Methods: We conducted whole-cell revealing a novel mechanism for excitatory: voltage and current clamp recordings from primary inhibitory balance. hippocampal cultures prepared from P0-P1 wild-type (WT) and PrP-null pups. Results: We found that the 2-B-24 Selective viral manipulation of neostriatal absence of PrP profoundly affected firing properties matrix compartment of hippocampal neurons. In the presence of synaptic blockers there was an increase in the number of Marianela Garcia-Munoz¹, Violeta Lopez-Huerta¹, action potentials (APs) and a decrease in the spike Yoko Nakano¹, Michael Lazarus², Gordon threshold (p < 0.001). However, no measurable Arbuthnott¹ differences in resting membrane potential, AP amplitude, AP duration at 50% amplitude, maximum ¹Okinawa Institute of Science and Technology rate of depolarization and threshold were found. In Graduate University, ²University of Tsukuba contrast, membrane impedance was greater in PrP- null neurons (p < 0.05), and this difference was Neostriatum is known to have a large neuronal abolished by the HCN blocker ZD7288. PrP-null network of high acetylcholine esterase activity neurons exhibited a decrease in Ih peak current, as (AChE) that configure the matrix compartment and a well as in the amplitude of voltage sag (p < 0.05). smaller set of neurons poorly stained for AChE that The time course of Ih activation became significantly form the striosome compartment. In spite of much slower in PrP-null neurons over a wide range of knowledge accumulated about these two command voltages. Conclusion: These data suggest compartments how they interact has been a matter that the absence of PrP down-regulates activity of of speculation. Since adeno-associate virus serotype HCN channels, which in turn reduces membrane rh10 (AAV10) expresses in striatal neurons located in impedance to potentiate neuronal excitability in the matrix compartment sparing most neurons in hippocampus. striosomes and all striatal interneuron subtypes, selective manipulation of neurons in the matrix has 2-B-23 Kainate receptor mediated regulation of become possible. Neuronal syntheses of channel chloride homeostasis rhodopsin 2 (ChR2) carried by AAVrh10 allowed us to evoke synaptic events by photo stimulation or Danielle Garand¹, Vivek Mahadevan¹, Melanie glutamate puff (1mM/20psi/50ms) and perform Woodin¹ whole cell patch-clamp recordings. We report that striatal and matrix compartments do not talk to each ¹University of Toronto other via direct monosynaptic connections. Alternative ways of communication between striatal The potassium-chloride cotransporter KCC2 plays a critical role in inhibitory neurotransmission through CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

compartments such as longer axonal influences or Early odor preference learning in rodents occur volume transmission must take place. within a critical period (≤ postnatal day 10- 12), during which pups show heightened ability to 2-B-25 Modulation of GABAA receptors by a novel form odor preference when the odor is paired with a associated protein tactile stimulation (e.g. stroking the pup's body with a brush). Norepinephrine (NE) release from the locus Yuan Ge¹, Yunhee Kang¹, Leonard Foster¹, Ann Marie coeruleus (LC) during stroking acts as an Craig¹ unconditioned stimulus to mediate this learning. However, in older pups, stroking losses its ability to ¹University of British Columbia induce learning when paired with an odor. This Gamma-Aminobutyric acid (GABA) is the major sensitive period for odor preference learning has inhibitory neurotransmitter in the adult mammalian been shown to be caused by changes in the central nervous system (CNS). The fast inhibitory expression of adrenergic autoreceptors in the LC actions of GABA are mediated by GABA type A during maturation. However, there is also evidence receptors (GABAARs). Deficits in GABAAR-mediated suggesting changes in adrenoceptor responsiveness transmission contribute to the etiology of epilepsy, to NE in the olfactory bulb (OB) neurons of older anxiety disorders, and mood disorders. In contrast pups. We have previously demonstrated that both with numerous studies of glutamate receptor OB and anterior piriform cortex (aPC) are critically associated proteins and their involvement in the involved in early odor preference learning. Activating modulation of excitatory synapses, much less is β-adrenoceptors in either structure is known about GABAergic synapses. Using a novel sufficient to induce learning when paired with an combined transgenic, tandem affinity purification, odor, while blocking β-adrenoceptors and proteomic approach, we did a sequential abolishes odor preference learning induced by purification from tagged GABAAR gamma2 subunit pairing an odor with stroking. Here we test whether transgenic mice followed by mass spectrometry, and there is developmental change in neuronal several associated proteins were identified including excitability and NE responsiveness in the aPC in GARP1 (GABAA Receptor associated Protein 1). neonatal mice. We show that odor paired with GARP1 is a novel trans-membrane protein, and no stroking induced odor preference in postnatal day 8- specific function has been reported. We found that 10 pups but not in postnatal day 14-16. We are overexpression of GARP1 dramatically decreases currently investigating intrinsic neuronal excitability, GABAAR-mediated currents by reducing surface synaptic properties and NE responsiveness of expression of GABAARs in HEK293 cells. In rat pyramidal cells in the aPC in different age groups. hippocampal cultured neurons, overexpression of 2-B-27 Semaphorin 5A in Synapse Pruning and GARP1 reduces inhibitory synaptic transmission Autism Spectrum Disorders without altering excitatory synaptic transmission. Furthermore, shRNA-mediated knockdown of GARP1 Rachel Gomm Kolisko¹, Wei Xiao¹, Riki Dingwall¹, D. selectively increases inhibitory but not excitatory Blair Jovellar¹, Shernaz Bamji¹, Timothy O'Connor¹ synaptic transmission, and promotes synaptic surface expression of GABAARs, which can be ¹University of British Columbia rescued by a shRNA-resistant GARP1. These results indicate GARP1 is a novel associated protein which Autism Spectrum Disorders (ASDs) are a complex modulates function and trafficking of GABAARs. group of neurodevelopmental disorders characterized by impairments in communication and 2-B-26 Age-Dependent Odor Preference: Neuronal social behaviour. Although there is a limited Properties and Responsiveness to Norepinephrine understanding of the neuropathology of ASDs, in the Anterior Piriform Cortex of the mouse previous work has shown decreased connectivity between brain regions and an overabundance of Abhinaba Ghosh¹, Nicole Purchase¹, Xihua Chen¹, Qi synaptic connections within specific regions of the Yuan¹ brain, leading to imbalanced neural networks. This increased connectivity is believed to occur through ¹Memorial University Of Newfoundland disruption of normal synaptic pruning during development. Surprisingly, our knowledge about the CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

molecular and cellular processes regulating synapse inflammation in particular setting of cellular stress elimination is still in its infancy. Here we such as observed during ischemic conditions. demonstrate that semaphorin 5A (Sema5A) plays a central role in synapse elimination and that neuronal 2-B-29 Nitric oxide modulation of activity regulates synapse formation and elimination phosphodiesterase activity and cAMP levels in by changing the subcellular localization of Sema5A. astrocytes This is of particular interest as Sema5A is genetically linked to ASDs and down-regulated in people with Rebecca Ko¹, Hyun Choi¹, Brian MacVicar¹ autism. Together, we suggest that Sema5A is ¹University of British Columbia essential for activity-dependent pruning of synaptic connections through regulation of its subcellular Astrocytic cAMP signaling plays an important role in localization and that down-regulation of Sema5A several crucial physiological processes in the brain, may account for the exuberant synaptic connectivity including metabolic coupling to neurons. However, observed in autistic patients. the regulation of cAMP levels by phosphodiesterases (PDEs) in astrocytes has not been determined. 2-B-28 Regulation of the transient receptor Recent transcriptome and protein analyses have potential vanilloid 1(TRPV1) channel by heat shock confirmed that astrocytes express the PDE isoform protein 70 (HSC70) PDE3, which is inhibited by cGMP. Here we Mircea Iftinca¹, Robyn Flynn¹, Christophe Altier¹ investigate the hypothesis that PDE3 is an important regulator of astrocytic cAMP levels in the brain. To ¹University of Calgary examine the role of PDE3 in modifying cAMP levels, we performed ELISAs in both acute hippocampal The transient receptor potential vanilloid 1 (TRPV1) brain slices and primary astrocyte cultures. Our channel is a non-selective cation channel that plays a preliminary data indicate that the PDE3 inhibitor, pivotal role in inflammatory pain signaling. TRPV1 is cilostamide (10µM), enhances forskolin-induced activated by chemical and physical noxious stimuli cAMP increase. In addition, application of the nitric and various inflammatory mediators. Lately its oxide (NO) donor, SNAP (100µM), also potentiated involvement in neuronal apoptosis and cell survival the cAMP increase, consistent with PDE3 sensitivity has come into focus. HSC70 is a constitutively and to cGMP. To further confirm that NO-induced cGMP ubiquitously expressed chaperone protein that was is modulating cAMP levels through PDE3 inhibition, classically described as having a central role in cell the experiment will be repeated in the presence of protection from damage caused by physical and the soluble guanylyl cyclase inhibitor, ODQ. We are chemical hazards. Here we set out to examine also examining the downstream consequences of whether HSC70 was involved in regulating the increasing astrocytic cAMP by NO modulation. activity and/or expression of TRPV1. Our results Previous studies have shown that cAMP modulates show that TRPV1 and HSC70 form a signaling connexin43 (Cx43) expression and gap junction complex and there is a significant decrease in the assembly in hepatoma and mammary tumor cells. capsaicin-induced TRPV1 current after heat shock We therefore predict that NO can alter Cx43 levels (1hour at 42⁰C) in both transfected HEK cells and subsequent gap junction coupling of astrocytes. and dissociated Dorsal Root Ganglion neurons. Thus we will perform immunoblotting and dye flux Furthermore, Bioluminescence Resonance Energy imaging to assess the level of plasma membrane Transfer (BRET) assay showed a decrease in TRPV1 Cx43 and astrocyte coupling, respectively. subunit association after heat shock. HSC-mediated inhibition of the channel was strongly dependent on 2-B-30 Synaptic mechanisms gating the cortico- the ATP/ADP ratio and triggered by Rho-associated hippocampal information flow through activation kinase (ROCK) inhibition. Altogether, we are showing of the CA1 disinhibitory circuit for the first time a role for HSC70 in regulating TRPV1 channel activity during conditions of cell Xiao Luo¹, Lisa Topolnik¹ stress and that this effect involves ROCK and ATPase ¹Université Laval activity. This regulation may represent a survival mechanism ensuring neuronal protection or Information processing in cortical circuits requires a preventing TRPV1-mediated neurogenic delicate balance between excitation and inhibition. CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

In addition to inhibitory interneurons that control impaired differentiation and myelination. We also the activation of pyramidal cells, there are observed these defects in organotypic cerebellar interneuron specific (IS) interneurons that slices from neonatal WT and KO mice. Slices were coordinate the level of network inhibition by grown for 10 and 20 DIV and immunostained as innervating interneurons. Here, we focused on the above, revealing reduced MBP/NFH co-localization in hippocampal CA1 disinhibitory circuit composed of KO slices as compared to WT controls. Moreover, the type 3 IS (IS3) interneurons. These cells immunostaining for paranodal Caspr revealed innervate the somatostatin-expressing interneurons, impairment in myelin-directed organization of which in turn control the integration of cortical input axonal domains in KO slices, confirming suboptimal by distal dendrites of pyramidal cells. To study the myelination. We are investigating PTPα- mechanisms of the temporoammonic (TA) pathway dependent signaling in OPC differentiation. We show integration by the IS3 cells, we used whole-cell patch that Akt is activated in differentiating WT OPCs, but clamp recordings in combination with two-photon not KO OPCs, as indicated by increased Ca2+-imaging in hippocampal slices from VIP-GFP phosphorylation of AktSer473 and Akt substrates. mice. Our data showed that EPSCs evoked in IS3 cells Future studies will elucidate how PTPα by the TA pathway stimulation had a small amplitude regulates Akt activity to promote OL differentiation. (15.3 ± 3.6 pA) and slow rise time (3.1 ± 0.6 ms), Improved knowledge of molecular pathways consistent with a distal location of TA synapses. orchestrating OL development will provide insights Moreover, TA-EPSCs had two components: fast and to developing effective and specific treatments to slow mediated by the activation of AMPA and NMDA promote myelin repair in demyelinating diseases. receptors, respectively. In addition, TA-EPSCs evoked at different frequencies of stimulation (5-40 Hz) 2-B-32 T-type-mediated calcium spikes in demonstrated the paired-pulse and multiple-pulse dendrites of CA3 pyramidal neurons couple to Kv4 facilitation, pointing to the increased recruitment of channels and mGluR1 receptors IS3 cells during physiologically relevant patterns of cortical activity. These results indicate that IS3 Aqsa Malik¹, Brian MacVicar¹ interneurons are well suited to integrate the ¹University of British Columbia consecutive excitation of TA afferents and provide disinhibition necessary for the selective gating of T-type voltage gated calcium channels are densely cortico-hippocampal information. expressed in the hippocampus, although their functional characteristics and interactions with 2-B-31 Protein Tyrosine Phosphatase Alpha- postsynaptic receptors are not well understood and mediated Akt activation is required for low threshold calcium spikes (LTS) have not been oligodendrocyte differentiation and myelination reported. Using whole-cell electrophysiology, we Philip Ly¹, Yuda Shih¹, Jing Wang¹, Catherine Pallen¹ demonstrate that LTS in CA3 pyramidal neurons can be evoked by somatic current injection. LTS were ¹University of British Columbia only evoked when 4-aminopyridine (4AP) was applied to depress A-type potassium channels. The brain-enriched tyrosine phosphatase PTPα Evoked LTS occurred independently from somatic regulates many cellular processes, including the sodium action potentials and high voltage activated differentiation of oligodendrocyte progenitor cells calcium channels, and were associated with fast- (OPCs) to oligodendrocytes (OLs) that is required for rising calcium transients in somatic and dendritic CNS myelination. PTPα-/- (ΚΟ) compartments. Using two-photon imaging of LTS- OPCs have impaired differentiation and brains of KO induced calcium transients, we mapped the mice are hypomyelinated. In our current study, we distribution of T-type channels in CA3 pyramidal recapitulated this myelination defect in neuron/OPC cells. We observed substantial calcium influx in co-cultures. WT and KO OPCs were grown on neurite dendrites with greater signals in the proximal versus beds formed by dorsal root ganglion neurons for 14 distal (>50μm) dendrites. In contrast, in CA1 days and immunostained for MBP (OLs) and NFH pyramidal neurons, LTS-associated calcium signals (axons). MBP expression and MBP/NFH co- were restricted to the somatic region and not localization were reduced in ΚΟ OPC observed in dendritic arbors. We further compared to WT OPC co-cultures, indicating demonstrate that mGluR1 activation inhibits LTS via CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

a phospholipase C-dependent pathway. Our data stroke recovery. There is considerable uncertainty identify a new T-type mediated calcium signalling regarding what structural changes could account for pathway in CA3 pyramidal cell dendrites that is BBB breakdown, particularly in aged animals. Here unlocked by A-type potassium channel blockade and we employed electron microscopy to analyze early inhibited by mGluR1 receptors. and late changes (3 vs. 72 hours) in the BBB in young and aged mice (3-5 vs. 18 month old) subjected to 2-B-33 Activity Dependent Changes to Resting photothrombotic stroke. At both time points and Astrocyte Ca2+ ages, BBB permeability was accompanied by swollen endothelial cells packed with small transcytotic Eslam Mehina¹, Grant Gordon ¹ vesicles (~60 nm diameter) and vacuoles (>100 nm diameter). In a small fraction of microvessel tight ¹University of Calgary junctions, we observed a fluid-filled space at the Astrocytes play an important role in the junction suggesting that partial disruption can occur. maintenance and regulation of synaptic function, Of note, ischemia in young adult mice led to an and are also capable of affecting brain blood vessel increase in pericyte area and coverage of endothelial tone. These functions are dependent on changes in cells, whereas in older mice, pericyte area and intracellular astrocyte calcium. While much research coverage was significantly reduced. In both age has been aimed at studying the effects of rapid and groups, the basement membrane was expanded, large increases in astrocyte calcium, the especially at 3 hours. Peri-vascular astrocytes and investigation of the role of resting calcium levels in their mitochondria were severely swollen (~2-3 fold astrocytes remains untouched. We sought to increase in area) at both times points and ages. At 3 address this deficiency by using two-photon days, astrocytes were replete with glycogen deposits microscopy and examined changes to astrocyte suggesting a change in their energy metabolism and resting calcium in response to specific patterns of storage. Our results indicate that upregulation of synaptic activity. By applying in situ theta burst endothelial transcytosis and vacuolation, rather than stimulation it was shown that astrocyte resting breakdown of endothelial tight junctions, mediates calcium levels decreased following stimulation and BBB permeability in the peri-infarct cortex. Further, were reset at a new, lower baseline. This effect was our data suggest that pericyte responses to ischemia successively compounded by subsequent are affected by aging. stimulations. Application of a glutamate receptor 2-B-35 Sensory-evoked dendritic activity and blocker cocktail, designed to target metabotropic somatic firing instruct morphogenesis in the awake glutamate receptors (mGluRs), N-methyl-D-aspartate brain receptors (NMDARs), and α-amino-3-hydroxy- 5-methyl-4-isoxazolepropionic acid receptors Kaspar Podgorski¹, Serhiy Opushnyev¹, Kurt Haas¹ (AMPARs), suppressed the effect suggesting a glutamatergic mechanism. These results may have ¹University of British Columbia functional consequences to the control of blood vessel tone by astrocytes, as well as their effects at Sensory activity is essential during normal the synapse, and may provide further insight into the development of neural circuits. However, the role means by which astrocytes perform their vascular that patterned sensory activity plays in the detailed and synaptic regulatory roles. structural reorganization of the dendritic arbor remains unknown. Using a custom made random- 2-B-34 Ultrastructural analysis of blood-brain access microscope that allows rapid simultaneous barrier breakdown in the peri-infarct zone of young activity sampling throughout the entire 3D dendritic adult and aged mice arbor in awake Xenopus Laevis tadpoles, in combination with targeted single cell electroporation Patrick Nahirney¹, Patrick Reeson¹, Craig Brown¹ to label single neurons with selected receptive field properties, we characterized the learning rules that ¹University of Victoria neurons follow to modify their detailed morphology Following ischemia the blood-brain barrier (BBB) is in response to sensory activity. We found that compromised in the peri-infarct zone, leading to neurons' somatic firing and plasticity patterns were secondary injury and dysfunction that can limit associated with the patterns of dendritic growth and CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

pruning. The observed motility was determined by Matthew Parsons¹, Matthieu Vanni¹, Timothy the combination of evoked calcium transients at Murphy¹, Lynn Raymond¹ filopodial tips and adjacent shafts in response to sensory stimulation. Our data show that sensory ¹University of British Columbia stimulation evoked activity passing through dendrites guides the specific filopodial growth and Upon synaptic release, glutamate is cleared from the retraction patterns, shaping how the developing extracellular space by diffusion as well as uptake brain processes the environment and how individual through glutamate transporters on neurons and neurons integrate into functional networks. astrocytes. The rate of glutamate clearance can critically affect neuronal health as excessive 2-B-36 Thalamic modulation of the cortical slow glutamate receptor activation can cause neuronal oscillation death. Here, we used widefield imaging of the recombinant glutamate sensor, iGluSnFR, in mouse Anastasiia Ozur¹, Sylvain Chauvette¹, Igor Timofeev¹ brain slices to quantify glutamate clearance in the striatum following synaptic release. Electrical ¹Université Laval stimulation of striatal afferents resulted in robust increases in iGluSnFR fluorescence intensity, and the The slow oscillation present during non-REM sleep decay of the signal was significantly slowed by partial and under different types of anesthesia has a cortical blockade of the glutamate transporter GLT-1. origin however a growing number of evidence Pharmacological experiments suggest that GLT-1 is suggest that the thalamus plays a significant role in responsible for maintaining a low, steady-state level the regulation of this rhythm, but also of faster of extracellular striatal glutamate whereas non-GLT- frequencies. The slow wave power, which includes 1 transporters are chiefly responsible for the rapid the slow oscillation and delta waves, is one of the clearance of glutamate following its evoked release. main quantifiable parameters characterizing the We are currently expressing iGluSnFR under quality of sleep. We hypothesize that the first-order different promoters to understand whether the (specific) thalamic nuclei provide a control of slow time-course of glutamate sensed by astrocytes waves in primary cortical areas, while high-order differs from that of neurons. Finally, we use this (non-specific) thalamic nuclei may synchronize the sensor to show that in Huntington disease (HD), a slow wave activities across wide cortical regions. We neurodegenerative disease in which striatal neurons analyzed local field potentials (LFP) from different are particularly vulnerable, glutamate uptake is cortical areas of mice while a thalamic nucleus was intact. This finding contrasts with traditional inactivated by either the sodium channel blocker QX- biochemical uptake assays and provides important 314 or the GABA-agonist muscimol. Microinjection insight into the mechanisms of neurodegeneration in of these substances blocked or significantly HD. In all, our data demonstrates that iGluSnFR is a decreased neuronal firing in the corresponding powerful tool that can increase our understanding of thalamic nuclei. Inactivation of specific thalamic glutamate clearance in both health and disease. nuclei significantly decreased the power of slow/delta and gamma waves in the cortex. 2-B-38 Synaptic Plasticity in the Globus Pallidus Inactivation of specific thalamic nuclei (VL, VPM) mainly affected primary cortical areas. The Ian Prescott¹, Rob Marino¹, Ron Levy¹ inactivation of non-specific nucleus (CL) affected all cortical areas. Generally, the use of QX-314 affected ¹Queen's University larger cortical territories as compared to muscimol, likely because it affected not only local neurons but Plasticity-based therapies using electrical stimulation also passing fibers. We conclude that the non- of brain circuits offer new therapeutic approaches in specific thalamic nuclei play a major role in the Parkinson's disease (PD). Field evoked potentials regulation of the global cortical slow wave activity. (fEPs) have previously been used to demonstrate synaptic plasticity in the basal ganglia (BG) of 2-B-37 Optogenetic quantification of glutamate patients with PD that is dependent on exogenous clearance following synaptic release in health and dopamine levels. Establishing how these findings disease translate to the healthy brain is essential in giving us a baseline of "normal" synaptic plasticity in the BG. CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

Here, we explore the effects of high frequency duration. Finally, a subset of axons exhibited stimulation (HFS) on synaptic plasticity induction in a functionally silent boutons that were unresponsive healthy non-human primate in the globus pallidus to single trial AP stimulation but responded to a (GP), a major output structure of the BG. Four stronger 50 AP train pattern. In these silent boutons, independent electrodes recorded neuronal activity a visible CaT signal evolved within 5-10 APs, possibly and stimulation-induced fEPs from sites in the GPe due to recruitment of Ca2+ channels or build-up of and GPi. At a given site, baseline fEP amplitudes and residual Ca2+. Altogether, our finding uncover large slope were monitored from 3 recording electrodes all-or-none variations in axonal CaT dynamics and for 1 minute using 0.25 Hz test pulses from a 4th leave ample room for Pr regulation, upstream of stimulating electrode, then HFS (four 2s trains, 100 SNAREs, via Ca2+ channel modulation. Hz, 100uA) was delivered through the stimulating electrode. Post HFS, 0.25 Hz test pulses were 2-B-40 The cellular mechanisms of neuronal resumed and fEP amplitudes and slopes were swelling underlying cytotoxic edema monitored for 10 minutes to measure changes in synaptic efficacy resulting from HFS. Following HFS, Ravi Rungta¹, Hyun Choi¹, John Tyson¹, Aqsa Malik¹, fEP amplitudes significantly increased above baseline Lasse Dissing-Olesen¹, Paulo Lin¹, Stuart Cain¹, Pieter in the GPe and GPi at 10 minutes, indicating changes Cullis¹, Terrance Snutch¹, Brian MacVicar¹ in synaptic plasticity are present in the BG of healthy ¹University of British Columbia subjects. The magnitude of change is intermediate to previous findings comparing PD patients ON and OFF Cytotoxic brain edema is the principal cause of medication, indicating that the "normal" response to mortality following brain trauma and cerebral infarct these stimulation paradigms is not the same as the yet the mechanisms underlying neuronal swelling PD ON response. are poorly understood. Here we show that neuronal swelling and death was triggered by activating either 2-B-39 All-or-none axonal Ca2+ dynamics in voltage-gated sodium channels or NMDA receptors recurrent circuits of the hippocampus and was independent of Ca2+ entry but required Cl- Israeli Ran¹, Richard Tsien¹ entry via an unknown pathway. During swelling, two photon fluorescence lifetime imaging demonstrated ¹NYU Neuroscience Institute that increases in intracellular sodium concentration ([Na+]i) were followed by a secondary Cl- influx An action potential (AP) is assumed to travel actively leading to volume increases. To identify the novel and reliably along axons and trigger Ca2+ entry into chloride influx pathway that caused neuronal nerve terminals without fail, leaving all-or-none swelling we first took a pharmacological approach to regulation of release probability (Pr) in the hands of narrow down a list of candidates followed by siRNA downstream SNARE proteins. Using viral delivery in knockdown of these targets using LNP delivery mature hippocampal slice cultures and two-photon systems. Surprisingly, knockdown of a previously imaging of fast genetically-encoded Ca2+ sensor, unidentified neuronal chloride channel attenuated GCaMP6f, we explored the dynamics of axonal Ca2+ both neuronal swelling and a Cl- current that was transients (CaTs) evoked by single AP stimulation of activated when cortical neurons were depolarized to CA3 pyramidal neurons in organotypic slices studied membrane potentials > -20mV. We conclude that at 30°C. CaT amplitudes followed a right-skewed cytotoxic brain edema occurs when sufficient Na+ distribution (>700 boutons). Strikingly, 1AP CaTs influx depolarizes neurons to activate Cl- entry, imaged along single axons failed intermittently on thereby causing subsequent neuronal swelling repeated (30) trials at neighbor boutons. leading to neuronal death. The identification of a Conservative histogram analysis of CaT amplitude unique Cl- channel that is activated by depolarization revealed a bimodal distribution with clear separation as a significant Cl- entry pathway during pathological of CaT successes and failures. CaT failures rarely swelling triggered after Na+ entry suggests that new spread across an entire branch, suggesting that they strategies could be developed towards reducing were not due to conduction failure. Notably, brain edema. prolonging AP duration with the K+ channel blocker 4-aminopyridine (100 μM) reduced CaT failure rate and increased both their amplitude and CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

2-B-41 The X-linked Intellectual Disability Gene, C (PLC)-mediated breakdown of PIP2 into inositol DHHC9, in Neurite Outgrowth and Synapse triphosphate (IP3) and diacylglycerol (DAG). We Formation examined the effects of OAG, a membrane- permeable analogue of DAG, as well as IP3, on Jordan Shimell¹, D. Blair Jovellar ¹, G. Stefano Brigidi¹, cultured bag cell neurons. OAG activated a Shernaz Bamji¹ prolonged, Ca2 -permeable inward current in a dose- dependent manner. Gd3 inhibited the current, but ¹University of British Columbia traditional cation channel blockers, MDL-12330A and flufenamic acid, did not. In addition, pretreatment Palmitoylation is a reversible post-translational with the protein kinase C (PKC) inhibitor, H7, modification involving the attachment of palmitate prevented the current. However, in an independent to cysteine residues on substrate proteins. This bioassay, unlike the phorbol ester PMA, OAG did not process is catalyzed by a family of palmitoyl activate PKC in bag cell neurons. Inclusion of IP3 in acyltransferase (PAT) enzymes that contain a the internal saline enhanced the OAG current. OAG conserved DHHC motif. Palmitoylation enhances the depolarized cultured bag cell neurons, increased recruitment of proteins to the membrane and the excitability, and, in some cases, caused palmitoylation of a number of synaptic proteins is afterdischarge-like action potential firing. Neurons believed to regulate synapse organization, function pretreated with H7 exhibited attenuated and plasticity. Although this is a relatively new field depolarization, with the majority of neurons not of research, disruption of DHHC function has been firing in response to OAG. OAG-induced implicated in a number of neurodegenerative and afterdischarge-like behaviour appears to require PKC neurodevelopmental disorders, underscoring their permitting lipid-gating of the channel. This suggests importance for proper brain development and an interaction between the PLC pathway and PKC to function. DHHC9 loss of function mutations have control the strength and duration of the been identified in patients with intellectual disability, afterdischarge. however its role in the development and function of neural circuits is still unknown. Here we demonstrate 2-B-43 Paradoxical excitation by primary afferent that DHHC9 is localized to both excitatory and depolarization requires dual changes in GABAergic inhibitory neurons where it plays an important role signalling and neuronal excitability in promoting dendritic outgrowth and arborisation and constraining exuberant synapse formation. Petri Takkala¹, Yi Zhu², Steven Prescott³ Preliminary data suggest that this is mediated through the palmitoylation of the DHHC9 substrate, ¹University of Toronto, ²University of Pittsburgh, Ras. Taken together, this work suggests that ³The Hospital for Sick Children palmitoylation-dependent regulation of Ras by DHHC9 modifies neural complexity by regulating The central terminals of primary afferent fibers neuronal growth and synaptic density. experience depolarization upon activation of GABAA receptors (GABAAR) due of their high intracellular Cl- concentration. Primary afferent depolarization (PAD) is normally inhibitory because of Na channel 2-B-42 Diacylglycerol and inositol triphosphate inactivation and shunting, but PAD can evoke spikes modulate a protein kinase C-dependent change in under certain pathological conditions. Using Aplysia bag cell neuron excitability computer simulations and dynamic clamp experiments, we sought to identify which biophysical Raymond Sturgeon¹, Neil Magoski¹ changes are required for PAD to become paradoxically excitatory and whether inhibitory ¹Queen's University effects of PAD are retained. Computational modeling In response to cholinergic stimulation, the bag cell predicted that GABAAR-induced spiking requires neurons of Aplysia californica undergo a long-term both a depolarizing shift in GABA reversal potential change in excitability, leading to an afterdischarge and increased intrinsic excitability such as that and the secretion of egg-laying hormone to initiate produced by reduced K channel function. We tested reproductive behaviour. A key pathway activated at our predictions experimentally by using dynamic the onset of the afterdischarge is the phospholipase clamp to insert virtual GABAAR conductances with CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

different reversal potentials and kinetics into dorsal maturation of glutamatergic synapses. We find that root ganglion neurons. Neurons from naïve rats were tadpoles raised in D-serine (100 µM) for 2 days have compared before and after pharmacological higher frequencies of miniature excitatory reduction of Kv1-type current, and against neurons postsynaptic AMPAR currents and higher retinotectal from nerve-inured rats. Results confirmed that both synaptic AMPA/NMDA ratios compared to control predicted changes are indeed necessary to yield animals. To examine the effects of D-serine on GABA-induced spiking. However, even when PAD can axonal development, images were collected daily, elicit spiking, sustained GABAAR input tends to block over 4 days to assess growth and branch elaboration spontaneous spike initiation and the propagation of and at shorter (10 min) intervals to assess branch spikes through the depolarized region, arguing that stabilization. We find that increasing available D- PAD retains its inhibitory effects. Unlike postsynaptic serine results in the hyperstabilization of retinal axon inhibition, which is readily disrupted by Cl- branches. Axonal arbors become less complex dysregulation, these findings argue that presynaptic compared to control axons over 4 days of treatment inhibition via PAD is resilient to pathological with D-serine. These results suggest that D-serine disruption. levels are modulated by glutamatergic neurotransmission in vivo and can influence the 2-B-44 Modelling morphology and integration in maturation of retinotectal synapses and circuit developing dendrites refinement.

Lara Thompson¹ 2-B-46 Glycine-mediated fast inhibitory synaptic transmission in the hypothalamic paraventricular ¹University of British Columbia nucleus

This poster will present modelling techniques and Vojtech Vavra¹ results of dendritic integration that are both informed and informing experiments in vivo of ¹University of Calgary xenopus tadpoles during development. Glycine is a major inhibitory neurotransmitter in the 2-B-45 D-Serine influences retinotectal synapse spinal cord/brainstem but in the forebrain it is maturation and axonal refinement in the largely thought to be restriced to modulatory actions developing visual system either on extrasynaptic glycinergic receptors or as a co-agonist to NMDA. Here we present functional Marion Van Horn¹, Loredano Pollegioni², Edward electrophysiological data from neurons in the Ruthazer¹ paraventricular hypothalamic nucleus (PVN) of mice demonstrating its role as a bona fide fast inhibitory ¹Montreal Neurological Institute, ²University of synaptic mediator. We performed whole cell Insubria recordings on slices from CRH:Cre:TdTomato mice. The gliotransmitter D-serine is a co-agonist for Inhibitors of glutamate and GABA-A receptors (CNQX synaptic N-methyl-D-aspartate receptors (NMDAR). 10 uM, D-AP5 50 uM, Bic 20 uM) were constantly Here we examined the role D-serine plays in present in the perfusion medium. In response to regulating synaptic transmission and axonal focal application of glycine (puff, 0.1-3 mM) we remodeling in the developing visual system of the observed a large inward current that was inhibited tadpole. We find acute D-serine (100 µM) wash-on by 0.6 uM strychnine in >90% of the PVN neurons enhances NMDAR currents of optic tectal neurons, tested. Electrical stimulation of the neuropil resulted whereas degradation of D-serine by RgDAAO in fast synaptic currents (-109±33 pA) that was reduces NMDAR currents, indicating that inhibited by 0.6 uM strychnine. These synaptic endogenous D-serine is normally present below events were observed in a fraction of cells in PVN saturating levels. To investigate the pathways (21%, 26 out of 126 cells), while being completely involved in modulating D-serine release we used D- absent in CRH-positive cells (n=19). We also noted serine amperometric biosensors and find that sporadic spontaneous synaptic release of glycine AMPAR activation results in an increase in D-serine (sIPSCs frequency: 0.16±0.06 Hz, amplitude: -85±17 release in vivo. We next tested whether chronically pA). Occasionally we observed bursts of high elevating D-serine levels could influence the frequency sIPSCs, suggesting there may be CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

conditions under which the glycinergic system can Nicholas Weilinger¹, Brooke Rakai¹, Alexander potently impact electrical activity in postsynaptic Lohman¹, Jennifer Bialecki¹, Nathan Ikuta², Lucas neurons. Here we show the first evidence for the fast Scott¹, Michael Colicos¹, Campbell Teskey¹, Ian glycine mediated synaptic transmission in the Winship², Roger Thompson¹ hypothalamus. Experiments designed to understand the physiological role of this signaling system are ¹Hotchkiss Brain Institute, ²Neurochemical Research ongoing. Unit / University of Alberta

2-B-47 Role of palmitoylation in NMDA receptor Over-activation of neuronal N-methyl-D-aspartate trafficking and function in corticostriatal co-culture receptors (NMDAR)s causes excitotoxicity and is critical for neuronal death. In the classical view, Liang Wang¹, Rujun Kang¹, Lynn Raymond¹ these ligand-gated Ca2+ permeable ionotropic receptors require co-agonists and membrane ¹University of British Columbia depolarization for activation. We report that NMDARs signal during ligand binding without Previous studies show a critical role of NMDA activation of their ion conduction pore. receptor (NMDAR) localization and subunit Pharmacological pore block with MK-801 or composition in determining its excitotoxicity in physiological pore block with Mg2+ prevented Huntington's disease (HD). Our lab has found in an NMDAR currents, but failed to block excitotoxic HD mouse model that GluN2B-NMDAR at membrane currents and dendritic blebbing induced extrasynaptic (Ex) sites are increased in striatum at by NMDA. Recruitment of pannexin-1 (Panx1) an early stage and lead to impaired striatal neuronal channels was critical in this excitotoxic response. survival signaling; however, the mechanism Indeed, Panx1 opening mediated the bulk of underlying altered NMDAR trafficking in HD remains excitotoxic Ca2+ influx during NMDA receptor unknown. Others have shown that posttranslational excitotoxicity. In contrast to MK-801, competitive modification of GluN2A and GluN2B subunits by antagonists that prevent ligand binding to the palmitoylation, the addition of palmitate to cysteines NMDAR prevented Panx1 opening, membrane in two C-terminal domain clusters, regulates surface currents and blebbing. NMDARs, Src family kinases expression and synaptic targeting of NMDAR. and Panx1 were found in a signaling complex and Notably, two palmitoyl acyl transferase (PAT) activation of Panx1 involved phosphorylation at enzymes, DHHC17 (HIP14) and DHHC13 (HIP14L), Y308. Block of this NMDAR-Src-Panx1 signalsome in also interact with huntingtin, the protein mutated in vitro, in situ, or in vivo by administration of a Y308 HD, and both HIP14- and HIP14L-deficient mice interfering peptide either before or 2 hours after develop features resembling HD. We have examined, ischemia/stroke was neuroprotective. Our for the first time, the role for palmitoylation and observations provide key insights into a novel HIP14 in regulating GluN2A-/GluN2B-NMDAR signaling modality of NMDARs that has broad trafficking and NMDAR functioning in corticostriatal reaching implications for brain physiology and co-culture. We found that reduced GluN2B-NMDAR pathology. palmitoylation may contribute to increased Ex- NMDAR in striatal neurons, but that decreased 2-B-49 Class 5 semaphorins mediate synaptic HIP14 function is not involved in either GluN2B- or elimination and activity-dependent plasticity in GluN2A-NMDAR trafficking. Further, knock-down of rodent hippocampal neurons HIP14 in co-culture has no effect on NMDAR function. These studies will grant us deeper Wei Xiao¹, Rachel Gomm Kolisko¹, Riki Dingwall¹, Blair understandings on the dynamics between Jovellar¹, Shernaz Bamji¹, Tim O'Connor¹ synaptic/Ex NMDAR trafficking and provide novel therapeutic targets for pharmacological ¹University of British Columbia interventions in HD. Supported by CIHR funding. Autism spectrum disorders (ASD) is a highly heritable 2-B-48 A new signaling modality for NMDA developmental brain disorder caused by altered receptors in excitotoxic cell death and ischemic synaptic connectivity and function. In 2009, a stroke genome-wide association study has identified Semaphorin 5A (Sema5A) as a novel autism CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

susceptibility gene. Sema5A is a member of the cholinergic tone may contribute to information semaphorin family, a large family consisting of retention during temporal association tasks. On the secreted and membrane-associated proteins that other hand, cholinergic system is also involved in play numerous key roles in the development and mesial temporal lobe epilepsy. In a relatively high function of the nervous system. Compared with concentration of carbachol (20 µM), the same brief other semaphorins, Sema5A's function in brain stimulation often drove a response similar to ictal development is largely unknown. Here, we provide depolarizations, which accompanied a depolarization evidence that Sema5A regulates synaptic elimination block. We further demonstrate that TRPC4/5 in hippocampal neurons. Both of the overexpression channels contribute to, and the SK and M-type of Sema5A as well as the bath application of potassium channels suppress this response. Our secreted Sema5A protein caused excitatory synaptic results indicate that individual neurons may exhibit elimination in hippocampal neurons without persistent firing and epileptiform responses affecting inhibitory synapses. In contrast the depending on the level of the cholinergic tone. knockdown of Sema5A significantly increased Downstream mechanisms involve the TRPC4/5 excitatory synaptic density. Further, we investigated channels and the AHP currents. These modulations the relationship between class five semaphorins of single cell properties might underlie contrasting in (Sema5A and Sema5B) and long-term potentiation vivo neural activity during memory tasks and (LTP), one of the most widely studied cellular models epilepsy. of synaptic plasticity. We demonstrated that the overexpression of class 5 semaphorins was capable 2-B-51 Regulation of endosome fusion by Cav2.2 of attenuating the increase of synaptic density caused by LTP, implicating the involvement of Fangxiong Zhang¹, Gerald Zamponi¹ Sema5A and Sema5B in activity-dependent plasticity. ¹University of Calgary Accompanied with our previous findings of Sema5B, these data reveal a new role for semaphorins in Voltage-dependent calcium channels (including mediating synapse maintenance and morphology Cav2.2) are a group of voltage-gated ion channels and therefore provide insights into the role that found in the membrane of excitable cells with these guidance molecules may play in the permeability to the calcium ion Ca2+. However, the developing brain. intracellular functions of these channels have been largely unexplored. In this study, we have 2-B-50 Persistent firing and its transition to ictal- investigated the role of Cav2.2 in endocytic like response in hippocampal CA1 pyramidal transport. In the presence of bafilomycin A1 which neurons inhibits the fusion of late endosomes and lysosomes, Motoharu Yoshida¹, Beate Knauer¹ the GFP tagged Cav2.2 channels expressed in tsA- 201 cells resided in the membrane of late ¹Ruhr University Bochum endosomes and co-localized with Rab7 (a late endosome/lysosome marker). These results then The hippocampal CA1 region is crucial for temporal suggested that Cav2.2 channels may affect late association tasks that require short-term (< 30s) endosome function. Indeed, Cav2.2 significantly retention of memory. These tasks also require an enhanced the degradation of peptides expressed in intact cholinergic system. However, it remains late endosomes, indicating that Cav2.2 may play a unclear what cellular mechanisms support short- general role in regulating endosomal membrane term memory retention in CA1. Here, using in vitro trafficking by increasing the fusion of late recordings from rats, we show that brief stimulation endosomes and lysosomes. Overall, we propose a (100pA, 2s) can initiate persistent firing in CA1 new role of Cav2.2 in regulating endocytic transport. pyramidal cells in the presence of cholinergic agonist carbachol (1-10 µM). This persistent firing lasted more than 30 s and its frequency was around 10 Hz. C - Disorders of the Nervous System Our observations suggest that the canonical transient receptor potential channels (TRPC4/5) 2-C-52 Glutamatergic transmission is enhanced in support persistent firing. These data suggest that the amygdala in Experimental Autoimmune persistent firing supported by a heightened Encephalomyelitis CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

Shaona Acharjee¹, Adrienne Benediktsson², Quentin vulnerable to degeneration. NG2 cells, characterized Pittman¹ by the near ubiquitous co-expression of platelet derived growth factor receptor α ¹University of Calgary, ²Mount Royal University (PDGFRα) in the uninjured central nervous system (CNS), are oligodendrocyte progenitors (OP)s Multiple sclerosis (MS) is often associated with co- which may serve as a source of new OLs following morbidities like neuropsychiatric and cognitive SCI. PDGFRα-CreERT mice were crossed with impairments, affecting around 50% of the patients. Rosa26-YFP mice and administered tamoxifen to We investigated these abnormalities in an animal label OPs two weeks prior to contusive thoracic model of MS, called experimental autoimmune spinal cord injury. In the uninjured spinal cord we encephalomyelitis (EAE) during the early onset of the found that YFP was expressed in NG2τ OPs at disease. We have shown that at this presymptomatic very high efficiency, as well as αSMAτ stage, the EAE mice show emotional and cognitive pericytes and fibronectinτ fibrocytic cells in deficits in absence of motor deficit. Herein, we the spinal roots. Following injury, many recombined investigated the potential synaptic changes in the cells continue to express the PDGFRατ, amygdala associated with inflammation, a brain Olig2 and NG2, indicative they have remained as region involved in emotional behaviour. EAE was OPs, but substantial differentiation into new induced in C57/BL/6 mice with MOG35-55 /CFA and oligodendrocytes (CC1τ) was observed, pertussis toxin (PTX). CFA and PTX only mice were responsible for de novo ensheathment of >30% of controls. Dendritic spines were counted after Golgi the myelinated axons by three months. Strikingly, staining. Whole-cell recording was carried out in the the majority of P0τ Schwann cells in the spinal principal neurons of basolateral amygdala (BLA). cord expressed YFP, suggesting they originated from Glutamatergic currents were recorded in the central nervous system PDGFRατ OPs. presence of GABA receptor blocker picrotoxin. However, further work is required to characterize if Investigation into glutamatergic synaptic other YFPτ populations like transmission revealed increased frequency of the αSMAτ pericytes or the peripheral mini-excitatory postsynaptic currents (mEPSC) fibrocytic-like cells can contribute to the formation without any changes in amplitude compared to the of myelinating Schwann cells or OL's in the injured controls; this is indicative of increased glutamate CNS. Overall, this work reveals phenotypic plasticity release. This was associated an increase in the of PDGFRα precursors following SCI as a source synaptic spines in the principal neurons of the BLA of the new remyelinating Schwann cells and and alteration in the AMPA receptor subunit oligodendrocytes in the injured cord. composition, with an increase in GluA2 subunit. In conclusion, emotional and cognitive deficits 2-C-54 Neuronal sodium elevation and COX-2 observed in EAE (and possibly MS) were associated activation in post-traumatic epileptogenesis in vitro with an increased dendrite spines, enhanced glutamatergic transmission and changes in AMPA Trevor Balena¹, Kevin Staley¹ receptor composition in the BLA. ¹Massachusetts General Hospital 2-C-53 PDGFRa-positive progenitor cells form myelinating oligodendrocytes and Schwann cells Post-traumatic accumulation of intracellular Cl- following contusion spinal cord injury results in GABA becoming depolarizing, which reduces inhibition, enhances propagation of Peggy Assinck¹, Greg Duncan², Jason Plemel³, neuronal firing, and may contribute to early post- Michael Lee², Jie Liu², Dwight Bergles⁴, Wolfram traumatic seizures. Charge balance dictates that Tetzlaff² increases in [Cl-]i may be accompanied by increases in cations, which could underlie cytotoxic edema and ¹ICORD/UBC, ²UBC/ICORD, ³University of Calgary, accompany epilepsy. We tested for changes in ⁴Johns Hopkins University School of Medicine intracellular Na+ concentration using organotypic hippocampal slice cultures from wild-type C57BL/6J Contusive spinal cord injury (SCI) results in mice, imaged with the Na+-sensitive dye SBFI. considerable demyelination of spared axons, which Immediately post-trauma, neurons had significantly impairs signal transduction and may leave axons higher [Na+]i than has been reported in undamaged CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

neurons, particularly near the cut surface of the Most importantly, AβO injections in macaques slice. After a briefly recovery period, [Na+]i again induced AD-type neurofibrillary tangle formation, rose to high levels and remained elevated for weeks. unlike most rodent models. In ongoing experiments, [Na+]i was found to depend on the activity of Aβ, total tau and phosphor-tau in Na+/K+ ATPases, cation/Cl- cotransporters, and cerebrospinal fluid, as well as blood chemistry and Na+/Ca2+ exchangers in order to support high rates endocrinology panels, are being examined before of transmembrane Na+ flux during epileptogenesis. and several time points after icv injection of Wash-in of the dye fluorescein indicated that AβOs. Behavioural phenotype is now being traumatized neuronal membranes may also allow characterized via activity tracking, and performance Na+ to leak into damaged neurons, resulting high on learning and memory tasks using touchscreen [Na+]i, propidium iodide-positive status, and cell CANTAB and saccadic eye movements (see Wither et swelling. Inhibition of COX-2 and related al, this meeting). inflammation pathways both significantly lowered [Na+]i and drastically reduced seizure activity in 2-C-56 Experimental traumatic brain injury: Bad epileptic slices. Overall, elevated [Na+]i is a to the bone? promising new biomarker for neuronal compromise, as it precedes many traditional indicators of epileptic Rhys Brady¹, Sandy Shultz², Mujun Sun², Tania activity and ictal cell death. Romano¹, David Wright³, John Wark⁴, Terrence O'Brien ¹, Brian Grills¹, Stuart McDonald¹ 2-C-55 Development of a primate model of Alzheimer’s Disease I. Characterization of molecular ¹La Trobe University, ²The University of Melbourne, pathology ³Florey Institute of Neuroscience and Mental Health, ⁴Royal Melbourne Hospital Susan Boehnke¹, Leticia Forny-Germano², Robert Wither¹, Ann Lablans¹, Brian Coe¹, Fernanda De Traumatic brain injury (TBI) has been associated with Felice², Douglas Munoz¹ accelerated bone fracture healing, however pathophysiological mechanisms involved in TBI have ¹Queen's University, ²Federal University of Rio de the potential to be detrimental to bone. The current Janeiro study assessed the effect of experimental TBI in rats on the quantity and quality of mineralized bone Alzheimer's disease (AD) is a devastating within the femur. Rats were randomly assigned into neurodegenerative disorder, and therapeutics have either sham or lateral fluid percussion injury (FPI) proven difficult to translate from mouse models to groups. Open-field testing assessed locomotion at 1, human clinical trials. An intermediary primate model 4, and 12 weeks post-injury, with the rats killed at 1 would greatly advance our understanding of and 12 weeks post-injury. Bones were analysed using mechanisms involved in AD pathogenesis and could peripheral quantitative computed tomography be used to vet promising therapeutics. Here, we (pQCT), histomorphometric analysis and three-point describe the molecular characterization of a non- bending. pQCT analysis revealed that at 1 and 12 human primate model of AD generated in macaque weeks post-injury, the distal metaphyseal region of monkeys by icv injections of amyloid-β femora from FPI rats had reduced cortical content oligomers(AβOs). Soluble AβOs (10% decrease at 1 week, 8% decrease at 12 weeks; accumulate in the brains of AD patients and p < 0.01) and cortical thickness (10% decrease at 1 correlate with disease-associated cognitive week, 11% decrease at 12 weeks p < 0.001). There dysfunction. In our first set of experiments molecular was also a 23% reduction in trabecular bone volume pathology was examined by immunohistochemistry ratio of this region at 1 week post-injury and a 27% on brains perfused several weeks after AβO reduction in FPI rats at 12 weeks post-injury (p < injection. AβOs diffused into the brain and 0.001). Despite the changes at the femoral distal accumulated in several regions associated with metaphysis we observed no changes in bone memory and cognitive functions. Cardinal features of quantity and quality at the diaphysis. Overall, our AD pathology, including synapse loss, tau results indicated that experimental TBI induced hyperphosphorylation, astrocyte and microglial region-specific bone loss. Importantly, there were no activation, were observed in regions of the macaque differences in locomotor outcomes, which suggested brain where AβOs were abundantly detected. that post-TBI changes in bone were not due to CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

immobility. These findings indicate that the Stuart Cain¹, Barry Bohnet¹, Andrew Yung¹, Huili pathological systemic effects of TBI also have a Han¹, Piotr Kozlowski¹, Brian MacVicar¹, Terrance negative effect on bone. Snutch¹

2-C-57 High density lipoproteins benefit function ¹University of British Columbia and reduce inflammation in human brain microvascular endothelial cells. Cortical Spreading Depression (CSD) is believed to be the pathophysiological trigger mechanism in Emily Button¹, Jerome Robert¹, Sophie Stukas¹, Cheryl migraine headaches. Familial Hemiplegic Migraine Wellington¹ Type-1 (FHM-1) patients suffer from migraine, sometimes including ataxia and seizures, resulting ¹University of British Columbia from gain-of-function mutations in the Cav2.1 (P/Q- type) calcium channel. The gabapentinoid Increasing evidence suggests that cerebrovascular neuropathic pain drug, Pregabalin (Lyrica) binds to dysfunction has a major role in Alzheimer's disease the alpha-2-delta calcium channel ancillary subunit (AD) as amyloid is found within the and is thought to inhibit Cav2.1 currents. Therefore, cerebrovasculature, integrity of the blood-brain we examined its potential for suppressing CSD in barrier is reduced, and cerebral blood flow becomes mice containing FHM-1 mutations, which display a dysregulated. Substantial research has reduced threshold for CSD. We utilized intrinsic demonstrated that high density lipoproteins (HDL) optical signalling to examine the rates of have profound vasoprotective properties in propagation of CSD in vitro using acute brain slices peripheral vessels. However, whether these benefits from wild-type and FHM-1 mice. In addition, we extend to the CNS have yet to be confirmed. Here have correlated these findings with we show that plasma-derived HDL increases nitric electrophysiological analysis of synaptic activity oxide (NO) production and decreases the using whole-cell patch clamp in acute brain slices inflammatory status of human brain microvascular and exogenously expressed Cav2.1 channels. endothelial cells (hBMECs). Plasma HDL was isolated Furthermore, we performed 7 Telsa diffusion- from healthy human volunteers by density gradient weighted, magnetic resonance imaging in FHM-1 ultracentrifugation and exposed to hBMECs to assess knock-in mice to visualize the speed and threshold of endothelial function and inflammation. NO CSD in vivo at high spatial and time resolution. This production was measured using 4,5- has allowed us to identity the specific brain regions diaminofluorescein (1 μM) in cells after affected by FHM-1 mutations during CSD and our incubation with HDL (100ug/ml, 15 min). HDL (50 findings indicate that both CSD speed and threshold ug/ml, 16 hr) suppression of tumour necrosis factor are differentially affected by action of the pregabalin α (TNFα)-induced inflammation (1 in wild-type versus FHM-1 mutant mice. ng/mL, 4 hr) was assessed by ELISA of human IL-6 in cell media and western blotting of vascular cell 2-C-59 A mouse model of SNCA multiplication adhesion molecule in cellular protein extracts. Production of NO in hBMECs is significantly Stefano Cataldi¹ increased and TNFα stimulated inflammation is significantly reduced with HDL treatment. Our ¹Centre for applied Neurogenetics results suggest that plasma HDL influences cerebrovascular endothelial cell health. As the The identification of several mutations causing cerebrovasculature system is emerging as one link familial forms of Parkinson's disease (PD) has led to between whole body health and the brain, the development of multiple mouse models capitalizing on the vasoprotective functions of HDL reproducing similar genetic alterations. Mutations may provide novel therapeutic opportunities for AD. and multiplications in the alpha synuclein (SNCA) gene have been linked to familial forms of PD. SNCA 2-C-58 Pregabalin Alters Cortical Spreading is ubiquitously expressed in neurons and Depression and Synaptic Function in a Model of intraneuronal accumulations of aSyn are the Familial Hemiplegic Migraine Type-1 pathological hallmark of the disease. SNCA overexpression in mice reproduced many features of sporadic PD, including motor activity alteration, CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

alphasynuclein pathology, deficits in nonmotor (r=0.75, p<0.001) and severity (r=0.77, p<0.001) functions and biochemical and molecular changes of seizures increased with session. Seizure onset similar to those observed in PD. The present study threshold was also reduced (r=-0.69, p<0.001), investigates the consequences of human SNCA and the average number of seizures increased over overexpression in mice, resembling pathogenic session (r=0.83, p<0.001). We find that repeated multiplication, through a P1-derived artificial optogenetic stimulation eventually elicits seizures in chromosome (PAC) vector. Striata from WT and TG awake behaving animals. This may occur through mice were processed for WB and probed for aSyn in repeated recruitment of Hebbian plasticity by driving both the supernatant and pellet fractions. An excessive neuronal activity. Our optogenetic established set of behavioral paradigms has been approach is highly cell-specific and has no used, including open field, novel object location, appreciable inflammation or injury. Our model thus novel object recognition and cylinder test. Open field allows the identification of directly activated cells, so measures locomotor activity and anxiety, novel that the role of specific cell populations in object location and novel object recognition tests epileptogenesis can be investigated. assess spatial and recognition memory respectively, and lastly, cylinder test analyzes spontaneous, 2-C-61 Chronic stress induces anxiety via vertical motor activity. All tests have been an amygdalar intracellular cascade that impairs performed on two separate cohorts of animals, at 3 endocannabinoid signaling: identification of a and 6 months of age, revealing progressive common therapeutic target for metabolic and hyperactivity and anxiety. anxiety disorders

The preliminary results support a key role for SNCA Zhaohong Qin¹, Xun Zhou¹, Nihar Pandey¹, Haley in synaptic function and revealed a behavioral Vecchiarelli², Chloe Stewart¹, Xia Zhang³, Diane phenotype in hSNCA OE mice. Lagace⁴, Jean Michel Brunel⁵, Jean-Claude Beique⁶, Alexandre Stewart⁷, Matthew Hill², Hsiao-Huei Chen¹ 2-C-60 A model of epilepsy based on optogenetic kindling ¹Ottawa Hospital Research Institute/ University of Ottawa, ²University of Calgary, ³Royal Ottawa Mental Elvis Cela¹, Andrew Chung¹, Taiji Wang¹, Per Jesper Health Centre, ⁴ University of Ottawa, ⁵Aix-Marseille Sjöström² Université, ⁶University of Ottawa, ⁷University of Ottawa Heart Institute ¹McGill University, ²The Research Institute of the McGill University Health Centre Collapse of endocannabinoid (eCB) signaling in the amygdala contributes to stress-induced anxiety, but To study circuit changes associated with the mechanisms of this effect remain unclear. eCB epileptogenesis, we developed a novel optogenetic production is tied to the function of the glutamate animal model of epilepsy. We hypothesized that receptor mGluR5, itself dependent on tyrosine repeated high-frequency stimulation (kindling) phosphorylation. Herein, we identify a novel pathologically rewires local circuits by excessive pathway linking eCB regulation of anxiety through recruitment of Hebbian plasticity. We targeted phosphorylation of mGluR5. Mice lacking LMO4, an Channelrhodopsin-2 (ChR2) to primary motor cortex endogenous inhibitor of the tyrosine phosphatase (M1) of male C57BL/6J mice by stereotactic delivery PTP1B, display reduced mGluR5 phosphorylation, of AAV-CaMKIIa-hChR2-E123T/T159C-p2A-EYFP. eCB signaling and display profound anxiety that is After 21 days of recovery, we stimulated M1 of reversed by genetic or pharmacological suppression awake behaving animals with a 445-nm laser while of amygdalar PTP1B. Chronically stressed mice recording EEG and video. Seizures were not elicited exhibited elevated plasma corticosterone, decreased in early stimulation sessions, but gradually emerged LMO4 palmitoylation, elevated PTP1B activity, in 6 out of 6 animals after ~15 sessions. These reduced amygdalar eCB levels and displayed anxiety seizures were defined as periods longer than 3 behaviours that were restored by PTP1B inhibition or seconds where EEG power exceeded a noise by glucocorticoid receptor antagonism. Consistently, threshold. We quantified seizure duration by EEG, corticosterone decreased palmitoylation of LMO4 and their severity by a modified Racine scale. In a and its inhibition of PTP1B in neuronal cells. representative animal, we found that the duration Collectively, these data reveal a stress-responsive CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

corticosterone-LMO4-PTP1B-mGluR5 cascade that Conclusion: These findings suggest that mild impairs amygdalar eCB signaling and contributes to repetitive TBI acutely exacerbates neuropathology in the development of anxiety. PTP1B is also known to APP/PS1 mice. The long term consequence in the affect metabolic disorders, including obesity and trajectory of Alzheimer pathology is being studied. type II diabetes (T2D). Elevated PTP1B activity interferes with leptin and insulin signaling. People 2-C-63 Chronic Minocycline Treatment Rescues with T2D have a higher prevalence of anxiety. Social Interaction Deficit in Fmr1 KO Mice Together with our findings, PTP1B is an attractive target for the treatment of metabolic and anxiety Christine Chiu¹, Mariana Vetrici¹, Suk-Yu Yau¹, Brian disorders. Christie¹

2-C-62 Neuropathology in APP/PS1 Mice is ¹University of Victoria Exacerbated after CHIMERA (Closed-Head Impact Fragile X syndrome (FXS) is the most common form Model of Engineered Rotational Acceleration)- of inherited intellectual disability. It is caused by a Induced Traumatic Brain Injury mutation in the Fmr1 gene which leads to silencing Wai Hang Cheng¹, Dhananjay Namjoshi¹, Kris of the gene and loss of its gene product, Fragile X Martens¹, Anna Wilkinson¹, Taylor Ward-Able¹, Arooj Mental Retardation Protein. Minocycline is a Hayat¹, Kurt McInnes¹, Peter Cripton¹, Cheryl tetracycline antibiotic with anti-inflammatory, Wellington¹ neurotrophic and neuroprotective properties and has been used as an effective treatment in clinical ¹University of British Columbia trials of FXS patients. Using the Fmr1 knockout mice, we examined if chronic minocycline treatment could Objectives rescue the behavioral deficit in social interaction in FXS. Minocycline was administered in drinking water Traumatic brain injury (TBI) may increase Alzheimer to the newborn mice until they reached two months Disease (AD) risk up to 10 folds. Mild TBI, which of age, followed by sociability and social preference comprises over 75% of all cases, upon repetitive tests using the three-chamber apparatus. Test mice exposure may lead to long-term development of AD- were introduced to a restrained stimulus mouse (S1) like neuropathologies. This study investigates if mild for 10 min to assess sociability, followed by repetitive TBI exacerbates neuropathologies in an AD introduction of a second restrained stimulus mouse mouse model. Methods: The novel experimental (S2) for 10 min to assess social preference. Neither rodent TBI model recently developed by our group - Fmr1 knockout nor minocycline treatment affects Closed-Head Impact Model of Engineered Rotational performance in sociability test. However, Fmr1 Acceleration (CHIMERA) is used to induce closed- knockout significantly decreased social preference to head impact-acceleration TBI. We subjected 5-mo S2 mice as indicated by decreased exploration ratio male APP/PS1 mice to two mild TBI spaced 24 hours to S2 mice. Conversely, minocycline treatment apart. The mice were sacrificed at 2 days post-TBI. effectively increased exploration ratio to S2 mice for Behavioral, histological and biochemical tests were Fmr1 knockout mice, without affecting performance conducted to assess post-TBI outcomes. Results: in their wild-type littermates. The findings suggest Immediately after TBI, APP/PS1 mice suffered a that minocycline may be a promising treatment for prolonged loss of righting reflex compared to sham- improving behavioural deficits in social interaction in operated APP/PS1 mice. By 2 days post-TBI, they FXS. showed increased neurological deficits (neurological severity score) and poorer motor coordination 2-C-64 Stimulatory effects of nACh-R agonist (Rotarod) compared to sham-operated APP/PS1 activation on open field locomotor behaviour in a mice. Immunohistochemical staining revealed Rett syndrome mouse model. increased 6E10%2Bve amyloid deposits, microglial activation (Iba-1), argyrophilic fibre (silver staining) David McPhee², Tony Renda², Jay Leung², Raad and axonal bulb-like structures (phospho- Nashmi², Kerry Delaney² neurofilaments). TBI also induced brain A-beta level. Cerebrovascular changes are being assessed by cell ¹Univ. of Victoria, ²University of Victoria adhesion molecules and tight junction proteins. CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

Rett syndrome (RTT) results from loss of function of found in neuronal tissues of ALS patients. We have the X-linked transcription factor MECP2. Several previously shown that cell-to-cell transmission of studies indicate that cholinergic hypofunction is one SOD1 misfolding can occur via the uptake of of the consequences of MeCP2 loss of function. nanometer sized vesicles collected from misfolded Acute nicotine (NIC) decreases open field movement SOD1-expressing cells. However, the mechanism by (OFM) of wild-type (WT) male and female mice in a which misfolded SOD1 is propagated in vivo remains dose-dependent manner with reduced movement ambiguous. We hypothesized that vesicles found in evident at 1mg/kg and immobility at 2mg/kg. the extracellular spaces of ALS neuronal tissues Compared to saline injection, NIC injected would bear misfolded SOD1 and participate in symptomatic male RTT mice showed increased OFM propagation of SOD1. We isolated and characterized injection at 0.5 mg/kg, no difference at 1mg/kg and extracellular vesicles (EVs) from frozen neuronal normal suppression at 2mg/kg. Early symptomatic tissues of ALS mouse models and human ALS female het mice showed no significant change in patients. Immunoprecipitation using conformation- activity following 0.5 or 1 mg/kg with normal specific antibodies that detect misfolded SOD1 immobility at 2mg/kg. QRT-PCR of midbrain tissue of showed the enrichment of misfolded SOD1 on ALS male mice (incl. VTA and S. nigra) showed a 4-fold tissue-derived EVs compared to control. When the reduction in α-4 & α-6 nAChR expression. secreted EV-containing fraction from mutant-SOD1 We therefore tested the effect of the selective expressing cells was applied onto wild-type cells in α-4/6 nAChR agonist TC-2559. TC-2559 culture we observed an induction of SOD1 suppresses WT-OFM above 1mg/kg with maximal misfolding, a phenomenon that was abolished by effect at 2.5 mg/kg. Unlike NIC complete locomotor heat-denaturation of the EV-containing fraction. Our suppression was not produced by doses up to 10 results suggest that EVs bearing misfolded SOD1 are mg/kg. Locomotor paths taken by WT in the test competent to induce misfolding of wild-type SOD1, chamber were significantly changed by 2.5 mg/kg implicating EV dissemination in the propagation of TC-2559. They walked more slowly, stopped and SOD1 misfolding seen in ALS. turned more often and spent significantly less time in the centre, away from the walls. In contrast RTT 2-C-66 Neonatal Odor Learning Impairments mice showed a doubling of average velocity during Following Prenatal Ethanol Exposure the 5 min. post injection test period, without changes in locomotor pattern. We conclude reduced Christine Fontaine¹, James Dunbar¹, Julie Munich¹, nAChR expression in RTT mice results in a reduced Anna Patten¹, Brian Christie¹ inhibitory effect of receptor activation on ¹University of Victoria locomotion revealing a net excitatory effect at submaximal doses. Fetal Alcohol Spectrum Disorders, which result when a mother consumes alcohol during pregnancy, are 2-C-65 Extracellular Vesicles from Amyotrophic the leading cause of mental disability in North Lateral Sclerosis Tissue have Misfolded SOD1 Cargo America. These disorders are characterized by a wide and Are Implicated in Propagation of Protein array of behavioral abnormalities in executive, motor Misfolding and sensory function. Simple sensory systems, such Sarah Fernando¹, Judith Silverman¹, Leslie Grad¹, Neil as the olfactory system, have been shown to be Cashman¹ structurally and functionally damaged by prenatal and early postnatal ethanol exposure (PNEE) and ¹University of British Columbia thus may serve as a unique diagnostic tool. Recent work from our laboratory has indicated a Amyotrophic Lateral Sclerosis (ALS) is a fatal relationship between hippocampal synaptic plasticity neurodegenerative disease affecting motor neurons. and reduced levels of the endogenous antioxidant ALS disease pathology is known to spread glutathione (GSH). GSH acts as a redox modulator in spatiotemporally through the neuroaxis from one the brain, and can be depleted by alcohol-induced contiguous area to the next, reminiscent of a prion- oxidative stress. The goal of this study was to like mechanism of propagation. Mutations in the examine whether olfactory learning in PNEE rodent Cu/Zn superoxide dismutase (SOD1) gene are linked offspring was impaired early in life and whether to inherited cases of ALS, and misfolded SOD1 is these behavioral impairments are paralleled by CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

alterations in GSH in brain areas responsible for this model will help us to better understand the learning. Offspring exposed to ethanol via a liquid contribution of CD8%2B T cells to CNS diet, an isocaloric liquid diet or regular chow autoimmunity. throughout gestation. We have found that PNEE offspring do not show conditioned odor preferences 2-C-68 Can five weeks of arm cycling training as observed in offspring of dams fed an isocaloric improve walking and interlimb coordination in liquid diet or regular chow. Biochemical analyses chronic stroke? were performed on key olfactory structures and found altered GSH levels in these areas. These data Chelsea Kaupp¹, Taryn Klarner¹, Natalia Zapotoczny¹, indicate a possible relationship in the olfactory Yao Sun¹, Hilary Cullen¹, Trevor Barss¹, Gregory system of PNEE offspring with GSH. Pearcey¹, Paul Zehr¹

2-C-67 CD8+ T cells increase the encephalitogenic ¹University of Victoria potential of CD4+ T cells in a novel mouse model of Strong interactions between the upper and lower multiple sclerosis body are well established across species and recent Prenitha Mercy Ignatius Arokia Doss¹, Andree- work has highlighted the implications of these Pascale Roy¹, Joanie Baillargeon¹, Manu Rangachari¹ connections for rehabilitation in humans. During walking, interlimb spinal networks regulate gait in ¹Centre Hospitalier Université Laval (CHUL), Quebec healthy individuals and remain at least partially city intact after stroke. What remains to be investigated is whether training the arms after stroke will Multiple sclerosis (MS) is a chronic autoimmune facilitate these networks and result in improved disease of the central nervous system in which T walking. Chronic stroke participants (at least 6 cells cross the blood-brain barrier, recognize myelin months post infarct) were recruited to a 5 week long self antigen and mediate an attack against (30 min x 3 / wk) arm cycling intervention with a oligodendrocytes resulting in neuronal dysfunction. within-subject multiple baseline control. Muscle Approximately 85% of MS patients display a activation during treadmill walking was assessed via relapsing-remitting (RR) to secondary phase (SP) surface electromyography (EMG) and functional disease course in which successive relapse and walking parameters were assessed through standard recovery cycles are ultimately followed by a phase of clinical tests. Strength in the legs was evaluated via chronically worsening disease. Recent findings maximum isometric plantarflexion and dorsiflexion. suggest that the frequency of cytolytic CD8%2B T Preliminary results suggest a "normalization" of cells greatly exceeds that of CD4%2B T cells in acute locomotor EMG in the arms and legs after training. MS lesions. Experimental autoimmune This effect is accompanied by increased strength in encephalomyelitis (EAE) is a murine model that the ankle musculature of both legs, particularly the recapitulates the immunopathogenesis of MS, and more affected side. Clinical outcomes show EAE induced in the non-obese diabetic (NOD) strain improvements in walking speed and an increase in follows a RR to SP disease course. Our group exploits distance walked in the six minute walk test. Taken T cell receptor transgenic 1C6 mice on the NOD together, these preliminary results suggest that background which possesses CD4%2B and CD8%2B T locomotor training with the arms may have a cells that has specificity for the encephalitogenic beneficial effect on walking ability after stroke. peptide MOG[35-55]. Here we describe a new model in which 1C6 CD4%2B and CD8%2B T cells, or 1C6 2-C-69 Seizures during brain circuit formation CD4%2B T cells alone, are stimulated in vitro and are adoptively transferred to lymphocyte deficient Dong Hwan Kim¹, Kurt Haas¹ NODscid mice. We found that transfer of 1C6 Th1 ¹University of British Columbia alone induced EAE with lesser severity in NODscid mice as compared to the co-transfer of Th1 and Tc1. The immature brain is exceptionally susceptible to The presence of CD8%2B T cells influenced the abnormal seizure activity, and in the majority of pathogenicity of CD4%2B T cells as evidenced by individuals who develop epilepsy, the onset of their increased production of pro inflammatory spontaneous seizures occurs during childhood. cytokines IFNγ, TNFα and IL-2. Thus, this However, it remains unclear whether early-life CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

seizures affect critical processes on synaptogenesis test. These results suggest that arm and leg cycling and how neurons affected by seizures can self- could be used as an additional modality to improve regulate and maintain homeostasis. Using in vivo interlimb coupling and walking ability after stroke. two-photon time-lapse imaging of growing neurons and calcium imaging of network activity within intact 2-C-71 Burst-Predicting Neurons Survive an in and awake embryonic Xenopus brain, we vitro Excitotoxic Injury Model of Cerebral Ischemia demonstrate that PTZ-induced seizures lead to destabilization of existing dendritic processes and Eric Kuebler¹, Joseph Tauskela², Amy Aylsworth², hyperstabilization of new extensions. These growth Xigeng Zhao², Jean-Philippe Thivierge¹ changes are persistent, leading to stunted dendritic ¹University of Ottawa, ²National Research Council of arbors in mature neurons. We hypothesize that Canada these events are mediated through aberrant activation of intrinsic plasticity mechanisms, not Network bursts, defined as transients of increased through excitotoxicity. multi-unit activity (MUA) flanked by silence, are related to the propagation of signals. Recent work 2-C-70 Arm and leg cycling training improves suggests that a subset of neurons - termed leaders - neurological function and walking ability after are predictive of upcoming network bursts, and may stroke promote information transmission. The loss of Taryn Klarner¹, Trevor Barss¹, Yao Sun¹, Chelsea leaders as a result of insult may affect the function Kaupp¹, Gregory Pearcey¹, Pamela Loadman¹, E Paul of the neuronal network. Here, we examined if Zehr¹ leaders were more likely than other neurons to survive and remain active after being subjected to an ¹University of Victoria in vitro excitotoxic model of cerebral ischemia, applied for two different durations to cause 'low' Rhythmic arm and leg (A&L) movements found in and 'high' levels of toxicity, as evaluated in live vs. walking, cycling, and stepping share elements of dead assays or vehicle (control). Dissociated cortical central neural control. Despite these shared neurons were plated on multi-electrode arrays and, connections, the extent to which A&L cycling can spontaneous electrical activity was first recorded for lead to training adaptations which transfer to 20 minutes at 17 days in vitro (DIV); followed by improved walking function remains untested. The exposure to the insult at DIV 18, and a post-insult purpose of this study was to test the efficacy of A&L recording at DIV 21. Leaders were identified in 17 cycling training as a modality to improve locomotor DIV recordings as electrodes that were active in a 50 function after stroke. Chronic stroke participants ms time window prior to network bursts. MUA rates (<6 months) were recruited and performed 30 for leaders did not differ between pre- (17 DIV) and minutes of A&L cycling training three times a week post- (21 DIV) insult recordings (Fig). In contrast, for 5 weeks. Changes in walking function were non-leaders showed large positive changes in vehicle assessed with: 1) gait analysis (e.g. joint range of and low-kill cultures, suggesting preservation of motion, muscle activity patterns, etc); 2) most neurons, but negative shifts were observed in neurophysiological measures (e.g. reflex excitability); high-kill cultures, indicating greater numbers of dead and 3) clinical tests (e.g timed up and go, 10 m and 6 neurons unable to contribute to activity (Fig). Thus, min walking tests). To test the strength of arm and leader neurons display heightened resilience to an leg coupling, interlimb cutaneous reflexes (evoked excitotoxic insult, possibly resulting from pre- and/or by simultaneous electrical stimulation (5x1.0ms post-synaptic signal transduction properties. trains@300Hz) to cutaneous nerves innervating the foot and hand) were tested during treadmill walking. 2-C-72 Cortical spreading depression induces a Strength during dorsiflexion and plantarflexion was transient disruption of the blood-brain barrier also tested. A multiple baseline (3 pre-tests) within- prevented by rho-kinase inhibition and associated subject control design was used. Preliminary data with increased transcytosis show that A&L cycling improves neurological function and walking ability as inferred by changes in Baptiste Lacoste¹, Homa Sadeghian¹, Roberto Rosa¹, gait characteristics, reflex function, ankle strength, Tao Qin¹, Cenk Ayata¹, Chenghua Gu¹ and increased distance walked in the six minute walk ¹Harvard University CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

The blood-brain barrier (BBB) is a specific property of graph theory concepts. Ten MS patients (9 females, brain microvessels, which allows maintenance of age 38.0±6.9) and 10 normal controls (NC) (5 brain homeostasis. Cerebral endothelial cells form females, age 31.1±4.75) were recruited. T1-weighted the BBB by virtue of interendothelial tight junctions image and 8-minute fMRI scan (TR 2 sec, 240 and restricted transendothelial vesicular trafficking volumes) were performed. Image preprocessing was (transcytosis). Cortical spreading depression (CSD) is performed with in-house scripts including SPM and the electrophysiological correlate of migraine aura FSL functions. Cortical parcellation was performed but has also been associated with traumatic head with Freesurfer and 38 cognition-association ROIs injury and stroke. CSD is suspected to disrupt the were chosen as nodes. Binary connectivity matrices BBB. Here, we aimed at assessing the integrity of the were derived using both partial correlation and BBB following CSD, and at exploring the underlying simple correlation approaches. With partial mechanisms in relation to rho-associated kinase correlation, NCs had significantly higher (ROCK) which inhibition leads to stroke protection. A betweenness and node degree than MS subjects in total of six CSDs were evoked over an hour by topical the right fusiform gyrus (p<0.005 and 0.002, application of 300 mM KCl over the right hemisphere respectively). On the other hand, MS subjects in anesthetized mice. BBB disruption was assessed demonstrated higher node degree in left postcentral by Evans Blue extravasation in piriform cortices at gyrus (p<0.002). With simple correlation, similar 6h, 12h and 24h after CSD. To assess BBB to the partial correlation results, control subjects morphology, endothelial cell ultrastructure was demonstrated higher node degree only in the examined by electron microscopy. Mice were fusiform gyrus (p<0.0003). Betweenness treated with vehicle, isoform non-selective ROCK represents how well a region integrates information inhibitor fasudil (10mg/kg), or ROCK2-selective from networks, which is an indicator of a "rich hub", inhibitor KD025 (200 mg/kg). EB leakage was and node degree measures the connections passing detectable within 6h, and increased over 24h. Both through the region. Our results imply that both fasudil and KD025 suppressed EB leakage. decreased and increased cortical connectivity can be Transcytosis was enhanced in the ipsilateral seen in MS, with the increased connectivity likely hemisphere at 6h, reached a peak around 12h, and representing compensatory changes. returned to baseline levels at 48h. Interendothelial tight junctions appeared unaffected by CSD. These 2-C-75 A comprehensive database of cell-type data suggest that CSD-induced BBB transient specific marker genes for the mammalian brain disruption can be prevented by ROCK inhibition and that transcytosis is the primary mechanism. Burak Mancarci¹, Ogan Mancarci¹, Lila Toker¹, Shreejoy Tripathy¹, Paul Pavlidis¹ 2-C-73 A graph theoretical approach to altered resting state fMRI cortical networks in Multiple ¹UBC Sclerosis Large-scale gene expression analyses have improved Sue-Jin Lin¹, Aiping Liu¹, Alex MacKay¹, Irene our understanding of the pathophysiology of Vavasour², Brenda Kosaka², Samantha Beveridge¹, complex psychiatric and neurodegenerative David Li³, Anthony Traboulsee¹, Yinshan Zhao¹, disorders like schizophrenia and Huntington's. Roger Tam³, Silke Appel-Cresswell¹, Martin Nevertheless, interpreting changes in gene McKeown¹ expression in bulk tissue from human post-mortem brains can be misleading, since such changes may ¹University of British Columbia, ²University of British stem from alterations in cellular composition often Columbia Hospital , ³University of British Columbia observed in neuropsychiatric disorders (e.g., loss of Hospital dopaminergic cells in Parkinson's). Such changes could potentially be inferred from the expression of Prior work has emphasized the association between cell-type specific marker genes, however, reliable specific lesions seen in multiple sclerosis (MS) and marker genes do not currently exist for the majority symptoms. However, recent studies suggested of brain cell-types. Here, we develop and apply a widespread disruption of cortical networks in MS, computational approach to identify changes in often remote from specific lesions. Here we cellular populations based on expression of newly- examined resting state fMRI networks in MS using established cell-type marker genes. We identified CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

novel marker genes by compiling a brain-wide proliferation, while longer duration may be database of expression datasets from ~35 cell-types detrimental, perhaps due to sustained increase in from mouse. Using this database, we created lists of metabolic load. marker genes for each of the available cell types. Specifically, we identified previously unknown 2-C-77 Using eye movements to identify early marker genes (such as Cox6a2 as a marker for biomarkers of disease progression in Parkinson's cortical fast-spiking basket cells) and show that some patients with and without LRRK2 gene mutations of the currently used marker genes are not cell-type specific and/or might not be present in all the cells Julia Morris¹, Don Brien¹, Brian Coe¹, Naomi Visanji², from the targeted population (like NeuN). By linking Taneera Ghate², Anthony Lang², Connie Marras², these novel mouse marker genes to their human Douglas Munoz¹ homologs, we show that these genes can further be ¹Queen's University, ²University Health Network used to inform cellular proportions in diseased and healthy human brains. In some patients with Parkinson's disease (PD), variations of the Leucine-rich repeat kinase 2 (LRRK2) 2-C-76 Exercise modulates neural stem cell gene has been associated with the development of proliferation in a mouse model of Fragile-X the disease. Patients with PD exhibit specific deficits syndrome when completing anti-saccades, an inhibitory Alicia Meconi¹, Zoe Sharp¹, Brian Christie¹ process that requires looking in the opposite direction of a peripheral visual stimulus. These ¹University of Victoria deficits include longer reaction times, more directional errors (erroneously looking at a stimulus), Fragile-X syndrome (FXS) is the most common type and hypometric saccades. We employed an of heritable intellectual disability, which affects 1 in interleaved pro- and anti-saccade task to age- 4000 male and 1 in 6000 female Canadians, and is matched controls, idiopathic PD patients, and LRRK2 caused by a mutation in the Fmr1 gene encoding mutation carriers either before (non-manifesting) or Fragile-X-Mental Retardation Protein (FMRP). This after they manifest PD (manifesting carriers). The transcriptional regulator is involved in mediating pro-saccade task (look at the peripheral stimulus) neuronal development by modulating progenitor cell assesses the basic sensory-motor processing of eye proliferation. In its absence, adult hippocampal movements via automatic tendencies to look at neurogenesis, a process long known to be crucial for salient visual stimuli, whereas the anti-saccade task learning and memory function, is significantly assesses the inhibitory control of this automatic reduced. This may contribute to intellectual deficits response and generation of a voluntary command to associated with FXS. Neurogenesis is subject to look in the opposite direction. We hypothesize that modulation by many extrinsic factors. Exercise is carriers of pathogenic LRRK2 genetic mutations, who known to enhance the proliferation of new neurons have not yet developed parkinsonism, will have anti- in the hippocampus, and to improve associated saccade deficits similar to PD patients. Preliminary learning and memory function. In order to data has revealed that non-manifesting carriers determine whether exercise can rescue resemble PD patients in terms of performance: they neurogenesis in FXS, we investigated how wheel make more direction errors in the anti-saccade task, running affects the proliferation of neural stem cells faster eye movements in the pro-saccade task, and in the subgranular layer in a mouse model of FXS. hypometric saccades. Follow up of these results will After one or four weeks of wheel running, P49 FMRP be important to identify pre-symptomatic knockout (KO), true wild type (tWT) and littermate behavioural biomarkers of PD that accurately predict wild type (lWT) were injected twice with BrdU 12 disease leading to an earlier detection of PD. hours apart. They were sacrificed 24 hours later, and proliferating cells were examined using IHC staining 2-C-78 A variant of the presenilin-1 protein of BrdU and proliferation marker Ki67. We found protects against an aggressive familial Azlheimer- that one week of exercise improved proliferation in related mutation tWT, lWT, and KO mice, while four weeks of exercise reduced proliferation in each group. We conclude Jennifer Nyarko¹, Paul Pennington¹, Jason Maley¹, that shorter duration of exercise reduced Darrell Mousseau¹ CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

¹University of Saskatchewan oral consumption. Nicotine self-administration was elevated in the PND 44 group, peaked at PND 54-60 Alzheimer's disease (AD) is identified by overt and then was drastically lower in the PND 65 symptomatology, at a stage when there is evidence through PND 86 groups. Furthermore, a three day of extensive aggregation (as plaques) of the â- abstinence period precipitated a significant surge in amyloid (Aâ) peptide, a hallmark of AD nicotine consumption in the PND54-60 mice. We neuropathology. However, this late-stage in disease also quantified α4 nAChR expression via progression precludes effective disease management confocal imaging of brain slices from α4YFP and underscores the crucial need to identify AD in knock-in mice, in which the α4 nAChR subunit earlier stages. Risk of AD is influenced by factors is tagged with a yellow fluorescent protein. such as advancing age, sex and genetics. Mutations Quantitative fluorescence revealed age-specific in presenilin-1 (PS-1) associated with the early- α4 expression in dopaminergic and GABAergic onset/familial form of AD cleave the Amyloid Protein neurons of the ventral tegmental area that showed a Precursor (APP) to yield the toxic and hydrophobic strong positive correlation with daily nicotine dose. Aâ42 fragment that is thought to cause AD. During a These results suggest that α4 nAChR screen of control and AD brain samples, we expression levels are age-specific and may identified a splice variant of PS-1 that appears to contribute to the propensity of individuals to self- protect against AD-related amyloid pathology. The administer nicotine. relative proportion of the wildtype and splice variant forms of PS-1 can be used as markers for diagnosis of 2-C-80 Determining the Efficacy of Endogenous AD. We are in preclinical development of antibodies Stem Cell Based Therapy as a Means to Promote designed to differentiate these forms of PS-1. Cognitive Recovery Post-Stroke in Adult Mice Surface plasmon resonance reveals the high-affinity and specificity of these antibodies for their Labeeba Nusrat¹, Nadia Sachewsky¹, Andrey Son¹, immunizing peptides. Specificity is confirmed by Dale Corbett², Cindi Morshead¹ western blot in human brain samples. We hope to validate these antibodies as diagnostic tools for the ¹University of Toronto, ²University of Ottawa earliest stages of AD, when treatment options would Current treatments for stroke, a leading cause of still provide benefit. death and chronic disability worldwide, are limited in 2-C-79 Age-dependent vulnerability to nicotine their function and availability. Direct activation of self-administration in mice correlates with adult neural stem and progenitor cells [collectively expression of a4* nicotinic receptors termed precursors (NPCs)] using small molecules in the adult mammalian brain may provide a novel self- Anthony Renda¹, Nora Penty¹, Pragya Komal¹, repair avenue for treating stroke. Our group has Thomas Hoos¹, Raad Nashmi¹ previously shown that Cyclosporine A (CsA) has direct pro-survival effects on NPCs in vivo, resulting ¹University of Victoria in a significant increase in the size of NPC pool. Upon systemic CsA administration post-stroke, NPCs Greater than 75% of smokers begin before age 20, a migrate to the injury site, promote tissue developmental period known for susceptibility to regeneration and ameliorate motor impairments in substance use disorders. However, it is unknown if two distinct models of sensorimotor stroke. the molecular composition of the adolescent brain Importantly, CsA administration starting at the time contributes to their heightened susceptibility to of stroke, as well as 4 days post-stroke, led to nicotine addiction. Nicotine is the pharmacological functional recovery. Herein, for the first time, we component of tobacco and binds to nicotinic investigated the efficacy of this endogenous cell- acetylcholine receptors (nAChRs) in the brain, the based therapy to promote recovery of post-stroke most prevalent being the α4β2 subtype. cognitive impairments, particularly executive Different age groups of mice, postnatal day (PND) dysfunctions, which heavily impact rehabilitation 40-86 days old, were exposed to a two bottle-choice outcome and quality of life. In the cognitive stroke oral nicotine self-administration paradigm for five model, adult mice received focal, bilateral days. We found age-dependent changes in the daily endothelin-1 induced ischemia in the medial dose of nicotine that mice self-administered through prefrontal cortex (mPFC). Expansion of NPC CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

population was observed at 4 and 7 days after the exact mechanism is unknown, the cytotoxic stroke, similar to observations following misfolding of SOD1 is remarkably specific for motor sensorimotor stroke. Most importantly, mPFC lesions neurons, despite SOD1 being ubiquitously expressed produced measurable cognitive deficits in the Puzzle in many cell types. Under oxidizing conditions, wild Box task, which persisted up to 45 days after stroke. type SOD1 misfolds and acquires the same cytotoxic We predict that CsA treatment will repair the injured properties as mutant SOD1. Previous work in our brain following stroke and contribute to cognitive laboratory has shown that misfolded SOD1 is recovery. immunoprecipitable from spinal cord homogenates from FALS (w/ SOD1 mutations) and from SALS. The 2-C-81 Functional Impairment among children phenomenon of wild type SOD1 misfolding in cases with neurodevelopmental disorders in Abeokuta, of SALS prompts the question of what is happening Nigeria with the normal SOD1 protein before the protein becomes misfolded and pathogenic. To examine this, Adeniran Okewole¹ misfolded SOD1 was examined in young non- transgenic mice. Fresh frozen spinal cord tissues ¹Neuropsychiatric Hospital Aro were analyzed for misfolded SOD1 with different BACKGROUND: Beyond symptomatology, functional cell-type specific markers. The results show that impairment has been shown to be an additional there is a small but distinct amount of misfolded dimension in neurodevelopmental disorders which SOD1 detectable in the dendrites of normal mouse influences the outcome for children with these spinal cords. The specificity of the signal to motor disorders. Very little is known about such functional neuron dendrites is revealing, given the selective impairment among African children. METHODS: vulnerability of motor neurons in ALS, and is Children with neurodevelopmental disorders consistent with a role for misfolded SOD1 in the receiving treatment at the Child and Adolescent Unit "dying back" of motor neurons in the disease of the Neuropsychiatric Hospital, Aro Abeokuta, progression of ALS. Nigeria, were assessed with a socio-demographic 2-C-83 Early cell death in oligodendrocytes questionnaire, the Children's Global Assessment measured by spectral changes of the fluorescent Scale and the World Health Organisation Disability nuclear dye acridine orange Assessment Schedule. RESULTS: Results are presented as frequencies, with descriptive and Jason Plemel¹, Michael Keough¹, Andrew inferential statistics as appropriate. CONCLUSION: Caprariello¹, Shigeki Tsutsui¹, Ileana Micu ¹, Evelyn relevant conclusions are drawn from the data on the Manford¹, V. Wee Yong¹, Peter Stys¹ prevalence and factors associated with functional impairment among children with ¹University of Calgary neurodevelopmental disorders. Cell death is a feature of all central nervous system 2-C-82 Evidence of motor neuron specific trauma and disease. To study cell death, it is possible misfolded SOD1 in wild type mice to model the normal central nervous system cytoarchitecture with culturing tissue slices or short- Megan O'Neill¹, Catherine Cowan¹, A. Jane Roskams², term maintenance of ex vivo samples. However, the Neil Cashman¹ thickness of tissue slices and ex vivo samples preclude the use of common antibody-based ¹University of British Columbia, ²Allen Institute for approaches to measure cell death in living samples. Brain Science Deep penetrating cell-impermeant nuclear dyes such ALS is a fatal neurodegenerative disease caused by as propidium iodide offer one strategy to label dead the loss of motor neurons, leading to progressive cells, but these dyes label a very late stage of paralysis and muscle atrophy. Familial cases of ALS apoptosis/necrosis and are thus not sensitive to (FALS) account for 10% of all cases, defining the detect early stages of injury. In the hopes of remaining 90% as sporadic (SALS). Mutations in detecting early apoptotic events we measured the superoxide dismutase 1 (SOD1), occurring in 2% of spectral changes of a nuclear dye, acridine orange, all cases of ALS, cause the protein to misfold under normal and pathological conditions in cell resulting in a cytotoxic gain-of-function. Although culture. A human oligodendroglial cell line and CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

mouse oligodendrocytes were cultured with or propagation of SOD1 misfolding. We believe that the without apoptosis and necrosis inducing agents and spread of SOD1 misfolding throughout the neuro- stained with acridine orange. Acridine orange emits axis plays a central role in the progression of ALS. in the green spectrum when bound to double- The inhibition of intercellular transmission and stranded DNA and in the red spectrum when bound propagation of SOD1 misfolding by these small to RNA or single-stranded DNA. We found that cell molecules may represent novel treatments for ALS. death induces a spectral change in cells, with less nuclear red emission. Importantly, the spectral 2-C-85 Modulation of ARNT2, a neuroprotective change of acridine orange preceded the entry of a transcription factor, as a regulator of cell impermeant dye, propidium iodide, in neurodegenerative processes in models of multiple agreement with our hypothesis that acridine orange sclerosis is a sensitive dye for early cellular damage. Imaging of acridine orange could provide a novel strategy to Tissa Rahim¹, Andrew Leung¹, Adam Yu¹, Jacqueline measure cell death in live samples allowing Quandt¹ additional mechanistic interrogation of early cell ¹University of British Columbia injury. Multiple sclerosis (MS) is characterized by immune 2-C-84 Blocking the propagation of misfolded mediated damage, excitotoxicity and oxidative SOD1 using small molecules as a potential stress. ARNT2 (aryl-hydrocarbon receptor nuclear treatment for ALS translocator 2) is a transcription factor that T. Dean Airey¹, Leslie Grad¹, Neil Cashman¹ influences neuronal survival/protection. Our objective is to characterize the role of ARNT2 ¹Brain Research Centre expression and associated changes in neuronal viability/function in MS models. E16-18 cortical Amyotrophic lateral sclerosis (ALS) is an incurable cultures were treated with KCl, glutamate or H2O2 motor neuron disease that is associated with the to examine their influence on ARNT2 expression. Cell mutation and misfolding of the Cu/Zn superoxide viability was assessed by morphological dismutase (SOD1) protein. analysis/lactate dehydrogenase (LDH) release. By 8h, 100mM KCl reduced ARNT2 expression by 90% We previously reported that mutant forms of SOD1 compared to control, associated with cell can induce the misfolding of endogenous wild-type swelling/cytotoxicity with LDH release. Glutamate (wt) SOD1 in human neuroblastoma and exposure had little effect at low doses, but by 1h of mesenchymal cells. Misfolded wtSOD1 is secreted 500µM glutamate exposure, ARNT2 levels decreased extracellularly where it can be transferred to fresh by 30%, concurrent with axonal/dendritic retraction. cell cultures to induce further wtSOD1 misfolding. ARNT2 declined to 50% of controls at 24h, Strikingly, the induction of misfolding by a mutant associated with toxicity/cell death. At 25, 50, 100, SOD1 template is restricted by a single tryptophan and 300µM H2O2 to model oxidative stress, ARNT2 (Trp) residue at position 32, indicating a possible levels increased up to 30% within 30min exposure point of contact between the converting and compared to control suggesting a protective converted protein species. X-ray crystallography has response to oxidative stress. At 100µM and 300µM, identified small molecules that bind SOD1 at or near ARNT2 levels declined over time, preceding increases the critical amino acid Trp32. Given the importance in LDH release and cell death by 24h. This work of the Trp32 residue to propagated SOD1 misfolding, suggests that increases in ARNT2 expression may we hypothesized that small molecules binding at or contribute to protective responses under certain near the Trp32 site will block this process and stresses, while declining expression is associated mitigate the spread of pathological SOD1 misfolding. with loss in cell integrity and viability. This work will Treatment of conditioned media containing characterize the influence of pathological mediators misfolded wtSOD1 seed with 25 μM of uridine involved in MS on ARNT2, improving current appears to completely block the induction of SOD1 understanding of endogenous neuroprotection. misfolding in the recipient cells, while 5 μM uridine reduces induction by over 70%. Other 2-C-86 The comparative predictive value of early structurally similar molecules also reduce the treatment response in antipsychotic-naïve patients CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

with first-episode psychosis: haloperidol versus Premanifest HD (pre-HD) subjects have a positive olanzapine genetic test but have not progressed to clinically defined HD. Magnetic resonance spectroscopy was Sean Rasmussen¹, Patricia Rosebush¹, Michael used to investigate brain metabolite concentration Mazurek¹ changes in pre-HD over 6 years. MR spectra (3T) were acquired of the left putamen in 15 controls and ¹McMaster University 12 pre-HD subjects annually over 6 years. LCModel was used to estimate metabolite concentrations. A Background: It has been proposed that early linear mixed effects model for each metabolite response to antipsychotic treatment can predict including age at baseline and gender as factors was longer term outcome for psychotic patients. used to compare groups over time. At baseline, However, it is not known to what extent this mean [tNAA] was lower in pre-HD than in controls (- relationship might apply to antipsychotic-naïve 0.40mM, p=0.04). Mean control [tNAA] and [mI] patients, or to affective symptomatology that often decreased over time; -0.06mM/yr, p=0.03 and - accompanies psychosis. Methods: We examined this 0.13mM/yr, p=0.004 respectively. Pre-HD subjects issue in a cohort of 125 consecutive antipsychotic- experienced an additional decrease over controls of - naïve, first-episode psychosis inpatients randomized 0.11mM/yr (p=0.007) for [tCr], an increase of to treatment with haloperidol or olanzapine. All 0.02mM/yr (p=0.04) for [tCho], and an increase of patients were assessed at baseline and three times 0.16mM/yr ( p=0.01) for [mI]. Age and gender had weekly thereafter using the Brief Psychiatric Rating no significant effect on the models except for [Glx], Scale (BPRS), Young Mania Rating Scale (YMRS), where men displayed higher [Glx] (p=0.004). Hamilton Depression Rating Scale (HAM-D), and Although progressive brain metabolic changes have Hamilton Anxiety Rating Scale (HAM-A). Regression been found in symptomatic HD, this work shows analyses were used to determine whether significant differences in putaminal metabolite improvements on these measures at two weeks concentrations with age between pre-HD subjects predicted improvements at discharge. Results: While and controls for the first time. We propose [tNAA], length of hospital stay and improvement at [tCr], and [mI] as biomarkers for progression from discharge were similar between treatment groups, pre-HD to manifest HD. In addition, subtle changes the predictive value of early treatment response in metabolite concentrations over time in controls differed between cohorts. In the haloperidol group, may provide insight into aging effects in brain week two improvement was associated with metabolism. improvement at discharge for BPRS (p=.001), YMRS (p=.003) and HAM-D (p<.001) scores, though not 2-C-88 Loss of the Huntington disease-associated HAM-A scores. In the olanzapine group, week two palmitoylacyltransferase HIP14 in adulthood leads improvement was not predictive of improvement at to sudden unexplained death, motor and discharge for any measure. Conclusions: Early psychiatric disturbances, and astrogliosis and response predicted eventual recovery with microglial activation haloperidol, but not olanzapine, in first-episode psychotic patients. This information has important Shaun Sanders¹, Matthew Parsons¹, Amber implications for physicians deciding whether to Southwell¹, Katherine Mui¹, Sonia Franciosi¹, Lynn switch antipsychotic medications early in treatment. Raymond¹, Michael Hayden¹

2-C-87 Longitudinal Magnetic Resonance ¹University of British Columbia Spectroscopy Changes in Premanifest Huntington's Disease Huntington disease (HD) is caused by a CAG expansion in HTT and is characterized by striatal Bretta Russell-Schulz², Terri Petkau², Blair Leavitt², atrophy and motor, cognitive, and psychiatric Alex MacKay² symptoms. The interaction between mutant HTT and HIP14 (zDHHC17), a palmitoyl acyltransferase for ¹UBC MRI Research Centre, ²University of British HTT, is disturbed, resulting in reduced palmitoylation Columbia of HTT and other HIP14 substrates. Hip14 deficient mice recapitulate many features of HD, including Huntington's Disease (HD) is a fatal disease causeing striatal atrophy and motor deficits. However, the cognitive, psychiatric and motor dysfunction. CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

phenotype is developmental, unlike in HD mice and groups. These changes occurred in the presence of patients. A model of post-developmental loss of heightened neuroinflammation in MULTI mice at HIP14 was generated to examine the role of HIP14 in both 24 h and 35 days post-injury. Together these neurological deficits and neurodegeneration findings indicate that a tibial fracture worsens TBI (Hip14F/F;Cre-ERT2). This mouse model allows for outcomes, and that an exacerbated inflammatory Hip14 deletion upon tamoxifen administration at 6- response may be an important factor contributing to weeks of age. This resulted in a >90% reduction in these effects and warrants further investigation. HIP14 protein and mRNA in Hip14F/F;Cre-ERT2 tamoxifen treated mice (iHip14Δ/Δ). 2-C-90 Improving molecular diagnostic predictions iHip14Δ/Δ mice show dramatically in infantile epileptic encephalopathies using reduced survival due to sudden unexplained death in structural modelling of SCN1A epilepsy ~10 weeks after loss of Hip14 and at 3 months (~7 weeks after loss of Hip14) show motor Alexander Smith¹, Gemma Pinchin¹, Tara Klassen¹ deficits, anhedonia, and increased escape response. ¹University of British Columbia Electrophysiological analysis suggests that iHip14Δ/Δ mice have striatal dysfunction Epilepsy is a heterogeneous group of neurological and an imbalance between excitatory and inhibitory disorders characterized by recurrent and synapses in the hippocampus. iHip14Δ/Δ unprovoked seizures impacting ~65 million people mice have increased cortical volume, likely due to worldwide. The clinical spectrum ranges from astrogliosis and microglial activation, and decreased extreme seizures and cognitive delay (Dravet corpus callosum volume. This indicates that loss of Syndrome) to the more moderate Genetic Epilepsy Hip14 from conception allows for developmental with Febrile Seizures Plus (GEFS ). Genetic testing has compensation that cannot take place if Hip14 revealed >600 variants in SCN1A, the gene encoding deficiency occurs in the adult. the voltage-gated sodium channel Nav1.1. The majority of SCN1A variants are de novo and not 2-C-89 Does multi-trauma worsen the outcome of previously reported in the pediatric population. traumatic brain injury? Currently, variants are classified as pathogenic using Sandy Shultz¹, Stuart McDonald² bioinformatic tools, but these reveal little correlation between disease severity and genotype. This ¹The University of Melbourne, ²La Trobe University drastically limits the application of SCN1A genetic testing in clinical decision making. We hypothesize Multi-trauma is an international medical problem that clinical severity is related to the altered and commonly involves traumatic brain injury (TBI) structural stability of the channel during its and bone fracture. Despite the high incidence of transition from the deactivated (closed) to active combined TBI and fracture, pre-clinical TBI research (open) state, impacting channel biophysics. commonly employs independent injury models that Homology models of the human Nav1.1 protein in fail to incorporate the pathophysiological the open and closed conformations were generated interactions occurring in multi-trauma. Therefore, using bacterial sodium channel crystal structures as here we developed a novel mouse model of multi- templates. In silico mutagenesis quantified the trauma, and assessed whether bone fracture relative change in energy caused by SCN1A disease- worsened TBI outcomes. Male mice were assigned causing amino acid mutations in each state. into four groups: sham-TBI and sham-fracture Mutations were ranked to establish the extent of (sham); sham-TBI and fracture (FX); TBI and sham- inherent energetic instability in each state. These fracture (TBI); and TBI and fracture (MULTI). The energy profiles when integrated with known injury methods included a weight-drop TBI model functional data and clinical phenotypes will improve and a closed tibial fracture. After a 35-day recovery, gene test interpretation, aiding diagnosis, prognosis, mice underwent behavioral testing and MRI. MULTI and therapeutic intervention. mice displayed abnormal behaviors in the open field compared to all other groups, had significant motor 2-C-91 Synaptic scaling in cultured neurons from impairments on the rotarod compared to the sham the YAC128 mouse model of Huntington disease and TBI groups, and had enlarged ventricles and diffusion abnormalities in compared to all other Amy Smith-Dijak¹, James Mau¹, Lynn Raymond¹ CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

¹University of British Columbia we explore strategies to inhibit Neogenin, thus simultaneously enhancing neuronal survival and Huntington disease (HD) is a neurodegenerative axonal regeneration. We show that the recruitment disorder caused by a polyglutamine expansion in the of Neogenin into lipid rafts is mediated through huntingtin protein, producing mutant huntingtin RGMa and bone morphogenic proteins (BMP). We (mHtt). Many pre- and postsynaptic proteins interact have mapped the domains of RGMa and Neogenin with mHtt, and the function of at least some of these involved in the recruitment into rafts and have proteins is affected by the disease-causing mutation. shown that this process can be prevented through One of the consequences of these changes in protein RGMa/Neogenin peptides, Noggin, or reduction of function is alterations in synaptic signaling and membrane cholesterol. Blocking Neogenin plasticity. Particularly affected are the cortico-striatal recruitment into rafts promotes neuronal survival synapses, especially those between cortical neurons and axonal regeneration in the injured adult optic and striatal spiny projection neurons (SPNs). We set nerve and restores locomotor function after spinal out to examine changes in synaptic scaling, a form of cord injury. These data reveal a unified strategy to homeostatic plasticity in which the strength of promote both survival and regeneration in the CNS. synapses in a network is increased or decreased in response to the overall level of activity in the 2-C-93 Optogenetic stimulation of thalamocortical network, in excitatory synapses onto cortical projections to promote structural plasticity and pyramidal neurons and striatal SPNs from the recovery of function after somatosensory cortex YAC128 HD mouse model. We used stroke immunocytochemical analyses and electrophysiological measurements to determine the Kelly Tennant¹, Craig Brown¹ effect of 48 hours of treatment with either tetrodotoxin, bicuculline or vehicle (water) on ¹University of Victoria synaptic strength and organization in striatal-cortical Most stroke survivors live with chronic disability, cocultures and cortical monocultures from often affecting the upper limbs. Improved use of the embryonic wild-type (WT) and YAC128 mice. stroke-affected limb is generally accompanied by Specifically, we analysed spine density, miniature neuroplasticity in intact brain areas surrounding the excitatory postsynaptic current amplitude and stroke. Modulating this innate plasticity should frequency, and the distribution of several synaptic promote further gains in recovery. Unpublished data proteins. We compare and contrast the responses of from our lab has shown that while peri-infarct our two genotypes in both types of culture to thalamocortical axons are relatively resilient to the determine whether a deficit in synaptic scaling exists effects of ischemia, they lose a significant number of at this early time point in a Huntington disease terminaux and en passant boutons in the first few model. weeks after stroke. Here, we ask whether 2-C-92 Modifying lipid rafts promotes optogenetic stimulation of peri-infarct regeneration and functional recovery thalamocortical projections promotes the re-wiring of axonal boutons and improves behavioural Nardos Tassew¹, Andrea Mothe², Alireza recovery after somatosensory cortex stroke. Shabanzadeh², Paromita Banjerjee², Philippe Thalamocortical axons from the VPL nucleus of the Monnier² thalamus were transfected with AAV2.CamKII.hChR2(E123A) and a chronic cranial ¹Toronto Western Research Hospital, ²Toronto window was implanted over the sensorimotor cortex Western Research Institute to allow for longitudinal in vivo two-photon imaging of axon terminals before and after photothrombotic Therapies aimed at regeneration of the CNS should stroke. Optogenetic stimulation was driven by a blue promote both neuronal survival and axon growth. LED magnetically attached to the cranial window and Neutralization of the Repulsive guidance molecule a was initiated 3 days after stroke. Optical stimulation (RGMa) after CNS injuries promotes regeneration. or control procedures were administered in awake However, its receptor, Neogenin, is a dependence mice for 1 hour per day, 5 days per week for 6 weeks receptor and causes apoptosis in the absence of after stroke. Behavioural performance was assessed RGMa, counteracting any positive outcomes. Here, once weekly. Changes in axonal branching patterns, CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

length, and the number of axonal varicosities were Deraredj Wissem¹, Séverine Chaumont², Laetitia analysed. Preliminary data suggest that post-stroke Cobret³, Hélène Benedetti³, Philippe Marin², optogenetic stimulation of thalamocortical Séverine Morisset-Lopez³ projections improves stroke-related deficits in tactile sensory function. ¹CNRS Orléans - France, ²CNRS IGF Montpellier , ³CNRS Orléans UPR 4301 - France 2-C-94 Dynamic changes in dendritic spine number in an animal model of Multiple Sclerosis The serotonin 6 receptor (5-HT6R) is almost exclusively localized in the CNS, predominantly in Megan Verbeek¹, Kristin Milloy¹, Shaona Acharjee², regions involved in the regulation of cognitive Quentin Pittman², Adrienne Benediktsson¹ processes. Using proteomic approaches, we identified novel signaling proteins associated with ¹Mount Royal University, ²University of Calgary the receptor. In this study, we characterize the interaction of the 5-HT6R with Neurofibromin (Nf1), Multiple sclerosis, a demyelinating disease with the protein responsible of the most common genetic sensory and motor deficits, is associated with diseases, type 1 neurofibromatosis (NF1). The behavioural co-morbidities such as neuropsychiatric phenotype of NF1 is highly variable, with benign and cognitive impairments. Inflammation occurring (neurofibromas) or malignant peripheral nerve even in the early stages of the disease can alter brain sheath tumors, CNS tumors (gliomas, astrocytomas) structure and function, leading to these and cognitive deficits in 40% of NF1 patients. We abnormalities, but the mechanism is poorly first characterized R5-HT6/Nf1 interaction using co- understood. We investigated if there were changes immunoprecipitation: three domains of Nf1 are in dendritic spines using an animal model of MS, capable of interacting with the receptor. Then, using called experimental autoimmune encephalomyelitis Bioluminescence Resonance Energy Transfer (BRET), (EAE). Neurons were labeled using Golgi staining at we demonstrated that PH (Plextrin Homology) two timepoints: day (d7), when behavioural changes domain of Nf1 interacts directly with the R5-HT6 and can be seen, and at d17, where motor deficits are with the strongest affinity compared to the other evident. Neurons were imaged with confocal domains. In order to explore the role of Nf1 on 5- microscopy and analyzed using Imaris software to HT6 receptor-operated signaling, we studied the examine dendritic spines, which form the consequence of down-regulating Nf1 expression on postsynaptic structure of the synapse. Spine number Gs-adenylyl cyclase pathway. Silencing Nf1 was increased by 22% (p<0.05) in the principal expression in primary striatal neurons resulted in neurons of the basolateral amygdala at d7, a stage reduction of the constitutive activation of the 5-HT6 when the animals do not show any sign of paralysis receptor: the basal level of cAMP induced by 5-HT6 but have increased levels of cytokines in the brain. receptor expression was reduced by at least 60% in At d17, the difference in the spine count between Nf1 depleted cells. In conclusion, 5-HT6R, which is the EAE and controls disappeared, indicating there known to control synaptic plasticity, learning and was most likely increased spine loss in EAE. We did memory formation and identified as a new partner not observe changes in the spine density in CA1 of Nf1 may constitute an interesting therapeutic pyramidal neurons of the hippocampus at d7, and target in NF1. d17 brains are currently being analyzed. There appears to be a temporal and regional alteration in 2-C-96 Studying the neuronal activity changes in spine density in the brains of EAE mice. Further the motor cortex after deep brain stimulation at analysis, such as electrophysiology, and further the subthalamic nucleus of Parkinson?s disease characterization of spines will shed light on synaptic model rat function and circuit dynamics that lead to these behavioural changes. Cheng Wei Wu¹

2-C-95 5-HT6 serotonin receptor is a new ¹National Tsing Hua University therapeutic target in Neurofibromatosis type 1: the first GPCR regulated by neurofibromin Parkinson's disease (PD) is a neurodegenerative disease of central nervous system, and PD patients generally have many motor problems. CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

High-frequency deep brain stimulation (DBS) of female heterzygoze Fmr1 knock out mice displays a subthalamic nucleus (STN) is an effective and the DG-specific decrease in long-term potentiation, that most common surgical procedure to sever PD can also be rescued by glycine. Whole cell patch patients. However, the exact mechanism of DBS is clamping showed significant decreases in á-amino-3- still unknown. In this research, we used rats as the hydroxy-5-methyl-4-isoxazolepropionic acid receptor model animals to study the mechanisms of STN-DBS. (AMPAR) and NMDAR-mediated currents as well as First, we used c-Fos as marker to know which brain decreased AMPA/NMDA ratio in the knockout mice areas were activated after STN-DBS, and we when compared to their wildtype littermates. observed a group of large and dark c-Fos positive Glycine potentiated NMDAR-mediated currents in cells (giant c-Fos positive cells) in the layer Vb of the both wildtype and knockout mice. The knocout mie ipsilateral motor cortex after ipsilateral STN-DBS in displayed learning deficit in a DG-specific catogorial PD rats, but in the contralateral side of PD rats or spatial processing task, but did not show learnining normal rats. Second, we used NeuN, GABA and deficit in temporal order task and depressive SMI32 to double stain these giant c-Fos positive behaviors in forced swim test and tail suspension cells, and we found that these giant c-Fos positive test. Our findings indicate that impairment in cells were almost pyramidal tract type (PT-type) synaptic plasticity in the DG of female FX mice can be neurons which sent the signals from layer Vb of the rescued by modulating NMDAR activity using its co- motor cortex to basal ganglia including STN. Resulted agonist glycine, suggesting a potential treatment for from these data we proposed that STN-DBS improving cognitive impairment in FX patients. antidromically excited afferent axons which originated from the PT-type neurons and the 2-C-99 Identification of a Novel Modulator of therapeutic effects of STN-DBS might be due to, at Apolipoprotein E in Astrocytes least partly, by the activation of these afferent axons. Last, we injected Fast blue between the Shahab Zareyan¹, Jianjia Fan¹, Iva Kulic¹, Yoko bipolar electrode tips in the STN of PD rats to Shimizu², Tom Pfeifer², Cheryl Wellington¹ retrograde label and check the neurons. And then, ¹Djavad Mowafaghian Centre for Brain Health, ²The we observed that the afferent axons we stimulate in Centre for Drug Research and Development STN are originated from the giant c-Fos positive cells we find in layer Vb of the motor cortex. Apolipoprotien E (apoE) is the most abundant apolipoprotein in the brain, where it is 2-C-98 Glycine rescues impaired hippocampal predominantly synthesized by astrocytes and synaptic plasticity in Female Fmr1 heterozygous mediates cholesterol transport in the central knockout mice nervous system. As APOE is the most highly Suk-yu Yau¹, Jason Chiu¹, Erica Truesdell¹, Brett associated susceptibility locus for Alzheimer's Hryciw¹, Christine Chiu¹, Brennan Eadie¹, Brian disease, modulating apoE levels or function is of Christie¹ therapeutic interest. To identify compounds that increase apoE secretion, we performed a high ¹University of Victoria throughput screen using a molecule library of 104,000 compounds in human CCF-STTG1 Fragile X Syndrome (FXS), the most common form of astrocytoma cells. A hit compound, CD82, belonging inherited intellectual disability, to the pyrethroid ester class of insecticides, was confirmed to increase both expressed and secreted is caused by over expansion of cytosine-guaine- apoE up to 7-fold or greater starting at a guanine (CGG) trinucleotide in Fmr1 gene, concentration of 10μM. Upregulation of apoE preventing production of fragile X mental was concomitant with an increase in other liver x retardation protein (FMRP). FXS affects receptor (LXR) target genes including LXR-α approximately 1 in 4000 males and 1 in 8000 itself, and a robust upregulation of the lipid females. We have previously reported that NMADR transporter ABCA1 (9-fold at 30μm). As apoE is co-agonist glycine or D-serine rescued N-methly-D- transcriptionally regulated though the LXR pathway, aspartate receptor (NMDAR)-dependent synaptic we evaluated the requirement of LXR function for plasticity in the dentate gyrus (DG) of Fmr1 knockout the observed effect using mouse embryonic male mice. In the current study, we report that fibroblast deficient in LXR-β or both LXR- CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

α and -β. Induction of both ABCA1 and apoE mRNA expression by CD82 required LXR activity. Importantly, CD82 shows minimal D - Sensory and Motor Systems upregulation of LXR target genes in HepG2 liver carcinoma cells. By contrast, a known LXR agonist, 2-D-101 Electrophysiological investigation of TMC9 GW3965, induced a clear increase in LXR target in mechanotransduction processes genes, including the undesirable upregulation of the transcription factor SREBP1c in HepG2 cells. Ongoing Lou Beaulieu-Laroche¹, Albena Davidova¹, Reza work is focused on evaluating the mechanisms by Sharif-Naeini¹ which CD82 mediates apoE upregulation and the ¹McGill University functional outcomes. Mechanosensitive ion channels (MSCs) are 2-C-100 Downregulation of MIF by NFκB membrane proteins that conduct ionic currents in signaling under hypoxia accelerated neuronal loss response to mechanical stimuli. They are thought to during stroke be present in most cell types and underlie processes Si Zhang¹ such as touch, hearing, and vascular homeostasis, but very few MSCs have been cloned. Previous ¹University of British Columbia experiments in the lab suggest that TMC9 is a novel non-selective cationic MSC. Here, we investigated Neuronal apoptosis is one of the major causes of the role of TMC9 in mechanotransduction in post-stroke neurological deficits. Inflammation nociceptors (pain-sensing neurons). These cells are during the acute phase of stroke results in dorsal root ganglion neurons specialized to NFκB undergoing nuclear translocation in transduce noxious mechanical forces into electric affected cells in the infarct area. Macrophage currents. We tested the hypothesis that TMC9 is migration inhibitory factor (MIF) promotes involved in this process by recording cardiomyocyte survival in mice following heart mechanosensitive currents in dissociated ischemia. However, the role of MIF during stroke nociceptors. To record those currents, we applied remains limited. In this study, we showed that MIF pulses of negative pressure through the recording expression is downregulated in the infarct area in electrode while recording in the cell-attached patch the mouse brains. Two functional cis-acting clamp configuration. Neurons transfected with TMC9 NFκB response elements were identified in the siRNA had significantly reduced mechanosensitive human MIF promoter. Dual activation of hypoxia and currents compared to mock-transfected neurons, NFκB signaling resulted in significant reduction indicating that TMC9 contributes to of MIF promoter activity to 0.86±0.01 fold of the mechanosensitive currents in nociceptors. To control. Furthermore, MIF reduced caspase-3 conclude, the present study identified a MSC activation and protected neurons from oxidative involved in mechanical pain transduction and, given stress- and in vitro ischemia/reperfusion-induced the ubiquitous expression of TMC9, provides a apoptosis. H2O2 significantly induced cell death with candidate channel for other mechanotransduction 12.81±0.58 fold increase of TUNEL-positive cells and processes where the molecular players are overexpression of MIF blocked the H2O2-induced unknown. cell death. Disruption of the MIF gene in MIF- knockout mice resulted in caspase-3 activation, 2-D-102 Relationship between neck muscle neural neuronal loss and accelerated infarct development control and biomechanics during stroke. Our study demonstrates that MIF exerts a neuronal protective effect and Jason Fice¹, Gunter Siegmund², Jean-Sebastien downregulation of MIF by NFκB-mediated Blouin¹ signaling under hypoxia accelerates neuronal loss ¹University of British Columbia, ²MEA Forensic during stroke. Our results suggest that MIF is an Engineers and Scientists important molecule for preserving a longer time window for stroke treatment, and strategies to The relationship between the biomechanics and control MIF expression at a therapeutic level could neural control of human neck muscles remains have beneficial effects for stroke patients. unclear. Here we hypothesized that the preferred CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

activation direction (neural control) and the cortico-cortical projections to PAF are altered electrically stimulated moment direction following deafness to determine the anatomical (biomechanics) of neck muscles would align. Eight basis of these functional changes. A retrograde male subjects sat with their torso constrained and neuronal tracer (BDA) was deposited in the PAF of their head rigidly fixed to a 6-axis load cell. hearing and ototoxically-deafened cats. Coronal Indwelling electrodes were inserted in the right sections were taken and neurons showing a positive sternocleidomastoid, splenius capitis, and retrograde labeling were counted and assigned to semispinalis capitis. The preferred activation cortical and thalamic areas according to published directions were calculated from each muscle's criteria. The proportion of labelled neurons in each spatial tuning curve, which was estimated using 7.5% area was determined in relation to the total number of maximum voluntary isometric contractions (MVC) of labeled neurons in the entire brain. Group level in 26 directions, including the principal directions of analyses of the proportion of labels arising from flexion, extension, lateral bending, and axial rotation auditory and non-auditory fields will be discussed to and various combinations. Electrical muscle illustrate the effect of hearing loss. Additionally, stimulation was bipolar and used the same these changes will be compared to changes in a indwelling electrodes to deliver currents that primary field (A1) to illustrate differences in the generated moment magnitudes similar to those capacity for reorganization between primary and recorded during the voluntary activation. The non-primary auditory cortex. preferred activation direction and muscle stimulation direction did not align for any of the 2-D-104 In vivo, mesoscale voltage imaging of three muscles (p<0.05). Variability was cortical dynamics as a platform for investigating consistently higher for the preferred activation mouse models of neurodegenerative and direction than for the muscle stimulation direction. psychiatric disease Our findings show that individual neck muscle biomechanics cannot be directly used to predict Allen Chan¹, Majid Mohajerani², Jeffrey LeDue¹, Yu neural control. The work also suggests that despite Tian Wang¹, Timothy Murphy¹ each subject having similar actuators (i.e. neck ¹University of British Columbia, ²University of muscles) available to control head position, their Lethbridge central nervous system uses these actuators in different ways. Increasingly, functional neuroimaging, principally using fMRI, is being applied to the investigation of 2-D-103 Differential Patterns of Projections to the psychiatric and neurodegenerative disease to reveal Posterior Auditory Field in Early- and Late-Deaf Cats underlying pathologies in brain function and the Blake Butler¹, Stephen Lomber¹ potential discovery of novel biomarkers. We propose that parallel neuroimaging approaches, using ¹University of Western Ontario modalities that more directly reflect neuronal activity, in mouse models of psychiatric and When one sensory modality is absent, compensatory neurodegenerative disease presents a advantages are often observed in remaining complimentary approach that can reveal much about modalities. These advantages are thought to result disease pathology not possible in human imaging from recruitment of cortical areas that typically paradigms alone and may provide a platform for process stimuli from the missing modality. For testing therapeutic interventions. We used high- example, evidence from both human and animal speed (150 Hz), wide-field (8.5x8.5 mm), voltage- studies suggests that auditory areas contribute to sensitive dye (RH1692) imaging to examine enhancements in the visual domain following spontaneous and sensory-evoked networks of deafness. Moreover, these changes have been cortical activity in awake and anesthetized C57Bl6 shown to take place predominantly in areas mice. We demonstrate that infraslow (<0.1 Hz) upstream from primary sensory cortices. Indeed, and slow (0.5-6.0 Hz) spontaneous activity can visually-evoked activity has been observed in the recapitulate analogs of human resting-state posterior auditory field (PAF) in the cat cortex using networks. In particular, we describe a mouse analog functional MRI. This current study sought to of the Default Mode Network, involving medial examine how patterns of thalamo-cortical and cortical structures centered on retrosplenial cortices, CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

alterations to which, are linked with abnormal brain 2-D-106 Neural coding strategies used by the function. More significantly, our approach also vestibular system are matched to the statistics of allows for analyses of cortical dynamics such as natural stimuli altered sensory processing, impaired plasticity, and excitation/inhibition imbalance that are common Kathleen Cullen¹, Mohsen Jamali¹, Jerome Carriot¹, features of disturbed brain function. These Adam Schneider¹, Maurice Chacron¹ approaches along with chronic imaging and the advent of genetically-encoded reporters of neuronal ¹McGill University activity hold great promise in furthering our Efficient processing of incoming sensory input is understanding of these complex pathologies. essential for an organism's survival. A growing body 2-D-105 A combined optogenetic and fMRI of evidence suggests that sensory systems have approach for the study of cerebellum-to-cerebrum developed coding strategies that are constrained by connections the statistics of the natural environment. Consequently, it is necessary to first characterize Katrina Choe¹, Paul Mathews¹, Ka-Hung Lee¹, Andrew neural responses to natural stimuli in order to Frew¹, Roger Woods¹, Thomas Otis¹ uncover the coding strategies used by a given sensory system. Here we report for the first time the ¹University of California, Los Angeles statistics of vestibular rotational and translational stimuli experienced by rhesus monkeys during Existing anatomical and functional evidence suggests natural (e.g. walking, grooming) behaviors. We find both motor and non-motor areas of the cerebrum that these stimuli can reach intensities as high as are influenced by multi-synaptic cerebellar input; 1500 deg/s and 8 G. Recordings from afferents however, these correlative pieces of evidence fail to during naturalistic rotational and linear motion address the functional impact of this cerebellar further revealed strongly nonlinear responses in the input. To directly examine this, we combined whole- form of rectification and saturation which could not brain functional imaging with precise manipulation be accurately predicted by traditional linear models of cerebellar output via in vivo optogenetics. Optic of vestibular processing. Accordingly, we used linear- fibers were unilaterally implanted into the cerebella nonlinear cascade models and found that these of adult transgenic mice expressing the light- could accurately predict responses to naturalistic activated outward proton pump Archaerhodopsin stimuli. Finally, we tested whether the statistics of (Arch) in Purkinje neurons (PNs), and Blood-Oxygen natural vestibular signals constrain the neural coding Level Dependent functional magnetic resonance strategies used by peripheral afferents. We found imaging (BOLD-fMRI) signals were collected using a that both irregular otolith and semicircular canal Bruker 7 Tesla MRI system. Laser-mediated afferents, because of their higher sensitivities, were activation of Arch in the cerebellar cortex markedly more optimized for processing natural vestibular reduced the intensity of the BOLD-fMRI signal over stimuli as compared to their regular counterparts. the area adjacent to the site of fiber implantation Our results thus provide the first evidence that the (n=3 mice), and these decreases were absent in neural coding strategies used by the vestibular control mice not expressing Arch. Furthermore, system are matched to the statistics of natural concomitant increases in the BOLD-fMRI signal were stimuli. detected in both the ipsilateral and the contralateral cerebellar nuclei containing neurons under constant 2-D-107 Prolonged cognitive-motor impairments in PN inhibition. These results suggest that optogenetic children with a history of concussion inhibition of PNs induces robust and reliable decreases in BOLD-fMRI signals in the cerebellar Marc Dalecki¹, Lauren Sergio¹ cortex as well as triggers disinhibition-mediated signal increases in the cerebellar nuclei. Future ¹York University experiments will involve a systematic brain-wide We have previously shown impaired cognitive-motor inspection and analysis of BOLD-fMRI signal integration (CMI) in asymptomatic adult athletes triggered by optogenetic stimulation of the following concussion. Here we investigate whether cerebellum. the same is seen for still-developing children. Asymptomatic children with concussion history CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

(n=23, 0.25-40 months post, mean 10; mean age yaw and roll directions against a constant load. The 13.17 yr) and age-matched no-history controls self-generated head movements were recorded and (n=23, mean age 12.30 yr) performed two tasks then externally imposed on the subjects using a head using a dual-touchscreen laptop in which they had to motion robot that allowed for both the slide a cursor from a central to a peripheral target measurement and application of loads while using their finger. There was one direct-interaction controlling angular position in three degrees of task where target location and motor action were freedom. We found that the VCR decreased during aligned, and a CMI task where targets were in a externally imposed and self-generated movements different plane from hand motion, and visual relative to isometric conditions. For some subjects, feedback was reversed. We observed a significant the VCR decreased during self-generated relative to impairment in both movement timing and trajectory externally imposed movements but only when the formation with concussion history, and an movement involved activity of homologous muscle interaction effect with CMI. Importantly, we pairs, e.g., the VCR in the sternocleidomastoid observed a significant regression whereby those with muscles decreased only during self-generated a history of concussion did not perform the CMI task movements in pitch. These results demonstrate that at the non-concussed baseline level until 18 months the VCR is mainly attenuated as a result of head following their concussion. We previously observed movement, while self-generated head movement similar timing but not trajectory deficits in varsity has a limited effect. athletes with concussion history. We suggest that these performance deficits are due to concussion- 2-D-109 Switch in the type of t-SNARE protein induced disruptions in the fronto-parietal networks during trafficking of the transient receptor potential responsible for rule-based movement guidance, vanilloid 1 (TRPV1) in a model of inflammatory pain networks that are likely vulnerable in the developing brain. The observed prolonged deficits in CMI Sahar Jaffal¹ suggest that current return to sport/school/work ¹McGill assessments that do not test this ability, crucial in sport, are not fully capturing functional abilities post- The transient receptor potential vanilloid 1 (TRPV1) concussion. plays an important role in inflammatory pain. The axonal trafficking of this receptor from the dorsal 2-D-108 Suppression of vestibulocollic reflexes root ganglia (DRGs) to the periphery plays an during head movements important role in its availability in the periphery and Patrick Forbes¹, Jason Fice², Alfred Schouten³, Gunter accordingly pain. In this work, I used male Sprague Siegmund⁴, Jean-Sébastien Blouin² Dawley rats and gave them intraplantar injection of 5µM of dmPGE2 and then isolated the DRGs, the ¹University of British Columbia/Delft University of sciatic nerve and the skin from these rats after 3 and Technology, ²University of British Columbia, ³Delft 6 days of injection to extract proteins and do University of Technology, ⁴MEA Forensic Scientists & western blot using antibodies for different t-SNAREs. Engineers Generally, the availability of a receptor on the surface of the membrane through synaptic vesicles A key feature of the vestibular system is its ability to requires one á helix from the v-SNARE and 4 á distinguish between externally imposed (i.e. passive) helices from t-SNAREs. My results show that there is and self-generated (i.e. active) movements. During switch in the type of t-SNARE protein during dmPGE2 the latter, vestibular signals are suppressed at the induced trafficking of TRPV1 from the DRGs to the earliest stage of vestibular processing. Our periphery. In more details, SNAP25 was the t-SNARE understanding of how vestibular suppression affects involved in the availability of TRPV1 in DRG neurons vestibulocollic reflexes (VCRs) during self-generated without involvement on syntaxin-1. In contrast, movements remains sparse. In this study, we syntaxin-1, but not SNAP25, is the t-SNARE involved examined the electrically-evoked VCR in humans to in the availability of TRPV1 in the periphery (sciatic assess vestibular processing during externally nerve and skin). Accordingly, these results indicate imposed and self-generated head movements. that there is switch in the type of t-SNARE during Subjects actively moved their heads to match an trafficking of TRPV1. Studying in more details the oscillating target at a frequency of 0.5 Hz in pitch, interaction between TRPV1 and syntaxin-1 (in CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

dmGE2 injected rats), the role of interaction in pain In a simple reaction time (RT) paradigm, a response and inhibiting this interaction can have therapeutic is known in advance thus allowing for response value in finding analgesics in the future. selection and preparation processes to occur prior to the imperative "go" signal (IS). These processes can 2-D-110Mere Expectation of Haptic Feedback be described using a neural activation model, in Facilitates Shift from Pantomimed to Natural Grasp which neural activity increases until an "ignition" threshold is reached. This model can be probed Nathan Katz¹, Robert Whitwell², James Enns², Melvyn using a startling acoustic stimulus (SAS), which is Goodale¹ known to elicit pre-programmed responses at a shorter latency. The mechanisms of this ¹University of Western Ontario, ²University of British phenomenon are currently debated; however, a Columbia recent study suggested that a cumulative effect of Skilled sensorimotor acts like grasping are normally both voluntary and startle-related initiation directed at goal objects, programmed using real- processes following the IS may be responsible. The time visual input, and entail tactile, proprioceptive, purpose of this experiment was to further probe this and kinaesthetic sources of haptic feedback. Studies cumulative effect by presenting a SAS at specific of visual form agnosic patient DF and of healthy time points following the IS. It is hypothesized that a participants suggest that 'natural' and pantomimed SAS presented at a short latency following the IS will (simulated) grasps rely on different cortical result in faster RTs than a SAS presented concurrent structures. Work in our laboratory (and others) has with the IS, which can only make use of startle- shown that denying a tangible object (or a proxy) at related initiation processes. Participants performed the end of the reach (haptic feedback) induces a shift 5 blocks of 20 trials involving a ballistic wrist in the response away from 'natural' grasps towards extension movement. In 20% of trials, a white noise pantomimed ones in blocked trial orders. SAS (120 dB) was randomly presented at 0, 12, 24, Interestingly, randomly interleaving trials with and 36 or 48 ms following the IS (82 dB). Preliminary without haptic feedback ameliorates these results have indicated that premotor RTs for control differences. However, because the trial orders were trials were 187 ms, and premotor RTs for SAS trials always either blocked or randomized, one cannot were 92, 89, 93, 111 and 126 ms respectively. The know whether 1) predictive knowledge of haptic faster RTs seen at 12 ms compared to at 0 ms lend feedback on the upcoming trial or 2) the trial history further support to the cumulative model and of haptic feedback (i.e. consistency) accounts for demonstrate that the additional activation provided these differences. Here, we remedied this confound by the SAS increases the rate of activation. by organizing trials with and without haptic feedback 2-D-112 The influence of somatosensory feedback into blocked, alternating, and two randomized trial on visuomotor adaptation orders - one with and one without predictive knowledge of the availability of haptic feedback. Sajida Khanafer¹, Keri-Lyn Andrus¹, Erin Cressman¹ Replicating our earlier work, we found that removing haptic feedback induced a shift from natural to ¹University of Ottawa pantomimed grasps. Critically, predictive knowledge of the availability of haptic feedback on the Subjects quickly adapt their movements when upcoming trial potentiated this effect. These findings aiming in a virtual reality environment in which the indicate that the mere expectation of haptic visual representation of their hand is rotated relative feedback can determine whether a grasp is to their actual hand motion. Specifically, if a visual controlled by dorsal or ventral stream processing. cursor representing the hand position is rotated 30° clockwise relative to actual hand motion, subjects 2-D-111 Cumulative activation effect predicts faster compensate for the visual distortion and aim reaction times compared to startle only related counter-clockwise of the target. Importantly, activity subjects continue to reach with adapted movements (i.e. exhibit aftereffects) in the absence of visual Michael Kennefick¹, Paul van Donkelaar¹, Anthony feedback. In the current study we looked to Carlsen² determine if providing additional somatosensory information during reaches would lead to benefits in ¹University of British Columbia, ²University of Ottawa CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

reach adaptation. Two groups of participants aimed whereas shifts in orientation preference rely on to targets when (1) the cursor accurately indicated other mechanisms. hand position and (2) the cursor was rotated 30 degrees clockwise from the actual hand position. To 2-D-114 Real-time in vivo measurement of determine the benefit of enhanced somatosensory corticostriatal afferent activity during skill learning information on reaching, one group of subjects was provided with additional haptic feedback at the end David Kupferschmidt¹, Guohong Cui², David Lovinger¹ of their reaching movements, such that the robot ¹NIH / NIAAA, ²NIH / NIEHS handle they were reaching with vibrated with a frequency of 5 Hz for 1500 milliseconds. All subjects Dynamic changes in cortico-basal ganglia circuits adapted their reaches after training with a rotated underlie action learning. How changes in discrete, cursor. Moreover, adaptation levels were similar connectivity-specified circuits manifest in vivo during across both groups of subjects, suggesting that such learning remains unknown. Using in vivo fiber additional somatosensory information did not photometry, we assessed real-time activity and benefit reach adaptation. These findings suggest that plasticity of distinct cortical inputs to the striatum the CNS may rely more on visual feedback and during motor skill learning. Emx1Cre mice expressing ignore somatosensory information during Cre recombinase in excitatory cortical neurons were visuomotor learning paradigms. injected with AAVs encoding Cre-dependent GCaMP6s, a calcium indicator, into the motor cortex 2-D-113 Optogenetic Silencing of Mouse Primary (M1) or medial prefrontal cortex (mPFC). An optical Visual Cortex Affects Orientation Adaptation fiber was implanted into the dorsolateral striatum of Jillian King¹, Nathan Crowder¹ M1-injected mice to target sensorimotor corticostriatal inputs, and the medial striatum of ¹Dalhousie University mPFC-injected mice to target associative corticostriatal inputs. Activity-dependent fluorescent Information processing in the visual system is shaped calcium dynamics were assessed in presynaptic by recent stimulus history, such that prolonged elements of these inputs as a proxy for projection viewing of an adaptor stimulus can alter the activity as mice trained on the accelerating rotarod. perception of subsequently presented stimuli and Preliminary work indicates that sensorimotor inputs modify the visual response properties of neurons in were engaged by performance on the rotarod, and multiple brain areas. In the tilt-aftereffect (TAE), the their activity scaled flexibly with rotarod velocity. perceived orientation of a grating is often repelled Velocity-correlated activity persisted across training, away from the orientation of a previously viewed despite a progressive decrease in overall adaptor grating. A potential neural correlate for this engagement of this pathway. Associative projection TAE has been described in cat and macaque primary activity was also engaged in a velocity-correlated visual cortex (V1), where adaptation produces manner during early rotarod performance, but was repulsive shifts in the orientation tuning curves of V1 markedly reduced with extended training. Our work neurons. We studied orientation adaptation in mice describes a novel approach to observe real-time with the hope of using the genetic tools available in activity dynamics in discrete corticostriatal inputs, this species to shed light on mechanisms underlying and reveals projection-specific plasticity that likely these tuning curve shifts. Adaptation in wildtype underlies motor skill learning. mice caused orientation tuning curves to shift like those in cats and primates, but also produced a large 2-D-115 Chloride dysregulation causes decrease in responsivity not seen in other species. disproportionate disinhibition of excitatory When the same adaptation paradigm was repeated interneurons in spinal dorsal horn: implications for in transgenic mice that express channelrhodopsin-2 neuropathic pain (ChR2) in GABAergic neurons, optogenetic cortical silencing of V1 during adaptation strongly Kwan Lee¹, Kwan Yeop Lee¹, Steven Prescott¹ attenuated the decrease in responsivity. This ¹Sickkids hospital, University of Toronto preliminary data suggests that adaptation induced changes in response gain are spike-rate dependent, Neuropathic pain is a debilitating condition whose symptoms arise from abnormal processing of CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

somatosensory input. Many features of neuropathic stimulation currents (5- 60 µA), frequency (50-300 pain are attributable to reduction of synaptic Hz), and duration (30-200 ms). Site-specific vectors inhibition in the spinal dorsal horn. Disinhibition can ranged from 5 to 20°. In 44% of the sites, we found a arise from reduced GABAergic or glycinergic significant increase in pupil diameter after transmission or from chloride dysregulation caused subsaccadic stimulation (2-way-ANOVA, p<0.05). by hypofunction of the potassium-chloride co- The level of the induced response was positively transporter KCC2. The contribution of each correlated with increasing stimulation factors. Our disinhibitory mechanism and the effects on network- results imply a contribution of FEF to pupil dilation, level processing remain poorly understood. Here we presumably mediated through the superior show, based on the differential susceptibility of each colliculus. They provide an important link for how disinhibitory mechanism to treatment by high-level processes may influence pupil diameter, acetazolamide, that chloride dysregulation which could serve as a biomarker for sub-threshold contributes significantly to neuropathic pain. We oculo-motor processes. also show that both excitatory and inhibitory interneurons experience chloride dysregulation but 2-D-117 Postural Threat Influences Vestibular- that excitatory interneurons are disproportionately Evoked Muscular Responses affected because they normally receive more inhibitory input than inhibitory interneurons. Shannon Lim², Taylor Cleworth², Jean-Sébastien Overall, reduction of surround inhibition and the Blouin², J. Timothy Inglis², Mark Carpenter² unmasking of subliminal excitatory input ¹University of British Columbia, ²The University of fundamentally change how low threshold inputs are British Columbia processed at the network level, resulting in mechanical allodynia. This work was supported by While vestibulo-ocular gain has been known to be NIH grant R21 NS074146. SAP is also a Canadian modulated by arousal and vigilance, the effect of Institutes of Health Research New Investigator and such threat-related factors on vestibulospinal the 53rd Mallinckrodt Scholar. reflexes and related balance responses are less clear. Recent studies using stochastic (Horlsen et al. 2014) 2-D-116 Subsaccadic FEF microstimulation induces and square-wave (Osler et al. 2013) galvanic- pupil dilation vestibular stimulation to examine height-induced Sebastian Lehmann¹, Brian Corneil¹ effects on vestibular-evoked responses provide conflicting results based on kinetic and kinematic ¹University of Western Ontario data. The current study used stochastic vestibular stimulation to examine the effect of postural threat The orienting response is an organism's reaction to on vestibular-evoked muscle responses. 25 subjects changes in its environment in order to heighten stood under 2 conditions. In the 'No-Threat' perception and prepare for action; this can include condition, subjects stood quietly on a stable surface. changes in gaze, attention, and pupil dilation. The In the 'Threat' condition, subjects' balance was frontal eye fields (FEF) are a part of the oculomotor perturbed by a series of rapid, unpredictable medial- system known to be involved in the generation of lateral surface tilts. Pre-perturbation periods of quiet voluntary saccadic eye movements and covert shifts stance (5 sec) were concatenated (total=115 sec) in visuo-spatial attention. While microstimulation of and compared to an equivalent time in the No- the FEF can evoke saccadic gaze shifts, lower levels Threat condition. Surface EMG was recorded from of stimulation current can modulate components of bilateral leg, hip, and trunk muscles. Leg and hip the orienting response, such as covert attentional muscles exhibited significant increases in the shifts, without evoking saccades. Based on recent amplitude of vestibular-evoked muscle responses in results showing that pupil dilation can be evoked by the Threat compared to No-Threat condition, and subsaccadic stimulation of the superior colliculus in these changes correlated with changes in reported primates, we investigated the effects of subsaccadic fear of falling and arousal. In contrast, paraspinals FEF microstimulation on pupil dilation. Two non- revealed decreased peaks in the Threat condition human primates performed a fixation task in which and external obliques showed no change. These we stimulated the right FEF with biphasic pulses. In a findings show a relationship between postural threat total of 101 sites, we parametrically varied and the vestibular-evoked muscle responses and CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

may provide some insight to muscle specific changes We have previously shown that people who have of balance responses in threatening situations. lost one eye early in life have enhanced sound localization (Hoover et al., 2011), lack visual 2-D-118 Is reduced cutaneous sensitivity predictive dominance (Moro & Steeves, 2011) and integrate of weakened synaptic coupling between skin and auditory and visual information optimally (Moro et muscle in the elderly? al., 2013) compared to binocular and eye-patched viewing controls. Structurally, people with one eye Ryan Peters¹, Monica McKeown¹, Mark Carpenter¹, have decreased lateral geniculate nuclei volume Tim Inglis¹ (LGN; thalamic visual relay station). However, this decrease is less severe in the LGN contralateral to ¹University of British Columbia the remaining eye, indicating altered structural One mechanism for age-related balance impairment development (Kelly, et al., 2013). The medial could be decreased coupling between cutaneous geniculate body (MGB; thalamic auditory relay receptors and postural muscles. A decline in station) plays a central role in auditory processing cutaneous sensitivity with age may lead to with both efferent and afferent tracts to primary decreased cutaneous drive to spinal reflex circuits. auditory cortex (Schönwiesner et al., 2007). Given We explored whether cutaneous reflex coupling is the existing audiovisual processing differences and degraded in the elderly, and tested the hypothesis LGN changes in people with one eye, we investigated that coupling strength is correlated with sensitivity. whether structural MGB changes are also present. We obtained monofilament, and vibratory MGB volumes were measured in adults who had thresholds at 30 and 250 Hz bilaterally on the medial undergone early unilateral eye enucleation and were forefoot. We also measured electromyography compared to binocularly intact controls using the (EMG) from Tibialis Anterior (TA) during a low-level current gold standard methodology for anatomical contraction while vibratory stimulation at 30 or 250 localization of the MGB (Devlin, 2006). Unlike Hz was applied. To analyze cutaneo-motor coupling, controls, people with one eye had a significant we performed spectral analysis in the frequency asymmetry with a larger MGB volume in the left (coherence) and time (cumulant density) domain compared to the right hemisphere, independent of using the probe displacement and EMG waveforms. eye of enucleation. The volume asymmetry in the Elderly adults had elevated pressure and vibratory MGB in people with one eye may represent thresholds, bi-laterally, compared to young adults. increased interaction between the left MGB and With 30 or 250 Hz vibration, we observed primary auditory cortex as compensation for the loss corresponding oscillations in the time cumulant, of one half of the visual inputs early in life. which we argue is the result of synaptic coupling 2-D-120 RAGE-dependent sensitization of sensory between vibration-sensitive skin receptors and neurons innervating airway submucosal glands: motor neurons innervating TA. At 30 Hz, the elderly possible role in airway hypersecretion adults appear to have both lower coherence, and lower peak-to-peak amplitude in the cumulant Manoj Nair¹, Yasuhiko Yamamoto², Juan Ianowski¹, density. At 250 Hz, coherence and cumulant density Veronica Campanucci¹ peaks failed to reach significance. While preliminary, our results suggest that reduced sensitivity is ¹University of Saskatchewan, ²Kanazawa University accompanied by decreased coupling between cutaneous receptors and primary motor neurons Neurogenic inflammation contributes to mucus and with age. fluid hypersecretion by submucosal glands (SMGs) in several airway diseases. "Sensory-efferent" 2-D-119 Asymmetrical medical geniculate body pathways, arising from thoracic dorsal root ganglia volume in people with one eye (DRG), stimulate SMGs and can trigger hypersecretion by neurogenic inflammation. Stefania Moro¹, Krista Kelly¹, Larissa McKetton¹, However the mechanisms underlying neurogenic Jennifer Steeves¹ inflammation in the upper airways are poorly understood. The receptor for advanced glycation ¹York University end-products (RAGE) plays a central role in inflammation in both, sensitization of pain fibers and CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

allergic airway responses. Therefore, we hypothesize 45.0%, and 13.3% of dural blood vessels, that RAGE contributes to neurogenic inflammation respectively. EAAT2 was the only transporter and airway hypersecretion. To test this idea we used expressed in the dura. MSG evoked a mean increase DRG primary cultures from wild type (WT) and RAGE of 24.5% in dural blood flow, and this increase was knock-out (RAGE KO) mice. To activate inflammatory reproducible one hour later with a mean increase of signaling, cells were exposed to lipopolysaccharide 23.4% following a second administration of MSG. (LPS; 24h, 1ug/mL). Next, we used whole-cell patch- Conclusion: Dural vasodilation evoked by MSG clamp to study capsaicin(CAP)-evoked currents suggests that activation of peripheral GluRs (1µM, 1s) and action potentials (APs) evoked by expressed in the dura mater may play a role in injection of depolarizing current (100pA, 500 ms). mediating headache pain. Our data indicates that LPS induced a significant increase in CAP-induced currents (amplitude, density 2-D-122 Does plasticity in muscle afferent reflex and charge) in DRGs from WT mice. Furthermore, pathways accompany cross-education of the wrist LPS caused a significant increase in the number of flexors? APs triggered by 200pA. Remarkably, LPS did not induce any changes on CAP currents or excitability in Gregory Pearcey¹, Trevor Barss¹, Yao Sun¹, Taryn RAGE KO cells. Taken together our data suggest that Klarner¹, E Paul Zehr¹ RAGE signalling mediates the sensitization of DRG ¹University of Victoria neurons during inflammation, which may play a role on neurogenic hypersecretion in chronic airway Cross-education refers to bilateral increases in disease such as asthma, cystic fibrosis or COPD. strength induced by training only one side of the body. The adaptations accompanying cross- 2-D-121 Activation of glutamate receptors in rat education have largely been attributed to cortical dural blood vessels mediates vasodilation mechanisms; however, spinal circuitry may also Melissa O'Brien¹, Xudong Dong¹, Brian Cairns¹ adapt. The purpose of this study was to examine bilateral spinally-mediated adaptations in muscle ¹University of British Columbia afferent reflex pathways in wrist flexors after unilateral handgrip training. Eleven neurologically Background: Glutamate is an excitatory intact, right-handed participants completed 6 weeks neurotransmitter involved in pain transmission. of unilateral handgrip training using the dominant Blood plasma glutamate concentration is elevated in hand across 3 sessions of 5 sets of 5 maximal migraineurs, but how this contributes to their voluntary contractions (MVC) each week. Handgrip headache is unknown. We hypothesized that MVC force, electromyography (EMG) of wrist flexor glutamate receptors (GluRs) are expressed by and extensor muscles and H-reflex recruitment afferent fibres that innervate dural blood vessels and curves (unconditioned and cutaneous[superficial that their activation causes vasodilation. Methods: radial nerve]-conditioned to modulate Group Ia Four male Sprague-Dawley rats were used for presynaptic inhibition) were assessed in both arms histology. Animals were perfused with before and after training. Handgrip force increased paraformaldehyde and the dura was extracted. bilaterally after training providing evidence for Antibodies were used to assess the expression of effective cross-education. Preliminary analysis GluRs; NMDA (NR2B subunit), AMPA (iGluR1 revealed that cutaneous-conditioned maximal H- subunit), kainate (iGluR5-7), and group 1 reflexes (Hmax) were greater than unconditioned metabotropic (mGluR5) receptor, in dural afferent Hmax, indicating a reduction in presynaptic fibres and blood vessels. The expression of amino inhibition during the conditioned response. After acid transporters 1-3 (EAAT1-3) was also assessed. training, there was little modulation of conditioned Tissue samples were visualized with a confocal or unconditioned Hmax amplitudes of both the microscope. Laser Doppler flowmetry was utilized to trained and untrained wrist flexors. Since plasticity measure potential changes in dural blood flow associated with training may be unevenly distributed evoked by systemic administration of 50mg/kg to motor unit subtype and excitability, further monosodium glutamate (MSG) in 5 male Sprague- analysis of possible adaptations at smaller reflex Dawley rats. Results: NMDA, AMPA, kainate, and amplitudes, particularly threshold responses, is mGluR5 receptors were expressed in 30.0%, 33.3%, warranted CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

2-D-123 a5GABAA receptors mediate tonic ¹University of British Columbia, ²University of Oregon inhibition and central sensitization in the dorsal horn of the spinal cord The vestibular control of standing balance is tightly coupled with head orientation suggesting a reliance Jimena Perez-Sanchez¹, Robert Bonin¹, Louis-Etienne on sensorimotor information regarding head-on- Lorenzo¹, Charalampos Labrakakis², Erica body posture. However, during sustained head- Bridgwater³, Beverly Orser³, Yves De Koninck¹ turned postures in which the face is directed over the shoulder, the vestibular response is proposed to ¹CRIUSMQ, Université Laval, ²University of Ioannina, be influenced by conscious perception of head ³University of Toronto orientation. Here, we attempted to determine whether conscious perception influences spatial The transmission of nociceptive information in the transformation of the vestibular control of balance dorsal horn (DH) of the spinal cord is constrained by during self and externally maintained head-turned persistent inhibitory control through the activation postures. Volunteers stood on a force plate with the of GABAA receptors. The loss of GABAergic inhibition head turned for a prolonged period and were can increase excitability of DH neurons and produce exposed to bouts of stochastic vestibular stimuli hyperalgesia. Tonic activation of extrasynaptic (SVS; 0-20 Hz, duration = 90 s). Vision was occluded α5 subunit-containing GABAA for segments of the trial and maintenance of head (α5GABAA) receptors is known to regulate posture was achieved through an external support or neuronal excitability in different brain regions. We self-generated neck muscle activity. When the head explored the role of tonic inhibition mediated by was externally supported, perception of head α5GABAA receptors in the processing of pain. orientation shifted in the same direction as the Immunohistochemical analyses showed that the vestibular balance response. However, visual expression of α5GABAA receptors in the dorsal recalibration of the head on body position did not horn follows a laminar pattern. Whole-cell affect the balance response direction. In self- recordings were obtained from DH neurons located maintained postures, perception of head orientation in laminae I and II from α5 subunit null mutant shifted minimally towards a neutral posture but the (Gabra5−/−) and wild type (WT) mice. balance response remained aligned with head We found no change in either frequency or position. We propose that sensorimotor signals amplitude of miniature inhibitory postsynaptic associated with self and externally maintained head currents (mIPSCs), consistent with the extrasynaptic postures predominate the spatial transformations nature of these receptors. Tonic current as underlying the vestibular control of balance, while measured by the inhibition of tonic GABAergic perception appears to be a secondary outcome of activity with bicuculline, was decreased only in cells these factors. from lamina II of Gabra5−/− mice. In behavioural tests, Gabra5−/− mice 2-D-125 Role of the Cav3-Kv4 complex in mediating exhibited increased responses in the late phase of synaptic learning in cerebellar granule cells the formalin test, associated with central sensitization in the DH. However, no difference was Arsalan Rizwan¹, Gerald Zamponi¹, Ray Turner¹ found between Gabra5−/− and WT mice in acute or thermal sensitivity, or in mechanical ¹The University of Calgary hyperalgesia produced by intraplantar administration of capsaicin. Our data suggest that Based on sensory information carried by mossy fibre α5GABAA receptors contribute to central (MF) inputs and related cerebellar outputs, a sensitization in the dorsal horn of the spinal cord in a compartmentalization of function can be found in modality specific manner. cerebellar lobules I-X. The granule cell (GrC) layer is the primary input layer of the cerebellum in direct 2-D-124 Spatial transformations of the vestibular receipt of MF inputs. We know that the subunits control of standing balance responsible for a Cav3-Kv4 interaction are differentially expressed across the lobules, with most Brandon Rasman¹, Brian Dalton², J Timothy Inglis¹, influence on GrC excitability in lobule 9. As a result, Jean-Sébastien Blouin¹ the functional ability of MF inputs to activate GrCs is lobule-specific. The high input transmission (1 kHz) CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

at the MF-GrC synaptic relay in cerebellum can the greater columnar organization of stimulus induce long term changes in synaptic efficacy features in cat V1 than in rodent V1. Travelling through pre- and postsynaptic mechanisms that waves of activation (UP phases) in the synchronized shape the response to subsequent inputs. We used state may interact differently with incoming stimuli in vitro slices of rat cerebellum to test the hypothesis in the two species. This explanation predicts a similar that LTP of MF EPSCs can differentially modify Kv4 A- result in anesthetized ferret and primate V1. type channel (IA) properties in GrCs across the cerebellar lobules. We found that LTP of MF input 2-D-127 The functional organization of local neural induced by pairing theta burst stimulation with networks providing input to single cortical neurons postsynaptic depolarization invoked a select leftward shift of IA voltage for inactivation (Vh) only in lobule Adrian Wertz¹, Stuart Trenholm¹, Botond Roska¹ 9. Moreover, a late long-lasting EPSC present in ¹FMI control conditions in lobule 2 cells was unmasked in lobule 9 cells after blocking the Cav3-Kv4 complex or Introduction: Many cortical neurons respond following LTP of MF input. These results indicate that selectively to specific cues. For instance, in visual MF repetitive synaptic input dynamically regulates cortex, many neurons respond to specific directions the biophysical properties of IA in posterior lobule 9 of visual motion. How the response selectivity of a GrCs. Funded through grants from the Canadian single cortical neuron relates to the selectivity of its Institutes of Health Research (RWT, GWZ). local presynaptic partners remains unclear. Methods: Here, we performed single cell initiated, 2-D-126 Natural scene movie responses are more monosynaptically restricted, retrograde precise in synchronized than desynchronized cat V1 transsynaptic tracing with rabies viruses expressing Martin Spacek¹, Nicholas Swindale¹ GCaMP6s to image, in vivo, visual motion evoked activity of individual layer 2/3 pyramidal neurons ¹University of British Columbia and their presynaptic neuronal networks in primary visual cortex. Results: Using this technique, we were We recorded spiking responses simultaneously from able to visualize > 200 presynaptic cells connected to dozens of single units across all layers of isoflurane- individual layer 2/3 pyramidal cells of primary visual anesthetized cat V1 using silicon polytrodes. Unlike cortex. The largest subset of presynaptic neurons responses to more artificial visual stimuli, responses was in primary visual cortex, and spanned across all to short repeated natural scene movie clips cortical layers. Longer range connections could also consisted of remarkably sparse, temporally precise, be consistently found, including inputs from the reliable events. Each unit had a distinct temporal lateral geniculate nucleus. In addition to mapping pattern of such response events, some precise to the location of presynaptic neurons, we used in vivo within as little as 20 ms. Cortical state was quantified calcium imaging to characterize the response by the power ratio of low and high frequency bands properties, to moving visual stimuli, of the of deep-layer local field potential. Cortical state electroporated cell (the postsynaptic cell) as well as spontaneously switched between synchronized (1/f the response properties of its local presynaptic distribution) and desynchronized (broadband). partners in primary visual cortex. We found the Contrary to reports in anesthetized rodent cortex existence of different functional organization [Goard2009,Marguet2011,Zagha2013,Pachitariu201 principles for networks of presynaptic neurons 5], responses were more precise and reliable during providing input to individual layer 2/3 pyramidal the synchronized than desynchronized state. This is neurons. Conclusion: Our results indicate the surprising, because the synchronized state under existence of multiple presynaptic network anesthesia is thought to correspond to quiet organization principles of layer 2/3 pyramidal wakefulness in awake animals, and the neurons. desynchronized state to alert attending periods. Neural responses are known to be more precise and reliable to attended than unattended stimuli. Our results therefore question the analogy between E - Homeostatic and Neuroendocrine Systems cortical states in anesthetized and awake animals. One possible reason for this conflicting result may be CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

2-E-128 cFos expression in newborn chicks: that contribute to coping such as grooming, but a relationship to sleep and waking cellular entry point into circuitry that links stressful experiences and internally focused behaviour is Aimee Chan¹, Si Han Li¹, Maria Pompeiano¹ unknown. Corticotropin releasing hormone (CRH) neurons in the paraventricular nucleus of the ¹McGill University hypothalamus (PVN) launch the endocrine response to stress, but here we show they drive rapid, cFos is a marker of neuronal activation that has been stereotyped, repetitive grooming behaviour and are extensively used to identify sleep- and wake-active also necessary for the expression of grooming areas in mammalian brains. Birds, including chickens, observed during recovery from acute stress. This show similar sleep and waking states as mammals rapid behaviour is initiated through a glutamatergic (Lesku & Rattenborg 2014). To determine the extent connection from CRH neurons to hypothalamic of the similarity in cFos expression patterns between perifornical neurons. These findings reveal a new avian and mammalian brain states, cFos expression role for these cells as drivers of a circuit for was examined in sleeping (S), sleep-deprived (SD), stereotyped behaviour following stress; and sleep-recovery (SR) newborn chicks using manipulating this circuit could serve as a new model immunohistochemistry. cFos staining was much for understanding core behavioural phenotypes in higher in SD compared to S and SR states in psychiatric disorders. analogous areas to those of awake rats, including the pallium, hippocampus, amygdala, thalamus, septum, 2-E-130 The Role of Ghrelin in the Mediation of the hypothalamus, and brainstem areas (Pompeiano et Stress Response in Female Mice al. 1994). This suggests that the waking state in birds is characterized by a similar pattern of cFos Rim Khazall¹, Zack Patterson¹, Meheria Arya¹, Alfonso activation as seen in mammals. In order to Abizaid¹ characterize the role of particular neuronal systems involved in arousal during waking, we next examined ¹Carleton University cFos expression in orexinergic, noradrenergic locus coeruleus, and serotonergic dorsal raphe neurons Ghrelin, an orexgenic gut hormone, plays an using fluorescent double-immunostaining important role in the metabolic response to animal techniques. We found that these populations models under chronic stress.These data, however, showed a much higher cFos expression in SD than in has been obtained using males, in spite of multiple S or SR chicks, similar to what has previously been studies suggesting that there are sex differences in described in mammals (Modirrousta et al. 2005; the stress response as well as in the behavioral Maloney et al. 1999). This suggests that the responses to exogenous ghrelin administration. This functional regulation of the waking state by these study was conducted to determine if behavioral and arousal systems may be very similar between birds metabolic alterations associated with the stress and mammals. Continuing work is aimed at response are also affected in female mice and if identifying and studying the cFos activation patterns ghrelin mediates the magnitude of these effects. We of sleep-active neurons involved in sleep regulation exposed female mice with a targeted deletion of the of newborn chicks. ghrelin receptor gene (GHSRKO) and their wildtype littermates (GHSRWT) to a chronic unpredictable 2-E-129 Hypothalamic CRH neurons are an entry stress paradigm. Our results show, regardless of point for a circuit that drives stress coping behavior genotype, all stressed animals showed greater stress induced depressive -like symptoms. Furthermore, Tamás Füzesi¹, Jaclyn Wamsteeker Cusulin¹, Jaideep stressed females ate less calories than controls Bains¹ during the stress paradigm, but maintained their body weight. In a second study, females were ¹University of Calgary allowed to recover period following the stress paradigm. As in Experiment 1, stressed females Survival threats require immediate actions, and showed significantly more signs of stress- induced trigger a distinct repertoire of externally focused depressive like behaviors. Interestingly, while there defensive behaviours and adjustments in hormonal were no differences in food intake between the state. In many species, acute stress is followed by groups during the experimental time points, stressed stereotyped, internally focused, repetitive actions CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

females ingested more calories during the recovery expression in obese rodents or humans. D2Rs are period and had elevated glucose levels.Taken expressed throughout the striatum at both together, these results suggest that chronic stress presynaptic and postsynaptic sites. D2Rs expressed causes a number of behavioral and metabolic on dopamine terminals act as autoreceptors to limit alterations in female mice, but the role of the ghrelin dopamine release. While diet induced obesity can receptor in these processes is not as well defined. decrease striatal D2Rs, it is unknown if this alters autoreceptor control of striatal dopamine. 2-E-131 Sex-specific consequences of neonatal Therefore, we investigated whether obesity altered stress on laryngeal chemoreflex stimulation in rat pre-synaptic D2R modulation of dopamine release. pups: Contribution of excitatory currents onto key Adult Long-Evans rats were given 6-8 weeks of brainstem regions unrestricted access (extended access), 1 hour access (restricted access) or no access (chow-fed) to a Richard Kinkead¹, Cécile Baldy¹, Simon Chamberland¹, cafeteria diet along with ad libitum standard Richard Kinkead¹ laboratory rat chow. Extended access rats consumed significantly more calories and were heavier than ¹Université Laval restricted access or chow fed rats after 40 days of In preterm infants and rat pups, the presence of food intake. Rats with extended, but not restricted liquids or solids in the airways stimulates the access to a cafeteria diet did not suppress their food laryngeal chemoreflex (LCR). In an immature intake in the presence of aversive cues. We mammal, LCR stimulation results in prolonged measured evoked dopamine concentrations before apneas, O2 desaturation and bradycardia with and after quinpirole in striatal slices using fast scan potentially life threatening consequences. LCR cyclic voltammetry. Quinpirole-induced suppression afferences arrive at nucleus tractus solitaris (NTS) of dopamine concentration in dorsolateral striatum and go to motor vagus nucleus (NX). NX is involved in or nucleus accumbens core was not significantly effect of LCR on heart rate in young pups. Previous different amongst extended access, restricted access experiments in our laboratory show that neonatal or chow-fed rats. Taken together, diet induced maternal separation (NMS) increases obesity does not alter autoreceptor control of cardiorespiratory responses evolved by LCR. Because dopamine release. neonatal stress interferes with respiratory control development, we tested the hypothesis that NMS has an impact on synaptic inputs converging in these F - Cognition and Behavior regions. Experiments were performed on 14 and 15 days old pups that were undisturbed (controls) or 2-F-133 Probing procedural strategy with a spatial subjected to NMS (3h/day each day beginning at P3 working memory task: A potential marker of intact to P13). Brainstem slices were obtained on frontal function anesthetized pups. Spontaneous EPSCs were recorded in NX region. We found that NMS increased Alenka Bullen¹, Robert Marino¹, Ron Levy¹ amplitude and frequency of spontaneous EPSCs in NX. This research was supported by CIHR. ¹Queen's University

2-E-132 D2 autoreceptor function is intact after When engaging in spatial working memory tasks, in diet induced obesity which subjects generate sequences of responses to spatial arrays of stimuli, patients with frontal lobe Kimberley Pitman¹, Michael Drysdale², Manpreet damage often fail to implement procedural Kaur², Jennifer Thompson², Stephanie Borgland² strategies to facilitate memory performance. Conversely, impaired performance among patients ¹University of British Columbia, ²HBI University of with temporal lobe damage is unrelated to strategy Calgary use. Assessing spatial working memory in a non- human primate (NHP) affords the ability to parse the Altered mesolimbic dopamine function is a well- contribution of higher executive functioning (e.g., researched adaptation associated with diet-induced strategy formation) on short-term memory. The obesity. Previous research has demonstrated present study aimed to examine the spatial working decreased striatal D2 dopamine receptor (D2R) CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

memory performance of a healthy rhesus macaque expression of ionized calcium-binding adaptor across six weeks of task acquisition. The NHP was molecule (iba-1), a cellular marker of microglial trained on the self-ordered spatial search (SOSS) task activation, and an upregulation of c-Fos, a marker of adapted from a human neuropsychological test neuronal activation. Intrathecal treatment with battery (CANTAB, Cambridge Cognition, Ltd). This A740003 significantly attenuated morphine touch-screen task required the NHP to produce self- withdrawal, and prevented the increase in iba-1 and ordered sequences of responses to spatial arrays of c-Fos expression. Collectively, our findings reveal a 2, 3 or 4 targets. Delay periods (0.1 - 2s) between critical role of spinal P2X7Rs in the development of responses probed short-term memory. The NHP morphine physical dependence. exhibited protracted learning to increases in task difficulty and reduced performance with additional 2-F-135 Variations in brain activity as a function of targets and longer delay periods, demonstrating task hand/target visual feedback availability sensitivity to short-term memory capacity. Analysis revealed evidence for a procedural strategy Darian Cheng¹, Krista Fjeld¹, Gordon Binsted¹ employed independent of delay duration, which ¹University of British Columbia predicted trial accuracy. These results suggest that the SOSS task is capable of modeling not only In this study, brain potentials associated with target learning and memory but also higher cognition in an encoding and movement execution under varying NHP, offering a means of investigating the cognitive visual conditions were examined using systems that are differentially impaired in clinical electroencephalography. Specifically, we were populations. interested in examining whether event related potentials (ERP) would differ as a consequence of 2-F-134 Morphine withdrawal critically involves visual feedback during movement execution. The spinal P2X7 receptors four visual conditions included vision of hand & Nicole Burma¹, Tuan Trang¹ target, hand only, target only, and no vision of hand & target. At the start of each trial, a target was ¹University of Calgary previewed, followed by a delay period. Participants executed a movement towards the target location Opioids, such as morphine, are among the most upon hearing an imperative auditory tone. Epochs powerful and widely prescribed analgesics for for ERP analyses were obtained by time locking EEG managing pain. However, their repeated use can segments to: 1) target preview, in order to explore if lead to opioid physical dependence, which manifests participants encoded the target differently when the as a withdrawal syndrome upon discontinuing opioid upcoming visual condition was known, and 2) use. Converging evidence suggests that opioid movement start, to examine if ERPs varied withdrawal is critically mediated by changes in the depending on visual feedback availability of the hand spinal dorsal horn, which is a primary site of action and/or target. While the findings indicate no for opioid analgesia. The present study examines the differences during the preview and encoding of the importance of spinal ATP-gated P2X7 purinoceptors target; potentials associated with movement (P2X7R) in the development of morphine physical execution first occur over motor areas, contralateral dependence. We treated rats using a 5-day to the acting hand, and migrate to medio-frontal escalating morphine dosing paradigm and assessed regions of the brain. In addition, activity in occipito- the role of spinal P2X7Rs in morphine physical parietal regions occurs when vision of the hand dependence by intrathecal injections of the selective (hand & target or hand only conditions) is made P2X7R antagonist A740003. On day 5, rats received a available to participants. Additionally, time single injection of morphine and 2 hours later frequency analyses were performed in order to challenged with an injection of the opioid receptor decipher the frequency band at which brain activity antagonist, naloxone, to rapidly precipitate was predominantly occurring and to investigate morphine withdrawal. We found that morphine whether these potentials are related to error treated animals exhibited a robust naloxone detection processes. precipitated withdrawal syndrome characterized by autonomic and somatic hyperactivity. The severity of withdrawal correlated with increased spinal CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

2-F-136 Disruption of AMPA receptor endocytosis vulnerable individuals, both by increasing the reward blocks context-dependent behavioral sensitization value of foods and interfering with self-control to amphetamine mechanisms. 22 non-obese subjects came in for two scanning sessions: one during a period of low Fiona Choi¹, Yu Tian Wang², Anthony Phillips³ academic stress and the other during the final examination period. We used the Behavioral ¹Institute of Mental Health, UBC, ²UBC, ³Institute of Inhibition Scale (BIS) to assess individual sensitivity Neurosciences, Mental Health and Addiction, UBC to stress. Participants underwent functional Magnetic Resonance Imaging (fMRI) while viewing Drug addiction is often characterized by a strong food and scenery pictures. All the data were association between the experience of drug-reward processed using FSL standard methods. Academic and environmental cues which may be crucial to the final exam period, resulted in higher perceived stress persistence of craving and in cue-induced relapse. levels measured by Perceived Stress Scale (PSS) (t Behavioral sensitization is the progressive and long- (21)=2.27,p=0.03). BIS scores correlated with the lasting increase in locomotor response following increases in the PSS (R=0.63,p=0.002) and with an repeated drug exposure and provides an animal increased response to food cues in regions that are model of craving. We previously demonstrated that thought to reflect stimulus value: the right OFC and Tat-GluA23Y, a peptide which disrupts regulated vmPFC, in the exam minus no exam comparison. AMPAR endocytosis and LTD, blocked amphetamine- vmPFC showed decreased connectivity with inferior induced sensitization in a single context. Behavioral frontal gyrus (IFG) as a function of the BIS score. sensitization is context-dependent, therefore this These regions have been implicated in self-control. study included a 2nd distinctive environment to Stress-vulnerable students (as indexed by the BIS) explore the role of regulated AMPAR endocytosis in show increased activation response to food cues in context-dependent sensitization. Context- vmPFC and decreased connectivity to IFG during dependence was confirmed in control groups, as academic stress. We interpret these results as drug challenge in a novel environment failed to showing enhanced reward value of food cues and produce sensitization. Importantly, Tat-GluA23Y reduced self-regulation during stress, which may eliminated the differential response between the account for these individuals' increased vulnerability conditioned environment and a novel context, to stress-related weight gain and obesity. indicating an absence of context-dependent sensitization when regulated AMPAR endocytosis is 2-F-138 A novel procedure for establishing disrupted. Furthermore, when animals were appetitive latent inhibition that is unaffected by conditioned in 2 different contexts, augmented disruption of regulated AMPA receptor endocytosis locomotor responses were still observed but were significantly smaller than in a single context. When Carine Dias¹, Donovan Ashby¹, Yu Tian Wang¹, Tat-GluA23Y was paired with amphetamine in 1 of Anthony Phillips¹ the 2 conditioning contexts, the magnitude of the sensitized response was significantly greater in the ¹University of British Columbia non-paired context. These results are consistent with 'occasion-setting', when rats are exposed to multiple An attentional deficit observed in schizophrenia can contexts. This in turn may involve active inhibitory be modeled in animals using a latent inhibition (LI) processes mediated by LTD. paradigm in which the pre-exposure to an auditory stimulus retards subsequent learning of the 2-F-137 Stress and personality interact to modulate association between this conditioned stimulus (CS) the neural response to food cues and an unconditional stimulus (UCS). Most latent inhibition research is performed using an aversive Selin Neseliler¹, Kevin Larcher¹, Beth Tannenbaum¹, UCS. In a related study, we observed an enhanced LI Maria Zacchia¹, Jens Pruessner¹, Alain Dagher¹ effect following administration of an interference peptide, Tat-GluA2-3Y which blocks alpha-amino-3- ¹McGill University hydroxy-5-methyl-isoxazole-4-propionic acid (AMPA) receptor endocytosis, a critical step in the induction Psychosocial stress is a contributor to weight gain in of long-term depression (LTD). The aim of the vulnerable individuals. Here we test the theory that present study was first to develop a LI protocol using psychosocial stress can lead to over-eating in CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

an appetitive UCS and then assess the possible role assessment of visual unattended space and control of LTD in this form of learning. The active peptide of orienting to objects in unattended space. The was administered intravenously (2.25 nmol/g) 60 reading task showed greater activation in regions min. prior to the acquisition of a two-way approach typically associated with visual word form and response in which an auditory stimulus signaled the speech. availability of food UCS in niches located in both end walls. Rats pre-exposed to the auditory CS required 2-F-140 Hippocampal activity during contextual significantly more trials to learn this conditioned learning and virtual navigation in non-human approach response than a group never exposed to primates the auditory CS. Tat-GluA2-3Y failed to disrupt appetitive LI, a finding that may reflect important Roberto Gulli¹, Guillaume Doucet¹, Benjamin procedural difference between an appetitive as Corrigan¹, Sylvian Williams¹, Julio Martinez-Trujillo² distinct from an aversive LI paradigm. These data ¹McGill University, ²University of Western Ontario may also indicate that LTD does not play a crucial role in switching the salience of a pre-exposed Contextual learning in complex environments auditory stimulus to an appetitive conditioned requires both exploration and context-dependent stimulus. association between stimuli and the condition in which they were encountered. Non-human primates 2-F-139 Neural networks in attention and reading are particularly useful for the study of contextual Marla Mickleborough¹, Layla Gould¹, Chelsea learning, since they: 1) rapidly form associations Ekstrand¹, Eric Lorentz¹, Tessa McKibben¹, Ron between stimuli, 2) show contextual learning deficits Borowsky¹ after hippocampal lesion similar to those observed in humans, and 3) rely on vision when gathering ¹University of Saskatchewan sensory information about their environments. However, there are few studies of single-neuron The processing of printed stimuli is facilitated by the activity and local field potentials (LFPs) recorded allocation of visuospatial attention and the from the primate hippocampus during contextual importance of attentional networks in reading has learning. We used an open-source video game recently been emphasized. Given this relationship engine (Unreal Engine 3) to create a contextual between attentional orienting networks and learning task embedded into a virtual reality networks involved with language processing when environment. Rhesus monkeys freely navigated reading words, we were interested in looking at through the virtual environment using a joystick overlapping networks of activation between these while we recorded hippocampal activity. We show two tasks. To address this we used fMRI to assess that 1) hippocampal LFPs show phase-alignment and the attentional control networks during visual increases in theta power after visual fixation; 2) spatial-orienting and the reading networks during hippocampal theta power is elevated prior to the lexical (or whole-word) reading of exception words presentation of rewarded objects in the contextual (e.g. yacht) in 16 participants. We employed two learning task; and 3) single-units form place-specific verbal tasks: 1) voluntary orienting to central arrow firing fields in the virtual environment. How these cues with a verbal discrimination task, and 2) reading activity patterns evolve over the course of aloud of exception words. A conjunction fMRI contextual learning continues to be investigated. analysis across attentional orienting and exception These results will provide valuable insight in to the word reading showed common eye-movement neural substrates that support context-dependent networks including frontal eye fields (FEF), associative learning, which may form the basis of supplementary eye fields (SEF), and intraparietal other known hippocampal functions like spatial sulci (IPS), as well as areas in attentional orienting mapping and episodic memory. such as superior parietal lobule (SPL), and reading processing (mid-inferior temporal activation). 2-F-141 Locomotor effects of cocaine are enhanced Contrasts revealed that activation in the attention by ghrelin delivered directly into the Nucleus task was greater than activation in the reading task accumbens in the temporal parietal junction (TPJ) and a portion of the SPL. These areas are known to be involved in CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

Marianne Klein¹, Lindsay Hyland², Alexander Four decades of research tacitly assume that such Edwards², Alfonso Abizaid² spatial representations are homogenous; this assumption has never been quantitatively verified. It ¹University of São Paulo, ²Carleton University is also unknown how correlated variability between neurons affects the fidelity of WM representations. Ghrelin is a gut hormone that acts in the ventral In order to investigate these issues, we used tegmental area (VTA), a region important for the microelectrode arrays to record neural ensemble reward seeking behaviors. Within the VTA, ghrelin activity in dlPFC area 8a of two Macaca fasciculares increases dopamine (DA) cell activity and it releases while they performed an oculomotor delayed- into the nucleus accumbens (NAc), an event response task, which required remembering one of associated with increased feeding and motivation. 16 potential locations across the visual field. We Peripheral injections of ghrelin enhance the found that spatial WM representations are biased in psychostimulant effects of cocaine, a drug that binds a quadrantic manner: WM representations of stimuli to DA transporters to block reuptake and enhances on the opposite side of a visual field meridian from a or prolongs the effects of DA. This suggests that neuron's preferred WM location are substantially ghrelin could act at presynaptic sites to alter the decreased relative to representations of stimuli on availability of DA transporters and enhance the the same side of a meridian. This bias is also present effects of cocaine. If this was true, ghrelin delivered in simultaneously-recorded populations, and in the into the NAc would have effects similar to those of structure of spike count correlations, a measure of cocaine, and would enhance the effects of a low correlated variability. Removing these correlations dose of cocaine. We examined this by conducting a facilitates decoding the contents of WM. Finally, study where Wistar male rats with a bilateral saccades to remembered locations repel away from cannula in the NAc were assigned to one of four meridians and attract towards quadrant centers. groups: GC (ghrelin; cocaine - n=9); GS (ghrelin; These results reveal the need to re-conceptualize saline - n=8); SC (saline; cocaine - n=10) and SS behavioral and neurobiological models of WM to (saline; saline - n=7). Animals were placed in accommodate the observed non-linearities in locomotor activity boxes and then received a central mnemonic representations of visual space. injection of either saline or ghrelin (0.5µg/0.5µl). 30 min later, they received an i.p. injection of cocaine 2-F-143 How to achieve and stay at the top (1mg/kg) or saline and had their locomotor activity percentile: practices pattern analysis from mobile recorded for the following 90 min. Results show that computerized cognitive trainings ghrelin infusion into the NAc increased the number of beam breaks, p<0.05. This effect was Conny Lin¹, Mark Baxter², Catharine Rankin¹, Paul potentiated in mice that received ghrelin and then Nussbaum³ cocaine. These data suggest that ghrelin may act presynaptically onto DA terminals in the NAc to ¹University of British Columbia, ²Fit Brains By Rosetta enhance DA release via a decrease in DA reuptake. Stone, ³University of Pittsburgh School of Medicine

2-F-142Remembering in quadrants: Non-linear Frequent training with computerized cognitive representation of mnemonic space in the primate training games may lead to benefits in cognitive brain function; however, prior to designing clinical evaluation on how training may lead to transferrable Matthew Leavitt¹, Adam Sachs², Julio Martinez- cognitive benefits, we first need to understand the Trujillo³ relationship between training frequency and performance within the training tasks. To do this, we ¹McGill University, ²Ottawa Hospital Research analyzed the database from the mobile Institute, University of Ottawa, ³University of computerized cognitive training application "Fit Western Ontario Brains", containing 20,660,413 scores generated by 727,390 users from 20-79 years old from twelve Single neurons in the primate dorsolateral prefrontal cognitive tasks each targeting 1 of 5 categories: cortex (dlPFC) are thought to encode working executive function, memory, concentration, memory (WM) representations of visual space via visiospatial and speed. We evaluated training sustained firing after the removal of external input. frequencies associated with attaining and CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

maintaining scores in the top (>90%), medium (60- mice. These results provide the first evidence for a 80%), and standard (40-60%) level. We found that role of these putative "social touch" MrgprB4+ age is the most important factor for how frequent a afferents in self-directed and social behaviour. user had to train on a particular task to attain and maintain score at the top percentile (90% or higher) 2-F-145 Feeling 'blue' and seeing 'red': Associations in all cognitive tasks. The age effect is the largest for of emotion and colour in variants of the Stroop task memory and visiospatial tasks, but smallest for executive function. Gender had a small effect on the Eric Lorentz¹, Marla Mickleborough¹, Layla Gould¹, performance of concentration tasks, but not other Chelsea Ekstrand¹, Ron Borowsky¹ tasks. Performance decay occurred fastest for ¹University of Saskatchewan concentration tasks, and second fastest for visiospatial tasks. This study provides In the Stroop task, emotion words like sad (in blue) recommendations for training frequency specific to and angry (in red) have demonstrated congruency tasks and age group that may be effective at effects with colour-naming (eg Sutton & Altarriba, attaining and maintaining scores at certain levels. 2008). Other research has not replicated these The results may be used to develop training congruency effects with color-naming, but rather frequencies and task combinations for clinical showed that the colour red facilitates categorizing evaluations. angry emotion relative to grey or blue font color (eg Fetterman et al, 2012). To address these findings, we 2-F-144 Sensory Afferents Activated by Gentle employed four tasks with mad and sad words in red Touch Contribute to Self-Grooming and Social or blue font color to fully evaluate the association Behaviour between colour and emotion: 1) Stroop task of color Mireille Desrochers-Couture¹, Robert Bonin¹, Yves naming; 2) Emotion categorization; 3) A modified De Koninck ¹, Anna Lomanowska¹ Stroop task naming red as 'mad' and blue as 'sad'; 4) A modified emotion categorizing task naming mad as ¹Laval University 'red' and sad as 'blue'. The colour-naming and emotion categorizing tasks evaluate any association The biological embedding of social experience between colors and emotions, and their direction. requires the integration of social information from The modified tasks are expected to enhance any multiple sensory systems. Touch is a key component effects found in the original tasks by highlighting the of social interactions in mammals, yet its irrelevant dimension. Our results showed consistent contribution to social experience or animal congruency effects in the emotion categorization behaviour is not well understood, owing in large part tasks, and no consistent effects in the Stroop tasks. to the difficulties in manipulating touch sensation. In We also found congruency effects for both mad and mice, social touch may be mediated by MrgprB4+ sad words in the emotion categorization tasks, sensory afferents that respond to gentle touch. extending the link previously shown only between Here, we characterize the effects of MrgprB4+ red colour and angry emotion. Overall, these results afferent activation and ablation in mice that express support a perceptual grounding of emotions in channelrhodopsin (ChR2) or the diphtheria toxin colour over and above semantic association of colour receptor (DTR) in MrgprB4+ afferents, respectively. and emotion. FMRI findings using an emotion Stroop The peripheral activation of MrgprB4-ChR2 afferents task in a patient with intractable depression with a produced mild behavioural responses that were not deep brain stimulator placed in the ventral ACC will indicative of noxious sensation. We observed subtle also be discussed. changes in behaviour after ablation of MrgprB4-DTR afferents with diphtheria toxin (DT). DT-injected 2-F-146 A glycine receptor subunit homologue, MrgprB4-DTR mice exhibited normal locomotor and AVR-14, alters short-term memory in an anxiety behaviour in light/dark box and open-field interstimulus interval-dependent manner in C. assays, but reduced self-grooming of the body Elegans compared to DT-injected MrgprB4-Cre mice that are insensitive to DT. In a social approach assay, DT- Troy McDiarmid¹, Evan Ardiel¹, Catharine Rankin¹ injected MrgprB4-DTR mice spent significantly less ¹Univerisity of British Columbia time near a novel mouse compared to MrgprB4-Cre CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

Habituation is a learned decrement in responding odor is paired with a reward, we tested the following repeated exposure to a stimulus. Despite hypothesis that CaMKII activation is critical for long- its importance the mechanisms underlying term memory and input-specificity of the odor habituation remain largely unknown. Repeated learning. Using behavioral pharmacology, we first exposure to taps (non-localized mechanosensory tested whether blocking CaMKII with KN- 62 infusion stimulation) leads to habituation of a reversal in the olfactory bulb blocks short-term (tested at 3 withdrawal response in C. elegans that is dependent hr) and long-term memories (tested at 24 hr). Both on glutamate transmission and postsynaptic AMPA memories were blocked. To test the role of CaMKII in receptors. Here we use high throughput behavioural input specificity of long-term memory, we used a analysis to characterize the role of AVR-14, an PKA agonist Sp-CAMP to induce 24 hr memory and inhibitory glutamate gated chloride channel tested whether blocking CaMKII in this model affects homologous to vertebrate glycine subunits. avr-14 memories for the learned odor (peppermint) as well loss of function mutants display a larger initial as a control odor (vanillin). Co-infusion of Sp-CAMP reversal duration in response to tap and faster with KN-62 did not impair 24 hr memory for habituation to tap stimuli than wild-type animals at a peppermint; however, the input specificity was lost 10s interstimulus interval (ISI). At long ISIs (60s), avr- since animals also showed preference to vanillin. 14 mutants habituated significantly less than wild- These experiments help us understand the specific type animals. The stark contrast in phenotypes at role of CaMKII in short and long-term odor short and long ISIs necessitated analysis of memories, its role as a synaptic tag, and in memory habituation across ISIs (10-60s ISIs). This revealed specificity. that mutations in avr-14 result in faster habituation at short ISIs, wild-type habituation at intermediate 2-F-148 The synthetic tetrahydroprotoberberine d- ISIs, and slower habituation and longer ISIs. Together Govadine facilitates extinction of conditioned place these studies suggest mutations in avr-14 alter preference induced by d-amphetamine or food habituation in an ISI-dependent manner. reward Experiments using cell-specific knockdown, rescue, and stimulation will localize the memory functions of Maya Nesbit¹, Carine Dias¹, Anthony Phillips¹ AVR-14 to elucidate how it modulates the tap ¹University of British Columbia habituation circuit. These studies will determine how the inhibitory functions of glutamate mediate short- Tetrahydroprotoberberines (THPB) derived from term habituation in C. elegans, furthering our traditional Chinese herbal medicines for the understanding of the processes underlying learning treatment of mental illnesses have high affinity for and memory. dopamine D1 and D2 receptors and have potential as novel treatments for drug addiction. This study 2-F-147 CaMKII mediates input-specific early odor assessed the effects of the THPB d-Govadine on the preference learning in rats acquisition, expression and extinction of Shirin Modarresi¹, Qi Yuan¹ amphetamine-induced conditioned place preference (d-AMPH CPP). CPP was established in rats by pairing ¹Memorial University of Newfoundland d-AMPH (1.5mg/kg, i.p.) or saline with a specific environmental context. In separate experiments, The synaptic tagging hypothesis explains how input rats received d-Govadine (0, 0.5, or 1mg/kg, s.c.) or specificity is preserved in long-term potentiation of vehicle, a) 5 min prior to each d-AMPH injection synapses. This phenomenon requires new proteins during the conditioning phase or b) immediately that are synthesized in the nuclei, to be shipped cell before tests for expression of d-AMPH CPP. CPP was wide. One specific molecule called calmodulin Kinase assessed as time spent in the d-AMPH- and saline- II (CaMKII) plays a major role and has been paired contexts. Although d-Govadine administered postulated to function as a synaptic tag due to its during the conditioning phase did not affect the unique properties such as staying phosphorylated in acquisition of d-AMPH CPP, it did facilitate the the absence of calcium. The behavioural relevance of extinction of amphetamine-induced CPP in a dose synaptic tagging has not been exclusively studied. dependent manner. In contrast, the expression of d- Using an early odor-preference learning model, AMPH CPP was not affected by d-Govadine which occurs in a week-old rat pup when a novel administered on the test day. In a separate CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

experiment, administration of d-Govadine (1mg/kg, 2-F-150 The effect of reduced neurogenesis on s.c.) prior to the induction of food CPP facilitated the visuo-spatial learning and memory in the GFAP-TK extinction process. Collectively, these data suggest rat. that d-Govadine affects a learning process that subserves extinction, rather than the addictive Timothy O'Leary¹, Jason Snyder¹ properties of d-AMPH itself. Investigations into the effect of d-Govadine on the reinstatement of d- ¹University of British Columbia AMPH CPP are ongoing. Hippocampal adult neurogenesis is associated with 2-F-149 Approach-avoidance processing: the role visuo-spatial learning and memory ability in rodents, of nucleus accumbens shell D2 receptors in conflict but its exact role is not clear given the growing resolution number of studies that fail to detect cognitive impairments following reductions in neurogenesis. David Nguyen¹, Victoria Fugariu¹, Suzanne Erb¹, Therefore, we assessed visuo-spatial learning and Rutsuko Ito¹ memory in a transgenic GFAP-thymidine kinase (TK) rat, in which adult neurogenesis was ablated with ¹University of Toronto the drug valgancyclovir. Male TK and WT rats were trained on the Morris water maze (5 days, 10 The nucleus accumbens (NAc) is importantly trials/day) followed by a probe trial to assess implicated in the processing of approach and memory 10 days later. TK rats performed worse than avoidance signals evoked by emotionally valenced WT rats on day 1 of training, which was partially due environmental stimuli. Currently, there is evidence to increased thigmotaxis. However, with further to suggest that such opposing motivational training (days 2-5) TK and WT rats performed processes are differentially mediated by similarly and did not differ in memory performance. subpopulations of NAc neurons expressing either Given that thigmotaxic behaviour is associated with dopaminergic D1- or D2-receptors (D1R, D2R). increased stress/emotionality, we next tested if the Further, it has been suggested that dysregulation of impairment in TK animals was dependent on the this system is implicated in disorders such as drug aversiveness of the maze, by testing rats in a short addiction, where the individual elicits aberrant training protocol (3 days, 4 trials/day) using either processing of competing motivational signals. It is cold (16°C) or warm (25°C) water. TK rats again therefore important to further elucidate the performed worse than WT rats during acquisition mechanisms that mediate approach-avoidance training, but learning performance was not processing in states of motivational conflict. The dependent on water temperature. During the probe present study utilized a mix-valenced conditioning trial, however, there was a trend for impaired paradigm to examine the effects of NAc shell D2R memory performance in TK rats in cold but not warm antagonism on approach-avoidance behavior. Male water. Overall these results suggest that reducing Long Evans rats were trained in a three-arm radial neurogenesis in TK rats impairs visuo-spatial learning maze to associate visuo-tactile cues with sucrose, during the early stages of acquisition, and that shock, or neutral outcomes delivered within the impairments in memory performance may be more arms in which the cues were presented. Following pronounced when tested under conditions of higher conditioning, rats were intracerebrally infused with stress. D2R antagonist Sulpiride in the NAc shell. Exploration time was then assessed in a conflict test 2-F-151 Catching the same wave: Successful where rats freely explored two maze arms teamwork is linked to between-brain synchrony containing either a neutral cue or a superimposition of the appetitive and aversive cues under extinction Ana Pesquita¹, Caroline Szymanski², Allison Brennan³, conditions. Our results revealed that D2R Dionysios Perdikis², James Enns¹, Müller Viktor², antagonism enhanced preference for the mix- Ulman Lindenberger² valenced arm. We conclude that NAc shell D2R is important for suppressing approach behaviors when ¹University Of British Columbia, ²Max Planck Institute the valence of the outcome is uncertain. for Human Development, ³Simon Fraser University Behavioral research shows that two person teams can perform a visual search task more efficiently CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

than two individuals working independently toluene misuse (immediately after the end of (Brennan & Enns, 2014). Here we use EEG toluene chronic inhalation and 90-day after the end hyperscanning with the same behavioral method to of toluene chronic inhalation, correspondingly) on measure within- and between-brain phase pyramidal cell loss in the CA1 and CA3 of the synchronization in the brains of individuals working hippocampus and exploratory behavior and as a team or alone. 22 pairs completed team and recognition memory in the open field were individual trial-blocks in counterbalanced order. We evaluated. The results reveal that toluene chronic computed three measures of phase synchronization: exposure affects the structure of the hippocampus, Phase-locked-index (PLI; within-brain phase exploratory activity and recognition memory in the invariance at a single electrode across trials), within- open field in adolescent and adult rats. In all cases brain phase-locking-value (w-PLV; degree of the effect is age-dependent. In particular: in constancy in phase difference across trials between adolescent rats the more significant structural and two electrodes in the same brain) and between- behavioral alterations were observed immediately brain phase-locking-value (b-PLV; phase locking after toluene chronic exposure, while in adult rats between two electrodes in different brains). Partial the most considerable was persisting effect (90 days Least Square analyses (PLS) showed that PLI and b- after withdrawal). Such data indicate that character PLV synchronization patterns were both stronger of alterations depends upon the postnatal age of when individuals performed as a team versus when testing of the animals. alone. Follow-up regression analysis on these brain- scores (index of how strongly a pair contributed to a 2-F-153 Adult neurogenesis increases preference PLS latent variable) showed that b-PLV is more for future rewards strongly correlated with PLI in the team than in the individual condition. Visual inspection indicates that Desiree Seib¹, Ru Qi Yu¹, Stan Floresco¹, Jason Snyder¹ task-dependent differences occur in frontal and ¹University of British Columbia central sites at 2-6 Hz. A positive relationship was found between team success and b-PLV "brain Neural progenitor cells in the hippocampal dentate scores", controlling for PLI and block order. These gyrus generate new neurons for the dentate gyrus' findings establish a functional link between granule cell layer throughout life. These newborn synchronized brain activity and team performance neurons are known to be involved in memory and on a visual search task. mood regulation. Patients with hippocampal atrophy show decreased value of imagined outcomes when 2-F-152 Toluene,Hippocampus Structure and they are less detailed. Similarly, depressive patients Recognition Memory: adult and adolescent rats discount future rewards at a higher rate than healthy Nino Pochkhidze¹ controls. Depression is characterized by decreased neurogenesis and reduced hippocampal volume. ¹Ilia state university, I.Beritashvili center of Thus, we wanted to investigate the effect of reduced Experimental Biomedicine hippocampal neurogenesis on cost/benefit decision- making in a delay-discounting task. Therefore, we Toluene and toluene-containing volatile substances used hGFAP-TK rats to deplete actively dividing are the most widely abused solvents with neural progenitors by administering Valganciclovir demonstrative addictive potential in humans. Clinical and consequently stop the production of new and experimental studies have demonstrated that neurons. Delay-discounting was assessed in a delay- the exposure to toluene vapor leads to diverse based decision making task where rats could choose consequences at the level ranging from the cell to between a low/immediate reward (1 press = 1 the whole organism. The present study has been pellet) and a high/delayed reward (1 press = 4 undertaken to determine whether toluene chronic pellets), with the delay time increasing over 4 blocks exposure provokes immediate and/or persistent of trials (0sec, 15sec, 30sec and 45sec). Rats with effect on the structure of hippocampus, learning and depleted neurogenesis showed a decreased memory in adolescent and adult rats. We exposed preference for the high reward option with male Wistar rats at ages P 28-32 (adolescents) and P increasing delay times. Our findings indicate that 150-160 (adults) to 2000 ppm inhaled toluene for 40 levels of adult neurogenesis could determine the days. The immediate and persisting effects of value of future rewards. These findings are CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

important in understanding future thinking and Nick Snow¹, Cameron Mang¹, Marc Roig², Michelle discounting of delayed rewards in several McDonnell³, Kristin Campbell¹, Lara Boyd¹ neurological disorders where neurogenesis is affected, such as depression, addiction or ¹University of British Columbia, ²McGill University, neurodegenerative diseases, where value of future ³University of South Australia rewards might be decreased. Learning skilled movements is necessary for the 2-F-154 ERPs differentially reflect automatic and successful execution of human motor behaviors. A deliberate processing of the functional single bout of high-intensity aerobic exercise manipulability of objects facilitates continuous motor skill learning in healthy young adults; yet, this effect has not been examined Christopher Madan¹, Yvonne Chen¹, Anthony Singhal¹ at lower intensities. In this preliminary report we investigated the effect of acute moderate-intensity ¹University of Alberta exercise on the learning of a continuous tracking task (CTT). Eleven healthy adults (mean±SD: age = An object's motor-related properties can influence 25.8±3.7 yr; height = 177.5±8.7 cm; mass = 70.4±8.7 later memory, particularly when motor aspects of kg) completed 10 min of CTT practice after 30 min of the object were not intentionally attended-to. To either seated rest or continuous cycling, at 60% peak better understand this effect we recorded EEG while aerobic capacity. CTT practice was followed by a 24- participants made judgments about images of hr retention test. Rest and exercise conditions were objects that were either high or low in functional separated by a ≥2 wk washout period. The manipulability (e.g., violin vs. vase). Using a CTT contained repeated and random sequences, to between-subjects design, participants judged evaluate learning versus general improvement in whether they (a) could manipulate the object using motor skill. Performance was separated into their hand (Functionality [Func]; N=31) or (b) have temporal precision and spatial accuracy. A seen the object in the past three days (Personal Condition×Sequence×Time rm-ANOVA revealed a Experience [PExp]; N=30). We focused on the P300 significant main effect of Sequence (p=0.035), as well and slow-wave ERP waveforms as indexes of as a significant Condition×Sequence interaction attentional allocation. In both groups, we observed (p=0.004) for temporal precision. Under the rest higher P300 and slow-wave amplitudes for low- condition there was reduced temporal error on the manipulability at both CPz and Pz. At both random sequence, at both practice and retention. electrodes, P300 was higher for the Func group. We also discovered a significant main effect of Time Slow-wave did not differ between groups. A more (p<0.001) and a significant Sequence×Time complex pattern was observed at Cz: In the Func interaction (p=0.005) for spatial accuracy - the group, high-manipulability elicited a larger P300, but repeated sequence was learned under both low-manipulability evoked a larger slow-wave. In the conditions. Results indicate that acute moderate- PExp group, high- and low-manipulability did not and high-intensity exercise may have different differ in either ERP. As P300 is thought to index effects on continuous motor skill learning. attentional recruitment, greater P300 for low- manipulability suggests that they may have received 2-F-156 Single-trial Decoding of Visual Attention more attention when being processed, and these from Local Field Potentials in the Primate Lateral effects were greater in the Func group. This Prefrontal Cortex differential recruitment of attention may have also played an important role in effects of manipulability Sébastien Tremblay¹, Guillaume Doucet¹, Florian on memory. These provide neural evidence that Pieper², Adam Sachs³, Julio Martinez-Trujillo⁴ effects of manipulability on stimulus processing are further mediated by automatic vs. deliberate motor- ¹McGill University, ²University Medical Center related processing. Hamburg-Eppendorf, ³University of Ottawa, ⁴Western University 2-F-155 Effects of an acute bout of moderate- intensity aerobic exercise on motor learning in a Studies of attention have shown that the amplitude continuous tracking task. of local field potential (LFP) oscillations in several brain areas is modulated by visual attention, with CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

modulations in the gamma frequency band being the hyperpolarization and inhibition of spiking activity. most commonly reported. However, it remains Following contextual fear conditioning, CNO or unclear whether LFP oscillations contain sufficient vehicle was administered via drinking water for 10 information to encode the allocation of attention days and then fear memory was tested. We within ecologically valid timeframes. Here we show independently inactivated 21/84 nodes during that the allocation of attention can be decoded on a memory consolidation and we found that single-trial basis from gamma band LFP (60-256 Hz) inactivation of hub but not non-hub nodes impaired recorded in prefrontal area 8A of macaque monkeys, memory consolidation and that "hubness" can but not from lower frequency bands (<60 Hz). predict consolidation deficits. These data support Importantly, the information contained in the the idea that highly-connected hub regions play a gamma band is fully redundant with the information disproportionately important role in the contained in the spikes fired by neurons in the consolidation of contextual fear memories. vicinity of the recording electrodes. Spikes and gamma LFP are highly similar both at a single- 2-F-158 Long-term memory formation is required channel and at an ensemble level, allowing cross- for training-associated changes in brain structure signal decoding. Finally, the decoding of attention volume from gamma frequency bands is very stable across time, twice as much as the spiking signal. Our Dulcie Vousden¹, Matthijs van Eede¹, Adelaide Yiu¹, findings demonstrate that gamma-band LFP Leigh Spencer Noakes¹, Brian Nieman¹, Mark recorded in prefrontal area 8A are a potential source Henkelman¹, Sheena Josselyn¹, Paul Frankland¹, of information that can be used by cognitive brain- Jason Lerch¹ machine interfaces to signal the allocation of ¹University of Toronto attention on a single-trial basis. Learning and memory formation require alternations 2-F-157 Targeted pharmacogenetic interrogation of to the brain. Initially, learning involves changes in a fear memory network synaptic strength; long-term memory (LTM) Gisella Vetere¹, Anne Wheeler¹, Justin Kenney¹, formation, however, requires new protein synthesis, Leonardo Restivo¹, Sheena Josselyn¹, Paul Frankland¹ enabling structural changes. Recent imaging studies in humans and rodents have provided intriguing ¹Hospital for Sick Children evidence that this type of plasticity may be able to be imaged with magnetic resonance imaging (MRI). The coordinated activation of a distributed network For example, training mice on a maze induces of brain regions is necessary to recall a consolidated volume changes in specific brain areas which can be memory trace. In recent work we used a global detected with MRI. However, the biological basis of mapping approach to identify networks of brain these volume changes, and whether they are driven regions co-activated during remote memory recall in by the cellular brain plasticity needed for LTM, is mice (Wheeler et al [2013] PLoS Comp Biol). unknown. We used mice with a disruption in a key Expression analysis of the activity-regulated gene, c- LTM signaling pathway to study whether training- fos, across 84 brain regions allowed us to identify associated volume changes depend on LTM. The regions that were co-active following memory recall, transcription factor CREB is critical for LTM. We and presumably form a network that is engaged by trained CREB mutant mice (CREB -/-, CREB +/-, & long-term memory recall. Graph theoretical analysis CREB +/+) on either the spatial or non-spatial water indicated that the remote memory network included maze, and used MRI to detect volumetric brain several highly-connected hub-like regions that may changes associated with training. All mice learned play privileged roles in memory expression. To the task, but CREB -/- mice had significant deficits in address the possibility that these hub regions can spatial memory. Consistent with prior studies, play disproportionately important roles in memory hippocampal volume was greater in spatially trained consolidation we virally expressed the inhibitory wildtype mice vs. controls. There was no effect of designer receptor exclusively activated by designer training on hippocampal volume in the CREB -/- drugs (DREADD) HM4Di in different brain regions. mice, suggesting that the volume changes following When bound to clozapine-N-oxide (CNO), this Gi- spatial learning depend on LTM and CREB- coupled DREADD induces membrane dependent signaling. Intriguingly, spatially trained CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

CREB +/- mice had normal LTM, but no difference in 2-G-160 Development of an intravital multi-plane hippocampal volume. This implies both LTM and multiphoton microscopy platform for functional CREB dosage underlie the volume changes seen with cellular imaging in living mice training. Erik Bélanger¹, Feng Wang¹, Sylvain Côté¹, Daniel 2-F-173 Effects of pre and post-training Côté¹, Yves De Koninck¹ administration of glucose and fructose: the importance of non-specific interpretations for ¹Université Laval memory consolidation Pain sensation is propagated from the periphery to Paul Marshall¹, Thomas Horman ¹, Francesco Leri ¹ the central nervous system by dorsal root ganglion (DRG) neurons. These neurons detect different ¹University of Guelph stimuli and convey information to the dorsal horn where they form synapses. The project focuses on Drug addiction is well-known, but addiction to other the development of an intravital multi-plane substances like sugar, is less clear. Therefore, to test multiphoton microscopy platform for functional the sugar addiction hypothesis a framework was cellular imaging in living mice, to study calcium applied that hypothesized that the addictive dynamics of DRG neurons stimulated peripherally. potential of a substance is determined in part by its We image DRG neurons labelled with the Ca2+ ability to promote memory consolidation (MC). But, indicator GCaMP6s directly through a laminectomy results with MC for sugars are mixed; thus and stimulate these with feedback-controlled experiments tested the difference in ability to thermal and mechanical stimulators applied to the promote MC for glucose (G) and fructose (F). Exp 1 paw. Subsequent Ca2+ responses are identified using administered G and F (2, 4, 6g/kg) 30 mins prior to a home-made software to find responsive neurons in self-administration (SA) as a manipulation check. real-time. The platform we developed allows online Injections dose dependently reduced intake, as adjustments of the digital zoom level, image size, expected, but also reduced locomotion. Exp 2 spatial sampling, acquisition speed and to trigger or showed that intragastric infusion of the same doses be triggered by external devices; all essential in the same task had minimal effects on locomotion, capabilities for live animals physiological which suggested these infusions reduced intake due experiments. The sensory-evoked activity from DRG to a non-specific effect. Exp 3, administered 2g/kg of neurons stimulated peripherally is recorded at video- G and F by intra-gastric infusion 5, 30 and 90 mins rate, and multi-plane capability is ensured by prior to SA and found locomotion was significantly mounting the objective on a piezoelectric actuator reduced at the 5 min time point and was significantly allowing nearly whole-DRG functional microscopy. larger for F, while insulin was identical. This Because animals' movement can seriously degrade confirmed a non-specific effect, not satiety. acquisitions, we register the resulting movies offline Experiment 4, which tested 100mg/kg and 2g/kg of using graphic card acceleration. Also, we developed G/F administered following a win-shift memory task, an automated pipeline for data processing in found the 2g/kg dose of F significantly increased addition to a database in the context of Big Data. The time to complete the task and reduced pellets eaten, system we built is therefore tailored to fit the suggesting the previous effects were due to malaise. specific needs of in vivo whole-organ functional While 100mg/kg G enhanced MC, this same dose of microscopy. F did not. This together suggests that high doses may mask effects of MC due to malaise, but low dose G 2-G-161 Self-directed, high-throughput, and can enhance MC more than F, and thus G may be automated mouse motor-learning home cage potentially more addictive than F. assays

Federico Bolaños¹, Gergely Silasi¹, Jamie Boyd¹, Jeff LeDue¹, Stephen Scott¹, Timothy Murphy¹ G - Novel Methods and Technology Development ¹UBC

Automated assessment of rodent behaviour is desired as it reduces experimenter bias, facilitates CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

high throughput, avoids disrupting circadian rhythms computer simulations of populations of 10 to 500 and eliminates stress in animals introduced by neurons and tested the inferred connections against experimenter handling. We developed an automated those used for the simulations. We observed that mouse lever pulling task that mice can perform 24/7 repeated stimulations of selected neurons drastically in the home cage to assess forelimb function. The increase the accuracy, especially with TE. We also apparatus consists of a small chamber attached to applied the inference methods to in vitro data. We the outside of the home cage, which contains a infected rat hippocampal cultures with gCamP6, a recessed lever that the mice can access with their fluorescent marker for intracellular calcium. Then, forelimb. The lever is attached to the axle of a rotary we electrically and selectively stimulated one neuron encoder allowing us to measure lever position during in the culture while measuring the calcium response each pulling event. A sensor on the roof of the in the adjacent neurons, where we were able to training compartment detects a unique RFID tag that detect calcium transients. Together these results is implanted subcutaneously in each mouse at the indicate that a new strategy of connectivity nape of the neck. Upon successful pulling of the inference, which combines TE and neuronal lever a solenoid dispenses a ~10uL water drop. In the stimulation, could be both theoretically acceptable initial phase of training mice receive a water reward and experimentally achievable. Further for just entering the training compartment, while development of this strategy will allow to test the subsequent phases require the mice to hold the formation/removal of connections under different lever in a rewarded position for incrementally longer paradigms of development, learning, and durations and a smaller range of movement. pathological conditions. Individualized performance is logged and task parameters are controlled by custom software 2-G-163 MiniPromoters Driving PAX6-like Retinal written in Python running on a Raspberry Pi. Expression Designed from Bioinformatically Preliminary data show that mice perform over 500 Predicted Regulatory Regions trials once they have acquired the task. The number of successful trials increased during the first week of Jack Hickmott¹, Chih-yu Chen¹, David Arenillas¹, training, and on average it takes ~7 days of Yifeng Li¹, Laurie Molday¹, Andrea Korecki¹, Siu Ling unsupervised training for mice to acquire a 1 second Lam¹, Russell Bonaguro¹, Michelle Zhou¹, Alice Chou¹, hold duration. Future experiments will introduce Sanford Boye², William Hauswirth², Robert Molday¹, lever perturbations to assess voluntary motor Wyeth Wasserman¹, Elizabeth Simpson¹ control. ¹University of British Columbia, ²University of Florida 2-G-162 Assessing connectivity in real neuronal Purpose: Although gene therapies may benefit from networks from cellular activity tissue- and cell-type specific promoters, capturing Patrick Desrosiers¹, Simon Labrecque¹, Paul De the expression of a human gene in a small Koninck¹, Daniel Côté¹ MiniPromoter (MiniP) is challenging. Paired box six (PAX6) causes the vision-loss disorder aniridia when ¹Université Laval mutated, and has a complex retinal expression pattern driven by discrete regulatory regions (RRs). Getting the ability to assess connectivity maps of Here we describe the bioinformatically driven design neuronal networks is a crucial step toward of MiniPs from the PAX6 gene. Methods: PAX6 RRs understanding the rules that govern information were predicted bioinformatically. MiniPs were encoding, circuit formation, and learning. Current cloned into AAV genomes containing emGFP and light microcopy technologies allow to record calcium WPRE, packaged into AAV2(Y272F, Y444F, Y500F, activity of large neuronal networks, but the Y730F, T491V), and injected intravitreally into evaluation of the connections, from activity data postnatal day 14 mice. Eyes were collected 30 days only, remains a challenging problem. Yet, statistical after injection and emGFP expression was evaluated methods for the inference of connectivity already by confocal microscopy. MiniPs driving PAX6-like exist, such as cross-correlations, Granger Causality, expression were examined for unique transcription and Transfer Entropy (TE). In order to compare factor binding sites (TFBSs) using oPOSSUM3. these methods based on their accuracy and Results: At the PAX6 locus, 31 RRs were numerical cost, we generated activity data from bioinformatically predicted and 9 were used to CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

construct 7 MiniPs. Two of the MiniPs did not drive can be used to characterize the impact of local or interesting expression in the retina and 5 drove widespread Ca2+ transients on downstream expression in the 2 retinal layers that express PAX6 signaling. (ganglion cell and inner nuclear). Unique to these 5 MiniPs were 21 TFBSs. One MiniP (Ple255) expressed 2-G-165 A Cortical Thickness Gowth Model for in all three cell types that express PAX6 (ganglion, Neurodegenerative Analysis amacrine, and horizontal). Conclusions: MiniPs that recapitulate the tissue-specific endogenous Poay Hoon Lim¹, Wee Keong Lim² expression of a gene can be designed using ¹Polytechnique Montreal & CHU Sainte-Justine, bioinformatic approaches. Such MiniPs may be of ²Dawson College & Marianopolis College general use in the study of the retina, and Ple255 in particular could be an important element in a PAX6 Widespread decline in cortical thickness across the gene therapy for aniridia. cerebral cortex have been observed during normal aging and in subjects with cognitive impairment. We 2-G-164 Localized light-induced stimulation of propose a vertex-wise cortical thickness growth hippocampal neurons with cell surface?bound gold model to analyze the dynamic of cortical thickness nanoparticles across the cerebral cortex. The growth model is Flavie Lavoie-Cardinal¹, Eric Bergeron², Charleen formulated as a series of differential equations using Salesse¹, Michel Meunier², Paul De Koninck¹ the subject's age and local geometrical structure of cortical surface, based on cortical thicknesses ¹Université Laval, ²Ecole Polytechnique de Montréal extracted from three longitudinal MRI scans (about 6 months inter-scan interval). This study focused on 20 Light-induced stimulation of whole neurons or mild cognitive impairment (MCI) (age 72.7±2.3 years) neuronal networks with optogenetic tools is a well- and 20 matched cognitive normal (CN) subjects (age established and powerful approach to study circuit 70.2±2.8 years) from ADNI cohort. Whist a mixed of function. On the other hand, local membrane increasing and declining cortical thickness change stimulation at the nm to µm scale, which would be rates were detected across the entire cortex in both useful to study the cellular rules governing neuronal MCI and CN subjects, MCI subjects exhibited greater and dendritic functions, remains a challenge. To cortical thickness absolute change rates address this problem we used off-resonance (0.11±0.02mm vs 0.07±0.02mmm per year) over CN plasmonic excitation of 100 nm gold nanoparticles subjects. In addition, MCI subjects showed higher (NPs) bound to cultured rat hippocampal neurons. absolute change rate on temporal lobe While non-specific binding of NPs onto the neurons (0.13±0.02mm vs 0.09±0.02mm per year in CN) and was possible through passive sedimentation, we cingulate cortex (0.11±0.02mm vs 0.08±0.02mm per designed a specific binding approach via surface year in CN). This sequence of changes corresponded functionalization of the NPs with antibodies to in vivo observation of cortical atrophy during targeting membrane receptors. To induce plasmonic degenerative process. With a natural exponentially excitation of the NPs, we applied femtosecond laser growth trajectory, our proposed growth model pulses at 800 nm in regions of interest on somato- enables estimation of cortical thickness change rate dendritic domains with one or more NPs. We within a continuous time frame. It allows vertex-wise monitored the neuronal response with confocal and region-wise analysis of cortical thickness imaging of Ca2+ fluctuations using GCaMP6 and with development for individual and population study. patch clamping. We were able to induce localized or widespread Ca2+ elevation inside the neurons, 2-G-166 NeuroFluor CDr3: A Novel Tool for the depending on i) laser intensity, ii) area of Detection of Live CNS and Human Pluripotent Stem illumination, or iii) number of functionalized NPs on Cell-Derived Neural Stem and Progenitor Cells targeted cells. We also observed light-induced whole-cell electrical response. Furthermore, we Carmen Mak¹, Vivian Lee¹, Sam Lloyd-Burton¹, Allen show variable levels of subcellular translocation of Eaves², Terry Thomas¹, Sharon Louis¹ the GFP-tagged Ca2+ signal decoder CaMKII. Our ¹STEMCELL Technologies Inc., ²Terry Fox Laboratory, results suggest that localized, controlled light-based BC Cancer Agency stimulation of a single functionalized NP on neurons CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

Conventional methods for identifying neural cell first time, in spinal cord in vivo models. The types are heavily dependent upon antibodies and effectiveness of the siRNA-LNP system was assessed mRNA probes. These approaches are labour- in the brain by direct injection into the cortex. LNPs intensive, often require optimization of individual were seen to be present in cortical neurons, where reagents, and frequently require fixation and delivery of the siRNA against PTEN exerted the permeabilization steps that limit further use of the desired changes in gene expression. Subsequently, cells. We have developed NeuroFluor CDr3, a LNPs were injected at the site of cervical spinal cord fluorescent membrane-permeant probe that injury and a decrease in expression of the target selectively labels live neural progenitor cells (NPCs). PTEN was observed in the vicinity of the NeuroFluor CDr3 is based on the boron- injury/injection site 10 days later. Moreover, the dipyrromethane (BODIPY) derivative compound presence of LNPs in the neurons of the red nucleus CDr3, which specifically binds to the NPC marker located in the brainstem, suggests that the lipid fatty acid binding protein 7 (FABP7, also known as nanoparticles are taken up by axons and brain lipid binding protein, BLBP; Yun et al. 2012; retrogradely transported. With no previous reports Leong et al. 2013). Here, we demonstrate that on this phenomenon, this study reflects the potential NeuroFluor CDr3 labels NPCs from the rodent central of siRNA-LNPs in advancing our understanding of the nervous system (CNS) and further demonstrate its central nervous system. Furthermore, the ability of application in the detection of human pluripotent this relatively novel siRNA-delivering LNP technology stem cell (hPSC)-derived NPCs. NeuroFluor CDr3 to successfully affect gene silencing in brain and labeled 99% of cells in NPC cultures (97% Nestin%2B) spinal cord in vivo, presents a promising prospect for generated from the adult mouse subventricular zone the development of new gene therapies to treat or the E18 rat cortex, as assessed by flow cytometry. neurological disorders. It also labeled Nestin%2B hPSC-derived NPCs within neural rosette structures, but not surrounding non- 2-G-168 Neuromodulatory opto-fMRI NPC cells, and also labeled single NPCs in subsequent passages. Together, our findings indicate that Bechara Saab¹, Joanes Grandjean², Edward Mann³, NeuroFluor CDr3 is a simple and effective detection Markus Rudin² tool for identifying rodent CNS- and hPSC-derived ¹University of Zürich, ²Swiss Federal Institute of NPCs in live cultures. NeuroFluor CDr3 is compatible Technology, ³University of Oxford with flow cytometry and can be used to enrich NPCs directly from live cultures and tissue samples. Visualising the functional connectivity of specific neural circuits in real-time would represent a new 2-G-167 Effective Gene Silencing in Brain and Spinal opportunity in neuroscience and medicine to probe Cord In Vivo Models Mediated by Lipid how predefined circuits are altered as a function of Nanoparticle Technology life experience and pharmacological treatment. Here James Taylor¹, Oscar Seira², Jie Liu², Aysha Ansari¹, we present the development of a whole-brain David Zwaenepoel¹, Colin Walsh¹, Anitha Thomas¹, readout of functional serotonergic connectivity in Timothy Leaver¹, Andre Wild¹, James Taylor¹, Euan the mouse originating from the dorsal raphe. The Ramsay¹, Pieter Cullis², Wolfram Tetzlaff² method is achieved by merging serotonergic neuron- restricted deep-brain optogenetics and small animal ¹Precision NanoSystems Inc., ²University of British fMRI. We demonstrate the feasibility and specificity Columbia of the system, provide a mechanistic explanation for the observed fMRI readout at the level of brain Lipid nanoparticles (LNP) are the leading systems for oscillations and neuronal spiking, and find specific in vivo delivery of short interfering RNA (siRNA) for changes in serotonergic functional connectivity as a therapeutic applications. The lack of an appropriate consequence of behavioural experience. protocol to administer LNP into the brain and spinal cord has limited the investigation of their potency to 2-G-169 A deterministic, rapid-access microscope silence neuronal genes in vivo. Here, we attempt to and monitoring system for high-throughput data bridge this gap in neuroscience research by acquisition of neuron activity in the awake brain describing the use of siRNA-LNP to efficiently knockdown gene expression in brain and, for the Kelly Sakaki¹, Kurt Haas¹ CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

¹Djavad Mowafaghian Centre for Brain Health our study we hypothesized that an external force to the head could dislodge almost entirely In this work, we describe a novel two-photon, laser- extarcellularly oriented cellular prion protein ( scanning, rapid-access microscope, combined with PrPC)to the extracellular compartment which calcium imaging, to investigate how sensory activity eventually enters into circulation. Using a modified is temporally and spatially coordinated within the ELISA kit, we discovered that blast-TBI is associated full, dendritic arbor of single neurons located in the with an elevation of soluble cellular prion protein optic tectum of the awake brain of a Xenopus Laevis. (PrPC) levels in the plasma of rats exposed (heads Random-access microscopy, is a burgeoning only) to various blast force magnitudes. We have technology, and cutting edge instrumentation is further supported our hypothesis from a pilot study used for high-throughput data acquisition making it on the University of Saskatchewan Huskies Athletic possible to capture activity throughout the arbor Teams. We detected higher levels of PrPC in post- providing real-time feedback indicating concussion plasma samples compared with the computational states of the neuron. This versatile plasma collected from healthy, non-concussive technology features a highly coordinated students. We therefore conclude that the plasma combination of optics, sensors and mechanical soluble PrPC may serve as a potential TBI biomarker. actuators for data-acquisition at ultra-fast rates. Our system achieves high rates of data acquisition by 2-G-171 Genome-wide association for sensory combining a new custom, deterministic, software neuron function in C. elegans using an automated system with a hardware platform designed using behavioural tracking system. high-speed, piezo-actuator Z-stage and acoustic- optic deflectors to scan preselected and scheduled Tiffany Timbers¹, Katherine Lee¹, Donald Moerman², points on the dendritic arbor. Using this system, we Michel Leroux¹ monitored the activity and the morphology in tips and branches of individual neurons using ¹Simon Fraser University, ²University of British randomized stimulation while constrained within a Columbia stimulation chamber. Nervous and muscular systems allow animals to 2-G-170 Plasma Soluble Prion Protein as a Potential sense, and appropriately respond to, the Biomarker for the Traumatic Brain Injury environment. Understanding the genetic basis of these processes requires an integrative approach, Nam Pham¹, Thomas Sawyer², Yushan Wang², probing the molecular mechanisms of distinct Rhonda Shishkin¹, Changiz Taghibiglou¹ components acting in complex neuronal circuits. Typical circuits include sensory neurons bearing cilia ¹University of Saskatchewan, ²Defence Research and (sensory organelles), interneurons, motor neurons, Development Canada and synapses that collectively transmit signals to muscle cells which impart movement and thus Traumatic brain injury (TBI) is a neurological behaviour. The systematic study of such behavioural disturbance caused by an external application of circuits on a large scale, termed 'behavioural force to the head. Globally, TBI is a major burden to phenomics', represents a sought-after area of public health and the leading cause of mortality and research, but which due to technical limitations in neurological disabilities in individuals under the age most animals, remains virtually unexploited. We are of 45. A vast majority of TBI patients (~ 80%) suffer working to establish a nematode, Caenorhabditis mild, non-penetrating closed head injuries (mTBI) elegans, as a platform for behavioural phenomics. and experience a short loss of consciousness (< 20 This is only now possible with the very recent min). Often these patients do not seek medical development of a deep-sequenced C. elegans multi- attention or their diagnosis is challenging as medical mutation library and newly developed automated imaging may not be able to detect pathology. behavioural tracking system. For each deep- Appropriate treatment in a timely manner is sequenced multi-mutant strain, sensory-related therefore not delivered. Significant changes in the phenotypes (> 20 morphological/behavioural concentration of certain proteins in biological fluids features) are combined to create a phenotypic following TBI can be used as biomarkers for 'fingerprint'. Next, we test for genome wide- diagnosis and prognosis as well as guide therapy. In associations (GWAS) between behavioural and CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

genetic variants to link genes to behaviour. We migration and production of inflammatory anticipate that these innovative behavioural mediators at infected dorsal root ganglia phenomic studies will successfully uncover many components and functional mechanisms of sensory Jaqueline Silva¹, Jhimmy Talbot¹, Alexandre Lopes¹, neuron function. Importantly, our findings are of Thiago Cunha¹, Fernando Cunha¹ distinct biomedical relevance, pertinent to a wide array of clinical ailments such as ciliopathies and ¹Ribeirao Preto Medical School of University of Sao sensory neuropathies. Paulo

2-G-172 Mesoscale transcranial cortical imaging Herpes Zoster (HZ) is a disease caused by with fast kinetic genetic-encoded glutamate sensor reactivation of latent herpesvirus Varicella Zoster in - iGluSnFr the sensory ganglion, characterized by dermal rash and pain. A murine model of HSV-1 infection on the Yicheng Xie¹, Timothy Murphy¹ hind paw skin has been used to study HZ, since mice develop HZ-like skin lesions and pain-related ¹University of British Columbia responses. The aim of this study was to evaluate cells and inflammatory mediators present in DRGs Wide field mesoscopic cortical imaging with genetic and its relationship with hiperalgesia during HSV-1 encoded sensors enables decoding regional activity infection. Mice developed hyperalgesia from 3 to 14 and connectivity in anesthetized and behaving mice dpi only in the ipsilateral paws. A higher viral load (Vanni and Murphy, 2014). Fast and sensitive sensors was detected in DRGs L4, L5 and L6 at 7 dpi. The are required to improve linkages to behavior. We intrathecal treatment of infected mice with the report that mesoscopic imaging of virally transduced steroidal anti-inflammatory drug dexamethasone (5 or transgenic expression of glutamate-sensing ug) or fucoidin resulted in a reduction of fluorescent reporter (iGluSnFr) can robustly report hyperalgesia, consistent with the inhibition of sensory stimulation-evoked and spontaneous leukocyte migration to infected DRGs. The leukocyte cortical activity through intact transparent skull infiltrate was composed by neutrophils and (Vanni and Murphy, 2014; Silasi et al., 2013) in macrophages. The mRNA expression of COX-2 and anesthetized or head-fixed awake mice (Guo et al., TNF-a was found to be up regulated at 7 dpi. 2014). Compared to EMX1:creRosa26-GGCaMP3 Moreover, the pharmacological blockage of COX-2 transgenic mice, EMX1:tTA-CamkII: iGluSnFr (Ai85, and TNF-a resulted in the reduction of hyperalgesia. Allen Institute for Brain Science) transgenic and Corroborating these data, the genetic deficiency of AAV1-synapsin-iGluSnFr virally transduced mice TNF-a receptor type I was associated with the showed faster kinetics for reporting regional cortical absence of hyperalgesia in infected mice. Our results activity, being comparable to the speed of RH1692 show the presence of an inflammatory infiltrate in voltage sensitive dye (VSD), but with larger signals. DRGs of infected mice, and the early expression of The seed pixel correlation maps of iGluSnFr inflammatory mediators that contribute for the spontaneous activity indicated functional circuits in induction of herpetic hyperalgesia. Financial support: cortex that were generally consistent with the maps FAPESP (2010/12309-8). generated from EMX-GCaMP3 mice and VSD spontaneous activity. In the current study, we 2-IBRO-176 Effects of Cold Exposure on present a mesoscopic imaging strategy using a fast Behavioral and Electrophysiological genetic-encoded sensor that is reporting regional Parameters.Related with Hippocampal Function in signals of extracellular glutamate concentration in Rats the cortex. It may help the study of cortical circuits following behavior training or brain injury. Hajar el Marzouki¹, Youssef Aboussaleh¹, Sonar Bitiktas², Cem Suer², Aise Seda Artis3, Nazan Dolu², Ahmed Ahami¹

IBRO – International Brain Research Organisation ¹lbn Tofail University Faculty of Sciences, Kénitra, ²Erciyes University School of Medicine, 3Istanbul 2-IBRO-175Nociceptive hypersensitivity induced by Medeniyet University Medical Faculty Herpes Simplex-1 is a consequence of leukocyte CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

This study examined spatial memory as measured by proyect is evaluate the neuroprotective effect in Morris Water Maze(MWM) performance and vitro and their dependence of the activation of EpoR hippocampal long-term potentiation(LTP) in the of a new isoform of Erythropoietin with low dentate gyrus after exposure to cold in a repeated glicosilation obtained from adenoviral transduction stress condition for 2 h/day for 5 days. Three to four of mammary gland of goats (EpoL). For this purpose month old rats were randomly divided into four we preincubated PC12 cells with EpoL for an hour groups to form a control group and a cold stress and then we incubated this cells with β-amyloid group for each sex. The groups of cold stressed peptide or with an uncoupling of respiratory chain of animals were placed in a cold room (ambient electrons in mitochondria (FCCP), like a model of temperature of (4oC) for 2 hours day. Adrenal glands oxidative stress. The cells preincubated with EpoL and body weight (g) were recorded in control and shown an increase of the cellular viability of 32% stressed rats during the cold exposure Spatial more than the control cells, and an increase of 26% learning (acquisition phase) and memory (probe more than cells incubated with an inhibitor of trial) were tested in the Morris water maze activation of EpoR. That difference was not shown in immediately after daily exposure. Latency to locate cells that incubated with a native isoform of Epo. the hidden platform, distance moved, mean distance Finally this results agree with the 50% of to platform, swim speed and time spent in the upregulation of BCL2 gene observed in the same platform quadrant were compared between genders treatments by qRTPCR experiments and with an and treatments. Field potential recordings were increase of immunorreactivity of EpoR in made, under urethane anesthesia, from the DG immunoflurescence data. These results suggested granule-cell layer, with stimulation of the medial that EpoL has a neuroprotective effect more potent perforant pathway 2 hours after the probe trial. The than native Epo. cold-exposed female rats needed less time to find the hidden platform on day 1, day 2 and on day 4, 2-IBRO-178 Cell-type specific chloride while cold-exposed male rats showed a decreased dynamics in epilepsy. escape latency on day 1 only. Cold-exposed male rats spent less time in the target quadrant than the Hayley Tomes¹, Lauriston Kellaway¹, Joseph control male rats. 2h cold exposure decreased Raimondo¹ population spike potentiation during both induction ¹University of Cape Town and maintenance intervals in male rats. Meanwhile cold exposure did not affect the body weight but it Epilepsy is the most common disorder of the impacts the adrenal gland relative weight. nervous system in sub-Saharan Africa with devastating socioeconomic effects. The central 2-IBRO-177 The neuroprotective effects of feature of all epileptic activity is a failure of recombinant erythropoietin isoform with low inhibitory signaling in the brain to contain the glicosilation is mediated by activation of BCL2 generation and spread of excessive neuronal pathway excitation. Neuronal inhibition is primarily mediated Carolina Castillo¹, Angela Hidalgo¹, Tiare Silva- by chloride permeable GABAA receptors making the Grecchi¹, Jorge Fuentealba¹, Jorge Toledo¹ neuronal transmembrane chloride gradient critical for setting the properties of inhibitory signaling. My ¹Universidad de Concepción research is investigating how dynamic changes in chloride concentration relate to the development of Erythropoietin is a glycoproteic hormone that weighs abnormal neural activity. Firstly, I am investigating 34 KDa. Its principal function is to regulate the the conditions under which transient changes in erythropoiesis, however, since the discovery of its neuronal intracellular chloride concentration have receptor (EpoR) in non erythroids tissues like the pathological effects on the strength of synaptic central nervous system (SNC), their function has inhibition within cortical circuits. Whilst astrocytes been related with another pleiotropic effects. In the have long been implicated in the regulation of SNC has been observed a neuroprotective effect of extracellular ionic environments in the brain, their this hormone that's related with the upregulation of role in maintaining/modulating chloride gradients is antiapoptotic pathways that directly related with not well understood and forms a further aim of this activation of its receptor. The objective of this research. Techniques, used for the first time in CAN-ACN 2015: Abstract Booklet Vancouver, May 24-27

Africa, including patch clamp and optogenetics have been set up. In promising preliminary data patch- clamp recordings have shown that during seizure- like events in hippocampal brain slices, the astrocytic membrane potential closely mirrors that of surrounding neurons. Further research utilizing transgenic mice is under way and will allow for the measurement of chloride regulation and changes to synaptic inhibition in both neurons and astrocytes, particularly in the context of epileptic seizures.

2-IBRO-179 Characterization of TDP43 misfolding in an experimental model of ALS/FTD

Leslie Bargsted¹, Danilo Medinas¹, Pablo Rozas¹, Claudio Hetz¹, Soledad Matus²

¹University of Chile, ²Neurounion Foundation

Introduction: TDP43 is a nuclear protein that has important cellular functions related to the regulation of RNA metabolism. TDP43 has been described as the major component of the pathologic inclusions present in post-mortem tissues of most cases of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). In this work, we characterized the pathogenesis of TDP43 in tissue extracts of a transgenic mouse model that overexpresses a mutant form of TDP43 (A315T) in the CNS. We also evaluated the expression of Unfolded Protein Response (UPR) markers in brain and spinal cord tissue. Methods: We obtained protein extracts and mRNA from cortex and spinal cord from transgenic animals (TDP43A315T) in a symptomatic stage and non-transgenic controls. Protein extracts were analyzed by western blot and filter trap. Finally, we did histological analysis in brain and spinal cord of TDP43A315T mice in symptomatic stage and non-transgenic littermates. Results: Biochemical analysis indicated the presence of disulfide-dependent TDP43 protein aggregates in cortex and spinal cord of TDP43A315T mice in symptomatic stage. We found altered levels of UPR markers in tissue extracts of TDP43A315T cortex compared with controls. Finally, by histological analysis we found the presence of ubiquitinated aggregates in cortex and spinal cord of symptomatic TDP43A315T mice. Discussion: The presence of TDP43 ubiquitinated aggregates could be generating alterations in ER proteostasis of neural cells, affecting the UPR machinery and the adaptive capacity against stress. The Canadian Association for Neuroscience presents 9th Annual Canadian Neuroscience Meeting 2015 Thanks to our Sponsors, supporters and Donors

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