Is It a European Car Or a Japanese Car? an ERP Study of Diagnostic Information Use in Visual Expertise

Wright State University CORE Scholar

Psychology Faculty Publications Psychology

11-2007

Is it a European car or a Japanese car? An ERP Study of Diagnostic Information Use in Visual Expertise

Assaf Harel Wright State University - Main Campus, [email protected]

Shlomo Bentin

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Repository Citation Harel, A., & Bentin, S. (2007). Is it a European car or a Japanese car? An ERP Study of Diagnostic Information Use in Visual Expertise. Neural Plasticity, 2007, 30585, 52. https://corescholar.libraries.wright.edu/psychology/254

This Abstract is brought to you for free and open access by the Psychology at CORE Scholar. It has been accepted for inclusion in Psychology Faculty Publications by an authorized administrator of CORE Scholar. For more information, please contact [email protected]. Hindawi Publishing Corporation Neural Plasticity Volume 2007, Article ID 30585, 168 pages doi:10.1155/2007/30585

Meeting Abstracts Abstracts of the 16th Annual Meeting of The Israel Society for Neuroscience Eilat, Israel, November 25–27, 2007

Received 9 October 2007; Accepted 9 October 2007 The Israel Society for Neuroscience—ISFN—was founded in 1993 by a group of Israeli leading scientists conducting research in the area of neurobiology. The primary goal of the society was to promote and disseminate the knowledge and understanding acquired by its members, and to strengthen interactions between them. Since then, the society holds its annual meeting every year in Eilat usually during December. At this annual meetings, the senior Israeli neurobiologists, their teams, and their graduate students, as well as foreign scientists and students, present their recent research ﬁndings in platform and poster presentations, and the program of the meeting is mainly based on the 338 received abstracts which are published in this volume. The meeting also oﬀers the opportunity for the researchers to exchange information with each other, often leading to the initiation of collaborative studies. Both the number of members of the society and those participating in the annual meeting is constantly increasing, and it is anticipated that this year about 600 scientists will convene at the Princess Hotel in Eilat, Israel.

Further information concerning the Israel Society for Neuroscience can be found at http://www.isfn.org.il.

Committee: Shlomo Rotshenker (President) Hebrew University of Jerusalem Talma Brenner Hadassah–Hebrew University Medical Center Yoram Rami Grossman Ben Gurion University of the Negev Mmouna Maroun University of Haifa Yoel Yaari Hebrew University of Jerusalem Gal Yadid Bar-Ilan University

Zvi Wollberg (Past President) Tel Aviv University

Lili Anglister (Treasurer) Michal Gilady (Administrator) Hebrew University of Jerusalem Rishon Le Zion

Copyright © 2007 Israel Society for Neuroscience. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 2 Neural Plasticity

Amyloid-beta peptide modulates the pattern of study was to gain insight into the role of L-Carnosine and N- transmitter release in hippocampal synapses Acetyl-L-Carnosine (NACar), a lipophilic synthetic derivative of L-Carnosine, on NO synthesis in microglia. It is shown Abramov E. and Slutsky I. here for the first time that L-Carnosine (10–20 mM) can inhibit LPS-induced NO synthesis by 75% in microglia. NACar Department of Physiology & Pharmacology, Sackler Faculty was even more potent than its parent drug, L-Carnosine, in of Medicine, Tel Aviv University, Israel inhibiting LPS-induced NO synthesis. It inhibits NO release by 40% to 80% at concentration as low as 0.5 mM. Our re- Aggregation of the amyloid-beta (A-beta) peptide in the ex- sults suggest that L-Carnosine and NACar may play a pro- tracellular space of the brain is central to Alzheimer’s dis- tective role in oxidative stress process in the brain. Further ease (AD) pathogenesis. Recent findings have shown that studies are needed aiming to understand the mechanism by synaptic activity promotes release of A-beta through vesi- which L-Carnosine and NACar act and to use these com- cle exocytosis. However, the relationship between vesicu- pounds as a potential treatment strategy for strategy for neu- lar release of A-beta and neurotransmitter release remains rodegenerative diseases. obscure. Current hypothesis of AD suggests that elevated neuronal activity leads to increased extracellular concen- Enhanced stress-induced responses in tration of A-beta, which in turn triggers reduction in the an atroglial NOS2 mouse mutant number, strength, and plasticity of synaptic connections, eventually resulting in memory impairments. According Abu-Ghanem Y.,1 Cohen H.,2 Amitai Y.,1 and Grauer E.3 to this hypothesis, decreased synaptic activity should pro- 1 mote memory function through reducing A-beta level. How- Department of Physiology, Faculty of Health Sciences, Ben-Gurion University Beer-Sheva, Israel ever, on the other hand, memory-related forms of synap- 2 tic plasticity are manifested as increase in synaptic activ- Mental Health Center, Ben-Gurion University, Beer-Sheva, Israel ity. To understand this paradox, we study the relationship 3 between different patterns of synaptic activity, A-beta re- Israel Institute for Biological Research, Ness-Ziona, Israel lease, and synaptic transmission using FM-based functional Nitric oxide (NO) is produced in the brain by both neurons imaging at the level of single synapse and in synaptic net- and astrocytes. Until recently, astrocytic NO production has works. Our results show that acute accumulation of endoge- been demonstrated mainly as a slow reaction to detrimen- nously released A-beta enhances presynaptic activity for sin- tal events through the activity of an inducible NOS isoform gle spikes that mimic background activity through increas- (iNOS). Prior data from our laboratory described for the first ing release probability and the number of functional presy- ff time rapid astrocytic NO release in brains of healthy ani- naptic terminals. However, A-beta does not a ect presy- mals. To further explore the role of astrocytic-produced NO, naptic activity associated with temporally correlated burst we examined the iNOS knockout (KO) mouse. NO imaging of spikes. These results suggest that A-beta might be a key and biochemical assays revealed compensatory NOS activity molecule transforming hippocampal synapses to a low-pass in mutants’ brain, which resulted in 30% higher basal NO filter mode, resulting in decreased short-term facilitation of levels compared with control animals. Evaluation of the mu- transmitter release during bursts. We hypothesize that ele- tants’ behavior in several behavioral tests revealed increased vation of background presynaptic activity by A-beta might anxiety-like responses, with no differences in motor activity be a trigger for homeostatic down-regulation in the number (Buskila et al., 2007). To further characterize the behavioral and plasticity of synapses and, eventually, memory decline phenotype, we compared the performance of mutant mice in AD. to their controls in their response to stress. Seven days after exposure to predator scent stimulation (PSS), mutants Protective effect of N-acetyl-L-Carnosine, exhibited higher anxiety-like behavior in the elevated-plus a lipophilic derivative of L-Carnosine, on maze and stronger acoustic startle response. No such differ- lipopolysaccaride-induced glial oxidative stress ences between groups were observed without the stress exposure. Plasma corticosterone levels were significantly higher Abramovitch-Dahan C., Beit-Yannai E., Ben-Shabat S., in mutant mice following PSS, further demonstrating their and Fleisher-Berkovich S. heightened sensitivity to stress. Interestingly, mutant mice performed better on the Morris water maze (MWM) under Department of Clinical Pharmacology, Faculty of Health control conditions. The possibility of improved cognition in Sciences, Ben Gurion University of the Negev, Israel these mice was not supported as these mutants failed to show improved performance in the object recognition test. The Neurodegenerative disorders pathology can be characterized MWM results are probably due to enhanced motivation un- by both chronic inflammation and oxidative stress. The most der water maze stress conditions in mutant mice compared dominant source of inflammatory and oxidative stress me- to controls. Taken together, our results confirm higher sus- diators like nitric oxide (NO), prostaglandins, and cytokines ceptibility to stressful conditions in an astrocytic NOS mouse are activated microglia. We used lipopolysaccharide (LPS) in mutant. order to induce oxidative stress in microglia. L-Carnosine is known as an efficient endgenous antioxidant. The aim of this Supported by a grant from the Israel Science Foundation to Y.A. Israel Society for Neuroscience 3

TheroleofCB1receptorsinthehippocampus some 6q23. Subsequent fine mapping, association, and repli- and nucleus accumbens in extinction learning cation studies identified AHI1 as a putative susceptibility and neural plasticity gene. The same genome scan revealed suggestive evidence for a schizophrenia susceptibility locus in the 10q23-26 region. Abush H. and Akirav I. Methods Department of Psychology, University of Haifa, Israel To refine the linkage interval on chromosome 10q and to The inability to extinguish maladaptive fear responses is seek candidate genes in this region, we genotyped 35 addi- a hallmark of anxiety disorders, particularly posttraumatic tional microsatellite markers in the previously studied Arab stress disorder. Thus, suppression of the fear response via Israeli sample, covering a 42.6 cM region between markers the behavioral paradigm of extinction receives increasing at- D10S583 and D10S217. Linkage and haplotype analyses were tention, since it could become an effective intervention for performed. treating fear-related disorders. The endocannabinoid system, particularly CB1 receptors, has recently emerged as considerably important in the extinction of fear-related learning. Results However, interest in their therapeutic applications has been restrained by potentially harmful consequences on memory. The strength of the linkage on chromosome 10q increased Given the well-established role of the hippocampus in learn- from a multipoint, parametric HLOD score of 2.77 to 3.42. The one-unit support interval surrounding this peak de- ing and memory processes, it is likely that the adverse ef- ff fects of cannabinoids on memory are attributable to their ac- creased from 32.3 cM to 3.79 cM. 35 out of 40 a ected in- tions within this brain region. The nucleus accumbens rep- dividuals that were found to share the same allele of marker D10S88 for which the best HLOD score was found. In ad- resents a brain area that is critical to the expression of re- ff warding and addictive properties of several classes of abused dition 26 out of 41 a ected individuals were found to share drugs including cannabinoids. Thus, we set out to examine the same haplotype, which consists of D10S88 and D10S1269 the role of CB1 receptors in extinction learning and plastic- markers. ity in the hippocampal-accumbens pathway. To that end, we have used 2 memory models: light-dark inhibitory avoidance Conclusions (IA) and LTP. We found that microinjecting the CB1 antagonist AM251 (0.5 μg/0.5 mL) to the hippocampus impaired This study revealed significant evidence for linkage of Arab ff extinction, but not acquisition of the IA task. However, Israeli families a ected with schizophrenia to chromosome the direct cannabinoid agonist WIN 55 212-2 (0.5 mg/kg or 10q25.1-25.2 with a substantially reduced HLOD-1 region. 6ng/0.5mL)hadnoeffect on the acquisition or extinction Haplotype analysis suggests a founder mutation between of IA in the hippocampus, but impaired LTP in the hip- markers D10S543 and D10S168 (10q25.2). There are 17 pocampal CA1 area and in the CA1/subiculum-NAc path- protein-coding genes in HLOD-1 region and most of them way. Importantly, using an inhibitor of cannabinoid reuptake are brain-expressed with potential pathophysiological rel- and breakdown AM404 (200 ng/0.5 mL) was found to facili- evance to schizophrenia. These findings are supported by tate extinction of IA. These observations are consistent with those of Levinson et al. (1998) and Mowry et al. (2000) in cannabinoid effects on memory, and suggest a twofold effect the same region. of cannabinoids on memory within the hippocampus: impairing and facilitating. This effect seems to be dependent on Modeling voltage-gated sodium conductances from the memory task under examination. cortical pyramidal neurons

1,2 1,2 1,2 Fine mapping of a schizophrenia susceptibility Almog M., Gurkiewicz M., and Korngreen A. locus on chromosome 10q23-q26: significant 1The Mina & Everard Goodman Faculty of Life Sciences, Israel evidence for linkage and a reduced linkage interval 2The Leslie & Susan Gonda Brain Research Center, Israel Alkelai A.,1 Kohn Y.,1 Kanyas K.,1 Hamdan A.,2 Transmembrane protein mechanisms such as ion channels Lancet D.,3 and Lerer B.1 and their activity are at the essence of neuronal transmis- 1Biological Psychiatry Laboratory, Department of Psychiatry, sion. The most accurate method, so far, for determining Hadassah, Jerusalem, Israel ion channel kinetic mechanisms is single-channel recording 2Regional Mental Health Center, Taibe, Israel and analysis. Nevertheless, single-channel recordings carry 3Department of Molecular Genetics, Weizmann Institute of several holdups and complexities, especially when dealing Science, Rehovot, Israel with voltage-gated channels. We have previously developed a method for fitting cell-attached and whole-cell voltage- Introduction clamp data to kinetic models of ion channels using genetic search algorithms (GAs). Here, we show the applica- A genome scan for schizophrenia related loci in Arab Israeli tion of this method for testing several previously published families detected significant evidence for linkage at chromo- and newly conceptualized kinetic models to voltage-gated 4 Neural Plasticity sodium channels currents recorded, in cell-attached configu- A major reason for this failure might be that the brain in ration of the patch-clamp technique, from layer 5 pyramidal the blind undergoes profound plastic changes and we do not neurons of the rat cortex. The results emphasize the inability know enough about vision and about how to communicate of the commonly used Hodgkin-Huxley paradigm to match with this altered cortex to generate meaningful visual percep- and reproduce recorded currents from mammalian cortical tion. In this presentation, new findings regarding the nature neurons. Further, initial tests suggest a trend towards a sim- of sensory representations and verbal memory information plified Markov scheme that adequately reproduces measured in sighted, blind, and week long blindfolded subjects will be sodium currents. Finally, experiments were performed to test presented. These studies show that interactions between sen- the robustness of the best putative Markov models, using sory modalities are critical to our understanding of sensory Monte Carlo simulations. perception in the brain. These findings also show that massive brain plasticity in the occipital cortex is possible dur- Mitochondrial DNA HV lineage increases ing development but possible even in the adult visual cortex. the susceptibility to schizophrenia among Here, I will highlight the role of transcranial magnetic stim- Israeli Arabs ulation (TMS) as a tool to assess the functional relevance of

1 1 2 3 these plastic changes. Finally, I will discuss the use of sensory Amar S., Shamir A., Ovadia O., Blanaru M., substitution devices (SSDs) in the context of blindness. In Reshef A.,3 Kremer I.,3 Rietschel M.,4 Maier W.,4 1 5 1 2 SSDs, visual information captured by an artificial receptor is Belmaker R., Ebstein R., Agam G., and Mishmar D. delivered to the brain of a blind person using nonvisual sen- 1Faculty of Health Sciences, Ben-Gurion University of sory information via a human-machine interface. I will show the Negev, Beer-Sheva, Israel that the use of an auditory-to-visual sensory substitution de- 2Department of Life Sciences, Ben-Gurion University of vice called “the vOICe” yields successful performance on ob- the Negev, Beer-Sheva, Israel ject recognition tasks, and specific recruitment of ventral and 3Department of Psychiatry, Haemek Medical Center, dorsal visual structures both in blind and sighted experts. I Afula, Israel will close by discussing the importance of “the vOICe” as a 4Department of Psychiatry, University of Bonn, device to be used for daily activities (e.g., object recognition Bonn, Germany and localization) and its potential use to “guide” the visual 5Department of Psychology, Hebrew University, Jerusalem cortex to “read” and interpret visual information arriving and S. Herzog Memorial Hospital, Israel from a retinal prosthesis. Haplotypes and haplogroups are linked sets of common A. A. is supported by the Human Frontiers Science Program DNA variants, acting as susceptibility or protective factors and an EU 7th Framework Program grant. to complex disorders. Growing evidence suggests that dysfunction of mitochondrial bioenergetics contributes to the The N170 sensitivity to faces is dissociated schizophrenia phenotype. We studied mitochondrial DNA from conscious awareness haplogroups in schizophrenia patients. Since mitochondria Amihai I.,1 Deouell L. Y.,2 and Bentin S.2 are inherited from the mothers, we used healthy fathers as an ideal case-control group. Analysis of the distribution of 1Neurobiology Department, Hebrew University of Jerusalem, mitochondrial haplogroups in schizophrenia patients com- Israel pared to their healthy fathers (202 pairs) resulted in an over- 2Psychology Department, Hebrew University of Jerusalem, representation of the mtDNA lineage cluster, HV, in the pa- Israel tients (P = .01), with increased relative risk (odds ratio) of 1.8. Since mitochondrial DNA is small relative to nuclear Converging evidence from numerous ERP and MEG studies DNA, a total mitochondrial genome analysis was possible points to a neural response which discriminates faces from in a hypothesis-free manner. However, mitochondrial DNA nonface objects, peaking at around 170 milliseconds follow- haplogroups are highly variable in human population and it ing stimulus onset. Here we ask whether this discrimination will be necessary to replicate our results in other human eth- at the neural level correlates with conscious detection of a nic groups. face, or with its mere presence in the visual field. To investigate this, we used “continuous flash suppression,” a binoc- Perception from a blind perspective: multisensory ular rivalry technique that effectively causes unawareness of integration and sensory substitution in blind and the stimulus presented to one eye. In each trial, a face or an sighted individuals Easter egg was continuously presented to one eye, but was temporarily masked after a delay by a dynamic stimulus pre- Amedi A. sented to the other eye. In a control condition, the face or Department of Physiology-Faculty of Medicine & Program of egg was physically removed for the duration of the dynamic Cognitive Science, The Hebrew University, Israel mask. In both conditions, the subjects’ subjective experience was of two presentations of a face or of an egg. The onset Restoration of sight in a blind person imposes great clini- of the first face elicited a typical N170 face-specific response cal and scientific challenges. Despite intensive efforts, recov- in both conditions. In contrast, the subjective reappearance ery of vision using neuroprostheses has not been achieved. of the face elicited a face-specific N170 response only in Israel Society for Neuroscience 5 the control condition, when physical face onset was intro- is disrupted in acute schizophrenia patients and in rats duced. Thus, extrastriate object-selective responses reflect and humans treated with the psychosis inducing drug the physical presence of relevant input, and are not corre- amphetamine. Disruption of LI is reversible by typical and lated with conscious awareness. atypical antipsychotic drugs (APDs). Our previous results suggested that LI was disrupted in ovariectomized (OVX) The effects of withdrawal from chronic rats and could be restored by 17 beta-estradiol (150 μg/kg) administration of estradiol on “compulsive” and the atypical APD clozapine (5 mg/kg), but was resistant lever-pressing of female rats—a preliminary study to the typical APD haloperidol (0.1, 0.2, 0.3 mg/kg). Here we show that haloperidol is able to restore LI only when Arad M.,1 Albelda N.,1 and Joel D.1 administered with 17 beta-estradiol (50 μg/kg). Further- more, under conditions that yield LI in both OVX and Department of Psychology, Tel-Aviv University, Israel sham female rats, amphetamine disrupts LI in all rats, but restoration of LI by haloperidol in amphetamine-treated rats Obsessive-compulsive disorder (OCD) is a psychiatric dis- is observed only in sham rats. While resistance of disrupted order psychiatric disorder affecting 1–3% of the popula- LI to haloperidol in the absence of estrogen is in line with tion and characterized by intrusive unwanted thoughts (ob- reduced efficacy of haloperidol in menopausal women, sessions) and repetitive ritualistic behaviors (compulsions). our results suggest that propsychotic action of dopamine Sex differences have been found in the phenomenology and (DA) releaser apparently does not require estrogen. This course of this disorder, and women have been reported to be differential sensitivity of OVX rats to DA stimulation and DA vulnerable to an onset or exacerbation of symptoms during blockade may have important implications for the clinical premenstruum, pregnancy and postpartum. This suggests a development of schizophrenia and APD treatment in women possible involvement of gonadal hormones in the pathopys- because it suggests that naturally occurring reduction in iology of OCD. In the signal attenuation rat model of OCD, hormonal levels may increase the danger of relapse/severity “compulsive” behavior is induced by attenuating a signal in- of symptoms while concomitantly reducing the efficacy of dicating that a lever-press response was effective in producing conventional treatment. food. The present study tested the effects of chronic administration and of withdrawal from chronic administration of 17 A novel approach for treatment of Alzheimer’s beta estradiol on compulsive lever-pressing of pre-pubertal disease: antibodies against beta-secretase cleavage female rats, in an attempt to mimic late gestation and post- site of APP partum. In order to assess the efficacy of the hormone regimen in mimicking the postpartum period, rats were as- Arbel M. and Solomon B. sessed for postpartum depression using the “forced swim test” (FST), an animal model of depression. Rats that were George S. Wise Faculty of Life Science, Tel-Aviv University, injected with 17 beta estradiol for 7 days and then underwent Israel a withdrawal phase for 3 days tended to exhibit more compulsive lever-pressing compared to control animals (P<.08). Although the extracellular A-beta plaques are the main hall- In the FST, the “withdrawal” rats exhibited significantly more mark and criteria for ultimately post mortem diagnosis immobility, the depressive-like behavior, than control rats, of Alzheimer’s disease (AD), it remains to be determined indicating that the hormone regimen was successful in mim- whether extracellular or intracellular A-beta accumulation icking the post-partum period. The results suggest that fluc- initiates the disease process. Intraneuronal A-beta accumula- tuations in estradiol levels can lead to the onset or exacerbation is increasingly linked with early preplaque synaptic and tion of OC symptoms. pathological abnormalities occur in brain of AD patients and transgenic animals. Understanding the mechanisms that un- Amphetamine and ovariectomy induced disruption derline A-beta accumulation in neurons and its relation with of latent inhibition in female rats can be reversed by the extracellular A-beta pool, may be beneficial in develop- haloperidol only in the presence of estrogen ing therapeutic tools for AD treatment. We developed a novel approach to inhibit A-beta production via antibodies against Arad M. and Weiner I. the beta-secretase cleavage site of APP. This approach limits APP processing by beta -secretase, mainly through the en- Department of Psychology. Tel-Aviv University, Israel docytic pathway and overcomes some of the limitations of BACE1 (beta-secretase) inhibition methodologies. Antibeta- Elevated relapse rates and symptoms remission in site antibodies bind human APP expressed by AD cellular schizophrenic schizophrenic women tend to correlate model and internalize into the cells after APP binding at with low and high estrogen levels, respectively. Conse- the plasma membrane. Antibodies mediated inhibition of quently, the estrogen hypothesis of schizophrenia postulates beta-secretase cleavage led to a 50% reduction of intracel- that estrogen is a neuroprotective factor delaying the on- lular A-beta levels. Intracerebroventricular injection of these set of schizophrenia and reducing its severity in women. antibodies to non transgenic mice in which neprilysin ac- Latent inhibition (LI), the capacity to ignore stimuli that tivity was inhibited led to 60% and 80% reduction in in- received nonreinforced preexposure prior to conditioning, tracellular and extracellular brain A-beta levels, respectively, 6 Neural Plasticity highlighting the therapeutic potential of these antibodies. Using odors to treat sleep apnea: Moreover, systemic administration of antibeta-site antibody a test of feasibility to tg2576 mice facilitated a beneficial effect on the mice cog- 1 1 1 2 nitive function and did not lead to any adverse effects. To Arzi A., Sela L., Haddad R., Green A., 2 1 the best of our knowledge this is the first attempt to inhibit Dagan Y., and Sobel N. beta-secretase cleavage of APP by blocking the cleavage site 1Department of Neurobiology, The Weizmann Institute of upon the substrate rather then a total inhibition the enzyme. Science, Rehovot 76110, Israel This approach overcomes some of the limitations presented 2Assuta Hospital, Petach Tikva 49361, Israel by both BACE1 inhibition methodologies and A-beta-based immunotherapies. Apnea, a repeated suspension of breathing during sleep, is a prevalent sleep disorder with significant impact on daily Modalities of feedback induce differential reaching life as well as on general health. We combined the following strategies in adaptations to force field information to generate a potential treatment:

Arce F.,1 Novick I.,1 Shahar M.,1 Ghez C.,2 (1) it is largely held that odorants fail to wake humans and Vaadia E.1,3 from sleep; (2) odorants modify respiratory patterns. Given this, we 1Department of Physiology, Hadassah Medical School, hypothesized that providing an odorant during apnea The Hebrew University, Jerusalem, Israel may “jumpstart” the respiratory pattern without wak- 2Center for Neurobiology and Behavior, Columbia University ing the individual. College of Physicians and Surgeons, NY, USA 3The Interdisciplinary Center for Neural Computation, To address this, we first set out to test the influence of ff The Hebrew University, Jerusalem, Israel di erent odorant regimens on patterns of sleep and sleep- respiration. Subjects slept in a stainless-steel-coated odor- Performance errors induced by perturbation during reaching ant nonadherent room where we measured an electroen- may drive adaptation differentially based on sensory modal- cephalogram, electrooculogram, electromyogram, electro- ities conveying them. Here we demonstrate that state esti- cardiogram, blood oxygenation, as well as overall and nasal mates based on vision and proprioception differentially in- respiration. Subjects wore a small nasal mask where we could fluence adaptive strategies used in force fields. We studied deliver odorants in a controlled fashion, with no nonolfac- ff the contributions of visual and proprioceptive feedback in tory cues as to odorant onset and o set. The odorant laven- a reaching task. Separate groups of human subjects adapted der oil was presented to sleeping subjects (using ISIs of 9, to viscous force fields with or without concurrent visual feed- 12, and 15 minutes, and stimulus durations of 5, 10, and back of their hand trajectory and were retested after 24 hours. 20 seconds). In an initial analysis of nasal respiration in the ff We found comparable levels of endpoint accuracy after adap- first subject, without odors we found a main e ect of sleep F = P<. tation to force field with and without visual feedback, how- stage ( 49, 0001) reflecting equally vigorous nasal t = . P = . ever, hand paths differed consistently. With visual feedback, respirations during stage 1 and 2 sleep ( 1 5, 14), and induced deviations in initial direction of hand movements equally significantly reduced respiratory magnitude in SWS t> P<. were rapidly reduced and paths became rectilinear. On day and REM ( 6, 0001). Whereas odorant presentations 2, adaptive changes in initial direction were accelerated and had no influence on respiratory magnitude during Stages 1 t = . P = . endpoint variability was reduced. Without visual feedback and 2 sleep ( 1 1, 27), they induced a significant (and proprioception alone), hand paths remained highly recovery in magnitude of nasal respiration during SWS and t = . P<. curved. While endpoint errors were reduced on day 2, ini- REM ( 3 5, 01), to levels even slightly higher than tial directions and curvature remained unchanged. The re- those seen at Stages 1 and 2 with and without odor. These sults indicate two different strategies to achieve final posi- pilot data point to feasibility of using odorants to treat sleep tion accuracy-one through changes in trajectory and another apnea. through changes in endpoint variability. In the presence of *These authors contributed equally to this work. combined visual and proprioceptive feedback, adaptation is dominated by control of trajectory and adjustments in di- Exposing rats to stressors during juvenility rection. With proprioceptive feedback alone, compensation increases morphine intake in adulthood for the perturbed dynamics is achieved primarily by adaptation of final equilibrium position. We argue that such stark Asbe M., Tsoory M. M., and Berger B. D. difference in the adaptive responses depends on the sensory sources of the estimates for trajectory and for final reach po- Department of Psychology, The Brain and Behavior Research sition. Our findings also support the notion that separate Center, University of Haifa, Haifa, Israel adaptive mechanisms operate to adjust trajectory and endpoint accuracy. Epidemiological studies indicate that exposure to stress early in life increases the risk to develop both mood and anx- Supported by BSF, ISF, Johnson & Johnson Fund for Innovative iety disorders as well as drug dependence or drug seek- Science, Rosetrees Trust, Ida Baruch Fund. ing behaviors in adulthood. Exposing rats to stress during Israel Society for Neuroscience 7 juvenility (27–29 days of age) was found to increase the L-LTPcanblockL-LTP,butapartialblockoftranslationin prevalence of altered stress responses which corresponded to the maintenance phase might not block L-LTP. both mood and anxiety disorders’ symptoms and thus was suggested as a model of induced predisposition for these dis- Mapping the environment-an experimental orders (Avital and Richter-Levin, 2005; Tsoory and Richter- model of spatial representation during exploration Levin, 2006; Tsoory et al., 2007a). The current study uti- and navigation lized the juvenile stress model and examined its effects on morphine intake in adulthood. Consumption of water alone Avni R. and Eilam D. and/or water + morphine sulfate (0.5 mg/cc) was monitored over several weeks. In comparison with control rats, adult Department of Zoology, Faculty of Life Sciences, juvenile stressed rats exhibited a higher morphine prefer- Tel Aviv University, Israel ence (morphine intake/ (morphine + water intake)). Recent findings suggest that exposure to juvenile stress may alter We present a hierarchal model and supporting data on spa- development-related processes and possibly sensitize stress tial representation during exploration, based on successive responses mechanisms (Tsoory et al., 2007b). Taken together phases of spatial information processing: (1) piloting (se- with the current data, it is suggested that such sensitized quential processing)—egocentric space representation con- stress responses mechanisms may increase drug seeking be- structed by traveling from one landmark to the next, chang- haviors. These findings support the validity of an animal ing heading direction (origin point for path integration) be- model for the study of the consequences of exposure to stress tween landmarks; (2) orienting (parallel processing)—space early in life regarding drug dependence or drug seeking be- is represented in relation to a fixed place that is a terminal haviors in adulthood. for repeated sequential processing, with the traveling paths varying yet heading direction points to the fixed location (path integration calculated from that place); (3) navigat- A Self-sustaining translational switch for regulating ing (continuous processing)—space representation (map) is the maintenance of synaptic plasticity constructed by orienting (continuously updating heading direction) in relation to several places. Empirically, we demon- Aslam N., Kubota Y., and Shouval H. strate a transition from sequential to parallel processing during gerbil exploration. Tested in an unfamiliar dark open The University of Texas Medical School at Houston, Tex, USA field, gerbils explored it using a looping mechanism: trav- Long term memory as well as synaptic plasticity outlast the eling slowly in an undulating path that forms a loop by re- lifetimes of the proteins that encode synaptic efficacies. Since turning to a previously visited place. In looping the gerbils synaptic plasticity is synapse-specific it is essential to identify rarely returned more than once to a previously visited place, a mechanism that can sustain changes in synaptic efficacies with no apparently fixed heading direction. Gradually, ger- is a synapse specific manner. One key observation that might bils shifted from looping to a home base mechanism, spend- supply a possible mechanism is that the consolidation of long ing increasingly greater time in one place and repeatedly re- term memory and long term plasticity depends on the pro- turning to it. Exploration became organized in relation to a duction of new proteins. Here we suggest that a feedback fixed place, with varying paths that share a heading direction loop between a translation factor and a plasticity related ki- computed in relation to that place. We suggest this shift from nase might provide this stability. Specifically we examine the looping to home base to reflect a change from momentary CaMKII-CPEB pair as a possible instantiation of this idea. to fixed heading direction and thus from piloting to the ori- Experimental evidence suggests that during the normal brain enting phase of the model. As the model involves transition function most of the CaMKII (83%) is synthesized in den- from orienting to navigating, a transition from home base to a higher level of spatial organization is predicted. Possible drites through local translation (Miller et al. 2002, Schuman ff et al. 2006). Here we propose that the synthesis of CaMKII at implications of the model to e ect of spatial representation active synapses can be regulated through a local translational damaging (e.g., lesions) are yet to be explored. switch. The proposed translational switch might provide a SupportedbytheIsraelScienceFoundation. self-sustaining mechanism to regulate the de novo synthesis of plasticity-related proteins during the maintenance phase Reorganized prospective and retrospective of late long-term potentiation (L-LTP). Our results show that hippocampal memory coding after switching a bistable switch can arise from CPEB mediated polyadeny- thestartandgoalofajourney lation of αCaMKII mRNA. Our results imply that L-LTP α should produce an increase in the total amount of CaMKII Bahar A. and Shapiro M. and fraction phosphorylated at potentiated synapses, which is consistent with experimental observations (Ouyang et al. Fishberg Research Center for Neurobiology, Mount Sinai 1999). Through bifurcation analysis, we identify the key pa- School of Medicine, NY, USA rameters that determine whether the system is in a bistable region, this could indicate the key parameters that should be Rat Hippocampal neurons encode the current location measured experimentally. We also demonstrate that a par- of the animal via place fields. Changes to distal cues tial block of αCaMKII translation in the induction phase of in the animal’s environment can modulate this encoding, 8 Neural Plasticity a phenomenon termed place field remapping. In a spatial 1Faculty of Medicine, Technion-Israel Institute of Technology, memory task on a + maze hippocampal cell activity was Haifa 32000, Israel also influenced by locations that were recently visited, or 2Faculty of Electrical Engineering, Technion-Israel Institute of are forthcoming (i.e., expressing retrospective or prospec- Technology, Haifa 32000, Israel tive memory coding, Ferbinteanu and Shapiro, 2003). Thus, hippocampal neurons can jointly express contextual and This study addresses the issue of relations that exist be- mnemonic information that relates to the present, past, and tween topology and dynamics of large sparsely connected future. This type of processing fits the view that the hip- neural networks. In particular, it examines the hypothesis pocampus supports episodic memory, and that memory de- that topology governs the source separation ability of neu- mands can modulate hippocampal coding. The present ex- ral networks endowed with structural characteristics of cor- periment tested the effects of changing memory demands on tical networks. For this purpose, extensive simulations of net- ff retrospective and prospective coding, and examined if mod- workswithdi erent topologies and similar structural fea- ulations of retrospective and prospective coding share the tures (e.g., similar average in- and out-degrees) were carried same dynamics as stimulus-induced place field remapping. out. Networks responses to various stimuli were analyzed in We trained rats to perform a win-stay task with serial rever- terms of neural recruitment order during a network burst. sals on a + maze. Hippocampal unit activity was recorded The latter measure is assumed to convey information rele- as rats placed on either a North or a South start arm nav- vant to source separation. The results showed that the re- igated to the correct East or West rewarded goal arm. In a sponses of networks with Gaussian in-degree and Scale Free ff novel condition, the start and goal arms were switched, so (SF) out-degree distributions to di erent stimuli varied sig- that the North and South arms served as the goal arms and nificantly more than those of Erdos¨ Renyi´ (ER) networks and the East and West arms served as the start arms. Preliminary networks with SF in-degree and Gaussian out-degree distri- data showed that all place fields remapped in the novel con- butions. These results support the hypothesis that topology dition. Concurrently, performance decreased in the Novel does indeed play a crucial role in source separation tasks ex- condition from 91% to 74% correct, as did the percent of ecuted by neural networks. fields showing prospective or retrospective coding (30% to 15% and 50% to 8%, respectively). In contrast, the percent AxCaliber—in-vivo measurement of axon of fields coding location alone increased in the novel condi- diameter distribution with MRI tion from 20% to 77%, though the fields were less stable. We Barazany D.,1 Basser P.,2 and Assaf Y.1 are collecting additional data from CA1/CA3 fields in order to better understand the influence of changes to memory de- 1Department of Neurobiochemistry, Faculty of Life Sciences, mand on hippocampal on-line processing. Tel Aviv University, Israel 2The National Institutes of Health, Bethesda, Md, USA Working memory: somatic spikes or synaptic calcium? The axon diameter distribution (ADD) is an important 1 2 1 Barak O., Mongillo G., and Tsodyks M. anatomical feature of nerve fascicles both in normal and abnormal development. Axon diameter directly affects nerve 1Department of Neurobiology, Weizmann Institute of function. It is well known that in myelinated axons, the con- Science, Israel duction velocity is directly proportional to axon diameter. 2Laboratory of Neurophysics and Physiology, UMR 8119, Thus, large-diameter axons generally arise in pathways that CNRS, UniversiteRen` e` Descartes, France require short conduction times while smaller axons arise in The notion that synaptic plasticity supports long-term mem- pathways that can tolerate longer conduction times. In ad- ory storage while persistent neuronal spiking activity main- dition, it is hypothesized that in amyotrophic lateral sclero- tains these memories in a short-term active form is widely sis (ALS) large diameter axons are damaged selectively, while held in theoretical neuroscience. We show that synapses can in autism, small-diameter axons are over-expressed. Despite also effectively implement active memory function through its importance, the ADD within nerve fascicles has not been their short-term plasticity. In this account, the short-term measurable in-vivo, and currently can only be assessed by in- synaptic variables are used as a “buffer” which is loaded, vasive histological means. Here, we propose a new magnetic- read-out and refreshed by neural activity. The refresh rate is resonance-imaging- (MRI-) based approach called AxCal- ff low, since it depends on the slow time constants associated iber that utilizes di usion MRI to extract the ADD, in-vivo ff with synaptic dynamics. The feasibility of this mechanism and noninvasively. Di usion MRI measures the micron-scale ff is demonstrated in a biologically plausible spiking network displacements of water molecules; by altering the di usion ff model. The resulting “working memory” system is robust, time and di usion weighting morphological parameters of metabolically efficient, and can help explain recent electro- the tissue, such as the ADD and axonal density, can be mea- physiological results. sured experimentally. In this work, AxCaliber was used to extract the ADD within the corpus callosum (CC) of the rat. Topology Regulates Source Separation in Using AxCaliber we were able to segment the CC to at least 3 Biologically Realistic Neural Networks distinct regions corresponding to the body, genu, and splenium of the CC. A narrow ADD with a mean of about 1 Barak E.,1 Eytan D.,2 Meir R.,2 and Zeevi Y. Y.2 micron characterized the genu and splenium while the body Israel Society for Neuroscience 9 of the CC had a much broader distribution with a mean of uine perceptual phenomenon, its underlying neural sub- about 4-5 microns. This segmentation resembles the known strates are not well understood. For example, the overall in- morphological arrangement of the CC as measured from his- tegrity of the visual system has never been assessed and it tology. Applications of AxCaliber are expected in longitudi- is not known whether differences in sensory-perceptual pro- nal studies designed to follow nerve growth in normal and cessing are associated with the condition. Here, we looked abnormal development, as well as in diagnosing disorders at visual evoked potentials (VEPs) to determine differences and diseases affecting specific populations of axons in the in sensory-perceptual processing using stimuli that differen- CNS and PNS. tially activate the magnocellular and parvocellular pathways of the visual system. High and low spatial frequency gratings Akt is differently activated in the amygdala-prefrontal (Gabors) and luminance-contrast squares were presented to cortex-insular cortices circuit in acquisition and 15 synesthetes and 15 controls. We report for the first time, extinction of CTA early sensory-perceptual differences in synesthetes. The differences were associated with stimuli that do not elicit synes- Bareni A., Maroun M., and Rosenblum K. thetic color experiences and were manifest in early C1 and P1 components of the visual evoked potential (VEP). The find- Department of Neurobiology and Ethology, Center of Brain ings were not confined exclusively to either magnocellular or and Behavior, University of Haifa, Israel parvocellular stimuli, but rather indicate widespread differences in the way that synesthetes process visual information In conditioned taste aversion (CTA) a single gustatory ex- during early time windows. perience (exposure to novel taste) is followed by visceral trauma. Consequently, the animal develops an aversion for the aversive taste. The memory of aversion is robust, how- Modulation of dendritic calcium spike by ever, repeated exposures to the taste without the association extracellular calcium concentration with the malaise leads to extinction of CTA. It is assumed 2 2 1,2 that consolidation and extinction of CTA are each subserved Bar-Yehuda D., Ben-Porat H., and Korngreen A. by different neuronal mechanism and various parts of the 1The Mina and Everard Faculty of Life Sciences, Israel brain are involved in these mechanisms. The neural circuit 2The Leslie and Susan Gonda Brain Research Center, that underlies the acquisition and the extinction of CTA in- Bar-Ilan University, Israel cludes the amygdala and the insular cortex. Recently research from our laboratory has shown that the ventromedial pre- It has been shown that in the apical dendrite of L5 pyrami- frontal cortex (vmPFC) has a role in extinction of CTA. In dal neurons, when a back-propagating action potential co- the current study, we examined the differential activation incides with distal synaptic input, a dendritic calcium spike of the phosphorylation levels of Akt, a serine/threonine ki- is generated, leading to the generation of a burst of action nase, which is a critical enzyme in signal transduction path- potentials at the soma. Many questions have been raised re- ways, in the amygdala-prefrontal cortex-insular cortices cir- garding the physiological role of this calcium spike. Lately, a cuit during acquisition and extinction of CTA. Our results different question has been raised whether the calcium con- show that following CTA acquistion there is an increased centration being used in the typical ACSF truly reflects the level of AKT phosphorylation in the amygdala, insular cor- concentration in the CSF. Recent studies have shown that the tex and the prefrontal cortex. In contrast, following extinc- calcium concentration in the ACSF is higher than in the CSF tion training there was a decrease of Akt phosphorylation in in vivo. We have performed in vitro recordings from acute the amygdala and PFC while no change was found in the IC. brain slices, using the whole-cell configuration of the patch- These results hint on the possibility that the amygdala-PFC- clamp technique in the current-clamp mode from L5 pyra- insular cortex circuit is differentially involved in acquisition midal neurons. Regenerative calcium spikes were recorded and extinction of CTA. and compared with calcium concentrations similar to the ACSF and CSF in the bath solution. Our results suggest that Differences in early visual processing in synesthesia: while the back-propagating action potential is robust under an ERP study reduced extracellular calcium concentration, the dendritic Barnett K. J.,1 Fox J. J.,2 Molholm S.,2 Kelly S. P.,2 calcium spike is suppressed by this modification. Shalgi S.,1 Mitchell K. J.,3 and Newell F. N.1 Lentiviral delivery of LMX1a into human 1Institute of Neuroscience (TCIN) and School of Psychology, Mesenchymal Stem Cells directs towards Trinity College, Dublin 2, Ireland dopaminergic differentiation 2Cognitive Neurophysiology Lab, Nathan Kline Institute for Psychiatric Research, USA Barzilay R.,1 Ben-Zur T.,1 Bulvik S.,2 Melamed E.,1 3Department of Genetics, Trinity College, Dublin 2, Ireland and Offen D.1

Stimuli that elicit synesthesia (e.g., letters of the alphabet) 1Neuroscience lab, Felsenstein Medical Research Center, activate cortical color regions of the brain, including V4. Sackler Faculty of Medicine, Tel Aviv University, Israel While it has been demonstrated that synesthesia is a gen- 2Laniado Medical Center, Netanya, Israel 10 Neural Plasticity

Human mesenchymal stem cells reside in the bone mar- neprilysin inhibition paradigm to analyze the brain patho- row and are known for their ability to differentiate along logical and cognitive effects which are induced by apoE4 and the mesenchymal lineage (fat, bone, and cartilage). Recent apoE3 at distinctive time intervals following activation of works suggest the possibility that these cells are also capa- the amyloid cascade and of the extent to which they corre- ble of differentiating towards the neuroectodermal lineage. late spatially and temporally with the accumulation of in- We aimed at inducing dopaminergic differentiation on hu- traneuronal A beta. This revealed that apoE4 stimulates iso- man mesenchymal stem cells as a possible source for au- form specifically the accumulation of intraneuronal A beta in tologous transplantation for Parkinsonian patients. Using hippocampal CA1 neurons. Furthermore, the accumulation lentiviral gene delivery, we sought to reprogram the bone of A beta in the CA1 neurons correlates spatially and tem- marrow derived mesenchymal stem cells towards dopamin- porarily (t 1/2∼1 week) with enhanced lysosomal activation ergic differentiation through delivery of LMX1a, which was and apoptosis of these neurons and with the occurrence of reported to be a key player in dopaminergic differentiation marked cognitive deficits. These findings render this model in both developmental animal models and embryonic stem uniquely suitable for detailed kinetic analysis of the early cells. Transduction of cells with fluorescent reporter genes stages of the amyloid cascade and of the biochemical mecha- confirmed efficiency of gene delivery. Upon incubation of the nisms underlying the effects thereon of apoE4 and other risk LMX1a transduced cells in differentiation medium we ob- factors of AD. served increased concentration of the LMX1a transcription factor in the cell nuclei. Several specific dopaminergic devel- Supported by The US-Israel Binational Foundation and the opmental genes were upregulated suggesting the generation Joseph and Inez Eichenbaum Foundation. of dopaminergic precursors derived from adult human bone marrow. Moreover, the transduced cells secreted significantly Secreted factor from mutant PC12 cells as higher level of dopamine in comparison to untransduced a potential element for neuronal survival cells. To our knowledge, this is the first time in which a factor involved in the natural dopaminergic neuron development Beltsov S. and Yaka R. directs adult stem cells towards the dopaminergic phenotype. Using ex vivo gene delivery to adult stem cells, our results Department of Pharmacology, School of Pharmacy, shed a new light on the molecular processes involved in adult The Hebrew University of Jerusalem, Israel stem cell dopaminergic differentiation, suggesting that the transcriptional cascade of adult stem cell dopaminegic dif- Rat pheochromocytoma (PC12) cells have been extensively ferentiation has parallel pathways to that of embryonic stem studied as a model for neuronal cell line since their first cells. cloning in 1976, because of their neuronal-like properties. Removal of the serum from the growth medium of PC12 Activation of the amyloid cascade in ApoE4 wild type (PC12-wt) cells induces cell death by apoptosis. transgenic mice induces neurodegeneration A mutant clone of PC12 cells (PC12-m), can survive up to resulting in marked cognitive deficits 5 days in a serum-free medium. Furthermore, it has been shown that PC12-m cells secrete an unknown factor that Belinson H.,1 Dolev I.,1 Lev D.,1 Masliah E.,2 1 prevents PC12-wt cells from serum deprivation-induced cell and Michaelson D. M. death; PC12-m cells were grown in a serum-free medium 1Department of Neurobiochemistry, Tel Aviv University, Israel for 5 days and the condition medium (CM) was collected. 2Department of Neurosciences & Pathology University of When PC12-wt cells were grown in CM, they survived for California San Diego, LaJolla Ca 92093-0624, USA up to 5 days. Here we show that the survival of PC12-wt cells in the CM was prevented when an inhibitor of the The allele E4 of apolipoprotein E (apoE4), which is the ma- TrkA receptor, K252a, was added together with the CM, jor genetic risk factor for Alzheimer’s disease (AD), is asso- thus showing that cell survival is mediated via TrkA recep- ciated histopathologically with elevated levels of brain amy- tor. This factor present in the CM is probably not NGF loid. This led to the suggestion that the pathological ef- (which previously has been shown to rescue PC12 cells from fects of apoE4 are mediated by cross talk interactions of serum deprivation-induced death), because boiling of the apoE4 with A beta and to the consequent accentuation of the CM for 10 minutes did not prevent PC12-wt survival ca- pathological effects of the amyloid cascade. The A beta re- pabilities, as opposed to boiling of serum-free medium with lated processes which are affected by apoE4 and the cellular NGF. Unlike NGF, acute treatment of PC12-wt cells with CM and molecular mechanisms which underlie their patholog- failed to induce ERK activity, suggesting that the secreted ical consequences are not known. We have recently shown factor acts via a mechanism different than NGF. Interest- that inhibition of the A beta degrading enzyme neprilysin ingly, CM from PC12-m cells also prevented cell death of by intracerebroventricular infusion of thiorphan into brains PC12-wt cells induced by high concentration of cocaine, in- of wild type apoE3 and apoE4 mice, results in a rapid and dependent of the TrkA receptor. These results suggest that similar increase of their total brain A beta levels. However, the CM has neuroprotective abilities; however, the signal- the nucleation and aggregation of A beta in these mice were ing pathways which underlie these abilities are different from markedly affected by apoE and were particularly and specifi- those induced by NGF, and dependent on the type of insult cally enhanced in the apoE4 mice. We presently employed the used. Israel Society for Neuroscience 11

Distinct pore properties of leak and voltage-activated Purpose potassium channels underlie their unique roles in electrical signaling The purpose is to evaluate the cerebral white matter quantitatively using diﬀusion tensor imaging (DTI) and high b- Ben Abou Y., Zilberberg N., and Yifrach O. value diﬀusion weighted imaging (DWI).

Department of Life Sciences, Zlotowski Center for Method Neuroscience, Ben-Gurion University, Israel MR protocol included T1, T2, DTI (b = 1000 s/mm2) and Voltage-activated (Kv) and leak (K2P) potassium channels high b-value DTI (b-values up to 12 000 s/mm2). Twenty- play key yet distinct roles in electrical signaling in the ner- three UMN ALS patients and 20 age match healthy volun- ff vous system. Here, we examined how di erences in the op- teers were scanned on a 3T GE MRI scanner. Diffusion tensor eration of the activation and slow inactivation pore gates of tracktography (DTT) was used and mean FA, Prob and Disp Kv and K2P channels underlie their unique roles in electri- were calculated for the motor and sensory fibers separately. cal signaling. Shaker Kv and KCNK0 leak channels demonstrate opposite closed and open pore conformational stability Results phenotypes, respectively. Replacement of the pore domain of the Shaker channel with that of KCNK0 resulted in a sub- On the data from axial images, reduced FA was detected in stantial stabilization of the open pore conformation. System- the study group compared to the control group (P<.05) in atic replacement of activation gate hydrophobic residues of both the motor and sensory fibers. Reduced FA, Prob, and in- the Shaker channel to the corresponding glycine residues of crease Disp values were also detected in the study group com- KCNK0 resulted in dramatic open-state stabilization effects. pared to the control group in the high b-value coronal data Complementary experiments revealed dramatic closed state set (P<.05 only for FA). Histogram analysis of FA, Prob, and stabilization effects. By using macroscopic and single chan- Disp revealed no differences between the two groups. No cor- nel recordings we were able to monitor the conformational relation was found between FA, Disp, and Prob values and states (whether closed or open) of both the activation and in- ALSFRS-R or with disease duration. Sub group of ALS pa- activation gates of KCNK0. Our results revealed that (1) leak tients with Buluar onset demonstrate significant correlation potassium channels also possess a lower activation gate, (2) between FA and Eigenvalues to disease duration. that the activation gate is an important determinant controlling the intrinsic conformational stability of the potassium Conclusion channel pore, (3) the lower activation and upper slow inacti- ff vation gates of leak channels cross-talk and (4) in contrast to This study shows that di usion tensor image is a sensitive Kv channels, where the two pore gates are negatively coupled, method to detect damage to the corticospinal tract. These that is, the opening of the lower activation gate stimulates methods may improve the early diagnosis of the disease and the closure of the upper slow inactivation gate, the two gates promote the appropriate treatment for the patients. In ad- are positively coupled in K2P channels. Our results demon- dition, also show sensory fibers impairment in ALS patients strate how basic thermodynamic properties of the potassium that has been reported previously only in few cases. channel pore, particularly, intrinsic conformational stability and coupling between the pore gates, underlie the specialized Immunotherapies for Alzheimer’s Disease roles of Kv and K2P channel families in electrical signaling. Ben Porata J., Terkieltaub D., Goren O., Yakov N., Abrameto J., Sharon N., Zaretsky I., White matter impairment in amyotrophic lateral Shaki-Loewenstein S., Hazum S., Gopher J., sclerosis (ALS): diffusion tensor imaging and high Ohayon T., and Eren R. b-value DWI study Intellect Neurosciences Ltd, Rehovot, Israel Ben Bashat D.,1 Drory V. E.,2,3 Artzi M.,1 Nefussy B.,2 Zachor T.,1 Assaf Y.,1,3 and Aizenstein O.1 The accumulation of amyloid-beta in the brain results in the formation of neurotoxic fibrillar intermediates, leading to a 1The Wohl Institute for Advanced Imaging, Tel Aviv Sourasky progressive, debilitating, ultimately fatal, neurodegenerative Medical Center, Israel cascade that results in Alzheimer’s disease (AD). Amyloid- 2ALS Clinic, Department of Neurology, Tel-Aviv Sourasky beta is generated by proteolytic cleavage of the ubiquitous Medical Center, Israel amyloid precursor protein (APP) which has important phys- 3Tel Aviv Universities, Israel iological functions. Current drug treatments for AD provide Background symptomatic relief of cognitive and memory impairments without addressing neurodegeneration and the underlying Amyotrophic lateral sclerosis (ALS) is a fatal neurodegener- causes of the disease. Immunotherapy emerged recently as ative disorder of the motor system causing damage to both an approach to prevent amyloid-beta accumulation. Studies the upper and lower motor neurons (UMN/LMN). To date, using AD transgenic mice as well as clinical trials provide en- there are no imaging techniques available for objectively as- couraging data for immunotherapy as an effective approach sessing the UMN damage. to reduce amyloid-beta toxicity with the potential to slow 12 Neural Plasticity or arrest disease progression, provided that key safety issues 1Department of Anatomy, Sackler Faculty of Medicine, are addressed and adverse reactions are reduced. The key to Tel Aviv University, Israel develop safe and effective AD immunotherapies lies in de- 2Department of Psychiatry, Schneider Children’s Medical signing vaccines and antibodies that are highly specific for Center of Israel, Petah Tikva, Israel amyloid-beta, do not cross react with endogenous functional 3Department of Human Microbiology, Sackler Faculty of proteins such as APP and do not activate cytotoxic T-cell Medicine, Tel Aviv University, Israel responses. Our immunotherapy programs consist of “free- 4Department of Hemato-Oncology, Schneider Children’s end specific” antibodies and chimeric-peptide vaccines that Medical Center of Israel, Petah Tikva, Israel recognize specifically the free N-terminus or C-terminus of amyloid-beta peptide and, consequently, are capable of dis- Background criminating between toxic amyloid-beta peptides and functional endogenous APP peptides. In addition, our vaccines It is known that the neuroendocrine system and the auto- use very short “free-end” peptide fragments that are devoid nomic nervous system are regulators of brain-immune inter- of harmful T-cell epitopes. This “free-end specific” immu- action. However, the functional significance of this interac- nization concept is likely to minimize the risks for an autoim- tion under a variety of conditions is not fully understood. mune response and has the therapeutic potential to promote clearance of amyloid-beta in a safe and effective manner. Objective Exploring Alpha Correlates In The Brain–An EEG-fMRI Study The objective is to investigate the effect of stress paradigm on behavioral tests, immune parameters, and tumor progression 1,2 1 1 Ben Simon E., Podlisky I., Zhdanov A., and survival of lymphoma-bearing mice. Papo D.,1 and Hendler T.1,2

1Functional Brain Imaging Unit, Wohl Institute for Advanced Methods Imaging, TASMC, Israel 2Sackler Faculty of Medicine, Tel Aviv University, Israel C3H mice were either exposed to an electric shock followed by 3 reminders (once a week) or were left untreated. Follow- The frequency of electrical brain activity is commonly ing stress paradigm mice behavior was tested in elevated plus thought to be functionally meaningful. However, exactly maze, staircase, hot plate and open field, and NK cell activ- what functional brain networks mediate activity at given fre- ity was measured. In addition, mice were tested for prolifera- quency bands remains largely unknown. The alpha rhythm tion of lymphocytes, spleen weight and number of leucocytes is considered the hallmark of the brain resting state and can in spleen. Different mice were vaccinated twice with the im- be modulated by simply opening or closing eyes. This study munoglobulin of the B-cell lymphoma 38C-13 and antiidio- aimed to match individually characterized EEG rhythms and type antibodies in sera of mice were determined by ELISA. simultaneously acquired whole brain functional magnetic Other mice were inoculated with tumor cells and monitored resonance (fMRI) BOLD activation associated with spon- for tumor development and for survival. taneous variations of the alpha rhythm (8–12 Hz), Subjects were instructed to close/open their eyes every 30 seconds. EEG activity was recorded from 32 electrodes simultaneously Results with whole brain fMRI in a 3T GE scanner. Activity in the alpha band was defined for each subject. Electrodes at which No major differences were found in behavior between the activity was maximal were then selected. The signal filtered stressed mice and control mice. However, significant dif- at the individually-defined frequency ranges was then con- ference were found in immunological and cancer parame- volved with the corresponding fMRI signal and used as a ters. The mice exposed to stress paradigm had higher cy- regressor for statistical parametric mapping. Preliminary re- tolytic activity than did the standard group (P<.05). When sults show that eyes closed and open are associated with dis- mice were immunized with an idiotype-vaccine, those ex- tinct widely distributed activation patterns. Preliminary re- posed to stress paradigm produced higher levels of antiid- sults for alpha band-related BOLD signals showed differen- iotype antibodies (P<.01). In addition, proliferation in tial peak activation distributions in occipital and frontal ar- the presence of mitogenes was higher in exposed group, so eas. Using EEG based fMRI analysis we then showed that did number of leucocytes in spleen. Exposed mice revealed the a priori defined oscillatory bands are associated with dis- attenuated tumor growth (P<.05), with no difference in tinct widely distributed activation patterns. The significance survival. of combined measurements will be discussed. Conclusions Acute stress in mice; alteration in behavior, immunity and cancer development Stress paradigm revealed significant immune changes and at- Benaroya-Milshtein N.,1,2 Hollander N.,3 Apter A.,2 tenuated tumor development, while no changes were found Yaniv I.,4 Haberman Y.,1 Halpert H.,1 and Pick C. G.1 in behavior or survival after tumor cells inoculation. Israel Society for Neuroscience 13

Evaluation of the interplay between procedural function (referred to as epileptogenesis) that ultimately lead learning and declarative learning systems revealed in to chronic epilepsy. One striking change is the upregulation a double-dissociation experiment among Alzheimer of CaV3.2 T-type calcium current, which causes many hip- disease and Parkinson disease patients pocampal pyramidal cells to display intrinsic bursting behavior. The processes which couple SE to T current upregulation Ben-Mair E.,1 Schonberg T.,1 Inzelberg R.,2 and Joel D.1 are not known. We hypothesized before that SE-induced ac-

1 cumulation of zinc may play a role in these processes and Department of Psychology, Tel Aviv University, we have found, that intracerebroventricular injection of zinc Ramat-Aviv, Tel Aviv 69978, Israel 2 transforms about 60% of CA1 pyramidal cells into burst- Rappaport Faculty of Medicine, Technion, Haifa, Israel ing neurons. Therefore, we examined here whether zinc also induces an increase in T current density in these neurons. The division of memory systems into declarative and proce- We injected saline with or without ZnCl2 (45 μM) into the dural is well established. The declarative system is involved right ventricles of adult Sabra rats. Zinc-induced neurode- in the acquisition and use of episodic and semantic mem- generation precluded recordings in the right (ipsilateral) hip- ory, and is related to the hippocampal system. The proce- pocampi. Sharp electrodes current-clamp, whole-cell patch- dural system is involved in the acquisition of habits and clamp recordings of T currents and immunostainings for skills, and depends on the striatum. Although the two sys- CaV3.2 were performed in slices from the contralateral hip- tems are thought to interact, the nature of interaction is not pocampi. We found that the bursting activity in CA1 pyra- well understood. Animal studies have suggested that under midal cells was suppressed by specific blockage of the T-type some conditions the two systems may interfere with each calcium current in 1/3 of the tested cells. Two days following other. Specifically, rats sustaining lesions to the hippocam- zinc injection the densitiy of T current was markedly (3-4 pus performed better than intact rats in a procedural task. fold) increased in approximately 1/3 of the neurons com- The present study tested whether such interference may also pared to neurons in the control group. Congruently, im- occur in humans. Healthy subjects, patients with Parkinson’s munostainings disclosed an increase in CaV3.2 abundance in disease (PD), in which the dopaminergic input to the stria- CA1 pyramidal cells in hippocampi from zinc injected rats. tum degenerates, and patients with mild Alzheimer disease Our findings show that an increase in brain zinc causes up- (AD), in which the hippocampal system is the first to degen- regulation of CaV3.2 abundance leading to an increase in T erate, were tested in a card betting task. This task is unique current and associated neuronal bursting. They support our in that about half of normal subjects do not acquire it, sug- hypothesis that an increase in free zinc during or shortly af- gesting that it is particularly sensitive to interference arising ter SE may contribute to epileptogenesis. These findings have from the declarative system. It was therefore hypothesized therapeutic implications for the prevention of epilepsy fol- that whereas PD patients will not be able to acquire the task, lowing brain insults. AD patients will perform better than controls, due to a defi- n = cient declarative system. AD patients ( 16), PD patients Supported by SFB TR3, BMBF, Humboldt Foundation and n = n = ( 17) and controls ( 21) performed the card bet- MOST. ting task as well as immediate and delayed recognition tasks that assess declarative functioning. PD patients were indeed Inhibitory effect of kinins on microglial inflammation impaired on the card betting task and AD patients were impaired on the “declarative” tasks. However, in contrast to our Ben-Shmuel S. and Fleisher-Berkovich S. hypothesis, AD patients did not perform better than controls on the card betting task. In summary, this study adds Department of Clinical Pharmacology, Ben Gurion University to previous demonstrations of a double dissociation between of the Negev, P.O. 653, Beer-Sheva, Israel the declarative and procedural systems in humans. However, there is no evidence for interference between these two sys- Increasing evidence suggests that inflammatory mechanisms tems in the acquisition of the card betting task. are a crucial component in neurodegenerative diseases, such as Alzheimer’s disease (AD), and may significantly contribute to the disease progression. One of the pathological hall- Zinc-induced Upregulation of T-type Calcium marks of AD is chronic microglial activation and conse- Currents in the Hippocampus quent over-production of proinflammatory mediators such Benninger F.,1 Ekstein D.,1,2 Becker A.,3 and Yaari Y.1 as prostaglandins, cytokines and nitric oxide (NO). The latter, at high concentrations, may be neurotoxic and can be 1Departments of Physiology, Hebrew University-Hadassah involved in the neurodegeneration process. Kinins are po- School of Medicine, Jerusalem, Israel tent stimulators of the production and release of NO in 2Departments of Neurology, Hebrew University-Hadassah many cells. Whether this is universal, remains to be investi- School of Medicine, Jerusalem, Israel gated. Recent reports suggest a possible neuroprotective role 3Department of Neuropathology, University of Bonn Medical of bradykinin (BK), probably mediated by microglial cells. Center, Bonn, Germany The aim of the present study was to investigate the role of BK in the regulation of basal and lipopolysaccharide (LPS)- A single episode of status epilepticus (SE) caused by pilo- induced NO synthesis in a microglial cell line, BV2, and carpine, triggers multiple changes in neuronal structure and to assess the involvement of each of the two BK receptors, 14 Neural Plasticity

B1 and B2, in this effect. Long-term (24–48 hours) exposure Face Recognition Inspired by the Visual Cortex of cells to BK (10 nM) reduced basal NO release by 75%. B1 1 2 1 receptor agonist, [Lys-des-Arg9]-BK, had the same effect as Berkovich E., Pratt H., and Gur M. BK, 70% reduction of NO synthesis at a concentration of 1Department of Biomedical Engineering, Technion, Israel 10 nM. BK also attenuated LPS-induced NO production by 2Evoked Potentials Laboratory, Technion, Israel 30% and 50% at concentrations of 1 nM and 10 nM, respectively. The B1 receptor agonist also attenuated LPS-induces Object recognition is one of the main functions of the hu- NO production by 30% at 1 nM. These preliminary results man visual system. It is performed intuitively and sponta- imply a novel neuroprotective role of BK via attenuation of neously. Unlike computer vision systems, the human visual NO released from microglial cells under both basal and in- system is known for its ability to identify an object after spa- flammatory conditions. tial transformation and change of viewing and illumination conditions. Mimicking the visual system can therefore en- This research was supported by the Israel Science Foundation hance computational object recognition. Hence, in this re- (Grant no. 349/07). search, low-level features of the image are extracted by appropriate filters, in a manner similar to the human visual Cone-shaped lysophospholipids modulate system. Previously, we have shown that our biologically mo- voltage-gated calcium channel currents in tivated model produces improved categorization results (e.g., pituitary cells distinguishing between cars, faces, etc.). In the current work we further analyze the contribution of our biological fea- Ben-Zeev G. and Nussinovitch I. tures to the recognition task. We demonstrate our results on the popular problem of face recognition. We analyze color Department of Anatomy and Cell Biology, Hebrew University face images (R,G,B channels) and show that recognition per- Medical School, Jerusalem, Israel formance improves as more biological principles are incor- porated into the model. Worst recognition results are ob- Lysophospholipids (LPLs) are lipophilic molecules consist- tained when the images are processed as grayscale (inten- ing of a hydrophilic head and a hydrophobic tail. LPLs con- sity channel); a significant improvement in performance is taining a large hydrophilic head and a thin hydrophobic tail achieved by representing images in the biological color-space were defined as cones. It was hypothesized that incorpora- by adding two opponent-color channels (B/Y, R/G) to the tion of cones into the outer leaflet of the phospholipid bi- intensity channel. Finally, we use the complete ensemble of layer increases membrane tension and it was demonstrated biological features—intensity and opponent-color channels that cone-shaped LPLs alter the gating of mechanosensi- shaped by appropriate filters at various scales and orienta- tive ion channels. Previous studies demonstrated modulation tions. On the ensemble of these features, we apply, iteratively, of voltage-gated calcium channels (VGCC) by membrane biologically inspired Boosting. At every iteration, the biolog- stretch. We therefore examined the effects of the cone-shaped ical features are used to construct weak (face) learners on the molecule, Lysophosphatidylchloline (LPC), on VGCC in pi- training data. The best weak learner is weighted by its accu- tuitary cells. Our findings may be summarized as follows: (1) racy and then added to the final strong learner. At the succes- LPC (10–30 μM) differentially suppressed L-type and T-type sive iteration, the training data is reweighted: examples that calcium channel currents (IL and IT, resp.); the effects on IT are misclassified gain weight and examples that are classified were faster and more prominent than the effects on IL; (2) correctly lose weight. This technique results in the best recog- the effects of LPC on IL started after long delays (50–100 sec- nition performance. onds), exhibited slow onset kinetics and were reversible only after washout with BSA; (3) the effects of LPC on IL were Implicit and explicit morphologically both dose-dependent and voltage-dependent with a right- related activation ward shift in the activation curve of about 9 mV; (4) the ef- Bick A. S.,1 Frost R.,2 and Goelman G.3 fects of LPC on IL persisted after block of G-proteins with GDPbetaS and after block of PKC with GF 109203X; (5) the 1ICNC, Hebrew University, Jerusalem, Israel effects of LPC on IL were mimicked by lysophosphatidyli- 2Psychology, Hebrew University, Jerusalem, Israel nositol (LPI), a negatively charged cone-shaped lipophilic 3Medical Biophysics, Hadassah Hebrew University Hospital, molecule; (6) the effects of LPC on IL were not mimicked Jerusalem, Israel by a short chain LPC (C6:0) and by phosphatidylcholine, a cylindrical-shaped lipophilic molecule. In summary, our re- A dispute exists as to whether morphology is a discrete and sults show that cone-shaped lipophilic molecules (LPC and independent element of lexical structure or whether it simply LPI) suppress VGCC in pituitary cells and that this suppres- reflects a fine-tuning of the system to the statistical correla- sion is independent on the polarity of the hydrophilic head. tion that exists among orthographic and semantic proper- Our results also suggest that incorporation of LPC and LPI ties of words. Imaging studies in English failed to show un- into the phospholipid bilayer underlies this suppression, and equivocal morphological activation that is independent of se- that molecular shape is a determinant in this suppression. mantic or orthographic activation (Devlin et al., 2004). In Hebrew, Cognitive research has revealed that morphologi- Supported by the Israel Science Foundation Grant 826/04. cal decomposition is an important component of reading Israel Society for Neuroscience 15

(Frost et al., 2000), and using fMRI we identified areas in on the upper or lower half of the screen. We administered 3 the brain, the lMFG and lIPS, activated distinctly during ex- equivalent conditions: NR, RU—the reference was always at plicit morphological processing (Bick et al., in press). In this the upper half of the screen, RU or L—the reference was ei- fMRI study, we aimed to replicate our results using an im- ther at the upper or the lower half of the screen. In the par- plicit task. This would further establish our results and show allel paradigm only the RU condition was better than NR, that morphological processing is automatic in reading He- indicating that spatial consistency is crucial for reference uti- brew. Words were presented in the mask priming paradigm lization in the visual domain. These findings show that re- (Forster & Davis, 1984) and subjects perform a lexical deci- peating a reference improves resolution only under specific sion task. Subjects were not aware of the presented prime. conditions. Temporal consistency is crucial in the auditory The manipulation was the relation between prime and tar- modality, whereas spatial consistency is crucial in the visual get. We used primes that were morphologically related, se- modality. mantically related and orthographically related to targets. In the morphology condition we used both words semantically The study was supported by ISF Center of Excellence grant and related to the target and words sharing the same root but bytheInstitueofPsychobiology. having quite distinct meanings. We found different patterns of activity in the different priming conditions. In the lMFG The effects of music background on sleep efficiency, and lIPS activation was significantly reduced when the prime anxiety and depression in Schizophrenia patients was morphologically related to the target. This effect was 1 2 2 2 not found in the semantic or orthographic condition. Fur- Bloch B., Haliba Y., Vadas L., Ben Shitrit Y., 2 2 2 thermore this attenuation was not influenced by the seman- Ehood Golz A., Shelahavich K., Tangi R., 2 2 1* 2* tic transparency of the morphological prime. These results Tavakuli H. R., Ziv N., Kremer I., and Haimov I. strongly resemble our previous results and reflect the impor- 1Psychiatric Department, Emek Medical Center, Afula, Israel tance of morphological processing in Hebrew reading. Scans 2Department of Behavioral Sciences, The Max Stern were performed in Hadassah Hebrew University Hospital, Academic College of Emek Yizreel, Israel Israel. Introduction Supported by Center for Complexity Science. Disturbed sleep is a common complaint among Schizophre- On the implicit usage of repeated reference nia patients. Since previous studies have demonstrated treat- stimuli in the visual modality ment resistance for sleep-medication treatment for insomnia Biron T.2,3 and Ahissar M.1,2 in these patients, the aim of the present study was to examine the effects of music background as treatment for insomnia in 1Interdisciplinary Center for Neural Computation, Israel Schizophrenia patients. 2Department of Psychology, Israel 3Neurobiology Department, Hadassah Medical School, Israel Methods

Most psychophysical tasks assess performance around a ref- Twenty four Schizophrenia patients, who had no other ma- erence stimulus. Previously (Lubin and Ahissar, 2005), we jor psychiatric, sleep, or neurological disorders, participated studied which types of reference repetitions improve reso- in the study (mean age = 45.67, SD = 9.6, 13 males and 11 lution in auditory 2-tone frequency discrimination. We had women). The study comprised one 7-day, running-in period, 3 conditions: no reference (NR)—no repetition across tri- followed by one 7-day experimental period. The treatment als; reference 1st (R1st)—reference tone (1000 Hz) was pre- was music background at desired bedtime. During each of sented in the first interval; reference 1st or 2nd (R1st-2nd)— these two experimental periods, subjects’ sleep was continu- reference tone was presented in the 1st or in the 2nd interval. ously monitored with a wrist actigraph (Ambulatory Moni- Surprisingly, compared to the NR, listeners’ frequency res- toring, Inc.) and subjects were asked to fill out several ques- olution was significantly improved only in R1st, indicating tionnaires concerned with a wide spectrum of issues, such as that consistent temporal position is crucial for reference uti- depression, anxiety, and life satisfaction. lization. We now asked whether consistency of temporal position is also crucial in the visual domain. We administered a Results spatial frequency discrimination paradigm analogous to the auditory paradigm, asking which of 2 sequentially presented A paired-sample t-test was conducted, comparing objective grating stimuli is denser. We used the same conditions: NR, sleep parameters manifested by patients with music back- R1st (0.5 c/deg) and R1st–2nd. In contrast to the auditory ground at desired bedtime and without music exposure. A results, the 2 reference conditions were performed similarly, significant difference was found in sleep latency (t(23) = and significantly better (7% ± 1.3) than the NR (22% ± 3.0) 3.01, P<.006), showing shorter sleep latency when music condition, indicating that temporal position is not crucial. background was played (21.04 ± 14.6) than when it was not We further assessed a simultaneous frequency discrimination (37.01±32.4). A significant difference was also found in sleep paradigm, in which the gratings were presented simultane- efficiency (t(23) =−3.35, P<.003), showing higher sleep ously and subjects were asked whether the denser grating was efficiency when music background was played (86.0 ± 15.5) 16 Neural Plasticity than when it was not (82.44 ± 18.3). A significant difference Department of Neurobiochemistry, Faculty of Life-Sciences, was found in depression level (t(23) = 2.96, P<.007), show- Tel Aviv University, Israel ing lower depression level after background music was played (12.29 ± 12.1) than when it was not (15.25 ± 10.6). No sig- The brain localization of cognitive functions is limited to nificant differences were found in anxiety level (t(23) = .22, invasive lesion or electrophysiological studies. Noninvasive P>.05), nor in life satisfaction (t(23) = 1.28, P>.05). imaging techniques such as functional magnetic resonance imaging (MRI) are less informative in rodents due to the use Conclusion of anesthetics. In this work we used a novel MRI-behavior correlation framework for localization of cognitive perfor- Overall, the findings imply the beneficial effect of music mance in rats. Thirty one rats underwent two MRI ses- background as treatment for insomnia in Schizophrenia pa- sions (at 7T) at ages of 9 and 12 months (MRI1 and MRI2, tients. resp.). The MRI session included a diffusion tensor imaging (DTI) protocol from which the fractional anisotropy The last two authors contributed equally to this research. (FA) and apparent diffusion coefficient (ADC) maps were extracted. While the FA is more sensitive to white matter the Integrating telemetry data in toxicological ADC represent both gray matter and white matter. Between studies: The effect of chronic exposure of rats to the two MRI sessions the rats performed a 6-day Morris wa- low doses of VX ter maze test. From the water maze we used the latency of the rats to reach the platform in the first (d1), fifth (d5), Bloch-Shiderman E., Rabinovitz I., Egoz I., Kapon J., and sixth day (d6) in which the platform was removed (re- Raveh L., Grauer E., and Allon N. versal trial). The comparison between the two imaging ses- Department of Pharmacology, Israel Institute for Biological sions revealed a significant FA and ADC signal changes in Research, Ness Ziona, Israel the hippocampus. Correlation analysis between the FA/ADC indices of MRI1 with latency of d1, d5, and d6 were local- Organophosphorus (OP) warfare nerve agents are highly ized at the amygdala, hippocampus and caudate/putamen re- toxic compounds that irreversibly inhibit cholinesterases gions, respectively. Correlation analysis between the FA/ADC (ChE). Inhibition of ChE results in the accumulation of indices of MRI2 with latency of d1, d5, and d6 was not local- acetylcholine in the synaptic cleft, leading to excessive stimu- ized to any specific region. These results manifest the differ- lation of cholinergic receptors. Following exposure to high ent cortical domains that affect the behavior at the different and lethal OP doses, signs of toxicity such as salivation, days of the water maze; while in d1 stress factors may con- tremors, convulsions and seizures, respiratory failure and ul- trol the performance of the rat, spatial memory skills and timately death are seen. Following exposure to lower sub- decision making affect the d5 and d6 performance. In addi- lethal OP doses none of these severe signs are observed. tion the fact that between the MRI sessions the hippocam- Therefore, it is impossible to elucidate any significant effect pus showed significant signal change may indicate on the following exposure to sub-lethal doses using the standard plasticity changes that this region underwent following the toxicity data. Comprehensive series of studies have shown Morris water maze. To conclude, MRI-behavioral correla- to have long-term neurological and psychological disorders tions can be used for localization of cognitive functions in (namely insomnia) following sub-lethal OP doses in hu- rodents. mans. Since the data suggested a continuous deterioration in the circadian rhythm, it was very challenging, technolog- Optimal multi-modal state estimation by neural ically and methodologically, to find a suitable marker for networks based on recursive spike train decoding such insult in an animal model. In this study we present an approach of measuring alterations in the circadian rhythm Bobrowski O., Meir R., and Eldar Y. C. body temperature and changes in ECoG activity by utilizing telemetry following chronic, sub-lethal doses of the nerve Department of Electrical Engineering, Technion, Israel agent VX. VX was administrated via Alzet mini osmotic pumps implanted in the rats for one month. Data was col- It is becoming increasingly evident that organisms acting in lected continuously 24 h/day during the 3 days preexposure uncertain dynamical environments employ exact or approx- and the following 1 month of VX exposure. Fast Fourier imate Bayesian statistical calculations in order to continu- transform spectrum analysis was performed for 30 s period, ously estimate the environmental state and integrate infor- every 3 hours of the EcoG recordings. Changes in circadian mation from multiple sensory modalities. What is less clear rhythm, as well as changes in individual brain wave were de- is how these putative computations are implemented by cor- tected. This approach might elucidate the potential damage tical neural networks. We show how optimal real-time state caused by chronic, low-dose OP exposure. estimation based on multi-modal sensory information may be effectively implemented by neural networks decoding sen- Localization of cognitive function in rats with sory spikes. We demonstrate the efficacy of the approach on magnetic resonance imaging static decision problems as well as on dynamic tracking problems, and relate the properties of optimal tuning curves to Blumenfeld-Katzir T. and Assaf Y. the properties of the environment. Israel Society for Neuroscience 17

Immunotherapy targeting pathologically disappears after few seconds. Following (100 milliseconds) phosphorylated tau conformers in a tangle Observers’ report of disappearance, a high-contrast Gabor mouse model probe was presented, and the target was removed within 200– 600 milliseconds. The probe often caused the reappearance Boimel M.,1 Grigoriadis N.,2 Lourbopoulos A.,2 1 1 of the invisible target within the limited trial time. Surpris- Abramsky O., and Rosenmann H. ingly, we found low reappearance rates when probes were 1The Department of Neurology, Hadassah University not in the proximity of the target or when orthogonal to it, Hospital, Jerusalem, Israel even when proximal. High reappearance rates were observed 2The Department of Neurology, AHEPA University Hospital, with probes proximal and similar to the target. Plaid tar- Thessaloniki, Greece gets made of superimposed orthogonal Gabor patches reap- peared when probes included only one component, but plaid While immunotherapy targeting amyloid-β has been in- probes were not very effective with component targets. The tensively investigated, only little is known regarding im- results show that subconscious objects preserve their loca- munotherapy targeting tau aggregates (neurofibrillary- tion and component-orientation and demonstrate that vi- tangles, NFTs), a major neuropathology in Alzheimer’s- sual processes sensitive to proximity and feature-similarity disease (AD) and tauopathies. We reported recently the haz- operate across the boundary of awareness. By controlling ardous potential of immunizing mice with full length re- the duration of target presentation we found that “reacti- combinant tau for targeting host normal tau protein, in- vating” the target may take 200–400 milliseconds, depending ducing neurological deficits and NFT-pathology. Here we on the depth of suppression. The asymmetric interaction be- investigated the effect of immunotherapy targeting specifi- tween visible and invisible plaids suggests that invisible ob- cally pathological tau conformers (phosphorylated, P) in a jects break into their feature components. NFT-mouse model. The results are of special interest since last month it has been published that using a similar ap- Training and behavioral recovery after proach by immunizing with peptide tau-P-Ser396,404 re- hippocampal lesion are coupled with changes duced robustly NFTs in NFT-mice (Asuni 2007). We im- in the pattern of connectivity munized NFT-mice with a mixture of P-tau peptides related to NFTs of AD/tauopathy patients and mice (tau- Boucard A., Micheau J., and Nogues` X. P-Ser202,Thre205, tau-P-Thre212,Ser214, tau-P-Thre221) Center for Cognitive and Integrative Neuroscience, with complete Freund’s adjuvant and pertussis. The mice University of Bordeaux, Paris, France were examined for clinical neurological deficits, and effect on NFT-burden. No neurological deficits were noted follow- We have previously shown that the activities of the brain ing tau-P-immunotherapy at least for 8 months. Reduced structures making up the memory systems defined by White Gallyas staining relative to controls (∼20%; P = .02), indi- and MacDonald (2002) are mainly correlated with the hip- cating a reduced NFT-burden, was detected. Some similar pocampus in the place condition of a water escape task, trend, yet smaller, was noted in IHC using AT8 and AT180 whereas they are correlated with the amygdala in the cue con- Abs (recognizing NFT-related P-tau), but did not reach a dition. This demonstrates a rearrangement of the functional statistic significance. To conclude, our results suggest a de- connectivity depending on the learning condition and sug- crease in NFT-burden following tau-P-immunotherapy (tau- gests that the activation of a memory system should be de- P-202,205,212,214,221), mostly demonstrated by Gallyas scribed as the focusing of functional connectivity toward the staining, but less by NFT-related IHC. The effect seems less central structure of the system. This may explain how several robust than that reported with tau-P396,404. This may be re- memory systems can share the same structures while remain- lated to the different tau-P peptides and immunization pro- ing independent. Della-Maggiore and coll. (2000) showed tocols used, or may point to the limited effectiveness of tau- that age-related alteration to the system sustaining delayed P-immunotherapeutic approach. Moreover, the lack of clin- visual discrimination could be compensated by the reconfig- ical deficits points that these specific peptide immunogens uration of the pattern of connectivity. Indeed, whereas the are encephalitogenic, encouraging further study of their anti- performances of young and old subjects were comparable, NFT potential. the activated cerebral networks were different. Although, this change in connectivity may be due to the use of a differ- Asymmetric visual interactions across ent strategy, this study gives an insight into understanding the boundary of awareness how decreasing cognitive resources due to age (or pathology) may be compensated. To support this concept, we induced Bonneh Y. S. and Sagi D. dorsohippocampal lesions to mice. Sham- and hippocampal- The Weizmann Institute of Science, Israel lesioned rodents were submitted to the place learning condition in the water cross-maze. Though impaired during the Motion-induced-blindness (MIB), Bonneh et al., Nature first three days, lesioned mice had the same level of perfor- 2001, was used to examine the accessible properties of high- mance than the sham-mice on the fifth day. We hypothesize contrast visual objects which are not consciously available. that this behavioural recuperation would be coupled with a Stimuli consisted of a static Gabor target embedded in a ro- change in the pattern of connectivity. The activities of mice tating grid. Under such conditions, the target perceptually brain structures are evaluated by counting the number of Zif 18 Neural Plasticity

268 immunoreactive cells after training in the place condi- 1Department of Psychology, Tel Aviv University, Israel tion of the aquatic cross-maze. By using structural equation 2Department of Biotechnology and Microbiology, modelling, the present study investigates how the pattern of Tel Aviv University, Israel effective connectivity induced by learning is changed face to 3Department of Microbiology and Immunology, the lesion of the hippocampus. University of Oklahoma, Okla, USA A poststreptococcal autoimmune process has been suggested DA inhibits mitochondrial membrane potential to be involved in the pathogenesis of a subgroup of children possibly through its interaction with complex I: with tics and obsessive compulsive disorder (OCD), iden- implications to DA related pathologies tified by the acronym PANDAS for Pediatric Autoimmune Neuropsychiatric Disorder Associated with Strepptococcal Brenner-Lavie H., Klein E., and Ben-Shachar D. infection. It has been suggested that antibodies produced against group A beta-hemolytic streptococci (GABHS) cross Laboratory of Psychobiology, B. Rappaport Faculty of react with neural cells, in a process involving molecular Medicine, Technion, Israel mimicry. Although PANDAS has received much attention in recent years, no study to date assessed compulsive-like be- Dopamine is suggested as a prominent etiological factor in haviors in an animal model of GABHS-related neuropsychi- several neuropsychiatric disorders such as Parkinson’s disease atric symptoms. The aim of the present study was therefore and schizophrenia. In such dopamine related pathologies mi- to test the hypothesis that group A streptococcal infection tochondrial dysfunction has been reported. Notably, mito- may lead to the emergence of OCD. To this end, Lewis rats chondria are target organelles for dopamine by the virtue were immunized with an extract prepared from GABHS, and of the fact that MAO, the main metabolizing enzyme of their compulsive behavior was assessed using two rat mod- dopamine, is located on their outer membrane. We have els of OCD, namely, the signal attenuation model and the recently demonstrated that dopamine reversibly inhibited induced-grooming assay. Sera taken from rats immunized complex I activity in isolated disrupted mitochondria. In or- with GABHS extract demonstrated stronger immuno reac- dertoinvestigatewhetherDA-complexIinteractionaffects tivity to streptococcus A and to neural tissue compared to mitochondrial function in viable cells, we studied the effect sera of control rats and in addition induced high levels of a of DA on mitochondrial membrane potential as a marker calcium/calmodulin-dependent protein (CaM) kinase activ- for the oxidative phosphorylation activity and mitochon- ity in human neuroblastoma cells. Antianibodies immuno- drial respiration in intact viable human neuroblastoma SH- labeling was stronger in the striatum and thalamus of im- SY5Y cells. DA significantly dissipated mitochondrial mem- munized rats compared to control rats (control rats’ brain brane potential and inhibited mitochondrial respiration in showed low level, if any, of anti-IgG immunolabeling). In cells, similarly to complex I inhibitor, rotenone. Complex parallel, rats immunized with GABHS antigens tended to I-DA interaction induced mitochondrial dysfunction as by- show increased compulsivity in two animal models of OCD. passing complex I of the respiratory system prevented the These preliminary results suggest that immunizing rats with DA induced depolarization of mitochondrial membrane po- GABHS extract can lead to the emergence of “compulsive” tential as well as the reduction in the respiration rate. Un- behavior. like complex I, DA did not inhibit complexes II, IV and V activities in disrupted mitochondria. Abnormal interaction Global leukocyte DNA methylation in between dopamine and mitochondrial complex I was ob- schizophrenia patients served in schizophrenia, as in patients dopamine inhibited complex I activity twice as much as that of control subjects Bromberg A.,1 Levine J.,1,2 Nemetz B.,2 or of patients with affective disorders. Notably, antipsychotic Belmaker R.,1,2 and Agam G.1 drugs but not antidepressants inhibit mitochondrial respira- 1 tion through complex I. The present study suggests that DA Psychiatry Research Unit, Faculty of Health Sciences, affects mitochondrial function through its interaction with Ben-Gurion University of the Negev, Beer-Sheva, Israel 2 complex I of the oxidative phosphorylation system. We fur- Beer-Sheva Mental Health Center, Israel ther hypothesize that the interaction between DA and mito- Meta-analysis recently suggested that a 5μM increase in chondria is associated with mitochondrial dysfunction ob- homocysteine is associated with a 70% higher risk for served in DA-related neuropsychiatric disorders, such as in schizophrenia. Elevated homocysteine is reported to alter schizophrenia. macromolecule methylation. We studied whether elevated plasma homocysteine levels in schizophrenia are associ- SupportedbytheChiefScientistIsraelMinistryofHealth. ated with altered global DNA-methylation. DNA was extracted from peripheral blood leukocytes of 28 schizophre- The possible association between streptococcus nia patients versus 26 matched healthy controls. Percent group A infection and the emergence of obsessive of global genome DNA-methylation was measured using compulsive disorder the cytosine-extension method. Homocysteine levels were higher in schizophrenia patients than in controls (15.8 μM Brimberg L.,1 Benhar I.,2 Cunningham M.,3 and Joel D.1 ± 10.5 versus 10.6 ± 2.7, P = .016). No difference in global Israel Society for Neuroscience 19

DNA methylation between schizophrenia patients and con- recorded the cellular response in acute brain slices from rats trol subjects was found (74.0% ± 14.8 versus 69.4±22.0, P = using the BG whole-cell configuration of the patch-clamp .31). A significant interaction between diagnosis and smok- technique. We present characterization of several types of ing on DNA methylation was obtained (F = 6.8, df = 1, 47, cells in the GP using whole-cell current clamp protocols and P = .032). Although leukocytes may be a useful cell model the effect of the stimulation on the spiking pattern of these toevaluateepigeneticchangessuchasglobalDNAmethyla- cells. The analysis of these cellular mechanisms of response to tion in brain, future studies are on the way to compare global stimulation are crucial for developing advanced therapeutic DNA methylation in peripheral tissue versus brain in labora- stimulation protocols and pave the way to close loop stimu- tory animals. lation devices.

Long-lasting olfactory-learning induced Reorganisation of motor deficits in patients modification in the reversal potential of with acute cerebellar stroke fast IPSPs in the piriofm cortex Bultmann U.,1 Frings M.,1 Pierscianek D.,1 Fritsche N.,1 Brosh I. and Barkai E. Gizewski E. R.,2 Timmann D.,1 and Maschke M.3 1 Departments of Biology and Neurobiology, Faculty of Department of Neurology, University of Duisburg-Essen, Sciences, University of Haifa, Haifa, Israel Germany 2Department of Diagnostic and Interventional Radiology We have previously shown that olfactory-discrimination and Neuroradiology, U of Duisburg-Essen, Germany learning results with a series of intrinsic and synaptic modifi- 3Department of Neurology, Hospital of the Barmherzigen cations in layer II piriform (olfactory) cortex pyramidal neu- Brueder, Trier, Germany rons, which last for days after learning completion. In particular, enhanced excitatory synaptic transmission is indicated Introduction by reduced paired-pulse facilitation, enhanced rate of rise Previous studies have shown an advantage of treadmill train- of EPSPs and increased spine density along basal and apical ing over conventional physiotherapeutic treatments in pa- dendrites of these neurons. The purpose of the present study tients with gait disturbances after acute supratentorial stroke. was to examine whether inhibitory synaptic transmission in- Likewise, repetitive exercises like the “arm ability training” put into pyramidal neurons is also modified after olfactory (Platz et al., 2001) lead to an improved motor performance. learning. Intracellular recordings with sharp electrodes were The present study investigated these therapies in patients made from layer II pyramidal neurons five days after train- with acute cerebellar stroke. ing completion, in the presence of APV and DNQX, to block glutamatergic synaptic transmission. IPSPs were evoked by Methods electrical stimulations applied in layer III. The averaged fast IPSP’s reversal potential was significantly lower in neurons Twelve patients with acute (territory of the superior or of the posterior inferior cere- sus −70.79+1.69, n = 18 for naive and −70.77+1.28, n = 19 bellar artery and twelve healthy control subjects were exam- for pseudo trained, P<.005). We suggest that olfactory ined. One half of the patients received a daily half-hour tread- learning is accompanied by hyper-polarization of the reversal mill training over two weeks. Patients with a relevant arm potential of fast inhibitory synaptic transmission. This shift ataxia received an additional “arm ability training.” The lo- enhances the effect of such inhibitory transmission, thereby calisation of the lesions was determined by 3D MRI. Gait dis- compensating for the increase in excitatory transmission. turbances and arm ataxia were quantified by clinical scores and by a 3D camera system. All examinations were per- Cellular Mechanisms of Deep Brain Stimulation formed in the acute phase, after two weeks and three months.

Bugaisen J.,1 Bar-Gad I.,1,2 and Korngreen A.1,2 Results 1The Mina and Everard Faculty of Life Sciences, Israel No significant effect of treadmill training or “Arm Ability 2The Leslie and Susan Gonda Brain Research Center, Training” could be shown. Treated as well as untreated pa- Bar-Ilan University, Israel tients showed a nearly complete restitution of motor symptoms after three months. In seven patients the ischemic lesion Deep brain stimulation (DBS) within the basal ganglia (BG) involved cerebellar nuclei in the acute phase, but only in one is a common treatment for Parkinson’s disease (PD) in its patient after three months. The clinical scores were worse in advanced stages and is used in an exploratory manner in those patients with involvement of cerebellar nuclei. multiple movement and behavioral disorders. Multiple experimental studies show that stimulation in globus pallidus Conclusions (GP) leads to complex modulation of the neuronal activity in the stimulated nucleus. In order to investigate the basic ef- The results of the present study suggest a relationship be- fect of DBS on single neurons we used DBS-like protocols us- tween the extent of the initial motor deficits and the ining extracellular electrodes similar to those used in vivo and volvement of cerebellar nuclei. No effects of the rehabilitative 20 Neural Plasticity therapies could be shown, possibly because of the good spon- Osmotic modulation of neuronal excitability is taneous recovery from symptoms in patients without perma- mediated by KV7/M channels nent lesions of the cerebellar nuclei. The results have to be controlled in a larger group of patients. Caspi A., Benninger F., and Yaari Y. Department of Physiology, School of Medicine, Supported by BMBF, German-Israeli Cooperation in Neu- The Hebrew University, Jerusalem, Israel roscience (01GA0508), and IFORES (D/107-20540; D/107- 20550). Modest reduction in extracellular osmotic pressure (pi) causes neuronal network hyperexcitability and epileptiform Tuning of the point of view of mirror neurons in seizures. It is commonly believed that this effect of low pi monkey premotor cortex is mediated by constriction of the extracellular space consequent to cell swelling, which enhances excitatory electric Caggiano V.,1 Fogassi L.,2 Giese M.,3,5 Rizzolatti G.,4 field effects. However, we have shown previously that low Thier P.,1 and Casile A.1 pi also increases intrinsic neuronal excitability in principal brain neurons. Specifically, we found that low pi promotes 1Department of Cognitive Neurology, Hertie Institute for bursting by facilitating the spike afterdepolarization (ADP) clinical brain research, University of Tuebingen, Germany in hippocampal pyramidal cells. Such an effect undoubtedly 2Department of Psychology, University of Parma, Italy would contribute to low pi-induced network hyperexcitabil- 3LARL, Hertie Institute for clinical brain research, ity. How does low pi facilitate the spike ADP and bursting? University of Tuebingen, Germany The waveform of the spike ADP is determined by interplay of 4Department of Physiology, University of Parma, Italy two low-threshold, noninactivating currents: persistent Na+ 5School of Psychology, University of Wales Bangor, current (INaP) and M-type K+ current (IM). Thus, facili- Gwynedd, UK tation of the ADP by low pi may be due to INaP enhancement and/or IM inhibition. We tested these two hypotheses Mirror neurons are a class of neurons in monkey pre-motor using intracellular sharp microelectrode recordings in CA1 cortex that respond both when the monkey performs an ac- pyramidal cells in situ. Our data favor the second hypothesis tion and when he sees the same action performed by humans for the following reasons: (1) after blocking IM with 20 μM or monkeys. While many studies have shown that such neu- XE991, which by itself caused ADP facilitation and bursting, rons are robustly activated under naturalistic conditions, it low pi had no further effect; (2) after blocking INaP with has been difficult to elicit single-cell responses using filmed 10 μM riluzole, which by itself caused ADP suppression, low stimuli. Here we present neurophysiological evidence in one pi still enhanced the ADP; (3) injection of positive current monkey showing that mirror neurons do respond to movies. ramps into neurons perfused with ACSF containing Na+ and In our experiments, we first isolated mirror neurons and fur- Ca2+ channel blockers, disclosed an increase in membrane ther tested them with filmed actions. To keep the monkey’s conductance at voltages positive to −60 mV (IM activation attention to the movie a fixation paradigm was used. The threshold), which was prevented by XE991 and enhanced by stimuli consisted of filmed goal-directed actions as observed the IM enhancer retigabine (10 μM). Low pi mimicked the from three different points of view: frontal view, side view effect of XE991 in reducing membrane conductance, and its and first person view (i.e., the forelimb seen by the acting effect was occluded by XE991. These and other data suggest monkey). About 40% (n = 34) of the recorded mirror neu- that low pi facilitates the spike ADP and bursting activity by rons responded also to filmed actions. Half of them (n = 17) inhibiting IM. This hypothesis is currently being examined preferentially responded to actions as seen from the first per- using voltage clamp techniques. son view. The remaining neurons responded either to multiple points of view (n = 10) or showed a preference for Supported by BSF and SFB-TR3. actions as seen from the side view (n = 1) or frontal view (n = 6). Our quantitative investigations show that the re- The compensation of oculomotor fatigue is sponses of mirror neurons are modulated by the point of based on the adjustment of a Purkinje cell simple view from which actions are observed. Two nonmutually ex- spike population signal clusive explanations can be given for this result. First, under Catz N., Dicke P. W., and Thier P. naturalistic conditions, monkeys as well as humans are more often visually exposed to their own actions (i.e., actions as Department of Cognitive Neurology, Hertie Institute for seen from the first person view). Second, the mirror neuron Clinical Brain Research, Tbingen, Germany system might have originally evolved to map monkey’s actions onto own motor representations possibly for refining Short-term saccadic adaptation (STSA) is a form of object manipulation behaviors. The same system was then, cerebellar-dependent motor learning in which a retinal vec- later in evolution, adapted to also understanding the manip- tor, defining a desired spatial location, becomes associated ulation behaviors of conspecifics. with a saccade vector, whose amplitude may differ from that of the retinal vector by up to 30%. We have previously re- Supported by the Deutsche Forschungsgemeinschaft (SFB 550- ported that STSA is based on adjusting a Purkinje cell (PC) C10). simple spike (SS) population signal and that disturbances of Israel Society for Neuroscience 21 saccadic adaptation, resulting from cerebellar disease may be examine the hypothesis that the CRF/Urocortin family of accompanied by an inability to maintain stable saccade am- peptides and receptors play an important role in modulat- plitudes if long series of stereotypic saccades have to be car- ing the neuroendocrine and behavioral responses to chal- ried out. We have interpreted the latter as uncompensated lenge. Defining the contributions of the individual ligands saccadic fatigue, an inability of the saccade system to account and receptors of the CRF/Urocortin family to the mainte- for changes of the plant due to usage, an idea which is sup- nance of stress-linked homeostasis may improve our ability ported by the comparison of the saccade kinematics of pa- to design therapeutic interventions for, and thus manage, tients and controls. Here we tested the idea that the cerebellar affective and stress-related disorders.We employ integrated mechanism used to compensate saccadic fatigue is the same molecular, biochemical, physiological and behavioral meth- as the one causing STSA. To this end, we recorded SS from ods, focusing on the generation of mice genetic models as nonsaccade related vermal PC in lobuli VI and VII while an in vivo tool, in order to study the central pathways and monkeys executed several hundred stereotypic saccades. In- molecular mechanisms mediating the stress response. deed, when the animals repeated the same saccades time and again, their kinematics changed while their accuracy was Epigenetic factors in the vulnerability to PTSD: maintained: a decrease in peak velocity was fully compen- theroleofDNAmethylation sated by an increase in saccade duration. Parallel to the in- 1 1 crease in saccade duration, many of the PC developed new, Chertkow-Deutsher Y., Ben-Shachar D., 2 3 late saccade-related bursts, fired around the time of the end Cohen H., and Klein E. of the altered saccade. These newly arising saccade-related 1Laboratory of Psychobiology, Department of Psychiatry, bursts were fully appropriate to extend the duration of a SS Faculty of Medicine, Technion, Haifa, Israel population response as based on the responses of PC, already 2Anxiety and Stress Research Unit, Faculty of Health Sciences, saccade-related at the outset, by an extent needed in order to Ben-Gurion University, Beer-Sheva, Israel account for the increase in saccade duration. These findings 3Department of Psychiatry, Rambam Medical Center, are in full accordance with the concept that the cerebellum Haifa, Israel controls behavior using a population code and, moreover, support the notion that STSA is the manifestation of a mech- Posttraumatic stress disorder (PTSD) develops in about 20% anism needed in order to compensate fatigue. of those exposed to a threat to life or physical integrity. This implies the participation of dynamic biological pro- Supported by the Deutschen Forschungsgemeinschaft SFB 550. cesses such as epigenetic modifications. This study investigated whether variations in DNA methylation pattern is Neurobiology of stress: the role of CRF/Urocortin associated with maladaptation to traumatic event in a rat family of peptides and receptors model of PTSD. Rats were exposed to a predator and clas- Chen A. sified into “PTSD-like” and “non-PTSD” according to their response in elevated plus-maze and acoustic startle response Department of Neurobiology, Weizmann Institute of Science, paradigm. Hippocampal global DNA methylation pattern Rehovot, Israel was assessed using amplification of inter-methylated sites method (AIMS): successive digestion of genomic DNA by Thebiologicalresponsetostressisconcernedwiththe SmaI and Cfr9I restriction enzymes, produced a mix of orig- maintenance of homeostasis in the presence of real or per- inally methylated fragments, which were amplified and ra- ceived challenges. This process requires numerous adaptive diolabeled by PCR and separated on 6% polyacrylamide de- responses involving changes in the central nervous and neu- natured sequencing gel. From the complex pattern of bands, roendocrine systems. When a situation is perceived as stress- we isolated 7 fragments displaying differential methylation ful, the brain activates many neuronal circuits linking cen- pattern between the “PTSD-like” and “non-PTSD” groups. ters involved in sensory, motor, autonomic, cognitive, and These fragments were amplified by PCR reaction, cloned and emotional functions in order to adapt to the demand. How- sequenced. Their location on the rat genome was established ever, the details of the pathways by which the brain trans- using the BLAST engine. Several sequences showed a com- lates stressful stimuli into the final, integrated biological re- plete homology with intron or intron-exon boundaries of sponse are presently incompletely understood. Nevertheless, known genes. The genes identified by this procedure Dll3, it is clear that dysregulation of these physiological responses PKCeta, Fstl3 and Rps6kb2 participate in synaptic formation to stress can have severe psychological and physiological con- and remodeling, differentiation of cells, protein phophoryla- sequences, and there is much evidence to suggest that in- tion and other cellular regulatory processes. We are now in a appropriate regulation, disproportional intensity, or chronic process of validation the methylation changes using bi-sulfite and/or irreversible activation of the stress response is linked assay and examining whether these variations have func- to the etiology and pathophysiology of psychological and tional significance by quantifying mRNA expression. Our physiological disorders. Understanding the neurobiology of initial results suggest that changes in DNA methylation pat- stress by focusing on the brain circuits and genes, which are tern may be associated with maladaptation to environmental associated with, or altered by, the stress response will pro- stress and the development of PTSD. vide important insights into the brain mechanisms by which stress affects psychological and physiological disorders. We Supported by The National Institute for Psychobiology, Israel. 22 Neural Plasticity

On the use of reference in auditory duration in vertebrates is derived from studies performed in Xenopus discrimination embryos. These studies led to the “default model” of neural induction, which proposes that cells within the ectoderm 2 1,2 Cochavi M. and Ahissar M. layer of the frog gastrula have an autonomous tendency to ff 1Interdisciplinary Center for Neural Computation (ICNC), di erentiate into neural tissue, which is inhibited by BMPs Hebrew University, Israel which act as an epidermal inducers. Later works in Xeno- 2Psychology Department, Hebrew University, Israel pus and chick models have shown a more complex picture in which FGFs are major players in addition to BMP inhi- The ability to estimate temporal intervals on the scale of tens bition and suggested BMP signaling-dependent and or inde- to hundreds of milliseconds is important for adequate motor, pendent roles of FGF. In attempting to understand the prin- visual and auditory abilities. Yet, little is known about how ciples that underlie neural induction in humans, we use the the brain estimates these durations. In a typical paradigm, human embryonic stem cell (hESC) model. We established listeners are asked which of 2 sequentially presented brief a simple one-step approach for derivation of neural precur- tones is longer. We now asked whether applying a consistent sors (NPs) from hESCs in chemically defined serum-free sus- reference improves the accuracy of temporal estimations. We pension culture conditions .This system serve as a defined applied 3 paradigms: reference short—a 100-millisecond ref- in vitro model to study early neural differentiation of hESC. erence tone was presented either in the 1st or in the 2nd in- Here we report that bFGF promotes the expression of early terval in each trial, and nonreference tone was always longer neural genes such as Musashi1 and NeuroD1, suggesting its (the typical paradigm applied in the literature); reference role in early neural specification. This effect is not associated 1st- the reference tone was always presented in the 1st inter- with neural cells proliferation. Moreover, this FGF effect is val, and the 2nd interval contained a shorter or longer tone; probably, at least in part, not mediated through antagonism no reference—there was no repeated reference across trials. of BMP signaling. Nevertheless, hESCs, when cultured in the Sixty six HU students participated in the experiment (31 with absence of FGF and BMP-signaling, differentiate towards a musical background), each tested with a single paradigm, ad- neural fate, suggesting a default mechanism of neural induc- ministered in 2 sessions (1 week apart). Each session con- tion, similar to that which was reported in amphibian mod- tained 5 subsequent 80-trial assessments, using an adaptive els. Our data suggest that bFGF plays a role, but is not essen- staircase procedure. The reference 1st paradigm was per- tial, in the neural induction process of hESCs, and supports formed significantly better than the other 2 paradigms from the “default model” of neural induction in mammals. the very first assessment. The small difference in protocol between reference 1st and reference short elicited a 2.6 fold dif- Protonation of extracellular histidine residues ference in thresholds, and a 4.8 fold difference in cross sub- facilitates C-type gating of the human potassium ject variability (11% ± .06 versus 29% ± .29). This benefit re- leak channel K2P2.1 mained constant within and across assessment sessions. The Cohen A., Chen S., Ben Abou Y., and Zilberberg N. no reference condition yielded even somewhat (though not significantly) poorer discriminations (36% ± .21). Musically The Department of Life Sciences and the Zlotowski Center for trained students performed significantly better. These results Neuroscience, Ben-Gurion, Israel indicate that a reference can dramatically sharpen discrimination. However, detecting a repeated duration is not imme- Potassium leak currents play a critical role in determin- diate for the auditory system. Temporal certainty is of crucial ing cell in determining cell resting membrane potential and importance, whereas duration certainty, even when consis- thus control nerve and muscle excitability. K2P2.1 (KCNK2, tently mapped to response category (always shorter) is not TREK-1), a member of the 2P-domain K+ channel (K2P) sufficient. family, is expressed in the central and peripheral nervous system, as well as in the heart, kidney and testis tissues. K2P2.1 ThestudywassupportedbytheISFCenterofExcellenceGrant activity is regulated by a variety of physical and chemical ef- &bytheInstituteofPsychobiology. fectors including temperature, fatty acids, internal pH, mechanical stretch and phosphorylation. Although K2P2.1 is The molecular mechanism of neural induction of classified as a leak channel, it was shown to posses an ex- human embryonic stem cells ceptional capability to reversibly convert between leak and voltage dependent phenotypes. Here, we report that human Cohen M. A.,1 Itsykson P.,1 and Reubinoff B. E.1,2 K2P2.1 channel, expressed in Xenopus oocytes, is inhibited 1The Hadassah Human Embryonic Stem Cell Research by external acidosis within the physiological range (pKa = Center, The Goldyne Savad Institute of Gene Therapy, Israel 7.3). Mutations in two outer pore histidine residues dramat- 2The Department of Gynecology; Hadassah Medical Center, ically decreased channel responsiveness to external acidosis. Jerusalem, Israel Mutation of a conserved glutamate residue (E84) known to be fundamental to C-type gating had a similar effect. Fur- The induction of neural tissue represents an early and funda- thermore, those three residues were found to be located in mental step in the generation of the vertebrate nervous sys- close proximity to one another. We thus propose a novel tem. During this process, pluripotent cells are directed to a mechanism for pH sensing in which protonation of histidine neural fate. Much of the understanding of neural induction residues destabilize hydrogen bonds, formed by E84, that are Israel Society for Neuroscience 23 necessary for maintaining the C-type gate at the open confor- Pyramidal neurons in the piriform cortex from olfactory- mation. In accordance with this proposed mechanism, pro- discrimination-trained rats show enhanced intrinsic neu- ton induced current decrease was inhibited by external potas- ronal excitability that lasts for several days after learning. sium ions and enhanced by a mutation (S164Y) known to Such enhanced intrinsic excitability is mediated by long-term accelerate C-type gating. Moreover, proton current inhibi- reduction of the postburst after-hyperpolarization (AHP) tion is voltage-dependent being more pronounced at nega- which is generated by repetitive spike firing. AHP reduc- tive potentials. The voltage-dependent current fraction was tion is due to decreased conductance of a calcium-dependent significantly decreased in the pHo insensitive mutants, pre- potassium current, the sIAHP. We have previously shown senting I-V relationship of an open rectifier channel. Thus, that such learning-induced AHP reduction is maintained by we suggest that voltage dependent C-type gating acceleration PKC activation. However, the sequence of protein activa- by protons, in physiological pHo, serves as a mechanism for tion which maintains this exceptionally long-lasting modu- the voltage dependent mode and the outward rectification lation of intrinsic excitability is yet to be fully described. Here behavior of K2P2.1. we examine whether ERKI/II, which has been implicated in learning and memory as well as in synaptic plasticity process, Exacerbated subthreshold oscillatory activity in is instrumental in this process. The MEK inhibitor, PD98059, rat model of essential tremor revealed by in-vivo that selectively blocks ERK, increased the AHP in neurons intracellular recordings of inferior olivary neurons from trained, but in neurons na¨ıve and pseudo trained rats. Cohen E. and Lampl I. Consequently, the difference in AHP amplitude and neuronal adaptation between neurons from trained rats and controls Weizmann Institute for Science, Israel were abolished. This effect was not mediated by modulation The inferior olive (IO), the sole provider of climbing fibers of basic membrane properties. Accordingly, the level of phos- to the purkinje cells (PCs), is suspected to be centrally in- phorylated ERK in the membranal fraction was significantly volved in the etiology of the most common movement disor- higher in pirifrom cortex samples taken of trained rats. The der, essential tremor (ET). ET is characterized by a 4–12 Hz PKC activator, OAG, that was shown to reduce the AHP in tremor of the limbs, head or jaw which is amplified during neurons from control rats, had no effect on these neurons intentional movements. Systemic application of harmaline, in the presence of PD98059. Our data show that ERK has a an alkaloid MAO inhibitor, causes tremor in animals com- key role in maintaining persistent PKC-mediated learning- parable to ET, while its bath application to in-vitro prepa- induced enhancement of neuronal excitability. rations increases the occurrence of subthreshold oscillations (STOs) and their amplitude in IO neurons. These combined Fast switching from computation based to findings, contributed to the view that oscillatory activity of memory based perception—evidence from ERP IO neurons is related to ET. Hence, harmaline treated ani- Daikhin L.,2 Nahum M.,1 and Ahissar M.1,3 mals have been used for many years as models for ET. The effect of harmaline on subthreshold activity of IO neurons in- 1Interdisciplinary Center for Neural Computation, Israel vivo, however, has never been examined. We have recorded 2Hadassah Medical School, The Institute of intracellularly IO neurons in anesthetized young adult rats. Medical Sciences, Israel Several minutes following the injection of harmaline (10– 3Department of Psychology, Hebrew University, 20 mg/kg, IP), in tune with muscle tremor appearance, IO Jerusalem, Israel neurons exhibited a remarkable transition in the oscillatory activity. Compared to control conditions, STOs exhibited at In two-tone frequency discrimination tasks, participants lis- least 2-fold increase in both amplitude and oscillatory epoch ten to sequentially presented tones and are asked to decide duration. This transition was also accompanied by a signif- which tone is higher. Recent results from our lab (Lubin and icant hyperpolarization and an increased firing rate due to Ahissar, ISFN 2005) showed that if one of the tones is re- the larger amplitude of STOs. Harmaline, however, did not peated across trials (reference) at a consistent temporal posi- have a drastic effect on the average frequency of STOs relative tion (either 1st or 2nd in each trial), performance quickly and to control conditions, nevertheless, it significantly narrowed significantly improves compared to a no-reference paradigm. their spectral distribution. Further investigation is required These findings indicate that the reference is used effectively, in order to relate the neuronal activity to muscle tremor and perhaps by eliminating the need for actual comparison be- examine possible strategies to negate the effects of harmaline tween the stimuli presented in each trial. In order to test this and restore normal STO activity. hypothesis, ERPs were measured while subjects performed the task. Two conditions were applied: reference 1st, in which Supported by Nella and Leon Benozyio Center for Neurological the reference tone was always in the first position, and the Diseases. second tone was either higher or lower, and reference 2nd, A novel role for ERK in maintaining long-term in which the reference was always second, and the first tone memory relevant excitability changes was either higher or lower. Thus, in reference 1st condition, trial-specific information, which is needed to resolve the task, Cohen-Matsliah S. I., Brosh I., Rosenblum K., is presented only at the second interval, whereas in refer- and Barkai E. ence 2nd condition, this information is provided already by University of Haifa, Israel the first interval. In the reference 1st condition both tones 24 Neural Plasticity induced N1-P2-N2 waves, but only the second tone induced phosphorylation were observed. Together, our findings sug- a P3 wave, indicating that a clear perceptual categorization gest that the combined treatment may downregulate GABA only occurred after the second tone. In the reference 2nd con- system in rat frontal cortex, and alter the PKC and MAPK dition, responses were similar, but the P3 decision wave was molecular signaling pathways. elicited after the first tone, and no P3 wave followed the second tone. The switch in the temporal position of P3 indicates Dopamine induces tyrosine phosphorylation that, in the reference 2nd condition, subjects indeed reach of the NR2A subunit (PY1325) in mature rat a decision after hearing only the first tone, before the sec- hippocampus ond stimulus was presented. Taken together, we find that the David O.,1 Kaphzan H.,1 Anderson C.,2 Grant S.,2 presence of a reference stimulus eliminates the need for on- 1 line comparisons within trials, and automatically enables the and Rosenblum K. use of a better strategy. Noticeably, participants are unaware 1Department of Neurobiology & Ethology, center for of this switch. brain and behavior, Haifa university,Haifa, Israel 2Team 32–Genes to Cognition, Wellcome Trust Sanger The study was supported by ISF Center of Excellence Grant and Institute, Hinxton CB10 1SA UK bytheInstitueofPsychobiology. Dopamine and NMDA receptor are playing a major role in The molecular mechanism of pharmacodynamic mature brain function and learning processes. Previous re- interactions between antipsychotic drugs and SSRI search in our laboratory identified convergence of NMDA antidepressants and dopamine on the levels of ERK2 activation and rsk2 expression in the hippocampus. Furthermore, it was shown Danovich L.,1,2 Weinreb O.,2 Youdim M. B. H.,2 that the dopamine activation of ERK2 is NMDA receptor and Silver H.1 dependent (Kaphzan et al., 2006, 2007). The molecular basis for this functional interaction between dopamine and the 1Molecular Neuropsychiatry, Brain Behavior Laboratory, NMDAreceptorsisnotclear.However,itsrelevancefordif- Shaar Menashe MHC, Israel ferent brain functions is highly important. We hypothesize 2Eve Topf Centers, Department of Pharmacology, that dopamine interacts with the NMDA receptor via mod- Technion–Faculty of Medicine, Haifa, Israel ulation of its tyrosine phosphorylation in the mature hippocampus. Using pharmacological set-up for mature hip- Clinical studies have shown that coadministration of se- pocampal slices and phospho-specific antibodies, we found lective serotonin reuptake inhibitor (SSRI) antidepressants that application of both high and low doses of dopamine for (e.g., fluvoxamine) and typical antipsychotics (e.g., haloperi- ten minutes (100 μM, 20 μM) induced the phosphorylation dol) can ameliorate negative symptoms in schizophrenic pa- of NR2A(Y1325) (P<.05, n = 4, P<.01, n = 8) but did not tients. Efficacy against negative symptoms is also seen with modulate the levels of NR2A protein itself. Moreover, appli- certain atypical antipsychotics (e.g., clozapine). The effect cation of the D2 and D1 dopamine antagonists, Etic (60 μM) of the combined treatment can not be explained by phar- and SCH23390 (40 μM) were sufficient to reduce basal phos- macokinetic interaction, implying that complex molecular phorylation of NR2A(Y1325, P<.05, n = 4), suggesting that mechanism might lie in the basis of the distinctive clinical intrinsic dopaminergic activity maintains tyrosine phospho- effect of this treatment. Our previous studies indicated that rylation of the NR2A in the mature hippocampus. In con- gamma-aminobutyric acid type A (GABA-A) beta3 receptor trast to dopamine, NMDA application, which induces ERK2 subunit, the enzyme glutamic acid decarboxylase (GAD67), phosphorylation, did not induce NR2A(Y1325) phosphory- and protein kinase C (PKC) beta2, known as important mod- lation (n = 8). Overall, our results suggest that dopamine ulators of GABA activity, might be distinctively regulated by interacts with the NMDA receptor via tyrosine phosphory- the combination of SSRIs and antipsychotics, compared to lation of NR2A(Y1325). We currently are analyzing the dif- each individual treatment alone. In the present study, we ferential effect of the different dopamine receptors on other have found that chronic coadministration (14 days, i.p.) of tyrosine residues and NR subunits. fluvoxamine (10 mg/kg) and haloperidol (1 mg/kg), as well as atypical antipsychotic clozapine (10 mg/kg), significantly Dynamic Properties of Martinotti-Pyramidal Synapses decreased GABA-A beta3 receptor subunit protein levels and in Layer 2/3 of the Rat Somatosensory Cortex induced receptor endocytosis in rat frontal cortex. Individ- 1,2 1,2 ual treatment of fluvoxamine or haloperidol did not produce Davidson K. and Korngreen A. changes in GABA-A beta3 receptor subunit expression or en- 1The Mina and Everard Goodman Faculty of Life Sciences, docytosis. In addition, we have shown that the combined Bar Ilan University treatment and clozapine similarly regulated molecular sig- 2The Leslie and Susan Gonda Multidisciplinary Brain naling pathways that modulate GABA-A receptor function, Research Center, Bar-Ilan University such as, PKC and ERK1/2. Furthermore, acute treatment (30 minute and 1 hour) with fluvoxamine and haloperidol It has previously been shown that the height and width of given together, or clozapine, altered ERK1/2 and PKC phos- APs recorded at the soma of bitufted interneurons from layer phorylation levels, and time-dependent dynamics of ERK 2/3 of the somatosensory cortex are sensitive to changes in Israel Society for Neuroscience 25 resting membrane potential, suggesting subthreshold activity Neonatal nitric oxide synthase inhibition leads to of voltage-gated conductances. It has also been found that the impaired reversal performance which is alleviated release of neurotransmitters from axon terminals of certain by clozapine: a neurodevelopmental model of vertebrate neurons is influenced by the somatic membrane negative symptoms potential and that the voltage fluctuations associated with dendrosomatic synaptic activity propagate significant dis- De Levie A. and Weiner I. tances along the axon. These minute fluctuations in the somatic membrane potential of the presynaptic neuron appear Department of Psychology, Tel-Aviv University, to modulate the amplitude and duration of axonal action po- Tel Aviv 69978, Israel tentials. We set out to identify and examine synaptic interac- Based on evidence on abnormalities in nitric oxide (NO) tions between bitufted interneurons and pyramidal cells in function in schizophrenia, we have developed a neurodevel- layer 2/3 of the somatosensory cortex of Wistar rats. Bitufted opmental model of negative symptoms based on neonatal in- interneurons were identified through their spindle-like so- hibition of NO synthase (NOS) during postnatal days 3–5. matic morphology and the observed characteristic pattern of In this model, neonatal NOS inhibition led in adulthood to AP discharge following depolarizing current injection into a cognitive deficit that is central to negative symptomatol- the soma. Current injections into interneurons produced AP ogy, namely, attentional perseveration/inflexibility, as mani- trains which height and width were observed to be sensitive fested in abnormally persistent latent inhibition. In support to dynamic changes in membrane potential. IPSP amplitude of its relevance to negative symptoms, this abnormality was in the post synaptic pyramidal cells depended on presynap- resistant to the typical antipsychotic drug haloperidol but al- tic membrane potential. These results confirm our initial hy- leviated by the atypical APD clozapine. Here we aimed to pothesis that not only it is possible for presynaptic somatic demonstrate neonatal NOS inhibition-induced attentional membrane potential to affect the magnitude of synaptic po- perseveration and its alleviation by clozapine using an ad- tentials in neurons other than cortical layer 5 pyramidal cells ditional selective attention task, discrimination reversal. Rats but that inhibitory post synaptic potentials may also be af- were required to learn left-right discrimination in a T-maze fected by this phenomenon. with the choice of one of the arms reinforced, and then the two reinforcement contingencies were reversed so that the Effect of exposure to a behaviourally relevant tone on choice of the opposite arm was reinforced. Typically, the auditory cortex responses to the same tone in mice transfer of behavioral control to the current contingencies is De Hoz L., Raizel H., and Nelken I. impeded by the previously acquired contingencies. We found that neonatal NOS inhibition did not hinder rats’ capacity Department of Neurobiology, The Hebrew University of to learn discrimination task or to retrieve the previously ac- Jerusalem, Israel quired stimulus-response contingency, but rather impaired their ability to shift behavioral strategy, that is, to choose the We studied the effects of behavioural experience on sen- previously unrewarded arm. Thus, attentional perseveration sory responses in mouse auditory cortex. Young C57BL/6J seen in abnormally persistent LI was paralleled by increased female mice were kept in a modified Intellicage (Newbehav- perseveration in reversal. Furthermore, as seen in LI, this perior,Zurich,SW),acageinwhichtheanimalreceivesfood severative behavior was alleviated by clozapine. These results /ad libitum/ but access to water is contingent upon a correct support the notion that neonatal NOS inhibition provides a nosepoke within a specialized drinking apparatus at a sin- model of negative symptoms with construct and predictive gle corner of the cage. The behavior of the mice is continu- validity. ously monitored using “transponders” (reporting chips) implanted subcutaneously. As a result, training can be achieved A psychophysical study of the thermal grill illusion in the home cage, totally avoiding human handling. To attribute behavioral significance to a tone, half the visits to Defrin R.1 and Arendt-Nielsen L.2 the drinking corner were accompanied by the presentation of a warning tone at a fixed frequency that was immediately 1Department of Physical Therapy, Sackler Faculty of followed by an aversive airpuff. Electrophysiological record- medicine, Tel-Aviv University, Tel-Aviv, Israel ings in auditory cortex were carried out in anaesthetized an- 2Center for Motor-Sensory Integration, Aalborg University, imals taken out of the cage at various time points before and Aalborg, Denmark during the behavioral training. Stimuli consisted of tone sequences in which the warning tone was embedded with vary- Interlaced hot and cold stimuli administered simultaneously ing probabilities. Preliminary results indicate that during be- on the skin induce a paradoxical heat sensation; a phe- havioural training animals learned to avoid the airpuff.Fur- nomenon termed the thermal grill illusion (TGI). Studies on thermore, the local field potentials in response to the warning the grill illusion have yielded contradictory results regard- frequency, when it was presented at a low probability as part ing its quality and intensity, which in turn led to controver- of an oddball sequence, were more salient than the responses sies concerning the underlying mechanism. The controver- to other frequencies under the same conditions. sies may result from testing the TGI with absolute stimulation temperatures thereby disregarding inter-subjects’ varia- This research is supported by an FP6 grant. tion in temperature sensitivity. Therefore, the first aim was 26 Neural Plasticity to measure the individual threshold of the TGI. Another aim strong pain, pain sensation gradually increases to unbearable was to measure the spatial boundaries of the TGI by spa- intensities. It is hypothesized that the lack of pain habitua- tially separating between the cooling and warming stimuli, tion at those circumstances serves as a protective mechanism in order to explore possible mechanisms. Subjects (10 males, against potential and actual tissue damage. It also appears 15 females) underwent measurements of heat-pain (HPT) from the results that individual variations in pain threshold and cold-pain thresholds (CPT) with 9 and 18 cm2 stimu- and responsiveness are less influential than stimulation pa- lating probes, on the forearm. Subjects also underwent mea- rameters on pain habituation and excitation. surement of pain threshold (PT), with one cooling and one 2 heating probes (9 cm each) activated simultaneously to pro- Selective hippocampal atrophy in Multiple Sclerosis duce the TGI. The stimuli were separated by 0–30 cm, dis- quantitave MRI studies tances which encompass one or two dermatomes. Simulta- neous cold and warm stimuli produced burning pain at all Deri Y.,1,2 Miron S.,2,3 Achiron A.,2,3 Hoffmann C.,4 ◦ separation distances. PT values (∼26 and 38 C) were signifi- Konan E.,4 and Biegon A.1,5 cantly lower than CPT and HPT, respectively, and were relatively fixed across all distances except for 30 cm at which PT 1The Joseph Sagol Neuroscience Center, increased towards CPT and HPT values. In conclusion, in- Sheba Medical Center, Israel nocuous cold and warm stimuli can spatially summate, both 2Sackler Faculty of Medicine, Tel Aviv University, Israel within and between dermatomes and evoke a painful TGI. 3Multiple Sclerosis Center, Sheba Medical Center, Israel Most likely, nonnociceptive cold and warm channels inte- 4Diagnostic Radiology, Sheba Medical Center, Israel grate onto 2nd or 3rd order nociceptive neurons which, in 5Brookhaven National laboratories, USA turn induce a unique painful burning resulting from this blend. Multiple sclerosis (MS) is an autoimmune disease characterized by inflammation and demyelination. A significant pro- Habituation to pain: the effect of absolute vs portion of MS patients also exhibit cognitive deficits. The relative stimulation intensity hippocampus is a brain region implicated in memory formation, and hippocampal volume decline has been demon- Defrin R.,1 Dror A.,1 Yulzari L.,2 and Pick C. G.2 strated in conditions associated with cognitive deficits such as Alzheimer, depression and aging. The aim of the present 1Department of Physical Therapy, Sackler Faculty of study was to test the hypothesis that hippocampal volume Medicine, Tel-Aviv University, Tel-Aviv, Israel declines as a function of disease duration in MS; using quan- 2Department of Anatomy, Sackler Faculty of Medicine, titative MRI. Twenty five women (age range 23–58) who un- Tel-Aviv University, Tel-Aviv, Israel derwent a brain MRI scan were included in the study. 9 subjects (age 23–50) with disease duration of less than 1 year Stimulation at a constant intensity and location usually in- had early (probable) MS (PMS) at the time of the scans. 10 duce a gradual decrease in receptors’ output leading to weak- additional subjects (age 29–58), with disease duration 3–24 ening of subjective sensation, a phenomenon termed habitu- years, had an established remitting-relapsing disease (RRMS) ation. Habituation to pain was not studied in depth and re- and 6 healthy women (age 30–54) served as controls. Hip- sults are controversial. The aim was to investigate the stim- pocampal volumes were measured off T2 weighted images ulation parameters allowing for pain habituation, that is, to (axial plane, slice thickness 2.6–3 mm, no gap) using quan- assess the role of absolute versus relative stimulation inten- titative image analysis software (Image J), and normalized sity. Subjects were administered with cold and hot stimuli to skull and whole brain volumes. ANOVA, t-tests and sim- of either various absolute temperatures or at intensities set ple regression were used for statistical analysis as appropri- individually to induce an initial visual analog scale (VAS) ate, α = 0.05. A significant decrease in Hippocampus/skull scores of 2, 4, and 6 (weak, moderate, and strong pain, and hippocampus/brain ratios was found when the RRMS, resp.). Subjects rated their perceived pain during stimula- but not the PMS, groups were compared to controls (hip- tion (3–5 minutes). Absolute temperature, initial VAS scores pocampus/skull: F = 8.12, P = .018 RRMS versus control, and time significantly affected pain ratings. Temperatures of P = .000 RRMS versus PMS, hippocampus/brain: F = 5.08, ◦ 43–45 C always induced reduction in pain ratings with time P = .006 RRMS versus control, and P = .04 RRMS ver- ◦ whereas 47-48 C always induced elevation in pain ratings sus PMS). Furthermore, there was a significant correlation with time, regardless of initial VAS scores. Stimuli equivalent between the hippocampus/brain ratio and disease duration to VAS 2 always induced reduction in pain ratings and those (R = 0.52, P<.03) among the MS patients. To the best of our equivalent to VAS 4 and 6 induced elevation in pain ratings knowledge this is the first report of a disease-related atrophy with time, regardless of absolute temperatures. Nevertheless, in hippocampus of RRMS. Considering the key role played absolute temperature and initial VAS scores cointeracted in by the hippocampal formation in memory processes, it is that they strengthened the patterns induced by one another. likely that preferential hippocampal atrophy is a significant Sex affected the value of pain ratings but not their change contributor to the mechanism underlying cognitive deficits with time. Habituation to pain occurs only for relatively in MS. weak temperatures or at low VAS levels. With strong stimulation temperatures and/or temperatures inducing moderate- SupportedbyJ.SagoldoctoralfellowshiptoYaelDeri. Israel Society for Neuroscience 27

Classification of executed movements from fMRI 1Department of Biochemistry, Tel Aviv University, Ramat Aviv response patterns in primary motor cortex 69978, Israel 2Department of Biological Regulation, The Weizmann 1 1 3 1,2 Dinstein I., Gardner J., Jazayeri M., and Heeger D. J. Institute of Science, Rehovot 76100, Israel 1Center for Neural Science, New York University, NY, USA Most receptor tyrosine kinases (RTKs) and G-protein cou- 2Department of Psychology, New York University, NY, USA pled receptors (GPCRs) activate MAPK cascades but still ex- 3Physiology and Biophysics Department, University of ert diverse functions and therefore signal specificity remains Washington, Wash, USA an enigma. Also, most GPCR ligands utilize families of re- Purpose ceptors for mediation of diverse biological actions; however the type I GnRH receptor (GnRHR) seems to be the sole re- Several recent studies have shown that fMRI response pat- ceptor mediating GnRH-induced gonadotropin release. Sig- terns from early visual areas enable accurate decoding of ori- naling complexes associated with GPCRs may provide the ented gratings and motion directions (Kamitani and Tong means for signal specificity. Here we describe a signaling 2005, 2006). Accurate classification is evidence of underlying complex associated with GnRHR, a unique GPCR lacking neural selectivity for the changing dimension of the stimulus a C-carboxy tail. Unlike in cases of other GPCRs this sig- in the area tested. We used the same classification methodol- naling complex is preformed and exposure of LbetaT2 go- ogy to decode executed movement responses in several cor- nadotropes to GnRH induces dynamic rearrangement of the tical areas including primary motor and somatosensory cor- complex. The signaling complex core is c-Src and its binding tex. partners include PKC delta, epsilon and alpha, Ras, MEK1/2, ERK1/2, tubulin, FAK, paxillin, vinculin, caveolin-1, KSR- Methods 1 and the GnRHR. A short exposure to GnRH (5 minutes) causes MEK1/2, ERK1/2, tubulin, vinculin, and the Gn- Twelve subjects played the common game rock-paper- RHR to detach from c-Src followed by reassociation with scissors against a video taped virtual opponent whose move- the complex by 30 minutes. On the other hand, FAK, pax- ments were randomized. Subjects chose their movements illin, the PKCs and caveolin-1 stay bound to c-Src and KSR freely with the objective of winning the game. We defined appears in the complex only after 30 min of GnRH stimu- several cortical regions of interest (ROIs) including primary lus. GnRH stimulated ERK1/2 activity in the complex in a motor and somatosensory cortex and extracted the spatial c-Src-dependent manner. The GnRH activated ERK1/2 then pattern of fMRI responses in each ROI associated with each phosphorylates FAK and paxillin, while caveolin-1 is phos- trial in the game. We then used Fisher linear discriminant phorylated on Tyr14 apparently by the activated c-Src. RTKs analysis to classify responses from the three movement types. and GPCRs translocate ERK1/2 to the nucleus to phospho- We tested the accuracy of the classification by decoding the rylate and activate transcription factors. Therefore the role of executed movements on independent trials not included in the multiprotein signaling complex seems to sequester a cy- those used to train the classifier (leave one out validation). tosolic pool of activated ERK1/2 to phosphorylate FAK and paxillin at focal adhesions apparently for cell migration and Results spreading. Executed movements were decoded from the fMRI response SupportedbyISFandGIF. patterns in primary motor and somatosensory areas with accuracy of ∼65%, significantly better than chance performance (33% because there were three possible movements). Less is more: the perceptual advantage of being color blinded Conclusions Doron R., Meshulam A., Mandel Y., Rosner M., Neural activity in human primary motor and somatosensory Belkin M., and Polat U. cortex is selective for executed movements. Classification can Sackler Faculty of Medicine, Goldschleger Eye Research be successfully used to decode executed movements, even Institute Tel Hashomer, Tel Aviv University, Israel when using a fast event related fMRI protocol, with sufficient ff reliability to distinguish small di erences in hand movement. Color vision enables discrimination and segmentation be- This methodology may, therefore, enable assessment of un- tween very similar objects, thus adding an important dimen- derlying neural selectivity in the study of motor control (e.g., sion to visual processing. One out of eight men has a lacks dissociating kinematics from dynamics). cones function in the retinal fovea, and as color blind, re- SupportedbytheHFSPandSeaverFoundation. lies only on monochromatic information. In this study we explored the possibility that the visual system has adapted A preformed signaling complex mediates GnRH to the loss of information provided by the color system by activated ERK phosphorylation of paxillin and FAK at achieving superior performance in the monochromatic sys- focal adhesions in LfiT2 gonadotrope cells tem to compensate for the missing information. We measured basic functions of the visual system such as visual Dobkin-Bekman M.,1 Seger R.,2 and Naor Z.1 acuity, stereopsis, day contrast sensitivity (CS), and foveal 28 Neural Plasticity mesopic CS. The mesopic CS was measured under condi- Interbarrel synaptic connections in tions of full darkness, and with natural density filters that the rat barrel cortex covered the monitor, transmitting background luminance of 0.03 cd/m2. The subjects were healthy young men (17– Dothan D. J. and Lampl I. 35), with corrected-to-normal vision acuity (6:6 or better), Department of Neurobiology, Weizmann Institute of Science, n = n = with color blinded individuals ( 9) or controls ( Rehovot 76100, Israel 7). The results show a significant advantage of the color- blinded persons in the perceptual functions: better visual A basic attribute of the neocortex is its organization into acuity, higher CS (average 35% during the day, and 24% at functional, vertically oriented columns, which is particularly night), and better stereopsis (53%). Thus, the results indi- prominent in the “barrel” field of the somatosensory cortex cate that the processing of monochromatic perceptual func- of the rat. Though the barrels in layer 4 have been exten- tions in color-blinded persons is superior to that of peo- sively investigated, there is disagreement regarding direct in- ple with normal color vision. This suggests that the advan- teractions between layer 4 neurons of neighboring barrels. tages of monochromatic vision lie in the consequence of Whether or not these interactions exist is fundamental to an adaptation process throughout development in order to our understanding of sensory integration of thalamic inputs compensate for the loss of the important dimension of color and the origin of multiwhiskers response of layer 4 cells. One vision. theory claims that direct interbarrel synaptic connections influence neighboring barrels. An opposing theory states that Novel taste elevates c-fos expression in GABAergic interactions between barrels are negligible and subcortical neurons in the dysgranular Insular Cortex mechanisms are responsible for multiwhisker responses. To test for monosynaptic interbarrel connections, we made in- Doron G.1 and Rosenblum K.2 vitro intracellular current-clamp recordings in layer 4 of thalamocortical slices. Dissected slices connected only through 1Department of Psychology, Israel layer 4 showed that electrical stimulation in one barrel trig- 2Department of Neurobiology and Ethology, Faculty of gers both antidromic and orthodromic responses in neurons Science, University of Haifa, Israel of neighboring barrels, although these responses did not necessarily always appear together. Although EPSPs evoked by Conditioned taste aversion (CTA) may be acquired when an stimulation of a neighboring barrel were smaller than those animal consumes a novel taste (conditioned stimulus, CS) evoked by direct barrel stimulation, this experiment provides and then experiences the symptoms of poisoning (uncondi- an indication of a direct flow of information between barrels tioned stimulus, US). Animals will later avoid the taste that and suggests it can play a significant role in cortical gain con- was previously associated with malaise. Several molecular trol and determination of the cortical receptive fields. changes were found to be correlated with novel taste learning and CTA in the insular cortex (IC). However, very little This work was supported by ISF grants. is known on the circuit level within the insular cortex sub- serving taste learning (i.e., the specific cortical layers and cell Advanced molecular genetic tools to further type which mediate the molecular changes). Previous stud- investigate the essential protein ADNP and ies, that used the immediate early gene (IEG) c-fos protein its family member ADNP2 as a functional marker of neuronal activity in the IC, have Dresner E., Kushnir M., and Gozes I. shown that c-fos expression is elevated in the IC following taste aversion learning. In the current study we used con- Human Molecular Genetics and Biochemistry, focal microscopy along with c-fos, the GABAergic GAD67 Sackler Medical School, Tel Aviv University 69978, Israel and nuclear immmunofluorescence markers, in order to determine whether the change in c-fos expression is localized Activity-dependent neuroprotective protein (ADNP) was to GABAergic interneurons in the IC following novel taste first discovered as a protein associated with neuroprotection. training and CTA. Our results indicate that although total c- The gene is highly conserved, and contains zinc fingers and fos expression is not changed following novel taste only, it is a homeobox domain. ADNP is essential for brain forma- specifically higher in GABAergic neurons in layers I-IV of the tion and ADNP knockout mice exhibit failure of neural tube dysgranular IC (DI). Moreover, in accordance with previous closure and death on E8.5-9.5. Upregulation of transcripts results, total c-fos expression is elevated in the IC following associated with lipid metabolism, and down regulation of CTA, but also specifically in GABAergic neurons in layers I- transcripts associated with neurogenesis and organogenesis IV and layers IV-VI. In contrast, no layer specific elevation of was observed in the knockout embryos. Recently, ADNP was c-fos expression in GABAergic neurons can be detected fol- found to interact with members of the mating type switch- lowing LiCl injection only, although the total c-fos expres- ing/sucrose nonfermenting (SWI/SNF) chromatin remodel- sion is higher following LiCl i.p. administration. We pro- ing complex. ADNP2 (KIAA0863) is a new protein, paralog pose that novel taste learning is mediated through GABAer- to ADNP, with a very similar structure and expression pat- gic layer specific activation in the DI, while CTA learning is tern. Our research aim is to further understand the function involved in more sparse activation of neurons in the insular of these proteins and their counter-relationship. Our find- cortex. ings indicate mutual regulation between ADNP and ADNP2. Israel Society for Neuroscience 29

A reduction in ADNP2 expression was seen in the ADNP Constraining neuron models by experimental data knock-out mice, and a reduction in ADNP was seen in knock down of ADNP2. As a first step, several research tools were Druckmann S.,1,2 Gidon A.,2 Schuermann F.,3 constructed. First, ADNP and ADNP2 knock down systems Markram H.,3 and Segev I.1,2 using siRNA technology were established in P19 cells. These 1 tools enable the examination and comparison of the phe- Interdisciplinary Center for Neural Computation, ff the Hebrew University of Jerusalem, Israel notypic e ect of ADNP and ADNP2 down regulation in 2 both pluripotent and neouro-differentiated P19 cells. In ad- Department of Neurobiology, Institute of Life Sciences, the Hebrew University of Jerusalem, Israel dition, in order to trace the cellular localization of ADNP2, 3 green fluorescent protein was attached to ADNP2 to form a Brain Mind Institute, Ecole Polytechnique Fed´ erale´ de chimeric protein, which was expressed in HEK293 cells. Fi- Lausanne, Switzerland nally, antibodies against two peptide sequences in ADNP2 The main challenge in constructing conductance-based com- were produced and affinity purified to identify the ADNP2 partmental conductance-based compartmental models that protein. Taken together, these tools will enable further inves- capture the firing pattern of neurons is constraining the den- tigations into the counter-relationship of the essential pro- sity of the various membrane ion channels that determine tein ADNP and its family member ADNP2. these firing patterns. Presently, quantitative data on the den- Support by BSF, ISF, Lily, and Avraham Gildor Chair, Adams sity of a certain ion channel along a specific dendritic region Super Center, and Allon Therapeutics Inc. is by and large lacking. The dominant method to date is to record the in vitro experimental response of the cell to a set Neuronal rescue in thiamine deficiency of current stimuli and then attempt to replicate the response in a detailed compartmental model of that cell. Yet, in ex- Dror V., Rehavi M., Assaf Y., and Eliash S. periments, intrinsic noise gives rise to a large variability in the voltage responses to repetitions of the exact same input. Physiology and Pharmacology, Sackler Faculty of Medical, Thus, the common approach of fitting models by attempt- Tel Aviv University, Israel ing to perfectly replicate, point by point, a single chosen trace out of the spectrum of variable responses does not seem to do Thiamine deficiency (TD) is a model of chronic impairment justice to the data. In addition, finding a single error function of oxidative metabolism leading to neuronal loss. Rats are fed that faithfully characterizes the distance between two spiking a thiamine-deficient diet accompanied by injections of the traces is not a trivial pursuit. To address these issues, we pro- central thiamine antagonist, pyrithiamine. They exhibit neu- pose to adopt a multiple objective optimization (MOO) ap- rological impairments, cognitive deficits as well well-defined proach that allows the use of several error functions jointly. neuropathological lesions. Neurodegeneration develops over When more than one error function is available, the com- a period of 12 to 14 days and can be reversed by thiamine parison between experimental voltage traces and model re- administration. Use of this model can help elucidate mecha- sponse can be performed on the basis of individual features nisms of neuronal degeneration as well as important paths of interest (e.g., spike rate, spike width). Each feature can be of neuronal rescue. Furthermore, since TD is partially re- ff compared between model and experimental mean, in units versible after thiamine administration, the e ect of neuro- of its experimental variability, thereby incorporating into the protective drugs on recovery can also be studied. In this study ff fitting a measure of this variability. We demonstrate the suc- we investigated the neuroprotective e ects of rasagiline, a cess of MOO when used in conjunction with genetic algo- MAO-B inhibitor, in TD rats, using neurological score, cog- rithm optimization, in generating an excellent fit between nitive testing and histopathology. Magnetic resonance imag- model behavior and the firing pattern of two distinct elec- ing (MRI) was used to study the pathology and brain changes trical classes of cortical interneurons, accommodating and in the rasagiline-treated and untreated-TD rats. Magnetic fast-spiking. We argue that the multiple, diverse models gen- resonance spectroscopy (MRS) was used measure metabolic erated by this method could serve as the building blocks for changes. We found that rasagiline significantly delayed the realistic simulation of large neural networks. induction of the TD syndrome and decreased the severity of the associated neuropathology. Rasagiline improved cogni- Endocrine regulation of serum butyrylcholinesterase tion in the Morris water maze. The severity of both the cog- activity: a study using dystrophin deficient mdx mice nitive and histopathological changes was significantly less in rasagiline-TD rats. T2-weighted MR imaging revealed severe Durrant A. R., Tamayev L., and Anglister L. time-dependent damages, mainly in the thalami and the inferior colliculi which were diminished with rasagiline treat- Department of Anatomy and Cell Biology, Hebrew University ment. We found that rasagiline both ameliorated and delayed Medical School, Jerusalem 91120, Israel neuronal injury. MRS showed an increase in lactate levels in the thalamus of untreated-TD rats which was postponed and Postpubertal dystrophin-deficient mutant (mdx) mouse has decreased in the thalami of the rasagiline-TD group. Our re- been reported to exhibit both muscular dystrophy and raised sults demonstrated significant neuroprotection by rasagiline serum acetylcholinesterase (AChE) concentrations [1]. In in this model which could have implications for clinical neu- this work we report a butyrylcholinesterase (BuChE) defi- rodegenerative disorders. ciency (>30%) in mdx-sera when compared to wild-type 30 Neural Plasticity

(wt). Since AChE activity appears to be down-regulated at Leader electrodes were defined as those few electrodes that puberty in wt-sera but not in mdx [1], and since serum consistently fired first in prebursts. We observed that these BuChEs in male rats is downregulated by the gonadal steroid leaders are stable over a few tens of hours, and that their dis- testosterone [2], then possibly both ChEs are subjected to tribution can only be temporarily disturbed using external hormonal regulation, which may be impaired in mdx mu- stimulation. We show that the identity of the leader initiat- tants. We therefore tested whether orchidectomy can attain ing the preburst of a given burst determines, statistically, the the agonadal baseline level of wt ChEs in the mdx mutants. electrode firing statistics during the following burst. Based Sera of adult (20–22 weeks old) male mdx and wt mice were on these results, we suggest that the leaders belong to a sub- collected and assayed for BuChE and AChE activities, by hy- network of neurons in the cultures and serve as nucleation drolysis of butyryl- and acetyl-thiocholine substrates, using centers for the recruitment of neural activity. selective inhibitors. Six days after orchidectomy, BuChE activities were elevated in both strains; yet, the BuChE defi- JPE, CZ were supported by the Fonds National Suisse, SM by ciency in mdx remained. Testosterone-replacement reversed the ISF, EM and SJ by the ISF and Minerva. the effect of orchidectomy. Gonadal modulation was specific for serum BuChE, not AChE. Our findings are consistent Association between DLG4 (PSD-95) scaffolding with the involvement of the hypothalamic-hypophyseal axis protein and autism: relations to adaptive behavior in the BuChE impairment of dystrophin-deficient mdx sera. and cognition 1 1 2 2 SupportedbyMDA(LA). Edelman S., Lerer E., Paz A., Zeev-Ben-Mordehai T., Israel S.,1 Nemanov L.,3 Sussman J. L.,2 Silman I.,2 Levi S.,4 Salomon S.,1 Yirmiya N.,1 and Ebstein R. P.1,3 References 1 [1] L. J. Oliver, J.-M. Chatel, J. Massoulie, M. Vigny, and F. M. Hebrew University, Jerusalem, Israel 2 Vallette, “Molecular forms of acetylcholinesterase in dystrophic Weizmann Institute of Science, Rehovot, Israel (mdx) mouse tissues,” Neuromuscular Disorders, vol. 2, no. 2, 3S. Herzog Memorial Hospital, Jerusalem, Israel pp. 87–97, 1992. 4Hadassah-Hebrew University Medical School, [2] N. P. Illsley and C. A. Lamartiniere, “Endocrine regulation of Jerusalem, Israel rat serum cholinesterase activity,” Endocrinology, vol. 108, no. 5, pp. 1737–1743, 1981. PDZ-domain scaffolding proteins such as PSD-95 (DLG4) along with neurexins, neuroligins, and SHANK3 comprise Leaders of Activity in Dissociated Neural Cultures the elements of trans-synaptic cell-adhesion complexes that are thought to bridge pre- and postsynaptic division. Neu- Eckmann J.,1,2 Jacobi S.,3 Moses E.,3 roligins, β-neurexins, and SHANK3 have all been linked by Zbinden C.,1 and Marom S.4 both linkage and association studies to autism spectrum disorder (ASD), however, PSD95 has not yet been studied in this 1Department of Theoretical Physics, University of Geneva, context. We identified and genotyped all six tagging SNPs Switzerland (htSNPs) across the DLG4 gene region using HapMap and 2Section of Mathematics, University of Geneva, Switzerland the Haploview program. PBAT-Helix tree was used to test 3Department of Physics of Complex Systems, The Weizmann association by family-based methods, in 152 probands from Institute of Science, Israel 133 families for htSNPs with DSM IV autistic disorder as well 4Department of Physiology and Biophysics, Faculty of as IQ and vineland adaptive behavior scales (VABSs) scores. Medicine, Technion, Israel The results were also verified using UNPHASED. Nominal association was observed between1htSNP (rs17203281) and Recently, it was shown that neurons bursting in culture have diagnosis (P value FBAT = .029), and 3 htSNPs were asso- a tendency to fire according to some order (Van Pelt 2005). ciated with IQ and VABS scores (IQ: rs929229 P = .043, Specifically, a subpopulation of the culture fires earlier than rs3826408 P = .008; VABS: rs929229 P = .005, rs3826408 average (Eytan and Marom 2006). The role of these early-to- P = .022, rs507506 P = .024). Multivariate and haplotype fire neurons in the population bursting is not clear, as they analysis showed significant association between DLG4 and all may be only probes of the ongoing population activity on three phenotypes (diagnosis, IQ and VABS). The FBAT-GEE one hand, or lead the recruitment of activity in the burst on multivariate statistic was significant for all four SNPs and for the other hand. In the light of this question, we have analyzed all three phenotypes (P = .0098). A common (25%) four- the spontaneous bursting activity data of dissociated rat hip- locus haplotype (rs17203281-rs3826408-rs929229-rs507506: pocampal and cortical neuron cultures that were recorded G-C-A-A) was significantly associated with all three pheno- over a few weeks using multi-electrodes. The cultures were types (FBAT-GEE, P = .03). Importantly, the current in- prepared and grown in three labs using different protocols. vestigation, by demonstrating association of common tag- Most of the bursts were preceded by a preburst activity, in- ging SNPS with ASD, VABS and IQ across the DLG4 gene dicating a slow recruitment of activity in the neurons sam- region, suggests that dysfunction of synaptic complex scaf- pled by the electrodes, and therefore, in the whole culture. folding proteins such as PSD-95 may be a general risk fac- Still, surprisingly, we find that the locality of the electrode tor in this disorder. The finding that IQ and VABS scores are firing occurs in the preburst but is diminished in the burst. also associated with DLG4 suggests that other disorders with Israel Society for Neuroscience 31 cognitive and social function deficits exhibited in daily liv- 2Geha Mental Health Center and Department of Psychiatry, ing skills might be profitably investigated for association with Tel-Aviv University, Israel PSD-95 and related scaffolding proteins. 3Department of Psychiatry and Behavioural Neurosciences, McMaster University, Canada Deficits in spatial learning in mice after minimal traumatic brain injury demonstrated by a novel dry A concept and methodology derived from animal studies maze test was utilized as a framework for studying rituals in obsessive compulsive disorder (OCD) patients and deriving objective Edut S.,1 Rubovitch V.,1 Schreiber S.,2 and observable criteria for compulsive rituals across patients. Feldon J.,3 and Pick C. G.1 OCD rituals performed by patients in their own home were videotaped and compared with the behavior of healthy in- 1Department of Anatomy and Anthropology, Sackler Faculty dividuals instructed to perform the same rituals. The video- of Medicine, Tel-Aviv University, Israel taped rituals were deconstructed into visits to specific loca- 2Department of Psychiatry, Tel Aviv Sourasky Medical Center tions or objects (ritual space), and to the acts performed at and Tel-Aviv Uni’Sackler Faculty of Medicine, Israel each location/object (ritual basic components). Quantitative 3Laboratory of Behavioural Neurobiology, Swiss Federal analyses revealed that compulsiveness emanates from the ex- Institute of Technology (ETH Zurich), Switzerland pansion of repeats for some acts and visits, and from the addition of superfluous act types. Best discrimination between Spatial learning and memory deficits in rodents have largely OCD and control rituals (90.9% success) was provided by the been studied using the Morris water maze (MWM). Al- parameter “maximum of act repeats in a ritual” (R2 = 0.77). though originally the water maze task was designed for rats, It is suggested that the identified properties of compulsive it has also been applied to mice. However, learning in the behavior are consistent with a recent hypothesis that ritual- MWM relies on swimming abilities, which evolutionary are ized behavior shifts the individual’s attention from a normal not well developed in mice. It is thus not surprising that mice focus on structured actions to a pathological attraction onto when compared with rats show an impairment. We have the processing of basic acts, a shift that invariably overtaxes therefore assessed spatial learning and memory in mice us- memory. Characteristics and mechanisms of compulsive rit- ing a dry maze. The dry maze is a paradigm for measuring uals may prove useful in objective assessment of psychiatric spatial learning and memory in mice. In the present study, disorders, behavioral therapy, and OCD nosology. evaluation of cognitive function was performed in ICR mice following minimal traumatic brain-injury (mTBI) or sham- Supported by Adams Super Center for Brain Studies, Tel-Aviv injury. Mice were tested 7 days or 30 days post injury. The University, Israel. dry maze is a circular plastic arena which comprises 20 small wells arranged in a circular manner. The maze paradigm in- Gene expression profiling in neuronal model of volves three parts: (1) training part, which lasts 2 days dur- Gaucher disease ing which all 20 wells are baited with drinking water; (2) learning part which lasts 7 days and only one of the wells Einat V., Farfel-Becker T., and Futerman A. is baited (the same well for the entire week); (3) probe part which lasts 2 days during which a different well was baited. Department of Biological Chemistry, Weizmann Institute of The mice were kept on water depravation (1 hour of water Science, Rehovot, Israel per day) during the entire experiment. Each animal’s path was tracked and its latency to reach the well was recorded. Gaucher disease is the most common lysosomal storage dis- In addition, the percentage of success in reaching the well order (LSD). This metabolic disorder is caused by mutations was calculated. Significant differences were observed between in the gene encoding glucocerebrosidase (GlcCerase), and the injured mice in comparison with the sham group fol- as a result, glucosylceramide (GlcCer) accumulates within lowing both time intervals. Seven days post mTBI the mice the cell. Types 2 and 3, the most severe forms of the dis- showed learning deficits in the learning part as well as in ease, are characterized by neurological impairment and neu- the probe part. Thirty days post mTBI, there were no sig- ronal cell death. Over the past few years, our laboratory ff has shown in neuronal models of Gaucher disease that Glc- nificant di erences in the learning part, but deficits were ev- 2+ ident in the probe part. These results demonstrate that there Cer enhances agonist-induced Ca -release from intracellular stores via the ryanodine receptor (RyR), and that the are long term deficits in cognitive learning abilities in mTBI 2+ mice which are measurable in the highly sensitive paradigm enhanced Ca -release is directly responsible for neuronal of the dry maze. cell dysfunction and death. Moreover, in in vitro studies, we have shown that GlcCer directly interacts with and modu- 2+ Obsessive-compulsive disorder: practical application lates the activity of the RyaR, the major Ca -release chan- of animal behavior as a conceptual model in studying nel in the ER, and that this also occurs in human brain tis- compulsive rituals in humans sue obtained post-mortem from Gaucher disease patients. These findings suggest that defective Ca2+-homeostasis may Eilam D.,1 Zor R.,1 Szechtman H.,3 and Hermesh H.2 be a mechanism responsible for neuropathophysiology in acute neuronopathic Gaucher disease. However, it is still not 1Department of Zoology, Tel-Aviv University, Israel clear how accumulated GlcCer leads to neuronal cell death. 32 Neural Plasticity

Thus, we are performing comprehensive gene arrays studies Patterns of brain language organization as of cultured hippocampal neurons. We compared untreated a function of linguistic performance following neurons to Gaucher disease biochemical model neurons us- recovery from childhood insults to ing conduritol-B-epoxide (CBE), an active site-directed in- the left hemisphere hibitor of GlcCerase. Our data suggest signiﬁcant alterations 1,2 2 3 2 in gene expression in this model. Among the genes that Elkana O., Ben Bashat D., Kremer U., Hendler T., 1 4 were transcriptionally regulated are genes related to ner- Fros R., and Schweiger A. vous system development and genes involved in mitochon- 1Psychology Department, Hebrew University, dria function. These results will hopefully shed light on Jerusalem, Israel the pathways activated in neurons upon GlcCer accumula- 2Wohl Institute for Advanced Imaging, Sourasky Medical tion, and will thus lead to a clearer picture of the cellu- Center, Tel-Aviv, Israel lar mechanisms involved in neuronal cell dysfunction and 3Pediatric Neurology, Sourasky Medial Center, Tel-Aviv, Israel death. 4Behavioral Sciences, Academic College of Tel Aviv-Yafo, Israel Inferring the representation of arm movements in the human motor cortex from the fMRI signal Introduction

Eisenberg M.,*1,2 Shmuelof L.,*3 Vaadia E.,1,2 Functional neuroimaging studies of aphasic stroke patients and Zohary E.1,3 offer the prospect of a better understanding of the neuronal mechanisms that underlie language recovery. There is ongo- 1Interdisciplinary Center for Neural Computation, ing debate concerning the capacity of the right hemisphere The Hebrew University, Jerusalem, Israel (RH) to takeover language abilities after a focal brain lesion 2Department of Physiology, Hadassah Medical School, to the left hemisphere (LH).In this study, we investigate sys- The Hebrew University, Jerusalem, Israel tematic patterns of brain language organization as a function 3Department of Neurobiology, Life Science institute, of linguistic performance following recovery from childhood The Hebrew University, Jerusalem, Israel insults to the language-dominant hemisphere. Neurons in the motor cortex are typically tuned to the direction of limb movements. There’s also evidence for sim- Methods ilar tuning of the local field potential (LFP), representing We present preliminary data of 7 children with a history the pooled neural activity (at roughly 1 mm). But it is cur- of single, left hemisphere CVAs, who were diagnosed with rently unclear if the different directions of movements are nonfluent aphasia at onset (ages 6–17) and subsequently re- represented in clusters within the limb areas of the human covered. Twelve age- and sex-matched healthy right han- brain. To that end, we conducted a functional MRI study ders served as controls. All underwent fMRI scanning during in which subjects performed a reaching task towards 4 tar- three linguistic activation tasks, during the chronic stage (at gets using an MRI-compatible joystick. Regions of interest least 2 years postonset). (ROIs) were selected on the basis of their activation during the various reaching conditions. In each ROI, we studied the Results degree to which the spatial patterns of the fMRI activation (across all voxels within an ROI) were correlated across tri- Outcomes yielded predominant tendency of RH Lateraliza- ffi als. The correlation coe cient was computed for trials re- tion in patients versus LH lateralization in the healthy con- peating the same motion (“same” condition) and for tri- trol group. The patterns of activation in the RH in pa- ff ff als with di erent directions of movement (“di erent condi- tients were in brain areas homologous to LH regions in- tion”). We found that in the primary motor cortex, premo- volved in language functioning under normal circumstances. tor cortex, supplementary motor area, and various regions However, correlation analyses with linguistic performance along the intraparietal sulcus, the spatial pattern of fMRI demonstrated that better linguistic performance is associated activation was positively correlated across repetitions in the with greater involvment of the left hemisphere. This finding “same” condition, whereas the correlation between trials in held true for patients’ linguistic performance inside the MRI ff di erent directions was slightly negative. The results indicate scanner (for Rhyming and Comprehension tasks), as well as that a non homogenous representation of directional move- for behavioral linguistic mesurments which were carried out ments is present in the human motor areas. While, clearly, outside the scanner (verbal fluency, naming and reading). important information may be lost due to the low spatial resolution of fMRI and its inherent noise, one can still pre- Conclusions dict the direction of hand movement on a single trial from the fMRI signal at a level better than chance. This method These findings imply that the left hemisphere becomes more may be a useful tool for investigating interactions and hier- involved as the patient becomes more proficient at the lin- archies of brain areas involved in sensorimotor action and guistic task. Hence, it appears that better recovery may reflect perception. more involvement of perilesional regions of the damaged LH.

The ﬁrst two authors contributed equally to this work. Funded by the Israel Science Foundation (ISF). Israel Society for Neuroscience 33

The role of PSD-95 in consolidation of taste learning suggests that calbindin could be a key endogenous regulator of the phosphatidylinositol cycle. Elkobi A.,1 Belelovsky K.,1 Barki-Harrington L.,1 1 2 Rosenblum K., and Ehrlich I. Aim

1 Center of Brain and Behavior, Department of Neurobiology Find out whether short oligopeptides comprised from the and Ethology, Haifa university, Haifa 30905, Israel IMPase sequence to which calbindin was shown to attach in- 2 Friedrich Miescher Institute, Maulbeerstrasse 66, 4057 Basel, terfere with the interaction and abolish IMPase activation by Switzerland calbindin. Taste learning is correlative with phosphorylation of proteins Methods regulating translation, in the brain area underlying its function. In addition, inhibition of protein synthesis in the gusta- IMPase activity in brain homogenates in the presence or tory cortex attenuates long but not short term taste memory. absence of 60 mM Li (to discriminate between IMPase and ff we employed two parallel di erent proteomic approaches nonspecific phosphatases), 20 μM recombinant calbindin to identify modulation on the protein expression levels in and with or without 10 μM specific peptides was quanti- the gustatory cortex in correlation with novel taste learning. fied spectrophotometrically by measuring Pi release from the Both screening and additional direct methods identified and substrate inositol-1-phosphate. verified the synaptic protein, PSD-95 as an induced protein. The correlative induction of PSD-95 with learning is MAPK Results and conclusion dependent and is also induced at synapses of the taste cortex. Moreover, the time window of PSD-95 increased expression Calbindin’s activation of IMPase by 1.66 fold was abolished is narrow and learning novel but not familiar taste induced by specific peptides derived from the sequence of the inter- its expression. This learning-related induction of PSD-95 was action site of the IMPase protein with calbindin but not by MAPK dependent, and was expressed locally at synapses of a scrambled peptide. This finding may lead to the develop- the taste cortex. To examine whether PSD-95 induction in ment of molecules capable of inhibiting endogenous IMPase the cortex was necessary for the taste memory trace forma- activity as an alternative mood stabilizing drugs. tion, we attenuated PSD-95 expression in the gustatory cortex in vivo, by temporally and spatially restricted lentiviral Supported by a Stanley Foundation grant to O. A. and G. A. mediated RNAi. Indeed, PSD-95 levels in the gustatory cortex were necessary for learning novel taste in thesiRNA in- Myoclonic bursting of the ankle joint musculature in jected rats. spinal cord injury patients is attenuated by activation of crossed-inhibitory pathways Novel approach to inhibit inositol monophosphatase 1 2 1 3 as an alternative to Lithium as a mood stabilizer Etlin A., Shamir B., Mor Y., Sasson D., Zeilig G.,2 and Lev-Tov A.1 Eskira Y.,1,2 Levi I.,1,2 Almog O.,1,2 and Agam G.1,2 1Department of Anatomy and Cell Biology, 1Department of Clinical Biochemistry and Psychiatry The Hebrew University Medical School, Jerusalem, Israel Research Unit, Ben-Gurion University, Israel 2Department of Neurological Rehabilitation, 2Mental Health Center, Beer Sheva, Israel The Chaim Sheba Medical Center, Tel Hashomer, Israel 3NBT Inc. Jerusalem Israel Background Spastic myoclonus produced in spinal cord injury patients Lithium salts (Li) are the standard treatment for bipolar dis- with incomplete thoracic lesions was studied using simulta- order. The “inositol depletion” hypothesis proposes that Li neous video monitoring and surface EMG (s-EMG) record- acts by depletion of brain inositol, based on the uncompeti- ings from the ankle joint antagonistic muscles tibialis ante- tive inhibition of inositol monophosphatase (IMPase) by Li, rior (TA) and lateral gastrocnemius (LG). Myoclonic activ- resulting in decreased inositol, and subsequent down regu- ity has been revealed in the recorded muscles following dor- lation of the phosphoinositide cycle (PI). Berridge proposed siflexion of the ankle joint, during body weight supported that depletion of brain inositol levels and the consequent re- (BWS) treadmill locomotion, and after BWS locomotion. duced rate of resynthesis of phosphatidilinositol and of sec- Statistical analysis of the myoclonic activity using Wavelet ond messenger signal generation leads to a decreased re- transform and coherence, showed that the myoclonus was sponse to neurotransmission through this pathway. It has re- characterized by a typical ∼6–8 Hz tremor and that the flexor cently been shown that IMPase is an activation target for cal- activity (TA) was slightly led by the activity of the extensor bindin D28k. Purified calbindin attaches to a specific amino (LG) during the dorsiflexion-induced myoclonus, but not acid sequence on purified IMPase enhancing its activity by during or following BWS treadmill locomotion. The my- severalfold.Theeffect of calbindin on IMPase activity is oclonus produced by dorsiflexion of the ankle could be at- most meaningful at conditions that otherwise lead to low tenuated in four out of the six patients by dorsiflexion of IMPase activity such as low substrate concentration. This the contralateral ankle. We suggest that the myoclonus is not 34 Neural Plasticity necessarily due to a repeated activation of stretch reflex and a dose-dependent manner. Therapeutic efficacy was delayed that it involves activation of spinal central pattern generators in concordance with the delay of therapeutic efficacy of an- (CPGs). We also propose that activation of intact crossed in- tidepressants routinely seen in clinic. These characteristics hibitory commissural pathways is capable of suppressing the make the DSR model a valuable tool for study etiology of de- contralateral myoclonus. pression and for the testing of antidepressants. The purpose of this study is to evaluate ability of outbreed Sabra mice to The Importins of Retrograde Transport in develop dominant submissive relationships. Two month old Injured Nerve male Sabra mice were subjected to the DSR test. The data show that about half of the animals developed strong and Fainzilber M. stable D-S relationships during second week of experiment that remain stable during third week of experiment. This Weizmann Institute of Science, Israel study revealed that Sabra outbred mice are able to develop strong D-S relationships and may serve as a potential model The long axonal process of a neuron poses a problem when for screening antidepressants and investigation of genetic el- information on damage to the axon must be conveyed to the ements that are responsible for dominant and/or submissive distant cell soma. It is known that injured peripheral nerve behavior. axons can signal to their cell bodies, and cause a “repro- gramming” of the cell body for long range elongating out- Transplanted fibroblasts reduce neuronal growth. We have recently discovered that the mechanism for synchronised bursting discharge and correct this process is based on local synthesis of nuclear import pro- Parkinsonian asymmetry and L-Dopa-induced teins in the axon at the injury site. These proteins can then dyskinetic movements in bind signaling proteins tagged with nuclear import signals, 6-hydroxydopamine-lesioned rats and transport them back to the cell body where they induce changes in the regenerative properties of the nerve. Our cur- Feld Y.,1 Finberg J. P.,2 Loboda Y.,2 Gluzman Z.,1 rent efforts are focused on understanding how the system is Mohsen O.,1 Reshef M.,1 and Marom S.3 regulated, what signals it transports, and what is the transcriptional response at the cell body. The presentation will 1Genegrafts Ltd, Israel focus on new data on regulation of the importins system in 2Molecular Pharmacology Department, Rappaport Faculty axons, initial identification of candidate signaling proteins, of Medicine, Technion, Haifa, Israel and characterization of the transcriptional response in neu- 3Physiology Department, Rappaport Faculty of Medicine, ronal cell bodies. Technion, Haifa, Israel Motor dysfunction in Parkinson’s disease results from de- Establishment of a dominant submissive creased striatal dopaminergic input, leading to increased relationships model in Sabra outbred mice neuronal activity in striatal output pathways, primarily GPi, Feder Y.,1,2 Ogran A.,1 Zinn A.,1 Yadid G., 2 SNr and STN. We are developing autologous fibroblast trans- and Pinhasov A.1 plantation in these areas of neuronal hyperactivity as a potential treatment for Parkinson’s disease, based on our ob- 1Department of Molecular Biology, Ariel University Center, servation that addition of dissociated fibroblasts to a pri- Ariel, Israel mary culture of cerebral cortical neurons reduces synchro- 2Leslie Susan Gonda Multidisciplinary Brain Research Center, nization of neuronal discharge. Primary cultures of rat cor- Bar-Ilan University, Ramat-Gan, Israel tical neurons were prepared and plated on multi-electrode arrays. Mature fibroblasts were added to the cultures and Depression is a multifactorial disease caused by both genetic electrical recording was taken 3-4 days later. Discharge rate and environmental factors and the prevalence of depressive of cortical neurons cultured on multielectrode array was re- disorders appears to be increasing in modern society. The duced to 32±5% control at 3 days following fibroblasts seed- major tools in the quest to reveal the molecular basis of de- ing. Unilateral 6-OHDA lesion in medial forebrain bundle pression and discover new antidepressants are animal mod- was carried out in Fischer rats. Syngeneic dermal fibroblasts els. Since depression in humans develops gradually and the (200 000) were transplanted at entopeduncular nucleus (EP; effect of antidepressant treatment in clinics is effective only rodent homologue of GPi) and SNr. Apomorphine-induced after chronic administration, development of animal models rotational behavior (0.25 mg/kg) was reduced 2, 4, 8, and 26 of chronic depression is essential. To meet this challenge, a weeks following transplantation, to 22 ± 9, 28 ± 12, 30 ± 11, Dominant Submissive Relationship (DSR) model was devel- and 24 ± 7% control respectively (P<.01 at each time point, oped for mood stabilizing and antidepressant drug testing. n = 4–6). Daily administration of L-Dopa (6 mg/kg) and car- In the DSR model pairs of animals compete during daily 5- bidopa (1.5 mg/kg) caused a gradual increase in dyskinetic min interactions for limited amounts of food. Under these movements in sham-operated rats, which reached a peak at conditions, about 30–40% of the pairs develop dominant- 3 weeks after commencing treatment. The intensity of dyski- submissive relationships that are characteristic of normal so- netic movements was reduced in rats which had been trans- cial behavior. Treatment of submissive animals with known planted with fibroblasts in STN or EP. In histopathologi- antidepressants significantly reduced submissive behavior in cal analysis performed 7 months following transplantation Israel Society for Neuroscience 35 the transplanted cells were located at the site of transplan- these interneurons and characterize their association with tation without signs of significant inflammation. We sug- the cholinergic system that has been shown to produce lo- gest that this technology can serve as a broad platform for comotor like episodes in the isolated spinal cord. Retrograde the treatment of various neurological disorders in which lo- fluorescent labeling of the cut VF at the lumbosacral junction cal areas of inappropriately high neuronal activity exist, and revealed several groups of S1–S4 interneurons contralateral specifically for Parkinson’s disease. to the fill. Labeled interneurons were mostly located in the intermediate gray, a few in the dorsal horn, and some in the Distinct involvement of the endothelin system in ventral horn. The laminar locations and trajectories of these glial inflammatory pathways neurons are similar to those of projection neurons of the spinothalamic, spinoreticular, and spinocerebellar tracts or Filipovich T. and Fleisher-Berkovich S. of ascending propriospinal pathways. Immunocytochemical Ben Gurion University of the Negev, Department of Clinical labeling of the cholinergic transmission components, choline Pharmacology, Israel acetyltransferase (ChAT), vesicular ACh-transporter, acetylcholinesterase and muscarinic AChRs, revealed that subpop- The endothelin system, comprising of three 21-amino acid ulations of these sacral interneurons produced and/or re- peptides, endothelin ET-1, ET-2, ET-3 and their receptors ceived cholinergic innervation. Further studies are required ETA and ETB, are synthesized and expressed in various to clarify the contribution of these cholinergic elements to cells and tissues, including the brain. Evidence suggests that pattern generation and inter-segmental communication in endothelins may play a key role in the regulation of in- the mammalian spinal cord. flammatory process under pathological conditions such as Alzheimer’s disease. We investigated the role of endothelins Effect of chronic stress and fluoxetine therapy on (ET-1, ET-2, ET-3) in the regulation of prostaglandin E2 IGF-1 receptor expression in the brain and on (PGE2) and nitric oxide (NO) synthesis, which are impor- behavioral and cognitive parameters of rats tant mediators of inflammatory responses. This was stud- First M.,1 Tarasenko I.,1 Taler M.,1 Grunbaum-Novak N.,1 ied both under basal conditions and in lipopolysaccharide Weizman R.,2 Gil-ad I.,1 and Weizman A.1,3 induced neonatal rat glial cells. Under basal conditions, all three endothelins, given at concentrations of 10 nM and 1Lab of Biological Psychiatry, FMRC and Sackler Faculty of 100 nM, increase PGE2 and NO release by about 2-3 fold in Medicine, Tel Aviv University, Israel a dose dependent manner. However, in LPS induced cells, 2Brull Community Mental Health Center, Sackler Faculty of all endothelins decrease the production of PGE2 and NO Medicine, Tel-Aviv University, Israel to about one half. BQ123 and BQ788, antagonists of ETA 3Research Unit, Geha Mental Health Center, Israel and ETB receptors, respectively, completely blocked both the stimulatory and inhibitory endothein actions. These results Chronic mild stress (CMS) in rats is a widely used model demonstrate for the first time the dual ability of endothelins, of depression, which is linked to stress-induced decreases acting via ETA and ETB receptors, to influence the produc- of neurogenesis in the hippocampus. Antidepressant treat- tion of inflammatory mediators in glial cells under basal and ments appear to protect against hippocampal volume loss. inflammatory conditions. Targeting the ET system may be a Moreover, antidepressants administration reverses the be- promising approach in modifying the course of inflamma- havior of stressed animals such as anhedonia (decreased su- tion during AD. crose preference) and increased immobility in the forced swim test. Our goals were to evaluate the effect of chronic This research was supported by the Israel Science Foundation mild stress and fluoxetine (5 mg/kg/day i.p.) therapy on the (Grant no. 500/04). IGF1 system in the rat brain and on behavioral and cognitive parameters.Maleratswereexposedsequentially,overape- Cholinergic involvement in sensory-induced riod of 3 weeks, to a variety of mild stressors (Wilner 1997), activation of locomotor networks in the mammalian and another control groups of rats received the same treat- spinal cord ment without stress. Body weight gain of fluoxetine treated rats did not differ from the control group. After 3 weeks of Finkel E., Blivis D., Etlin A., Lev-Tov A., and Anglister L. CMS animals were exposed to the open field (OF) test fol- Department of Anatomy and Cell Biology, Hebrew University lowed by a Morris water maze (MWM). In the OF fluoxe- Medical School, Jerusalem 91120, Israel tine treated stressed rats showed decreased immobility, and increased frequency and duration time spent in the inner Stimulation of sacrocaudal afferents (SCA) has been found zones of the arena, suggesting anxiolytic and more moti- to induce a locomotor-like and body-axis stabilizing rhythm vated behavior. However, in the MWM we observed a signif- in the isolated spinal cord of the neonatal rat and mouse. icant facilitating effect of fluoxetine in the acquisition phase The SCA-induced rhythm depended on synaptic activation in the nonstressed animals only. After autopsy we dissected of sacral interneurons whose axons cross the cord and as- brains and separated the cortex and hippocampus. IGF- cend rostrally mainly through the contralateral ventral fu- 1 receptor (IGF-1R) expression was determined by West- niculus (VF). In the present work we have used fluores- ern blot analysis. We found that CMS significantly reduced cent labeling techniques and confocal microscopy to identify the IGF-1R levels in the cortex and the hippocampus, and 36 Neural Plasticity

fluoxetine treatment reversed the expression to normal lev- showed a clear object selectivity. The results point to the po- els. We suggest that decreased IGF-1R in the brain following tential power of intracranial recordings to uncover neuronal CMS may contribute to depression and anxiety, which are correlates of perceptual awareness. reversed by fluoxetine therapy. However, fluoxetine therapy slightly improved performance in the MWM in normal but Supported by ISF grant to R. Malach and US-Israel BSF grant not in stressed rats suggesting that more factors are involved to Malach and Fried. in the process of improving cognition. Physiological Mechanisms of Neurodegeneration Induced by Activity Deprivation Neural correlates of visual recognition revealed through backward masking and intracranial electrode Fishbein I., Schonfeld E., Greenberger V., and Segal M. recordings Department of Neurobiology, Weizmann Institute of Science, Israel Fisch L.,1 Privman E.,1 Kramer U.,2,4 Kipervasser S.,2,3 4 2,3 2,5 1 Andelman F., Neufeld M., Fried I., and Malach R. When deprived of spontaneous network activity by chronic exposure to tetrodotoxin (TTX), cultured cortical and stri- 1Department of Neurobiology, Weizmann Institute of atal neurons die over a period of one to two weeks. Prior Science, Rehovot 76100, Israel to their death neurons retract their dendrites, lose dendritic 2Sackler School of Medicine, Tel Aviv University, spines yet express a two fold increase in miniature exci- Tel Aviv 69978, Israel tatory postsynaptic currents (mEPSCs). Unlike TTX treat- 3EEG and Epilepsy Unit, Department of Neurology, ment, chronic blockage of glutamate receptors does not have Tel Aviv Medical Center, Tel Aviv 64239, Israel atoxiceffect of its own. Moreover, blocking the AMPA sub- 4Functional Neurosurgery Unit, Tel Aviv Medical Center, type of the glutamate receptor protects TTX-silenced neu- Tel Aviv 64239, Israel rons from degenerating, indicating that mEPSCs becomes 5Division of Neurosurgery, David Geffen School of Medicine, toxic to chronically silenced neurons. Further investigation Semel Institute for Neuroscience, UCLA, USA revealed that chronically silenced neurons are impaired also in their ability to clear out calcium from the cytoplasm, Backward masking—where visual images are briefly (10– which may explain their vulnerability to relatively small cal- 100 milliseconds) flashed and followed by a mask, often ren- cium changes. The molecular mechanism of TTX-induced dering them unrecognizable—offers an opportunity to study neuronal death exhibited some apoptotic characteristics such neural correlates of object recognition. Previous fMRI stud- as the upregulation of the Bax and Bak genes, mitochon- ies of this phenomenon have revealed that recognition is drial fission and DNA fragmentation. On the other hand, it tightly correlated to high BOLD activity in ventral stream lacked caspase-3 activation, indicating that a caspase inde- visual areas. Here, we used intracranial EEG (iEEG) record- pendent form of apoptosis is activated once action potentials ings, which offer good localization and a msec temporal res- are blocked. We conclude that neuronal activity is beneficial olution, to investigate in more detail the neuronal events to neuronal survival only when it involves spontaneous trains which correlate to recognition in this paradigm. Record- of action potential, and that in the absence of network activ- ings were done using subdural intracranial electrodes, imity, subthreshold synaptic currents are in fact toxic and may planted in epilepsy patients strictly for clinical purposes. set in motion mechanisms of programmed cell death. Patients viewed a briefly (16 milliseconds) presented target image belonging to one of three categories—faces, houses, Unsupervised learning in network of temportrons and tools—followed by a fixed mask image. Interposed be- Fisher D.,1,2 Tsodyks M.,1 and Sompolinsky H.3,4 tween target and mask was a blank period of variable du- ff ration, resulting in a total time di erence (SOA) of 16– 1Neurobiology Department, Weizmann Institute of Science, 200 milliseconds between target and mask onset. The sub- Rehovot 76100, Israel ject had to overtly name the target’s category. Speech utter- 2Faculty of Physics, Weizmann Institute of Science, ances were recorded. Working at threshold SOA, where im- Rehovot 76100, Israel age recognition was successful in only about half the trials, 3Racah Institute of Physics and ICNC, Hebrew University, allowed comparison between trials identical in terms of ob- 91904 Jerusalem, Israel ff jective parameters (SOA and retinal stimulation) but di er- 4Center for Brain Science, Harvard University, ing in the subject’s state of recognition. Our results showed Cambridge MA 02138, USA a drastic recognition-associated increase in LFP parameters. The amplitude of gamma activity was highly correlated to Tempotron learning rule [1] for a leaky integrate-and-fire the state of recognition in a number of electrodes. Inter- (LIF) neuron provides a powerful method for learning and estingly, the duration of these gamma power increases of- decoding time- and synchrony-based neuronal code. Tem- ten outlasted the image exposure duration. In other elec- potron learning rule is supervised, that is, the modification trode sites, recognition-related changes were more promi- of LIF input synaptic strengths is governed by the exter- nent in the shape and amplitude of the N170 evoked poten- nal teaching signal which specifies the correct spiking be- tial recorded. These effects were only found in electrodes that havior for each given input. However, in biological systems Israel Society for Neuroscience 37 the learning of temporal code is not necessarily super- model of sporadic PD based on viral-mediated RNAi deliv- vised. In present work we design architecture and learn- ery which will be of help for developing novel neuroprotec- ing rules for a small LIF network capable of unsupervised tive drugs with possible disease modifying activity. (self-supervised) learning of temporal neuronal code. The learning rule for every LIF is based on the tempotron learn- A novel mechanism regulating the synthesis of ing rule with additional long-term synaptic depression. Re- the NMDA receptor coagonist D-serine: implications current connectivity and signaling rules provide for self- for NMDA receptor activation supervision in the network. As an example, we demonstrate the capability of this “network of tempotrons” to distinguish Foltyn V. N., Balan L. F., Dumin E., and Wolosker H. between Poisson-spiking representations of two or more different spatio-temporal sequences with identical average spike Department of Biochemistry, Faculty of Medicine, counts in each channel. Technion-Israel Institute of Technology, Haifa 31096, Israel The NMDA-type of glutamate receptors play major roles in References excitatory neurotransmission, synaptic plasticity and memory formation. Data from several laboratories have shown ¨ [1] R. Gutig and H. Sompolinsky, “The tempotron: a neuron that the unusual D-amino acid, D-serine, is a physiological that learns spike timing-based decisions,” Nature Neuroscience, vol. 9, no. 3, pp. 420–428, 2006. regulator of NMDA receptors by binding to the “glycine site” at the NR1 subunit. Brain D-serine is synthesized from L- serine by the serine racemase enzyme. Serine racemase was Silencing plus over-expression of selected genes as shown to be expressed in astrocytes and recently demon- a novel model of sporadic Parkinson’s disease strated in neurons as well, but little is known on its regulation. We now explored mechanisms regulating serine Fishman T., Youdim M. B. H., and Mandel S. racemase enzyme and D-serine synthesis in the brain. De- spite the fact that serine racemase lacks transmembrane do- Eve Topf Center, Technion, Department of Pharmacology, mains, a significant portion of the enzyme is tightly bound Faculty of Medicine, Israel to detergent-resistant membranes from brain. Immunocyto- chemical experiments revealed highest levels of membrane- bound serine racemase at the plasma membrane of neuronal Our objective is to develop a model of sporadic PD by se- processes. We found that membrane association of serine lectively silencing genes identified in our transcriptomic and racemase is mediated by palmitoylation, which leads to al- protein profiling of human SNpc from sporadic PD brains, most complete inactivation of the enzyme. Treatment of pri- while enforcing the expression of others. The mouse substan- mary cultures with NMDA increased several fold the lev- tia nigra-derived cell-line SN4741 was employed as a model els of membrane-bound serine racemase by enhancing the to study the involvement of the identified proteins intimately palmitoylation of the serine racemase enzyme. Our data in- connected to the neurotoxic cascade (e.g., SKP1A, HSC-70 dicates that NMDA receptor activation promotes feedback and ALDH1A) and the response to cell injury induced by inhibition of serine racemase to downregulate D-serine lev- the dopaminergic neurotoxin MPP+, serum deprivation and els. Palmitoylation of serine racemase provides a novel mech- H2O . SN4741 cells were infected with small-hairpin RNA 2 anism regulating D-serine synthesis, with implications for (shRNA)-encoding lentiviruses targeting the selected tran- NMDA receptor transmission. scripts or with nontarget shRNA control (scramble). The percentage of silencing was evaluated using real-time PCR Development of the endocannabinoid system: and Western blot analysis with specific antibodies. Param- its critical importance for embryonal implantation, eters of cell survival were assessed. Alterations in cell cycle neuronal development and postnatal suckling; were analyzed by flow cytometry. MPP+ and H2O induced a 2 implications of its pre- or postnatal manipulation time and dose-dependent alteration in the protein expression of the oxygen and iron-regulated proteins transferrin recep- Fride E. tor and prolyl hydroxylase (PHD2/EGLN1) and decreases in SKP1A, HSC-70 and ALDH1A. ShRNA-mediated silencing Ariel University Center of Samaria, Israel of Skp1A, a component of the SCF ubiquitin (E3) ligase complex, showed a significant delay in completion of the cell cycle Cannabinoid (CB1,CB2) receptors are activated by delta- and an increased susceptibility to MPP+ and serum starva- 9-tetrahydrocannabinol (THC), the major biologically action. The approach to develop an “ultimate model” of PD by tive ingredient of the Cannabis sativa plant, or by en- silencing or over expressing single genes that were identified dogenous (endo)cannabinoids such as anandamide and 2- as mutated in the familial cases has not met with the expected arachidonoyl glycerol (2AG). The “endocannabinoids” and success. We have reproduced to a significant extent the gene their synthesizing and degrading enzymes as well as the and protein alterations initially described in our studies with CB receptors form the “endocannabinoid” system (ECS) SNpc from Parkinsonian subjects, in a dopaminergic cell line which appears to be an important regulator of many from mice SNpc. The successful results obtained with the (neuro)physiological functions including feeding, appetite, present study will help us to develop an experimental mice motor functions and inflammation. The ECS has also been 38 Neural Plasticity shown to play an essential role in several developmental Improved cognition in female triple transgenic functions. Thus high levels of anandamide degradation en- AD mice treated with lipophilic metal chelators is able uterine implantation of the embryo. Further it has been associated with reduced astrocyte activation, shown that the endocannabinoids and their receptors play a amyloid-Beta, and p-tau pathology fundamental role in axon guidance and synaptogenesis during mid gestation. During postnatal life, CB1 receptor acti- Friedman J. E.,1 Eilam R.,2 Madala Halagappa K. V.,3 vation in the newborn is essential for the initiation of milk Mattson M. P.,3 Bush A. I.,4 Adlard P. A.,4 David Y.,1 suckling. Thus we have shown that two different CB1 recep- and Kozak A.1 tor antagonists (SR141716 and VCHSR1) impair mouse pup development and suckling, when administered within 24 h 1D-Pharm Ltd., Rehovot, Israel of birth. Further, intracerebral injections of SR141716 also 2Department of Vet. Resources, Weizmann Inst. Sci., impair pup development but only if injected at the base of Rehovot, Israel the brain, suggesting a role for hypothalamic or basal ganglia 3Laboratory of Neurosciences, Natl. Inst. on Aging Intramural receptor activation in pup suckling. Finally, prenatal mari- Res. Program, Baltimore, Md, USA huana, THC or anandamide exposure have been shown to 4Oxidation Disorders Laboratory, The Mental Health affect midgestational weight and the development of the pre- Research Institute of Victoria, Parkville, Victoria, Australia frontal cortex, dopamine system and CB1 receptors in the mature offspring. In conclusion, the ECS fulfills many physi- Transition metals such as zinc and copper contribute to the ological functions in the mature organism. However, only at pathologies inherent in Alzheimer’s disease (AD). This in- several junctions during development, seems the ECS to play cludes not only zinc-dependent amyloid-beta aggregation a critical role. Therefore, the repercussions of pre- or postna- and precipitation but also astrocyte activation, release of in- tal exposure to (endo)cannabinoids should be studied more flammatory cytokines and tau hyperphosphorylation. Treat- extensively. ment with lipophilic chelators (neuron 30, 665, 2001; neurobiol; aging 25:1315, 2004) has been shown to reduce the Characteristics and possible role of microsaccades plaque load and level of insoluble ABeta. Lee et al. have during visual fixation shown (PNAS 99:7705, 2002) in Tg2576 mice that synaptic zinc is gender dependent, being greater in females, and Fried M. and Arieli A. is correlated with significantly higher levels of ABeta plaques and insoluble ABeta. 18-month-old 3xTgAD mice that ex- Weizmann Institute of Science, Israel press mutations in presenilin-1, APP and tau, demonstrate The role of fixational eye-movements (FeyeMs), which are severe memory deficits when tested in the Morris water maze composed of drifts, tremors and microsaccades (MSs), in vi- (MWM). We have found that female 18 month-old 3xTgAD sual perception is controversial. There is a long-standing de- mice have greater deficits than do males, never achieving a bate about MSs whether they contribute to vision. A recent significant improvement in performance over an 8-day pe- debate is whether MSs and the so-called saccadic-intrusions riod. This correlates with higher levels, in females, of p-tau- (SI) are different names to the same phenomenon. We have 2.8-fold on immunoblots from cortical extracts and higher astrocyte activation (GFAP immunostaining) than do simi- recorded systematically FeyeM at high resolution from 4 P< na¨ıve human subjects under various conditions. We report larly aged males, .01. Performance in females is improved here that (i) in all subjects spontaneous MSs are primarily in by treatment with the membrane activated chelators (MACs) DP-109 and DP-460, resulting in significant learning within the horizontal plane (80.1%: 2766 Horizontal MS with me- P<. dian amplitude of 0.34 degrees versus 687 Vertical MS with 3days( 01). P-tau immunoreactivity in female mice, median amplitude of 0.12 degrees); (ii) voluntary saccades following treatment with MACs, was significantly reduced are often accompanied by an overshooting component which in the same areas that GFAP staining was reduced. Synap- is larger in the horizontal direction. This overshooting com- tophysin staining was increased, indicating increased synaptic densities, particularly in the cingulate cortex of females ponent is independent of the size and duration of the sac- P<. cade, but has the same size and duration distributions as the ( 05) in response to treatment, possibly explaining the spontaneous MSs, and thus might be generated by the same improvement in MWM behavior. Our data suggest that ame- lioration of cognitive deficits in aged 3xTgAD mice treated mechanism generating spontaneous MSs; (iii) moving ele- ff ments in the background reduce the amount of spontaneous with MACs is associated with a multifaceted e ect of MACs MSs, in a direction specific manner, suggesting that MSs have on the pathologies characteristic of AD, that is, reducing the a role in vision that might be related to the sensed image; (iv) toxic ABeta species, inhibition of astrocyte activation and tau the kinematics of MSs and SIs are similar. These results sup- hyperphosphorylation. port the claim that while a single MS changes the position of JEF, YD, and AK are employees of D-Pharm. theeye,SIiscomposedofasequenceoftwoormoreMSs which eventually return the eye to the original position. Recruitment order coding in large-scale recurrent This work was supported by the German Federal Ministry of networks of cortical neurons Education and Research, Israeli Ministry of Science and Tech- nology Foundation. Gal A.,1,2 Eytan D.,1 and Marom S.1 Israel Society for Neuroscience 39

1Network Biology Laboratories, Technion, Haifa, Israel Department of Neurobiology, Weizmann Institute of Science, 2Interdisciplinary Center for Neural Computation, Israel The Hebrew University, Jerusalem, Israel Standard short term synaptic plasticity models (Tsodyks and Perhaps the most severe constraint on the nature of neu- Markram, PNAS 1997) predict that higher probability of re- ral representation is the multiplicity and wide range of lease will entail more rapid adaptation. In layer 4 of the timescales that are characteristic of processes underly- somatosensory cortex adaptation is believed to result from ing neuronal excitability and synaptic communication. We short term synaptic depression of thalamocortical synapses. suggest that under this constraint, the order in which We observed in vivo that both excitatory and inhibitory in- neurons are recruited following a stimulus is an invari- puts (estimated using intracellular recordings) evoked by ant, information-carrying statistic of response features. We strong whisker stimulation adapt more than the input evoked demonstrate experimentally that in spontaneously formed by weaker stimulation. Assuming that stronger whisker stim- networks of cortical neurons in vitro, the information that uli increase presynaptic firing rate and are associated with the response carries about the stimulation source is preserved higher probability of release in the synapses of the sensory when precise times to first-spikes are reduced to recruitment pathway, these results cannot be explained by synaptic de- order. We looked into the nature of order coding by consid- pression mechanisms. In an attempt to explain this observa- ering its dependence upon precise firing times of individual tion we recorded from single units in the ventro posterior neurons and correlations between pairs of neurons. medial thalamic nucleus (VPM) and applied the same stimuli. Although VPM firing adapted profoundly less than corti- Venomous wasp targets different head ganglia to cal synaptic inputs, PSTH of VPM cells showed similar stim- manipulate specific behaviors of its cockroach prey ulus strength dependent adaptation rate providing an expla- Gal R. and Libersat F. nation to the results observed in the cortex. This, nevertheless, raised the question of how the phenomenon occurs in Ben-Gurion University of the Negev and the Zlotowski Center the VPM. Next we investigated a possible role for the retic- for Neuroscience, Israel ular thalamic nucleus (RT), which provides feedback inhibition to VPM cells, in the observed stimulus strength depen- The parasitoid wasp A. compressa manipulates cockroaches dent adaptation rate. Paired recordings of single VPM units ff to serve as live food supply for its o spring. To do so, the and multiunit activity in the RT before and after electrolytic wasp injects a venom cocktail specifically into two ganglia lesion of the RT show that the RT plays a major role in shap- located in the head of the cockroach prey. This sting evokes ing the adaptation of VPM cells as previously shown ([1]). ff two unique behavioral e ects on the stung cockroach: first, However, even following RT lesion stimulus strength depen- the cockroach grooms spontaneously and excessively for 30 dent adaptation rate was observed, suggesting that RT-VPM minutes. Second, the cockroach enters a long-lasting hypoki- interplay cannot explain the counterintuitive phenomenon, netic state during which it does not initiate spontaneous lo- and points to the trigemino-thalamic synapse as the next sus- comotion and is less responsive to aversive stimuli. The goal pected sight which may explain this behavior. of the present study was to identify which of the two cockroach head ganglia, namely the supra- and subesophageal This work was supported by The Israel Science Foundation ganglia, is responsible for which of the two venom effects. Grant 1037/03. To achieve this goal we manually injected crude venom (300 ug/ul, or saline in controls) into either ganglion (115 nl References and 70 nl, respectively) and quantified the behavioral outcome in an open-field arena. Venom injected directly into [1] M. A. Castro-Alamancos, “Different temporal processing of the supraesophageal ganglion significantly increased spon- sensory inputs in the rat thalamus during quiescent and infor- taneous grooming and general locomotion without affect- mation processing states in vivo,” Journal of Physiology, vol. 539, ing responsiveness to aversive stimuli. In contrast, venom in- no. 2, pp. 567–578, 2002. jected directly into the subesophageal ganglion significantly decreased general locomotion and responsiveness to aversive Robustness and structure of 2nd-order maximum stimuli but did not initiate grooming. We therefore conclude entropy models describing the state distribution of that the two distinct venom-induced behavioral effects ob- neural populations served in cockroaches stung by A. compressa can be traced, 1 2 1 at least in part, to specific ganglia in the cockroach head. Our Ganmor E., Segev R., and Schneidman E. results suggest that the venom induces excessive grooming 1 by manipulating neuronal circuits in the supra-esophageal Department of Neurobiology, Weizmann Institute of Science, Israel ganglion and the hypokinetic state by manipulating neuronal 2 circuits in the subesophageal ganglion. Department of Life Sciences, Ben Gurion University of the Negev, Israel Sensory Adaptation to Different Stimulus Strengths in ffi Rat Whisker to Barrel Pathway One of the key di culties in describing and analyzing the simultaneous spiking activity of large groups of neurons, is Ganmor E., Katz Y., Mazig V., Heiss J., and Lampl I. that the number of possible activity patterns of the group 40 Neural Plasticity grows exponentially with the size of the population. We have in the regulation of emotionality and stress, and in extinc- recently shown that the minimal mathematical model that tion of fear-related learning. CB1 receptors are highly ex- relies only on the pairwise relations between cells but as- pressed in the amygdala, which is known to be important sumes no higher-order interactions gives a surprisingly ac- for anxiety and emotional learning. The main purpose of curate description of the distribution of network states in this study is to examine the effects of exposure to a stress- several neural systems ([1]). Notably, these maximum en- ful experience on inhibitory fear avoidance extinction, and tropy models ([2, 3]) are defined by only a quadratic num- the potential involvement of CB1 receptors in these member of parameters. This study investigates the properties of ory processes in the amygdala. We found that exposure to these 2nd order models for describing network state distri- a stressful experience of placing rats on an elevated plat- bution. Using joint recordings of dozens of retinal ganglion form for 30 min impaired consolidation of extinction of in- cells responding to natural and artificial movies, we tested hibitory avoidance. Injecting rats with a low dose of the several different simplified 2nd order models and approx- CB1 agonist WIN55,212-2 (0.25 mg/kg) prior to exposing imations. While a model assuming independence of single them to the stressor, resulted in intact extinction. Thus, neurons clearly fails, a proper choice of pairwise interactions the CB1 agonist reversed the impairing effects of the stres- allows for an accurate description using a number of param- sor on extinction learning. Importantly, we were able to lo- eters which is linear in the size of the network. Furthermore, calize the blocking effect of the CB1 agonist to the amyg- although coincident firing is rare relative to the firing rate dala; accordingly, WIN55,212-2 (6 ng/0.5 ml) reversed the of single neurons, learning the pairwise model from sam- impairing effects of the stressor on extinction when mi- ples converges at a rate similar to that of the independent croinjected to the amygdala before placing rats on the el- model. The pairwise model proved to be the best model for evated platform. These results may support a wide thera- windows shorter than 20 seconds. We used graph theoret- peutic application of cannabinoids in the facilitation of ex- ical tools to explore the detailed structure of the networks tinction therapy that is often accompanied by stressful life ([4]), and found several local subnetwork structures that are events. over represented in the studied networks. This may help in further reducing the complexity of accurate models for these Single cell resolution network dynamics in the rat networks. Finally we show that the pairwise model allows us barrel cortex using calcium imaging two-photon to discriminate between different visual stimuli based on sin- microscopy in vivo gle trial analysis. Garion L.,1 Pehter I.,1 Azouz R.,2 and Schiller J.1 This work was supported by the Center for Complexity Science 1Techion Medical School, Israel (RS and ES). 2Ben-Gurion University, Israel References One of the major challenges in studying the function of sen- [1] E. Schneidman, Nature, 2006. sory circuits is to understand how the representation of com- [2] E. T. Jaynes, “Information theory and statistical mechanics,” plex, natural stimuli arises from the basic response properties Physical Review, vol. 106, no. 4, pp. 620–630, 1957. of neurons. Rodents in their natural environment use their [3]E.Schneidman,S.Still,M.J.BerryII,andW.Bialek,“Network whiskers to distinguish between surfaces having subtly differ- information and connected correlations,” Physical Review Let- ent textures and shapes. They do so by actively sweeping their ters, vol. 91, no. 23, Article ID 23870, 4 pages, 2003. whiskers across surfaces in a rhythmic forward and backward [4] R. Milo, S. Shen-Orr, S. Itzkovitz, N. Kashtan, D. Chklovskii, motion. While it is widely accepted that the brain “recon- and U. Alon, “Network motifs: simple building blocks of structs” these complex sensory stimuli from the information complex networks,” Science, vol. 298, no. 5594, pp. 824–827, contained in the concerted activity of ensembles of neurons, 2002. the nature and mechanisms underlying this sensory information processing remains largely unknown. To determine The involvement of stress and cannabinoid CB1 the role of neuronal interaction in coding of tactile infor- receptors in extinction of inhibitory avoidance in mation we employed two-photon laser Scanning Microscopy the amygdala in combination with loading of the cortex with membrane permeable calcium sensitive indicators (AM dyes) which is Ganon E.1 and Akirav I.1 loaded in a large fraction of the neurons in the layer 2/3 net- 1Department of Psychology, University of Haifa, Israel work. This new method enabled us to simultaneously measure from many cells in the activated network. Upon effec- The ability to extinguish emotional responses in the face of tive tactile stimulation the electrical activity of neurons in a no-longer relevant conditioned cue is an essential part of the network were monitored via the calcium signal evoked a healthy emotional memory system. Despite the efficacy of by the action potentials. To measure from large number of behavior therapy for anxiety disorders, extinction-like treat- neurons and yet keeping good temporal resolution we devel- ments require repeated cue exposures and are vulnerable to oped a new scanning methods that scans a random line scan reversal by a number of environmental factors, particularly path that was defined a priori by the user. We have been able stress. The endocannabinoid system and CB1 receptors in to record calcium transient signals from tens of neurons up particular, has recently emerged as considerably important to 400 μm deep in the tissue. We find that the spatiotemporal Israel Society for Neuroscience 41 pattern of activation was critically dependent on the nature prior to stinging by A. compressa. We then tested the re- of the stimulation delivered. sponsiveness of these cockroaches to electric foot shocks in a shuttle box. All opioid-receptor antagonists significantly de- Learning temporal representations through reward creased the avoidance threshold of stung cockroaches to foot dependant expression of synaptic eligibility traces in shocks. The most profound effect, however, was achieved recurrent networks with the kappa-specific antagonist Nor-BNI. These results suggest that the venom of A. compressa might manipulate Gavornik J.,1 Loewenstein Y.,2 and Shouval H.1 responsiveness in stung cockroaches by affecting the opioid system predominantly via kappa-opioid receptors. If true, to 1 University of Texas Medical School at Houston, Tex, USA our knowledge, this would be the first evidence of a behav- 2 Hebrew University, Israel ioral manipulation of one insect by another mediated via the opioid system. Experimental recordings have demonstrated that neurons in the primary visual cortex are able to learn to express tem- BL-1020, first in class GABA enhanced antipsychotic poral intervals as a function of reward timing (Shuler and candidate: results of a D2 receptor occupancy study in Bear, 2006). The form of this expression is a stimulus evoked humans period of transient activity that persists until the expected reward time. It is not known how biological networks are Geffen Y.,1 Appel L.,2 Davidson M.,3 and Kapur S.4 able to learn temporal representations with time scales that are orders of magnitude larger than the intrinsic excitabil- BioLineRx Ltd, Jerusalem, Israel ity time constants of individual neurons. We have previously 2GEHC Uppsala Imanet, Sweden developed a synaptic plasticity rule that allows a network 3Sheba Medical Center, Israel with recurrent lateral connections to learn synaptic weights 4 Department of Psychological Medicine, Institute of sufficient to set network decay times that correspond with Psychiatry, King’s College London, UK trained temporal intervals by expressing novel plasticity eligibility traces, called protoweights, as permanent lateral recur- Background rent synaptic weights. We demonstrate that our rule is able to encode multiple intervals in both deterministic networks BL-1020 is a novel compound composed of the dopamine- of passive integrator neurons and noisy stochastic networks 2 (D2) antagonist Perphenazine and the inhibitory neuro- of nonlinear integrate and fire neurons. An extension to non transmitter GABA (gamma-amino-butyric acid), indicated orthogonal inputs is examined. Synaptic expression in our for the treatment of schizophrenia. Preclinical studies show model is modulated by an external reward signal that is in- that BL-1020 delivers GABA to the brain, increases corti- ff hibited by activity at the network or single neuron level, this cal dopamine, binds to GABA-A receptors and e ectively re- ff distinction has implications for possible biological mecha- duces psychotic behavior with significantly fewer side e ects nisms and possible consequences under different experimen- than Perphenazine. A single dose escalating, double blind, tal conditions. We examine the temporal structure of both placebo controlled Phase 1 trial, in 48 healthy volunteers noise and stimulus evoked correlations, in order to make ex- indicated that BL-1020 is safe, well tolerated with a wide perimentally testable predictions for key elements of our en- therapeutic window, an MTD phase IIa, 6 weeks, study in coding and learning paradigms. schizophrenic patients is ongoing.

Involvement of the opioid system in the decreased Method responsiveness induced in cockroaches stung by A PET study to assess the degree of D2 receptor occupancy a parasitoid wasp in the human brain was conducted in healthy male vol- Gavra T., Gal R., and Libersat F. unteers, following administration of BL-1020, using [11C] raclopride as PET tracer. The trial (Uppsala’s Imanet, Swe- Ben-Gurion University of the Negev and the Zlotowski Center den), consisted of 12 healthy volunteers (3 cohorts of n = 4) for Neuroscience, Israel that received a single oral administration of BL-1020 (16, 24, and 32 mg). PET scans were done at baseline, 6 hours, and Cockroaches stung in the brain by the parasitoid wasp Am- 24 hours post dosing. The volunteers were also monitored for pulex compressa enter a long-lasting hypokinetic state. This safety, PK and changes in plasma prolactin levels. state is characterized by decreased responsiveness to aversive stimuli, suggesting a manipulation of a neuromodula- Results tory system in the cockroach brain. A likely candidate is the opioid system, which is known to affect responsiveness to PET data showed that BL-1020 caused a dose dependent D2 stimuli in insects. The aim of the present study was to ex- receptor occupancy in the striatum. Oral administration of plore this possibility. To achieve this goal we injected dif- BL-1020 (32 mg) resulted in occupancy of 50% at 6 hours. ferent opioid-receptor antagonists (Naloxone, nonspecific; PK modeling suggests that this dose is sufficient to obtain D2 Nor-BNI, kappa-receptors; Naloxonazine, mu-receptors; ICI occupancy greater than 70% in a multiple dosing scenario, 174,864, delta-receptors; or saline in controls) to cockroaches and thus should be within the therapeutic window. There 42 Neural Plasticity was a linear correlation between plasma prolactin levels and of specific items, and hint to a possible role of these neurons estimated striatal D2 occupancy. There were no significant in initiating the process of recollection. changes in ECG, vital signs, physical examination or laboratory values. NINDS grant to I. Fried ISF to R. Malach Binational US-Isreal grant to R. Malach and I. Fried. Conclusion Can the effects of putative human pheromones be These results are consistent with BL-1020 product profile of attributed to chemical sensing? a safe, well tolerated, and provide the opportunity to test the 1 1 2 hypothesis that GABA-enhanced D2 blockade may offer en- Gelstein S., Sobel N., and Roth Y. ff hanced antipsychotic activity with minimal side e ects. 1Department of Neurobiology, The Weizmann Institute of Science, Rehovot 76110, Israel This work has been supported by BioLinRx. 2Department of Otolaryngology, the Edith Wolfson Medical Center, Israel Neural correlates of free recall in the human medial temporal lobe Exposing humans to several specific steroidal compounds induces compounds induces pheromonal like responses, such 1 2 1 Gelbard-Sagiv H., Mukamel R., Harel M., as alterations in mood, hormonal state, and psychophysiol- 1 2,3 Malach R., and Fried I. ogy. However, it is not yet clear whether these compounds ff 1 a ect through chemical sensing or through alternative phar- Neurobiology Department, Weizmann Institute of Science, macologicalroutessuchastransdermaldiffusion. In order Rehovot, Israel 2 to address this, we set out to replicate previous experiments, David Geffen School of Medicine, University of California but here include a group of anosmic (without a sense of Los Angeles, USA ff 3 smell) women. We hypothesized that if the e ect is through Functional Neurosurgery Unit, Tel Aviv Medical Center, transduction in the main olfactory system, then these women Sackler School of Medicine, Tel Aviv University, Israel should not show the effects. The putative pheromone 4, 16- Androstadiene (AND) or placebo (yeast) were sniffed 10 The process that leads to the moment of free recollection times at the beginning of a ∼2 hour recording session where is still a major puzzle in human memory research. We di- we measured psychophysiological parameters (skin conduc- rectly investigated the involvement of the medial temporal tance, electrocardiogram, ear pulse, finger pulse, abdominal lobe (MTL) in this process by recording from single neurons respiration, thoracic respiration, skin temperature, and body in neurosurgical epilepsy patients while they were watching movement), mood (17 emotional descriptors), and salivary short movie clips and later were freely recalling them. Pa- hormones (testosterone and cortisol), while subjects viewed tients provided written informed consent to participate in mood-inducing video clips. To date, 3 subjects have been the experiment and the study conformed to the guidelines studied. Consistent with previous reports, this experimen- of the Medical Institutional Review Board at UCLA. Each tal arrangement modulated mood states and physiological recording session was composed of two parts. In the first arousal in the intended manner in all 3 subjects. Data from part, (viewing session) patients were exposed to a sequence an intended cohort of 30 subjects will be presented. of short (5–10 seconds) audio-visual clips with well known content such as famous movie scenes, people, locations or The antidepressant effect of repeated subconvulsive events. Each clip was presented 6 times in a pseudo-random electrical stimulation of reward related brain sites in order. Interleaved blanks of 0–5 seconds were used after each a rat model for depressive behavior: a comparison to clip. A typical session contained 10–16 different clips and the effect of electroconvulsive therapy lasted about 10 min. In the second part of the experiment (free recall session), following a short (1–5 minutes) break, Gersner R., Toth E., and Zangen A. patients were asked to name the clips they remembered regardless of order. Performance on this task was 90.7% on Weizmann Institute of Science, Israel average. Recordings were obtained from 332 MTL single or multiunits in 16 recording sessions with 9 patients. Of these, Electroconvulsive therapy (ECT) is the most effective treat- 30 neurons (9%) exhibited strikingly selective firing in re- ment for major depression. Our aim was to test whether sub- sponse to a specific clip, which persists throughout clip du- convulsive electrical stimulation (SCES) of specific reward- ration as long as 10 seconds and even following clip offset. related brain regions such as the prelimbic cortex (PLC) Importantly, we found that verbal reports of memories of or nucleus accumbens (NAC) can induce an antidepressant these specific clips at the time of free recall were preceded effect in a widely used rat model for depressive behavior. and accompanied by highly selective firing of these same We have utilized a battery of behavioral tests including su- neurons. This phenomenon was manifested mainly in hip- crose preference, forced swimming test, home-cage locomo- pocampus and entorhinal cortex neurons and rarely in other tion, exploration of a novel environment and the Morris MTL structures. These results suggest that a subset of neu- water maze. Also, we measured the levels of brain-derived rons in MTL participates in both perceiving and retrieving neurotrophic factor (BDNF). We found that repeated SCES Israel Society for Neuroscience 43 treatment of either the NAC or the ventral (but not the dor- (CR3) and phagocytosis of nonopsonized myelin by CR3 sal) PLC reversed the main behavioral deficit and the reduc- and scavenger receptor-A (SRA). Small GTPases of the Rho tion of BDNF levels in the dorsal hippocampus induced by family play a central role in motile responses that involve CMS, much like ECT did, but without causing cognitive side actin and/or microtubule networks, from neurite extension effects. These results suggest that SCES treatment of ventral to phagocytosis. Among these, Rho, Rac and CdC42 regulate PLC and NAC can induce an antidepressant effect similar actin. C3 transferase toxin (Clostridium botulinum) that se- to ECT, but without causing a cognitive deficit, implicating lectively inhibits Rho, enables studying rho-dependent sig- these areas in the pathophysiology of depression. nalling. Rho activates ROCK (Rho kinase; serine/threonine protein kinase) that phosphorylates myosin light chain phos- Stochastic synaptic transmission is advantageous for phatase, increasing thereby myosin II activity and the forma- learning complex temporal firing patterns in neurons tion of stress-fibers (bundles of F-actin and myosin). In the present study we examined the role of Rho/ROCK signalling Gidon A.,1 London M.,2 and Segev I.1,3 on myelin phagocytosis and stress-fiber formation in microglia. Rho-inhibitor C3 augmented phagocytosis of C3bi- 1 Department of Neurobiology, Institute of Life Sciences, opsonized and nonopsonized myelin in microglia that ex- the Hebrew University of Jerusalem, Israel press CR3 and SRA combined and separately, suggesting that 2 Wolfson Institute for Biomedical Research, Rho down-regulates CR3 and SRA mediated myelin phago- University College London, WC1E 6BT London, UK cytosis. Phagocytosis of C3bi-opsonized and nonopsonized 3 Interdisciplinary Center for Neural Computation, myelin was further augmented by ROCK-inhibitor Y-27632, the Hebrew University of Jerusalem, Israel suggesting that ROCK also downregulates myelin phagocytosis. F-actin, visualized by phalloidin staining, formed a Classical supervised learning algorithms (e.g., the Perceptron network of stress-fibers throughout the cytoplasm of nor- learning rule) implicitly use the contribution of an input mal microglia, and was further present at the perimeter synapse to the firing output by changing the synaptic weight of cells. F-actin fibers became disassembled in ROCK in- in proportion to its correlation with the output. In the bio- hibited microglia that further displayed many more filopo- logical context, however, the contribution of a specific input dia than normal, suggesting that Rho/ROCK signalling up- to the final neuronal output might be difficult to calculate regulates stress-fibers and downregulates filopodia. Notably, and, in particular, it might not be available as an explicit pa- filopodia engulf myelin in the course of phagocytosis. Thus rameter for plasticity. Here we propose a novel idea for the Rho/ROCK may downregulate myelin phagocytosis by up- role of the inherent probabilistic nature of synaptic release regulating stress-fibers and downregulating filopodia. (the occasional failures of vesicle secretion at the pre-synaptic terminal) for learning. We present an algorithm that utilizes Supported by Israel Science Foundation 11/06. synaptic stochasticity in order to sample the input space and to implicitly estimate the contribution of each synapse for Sensory-motor processes in the understanding of the “success” of the desired target output. The algorithm is spoken words: an fMRI study based on the positive correlation between the contribution of a synapse and the “achievement” in attaining the desired Glick I.1,2 and Hadar U.1 output of randomly sampled input subgroups in which it 1 participates (i.e., positively contributing synapses are more Department of Psychology, Tel Aviv University, Israel 2 abundant in “successful” input subgroups and vise versa for Wohl Institute for Advanced Imaging, Tel Aviv Sourasky “unsuccessful” input subgroups) . We further examine the Medical Center, Israel performance of this learning rule in terms of memory capac- Recent neuropsychological and neuroimaging evidence sug- ity and convergence time and in terms of its robustness to a gests that the cerebral language system may be described as high variability in the synaptic weights. Finally we demon- a distributed functional network, rather than the traditional strate how this abstract idea can simplify a complex learning view of two localized centers. Within this network, the classi- task of mapping temporal input pattern to an arbitrary out- cal language sites (Broca’s and Wernicke’s areas) may process put pattern in a realistic model neuron. such word attributes as morphology, phonology and syntax, whereas the network of sensory-motor properties may pro- Rho/ROCK signalling down-regulates myelin cess specific semantic information. This sensory-motor se- phagocytosis in microglia mantic network may engage various nonlinguistic areas that Gitik M., Reichert F., and Rotshenker S. are close to the related sensory or motor processors. Us- ing fMRI, we identified two separate centers in the sensory- Department of Anatomy and Cell Biology, Faculty of motor network that process two aspects of word semantics, Medicine, Hebrew University, Israel one related to motor and one to somatosensory properties of words. Twelve right-handed, native Hebrew speakers par- Microglia play a critical role in the innate immune response ticipated in this study. Stimuli words were divided into dif- of the CNS to injury and disease by removing degener- ferent categories according to their semantic properties: mo- ating myelin through phagocytosis. Phagocytosis of C3bi- tor, somatosensory and control (animal names). Words were opsonized myelin is mediated by complement receptor-3 presented in category blocks and, for each word, subjects 44 Neural Plasticity performed a semantic decision (is the word pleasant or un- upregulation of ACHE during the latent period of epilepto- pleasant?) or a phonological decision (does the word have genesis suggest a role for cholinergic dysfunction in epilepto- two syllables). Compared to control, the semantic process- genesis. ing of motor words yielded activation in left MTG and bilaterally in the fusiform gyrus. Previous studies (Chao 1999; Impaired migration signaling in the hippocampus Price 2003) found that these areas are activated when con- following prenatal hypoxia trasting the naming of tools with the naming of animals. Ad- ditionally, the semantic processing of somatosensory words, Golan H. M.,1 Kaplan-Louzone V.,1 Zuckerman M.,1 compared to control, yielded activation in left inferior pari- and Perez-Polo R. J.2 etal lobule (ba40), an area which is part of the secondary so- 1 matosensory cortex (Eickhof 2006). By contrast, the phono- Developmental Molecular Genetics, and Zlotowski ctr for logical processing of the stimuli did not exhibit differential Neuroscience, BGU, Israel 2 activations according to the semantic properties of the words. Biochemistry and Molecular Biology, UTMB, Galveston, We concluded that the processing of motor and somatosen- Tex, USA sory semantic properties of words are subserved by distinct cortical sites. Prenatal hypoxia ischemia is a major cause of neurodevelopmental impairment in the newborn, associated with risk This study was supported by the Levie-Edersheim-Gitter Insti- for motor, behavioral and cognitive impaired outcomes. We tute For Functional Brain Imaging. have previously shown, in a mouse model, that maternal pretreatment with magnesium sulfate (Mg) partially prevented Altered cholinergic gene expression in the behavioral consequences of maternal hypoxia in the adult pilocarpine-treated mice offspring. We now used this mouse model of maternal hypoxia to examine the immediate molecular responses of sig- Gnatek Y., Najami N., Bitan Y., and Friedman A. naling pathways associated with both cell death and neurogenesis. We also characterized responses to maternal pre- Departments of Physiology and Neurosurgery, Soroka treatment with MgSO4. Maternal hypoxia at embryonic day Medical Center, Ben Gurion University, Israel 17 (E17) failed to trigger inflammation or cell death in fetal Temporal lobe epilepsy (TLE) is the most common form of brain at 24 hours after hypoxia. However, maternal hypoxia decreased in the hippocampus levels of neuronal migration partial epilepsy and is associated with significant morbidity. P<. TLE patients often show hippocampus histopathology char- signaling: Reelin (53 % of control, 05), Disable 1 (Dab1, 77% of control, P<.01), and amyloid precursor protein acterized by cell loss in the CA3 and CA1 subfields and in the P<. dentate hilus. In experimental animals injection of the mus- (APP, 64% of control, 01) 2 hours after the insult. These carinic agonist, pilocarpine, induces status epilepticus (SE), changes persisted for 24 hours. At later times, Reelin levels followed 2-3 weeks later by the appearance of spontaneous in hippocampi of newborns in the maternal hypoxia treated seizures and hippocampal damage similar to that observed group increased compared to controls (14% and 51% of control, 5 and 20 days after the insult, respectively, P<.05). in human TLE patients. Temporal lobe structures, including ff the hippocampus, are enriched with cholinergic innervation Full protection from maternal hypoxia e ects on hippocam- and dysfunction of the cholinergic system is well known in pal Reelin levels resulted from maternal pretreatment with several neurological disorders. However, it is not known what MgSO4. In the newborn cortex, there was a higher sensitivity role cholinergic dysfunction may have in TLE. The aim of the to MgSO4 treatment. Taken together, the long-term neurodevelopmental outcome of prenatal and perinatal hypoxia may present study was to explore changes in cholinergic trans- ff mission and their role in the pathogenesis of TLE. To this depend on perturbation of developmental signals that a ect end we have established the pilocarpine model in mice and neuronal migration. searched for changes in expression of key cholinergic genes Supported by BSF Grant no. 2003166. during epileptogenesis. 97 FVB/N mice were injected with pilocarpine (280–340 mg/Kg). Continuous video recordings The transcription factor Nato3 is implied as a novel made in 11 mice showed high rate of spontaneous seizures regulator of floor plate and spinal cord development (82%) 4–8 weeks after SE. RT-PCR demonstrated increased mRNA levels in both the synaptic (S) and readthrough (R) Golan-Lev T.,1 Nissim-Eliraz E.,1 Mansour A.,1 alternatively spliced transcripts of the ACHE gene. ACHE Zisman S.,2 Schatz O.,1 Klar A.,2 and Ben-Arie N.1 upregulation was noticed already at 48 hours following SE and correlated with an increase in the enzyme activity as was 1Cell and Animal Biology, Institute of Life Sciences, shown in activity gel and Karnovski staining. Increased ex- The Hebrew University of Jerusalem, Israel pression lasted for two weeks and were found to be signifi- 2Anatomy and Cell Biology, Hadassah Medical School, cantly increased in both the hippocampus and temporal cor- The Hebrew University of Jerusalem, Israel tex. In situ hybridizations confirmed the expression of ACHE in all regions of the hippocampus, and immunostainings The floor plate is one of the key organizers of the central confirmed its expression in principal pyramidal neurons, nervous system in vertebrates and plays important roles in GABAergic interneurons, but only rarely in astrocytes. The both ventral patterning and axonal guidance in the neural Israel Society for Neuroscience 45 tube. The floor plate is induced at the ventral midline of References the neural tube through the action of Sonic hedgehog (Shh), [1] F. Pouille and M. Scanziani, “Routing of spike series by dynamic which in turn activates the transcription of target genes. circuits in the hippocampus,” Nature, vol. 429, no. 6993, pp. Nato3 is a member of the basic Helix-Loop-Helix (bHLH) 717–723, 2004. family of transcription factors, which regulate the specifi- [2]T.Klausberger,P.J.Magill,andL.F.Marton,´ “Brain-state- and cation/differentiation of specific cell lineages during neuro- cell-type-specific firing of hippocampal interneurons in vivo,” genesis. We found that within the developing spinal cord Nature, vol. 421, no. 6925, pp. 844–848, 2003. MNato3 and CNato3 expression is restricted to the floor [3]T.Klausberger,L.F.Marton,´ A. Baude, J. D. B. Roberts, P. J. plate in mouse and chick, respectively. However, the signal- Magill, and P.Somogyi, “Spike timing of dendrite-targeting bis- ing pathway through which MNato3 acts is currently un- tratified cells during hippocampal network oscillations in vivo,” known. Here, we aimed at identifying cis control elements Nature Neuroscience, vol. 7, no. 1, pp. 41–47, 2004. and molecular mechanisms that target MNato3 expression [4]R.Miles,K.Toth,´ A. I. Gulyas,´ N. Hajos,´ and T. F. Freund, “Dif- ferences between somatic and dendritic inhibition in the hip- to the floor plate. To identify the DNA regions that direct pocampus,” Neuron, vol. 16, no. 4, pp. 815–823, 1996. MNato3 expression to the floor plate we applied a reporter [5] E. C. Fuchs, H. Doheny, H. Faulkner, et al., “Genetically altered gene assay in chick embryos using in ovo electroporation. AMPA-type glutamate receptor kinetics in interneurons disrupt Our results reveal a short genomic DNA region upstream of long-range synchrony of gamma oscillation,” Proceedings of the MNato3,whichisnecessaryandsufficient to derive mouse National Academy of Sciences of the United States of America, Nato3 expression in the chick floor plate. We next looked for vol. 98, no. 6, pp. 3571–3576, 2001. evolutionarily conserved transcription factor binding sites [6] F. Pouille and M. Scanziani, “Routing of spike series by dynamic within this region, which may regulate the expression of circuits in the hippocampus,” Nature, vol. 429, no. 6993, pp. MNato3. In vitro studies confirmed that the putative con- 717–723, 2004. served binding sites identified in vivo and in silico are indeed [7] R. D. Traub, The Journal of Physiology, 1993. functional, and relate MNato3 to the Shh signaling pathway. [8] R. Cossart, J. Epsztein, R. Tyzio, et al., “Quantal release of gluta- Our results provide the first linkage between MNato3 and mate generates pure kainate and mixed AMPA/Kainate EPSCs in hippocampal neurons,” Neuron, vol. 35, no. 1, pp. 147–159, the signaling pathway these factors regulate, and suggest that 2002. MNato3 may have an important role in spinal cord development. Influence on offspring behavior of stress to the rat dam before she becomes pregnant: A specific processing of afferent theta inputs via effects of cross-fostering synaptic kainate receptors in O-LM neurons Gonen G.,1 Ferdman N.,1 Even B.,1 Maroun C.,1 Katz O.,1 Pershin L.,1 Schulkin J.,2 and Leshem M.1 Goldin M., Epsztein J., Jorquera I., Represa A., Ben-Ari Y., Cre’pel V., and Cossart R. 1Department of Psychology, University of Haifa, Israel 2Department of Physiology and Biophysics and Institut de Neurobiologie de la Me’diterane’e, Neuroscience, Georgetown University, DC, USA Marseille, France Pregestational adversity impacts offspring affective behavior (Shachar-Dadon et al., 2006). To discover whether precon- GABAergic interneurons are a diverse population with an ception stress might exert its effects by altering the dam’s ma- important role in network function. Distinct GABAergic cir- ternal behavior, in turn influencing the development of off- ff cuits were shown to di erentially process information dy- spring behavior, we investigated the effects of cross-fostering namics ([1–4]). This integrative specificity of GABAergic cir- offspring of preconception stressed dams to control dams cuits was partly attributed to the kinetics of their glutamater- and vice versa. Virgin rats were undisturbed (controls), or ff ff gic a erents ([5–7]). Di erent glutamate receptor subtypes exposed to varied, unpredictable, stressors for 7 days, ending can mediate synaptic currents with specific temporal prop- 1 week prior to mating. Pregestational stress did not affect erties. In particular, kainate receptors (KA-R) were shown conception rates, duration of pregnancy, litter size, or gen- to be preferentially expressed in CA1 stratum oriens in- der ratio of offspring, but offspring of stressed dams were terneurons ([8]) but little is known about their functional marginally lighter at birth as well as at 2 months, whereas distribution among cell types. Combining multibeam two- fostering increased body weight. Two hundred and eighty photon imaging of network activity in the CA1 region from eight offspring in 6 experimental groups were tested in a va- somatostatine(SOM)-GFP mice with targeted electrophys- riety of tasks to evaluate affective and social behavior. There iological recordings and morphological analysis, we show were complex interactions due to influence of preconcep- that SOM-EGFP+ interneurons are preferentially recruited tion stress, gender, and fostering, which suggested that pre- by synaptic stimulations at theta frequency and that KA-Rs conception stressed mothers contribute partially to the al- selectively participate in this activation in O-LM cells. Such terations in offspring behavior. However, some of the vari- preferential processing of excitatory inputs via KA-Rs by dis- ance was also explained by offspring differences—that is, tally projecting GABAergic microcircuits may explain their even if raised by control mothers, offspring of preconception pivotal role in theta band frequency generation. stressed dams showed behavioral changes. SupportedbyMarieCuriegrant. Supported by the BSF to ML and JS. 46 Neural Plasticity

Stable firing patterns in neural networks: a treatment of amblyopia tailored to LG, training him twice a a three-level model of consciousness week, monocularly and binicularly. After six months of training, a remakable improvement in all visual parameters was Gordon G. noted: Distance VA (LogMar) from 0.66 to 0.4 and 0.5 to 0.46 (R, L), near VA from 0.48 to 0.36 and 0.4 to 0.32, Lat- Department of Chemical Physics, Weizmann Institute of eral interactions, from 0.08 (suppression, log units) to −0.35 Science, Rehovot 76100, Israel (facilitation) and from −0.1to−0.36. The crowding effect was reduced from 0.233 to 0.06 and from 0.17 to 0.02. Stere- A novel, comprehensive theory of the neural correlates of opsis improved from 30 to 20 arcsec. Very importantly, we consciousness is presented. It states that two types of neural noticed a subjective improvement in his processing time for networks, namely feedforward networks and Hopfield-like recognition and the ability to identify objects and shapes re- feedback loops, compose three levels of consciousness: a low, quiring global integration. Thus, improvement of the visual unconscious processing level, a middle, conscious perception functions may be transferred to improvement—perhaps on level, and a high level, integrating consciousness. We claim a slower time scale—of cognitive functions and brain areas that only stable firing patterns of complex Hopfield-like feed- that were impaired. back neural networks give rise to conscious perception. Thus, low-level feedforward networks of sensory processing do not involve conscious perception, whereas the high-level feed- SupportedbyagrantfromtheIsraelScienceFoundation. back loops of many middle-level areas give rise to one, cohe- sive consciousness. Examples from visual and auditory sys- NAP reduces TAU hyperphosphorylation and tems are presented, as well as a thorough discussion on the enhances learning in a novel transgenic mouse model role of attention and subcortical areas within this framework. Several new conjectures arise from this theory and new ex- Gozes I.,1 Pinhasov A.,1 Mandel S.,1 Pikman R.,1 perimental designs are suggested. Grigoriadis N.,2 Touloumi O.,2 Pittel Z.,1 and Vulih-Shultzman I.1 Does abnormal binocular experience during critical period limit normal development of visual 1 cognitive functions? Human Molecular Genetics and Biochemistry, Sackler Medical School, Tel Aviv University, Israel Gotthilf-Nezri D.,1 Gilaie-Dotan S.,2 Perry A.,3 2Aristotle University of Thessaloniki, Stilp. Kyriakidi str 1, Bonneh Y.,2 Bentin S.,3,4 Malach R.,2 and Polat U.1 GR-54636 Thessaloniki, Greece

1Tel Aviv University, Sackler faculty of medicine, Complete deficiency of activity-dependent neuroprotective Goldschleger Eye Research Institute,Tel Hashomer, Israel protein (ADNP) is embryonic lethal, hence, the outcome 2Department of Neurobiology, Weizmann Institute of of partial ADNP deficiency was examined. ADNP+/- mice Science, Rehovot, Israel exhibited cognitive deficits, significant increases in phos- 3Department of Psychology, The Hebrew University of phorylated tau, tangle-like structures and neurodegenera- Jerusalem, Jerusalem, Israel tion as compared to ADNP+/+ mice. Increased tau hyper- 4Center for Neural Computation, The Hebrew University of phosphorylation is known to cause memory impairments Jerusalem, Jerusalem, Israel in neurodegenerative diseases associated with tauopathies, Amblyopia is a reduction of best-corrected visual acuity including the most prevalent Alzheimer’s disease. The cur- caused by abnormal visual experience during the “critical pe- rent study suggested that ADNP is an essential protein for brain function and plays a role in normal cognitive perfor- riod,” which prevents normal development of the visual per- ff ceptual functions, usually in one eye. The cognitive functions mance and social interactions. ADNP-deficient mice o er an are not affected, probably due to normal visual input from ideal paradigm for evaluation of cognitive enhancers. NAP the other eye. Does abnormal binocular visual experience (NAPVSIPQ) is a peptide derived from ADNP that inter- limit the development of normal visual cognition? Here we acts with microtubules and provides potent neuroprotection. report the case of LG, a 20-year-old male, with reduced visual NAP treatment partially ameliorated cognitive deficits and acuity in both eyes, which does not result from a known op- reduced tau hyperphosphorylation in the ADNP+/- mice tical deficiency and could not be corrected by spectacles. He ([1]). NAP is currently being tested by Allon Therapeutics has been diagnosed as congenital associative visual agnosia Inc. (www.allontherapeutics.com) in a phase II program in with severely impaired face identification; he does not rec- Alzheimer’s disease. ognize very familiar faces including his own and his parents’, and has dificulies identifying distant objects. He has no other Supported by BSF, ISF, Lily, and Avraham Gildor Chair, Adams neurological disorders, he can read, his IQ is above average, Super Center and Allon Therapeutics Inc. and he functions normally in any other aspect. His early and high-level visual areas displayed robust fMRI activation by References visual stimuli, whereas intermediate visual areas displayed profound ihibition during visual processing. We employed [1] Journal of Pharmacology and Experimental Therapeutics, 2007. Israel Society for Neuroscience 47

Movement parameters are related to inter-trial the two contextual factors affect object recognition with or variability of single units activity in motor cortex without interacting, supporting a unified versus independent representations, respectively. Results revealed a semantic by Grinvald Y.,1 Inbar D.,1,2 Zach N.,1,2 and Vaadia E.1,2 spatial interaction in reaction times for target object recognition. Namely, significant semantic priming was obtained 1Physiology Department, Hadassah Medical School, when targets were positioned in expected (congruent), but Hebrew University, Jerusalem, Israel not in unexpected (incongruent) locations. fMRI results 2Interdisciplinary Center for Neural Computation (ICNC), showed corresponding interactive effects in brain regions as- Hebrew University, Jerusalem, Israel sociated with semantic processing (inferior prefrontal cortex), visual contextual processing (parahippocampal cortex), Common analysis of neuronal data involves averaging of ac- and object-related processing (lateral occipital complex). In tivity across many trials or events ignoring possible effects addition, activation in frontoparietal areas suggests that at- of trial-by-trial variability. The objective of this study is to tention and memory-related processes might also contribute examine representations of behavioral parameters with sin- to the contextual effects observed. These findings indicate gle trial resolution. We simultaneously recorded, single unit that object recognition benefits from associative representa- activities using 32 independently moveable microelectrodes tions that integrate information about objects’ identities and from primary motor (M1) and pre-motor areas of the mon- their locations, and directly modulate activation in object- key during performance of “center-out” reaching movements processing cortical regions. Such contextual schemas are use- and during visuomotor learning. We computed the relations ful in maintaining a coherent and meaningful representation between firing rate of single cells in single trials to several of the visual world, and in providing a platform from which behavioral parameters (reaction time, movement time, peak predictions can be generated to facilitate perception and ac- velocity, trajectory curvature and others). We found that fir- tion. ing rate variability of single cells could be significantly correlated with behavioral events, and in many cases with more RHO/ROCK signaling negatively modulates than one behavioral parameter. The correlation was highest delimination of neural crest cells downstream of during movements towards the cell’s preferred direction. In- BMP and G1/S transition terestingly, the degree of correlation could change at different time windows and was not restricted to the time of increased Groysman M. and Kalcheim C. mean firing rate. Further, the trial-by-trial analysis revealed relations that could not be observed in the averaged evoked Department of Anatomy and Cell Biology, Hebrew University response of the cell. These findings show a useful tool for ob- of Jerusalem-Hadassah Medical School Jerusalem, Israel serving relations between the activities of single cells at the level of single trials and may explain variability in behavioral During neural crest (NC) ontogeny, an epithelial to mes- performance. These correlates may improve inference of be- enchymal transition is necessary for cell emigration from havior on the basis of neural activity. the dorsal neural tube. This process is likely to involve a network of gene activites which remain largely unex- Supported by BSF, J and J Fund for Innovative Science, FIF by plored. We demonstrate that Rho signaling, via Rock, in- Rosetrees Trust, Abraham and Ida Baruch Foundation. hibits the onset of NC delamination. In vivo loss-of-function of RhoA or RhoB or of general Rho signaling by C3 trans- Integrated contextual representation for ferase enhanced NC delamination. Consistently, treatment objects’ identities and their locations of neural primordia with C3 or with the Rock inhibitor Y27632 both accelerated and enhanced NC emigration. Re- Gronau N.1,2 and Bar M.2 ciprocally, Rho activation by LPA inhibited the process. Next, we analyzed the responsible mechanisms. Inhibition 1The open university of Israel, Raanana, Israel of Rho/Rock profoundly affected the morphology of NC 2Martinos Center for Biomedical Imaging at MGH, Harvard cells by disrupting actin stress fibers and vinculin focal ad- Medical School, Mass, USA hesions. Moreover, it stimulated a premature downregulation of N-cadherin and of cell-cell adhesions. Reciprocally, Visual context plays a prominent role in every day percep- retention of stress fibers, focal adhesions and N-cadherin tion. Contextual information can facilitate recognition of ob- were monitored upon treatment with LPA. Possible interac- jects within scenes by providing predictions about objects tions between Rho and the BMP-dependent pathway lead- that are most likely to appear in a specific setting, along ing to NC delamination were addressed. Blocking Rho or with the locations that are most likely to contain objects in Rock function rescued NC delamination in explants treated the scene. Is such identity-related (semantic) and location- with noggin or with the cell-cycle inhibitor mimosine. In related (spatial) contextual knowledge represented separately the latter case, NC cells emigrated while arrested at G1. or jointly as a bound representation? We conducted an fMRI Hence, Rho signaling negatively regulates NC delamina- priming experiment whereby semantic and spatial relations tion through modification of cytoskeleton assembly and cell- between prime and target object pictures were independently cell adhesions by acting downstream of BMP and of G1/S manipulated. This method allowed us to determine whether transition. 48 Neural Plasticity

The restless mind—a relation between rest and 2Interdisciplinary Center for Neural Computation, the self in the brain—a deep-TMS study-presentation Hebrew University, Israel of preliminary results 3Center for Brain Science, Harvard University, Mass, USA

Gruberger M.,1,2,3 Hendler T.,1,3,4 Zangen A.,5 In many natural tasks auditory systems must satisfy two and Levkovitz Y.2,4 seemingly conflicting requirements: on one hand, information processing often relies on exquisite sensitivity to fine 1Department of Psychology, Tel-Aviv University, Israel temporal features of the incoming signal. On the other hand, 2The Emotion-Cognition Research Center, The Shalvata the overall time scale of these input signals can be subject Mental Health Center, Hod-Hasharon, Israel to substantial variability. For instance in speech, variations 3Functional Brain Center, Tel-Aviv Sourasky Medeical Center, in speaking rate can readily introduce a time warp rang- Tel-Aviv, Israel ing from two fold compression to two fold dilation. How 4Sackler Faculty of Medicie, Tel-Aviv University, Israel does the neural system overcome this challenge? To address 5Department of Neurobiology, The Weizmann Institute of this question we study a neural model of spike-based learn- Science, Rehovot, Israel ing of an auditory discrimination task, extending our recent tempotron model. In our present model, synaptic inputs are The human tendency to think spontaneously in the absence modeled as conductances rather than current pulses. In the of cognitive load is one aspect of the “self” challenging neu- conductance-based tempotron the time scale of the voltage roscience research. This tendency was suggested to be re- dynamics strongly depends on the total synaptic conduc- lated to the “default-mode” brain network, which shows in- tance rather than being a fixed parameter. As a result, the creased activity at rest. Support for this notion stems from statistics of inputs as well as the synaptic learning rule, inter- studies indicating that the medial prefrontal cortex (MPFC), act with the time scale of neural information processing by a main component of this network, is associated with self- changing the effective integration time constant of the cell. related functioning. The current study examined a direct Importantly, since the effective membrane time constant of manipulation of MPFC, an important addition to prior re- the neuron scales inversely with its total conductance, the search which used only correlative imaging techniques. The neuron exhibits a high degree of time warp invariance. We manipulation of MPFC in conscious participants was per- have applied our model to speech recognition problems. Us- formed by means of deep transcranial magnetic stimulation ing a simple model of the auditory periphery, sound sig- (dTMS) administered with the H-coil, a novel TMS coil for nals are converted into spike patterns by thresholding their ff deep brain stimulation. The e ect of a “temporary lesion” in power-spectral densities, and fed into a small population the MPFC was assessed using inhibitory dTMS, followed by a of conductance-based Integrate and Fire neurons. Surpris- 2-minute “rest” period. This “lesion” was expected to atten- ingly, using our tempotron learning rule, the system achieved uate “default-mode” activity during rest, resulting in an al- nearly perfect word recognition accuracy on a standardized tered sense of “self” and induced sense of dissociation. Forty digit recognition task. Our results show that simple biolog- subjects are planned to participate in this study, which will ically plausible mechanisms of spatio-temporal integration include real versus sham dTMS conditions and “rest” ver- and synaptic plasticity, can endow the neural system with sus “no-rest” conditions. Here we present preliminary results powerful time warp invariant auditory processing capabili- obtained from the first ten participants, five in the “dTMS + ties. rest” condition and five in the “dTMS + no-rest” condition. Senses of self and of dissociation were examined using situ- Supported by Minerva Foundation, ISF (Center of Excellence ational self-awareness questionnaires and a situational sense no. 8006/00), MAFAT. of dissociation questionnaire. Results show that whereas subjects in the “dTMS + no-rest” condition did not experience Visual-auditory integration in the barn owl: a noticeable change, subjects in the “dTMS + rest” experi- a neuroethological approach enced a dissociative sensation, accompanied by alterations in the level of self-awareness. Subjects’ free reporting support Gutfreund Y., Reches A., and Zachar Y. this data, and include describing a temporary feeling of de- tachment and numbness. These preliminary results support Department of Physiology, The Faculty of Medicine, the notion that MPFC activity during rest might be signifi- The Technion, Israel cant for an integrative, on-going sense of self in humans. Research on multisensory integration has expanded rapidly This study was supported by the Adams Super-Center for Brain in recent years attracting scientists from a variety of fields in- Studies, Tel-Aviv University, Israel. cluding psychophysics, MRI, robotics and single cell studies. In my presentation I will highlight the potential of the barn The conductance-based tempotron: a model for owl as a unique animal model for research on visual auditory ffi time warp invariant auditory processing integration. Barn owls are highly e cient nocturnal predators that have evolved precise and sensitive visual and au- Guetig R.1,2 and Sompolinsky H.1,2,3 ditory systems. Barn owls operate in noisy and dim lighted environments, environments where the benefit of merging 1Racah Institute of Physics, Israel information from different modalities is substantial. Thus, Israel Society for Neuroscience 49 the ability to integrate visual and auditory signals may be Lithium has been the standard pharmacological treatment critical to the survival of this species. I will describe recent re- for bipolar disorder over the last 50 years, however the sults from my lab on the properties of multisensory neurons molecular targets through which lithium exerts its therapeu- in the forebrain and midbrain of the barn owl and will com- tic effects are still not defined. Inhibition of the activity of pare these findings with results obtained from cats (an ani- the enzyme inositol monophosphatase by therapeutically rel- mal model commonly used for the study of visual-auditory evant lithium concentrations raised the possibility that this integration). enzyme is the primary target of this drug. Mammalian inositol monophosphatase is coded by two genes, IMPA1 and This work was supported by an ISF BIKURA grant. IMPA2. IMPase activity levels were found to be reduced (up to 65% in hippocampus) however inositol levels were not Where are my arms? An octopus visually controlling found to be altered and animals survived during two weeks its arm movements on inositol deficiency food. We characterized the behavioral phenotype of mice with a knockout IMPA1 gene (IMPA1-/- Gutnick T., Byrne R. A., Kuba M. J., and Hochner B. ) to study the in vivo physiological functions of IMPA1, in general, and more specifically its potential role as a molec- Department of Neurobiology, Institute of Life Sciences and ular target in mediating lithium-dependent physiological ef- Interdisciplinary Center for Neural, Israel fects. In brains of adult IMPA1-/- mice Behavioral analysis of the IMPA1-/- mice indicated an increased motor activity in Octopuses depend on the high flexibility of their arms to the open-field test, the forced-swim test and the tail suspen- carry their arms to carry out a large variety of task like hunt- sion test. In conclusion the IMPA1-/- mouse indicates that ing, swimming and mating. Thus far only the motor primi- genetic inactivation of IMPA1 can mimic some actions of tive reaching for a target movement has been shown to be vi- lithium. sually guided. Other movements that do utilize the high flexibility of the arms, like those used for searching and probing, Transcriptional control of commissural have been hypothesized to be largely autonomous and not di- neuron cell fate rectly controlled by the central nervous system. We designed a behavioral task allowing us to define a relationship between the CNS and the peripheral nervous system that enables di- Hadas Y., Shkolnik N., and Klar A. rected arm movement. Eye-arm coordination was tested using a transparent Plexiglas maze. 9 adult Octopus vulgaris Department of Anatomy and Cell Biology, Hebrew University, were trained to insert a single arm through a tube for a food Hadassah Medical School, Jerusalem, Israel reward. Initially, food was presented inside a tube for several days, and animals learned to reach in to collect a food The dI1, dI2, and dI3 classes of interneurons originate at reward. Next, the transparent three armed maze was intro- the dorsal spinal cord, from a group of progenitors defined duced fully baited. These introductory phases accustomed by the expression of bHLH transcription factors: Math1, the subjects to reach through a tube, out of the water and Ngn1+Ngn2, and Mash1, respectively. The expression of the into a goal box in order to retrieve food. In the experimental bHLH transcription factors is followed by the expression of phase a food reward was placed in only one of the three com- Lim-HD transcription factors Lhx2 + Lhx9, Lim1 and Isl1, partments that was visually cued, octopuses were required to respectively. In all postmitotic dI neurons sequential activa- guide their arms towards the rewarded compartment. Cri- tion of other transcription factors leads to the expression of teria for successful learning were the completion of 5 cor- receptors for floor plate derived guidance molecules (DCC, rect trials in a row. 6 of the 9 animals completed the exper- Rig1, TAG-1) which enable the commissural interneuron to iment, reaching criterion within 22 to 208 trials. After cri- reach the floor plate. Ectopic expression in the chick neu- terion was reached 20 control trials were preformed using ral tube was used in order to investigate the role of differ- an opaque maze. During control trials the animals’ perfor- ent transcription factors in the determination of dI neurons mances fell back to chance level. This study is the first behav- and the segregation of dI neurons to different dI subclass. We ioral test showing that octopuses can learn to visually control found that a bHLH gene, NSCL1 transiently induce expres- arm movements that are not restricted to the control of few sion of the commissural neuron receptors TAG1 and Rig1 degrees of freedom (like reaching). Our findings suggest that but does not induce the expression of Lim-HD proteins. Ec- octopuses are capable of central control of arm movements topic expression also demonstrated corepression between the and perhaps cross reference between different sensory inputs lim-homeodomain proteins: Lhx9 inhibits the expression of and motor outputs. Lim1 and Isl1, Lim1 inhibits the expression of Lhx2/9 and Isl1 inhibits the expression of Lhx2\9 and Lim1. Thus, two IMPA1 and lithium-like behavior parallel differentiation pathways may regulate commissural interneuron fate. The initial commissural axonal trajectory Hadas I., Agam G., Belmaker R., and Bersudsky Y. might be governed by the activation of TAG1/Rig-1/DCC expression by the bHLH protein NSCL1. Subsequently, subtype Stanley Research Center, Faculty of Health Sciences, Ben specification is determined by the expression of Lim-HD Gurion University and Mental Health Center, Israel proteins. 50 Neural Plasticity

Tyrosine kinase Syk regulates differentially myelin frequency, respectively, there is no equivalent metric in olfac- and pathogen phagocytosis mediated by complement tion, and the rules linking neural responses to odorant fea- receptor-3, dectin-1, and mannose receptor tures remain unknown. Several studies have linked response patterns to restricted odorant features, such as number of Hadas S., Reichert F., and Rotshenker S. carbons, and type/position of functional group. These met- rics, however, fail to account for response patterns to odor- Department of Anatomy and Cell Biology, Faculty of ants varying along other structural dimensions. To generate Medicine, Hebrew University, Israel a multidimensional odor metric, we obtained 1664 molecular odorant features, and generated a metric where each Microglia play a critical role in the innate immune response molecule was represented as a vector of descriptor values. Re- of the CNS to injury and disease by removing, through visiting numerous studies, we found that this novel olfactory phagocytosis, tissue debris (degenerating myelin in injury metric was always better at accounting for neural responses and demyelinating diseases) and pathogens (yeast). Phago- than the specific metric used in each study. Critically, this sin- cytosis of C3bi-opsonized myelin is mediated by Comple- gle metric was equally applicable across studies in different ment Receptor-3 (CR3) and phagocytosis of nonopsonized animals, and olfactory neurons that used odorants varying myelin by CR3 and Scavenger Receptor-A (SRA). Phagocy- along different feature types and different neuronal response tosis of C3bi-opsonized Zymosan (yeast derived particle) is measurement methods, where it explained previous anoma- mediated by CR3, and phagocytosis of nonopsonized Zy- lies in odorant response profiles. Thus, we propose an olfac- mosan by Dectin-1 (beta-glucan receptor) and mannose re- tory metric that provides a unified account of independently ceptor (MR; alpha-mannan receptor). The protein tyrosine obtained results, and offers a quantitative measure for odor- kinase spleen tyrosine kinase (Syk) is critical for immune ant comparison. Finally, we recommend on sets of odorants responses. In the present study, we tested the role of Syk that are best in terms of spanning the physicochemical space in regulating phagocytosis of myelin and Zymosan in mi- for use in olfactory neuronal response experiments. croglia. Syk inhibitors, Syk-Inhibitor and R406, augmented phagocytosis of C3bi-opsonized and nonopsonized myelin in Novel spine-like gold structures as microglia expressing CR3 and SRA combined or separately. a three dimensional substrate for Syk thus downregulates phagocytosis of C3bi-opsonized and neuro-electronic hybrids nonopsonized myelin by CR3 and SRA. Syk-Inhibitor did not modulate phagocytosis of C3bi-opsonized Zymosan but Hai A.,1 Kamber D.,1 Dormann A.,1 Shappir J.,2 inhibited phagocytosis of nonopsonized Zymosan. Syk thus Yitzchaik S.,3 and Spira M.1 upregulates Dectin-1 and/or MR mediated phagocytosis of nonopsonized Zymosan and down-regulates CR3 mediated 1Department of Neurobiology, The Life Sciences Institute phagocytosis of C3bi-opsonized Zymosan. Syk-Inhibitor in- 2School of Engineering, Israel hibited phagocytosis of C3bi-opsonized and nonopsonized 3Department of Inorganic and Analytical Chemistry, Zymosan in microglia lacking CR3, thus no CR3 mediated The Hebrew University of Jerusalem, Israel phagocytosis, supporting the suggestion that Syk upregu- Integration of neurons with microelectronic devices has been lates Dectin-1 and/or MR mediated phagocytosis of nonop- a subject of intense studies over the last decade. One of the sonized Zymosan. Syk-Inhibitor augmented phagocytosis of major problems in assembling efficient neuroelectronic hy- C3bi-opsonized Zymosan in HL60 cell line that express CR3 brid systems is the weak electrical coupling between the com- but neither Dectin-1 nor MR, thus CR3 mediated phago- ponents. This is mainly due to the fundamental property of cytosis only, supporting the suggestion that Syk downregu- living cells to form and maintain an extracellular cleft be- lates CR3 mediated phagocytosis of nonopsonized Zymosan. tween the plasma membrane and any substrate to which they Thus altogether, Syk downregulates CR3 and SRA mediated adhere. This cleft shunts the current generated by the neuron phagocytosis and upregulates Dectin-1 and/or MR mediated and the device and thus reduces the signal-to-noise ratio. In- phagocytosis. creasing the seal resistance formed between the neurons and SupportedbyNiderSachsenIsraeliCooperation. the gate surface is thus a challenge which could improve the coupling coefficient. Here we report a new approach to im- A Method for Odorant Comparison prove the physical and electrical coupling between neurons and the surface of electronic chip by harnessing a basic prop- Haddad R.,1 Kahan R.,2 Harel D.,1 and Sobel N.2 erty of cells namely, the internalization of particles by phagocytosis. To that end we fabricate gold micro-structures in the 1Department of Computer Science and Applied form of dendritic spines that protrude from the transistor Mathematics, the Weizmann Institute of Science, Israel gate surface (micrometer scale). The protruding structures 2Department of Neurobiology, Weizmann Institute of were functionalized by poly-l-lysine. Using on line confocal Science, Israel microscope imaging of neurons expressing GFP-actin we observed that cultured Aplysia neurons readily engulf the gold- In order to study a sensory system, one needs to quantify the spines forming tight physical contact between the cells and response to stimuli that vary systematically. Whereas in vi- the surface of the device. Electron micrographs of the con- sion and audition one can vary the stimuli by wavelength and tact area confirm that the plasma membrane of the neurons Israel Society for Neuroscience 51 engulfs the gold-spines and that the gap formed between the 2Neurobiology Department, Institute of Life Sciences, Israel plasma membrane and the artificial spine is 30–70 nm. Mea- 3School of Computer Sciences and Engineering, Hebrew surements of the extracellular field potentials by passive gold University, Jerusalem, Israel spines indicate that the neuron-gold spine junction may im- 4Gonda Brain Research Center and Department of prove the electrical coupling of neuro electronic hybrids sig- Psychology, Bar-Ilan University, Ramat-Gan, Israel nificantly. Category learning is a fundamental cognitive capacity that Sensory gating in primary insomnia: A potential enables meaningful and economical representations of ob- objective measure of reduced sleep quality jects and events. Recent studies, both in the field of machine learning and in the field of cognitive development, stressed Hairston I. S., Talbot L. S., Polina E., June G. L., the importance of objects comparison for the process of cat- and Harvey A. G. egory learning. We claim that although theoretically cate- Psychology Department, University of California, gories can be learned and refined by either identifying at- Berkeley, Calif, USA tributes shared by objects within specific categories as well as identifying the attributes discriminating objects from dif- Primary insomnia (PI) is the difficulty initiating and/or ferent categories, there is a difference in the usability of these maintaining sleep, or experiencing nonrestorative sleep in two types of comparison by humans. In a recent study we the absence of another sleep disorder, psychiatric or physi- compared adults’ performance with that of children in a cat- cal cause. The hyperarousal hypothesis is the leading theory egory learning task. We discovered that when presented only for the aetiology of PI. The model poses that due to cogni- with objects known to be from the same category, children tive and physiological hyperarousal, individuals with PI fail learned the categorization rules as well as adults. However, to experience the full deactivation of sensory and cognitive when presented only with objects from different categories, processing which normally occurs during sleep. A potential unlike adults, most children failed to learn the categorization implication of this hypothesis is that processing of informa- rules. This difference between learning from pairs of the same tion during sleep would differ between people with PI and versus different categories may explain known phenomena healthy sleepers. In this study we tested whether participants in cognitive development, such as the common difficulty of with PI exhibit impaired gating of external sensory stimu- young children in learning subordinate-level categories, and lation during sleep. The markers of sensory processing in- the late emergence of expertise. We suggest that such diffi- cluded evoked K-complexes and changes in event-related po- culties results from cognitive, not perceptual, immaturity– tentials (ERPs). 15 participants meeting DSM criteria for in- mainly poor logico-inferential capacity for extracting infor- somnia, for a minimum of six months, and 15 controls slept mation from exemplars identified as belong to different cat- in the lab for polysomnography and ERP testing. The ERP egories. stimulus consisted of pairs of clicks (10 milliseconds ∼50 dB, ISI = 500 milliseconds, ITI = 3000 milliseconds). This stimu- This study was supported by a “Center of Excellence” grant from lus was presented during wake, while watching a silent movie, the Israel Science Foundation, a grant from the US-Israel Bina- and then during subsequent sleep. Polysomnography data tional Science Foundation, and a grant by the EU under the was staged, and blocks of stimuli that occurred during stage DIRAC integrated project IST-027787. II were used for ERP analysis. The number of evoked K complexes was quantified by comparing number of K complexes without stimuli, to an equivalent period when stimuli were Purinergic signaling in satellite glial cells in sensory presented. Participants with insomnia had significantly in- ganglia is enhanced in mouse models of chronic pain creased P300 during wake and sleep, with a smaller attenuation to the second stimulus. During sleep, both groups Hanani M., Kushnir R., and Cherkas P. S. showed an equivalent amount of evoked in K complexes in response to stimulation. However, overall participants with Hebrew University, Hadassah Medical School, Hadassah insomnia had more K complexes. These findings indicate University Hospital, Jerusalem 91240, Israel that PI is associated with altered gating mechanisms in both sleep and wake, and is the first objective measure for sleep Satellite glial cells (SGCs) are the main type of glial cells in disorder known in this population. sensory ganglia. The morphology of these cells has been described in detail, but little is known about the physiologi- Supported by NARSAD, APA postdoctoral fellowship, and cal and pharmacological properties. We have shown previ- UNCF-Merck postdoctoral fellowship. ously that SGCs in trigeminal ganglia (TG) are endowed with functional P2Y purinergic receptors, and the objective of the The role of object comparison in category learning present work was to find out whether these receptors are al- and the emergence of expertise tered under pathological states–axotomy of the infraorbital Hammer R.,1,2 Diesendruck G.,4 Weinshall D.,1,3 nerve or complete Freund’s adjuvant (CFA) injection in the and Hochstein S.1,2 submandibular region of mice. Trigeminal ganglia were removed 4–7 days after treatments and were tested in vitro. We 1Interdisciplinary Center for Neural Computation, Israel examined changes in intracellular Ca2+ in SGCs in TG in 52 Neural Plasticity response to ATP using Fluo-3 or Fura-2 as Ca2+ indi- sis was used. Three gene sets were modulated in at least cators. The effects of submandibular inflammation were 2 time points (FDR < 0.05). Cell cycle gene set was up- tested in short term cultures (20 h), and that of axotomy regulated 2 h after hypoxia followed by down-regulation at in intact ganglia. In controls the threshold of SGC re- later time points. Mg induced opposite influence upregu- sponse to ATP concentration was 5 microM (>20% of the lating cell cycle genes 24 hours and 20 days after the insult. cells responded), and reached maximum at 100 microM; Mitochondria gene set was downregulated at all times fol- at least 25 cells were examined at each concentration. In lowed SH. Mg caused downregulation at 2 h and 20 days, in SGCs from treated mice the threshold for ATP effect was contrast to upregulation at 24 hours after the insult. Over- 0.01 microM (i.e., 500-fold lower than control) and reached all, prenatal hypoxia effect is most noticeable 20 days after maximum at 10 microM. These results apply for both treat- the injury. Opposite change due to Mg pretreatment was ments. In this work we showed for the first time that observed in some times, suggesting interference in similar the sensitivity of SGCs in TG to the inflammatory me- mechanism. diator ATP greatly increased after axotomy and inflammation. We conclude that SGCs are likely to be involved Supported by BSF Grant no. 2003166. in pathological changes in TG and might contribute to the abnormal signaling that takes place in chronic pain Is it a European car or a Japanese car? An ERP study of states. diagnostic information use in visual expertise 1 1,2 SupportedbyBSFandISF. Harel A. and Bentin S. 1Department of Psychology, Hebrew University of Prenatal hypoxia influences cerebellum Jerusalem, Israel gene expression 2Center of Neural Computation, Hebrew University of Haramati O.,1 Chalifa-Caspi V.,2 Perez-Polo J.,3 Jerusalem, Israel and Golan H.4 Expertise in object recognition requires knowledge of the di- 1Developmental Genetics Faculty of Health Sciences and agnostic visual features of the object. The nature of the di- Bioinformatics Core Facility, Ben Gurion University, Israel agnostic information and the stage in the visual processing 2Bioinformatics Core Facility and the National Institute of hierarchy at which it is utilized are still unknown. We com- Biotechnology, Ben Gurion University, Israel pared performance and event-related potentials (ERPs) of 3Biochemistry and Molecular Biology, University of Texas 15 car experts and 15 novices performing a category veri- Medical Branch, Galveston, Tex, USA fication task. The objects categorized were from categories 4Developmental Genetics Faculty of Health Sciences and with which the two groups had different levels of experience Zlotowski Center, Ben Gurion University, Israel (faces, cars, and airplanes) and were categorized at the basic and subordinate levels. The information contained in the Prenatal hypoxia is related to a variety of motor dysfunc- images was manipulated by filtering them at different spa- tions and behavioral problems in the adult life. One of tial frequencies (SF). Experts and novices showed equiva- the treatments used for prenatal hypoxia is MgSO4 (Mg), lent performance for faces and airplanes. Face subordinate although the exact mechanism is unknown. Our primary categorization relied more on low SFs than on high SFs, goal was to find gene networks that were modulated by hy- while subordinate categorization of airplanes relied more poxia and elucidate the mechanisms involved in Mg pro- on high SFs. Subordinate categorization of cars, however, phylactic action. Pregnant mice were treated i.p. at 17 days differed between experts and novices. Experts relied more gestation with Mg/PBS every 20 minutes (4 hours) followed on high SFs than on low SFs while novices performed at by 2-hour hypoxic (9% O2,3%CO2) or normoxic condi- chance level irrespective of SF. Electrophysiologically, N170, tions. The mice divided for 3 groups: SA (PBS+normoxia), an early face-selective ERP component, was modulated by SH (PBS+hypoxia) and MgH (Mg+hypoxia). Fetus cere- expertise but this effect did not interact with SF or cate- belli were isolated 2 hours, 24 hours, and 20 days after in- gorization level. In the experts’ left hemisphere N170 am- sult. mRNA was extracted and gene expression was ana- plitude in response to cars was equivalent to N170 am- lyzed by affymetrix DNA chips (mouse 430 2.0). Mixed- plitude to faces, both higher than to airplanes. In novices model 2-Way ANOVA (Partek) was used to compare effect the N170 in response to cars was equivalent in response to of treatment (SH-SA and MgH-SA). SH modified the ex- airplanes, both being smaller in amplitude than the N170 pression of 7, 3 and 1127 genes, at 2 h, 24 h and 20 days to faces. Our findings suggest that the diagnostic infor- after hypoxia, respectively (at least 1.5 folds change com- mation needed for expert object recognition is quantita- pared to SA group (FC) P<.05), while pretreatment with tively and not qualitatively different from everyday object Mg followed by hypoxia changed the expression of 10, 10 recognition, as similarly to airplane subordinate categoriza- and 832 genes at parallel times. Among the genes changed tion in novices, expert subordinate car categorization re- 20 days after insult 74 were modified more than 2.5 FC lied on high SFs. Furthermore, the expert use of specific SF by SH and only 15 when Mg was applied (14 appeared in scales does not occur at the early perceptual stages reflected both comparisons). To identify signaling pathways modu- by the N170 and may be related to later post-perceptual lated by the treatments, the Gene Set Enrichment Analy- processes. Israel Society for Neuroscience 53

Attentional resources become available to Methods the auditory system during the Visual Attentional Blink Spontaneously hypertensive rats underwent permanent middle cerebral artery occlusion (PMCAO) and were given BrdU Haroush K.,1 Hochstein S.,1,3 and Deouell L. Y.2,3 to label newborn cells. Animals were treated with vehicle or with PMPs delivered via a biodegradable polymer applied 1Department of Neurobiology, Israel to the brain surface immediately following injury. Animals 2Department of Psychology, Israel were tested with a reproducible motor and sensory score 3The Interdisciplinary Center for Neural Computation, Israel for 90 days after PMCAO. Infarct volumes were measured at 90 days post—PMCAO. We used immunohistochemistry to evaluate the fate of newborn cells in the ischemic brain. The Attentional Blink (AB) is a well-explored phenomenon Newly formed blood vessels were counted in the brains to during which a first target within a rapid sequence of stim- evaluate angiogenesis. uli is successfully detected yet a second target fails to be reported. The question whether the AB deficit is of merely visual nature or affects several modalities, such as auditory and Results tactile, has been extensively debated. Previous studies used Our results demonstrate a dose dependent increase in the dual task paradigms to address this question. The main prob- number of newborn cells in animals treated with PMPs and lem with this approach is that the dual tasking effect could a significant increase in the number of blood vessels ob- not be separated from the blink effect. In the current study, served at the infarct boundary zone. Treatment with PMP we bypassed this obstacle by registering Event-Related Poten- significantly improved behavioral deficits in a dose depen- tials (ERPs) to an unattended deviant stimulus within an au- dent manner and there were no significant differences in in- ditory stream while participants are engaged in a visual AB farct volumes between the different treatment groups. paradigm as their only behavioral task. The mismatch neg- ativity (MMN) ERP signature of involuntary change detec- Conclusions tion is the difference between the response to auditory standards and deviants. Surprisingly, we find that when condi- PMPs significantly induce neurogenesis and angiogenesis af- tional identification of the second visual target fails (at lag ter PMCAO in a dose-dependent manner and these effects 3), the MMN significantly increases. We suggest that when are correlated with better functional outcome and reduced the visual system blinks, attentional resources are freed up for disability in the long term after stroke despite the lack of a use by the auditory modality, resulting in facilitated change neuroprotective effect. This strategy can be used in subse- detection processes as reflected in the augmented MMN re- quent studies to further improve functional gain after brain sponse. injury.

Supported by the Israel Science Foundation and the US-Israel Supported by Peritz and Chantel Scheinberg. Binational Science Foundation. Adaptation to repetitive whisker stimulation is highly Cell-driven angiogenesis and neurogenesis after correlated among neurons in the rat barrel cortex stroke with platelet derived microparticles Heiss J., Oron E., Grinvald A., and Lampl I. Hayon Y.,1 Leker R.,1 Varon D.,2 and Brill A.2 Department of Neurobiology, Weizmann Institute of Science, Israel 1Neurology, Hadassah Medical Center, Hebrew University, Jerusalem, Israel It is thought that adaptation in the barrel cortex results 2Hematology, Hadassah Medical Center, Hebrew University, from short term synaptic depression of thalamocortical in- Jerusalem, Israel puts. The probabilistic nature of synaptic transmission and its modulation by short term depression should contribute Background to cell-specific trial to trial variability during repetitive stimulation. Here we compared the trial to trial variability of Activation of endogenous neural stem cells (eNSCs) has been subthreshold synaptic adaptation in vivo, during periodic proposed as a novel form of therapy in a variety of neuro- whisker deflection in couples of simultaneously recorded logical disorders, including stroke. Previous data suggest that cells. Additionally, we compared the adaptation exhibited by application of external factors can boost a long-term endoge- a large population of neurons, which was detected using fast nous repair mechanism. Upon activation platelets shed mi- optical imaging based on voltage sensitive dyes (VSDs), with croparticles (PMPs) which contain a variety of growth fac- the adaptation of intracellularly recorded cells. Because the tors that are central to angiogenesis and neurogenesis. Be- VSDs signal reflects primarily the average synaptic potentials cause interrelations between newborn neural and endothelial of the neuronal population, rather than spiking activity, this cells are essential to eNSC survival, maturation and differen- allowed us to extend the comparison of adaptation of synap- tiation we evaluated the effects of PMP after brain ischemia. tic inputs to the population level. Considerable trial to trial 54 Neural Plasticity variability in adaptation was reveled by measuring the re- 2Interdisciplinary Center for Neural Computaion, sponsiveness of the cell to repetitive stimulation. These ex- Hebrew University, Jerusalem, Israel periments showed a high correlation of the adaptation between nearby neurons recorded simultaneously as well as be- Sounds in natural settings always appear over a noisy back- tween a single cell and the optically monitored large popula- ground, and the way the auditory system extracts sounds tion of responsive neurons in its vicinity. These results sug- from such backgrounds is of extreme importance both the- gest that adaptation of cortical neurons depends not only on oretically and practically. The theory of masking of tones by short term synaptic depression, but also on a coordinated noise drove human psychoacoustic research and resulted in process that homogenize adaptation among nearby neurons arguably the most important concept in hearing, that of the either at the thalamic or cortical level. critical band. In the mouse, the critical band is wide relative to other mammals. As a result, the mouse is a useful model This work was supported by ISF–The Charles H. Revson Foun- for discriminating between peripheral and central process- dation and the Goldsmith foundation. ing mechanisms in masking. We are using intracellular and extracellular recordings in vivo in mice to study neuronal re- The Origin of Hering’s Law of Equal Innervation sponses in the auditory cortex to tones masked by broadband noise or by slowly fluctuating broadband noise maskers. The Hendel T. and Gur M. masked threshold (lowest level at which the presence of a Faculty of Biomedical Engineering, Technion–Israel Institute tone can be observed in the neuronal responses in presence of Technology, Israel of a masker) increases with noise level. Such results can be explained by energy masking in the peripheral auditory sys- Hering’s law of equal innervation implies that eye move- tem: once the signal-to-noise ratio within the critical band ments are accomplished by two independent subsystems: one centered at the target tone frequency is high enough, the for purely conjugate movements (version) and one for purely tone is detected. However, when Additional information is disconjugate movements (vergence). Thus, in order to fix- supplied to the auditory system by slowly modulating the ate a certain point in space, the oculomotor system does not masker, masking can be reduced substantially below the val- move each eye separately, but, rather, sends the extra-ocular ues expected from pure energy masking. muscles a combination of version and vergence signals to direct the eyes to the sought for fixation point. Experiments Supported by a grant from the Joint Niedersachsen–Israel pro- devised to test Hering’s law have indeed verified the existence gram. of two types of eye movement, each with its own characteristics: versional movements are either extremely fast (hun- Recognising your own hands: attribution biases & dreds of degrees/sec) preprogrammed saccadic movements brain mechanisms or slow smooth pursuit movements, whereas vergence movements are slow (tens of degrees/sec) smooth eye movements Holmes N. P.,1,2 Revol P.,1 FarneA.,` 1 Rode G.,1 that are evoked by retinal disparity and rely on visual feed- Spence C.,3 Calvert G.,4 and Rossetti Y.1 back. The clear discrepancy between the two types of eye movements has usually been taken as a confirmation of Her- 1Espace et Action, INSERM Unite 864, Bron, France ing’s suggested law. However, more precise measurements of 2Department of Psychology, Hebrew University, eye movements have shown seeming deviations from Her- Jerusalem, Israel ing’s law in accommodative vergence experiments. In light 3Department of Experimental Psychology, of these apparent deviations from Hering’s law, some re- Oxford University, Oxford, UK searchers have completely abandoned the concept of equal 4Department of Psychology, Bath University, Bath, UK innervation to the two eyes. Others retained the basic law, but hypothesized a “holding reflex,” which needs to be added to the other known types of eye movements. In contradis- Visual self-recognition in humans is thought to depend tinction, we argue that Hering’s law of equal innervation is upon activity in a number of frontal brain regions, particu- actually demanded by the existence of the ancient (in evo- larly in the right hemisphere. Behaviourally, self-recognition lutionary terms) conjugate system in the visual system. We tasks elicit a number of response-related biases. For exam- then explain the “deviations” from Hering’s law both qual- ple, in previous experiments investigating hand-response itatively and quantitatively within the paradigm of equal preferences in self-face-recognition, groups of participants innervation using the well-known mechanism of smooth who responded “self” (or “mine”) with the left hand and pursuit. “other” (or “not mine”) with the right hand, performed better than other groups of participants responding with Tone Detection in Noise in the Mouse Auditory Cortex the opposite stimulus-response mapping. It was suggested that such hand-response differences implicated a right hemi- Hershenhoren I.1,2 and Nelken I.1,2 sphere specialisation for self-recognition. We report experiments exploring an alternative hypothesis: that im- 1Department of Neurobiology, Edmund Safra Campus, proved performance when using the left hand to respond Givat Ram, Israel “self” may reflect the interaction of two different response Israel Society for Neuroscience 55 tendencies. Our results showed that, when uncertain about Individual differences in stress responsiveness the correct response, participants tended to press the left affect the consequences of juvenile stress on button, regardless of the stimulus-response mapping, and coping with stress in adulthood also tended to press the “not mine” button, reflecting a failure to recognise the stimulus. When “self” responses were Horovitz O.,1,2,3 Tsoory M. M.,1,2,3 made with the left hand, these two tendencies worked in op- and Richter-Levin G.1,2,3 posite directions, equalising the proportions of “self” and 1 “other” responses. When the reverse stimulus-response map- Psychology Department, University of Haifa, Israel 2The Brain and Behavior Research Center, Israel ping was used, however, both tendencies resulted in more 3 ‘other’ than “self” responses, decreasing self-recognition per- The Institute for the Study of Affective Neuroscience (ISAN), formance. In order to dissociate the neural mechanisms of Israel self-recognition from those of decision-making, we also used Epidemiological studies associate early life stress (ELS) with slow event-related functional magnetic resonance imaging increased risk to develop PTSD and depression (Agid et al., (ER-fMRI) and analysed blood-oxygenation level dependent 2000). While most ELS animal models concentrate on the (BOLD) activity in a number of right hemisphere regions of perinatal to pre-weaning period (Sanchez et al., 2001) re- interest. cent studies indicated “juvenility” in rats (∼28 days of age) as an ELS sensitive age (Tsoory and Richter-Levin, 2006). Stereotyped whisker and head movements Sex and individual differences in novel setting exploration are associated with object localization in were associated with trait anxiety and stress responsiveness unrestrained rats in both humans and animals (Shear et al., 2005, Muallaˆ et al., 1993, Wood and Shors, 1998, Cavigelli and McClin- Horev G., Knutsen P. M., Pietr M., and Ahissar E. tock, 2003; Mallo¨ et al., 2005; Mallo¨ et al., 2007). There- fore, the current study assessed the rats’ novel setting ex- Department of Neurobiology, The Weizmann Institute of ploration as an index of stress responsiveness and evaluated Science, Israel how it affects the consequences of juvenile stress on coping with stressful challenges in adulthood by utilizing the two It has been shown that rats use an active sensing process ff way shuttle avoidance task and Saccharine preference. Com- to discriminate o sets in horizontal (antero-posterior) lo- pared with controls, adult juvenile stressed rats exhibited cation with their whiskers. The rats were trained to locate poor avoidance learning and a lower Saccharin preference the position of two objects using their whiskers alone and to following the avoidance task; No differences in Saccharine associate between the position of the objects and the posi- preference were evident prior to the avoidance task. Further- tion of a reward. Our goal here is to identify motor strate- more, “Low explorer” Controls exhibited a higher Saccharine gies that underlie this association. Kinematic variables of preference than “High explorer” Controls, while an opposite head and whiskers trajectories were compared between se- trend was evident among adult juvenile stressed rats. These quential contacts made with the objects in each trial, in rats results lend further support for the juvenile stress as a model that were trained to associate (Trained) and in rats that were of induction of predisposition to develop mood and anxiety trained to sense the objects but received the reward con- disorders following subsequent stress exposure in adulthood. stantly (Na¨ıve). Out of 12 variables tested, 3 showed significant changes between sequential contacts. These variables Lesions of the posterior vermis in the rhesus monkey were whisker’s angle relative to the head, head velocity, and cause deficits in visual motion perception touch duration. These dependencies were observed in both ff Trained and Na¨ıve rats, however values di ered significantly Ignashchenkova A., Dash S., Dietrich H., between the groups. We also observed that the variance of 3 Haarmeier T., and Thier P. variables: whisker angle velocity, whisker curvature and head velocity was significantly lower in Trained rats. Another vari- Department of Cognitive Neurology, Hertie Institute for able, the distance between the eyes, was significantly higher Clinical Brain Research, Germany in Trained rats. This parameter is highest when the head of the rat is parallel to the ground; therefore we conclude Patients with lesions of the cerebellum are often impaired in that in this task Trained rats tilt their head less than Na¨ıve performing tasks involving motion perception, but the crit- rats. Our results indicate that the behavior of Trained rats ical locus for such lesions remains vague. In order to study is more stereotyped than the behavior of Na¨ıve rats. Mean- the nature of the deficit and to identify the region of the ing that in order to associate between the positions of the cerebellum that may be involved, we trained monkeys in poles and the reward, these rats learned to control specific tasks of visual acuity, spatial attention, luminance change de- aspects of their behavior. Variables with reduced variance tection, and the detection of coherent motion in a subset in trained rats are candidates to be controlled by the rats. of dots moving within a random dot field. Two regions of The relations between these variables and more refined tem- the cerebellar cortex, namely, the oculomotor vermis (lob- poral and spatial variables which might encode spatial off- uli VI to VIII) and the dorsal paraflocculus, are likely can- sets for these rats during task performance will be studied didates, since they receive visual inputs and hence may be next. involved in the motion perception. As a first step towards 56 Neural Plasticity analyzing the critical locus we made vermal lesions includ- This work was supported by the EU’s PROMEMORIA Grant ing lobulus VI through VIII in three monkeys and tested no. 512012 to G.R-L. them postoperatively on visually guided saccades and the perceptual tasks described before. All the monkeys showed Correlated neuronal activity in primary and pre motor the expected saccadic dysmetria immediately after the lesion, cortices of monkeys during performance of different which subsided after a few days. Two monkeys tested for vi- visuomotor association tasks sual acuity showed opposite effects, one improved postle- sion and another had deteriorated visual acuity, but both Inbar D.,1,2 Grinvald Y.,1 Zach N.,1,2 and Vaadia E.1,2 these monkeys showed preserved improvement in allocating 1 covert visuo-spatial attention upon cueing. The third mon- Department of Physiology, Hadassah Medical School, Israel 2 key was tested on luminance change detection task and had Interdisciplinary Center for Neural Computation (ICNC), no impairment after the lesion. Overall, there were no gen- Hebrew University, Jerusalem, Israel eral visual deficits in these monkeys after the lesion. Two out of the three monkeys tested for coherent motion de- It has been shown that patterns of neuronal activity in mo- tection task were impaired after the lesion. The third mon- tor cortices and tuning curves might change during sensori- key which did not show any deficits after the lesion had a motor learning (Mitz et al., 1991, Gandolfo et al., 2000, Paz relatively small lesion. One of the impaired monkeys never et al., 2003). In this study, we examine co-variation of re- recovered for a particular spatial location (16 deg, down- sponse patterns and temporal cross-correlation to study dy- ff namics of interactions between cells during performance and ward) where the e ect of lesion was most profound. We con- ff clude that the vermis plays a critical role in motion per- adaptation to di erent visuomotor tasks. Neuronal activity ception although other cerebellar areas might contribute as from monkeys’ motor cortices was recorded in each session well. by a multimicroelectrode array. Each recording session was comprised of the following blocks of trials: (1) standard 8- The interplay between Juvenile stress and direction center-out task (a well-known task); (2) adaptation Enriched Environment on behavior and L1-CAM to visuomotor-rotation; and/or (3) adaptation to arbitrary- association (two colors associated with two different move- Ilin Y. and Richter-levin G. ment directions); (4) repetition of the standard center-out task. This poster presents patterns of correlation found in The Brain and Behavior Research Center, University of Haifa, these different behavioral states. First, we demonstrate that Haifa, Israel correlation patterns between neighboring cells in M1 and Recent evidence support the hypothesis that exposure to Premotor cortices may change and examine if and how these stress or trauma during early childhood may disturb the changes are related to behavior. Pairs of cells with correlated formation of functional brain pathways, in particular, of firing patterns during performance of standard task, tend the limbic circuits. Previous findings from our lab indicate to change correlation strength or pattern during adaptation. that an exposure of rats to a relatively brief stressful expe- This change may last during the repetition of the standard rience during juvenility (27–29 days of age) has profound center-out task that ends the session. Second, the strength and long-lasting behavioral effects (Avital and Richter-Levin, and pattern correlation between pairs of cells at the begin- 2005; Tsoory et al., 2006). The importance of the environ- ning of the trials might imply the responsiveness of these cells ment in the regulation of brain, behavior and physiology to behavioral events that follow. These results may suggest has long been recognized in biological, social and medi- that the cortical network can reorganize during performance cal sciences. Animals maintained under enriched conditions of visuomotor associations to generate correct behavior. have clearly been shown to have better learning abilities than Supported by a Center of Excellence grant (1564/04) by the Is- those maintained under standard conditions. We set out to ff rael Science foundation (ISF), by Bundesministerium fr Bil- investigate the long-term e ects of Juvenile stress and ef- dung und Forschung (BMBF-DIP), and by the US-Israel Bi- fects of enriched environment (EE) on the ability of ani- national Science Foundation (BSF). mals to cope with subsequent learning tasks and on the expression of the cell adhesion molecule L1, suggested to be Molecular correlations following mating in involved in environment-induced neuronal re-organization. the rodent female olfactory bulb Three groups were tested: Juvenile Stress–subjected to Ju- venile stress; Enriched Environment–subjected to Juvenile Inberg S., Rosenblum K., and Wagner S. stress and then, from day 30 on to EE; and Na¨ıves. In adulthood, coping and stress responses were examined using the Center for Brain and Behavior, Department of Neurobiology elevated plus-maze, open field, exploration and avoidance and Ethology, Haifa University, Israel learning. In adulthood, “juvenile” stressed rats exhibited reduced exploration in a novel setting, and poor avoidance Mated female mouse learns the individual identity of the learning, with learned helplessness-like behaviors, while ex- male during the mating and critical period of 4–6 hrours af- posure to EE impede these long lasting effects of juvenile ter the mating, subsequent exposure to another mouse or stress. Preliminary findings suggest that these where associ- to his bedding during the 3-4 following days cause preg- ated also with lasting alterations in the expression of L1. nancy block. This pregnancy failure is named “Bruce effect.” Israel Society for Neuroscience 57

The neural changes underlying this associative memory to Association between the oxytocin receptor (OXTR) stud male occur in the accessory olfactory bulb at the first gene and pro-social behavior in two economic games: stage of sensory processing system, but it do not exclude the the Dictator and Social Value Orientations role of the main olfactory bulb in processing of olfactory cues in different social relationships, including in the case of fe- Israel S.,1 Knafo A.,1 Reibold M.,2 Lerer E.,3 male’s memory formation to stud male. We are investigat- Bornstein G.,1 and Ebstein R. P.1,2 ing the changes in both protein expression and protein post 1 translation modifications induced in the olfactory bulb of fe- Department of Psychology, Hebrew University, male mice by mating. We found that there is an increase in Jerusalem, Israel 2S. Herzog Memorial Hospital, Jerusalem, Israel GABAAReceptor-alpha1subunitlevelindays1,3aftermat- 3 ing, followed by a return to basal levels (control group) in Human Genetics, Hebrew University, Jerusalem, Israel day 6. These changes occur in parallel to an increase in p- Animal models demonstrate the role of oxytocin in modu- ERK levels in days 1, 3 and return to basal levels in day 6. lating affiliative behaviors. Oxytocin (OXT) is linked to ma- We hypothesize that these changes are part of the molecu- ternal and psychosexual behaviors in lower mammals and lar mechanism mediating the female’s memory formation to pair-bond formation in prairie voles. Moreover, recent in- stud male. vestigations show that OXT facilitates social cognitive abilities: for example, OXT knockout mice show deficits in so- Neural correlates of recollection- and cial memory. Recent research suggests that OXT is involved familiarity-based memory decisions in prosocial behavior in healthy humans; intranasal OXT in- Ishai A.1 and Wiesmann M.2 creases trust, recognition of emotion in faces, and reduces social anxiety. Importantly, three recent investigations pro- 1Institute of Neuroradiology, University of Zurich, vide convergent evidence for association between oxytocin Switzerland receptor (OXTR) single nucleotide polymorphisms (SNPs) 2Institute of Neuroinformatics, University and ETH Zurich, and autism. Our own study, shows that association with Switzerland autism is mediated by acquisition of adaptive social skills. In two independent studies, we have recently demonstrated We used event-related fMRI to investigate whether that a related nonapeptide receptor, arginine vasopressin 1a recollection- and familiarity-based memory judgments (AVPR1a), is associated with both autism and pro-social giv- are modulated by the degree of visual similarity between ing behavior in economic tasks. In the current investiga- old and new art paintings. During the study phase, subjects tion, we demonstrate that OXTR SNPs and haplotypes pre- performed a flower detection task, followed by a Remem- dict pro-social allocation of funds in two economic games, ber/Know/New surprise memory test. The old paintings Dictator and Social Value Orientations. Using a family based were randomly presented with new paintings, which were method, we observed preferential transmission of individ- either visually similar or visually different from the old items. ual alleles in the Dictator Game (UNPHASED) for SNPs Consistent with our prediction, subjects were significantly rs1042778 (P = .0504) and rs2268494 (P = .0218) as well faster and more accurate to reject new, visually different as in Social Value Orientations (PBAT) for SNP rs2268494 paintings than new, visually similar ones. The proportion (P = .0009). Notably, these two SNPs also conferred risk of false alarms, namely Remember and Know responses for autism in our recently published study. In summary, our to new paintings, significantly decreased with decreased laboratory has shown association for two social neuropep- visual similarity. Moreover, Know responses were associated tide receptors OXTR and AVPR1a with both autism and pro- with significantly longer latencies. The retrieval task evoked social behavior as measured in economic games. Acknowl- activation within multiple visual, parietal and prefrontal edgements: Hebrew University BINCA grant (GB, RPE and regions, within which Remember responses elicited stronger AK), the Israel National Institute for Psychobiology (AK), the activation than Know responses. New, visually different Israel Science Foundation (GB) and Phillip Morris Interna- paintings evoked weaker activation than new, visually simi- tional (RPE) lar items in the intraparietal sulcus. Contrasting Recollection with Familiarity revealed activation predominantly within Comparing eye movements to detected vs. the precuneus, where the hemodynamic response elicited un-detected stimuli by Recollection peaked earlier than the hemodynamic response evoked by Familiarity. Our results suggest that Jacob M.1,2 and Hochstein S.1,2 successful memory retrieval of complex pictures is mediated by a distributed cortical network with differential hemody- 1Interdisciplinary Center for Neural Computation, Israel namic profiles during Recollection- and Familiarity-based 2Department of Neurobiology, The Hebrew University of judgments, and support the “mnemonic accumulator” hy- Jerusalem, Israel pothesis, according to which recognition memory decisions are based on the integration of sensory signals. Why do we perceive some elements in a visual scene, while other stimuli remain un-detected? To learn about the se- SupportedbytheSwissNationalScienceFoundationGrant quence of events leading to detection, we are studying the 3200B0-105278 and Swiss NCCR: Plasticity and Repair. difference between fixations on detected versus un-detected 58 Neural Plasticity stimuli. We are using two tasks for this study, the Set and adult rats were injected with corticosterone thirty min- game§(ISFN, 2005-6) and a novel Identity Search task, de- utes before tested. Nevertheless, in comparison with na¨ıve signed to contain detected and comparable un-detected rats, rats that were exposed to “juvenile stress” and chal- stimuli, and a division into distinct search-fixation regions. lenged in the open field and elevated plus maze exhibited In addition, it is easy to generate numerous displays for ei- increased CORT levels both soon after the exposure and in ther task, and they require several seconds of search, but re- adulthood. sult in momentary recognition. Cards in the Identity Search task contain a square array of scrambled mixtures of black Conclusions and white square units. Card number, array size and choice of number of black square units are under experimenter con- Opposite pattern of effects was found in juvenility and in trol. Within each display, all cards are different, except for adulthood, but increased levels of CORT seems to be in- two pairs of identical cards. Subject task is to find one of volved in both. Taken together, this differential outcome may these pairs, indicating the cards with mouse clicks. The en- correspond with different age-dependent reactivity to stress tire display is replaced for each trial. We compared fixations hormones. on cards belonging to the detected pair with those on the undetected pair in the same display. We find that detected This work was supported by the EU’s PROMEMORIA Grant pair cards are fixated more frequently than undetected pair no. 512012 to GRL. cards, and that within the search sequence, there are fewer intervening fixations on other cards between fixations on de- Mapping regions for high frequency stimulation in tected than on undetected pair cards. These findings raise the two rat models of obsessive-compulsive disorder question of what comes first: does observing certain cards more frequently and more closely lead to finding the pair, or Joel D.,1 Klavir O.,1 and Winter C.2 does an implicit sense of the presence of a pair lead to these features and ultimately to the explicit “aha” discovery of the 1Department of Psychology, Tel-Aviv University, Israel pair? Analysis of the break point between selective fixations 2Department of Psychiatry and Psychotherapy, Charite´ on detected cards, as found for the Set game, may provide an Campus Mitte, University Medicine Berlin, Germany answer to this question. Obsessive-compulsive disorder (OCD) represents one of the Supported by the Israel Science Foundation(ISF) and the US- most common psychiatric disorders. Functional and struc- Israel Binational Science Foundation(BSF). tural imaging studies implicate the involvement of basal ganglia-thalamo-cortical circuits in the pathophysiology of Short and long term consequences of exposing rats to this disorder. In patients remaining resistant to pharmaco- stressors during juvenility and behavioral therapy, ablative lesions of structures and pathways within these circuits have been shown to reverse Jacobson-Pick S. and Richter-Levin G. clinical symptoms. Following the finding that high frequency stimulation (HFS) can replace lesion in the treatment of The Brain and Behavior Research Center, University of Haifa, Parkinson’s disease and other motor disorders, there have Mount Carmel, 31905 Haifa, Israel been attempts to establish HFS also for the treatment of OCD. To date there have been several case reports on the ef- Background fects of HFS of the anterior limb of the internal capsule and of the ventral striatum in OCD patients, and of the subthalamic Previous studies indicate that childhood emotional trauma nucleus in patients with comorbid Parkinson’s disease and serves as a major predisposing factor for the emergence of OCD. The results of these studies are encouraging in show- affective disorders later in life. It is not clear thoughwhether ing that HFS may be effective in the treatment of OCD. Yet childhood stressful experiences serve as a predisposing factor the variety of targeted brain areas, the inconsistency in the or perhaps they prompt the onset of the disorder itself. Meth- demonstration of beneficial effect and the variability in the ods: the current study utilized the “juvenile-stress” model to time needed to obtain a therapeutic effect, highlight the need examine its effects on anxiety indices and exploratory behav- for better mapping of brain regions whose stimulation may ior in the open field and elevated plus maze, as well as on produce beneficial effects in OCD patients. We have recently circulating corticosterone levels. These effects were evaluated addressed this issue by assessing the effects of HFS of the sub- both soon after the exposure and in adulthood, compared to thalamic nucleus, nucleus accumbens and globus pallidus in controls. Additionally, the effects of acute corticosterone ad- two rat models of OCD, the signal attenuation model and the ministration on anxiety indices and exploratory behavior of quinpirole model. These models differ in terms of the manip- juvenile and adult rats were also examined compared to con- ulation used to induce compulsive-like behavior, the nature trols. Results: soon after the exposure, juvenile stressed rats of the compulsive-like behavior, and the response to phar- exhibited increased levels of activity and spent more time in macological treatment. These differences make it more likely the “unsafe” regions of the arenas compared with unexposed that a demonstration in the two models of an anticompul- rats. A reverse pattern of effects was evident when tested sive effect, reflects a genuine anticompulsive effect of HFS of in adulthood. Similar results were obtained when juvenile the brain region assessed, rather than being specific to some Israel Society for Neuroscience 59 parameter of a particular model that is not necessarily related a factor which critically interferes with regeneration by the to the modeled disorder. pioneering studies of Ramon y Cajal (1928). Nevertheless, whereas the mechanisms that transform the cut axonal end Local circuit plasticity in the dentate gyrus induced by into a competent GC have been investigated, the mecha- a week titanic stimulation nisms underlying endbulb formation and preventing regenerative processes still remain elusive. In the symposium I Jubran M. and Richter-Levin G. will (a) describe the self-assembly mechanisms that underlie the transformation of a differentiated axon into a func- Department of Neurobiology and Ethology, Center of Brain tional growth cone after axotomy (Erez et al., 2007); (b) and Behavior, University of Haifa, Israel analyze recent experimental results that relate improper re- structuring of cytoskeletal elements at the cut axonal end The hippocampus plays an integral role in learning and to the failure to assemble a competent GC by neurons with memory processes via its multiple intra and extra neuronal high capacity to regenerate; finally (c), I will discuss phar- connections. Hippocampal long-term potentiation (LTP) of macological and molecular approaches to overcoming the excitatory synaptic transmission was extensively examined subcellular barriers that impede regrowth from the end- and was proven to be accompanied by lasting modifications bulbs. of GABAergic interneurons. However, several studies suggest that these two seemingly analogous forms of plasticity might exhibit dissociated pharmacological sensitivity and di- On the mechanism that promote controlled and verse susceptibility to modulation. In the present study, we targeted regrowth of an injured axonal branch out examined the in vivo effect of a week titanic stimulation of many (WTS), ineffective in producing efficient LTP, to the per- forant path (PP) on GABAergic interneurons activity and Kamber D. and Spira M. E. plasticity in the hippocampal dentate gyrus (DG) of the Department of Neurobiology, The Hebrew University of anesthetized rat. Frequency-dependent inhibition (FDI), a Jerusalem, Israel GABA mediated feed-forward inhibition, and paired-pulse inhibition (PPI), a form of feed-back inhibition were used Following three days in culture, the morphology and dimen- to reflect the activity of GABAergic interneurons in the sions of cultured Aplysia neurons reach stead state (SS). We DG. We report here that although the application of WTS found that under these conditions transection of one ax- did not induce long-lasting modifications of the popula- onal branch is followed by its regrowth while other nonin- tion excitatory post-synaptic potential in the granule cells jured branches maintain their morphology unchanged. Two of the dentate gyrus, it succeed to induce lasting reduce mechanisms can account for this differential regrowth: ax- baseline inhibition as indicated by FDI and PPI. These re- onal injury “label” the microtubule (MT) tracks that con- sults demonstrate a potential involvement of interneuronal nect the site of injury with the cell body. Thereby, recruited plasticity in conditions where electrically induced princi- cellular components are preferentially transported to the pal cells plasticity is not apparent or fails to be main- site of injury. Alternatively, the recruited cellular resources tained. are equally transported to all branches but are preferentially “captured” and utilized at the site of injury by a newly Failure of neurons to regenerate after axotomy formed growth cone. The termination of the preferential stems from the assembly of an endbulb rather than growth process should involve timely down regulation of a competent a growth cone the preferential supply or the “capture” of the cellular re- Kamber D., Erez H., and Spira M. E. sources. Using on line confocal imaging of the cytoskeletal elements and organelles we suggest that simple principals Department of Neurobiology, Institute of Life Science, The govern the phenomenon of preferential growth. Non grow- Hebrew University of Jerusalem, Israel ing neurons maintain SS dimensions by the equal rates of membrane retrieval and membrane fusion within any ax- Current understandings of the mechanisms that underlie onal segments. Axonal transaction reduces the rate of mem- success or failure of neurons to regenerate after axotomy brane retrieval in proportion to the removed surface area of emphasize two classes of factors: the intrinsic capacity of the distal branch(s), while the rate of transport of Golgi de- the neuron to regenerate, and the presence of extrinsic rived vesicles to the site of injury remains unchanged and factors that either inhibits or support regrowth. A criti- is proportional to the number of MT tracks leading from cal step in regeneration of transected axon is the trans- the somata to the site of injury. The anterogradely transformation of the cut axonal end into a specialized com- ported vesicles fuse with the plasma membrane at the newly partment which orchestrates in time and space the use of formed GC. We suggest that since the rate of membrane re- cell resources for growth processes, and integrates extracel- trieval is proportional to the surface area, while the regen- lular signals into growth patterns, target recognition and erating branch grow to its original dimensions the rate of synaptogenesis. The failure of a cut axonal end to transmembrane retrieval increases until it equals the rate of mem- form into a competent GC apparatus and it’s transforma- brane supply. At this point the regrowth processes will be tion into an endbulb (retraction bulb) was recognized as terminated. 60 Neural Plasticity

Boundary conditions of corticosterone-dependent can serve as a coincidence detector for fast and slow neu- enhancement or alteration of memory consolidation rotransmission in the hippocampus, we analyzed the status of RSK2 phosphorylation subsequent to application of 1 1 1 Kaouane N., Calandreau L., Esclassan F., NMDA, dopamine, or both to preparations of mature hip- 2 1 1 2 2 Tronel S., Mons N., Jaffard R., Abrous N., Piazza P., pocampal slices in Sprague–Dawley rats. RSK2 was indeed 1 and Desmedt A. phosphorylated; however, in addition, the amount of RSK2 1CNIC, CNRS UMR 5228, Bordeaux 1, France protein (60%) was induced within 10 min following stimu- 2INSERM U588, Bordeaux 2, France lation. Moreover, the induced expression of RSK2 could be detected in both the cell body layer and the dendrites of hip- Extensive evidence indicates that administration of the pocampal CA1 cells. Pharmacological analysis showed that adrenocortical hormone corticosterone (CORT) facilitates RSK2 induction was MAPK ERK Kinase (MEK)-ERK inde- the consolidation of emotional experience. Nevertheless, pendent, but mammalian Target of Rapamycin (mTOR) and high release of CORT, which can occur in extreme stress- translation dependent. We suggest that the fast kinetics of ful situation, can result in memory deficits. This suggests RSK2 translation that follows physiological stimulations, to- that beyond a certain level of stress, the influence of CORT gether with recent observations that its overexpression is vi- on memory consolidation may switch from a facilitating ef- tal for the attenuation of major signal transduction cascades, fect to a deleterious effect, leading to maladaptive emotional indicate an expanded physiological function of RSK2 in neu- responses with regards to the aversive learning experience. rons, and sheds new light on the role of RSK2 in the Coffin– Nevertheless, the boundary conditions under which such a Lowry syndrome. switch can be observed are still elusive. In order to spec- ify these conditions, we used in mice two fear condition- The correlation of intracellular zinc, zinc homeostatic ing procedures known to result in a preferential conditioned proteins and apoptosis fear response either (i) to a discrete tone (i.e., tone-shock Karol N.,1 Hershfinkel M.,1 Forberg M.,1 Kaisman T.,1 pairing: the tone is predictive of a mild footshock occur- Fishman D.,1 Sekler I.,2 and Silverman W.1 rence) or (ii) to contextual cues (i.e., tone-shock unpair- 1Department of Morphology, Zlotowski Center for ing: tone not predictive). First, we show that increasing the Neuroscience Ben-Gurion University Beer Sheva, Israel intensity of footshock from a very low (0.3 mA) to a rela- 2Department of Physiology Zlotowski Center for tively high (1 mA) level gradually enhances conditioned fear Neuroscience Ben-Gurion University Beer Sheva, Israel responses in an adaptive manner, i.e., as a function of the tone-shock contingency. However, beyond the critical foot- A rise in intracellular Zn2+ has long been considered the shock intensity of 1 mA, fear responses become maladap- principle challenge necessitating the impressive array of zinc tive, i.e., independent on the conditioning procedure. Sec- homeostatic proteins present in mammalian cells. We and ond, preliminary results indicate that under mild footshock others have begun to focus on another, separate pool of Zn2+, intensity (0.5 mA), post-training intra-hippocampal infu- associated with zinc homeostatic proteins (ZHP) and mi- sions of CORT dose-dependently enhance adaptive condi- tochondria which is dynamically regulated. These proteins tioned fear responses. However, beyond a critical dose mal- bind zinc with a relatively high affinity but release it in re- adaptive conditioned fear responses are again observed. Fi- sponse to oxidative stimuli, for example, reactive oxygen nally, we also assessed whether the CORT-dependent switch species, hypoxia or nitric oxide (NO). By virtue of its abil- from adaptive to maladaptive fear responses was associated ity to damage mitochondria and activate apoptoptic signal- with changes in ERK1/2 activation-related recruitment of ing cascades, Zn2+ released in this way could play an impor- the hippocampal-amygdalar circuit. Altogether, these results tant role in cell death in the developing and ischemic CNS. throw light on boundary conditions of CORT-dependent To establish an association between developmental cell death normal and pathological fear learning. and intracellular zinc (Zni), we have adopted a flow cytometry strategy designed to analyze large numbers of develop- This study was supported by the CNRS, the FRC, and a PICS ing cells from two brain regions: the olfactory bulb (OB) and No. 3939. cerebellum (CB). After isolating the cells in suspension, they are loaded with a zinc-sensitive dye, Zinpyr-1, and briefly Novel environment and co-application of NMDA exposed to a cell death marker, e.g., propidium iodide or and dopamine induce rapid translation of RSK2 in Annexin-V prior to analysis in a FACSCanto flow cytome- the Mature Hippocampus ter. Induction of Zn2+ release from metallothioneins, e.g., by Kaphzan H., Doron G., and Rosenblum K. addition of a nitric oxide donor, or cell death in an identified neuronal population, e.g., by fetal ethanol exposure, allows Department of Neurobiology and Ethology, Faculty of us to correlate the specific challenge to observed levels of Zni Science, University of Haifa, Israel in dying or surviving cells. Through these experiments, and together with in vitro studies we are conducting, we hope to Ribosomal S6 kinase2 (RSK2) is known to take part gain insight into the role of intracellular zinc in basic physi- in several signal transduction cascades including Mito- ological processes such as cell death. gen Activated Protein Kinase/Extracellular Regulated Kinase (MAPK/ERK). Following our recent observation that ERK Supported by Israel Science Foundation (572/04) WS. Israel Society for Neuroscience 61

Effect of anesthesia and breathing on for generating an action potential at the axon hillock. In or- the receptive field size of thalamic cells in der to estimate the parameters of a compartmental model de- the somatosensory system scribing only the somato dendritic section of the neuron we have developed a progressive process that fits the data using Katz Y. A. and Lampl I. a parameter pealing procedure. In this procedure we assume recorded experimental data from both the soma and den- Weizmann Institute of Science, Israel drite. We use a voltage-clamp placed at the soma to inject the voltage read from experimental data, and a current-clamp The concept of receptive field (RF), the set of external stimuli electrode at the dendrite to fit by the experimental data. This external stimuli that will significantly alter the firing pattern method allows us to disregard complexities arising from ax- of a neuron, is fundamental to sensory processing. Whether onal physiology. In addition, in each step we constrain only RF structure and size depends on the state of wakefulness or part of the parameters thus making sure that we do not fall the physiology of the animal or not, is controversial. Cor- into local minima. Our results show accurate parameters fit tical neurons of the somatosensory cortex (S1) of the rat and propose a protocol for constraining a model for a seg- respond to several whiskers. The origin of large RF of S1 ment of a complex neuron. neurons remains unclear. In a previous study we suggested that large RF emerged by cortical integration and that the ERP Source estimation by MRI constrained RF of cells in the ventral posterior medial thalamic nucleus linear solutions (VPM) are confined mostly to a single whisker. Other studies suggested that large RF of cortical cells reflect large RF Keren A. S.,1 Geva A. B.,3 and Deouell L. Y.1,2 in the VPM. In particular, large RF was demonstrated un- 1 der light anesthesia or when a state of wakefulness is mim- The Interdisciplinary Center for Neural Computation, The Hebrew University of Jerusalem, Israel icked by stimulation of the brainstem reticular formation. 2 In contrast, we found that under very light anesthesia RF in Department of Psychology, The Hebrew University of Jeruslalem, Israel the VPM is mostly confined to one whisker. Hence, vary- 3 ing the level of anesthesia does not have a significant ef- Electrical and Computer Engineering, Ben-Gurion University fect on their RF size. In these experiments, however, tra- of the Negev, Israel cheotomized rats were artificially respirated. In self breath- Intensive efforts are made to integrate EEG and fMRI data in ing rats, showing similar reflexes and fast EEG spectrum as order to benefit both from the high temporal resolution of ± in respirated rats, RF size was larger (2.1 0.4 compared the first and from the good spatial localization of the latter. ± to 1.2 0.1 in respirated rats). Despite the larger thalamic Here we propose a platform based on structural and func- RF in self breathing rats, the number of whiskers that evoke tional MRI, where established as well as novel estimation response falls short of the size that was reported in several methods can be applied in order to estimate the sources of other studies. Further study is required in order to reveal Event Related Potentials (ERP). The extraction of anatomi- the physiological factors which determine the RF of thalamic cal and functional constraints is accomplished by incorpo- cells. ration of imaging, experimental and computational tools: Both fMRI and ERP data are collected from the same sub- This work was supported by The Israel Science Foundation ject in similar paradigms. The cortical surface of the sub- Grant 1037/03. ject is extracted from the structural MRI and represented as tiled triangles or linked nodes. On each node marked as Constraining compartmental models using active by a relevant fMRI contrast a dipole is seeded, ori- a parameter peeling procedure ented orthogonally to the cortical mesh. An electric model of the head is used to estimate the projection of the dipole Keren N.1,2 and Korngreen A.1,2 at each node on each scalp electrode. Based on the resultant 1Mina and Everard Faculty of Life Sciences; Leslie and projection or “lead filed” matrix, linear estimation methods Susan Gonda Brain Research Center, Israel such as Weighted Minimum Norm and Weighted Minimum 2Bar-Ilan University, Israel Laplacian (AKA LORETA) can be applied with proper adjustments to surface geometry. The linear framework can be Constraining compartmental models of neurons using generalized to incorporate spatiotemporal constraints and stochastic algorithms has become a critical task in the study filters, which capture richer physiological mechanisms. The and understanding of neuronal behaviour. We have recently proposed platform is demonstrated on real data from a hu- suggested that measurements from multiple different loca- man subject. tions along the dendrite and the axon facilitate in fitting a set of model parameters. However, practical data recordings A functional circuit underlying male sexual behavior from L5 pyramidal rat neurons are feasible from two loca- uncovered in the adult female mouse brain tions simultaneously (soma + dendrite). Moreover, the com- Kimchi T., Xu J., and Dulac C. mon simulative model assumes axonal physiology which has several erroneous assumptions such as high channels con- 1Department of Molecular and Cellular Biology, HHMI, centrations that try to overcome the high potential needed Harvard University, Cambridge, Mass, USA 62 Neural Plasticity

Pheromones regulate aspects of social and sexual behaviors lent modification with thermal regulation and neuronal plas- throughout the animal kingdom. In mice, pheromone de- ticity, the feasibility of BDNF for transcription during heat tection is mediated by the vomeronasal organ (VNO) and conditioning was analyzed using the chromatin immuno- the main olfactory epithelium (MOE). Male mice deficient precipitation technology (ChIP). It was established that H3- for TRPC2 (TRPC2-/-), an ion channel essential for VNO K9 and H3-K27 exert different effects on the DNA-histone sensory transduction, are impaired in sex discrimination proximity in the promoter area of BDNF. Taken together, and male-male aggression. We report here that TRPC2-/- these results correlate epigenetic chromatin methylation with female mice show loss of sex discrimination and reduc- thermal- adaptation-related hypothalamic plasticity. tion in female-specific behavior, which includes maternal aggression and lactating behavior. Most strikingly, mutant SupportedbyISF. females display unique characteristics of male sexual and courtship behaviors such as mounting, pelvic thrust, solic- The effects of high frequency stimulation and itation, anogenital olfactory investigation, and emission of temporary inactivation of the globus pallidus in complex ultrasonic vocalizations. The same behavioral phe- the signal attenuation rat model of obsessive notype is observed after VNO surgical removal in adult compulsive disorder animals, and is not accompanied by disruption of the es- Klavir O.,1 Winter C.,2 and Joel D.1 trous cycle and sex hormone levels. These findings suggest that VNO-mediated pheromone inputs act in wild-type fe- 1Department of Psychology, Tel-Aviv University, Israel males to repress male behavior and activate female behav- 2Department of Psychiatry and Psychotherapy, Charite´ iors. Moreover, they imply that functional neuronal circuits Campus Mitte, University Medicine Berlin, Germany underlying male-specific behaviors exist in the normal female mouse brain. Last, we have preliminary evidence that Obsessive-compulsive disorder (OCD) is a common psy- the neuronal switch that regulates sex-specific mating behav- chiatric disorder. Functional and structural imaging stud- ior might be related to dopaminergic cell population in the ies implicate the basal ganglia-thalamo-cortical circuits in hypothalamus. the pathophysiology of this disorder. In patients remaining resistant to pharmaco- and behavioral therapy, ablative le- A critical role for histone 3 methylation in sions within these circuits have been shown to reverse clin- thermal control development ical symptoms. Following the finding that high frequency stimulation (HFS) can replace lesion in the treatment of Kisliouk T. and Meiri N. Parkinson’s disease and other motor disorders, there have been some encouraging attempts to establish HFS also for the Institute of Animal Science, ARO, The Volcani Center, treatment of OCD. Yet the variety of targeted brain areas, the Bet Dagan, 50250 Israel inconsistency in the demonstration of beneficial effect and Thermoregulation like other sensory mechanisms develops the variability in the time needed to obtain a therapeutic ef- during a critical period. Neuroanatomically, the body tem- fect, highlight the need for better mapping of brain regions ff perature is balanced by the preoptic anterior hypothala- whose stimulation may produce beneficial e ects in OCD mus (PO/AH) and controlled by thermo-sensitive neurons. patients. We are attempting to address this issue by mapping Thermal-input during the critical period of thermal con- regions for HFS for the treatment of OCD, using the sig- trol establishment causes a plastic change in the ratio be- nal attenuation rat model of this disorder. In this model, the tween thermo-sensitive neurons and innate PO/AH cells and attenuation of an external feedback for lever-press respond- can modulate temperature tolerance. Here we describe epi- ing leads, in a subsequent extinction test, to excessive lever- genetic changes associated with thermal-control establish- pressing that is not accompanied by an attempt to collect ment in chicks. During thermal conditioning (Heat expo- a reward. This behavior, which has been named “compul- sure of 37.5◦C of 3-day-old chicks, for 24 hours) there is a sive” lever-pressing, has been shown to have face, predictive transient induction in both histone H3 dimethylation at ly- and construct validity as a model of compulsive behavior in sine 9 (H3-K9) and at lysine 27 (H3-K27) in the PO/AH. OCD patients. We have recently found that HFS of the sub- The peak of dimethylation occurred at 2 h for H3-K9 and thalamic nucleus (STN) reduces compulsive lever-pressing. ff at 6 h for H3-K27. These chromatin modifications are lim- The present study tested the e ect of HFS of the globus pal- ited to the critical period of thermal control establishment. lidus (GP), which is interconnected with the STN, on com- When chicks that had passed the critical age (10-day-old) pulsive lever-pressing. In addition, in order to better under- were exposed to similar thermal treatment there were no sig- stand the mechanism of action of HFS, we have also tested ff nificant changes in histone H3 methylation. The enzymes the e ect of temporary inactivation of the GP. that catalyze these modifications, G9a and EZH2 respectively are induced during similar time windows. Co-localization of In vivo two-photon calcium imaging of periglomerular H3-K27 and EZH2, during heat conditioning was verified by neurons in the mouse olfactory bulb double immunofluorescence staining. Furthermore, attenu- Kopel H. and Mizrahi A. ation of EZH2 expression using antisense inhibition alters thermal responses both during heat conditioning and dur- Department of Neurobiology and the ICNC, the Hebrew ing heat challenge later in life. To correlate the histone cova- University of Jerusalem, Israel Israel Society for Neuroscience 63

Adult neurogenesis is restricted to a few regions in the mam- of FVB/N mice, suggesting that the more severe neurolog- malian brain. One of these regions is the olfactory bulb (OB), ical impairment in C57BL mice was due to greater impair- the first station in olfactory processing pathway. In the OB, ment of axonal output from the cerebellar cortex. Toward newborn neurons integrate into the circuitry as fully func- understanding axonal pathology in this model, we focused tional local interneurons (INs). These INs form the local net- on a structure formed by basket cell fibers around the PC work of granule cells and periglomerular neurons (PGNs), axon initial segment called the “pinceau”. The results indi- both of which are thought to modulate incoming and outgo- cate that higher basal expression of certain pinceau elements, ing olfactory input, respectively. However, the contribution including the voltage gated potassium channel Kvbeta2 and of the newborn cells to the activity of the existing networks, potassium hyperpolarization-activated channel, HCN1, pre- if any, remains unknown. The long-term goal of this study is dict greater resistance to glutamatergic neurotoxicity in the to reveal the functional role of PGNs within their local net- cerebellum. works. To address this issue, we first developed an experimental system to record sensory-evoked physiological activ- Supported by Israeli MOST and German BMBF. ity from PGNs, in vivo. Here we report preliminary data of PGNs physiological responses based on imaging of calcium Characterization of the first anti-Shaker specific transients and describe our experimental protocol for target- toxin from the venom of the Israeli scorpion Buthus ing adult-born PGNs. We imaged PGNs located at the dorsal occitanus israelis surface of the OB using bolus loading of the calcium indicator oregon green bapta-1 AM (OGB) into the glomerular Kozminsky-Atias A. and Zilberberg N. layer. OGB loading resulted in labeling of hundreds of neu- Department of Life Sciences and the Zlotowski Center for rons that showed strong calcium responses (upto 30% dF/F) Neuroscience, Ben-Gurion University, Israel to electrical stimuli. In order to characterize the sensory response profiles of the PGNs we are currently mapping the Scorpion venoms are a rich source of varies potassium chan- activated regions of the OB in response to specific olfactory nel blocking peptides. To identify novel toxins with unique stimuli using intrinsic-signal imaging (ISI). IS maps are then selectivities we studied the polypeptide content of the Is- used to identify the activated glomeruli that are subsequently raeli scorpion Buthus occitanus israelis (Boi). Seventy three imaged with two-photon calcium imaging. In addition, to novel putative toxins were discovered following analysis of directly study the newborn neurons, we are using lentivirus- 400 randomly chosen venom gland-derived cDNA clones. mediated labeling of the progenitor stem cells (using red flu- Twenty toxins were predicted to block potassium channels. orescent proteins) together with the calcium imaging tech- Accordingly, we identified more than 20 distinct peptides nique. This experimental strategy now allows us to examine from Boi crude venom which are active against different the functional contribution of the newborn cells to the exist- potassium channels, for example, Shaker, Kv1.3 and RomK1. ing network and may reveal the role of newborn neurons in Here we describe the isolation, cloning and genomic orga- olfactory coding and plasticity. nization of BoiTx1, the first toxin from the Israeli scorpion Buthus occitanus israelis. BoiTx1 is a 37 amino acid-long Glutamatergic excitotoxicity in cerebellar stroke: peptide with six conserved cysteines. BoiTx1 shows 82%– contribution of genetic background to neurological 75% homology to members of the alpha-KTx3 toxin fam- and histopathological outcomes in a mouse model ily, thus classified as an alpha-KTx3.10. The pharmacological effects of BoiTx1 were studied on various cloned potas- Kovalev E.,1 Tal Z.,2 Zimmermann G.,3 Ben-Ari S.,3 sium channels expressed in Xenopus laevis oocytes. BoiTx1 Soreq H.,3 Yarom Y., 2 and Shoham S.1 inhibited currents through Drosophila Shaker channels with an IC50 value of 3.5 ± 0.5 nM. In contrast to its structurally 1 Research department, Herzog Hospital, Jerusalem, Israel related toxins, BoiTx1 is at least hundred-fold more potent 2 Neurobiology, Hebrew University, Jerusalem, Israel against the fly, Shaker channel, then towards its mammalian 3 Biological chemistry, Hebrew University, Jerusalem, Israel homologs, Kv1.1 and Kv1.3. Thus, BoiTx1 is the first member of the alpha-KTx3 family that preferentially affects insect Acute stroke to the human cerebellum involves glutamater- potassium channels. This finding could lead to better un- gic excitotoxicity and causes variable degrees of motor im- derstanding of the structural basis of channel selectivity in pairment. The present study focuses on the contribution potassium channel blocking peptides. of genetic background to the variability in stroke outcome. Kainate, a glutamate analog, was microinjected to cerebellum Testosterone improves visual-spatial memory in in two inbred strains of mice–FVB/N and C57BL. One and hypogonadal men 14 days post injection, C57BL mice displayed more severe neurological outcome compared to FVB/N mice. Damage to Kravitz E.,1,2 Davidson M.,2,3 Gigi A.,1 Orr G.,2,3 the Purkinje layer and electrophysiological response of Purk- Seidman S.,4 Weiser M.,2,3 and Biegon A.1,5 inje cells (PC) to kainate in a slice preparation were similar in both strains. However immunohistochemical staining of cal- 1The Joseph Sagol Neuroscience Center, Sheba Medical cium binding proteins calbindin and parvalbumin revealed Center, Israel greater morphological pathology in PC axons of C57BL than 2Sackler Faculty of Medicine, Tel Aviv University, Israel 64 Neural Plasticity

3Department of Psychiatry, Sheba Medical Center, Israel several recent studies. In our present studies we investigate 4Department of Psychiatry, Columbia University, Israel the ability of the octopuses motor output programs to adapt 5Brookhaven National laboratory, NY, USA to new tasks. To do so we forced our animals to perform tasks challenging their standard repertoire of arm move- Background ments. We conducted a set of experiments that effected either, bend propagation and fetching movements, or required Testosterone, the primary gonadal hormone in males, is as- on-line central control of searching movements and an es- sociated with some cognitive functions, particularly spatial tablishment of learning processes. In our first experiment we skills and spatial memory. This hormone may also have neu- introduced a physical constrain to the base of the octopus ff roprotective properties. We studied the e ects of exogenous arm. Animals were placed inside a transparent Perspex box testosterone on cognitive functioning in middle-aged hypog- (40 × 40 × 40 cm) with a hole at the center of every surface onadal men with dysthymia (a mild, chronic depressive dis- that allowed the insertion of a single arm only (1.5 cm∅). order). Methods: Fifteen hypogonadal men (41–66 years old, During the experiment the subjects had to reach out through ff mean 49.8, SD 7.3), su ering from dysthymia were enrolled aholetoretrieveafoodrewardoffered outside the box. The in a randomized, double-blind clinical trial in which they re- accuracy of the reaching towards a target movement did not ceived testosterone 200 mg or matched placebo IM biweekly improve in consecutive experimental sessions. However, the for seven weeks. Subjects completed a neuropsychological accuracy and speed of fetching movements improved both test battery at the time of enrollment and at the end of the within and across sessions. A second set of experiments in- double-blind phase. The battery included the Rey auditory- vestigated the ability of octopuses to learn to turn their arm verbal learning test (Rey-AVLT), Rey Osterreich complex fig- in a specific direction in an opaque Y shaped maze. The an- ure test (Rey-CFT, tests visual-spatial memory abilities), and imals received neither chemical nor tactile information on digit-symbol coding test (tests visual-motor coordination the direction of the turn. Therefore the correct decision to and attention). turn left or right inside the maze could only be made based on proprioceptive information on the position of the arm. 4 Results out of 6 subjects were able to successfully complete this task in less then 90 trials. Further experiments investigated if the Repeated Measures ANOVA showed a significant improve- octopus can turn its arm inside a maze according to visual ment in the visual-spatial memory abilities of the testos- feedback. 6 out of 9 animals learned to direct the movement terone treated group (N = 8) compared with the placebo N = of their arms inside a three ways choice maze based on visual group ( 7) in the immediate-recall trial (T2) and information. These experiments show that octopuses are able delayed-recall trial (T3) of the Rey-CFT. This was exempli- to modify the execution of motor primitives as well as more fied by a significant time by treatment interaction in per- searching and crawling related movements. formance on the T2 and T3 of Rey-CFT (F(1, 13) = 5.127, P<.05, and F(1, 13) = 4.7, P<.05, resp.). No such interac- Supported by Israel Science Foundation. M. Kuba was sup- tion was found in performance on either the auditory-verbal ported by a Golda Meir fellowship. memory test or the digit-symbol coding test. Conclusion: Normal testosterone levels may be important in the main- Role of the 18 kDa Translocator protein and tenance of specific cognitive abilities, contributing to better the adenine nucleotide transporter in performance of visual-spatial tasks but not auditory-verbal erucylphosphohomocholine-induced cell death or attention tasks. These finding have implications for the in human glioma cells assessment and treatment of age-related hypogonadism and possibly also Alzheimer’s disease, and should be replicated in Kugler W.,1 Veenman L.,2 Gavish M.,2 and Lakomek M.1 a larger sample, and in nondepressed men. 1Universitats-Kinderklinik,¨ D-37075 Gottingen,¨ Germany Supported by J. Sagol doctoral fellowship to Efrat Kravitz. 2Technion-Israel Institute of Technology, 31096 Haifa, Israel The 18 kDa Translocator protein (TSPO), formerly called Modifications and adaptations of arm use in peripheral-type benzodiazepine receptor (PBR), exerts var- Octopus vulgaris ious cell functions and is involved in a functional structure Kuba M. J.,1 Byrne R. A.,1 Gutnick T.,1 Zullo L.,1,3 designated as the mitochondrial permeability transition pore Thonhauser K. E.,2 and Hochner B.1 (MPTP). Our previous studies indicated that TSPO may be an important component in the MPTP related pro-apoptotic 1Department of Neurobiology & ICNC, mechanisms activated by the novel membrane-seeking anti- Hebrew University, Israel neoplastic agent erucylphosphohomocholine (ErPC3). Thus, 2Institute of Zoology, Karl-Franzens-University, Graz, Austria we decided to use two well-known TSPO ligands, PK 11195 3Department of Neuroscience and Brain Technologies, and Ro5 4864, to study their interference with ErPC3’s pro- The Italian Institute of Technology, Italy apoptotic activity. Surprisingly, PK 11195 and Ro5 4864 inhibited apoptosis induction by ErPC3 in a concentration- The motor control of the highly flexible eight arms of the dependent manner. In addition, they appeared to block common octopus (Octopus vulgaris) has been the focus of cytochrome c release, and caspase-9 and -3 activation Israel Society for Neuroscience 65 typically induced by ErPC3. This indicates that the MPTP The study of the neural correlates of consciousness (NCC) and TSPO take part in the activation of the mitochon- has typically focused on a subjective definition of awareness. drial apoptosis pathway by ErPC3. TSPO molecules are of- Using a backward masking paradigm, we dissociated between ten found in conjunction with VDAC and ANT, which are objective awareness and subjective awareness by having par- suggestedcorecomponentsoftheMPTP.ANTappearsasa ticipants first produce a forced-choice response to the loca- bi-functional protein: an ADP/ATP translocator and a lethal tion of a liminal target, and then report on their subjective pore regulated by multiple apoptosis regulators. To study in awareness of the target presence. We recorded event-related more detail the mechanisms whereby ErPC3 may affect mito- brain potentials (ERPs) and compared neural activity when chondrial functions, for example, membrane potential, ATP observers reported being aware versus unaware of the target production, we analysed in a first attempt a possible corre- but localized it correctly, thereby isolating the neural correlation between ErPC3, TSPO, and ANT by investigating cel- lates of subjective awareness while controlling for differences lular ATP levels using human glioblastoma cell lines U87MG in objective performance. In addition, we compared neural and U118MG. Treatment of these cells with TSPO ligands activity when participants were subjectively unaware of the and ErPC3 affected ATP levels. Depending on the cell type, target presence and localized it correctly versus incorrectly, PK 11195 and Ro5 4864 enhanced or reduced ATP levels, thereby isolating the neural correlates of objective awareness. whereas ErPC3 reduced cellular ATP levels in all cell lines Importantly, all conditions involved stimuli that were physi- tested. Interestingly, co-administration of these TSPO lig- cally identical and were presented for the same duration. The ands with ErPC3 restored cellular ATP levels. Together, these results show that the amplitude of the P3 component corre- results suggest that not only TSPO but also ANT is involved lates with the degree to which the target is consciously per- in ErPC3’s action. ceived

Supported by the Volkswagen-Stiftung (Joint Lower Saxony- Different effects of voluntary and involuntary Israeli Research Projects; VWZN2047). attention on EEG activity in the gamma band Shaping of tuning properties in motor cortex Landau A.,1 Esterman M.,1 Robertson L.,1 Bentin S.,2 during Long term visuoMotor learning and Prinzmental W.1 Lalazar H.,1,2 Shahar M.,2 and Vaadia E.1,2 1University of California, Berkeley, Calif, USA 1 Interdisciplinary Center for Neural Computation The 2Hebrew University, Jerusalem, Israel Hebrew University of Jerusalem, Israel 2Department of Physiology Hadassah Medical School The Recent studies in animals and humans have shown that EEG Hebrew University of Jerusalem, Israel activity in the gamma range can be modulated by attention. In the present study we compared this activity for voluntary Many studies have examined the relation between various and involuntary allocation of spatial attention in a spatial- movement parameters and the neural responses in the motor cuing paradigm with faces as targets. The visual stimuli and cortex of behaving primates. Encoding for many movement trial timing were kept constant across attention conditions parameters have been shown, such as speed and direction, with only the predictive value of the cue changing. Gamma- muscle activations, joint angles, and the sensory cues for band response was linked to voluntary shifts of attention but movement. In such studies the primates are “overtrained”— not to the involuntary capture of attention. The presence of trained for many months or years until they reach expert and increased gamma responses for the voluntary allocation of constant performance. In the current study we recorded from attention, and its absence in cases of involuntary capture, the primary motor cortex of a monkey for several months suggests that the neural mechanisms governing these two as she learned a three-dimensional point-to-point reaching types of attention are different. Moreover, these data allow task. During this period her behavioral performance im- a description of the temporal dynamics contributing to the proved from a novice level to highly proficient. We recorded dissociation between voluntary and involuntary attention. the full arm kinematics (using optic sensors), and 96 neu- The scalp distribution of this correlate of voluntary atten- ral signals from a chronically implanted electrode array. Our tion is consistent with a top-down process involving primar- task involved a wide variety of movements in order to span ily contralateral anterior and posterior regions. a large portion of the movement space and thus allow us to sample the tuning properties in a broad manner. We exam- Predicting pleasantness of binary mixtures ined the changes in the encoding of these motor parameters in olfaction in relation to the parameters of the enhanced movements. In some cases we could track the encoding of a single neuron Lapid H.,1,2 Harel D.,2 and Sobel N.1 for several days, as they remained convincingly well isolated and identifiable. 1Department of Neurobiology, Weizmann Institute of Science, Israel Neural correlates of subjective and objective 2Department of Computer Science and Applied awareness: An ERP study Mathematics, Weizmann Institute of Science, Israel Lamy D., Salti M., and Bar-Haim Y. Although the rules underlying the perceived intensity of bi- Tel Aviv University, Israel nary mixtures has been investigated, only minimal efforts 66 Neural Plasticity have been directed at elucidating the rules underlying the potentials that respectively decreased and increased in am- perceived pleasantness of such mixtures. To address this, plitude upon depolarization, which suggests that they rep- 84 subjects ranked the relative and absolute pleasantness of resents chemical synaptic inputs. Supra-threshold activity, 4 distinct binary mixtures (15 pairs, ISI = 4s, ITI = 30 s, which was often observed, was manifested as overshooting flow = 6 l/min, pulse = 2sec)madeofdifferent mixing ra- action potentials that were carried by Na+ and Ca++ currents. tios (0:100%, 25:75%, 50:50%, 75:25% and 100:0%, olfac- Since PCs retain their physiological and morphological char- tometer generated vapor phase) and of the separated con- acteristics, it is reasonable to assume that this organotypic stituents of the mixtures diluted with clean air to the over- culture will pave the way for reconstruction of the olivo- all air flow of the mixture. 3 mixtures consisted a relatively cerebellar loop in a dish, which will allow for simultaneous pleasant odorant mixed with an unpleasant one (L-Carvone- recording from all the major components of the system. IsoValericAcid, Linalool-ValericAcid, PhenylethylAlcohol- ButanoicAcid) and one mixture consisted of two unpleas- Collinear facilitation at the periphery: ant odorants (IsoValericAcid-ValericAcid). Each trial was does it differ from the fovea? repeated twice with odorant order counter-balanced and trial order randomized. The mixture’s separated constituents Lev M. and Polat U. were in turn ranked for their intensity on a VAS scale. Based on these results, we propose here a novel prediction model Sackler Faculty of Medicine, Goldschleger Eye Research for the pleasantness of binary mixtures from the pleasant- Institute, Tel Aviv University, Tel Hashomer, Israel ness of their separated components at different mixing concentrations and their respective intensities. This model does Collinear facilitation is a common phenomenon, but it has not require presetting of an interaction constant between the been challenged recently at the human periphery. We probed mixture components, nor does it require any factorization of the facilitation using a Yes/No detection task by measuring the pleasantness weights. It does, nonetheless, require solid the false-positive reports (false-alarm, Pfa) and hit rate (Phit) psychophysical data of the separated components at their dif- for a low-contrast Gabor target (between two flankers) that ferent concentrations, and currently it can only explain the appeared randomly at the fovea or at the periphery (2.4 deg) behavior of intermediate pleasantness of the mixture. to the right or left side. We compared three target-flanker configurations: orthogonal at a distance of 15-lambada (tar- Reconstructing the olivo-cerebellar system in a dish get alone), and collinear or orthogonal at 5-lambada. The report for the target present was high (Phit, Pfa) for the Lefler Y.,1 Belenky M.,2 and Yarom Y.1 collinear but not for the other configurations. The overall increase in the target-present responses only for the collinear 1 Department of Neurobiology and The ICNC, configuration is consistent with the excitatory range of in- The Hebrew University of Jerusalem, Israel teractions. However, the sensitivity of the collinear config- 2 Department of Cell and Animal Biology, uration at 5-lambada is higher than the target but only The Hebrew University of Jerusalem, Israel slightly higher than the orthogonal configuration. There- ff In order to unravel the functional organization of the olivo- fore, the usual expression of a facilitation e ect as a sen- cerebellar loop, one needs a simultaneous access to all its sitivity measure is distorted by the strong excitation (Po- components. Since it is rather impossible to achieve this in lat & Sagi, 2006). The existence of a similar pattern of in-vivo conditions, we are developing a culture system that higher Phit and Pfa for the collinear configuration at the fovea and periphery suggests that collinear facilitation is a captures the entire circuit, which is based on brain slices ff of 7 to 18-day-old rats. Once isolating the brain, the cere- common phenomenon that a ects both the periphery and bellum and the attached brain stem were sliced into 250– fovea. μ 500 M-thick slices, in a plain that ought to preserve the Supported by the Israel Science Foundation and the National inferior olive, the deep cerebellar nuclei and a parasagit- Institute for Psychobiology in Israel. tal portion of the cerebellum. Slices were then placed on membranes of 30-mm culture inserts with 0.4 μMporesize Gender dependent behavioral effects of perinatal (Millicell, Millipore) and cultured over culture medium con- gamma-aminobutyric acid (GABA) potentiation and taining 50% basal medium, 25% Hanks’ balanced salt so- methylenetetrahydrofolate reductase (MTHFR) lution, 25% horse serum, L-glutamine, antibiotics and glu- deficiency in mice cose. Slices were maintained in culture for 1–6 weeks at 37◦C with 5% CO2 enriched atmosphere. Whole cell patch-clamp Levav T., Blumkin E., and Golan H. recordings from Purkinje cells (PCs) were made after removing the inserts’ wall and placing it in a recording chamber Department of Developmental Genetics, Ben-Gurion perfuse with 5% CO2 and 95% O2 enriched Ringer’s solu- University, Zlotowski Center for Neuroscience, Israel tion. Our results show that these cultures form an active network of cerebellar neurons. PCs preserved their charac- Fetal-Anticonvulsant Syndrome may cause developmental teristic two-dimensional dendritic tree, and displayed sub- delay, cognitive dysfunction, and behavioral impairments: and supra-threshold spontaneous activity. The subthresh- hyperactivity, attention deficit disorder and autistic-like old activity consisted of depolarizing and hyperpolarizing behavior. We examined the interactions between genetic Israel Society for Neuroscience 67 susceptibility and anticonvulsant drug treatment, by per- be strongly reduced (up to 65% in hippocampus). How- forming behavioral phenotyping of MTHFR deficient off- ever, inositol levels were not found to be changed. Res- spring perinatally treated with a GABA potentiating sub- cued adult IMPA1-/- mice exhibit a strongly increased sen- stance. Four groups of offspring were compared: Balb/c wild- sitivity to pilocarpine-induced seizures, supporting the idea type (wt) and Mthfr-/+ mice injected daily subcutaneously that IMPA1 represents a physiologically relevant target of on postnatal days 4–10 with saline (Ct) or vigabatrin (GVG; lithium. The IMPA1-/- mouse represents a novel model to 50 mg/kg). GVG treatment, but not MTHFR, delayed mo- study inositol homeostasis, and indicates that genetic in- tor and sensory reflex development. In the open field task, activation of IMPA1 can mimic some lithium behavioral adult male GVG treated mice demonstrated increased mo- effects. bility, regardless of genetic background. Hyperactivity was expressed in a longer distance moved by GVG-wt and GVG- Emotion recognition vs. non-effective Mthfr-/+ mice (1255.6 and 1363.2 cm) and a higher veloc- visual processing deficits in schizophrenia ity (4.2 and 4.5 cm/s), compared with Ct-wt mice (965.1 cm and 3.2 cm/s, resp.; P<.05). In adult female mice no signif- Levin R.,1 Elran S.,2 Ermilov M.,1,2 Edelman S.,1 icant alterations in mobility were observed. Anxiety was re- Javitt D. C.,3 and Heresco-Levy U.1,2 duced in male GVG-wt and GVG-Mthfr-/+ mice, expressed by a higher duration ratio center/margin, compared to Ct- 1Psychiatry Department, Ezrath Nashim-Herzog wt mice (0.35 and 0.40 versus 0.18, resp.; P<.05). In fe- Memorial Hospital, Jerusalem, Israel male mice, anxiety was reduced in GVG-wt and Ct-Mthfr-/+, 2Hadassah Medical School, Hebrew University, compared to Ct-wt, and MTHFR deficiency combined with Jerusalem, Israel GVG treatment abolished the anxiety related effect. Recog- 3Nathan S. Kline Institute for Psychiatric nition memory was impaired, regardless of gender, in both Research and NYU School of Medicine, GVG-wt and GVG-Mthfr-/+ mice, as well as in Ct-Mthfr-/+ NY, USA mice. These mice did not distinguish between novel and familiar objects. In a sociability task, a genotype effect was ob- Deficits in face emotion identification and discrimination served in male and female. This genotype effect was not ob- were previously reported in schizophrenia. However, it is not served in a social preference test, while in female GVG treat- clear whether the impairment in decoding emotion based ment in wt and Mthfr-/+ mice reduced preference to an un- on facial expression represents a specific dysfunction do- familiar mouse (P<.05) Overall, MTHFR deficiency and main or may reflect generalized visual processing deficits. GABA potentiation differentially affects a spectrum of behav- In the present study, we evaluated both emotion recog- iors in male and female mice. nition and generalized, nonaffective visual processing parameters (GVP) and their relationship with clinical state Supported by Eshkol Fellowship, Israeli Ministry of Science, in schizophrenia patients. Thirty stable schizophrenia inpa- Culture and Sport, for Tamar Levav. tients and 15 age- and sex-matched control subjects participated in the study. Decoding emotion processing assessed by Characterization of the IMPA1 deficient mouse (1) the face emotion identification test (FACE-ID); (2) the face emotion discrimination test (FACE-DIS). GVP was as- Levi I.,1 Shamir A.,2 Cryns K.,3 Steckler T.,3 Moechars D.,3 sessed using (1) the closure flexibility-concealed figure task Belmaker R.,2 and Agam G.1 (CFT); (2) the perceptual organization (PO). For all patients, 1Department of Clinical Biochemistry, Faculty of Health the positive and negative syndrome scale (PANSS) was ad- Sciences, Ben Gurion University of the Negev, Israel ministered. Patients showed significantly impaired perfor- 2Psychiatry Research Unit, Faculty of Health sciences, mance on FACE-DIS, although between-group differences Ben Gurion University and Mental Health Center, Israel in FACE-ID were not statistical significance. Large effect- 3Research and Early Development Europe, size between-group differences were also observed on both Johnson and Johnson Pharmaceutical Research and GVP tasks. A MANOVA analysis including all four test mea- Development, USA sures simultaneously indicated both a main effect of group (F = 29.1, df = 1, 40, P<.0001) and a significant (F = 7.91, Lithium has been used to treat bipolar disorder over the df = 3, 38, P<.0001) group x test effect. Post-hoc t- last five decades, but the molecular mechanism of its ther- tests indicated the existence of a greater deficit among pa- apeutic effect has not yet been unraveled. We pheno- tients on the nonaffective relative to affective visual pro- typed IMPA1 knockout mice to study the possibility that cessing tests used in this study. Significant positive correla- the product of this gene, the enzyme inositol monophos- tions were found among patients between impaired FACE- phatase, is a molecular target in mediating lithium depen- DIS and FACE-ID performance and the GVP measures. Pos- dant physiological effects. The IMPA1-/- mice die in utero itive, negative and total PANSS scores correlated significantly between day 9.5 and 10.5 post coitum (p.c.) demonstrat- with FACE-DIS (r =−0.48, P<.05) and FACE-ID (r = ing the importance of IMPA1 in early embryonic develop- −0.65, P<.01) performance. These findings indicate that in ment. The embryonic lethality could be reversed by myo- schizophrenia, basic visual processing deficits may contribute inositol supplementation via the pregnant mothers. In the to the impaired ability to decode emotions based on facial adult’s IMPA1-/- brain IMPase activity levels were found to expression. 68 Neural Plasticity

The importance of being stable and T3 alone or combined with fluoxetine. Reduction in the ac- balanced-a therapy inspired network approach tivity of 5HT1b autoreceptors was observed in the hypothalamus of rats receiving T3 plus fluoxetine, but not in those Levit-Binnun N. and Moses E. receiving either compound alone. The novelty suppressed feeding test was used to explore the effects of fluoxetine Department of Physics of Complex Systems, The Weizmann 10 mg/kg, T3 20 mcg/kg and the combination of fluoxetine Institute of Science, Rehovot, Israel 5mg/kg+T320mcg/kg,for12days,onthetimerequired for a food deprived animal to commence eating in an unfa- We combine recent understanding obtained on the activation miliar environment (latency). Only the fluoxetine 5 mg/kg+ of networks in the brain with experience of therapists and T3 20 mcg/kg combination caused a significant shortening of clinicians dealing with developmental disorders, to propose latency. Finally, we studied the effects of fluoxetine 5mg/kg, a novel paradigm that can explain several aspects of behavior T3 20mcg/kg and their combination, administered for 7 days, and development. The major input from the clinic is in find- on mRNA levels of 5HT1a and 5HT1b receptors in different ing the efficient modes of intervention and therapy methods brain areas. In the raphe nucleus the combination of T3+ flu- that enable the re-shaping of behavior. This allows us to iden- oxetine caused a decrease in mRNA for both receptors. Simi- tify susceptible or weak parts of the network that, when func- lar reductions were observed in rats treated with T3 alone or tioning normally, underlie the development of a purposeful combined with fluoxetine in the amygdala, CA1 and dentate self. Their abnormal functioning, on the other hand, seems gyrus (5HT1a receptor mRNA) and the frontal and enthori- to lead to disturbed human experiences such as autism and nal cortices (5HT1b receptor mRNA). Taken together, the re- schizophrenia. A careful interpretation of the most up-to- sults of these different experimental paradigms suggest that date clinical work reveals the specific components and the the mechanisms underlying the antidepressant activity of T3 underlying dynamics of a fundamental network that are re- may be mediated by changes in the activity of presynaptic quired for normal development. These components include serotonergic autoreceptors. the sensory, emotion and motor systems, each of which has a critical influence on the functionality of the other two com- Regional sensitivity to neuroinflammation: ponents and on the recruitment of other important func- in vivo and in vitro studies tions (such as memory and motivation). The dynamic no- tions that we find as crucial for the functioning of the net- Liraz-Zaltsman S.,1,2 Fishbein I.,3 Greeneberger V.,3 work are balance and stability. Balance refers to the function- Shohami E.,2 and Biegon A.1,4 ing of the network and its components within a range of parameters that enable good functionality. Stability assures that 1The Joseph Sagol Neuroscience Center, Sheba Medical fluctuations in the input and output of the network are not Center, Israel prohibitively large. Severe instability may drive the develop- 2The Hebrew university Department of pharmacology, ment away from its normal route (as in autism), and may Jerusalem, Israel even lead to network collapse (as in schizophrenia). Regain- 3Weizmann institute of science, Rehovot, Israel ing stability and balance is therefore the goal of a successful 4Brookhaven National laboratory, USA intervention. Neuroinflammation is believed to play a major role in sev- Biochemical and behavioral effects of eral acute human neuruopathologies and chronic conditions triiodothyronine (T3) may provide a basis for such as Alzheimer’s and Parkinson’s disease. Recent observa- the antidepressant attributes this compound tions suggest that the intensity of the neuroinflammatory response to various challenges is region dependent. The goal Lifschytz T., Shalom G., Golzer T., Segman R. H., of our study is to expand and substantiate our knowledge Lerer B., and Newman M. E. of regional sensitivity to neuroinflammation and explore the underlying mechanisms. Neuroinflammation was induced in Biological Psychiatry Laboratory, Hadassah Hebrew vivo by intracisternal (ic) injections of endotoxin (LPS) in University Medical Center, Jerusalem, Israel male Sabra mice. Animals were tested for neurological and cognitive deficits using a neurological severity score (NSS) Thyroid hormones had been long used in the treatment of and the novel object recognition test (ORT). Regional neu- depression, mostly as supplements to antidepressants, to en- roinflammation was measured by quantitative autoradiog- hance or accelerate clinical response. Little is known of the raphy with [3H] PK11195 a peripheral benzodiazepine re- mechanisms underlying these effects, which we attempted to ceptor ligand that marks the activation of Microglia. Quan- uncover by using different pharmacological, behavioral and titative analysis of neuroinflammation was performed in molecular paradigms. In vivo microdialysis was used to eval- five brain areas. In vitro, we employed mixed (e.g., cor- uate the effects of fluoxetine 5mg/kg, T3 20mcg/kg and their tex/striatum) neuronal cultures exposed to glutamate and/or combination, administered to male Sabra rats for 7 day, on TNFalpha, for 24 h, with neuronal survival as an endpoint. serotonin levels and the activity of presynaptic serotonergic ic LPS Mice showed moderate neurological deficits and sig- receptors in the cortex and hypothalamus. Reduction of hy- nificant deficits in the ORT. Increased [3H]PK11195 den- pothalamic serotonin levels was observed in rats treated with sity was found in all regions, with the highest increase (26%, Israel Society for Neuroscience 69

P<.0001) in entorhinal cortex, followed by perirhinal, tem- hyper-direct pathways, and output back to cortex via globus poral and cingulate cortex (P<.05). The striatum had the pallidus and thalamus. smallest increase (13%, NS). In vitro, we found a significant survival difference between cortical and striatal neurons ex- Supported by Marie Curie Intra European fellowship (contract posed to glutamate (P = .01) and TNFalpha (P = .002). MEIF-CT-2006-038858), British Technion Society. Exposure to glutamate and TNFalpha reduced the number of cortical neurons to 5.68%+/-4.3 74.55%+/-18.6 of con- Synaptogenesis of adult-born neurons in trol respectively while the number of striatal neurons was re- the mouse olfactory bulb duced to 21.04%+/-14.09 and 115.69%+/-25.01 respectively. A better understanding of the regional determinants govern- Livneh Y., Raday G., and Mizrahi A. ing sensitivity to neuroinflammation may help in identifying Department of Neurobiol & ICNC, The Hebrew University of new targets for treatment or prevention of neuroinflamma- Jerusalem, Israel tory damage in human disease Throughout adulthood, the olfactory bulb (OB) contin- Simultaneous MEG and subthalamic local field uously receives newborn neurons that integrate into the potential recordings in Parkinson patients reveal network as functional interneurons. This unique popula- the frequency-specific spatial pattern and tion serves as a model system to study how synapses are directionality of subthalamo-cortical interactions formed during neuronal integration into a preexisting net- Litvak V.,1 Penny W.,1 Eusebio A.,1 Chen C. C.,1 work. Here, we set out to directly image newborn neurons Oostenveld R.,2 Kilner J.,1 Limousin P.,1 Zrinzo L.,1 and their underlying synapses by combining in vivo imaging Hariz M.,1 Friston K.,1 and Brown P.1 and electron microscopic (EM) analysis. Adult-born neurons were transduced at the subventricular zone with lentiviruses 1Institute of Neurology, University College London, to express a postsynaptic density protein fused with green London, UK fluorescent protein (PSD95-GFP) revealing both dendrites 2F.C. Donders Centre for Cognitive Neuroimaging, and synapses. We first carried out an EM analysis of the University of Nijmegen, Nijmegen, The Netherlands PSD95-GFP puncta. To this end, we analyzed young developing neurons 10-14 days post injection (DPI) where only Insight into how brain structures interact is critical for un- 63% of PSD95-GFP puncta had a clear pre-synaptic part- derstanding the principles of brain function and may lead to ner. This indicates that 37% of the synapses are still devel- better diagnosis and therapy. To study interactions between oping. Notably, newborn neurons made synapses almost ex- the cortex and deep brain structures (basal ganglia and the clusively with axons of olfactory receptor neurons. Second, thalamus) we recorded simultaneously local field potentials we analyzed synaptic distributions and dynamics of whole (LFPs) from deep brain stimulation (DBS) electrodes and neurons. At 10–14 DPI, newborn puncta were sparsely dis- magnetoencephalographic (MEG) signals from the cerebral tributed along dendrites (up to 20 microns between synap- cortex (CTF 274 channel system) in Parkinson’s disease (PD) tic puncta). In marked contrast, puncta of mature neurons patients with bilateral DBS electrodes in the subthalamic nu- (at 57 DPI) were distributed more densely (peak distance– cleus (STN). We report the results from two patients. Infor- 3 μm between puncta). Finally, in vivo two-photon time- mation transfer between the STN and cortex was evaluated lapse imaging of newborn neurons over 36 hours revealed using a multivariate autoregressive (MAR) model in combi- that synaptic puncta display a rich repertoire of dynamics, nation with whole-head topographical mapping and source continuously appearing and disappearing. For example, only localization. In case 1 (male, 38 y.o., left-handed, 10 years ∼60% of synaptic puncta remained stable through the imag- post PD onset) the right STN LFP predicted the MEG signal ing session. Taken together, these experiments provide an ex- over the right sensorimotor area and the MEG from the right perimental “snapshot” into the dynamic behavior of synapse sensorimotor and mesial areas predicted the right STN LFP. formation in the intact mammalian brain. Similar bidirectional interactions were observed for left STN with the signals predicted by STN LFP more focal over the Variable Processing of Texture Signals by left sensorimotor area and the signals predicting STN activ- Whisker Vibrations ity found over bilateral sensorimotor cortex. In case 2 (male, 54 years old, right-handed, 18 years post PD onset) bidirec- Lottem E. and Azouz R. tional interactions were observed between the right STN and mesial areas. The left electrode in case 2 passed about 2 mm Department of Physiology, Faculty of Health Sciences, postero-medial to the sensorimotor area of the STN. No cou- Ben Gurion University of the Negev, Israel pling was detected between this left channel and MEG; con- firming the regional specificity of the cortico-STN coupling. Rodents in their natural environment use their whiskers to We conclude that simultaneous recording of the LFP from distinguish between surfaces having subtly different textures DBS electrodes and MEG enables one to establish patterns and shapes. They do so by actively sweeping their whiskers of coupling between cortex and focal subcortical structures. across surfaces in a rhythmic motion. To determine how tex- In the case of the STN, this coupling is clearly bidirectional, tures are transformed into vibration signals in whiskers and in keeping with its cortical input via the corticostriatal and how these vibrations are expressed in neuronal discharge 70 Neural Plasticity patterns, we induced active whisking in anaesthetized rats, in Mn-SOD (indicating the presence of OS) in the basal fore- monitored the movement of whiskers across surfaces, and brain including diagonal band, medial septum, (the major concurrently recorded from trigeminal ganglion (TG) neu- sources of cholinergic input to the hippocampus and cingu- rons. We found that whisker movements across surfaces are late cortex) and in the hippocampus. At 5 weeks, there was composed of whisking and texture-related vibration signals, a reduction of 20% in mean size of cholinergic neurons in both carrying information about surface roughness. During the diagonal band, suggesting that these neurons were un- contact with textures, TG neurons presented a broad range der stress although cholinergic neuron loss was not observed. of responses, which encoded the two signals. To determine There was a compensatory increase of about 100% in im- whether these signals can support texture discrimination we munoreactive varicosities and GAP-43 (a presynaptic mem- examined their dependence on surface roughness. We found brane phosphoprotein marker of plasticity) in the subgranu- that despite a large variability in this translation process, dif- lar layer of the dentate gyrus. ferent textures are translated into distinct vibrations profiles. These response profiles vary across whiskers, are dependent Conclusions on the radial distance of the textures, on whisking frequency, and may be influenced by head movements. Using the char- The present study demonstrates a unique sensitivity of acteristics of these signals, we employed discriminant analy- certain neuronal populations, among them, the septo- sis to statistically evaluate the ability of whiskers to discrim- hippocampal system, to reduction in cytochrome oxidase ac- inate between textures. Texture identity was correctly classi- tivity. The present study also suggests that oxidative stress is fied in 87% of whisks. This classification did not depend on involved in this process. whisker identity and whisking frequency, while deteriorating with radial distance. Finally, increasing the number of whisks Attentional demands predict short-term memory and integration of information from multiple whiskers im- load response in posterior parietal cortex proved texture discrimination. These results indicate that 1 2 2 surface roughness is translated into distinct whisker vibra- Magen H., Kastner S., and Treisman A. tion signals that result in neuronal discharge pattern. 1Psychology Department, the Hebrew University, Israel 2Psychology Department, Princeton University, USA Chronic inhibition of brain cytochrome oxidase in rats induces memory deficits and associated with oxidative The ability to maintain information for short periods of time stress and alterations in cholinergic transmission plays an essential role in cognition. One of the most intriguing aspects of short-term memory is its limited capacity, typ- 1 2 1 Luques L., Shoham S., and Weinstock M. ically around 3 or 4 items. Functional magnetic resonance

1 imaging (fMRI) research revealed a large network of brain Department of Pharmacology School of Pharmacy Hebrew areas involved in the short-term retention of information. University of Jerusalem, Israel 2 Recently it has been suggested that activity in a specific part Research Department Herzog Hospital, Jerusalem, Israel of this network, the posterior parietal cortex (PPC), is correlated with the behavioral estimates of capacity limitations The present study tests the hypothesis that in Alzheimer’s and might serve as a capacity-limited store (Todd & Marois, disease early reduction in cytochrome oxidase (COx) activ- 2004). We present the results of a set of experiments that ity could initiate a cascade of events which includes oxidative failed to find this close correlation between fMRI activity and stress (OS) leading to cognitive impairment via involvement behavioral capacity limitations. Instead, we show that when of cholinergic neurons. Reduction in COx and memory im- visual rehearsal is more prominent in the task, fMRI activity pairment can be mimicked in rats by chronic administration in PPC increase with memory load beyond the behaviorally of sodium azide (NaN3). determined limits of capacity. We suggest that activity in PPC reflects the attentional demands of the short-term memory Methods task rather than a capacity limited store. This interpretation is consistent with the role of PPC in attentional processes and NaN3 or saline was given s.c. for 4 weeks (1 mg/kg/hr) by with the close correlation between brain areas that are in- minipumps to male Sprague-Dawley rats. After 2 or 5 weeks, volved in attention and those that mediate short-term mem- brains were fixed and sectioned for immunohistochemical ory. mapping of the marker of OS, manganese-dependent su- peroxide dismutase (Mn-SOD), and markers of cholinergic Cannabidiol (CBD) ameliorates cognitive neurons, choline acetyltransferase (ChAT) and of vesicular impairments associated with a model of acetylcholine transporter (VAChT). chronic liver disease in mice

Results Magen I.,1 Avraham Y.,1 Berry E.,1 Ackerman Z.,2 and Mechoulam R.3 NaN3–treated rats showed a signiﬁcant decrease in COx activity in the cingulate and parietal cortex and in the hip- 1Department of Human Nutrition and Metabolism, pocampus. At 2 weeks, NaN3 induced a signiﬁcant increase Braun’s School of Public Health, Hebrew University, Israel Israel Society for Neuroscience 71

2Department of Internal Medicine, Hadassah–Hebrew ment of the archetypical Shaker Kv channel (ShB-C) is a University Medical Center, Mount Scopus, Israel random coil, suggesting that ShB-C belongs to the recently- 3Department of Medicinal Chemistry and Natural Products, defined class of intrinsically disordered proteins. We show Medical Faculty, Hebrew University, Israel that isolated ShB-C is still able to bind its scaffold protein partner and support protein clustering in vivo, indicating Background that unfoldedness is compatible with ShB-C activity. Pull- down experiments involving C-terminal chains differing in Hepatic encephalopathy (HE) is a major neuropsychiatric flexibility or length further demonstrate that intrinsic disor- complication of both acute and chronic liver failure. How- der in the C-terminal segment of the Shaker channel mod- ever, its pathogenesis is still unknown. It has been sug- ulates its interaction with the PSD-95 protein. Our results gested that the cognitive deficits characterizing this state re- thus suggest that the C-terminal domain of the Shaker Kv sult, at least in part, from an inflammatory response in the channel behaves as an entropic chain and support a “fish- brain. Cannabidiol (CBD) is an active compound of the plant ing rod” molecular mechanism for Kv channel binding to Cannabis Sativa known for its antiinflammatory properties. scaffold proteins. The importance of intrinsically disordered We hypothesized that CBD may have therapeutic potential protein segments to the complex processes of synapse assem- in chronic liver disease through antiinflammatory actions. bly, maintenance, and function is discussed. Methods: Female Sabra mice were subjected to ligation of the bile duct (BDL). Sham operated animals were used as controls. 2 weeks and 3 weeks post-surgery, animals receiv- Towards behavioural measures of action ing either vehicle or 5 mg/kg CBD were evaluated for cogni- space–manipulability vs. compatibility in tive function in the Eight Arm Maze and the T-maze tests. objects affordances The animals were sacrificed and their hippocampi were an- Makin T.,1 Vax M.,1 and Zohary E.1,2 alyzed for mRNA levels of IL-1 beta by RT-PCR analysis, and their livers were analyzed for MDA levels, indicating ox- 1Neurobiology Department, Life Science Institute, Israel idative stress by the TBARS method. Results: IL-1 beta ex- 2Interdisciplinary Center for Neural Computation, pression in the hippocampus increased significantly in BDL Hebrew University of Jerusalem, Israel mice 3 weeks post-surgery, and was restored to normal values by CBD. Oxidative stress in the liver increased in BDL We perceive in order to act on the environment. Affordance animals and was decreased by CBD. Cognitive function was theory states that objects are perceived not only in terms of significantly impaired in BDL mice and these impairments shapes and spatial relationships but also in terms of possibili- were also ameliorated by CBD. Conclusion: These results in- ties for action (affordances). That is, perception drives action dicate an involvement of inflammatory processes in the hip- in a direct and immediate way. According to this assertion, pocampus in the pathogenesis of HE. This inflammatory re- seen objects should automatically potentiate components of sponse may be associated with the behavioral impairments, the actions they afford. Previous studies have demonstrated and both were ameliorated by CBD. CBD may act via the affordance by showing nonspatial compatibility effects for adenosine system, since an upregulation of this system was central objects, based on the orientation of their handles. observed in hippocampal slices of human HE patients, post However, it is possible that the visual asymmetry created by mortem. the handles directed the subjects’ attention towards one side, thus creating spatial compatibility effects, irrespective of any The role of intrinsically-disordered protein segments affordances. In order to dissociate between affordance and in mediating Kv channel clustering: implications for spatial compatibility effects, we tested whether responding synapse assembly, maintenance and function to manipulable objects could result in speeded responses, Magidovich H.,1 Orr I.,1 Fass D.,2 Abdu U.,1 as compared to nonmanipulable objects with similar visual and Yifrach O.1 asymmetries. To this end, we presented pictures of manipulable and nonmanipulable objects, half of which contained 1Department of Life Sciences, Ben-Gurion University of metal, on the right or left side of the screen. On each trial, the Negev, Zlotowski Center for Neurosciences, Israel subjects were required to judge whether the depicted object 2Weizmann Institute of Science, Israel contained metal or not, by pushing a button with their left or right hand. Our results showed significant effects of both spa- The interaction of membrane-embedded voltage-activated tial compatibility and of manipulability: Subjects responded potassium channels (Kv) with intracellular scaffold proteins, quickest and most accurately when manipulable objects were such as the post-synaptic density 95 (PSD-95) protein, is me- presented compatibly with the responding hand, and slowest diated by the channel C-terminal segment. This interaction when nonmanipulable objects were presented incompatibly underlies Kv channel clustering at unique membrane sites with the responding hand. These results suggest that both ef- and is important for the proper assembly and functioning of fects may prime responses equally. However, subjects’ perfor- the synapse. In the current study, we address the molecular mance in a separate spatial perception task (landmark) cor- mechanism underlying Kv/PSD-95 interaction. We provide related with the effect of compatibility, but not of manipula- experimental evidence, based on hydrodynamic and spectro- bility, suggesting that whereas the former relies on perception scopic analyses, indicating that the isolated C-terminal seg- space, the latter might rely more on action space. 72 Neural Plasticity

Rapid modulation of motor cortex Synaptogenesis is a fundamental process during neuronal excitability–TMS evidence for hand-centered development, learning processes, and regeneration after visual representations of space trauma. We have recently argued that in cultured Aplysia neurons prefabricated varicosities (VRs) serve as ready-to-go Makin T.,1 Holmes N. P.,2,3 Brozzoli C.,3,4,5 presynaptic compartments. Thus VRs exocytose their vesic- Rossetti Y.,3,4,5 and Farne A.3,4,5 ular contents in a spike activity-dependent manner. The mechanisms by which VRs are formed are not entirely un- 1Neurobiology Department, Life Sciences Institute, derstood. Real-time confocal imaging of growth cones (GCs) Hebrew University of Jerusalem, Israel and VRs revealed that VR formation is preceded by accu- 2Psychology Department, Hebrew University of Jerusalem, mulation of vesicles and cytoskeletal elements in the cen- Israel tral domain of a pausing GC. During the phase of organelle- 3INSERM, U864, Espace et Action, Bron, France accumulation, (lasting 8–22 minutes), the actin-rich periph- 4Universite Lyon, UMR-S 864, Lyon, France eral domain continues to extend and retract. When a “large” 5Hospices Civils de Lyon, Hopital Neurologique, mass of organelles accumulates in the central domain, the GC Mouvement et Handicap, Lyon, France resumes its net growth by actin-rich lamellipodia and filopodia, invaded by MTs. It is important to note that while the Perception and action are interdependent and inseparable– advancing GC does not contain large quantities of organelles, an animal’s motor behavior should be reflected in its percep- it leaves behind a VR loaded by a mass of organelles. With tion. Indeed, electrophysiological studies in premotor cor- time (8–25 minutes), the splayed MTs within the VR bun- tex have revealed visual receptive fields, selective for mov- dle to form the core of the VR. This core is very dynamic and ing 3D objects, that shift with the position of a monkey’s can splay or even bend when the VR moves along the neurite. arm, regardless of gaze direction. This suggests a represen- Imaging of Golgi derived vesicles labeled by synaptopHluo- tation of visual space in hand-centered coordinates. In the rins revealed that the growth process is associated with con- present study, we explored hand-centered modulation of vi- stitutive fusion of vesicles with the GC’s plasma membrane. sual space in the human motor cortex. Subjects performed Evoked exocytosis coupled to membrane retrieval operates a simple “Go” response task to a central visual target, by in both GCs and VRs. Taken together our observations are pushing a button on the left or right side of fixation, while consistent with the hypothesis that VRs are formed when simultaneously a 3D ball approached the left or the right the supply of anterogradely transported vesicles exceed the side. Between 40–120 ms later, a single TMS pulse was ap- amount needed to support the elongation process, which is plied to the primary motor cortex contralateral to the re- limited by the assembly of the actin and MT skeleton. This is sponding finger in order to elicit motor evoked potentials also consistent with the finding that VRs are almost homo- (MEPs). We found that the mean peak- to-peak MEP am- geneously spaced along individual neurites, which represents plitude was smaller when the ball approached the position of the local balance between organelle supply and elongation. the responding hand, as compared to far from the hand, regardless of the hand position with respect to fixation. We hy- Activity–dependent neuroprotective protein pothesized that this rapid modulation reflected the suppres- constitutes a novel element in the SWI/SNF chromatin sion of an existing motor plan (the “Go” response), caused remodeling complex and modulates neural shape by the approaching object. We designed a battery of experiments to test this hypothesis, manipulating the type of visual Mandel S. and Gozes I. stimulus presented, the required motor task, and the direc- Human Molecular Genetics and Biochemistry, tion of subject’s overt (changing fixation position) and covert Sackler Medical School,Tel Aviv University, Israel visual attention (presenting peripheral cues). We found that the hand-centered modulation of MEP amplitudes was crit- Complete deficiency in activity-dependent neuroprotective ically dependent upon the timing of the TMS pulse (70– protein (ADNP), a multifunctional, heterochromatin 1- 80 ms), the type of visual stimulus (moving balls versus static binding protein, results in dramatic changes in gene expres- LEDs), and the presence of an ongoing motor plan. Manip- sion, neural tube closure defects and death at gestation day ulating the location of visual attention only partially modu- 9 in mice. To further understand the cellular roles played lated these hand-centered effects, suggesting contributions of by ADNP, the HEK293 human embryonic kidney cell line both eye- and hand-centered spatial representations to activ- was used as a model for the identification of ADNP in- ity in primary motor cortex. teracting proteins. Recombinant green fluorescent protein (GFP)-ADNP was localized to cell nuclei. When nuclear Watching synapses form: live imaging of extracts were subjected to immunoprecipitation with spe- the formation of presynaptic boutons by growth cific GFP antibodies followed by protein gel electrophore- cones of cultured aplysia neurons sis, several minor protein bands were observed in addition to GFP-ADNP. In-gel protein digests followed by mass spec- Malkinson G. and Spira M. E. trometry identified BRG1, BAF250a and BAF170, all components of the SWI/SNF (mating type switching/sucrose non- Department of Neurobiology, The Life Sciences Institute, fermenting) chromatin remodeling complex as proteins that The Hebrew University of Jerusalem, Israel coimmunoprecipitate with ADNP.These results were verified Israel Society for Neuroscience 73 utilizing BRG1 antibodies. ADNP shRNA down-regulation in M1 by an increase followed by a decrease in neuronal vari- resulted in microtubule reorganization and changes in cell ability. Furthermore, they strengthen the notion that adapta- morphology including reduction in cell process formation tion process starts in SMA and M1 follows it. and cell number. These morphological changes are closely associated with the SWI/SNF complex multifunctionality Supported by Mafat, Johnson and Johnson,BSF, and by a con- (JBC 2007). Furthermore, using P19 cells as a differentia- tributions of Abraham and Ida Baruch Foundation and the tion model, we showed that ADNP expression and cyto- Rosetrees trust. plasm/nuclar distribution is unique in neuronal differentiated cells compared to cardiovascular and nondifferentiated Novel TSPO ligands as neuroprotective agents pluripotent cells. Small hairpin RNA down regulation was 1 1 1 1 used to further investigate ADNP involvement in p19 neu- Maniv I., Veenman L., Leschiner S., Spanier I., 2 2 2 1 rodifferentiation. A ∼80% reduction in ADNP led to a sub- Marek I., Shterenberg A., Hadad E., and Gavish M. stantial reduction in embryoid body formation and to a sig- 1 nificant reduction (∼50%) in neurite number. These results Faculty of Medicine, Technion-Israel Institute of Technology, 31096 Haifa, Israel position ADNP in direct association with neuronal cell dif- 2 ferentiation and maturation. Faculty of Chemistry, Technion-Israel Institute of Technology, 32000 Haifa, Israel Supported by BSF, ISF, Lily, and Avraham Gildor Chair, Adams Super Center and Allon Therapeutics Inc. Secondary brain damage often occurs after traumatic brain injury traumatic brain injury (TBI). TBI can result from ex- plosions, including terrorist attacks, traffic and household Dynamics of neuronal variability in motor cortical accidents, and other forms of violence. Neuronal death due areas during and switching between different tasks. to secondary brain damage and neurodegeneration have in What may it reflect? common an excitotoxic process leading from overexcita-

1 1,2 tion of glutamate receptors to mitochondrial damage. The Mandelblat-Cerf Y. and Vaadia E. mitochondrial damage can lead to neuronal death, including apoptosis. Our studies suggest that the mitochondrial 1Department of Physiology, Faculty of Medicine, Translocator Protein (TSPO) plays an important role in this Hebrew university, Jerusalem, Israel process. Recently, we have developed compounds that bind 2The Interdisciplinary Center for Neural Computation (ICNC), with high affinity to the TSPO and apparently block its apop- Hebrew University, Jerusalem, Israel totic function. These novel compounds reduced basal apoptotic levels in neuronal cells. Some of them also reduced We present analyses designed to test the idea that variability apoptosis induced by glutamate in the SH-SY5Y cell line by of single cells’ activity in motor cortical areas, reflects under- more than 50%. In our in vivo experiments we found that lying processes associated with nonadaptation (over trained, one of our ligands (9a) (15 mg/kg) reduces the adverse effects center-out reaching, standard task), adaptation (visuomotor of kainic acid (9-10 mg/kg) in rats. For example, seizures in- rotation) tasks, and switching from one to the other. Under duced by kainic acid are indicative for neurodegeneration in the assumption that increase in variability is a result of neu- the hippocampus. Severe seizure activity was reduced by 9a ronal processes, we investigate the hypothesis that adaptation by more than 67%. As some of our compounds show an- starts at pre-motor areas, higher in the hierarchy of compu- tiapoptotic effects others show pro-apoptotic effects, which tation, gradually transfers to primary areas, until a stable rep- may have implications for the development of potential anti- resentation is formed there. In contrast, a standard task, that cancer drugs. We envision that secondary brain injury due to incorporates merely the retrieval of an internal model and TBI may be prevented by soldiers and paramedics carrying not its formation, is expressed mainly by changes in primary with them one of the antiapoptotic drugs we have developed areas. To this end, we measured the across-trial variability and use it on site. This may reduce the incidence of disabili- of single cells responses, and found it has a significant dy- ties presently occurring in the aftermath of TBI. In addition, namics for movement preparation period. During standard such a drug might also find application in the treatment of task, although it is assumed to be a stationary process, single neurodegenerative diseases. cells in M1 showed a tendency of a gradual decrease in variability but neuronal activity in SMA did not show any sig- Supported by Dan Horovitz fund (L.V.,M.G) Center for Ab- nificant dynamics. Switching to adaptation task, caused vari- sorption in Science, Israel (L.V). ability in M1 to increase, and later on, decreased back to initial level. Interestingly, similar dynamics was found in SMA, The Inhibitory Effect of Mood Stabilizers on but earlier in the adaptation session, returning to initial level Adenylyl Cyclase Isoforms approximately when movement reached its asymptotic best level according to the learning curve. Surprisingly, when re- Mann L.,1 Heldman E.,1 Belmaker R. H.,2 and Agam G.1,2 turning to standard task the dynamics in M1 was similar to that during adaptation task and no significant dynamics was 1Department of Clinical Biochemistry, Israel seen in SMA as in the first standard task. These results sug- 2Stanley Research Center, Ben-Gurion University of gest that any switching between internal models is reflected the Negev and Mental Health Center, Beer-Sheva, Israel 74 Neural Plasticity

Bipolar disorder has been hypothesized to be associated with when microinfused immediately before the test 24 hours af- an enhanced signaling activity of the cAMP cascade. The ter training, indicating also that cytochalasin D did not im- mood stabilizers lithium (Li+), carbamazepine (CBZ) and pair normal synaptic transmission in LA. The present results valproate, at therapeutic concentrations, exert an inhibitory show that actin polymerization in LA is essential for fear con- effectonforskolinandGαs-coupled receptor activated cAMP ditioning memory formation. accumulation. The aim of this work was to study the effects of lithium and carbamazepine on each of the membrane-bound The interaction of the drug candidate NAP with isoforms of aednylyl cyclase (1–9). COS7 cells were trans- microtubules in the presence of tau fected with each of the AC isoforms cDNAs with or without D1-dopamine receptor cDNA. AC activity was measured Maor M., Dangoor D., and Gozes I. as [3H]cAMP accumulation in cells pre-incubated for two hours with 1 mM Li or 0.1 mM CBZ followed by incuba- Human Molecular Genetic & Biochemistry Sackler Medical tion with either the D1 agonist FKS-82958 or forskolin. The School, Tel Aviv University 69978, Israel role of Mg2+ in Li’s inhibition of AC was studied in membrane preparations from cells expressing AC5. When stimu- NAP (NAPVSIPQ), a short peptide, derived from activity- lated by forskolin, a direct activator of AC, both 1 mM Li+ dependent neuroprotective protein (ADNP), was revealed and 0.1 mM CBZ inhibited only AC5 activity. When stim- to be a novel neuroprotective drug candidate. Femtomolar ulated via D1 receptors, Li+-inhibitable isoforms were AC5 concentrations of NAP appear to provide neuroprotection and AC7 (∼40–50% inhibition) while CBZ inhibited all iso- in vitro against tetrodotoxin, N-methyl-D-aspartate, natu- ∼ rally occurring cell death, dopamine toxicity, tumor necrosis forms studied (AC5, 7, 3, 2) by 50%. In isolated membrane α preparations of AC5-transfected cells stimulated AC5 activ- factor- toxicity and oxidative stress. NAP was further shown ity was completely abolished by 1 mM Li, and 10 mM Mg2+ to reduce mortality and morbidity, produce cerebroprotec- significantly counteracted Li’s inhibition. Since forskolin is tion, reduce apoptosis and accelerate learning and memory a direct activator of AC, the specific inhibition of forskolin- abilities in a broad variety of in vivo models. A significant stimulated AC5 by both Li and CBZ suggests a direct effect interaction between NAP and tubulin unraveled a possible of these drugs on this specific isoform. Reversal of Li’s in- mechanism of this novel peptide. Through this interaction hibition of AC5 activated via the D1-dopamine receptor by NAP seems to promote tubulin assembly and microtubules Mg2+ suggests that competition with endogenous Mg2+ ions reorganization even in the presence of zinc intoxication. This is involved in the mechanism of the inhibition. Since CBZ study is aimed to assess the characteristics of NAP interaction with microtubules. Pelleting assays were used to determine inhibited all studied isoforms including AC5 and AC7, it is ff possible that AC5 and AC7 are involved in the mechanism of the e ect of NAP on tubulin and co-assembly into micro- mood stabilization. tubules, in the presence of tau. The assembled microtubules were examined by electron microscopy. NAP (1 pM) treat- μ Actin polymerization in lateral amygdala is ment increased microtubule density (10 M), in the presence μ essential for fear memory formation of tau (1 M), as evaluated by electron microscopy. Addi- tionally, NAP-treated microtubules appear to be significantly Mantzur L. and Lamprecht R. longer and more curved compared to the rigid, short microtubules that were observed in the absence of NAP. In conclu- Department of Neurobiology and Ethology, University of sion, NAP treated microtubules assume a different structure– Haifa, Israel namely longer and smoother microtubular structures are The actin cytoskeleton is involved in key neuronal functions formed when NAP is present. Thus, perhaps the interaction such as synaptic transmission, proteins and vesicles traffick- between NAP and microtubules resulting in conformational ing and morphogenesis. The addition of actin monomers to changes (length and shape) leads to the assembly and micro- actin filaments in the processes of polymerization has been tubules reorganization. These findings may be of great im- shown to be involved in these functions and is tightly regu- portance in elucidating the mechanism of NAP nueroprotec- lated in neurons. The aim of the present study is to elucidate tive and neurotrophic roles. the role of actin polymerization in learning and memory. To- Supported by BSF, ISF, Lily and Avraham Gildor Chair, Adams ward this end, we used the fear conditioning paradigm in Super Center, and Allon Therapeutics Inc. which a rat is exposed to a tone (conditioning stimulus (CS); 40 seconds, 5 kHz) that coterminates with a mild footshock Neuronal substrates of head gaze following in (unconditioned stimulus (US); 0.5 seconds, 1.5 mA). Rats monkeys: an fMRI study were trained with 5 consecutive CS-US pairings with average ITI of 180 seconds. We microinfused the actin polymeriza- Materna S., Dicke P. W., and Thier P. tion inhibitor cytochalasin D into the lateral amygdala (LA), a brain area mediating fear conditioning, and studied its ef- Department of Cognitive Neurology, Hertie Institute for fects on memory formation. Microinfusion of cytochalasin D Clinical Brain Research, Tuebingen, Germany immediately before fear conditioning training impaired the formation of long-term fear conditioning memory. Cytocha- The ability to follow the gaze of another person is crucial for lasin D had no effect on fear conditioning memory retrieval normal social interactions. This is not only true for humans, Israel Society for Neuroscience 75 also in other social animals, like nonhuman primates, gaze from brain into blood. Methods: Cultured C6 glioma cells following plays an important role for example in detecting were implanted in rat brain to induce tumor growth and its the location of food and predators. However, compared to accompanying neovascularization. OxAc was daily prepared humans, nonhuman primates rely more on the head than on and added to the drinking water of the implanted rats while the eyes during gaze following. In this study, we attempted to the rats in the control group drunk a NaCl solution at the reveal the neuronal substrates involved in head gaze follow- same osmolarity of the OxAc solution (0.4 M). Each group ing in rhesus monkeys using functional magnetic resonance consisted of 12 rats housed in individual cages. The OxAc or imaging. In the first condition (gaze following) the monkeys NaCl treatment was started five days after glioma implanta- had to detect the head direction of another monkey (pre- tion and the tumor development was followed using Mag- sented on a screen) and to use this information to make a netic Resonance Imaging (MR)I up to three weeks. Results: saccade to one of two dots (either left or right of the monkey MRI analysis shows that OxAc-treated rats displayed a fold face). In the control condition (color matching) the monkeys tumor growth of 8.9 ± 1.9 (n = 12) while that of the NaCl- had to use the color information provided by the fixation dot treated rats was 20.5 ± 4.6 (n = 8; P = .018). Conclusion: (presented in between the eyes of the monkey face) to make The preliminary results obtained support the concept that a saccade to the dot with the same color. Eye movements of decreasing excess glutamate in blood/brain may serve as an the monkeys were recorded using a homemade iris-fit-eye- alternative therapeutic strategy in the management of malig- tracking system. During both conditions, i.e., independent nant gliomas. of which cue was used, activation was found bilaterally in (or near) the frontal eye fields, probably reflecting the need The neurophysiological correlates of abnormal to make saccades. For the contrast “color matching minus behavior in a primate model of Tourette syndrome gaze following” specific activation was found bilaterally in and their response to high frequency stimulation the inferior temporal gyrus, a region known to be involved in color processing. The opposite contrast (gaze following mi- McCairn K., Bronfeld M., and Bar-Gad I. nus color matching) revealed a bilateral activation in the su- Gonda Brain Research Center & Goodman Faculty of Life perior temporal sulcus (STS), most consistently in the mid- Sciences, Bar-Ilan University, Israel dle part of the sulcus: the mSTS. A region in the posterior STS is known to underlie eye gaze following in humans. Hence, Tourette syndrome (TS) is characterized by chronic mo- although human and nonhuman primates seem to rely on tor and vocal tics and has a high comorbidity rate different directional cues, they may deploy similar and possi- with obsessive compulsive behavior (OCB) and attention bly homologous cortical areas to follow the gaze of a conspe- deficit/hyperactivity disorder (ADHD). Despite the different cific. clinical manifestations of these disorders, they have all been associated with a common neuronal pathway: the cortico- Supported by the EU program “PERACT” and a grant from the basal ganglia loop. Most of the nuclei of the basal ganglia use BMBF (01GA0503). GABA (gamma-aminobutyric acid) as their primary neurotransmitter for both inter and intranucleus information Blood glutamate scavenging in the prevention of transfer. Bicuculline (GABAA antagonist) injection to the glioma invasiveness primate putamen evokes motor tics resembling the primary TS symptoms while injections to different domains within Matuzany-Ruban A. and Teichberg V. I. the globus pallidus external segment (GPe) produce behav- Department of Neurobiology, Weizmann Institute of Science, ioral correlates of the comorbid disorders (stereotypy and hy- Rehovot, Israel peractivity with attention deficits). In our study we use extracellular multielectrode recording to characterize the changes Studies performed in the last few years have shown that main firing patterns of multiple single neurons and to uncover lignant glioma cells secrete in the peritumoral space massive the neuronal interaction within small neuronal networks amounts of the neurotransmitter glutamate, and by doing following the injection. Our results demonstrate that local so, promote their own expansive growth at the expense of blockade of GABA leads to the formation of intermittent the neighboring neurons that undergo excitotoxic cell death. high-frequency activity within the GPe. Moreover, neurons Since these studies suggest now that interfering with brain within the injected domain transition from uncorrelated fir- glutamate may control glioma cell proliferation and invasion, ing to a synchronized firing pattern. The observed changes and may limit brain neuronal injury caused by glutamate ex- in neuronal activity are highly correlated to the behavioral cess, we have evaluated in the present study the therapeu- symptoms as assessed by the limb kinematics and video anal- tic efficacy against glioma of a novel neuroprotective strat- ysis of expressed behaviors. Neurons within the GPi display egy recently developed in our laboratory that is based on highly locked activity prior to the tic performance. This in- the ability to cause a decrease of excess brain glutamate lev- vestigation of GABAergic transmission within the cortico- els. By accelerating a naturally occurring brain-to-blood glu- basal ganglia loop provides unique insight into the informa- tamate efflux, we cause a decrease of deleterious glutamate tion encoding within these circuits and how the breakdown levels in brain. This is achieved by the administration of ox- of normal activity leads to the severe clinical symptoms as- aloacetate (OxAc) which, by scavenging blood glutamate lev- sociated with TS. Our studies of HFS within the GP demon- els, increases the driving force for the efflux of glutamate strate that it leads to a locked response to stimulation which 76 Neural Plasticity changes the firing rates and breaks down abnormal corre- fMRI opened new horizons of this methodology. Here we lated activity. show that cluster analysis of the repeated blood oxygenation level dependent (BOLD) measurements of the resting- Visual processing under limiting visual conditions state signal resembles the anatomical and cyto-architectonic arrangement of the tissue in cortical and subcortical gray Meshulam A., Yehezkel O., Mandel Y., Rosner M., matter as well as in the white matter. Therefore, with- Belkin B., and Polat U. out imposing functional paradigms on the BOLD signal (as in rest fMRI), separating the functional contribution Tel Aviv University, Sackler Faculty of Medicine, Goldschleger to the signal fluctuation from the anatomical contribu- Eye Research Institute, Tel Hashomer, Israel tion is challenging. Nevertheless we suggest that multidimensional brain MRI acquisition (like the repeated rest Visual perception changes dramatically under day and night BOLD signal) can be used for parcellation of the brain conditions. Visual performance under vision-limiting condi- into regions that could not be extracted with conventional tions, for example, night vision of all people with either im- MRI. paired or outstanding night-vision, is affected. In this study we explored how different light conditions change the visual abilities of humans. We measured basic functions of the vi- Acute dopamine exposure attenuates GABAA sual system such as visual acuity (VA), day contrast sensi- receptor currents in the VTA through D1 and D2 tivity (CS), and foveal mesopic CS. The subjects were tested dopamine receptors monocularly (N = 30 eyes) and had corrected-to-normal visual acuity. The mesopic CS was measured under condi- Michaeli A. and Yaka R. tions of full darkness, using natural density filters to cover the Department of Pharmacology, School of Pharmacy, monitor, allowing a background luminance of 0.03 cd/m2. The Hebrew University of Jerusalem, Israel The CS measured for Gabor targets was with spatial frequencies of 3–9 cpd. In addition, we tested the influence of exter- Drugs of abuse act through intervening in the normal activity nal blur (+0.50 diopter, inducing night myopia) on the tol- of the reward system. The reward system is composed from erance of the visual functions at night. The results show that interconnected distinct brain regions, including the ventral CS was affected twofold more than the VAunder night condi- tegmental area (VTA), the main source of dopamine in the tions (reduced by a factor of 7.2, 0.85 log units vs 2.6, 0.4 log brain, which synapses onto the nucleus accumbens (NAc) unit), compared with the day conditions. The crowding effect neurons. The psychostimulant cocaine inhibits dopamine re- did not increase under night conditions. Under the blur con- uptake to VTA neurons, as a consequence synaptic dopamine dition, VA is only slightly affected, whereas CS is remarkably concentration in the NAc elevates, and a typical psychostim- reduced (66%). Thus, visual functions are affected differently ulant effect is achieved. NAc dopamine levels can also be under different visual conditions; while tasks performed near modulated by changes in the activity of VTA dopaminergic threshold are affected remarkably, supra-threshold tasks are neurons. Over excitation of these neurons or its reduced in- less affected. Therefore, visual perception cannot be pre- hibition can lead to enhanced dopamine release in the NAc. dicted from standard visual acuity test. Therefore we aimed to determine whether cocaine increases Supported by a grant from the Ran Naor Foundation for the the activity of VTA neurons through inhibition of GABAA Advancement of Road Safety Research. receptors-mediated currents. Rat brain slices containing the VTA were prepared, and VTA dopaminergic neurons were The anatomical basis of functional MRI identified morphologically and electrophysiologically. Whole cell GABAA inhibitory post synaptic currents (IPSCs) were Mezer A.,1 Yovel Y., 2 Pasternak O.,3 Gorfine T.,2 recorded using standard patch clamp technique, in response and Assaf Y.2,4 to electrical stimulation of the pre frontal cortex (PFC) afferents and bath application of dopamine. We found a signifi- 1Department of Biochemistry, Faculty of Life Sciences, cant reduction of GABAA-mediated IPSCs following appli- Tel Aviv University, Tel Aviv, Israel cation of 30 microM dopamine. This reduction was blocked 2Department of Neurobiochemistry, Faculty of Life Sciences, either by dopamine D1/D5 receptors antagonist SCH23390 Tel Aviv University, Tel Aviv, Israel or by the dopamine D2 receptor antagonist eticlopride. Al- 3School of Computer Sciences, Faculty of Exact Sciences, though the molecular mechanism by which dopamine re- Tel Aviv University, Tel Aviv, Israel duces IPSCs is not fully understood, these results reveal a new 4Functional Brain Imaging, The Wohl Institute for Advanced possible aspect of cocaine action in the VTA. This finding Imaging.Tel Aviv Sourasky Medical Center, Israel suggests that in addition to cocaine inhibition of dopamine reuptake, a reduction of IPSCs occurs, and together these Functional MRI (fMRI) has become one of the leading events mediate the development of cocaine addictive prop- methods in neuroscience. It was recently suggested that erties. resting state fMRI can be used to define the default state of brain activity, functional connectivity and basal activ- Supported partially by grant from the National Institute for ity. The measurement of basal activity through resting-state Psychobiology in Israel. Israel Society for Neuroscience 77

ADNP messenger RNA knock down—a novel 3The Eric Roland Center for Neurodegenerative Diseases, approachforcancertherapy Hebrew University-Hadassah School of Medicine, Israel

Michailovici I., Dangoor D., and Gozes I. Dopamine (DA) neurons in the basal ganglia (BG) play a major role in reinforcement learning, as the DA signal is propor- ff Human Molecular Genetic and Biochemistry Sackler Medical tional to the di erence between actual and predicted reward. School, Tel Aviv University 69978, Israel Such a signal could play the role of the prediction error signal of a TD learning algorithm implemented in the BG (1-4). In- deed, a proportional increase in the firing of DA neurons has The human activity-dependent neuroprotective protein been found in cases of positive errors (event’s value higher (ADNP) gene was mapped to chromosome 20q12-13.2, a thanexpected).However,nosuchoutcomeshavebeenre- region associated with aggressive tumor growth, frequently ported in the negative domain (lower than expected value). amplified in many neoplasias. Human ADNP mRNA ex- Instead, the decrease in firing rate is either by a smaller gain pression was shown to be significantly increased in colon than of the positive domain (1), or it is lowered to a con- and breast cancer tissues in comparison to normal adjacent stant level (2). Our work focuses on the possibility of such tissues, while inhibition of ADNP expression by antisense asymmetric signals to be an error signal in a TD-like algo- oligodeoxynucleotides results in HT-29 (colon cancer) cell rithm. We simulated a probabilistic task, in which the agent death associated with increases in P53 expression. The cur- sequentially received a set of stimuli, with different proba- rent research aims at improving ADNP knockdown in or- bilities of reward or aversion. The algorithm calculated the der to potently inhibit cell proliferation in cancer therapy. value of each of the stimuli, using a method similar to TD, Assays were preformed using 3 cell lines: HT29 (colon can- but negative error values were decreased by a multiplicative cer), A375 (melanoma) and PC3 (prostate cancer). Cell via- factor, S, which can vary between 0 and 1, imitating the ob- bility was measured by the MTS colorimetric assay. Inhibi- served asymmetric DA signal. The calculated values are pro- tion of growth was performed by antisense oligodeoxynu- portional to the stimulus outcome and probability even with cleotides. ADNP knockdown was examined at the mRNA S close to 0. When S is closer to 0, the learned values are less level, using quantitative real time PCR, and at the pro- linear and learning speed decreases. The nonlinearity is al- tein level, using western blot analysis. Dramatic enhance- ways an increase of the calculated values, in comparison with ments in ADNP knockdown were obtained as follows: (1) theoriginalTDvalues.Thedifferences between the calcu- The use of a transfection reagent that increases the uptake lated and the original values are dependent on the probabil- of the ADNP antisense into cells. (2) The use of the au- ity of future reward/aversive. We conclude that TD asymmet- reolic acid antibiotic, Mithramycin, which binds selectively ric signal could be used as an error signal in a reinforcement to GC-rich DNA sequences and blocks preferential binding learning algorithm, as implemented in the BG; though the of proteins to GC-rich elements in gene promoters (such resulted learning is slower and less accurate than with a sym- as the ADNP promoter). Both inhibition of ADNP mRNA metric signal. by antisense oligonucleotides, and inhibition through the blockade of ADNP transcription factor from binding to its References promoter caused a significant decline in ADNP expression. Down regulation of ADNP inhibited cell proliferation, sug- [1] T. Satoh, S. Nakai, T. Sato, and M. Kimura, “Correlated coding gesting ADNP inhibition as a novel approach for cancer ther- of motivation and outcome of decision by dopamine neurons,” apy. Previous studies have shown that ADNP is essential Journal of Neuroscience, vol. 23, no. 30, pp. 9913–9923, 2003. for brain function ([1]), requiring tissue-specific targeting [2] H. M. Bayer and P. W. Glimcher, “Midbrain dopamine neurons methods. encode a quantitative reward prediction error signal,” Neuron, vol. 47, no. 1, pp. 129–141, 2005. [3] A. S. Schultz, Science, 1997. Lily and Avraham Gildor Chair for the Investigation of Growth [4] R. S. Sutton and A. G. Barto, Reinforcement Learning, 1998. Factors. Facilitating synapses mediate working memory References Mongillo G.,1 Barak O.,2 and Tsodyks M.2 [1] Journal of Pharmacology and Experimental Therapeutics, 2007. 1Laboratory of Neurophysics and Physiology, UMR 8119, CNRS–UniversiteRen` e` Descartes, France Is it possible to learn with asymmetry between the 2Department of Neurobiology, Weizmann Institute of “good teacher” and the “bad teacher”? Science, Israel

Mitelman R.1,2 and Bergman H.1,2,3 The common mechanistic account of short term memory (for several seconds) requires persistent firing of selective 1The Interdisciplinary Center for Neural Computation, groups of neurons. This mechanism suffers from a substan- Hebrew University, Jerusalem, Israel tial metabolic cost, and is vulnerable to interference. Recent 2Department of Physiology, Hebrew University-Hadassah experiments also show that persistent firing often has a very School of Medicine, Jerusalem, Israel low rate and can even disappear for parts of the period. We 78 Neural Plasticity propose a different mechanism, based on short term synaptic fects of fear conditioning on LTP and we found differential plasticity, where the information about memories is stored effects on LTP depending on time of memory retrieval fol- using pre synaptic calcium that mediates synaptic facilita- lowing fear conditioning, the strength of memory and the tion. We implement this mechanism using a rate model and context of retrieval. Specifically, rats that underwent memory a large scale simulation of spiking neurons. The advantages retrieval one hr after conditioning showed impaired LTP, and of this mechanism are illustrated and discussed. rats undergoing retrieval 24 hrs after conditioning showed reduced levels of LTP. Moreover, short-term memory “re- Statistical analysis of rhythmic motor patterns trieval” in a different context than the conditioning context produced by the spinal cord resulted in enhanced levels of potentiation, whereas long- term memory “retrieval” resulted in blockade of the LTP in Mor Y. and Lev-Tov A. CA1 area. The injection of the NMDA receptor antagonist Department of Anatomy and Cell Biology, MK-801 (300 microgram per kilogram) before fear condi- ff The Hebrew University Medical School, Jerusalem, Israel tioning, prevented the associated e ects of fear conditioning on LTP, showing that the effects obtained in this experiment The central pattern generator (CPG) is a network of spinal are due to fear conditioning. These data suggest that the in- neurons that produces the rhythmic motor patterns required teraction between stress and learning process could be of a for coordinated walking running, and swimming. Accurate crucial significance in determining the net effect on CA1 LTP. reproducible quantification is crucial for the proper interpretation of the rhythm produced under normal and patholog- Incensole acetate, an incense component, elicits ical conditions. Because the output of the CPG varies with psychoactivity by activating TRPV3 channels time its analysis cannot be performed by statistical meth- Moussaieff A.,1,2 Fride E.,3 Shohami E.,2 ods that assume data stationarity. The present work intro- and Mechoulam R.1 duces the Wavelet (WT) and WT coherence as tools for automated quantitative analysis of the nonstationary rhyth- 1Department of Medicinal Chemistry, Medical faculty, mic patterns produced by the spinal pattern generating cir- Hebrew University of Jerusalem, Israel cuitry in the isolated spinal cord preparation of the neona- 2Department of Pharmacology, School of Pharmacy, tal rat, and of the surface EMG signals recorded from limb Hebrew University of Jerusalem, Israel muscles of spinal cord injury patients during body weight 3Department of Behavioral Sciences, Ariel University Center supported treadmill locomotion. The analyses enabled us to of Samaria, Israel characterize the dynamic profile of the signals, to assess the linear relation between spectra of any given pair of signals Burning of Boswellia resin as incense has been part of reli- and to uncover hidden components of the rhythm in the gious and cultural ceremonies for millennia and is believed time/frequency domain. The quantitative indices extracted to contribute to the spiritual exaltation associated with such from the spectra can be used for routine characterization of events. Transient receptor potential vanilloid 3 (TRPV3) is motor rhythms in experimental animals and for assessing the an ion channel implicated in the perception of warmth in effectiveness of clinical treatments in spinal cord injury pa- the skin. TRPV3 mRNA has also been found in neurons tients. The ability of the WT and WT coherence algorithms throughout the brain; however, the role of TRPV3 there re- to extract the rhythmic parameters of complex nonstation- mains unknown. Here we show that incensole acetate (IA), a ary behaviors over a wide range of frequencies as a function major Boswellia resin constituent, is a potent TRPV3 agonist of time, will be demonstrated and its implications will be dis- that causes anxiolytic-like and antidepressive-like behavioral cussed. effects in wild type (WT) mice with concomitant changes in c-Fos activation in the brain. These behavioral effects were Alterations in hippocampal long-term potentiation not noted in TRPV3-/- mice, suggesting that they are medi- following fear conditioning ated via TRPV3 channels. IA robustly activated TRPV3 channels stably expressed in HEK293 cells and in keratinocytes Motanis H. and Maroun M. from TRPV3+/+ mice. It had no effect on keratinocytes from TRPV3-/- mice and showed modest or no effect on TRPV1, Department of Neurobiology and Ethology, Center of Brain TRPV2 and TRPV4, as well as on 26 other receptors, ion and Behavior, University of Haifa, Israel channels and transport proteins. Collectively, our results im- Studies have shown that exposure to a stressful experience ply that TRPV3 channels in the brain play a role in emo- impairs long-term potentiation (LTP) in the CA1 subregion tional regulation. Furthermore, IA’s biochemical and phar- of the hippocampus. In the current study we assessed the macological effects may also provide a biological basis for potential differences that contextual fear conditioning could deeply rooted cultural and religious traditions. elicit in hippocampal CA1 LTP as compared to exposure to elevated platform stressor. In accordance with previous re- Limitations of stimulus-anchoring mechanisms: sults, thirty minutes of prior exposure to the elevated plat- evidence from behavioral and ERP data form inhibits the induction of LTP in the CA1 hippocampal Nahum M.,1 Levi M.,2 and Ahissar M.1,2 region, whereas fear conditioning reduced CA1 LTP without inhibiting it completely. We further investigated the ef- 1ICNC, The Hebrew University of Jerusalem, Israel Israel Society for Neuroscience 79

2Psychology Department, The Hebrew Univerisry of adaptation to matching behavior are a subject of debate. Me- Jerusalem, Israel lioration theory posits that organisms are sensitive to the local rates of return (number of reinforcements obtained at an In 2-tone frequency discrimination tasks, participants listen alternative divided by time spent at that alternative) and shift to two sequentially presented tones and are asked to decide their choice preference in the direction of the more profitable which tone is higher. Recent results from our lab (Lubin & alternative. Alternatively, it has been suggested that choice Ahissar, ISFN 2005) showed that if one of the tones is re- preference depends only on the estimated income from the peated across trials (“reference”) at a consistent temporal two alternatives and has no direct dependence on the actions position, performance dramatically improves compared to a made by the subject. We formalize representatives of the two no-reference condition. However, if the location of the ref- classes of models in a two-state Markov model in which the erence randomly varies between first and second positions, transition probabilities are adjustable. We show that in both subjects perform as if there is no reference at all. In order models, changes in the transition probabilities are driven by to better understand the reference-anchoring mechanism, we the covariance of reward and action and that the two mod- designed a 1-1 paradigm (“1-1 reference”), in which the ref- els differ only in their learning rate. Thus, we argue that the erence was first on odd trials and second on even trials. Thus, separation between return-based and income-based models there is no uncertainty in reference position across trials, but is artificial. We compare adaptation of a two-state Markov there is no consistency across consecutive trials either. We model in which learning is driven by the covariance of reward found that overall performance in this condition was signifi- and action with behavior of rats responding on two levers for cantly worse than when the two reference conditions were as- pleasurable brain stimulation in a concurrent variable inter- sessed separately, mainly due to poor performance on trials val schedule. We show that the behaviors of the model and with reference at the second position. This worsening sug- the rat are very similar. In particular, we show that the model gests that our reference-anchoring mechanism cannot fully reproduces the experimentally observed fast adaptation to benefit even from a very simple temporal structure. We fur- matching following a change in the reward schedule. ther asked whether training enables better use of the reference in the reference-second condition. We therefore trained Slow modulations of spontaneous firing rates and a group of subjects for 5 days on this protocol. Training im- LFP Gamma power in human auditory cortex during proved both reference-first and reference-second thresholds, wakefulness and sleep which reached a plateau by the third day of training. How- 1 2 3 1 ever, performance in reference-second remained poorer than Nir Y., Dinstein I., Mukamel R., Fisch L., 1 1 3,4 1 performance in reference-first. ERP data recorded from well- Gelbard-Sagiv H., Arieli A., Fried I., and Malach R. trained subjects showed a clear correlate of this learning, as Department of Neurobiology, Weizmann Institute of Science, well as the remaining superiority of the reference-first condi- Rehovot 76100, Israel tion. Together, these results indicate that reference-anchoring 2Center for Neural Science, New York University, favors consistency at trial onset, and can only partially bene- NY 10003, USA fit from a consistent temporal pattern across nonconsecutive 3David Geffen School of Medicine, University of California trials. Training improves but does not eliminate this bias. Los Angeles (UCLA), CA 90095, USA 4Functional Neurosurgery Unit, Tel Aviv Medical Center, This study was supported by an ISF Center of Excellence grant Tel Aviv University, 69978, Israel and by the Institue of Psychobiology. Recently, many fMRI studies have focused on spontaneous A dynamic model for matching behavior that is waves of activity in human cortex, in the absence of sensory based on the covariance of reward and action stimulation. However, it is still not clear what neuronal activity may underlie these fluctuations. In this study, we ex- Neiman T.3 and Loewenstein Y.1,2,3 amined neuronal action potentials and local field potentials (LFP) in human auditory cortex during spontaneous activ- 1Department of Neurobiology, Israel ity in wakefulness and sleep, in order to examine the dy- 2Department of Cognitive Science, Israel namics of neuronal activity that may give rise to sponta- 3the Interdisciplinary Center for Neural Computation, neous fMRI fluctuations. Three patients underwent moni- the Hebrew University, Jerusalem, Israel toring with intracranial depth electrodes for potential surgical treatment. Patients provided written informed consent, According to Herrnstein’s “matching law” that describes and the study conformed to the guidelines of the Medical choice behavior in a foraging-like reward schedule, the frac- IRB at UCLA. Simultaneous recordings of single unit and tion of time allocated to an alternative is proportional to the LFP activity from multiple electrodes in human auditory number of rewards harvested from that alternative. A change cortex were collected while patients rested in a dimly-lit, in the reward schedule results in a modification of choice silent room (a total of 11 recording sessions in 3 patients). preference such that the matching law is retained. This pro- The sound during the experimental session was recorded cess of adaptation can be remarkably fast. It has been re- along with the neuronal data to verify quiet recording con- ported that the rate of adaptation in rats is comparable to ditions. Very slow (<0.1 Hz) fluctuations in gamma power the limit set by an ideal observer. The algorithms underlying and neuronal firing rates in auditory cortex exhibited high 80 Neural Plasticity correlation between the two hemispheres. Such correlations rents (early and late) through Nav. 1.8, which is associated were selective for these regions, and did not spread to other with Neuropathic pain. recorded locations. These results suggest that large spontaneous fMRI fluctuations could result from slow, coher- This work was supported by BioLineRx. ent modulations in neuronal activity, rather than relatively fast, stimulus-evoked bursts of activity, which are typical of Perceptuo-motor transparency in sensory-driven responses. Therefore, these results emphasize bilateral teleoperation the caution that should be exercised when interpreting fMRI data, and may help resolve the paradox of similar fMRI re- Nisky I. and Karniel A. sponse patterns in sensory cortex in the presence and absence Department of Biomedical Engineering, Ben-Gurion of sensory stimulation. University of the Negev, Israel Funded by a US-Israel BSF grant to I. Fried and R. Malach. In bilateral teleoperation, the operator holds a local robot which local robot which determines the motion of a remote BL-1021: a new chemical entity for treatment of robot and continuously receives delayed force feedback. The naturopathic and acute pain delay may cause instability, distortion in perception, and distortion of action. The nervous system inherently includes 1 1 1 1 Nisemblat Y., Geffen Y., Winkler I., Klapper L., significant time delays, and therefore we expect the motor 1 2 3 3 Savitsky K., Nudelman A., Rephaeli A., Gilad I., system to be capable of handling delayed feedback. Trans- 3 and Weizman parency is a measure of teleoperation system fidelity. The ideal teleoperator system is the identity channel, where there 1BioLineRx, Ltd., Jerusalem, Israel 2 is no delay or distortion. In measuring transparency, one Department of Chemistry, Bar Ilan University, should consider also the human operator and therefore we Ramat Gan, Israel 3 propose the following three components of transparency: Felsenstein Medical Research Center, Tel Aviv University, (a) perceptual transparency: the operator cannot distinguish Beilinson Campus, Petach Tikva, Israel between the teleoperation channel and an identity channel; (b) local motor transparency: the movement of the opera- Neuropathic pain (NP) is a pain which initiated or caused tor does not change when the teleoperation channel is be- by a primary lesion or dysfunction in the nervous system. It ing replaced by an identity channel; (c) remote transparency: is associated with various conditions including shingles and ff the movement of the remote robot does not change when diabetes and a ects 15 million people in the USA alone. The the teleoperation channel is being replaced by an identity available treatment includes antidepressants (as TCAs) and channel. We report series of our recent studies with this con- anticonvulsants and consider limited with only 30–50% re- text in mind. In our studies of perceptual transparency of ductioninpainin∼50% of the patients. Most of these drugs ff spring like surfaces we found that subjects overestimate de- are associated with significant side e ects most noted are se- layed spring-like surfaces with boundary and underestimate dation and cardiac arrhythmia, which create an urgent need nondelayed boundary shifted surfaces. In our studies of lo- for a new class of medications. BL-1021 is an orally available cal motor transparency we used an adaptation protocol to small molecule which is designated for the treatment of NP. extract the behavioral implications of the subjects’ expecta- The molecule was orally given to a variety of animal models tion. We found that the subjects’ answers matched our mea- of acute and chronic pain. In the acute hot plate model, BL- sure of the motor behavior in the case of delayed stiffness 1021 demonstrated rapid onset and longer latency of noci- but not in the case of shifted boundary. These discrepan- ceptive reaction to heat as compared to Nortriptyline (a com- cies clearly demonstrate that a multidimensional measure of mon antineuropathic TCA). In the acute formalin model, transparency must be employed in the design of teleopera- BL-1021 reduced the early nonciceptive response and the tion systems. late imunological response and was more effective than Nor- triptyline. In the Chung model (spinal nerve ligation) of neu- Supported by Grant no. 2003021 from the United States-Israel ropathic pain, BL-1021 was significantly more effective than Binational Science Foundation and by the National Institute Nortriptyline in reducing mechanical allodynia and thermal for Psychobiology in Israel. hyperalgesia. Moreover, BL-1021 was more effective in reducing thermal hyperalgesia than Gabapentin, the gold stan- Tempol Diminishes Oxidative Damage and dard drug for the treatment of neuropathic pain. BL-1021 Attenuates Behavioral Sensitization Following ff showed low side e ects relatively to other TCAs used for the Cocaine Administration in Rats treatment of Neuropathic pain: no sedation up to 80 mg/kg in the Irwin test, no decrease in the time spent on the Rotarod Numa R.,1,2 Kohen R.,2 and Yaka R.1 as found in Nortriptyline and moreover, BL-1021 was found to be safe at the effective doses observed in the Chung model 1Department of Pharmacology, School of Pharmacy, in the hERG model for the prediction of cardiac arrhythmia,. The Hebrew University of Jerusalem, Israel Additionally, BL-1021 was found to inhibit sodium currents 2Department of Pharmaceutics, School of Pharmacy, in neuroblastoma cells and more specifically, sodium cur- The Hebrew University of Jerusalem, Israel Israel Society for Neuroscience 81

Oxidative stress (OS) and reactive oxygen species play an im- and to the haptic targets. The subjective affective valence of portant role in cocaine addiction and neurotoxicity, through- the first names was assessed by a questionnaire (Ofek). out excessive production of 6-OHDA or by redox cycling of cocaine oxidized metabolites. Cocaine stimulates the pro- Results duction of OS in a range of organs including the brain. How- ever, the association between acute or repeated cocaine ad- Shorter reaction times to haptic targets were found after sub- ministration and overall antioxidant power in the brain re- jective negative names. Distinct response was found to dif- ward system is poorly understood. Here we examine the hy- ferent names, differentiated by their subjective affective va- pothesis that enrichment of antioxidant power in the brain lence. Stronger brain response was found to haptic stimuli will attenuate cocaine-induced oxidative damage and in turn after subjective positive names. Distinct brain responses to will reduce cocaine-induced behavior. In-vitro: PFC and NAc the same haptic stimuli were found, when administered after slices were treated with cocaine or tempol + cocaine for names with differential subjective affective valence. 15 min, homogenized and frozen for analysis. In-vivo: rats were received 2 daily i.p. injections of tempol or vehicle fol- Discussion lowed by cocaine, and locomotor activity was measured for 45 min. On day 19, all rats received a single cocaine challenge As proposed, subjective emotions and haptic processing in- and locomotor activity was measured. At the end of these ses- teract. Negative subjective significance, rather than positive, sions, the PFC and NAc were dissected and frozen for anal- improved haptic performance, suggesting that “threat” may ff ysis. Analysis of oxidative stress markers were evaluated us- be more e ective in improving manual performance. Impli- ing TBARS and Griess assays and total antioxidant capac- cations are mainly for design of (tele)manipulation. ity was quantified using FRAP and ORAC assays. We found that acute cocaine exposure increases OS markers and TAC Development of declarative memory systems in both in slices and in-vivo. However, treatment with tempol the human brain reduces OS markers and preserves TAC both in vitro and in Ofen N.,1,2 and Gabrieli J. D.1,2 vivo. Interestingly, pretreatment with tempol attenuated initiation and expression of cocaine-induced behavioral sensi- 1Psychology Department, Stanford University, tization, without affecting basal levels of locomotor activity. Stanford, Calif, USA Finally, tempol prevented the expansion of OS markers fol- 2Brain and Cognitive Sciences, MIT, Cambridge, lowing repeated administration of cocaine. Our findings sug- Mass, USA gest that tempol has a neuro-protective effect against cocaine toxicity, by averting oxidative stress amplification in princi- Multiple brain regions including medial temporal (MTL) lat- ple areas of the reward system. These findings implicate that eral prefrontal (LPFC) and parietal cortex are involved in administration of this agent might be considered as an op- successful memory encoding for adults. This study is the first tional treatment of cocaine addiction. to investigate the development of brain regions involved in successful encoding. Adults (n = 14, age range 19–24) and Haptics and subjective emotional significance children (n = 35, age range 8–17) studied pictures of scenes while being scanned with 1.5T fMRI scanner. Following the Ofek E. and Reiner M. study phase, a recognition test was administrated to all participants. Items that were recognized were further judged as Human Virtual Reality Lab, Technion, Israel either familiar or remembered. Occipital, parietal, and tem- Introduction poral visual regions as well as MTL and DLPFC regions were found to be more active for items that were later remembered a sympathetic pat on the friend’s shoulder, a gentle stroke on compared to items that were later forgotten. However, within the face of a crying baby, an enthusiastic handshake or a vio- these regions activations associated with successful encoding, lent slap, are all related to a kind of touch. Patterns of touch positively correlated with age in the DLPFC, but not in MTL, are used to convey emotions. Manual performance involves regions. Within parietal regions, right superior parietal lobe touch. How would manual performance be affected once the (Brodmann area, BA 7) showed increased subsequent mem- subject’s emotional state changes? Improved? Worsened? In ory activation with. In contrast, bilateral lateral parietal re- this study we used subjectively significant cues (first names) gions (BA 39/40) and a posterior cingulate/precuneus region to assess the impact of emotional states on haptic perfor- (BA 7/31), showed increased deactivations with increased age mance of a task in a hapto-visual virtual world. The purpose for items later remembered compared to items later forgot- of this study was to describe the behavioral and neural cor- ten. In adults, adjacent regions within the parietal cortex relates of emotional and haptic processing. Methods: RT and demonstrate opposite subsequent memory effects. Moreover, ERPs were measured from 10 subjects engaged in a haptic these lateral and posterior parietal regions are within iden- task. The subjects were listening to names, while holding a tified brain regions that are activated during rest and deac- PHANTOM arm in their right hand. They pressed a button tivated during attention-demanding goal-directed tasks, the when the PHANTOM moved. The effect of subjective va- so called “default mode of brain functions.” Together, these lence of the names on the response-time to the haptic targets data suggest that with age prefrontal and parietal regions are was assessed. ERPs were measured both to the first names progressively recruited to reach adult-like brain activation 82 Neural Plasticity during successful encoding. Furthermore, these data suggest sequences revealed that during an active search task owls that the magnitude of deactivations in regions previously de- repeatedly and consistently direct their gaze in a way that scribed as part of the default mode of brain functions in- brings objects of interest to a specific area in their retina crease during development. (fixation area). Recording in various types of environments (aviary, office, outdoors) revealed significant statistical dif- Effects of early auditory experience on ferences of low level image properties at the fixation area the auditory space map in the barn owl’s brain compared to values extracted at random image patches. These differences are in agreement with results obtained Oged A. and Gutfreund Y. on primates in similar studies. To investigate the role of saliency and its contribution to drawing the owl’s atten- Department of Physiology, The Faculty of Medicine, tion, we used a popular bottom-up computational model. The Technion, Israel Saliency values at the fixation area were typically greater than at random patches, yet were only 25% out of the maximal In the midbrain of the barn owl, an auditory localization saliency value, suggesting a top-down modulation of gaze “specialist,” there are auditory spatial maps based on the control. computation of monaural and binaural localization cues. Be- cause the association between the auditory localization cues Knowing left from right: a combined ERP-fMRI and the corresponding locations in space depends on factors study of visuospatial attention that can change throughout the life of an animal (e.g., head size) it is expected that the maps are shaped by sensory ex- Okon-Singer H.,1 Podlipsky I.,1 Yovel G., 2 perience. We investigated the importance of normal early ex- Siman-Tov T.,1 and Hendler T.1 perience on the development of the auditory map in the op- 1 tic tectum (OT) by raising newly hatched barn owls in om- Functional Brain Imaging Unit, Wohl Institute for Advanced nidirectional broad-band masking noise (1–15 kHz, 90 dB Imaging, Tel Aviv Sourasky Medical Center, Israel 2 SPL), depriving them from coherent binaural experience. We Department of Psychology, Tel Aviv University, Israel ff found that the mapping of interaural level di erence (ILD), Right hemisphere (RH) specialization for spatial attention the main cue for elevation in owls, was deteriorated in noise- has been suggested in numerous studies (e.g., Heilman, 1980; reared owls. On the other hand, the map of interaural time ff Mesulam, 1999). A recent functional magnetic resonance di erence (ITD), the main cue for horizontal location, was imaging (fMRI) study from our laboratory (Siman-Tov et al., found to be less sensitive to early experience. Only in one in press) found higher activation for left-compared with out of five tested owls we found significant deficits in ITD right-visual field stimulation, in a bilateral attentional net- mapping. Following the removal from the noise box, the work. These findings suggest that the RH advantage relies tuning of the neurons gradually improved and their map- on efficient recruitment of attention-related regions in both ping resembled more closely that of a normal owl. These re- hemispheres, in contrast to the LH attentional network that sults imply that early coherent binaural experience is essen- is unilateral. One possible explanation for such advantage is tial for the correct formation of the auditory map in the barn faster neural conductivity from RH to LH, as has been shown owl, especially along the vertical domain and that deficits in reaction time and evoked response potential (ERP) stud- due to early abnormal experience can be corrected with ies (Barnett and Corballis, 2005). In the current study, we time. used simultaneous recording of ERP and fMRI, in order to This work was supported by an ISF personal grant. further investigate the neural basis for the RH advantage in spatial attention. Ten right-handed subjects were asked to ignore pictures of faces or geometric patterns. The pictures Through a barn owl’s eyes: interactions between were presented for 200 milliseconds, in either the right or the scene content and visual attention left visual field, while subjects engaged a competing central Ohayon S.,1 Harmening,2 Wagner H.,2 task. Preliminary fMRI results replicated previous findings, and Rivlin E.1 showing activation in brain regions involved in visual processing and attention, such as the fusiform face area (FFA) 1Computer Science Department Israel Institute of and parietal areas, as well as higher activation for left visual Technology Haifa 32000, Israel field stimulation. Preliminary ERP findings reveal visual and 2Institute of Biology II, RWTH University, Kopernikusstrasse attentional components, such as P1 and N170, and faster sig- 16, 52074 Aachen, Germany nal transfer from RH to LH, than vice versa. Further analysis will examine the correlation between the latency and ampli- In this study we set to investigate visual attention proper- tude of specific evoked potentials, such as N170, and activa- ties of freely behaving barn owls using a miniature wire- tion in regions of interest, such as the FFA. Understanding less camera attached to their heads. The tubular eye struc- the basis of attention asymmetry might help in formulating ture of barn owls makes them ideal subjects for this re- a neural model of lateralization in general. Furthermore, it search since it limits their eye movements. Video sequences may guide diagnosis and treatment of attention-related dis- recorded from the owl’s point of view capture part of the vi- orders, as well as other disease states characterized by abnor- sual scene as seen by the owl. Automatic analysis of video mal lateralization. Israel Society for Neuroscience 83

Synchronized excitation and inhibition during may play an important role in cortical processing and chal- spontaneous and sensory evoked responses in lenge the classical notion which considers spontaneous ongo- the rat barrel cortex ing cortical activity as noise (Ferster D., 1996; Ringach D. L., 2003; Fox et al., 2007a). We preformed VSDI of ongoing cor- Okun M. and Lampl I. tical activity in the visual cortices of awake and anesthetized Weizmann Institute of Science, Israel monkeys. Our results shows that in the anesthetized monkey spontaneous cortical activity shows larger repertoire of The activity of neurons depends both on excitatory and in- cortical states which resemble both Ocular Dominance do- hibitory inputs, yet the relationship between the two remains mains as well as Orientation domains. We found large bias poorly understood. In particular, a controversy exists regard- toward the representation of cortical states which resemble ing the extent of correlation between excitation and inhibi- ocular dominance domains rather than orientation domains. tion during spontaneous and sensory evoked activity in the In comparison to the spontaneous ongoing activity in the cortex. In the present work we demonstrate a novel approach anesthetized monkey the dynamics of ongoing activity in the which allows to present adequate real-time picture of the cor- awake monkey is much faster, and the coherence-length is relation between excitatory and inhibitory inputs to cortical much smaller. cells. It is based on simultaneous intracellular recording from pairs of nearby neurons that receive similar synaptic inputs. Supported by the Daisy EU grant and the Goldsmith Founda- We have performed such recordings in the barrel cortex of tion. halothane anesthetized rats (in which the spontaneous activity is similar to that observed in awake animals). A marked The influence of NAP treatment on the severity of correlation was observed between excitatory inputs of the experimental autoimmune encephalomyelitis neurons (both cells were hyperpolarized, activity was dom- Oz S. and Gozes I. inated by EPSCs) and between inhibitory inputs (both cells were depolarized, activity was dominated by IPSCs). To es- Human Molecular Genetics and Biochemistry, Sackler timate the correlation between excitatory and inhibitory in- Medical School, Tel Aviv University, Israel puts, one cell was depolarized and the other hyperpolarized (in both possible combinations). In this case a high (nega- Activity-dependent neuroprotective protein (ADNP) was tive) correlation was found in all the pairs that were recorded, shown to be essential for brain formation (Brain Res. 2003 which implies that EPSCs and IPSCs of individual cells are 144:83). Peptide scanning identified a motif on ADNP, also highly correlated. We also found that spontaneous in- NAPSVIPQ (NAP) that provides femtomolar neuroprotec- hibitory potentials lag behind excitatory potentials by several tion ([1]). Multiple sclerosis (MS) is a chronic disabling dis- milliseconds. In addition to this high temporal coupling be- ease of the CNS. MRI studies in very early disease stages sug- tween the EPSPs and IPSPs, the amplitudes of the excitatory gest that inflammation and neuronal injury are not strictly and inhibitory events were also highly correlated. A strong related ([2]). These experiments showed that significant ax- correlation was also observed between the amplitudes and onal injury occurs early in the disease and that this is only the temporal patterns of excitatory and inhibitory synaptic indirectly linked to inflammatory activity. These studies sug- inputs evoked by whisker stimulation. Our study provides gested that treatment strategies for MS need to address both the first direct indication that a strong coupling exists in the the inflammatory and neurodegenerative components of the cortex between excitation and inhibition during both spon- disease, and that antiinflammatory therapies may only be taneous activity and evoked responses. able to control the inflammation-related process adequately ([3]). In order to assess the influence of NAP, a series of SupportedbygrantsfromtheISFandtheNationalInstitutefor experiments on C57BL/6 female mice, were conducted, in Psychobiology. which experimental autoimmune encephalomyelitis (EAE), a model for MS, was induced by immunization with a peptide Comparing the dynamics of ongoing activity in derived from myelin oligodendrocyte glycoprotein (MOG). awake and anesthetized monkey Intraperitoneal daily treatment with NAP that started 10 days after MOG immunization and continued for 17–47 days Omer D. B., Rom L., Ulchin Y., and Grinvald A. showed that the severity of the disease, represented by the degree of motor dysfunction was reduced in the NAP treated Department of Neurobiology, Weizmann Institute of Science, ± μ Rehovot, Israel mice with dosages of 2 1 g/animal. These results complement previous studies with intranasal and intravenous Previous studies using Voltage sensitive dyes imaging on administration of NAP. BSF, ISF, Lily and Avraham Gildor anesthetized cats reported that spontaneous ongoing corti- Chair, Adams Super Center and Allon Therapeutics Inc. cal activity in the primary visual cortex represents dynamic spatial patterns many of which resembling the functional ar- References chitecture of Orientation domains, and span large cortical [1] M. Bassan, R. Zamostiano, A. Davidson, et al., “Complete se- areas (Grinvald et al., 1989; Arieli et al., 1995; Arieli et al., quence of a novel protein containing a femtomolar-activity- 1996; Tsodyks et al., 1999; Kenet et al., 2003; Fox et al., 2006; dependent neuroprotective peptide,” Journal of Neurochemistry, Fox et al., 2007b). Those results suggest that ongoing activity vol. 72, no. 3, pp. 1283–1293, 1999. 84 Neural Plasticity

[2] Neurological Sciences, no. 5, p. S275, 2003. However the contribution of astrocytes may not only result [3] T. Chitnis, J. Imitola, and S. J. Khoury, “Therapeutic strate- from individual cells, but also from cellular networks, as they gies to prevent neurodegeneration and promote regeneration expressnumerousgapjunctions.Theaimofthisworkwas in multiple sclerosis,” Current Drug Targets: Immune, Endocrine to determine whether the connectivity of astrocytic networks and Metabolic Disorders, vol. 5, no. 1, pp. 11–26, 2005. participate in hippocampal neurotransmission and plasticity. Synaptic transmission was studied in Cx30 (one of the two Ladostigil reduces release of NO from activated gap junction proteins in astrocytes) knockout mice, whose microglia and oxidative stress in neuronal cells by astrocytic network connectivity is reduced by ∼50%. Field different mechanisms excitatory postsynaptic potentials in Cx30-/- mice are re- ∼ Panarsky R. and Weinstock M. duced by 35% compared to wild-type mice. This decrease is not due to changes in intrinsic properties and excitability of Department of Pharmacology, School of Pharmacy, CA1 pyramidal neurons or postsynaptic receptor density. It is Hebrew University of Jerusalem, Israel rather due to a decrease in glutamate synaptic concentration, as the frequency but not amplitude, of mEPSCs is decreased Ladostigil [Ethyl-methyl-carbamic acid (R)–3-prop-2- in Cx30-/- mice and the ratio of AMPA to NMDA synap- ynylamino-indan-5-yl ester], a cholinesterase (ChE) and tic currents is unchanged. The altered synaptic transmission monoamine oxidase inhibitor with neuroprotective activity, is due to Cx30 deletion, as it is not observed in young mice given orally for 2 weeks at a dose of 2.9 mumoles/kg, (?P10), where Cx30 is not yet expressed. In addition, this ef- prevented microglial activation and the appearance of fect is specific to glutamatergic transmission of CA1 pyra- oxidative-nitrative stress in discrete brain areas induced by midal cells, as miniature IPSCs from pyramidal cells, as well icv injection of streptozotocin. This dose was too small to as mEPSCs from interneurons, are not changed in Cx30-/- inhibit either enzyme. mice. The contribution of astrocytic networks to short and long-term synaptic plasticity was also studied. Paired-pulse Aim facilitation was increased, whereas post-tetanic potentiation The aim is to determine whether ladostigil produced these was reduced in Cx30-/- mice. Prolonged repetitive stimula- effects by acting directly on microglia, and/or indirectly, tion (10 Hz, 30 sec) led to an increased initial facilitation, by preventing neuronal damage. Methods: The effect of la- followed by a slower synaptic depression. Furthermore long- dostigil and its active metabolites was measured on the re- term plasticity is also altered in Cx30-/- mice, as they show lease of NO induced by LPS (10 mug/ml) from mouse mi- a 70% decrease in the amplitude of LTP. Altogether these re- croglia, and on cytotoxicity induced by the tert-butyl hy- sults indicate for the first time that astrocytic gap junctions droperoxide (TBHP) in SNKMC cells. The nitrite levels were regulate neuronal excitatory transmission and plasticity. determined spectrophotometrically with Griess reagent. The antiapoptotic effect of the compounds was measured by de- Supported by Human Frontier Science Program, Agence Na- crease in caspases 3/7 or prevention of the fall in the mito- tionale de la Recherche, French Ministry of Research. chondrial potential by JC1, and cell death, by trypan blue staining. Results: Ladostigil, its metabolites which lacked ei- Membrane lipids modulation removes divalent open ther the propargyl or the carbamate moieties or aminoin- channel block of TRPL and NMDA channels dan itself at concentrations of 1 nM-1 muM reduced by al- Parnas M., Katz B., Lev S., Tzarfaty V., Gordon-Shaag A., most 50% the release of NO from microglia. Higher con- and Minke B. centrationswerelesseffective. On the other hand, only ladostigil and metabolites containing a propargylamine group The Hebrew University, Israel (100 nM-10 muM) significantly reduced apoptosis, the fall in mitochondrial potential and cell death induced by TBHP in Removal of divalent open channel block by depolarization SKNMC cells indicating that two different mechanisms were plays a critical role in learning and memory, which is medi- involved in these actions of ladostigil. Conclusion: The re- ated by the N-methyl-D-aspartate (NMDA) channel. Other duction of microglial activation and nitrative stress induced channels also exhibit open channel block, but the physiolog- by a low dose of ladostigil in the rat brain can result from a ical mechanism of its removal is still unknown. We show here direct action on microglia. that lipids produced by phospholipase C (PLC) and hypoos- motic solutions remove divalent open channel block from Synaptic strength regulated by astrocytic gap the Drosophila Transient Receptor Potential-Like (TRPL) junctions channels by bending the plasma membrane. Membrane bending increased single channel current and caused imper- Pannasch U., Ezan P., Willecke K., Giaume C., meable cation influx. The GsMTx-4 toxin, which specifically and Rouach N. inhibits mechanosensitive channels, blocked the lipids effect. ff INSERM U840, College´ de France, 11 place Marcelin Berthelot, We found remarkable commonality between the e ects of 75005 Paris, France lipids on the Drosophila TRPL and the mammalian NMDA and TRPV3 channels. We suggest a new lipid-dependent Recent data suggest an active participation of astrocytes in mechanism to alleviate open channel block, which op- neurotransmission by dynamic interactions with neurons. erates under physiological conditions, in synergism with Israel Society for Neuroscience 85 depolarization. The profound effect of lipids modulation al- The expectation from receptive field size is that low levels in lows cross talk between channel activity and lipid-producing the visual hierarchy will be small, leading to specific local im- pathways. provement, while higher levels will reflect generalized training, learned and remembered by all (Hochstein & Ahissar, Mapping and Eliminating Free Water in Neuron, 2002). These tasks were always performed with test the Brain by Diffusion Imaging arrays in the center of the test screen. More recently, we introduced eccentric search arrays (Pavlovskaya et al., Spatial Pasternak O.,1 Sochen N.,2 Intrator N.,1 and Assaf Y.3,4 Vision, 2001), which were exploited later to test transfer of learning effects between hemispheres. We found transfer for 1 School of Computer Science, Tel Aviv University, Israel easy tasks and not for hard tasks when subjects performed 2 Department of Applied Mathematics, Tel Aviv University, color and orientation feature search, each within one hemi- Israel field. However, the method used left an ambiguity that the 3 Department of Neurobiochemistry,Tel Aviv University, Israel transfer we found could be interpreted as transfer across 4 Functional Brain Imaging Unit, Tel Aviv Sourasky Medical tasks, and not between hemispheres. We now test the possi- Center, Israel bility of cross-hemisphere transfer by designing a paradigm ff ff whereby two independent tasks with very similar average de- We o er a novel mathematical analysis for di usion imag- grees of difficulty are performed in the two hemifields. We ing data, which is able to separate between free water and ff trained subjects on a local detection (orientation pop-out the remaining brain tissue. In di usion imaging we are able task) in one hemifield and on global identification (vertical to magnetically trace the motion of water molecules. Proper- versus horizontal array orientation) in the other hemifield. ties of the motion depend on the surrounding tissue, and the Following training, we switched the sides of the tasks. We amount of hindrance the molecules face. By analyzing those ff found transfer for the trained dimension for easy cases, sug- propertiesweareabletodi erentiate between tissue types gesting that the transfer was due to a hemifield transfer. We (CSF, white matter and gray matter). We can also analyze the confirm the Reverse Hierarchy Theory that as long as the per- directionality of the tissue (for white matter), which allows us ff ceptual task is easy enough to be performed at high cortical to infer connectivity measures between di erent parts of the levels, transfer will occur to new conditions that depend on brain. The conventional way to analyze the diffusion proper- ff the same, broad-spectrum, receptive fields. Results support ties of water molecules is named Di usion Tensor Imaging cross-hemispere transfer for easy task conditions. (DTI), but this analysis fails to describe a tissue, which is in closeproximitytofreewater.Forhealthypatientsfreewater Supported by National Institute for Psychobiology in Israel, US- in the brain is found in the ventricles, and CSF filled cavi- Israel Binational Science Foundation. ties. Clinically, there are diseases and conditions that can be related with free water in the brain, especially in the form of Parameters distributions and interrelations in edema. Edema is common, for instance, for patients suffer- compartmental models of neurons ing from brain tumors, stroke or other brain trauma. By applying our framework on such datasets we were able to map Peled N.1,2 and Korngreen A.1,2 the relative volume of the free water compartment across the 1 brain. Once the free water is mapped we can eliminate it in The Mina and Everard Goodman Faculty of Life Sciences, Israel order to measure the properties of the remaining brain tissue. 2 Using this method we have correctly identified white matter The Leslie and Susan Gonda (Goldschmied) Multidisiplinary tracts that pass next to the ventricles, and more importantly Brain Research Center, Israel were able to delineate the tract of white matter bundles that Parameters distributions and interrelations in compartmen- pass through edematous areas. This analysis allows better in- tal models of neurons Noam Peled and Alon Korngreen The ference as to the condition of the tissue due to the edema. Mina and Everard Goodman Faculty of Life Sciences and Supported by the Edersheim-Levi-Gitter Institute. The Leslie and Susan Gonda (Goldschmied) Multidisiplinary Brain Research Center, Bar-Ilan Univ., Ramat-Gan, Israel. Our understanding of the input-output function of single Does the right side remember what the left side neurons has been advanced by biophysically accurate multi- learned? hemispheric transfer of perceptual learning compartmental models. The large number of free parameters effects in these models requires the use of automated approaches Pavlovskaya M.1 and Hochstein S.2 for finding their optimal values in a very multidimensional parameter-plane. Here we use genetic algorithm as a stochas- 1Loewenstein Rehabilitation Hospital, Raanana, Sackler tic optimization algorithm. Due to inherent noise in measur- School of Medicine, Tel Aviv University, Israel ing equipment and the stochastic nature of the neuron, the 2Life Science Institute and Neural Computation Center, determination of the accuracy of the obtained parameters is Hebrew University, Jerusalem, Israel near impossible. Here we show that finding the parameters distribution via Monte Carlo simulations reveals the sensitiv- When one side of the brain learns to perform a perceptual ity of each parameter to noise. Furthermore, we calculate the task, does the other side remember what has been learned? average Hessian matrix over all the global minima to discover 86 Neural Plasticity the interrelations between the parameters. To use a stochas- Introduction Previous studies suggested an impairment of tic optimization algorithm a distance function must be de- executive functions in patients after cerebellar stroke. Other clared, which calculates the distance between a given model studies showed contradictory results. The specific role of output and the desire one. In this work we used several dis- the cerebellum in cognition is still unknown. The present tance functions which are in used in this field. We compare study investigated cognitive deficits in the acute phase af- between them, and discuss which can be suitable for such ter cerebellar stroke, the recovery of possible symptoms and kind of a problem and which one not. the effect of a cognitive training. Moreover, differences between the vascular territories, the lesion side and the involve- The representation of saccadic eye movements in ment of cerebellar nuclei were examined. Methods Twelve human cortical regions patients with acute cerebellar stroke of the superior or of the posterior inferior cerebellar artery were matched with Pertzov Y.,1 Avidan G.,2 and Zohary E.1 healthy controls and were examined by an extensive neu- 1Department of Neurobiology & Interdisciplinary Center for ropsychological test battery in the acute phase, after two Neural Computation Hebrew University, Israel weeks and three months. Lesions were localised by mag- 2Department of Psychology, Ben Gurion University of netic resonance imaging in the acute phase and after three the Negev, Israel months. One half of the patients received a cognitive training, which was developed for patients with an impairment It is well established that various brain regions, such as the of executive functions after damage to the prefrontal cortex. frontal eye fields (FEF), supplementary eye fields (SEF), and Results A significant impairment in the Wisconsin Card Sort- the intraparietal sulcus (IPS), are involved in various aspects ing Test as a measure of action planning could be shown. Pa- of eye movement planning and execution in both humans tients were also impaired in changing categories of a verbal and primates. However, the reference frames in which in- fluency test (Regensburger Wortfluessigkeitstest) as a mea- formation is represented in each of these areas is hotly de- sure of cognitive flexibility. After three months differences bated. Specifically, it is unclear whether the direction of a were no longer significant. There was no difference between saccade, its exact origin, final destination point (relative to treated and untreated patients and no effect of the location the head, body or world) or combinations of these represen- of the stroke. Conclusions The present study suggests an im- tations are multiplexed in these regions. Recently, new mul- pairment of executive functions in the acute phase after cere- tivariate classification methods have been used to assess the bellar stroke. These deficits could not be explained by dis- reliability of distinctive spatial patterns of the fMRI responses turbances of attention or visuospatial abilities or by depres- (SPfR) in the visual cortex. We applied similar methods in or- sion. No effect of the neuropsychological training could be der to examine the spatial nature of representation of mem- shown, possibly because of the small number of patients and ory based saccades in cortical regions. Human subjects per- a spontaneous recovery of symptoms. The effect of the cog- formed a memory saccade task in which equal amplitude sac- nitive training should be investigated in a larger group of cades could be executed from several starting points and in patients. a number of directions. We find that the SPfR in the FEF, SEF and IPS are positively correlated when the same saccades Supported by BMBF, German-Israeli Cooperation in Neu- are repeatedly executed. The patterns become uncorrelated roscience (01GA0508) and IFORES (D/107-20540; D/107- when saccades of the same magnitude and direction are ex- 20550). ecuted from different starting points. These findings suggest that these regions all contain a neural representation which is Neuropeptides, Antidepressants and Depression sensitive to both the direction and starting point of the saccade and thus, the representation is not entirely oculucentric Pinhasov A., Reichenstein M., Feder Y., based, but rather, it is also coded in head, body or world co- and Schneider J. ordinate frames. Department of Molecular Biology, Ariel University Center, Ariel, Israel Rehabilitation of cognitive impairment in patients with acute cerebellar stroke Depression is a highly prevalent, severe and often life- Pierscianek D.,1 Frings M.,1 Bultmann U.,1 threatening disorder. Despite the advances that have been Fritsche N.,1 Gizewski E. R.,2 Flossdorf A.,3 made in the development of antidepressants, there are clearly Timmann D.,1 and Maschke M.4 still unmet clinical needs that should be addressed. To answer these needs, neuropeptide systems have started receiv- 1Department of Neurology, University of Duisburg-Essen, ing increasing attention for the development of novel antide- Germany pressants. Pituitary Adenylate Cyclase Activating Polypep- 2Department of Diagnostic and Interventional Radiology tide (PACAP) is a neuropeptide that exhibit central and and Neuroradiology, University of Duisburg-Essen, Germany peripheral effect via selective G-protein coupled receptors 3Department of Neurology, Fachklinik Rhein-Ruhr, namely PAC1, VPAC1 and VPAC2. We are investigating in- Essen, Germany volvement of PACAP and its receptors in the etiology of 4Department of Neurology, Fachklinik Rhein-Ruhr, psychiatric disorders. Using primary rat enriched neuronal Essen, Germany cell cultures we have demonstrated that acute (6 hours) and Israel Society for Neuroscience 87 prolonged (48–72 hours) treatment with PACAP38 signif- Detection of differences in learning strategy and icantly up-regulates mRNA levels of Brain Derived Neu- reference memory in young and old rats: Prevention rotrophic Factor (BDNF), the neurotrophin that is thought of memory deficits by ladostigil to be involved in the etiology of affective disorders and in the mechanism of action of antidepressants.. Our results Poltyrev T., Bejar C., and Weinstock M. have also revealed that expression of PACAP and its re- Department of Pharmacology, School of Pharmacy, ceptors are affected in primary cortical and hippocampal Hebrew University, Jerusalemz, Israel cell cultures treated for 72 hours with antidepressants representing distinct classes. Interestingly, changes in PACAP The aim of the study is to investigate memory and learning receptors expression resulting from antidepressant treat- in aged rats in tests based on differential task demands and to ment were highly and negatively correlated with BDNF ex- assess the potential of ladostigil (TV-3326) (a novel drug with pression. To examine these findings in vivo, we adminis- antiinflammatory activity)1 to prevent aged-related cogni- tered imipramine (3 mg/kg) for 21 days to C57Bl6 mice. tive decline. This chronic treatment resulted in a significant increase in PAC1 mRNA expression in hippocampus and a de- Methods crease in BDNF expression both in hippocampus and prefrontal cortex. Our findings suggest that antidepressants Place memory and detection of novelty in open field test may influence synaptic plasticity via modulation of PACAP- (OF) were evaluated in male Wistar rats, aged 2.5 months BDNF signaling and further understanding of these phe- (YC, n = 10) and 15–16 months (AC, n = 24) in the course nomena might contribute to the understanding of etiology of habituation during 4 consecutive days followed by sud- of affective disorders and development of novel antidepres- den change in this environment. Ten rats from AC were then sants. randomly assigned for chronic oral treatment with ladostigil (1 mg/kg/day) till the end of testing (A-TV). To assess refer- Effects of neonatal administration of ence memory (RM) YC at the age of 3.5 months and aged rats polyinosinic-polycytidilic acid (Poly I:C) on latent at 19–20 months were trained in the holebox (HB) to search inhibition and discrimination reversal for food in 4 fixed positioned holes, marked by light. Spa- in adulthood tial memory was also assessed one month later in the Morris Water Maze (MWM) test. Piontkewitz Y., Arad M., and Weiner I. Results Department of Psychology. Tel-Aviv University, Israel At 16 months rats showed less exploratory activity than YC in Association between maternal exposure to infection during OF but their response to novelty did not differ. At 20 months pregnancy with increased liability to schizophrenia in the the temporal organization of behavior in HB did not differ offspring has inspired the development of the prenatal im- between AC and YC, but AC were much more dependent on mune challenge model of schizophrenia in which the syn- the presence of visual cues, and less able to remember the po- thetic cytokine releaser polyinosinic-polycytidilic acid (Poly sition of all 4 baited holes than YC and A-TV. In MWM, AC I:C) is used to activate the maternal immune system. Adult demonstrated marked thigmotaxis and took much longer to offspring of poly I:C treated dams exhibit a wide spectrum escape onto the platform, even when close to it in contrast of cognitive deficits reflective of schizophrenia, including se- to YC and A-TV. AC had significantly more glial cells in the lective attention abnormalities as measured in latent inhibi- hippocampus and corpus striatum than YC, which were sig- tion (LI) and discrimination reversal (DR). Importantly, the nificantly reduced by ladostigil. nature of deficits exhibited in the two tasks were reported to differ depending on the time of poly I:C challenge, with Conclusions challenge early in gestation leading to attentional overswitch- ing (disrupted LI and rapid DR) and late in gestation to at- In both learning tasks it was possible to detect impairment tentional perseveration (intact LI and slow DR). We here of RM in AC aged 20-21 months. Daily treatment with la- tested the effects of neonatal poly I:C administration on these dostigil for 3–5 months from the age before learning deficits two tasks. Male rats were injected on postnatal day 4 with were detected, improved memory at the age of 21 months to poly I:C (2 mg/kg or 4 mg/kg) and tested at adulthood in LI resemble that of YC. The antiinflammatory effect of ladostigil and DR. Neonatally treated rats had disrupted LI and slow may contribute to the prevention of age-related cognitive de- DR superimposed on learning and/or performance deficit terioration. in both tasks. This deficit pattern may have relevance to chronic schizophrenia or autism. While present results sup- References ff port the notion that the long-term deleterious e ects of poly [1] S. Shoham, C. Bejar, E. Kovalev, D. Schorer-Apelbaum, and I:C challenge depend on the timing of the challenge, compar- M. Weinstock, “Ladostigil prevents gliosis, oxidative-nitrative ison to another neonatal manipulation shows that the na- stress and memory deficits induced by intracerebroventricular ture of the insult and not only its timing, determines the injection of streptozotocin in rats,” Neuropharmacology, vol. 52, outcome. no. 3, pp. 836–843, 2007. 88 Neural Plasticity

Real-time monitoring of blood-brain barrier 4Electroencephalography and Epilepsy Unit, disruption in the rat cerebral cortex Tel Aviv Medical Center, Tel Aviv, Israel 5Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel Prager O., David Y., and Friedman A. A fundamental issue in the study of the human visual sys- Departments of Physiology and Neurosurgery, Soroka tem concerns the neuronal dynamics that may underlie the Medical Centre,Ben-Gurion University, Israel emergence of a visual percept. In local field measurements a number of putative signals have been described as related The blood–brain barrier (BBB) is designed to separate the to visual processing including transient potentials (ERP), brain’s interstitial space from the blood. In both human delta waves, alpha-beta power disynchronizaiton (ERD) and and animal models there is still lack of reliable quantita- gamma power modulations. A striking characteristic of hu- tive methods for studying the mechanisms underlying ves- man perception is the ability to maintain a conscious visual sel permeability under healthy and disease conditions.We percept for an extended period of time. Here we employed report here a new method for estimating BBB perme- this phenomenon to identify putative candidates for object ability based on analysis of fluorescent images of surface perception. Recording was done using sub-dural electrodes vessels in the rat cerebral cortex. Rats are anaesthetized that were implanted in patients with epilepsy strictly for clin- and fixed under a fluorescent stereo-microscope. A cranial ical purposes. During recordings subjects were exposed to window is opened over the cerebral cortex and the dura images of objects lasting 2 seconds. The task of the subjects is removed. During the experiment the brain is continu- was to report contrast changes in the images. Our results ously superfused with artificial cerebrospinal fluid (ACSF). point to gamma power as the most consistent electrophysio- The animals are then injected intravenously (IV) with the logical marker whose activity was maintained in close corre- albumin-binding, BBB nonpermeable dye Evans Blue (1 ml, lation with the perceptual state of the subjects. Another clear 2%) or with Lucifer Yellow (1 ml, 10 mM). Fluorescent im- cut electrophysiological signal whose activity was maintained ages of the cortical surface are collected at fixed inter- throughout the percept was ERD. In contrast to the gamma vals before, during and following dye injection to iden- enhancement, this signal showed a much broader tuning to tify blood vessels and to follow changes in fluorescent in- various image properties. tensity within the brain parenchyma. To disrupt the BBB brain was perfused with the bile-salt sodium deoxycholate Supported by ISF grant to R. Malach and US Israel BSF grant (DOC, 2 mM), Na+/K+ ATPase inhibitor, Ouabain (5 uM), to Malach and Fried. the GABA receptor antagonist, penicillin (100 U/uL) or by electrical stimulation of the SPG. Laser Doppler flowme- Behavioral and cortical activation patterns following try and EEG are simultaneously recorded over the surface an optic neuritis episode of the treated region to monitor brain perfusion and neuronal activity, respectively. Vessels diameters and BBB per- Raz N.,1 Dotan S.,2 Zohary E.,3 Arkadir D.,1 meation are measured offline using homemade MATLAB Chokron S.,4 and Levin N.1 scripts. The analysis entails vessels identification following 1 dye injection under control conditions, followed by measure- Department of Neurology, Hadassah Hebrew-University ments of changes in extravascular fluorescent intensity. His- Hospital, Jerusalem, Israel 2 tological analysis was assessed following the in-vivo exper- Department of Ophtalmology, Hadassah iment to confirm BBB opening.The presented method of- Hebrew-University Hospital, Jerusalem, Israel 3 fers a new tool to study mechanisms underlying alterations Department of Neurobiology, Hebrew University, to brain vascular characteristics including vessels diame- Jerusalem, Israel 4 ter and permeability under normal and pathological condi- Service de Neurologie, Fondation Ophtalmologique tions. Rothschild, France

This work was supported partly by “BrainsGate.” Optic neuritis (ON) is a common condition that causes reversible loss of vision in young patients. It derives from id- Sustained image presentation supports a role for iopathic inflammatory demyalination. There is an ongoing gamma LFP in object perception debate about whether ON derives from parvocelluar or magnocelluar deficit. Visual function improvement is common Privman E.,1 Fisch L.,2 Kramer U.,3,5 Kipervasser S.,4,5 in this disease, and is usually attributed to peripheral nerve Andelman F.,3 Neufeld M. Y.,4,5 Yehezkel Y., 1 Fried I.,3,5 recovery. Our previous study has suggested that central re- and Malach R.2 organization processes, that is, the lateral occipital complex (LOC), may also be involved in recovery. The aim of the 1School of Computer Science, Sackler Faculty of Exact present work is to study the behavioral and cortical changes Sciences, Tel Aviv University, Tel Aviv, Israel taking place following an ON episode, in a longitudinal 2Department of Neurobiology, Weizmann Institute of study. We have found that, after the acute phase, ON eyes Science, Rehovot, Israel had normal or near normal visual acuity, contrast sensitiv- 3Functional Neurosurgery Unit, Tel Aviv Medical Center, ity and color perception; however, they still had difficulties Tel Aviv, Israel in recognizing objects defined by motion. This may support Israel Society for Neuroscience 89 a specific magnocelluar deficit in ON. In order to study a Effect of antidepressants on PACAP and its receptors possible cortical origin for the behavioral results, we have in rat primary neurons studied fMRI activation pattern in the ventral and dorsal pathways. While the former may be more concerned with Reichenstein M.,1,2 Rehavi M.,2 and Pinhasov A.1 visual acuity and is mainly considered to be stimulated by 1 the parvocelluar system, the latter may contribute to motion Department of Molecular Biology, Ariel University Center,Ariel, Israel perception and is mainly stimulated by the magnocelluar 2 system. We have compared the patterns of fMRI activation Department of Physiology and Pharmacology, elicited by stimulation of the affected and the healthy eyes, Sackler Faculty of Medicine, Tel Aviv University, Israel along the visual cortical hierarchy. As previously, we found According to the monoaminergic hypothesis of depres- reduced fMRI activation in V1 during stimulation of the af- sion, most of the antidepressants are aimed to stimulate fected eye compared with the healthy eye. However, the mag- monoamine systems. In spite of their predominant effect nitude of difference in fMRI signal decreased with progres- on monoamine neurotransmitter levels, these drugs may sion along the visual hierarchy, both in objects and motion also mediate changes in synaptic plasticity by modulat- related areas, suggesting cortical adjustment to abnormal ining neuropeptide action in brain areas, such as hippocam- put. Those preliminary fMRI results, however, did not sup- pus and prefrontal cortex. Pituitary Adenylate Cyclase Ac- port a different role for the affected eye in ventral and dorsal tivating Polypeptide (PACAP) is a neuropeptide exerting pathways. pleiotropic effects via three types of receptors, PAC1, VPAC1 and VPAC2. We have investigated the effects of various an- Supported by The Caesarea Edmond de Rothschild foundation. tidepressants on the expression of PACAP, its receptors and brain derived neurotrophic ffactor (BDNF), a neurotrophin Auditory and visual responses in the tectofugal implicated in the mechanism of action of antidepressants. pathway of the barn owl Using a real-time PCR analysis, we found that selective serotonin reuptake inhibitors, Paroxetine and Citalopram, signif- Reches A. and Gutfreund Y. icantly and dose-dependently decreased PAC1 and VPAC2 mRNA levels following 72-hour treatment, whereas tricyclic Department of Physiology and Biophysics, The Faculty of antidepressant Imipramine exhibited an opposite effect. No Medicine, The Technion, Israel effect on VPAC1 expression was observed. Furthermore, we found an intriguing correlation between the changes in The entopallium (E) in birds is the major thalamorecipient PAC1/VPAC2 and BDNF expression after treatment with an- forebrain structure of the tectofugal pathway The E receives tidepressants. In addition, we examined the effect of these an- most of its input from the nucleus rotundus, the avian ho- tidepressants on neuronal cell survival, using a cell prolifera- molog of the mammalian thalamic pulvinar complex . Pre- tion assay based on metabolic activity. Incubation of cortical vious research has characterized the tectofugal pathway in neurons for 24 hours with antidepressants (0.3–10 μM) had mammals and pigeons as an extra geniculate pathway lead- no effect on metabolic activity and cell viability. Incubation ing visual information to the cortex. This pathway has been for 72 hours increased cell metabolic activity with the excep- suggested to be involved in bottom-up attentional control. tion of Paroxetine and Imipramine at 10 μM that proved to We show that, in the barn owl, entopallial cells respond to be cytotoxic. Cotreatment with antidepressants (3–10 μM) auditory as well as visual stimuli, suggesting that the tectofu- and PACAP or it’s antagonist PACAP(6–38) was ineffective in gal pathway is not strictly visual but carries multisensory in- cells exposed to Paroxetine 10 μM. Moreover, co-treatment formation. We characterized single unit responses in the E with PACAP and Imipramine 3–10 μM had an adverse ef- to binaural localization cues including interaural time dif- fect on cell viability. In summary, our results point toward ff ference (ITD) and interaural level di erence (ILD), as well PACAP signaling involvement in synaptic plasticity processes as average binaural sound intensity (ABSI). Similar to visual mediated by antidepressants. receptive fields, auditory receptive fields were typically large and covered most of the contralateral space. In addition, a Amidic GABA derivatives of antidepressants display majority of the cells presented nonmonotonic rate level func- improved pain suppressing activity tions with a preference towards weak intensity sounds. In- terestingly, most multisensory neurons in the E responded Rephaeli A.,1 Gil-Ad I.,1 Trasenko N.,1 Tarasenko I.,1 stronger to spatially aligned visual and auditory stimuli than Aharoni A.,2 Geffen Y.,3 Savitsky K.,3 Weizman A.,1 to the sum of the responses to the unimodal components (su- and Nudelman A.2 peradditive enhancement). Finally, we show that the bimodal enhancement is context dependent appearing more robustly 1Felsenstein Medical Research Center, Tel-Aviv University, in responses to rare stimuli, a result that is in-line with the Israel notion that the E is involved in multisensory control of spa- 2Department of Chemistry, Bar Ilan University, Ramat Gan tial attention. 3BioLineRx Ltd., Jerusalem, Israel

This work was supported by a grant from the National Institute Inadequate pain management, which is widely prevalent, for Psychobiology in Israel and a BIK. raisestheurgentneedtodevelopnewandimproveddrugs. 90 Neural Plasticity

Some antidepressants, antiepileptics and GABAergic drugs to an statistically insignificant change in the proportion be- are used for management of pain syndromes. To improve tween large (half width at 7–12 pA) and small (half width the activity of these agents, GABA derivatives of GABA, val- at 2–5 pA) events. In contrast, in neurons from trained rats, proic acid, nortriptyline and fluoxetine, were synthesized and when compared with pseudo-trained, only a fraction of the tested in animal models of pain. In the hot plate model, the small sEPSCs (3.75–7.25) in each cell was substituted by very GABA esters of GABA (AN-214) or valproic acid (AN-216) largesEPSCs(10–25pA).Thesizeofthisfractionvariedbe- did not elicit a significant effect. The GABA amides of the tween cells and ranged between 0–100% of the small sEPSCs antidepressant nortriptyline, BL1021, or fluoxetine, BL1024, in the averaged pseudo-trained cell. Our data show that while significantly increased the latency of nociceptive reaction of the change between the pseudo-trained and the na¨ıve groups Balb/c mice to heat and displayed significantly higher anal- could be described as a uniform change over the whole pop- gesic effects than the parent antidepressants. Intraplantar in- ulation of cells and synapses, the change between the trained jection of formalin to Balb/c mice resulted in a typical bipha- and the pseudo-trained group is apparent in only fraction sic flinching behavior of the injected paw. In this model of synapses and to a different extent in each cell, imposing a BL1021 and BL1024 significantly reduced the early nocicep- fundamental change in the information processing and cod- tive and the late inflammatory peripheral responses com- ing within the piriform cortex network. pared to equimolar po doses of nortriptyline, fluoxetine, or equimolar mixtures of the antidepressants and GABA or The Neurorestorative Effect of the Green Tea gabapentin. Skin samples from the injected paws, exhibited Polyphenol (-)-Epigallocatechin-3-Gallate Combined significantly lower levels of interferon- gamma and TNF-alfa With the Selective MAO-B Inhibitor, Rasagiline in in mice treated with BL1021 compared to those treated with MPTP Mice Model nortriptyline, and to the mixture of nortriptyline and GABA or gabapentin. In Wistar rats injected intraplantarly with car- Reznichenko L., Youdim M. B. H., and Mandel S. A. rageenan, BL1021 showed significantly better efficacy in inhibiting edema, than those treated with nortriptyline. In ad- Eve Topf Centers, Department of Pharmacology, Faculty of dition, a significantly increased latency of nociceptive reac- Medicine, Technion, Haifa, Israel tion by these rats was demonstrated using the hot-plate-test. The notably better efficacy of the amides compared to their The neuropathology of neurodegenerative diseases is asso- parent drugs towards both the central perception and the pe- ciated with a gradual loss of neurons in the respective af- ripheral phase of pain, make them promising candidates for fected brain areas. Our previous studies have shown that the the treatment of acute and neuropathic pain conditions. green tea polyphenol (-)-epigallocatechin-3-gallate (EGCG) prevented neuronal cell death, both in vivo and in vitro, as This research was partially supported by BioLineRx. well as revealed a neurorescue effect against several toxins- induced cell death. It has been clearly demonstrated that a Associative odor learning induces non uniform “domino” cascade of neurotoxic complex events can initiate increase in the synaptic efficacy neurodegeneration in Parkinson’s (PD) and Alzheimer’s diseases (AD). Thus, it is assumed that a combination of well Reuveni I., Saar D., and Barkai E. established neuroprotective drugs, such as antioxidants and Department of Neurobiology and Ethology, Faculty of iron chelators (e.g., EGCG), and neurotrophic drugs (e.g., Sciences, Haifa University, Israel rasagiline), will be a more effective therapy for these diseases. In the present work, EGCG alone (5 mg/kg/day, 14 days) and We have previously shown that rule learning of an olfactory in combination with rasagiline (0.05 mg/kg/day, 14 days) has discrimination task is accompanied by increased synaptic ef- been studied in vivo, using neurorescue paradigm of MPTP ficacy in the piriform cortex. In the current study we inves- model of PD. The drugs were administered orally to mice tigated the quality of this change by recording spontaneous C57/Bl, 4 days after MPTP (4 × 20 mg/kg/day). The MPTP excitatory post synaptic currents (sEPSC) in piriform cortex treated mice demonstrated a progressive demise of dopamin- pyramidal neurons. The averaged amplitude of the sEPSCs ergic neurons in substantia nigra (SN) (assessed by immuno- in neurons from trained rats (13.5 ± 6.5 pA, n = 19) was histochemistry), followed by significant decrease in the stri- 55% larger (P<.002) than the averaged sEPSCs in neurons atal dopamine (DA) content (assessed by HPLC), as previ- from pseudo-trained (8.7 ± 1.7, n = 14) and na¨ıve rats (9.2 ously reported by us. However, EGCG alone, and more im- ± 4.5, n = 15), which had similar values. Principal compo- portantly, the cocktail of EGCG plus rasagiline, significantly nent analysis (PCA) of the amplitude distributions was ap- rescued cell function of SN dopaminergic neurons, indicated plied to further characterize the nature of the change. PCA by elevation of the DA content in the striata. Additionally, showed that the variability between cells resulted from two the administration of these drugs significantly attenuated cell different components: (1) Homogenous change of all sEPSCs death of SN DA-containing neurons, as demonstrated by ty- in a given cell. (2) The proportion of large versus small spon- rosine hydroxylase-cell labeling. The present findings indi- taneous events. Such analysis showed homogenous increase cate that EGCG alone and in combination with rasagiline of around 1.5 pA in all synapses in pseudo-trained compared may have a positive impact on aging and neurodegenerative to na¨ıve (P<.02). Such increase was not paralleled with in- diseases to retard or perhaps even reverse the accelerated rate crease in the averaged amplitude of spontaneous events due of neuronal degeneration. Israel Society for Neuroscience 91

Microsomal enzymes metabolize the endogenous often similar to Parkinson’s disease (PD) tremor, but their re- lipid, N-arachidonoyl dopamine, to hydroxylated lationship to the tremor and other Parkinsonian symptoms is metabolites active at recombinant human TRPV1 still under debate. We studied the frequency-dependency of receptors information transmission in the BG networks by recording simultaneously from multiple electrodes located in the pri- Rimmerman N., Bradshaw H. B., Tan B., and Walker J. M. mary motor cortex (MI) and in the globus pallidus (GP) of two vervet monkeys before and after MPTP treatment and Psychological and Brain Sciences and the Gill Center for induction of PD symptoms. We mimicked the PD bursting BioMolecular Sciences, Indiana University, Ind, USA oscillations by stimulating at different frequencies (1–15 Hz) through micro-electrodes located in MI or GP. Since the N-arachidonoyl dopamine (NADA) is an endogenous lipid bursts used in this study contained 8 pulses given at 200 Hz, identified in our lab, which modulates signal transduction in the high (10,15 Hz) frequency, 20 seconds long, tests can be nociceptive pathways (Huang et al., 2002). NADA is found depicted as fragmented-DBS pattern, enabling us to exam- in the mammalian nervous system and activates the nonse- ine the effects of high frequency DBS without the distortion lective cation channel, transient receptor potential vanilloid of stimulation artifact. Our findings show that in the nor- type 1 (TRPV1). NADA also activates cannabinoid receptor mal state, micro-stimulation of one structure does not mod- 1 and inhibits the NF-kappa B, NFAT and Activator Pro- ulate the discharge rate in the other structure. The functional tein 1 signaling pathways. To investigate the metabolism of connectivity between MI and GP is greatly enhanced fol- NADA through the cytochrome P450 (CYP450) metabolic lowing MPTP treatment. In the frequency domain, GP neu- pathway, we studied the in vitro production of hydroxy- rons usually responded equally to 1–15 Hz stimulation bursts lated metabolites and their activity at recombinant human in both states. By contrast, MI neurons expressed low-pass TRPV1 receptors. Method: Rat liver and brain microsomal filter properties, with a cut-off frequency around 5 Hz. Fi- fractions were isolated using differential centrifugation. The nally, muscle activation evoked by MI micro-stimulation was microsomal metabolites of NADA were partially purified markedly attenuated at frequencies higher than 5 Hz. The from methanolic extracts on solid phase cartridges.. Metabo- low-pass properties of the BG networks suggest that despite lites were were identified by HPLC/quadrupole time-of-flight their similar frequencies-PD tremor is not directly driven mass spectrometry and quantified tandem mass spectrom- (beat to beat) by the BG 5–10 Hz burst oscillations. BG high etry. Major hydroxylated metabolites were tested for cal- frequency stimulation would similarly be filtered in the cor- cium influx on human recombinant TRPV1 receptors over- tex or in previous level. We therefore suggest that DBS allevi- expressed in human embryonic kidney cells (HEK293). Key ates the PD symptoms by blocking the abnormal oscillations results: Following microsomal activation in the presence of of the BG networks and re-establishment of downstream to NADA, omega and (omega-1) hydroxylated metabolites were the BG compensatory processes. formed. These hydroxylated NADA metabolites were active at recombinant human TRPV1 receptors, inducing a dose- Cerebellar cortical responses to mossy fiber repetitive dependent calcium influx (EC50: 1.3, 1.2 microMolar, re- stimulation are enhanced by dissinhibition spectively). Both metabolites exhibited lower potency and efficacy compared to NADA. Conclusions and implications: Rokni D. and Yarom Y. CYP450 enzymes are capable of metabolizing several fatty acids (e.g., arachidonic acid) and fatty acid-containing lipids Department of Neurobiology, and ICNC, Hebrew University, (e.g., N-arachidonoyl ethanolamine) forming a larger family Jerusalem, Israel of neuromodulators with potential activity at various lipid Cerebellar Purkinje cell (PC) responses to mossy fiber (MF) receptors. The current study shows that NADA metabolism stimulation, are composed of a fast excitatory component occurs through microsomal enzymes. Future studies will ex- followed by prolonged inhibition. It was suggested that the amine the antiinflammatory activity of these metabolites. inhibitory component, generated by the molecular layer in- Supported by NIDA (DA-018224, DA-020402, F32-DA- terneurons (MLIs), limits the time window for synaptic in- 016825). tegration, and ensures a precisely timed output (Mittmann et al. 2005). However, it was previously shown that a single Low-pass filter properties of basal ganglia (BG) stimulus to the parallel fibers (PFs) inactivates the inhibitory networks and possible mechanisms of action of component for tens of milliseconds (Cohen and Yarom 2000, high-frequency deep brain stimulation (DBS) Mann-Metzer and Yarom). Thus, inputs that are composed of high frequency spike trains (Chadderton et al. 2004), are Rivlin-Etzion M., Marmor O., Rosin B., Slovik M., likely to inactivate the inhibitory component. To asses the and Bergman H. role of the MLIs in shaping the time course and spatial organization of MF responses, we used the voltage sensitive Physiology and ICNC, The Hebrew University, Jerusalem, dye RH-414, and imaged responses to stimulation of MFs Israel in the isolated cerebellum of a Guinea pig. We confirmed that the responses to MF stimulation are spatially organized Oscillatory bursting activity is commonly found in the BG of in a radial patch occasionally bounded by measurable in- the Parkinsonian brain. The frequency of these oscillations is hibitory responses. We found that this inhibition which exists 92 Neural Plasticity throughout the responding patch, shapes the time course 1Wohl Institute for Advanced Imaging, Tel-Aviv Sourasky but not the spatial organization of MF responses. Responses Medical Center, Israel were prolonged when either (1) GABAergic transmition was 2Epilepsy and Functional Neurosurgery Unit, blocked (GABAzine 5 μM), (2) MF stimulation was preceded Tel-Aviv Sourasky Medical Center, Israel by activation of the MLIs by surface stimulation, (3) MF 3Sackler Faculty of Medicine, Physiology department, stimulation was preceded by another MF stimulation (repet- Tel-Aviv University, Israel itive stimulation). However, no further prolongation of the responses in conditions 2 and 3 occurred in the presence of A close relation between structural and functional features GABAzine. This indicated that prolongation of the responses in the brain is a long-standing axiom, albeit its mechanism is in these conditions was due to a lack of the inhibitory compo- poorly understood. The Supplementary Motor Area (SMA), nent, and not a change in the excitatory component. When a brain area in the medial wall of Brodmann’s area 6, has been MLIs receive input from MFs they inhibit other MLIs thus subdivided based on cytoarchitectonic features into poste- preventing them from contributing to following MF inputs. rior and anterior parts: SMA proper and pre-SMA, respec- Therefore, the possibility that the MLIs act to limit the time tively. However, the functional relevance of these subdivi- window of PC integration is of limited significance. sions has not yet been fully revealed. The location of the SMA between areas involved in executive and cognitive as- Toll-like receptors regulate adult neurogenesis pects of action in the prefrontal cortex points to a possible in-between representation of functional hierarchy within it. Rolls A., Shechter R., London A., Ziv Y., Ronen A., On the whole, animal and human studies suggested the in- Levy R., and Schwartz M. volvement of the SMA in processing voluntary aspects of action that underlie self-generated processes such as volition Department of Neurobiology, Weizmann Institute of Science, and planning. The goal of our study is to uncover principles Israel of functional organization in the human SMA. For that purpose we will use fMRI on healthy subjects with paradigms Neurogenesis—the formation of new neurons in the adult that differ in their mode of action (language versus motor), brain—is considered to be one of the mechanisms by which planning load (simple versus complex) and the source of act the brain maintains its lifelong plasticity in response to ex- initiation (internal versus external). Based on these tasks, we trinsic and intrinsic changes. The mechanisms underlying will establish an SMA-selective functional localizer. Thirteen the regulation of neurogenesis are largely unknown. We dis- healthy subjects participated in the study. The “complex” ver- covered that Toll-like receptors (TLRs), a family of highly sus “simple” condition activated the SMA proper, while the conserved pattern-recognizing receptors involved in neural “internally guided” versus “complex” condition activated the system development in Drosophila and innate immune ac- Pre-SMA. The results demonstrated functional organization tivity in mammals, regulate adult hippocampal neurogene- within the SMA area with the pre-SMA more related to the sis. We show that TLR2 and TLR4 are found on adult neural complex and internally guided acts then the SMA proper. stem/progenitor cells (NPCs) and have distinct and opposing functions in NPC proliferation and differentiation both This research was supported by the Adams Super Center for in vitro and in vivo. TLR2 deficiency in mice impaired hip- Brain Studies. pocampal neurogenesis, whereas the absence of TLR4 resulted in enhanced proliferation and neuronal differentia- The contribution of forced oscillations of the arm to tion. In vitro studies further indicated that TLR2 and TLR4 the discharge pattern of primary motor cortex (M1) directly modulated self-renewal and the cell-fate decision of and globus pallidus (GP) neurons NPCs. The activation of TLRs on the NPCs was mediated via MyD88 and induced PKCalpha/beta-dependent activa- Rosin B.,1 Slovik M.,1 Mitelman R.,1,2 Rivlin-Etzion M.,1,2 tion of the NF-kappaB signalling pathway. Thus, our study and Bergman H.1,2,3 identified TLRs as players in adult neurogenesis and empha- sizes their specified and diverse role in cell renewal. These 1Department of Physiology, Hebrew University-Hadassah results were recently published in Nature Cell Biology in the School of Medicine, Jerusalem, Israel cover and were accompanied by News and views by Marino 2The Interdisciplinary Center for Neural Computation, and Pluchino. It was also chosen as editor’s choice in Science Hebrew University, Jerusalem, Israel STKE. 3The Eric Roland Center for Neurodegenerative Diseases, Hebrew University-Hadassah School of Medicine, Israel This study was supported, in part, by an NRSAD award and by a research grant from Mr and Mrs Richard D. Siegal. Low-frequency tremor is one of the pivotal symptoms of Parkinson’s disease (PD). In parallel, the firing pattern of Searching for anatomical based functional the basal ganglia (BG) and cortical neurons becomes bursty organization in the human brain: The case of and, in part, oscillatory and synchronized. Albeit the co- the Supplementary Motor Area appearance of the tremor and the changes in discharge pattern suggests a connection between them, their interrelation Rosenberg K.,1,3 Fried I.,2 and Hendler T.1,3 remains illusive. Either one of the phenomena could cause Israel Society for Neuroscience 93 the other, both could be caused by some unknown confound- 1Neurobiology Deparment, Institute of Life Science, ing factor and, finally, they could be completely unrelated Hebrew University of Jerusalem, Israel and caused by different aspects of the disease. In this study we 2Otto Loewi Minerva Center, Inter-University Institute for examined the contribution of sensory feedback paths to the Marine Biology, Eilat, Israel discharge patterns of GP and M1. We have recorded from the 3Department of Medical Physiology, Panum Institute, arm related area of M1 and the GP of a healthy African green University of Copenhagen, Denmark monkey (Cercopithecus aethiops), while applying forced oscillations (artificial tremor) to the left arm at several discrete Learning to predict the sensory component resulting from frequencies for a duration of 90 seconds per frequency. We the organism’s own activity enables it to respond appropri- report the following results: 60/152 (39%) of the M1 neu- ately to unexpected stimuli. In sharks, predictable electric rons displayed a discharge pattern that was phase locked and fields of the electrosensory sense are filtered in the principal coherent to the movement induced by the experimental pro- neuron of the Dorsal Octavolateral Nucleus (DON). Postsy- cedure. The coherence showed a tendency to increase with naptic interactions between the electro-sensory primary af- the increase in movement frequency and amplitude, perhaps ferents (aff) and parallel fibers (pf) are the proposed un- suggesting reaction to acceleration rather than to movement derlying mechanism. We used the isolated brain stem of the frequency. 12/62 (19%) of neurons in the GPe showed a dis- shark to characterize these two inputs. Intracellular record- charge pattern that was phase locked and coherent with the ing and labeling ensure that our study in confined to the movement. Interestingly, the maximal coherence in the ma- principal neuron and application of extracellular field ensure jority of neurons was achieved at 5 Hz, which is coincidently voltage modulation at remote areas. We found that: (a) the the frequency of the PD tremor. The phase locking did not aff postsynaptic potential (EPSP) has a faster rise time (3.9 seem to be affected by amplitude changes, suggesting that the ± 1.8 ms), low amplitude (2.9 ± 1.74 mV) and short dura- reaction was indeed to movement frequency rather than to tion (17.4 ± 7.8 ms); (b) facilitation was never encountered; acceleration. Our results imply that PD tremor is probably (c) threshold for action potentials was 3.5 mV when evoked not the cause of the change of discharge patterns of M1 and by aff stimulation. (d) The EPSP was insensitive to change in GP neurons in MPTP-treated primates. Future recordings in postsynaptic potential, induce by intracellular current injec- the GPi and in the MPTP-treated primate model of PD will tion or by applied extracellular fields. Hence, the aff input is be performed to validate this conclusion. located close to the spike initiation site and the EPSP has the characteristics of electric transmission. The pf input is char- Magnetic stimulation of living and dissociated brains acterizedby(a)EPSPhadaslowrisetime(8.8± 3.5 ms), ± Rotem A. and Moses E. a high maximal amplitude (12 5.58 mV) and long duration (36 ± 15.1 ms); (b) prominent facilitation was elicited Physics of Compex Systems, Weizmann Institute of Science, by short train of stimuli; (c) threshold for action potential Israel was 20 mV when evoked by pf stimulation. The highly efficient connection between the afferent input and the prin- Magnetic stimulation of nerves is attracting increased at- cipal neuron leaves little room for summation with parallel tention recently, as it has been found to be useful in ther- fibers response. Hence the filtering is most likely mediated ff apy of neural disorders in humans. In an e ort to uncover via secondary neurons that adjust the sensitivity to afferent the mechanisms of magnetic stimulation we apply magnetic input. stimulation on ex-vivo neuronal preparations and demonstrate the first magnetically evoked activity in cultures. Mag- Microglia activation is subject to modulation in netic pulses initiate neuronal activity only in 1D patterned injury and disease cultures of hippocampal and cortical neurons. The sensitivity of neurons to the magnetic pulses is affected by coil orien- Rotshenker S. tation, geometry, morphology, pharmacology, neural activity and neuronal density. Reciprocally, magnetic stimulation, ff Department of Anatomy and Cell Biology, Faculty of with either single or repetitive pulses, has an obvious e ect Medicine, Hebrew University, Israel on immediate and progressive neuronal activity. In a related experiment the interaction between myelination and TMS is The removal of degenerated myelin is essential for repair by explored by applying TMS on Wistar and Myelin Deficient regeneration after injury to axons and for minimizing dam- (MD) rats and by magnetically stimulating myelinated cul- age to intact axons and myelin in multiple sclerosis. Mi- tures. Intriguing findings regarding TMS on rats in general ff croglia remove degenerated myelin by phagocytosis. We fo- and di erences between myelinated and non myelinated sys- cus presently on complement receptor-3 (CR3) and scav- tems will be described. These findings may have an impact enger receptor-AI/II (SRA) mediated myelin phagocytosis in on the way TMS research is conducted on humans. microglia. Paradoxically, these receptors are expressed in microglia after injury to CNS axons but myelin is not phago- Differential postsynaptic efficiency of electrosensory cytosed, suggesting that phagocytosis can be modulated be- afferents and parallel fibers in the principal neurons of tween efficient and deficient states. We sought after mecha- the shark dorsal octavolateral nucleus nisms that modulate myelin phagocytosis and shall presently Rotem N.,1,2 Sestieri E.,1,2 Hounsgaard J.,3 and Yarom Y.1 discuss three that involve Galectin-3 (Gal-3), cAMP and 94 Neural Plasticity

Rho/Rock. First, Gal-3 is expressed in microglia that phago- cell proliferation demonstrates that Wnt restricts the amount cytose but not in microglia that do not phagocytose myelin. of DA progenitors during a window of plasticity, which oc- Additionally, Gal-3 stabiles K-Ras-GTP that activates PI3K curs at primary neurogenesis. Our findings show that dien- which, in turn, activates phagocytosis. An explanation is of- cephalic DA population size is modulated inside the neural fered, thereby, for efficient and deficient phagocytosis by mi- plate, much earlier than expected, and illustrate how robust croglia that, respectively, express or do not express Gal-3. patterning signals precisely regulate cell number. Second, cAMP plays a dual role in phagocytosis in a concentration dependent manner: it activates phagocytosis at nor- Supported by National Institute for Psychobiology, Benozyio mal levels through PKA and inhibits phagocytosis at high Center, National Parkinson Foundation, Israel Science Foun- levels through PKA and Epac. Thus, phagocytosis is inhib- dation. ited by increasing cAMP levels pharmacologically. Third, Rho/ROCK signaling activates the production of stress fibers The reliability and validity of the face-specific and downregulates filopodia formation. Conversely, the inhi- N170 ERP component recorded simultaneously with bition of Rho/ROCK signaling disrupts stress fibers and up- functional MRI regulates filopodia formation along with augmenting phago- Sadeh B.,1 Podlipsky I.,2 Zhdanov A.,1,2 cytosis, thus suggesting that the three are causally linked. No- Hendler T.,1,2 and Yovel G.1 tably, the latter two mechanisms are of special interest with respect to regeneration in view of the observations that ele- 1Department of Psychology, Tel Aviv University, Israel vated cAMP levels and Rho/ROCK inhibition promote re- 2Functional Brain Imaging Unit, Tel-Aviv Sourasky Medical generation by overriding growth-cone collapse induced by Center, Israel degenerated myelin. The ERP component N170 is a well-established ERP marker Supported by Israel Science Foundation and the Ministry of of face-selective neural response. Although numerous stud- Health. ies have investigated face-selective neural responses with ERP and functional MRI, the current study is the first to measure Dopaminergic Neuronal Cluster Size is Determined face-selective ERP response simultaneously with MR acquisi- During Early Forebrain Patterning tion. Given the massive distortion MR acquisition generates

1 1 1 in the EEG signal, our goal here was to assess the reliability Russek-Blum N., Gutnick A., Nabel-Rosen H., and validity of the N170 during functional MRI data collec- Blechman J.,1 Staudt N.,2 Dorsky R.,3 Houart C.,2 1 tion. To that end, 10 individuals participated in an ERP ex- and Levkowitz G. periment in the scanner. Half of the scans were collected dur- 1Department of Molecular Cell Biology, Weizmann Institute ing and half without MR acquisition. Reliability and validity of Science, Rehovot, Israel of the N170 were measured by correlating, across subjects, 2Medical Research Council Center for Developmental several measures that were recorded during MR acquisition Neurobiology, King’s College, London, UK following artifact removal, with the same measures that were 3 collected without MR acquisition. These measures were am- Department of Neurobiology and Anatomy, ff University of Utah, Salt Lake City, Utah, USA plitude, latency, face-selectivity (the di erence between the amplitude to faces and nonface objects) and laterality (the The population size of distinct nerve cell types is determined difference between the amplitude to faces over the right and by intracellular programming that is later modified by ex- the left hemispheres). We found very high test-retest relia- tracellular signals. Uncovering developmental cues that reg- bility coefficients for the N170 peak amplitude (r = 0.93 ulate the nearly fixed number of dopaminergic (DA) neurons and r = 0.75, right and left hemisphere respectively), for is important for understanding the contribution of aber- the N170 latency (r = 0.91, r = 0.98, right and left hemi- rant DA development to neurological disorders. Although sphere respectively), as well as high validity measures for the the physiological and clinical aspects of the DA system have N170 laterality (r = 0.71) and its face selectivity (r = 0.76). been intensively studied, relatively little is known about the Our results suggest that the face-selective N170 can be reli- lineage of DA cell clusters and the mechanisms controlling ably measured in a simultaneous ERP-fMRI setup after the their progenitors number. We demonstrate in zebrafish em- application of proper artifact removal tools. bryos that the number of diencephalic DA cells increases following attenuation of canonical Wnt pathway without af- The role of monoamine oxidase subtypes in striatal fecting the fates and number of neighboring neurons. We metabolism of dopamine produced from l-dopa in found that Wnt8b is a modulator of DA cell number that the rat requires the activity of the Fezf2/Fezl transcription factor in Sader-Mazbar O. and Finberg J. P. this process. Birthdating analysis indicates that Wnt inhibition does not delay proper exit of DA progenitors from the Molecular Pharmacology Department, Rappaport Medical cell cycle. Fate mapping identified the DA progenitor zone Faculty,Technion,Haifa,Israel in the diencephalic anlage of the neural plate and show that this neurogenin- positive DA progenitor domain is affected The MAO-B inhibitor drug, rasagiline is an effective adjunct by Wnt attenuation. Conditional inhibition of Wnt and of treatment to L-DOPA in Parkinson’s disease (PD), however Israel Society for Neuroscience 95 its precise action on dopamine (DA) metabolism still needs horizontal and radial dimensions, and 3D shape recognition. to be clarified. Since in advanced PD there is pronounced de- Interestingly, with little or no practice humans were able to generation of serotonergic and noradrenergic, as well as DA localize objects and estimate roughness as accurate as, and neurons, we have used a model of serotonergic (5-HT) as well even better than, rats in equal tasks. The number of available as DA depletion in the rat striatum as a closer model of PD, whiskers did not affect horizontal or radial localization ac- and have investigated the striatal metabolism of L-DOPA- curacy, while significantly affecting shape recognition. For a derived DA by MAO subtypes in this model system. Striatal horizontal localization task, active sensing was significantly MAO activity and GFAP expression were investigated fol- superior to passive sensing. Contact time analysis revealed lowing DA lesion with 6-hydroxydopamine alone (single) or that subjects rely primarily on temporal cues in horizon- with additional 5-HT lesion with 5,7-dihydroxytryptamine tal localization, and ignore proprioceptive information. Fur- (combined). There was a significant increase (137.5 +/- ther analysis in humans and rats is required in order to test 0.06%, P<.01) in MAO-B activity in the combined le- whether these two species use similar sensory-motor mech- sion model, with no significant change in MAO-A activity. anisms when faced with similar tasks, and, more globally, to The increase in MAO-B activity following the combined le- understand how brains learn to adopt new sensory modali- sion was associated with a significant increase in GFAP ex- ties and how to optimize such learning. pression. Using microdialysis technique, the effect of chronic MAO-A and MAO-B inhibition in rats bearing either sin- This work was supported by the German BMBF–Israeli MOS gle or combined lesion was investigated. Rats were treated Foundation. daily with either saline, clorgyline (1 mg/kg) or rasagiline (0.05 mg/kg) and on the 14th day striatal microdialysates Maternal corticosterone mediates anxiety but not were collected following a single systemic injection of L- learning deficits induced by prenatal stress in rats DOPA/Carbidopa (25 and 6 mg/kg respectively). DA levels were 10 fold higher in the clorgyline groups in both types of Salomon S. and Weinstock M. lesions compared to controls. Rasagiline, on the other hand, Department of Pharmacology, School of Pharmacy, Hebrew increased DA levels moderately with more pronounced ef- University of Jerusalem, Israel fect in the combined lesion than in the single lesion group (an increase of 3 and 2 folds, resp.). These results indicate In previous studies we found that prenatal stress during the that most of the MAO-A activity in striatum is not located in last week of gestation in rats impairs spatial learning only in either DA or 5-HT axonal varicosities. In addition, MAO-B the male offspring but induces anxiety in both genders. inhibition becomes important in the maintenance of higher L-DOPA-derived DA levels in the striatum in advanced stages Aim of PD. The aim is to determine whether excess maternal corticos- The “human rat”—learning to use a new sense via terone (COR) alters programming of the fetal brain thereby sensory substitution principles inducing learning deficits and anxiety. Saig A., Arieli A., and Ahissar E. Methods Department of Neurobiology, The Weizmann Institute of Science, Israel Pregnant Wistar rats (n = 6) were adrenalectomized (ADX) on day 9 of pregnancy via the dorsal approach, 3 were sham- Sensory-substitution is a device that attempts to substitute operated (SO) and the remaining 3 rats were left undisturbed one sensory modality (e.g., vision) by another (e.g., touch). and served as controls (C). Maternal resting levels of COR This field has practical implications as a mean to allevi- were maintained by addition to the drinking fluid (0.9% ate sensory deficits for populations, such as the blind and saline) of 25 μg/ml. On days 13–21 of gestation, 3 ADX and the deaf, who may be able to rely on an alternative sen- the 3 SO rats were stressed once daily by varied stressors. In sory modality to gain missing information about the out- order to replicate the elevation of plasma COR induced by side world. How does the brain learn to adopt and optimize stress, 3 ADX rats were injected s.c, once daily with COR a new sensory modality? Several fundamental questions in- (3 mg/kg). All the offspring were tested at the age of 60 days volve mapping of one sensory modality onto another: Is ac- for spatial memory deficits in the Morris water maze and for tive sensing crucial for a significant learning progress? What anxiogenic behavior in the plus maze (PM). are the dynamics involved? Which motor strategies are optimal and how they can be achieved? Addressing these ques- Results tions is valuable for understanding how the human brain represents the outside world through the senses. In the cur- Both male and female offspring of SO rats spent less time rent research, an adaptation of a novel sensory modality was than controls in the open arms of the PM. This increased investigated in normal human subjects. Adult human partic- anxiety was abolished by maternal ADX and restored by ipants were dressed with long elastic rods on their fingers, COR. Spatial learning of male offspring of SO rats showed mimicking rat’s whiskers. The participants were given 4 per- a clear learning deficit that was also abolished by maternal ceptual tasks: roughness estimation, poles localization in the ADX, but was not restored by COR. 96 Neural Plasticity

Conclusions expression of type I receptor in the hippocampus was significantly higher in females than in males, whereas no signifi- Maternal adrenal hormones mediate both the anxiety, seen cant difference was observed in the sexually mature animals. in the offspring of both sexes, and the learning deficits seen No sex dependent differences in expression were observed for only in males. Of these, COR appears to be responsible for the type II receptors. When we examined the expression pat- the anxiogenic behavior but not the learning deficits. terns of type I and type II in the cortex, hippocampus, cerebellum and striatum, we found that type I receptor predom- Is That Me in the Mirror? The neural correlates of inates in the hippocampus, while expression of VPAC1 was self recognition through movement more prominent in the cortex and VPAC2 in the striatum. In summary, our experiments confirm that type I and type Salomon R.,1 Malach R.,2 and Lamy D.1 II receptors are differentially expressed during postnatal development in various parts of the brain. High expression of 1Department of Psychology, Tel Aviv University, Israel ff 2 type I binding sites and its gender di erences in the devel- Department of Neurobiology, Weismann Institue of Science, oping hippocampus will contribute to our understanding of Israel the role of PAC1 receptor in normal brain development and function. The question of how people recognize themselves and separate themselves from the environment and others has in- An fMRI study of striatal activity during reinforcement trigued scientists for centuries. Currently the study of self learning in Parkinson’s Disease recognition is in the forefront of neuroscientific research. Re- cent findings have linked several regions of the brain corre- Schonberg T.,1 Daw N.,2 Inzelberg R.,3 O‘Doherty J.,4 sponding to the “default brain” or “intrinsic system” to self and Joel D.1 related processing. The current study used a fMRI paradigm in which subjects were asked to decide if a viewed movement 1Department of Psychology, Tel Aviv University, Tel Aviv, Israel belonged to them or another person based on minute syn- 2Center for Neural Science and Department of Psychology, chronization differences. The results show differential brain New York University, NY, USA activity in the self recognition condition in several ROIs of 3Rappaport Faculty of Medicine, Technion, Haifa, Israel the intrinsic system. The findings shed light on the neural 4Division of the Humanities and Social Sciences, Caltech, systems underlying bodily self recognition. Calif, USA 5Department of Psychology, Tel Aviv University, Tel Aviv, Israel This study was supported by the Levie-Edersheim-Gitter Insti- tute For Functional Brain Imaging. Dopamine serves a crucial role in classical and instrumental conditioning. Animal studies have shown that activity Gene expression profile of Pac1 and Vpac1/2 receptors of midbrain dopamine neurons can be described accurately in developing and adult rat brain by computational models of reinforcement learning, and specifically by the temporal difference model. Projections of Schneider J., Feder Y., Reichenstein M., and Pinhasov A. dopamine neurons have been suggested to provide the striatum information on the temporal difference error during re- Department of Molecular Biology, Ariel University Center, inforcement learning. Recent fMRI studies have used rein- Ariel, Israel forcement learning models to analyze neuroimaging data obtained in healthy subjects during learning, and have shown Pituitary Adenylate Cyclase Activating Polypeptide (PACAP) that this approach allows tracking putative activity of mid- is a Polypeptide (PACAP) is a multifunctional neuropeptide brain dopamine neurons in the striatum. Parkinson Disease that binds to two classes of GPCR receptors. Type I is known (PD) is known to involve depletion of midbrain dopamine as the PAC receptor and type II (VPAC1 and VPAC2) recep- neurons. As expected, this depletion has been shown to re- tors are known as VIP receptors. In this study, we have insult in deficiency to acquire tasks which depend upon investigated gene expression profiles of PAC1 isoforms (hop1, tact functioning of the dopamine system and the striatum hop2, hip, hip-hop1 and short are results of alternative splic- in particular. No imaging study so far, however, tested the ing in the third intracellular loop) and type II receptors in functionality of dopamine activity in the striatum of PD pa- the developing and aging rat brain. Gene expression studies tients using computational reinforcement learning models. were performed using Stratagene MxPro Real Time PCR ap- The aim of this project was therefore to study dopamine ac- paratus. Our data show that type I splice variants were highly tivity in the striatum of PD patients compared to healthy expressed in the rat brain of newborns with marked decrease controls using computational reinforcement learning models in expression during later stages of development. The mRNA and fMRI. Nine PD patients and 16 age matched healthy con- levels of VPAC2 receptor were significantly lower than that of trols were scanned while performing a reinforcement learn- type I receptors in newborns. Yet, during maturation there ing task. Subjects’ choice behavior and actual rewards ob- was significant upregulation of VPAC2 mRNA expression. tained during the task were analyzed using a temporal dif- VPAC1 mRNA was hardly expressed in newborns, but its lev- ference learning model. The output of the model includes els increased with age in a pattern similar to that observed a prediction error (PE) term which is the delta between ex- for VPAC2. During early stages of postnatal development the pected and actual outcome of a certain stimuli chosen by Israel Society for Neuroscience 97 the subjects. This PE regressor is then correlated with fMRI of birth and present hyperphagic characteristics early in life. brain activity. If dopamine activity is providing prediction In the present study, we used cross-fostering to assess the in- error to the striatum, and is the source of the correlation ob- fluence of the postnatal environment on short and long term served in healthy subjects between the striatal fMRI signal obesity and examined differences between the sexes. Body and the PE regressor, such a correlation should not be ob- weight was examined from birth every fifth day and intake af- served in PD patients. ter weaning was assessed daily. In the second lactating week, an independent ingestion test was performed. The pups were Molecular correlates of TTX-induced cell death sacrificed and blood plasma was collected for Leptin analysis at weaning or at postnatal day (PND) 90. Three differ- Schonfeld E., Fishbein I., Greenberger V., and Segal M. ent fat pads were collected and weighed. The estrous cycle of the females was monitored from PND 40 until PND75. Department of Neurobiology, The Weizmann Institute of The postnatal environment appeared to have a strong influ- Science, Israel ence on short term obesity. OLETF males and females raised by LETO dams were leaner than controls, with normalized Spontaneous neuronal network activity is an essential at- (to LETO controls) fat levels. LETO pups raised by OLETF tribute of the nervous system. Such activity is also found in dams were only slightly heavier than LETO controls, but with primary neuronal cultures, which we used to investigate the significantly higher fat percentages. Interestingly, in the in- possible contribution of network activity to neuronal sur- dependent ingestion test, the genotype of the pups instead vival. We have previously demonstrated that when chroni- of their phenotype determined intake: OLETF pups overate cally silenced by tetrodotoxin (TTX), cultured cortical neu- even when their body weight was normal. On the other hand, rons undergo a process of progressive cell death over a period LETO pups ate as controls regardless of their body weight of up to two weeks. In addition we found that the remaining or fat percentages. After weaning, even though they became miniature excitatory synaptic currents (mEPSCs) have a cru- overweight, OLETF males remained leaner than controls un- cial role in the induction of this neuronal death, pointing to til the end of the experiment. OLETF females managed to a cellular inability to cope with otherwise nontoxic calcium recover all the fat and weight. LETO rats returned to their inward currents. In the current study we set to investigate lean genotypical profile. Furthermore, the structure of the the molecular mechanisms responsible for this TTX induced estrouscyclewasaffected by the postnatal environment. In neuronal degeneration. The relatively slow rate of neuronal sum, there is a gender effect: Males can be successfully biased degeneration and the absence of necrotic features such as to a more “lean” adulthood, while females, though affected, cell swelling and membrane rupture, made apoptosis a major manage to show an almost complete recovery. candidate for the observed neurodegeneration. We therefore ff tested TTX treated neurons for the expression of di erent Supported by NIH/NIDDK R01DK057609-06A1. apoptotic markers. While some classical apoptotic features such as positive TUNEL staining, mitochondria fission and Repeated cocaine exposure induces long term the enhanced transcription of proapoptotic genes were in- alterations in NMDAR subunits in the nucleus deed present, neither caspase 3 activation nor DNA ladder- accumbens (NAc) ing were evident. As to the upstream death signal, we found the calcium sensitive enzyme calpain to be involved, since its Schumann J. and Yaka R. blockade by its endogenous blocker calpastatin significantly reduced neuronal death triggered by TTX. This result con- Department of Pharmacology, School of Pharmacy, curred with our original hypothesis regarding the involve- The Hebrew University of Jerusalem, Israel ment of calcium in the apoptotic process. In summary, TTX Cocaine-induced modifications of glutamatergic synaptic induced neuronal death appears to be a caspase-independent transmission in the brain reward system play a key role form of programmed cell death that shares at least part of the in adaptations that promote addictive behaviors. In par- apoptotic pathway. ticular, the activation of ionotrophic glutamate N-Methyl- D-Aspartate receptor (NMDAR) in the VTA is critical for Gender differences in coping with “lean” and “obese” the initiation of cocaine sensitization. However, the role of postnatal environments in a rat model of obesity NMDARs in the NAc, the brain region that mediates the Schroeder M.,1,2 Shbiro L.,3,2 Moran T. H.,4 expression of sensitization, remains to be explored. Using and Weller A.3,2 locomotor-sensitization as a behavioral paradigm, we found that repeated cocaine injections resulted in an increase in 1Faculty of Life Sciences, Israel NR1, NR2A and NR2B subunits of the NMDAR in the NAc, 2Gonda Brain Research Center, Bar Ilan University, Israel 21 days after the last cocaine injection. However, no change 3Psychology Department, Bar Ilan University, Israel in these subunits was found one day following the last co- 4Department of Psychiatry and Behavioral Sciences, Johns caine injection. These changes were associated with an in- Hopkins University School of Medicine, Israel crease in the GluR1 subunit of the AMPA receptor. Inter- estingly, we found an increase in ERK activity which corre- OLETF rats are a model of hyperphagia-induced obesity. lated with the increase in NMDAR subunits 21 days following OLETF pups are heavier than their LETO controls at the time cessation of cocaine injections. Taken together these results 98 Neural Plasticity suggest that the NMDAR system, through activation of ERK Backround signaling, is part of the long term neuroadaptations that results in the expression of cocaine sensitization. Understand- The International Headache Society defined trigeminal neu- ing the mechanisms that underlie the alterations of NMDAR ralgia as unilateral disorder characterized by paroxysmal sud- activity following repeated cocaine exposure, will enable us den, intense attacks of facial or frontal pain that last for a few to identify targets for the design of therapeutic agents in seconds and is limited to the distribution along one or more brain areas that mediate not only the development of cocaine divisions of the trigeminal nerve. Important in the history addiction, but also addiction to other drugs of abuse. of medical treatment and today still, gold standard’ was the successful treatment with carbamazepine in 1962. Pregabalin Supported by grant from the Israel Science Foundation (ISF). has shown good results in the treatment of neuropathic pain associated with postherpetic neuralgia and diabetic periph- Population code for moving target in eral neuropathy. The aim of this observational study was con- the archer fish retina sidering the possible benefits of pregabalin in the treatment of trigeminal neuralgia. Methods: We investigated 53 patients Segev R. suffering from classical, chronic and symptomatic trigeminal neuralgia. They have been treated with pregabalin tittraded Department of Life Sciences, Ben Gurion University of from 75 mg to 600 mg daily. Over a period of one year they the Negev, Israel were prospectively followed and every patient was asked to fill out a standardized individual pain diary. Archer fishes (Toxotes jaculatrix) are famed for their ability to shoot down insects resting on foliage above water using Results a jet of water from their mouth. To get a good jet of water, the snout sticks out of the water while the rest of the fish After a period of 8 weeks 24.5 percent of patients experi- remains underwater. They direct the jet of water by pressing enced complete pain relief remaining over the whole year of their tongue against a groove in their mouth while forcing the observation. The majority of patients (49,1 percent) showed gills’ covers inwards. After the prey is dislodged from its posi- a remarkable pain reduction and reduction of attack fre- tion, several archerfish compete for the falling prey by rapidly quency. Under 50 percent pain reduction under treatment predicting the point where the insect will later land at the only with pregabalin was observed by 26.4 percent. 4.8 per- water surface. Each fish can initiate a single turn to point its cent terminated the treatment. Conclusion: In this prospec- body towards the position where the prey will later land. This tive clinical trial pregabalin has proven to be effective con- turn occurs within 120–150 ms after the prey is dislodged. An cerning the relief and reduction of pain as well as the reduc- open question is how the retina encodes visual information tion of attack frequency. The positive effect of pregabalin on in order for the fish to achieve rapid reaction to prey land- patients suffering from trigeminal neuralgia is comparable to ing. This extreme behavior of the archer fish is interesting to other anticonvulsant drugs reported for carbamazepine and study and may serve as an important test case for our under- gabapentin. Of importance are pharmacological characteris- standing of population neural codes of the retina. In order tics of pregabalin. Pregabalin has shown less side effects, has to predict the target landing position, the archer fish retina the advantage of a rapid titration potential, fast pain reduc- needs to transmit information to the brain about target po- tion and it is easy to use by its administrations twice a day. sition, speed and direction of flight. One possibility for such information transmission from the retina is by specialized di- Effects of weanling stress and acute pre-mating shock rection and speed selective ganglion cell. Another possibility on affect in progeny in rats is integration of information from several ganglion cells by the fish brain to estimate the target’s initial trajectory. Us- Shachar-Dadon A.,1 Even B.,1 Maroun C.,1 Galon I.,1 ing a 256 multielectrode array to record from the archerfish Schulkin J.,2 and Leshem1 retina we study how visual information critical for detection of target trajectory is encoded in the ganglion cell spikes. 1Department of Psychology, University of Haifa, Israel 2Department of Physiology and Biophysics and This work was supported by The Center for Complexity Science, Neuroscience, Georgetown University, DC, USA Rich Foundation and Zlotowski Center. Pregestational adversity impacts offspring affective behavior Pregabalin in the treatment of trigeminal neuralgia: (Shachar-Dadon et al., 2006). Here, as a model of the possible ff a prospective open-label clinical trial e ect of childhood abuse to a mother, we examined whether 3 days of varied, unpredictable, stress to a weanling female Sensen K.,1 Obermann M.,1 Yoon M.,1 Maschke M.,1,2 rat would impact its future progeny. Stress protocol was PN Diener H.,1 and Katsarava Z.1 27:10 minutes swim, room temperature. PN 28:3 × 0.5hours raised platform, 1-hour intervals. PN 29: shock 6×0.8 mA/1s, 1Department of Neurology, University of Duisburg-Essen, 0.5 min intervals. In another group, we modeled the possi- Essen, Germany ble effects of rape on the offspring by shocking female rats 2Department of Neurology and Neurophysiology, immediately before mating (6 × 2 mA/2s, 1-minute inter- Bruederkrankenhaus Trier, Germany vals). Conception rates of weanling stressed females were Israel Society for Neuroscience 99 very low (3/9), but shock before mating did not affect con- val66met and sex. Tests of within-subjects effects showed a ception rates. One-hundred-and-seventy-one offspring were significant three way interaction (SPSS GLM; Time x BDNF x evaluated. Birth-weight of offspring of childhood stressed sex: P = .018). In male subjects val/val homozygotes showed dams was 10% lower (P<.001). However, offspring of fe- a greater rise in salivary cortisol than val/met heterozygotes males that underwent weanling stress or acute shocks be- whereas in female subjects the opposite was observed. Tests fore mating were 6% heavier at weaning (P<.001). Per- of between subjects affects showed a significant BDNF x sex formance in shuttle avoidance, and activity in the open field, interaction (P = .040). This is the first report showing as- were not altered by either preconception stress model. Child- sociation between the BDNF val66met polymorphism and hood stress to the mother marginally decreased anxiety in el- quitting smoking. The val allele is preferentially transmit- evated maze, but acute preconception shocks had little effect. ted to female ex-smokers. Moreover, val/val female ex- and In contrast, acoustic startle response was doubled in males never smokers show blunted salivary cortisol responses to of both experimental groups. These initial findings suggest the TSST suggesting that the effect of BDNF on smoking that adversity to a female, even before sexual maturity, as in cessation is partially mediated by modulation of HPA-axis childhood abuse, may affect her fertility, and in her future responsivity. progeny, birth-weight and aspects of their behavior, depending upon their gender. Our findings also suggest that trauma, Absent minded but accurate: proximate to conception as in rape, may alter offspring delaying responses increases accuracy behavior. but decreases error awareness

Supported by the BSF to ML and JS. Shalgi S.,1 O‘Connell R. G.,2 Deouell L. Y.,3 and Robertson I. H.1 The role of BDNF Val66Met and stress response in smoking cessation in young women 1Department of Cognitive Science, The Hebrew University of Jerusalem, Israel Shalev I.,1 Meron Y.,1 Laibe G.,2 Lerer E.,2 Laiba E.,2 2Institute of Neuroscience (TCIN) and School of Psychology, Raz Y.,1 Israel S.,3 Bachner-Melman R.,3 Uzefovsky F.,3 Trinity College, Dublin 2, Ireland Dina C.,4 Kaitz M.,3 and Ebstein R. P.3,5 3Department of Psychology and the Interdisciplinary Center, The Hebrew University of Jerusalem, Israel 1Brain and Behavior Science, Hebrew University, Jerusalem, Israel Previous work has suggested that conscious error aware- 2Human Genetics, Hebrew University, ness may fluctuate with levels of attention. Here, we ex- Jerusalem, Israel plore this relationship by showing that error awareness can 3Psychology Department, Hebrew University, be impaired when exogenous support to attentional sys- Jerusalem, Israel tems is reduced by decreasing task demands. Twenty partic- 4CNRS 8090-Institute of Biology, Pasteur Institute, ipants performed a manual Go/No-Go response-inhibition Lille, France task optimized to examine error awareness. In one con- 5S. Herzog Memorial Hospital, Jerusalem, Israel dition (Immediate), participants were asked to respond as quickly and as accurately as possible to each Go stimulus, Attempts to prevent young people from initiating smoking and in the other condition (delayed) they were asked to time have been notably unsuccessful suggesting that focusing on their responses to the offset of the stimulus, thereby de- the underlying genetic and psychosocial factors in encourag- creasing task difficulty and imposing a more automated re- ing smoking cessation is an important public health strategy. sponse set. As expected, speeding increased the error rate. Towards this end, we investigated the role of the val66met However, contrary to the expectation (and to participants’ BDNF polymorphism in contributing to “kicking the habit” subjective reports), that speeding would impair awareness in a group of young smokers. Since psychological stress is hy- of performance, we found the opposite to be true–errors pothesized to be a principal component in initiating, main- were more likely to be unnoticed when the task was easier. taining and cessation of smoking the effect of val66met on We suggest that this tradeoff reflects two qualitatively differ- salivary cortisol responses in a laboratory stress test was ex- ent types of errors arising from the different cognitive de- plored. Three young groups (<35 years) were genotyped for mands of the Immediate and Delayed conditions. We pro- the val66met polymorphism: 275 ex-smokers (1 year absti- pose that unaware errors reflect pure lapses of sustained at- nent), 233 current smokers and 1017 never smokers. 57 sub- tention and are therefore more susceptible to changes in task jects (never and ex-smokers) were also examined in the Trier demands, while aware errors mostly reflect failures to in- Social Stress Test (TSST). Significant association was ob- hibit responses, and are therefore most susceptible to in- served between BDNF and the ex-smoking phenotype (UN- creased response speed. This finding is important because PHASED; global P value = .00086). The val allele was sig- it identifies the conditions under which error awareness can nificantly overtransmitted from a heterozygote parent to fe- be maximally challenged, which is especially useful for ERP male ex-smokers and not to male ex-smokers. There was and fMRI experiments which require a significant num- no association between BDNF and current smoking status. ber of aware and unaware errors for comparison between Changes in salivary cortisol in the TSST were modulated by them. 100 Neural Plasticity

Translocator Protein ligands attenuate have run a series of experiments on human participants in- the mitochondrial membrane collapse normally vestigating to what extent it affects our behavior and whether induced by the antineoplastic agent ongoing activity expresses the brain’s internal context: what Erucylphosphohomocholine information it contains and what cortical regions represent it. For assessing the effect of prior information on perfor- 1 1 1 2 Shandalov Y., Veenman L., Leschiner S., Kugler W., mance we have developed a behavioral paradigm in which 2 1 Lakomek M., and Gavish M. an orientation cue informs participants about subsequent 1Faculty of Medicine, Technion-Israel Institute of Technology, target shape. We used a spatial 2-alternative-forced-choice 31096 Haifa, Israel contrast discrimination task, while pre-cueing target orien- 2Padiatrie¨ I, Universitatsklinikum¨ Gottingen,¨ tation (cued condition) or not (un-cued condition) for ma- Gottingen,¨ Germany nipulating expectation on the orientation domain. During the performance of the psychophysical task, EEG activity was Malignant gliomas are the most common brain tumors, recorded from the entire skull (64 electrodes) simultaneously which in most instances are resistant to radiation and with high resolution recording of eye movements. We found chemotherapy and therefore remain largely incurable. The a significant effect of pre-cueing target orientation on detect- novel chemotherapeutic drug, Erucylphosphohomocholine ing target location, providing positive evidence for the debat- (ErPC3) has shown potent antineoplastic activity on variable effects of attention to stimulus features on task perfor- ous malignant tumor cell lines. ErPC3 activates the mito- mance. Preliminary analysis shows that this behavioral effect chondrial apoptosis pathway. The mitochondrial apoptosis was accompanied by reduced ocular activity before and dur- pathway is triggered by opening of the mitochondrial per- ing target onset. On the brain activity level (EEG), we are meability transition pore (MPTP). By genetic manipulation, currently examining the manifestation of these interactions we found previously that the MPTP associated Translocator on the correlations between the single-trial pre-stimulus (on- Protein (TSPO) is needed for apoptosis induction by ErPC3. going) activity and the participant’s prediction of target ori- Presently, we study ErPC3 induced apoptosis levels in the entation (cue versus un-cued conditions), as well as on task- glioma cell lines, U118MG, A172 and U87MG: (1) by us- related cortical dynamics in related areas. ing the cell death detection ELISAplus kit of Roche, and (2) by Fluorescence Assisted Cell Sorting (FACS) determining This work was supported by the German Federal Ministry of the percentage of cells in the pre-G1 phase of the cell cycle. Education and Research, Israeli Ministry of Science and Tech- We found, for example, that the classical TSPO ligand, PK nology Foundation. 11195 (25 uM), reduces the levels of apoptosis triggered by ErPC3 in the U118MG glioma cells by 80%. We also show The Ectosylvian Sulcal Audiotory Field (FAES) and by viability experiments using Propidium Iodide that PK Localization of Sounds 11195 reduces the percentage of dead cells after ErPC3 treat- Shapira A.,1 Jacobson G.,1 and Nelken I.1,2 ment, e.g., PK 11195 (25 uM) reduces the proportion of dead U118MG cells by 75%. Using the dye JC-1, we found that PK 1Neurobiology Department, Life Science Institute, 11195 attenuates ErPC3 induced opening of the MPTP in the Hebrew University of Jerusalem, Israel U118MG, A172 and U87MG glioma cell lines. For example, 2Interdisciplinary Center for Neural Computation, PK 11195 (25 uM) causes a 57% reduction in the number of Hebrew University, Israel U118MG cells displaying opening of the MPTP. Thus, it appears that ErPC3 reduces viability of cancer cells via opening Both the primary auditory cortex (A1) and Anterior Ectosyl- of the MPTP leading to cell death, including apoptosis. Fur- vian Sulcal Auditory Field (FAES) are believed to be involved thermore, it appears that the TSPO ligand PK 11195 can pre- in localization of sound. In both fields, neurons have been vent antineoplastic effects of ErPC3 by preventing the open- found to be sensitive to the direction of sound sources. Fur- ing of the MPTP and cell death, including apoptosis. These thermore, FAES is known to project heavily to the deep layers data provide further evidence that the TSPO can be targeted of the superior colliculus. We have recently shown that the for novel approaches to treat cancer. posterior part of AES has special response properties, with an over-representation of frontal space relative to A1 and the Research support: WK, LV, ML, and MG (Joint Lower Saxony- anterior part of AES. We examined the selectivity of a sin- Israeli Research Projects, VWZN2047). gle unit to azimuth and elevation in the FAES (aAES and pAES) and compared it to neural responses in A1. We used The effects of stimulus expectation on perception and virtual space stimuli consisting of short noise bursts (100 ms) the dynamics of cortical activity filtered through head-related transfer functions covering the frontal region (from −75 to 75 degrees in azimuth, −60 to Shani-Hershkovich R. and Arieli A. 30 degrees in elevation). In order to find the physical cues to The Weizmann Institute of Science, Rehovot, Israel which the neurons were sensitive, we tested the same neurons with modified stimuli in which some of the physical cues The notion that context influences perception and behavior were changed (spectral notches, interaural time differences, is not new. Yet, there is little knowledge about the princi- interaural level differences). Spatial sensitivity was quanti- ples and the actual details of this process. In this study we fied by the mutual information (MI) between stimuli and Israel Society for Neuroscience 101 responses. The overall selectivity to spatial location was sim- 1Psychology Department, Israel ilar in A1, posterior AES and anterior AES. Single neurons 2Gonda Brain Research Center, Bar Ilan University, Israel showed sensitivity to all three physical cues. However, at the 3Faculty of Life Sciences, Bar Ilan University, Israel population level, modifying any of the physical parameters 4Department of Psychiatry and Behavioral Sciences, Johns resulted in significant reduction in the sensitivity to azimuth Hopkins University School of Medicine, Md, USA of neurons in pAES, but not in aAES nor in A1, and a significant reduction in the sensitivity to elevation in both pAES The OLETF rat has been extensively studied as a model of and aAES but not in A1. We conclude that integration mech- hyperphagia-induced obesity. OLETF pups are heavier than anisms underlying spatial sensitivity in pAES are different their LETO controls at the time of birth and they present hy- from aAES and A1: azimuth sensitivity in pAES is not due perphagic characteristics in independent ingestion and nurs- to interaural level differences only, but is shaped in addition ing tests throughout lactation. In the present study, we used by the direction-dependent spectral cues. the cross-fostering strategy to assess the influence of the pups’ genotype on the dams’ obesity levels at the time of Towards a characterization of natural sounds weaning. The aim was to attain a better understanding of the interaction between the dams and the pups and how this in- 1 1,2 Shayevitz O. and Nelken E. fluences their tendency towards obesity. Body weight of the 1Department of Neurobiology, Institute of Life Sciences, dam was examined every fifth day and her intake was assessed The Hebrew University of Jerusalem, Israel daily. At the end of the third postnatal week, a nursing test 2 was performed. At the time of weaning the dams were sac- Interdisciplinary Center for Neural Computation, ff The Hebrew University of Jerusalem, Israel rificed and blood plasma and three di erent fat pads were collected and weighed. LETO dams appeared not to be influ- It is often assumed that the auditory system is adapted, enced by the strain of the pups, and presented similar physio- through both evolutionary and developmental processes, to logical parameters at the time of weaning, when raising pups the statistics of the sounds to which it is exposed. However, of both strains. In contrast, OLETF females were strongly in- actual examples of auditory adaptation to the structure of fluenced by the strain of the pups: raising genetically “lean” natural sounds are rare. In a groundbreaking study, Aertsen offspring induced them to accumulate even greater amounts and collaborators (1979) coined the term “acoustic biotope” of fat, and to present increased body weight and Leptin lev- and studied neural responses to a small set of representative els at the time of weaning, even though their intake was natural sounds. Yet, while natural sounds are obviously only the same as controls. In the nursing test, both OLETF and a small subset of all possible sounds, there is no statistical LETO dams nursed for similar durations when raising pups characterization of this set among all sounds. A parametric from the opposite strain. This nursing length was signifi- representation of natural sounds could be used to guide ex- cantly longer than that observed in the LETO control strain, periments that appropriately sample the space of all sounds, but significantly lower than the time usually observed in the thus exploring the nature of the neural responses to relevant OLETF strain. Taken together, the results suggest a strong sounds. Furthermore, better understanding of the structure influence of the offspring’s characteristics on maternal be- of natural sounds could reveal the underlying evolutionary havior and the dam’s physiological adaptation to lactation. reasons for perceptual phenomena such as auditory mask- Obese OLETF dams appear more susceptible than controls ing, temporal integration, and auditory pattern recognition. to this influence. For example, Nelken et al. (1999) analyzed a large set of natural sounds and suggested that comodulation masking release Supported by NIH/NIDDK R01DK057609-06A1. is an adaptation of the auditory system to natural statistics. We explored the structure of natural sounds using dimen- Identification of neuroprotective pathways in brain sionality reduction methods. By resynthesizing sounds from trauma using heat acclimation preconditioning reduced representations, we evaluated the importance of the 1,2 2 1 ignored dimensions. Principal component analysis of spec- Shein N. A., Horowitz M., and Shohami E. trograms showed that spectro-temporal structure could be 1Department of Pharmacology, The Hebrew University, substantially reduced (to about 6 components) without af- Jerusalem, Israel fecting the naturalness of the sounds. On the other hand, the 2Department of Physiology, The Hebrew University, phases had to be represented relatively faithfully in order to Jerusalem, Israel avoid serious distortions. We explored parametric representations of phases using linear regression and reduced encod- The development of therapeutic strategies in traumatic brain ing of the regression errors. injury (TBI) is hampered by insufficient understanding of pathological and protective roles played by discrete molec- Maternal obesity levels at the time of ular processes. Experimental induction of protective path- weaning are influenced by the strain of the pups: ways is therefore a powerful research model, possibly con- insights from a cross-fostering study in tributing to future drug design and testing. In our ongo- the OLETF rat model of obesity ing work, endogenous protective pathways were induced Shbiro L.,1,2 Schroeder M.,3,2 Moran T. H.,4 in a mouse model of closed head injury (CHI) by us- and Weller A.1,2 ing long-term heat-acclimation (HA, 30 days at 34 ± 1◦C), 102 Neural Plasticity a physiological model which is capable of facilitating protec- and postsynaptic depolarization resulted in a transient (30– tion against various stressors including TBI. The benefits of 50 seconds) decrease in sIPSC frequency and amplitude. Ap- HA on motor and cognitive functions, neurodegeneration plication of DHPG alone had no effect on sIPSCs. The and brain edema were initially established. Subsequently, depolarization/DHPG-induced STD was blocked by the CB1 multiple pathways suggested as being pivotal in either HA antagonist SR141716A and the mGluR5 antagonist MPEP, or neuroprotection (NP) were studied in an effort to inves- and was sensitive to intracellular calcium concentration. The tigate their involvement in endogenous NP following CHI. observed STD was not related to depletion of the readily- HA-induced NP was associated with a network of concerted releasable pool of neurotransmitter, probed with high su- changes consisting of absolute and dynamic alterations of crose challenges. Comparing the present findings with ear- factors and processes. These included augmented pre-injury lier works in hippocampal slices and BLA, it appears that en- levels of hypoxia-inducible factor-1, erythropoietin recep- docannabinoid release is less robust in isolated hippocampal tor, brain-derived neuroptrophic factor (BDNF) and anti- neurons. inflammatory cytokines, all of which are well-established as being neuroprotective. Pre-injury changes were comple- MRI detects in vivo migration of rat’s bone marrow mented by modified post-injury dynamic responses harbor- derived mesechymal stem cells towards quinolinic ing sustained post-injury hypothermia, reduced expression acid lesion of pro-inflammatory cytokines and selective enhancement of Shemesh N.,1 Sadan O.,2 Offen D.,2 Melamed E.,2 BDNF-positive microglia after injury. When combined with and Cohen Y.1 selective pharmacological manipulation, the use of the HA- 1Department of Chemistry, Faculty of Exact Sciences, CHI model enabled us to determine the necessity of Akt Tel Aviv Univeristy, Israel phosphorylation for NP,bringing to light the potential thera- 2Laboratory of Neurosciences, FMRC, Rabin Medical Center, peutic value of this pathway. Taken together, the findings sub- Sackler School of Medicine, Tel Aviv University, Israel stantiate the use of this paradigm for the study of endogenous protection, providing valuable insight which can conceivably MRI is the most important imaging method in studying mi- be utilized for development of treatment interventions in a crostructures and functions of normal and diseased CNS. physiological-mimetic manner. Huntington’s disease (HD) is a hereditary neurodegenerative disease, manifested mainly by a cognitive decline and hyper- Endocannabinoid- and mGluR5-dependent short-term kinetic movement disorder. The hallmarks of the condition synaptic depression in an isolated neuron/bouton include striatal neurodegeneration. Quinolinic acid (QA) in- preparation from the hippocampal CA1 region jection to the mid-striatum unilaterally causes a slowly pro-

1,2 1 gressing excitotoxic lesion which resembles the neurodegen- Sheinin A. and Lovinger D. M. eration in HD (1). Stem cells have been proposed as a pos- 1National Institute on Alcoholism and Alcohol Abuse, sible treatment to neurodegenerative disorders. However, a National Institutes of Health, Md, USA major setback post-implantation is proving the viability of ffi 2Department of Neurobiochemistry, George W. Wise School the implanted cells. It is di cult to delineate these cells from of Life Sciences, Tel-Aviv University, Israel normal brain tissue noninvasively. In this study, we labeled mesenchymal stem cells (MSC) post differentiation to neu- Endocannabinoids released from the postsynaptic neurotrophic factors producing cells with superparamagnetic ronal membrane can activate the presynaptic CB1 recep- iron oxide (SPIO) particles, and transplanted them posterior tors and inhibit neurotransmitter release. In hippocampal to the QA lesion. We were able to detect the migration of the slices, depolarization of the CA1 pyramidal neurons elic- SPIO labeled cells towards the lesion over a period of sev- its an endocannabinoid-mediated inhibition of GABA re- eral weeks. The MRI images clearly show the accumulation lease known as depolarization-induced suppression of inhi- of SPIO in the lesion and mainly on its borders. Moreover, bition (DSI). Utilizing the highly reduced postsynaptic neu- one animal that had a cortical damage showed accumula- ron/synaptic bouton preparation from CA1 region of hip- tion of the SPIO in the cortex, implying that the cells can pocampus, we have begun to examine endocannabinoid- react to chemotactic signals derived from the lesion site, and dependent short-term depression (STD) of inhibitory synap- find the paths to migrate towards it. Control animals were tic transmission under well-controlled physiological and injected with SPIO particles alone, and exhibited no accu- pharmacological conditions in an environment free of other mulation and no path of migration. Post-mortem histologic cells. Application of the CB1 synthetic agonist WIN55212- evaluation demonstrated that the distribution of the cells was 2 and endogenous cannabinoid 2-AG produced a decrease comparable to the MRI images. These findings prove that in in sIPSC frequency and amplitude, indicating the pres- this experimental model of HD, the cells are viable, and that ence of CB1 receptors at synapses in this preparation. MRI can be used as a platform to detect the paths of migra- Endocannabinoid-dependent STD is different from DSI tion. This gives hope to future research on these cells, chiefly found in hippocampal slices and the neuron/bouton prepa- on their pharmaceutical capacity ([1]). ration from basolateral amygdala (BLA) since depolarization alone was not sufficient to induce suppression of spon- References taneous inhibitory postsynaptic currents (sIPSCs). How- [1] R. Schwarcz, W. O. Whetsell, R. M. Mangano, Science, 219, pp. ever, concurrent application of the mGluR agonist DHPG 316–318, 1983. Israel Society for Neuroscience 103

Tau-induced microtubules polarity reorientation leads identifying their cortical locations and patterns of activation. to axonal trafﬁc jams and neurodegeneration Stimuli were either verbs that select prepositional-phrases (PP) or noun phrases (NP), but not sentential complement Shemesh O. A.,1 Erez H.,1 Ginzburg I.,2 and Spira M. E.1 (CP; e.g., taste from.../the...), or verbs that select PP or

1 CP,butnotNP(e.g.,complainabout.../that...).Forsyntac- Department of Neurobiology, Institute of Life Science, tic differences, we compared sentences containing syntacti- The Hebrew University, Jerusalem, Israel 2 cally complex complements (CP) with sentences containing Department of Neurobiology, Weizmann Institute of syntactically simpler complements (NP). For lexical differ- Science, Rehovot, Israel ences, PP-complements were used, allowing comparison of syntactically identical structures, but differential lexical in- At the forefront of tauopathies research are the attempts to formation. Nineteen Hebrew speakers performed a seman- understand the molecular and cellular cascades that lead to tic decision task on auditorily presented sentences. Com- the pathologies, in particular Alzheimer’s disease (AD). It is paring CP-complements with NP-complements resulted in generally accepted that the cascade generated by tau overex- clear activations in several areas, including left-IFG (Broca’s pression culminates in impaired organelle transport leading area), bilateral STG (Wernicke’s area), MTG and SMG, as to neurodegeneration. Several mechanisms have been pro- well as medial precuneus. Comparing sentences including posed to link tau overexpression and impaired axoplasmic CP-verbs with PP-complements and sentences including NP- transport. Nevertheless, the underlying mechanisms are not verbs with PP-complements (CP-verbs > NP-verbs) revealed clear. Here we developed a novel cellular platform and used activations only in bilateral MTG and medial precuneus. confocal microscope imaging to address the above questions. The reverse comparisons yielded no activations. The re- For the study, we overexpressed human wild-type tau or sults regarding the lexical activations can be attributed to ei- double mutant tau (containing both mutations K257T and ther lexical-syntactic differences between the sentences, or to P301S) fused with cerulean. In order to label polymerizing lexical-semantic differences between the verbs. However, the microtubules we expressed the plus end microtubule track- extensive network of areas identified in the syntactic comparing protein EB3-GFP. For imaging of anterograde and ret- ison can clearly be attributed to the syntactic processing of rograde transport we imaged cherry-SNAP-25 and the fluid embedding, in this case CP-complements of verbs. This indi- phase endocytotic marker–sulphorhodamin 101 respectively, cates that complex syntactic structure load on many cortical and for imaging of mitochondria we used the mitotracker resources. –RPAC. Overexpression of cerulean-tau generates three abnormal phenotypes characterized by (1) transient appear- This study was supported by The Levie-Edersheim-Gitter Insti- ance of MicroTubules-Array (MTA) in the axon. The MTA tute For Functional Brain Imaging. locally disrupted the axonal transport and spontaneously dis- appeared within 48–72 hours; (2) reversal of the polar orien- Viewpoint dependent representation of tation of a significant fraction of the MTs. This led to massive observed actions mitochondria and vesicular “traffic jam;” (3) the accumulation of tau and MTs at the submembranal domain, concomi- Shmuelof L.,1 Hertz U.,2 and Zohary E.1,2 tant with condensation of organelles within the axon core followed by neurodegeneration. As in other model systems, 1Neurobiology Department, Hebrew University, the pathological effects of the mutant form of human tau Jerusalem, Israel were more prominent than its wild type form, indicating our 2Interdisciplinary Center for Neural Computation, model system may be suitable for the study of tauopathies.To Hebrew University, Jerusalem, Israel conclude, we unraveled a new mechanism that underlies the aberrant transport characteristic of tau overexpressing neu- The anterior intraparietal cortex (aIPS) is known to be in- rons, namely, the reorientation of MTs polarity and their dis- volved in visually guided grasping. Recently, we have shown placement. that this area is also active when we observe grasping movements. Here we investigate to what extent the performance in an imitation task and the aIPS activation is dependent on the Syntactic processing and lexical retrieval during viewpoint of the observer. Ten subjects observed video clips sentence comprehension: an fMRI study of right or left hands making grasping movements. Impor- Shetreet E.,1 Friedmann N.,2 and Hadar U.1 tantly, in one set of clips the hands were shown from an egocentric point of view (as if the observer is the actor), while 1Department of Psychology, Tel Aviv University, Israel in the other set the clips were shown from an allocentric 2School of Education, Language and Brain Laboratory, point of view (as if the actions are made by an actor facing Tel Aviv University, Israel the subject). The results confirm our previous findings that in the egocentric point of view, the fMRI activation in the The construction of grammatical sentences relies on syntac- aIPS is contralateral to the observed hand (i.e., the right aIPS tic rules, as well as on lexical information associated with the was significantly more active during observation of left hand verb in the sentence. This fMRI study explored the retrieval clips than right hand clips. In the left aIPS, the preference was of verb-dependant lexical information and the processing the opposite). Interestingly, for an allocentric point of view, of syntactic structures during sentence comprehension, by the representation is ipsilateral. Subsequently, we looked for 104 Neural Plasticity a behavioral correlates for this phenomenon: Subjects ob- Visual deprivation for a short (e.g., 90 minutes), medium served sequences of finger tapping movements made by the (e.g., 5 days) or long (e.g., blindness) duration increases the right or left hand from an egocentric or allocentric point of neural response to, and behavioural accuracy with, a tac- view and had to imitate them with their right hand. Imitation tile target. At the same time, simply closing the eyes can of the right egocentric and left allocentric clips was signifi- affect the cortical representation of a tactile stimulus. Us- cantly faster than imitation of the left egocentric and right al- ing a novel active tactile search task, we explored the effect locentricly aligned clips, respectively. To summarize: actions of closing the eyes in a completely dark room. Matching of seen from an egocentric point of view elicit greater activa- mechanical nuts and bolts was both faster and more effi- tion in the contralateral aIPS, and consistently, faster imita- cient when the eyes were closed compared to when they were tions with the observed hand. Actions seen from an allocen- open, despite equal amounts of visual information. Thus, tric view point (as performed by someone else) elicit greater the simple act of closing the eyes can modulate behavioural ipsilateral aIPS activation and faster imitation of the opposite performance, and presumably the underlying neural pro- hand. The results suggest that simulation of observed actions cessing. These transient changes in connectivity may rep- is affected by the field of interaction between the action of resent the starting point for the more substantial changes the actor and the viewer’s mental simulation. involved in the visuotactile plasticity seen with longer deprivation. Serotonin is a neuromodulator of short- and long term synaptic plasticity in the octopus vertical lobe SupportedbytheNaturalScienceandEngineeringCouncilof Canada. Shomrat T.,1 Feinstein N.,1 Klein M.,2 and Hochner B.1 Hemispace- rather than hemisphere-superiority 1Department of Neurobiology, Institute of Life Sciences and as the basis for visuospatial attention asymmetry: the ICNC, Hebrew University, Jerusalem, Israel new insights from fMRI 2Department of Physiological Science, UCLA; Los Angeles, Calif, USA Siman-Tov T.,1 Mendelssohn A.,1 Schonberg T.,1 Avidan G.,1,2 Pessoa L.,3,4 Gadoth N.,5 Ungerleide L.,3 Comparative analysis of brain function in invertebrates with Podlipsky I.,1 and Hendler T.1,5 sophisticated behaviors, such as the octopus, may advance our understanding of the evolution of the neural pro- 1Functional Brain Imaging Unit, Wohl Institute for Advanced cesses that mediate complex behaviors. In a previous study Imaging, Tel Aviv Sourasky Medical Center, Israel (Hochner et al., 2003) we discovered a hippocampal-like LTP 2Department of Behavioral Sciences, Ben Gurion University in the octopus vertical lobe (VL), an area of the octopus brain of the Negev, Beer Sheva, Israel involved in learning and memory. Here we studied whether 3Laboratory of Brain and Cognition, National Institute of the well known mechanisms of molluscan 5HT-dependent Mental Health, Bethesda, Md, USA synaptic plasticity are conserved in the octopus VL system. 4Department of Psychological and Brain Sciences, We found that as in other mollusks, and in contrast to ver- Bloomington, Ind, USA ff tebrates, 5HT has a facilitatory e ect on synaptic transmis- 5Sackler Faculty of Medicine, Tel-Aviv University, Israel sion, albeit at about one order of magnitude higher concentrations (e.g., 100 versus 10 μM in Aplysia). In contrast to Neurologists have long noted the asymmetry of hemispa- Aplysia sensory-motor synapses, repetitive exposures to 5HT tial neglect, which is much more frequent and disabling do not lead to long-term facilitation. This suggests that in following lesions of the right hemisphere (RH). RH domi- the octopus 5HT is not directly involved in mediation of nance for spatial attention has been proposed, but its neural long-term synaptic modifications. However, we describe a bases have not been elucidated. The present fMRI study re- strong 5HT reinforcing effect on LTP induction whereby in veals bi-hemispheric left-hemifield superiority in activation the presence of 5HT high-frequency stimulation trains of a of the intact visuospatial attention network, thus proposing shorter duration than in control, are required for induction a hemispace- rather than hemisphere-superiority as the ba- of a saturated level of LTP. Our study therefore supports the sis for attention asymmetry. Using mixed block-event related notion raised by recent experimental and theoretical studies design paradigm we presented pictures of either facial ex- suggesting that heterosynaptic modulation of homosynaptic pressions or houses for 150 ms to the left and the right hemi- activity-dependent long-term synaptic plasticity is an impor- fields separately. Nineteen right-handed healthy adult fe- tant and universal principle in complex learning systems. males participated in the studies. Multistudy statistical brain maps of the left versus right visual field contrast revealed that Supported by Israel-US BSF and Smith Laboratory for Collabo- LVF epochs differentially activated a cortico-subcortical net- rative Research, the National Institute for Psychobiology, Israel. work, which has previously been associated with covert visuospatial attention. This LVF enhanced activation was evident Work better in the dark: close your eyes bilaterally .The magnitude of the LVF superiority effect was Shore D. I. estimated by a ROI analysis on the right and left IPS. Three- way ANOVA disclosed an overall LVF superiority, which was Department of Psychology, Neuroscience and Behaviour more prominent in the RH. Our study disclosed bilateral McMaster University, Canada LVF superiority in a network that has been associated with Israel Society for Neuroscience 105 covert visuospatial attention, thus suggesting a hemispace- To freeze or not to freeze? Cognitive enhancement rather than hemisphere-based model for attention asymme- in the modulation of associative learning: try. This model first offers a unified framework for under- a study of forebrain neuronal glycine transporter 1 standing manifestations of visuospatial attention asymmetry (GlyT1) deletion in both the lesioned and the intact brain. In view of recent 1 1 2 3 intra-operative and electrophysiological findings we propose Singer P., Yee B. K., Boison D., Mohler H., 1 that superior neural connectivity within the RH and/or from and Feldon J. the RH to the LH might underlie the bi-hemispheric left- 1Laboratory of Behavioural Neurobiology, ETH Zurich, ward bias. This new insight may shed light on the mecha- Schorenstrasse 16, CH-8603 Schwerzenbach, Switzerland nisms of functional hemispheric lateralization in the intact 2R.S. Dow Neurobiology Laboratories, Legacy Research, brain and may help elucidating the neural bases of attention Portland, OR 97232, USA disorders. 3Institute of Pharmacology, University of Zurich, Winterthurerstr. 190, CH-8057 Zurich, Switzerland Role of Sensory Feedback in determining the Firing Patterns of Vibrissa Motoneurons The NMDA receptor (NMDAR) is critically involved in the induction of long-term potentiation (LTP)–a type of experi- Simony E.,1 Ahissar E.,1 and Golomb D.2 ence dependent change in synaptic strength considered being the cellular basis of learning and memory. Under phys- 1Department of Neurobiology, The Weizmann Institute of iological conditions, NMDAR activity is tightly regulated Sciecne, Rehovot 76100, Israel by glycine–the endogenous obligatory co-agonist of NM- 2Department of Physiology and Zlotowski Center for DARs. In turn, the synaptic availability of glycine is con- Neuroscience, Ben-Gurion University, Be‘er-Sheva, Israel trolled by glycine transporter 1 (GlyT1). Elevation in extracellular glycine levels can be achieved by knockout of the The vibrissa sensory-motor system is organized as nested Glyt1 gene in forebrain neurons, which augments NMDAR- loops. In the lowest order loop in the brainstem, sensory mediated currents, and is sufficient to influence and bias as- neurons in the trigeminal nucleus project to the motoneu- sociative learning as shown here using the Pavlovian condi- rons in the facial nucleus. What is the role of this excita- tioned fear procedures. First, forebrain neuronal GlyT1 dele- tory feedback in controlling the firing patterns of motoneu- tion enhanced both the magnitude and persistence of the rons? We explore this issue using a simplified model of the conditioned freezing response to a tone conditioned stim- system, which includes a neuron coupled to itself with a ulus (CS) previously having been paired with a foot shock delay. This conceptual single-neuron model stands for any unconditioned stimulus (US). This effect remained apparent loop where all the neurons in each nucleus fire in full syn- even in aged 24-month old mice. Second, enhanced contex- chrony. Preliminary results reveal that feedback effects de- tual fear was observed in these mutant mice when the ani- pend on the factors that cause motoneurons to fire. One pos- mals were explicitly conditioned to a novel context in the ab- sibility is that the facial motoneurons are stimulated period- sence of any discrete CS. Third, such excessive conditioned ically by a central pattern generator (CPG). Assuming a si- responding was not at a cost to the selectivity of associa- nusoidal stimulation, we find that the average firing rate de- tive learning. Indeed, sensitivity to the CS pre-exposure effect pends on the stimulus frequency via an inverted U-shaped (i.e., latent inhibition) and protracted CS-US intervals (i.e., function. At low frequencies, the neuron fires one spike per trace conditioning effect) was more pronounced in these an- cycle, whereas at high frequency the neuron fires once every imals. The responsiveness to CS preexposure or CS-US trace few cycles or not at all. The sensory feedback can increase interval was enhanced in the mutant mice. Hence, rather the number of spikes per cycle, and hence the firing rate, but than simply strengthening any potential associative links be- not the underlying frequency, which is governed by the CPG. tween stimuli, increased ambient glycine concentration in Another possibility is that motoneurons are pacemakers. In synapses can facilitate selective learning and enhance cogni- this case, weak or moderate feedback has almost no effect tive flexibility. We propose that factors such as CS-US con- if the delay duration is on the order of 10 ms, which is the tiguity/contingency and CS/US associative history ought to experimentally-measured value of the first peak feedback re- be taken into consideration when evaluating potential cog- sponse. With weak to moderate feedback, and our simpli- nitive improving interventions using Pavlovian conditioning fied model of the loop, only sensory neurons that fire at the procedures. second half of the whisking cycle, such as specific Whisk- ing cells, Detach cells, or Touch cells that encounter ob- Sequence structure identification and ff jects during retraction, can a ect the timing of the next mo- characterization of C6orf217: a positional toneurons spike. Analysis of a network model, in which di- candidate gene for schizophrenia verging feedback events induce a positive (delayed) coupling between different pacemaking motoneurons, is currently in Slonimsky A.,1 Alkelai A.,1 Amann-Zalcenstein D.,2 progress. Olender T.,2 Ben-Asher E.,2 Lancet D.,2 and Lerer B.1

Supported by ISF Grant 311/04, ISF Grant 959/06, and BSF 1Biological Psychiatry Laboratory, Hadassah Ein Karem, Grant 2003222. Jerusalem, Israel 106 Neural Plasticity

2Department of Molecular Genetics, Weizmann Institute of Therefore, decreased synaptic activity reduces A-beta level, Science, Rehovot, Israel a process that should improve memory function. However, on other hand, memory-related forms of synaptic plasticity Genome scan and fine mapping of an inbred Arab-Israeli are manifested as increase in synaptic activity. We use op- family sample mapped a schizophrenia susceptibility lo- tical, electrophysiological, and molecular techniques in hip- cus to human chromosome 6q23 (Lerer et al.,2003; Levi pocampal cultures to explore the casual relationship between et al.,2005). Genotyping of single nucleotide polymorphisms synaptic activity, A-beta release and plasticity of synaptic net- (SNPs) was performed (Amann-Zalcenstein et al.,2006). The works at physiological and pathological conditions. We ad- most significant genetic association with schizophrenia for dress following questions. First, whether amount and pat- single SNPs and haplotypes was within a 500 kb genomic tern of neuronal activity differentially affect A-beta release? region, which harbors the Abelson Helper Integration Site Second, what are the immediate effects of endogenously re- 1 (AHI1) gene and an adjacent putative gene, C6orf217. leased A-beta on transmitter release associated with different AHI1 is a well-established neurodevelopmentally implicated patterns of neuronal activity? And third, what are the mech- gene, involved in Joubert Syndrome with brain malforma- anisms transforming accumulation of A-beta to synapse loss, tion and mental retardation (Ferland et al., 2004). In con- the primary factor contributing to memory decline in AD trast, C6orf217 is a putative gene of unknown function. In patients. Understanding the initiation phase of synaptic dys- silico analysis in our laboratory predicted the gene coding function by A-beta is essential for the development of new sequence of C6orf217 on the basis of ESTs cluster (Uni- strategies to prevent memory decline in AD. Gene Hs.510098). The longest open reading frame of existing shows no structural similarity to any known protein. The pu- Development of input connections in neural cultures tative coding sequence and protein show similarity to chim- panzee and rhesus monkey genomes, but is not conserved Soriano-Fradera J., Rodriguez Martinez M., in other organisms. Relatively highly conserved regions were Tlusty T., and Moses E. found inside intronic sequences of the gene. Possible respon- sibility of the sequence for regulatory or other functions on Department of Physics of Complex Systems, anRNAlevelwasexplored.Theputativegenewasfoundto Weizmann Institute of Science. Rehovot 76100, Israel be a primate specific unique RNA or protein-coding gene. Rapid amplification of cDNA ends PCR of the transcript We introduce a novel approach for the quantitative assess- from whole brain cDNA library confirmed the expression of ment of the connectivity in neuronal cultures, based on the mRNA sequence in brain, defined the transcript boundaries statistical mechanics of percolation on a graph. This allows us and identified the unique splice variant that is expressed in to follow the development of the culture and see the emer- the human brain (Accession number EU130902).DNA and gence of connectivity in the network. The culture becomes cDNA samples from 35 schizophrenic, 35 bipolar and 35 fully connected at a time equivalent to full term. The spon- healthy control brains were obtained from the Stanley Array taneous bursting activity that characterizes cultures devel- collection (www.stanley.org). Taqman gene expression anal- ops in parallel with the connectivity. The average number ysis for both C6orf217 and AHI1 transcripts is in progress. of inputs per neuron can be quantitatively determined in Further analysis will explore the possible role of C6orf217 in units of m0, the number of activated inputs needed to ex- m = schizophrenia pathogenesis. cite the neuron. For 0 10 we find that hippocampal neurons have on average 40–80 inputs while cortical neu- The physiological and pathological activities of rons have 50–100, depending on neuronal density. The ra- amyloid-beta peptide: From synaptic release to tio of excitatory to inhibitory neurons is determined using information processing in neuronal networks the GABAA antagonist bicuculine. This ratio changes during development and reaches the final value at day 7-8, co- Slutsky I., Abramov E., and Ruff E. inciding with the expected time of the GABA switch. For hippocampal cultures the inhibitory cells comprise about Department of Physiology and Pharmacology, 30% of the neurons in the culture while for cortical cul- Sackler School of Medicine, Tel Aviv University, Israel tures they are about 20%. Such detailed global information on the connectivity of networks in neuronal cultures is Alzheimer’s Disease (AD) is the most common late-life de- at present inaccessible by any electrophysiological or other mentia. Diverse lines of evidence suggest that amyloid-beta technique. polypeptide (A-beta) plays a central role in pathogenesis of AD. Current AD hypothesis states that soluble A-beta assem- The involvement of the raphe nuclei in blies form in a concentration-dependent manner and trig- parkinson’s disease ger down-regulation in the number, strength and plasticity of synaptic connection, resulting eventually in cognitive Sourani D.1,2,3 and Goelman G.1,2,3 decline. Although A-beta hypothesis gains strong support, the endogenous processes triggering synaptic dysfunction in 1MRI\MRS Laboratory of the Human Biology Research AD remain obscure. Recent findings suggest that A-beta re- Center, Israel lease and, therefore, its concentration in extracellular space 2Department of Medical Biophysics and Nuclear Medicine, are regulated by synaptic activity through vesicle exocytosis. Israel Israel Society for Neuroscience 107

3Hadassah Hebrew University Medical Center, chotic drug, haloperidol, in a neurodevelopmental mouse Jerusalem, Israel model of schizophrenia-related disorders. This model is based on prenatal immune activation by the viral mimic, Parkinson’s disease (PD) is a neurodegenerative disease polyriboinosinic-polyribocytidilic acid (PolyI:C), which is which is primarily considered to affect movement due to loss known to precipitate a wide variety of post-pubertal behav- of dopaminergic cells. However, a large percentage of PD pa- ioral, cognitive and pharmacological abnormalities impli- tients suffer, in addition, from mental disorders. This sug- cated in schizophrenia. The prenatal PolyI:C model also cap- gests the involvement of the serotonergic system in the dis- tures a “prodromal phase” in the form of enhanced sensi- ease. Our previous studies demonstrated reduced connectivity to acute dopaminergic stimulation by amphetamine, tivity between the basal ganglia and the raphe nuclei (the which is apparent already before the onset of the full- main serotonin generator) through the habenula complex blown schizophrenia-related phenotype in adulthood. Us- in unilateral 6-OHDA injected rats. Our aim in this study ing this model, we revealed that chronic haloperidol expo- was to evaluate these findings by comparing the antero- sure (5 mg/kg/day, delivered in drinking water) during peri- grade connectivity of the raphe nuclei between sham and adolescence (day 35 to 70) did not confer any protective ef- 6-OHDA rats. Direct intracranial injection to the raphe nu- fects against prenatal infection-induced sensorimotor gating clei (AP:-0.93,ML:0.03,DV:-0.8) of paramagnetic manganese deficiency emerging in adulthood (PND 90). In fact, peri- ions which are known to enter neurons, transfer antero- adolescence haloperidol treatment in control animals led to gradely and cross synapses, was monitored for 96 hours adult sensorimotor gating deficits (comparable to the deficit by T1-weighted MRI. A unique model-free principal com- observed in the treated animals). On the other hand, the ponent analysis was used and comparison between groups prenatal infection-induced potentiation of psychostimulant (sham:N=7, 6-OHDA:N=8) performed. Significant signal sensitivity in adulthood was blocked by preventive haloperi- enhancement (compared to baseline) was observed in the lat- dol treatment. Our experimental findings thus highlight both eral habenula (P<.0004), in the thalamic and hypothalamic beneficial as well as detrimental long-term effects of chronic areas (P<.001), in field CA3 of the hippocampus (P<.001), exposure to the typical antipsychotic drug haloperidol dur- and in left entorhinal and perirhinal cortex (P<.002). In ing peri-adolescence. 6-OHDA rats, signal enhancement was found in the lateral P<. habenula ( 003), in the thalamic and hypothalamic ar- Functional architecture of collinear interactions P<. P< eas ( 001) and in field CA3 of the hippocampus ( induce spatial and temporal correlation as a basis for . 003). No significant signal enhancements in left entorhinal binding or perirhinal cortex were found. Comparison of signal enhancement volume between sham and 6-OHAD rats reviles Sterkin A. and Polat U. a reduction of 64% (P<6 ∗ 10-7) and 69% (P<5 ∗ 10-8) in the left and right lateral habenula respectively and of 82% Tel Aviv University, Sackler Faculty of Medicine, Goldschleger (7 ∗ 10-9) and 64% (P<5 ∗ 10-6) in left and right field CA3 Eye Research Institute, Tel Hashomer of the hippocampus respectively in 6-OHDA rats. These results support our previous hypothesis of reduced raphe ac- Grouping of small stimuli, presented in the visual field, into tivity in 6-OHDA rats suggesting alternations in the cou- global objects is an important question in contemporary pling between the dopaminergic and serotonergic systems neuroscience. Studies have found that principles of percep- in PD. tual organization exist, suggesting that the spatial relationships between the local retinal inputs are the parameters Evaluating early preventive antipsychotic drug that may determine the observer’s performance in grouping treatment during the prodromal phase in global images. An alternative view for grouping is to consider a neurodevelopmental animal model of schizophrenia the temporal activity of the neural representations, suggesting that binding induces a stimulus-dependent synchrony Spoerri E., Meyer U., Yee B. K., and Feldon J. between the grouped elements. It was previously shown that detection of low-contrast Gabor patches (GPs) is improved Laboratory of Behavioural Neurobiology, ETH Zurich, when flanked by collinear GPs, whereas suppression is ob- Schorenstrasse 16, CH-8603 Schwerzenbach, Switzerland served for high-contrast GPs. The facilitation resembles the principles of Gestalt theory of perceptual organization. We Early pharmacological treatment during the prodromal propose a model for contour integration in the context of state of schizophrenia might represent an early preventive noise that incorporates a temporal element into this spatial strategy to suppress the onset of a full-blown psychotic architecture. It is based on the following principles: (1) the episode in adulthood. Studying in humans the long-term response increases with increasing contrast, whereas the la- consequences of early preventive antipsychotic drug treat- tency decreases; (2) activity-dependent interactions: facilita- ment in peri-adolescence clearly constitutes an ethical is- tion for low and suppression for high activity (3) the variance sue. Therefore, the explorative investigation of early pre- increases with contrast for both responses, rates, and latency; ventive strategies in animal models of schizophrenia is war- (4) inhibition has a shorter time-constant than excitation. ranted. The present study evaluated the long-term effects When a texture of randomly oriented GPs is presented, the of peri-adolescent administration with the typical antipsy- response to every element is decreased due to fast inhibition 108 Neural Plasticity between the neighboring elements, thus shifting the activity Context-dependent Stimulus-Specific Adaptation in to the facilitatory regime of the collinear interactions. During Rat Auditory Cortex the next stage, the slower excitation induces selective facilitation only along the contour elements. Consequently, the Ta‘aseh N., Yaron A., and Nelken I. response to the contour is increased, resulting in decreased variance of the response rate and latency, an effect that pro- Department of Neurobiology and the Interdisciplinary vides better correlation between the contour elements. Thus, Center for Neural Computation, The Hebrew University, Israel collinear facilitation increases the saliency of contours by de- Stimulus-specific adaptation (SSA) in auditory cortex was creasing the response variance of both the rate and temporal investigated in the halothane-anesthetized rat. We used odd- codes. ball sequences, in which a rare (deviant) tone appeared over Supported by the Israel Science Foundation and the National a background of common (standard) tones. We recorded lo- Institute of psychobiology in Israel. cal field potentials and multiunit activity. The response to a tone, when deviant, was substantially stronger than the responses to the same tone when used as standard. The fre- Synaptic and dendritic plasticity in aged ff mammalian hippocampus induced by quency di erence between deviants and standards could be as small as 20%, substantially smaller than the typical width a cell adhesion molecule mimetic, FGL peptide: ff a 3-D ultrastructural study of cortical tuning curves. At a frequency di erence of 10%, the responses to standard and deviants were mostly the same. Stewart M. G. The stronger response to the deviant may be due to a reduction in the responses to the standard, but may also be due Department of Life Sciences, The Open University, to change potentials evoked by the violation of the expecta- Milton Keynes, MK7 6AA, UK tions created by the presentations of the standard tone. To test for change potentials, we embedded the deviant tones in We have carried out a 3-dimensional (3D) morphometric a sequence in which many different tones were played ran- study at electron microscope (EM) level to investigate the ef- domly, so that each tone was as frequent as the deviant in fect of a Neural Cell Adhesion Molecule (NCAM) mimetic the oddball sequence. In such a sequence, the appearance of on synaptic and dendritic spine plasticity in the hippocam- the deviant tone is not associated with violation of expecta- pus of aged rats. NCAMs are members of the Ig superfam- tions and change potentials are not expected. We show that ily expressed on the surface of neural cells involved in cell- the response to a deviant over a background of many stan- cell interactions and synaptic plasticity. NCAM signals via a dards is similar to the response to the deviant over a back- direct interaction with the fibroblast growth factor receptor ground of a single standard. Nevertheless, a simple model (FGFR). FGL (Fibroblast Growth Loop, provided by Eliza- based on fatigue cannot account for the qualitative pattern beth Bock and Vladimir Berezin, University Copenhagen) is the results, and it seems that the fact that a stimulus is novel an NCAM mimetic consisting of a 15 amino acid peptide de- in the sensory scene plays a significant role in cortical SSA. In rived from the FGF binding site of NCAM. FGL (icv) facil- an attempt to generate change potentials, we assigned a be- itates learning and spatial memory consolidation, and can havioral importance to a specific frequency by using it as a reduce the B-amyloid load in rats. Aged rats (22 months, conditioned stimulus (CS) in a fear conditioning procedure. ∼560 g) (Marina Lynch TCD, Dublin) were injected sub- Preliminary results suggest an enhancement in the responses cutaneously with FGL (8 mg/kg) at 2-day intervals until to CS and the presence of change potentials when the CS is 19 days after the experiment start; control rats were injected used as a deviant, but not when other tones are used as de- with sterile water. Animals were perfused with fixative, and viant, in oddball sequences. coronal brain sections containing the hippocampus cut at 100 um, and hippocampal volume was measured. Tissue was When noise can mask visual targets embedded and ultrathin sections viewed in a new JEOL 1400 EM (120 kv) with a high resolution AMT digital camera used Tadmor S. and Polat U. for image capture. Analyses were made of synaptic and dendritic parameters following stereological analyses and 3D re- Sackler Faculty of Medicine, Tel Aviv University, Goldschleger construction via images from up to 150 serial sections (see Eye Research Institute, Tel Hashomer, Israel http://synapses.bu.edu). FGL altered neither hippocampal volume, nor spine or synaptic density in the medial molec- The masking (suppression) effect can be achieved either ular layer. However, it increased the ratio of mushroom to when noise is used, or when the target and mask share thin spines, the number of endosomes, and the abundance of the same physical properties. Thus, the properties of effi- spine apparatus, whilst it decreased synaptic and spine cur- cient masking are not well defined. We probed the efficacy vature. This indicates that FGL induces large scale changes of the suppression effect on target threshold by manipulat- in synapses and dendritic spines in the hippocampus of aged ing the ISI (0–120 milliseconds), contrast (0–80%), spatial rats complimenting data showing its marked effect on cogni- frequency (SF, 0-factor of two), and orientation (0–90 de- tive processes. grees). The relationships between facilitation using collinear flankers and suppression were also tested under these condi- Supported by EU FPVI Promemoria Contract no. 51201. tions. We found that suppression increased with increasing Israel Society for Neuroscience 109 contrast (being effective above 4.25 times the target thresh- 2Department of Psychology, University of Western Ontario, old); it was maximal for simultaneous presentation (ISI = Canada 0, mask contrast = 80%) and equal target-mask SF but decreased with increasing ISI. Suppression is maximal for near A large body of evidence from behavioral, neuropsychologi- iso-orientations and decreased for increasing orientation dif- cal, and neuroimaging studies, supports the idea that vision- ferences. Collinear flankers did not produce facilitation for for-action and vision-for-perception are mediated by distinct ISI = 0 but it produced more suppression for ISI = 30. Thus, neuroanatomical and functional systems. Yet, an ongoing de- efficient masking is not noise per se, rather, it is determined bate exists as to whether visual illusions, that by definition by combining parameters such as the similarity between the affect the way people perceive objects, have similar effects target and mask in their temporal presentation as well as on visuomotor control. In this study we have attempted to their physical properties (similar SF and orientations) and differentiate–within the same experimental design–the ef- the balance between excitation and inhibition. The results fects of the real size and the apparent size of objects on ac- suggest that iso-orientation inhibition is stronger than cross- tion and perception. To this end, two real rectangular objects orientation inhibition. of different sizes were presented within a variant of the Ponzo size-contrast illusion. Most experimental trials were designed SupportedbyagrantfromtheIsraelScienceFoundation. such that the object that was perceived as the larger one was actually physically smaller than the other object. This design State dependant modification in the waveform of allowed us to focus on trials in which subjects have overtly the complex spikes decided that one of the objects is the smaller (or larger) of the pair, and to test whether or not the opening between the Tal Z. and Yarom Y. fingers of the grasping hand goes in the direction of this erroneous decision. The results showed that although subjects Department of Neurobiology and The ICNC, were affected by the illusion when making size decisions, the The Hebrew University of Jerusalem, Israel opening of their fingers in flight reflected the real size differences between the two objects. This pattern of results was re- Climbing fiber activation evokes a large all-or-none response versed in a second experiment, in which subjects were asked in Purkinje cells (PCs), known as the complex spike (CS). to make perceptual estimations of size. In this case, the esti- The CS, triggered by massive EPSPs to the dendritic arbor, mates reflected the illusory size of the objects. Thus, the real consists of dendritic calcium currents and somatic sodium and apparent differences in the size of the objects had oppo- spikes. It is thus expected that the properties of these events site effects on action and perception. These findings provide will depend on the PCs membrane potential. Furthermore, evidence for a double dissociation between visuomotor con- we have recently showed that the membrane potential of PC trol and visual perception in the context of visual illusions attains two stable state values: a hyperpolarized quiescent and support the idea that visuomotor control and visual per- state (down state) and a depolarized active state (up state). ception are mediated by distinct functional systems. Therefore, we examined the CS waveform that was elicited during the up state and compared it to the waveform ob- Vascular endothelial growth factor increases tained during the down state. To this end, we performed in- neurogenesis following traumatic brain injury vitro whole cell and loose-patch recordings from PCs. We use concentric metal electrode to stimulate the climbing fibers Thau-Zuchman O.,1 Shohami E.,2 Ovadia H.,1 and to evoke CSs. Intracellular current injection was used to and Leker R. R.1 shift the cells between the two stable states. We found that during the down state the CSs, which waveform tends to be 1Department of Neurology, Hebrew University-Hadassah more stable, were characterized by 4–6 fast fluctuations that Medical Center, Jerusalem, Israel followed the initial spike. In the upstate the CSs, which wave- 2Department of Pharmacology, School of Pharmacology, form tends to have a longer duration, were characterized by The Hebrew University, Jerusalem, Israel significantly higher variability of fewer and slower fluctuations. These differences may account for a lower threshold Background for calcium activation during up state. Since calcium concentration has been shown to play a pivotal role in synaptic Activation of endogenous stem cells has been proposed as a plasticity, it is tempting to speculate that plastic processes in novel form of therapy in a variety of neurological disorders, the cerebellar cortex, which are triggered by climbing fibers, including traumatic brain injury (TBI). Vascular endothelial are more effective during the up state. growth factor (VEGF) is expressed in the brain following TBI and serves as a potent activator of angiogenesis and neuroge- Dissociable effects of real and illusory size on nesis. Methods: TBI was induced with closed head injury in perception and visuomotor control sabra mice. Mice were injected with BrdU to label newborn cells. We administered exogenous VEGF into the lateral ven- Tanzer M.,1 Goodale M. A.,2 and Ganel T.1 tricles using miniosmotic pumps to evaluate the effects on recovery and functional outcome as assessed with the neuro- 1Department of Behavioral Science, Ben-Gurion University of logical severity scale score. Immunohistochemistry was used the Negev, Israel to study the fate of newborn cells at 90 days post TBI. 110 Neural Plasticity

Results Supported by Israel Science Foundation. M. Kuba was supported by a Golda Meir fellowship. Our results show that VEGF significantly increases the number of proliferating cells in the subventricular zone and in the The role of members of the BMP 60A subgroup in peri-lesion cortex. This increase is associated with a signifi- the development of catecholaminergic neurons and cantly better functional outcome following TBI as measured the anterior pituirary with the neurological severity scale. Fate analysis showed that most newborn cells differentiated into astrocytes and oligo- Tilleman H., Liser K., Scheffner O., Nashelsky L., dendroglia and not into neurons. Meir I., Lanir A., and Brodski C. Department of Morphology, Faculty of Health Sciences, Conclusions Ben-Gurion University of the Nege, Israel VEGF significantly augments angiogenesis and neurogenesis Studies performed in zebrafish and chicken indicate that after TBI but most newborn cells adopt a glial fate. Neverthe- Bone Morphogenetic Proteins (BMPs) play an important less, there is a significant improvement in recovery rates and role in the development of catecholaminergic (dopaminer- functional outcome as a result of these changes. gic and noradrenergic) neurons in the CNS. However, the This work was supported in part by a grant form the Israeli Bmp or combination of Bmps controlling the development Defense Forces. of these cell populations in mammals is still elusive. In addition Bmp2 and Bmp4 have been implicated in pituitary development. However, the role of other Bmps in this process Learning to move an arm inside a maze is still elusive. Using in situ hybridization, we compared the ff Thonhauser K. E.,1 Zullo L.,2,3 Byrne R. A.,2 spatio-temporal expression pattern of di erent BMPs to de- Hochner B.,2 and Kuba M. J.2 veloping catecholaminergic neurons in mice. We found that members of the 60A subgroup, Bmp-5, -6 and -7, are ex- 1Institute of Zoology, Karl-Franzens-University, pressed in close vicinity to the neuronal population of our Graz, Austria interest. Next, we could show that dopaminergic, and nora- 2Department of Neurobiology & ICNC, drenergic markers are normally expressed at postnatal day Hebrew University, Israel 0, in Bmp-5, -6, and -7 knockout mice. This indicates that 3Department of Neuroscience and Brain Technologies, BMP5, BMP6, and BMP7 as individual genes are not essen- The Italian Institute of Technology, Italy tial for the presence of dopaminergic and noradrenergic neurons in vivo. These results are very surprising, since previous The arms of an octopus, the therewith-conducted move- in vitro data and results obtained in chicken and zebrafish, ments and the coordination of these movements play an es- suggested the dependency of noradrenergic neurons on those sential role in the natural behaviour of this animal. Locomo- BMPs. Based on our results we hypothesize that BMPs are tion, foraging, probing and mating are dependent on pro- functionally compensating for each other. In order to test ficient arm use. In particular searching and probing move- our hypothesis, we will characterize monoaminergic popu- ments are hypothesized to be largely autonomous (i.e., con- lations in BMP compound mutants. In addition, Current ex- trolled by the peripheral motor system). For the octopus sur- periments aim to characterize the role of BMPs in pituitary vival, nonvisual arm coordination and also the ability to re- development. For this purpose we are analyzing the mRNA member a beneficial food patch are essential for its daily sur- expression of different hormones produced by the anterior vival. These two issues became the basis for our experimental pituitary by in situ hybridization and RT-PCR. design. Our present study seeks to investigate if an octopus can learn to navigate a two ways choice maze based only on The work was supported by the ISF, The National Institute of proprioceptive information. We used a plexiglass plate with Psychobiology, and the Ministry of Health. a Y shaped maze glued to it. The octopus had to insert only one of its arms into the maze and reach a goal box located Effects of mid-hindbrain organizer genes and on both ends of the Y maze. Six adult Octopus vulgaris were members of the Bmp 60A subgroup in introduced to the maze baited on both sides to determine the development of noradrenergic locus coeruleus the individual side preferences of the animals. Once this was neurons tested the goal side was either ascribed at random, or con- Tilleman H., Hakim V., Liser K., Scheffner O., trary to the animals side preference. To control that chem- Nashelsky L., Meir I., Lanir A., and Brodski C. ical cues did not influence the animals’ decision an equal amount of food was put into both goal boxes, but only avail- Department of Morphology, Faculty of Health Sciences, able in the correct goal box. A criterion for successful learn- Ben-Gurion University of the Negev, Israel ing was the completion of 8 out of 10 trials. Four out of six animals complete this task in less than 90 trials. Using a sim- The embryonic mid-hindbrain organizer (MHO) is comple two ways choice discrimination-learning paradigm, our posed of a transient cell population located at the devel- study shed new light on the ability of the octopus to control oping midbrain-hindbrain junction, that controls the for- its motor output based on proprioceptive information only. mation of the brain stem. Mouse mutants with a caudally Israel Society for Neuroscience 111 shifted MHO show an increase in number of dopaminer- sharp peak which appears strongly (but in opposite polar- gic neurons and a decrease in number of serotonergic neu- ities) in central channels and in the electroocular channels rons. Interestingly, cranial nerves, originating close to the (EOG). In all four EOG channels (vertical-superior, vertical- MHO are not affected in these mutants, indicating that the inferior, horizontal-left, horizontal-right) the peak appears MHO has a specific effect on cell populations forming ad- at the same polarity. The pattern in the EOG channels de- jacent to it. Behavioral studies revealed that these mutants scribed above cannot represent a simple saccade. Since a ver- show increased activity and altered locomotor response to tical (or horizontal) saccade will typically be demonstrated psychostimulants. The major noradrenergic nucleus in the by opposite polarization of the vertical superior and inferior brain, the locus coeruleus originates at the intersection of channels (or the horizontal left and right channels respec- Fgf8 that mediates MHO activity and dorsalizing Bmp sig- tively). We discuss the possible involvement of a convergence nals. Deleting Fgf8, leads to a loss of the whole mid- and or divergence movement in the manifestation of the iGBR. hindbrain region including the locus coeruleus. However, the specific role of MHO position and activity for the generation Blood-brain barrier disruption in of the locus coeruleus has so far been unknown. Inactivat- post-traumatic epilepsy ing bmp7 in zebrafish or blocking Bmp-5 and -7 signaling Tomkins O.,1 Shelef I.,2 Kaizerman I.,1 Zumsteg D.,3 in chicken have indicated that these morphogens are neces- 1,4 sary for the formation of the LC. However, if Bmp function is and Friedman A. conserved in mammals and if Bmp-5 and -7 have redundant 1Departments of Physiology and Neurosurgery, functions is elusive. Here we provide evidence that mouse Soroka Medical Center, Ben-Gurion University, Israel mutants with a caudally enlarged Otx2 expression domain 2Department of Neuroradiology, Soroka Medical Center, and concomitantly caudally shifted MHO (En1+/Otx2) have Beer-Sheva, Israel less noradrenergic neurons. Unexpectedly En1+/Otx2 mu- 3Department of Neurology, University Hospital Zurich, tants showed an enlarged Fgf8 expression domain and no Zurich, Switzerland changes in Bmp-5, -6, or -7 expression. A further analysis 4Institute for Neurophysiology, Charite´ University Medicine, of Bmp-5, -6 or -7 knockout mice indicate that the LC de- Berlin, Germany velops normally in these mutants. Taken together, our data indicates that the MHO controls the development of the LC Background through an Otx2/Gbx2 interaction and that Bmp-5, -6 or -7 are not required, as individual genes, for the formation of the Traumatic brain injury (TBI) is an important cause of focal mammalian LC in vivo. epilepsy. Animal experiments indicate that disruption of the blood-brain barrier (BBB) plays a critical role in the patho- This work was supported by ISF, National Institute of Psychobi- genesis of post-traumatic epilepsy (PTE). Objective: To in- ology in Israel, and Ministry of Health. vestigate the frequency, extent and functional correlates of increased BBB permeability in PTE patients. Keeping an eye on induced Gamma activity: Methods a study of combined EEG and eye-tracking Thirty two patients were included in the study, with 17 1 2 2,3 Tomer O., Yuval-Greenberg S., and Deouell L. Y. suffering from PTE. All underwent brain magnetic resonance imaging (bMRI) and were evaluated for BBB disrup- 1 Hadassah Medical School, The Institute of Medical Sciences tion, using novel quantitative techniques. Cortical dysfunc- 2 Department of Psychology, Israel tion was measured using quantitative electroencephalogra- 3 Interdisciplinary Center of Neural Computation, phy (qEEG), and localized using standardized low resolution The Hebrew University of Jerusalem, Israel brain electromagnetic tomography (sLORETA).

In the last decade a large amount of electrophysiological re- Results search has focused on high frequency brain activity in humans, and specifically on the “induced gamma response” TBI patients displayed significant pathological qEEG slow- (iGBR). The scalp recorded iGBRs is manifested typically as ing. No significant differences were found between spectral an increase in the gamma band (>30 Hz) peaking around qEEG analyses from PTE and nonepileptic patients. While 250 milliseconds post stimulus, following the presentation bMRI revealed that PTE patients were more likely to present of a visual stimulus. The iGBR was hypothesized to repre- with intracortical lesions (P = .02), no relation to the size sent the neural synchronization involved in various cognitive of the cortical lesion (P = .19) was found. Increased BBB functions such as binding and consciousness. Our findings permeability was found in 76.9% of PTE patients compared show a strong correlation between the induced gamma activ- to 33.3% of nonepileptic patients (P = .047), and could be ity and eye movements (recorded by an eye tracker). How- observed several years following the trauma. Cerebral cor- ever, the direction of causality is still unclear. In the current tex volume with BBB disruption was larger in PTE patients study we present a possible model explaining the appearance (P = .001). In 70% of patients, slow (delta band) activity of iGBR in the EEG data and its relation to eye movements. was co-localized, by sLORETA, with regions showing BBB In filtered (30–100 Hz) single trials the iGBR is seen as a disruption. 112 Neural Plasticity

Conclusions 3Pediatric Neurosurgery Dana Children’s Hospital, Sourasky Medical Center, Israel Lasting BBB pathology is common in mild TBI patients, with 4Neurobiochemistry, Tel-Aviv University, Israel increased frequency and extent in PTE patients. A correlation between disrupted BBB and abnormal neuronal activity Memory and neurobehavioral dysfunctions typically occur is suggested. after human and experimental traumatic brain injury. A Neurological Severity Score (NSS, range 0–10) was devel- Computer-assisted diagnosis of blood-brain oped for evaluation of trauma severity in mice. The object barrier disruption recognition task (ORT) measures specific episodic memory Tomkins O.,1 Shelef I.,2 Kaizerman I.,1 in rodents, and is expressed by the percent time spent at a and Friedman A.1,3 novel object (discrimination index, DI). The present study describes the effect of injury severity on the spontaneous re- 1Departments of Physiology and Neurosurgery, covery of neurobehavioral and cognitive outcome after se- Soroka Medical Center, Ben-Gurion University, Israel vere and mild focal trauma in mice. Mice were subjected to 2Department of Neuroradiology, Soroka Medical Center, closed head injury (NSS at 1h post injury of 7.52 ± 0.34 and Beer-Sheva, Israel 4.62 ± 0.14, resp.) and NSS was further evaluated during 25d. 3Institute for Neurophysiology, Charite´ University Medicine, NSS decreased by 3.86 ± 0.26 and 2.54 ± 0.35 units in the se- Berlin, Germany vere and mild injured mice, respectively. ORT was performed between days 3 and 28 after trauma. Whereas DI in nonin- Blood brain barrier (BBB) disruption occurs under many di- jured mice is ∼75%, se51.7 ± 6.15% on 3rd day and 66.2 ± verse pathological conditions, and recent studies suggest it 6.81% verely injured animals show DI of 51.7 ± 6.15 % and may be involved in the pathogenesis of neurological disor- 66.2 ± 6.81% at days 3 and 21 after trauma, indicating in- ders. Visually based evaluation of contrast-enhanced brain ability to distinguish between familiar and novel objects. In imaging is often used to detect BBB disruption. However, no contrast, mildly injured mice do not show cognitive impair- established method exists for the quantitative evaluation of ment throughout the same period. NSS1h strongly correlated BBB permeability in human patients. We have recently estab- with the damage seen on MRI 24 h post injury (R = 0.8, lished two methods for evaluating BBB permeability in hu- P<.001). We suggest that NSS is a reliable tool for in- mans, utilizing brain MRI scans. The first method compares vivo continuous evaluation of neurological damage in head- T1- weighted magnetic resonance brain scans before and fol- injured mice, and its value at 1 h predicts the extent of mo- lowing the administration of Gadolinum-DTPA. Examining tor dysfunction, cognitive damage and brain water charac- groups of 16 voxels at a time and searching for statistically teristics as depicted by T2-weighted MRI. Combined assess- significant changes in signal enhancement results in a semi- ment of neurobehavioral and cognitive functions along with quantitative estimation of the spatial location and extent MRI is most useful in evaluating recovery from injury, and of BBB disruption. In the second, dynamic method, repet- was successfully applied in testing of novel pharmacological itive T1 scans are performed during contrast agent admin- treatments. istration. Following blood vessels elimination the dynamics of contrast agent concentration in each pixel are calcu- Maintaining the presynaptic site—questions lated. A quantitative map of BBB function is created accord- arising from live imaging experiments ing to the activity of the BBB throughout the parenchyma. Using both methods we receive a highly sensitive estimate Tsuriel S., Stern M., Kahana R., and Ziv N. of BBB patency throughout the brain parenchyma. Our study shows that BBB disruption is common in diverse Rappaport Institute and the Department of Physiology, neurological and systemic conditions and possibly lasts for Technion Faculty of Medicine, Haifa 31096, Israel long periods. Furthermore, the extent of disruption, its progression with time, and functional correlations can be Presynaptic sites of CNS synapses appear as small axonal identified. varicosities often formed en passant along axons. These specializations are not closed compartments, but are continu- Dynamic changes in the recovery after ous, to a large degree, with the axonal cytoplasm and mem- traumatic brain injury in mice: branes. Yet, in spite of this lack of obvious physical barriers, effect of injury severity on T2-weighted presynaptic structures manage to maintain their unique or- MRI and functional recovery ganization. If presynaptic specializations were static struc- Tsenter J.,1,2 Beni-Adani L.,3 Assaf Y.,4 tures, this would not be that remarkable. However, presy- Alexandrovitch A. G.,1 Trembovler V.,1 naptic sites are loci of extensive membrane dynamics, that ffi and Shohami E.1 involve exocytosis, endocytosis and synaptic vesicle tra ck- ing, all of which are accelerated by synaptic activity. This be- 1Department of Pharmacology, Hebrew University and ing the state of affairs, the persistent, focal organization of Hadassah Medical Center, Jerusalem, Israel presynaptic sites is not an obvious outcome. As a step to- 2Rehabilitation, Hebrew University and Hadassah Medical ward a better understanding the processes involved in main- Center, Jerusalem, Israel taining presynaptic structure we set out to examine some Israel Society for Neuroscience 113 of the molecular dynamics exhibited by several presynap- ture plans include recording of neural activity from the hip- tic molecules of various classes, including cytomatrix, mem- pocampus of freely-flying bats, using a telemetry system–as brane and active-zonal proteins. Fluorescence recovery af- well as the analysis of the relation between the animal’s be- ter photobleaching (FRAP) and photoactivation experiments havior and the network activity of dozens of simultaneously- revealed that presynaptic molecules are continuously incor- recorded single units from bat hippocampus. porated into and lost from individual synaptic structures over various times scales, from minutes to many hours. Non stationary fluctuation analysis of calcium in Moreover, these dynamics can be accelerated is some cases by secretory vesicles synaptic activity. Finally, we find that synaptic molecules can be continuously exchanged between nearby synaptic struc- Valitsky M.,1 Blank P.,2 Raveh A.,1,3 Coorssen J.,2,4 tures at significant rates that greatly exceed the rates at which Zimmerberg J.,2 and Rahamimoff R.1 synapses are replenished with molecules arriving from so- 1 matic sources. Our findings thus support the possibility that Department of Physiology, The Hebrew key presynaptic molecules are continuously lost from, incor- University-Hadassah Medical School, Jerusalem, Israel 2 porated into and exchanged among nearby presynaptic sites Laboratory of Cellular and Molecular Biophysics, at significant rates and thus further highlight questions as NICHD/NIH, Bethesda, Md, USA 3 to how presynaptic sites manage to maintain their structural Weizmann Institute of Science, Rehovot, Israel 4 and functional characteristics over long durations. Department of Physiology and Biophysics, Faculty of Medicine, University of Calgary, Canada Supported by US-Israel Binational Science Foundation (BSF), German Israel Foundation for scientific R and D (GIF). Calcium ions have several important functions in synaptic in synaptic communication. They are directly involved in the Hippocampal neural activity in freely moving triggering of secretory vesicle content release by exocytosis. echolocating bats Synaptic vesicles however, are too small for confocal optical analysis. Sea urchin eggs have larger vesicles (∼1 μM) and are Ulanovsky N.1 and Moss C. F.2 suitable and convenient for studying calcium dependent exocytosis. Previous work has shown that sea urchin vesicles 1 Department of Neurobiology, Weizmann Institute of contain a high calcium concentration. Fluorescent confocal Science, Rehovot 76100, Israel microscopy demonstrated well defined calcium dynamics. 2 Department of Psychology, University of Maryland, Here we analyzed the calcium fluctuations. The presence of College Park, MD 20742, USA bleaching required the use of nonstationary stochastic analysis. This analysis showed that the variance of the calcium The hippocampus is crucial for episodic and spatial mem- signal is larger than the mean; the calcium signal can not be ory. In freely-moving rodents, hippocampal pyramidal neu- described as a Poisson process. We speculate that this extra- rons exhibit spatially-selective firing when the animal passes variance analysis can contribute to the understanding of the through a neuron’s “place field,” and theta-band oscillation processes that control intracellular calcium. We found that, is continuously present during locomotion. Here we report as expected, the highest levels of calcium induced fluores- on the first hippocampal recordings from echolocating bats, cence were in the center of the secretory vesicle. The Fano mammals phylogenetically distant from rodents. Big brown factor (variance\mean fluorescence) is the lowest in the cen- bats (Eptesicus fuscus) were trained to crawl and forage for ter and increased monotonically towards the edge of the vesi- mealworms in an open-field arena, while we recorded local cle. The highest extravariance is at the edges of the secretory field potentials and single unit activity from hippocampal vesicle. Due do this extra variance, we speculate that there area CA1 using a tetrode microdrive, and tracked the po- is an interaction between the calcium in the vesicle and the sition of light-emitting diodes on the animal’s head. These calcium in the cytosol. Moreover, we speculate that the secre- recordings revealed place-cells very similar to rodents, as well tory vesicle takes part in the regulation of cytosolic calcium as rodent-like high frequency ‘ripple’ oscillations. Theta os- concentration and may dramatically alter the local calcium cillation, however, differed from rodents in two important concentration near the surface of the vesicle. ways: (i) theta occurred when bats explored the environment without locomoting, using distal sensing via echolocation; Supported by The Israel Science Foundation. (ii) theta was not continuous but occurred in short intermittent bouts. The intermittence of theta suggests that mod- Multisensory integration of speech and els of hippocampal function relying explicitly on continuous script in fluent and dyslexic readers theta may not apply to bats. These data support the hypothesis that theta in mammals is involved in sequence-learning, Van Atteveldt N. M.,1,2 Blau V.,1,2 Formisano E.,1,2 and hence theta power increases with sensory-input rates– Roebroeck A.,1,2 Blomert L.,1,2 and Goebel R.1,2 explaining why theta-power correlates with running-speed in rodents and with echolocation-call-rate in bats. Finally, we 1Department of Cognitive Neuroscience, Faculty of demonstrate rapid modulation of hippocampal spatial rep- Psychology, Maastricht University, The Netherlands resentation in the bat, with a ∼1-second timescale, which is 2Maastricht Brain Imaging Center (M-BIC), Maastricht, 1-2 orders of magnitude faster than previously reported. Fu- The Netherlands 114 Neural Plasticity

In alphabetic scripts, letters and speech sounds are the basic the degree of presynaptic facilitation for bursts is maximized elements of correspondence between spoken and written lan- at the optimal level of GABA(B)-Rs activation. At low ba- guage. Therefore, investigations of the mechanism by which clofen concentrations (∼0.1 uM) hippocampal synapses act letters and speech sounds are associated in the brain increase as band-pass filters with low degree of short-term facilitation; our understanding of the neural basis of literacy. Using func- moderate concentrations of baclofen (∼1 uM) significantly tional magnetic resonance imaging (fMRI), we showed in increase facilitation index, whereas higher baclofen concen- fluent readers that the response to speech sounds in the audi- trations (>20 uM) induce pattern-independent inhibition, tory association cortex is enhanced by congruent letters (e.g., and consequently reduces presynaptic facilitation. Interest- letter “a” with phoneme /a/) and suppressed by incongru- ingly, chronic treatment of hippocampal neurons with 1 uM ent letters (e.g., “o” with /a/). Interestingly, temporal prox- baclofen resulted in enhanced long-term presynaptic plastic- imity between auditory and visual input was critical for this ity. However, 50 uM does not affect the capacity of synaptic congruency effect to occur. We interpreted these results as network for modifications. These findings indicate that the a neural correlate of letter-sound integration, driven by the capacity of neuronal network to undergo persistent modifi- congruency of letter-sound pairs learned during reading ac- cations is regulated by the level of ongoing background acquisition. Furthermore, we suggested that the modulation of tivity through presynaptic GABA(B)-Rs. auditory cortex was the result of feedback from the superior temporal sulcus (STS). In a subsequent study, we used Vergence in reverspective: ff event-related fMRI to investigate the e ect of task instruc- effects of real and virtual depth cues tions on neural letter-sound integration, and investigated the interactions between STS and auditory cortex directly Wagner M.,1 Ehrenstein W. H.,2 and Papathomas T. V.3 through the analysis of effective connectivity using Granger Causality Mapping. Our findings indicated that top-down 1Ariel University Center of Samaria and Smith Psychobiology task demands can overrule the stimulus-driven (bottom-up) Laboratory, Hebrew University of Jerusalem, Israel integration mechanism. Furthermore, effective connectivity 2Leibniz Research Center for Working Environment and analysis provided support for the feedback modulation of au- Human Factors, University of Dortmund, Germany ditory cortex by STS based on the letter-sound congruency. 3Rutgers University, Laboratory of Vision Research, 152 These findings provide a working model for letter-sound in- Frelinghuysen Road, Piscataway, NJ 08854-8020, USA tegration in the “literate brain,” which serves as a basis for investigating deviant literacy development. Recent findings “Reverspectives” (by artist Patrick Hughes) consist of trun- from our lab indicate anomalous processing of letter-sound cated pyramids with their smaller faces closer to the viewer pairs in auditory cortex and STS in dyslexic readers. such as to allow a realistic scene to be painted on them. With Optimal activity level of presynaptic GABAB their pictorial perspectives that reverse the physical depth receptors maximizes the capacity of synapses for arrangement, reverspectives provide a bistable paradigm correlation-based plasticity of competing depth percepts, with illusory depth being strongest monocularly and beyond (individually varying) Vertkin I.,1 Bettler B.,2 and Slutsky I.1 critical viewing distances (Papathomas, Perception 2002). “Properspectives” are the same solid pyramids, painted on 1 Department of Physiology and Pharmacology, the inside, thus possessing a pictorial perspective that con- Sackler School of Medicine, Tel Aviv University, Israel forms with (and thus augments) real depth. Vergence eye 2 Pharmacenter, University of Basel, Switzerland movements were recorded (EyeLink II system) comparatively for monocular and binocular reverspective and binocular Presynaptic GABA(B1a)-Rs play an important role in properspective conditions (optimized to obtain illusory, illu- hippocampus-dependent synaptic plasticity, learning and sory/veridical, or veridical depth percepts, respectively). Gaze memory. However, the mechanisms transforming activation locations were signaled by LEDs, inserted in 8 positions on of GABA(B1a)-Rs to plasticity and memory function re- the model. While fixating identical LED-positions, the eyes main elusive. To address this question, we use functional converged with veridical depth percepts and diverged with FM-based imaging to quantify probability of transmitter re- illusory depth percepts. These results indicate that pictorial lease and distribution of functional presynaptic terminals at cues are as effective as physical cues for vergence control. the level of single synapses in hippocampal cultures. Our results show that mice lacking presynaptic GABA(B1a)-Rs exhibit reduced short-term and long-term presynaptic plastic- Involvement of plasminogen activator system in ity. Given that presynaptic GABA(B)Rs act as a high-pass immunomoudulation of experimental autoimmune filter, preferentially inhibiting transmission of single spikes, myasthenia gravis we propose that these receptors might regulate synaptic plasticity through fine-tuning the level of ongoing background Wald H.,1 Sicsic C.,1 Irony-Tur-Sinai M.,1 Akkawi S.,2 synaptic activity. To test this hypothesis, we first quantified Higazi A. E.,2 and Brenner T.1 the effect of baclofen, an agonist of GABA(B)Rs, on transmitter release for single spikes (mimicking background ac- 1Department of neurology, Hadassah Hebrew University tivity) versus burst inputs in WT cultures. Our results show Medical Center, Jerusalem, Israel Israel Society for Neuroscience 115

2Department of biochemistry, Hadassah Hebrew University the ARTS cDNA from rat brain. Alignment between the pu- Medical Center, Jerusalem, Israel tative amino acid sequences of human and rat ARTS shows 83% identity. Rat brain ARTS lacks 5 amino acids in the N- Myasthenia gravis (MG) is an autoimmune disease charac- terminal region, a 14 amino acid sequence between amino terized by muscle weakness caused by antibodies to the nico- acids 76 and 89 and 3 amino acids between 123–125. The tinic acetylcholine receptor (nAChR) at the post-synaptic effect of a few apoptotic stimuli were tested on rat E18 cor- site of the neuromuscular junction (NMJ). Experimental au- tical primary neuronal cells for their effect on the expres- toimmune MG (EAMG), the animal model of MG, whose sion of ARTS and active caspase-3 (apoptosis indicator). chronic phase closely resembles human MG, is widely used Neurons were grown in Neurobasal medium containing B- to study numerous aspects of MG. The plasminogen activa- 27 additives. Removal of B-27 at DIV 7 induced apoptosis. tor (PA) system and matrix metalloproteinases (MMP) are Western blot showed an increase in ARTS protein expres- extracellular proteolytic enzymes which modulate cell mi- sion in cells which were incubated 24 h in medium with- gration, cell-matrix interactions and signaling pathways. It out B27. High concentrations of glutamate (1–75 mM) also is also known that inflammatory cells express the uPA recep- induced apoptosis. At 50 mM, glutamate increased expres- tor (UPAR) and that tissue PA (tPA) and urokinase PA (UPA) sion of ARTS and active caspase-3 (P<.05). ARTS may activities are elevated in inflammatory areas. A part from ex- be involved in neuronal apoptosis, but its precise role is still ploring the inflammatory aspect of the myasthenic NMJ and unclear. based on our previous findings on the involvement of the PA system in CNS autoimmune conditions, in the present study Expression level-dependent changes in GIRK1/2 we tested the association of the PA system with EAMG patho- activity in Xenopus laevis oocytes: a modeling study genesis. EAMG was induced in female C57bl mice by immunization with purified Torpedo AChR. Four groups were Yakubovich D. and Dascal N. used: mice genetically deficient in UPA, UPAR, and tPA and wild type (wt). In comparison to the wt all the knock out (ko) Department of Physiology and Pharmacology, mice developed a more severe disease: disease incidence was Sackler School of Medicine, Tel Aviv University, Israel 30% in the control wt group, versus 60%, 100% and 80% in the UPA-/-, UPAR-/- and tPA-/- groups respectively. How- Increase of injected m-RNA concentration of GIRK1/2 chan- ever, lymphocyte reactivity towards mitogens was reduced nel in Xenopus laevis oocytes causes increase in basal in cells derived from all the ko mice. The addition of pep- (agonist–independent) and either no change or decrease in tides derived from PAI-1 increased T-cell reactivity in vitro evoked (agonist-induced) activity in whole cell two-electrode by 20–70%, whereas, tPA caused inhibition. Our results im- voltage clamp experiments. The same phenomenon is ob- ply that a network of functionally redundant proteases is in- served when the channels are activated in a receptor- volved in EAMG pathogenesis. Modulation of the PA system independent manner, by co-expression of G[betagamma] could serve as a potential target for treatment of EAMG and subunits or by application of G[betagamma] to bath solu- MG. tion in excised patches. These changes are completely reversed by co-expression of G[alpha]i subunits. Paradoxi- ARTS structure and expression in rat cortical neurons cally, the total activity (sun of basal and evoked activity) remains unchanged. In contrast, coexpression of phosducin Weinstein N. and Finberg J. P. (common G[betagamma] scavenger molecule) reduced the Molecular Pharmacology Department, Rappaport Faculty of total activity. Biochemical data suggested that the rise in Medicine,Technion, Haifa, Israel GIRK1/2 density is accompanied by increase in the concentration of G protein subunits (mostly G[betagamma]) in The pro-apoptotic protein ARTS is a member of the plasma membrane (co-trafficking). We developed a kinetic septin family, but is derived by alternate splicing from the model of GIRK1/2 activation by G[betagamma] which ac- H5/PNUTL2/hcdcrel2a/2b gene and differs in its C-terminal counts for the activation of the channel via G protein cy- from other products of this gene. ARTS promotes apopto- cle. This model is based on the idea of graded contribution sis induced by a variety of apoptotic stimulators. In cells of of each G[betagamma] liganded GIRK monomer to chan- human peripheral tissue origin, ARTS is located in the mito- nel opening. The model renders sufficiently fast activation chondria and translocates to the nucleus at the start of apop- rate by agonist application (tau of 1-2 s). We assumed co- tosis, but in rat cortical neurons ARTS is localized in both trafficking of GIRK1/2 with different amounts of G protein cytoplasm and nucleus. ARTS induces apoptosis by bind- subunits to the membrane and simulated the channel activ- ing to and antagonizing IAPs (inhibitors of apoptosis pro- ity with different channel concentrations in membrane (den- teins), thus removing caspase inhibition and activating the sity effect). The model reasonably reproduced the observed apoptotic cascade. ARTS is strongly expressed in the brain data (changes in basal, evoked, total activities and the acti- and may play an important role in the nervous system. The vation ratio). However, the model failed to account for the ARTS protein in peripheral cells has a molecular size on gel difference observed between the co-expression of G[alpha]i electrophoresis of 32 kDa in human and 28kDa in rat. How- and phosducin. This fact points towards additional, possi- ever ARTS in human brain tissue has a molecular weight of bly allosteric, function of G[alpha]i subunit in modulation 28 kDa and 22 kDa in rat brain tissue. We have sequenced of GIRK channel activity. 116 Neural Plasticity

A Complex Norepinephrine and Glucocorticoid Recently, with the advance of intracellular recording, it was Intercellular Interaction: Relevance to Plasticity found that neurons in the mammalian cortex exhibit sponta- Hypothesis of Depression neous transition in membrane potential from UP to DOWN states. It has been suggested that these oscillatory fluctua- Yaniv S. P.,1 Klein E.,2 and Ben-Shachar D.1 tions in membrane potential, which are the cellular manifestation of the brain’s rhythmic activity, reflect network- rather 1Laboratory of Psychobiology, B. Rappaport Faculty of than cellular-properties. However, the biophysical mecha- Medicine, Technion, Israel nisms underlying these network oscillations are still debated. 2Department of Psychiatry, Rambam Medical Center, Israel Using an in-vivo whole cell technique, we recorded from 56 pyramidal neurons in the prefrontal and somatosensory cor- The plasticity hypothesis of major depression states that glu- tices of adult rats under Ketamine-Xylazine anesthesia. The cocorticoids (GCs) may be detrimental to neuronal plasticity membrane potential of the cells displayed rhythmic alterna- while monoamines, as well as antidepressants, may recon- tions (average frequency of 3 Hz), between high and low lev- stitute cellular plasticity. Given the key role norepinephrine els of membrane potentials and were manifested as a promi- (NE) and GC play in stress and depression, our aim is to nent peak in the voltage spectrogram. Overshooting action search for a shared NE and GC intracellular pathway affect- potentials occurred solely during the depolarized levels. The ing plasticity with relevance to depression and its treatment. distributions of the recorded voltage were either unimodal In SH-SY5Y human neuroblastoma cells, DEX, a synthetic (with a prolonged tail) or bimodal. DC current injection into GC receptor agonist, altered cellular morphology opposite cells that showed bimodal distribution revealed that, in 37% to the differentiative effects of NE. This was accompanied of these cells, the voltage distribution was independent of the by a reduction in mRNA and protein expression of the dif- average membrane potential. In the remaining cells, chang- ferentiation markers Gap-43 and L1 as well as protein levels ing the holding potential significantly alters the voltage dis- of an additional marker laminin. Down-regulation was also tribution, increasing the voltage difference between the two observed in the transcription factor CREB and in phospho- peaks of the histogram upon hyperpolarization. This effect rylated CREB (pCREB). NE treatment increased Gap-43, L1 on the voltage distribution can only be accounted for if each and laminin protein and mRNA levels as well as pCREB pro- of the two peaks represents a different conductance state. In- tein levels. The opposite effects of NE and DEX on identical deed, an average 54% change in input conductance between genes suggest a common signaling pathway. The MAPK in- the UP and DOWN states was calculated for 10 cells. The duced transcription factor AP-1 (c-Jun/c-Fos) can modulate similar dependence of the two states on the current injection the aforementioned genes. Both ERK and c-Jun were acti- can be explained by assuming that the location of the con- vated following NE treatment, while DEX did not affect these ductance change that generates the UP and/or DOWN state proteins yet reduced c-Fos expression. Co-administration of is spatially remote from the recording electrode. Hence the DEX and NE resulted in over-activation of the ERK path- integrative capabilities of a population of cortical neurons way, associated with an increase p-c-Jun and c-Fos, and was can be independent of their state. accompanied by differentiative morphology. In addition, coadministration, as well as NE, increased AP-1 activity. Fur- The impact of geometry in shaping exploratory thermore, in these cells expressing solely the Gi coupled al- behavior in rats: interpretation in terms of urban pha2 adrenergic receptor, pCREB was hyper-activated in an planning ERK independent manner. These results suggest AP-1 as a 1 2 convergent point for NE and DEX induced signaling path- Yaski O. and Eilam D. ff ways. Elucidating a pathway a ected by stress and antide- Department of Zoology, Faculty of Life Sciences, pressants, represented by DEX and NE, respectively, involved Tel Aviv University in neuronal plasticity may contribute to understanding the biological basis of depression, its etiology and treatment. In order to study the impact of the surrounding landscape on exploratory behavior of rats, two experiments were con- SupportedbyIsraelMinistryofHealth. ducted. In the first rats were tested in a square arena with additional free-standing (portable) corners, featuring the same Is conductance change involved in the shift between properties as the arena corners. It was found that the routes UP and DOWN states of rat neocortical neurons? of progression converged upon the added corners probably since the added corners were distinct against the background Yaron-Jakoubovitch A.,1,2 Koch C.,3 Segev I.,1,2 of the arena enclosure. This implies that the four arena cor- and Yarom Y.1,2 ners and walls were encoded as one geometric module, and the distinctness of the added corners made them a target 1Department of Neurobiology, The Hebrew University, of exploration. Thus, the impact of a corner extended be- Jerusalem, Israel yond the specific self-geometry and depends on the back- 2The Interdisciplinary Center for Neural Computation, ground environment. In the second experiment rats were The Hebrew University, Jerusalem, Israel introduced into either a round or a square arena with var- 3Computation and Neural Systems Program, ious arrays of free-standing corners that differed in spac- California Institute of Technology, Pasadena, Calif, USA ing, orientation, and number. The rats were able to detect Israel Society for Neuroscience 117 the geometry of the enclosure, the array, and the landmarks: Working memory across nostrils they favored the added corners particularly in the round compared with the square arena, and stayed at the interior Yeshurun Y., Dudai Y., and Sobel N. of the added corner regardless of their orientation in the ff Department of Neurobiology, The Weizmann Institute of arena. Only geometric changes in landmark array a ected Science, Rehovot 76110, Israel rats’ level of activity. It is suggested that the context and geometry of the environment affects the distinctness and the Olfactory working memory (OWM) maintains information meaning of landmarks for the observer, which in turn results over short information over short time frames. Whether in a different distribution of activity. Altogether, the two ex- this involves verbal representations or neural images of odor periments illustrate that the impact of the environment on per se, is unknown. Also, the contribution of primary ol- exploratory behavior of rats resembles that of environmental factory structures versus higher-order brain systems is un- elements in urban environments. We suggest that principles clear. To address this, we set out to test OWM across nos- involved in shaping the image of a city in urban planning may trils. Considering the predominantly ipsilateral nature of ol- be applicable for understanding how the physical structure factory projections, we hypothesized that nonverbal OWM of the environments shapes exploration and navigation in images would result in no effect of nameability and better animals. overall performance within the same nostril, and in contrast, that verbal OWM images would result in a main effect of Natural developmental optical astigmatism during nameability, and a possible left nostril advantage. Twenty- childhood induces “cortical astigmatism” in the adult one subjects participated in a button-press delayed-match- visual cortex to-sample task (trials = 96, ISI = 12 s, ITI = 30 s), with 10 nameable and 10 unnameable odorants, chosen per subject. Yehezkel O. and Polat U. In 1/3 of the trials “sample” and “match” were presented in Sackler Faculty of Medicine, Tel Aviv University, Goldschleger the same nostril, 1/3 of the trials “sample” was presented Eye Research Institute, Tel Hashomer, Israel in one nostril, and “match” in the other, and in 1/3 of the trials “sample” and “match” were delivered to both nostrils. Maturation of neural connectivity is experience dependent in Odorant order was randomized, and test side was counter- such a way that the state of the visual input during the criti- balanced. Presented results refer to trials where “sample” and cal period can be inferred from the visual functions in adults. “match” were the same. There was a nameability main effect In meridional amblyopia, the visual input during the criti- (F(1,20) = 8.75, P<0.0077), reflecting more mistakes when cal period was asymmetrical; hence, the perception in one the odorants were not nameable. Reaction time (RT) mea- meridian was blurred, whereas the orthogonal one was nor- surements revealed a nostril-side main effect (F(2,40) = 5.1, mal. Consequently, in adults, the contrast sensitivity and the p<0.01), reflecting overall longer RT when the odor was lateral interactions are dramatically reduced in the blurred delivered across nostrils then in both nostrils, and a name- meridian, whereas they are practically normal in the orthog- ability by side interaction (F(2,40) = 6.33, P<.004) implying onal one. However, asymmetric visual input is common dur- that the nameability effect (longer RT for unnameable odors) ing normal development and children below four years of age wasmorepronouncedwhensubjectsweretestedacrossnos- tend to be astigmatic (with the vertical meridian being more trils (P<.015). These findings imply dual representations in blurred than the horizontal meridian). However, this effect OWM: when a verbal representation is available, it is equally decreases and usually disappears with increasing age. Here accessible to both nostrils, but when an odor image is re- we explored whether this visual asymmetry during the criti- membered, it offers preferred access to the nostril that gen- cal period, shaped the development of the visual connectiv- erated it. ity and induced cortical asymmetry that was retained during adulthood in people with normal vision (i.e., better devel- The endocannabinoid-like N-arachidonoyl-L-serine opment of the horizontal meridian). We tested subjects with improves outcome after traumatic brain injury corrected vision of 6/6 or better (n = 11). Contrast sensitiv- Yeshurun-Cohen A.,1,2 Leker R.,3 Alexandrocivh A.,1 ity (CS) to Gabor patches (GP) was measured for a few spa- 2 1 tial frequencies (3, 6, 9, and 12 cpd) under monocular condi- Mechoulam R., and Shohami E. tions. We also measured the monocular collinear facilitation 1Department of Pharmacology, The Hebrew University (9 cpd, target-flanker separation of 3 lambada). We found a School of Pharmacy, Jerusalem, Israel significant asymmetry in monocular CS; it was better in the 2Department of Medicinal Chemistry, The Hebrew Unviersity horizontal meridian. The facilitation was significantly dif- Faculy of Medicine, Jeursalem, Israel ferent between the two meridians regardless of the contrast 3Department of Neurology, Hadassah University Hospital, thresholds of the single target. Our results show that neural The Hebrew University, Jerusalem, Israel connectivity in the normal visual cortex of adults is asymmetric, displaying “cortical astigmatism,” thus mirroring the Background early optical asymmetry during the developmental period in childhood. The endocannabinoid 2-arachidonoyl-glycerol (2-AG) was shown to afford neuroprotection via CB1-receptor mecha- SupportedbyagrantfromtheIsraelScienceFoundation. nisms. Recently a non-fCB1, non-CB2 endocannabinoid-like 118 Neural Plasticity

N-arachidonoyl-L-serine (AraS) was found in the brain. It realized by the subset of proteins which are expressed. Epi- is an endothelium-dependent vasodilator with antiapoptotic genetic mechanisms such as DNA methylation are emerging effects, and was shown to stimulate Akt phosphorylation in as important regulators of neuronal gene expression. Hence human umbilical vein endothelial cells and suppress LPS- the present study analyzed the patterns of methylation of the induced TNFalfa in macrophages. We here compared the ef- promoter of a known regulator of neuronal plasticity, the fects of this compound after traumatic brain injury (TBI) to brain-derived neurotrophic factor (BDNF), during a 24 hour those of 2-AG. heat conditioning of chicks on the third postnatal day and during 24 hours of thermal challenge a week later. The exper- Methods iments looked at the expression of the BDNF gene along with the levels of DNA methylation of 6 different CpG positions Mice were subjected to TBI and treated 1 h later with either on the BDNF promoter at different time points during heat AraS, 2-AG or vehicle. Neurobehavioral function of the in- conditioning and challenge (day 10). Our data show a tran- jured mice was assessed by the Neurological Severity Score sient increase in BDNF expression during heat condition- (NSS), and lesion volume was evaluated by staining with ing which peaked 6 and 12 hours into conditioning. Concur- 2,3,5-triphenyltetrazolium chloride, that binds to viable mi- rently, there was a transient induction of methylation of two tochondria. In addition, the effect on the proliferation of CpG positions (the first and the third CpG location down- neural progenitor cells was assessed in-vitro by the size of stream from the BDNF-ATG) and a reduction of methylation neurospheres isolated from embrional mouse brain tissue of one CpG position (1000 bp downstream from the BDNF- (E15) and grown for 4d, using the Image-Pro-Plus software. ATG), while the other positions did not show significant change. Furthermore, our data demonstrate a significant dif- Results ference between the levels of methylation of the BDNF promoter of conditioned compared to nonconditioned chicks During 90d after injury the neurobehavioral outcome of the during a thermal challenge, which correlates with the differ- mice treated with 2-AG or AraS was significantly better than ent levels of BDNF in the two groups. These data suggest that that of the vehicle-treated mice. In addition, lesion volume complex and dynamic changes in DNA methylation might measured 24 hours after trauma was smaller in the groups be involved in the regulation of thermotolerance acquisition subjected to either 2-AG or AraS compared to vehicle. More- and support the role of DNA methylation in the regulation over, preliminary experiments showed that exposure of neu- of gene expression during neuronal plasticity. rospheres, consisted of multipotential neural precursor cells to AraS led to a 2 to 4-fold increase in the size of the treated Coding selectivity of object location in the secondary spheres after 4d as compared to untreated ones. somatosensory cortex during active vibrissal touch

Conclusion Yu C., Haidarliu S., Derdikman D., Rubin N., and Ahissar E. The endocannabinoid-like AraS, similarly to the 2-AG, may act as a neuroprotectant after TBI by reducing infarct vol- Department of Neurobiology, Weizmann Institute of ume, facilitating long-term function recovery and probably Science, Israel also by promoting proliferation of neural precursor cells. The ff cellular mechanisms of these e ects are currently being inves- Sensation is an active process. When the sensors move, both tigated. motion and touch signals are crucial for sensory processing. Recently, we showed that whisker-motion and contact signals Supported by grants from AMRF/APNRR and from NIDA no. are conveyed in parallel via the thalamus. Yet, it is unknown DA9289. how downstream brain areas process these signals to localize objects. Specifically, the function of secondary somatosen- Dynamic changes in DNA CpG dinucleotide sory cortex (S2), which receives massive thalamic projections methylation in the brain-derived neurotrophic factor from both whisker-motion and contact pathways, is poorly (BDNF) promoter area during thermal control understood. Here, neuronal activities from S2 in response establishment to object touch were recorded using artificial whisking in Yossifoff M., Kisliouk T., and Meiri N. anesthetized rats. We found that high proportion of neurons (41%) in deeper layers (layers 4, 5 and 6) of S2 (S2-L46) Institute of Animal Science, ARO, The Volcani Center, show significant selectivity to object location, in distinction Bet Dagan 50250, Israel with the superficial layers (layers 2/3) of S2 (20%). Similar to the latter, small fractions (<23%) of neurons in three thala- The critical period for thermal control establishment in mic nuclei (POm, VPMdm, VPMvl) and three layers (2/3, 4 chicks spans between postnatal days three and five. Heat con- and 5a) of the primary somatosensory cortex (S1) displayed ditioning of chicks during that time frame enables them to be significant selectivity to object location. We further investi- more tolerant to heat later in life. This modulation is thought gated the dynamics of responses in all these somatosensory to be carried out by alteration of neuronal properties in the sites during whisking in free air and against objects in various preoptic anterior hypothalamus (PO/AH) which is probably locations. Comparison of the dynamics of location-selective Israel Society for Neuroscience 119

(S) cells with those of nonselective cells revealed several dif- Circuitry underlying perceptual learning in ferences. Among these differences was a lack of a slow-wave behaving monkeys dynamics in S cells, different response dynamics during retraction, and a weaker response of S cells to the first cycle Zach N.,1,2 Inbar D.,1,2 Grinvald Y.,1 and Vaadia E.1,2 in VPMdm and S1-L4. Comparison of response dynamics across nuclei revealed two major patterns of cortical dynam- 1Physiology Department, Hadassah Medical School, ics, one evident in S2-L46 and S1-L5a and another in S2- Hebrew University Jerusalem, Israel L23 and S1L4. The analysis so far thus suggests that cortical 2ICNC, Interdisciplinary Center for Neural Computation, processing of active touch is done in parallel in at least two Hebrew University Jerusalem, Israel streams, that processing of object location involves several brain sites, among which a significant processing of object Learning new sensorimotor tasks involves plastic changes in location is performed in the deep layers of S2. responses of the primary motor cortex (M1) and the Premo- tor area (PM). We have shown such changes accompanying Induced gamma in the eye of the beholder: both the learning process and the consolidation into long single trial analysis of induced gamma band term memory that follows learning. Since contextual infor- responses in human observers mation has been shown to affect the learning of various sensorimotor tasks, we investigated the effect of context on neu- 1 1,2 3 Yuval-Greenberg S., Tomer O., and Deouell L. Y. ronal response in the motor cortices. In order to do so, we si- 1Department of Psychology, The Hebrew University of multaneously recorded neuronal activity from 32 electrodes Jerusalem, Israel in M1 and Premotor cortices of two behaving monkeys. In 2The Interdesciplinary Center for Neural Computation, each session, the monkeys performed first a center-out task The Hebrew University of Jerusalem, Israel and then, they had to learn a novel arbitrary associations 3Department of Neurobiology, The Hebrew University of task (where they had to learned a color-direction associa- Jerusalem, Israel tion), and then they performed a second block of the center- out task. We compared neuronal responses during trials fea- In the last decade a large amount of electrophysiological re- turing the same movement direction and target color, either search has focused on high frequency brain activity in hu- made during the center-out task or during the arbitrary as- mans, and specifically on the “induced gamma response” sociation task (only trials of stable plateau performance was (iGBR). This response is a typical increase in the gamma included). Also, we compared the two center-out blocks to band (>30 Hz) peaking around 250 milliseconds post stimu- eliminate effects of passage of time. We found that about 65% lus, following the presentation of a visual stimulus. The iGBR of the neurons showed significant difference in responses was hypothesized to represent the neural synchronization in- when the very similar movements made in different contexts. volved in various cognitive functions such as binding and Differences included both firing rate change and change in consciousness. The iGBR is calculated by averaging single tri- response pattern. These differences could not be accounted als’ spectral data, circumventing phase cancellation due to for by any change in movement parameters. These results inter-trial latency jitter Our study is the first attempt to look demonstrate that the motor cortices are liable to contextual at gamma responses in single trials. Subjects performed a vi- modulation, and broaden our knowledge on motor cortices sual paradigm in which all subjects demonstrated a promi- dynamics. nent iGBR. In each subject many of the single trials exhibit a gamma increase at a similar latency, topography and fre- Capacity of binned neural channels during quencies as the average iGBR. Examination of the EEG data experiments with brain-machine-interfaces shows that each gamma increase is characterized by a sharp peak in the filtered data (30–100 Hz) of central channels. In Zacksenhouse M.,1 Lebedev M.,2 and Nicolelis M.2 addition, a prominent peak with an opposite polarity appears at the EOG channels placed around the eyes. In a simultane- 1Faculty of Mechanical Engineering, Technion-IIT, ous recording of eye position (using an eye tracker device) it Haifa, Israel was found that these gamma increases are frequently accom- 2Center for Neuroengineering, Duke University, panied by an eye movement. As a further analysis, trials were Durham, NC, USA sorted according to eye movements in the relevant time window. Averaging across the third of trials with the strongest eye Brain machine interfaces extract relevant information, like movements, the iGBR was exceptionally high. In contrast, the velocity of the intended movement, from recorded neu- when the average was performed across a third of trials show- ral activity. However, while the recorded neural activity is in ing the least eye movements, the iGBR was eliminated. The the form of spike trains, most decoding algorithms are based relation between eye movements and gamma power was fur- on the binned spike counts. The bin-width (BW) is usually ther demonstrated when sorting by gamma power and exam- determined by trial and error or based on previous expe- ining the eye movements. These findings show a strong rela- rience. Here we investigate the effect of the bin-width on tion between iGBR and eye movements, challenging prevail- the signal-to-noise ratio (SNR), and on the ratio SNR/BW. ing models of the neural origin of the scalp recorded iGBR The latter is shown to be related to the capacity of the neu- and the related cognitive processes. ral channel under different assumptions. Furthermore, while 120 Neural Plasticity the SNR increases with the BW, the update rate decreases, The correlation between the Translocator Protein suggesting that the ratio SNR/BW should be considered as (TSPO) and apoptosis in human glioma cells under a relevant criterion. The SNR is estimated under the as- hypoxia sumption that the neural spike trains are realization of dou- bly stochastic Poisson processes–the simplest point processes Zeno S.,1 Veenman L.,1 Leschiner S.,1 Zaarur M.,2 that can encode stochastic signals. Analysis of neural spike- and Gavish M.1 ff trains recorded during BMI experiments from di erent cor- 1 tical areas, indicate that the mean SNR/BW had a broad peak Neurology, Medical Faculty, Technion-Israel Institute of Technology, 31096 Haifa, Israel around 100 milliseconds—the bin-width that was selected by 2 trial and error. However, detailed analysis indicates that the Rambam Medical Center, 31096 Haifa, Israel SNR/BW of different neurons peak at different bin-widths. The translocator protein (TSPO) can be found in conjunc- In particular, the SNR/BW of M1 neurons peak at shorter tion with the mitochondrial 32 kDa voltage-dependent anion bin-widths, while that of PMd neurons peak at longer bin- channel (VDAC) and the 30 kDa adenine nucleotide trans- widths. porter (ANT). The VDAC and ANT form the core elements Supported by Fund for Promotion of Research at the Technion, of the mitochondrial permeability transition pore (MPTP). DARPA, NIH, NSF. Opening of the MPTP can start the mitochondrial apoptosis cascade. Furthermore, the TSPO has been suggested to Adaptive motor control during experiments with act as an oxygen sensor. Oxygen related mechanisms induce Brain Machine Interfaces prominent clinically relevant changes in cancer cells and tumor biology through the control of gene expression. There- Zacksenhouse M. and Beiser K. fore, we studied the levels of TSPO and apoptosis in glioma cells under hypoxic conditions. To do this, we applied ei- Faculty of Mechanical Engineering, Technion-IIT, Haifa, Israel ther an environment with 1% oxygen (hypoxia) or added CoCl2 to the medium (0.25 mM, 0.4 mM, and 1 mM). Treat- Recent experiments with Brain Machine Interfaces indicate ments with 1% oxygen resulted in an increase in the levels that the extent of neural modulations increases abruptly of TSPO (Western) and an increase in TSPO binding den- upon starting to operate the interface. In contrast, neural sity. Furthermore, 1% oxygen levels resulted in an increase in modulations due to the trajectory profile remain relatively apoptosis levels (50%). Adding CoCl2 (0.25 mM) to the cells unchanged. Furthermore, the enhanced modulations sub- also resulted in an increase in apoptosis levels (40%). How- side with further training, mirroring the trend in task per- ever, the binding density of TSPO was unchanged with ap- formance, which degraded upon starting to operate the in- plication of CoCl2. We also found that under treatment with terface and improved gradually with training. Here we in- CoCl2, the amount of P53 is decreased, suggesting a dereg- vestigate the hypothesis that the enhanced modulations re- ulation of the cell cycle. Stabilization of HIF1-α level indi- flect internal representation of trajectory errors, which re- cated that in our model CoCl2 (0.25 mM) treatment indeed sults in corrective commands in the short term and adap- mimics hypoxia conditions. Our results indicate that reduced tive modifications of internal models in the long term. A oxygen levels affect both TSPO levels and apoptosis, while simplified unidimensional model is analyzed to demonstrate CoCl2 only affects apoptosis. Other preliminary results, from the observed transient enhancement in neural modulations TSPO knockdown with siRNA, suggest however that CoCl2 during the operation of Brain machine Interfaces. Identify- also induces apoptosis via TSPO. These results suggest that ing the source of the transient enhancement in neural mod- TSPO as an oxygen sensor may play a role in the induc- ulation would provide insight into adaptive motor control tion of apoptosis levels due reduced oxygen levels. This may and facilitate the improvement of future Brain Machine In- have implications for our understanding of the involvement terfaces. Analysis of the model yields the conditions under of TSPO in pathological conditions such as ischemia and which it is stable, reduces the motor error and acquires the cancer. correct inverse internal model/feedforward controller. Sim- ulations of both skilled and BMI operations, using param- Research support: WK, LV, ML, and MG (Joint Lower Saxony- eters and signals from experiments, yield results with sim- Israeli Research Projects, VWZN2047). ilar characteristics as those observed in experiments in regards to both tracking performance and to neuronal mod- Inferring cognitive states from ulation levels. Our model gives rise to the hypothesis that magnetoencephalographic (MEG) signals: motor neurons are tuned both to preferred desired direc- feature selection framework tions and preferred error directions, further more, it stresses the importance of adequate tuning to error directions with- Zhdanov A.,1,4 Hendler T.,1,2 Ungerleider L.,3 out which the model is not stable and unable to reduce and Intrator N.4 the motor error by feedback control or to adapt the cor- 1 rect internal inverse model that will perform as feedforward Functional Brain Imaging Unit, Tel Aviv Sourasky Medical controller. Center, Israel 2Psychology Department and Faculty of Medicine, Fund for Promotion of Research at the Technion. Tel Aviv University, Israel Israel Society for Neuroscience 121

3Lab of Brain and Cognition, NIMH, NIH, Bethesda, USA Hits elicited smaller Gamma amplitudes than CR, which is 4School of Computer Science, Tel Aviv University, Israel in line with previous studies demonstrating a reduction in Gamma activity for repeated stimuli and has been attributed We develop a robust linear classification framework for in- it to a “sharpening” of the cortical representation activated ferring mental states from electrophysiological (MEG and by the stimulus. This study demonstrates that both Theta EEG) signals. The framework is centered around the concept and gamma activity play a role in retrieval of memories for of temporal evolution of regularized Fisher Linear Discrim- faces, and suggests that whereas Theta activity is related to inant classifier constructed from the instantaneous signal mnemonic processing irrespective of pre-experimental fa- value. The value of the regularization parameter is selected miliarity with the stimuli, Gamma activity is involved in the to minimize the classifier error estimated by cross-validation. activation of neural representations and is modulated by re- We build upon the proposed framework to develop a feature cent exposure to the same stimulus. selection technique. We demonstrate the framework and the feature selection technique on MEG data recorded from 10 Proteolysis and membrane capture of F-spondin subjects in a simple visual classification experiment. We show generates combinatorial guidance cues from that using a very simple adaptive feature selection strategy a single molecule yields considerable improvement of classifier accuracy over the strategy that uses fixed number of features. Zisman S., Marom K., Avraham O., and Klar A.

This research was supported by a Bikura grant from the Israel Department of Anatomy and Cell Biology, Hebrew University, Science Foundation and by a grant from the US-Israel Bina- Hadassah Medical School, Jerusalem, Israel tional Science foundation (BSF). The formation of neuronal networks is governed by a lim- Do you remember me? retrieving memories for ited number of guidance molecules, yet it is immensely com- faces—evidence from theta (4–8 Hz) and gamma band plex. The complexity of guidance cues is augmented by post- (>30 Hz) Activity translational modification of guidance molecules and their receptors. We report here that cleavage of the floor plate Zion Golumbic E.,1 Kutas M.,2 and Bentin S.3,4 guidance molecule F-spondin generates two functionally opposing fragments: a short-range repellent protein deposited 1 Department of Cognitive Science, The Hebrew University of in the membrane of floor plate cells, and an adhesive pro- Jerusalem, Israel tein that accumulates at the basement membrane. Their co- 2 Department of Cognitive Science, University of California, ordinated activity, acting respectively as a short-range repel- San Diego, Calif, USA lant and a permissive short-range attractant, constricts com- 3 Department of Psychology, The Hebrew University of missural axons to the basement membrane beneath the floor Jerusalem, Israel plate cells. We further demonstrate that the repulsive ac- 4 Center for Neural Computation, The Hebrew University of tivity of the inhibitory fragment of F-spondin requires its Jerusalem, Israel presentation by LRP receptors ApoER2, LRP2/megalin and LRP4, which are expressed in the floor plate. Thus, prote- Social interaction depends on our ability to create, store and olysis and membrane interaction coordinate combinatorial retrieve memories for human faces. Learning new faces is guidance signaling originating from a single guidance cue. unique not only due to the special nature of face processing but also because it requires forming detailed neural rep- Early perceptual loss in depression resentations. To date few studies have investigated the neural mechanism involved in learning new faces. In the present Zomet A.,1,3 Amiaz R.,2,3 and Polat U.1,3 study subjects studied a series of faces and were then tested on their memory for them when presented again interspersed 1Goldschleger Eye Research Institute, Tel-Aviv University among new faces. Both famous and nonfamous faces were 2Department of Psychiatry, Israel used, in separate blocks, in order to compare memory for 3Sheba Medical Center, 52621 Tel Hashomer, Israel faces which subjects have prior experience with and new faces which subject have no previous representation for. EEG was In our previous study, we found that the filling-in process recorded and we focused primarily on two electrophysio- is impaired in patients with depression, as evident by their logical measures of neural activity: theta-band activity (4- reporting less target present than the control group. We sug- 8Hz) which has been associated with successful encoding and gested that this deficit is due to an abnormal balance of the retrieval of memories and Gamma-band activity (>30 Hz) excitation and inhibition between neurons. However, it is still which has been linked to activating a neural representation possible that the response criterion in these subjects is more matching an incoming stimulus. We compared activity dur- conservative, due to general indifference. In this study, we ing the test phase in response to correctly remembered faces used a forced choice task (to neutralize the internal crite- (hits) with correctly categorized new faces (CR). Theta ac- rion), and a static presentation (no limitation of information tivity was similar for both famous and nonfamous faces and processing time) to minimize the attentional effect. We mea- was larger for hits than for CRs. In contrast, Gamma activ- sured the contrast threshold of a Gabor target that was pre- ity was larger for famous faces than for nonfamous faces. sented at the left or the right side of the screen (1.2◦ each side) 122 Neural Plasticity between two flankers (12 cpd), separated at 7 distances from 0 to 12 lambda. The short distances test contrast discrimination and the far distances contrast detection. We found that the function of the control group is similar to the standard function, found when using 2 temporal alternative forced choice (2AFC), showing suppression in 0 and 1 lambda and facilitation at the far distances. On the other hand, the depressed subjects performed like the control subjects only at the far distances, whereas at the short distances (contrast discrimination), the expected suppression is absent and is replaced by facilitation. Since suppression in contrast discrimination tasks is explained as largely due to response saturation of neurons, we suggest that high levels of inhibition prevent the neurons from reaching saturation. High levels of inhibition reduced the level of excitation, which in turn will lead to an impaired filling-in process in depressed subjects.

Supported by the National Institute of Psychobiology in Israel. Author Index

A reduced astrocyte activation, amyloid-Beta and Abdu U. (with Magidovich H., Orr I., Fass D., and Yifrach p-tau pathology, 38 O.): The role of intrinsically-disordered protein Agam G. (Mann L., Heldman E., and Belmaker R. H.): segments in mediating Kv channel clustering: The Inhibitory Effect of Mood Stabilizers on implications for synapse assembly, maintenance Adenylyl Cyclase Isoforms, 73 and function, 71 Agam G. (with Amar S., Shamir A., Ovadia O., Blanaru Abrameto J. (with Ben Porata J., Terkieltaub D., Goren O., M., Reshef A., Kremer I., Rietschel M., Maier Yakov N., Sharon N., Zaretsky I., W., Belmaker R., Ebstein R., and Mishmar D.): Shaki-Loewenstein S., Hazum S., Gopher J., Mitochondrial DNA HV lineage increases the Ohayon T., and Eren R.): Immunotherapies for susceptibility to schizophrenia among Israeli Alzheimer’s Disease, 11 Arabs, 4 Abramovitch-Dahan C., Beit-Yannai E., Ben-Shabat S., Agam G. (with Bromberg A., Levine J., Nemetz B., and and Fleisher-Berkovich S.: Protective effect of Belmaker R.): Global leukocyte DNA N-acetyl-L-Carnosine, a lipophilic derivative of methylation in schizophrenia patients, 18 L-Carnosine, on lipopolysaccaride-induced glial Agam G. (with Eskira Y., Levi I., and Almog O.): Novel oxidative stress, 2 approach to inhibit inositol monophosphatase Abramov E. (with Slutsky I. and Ruff E.): as an alternative to Lithium as a mood The physiological and pathological activities of stabilizer, 33 amyloid-beta peptide: From synaptic release to Agam G. (with Hadas I., Belmaker R., and Bersudsky Y.): information processing in neuronal IMPA1 and lithium-like behavior, 49 networks, 106 Agam G. (with Levi I., Shamir A., Cryns K., Steckler T., Abramov E. and Slutsky I.: Amyloid-beta peptide Moechars D., and Belmaker R.): modulates the pattern of transmitter release in Characterization of the IMPA1 deficient hippocampal synapses, 2 mouse, 67 Aharoni A. (with Rephaeli A., Gil-Ad I., Trasenko N., Abramsky O. (with Boimel M., Grigoriadis N., Tarasenko I., Geffen Y., Savitsky K., Weizman Lourbopoulos A., and Rosenmann H.): A., and Nudelman A.): Amidic GABA Immunotherapy targeting pathologically derivatives of antidepressants display improved phosphorylated tau conformers in a tangle pain suppressing activity, 89 mouse model, 17 Ahissar E. (with Horev G., Knutsen P. M., and Pietr M.): Abrous N. (with Kaouane N., Calandreau L., Esclassan F., ff Stereotyped whisker and head movements are Tronel S., Mons N., Ja ard R., Piazza P., and associated with object localization in Desmedt A.): Boundary conditions of unrestrained rats, 55 corticosterone-dependent enhancement or Ahissar E. (with Saig A. and Arieli A.): The “human alteration of memory consolidation, 60 rat”–learning to use a new sense via sensory Abu-Ghanem Y., Cohen H., Amitai Y., and Grauer E.: substitution principles, 95 Enhanced stress-induced responses in an Ahissar E. (with Simony E. and Golomb D.): Role of atroglial NOS2 mouse mutant, 2 Sensory Feedback in determining the Firing Abush H. and Akirav I.: The role of CB1 receptors in the Patterns of Vibrissa Motoneurons, 105 hippocampus and nucleus accumbens in Ahissar E. (with Yu C., Haidarliu S., Derdikman D., and extinction learning and neural plasticity, 3 Rubin N.): Coding selectivity of object location AchironA.(withDeriY.,MironS.,Hoffmann C., Konan in the secondary somatosensory cortex during E., and Biegon A.): Selective hippocampal active vibrissal touch, 118 atrophy in Multiple Sclerosis quantitave MRI Ahissar M. (with Biron T.): On the implicit usage of studies, 26 repeated reference stimuli in the visual Ackerman Z. (with Magen I., Avraham Y., Berry E., and modality, 15 Mechoulam R.): Cannabidiol (CBD) Ahissar M. (with Cochavi M.): On the use of reference in ameliorates cognitive impairments associated auditory duration discrimination, 22 with a model of chronic liver disease in mice, 70 Ahissar M. (with Daikhin L. and Nahum M.): Fast Adlard P. A. (with Friedman J. E., Eilam R., Madala switching from computation based to memory Halagappa K. V., Mattson M. P., Bush A. I., based perception–evidence from ERP, 23 David Y., and Kozak A.): Improved cognition in Ahissar M. (with Nahum M. and Levi M.): Limitations of female triple transgenic AD mice treated with stimulus-anchoring mechanisms: evidence from lipophilic metal chelators is associated with behavioral and ERP data, 78

123 124 Neural Plasticity

Aizenstein O. (with Ben Bashat D., Drory V. E., Artzi M., Amar S., Shamir A., Ovadia O., Blanaru M., Reshef A., Nefussy B., Zachor T., and Assaf Y.): White Kremer I., Rietschel M., Maier W., Belmaker R., matter impairment in Amyotrophic Lateral Ebstein R., Agam G., and Mishmar D.: Sclerosis (ALS): Diffusion tensor imaging and Mitochondrial DNA HV lineage increases the high b-value DWI study, 11 susceptibility to schizophrenia among Israeli Akirav I. (with Ganon E.): The involvement of stress and Arabs, 4 cannabinoid CB1 receptors in extinction of Amedi A.: Perception from a blind perspective: inhibitory avoidance in the amygdala, 40 Multisensory integration and sensory Akirav I. (with Abush H.): The role of CB1 receptors in substitution in blind and sighted individuals, 4 the hippocampus and nucleus accumbens in Amiaz R. (with Zomet A. and Polat U.): Early perceptual extinction learning and neural plasticity, 3 loss in depression, 121 Akkawi S. (with Wald H., Sicsic C., Irony-Tur-Sinai M., Amihai I., Deouell L. Y., and Bentin S.: The N170 Higazi A. E., and Brenner T.): Involvement of sensitivity to faces is dissociated from conscious plasminogen activator system in awareness, 4 immunomoudulation of experimental Amitai Y. (with Abu-Ghanem Y., Cohen H., and autoimmune myasthenia gravis, 114 Grauer E.): Enhanced stress-induced responses Albelda N. (with Arad M. and Joel D.): The effects of in an atroglial NOS2 mouse mutant, 2 withdrawal from chronic administration of Andelman F. (with Fisch L., Privman E., Kramer U., estradiol on “compulsive” lever-pressing of Kipervasser S., Neufeld M., Fried I., and Malach female rats–A preliminary study, 5 R.): Neural correlates of visual recognition Alexandrocivh A. (with Yeshurun-Cohen A., Leker R., revealed through backward masking and Mechoulam R., and Shohami E.): The intracranial electrode recordings, 36 Endocannabinoid-Like Andelman F. (with Privman E., Fisch L., Kramer U., N-Arachidonoyl-L-Serine Improves Outcome Kipervasser S., Neufeld M. Y., Yehezkel Y., Fried after Traumatic Brain Injury, 117 I., and Malach R.): Sustained image Alexandrovitch A. G. (with Tsenter J., Beni-Adani L., Assaf presentation supports a role for gamma LFP in Y., Trembovler V., and Shohami E.): Dynamic object perception, 88 Changes in the Recovery after Traumatic Brain Anderson C. (with David O., Kaphzan H., Grant S., and Injury in Mice: Effect of Injury Severity on Rosenblum K.): Dopamine induces tyrosine T2-Weighted MRI and functional recovery, 112 phosphorylation of the NR2A subunit (PY1325) Alkelai A. (with Slonimsky A., Amann-Zalcenstein D., in mature rat hippocampus, 24 Olender T., Ben-Asher E., Lancet D., and Anglister L. (with Durrant A. R. and Tamayev L.): Lerer B.): Sequence structure identification and Endocrine regulation of serum characterization of C6orf217: A positional butyrylcholinesterase activity: a study using candidate gene for schizophrenia, 105 dystrophin deficient mdx mice, 29 Alkelai A., Kohn Y., Kanyas K., Hamdan A., Lancet D., and Anglister L. (with Finkel E., Blivis D., Etlin A., and Lerer B.: Fine mapping of a schizophrenia Lev-Tov A.): Cholinergic involvement in susceptibility locus on chromosome 10q23-q26: sensory-induced activation of locomotor Significant evidence for linkage and a reduced networks in the mammalian spinal cord, 35 linkage interval, 3 Appel L. (with Geffen Y., Davidson M., and Kapur S.): Allon N. (with Bloch-Shiderman E., Rabinovitz I., Egoz I., BL-1020, First in Class GABA Enhanced Kapon J., Raveh L., and Grauer E.): Integrating Antipsychotic Candidate: Results of a D2 telemetry data in toxicological studies: The Receptor Occupancy Study in Humans, 41 effect of chronic exposure of rats to low doses of Apter A. (with Benaroya-Milshtein N., Hollander N., VX, 16 Yaniv I., Haberman Y., Halpert H., and Pick Almog M., Gurkiewicz M., and Korngreen A.: Modeling C. G.): Acute stress in mice; alteration in voltage-gated Sodium conductances from behavior, immunity and cancer cortical pyramidal neurons, 3 development, 12 Almog O. (with Eskira Y., Levi I., and Agam G.): Novel Arad M. (with Piontkewitz Y. and Weiner I.): Effects of approach to inhibit inositol monophosphatase neonatal administration of as an alternative to Lithium as a mood polyinosinic-polycytidilic acid (Poly I:C) on stabilizer, 33 latent inhibition and discrimination reversal in Amann-Zalcenstein D. (with Slonimsky A., Alkelai A., adulthood, 87 Olender T., Ben-Asher E., Lancet D., and Arad M. and Weiner I.: Amphetamine and ovariectomy Lerer B.): Sequence structure identification and induced disruption of latent inhibition in characterization of C6orf217: A positional female rats can be reversed by haloperidol only candidate gene for schizophrenia, 105 in the presence of estrogen, 5 Author Index 125

Arad M., Albelda N., and Joel D.: The effects of Assaf Y. (with Dror V., Rehavi M., and Eliash S.): withdrawal from chronic administration of Neuronal rescue in thiamine deficiency, 29 estradiol on “compulsive” lever-pressing of Assaf Y. (with Mezer A., Yovel Y., Pasternak O., and female rats–A preliminary study, 5 Gorfine T.): The Anatomical Basis of Functional Arbel M. and Solomon B.: A novel approach for treatment MRI, 76 of Alzheimer’s disease: antibodies against Assaf Y. (with Pasternak O., Sochen N., and Intrator N.): beta-secretase cleavage site of APP, 5 Mapping and Eliminating Free Water in the ff Arce F., Novick I., Shahar M., Ghez C., and Vaadia E.: Brain by Di usion Imaging, 85 Modalities of feedback induce differential Assaf Y. (with Tsenter J., Beni-Adani L., Alexandrovitch reaching strategies in adaptations to A. G., Trembovler V., and Shohami E.): force field, 6 Dynamic Changes in the Recovery after Traumatic Brain Injury in Mice: Effect of Injury Arendt-Nielsen L. (with Defrin R.): A psychophysical Severity on T2-Weighted MRI and functional study of the Thermal Grill illusion, 25 recovery, 112 Arieli A. (with Fried M.): Characteristics and possible role Avidan G. (with Pertzov Y. and Zohary E.): The of microsaccades during visual fixation, 38 representation of saccadic eye movements in Arieli A. (with Nir Y., Dinstein I., Mukamel R., Fisch L., human cortical regions, 86 Gelbard-Sagiv H., Fried I., and Malach R.): Slow Avidan G. (with Siman-Tov T., Mendelssohn A., modulations of spontaneous firing rates and Schonberg T., Pessoa L., Gadoth N., Ungerleide LFP Gamma power in human auditory cortex L., Podlipsky I., and Hendler T.): Hemispace- during wakefulness and sleep, 79 rather than hemisphere-superiority as the basis Arieli A. (with Saig A. and Ahissar E.): The “human for visuospatial attention asymmetry: new rat”–learning to use a new sense via sensory insights from fMRI, 104 substitution principles, 95 Avni R. and Eilam D.: Mapping the environment- an experimental model of spatial representation Arieli A. (with Shani-Hershkovich R.): The effects of during exploration and navigation, 7 stimulus expectation on perception and the dynamics of cortical activity, 100 Avraham O. (with Zisman S., Marom K., and Klar A.): Proteolysis and membrane capture of Arkadir D. (with Raz N., Dotan S., Zohary E., Chokron S., F-spondin generates combinatorial guidance and Levin N.): Behavioral and cortical cues from a single molecule, 121 activation patterns following an optic neuritis Avraham Y. (with Magen I., Berry E., Ackerman Z., and episode, 88 Mechoulam R.): Cannabidiol (CBD) Artzi M. (with Ben Bashat D., Drory V. E., Nefussy B., ameliorates cognitive impairments associated Zachor T., Assaf Y., and Aizenstein O.): White with a model of chronic liver disease in mice, 70 matter impairment in Amyotrophic Lateral Azouz R. (with Garion L., Pehter I., and Schiller J.): Single Sclerosis (ALS): Diffusion tensor imaging and cell resolution network dynamics in the rat high b-value DWI study, 11 barrel cortex using calcium imaging Arzi A., Sela L., Haddad R., Green A., Dagan Y., and Sobel two-photon microscopy in-vivo, 40 N.: Using odors to treat sleep apnea: A test of Azouz R. (with Lottem E.): Variable Processing of Texture feasibility, 6 Signals by Whisker Vibrations, 69 Asbe M., Tsoory M. M., and Berger B. D.: Exposing rats to stressors during juvenility increases morphine intake in adulthood, 6 B Aslam N., Kubota Y., and Shouval H.: A Self-sustaining Bachner-Melman R. (with Shalev I., Meron Y., Laibe G., Translational Switch for Regulating the Lerer E., Laiba E., Raz Y., Israel S., Uzefovsky F., Maintenance of Synaptic Plasticity, 7 Dina C., Kaitz M., and Ebstein R. P.): The role of BDNF Val66Met and stress response in Assaf Y. (with Barazany D. and Basser P.): smoking cessation in young women, 99 AxCaliber–in-vivo measurement of axon Bahar A. and Shapiro M.: Reorganized prospective and diameter distribution with MRI, 8 retrospective hippocampal memory coding after Assaf Y. (with Ben Bashat D., Drory V. E., Artzi M., switching the start and goal of a journey, 7 Nefussy B., Zachor T., and Aizenstein O.): White Balan L. F. (with Foltyn V. N., Dumin E., and Wolosker matter impairment in Amyotrophic Lateral H.): A novel mechanism regulating the synthesis Sclerosis (ALS): Diffusion tensor imaging and of the NMDA receptor coagonist D-serine: high b-value DWI study, 11 implications for NMDA receptor activation, 37 Assaf Y. (with Blumenfeld-Katzir T.): Localization of Bar M. (with Gronau N.): Integrated Contextual Cognitive Function in Rats with Magnetic Representation for Objects’ Identities and their Resonance Imaging, 16 Locations, 47 126 Neural Plasticity

Bar-Gad I. (with McCairn K. and Bronfeld M.): The Beit-Yannai E. (with Abramovitch-Dahan C., neurophysiological correlates of abnormal Ben-Shabat S., and Fleisher-Berkovich S.): behavior in a primate model of Tourette Protective effect of N-acetyl-L-Carnosine, a syndrome and their response to high frequency lipophilic derivative of L-Carnosine, on stimulation, 75 lipopolysaccaride-induced glial oxidative Bar-Gad I. (withBugaisen J. and Korngreen A.): Cellular stress, 2 Mechanisms of Deep Brain Stimulation, 19 Bejar C. (with Poltyrev T. and Weinstock M.): Detection ff Bar-Haim Y. (with Lamy D. and Salti M.): Neural of di erences in learning strategy and reference correlates of subjective and objective awareness: memory in young and old rats: Prevention of An ERP study, 65 memory deficits by ladostigil, 87 Bar-Yehuda D., Ben-Porat H., and Korngreen A.: Belelovsky K. (with Elkobi A., Barki-Harrington L., Modulation of Dendritic Calcium Spike by Rosenblum K., and Ehrlich I.): The role of Extracellular Calcium Concentration, 9 PSD-95 in consolidation of taste learning, 33 Belenky M. (with Lefler Y. and Yarom Y.): Reconstructing Barak E., Eytan D., Meir R., and Zeevi Y. Y.: Topology the olivo-cerebellar system in a dish, 66 Regulates Source Separation in Biologically Belinson H., Dolev I., Lev D., Masliah E., and Michaelson Realistic Neural Networks, 8 D. M.: Activation of the Amyloid Cascade in Barak O. (with Mongillo G. and Tsodyks M.): Facilitating ApoE4 transgenic mice induces synapses mediate working memory, 77 neurodegeneration resulting in marked Barak O., Mongillo G., and Tsodyks M.: Working cognitive deficits, 10 memory: somatic spikes or synaptic calcium?, 8 Belkin B. (with Meshulam A., Yehezkel O., Mandel Y., Barazany D., Basser P., and Assaf Y.: AxCaliber–in-vivo Rosner M., and Polat U.): Visual processing measurement of axon diameter distribution under limiting visual conditions, 76 with MRI, 8 Belkin M. (with Doron R., Meshulam A., Mandel Y., Bareni A., Maroun M., and Rosenblum K.: Akt is Rosner M., and Polat U.): Less is more: The differently activated in the amygdala-prefrontal perceptual advantage of being color blinded, 27 cortex-insular cortices circuit in acquisition and Belmaker R. (with Amar S., Shamir A., Ovadia O., extinction of CTA, 9 Blanaru M., Reshef A., Kremer I., Rietschel M., Barkai E. (with Brosh I.): Long-lasting olfactory-learning Maier W., Ebstein R., Agam G., and Mishmar induced modification in the reversal potential of D.): Mitochondrial DNA HV lineage increases fast IPSPs in the piriofm cortex, 19 the susceptibility to schizophrenia among Israeli Barkai E. (with Cohen-Matsliah S. I., Brosh I., and Arabs, 4 Rosenblum K.): A novel role for ERK in Belmaker R. (with Bromberg A., Levine J., Nemetz B., and maintaining long-term memory relevant Agam G.): Global leukocyte DNA methylation excitability changes, 23 in schizophrenia patients, 18 Barkai E. (with Reuveni I. and Saar D.): Associative odor Belmaker R. (with Hadas I., Agam G., and Bersudsky Y.): learning induces non uniform increase in the IMPA1 and lithium-like behavior, 49 synaptic efficacy, 90 Belmaker R. (with Levi I., Shamir A., Cryns K., Steckler T., Barki-Harrington L. (with Elkobi A., Belelovsky K., Moechars D., and Agam G.): Characterization Rosenblum K., and Ehrlich I.): The role of of the IMPA1 deficient mouse, 67 PSD-95 in consolidation of taste learning, 33 Belmaker R. H. (with Mann L., Heldman E., and Agam G.): The Inhibitory Effect of Mood Stabilizers Barnett K. J., Fox J. J., Molholm S., Kelly S. P., Shalgi S., on Adenylyl Cyclase Isoforms, 73 Mitchell K. J., and Newell F. N.: Differences in Beltsov S. and Yaka R.: Secreted factor from mutant PC12 Early Visual Processing in Synesthesia: an ERP cells as a potential element for neuronal study, 9 ff survival, 10 Barzilay R., Ben-Zur T., Bulvik S., Melamed E., and O en Ben Abou Y. (with Cohen A., Chen S., and Zilberberg N.): D.: Lentiviral delivery of LMX1a into human Protonation of extracellular histidine residues Mesenchymal Stem Cells directs towards ff facilitates C-type gating of the human dopaminergic di erentiation, 9 potassium leak channel K2P2.1, 22 Basser P. (with Barazany D. and Assaf Y.): Ben Abou Y., Zilberberg N., and Yifrach O.: Distinct pore AxCaliber–in-vivo measurement of axon properties of leak and voltage-activated diameter distribution with MRI, 8 potassium channels underlie their unique roles Becker A. (with Benninger F., Ekstein D., and Yaari Y.): in electrical signaling, 11 Zinc-induced Upregulation of T-type Calcium Ben Bashat D. (with Elkana O., Kremer U., Hendler T., Currents in the Hippocampus, 13 Fros R., and Schweiger A.): Patterns of brain Beiser K. (with Zacksenhouse M.): Adaptive motor language organization as a function of linguistic control during experiments with Brain Machine performance following recovery from Interfaces, 120 childhood insults to the left hemisphere, 32 Author Index 127

Ben Bashat D., Drory V. E., Artzi M., Nefussy B., Ben-Shachar D. (with Chertkow-Deutsher Y., Cohen H., Zachor T., Assaf Y., and Aizenstein O.: and Klein E.): Epigenetic Factors in the White matter impairment in Amyotrophic Vulnerability to PTSD; The Role of DNA Lateral Sclerosis (ALS): Diffusion tensor Methylation, 21 imaging and high b-value DWI study, 11 Ben-ShacharD.(YanivS.P.andKleinE.):AComplex Ben Porata J., Terkieltaub D., Goren O., Yakov N., Norepinephrine and Glucocorticoid Abrameto J., Sharon N., Zaretsky I., Intercellular Interaction: Relevance to Plasticity Shaki-Loewenstein S., Hazum S., Gopher J., Hypothesis of Depression, 116 Ohayon T., and Eren R.: Immunotherapies for Ben-Shmuel S. and Fleisher-Berkovich S.: Inhibitory effect Alzheimer’s Disease, 11 of kinins on microglial inflammation, 13 Ben Shitrit Y. (with Bloch B., Haliba Y., Vadas L., Ehood Ben-Zeev G. and Nussinovitch I.: Cone-shaped Golz A., Shelahavich K., Tangi R., Tavakuli lysophospholipids modulate voltage-gated H. R., Ziv N., Kremer I., and Haimov I.): The calcium channel currents in pituitary cells, 14 effects of music background on sleep efficiency, Ben-Zur T. (with Barzilay R., Bulvik S., Melamed E., and anxiety and depression in Schizophrenia Offen D.): Lentiviral delivery of LMX1a into patients, 15 human Mesenchymal Stem Cells directs towards ff Ben Simon E., Podlisky I., Zhdanov A., Papo D., and dopaminergic di erentiation, 9 Hendler T.: Exploring Alpha Correlates In The Benaroya-Milshtein N., Hollander N., Apter A., Yaniv I., Brain–An EEG-fMRI Study, 12 Haberman Y., Halpert H., and Pick C. G.: Acute Ben-Ari S. (with Kovalev E., Tal Z., Zimmermann G., stress in mice; alteration in behavior, immunity Soreq H., Yarom Y., and Shoham S.): and cancer development, 12 Glutamatergic excitotoxicity in cerebellar Benhar I. (with Brimberg L., Cunningham M., and Joel stroke: contribution of genetic background to D.): The possible association between neurological and histopathological outcomes in streptococcus group A infection and the a mouse model, 63 emergence of obsessive compulsive disorder, 18 Beni-Adani L. (with Tsenter J., Assaf Y., Alexandrovitch Ben-Ari Y. (with Goldin M., Epsztein J., Jorquera I., A. G., Trembovler V., and Shohami E.): Represa A., Cre’pel V., and Cossart R.): A Dynamic Changes in the Recovery after specific processing of afferent theta inputs via Traumatic Brain Injury in Mice: Effect of Injury synaptic kainate receptors in O-LM neurons, 45 Severity on T2-Weighted MRI and functional Ben-Arie N. (with Golan-Lev T., Nissim-Eliraz E., recovery, 112 Mansour A., Zisman S., Schatz O., and Klar A.): Benninger F. (with Caspi A. and Yaari Y.): Osmotic The transcription factor Nato3 is implied as a modulation of neuronal excitability is mediated novel regulator of floor plate and spinal cord by KV7/M channels, 20 development, 44 Benninger F., Ekstein D., Becker A., and Yaari Y.: Ben-Asher E. (with Slonimsky A., Alkelai A., Zinc-induced Upregulation of T-type Calcium Amann-Zalcenstein D., Olender T., Lancet D., Currents in the Hippocampus, 13 and Lerer B.): Sequence structure identification Bentin S. (with Amihai I. and Deouell L. Y.): The N170 and characterization of C6orf217: A positional sensitivity to faces is dissociated from conscious candidate gene for schizophrenia, 105 awareness, 4 Ben-Mair E., Schonberg T., Inzelberg R., and Joel D.: Bentin S. (with Gotthilf-Nezri D., Gilaie-Dotan S., Perry Evaluation of the interplay between procedural A., Bonneh Y., Malach R., and Polat U.): Does learning and declarative learning systems abnormal binocular experience during critical revealed in a double-dissociation experiment period limit normal development of visual among Alzheimer disease and Parkinson disease cognitive functions?, 46 patients, 13 Bentin S. (with Harel A.): Is it a European car or a Ben-Porat H. (with Bar-Yehuda D. and Korngreen A.): Japanese car? An ERP study of diagnostic Modulation of Dendritic Calcium Spike by information use in visual expertise, 52 Extracellular Calcium Concentration, 9 Bentin S. (with Landau A., Esterman M., Robertson L., Ben-Shabat S. (with Abramovitch-Dahan C., and Prinzmental W.): Different Effects of Beit-Yannai E., and Fleisher-Berkovich S.): Voluntary and Involuntary Attention on EEG Protective effect of N-acetyl-L-Carnosine, a Activity in the Gamma Band, 65 lipophilic derivative of L-Carnosine, on Bentin S. (with Zion Golumbic E. and Kutas M.): Do you lipopolysaccaride-induced glial oxidative remember me? Retrieving Memories for stress, 2 Faces–Evidence from Theta (4–8 Hz) and Ben-Shachar D. (with Brenner-Lavie H. and Klein E.): DA Gamma Band (>30 Hz) Activity, 121 Inhibits Mitochondrial Membrane Potential Berger B. D. (with Asbe M. and Tsoory M. M.): Exposing Possibly through its Interaction with Complex I: rats to stressors during juvenility increases Implications to DA related Pathologies, 18 morphine intake in adulthood, 6 128 Neural Plasticity

Bergman H. (with Mitelman R.): Is it possible to learn Blechman J. (with Russek-Blum N., Gutnick A., with asymmetry between the ‘good teacher’ and Nabel-Rosen H., Staudt N., Dorsky R., Houart the ‘bad teacher’?, 77 C., and Levkowitz G.): Dopaminergic Neuronal Bergman H. (with Rivlin-Etzion M., Marmor O., Rosin B., Cluster Size is Determined During Early and Slovik M.): Low-pass filter properties of Forebrain Patterning, 94 basal ganglia (BG) networks and possible Blivis D. (with Finkel E., Etlin A., Lev-Tov A., and mechanisms of action of high-frequency deep Anglister L.): Cholinergic involvement in brain stimulation (DBS), 91 sensory-induced activation of locomotor BergmanH.(withRosinB.,SlovikM.,MitelmanR.,and networks in the mammalian spinal cord, 35 Rivlin-Etzion M.): The contribution of forced Bloch B., Haliba Y., Vadas L., Ben Shitrit Y., Ehood Golz oscillations of the arm to the discharge pattern A., Shelahavich K., Tangi R., Tavakuli H. R., Ziv of primary motor cortex (M1) and globus N., Kremer I., and Haimov I.: The effects of pallidus (GP) neurons, 92 music background on sleep efficiency, anxiety Berkovich E., Pratt H., and Gur M.: Face Recognition and depression in Schizophrenia patients, 15 Inspired by the Visual Cortex, 14 Bloch-Shiderman E., Rabinovitz I., Egoz I., Kapon J., Berry E. (with Magen I., Avraham Y., Ackerman Z., and Raveh L., Grauer E., and Allon N.: Integrating Mechoulam R.): Cannabidiol (CBD) telemetry data in toxicological studies: The ameliorates cognitive impairments associated effect of chronic exposure of rats to low doses of with a model of chronic liver disease in mice, 70 VX, 16 Bersudsky Y. (with Hadas I., Agam G., and Belmaker R.): IMPA1 and lithium-like behavior, 49 Blomert L. (with Van Atteveldt N. M., Blau V., Formisano Bettler B. (with Vertkin I. and Slutsky I.): Optimal activity E., Roebroeck A., and Goebel R.): Multisensory level of presynaptic GABAB receptors integration of speech and script in fluent and maximizes the capacity of synapses for dyslexic readers, 113 correlation-based plasticity, 114 Blumenfeld-Katzir T. and Assaf Y.: Localization of Bick A. S., Frost R., and Goelman G.: Implicit and Explicit Cognitive Function in Rats with Magnetic Morphologically Related Activation, 14 Resonance Imaging, 16 Biegon A. (with Deri Y., Miron S., Achiron A., Hoffmann Blumkin E. (with Levav T. and Golan H.): Gender C., and Konan E.): Selective hippocampal dependent behavioral effects of perinatal atrophy in Multiple Sclerosis quantitave MRI gamma-aminobutyric acid (GABA) studies, 26 potentiation and methylenetetrahydrofolate Biegon A. (with Kravitz E., Davidson M., Gigi A., Orr G., reductase (MTHFR) deficiency in mice, 66 Seidman S., and Weiser M.): Testosterone Bobrowski O., Meir R., and Eldar Y. C.: Optimal improves visual-spatial memory in multi-modal state estimation by neural hypogonadal men, 63 networks based on recursive spike train Biegon A. (with Liraz-Zaltsman S., Fishbein I., decoding, 16 Greeneberger V., and Shohami E.): Regional Boimel M., Grigoriadis N., Lourbopoulos A., Abramsky sensitivity to Neuroinflammation: In vivo and O., and Rosenmann H.: Immunotherapy in vitro studies, 68 targeting pathologically phosphorylated tau Biron T. and Ahissar M.: On the implicit usage of repeated conformers in a tangle mouse model, 17 reference stimuli in the visual modality, 15 Boison D. (with Singer P., Yee B. K., Mohler H., and Bitan Y. (with Gnatek Y., Najami N., and Friedman A.): Feldon J.): To freeze or not to freeze? Cognitive Altered Cholinergic Gene Expression in enhancement in the modulation of associative Pilocarpine-Treated Mice, 44 learning: A study of forebrain neuronal glycine Blanaru M. (with Amar S., Shamir A., Ovadia O., Reshef transporter 1 (GlyT1) deletion, 105 A., Kremer I., Rietschel M., Maier W., Belmaker R., Ebstein R., Agam G., and Mishmar D.): Bonneh Y. (with Gotthilf-Nezri D., Gilaie-Dotan S., Perry Mitochondrial DNA HV lineage increases the A., Bentin S., Malach R., and Polat U.): Does susceptibility to schizophrenia among Israeli abnormal binocular experience during critical Arabs, 4 period limit normal development of visual Blank P. (with Valitsky M., Raveh A., Coorssen J., cognitive functions?, 46 Zimmerberg J., and Rahamimoff R.): Non Bonneh Y. S. and Sagi D.: Asymmetric visual interactions Stationary Fluctuation Analysis of Calcium in across the boundary of awareness, 17 Secretory Vesicles, 113 Bornstein G. (with Israel S., Knafo A., Reibold M., Lerer Blau V. (with Van Atteveldt N. M., Formisano E., E., and Ebstein R. P.):Association between the Roebroeck A., Blomert L., and Goebel R.): oxytocin receptor (OXTR) gene and pro-social Multisensory integration of speech and script in behavior in two economic games: the Dictator fluent and dyslexic readers, 113 and Social Value Orientations, 57 Author Index 129

Boucard A., Micheau J., and Nogues` X.: Training and Brozzoli C. (with Makin T., Holmes N. P., Rossetti Y., and behavioral recovery after hippocampal lesion Farne A.): Rapid modulation of motor cortex are coupled with changes in the pattern of excitability–TMS evidence for hand-centered connectivity, 17 visual representations of space, 72 Bradshaw H. B. (with Rimmerman N., Tan B., and Walker Bugaisen J., Bar-Gad I., and Korngreen A.: Cellular J. M.): Microsomal Enzymes Metabolize the Mechanisms of Deep Brain Stimulation, 19 Endogenous Lipid, N-arachidonoyl dopamine, Bultmann U. (with Pierscianek D., Frings M., Fritsche N., to Hydroxylated Metabolites Active at Gizewski E. R., Flossdorf A., Timmann D., and Recombinant human TRPV1 Receptors, 91 Maschke M.): Rehabilitation of cognitive Brenner T. (with Wald H., Sicsic C., Irony-Tur-Sinai M., impairment in patients with acute cerebellar Akkawi S., and Higazi A. E.): Involvement of stroke, 86 plasminogen activator system in Bultmann U., Frings M., Pierscianek D., Fritsche N., immunomoudulation of experimental Gizewski E. R., Timmann D., and Maschke M.: autoimmune myasthenia gravis, 114 Reorganisation of motor deficits in patients Brenner-Lavie H., Klein E., and Ben-Shachar D.: DA with acute cerebellar stroke, 19 Inhibits Mitochondrial Membrane Potential Bulvik S. (with Barzilay R., Ben-Zur T., Melamed E., and Possibly through its Interaction with Complex I: Offen D.): Lentiviral delivery of LMX1a into Implications to DA related Pathologies, 18 human Mesenchymal Stem Cells directs towards Brill A. (with Hayon Y., Leker R., and Varon D.): dopaminergic differentiation, 9 Cell-driven angiogenesis and neurogenesis after Bush A. I. (with Friedman J. E., Eilam R., Madala stroke with platelet derived microparticles, 53 Halagappa K. V., Mattson M. P., Adlard P. A., Brimberg L., Benhar I., Cunningham M., and Joel D.: The David Y., and Kozak A.): Improved cognition in possible association between streptococcus female triple transgenic AD mice treated with group A infection and the emergence of lipophilic metal chelators is associated with obsessive compulsive disorder, 18 reduced astrocyte activation, amyloid-Beta and Brodski C. (with Tilleman H., Hakim V., Liser K., p-tau pathology, 38 Scheffner O., Nashelsky L., Meir I., and Lanir ff Byrne R. A. (with Gutnick T., Kuba M. J., and Hochner A.): E ects of mid-hindbrain organizer genes B.): Where are my arms? An octopus visually and members of the Bmp 60A subgroup in the controlling its arm movements, 49 development of noradrenergic locus coeruleus ByrneR.A.(withKubaM.J.,GutnickT.,ZulloL., neurons, 110 Thonhauser K. E., and Hochner B.): Brodski C. (with Tilleman H., Liser K., Scheffner O., Modifications and adaptations of arm use in Nashelsky L., Meir I., and Lanir A.): The role of Octopus vulgaris, 64 members of the BMP 60A subgroup in the Byrne R. A. (with Thonhauser K. E., Zullo L., Hochner B., development of catecholaminergic neurons and and Kuba M. J.): Learning to move an arm the anterior pituirary, 110 inside a maze, 110 BrombergA.,LevineJ.,NemetzB.,BelmakerR.,and Agam G.: Global leukocyte DNA methylation in schizophrenia patients, 18 Bronfeld M. (with McCairn K. and Bar-Gad I.): The C neurophysiological correlates of abnormal Caggiano V., Fogassi L., Giese M., Rizzolatti G., Thier P., behavior in a primate model of Tourette and Casile A.: Tuning of the point of view of syndrome and their response to high frequency mirror neurons in monkey premotor cortex, 20 stimulation, 75 Calandreau L. (with Kaouane N., Esclassan F., Tronel S., Brosh I. (with Cohen-Matsliah S. I., Rosenblum K., and Mons N., Jaffard R., Abrous N., Piazza P., and Barkai E.): A novel role for ERK in maintaining Desmedt A.): Boundary conditions of long-term memory relevant excitability corticosterone-dependent enhancement or changes, 23 alteration of memory consolidation, 60 Brosh I. and Barkai E.: Long-lasting olfactory-learning Calvert G. (with Holmes N. P., Revol P., FarneA.,RodeG.,` induced modification in the reversal potential of Spence C., and Rossetti Y.): Recognising your fast IPSPs in the piriofm cortex, 19 own hands: Attribution biases & brain Brown P. (with Litvak V., Penny W., Eusebio A., Chen mechanisms, 54 C. C., Oostenveld R., Kilner J., Limousin P., Casile A. (with Caggiano V., Fogassi L., Giese M., Zrinzo L., Hariz M., and Friston K.): Rizzolatti G., and Thier P.): Tuning of the point Simultaneous MEG and subthalamic local field of view of mirror neurons in monkey premotor potential recordings in Parkinson patients reveal cortex, 20 the frequency-specific spatial pattern and Caspi A., Benninger F., and Yaari Y.: Osmotic modulation directionality of subthalamo-cortical of neuronal excitability is mediated by KV7/M interactions, 69 channels, 20 130 Neural Plasticity

Catz N., Dicke P. W., and Thier P.: The compensation of Cohen H. (with Abu-Ghanem Y., Amitai Y., and oculomotor fatigue is based on the adjustment Grauer E.): Enhanced stress-induced responses of a Purkinje cell simple spike population in an atroglial NOS2 mouse mutant, 2 signal, 20 Coorssen J. (with Valitsky M., Blank P., Raveh A., Chalifa-Caspi V. (with Haramati O., Perez-Polo J., and Zimmerberg J., and Rahamimoff R.): Non Golan H.): Prenatal hypoxia influences Stationary Fluctuation Analysis of Calcium in cerebellum gene expression, 52 Secretory Vesicles, 113 Chen A.: Neurobiology of Stress: The role of Cossart R. (with Goldin M., Epsztein J., Jorquera I., CRF/Urocortin family of peptides and Represa A., Ben-Ari Y., Cre’pel V.): A specific receptors, 21 processing of afferent theta inputs via synaptic Chen C. C. (with Litvak V., Penny W., Eusebio A., kainate receptors in O-LM neurons, 45 Oostenveld R., Kilner J., Limousin P., Zrinzo L., Cre’pel V. (with Goldin M., Epsztein J., Jorquera I., Hariz M., Friston K., and Brown P.): Represa A., Ben-Ari Y., and Cossart R.): A Simultaneous MEG and subthalamic local field specific processing of afferent theta inputs via potential recordings in Parkinson patients reveal synaptic kainate receptors in O-LM neurons, 45 the frequency-specific spatial pattern and CrynsK.(withLeviI.,ShamirA.,StecklerT.,Moechars directionality of subthalamo-cortical D., Belmaker R., and Agam G.): interactions, 69 Characterization of the IMPA1 deficient Chen S. (with Cohen A., Ben Abou Y., and Zilberberg N.): mouse, 67 Protonation of extracellular histidine residues Cunningham M. (with Brimberg L., Benhar I., and Joel facilitates C-type gating of the human D.): The possible association between potassium leak channel K2P2.1, 22 streptococcus group A infection and the Cherkas P. S. (with Hanani M. and Kushnir R.): emergence of obsessive compulsive disorder, 18 Purinergic signaling in satellite glial cells in sensory ganglia is enhanced in mouse models of D chronic pain, 51 Dagan Y. (with Arzi A., Sela L., Haddad R., Green A., and Chertkow-Deutsher Y., Ben-Shachar D., Cohen H., and Sobel N.): Using odors to treat sleep apnea: A Klein E.: Epigenetic Factors in the Vulnerability test of feasibility, 6 to PTSD; The Role of DNA Methylation, 21 Daikhin L., Nahum M., and Ahissar M.: Fast switching Chokron S. (with Raz N., Dotan S., Zohary E., Arkadir D., from computation based to memory based and Levin N.): Behavioral and cortical perception–evidence from ERP, 23 activation patterns following an optic neuritis Dangoor D. (with Maor M. and Gozes I.): The interaction episode, 88 of the drug candidate NAP with microtubules in Cochavi M. and Ahissar M.: On the use of reference in the presence of tau, 74 auditory duration discrimination, 22 Dangoor D. (with Michailovici I. and Gozes I.): ADNP Cohen A., Chen S., Ben Abou Y., and Zilberberg N.: messenger RNA knock down–a novel approach Protonation of extracellular histidine residues for cancer therapy, 77 facilitates C-type gating of the human Danovich L., Weinreb O., Youdim M. B. H., and Silver H.: potassium leak channel K2P2.1, 22 The molecular mechanism of Cohen E. and Lampl I.: Exacerbated Subthreshold pharmacodynamic interactions between Oscillatory Activity in Rat Model of Essential antipsychotic drugs and SSRI Tremor Revealed by In-Vivo Intracellular antidepressants, 24 Recordings of Inferior Olivary Neurons, 23 Dascal N. (with Yakubovich D.): Expression Cohen H. (with Chertkow-Deutsher Y., Ben-Shachar D., level-dependent changes in GIRK1/2 activity in and Klein E.): Epigenetic Factors in the Xenopus laevis oocytes: a modeling study, 115 Vulnerability to PTSD; The Role of DNA Dash S. (with Ignashchenkova A., Dietrich H., Haarmeier Methylation, 21 T., and Thier P.): Lesions of the posterior vermis Cohen M. A., Itsykson P., and Reubinoff B. E.: The in the rhesus monkey cause deficits in visual molecular mechanism of neural induction of motion perception, 55 human embryonic stem cells, 22 David O., Kaphzan H., Anderson C., Grant S., and Cohen Y. (with Shemesh N., Sadan O., Offen D., and Rosenblum K.: Dopamine induces tyrosine Melamed E.): MRI detects in vivo migration of phosphorylation of the NR2A subunit (PY1325) rat’sbonemarrowderivedmesechymalstem in mature rat hippocampus, 24 cells towards quinolinic acid lesion, 102 David Y. (with Friedman J. E., Eilam R., Madala Cohen-Matsliah S. I., Brosh I., Rosenblum K., and Barkai Halagappa K. V., Mattson M. P., Bush A. I., E.: A novel role for ERK in maintaining Adlard P. A., and Kozak A.): Improved long-term memory relevant excitability cognition in female triple transgenic AD mice changes, 23 treated with lipophilic metal chelators is Author Index 131

associated with reduced astrocyte activation, Deri Y., Miron S., Achiron A., Hoffmann C., Konan E., amyloid-Beta and p-tau pathology, 38 and Biegon A.: Selective hippocampal atrophy David Y. (with Prager O. and Friedman A.): Real-time in Multiple Sclerosis quantitave MRI studies, 26 monitoring of blood-brain barrier disruption in Desmedt A. (with Kaouane N., Calandreau L., Esclassan the rat cerebral cortex, 88 F., Tronel S., Mons N., Jaffard R., Abrous N., Davidson K. and Korngreen A.: Dynamic Properties of and Piazza P.): Boundary conditions of Martinotti-Pyramidal Synapses in Layer 2/3 of corticosterone-dependent enhancement or the Rat Somatosensory Cortex, 24 alteration of memory consolidation, 60 Davidson M. (with Geffen Y., Appel L., and Kapur S.): Dicke P. W. (with Catz N. and Thier P.): BL-1020, First in Class GABA Enhanced The compensation of oculomotor fatigue is Antipsychotic Candidate: Results of a D2 based on the adjustment of a Purkinje cell Receptor Occupancy Study in Humans, 41 simple spike population signal, 20 Davidson M. (with Kravitz E., Gigi A., Orr G., Seidman S., DickeP.W.(withMaternaS.andThierP.):Neuronal Weiser M., and Biegon A.): Testosterone substrates of head gaze following in monkeys: improves visual-spatial memory in an fMRI study, 74 hypogonadal men, 63 Diener H. (with Sensen K., Obermann M., Yoon M., Daw N. (with Schonberg T., Inzelberg R., O‘Doherty J., Maschke M., and Katsarava Z.): Pregabalin in and Joel D.): An fMRI study of striatal activity the treatment of trigeminal neuralgia: a during reinforcement learning in Parkinson’s prospective open-label clinical trial, 98 Disease, 96 Diesendruck G. (with Hammer R., Weinshall D., and De Hoz L., Raizel H., and Nelken I.: Effect of exposure to a Hochstein S.): The Role of Object Comparison behaviourally relevant tone on auditory cortex in Category Learning and the Emergence of responses to the same tone in mice, 25 Expertise, 51 De Levie A. and Weiner I.: Neonatal nitric oxide synthase Dietrich H. (with Ignashchenkova A., Dash S., Haarmeier inhibition leads to impaired reversal T., and Thier P.): Lesions of the posterior vermis performance which is alleviated by clozapine: in the rhesus monkey cause deficits in visual a neurodevelopmental model of negative motion perception, 55 symptoms, 25 Dina C. (with Shalev I., Meron Y., Laibe G., Lerer E., Laiba E., Raz Y., Israel S., Bachner-Melman R., Defrin R. and Arendt-Nielsen L.: A psychophysical study Uzefovsky F., Kaitz M., and Ebstein R. P.): The of the Thermal Grill illusion, 25 role of BDNF Val66Met and stress response in Defrin R., Dror A., Yulzari L., and Pick C. G.: Habituation smoking cessation in young women, 99 to pain: the effectofabsolutevsrelative Dinstein I. (with Nir Y., Mukamel R., Fisch L., stimulation intensity, 26 Gelbard-Sagiv H., Arieli A., Fried I., and Malach Deouell L. Y. (with Amihai I. and Bentin S.): The N170 R.): Slow modulations of spontaneous firing sensitivity to faces is dissociated from conscious rates and LFP Gamma power in human awareness, 4 auditory cortex during wakefulness Deouell L. Y. (with Haroush K. and Hochstein S.): and sleep, 79 Attentional resources become available to the Dinstein I., Gardner J., Jazayeri M., and Heeger D. J.: auditory system during the Visual Attentional Classification of executed movements from Blink, 53 fMRI response patterns in primary motor DeouellL.Y.(withKerenA.S.andGevaA.B.):ERP cortex, 27 Source Estimation by MRI Constrained Linear Dobkin-Bekman M., Seger R., and Naor Z.: A preformed Solutions, 61 signaling complex mediates GnRH activated Deouell L. Y. (with Shalgi S., O‘Connell R. G., and ERK phosphorylation of paxillin and FAK at RobertsonI.H.):AbsentMindedbutAccurate: focal adhesions in LfiT2 gonadotrope cells, 27 Delaying responses increases Accuracy but Dolev I. (with Belinson H., Lev D., Masliah E., and decreases Error Awareness, 99 Michaelson D. M.): Activation of the Amyloid Deouell L. Y. (with Tomer O. and Yuval-Greenberg S.): Cascade in ApoE4 transgenic mice induces Keeping an eye on induced Gamma activity: a neurodegeneration resulting in marked study of combined EEG and eye-tracking, 111 cognitive deficits, 10 Deouell L. Y. (with Yuval-Greenberg S. and Tomer O.): Dormann A. (with Hai A., Kamber D., Shappir J., Induced Gamma in the Eye of the Beholder: Yitzchaik S., and Spira M.): Novel spine-like Single Trial Analysis of Induced Gamma Band gold structures as a three dimensional substrate Responses in Human Observers, 119 for neuro-electronic hybrids, 50 Derdikman D. (with Yu C., Haidarliu S., Rubin N., and Doron G. (with Kaphzan H. and Rosenblum K.): Novel Ahissar E.): Coding selectivity of object location Environment and Co-application of NMDA and in the secondary somatosensory cortex during Dopamine Induce Rapid Translation of RSK2 in active vibrissal touch, 118 the Mature Hippocampus, 60 132 Neural Plasticity

Doron G. and Rosenblum K.: Novel taste elevates c-fos (PSD-95) Scaffolding Protein and Autism: expression in GABAergic neurons in the Relations to Adaptive Behavior and dysgranular Insular Cortex, 28 Cognition, 30 Doron R., Meshulam A., Mandel Y., Rosner M., Belkin M., Ebstein R. P. (with Israel S., Knafo A., Reibold M., Lerer E. and Polat U.: Less is more: The perceptual and Bornstein G.):Association between the advantage of being color blinded, 27 oxytocin receptor (OXTR) gene and pro-social Dorsky R. (with Russek-Blum N., Gutnick A., behavior in two economic games: the Dictator Nabel-Rosen H., Blechman J., Staudt N., Houart and Social Value Orientations, 57 C., and Levkowitz G.): Dopaminergic Neuronal EbsteinR.P.(withShalevI.,MeronY.,LaibeG.,LererE., Cluster Size is Determined During Early Laiba E., Raz Y., Israel S., Bachner-Melman R., Forebrain Patterning, 94 Uzefovsky F., Dina C., and Kaitz M.): The role Dotan S. (with Raz N., Zohary E., Arkadir D., Chokron S., of BDNF Val66Met and stress response in and Levin N.): Behavioral and cortical smoking cessation in young women, 99 activation patterns following an optic neuritis Eckmann J., Jacobi S., Moses E., Zbinden C., and Marom episode, 88 S.: Leaders of Activity in Dissociated Neural Dothan D. J. and Lampl I.: Interbarrel synaptic Cultures, 30 connections in the rat barrel cortex, 28 Edelman S. (with Levin R., Elran S., Ermilov M., Javitt Dresner E., Kushnir M., and Gozes I.: Advanced D. C., and Heresco-Levy U.): Emotion molecular genetic tools to further investigate the recognition vs. non-effective visual processing essential protein ADNP and its family member deficits in schizophrenia, 67 ADNP2, 28 Edelman S., Lerer E., Paz A., Zeev-Ben-Mordehai T., Israel Dror A. (with Defrin R., Yulzari L., and Pick C. G.): S., Nemanov L., Sussman J. L., Silman I., Levi S., Habituation to pain: the effect of absolute vs Salomon S., Yirmiya N., and Ebstein R. P.: relative stimulation intensity, 26 Association between DLG4 (PSD-95) Dror V., Rehavi M., Assaf Y., and Eliash S.: Neuronal Scaffolding Protein and Autism: Relations to rescue in thiamine deficiency, 29 Adaptive Behavior and Cognition, 30 Drory V. E. (with Ben Bashat D., Artzi M., Nefussy B., Edut S., Rubovitch V., Schreiber S., Feldon J., and Pick Zachor T., Assaf Y., and Aizenstein O.): White C. G.: Deficits in spatial learning in mice after matter impairment in Amyotrophic Lateral minimal traumatic brain injury demonstrated Sclerosis (ALS): Diffusion tensor imaging and by a novel dry maze test, 31 high b-value DWI study, 11 Egoz I. (with Bloch-Shiderman E., Rabinovitz I., Kapon J., Druckmann S., Gidon A., Schuermann F., Markram H., Raveh L., Grauer E., and Allon N.): Integrating and Segev I.: Constraining Neuron Models by telemetry data in toxicological studies: The Experimental Data, 29 effect of chronic exposure of rats to low doses of Dudai Y. (with Yeshurun Y. and Sobel N.): Working VX, 16 memory across nostrils, 117 Ehood Golz A. (with Bloch B., Haliba Y., Vadas L., Ben Dulac C. (with Kimchi T. and Xu J.): A functional circuit Shitrit Y., Shelahavich K., Tangi R., Tavakuli underlying male sexual behavior uncovered in H. R., Ziv N., Kremer I., and Haimov I.): The the adult female mouse brain, 61 effects of music background on sleep efficiency, Dumin E. (with Foltyn V. N., Balan L. F., and Wolosker anxiety and depression in Schizophrenia H.): A novel mechanism regulating the synthesis patients, 15 of the NMDA receptor coagonist D-serine: Ehrenstein W. H. (with Wagner M. and Papathomas implications for NMDA receptor activation, 37 T. V.): Vergence in reverspective: Effects of real Durrant A. R., Tamayev L., and Anglister L.: Endocrine and virtual depth cues, 114 regulation of serum butyrylcholinesterase Ehrlich I. (with Elkobi A., Belelovsky K., activity: a study using dystrophin deficient mdx Barki-Harrington L., and Rosenblum K.): mice, 29 The role of PSD-95 in consolidation of taste learning, 33 E Eilam D. (with Avni R.): Mapping the environment- an Ebstein R. (with Amar S., Shamir A., Ovadia O., Blanaru experimental model of spatial representation M., Reshef A., Kremer I., Rietschel M., Maier during exploration and navigation, 7 W., Belmaker R., Agam G., and Mishmar D.): Eilam D. (with Yaski O.): The impact of geometry in Mitochondrial DNA HV lineage increases the shaping exploratory behavior in rats: susceptibility to schizophrenia among Israeli Interpretation in terms of urban planning, 116 Arabs, 4 Eilam D., Zor R., Szechtman H., and Hermesh H.: Ebstein R. P. (with Edelman S., Lerer E., Paz A., Obsessive-Compulsive Disorder: Practical Zeev-Ben-Mordehai T., Israel S., Nemanov L., application of animal behavior as a conceptual Sussman J. L., Silman I., Levi S., Salomon S., model in studying compulsive rituals in and Yirmiya N.): Association between DLG4 humans, 31 Author Index 133

Eilam R. (with Friedman J. E., Madala Halagappa K. V., corticosterone-dependent enhancement or Mattson M. P., Bush A. I., Adlard P. A., David Y., alteration of memory consolidation, 60 and Kozak A.): Improved cognition in female Eskira Y., Levi I., Almog O., and Agam G.: Novel approach triple transgenic AD mice treated with to inhibit inositol monophosphatase as an lipophilic metal chelators is associated with alternative to Lithium as a mood stabilizer, 33 reduced astrocyte activation, amyloid-Beta and Esterman M. (with Landau A., Robertson L., Bentin S., p-tau pathology, 38 and Prinzmental W.): Different Effects of Einat V., Farfel-Becker T., and Futerman A.: Gene Voluntary and Involuntary Attention on EEG expression profiling in neuronal model of Activity in the Gamma Band, 65 Gaucher disease, 31 Etlin A. (with Finkel E., Blivis D., Lev-Tov A., and Eisenberg M., Shmuelof L., Vaadia E., and Zohary E.: Anglister L.): Cholinergic involvement in Inferring the representation of arm movements sensory-induced activation of locomotor in the human motor cortex from the fMRI networks in the mammalian spinal cord, 35 signal, 32 Etlin A., Shamir B., Mor Y., Sasson D., Zeilig G., and Ekstein D. (with Benninger F., Becker A., and Yaari Y.): Lev-Tov A.: Myoclonic bursting of the ankle Zinc-induced Upregulation of T-type Calcium joint musculature in spinal cord injury patients Currents in the Hippocampus, 13 is attenuated by activation of crossed-inhibitory Eldar Y. C. (with Bobrowski O. and Meir R.): Optimal pathways, 33 multi-modal state estimation by neural Eusebio A. (with Litvak V., Penny W., Chen C. C., networks based on recursive spike train Oostenveld R., Kilner J., Limousin P., Zrinzo L., decoding, 16 Hariz M., Friston K., and Brown P.): Eliash S. (with Dror V., Rehavi M., and Assaf Y.): Simultaneous MEG and subthalamic local field Neuronal rescue in thiamine deficiency, 29 potential recordings in Parkinson patients reveal Elkana O., Ben Bashat D., Kremer U., Hendler T., Fros R., the frequency-specific spatial pattern and and Schweiger A.: Patterns of brain language directionality of subthalamo-cortical organization as a function of linguistic interactions, 69 performance following recovery from Even B. (with Gonen G., Ferdman N., Maroun C., Katz O., childhood insults to the left hemisphere, 32 Pershin L., Schulkin J., and Leshem M.): Elkobi A., Belelovsky K., Barki-Harrington L., Rosenblum Influence on offspring behavior of stress to the K., and Ehrlich I.: The role of PSD-95 in rat dam before she becomes pregnant: effects of consolidation of taste learning, 33 cross-fostering, 45 Elran S. (with Levin R., Ermilov M., Edelman S., Javitt Even B. (with Shachar-Dadon A., Maroun C., Galon I., D. C., and Heresco-Levy U.): Emotion Schulkin J., and Leshem): Effects of weanling recognition vs. non-effective visual processing stress and acute pre-mating shock on affect in deficits in schizophrenia, 67 progeny in rats, 98 Epsztein J. (with Goldin M., Jorquera I., Represa A., EytanD.(withBarakE.,MeirR.,andZeeviY.Y.): Ben-Ari Y., Cre’pel V., and Cossart R.): A Topology Regulates Source Separation in specific processing of afferent theta inputs via Biologically Realistic Neural Networks, 8 synaptic kainate receptors in O-LM neurons, 45 EytanD.(withGalA.andMaromS.):RecruitmentOrder Eren R. (with Ben Porata J., Terkieltaub D., Goren O., Coding in Large-Scale Recurrent Networks of Yakov N., Abrameto J., Sharon N., Zaretsky I., Cortical Neurons, 38 Shaki-Loewenstein S., Hazum S., Gopher J., and Ezan P. (with Pannasch U., Willecke K., Giaume C., and Ohayon T.): Immunotherapies for Alzheimer’s Rouach N.): Synaptic strength regulated by Disease, 11 astrocytic gap junctions, 84 Erez H. (with Kamber D. and Spira M. E.): Failure of neurons to regenerate after axotomy stems from F the assembly of an endbulb rather than a Fainzilber M.: The Importins of Retrograde Transport in competent a growth cone, 59 Injured Nerve, 34 Erez H. (with Shemesh O. A., Ginzburg I., and Spira Farfel-Becker T. (with Einat V. and Futerman A.): Gene M. E.): Tau-induced microtubules polarity expression profiling in neuronal model of reorientation leads to axonal trafficjamsand Gaucher disease, 31 neurodegeneration, 103 Farne` A. (with Holmes N. P., Revol P., Rode G., Spence C., Ermilov M. (with Levin R., Elran S., Edelman S., Javitt Calvert G., and Rossetti Y.): Recognising your D. C., and Heresco-Levy U.): Emotion own hands: Attribution biases & brain recognition vs. non-effective visual processing mechanisms, 54 deficits in schizophrenia, 67 Farne A. (with Makin T., Holmes N. P., Brozzoli C., and Esclassan F. (with Kaouane N., Calandreau L., Tronel S., Rossetti Y.): Rapid modulation of motor cortex Mons N., Jaffard R., Abrous N., Piazza P., and excitability–TMS evidence for hand-centered Desmedt A.): Boundary conditions of visual representations of space, 72 134 Neural Plasticity

Fass D. (with Magidovich H., Orr I., Abdu U., and Yifrach Finberg J. P. (with Weinstein N.): ARTS structure and O.): The role of intrinsically-disordered protein expression in rat cortical neurons, 115 segments in mediating Kv channel clustering: Finkel E., Blivis D., Etlin A., Lev-Tov A., and Anglister L.: implications for synapse assembly, maintenance Cholinergic involvement in sensory-induced and function, 71 activation of locomotor networks in the Feder Y. (with Pinhasov A., Reichenstein M., and mammalian spinal cord, 35 Schneider J.): Neuropeptides, Antidepressants First M., Tarasenko I., Taler M., Grunbaum-Novak N., and Depression, 86 Weizman R., Gil-ad I., and Weizman A.: Effect Feder Y. (with Schneider J., Reichenstein M., and Pinhasov of chronic stress and fluoxetine therapy on A.): Gene Expression Profile of Pac1 and IGF-1 receptor expression in the brain and on Vpac1/2 Receptors in Developing and Adult Rat behavioral and cognitive parameters of rats, 35 Brain, 96 Fisch L. (with Nir Y., Dinstein I., Mukamel R., Feder Y., Ogran A., Zinn A., Yadid G., and Pinhasov A.: Gelbard-Sagiv H., Arieli A., Fried I., and Malach Establishment of a Dominant Submissive R.): Slow modulations of spontaneous firing Relationships Model in Sabra Outbred mice, 34 rates and LFP Gamma power in human Feinstein N. (with Shomrat T., Klein M., and Hochner B.): auditory cortex during wakefulness Serotonin is a neuromodulator of short- and and sleep, 79 long term synaptic plasticity in the octopus Fisch L. (with Privman E., Kramer U., Kipervasser S., vertical lobe, 104 Andelman F., Neufeld M. Y., Yehezkel Y., Fried Feld Y., Finberg J. P., Loboda Y., Gluzman Z., Mohsen O., I., and Malach R.): Sustained image Reshef M., and Marom S.: Transplanted presentation supports a role for gamma LFP in fibroblasts reduce neuronal synchronised object perception, 88 bursting discharge and correct Parkinsonian Fisch L., Privman E., Kramer U., Kipervasser S., asymmetry and L-Dopa-induced dyskinetic AndelmanF.,NeufeldM.,FriedI.,andMalach movements in 6-hydroxydopamine-lesioned R.: Neural correlates of visual recognition rats, 34 revealed through backward masking and Feldon J. (with Edut S., Rubovitch V., Schreiber S., and intracranial electrode recordings, 36 Pick C. G.): Deficits in spatial learning in mice Fishbein I. (with Liraz-Zaltsman S., Greeneberger V., after minimal traumatic brain injury Shohami E., and Biegon A.): Regional sensitivity demonstrated by a novel dry maze test, 31 to Neuroinflammation: In vivo and in vitro Feldon J. (with Singer P., Yee B. K., Boison D., and Mohler studies, 68 H.): To freeze or not to freeze? Cognitive Fishbein I. (with Schonfeld E., Greenberger V., and Segal enhancement in the modulation of associative M.): Molecular correlates of TTX-induced cell learning: A study of forebrain neuronal glycine death, 97 transporter 1 (GlyT1) deletion, 105 FeldonJ.(withSpoerriE.,MeyerU.,andYeeB.K.): Fishbein I., Schonfeld E., Greenberger V., and Segal M.: Evaluating early preventive antipsychotic drug Physiological Mechanisms of treatment during the prodromal phase in a Neurodegeneration Induced by Activity neurodevelopmental animal model of Deprivation, 36 schizophrenia, 107 Fisher D., Tsodyks M., and Sompolinsky H.: Unsupervised Ferdman N. (with Gonen G., Even B., Maroun C., Katz O., learning in network of temportrons, 36 Pershin L., Schulkin J., and Leshem M.): Fishman D. (with Karol N., Hershfinkel M., Forberg M., Influence on offspring behavior of stress to the Kaisman T., Sekler I., and Silverman W.): The rat dam before she becomes pregnant: effects of correlation of intracellular zinc, zinc cross-fostering, 45 homeostatic proteins and apoptosis, 60 Filipovich T. and Fleisher-Berkovich S.: Distinct Fishman T., Youdim M. B. H., and Mandel S.: Silencing involvement of the endothelin system in glial plus over-expression of selected genes as a novel inflammatory pathways, 35 model of sporadic Parkinson’s disease, 37 Finberg J. P. (with Feld Y., Loboda Y., Gluzman Z., Fleisher-Berkovich S. (with Ben-Shmuel S.): Inhibitory Mohsen O., Reshef M., and Marom S.): effect of kinins on microglial inflammation, 13 Transplanted fibroblasts reduce neuronal Fleisher-Berkovich S. (with Filipovich T.): Distinct synchronised bursting discharge and correct involvement of the endothelin system in glial Parkinsonian asymmetry and L-Dopa-induced inflammatory pathways, 35 dyskinetic movements in Fleisher-Berkovich S. (with Abramovitch-Dahan C., 6-hydroxydopamine-lesioned rats, 34 Beit-Yannai E., and Ben-Shabat S.): Protective Finberg J. P. (with Sader-Mazbar O.): The role of effect of N-acetyl-L-Carnosine, a lipophilic monoamine oxidase subtypes in striatal derivative of L-Carnosine, on metabolism of dopamine produced from l-dopa lipopolysaccaride-induced glial oxidative in the rat, 94 stress, 2 Author Index 135

Flossdorf A. (with Pierscianek D., Frings M., Friedman A. (with Gnatek Y., Najami N., and Bitan Y.): Bultmann U., Fritsche N., Gizewski E. R., Altered Cholinergic Gene Expression in Timmann D., and Maschke M.): Rehabilitation Pilocarpine-Treated Mice, 44 of cognitive impairment in patients with acute Friedman A. (with Prager O. and David Y.): Real-time cerebellar stroke, 86 monitoring of blood-brain barrier disruption in Fogassi L. (with Caggiano V., Giese M., Rizzolatti G., Thier the rat cerebral cortex, 88 P., and Casile A.): Tuning of the point of view of Friedman A. (with Tomkins O., Shelef I., and mirror neurons in monkey premotor cortex, 20 Kaizerman I.): Computer-Assisted Diagnosis of Foltyn V. N., Balan L. F., Dumin E., and Wolosker H.: Blood-Brain Barrier Disruption, 112 A novel mechanism regulating the synthesis of Friedman A. (with Tomkins O., Shelef I., Kaizerman I., the NMDA receptor coagonist D-serine: and Zumsteg D.): Blood-Brain Barrier implications for NMDA receptor activation, 37 Disruption in Post-Traumatic Epilepsy, 111 Forberg M. (with Karol N., Hershfinkel M., Kaisman T., Friedman J. E., Eilam R., Madala Halagappa K. V., Fishman D., Sekler I., and Silverman W.): The Mattson M. P., Bush A. I., Adlard P. A., David Y., correlation of intracellular zinc, zinc and Kozak A.: Improved cognition in female homeostatic proteins and apoptosis, 60 triple transgenic AD mice treated with Formisano E. (with Van Atteveldt N. M., Blau V., lipophilic metal chelators is associated with Roebroeck A., Blomert L., and Goebel R.): reduced astrocyte activation, amyloid-Beta and Multisensory integration of speech and script in p-tau pathology, 38 fluent and dyslexic readers, 113 Friedmann N. (with Shetreet E. and Hadar U.): Syntactic Fox J. J. (with Barnett K. J., Molholm S., Kelly S. P., Shalgi Processing and Lexical Retrieval during S.,MitchellK.J.,andNewellF.N.):Differences Sentence Comprehension: An fMRI study, 103 in Early Visual Processing in Synesthesia: an Frings M. (with Bultmann U., Pierscianek D., Fritsche N., ERP study, 9 Gizewski E. R., Timmann D., and Maschke M.): Reorganisation of motor deficits in patients Fride E. (with Moussaieff A., Shohami E., and Mechoulam with acute cerebellar stroke, 19 R.): Incensole acetate, an incense component, elicits psychoactivity by activating TRPV3 Frings M. (with Pierscianek D., Bultmann U., Fritsche N., channels, 78 Gizewski E. R., Flossdorf A., Timmann D., and Maschke M.): Rehabilitation of cognitive Fride E.: Development of the Endocannabinoid system: impairment in patients with acute cerebellar Its critical importance for embryonal stroke, 86 implantation, neuronal development and Friston K. (with Litvak V., Penny W., Eusebio A., Chen postnatal suckling; implications of its pre- or C. C., Oostenveld R., Kilner J., Limousin P., postnatal manipulation, 37 Zrinzo L., Hariz M., and Brown P.): Fried I. (with Fisch L., Privman E., Kramer U., Kipervasser Simultaneous MEG and subthalamic local field S., Andelman F., Neufeld M., and Malach R.): potential recordings in Parkinson patients reveal Neural correlates of visual recognition revealed the frequency-specific spatial pattern and through backward masking and intracranial directionality of subthalamo-cortical electrode recordings, 36 interactions, 69 Fried I. (with Gelbard-Sagiv H., Mukamel R., Harel M., Fritsche N. (with Bultmann U., Frings M., Pierscianek D., and Malach R.): Neural correlates of free recall Gizewski E. R., Timmann D., and Maschke M.): in the human medial temporal lobe, 42 Reorganisation of motor deficits in patients Fried I. (with Nir Y., Dinstein I., Mukamel R., Fisch L., with acute cerebellar stroke, 19 Gelbard-Sagiv H., Arieli A., and Malach R.): Fritsche N. (with Pierscianek D., Frings M., Bultmann U., Slow modulations of spontaneous firing rates Gizewski E. R., Flossdorf A., Timmann D., and and LFP Gamma power in human auditory Maschke M.): Rehabilitation of cognitive cortex during wakefulness and sleep, 79 impairment in patients with acute cerebellar Fried I. (with Privman E., Fisch L., Kramer U., stroke, 86 Kipervasser S., Andelman F., Neufeld M. Y., Fros R. (with Elkana O., Ben Bashat D., Kremer U., Yehezkel Y., and Malach R.): Sustained image Hendler T., and Schweiger A.): Patterns of brain presentation supports a role for gamma LFP in language organization as a function of linguistic object perception, 88 performance following recovery from Fried I. (with Rosenberg K. and Hendler T.): Searching for childhood insults to the left hemisphere, 32 anatomical based functional organization in the Frost R. (with Bick A. S. and Goelman G.): Implicit and human brain: The case of the Supplementary Explicit Morphologically Related Activation, 14 Motor Area, 92 Futerman A. (with Einat V. and Farfel-Becker T.): Gene Fried M. and Arieli A.: Characteristics and possible role of expression profiling in neuronal model of microsaccades during visual fixation, 38 Gaucher disease, 31 136 Neural Plasticity

G Gavish M. (with Zeno S., Veenman L., Leschiner S., and Gabrieli J. D. (with Ofen N.): Development of declarative Zaarur M.): The correlation between the memory systems in the human brain, 81 Translocator Protein (TSPO) and apoptosis in Gadoth N. (with Siman-Tov T., Mendelssohn A., human glioma cells under hypoxia, 120 Schonberg T., Avidan G., Pessoa L., Ungerleide Gavornik J., Loewenstein Y., and Shouval H.: Learning L., Podlipsky I., and Hendler T.): Hemispace- temporal representations through reward rather than hemisphere-superiority as the basis dependant expression of synaptic eligibility for visuospatial attention asymmetry: new traces in recurrent networks, 41 insights from fMRI, 104 Gavra T., Gal R., and Libersat F.: Involvement of the Gal A., Eytan D., and Marom S.: Recruitment Order opioid system in the decreased responsiveness Coding in Large-Scale Recurrent Networks of induced in cockroaches stung by a parasitoid Cortical Neurons, 38 wasp, 41 GalR.(withGavraT.andLibersatF.):Involvementofthe Geffen Y. (with Nisemblat Y., Winkler I., Klapper L., opioid system in the decreased responsiveness Savitsky K., Nudelman A., Rephaeli A., Gilad I., induced in cockroaches stung by a parasitoid and Weizman): BL-1021: A New Chemical wasp, 41 Entity for Treatment of Naturopathic and Acute Gal R. and Libersat F.: Venomous wasp targets different Pain, 80 head ganglia to manipulate specific behaviors of Geffen Y. (with Rephaeli A., Gil-Ad I., Trasenko N., its cockroach prey, 39 Tarasenko I., Aharoni A., Savitsky K., Weizman Galon I. (with Shachar-Dadon A., Even B., Maroun C., A., and Nudelman A.): Amidic GABA ff Schulkin J., and Leshem): E ects of weanling derivatives of antidepressants display improved ff stress and acute pre-mating shock on a ect in pain suppressing activity, 89 progeny in rats, 98 Geffen Y., Appel L., Davidson M., and Kapur S.: BL-1020, Ganel T. (with Tanzer M. and Goodale M. A.): Dissociable ff First in Class GABA Enhanced Antipsychotic e ects of real and illusory size on perception Candidate: Results of a D2 Receptor Occupancy and visuomotor control , 109 Study in Humans, 41 Ganmor E., Katz Y., Mazig V., Heiss J., and Lampl I.: ff Gelbard-Sagiv H. (with Nir Y., Dinstein I., Mukamel R., Sensory Adaptation to Di erent Stimulus Fisch L., Arieli A., Fried I., and Malach R.): Slow Strengths in Rat Whisker to Barrel Pathway, 39 modulations of spontaneous firing rates and Ganmor E., Segev R., and Schneidman E.: Robustness and LFP Gamma power in human auditory cortex Structure of 2nd Order Maximum Entropy during wakefulness and sleep, 79 Models Describing the State Distribution of Gelbard-Sagiv H., Mukamel R., Harel M., Malach R., and Neural Populations, 39 Fried I.: Neural correlates of free recall in the Ganon E. and Akirav I.: The involvement of stress and humanmedialtemporallobe,42 cannabinoid CB1 receptors in extinction of ff inhibitory avoidance in the amygdala, 40 Gelstein S., Sobel N., and Roth Y.: Can the e ects of Gardner J. (with Dinstein I., Jazayeri M., and Heeger putative human pheromones be attributed to D. J.): Classification of executed movements chemical sensing?, 42 Gersner R., Toth E., and Zangen A.: The antidepressant from fMRI response patterns in primary motor ff cortex, 27 e ect of repeated subconvulsive electrical Garion L., Pehter I., Azouz R., and Schiller J.: Single cell stimulation of reward related brain sites in a rat model for depressive behavior: A comparison to resolution network dynamics in the rat barrel ff cortex using calcium imaging two-photon the e ect of electroconvulsive therapy, 42 microscopy in-vivo, 40 Geva A. B. (with Keren A. S. and Deouell L. Y.): ERP Gavish M. (with Kugler W., Veenman L., and Lakomek Source Estimation by MRI Constrained Linear M.): Role of the 18 kDa Translocator protein Solutions, 61 and the adenine nucleotide transporter in Ghez C. (with Arce F., Novick I., Shahar M., and Vaadia erucylphosphohomocholine-induced cell death E.): Modalities of feedback induce differential in human glioma cells, 64 reaching strategies in adaptations to force field, Gavish M. (with Maniv I., Veenman L., Leschiner S., 6 Spanier I., Marek I., Shterenberg A., and Hadad Giaume C. (with Pannasch U., Ezan P., Willecke K., and E.): Novel TSPO ligands as neuroprotective Rouach N.): Synaptic strength regulated by agents, 73 astrocytic gap junctions, 84 Gavish M. (with Shandalov Y., Veenman L., Leschiner S., Gidon A. (with Druckmann S., Schuermann F., Markram KuglerW.,andLakomekM.):Translocator H., and Segev I.): Constraining Neuron Models Protein ligands attenuate the mitochondrial by Experimental Data, 29 membrane collapse normally induced by the Gidon A., London M., and Segev I.: Stochastic synaptic antineoplastic agent transmission is advantageous for learning Erucylphosphohomocholine, 100 complex temporal firing patterns in neurons, 43 Author Index 137

Giese M. (with Caggiano V., Fogassi L., Rizzolatti G., Goebel R. (with Van Atteveldt N. M., Blau V., Thier P., and Casile A.): Tuning of the point of Formisano E., Roebroeck A., and Blomert L.): view of mirror neurons in monkey premotor Multisensory integration of speech and script in cortex, 20 fluent and dyslexic readers, 113 Gigi A. (with Kravitz E., Davidson M., Orr G., Seidman S., Goelman G. (with Bick A. S. and Frost R.): Implicit and Weiser M., and Biegon A.): Testosterone Explicit Morphologically Related Activation, 14 improves visual-spatial memory in Goelman G. (with Sourani D.): The involvement of the hypogonadal men, 63 raphe nuclei in parkinson’s disease, 106 Gil-ad I. (with First M., Tarasenko I., Taler M., Golan H. (with Haramati O., Chalifa-Caspi V., and Grunbaum-Novak N., Weizman R., and Perez-Polo J.): Prenatal hypoxia influences ff Weizman A.): E ect of chronic stress and cerebellum gene expression, 52 fluoxetine therapy on IGF-1 receptor expression Golan H. (with Levav T. and Blumkin E.): Gender in the brain and on behavioral and cognitive dependent behavioral effects of perinatal parameters of rats, 35 gamma-aminobutyric acid (GABA) Gil-Ad I. (with Rephaeli A., Trasenko N., Tarasenko I., ff potentiation and methylenetetrahydrofolate Aharoni A., Ge en Y., Savitsky K., Weizman A., reductase (MTHFR) deficiency in mice, 66 and Nudelman A.): Amidic GABA derivatives of antidepressants display improved pain Golan H. M., Kaplan-Louzone V., Zuckerman M., and suppressing activity, 89 Perez-Polo R. J.: Impaired migration signaling ff in the hippocampus following prenatal Gilad I. (with Nisemblat Y., Ge en Y., Winkler I., Klapper hypoxia, 44 L., Savitsky K., Nudelman A., Rephaeli A., and Weizman): BL-1021: A New Chemical Entity for Golan-Lev T., Nissim-Eliraz E., Mansour A., Zisman S., Treatment of Naturopathic and Acute Pain, 80 Schatz O., Klar A., and Ben-Arie N.: The transcription factor Nato3 is implied as a novel Gilaie-Dotan S. (with Gotthilf-Nezri D., Perry A., regulator of floor plate and spinal cord Bonneh Y., Bentin S., Malach R., and Polat U.): development, 44 Does abnormal binocular experience during critical period limit normal development of Goldin M., Epsztein J., Jorquera I., Represa A., Ben-Ari Y., visual cognitive functions?, 46 Cre’pel V., and Cossart R.: A specific processing of afferent theta inputs via synaptic kainate Ginzburg I. (with Shemesh O. A., Erez H., and Spira receptors in O-LM neurons, 45 M. E.): Tau-induced microtubules polarity reorientation leads to axonal trafficjamsand Golomb D. (with Simony E. and Ahissar E.): Role of neurodegeneration, 103 Sensory Feedback in determining the Firing Patterns of Vibrissa Motoneurons, 105 Gitik M., Reichert F., and Rotshenker S.: Rho/ROCK signalling down-regulates myelin phagocytosis Golzer T. (with Lifschytz T., Shalom G., Segman R. H., in microglia, 43 Lerer B., and Newman M. E.): Biochemical and ff Gizewski E. R. (with Bultmann U., Frings M., Pierscianek behavioral e ects of triiodothyronine (T3) may D., Fritsche N., Timmann D., and Maschke M.): provide a basis for the antidepressant attributes Reorganisation of motor deficits in patients this compound, 68 with acute cerebellar stroke, 19 Gonen G., Ferdman N., Even B., Maroun C., Katz O., Gizewski E. R. (with Pierscianek D., Frings M., Pershin L., Schulkin J., and Leshem M.: Influence on offspring behavior of stress to the Bultmann U., Fritsche N., Flossdorf A., ff Timmann D., and Maschke M.): Rehabilitation rat dam before she becomes pregnant: e ects of of cognitive impairment in patients with acute cross-fostering, 45 cerebellar stroke, 86 Goodale M. A. (with Tanzer M. and Ganel T.): Dissociable ff Glick I. and Hadar U.: Sensory-motor processes in the e ects of real and illusory size on perception understanding of spoken words: An fMRI study, and visuomotor control , 109 43 Gopher J. (with Ben Porata J., Terkieltaub D., Goren O., Gluzman Z. (with Feld Y., Finberg J. P., Loboda Y., Yakov N., Abrameto J., Sharon N., Zaretsky I., Mohsen O., Reshef M., and Marom S.): Shaki-Loewenstein S., Hazum S., Ohayon T., Transplanted fibroblasts reduce neuronal and Eren R.): Immunotherapies for Alzheimer’s synchronised bursting discharge and correct Disease, 11 Parkinsonian asymmetry and L-Dopa-induced Gordon G.: Stable Firing Patterns in Neural Networks: dyskinetic movements in A Three-Level Model of Consciousness, 46 6-hydroxydopamine-lesioned rats, 34 Gordon-Shaag A. (with Parnas M., Katz B., Lev S., Gnatek Y., Najami N., Bitan Y., and Friedman A.: Tzarfaty V., and Minke B.): Membrane lipids Altered Cholinergic Gene Expression in modulation removes divalent open channel Pilocarpine-Treated Mice, 44 block of TRPL and NMDA channels, 84 138 Neural Plasticity

GorenO.(withBenPorataJ.,TerkieltaubD.,YakovN., Greeneberger V. (with Liraz-Zaltsman S., Fishbein I., Abrameto J., Sharon N., Zaretsky I., Shohami E., and Biegon A.): Regional sensitivity Shaki-Loewenstein S., Hazum S., Gopher J., to Neuroinflammation: In vivo and in vitro Ohayon T., and Eren R.): Immunotherapies for studies, 68 Alzheimer’s Disease, 11 Grigoriadis N. (with Boimel M., Lourbopoulos A., Gorfine T. (with Mezer A., Yovel Y., Pasternak O., and Abramsky O., and Rosenmann H.): Assaf Y.): The Anatomical Basis of Functional Immunotherapy targeting pathologically MRI, 76 phosphorylated tau conformers in a tangle Gotthilf-Nezri D., Gilaie-Dotan S., Perry A., Bonneh Y., mouse model, 17 Bentin S., Malach R., and Polat U.: Does Grigoriadis N. (with Gozes I., Pinhasov A., Mandel S., abnormal binocular experience during critical Pikman R., Touloumi O., Pittel Z., and period limit normal development of visual Vulih-Shultzman I.): NAP reduces TAU cognitive functions?, 46 hyperphosphorylation and enhances learning in Gozes I. (with Dresner E. and Kushnir M.): Advanced a novel transgenic mouse model, 46 molecular genetic tools to further investigate the Grinvald A. (with Heiss J., Oron E., and Lampl I.): essential protein ADNP and its family member Adaptation to repetitive whisker stimulation is ADNP2, 28 highly correlated among neurons in the rat Gozes I. (with Mandel S.): Activity–dependent barrel cortex, 53 neuroprotective protein constitutes a novel Grinvald A. (with Omer D. B., Rom L., and Ulchin Y.): element in the SWI/SNF chromatin remodeling Comparing the dynamics of ongoing activity in complex and modulates neural shape, 72 awake and anesthetized monkey, 83 Gozes I. (with Maor M. and Dangoor D.): The interaction Grinvald Y. (with Inbar D., Zach N., and Vaadia E.): of the drug candidate NAP with microtubules in Correlated neuronal activity in Primary and Pre the presence of tau, 74 motor cortices of monkeys during performance of different visuomotor association tasks, 56 Gozes I. (with Michailovici I. and Dangoor D.): ADNP Grinvald Y. (with Zach N., Inbar D., and Vaadia E.): messenger RNA knock down–a novel approach Circuitry underlying perceptual learning in for cancer therapy, 77 behaving monkeys, 119 Gozes I. (with Oz S.): The influence of NAP treatment on Grinvald Y., Inbar D., Zach N., and Vaadia E.: Movement the severity of experimental autoimmune parameters are related to inter-trial variability encephalomyelitis, 83 of single units activity in motor cortex, 47 Gozes I., Pinhasov A., Mandel S., Pikman R., Grigoriadis Gronau N. and Bar M.: Integrated Contextual N., Touloumi O., Pittel Z., and Vulih-Shultzman Representation for Objects’ Identities and their I.: NAP reduces TAU hyperphosphorylation and Locations, 47 enhances learning in a novel transgenic mouse Groysman M. and Kalcheim C.: RHO/ROCK signaling model, 46 negatively modulates delimination of neural Grant S. (with David O., Kaphzan H., Anderson C., and crest cells downstream of BMP and G1/S Rosenblum K.): Dopamine induces tyrosine transition, 47 phosphorylation of the NR2A subunit (PY1325) Gruberger M., Hendler T., Zangen A., and Levkovitz Y.: in mature rat hippocampus, 24 The Restless Mind–A relation between rest and Grauer E. (with Bloch-Shiderman E., Rabinovitz I., Egoz the self in the brain–A deep-TMS I.,KaponJ.,RavehL.,andAllonN.):Integrating study-Presentation of preliminary results, 48 telemetry data in toxicological studies: The Grunbaum-Novak N. (with First M., Tarasenko I., Taler ff e ect of chronic exposure of rats to low doses of M., Weizman R., Gil-ad I., and Weizman A.): VX, 16 Effect of chronic stress and fluoxetine therapy Grauer E. (with Abu-Ghanem Y., Cohen H., and on IGF-1 receptor expression in the brain and Amitai Y.): Enhanced stress-induced responses on behavioral and cognitive parameters of rats, in an atroglial NOS2 mouse mutant, 2 35 Green A. (with Arzi A., Sela L., Haddad R., Dagan Y., and Guetig R. and Sompolinsky H.: The conductance-based Sobel N.): Using odors to treat sleep apnea: A tempotron: a model for time warp invariant test of feasibility, 6 auditory processing, 48 Greenberger V. (with Fishbein I., Schonfeld E., and Segal Gur M. (with Berkovich E. and Pratt H.): Face M.): Physiological Mechanisms of Recognition Inspired by the Visual Cortex, 14 Neurodegeneration Induced by Activity Gur M. (with Hendel T.): The Origin of Hering’s Law of Deprivation, 36 Equal Innervation, 54 Greenberger V. (with Schonfeld E., Fishbein I., and Segal Gurkiewicz M. (with Almog M. and Korngreen A.): M.): Molecular correlates of TTX-induced cell Modeling voltage-gated Sodium conductances death, 97 from cortical pyramidal neurons, 3 Author Index 139

Gutfreund Y. (with Oged A.): Effects of early auditory Haidarliu S. (with Yu C., Derdikman D., Rubin N., and experience on the auditory space map in the Ahissar E.): Coding selectivity of object location barn owl’s brain, 82 in the secondary somatosensory cortex during Gutfreund Y. (with Reches A.): Auditory and visual active vibrissal touch, 118 responses in the tectofugal pathway of the barn Haimov I. (with Bloch B., Haliba Y., Vadas L., Ben Shitrit owl, 89 Y., Ehood Golz A., Shelahavich K., Tangi R., Gutfreund Y., Reches A., and Zachar Y.: Visual-auditory Tavakuli H. R., Ziv N., Kremer I.): The effects of integration in the barn owl: A neuroethological music background on sleep efficiency, anxiety approach, 48 and depression in Schizophrenia patients, 15 Gutnick A. (with Russek-Blum N., Nabel-Rosen H., HairstonI.S.,TalbotL.S.,PolinaE.,JuneG.L.,and Blechman J., Staudt N., Dorsky R., Houart C., Harvey A. G.: Sensory gating in primary and Levkowitz G.): Dopaminergic Neuronal insomnia: A potential objective measure of Cluster Size is Determined During Early reduced sleep quality, 51 Forebrain Patterning, 94 Hakim V. (with Tilleman H., Liser K., Scheffner O., Gutnick T. (with Kuba M. J., Byrne R. A., Zullo L., Nashelsky L., Meir I., Lanir A., and Brodski C.): Thonhauser K. E., and Hochner B.): Effects of mid-hindbrain organizer genes and Modifications and adaptations of arm use in members of the Bmp 60A subgroup in the Octopus vulgaris, 64 development of noradrenergic locus coeruleus Gutnick T., Byrne R. A., Kuba M. J., and Hochner B.: neurons, 110 Where are my arms? An octopus visually Haliba Y. (with Bloch B., Vadas L., Ben Shitrit Y., Ehood controlling its arm movements, 49 Golz A., Shelahavich K., Tangi R., Tavakuli H. R., Ziv N., Kremer I., and Haimov I.): The effects of music background on sleep efficiency, H anxiety and depression in Schizophrenia Haarmeier T. (with Ignashchenkova A., Dash S., Dietrich patients, 15 H., and Thier P.): Lesions of the posterior Halpert H. (with Benaroya-Milshtein N., Hollander N., vermis in the rhesus monkey cause deficits in Apter A., Yaniv I., Haberman Y., and Pick C. G.): visual motion perception, 55 Acutestressinmice;alterationinbehavior, Haberman Y. (with Benaroya-Milshtein N., Hollander N., immunity and cancer development, 12 Apter A., Yaniv I., Halpert H., and Pick C. G.): Hamdan A. (with Alkelai A., Kohn Y., Kanyas K., Lancet Acute stress in mice; alteration in behavior, D., and Lerer B.): Fine mapping of a immunity and cancer development, 12 schizophrenia susceptibility locus on Hadad E. (with Maniv I., Veenman L., Leschiner S., chromosome 10q23-q26: Significant evidence Spanier I., Marek I., Shterenberg A., and Gavish for linkage and a reduced linkage interval, 3 M.): Novel TSPO ligands as neuroprotective Hammer R., Diesendruck G., Weinshall D., and Hochstein agents, 73 S.: The Role of Object Comparison in Category Hadar U. (with Glick I.): Sensory-motor processes in the Learning and the Emergence of Expertise, 51 understanding of spoken words: An fMRI study, Hanani M., Kushnir R., and Cherkas P. S.: Purinergic 43 signaling in satellite glial cells in sensory ganglia Hadar U. (with Shetreet E. and Friedmann N.): Syntactic is enhanced in mouse models of chronic pain, Processing and Lexical Retrieval during 51 Sentence Comprehension: An fMRI study, 103 Haramati O., Chalifa-Caspi V., Perez-Polo J., and Golan Hadas I., Agam G., Belmaker R., and Bersudsky Y.: IMPA1 H.: Prenatal hypoxia influences cerebellum gene and lithium-like behavior, 49 expression, 52 Hadas S., Reichert F., and Rotshenker S.: Tyrosine kinase Harel A. and Bentin S.: Is it a European car or a Japanese Syk regulates differentially myelin and pathogen car? An ERP study of diagnostic information phagocytosis mediated by Complement use in visual expertise, 52 Receptor-3, Dectin-1 and Mannose Receptor, 50 Harel D. (with Haddad R., Kahan R., and Sobel N.): A Hadas Y., Shkolnik N., and Klar A.: Transcriptional Method for Odorant Comparison, 50 control of commissural neuron cell fate, 49 Harel D. (with Lapid H. and Sobel N.): Predicting Haddad R. (with Arzi A., Sela L., Green A., Dagan Y., and pleasantness of binary mixtures in olfaction, 65 Sobel N.): Using odors to treat sleep apnea: A Harel M. (with Gelbard-Sagiv H., Mukamel R., Malach R., test of feasibility, 6 and Fried I.): Neural correlates of free recall in Haddad R., Kahan R., Harel D., and Sobel N.: A Method thehumanmedialtemporallobe,42 for Odorant Comparison, 50 Hariz M. (with Litvak V., Penny W., Eusebio A., Chen Hai A., Kamber D., Dormann A., Shappir J., Yitzchaik S., C. C., Oostenveld R., Kilner J., Limousin P., and Spira M.: Novel spine-like gold structures Zrinzo L., Friston K., and Brown P.): as a three dimensional substrate for Simultaneous MEG and subthalamic local field neuro-electronic hybrids, 50 potential recordings in Parkinson patients reveal 140 Neural Plasticity

the frequency-specific spatial pattern and Hendler T. (with Sadeh B., Podlipsky I., Zhdanov A., and directionality of subthalamo-cortical Yovel G.): The reliability and validity of the interactions, 69 face-specific N170 ERP component recorded Harmening (with Ohayon S., Wagner H., and Rivlin E.): simultaneously with functional MRI, 94 Through a barn owl’s eyes: interactions between Hendler T. (with Siman-Tov T., Mendelssohn A., scene content and visual attention, 82 Schonberg T., Avidan G., Pessoa L., Gadoth N., Haroush K., Hochstein S., and Deouell L. Y.: Attentional Ungerleide L., and Podlipsky I.): Hemispace- resources become available to the auditory rather than hemisphere-superiority as the basis system during the Visual Attentional Blink, 53 for visuospatial attention asymmetry: new Harvey A. G. (with Hairston I. S., Talbot L. S., Polina E., insights from fMRI, 104 and June G. L.): Sensory gating in primary Hendler T. (with Zhdanov A., Ungerleider L., and Intrator insomnia: A potential objective measure of N.): Inferring Cognitive States From reduced sleep quality, 51 Magnetoencephalographic (MEG) Signals: Feature Selection Framework, 120 Hayon Y., Leker R., Varon D., and Brill A.: Cell-driven Heresco-Levy U. (with Levin R., Elran S., Ermilov M., angiogenesis and neurogenesis after stroke with Edelman S., and Javitt D. C.): Emotion platelet derived microparticles, 53 recognition vs. non-effective visual processing Hazum S. (with Ben Porata J., Terkieltaub D., Goren O., deficits in schizophrenia, 67 Yakov N., Abrameto J., Sharon N., Zaretsky I., Hermesh H. (with Eilam D., Zor R., and Szechtman H.): Shaki-Loewenstein S., Gopher J., Ohayon T., Obsessive-Compulsive Disorder: Practical and Eren R.): Immunotherapies for Alzheimer’s application of animal behavior as a conceptual Disease, 11 model in studying compulsive rituals in Heeger D. J. (with Dinstein I., Gardner J., and Jazayeri humans, 31 M.): Classification of executed movements from Hershenhoren I. and Nelken I.: Tone Detection in Noise fMRI response patterns in primary motor in the Mouse Auditory Cortex, 54 cortex, 27 Hershfinkel M. (with Karol N., Forberg M., Kaisman T., Heiss J. (with Ganmor E., Katz Y., Mazig V., and Lampl I.): Fishman D., Sekler I., and Silverman W.): The Sensory Adaptation to Different Stimulus correlation of intracellular zinc, zinc Strengths in Rat Whisker to Barrel Pathway, 39 homeostatic proteins and apoptosis, 60 Heiss J., Oron E., Grinvald A., and Lampl I.: Adaptation to Hertz U. (with Shmuelof L. and Zohary E.): Viewpoint repetitive whisker stimulation is highly dependent representation of observed actions, correlated among neurons in the rat barrel 103 cortex, 53 Higazi A. E. (with Wald H., Sicsic C., Irony-Tur-Sinai M., Heldman E. (with Mann L., Belmaker R. H., and Agam Akkawi S., and Brenner T.): Involvement of G.): The Inhibitory Effect of Mood Stabilizers plasminogen activator system in on Adenylyl Cyclase Isoforms, 73 immunomoudulation of experimental Hendel T. and Gur M.: The Origin of Hering’s Law of autoimmune myasthenia gravis, 114 Equal Innervation, 54 Hochner B. (with Gutnick T., Byrne R. A., and Kuba M. J.): Where are my arms? An octopus visually Hendler T. (with Ben Simon E., Podlisky I., Zhdanov A., controlling its arm movements, 49 and Papo D.): Exploring Alpha Correlates In Hochner B. (with Kuba M. J., Byrne R. A., Gutnick T., The Brain–An EEG-fMRI Study, 12 Zullo L., and Thonhauser K. E.): Modifications Hendler T. (with Elkana O., Ben Bashat D., Kremer U., and adaptations of arm use in Octopus vulgaris, Fros R., and Schweiger A.): Patterns of brain 64 language organization as a function of linguistic Hochner B. (with Shomrat T., Feinstein N., and Klein M.): performance following recovery from Serotonin is a neuromodulator of short- and childhood insults to the left hemisphere, 32 long term synaptic plasticity in the octopus Hendler T. (with Gruberger M., Zangen A., and Levkovitz vertical lobe, 104 Y.): The Restless Mind–A relation between rest Hochner B. (with Thonhauser K. E., Zullo L., Byrne R. A., and the self in the brain–A deep-TMS and Kuba M. J.): Learning to move an arm study-Presentation of preliminary results, 48 inside a maze, 110 Hendler T. (with Okon-Singer H., Podlipsky I., Yovel G., Hochstein S. (with Hammer R., Diesendruck G., and and Siman-Tov T.): Knowing Left from Right: A Weinshall D.): The Role of Object Comparison Combined ERP-fMRI Study of Visuospatial in Category Learning and the Emergence of Attention, 82 Expertise, 51 Hendler T. (with Rosenberg K. and Fried I.): Searching for Hochstein S. (with Haroush K. and Deouell L. Y.): anatomical based functional organization in the Attentional resources become available to the human brain: The case of the Supplementary auditory system during the Visual Attentional Motor Area, 92 Blink, 53 Author Index 141

Hochstein S. (with Jacob M.): Comparing Eye Movements Inbar D. (with Zach N., Grinvald Y., and Vaadia E.): to Detected vs. Un-detected Stimuli, 57 Circuitry underlying perceptual learning in Hochstein S. (with Pavlovskaya M.): Does the Right Side behaving monkeys, 119 Remember what the Left Side Learned? Inbar D., Grinvald Y., Zach N., and Vaadia E.: Correlated Hemispheric Transfer of Perceptual Learning neuronal activity in Primary and Pre motor ff E ects, 85 cortices of monkeys during performance of ff Ho mann C. (with Deri Y., Miron S., Achiron A., Konan different visuomotor association tasks, 56 E., and Biegon A.): Selective hippocampal atrophy in Multiple Sclerosis quantitave MRI InbergS.,RosenblumK.,andWagnerS.:Molecular studies, 26 correlations following mating in the rodent female olfactory bulb, 56 Hollander N. (with Benaroya-Milshtein N., Apter A., Yaniv I., Haberman Y., Halpert H., and Pick Intrator N. (with Pasternak O., Sochen N., and Assaf Y.): C. G.): Acute stress in mice; alteration in Mapping and Eliminating Free Water in the behavior, immunity and cancer Brain by Diffusion Imaging, 85 development, 12 Intrator N. (with Zhdanov A., Hendler T., and Holmes N. P. (with Makin T., Brozzoli C., Rossetti Y., and Ungerleider L.): Inferring Cognitive States From Farne A.): Rapid modulation of motor cortex Magnetoencephalographic (MEG) Signals: excitability–TMS evidence for hand-centered Feature Selection Framework, 120 visual representations of space, 72 InzelbergR.(withBen-MairE.,SchonbergT.,andJoel Holmes N. P. , Re vol P. , Fa r ne` A., Rode G., Spence C., D.): Evaluation of the interplay between Calvert G., and Rossetti Y.: Recognising your procedural learning and declarative learning own hands: Attribution biases & brain systems revealed in a double-dissociation mechanisms, 54 experiment among Alzheimer disease and Horev G., Knutsen P. M., Pietr M., and Ahissar E.: Parkinson disease patients, 13 Stereotyped whisker and head movements are associated with object localization in Inzelberg R. (with Schonberg T., Daw N., O‘Doherty J., unrestrained rats, 55 and Joel D.): An fMRI study of striatal activity Horovitz O., Tsoory M. M., and Richter-Levin G.: during reinforcement learning in Parkinson’s Individual differences in stress responsiveness Disease, 96 affect the consequences of juvenile stress on Irony-Tur-Sinai M. (with Wald H., Sicsic C., Akkawi S., coping with stress in adulthood, 55 Higazi A. E., and Brenner T.): Involvement of Horowitz M. (with Shein N. A. and Shohami E.): plasminogen activator system in Identification of Neuroprotective Pathways in immunomoudulation of experimental Brain Trauma Using Heat Acclimation autoimmune myasthenia gravis, 114 Preconditioning, 101 Ishai A. and Wiesmann M.: Neural correlates of Houart C. (with Russek-Blum N., Gutnick A., recollection- and familiarity-based memory Nabel-Rosen H., Blechman J., Staudt N., Dorsky decisions, 57 R., and Levkowitz G.): Dopaminergic Neuronal Cluster Size is Determined During Early Israel S. (with Edelman S., Lerer E., Paz A., Forebrain Patterning, 94 Zeev-Ben-Mordehai T., Nemanov L., Sussman Hounsgaard J. (with Rotem N., Sestieri E., and Yarom Y.): J. L., Silman I., Levi S., Salomon S., Yirmiya N., ff ffi and Ebstein R. P.): Association between DLG4 Di erential postsynaptic e ciency of ff electrosensory afferents and parallel fibers in the (PSD-95) Sca olding Protein and Autism: principal neurons of the shark Dorsal Relations to Adaptive Behavior and Octavolateral Nucleus, 93 Cognition, 30 Israel S. (with Shalev I., Meron Y., Laibe G., Lerer E., Laiba E., Raz Y., Bachner-Melman R., Uzefovsky F., I Dina C., Kaitz M., and Ebstein R. P.): The role Ignashchenkova A., Dash S., Dietrich H., Haarmeier T., of BDNF Val66Met and stress response in and Thier P.: Lesions of the posterior vermis in smoking cessation in young women, 99 the rhesus monkey cause deficits in visual motion perception, 55 IsraelS.,KnafoA.,ReiboldM.,LererE.,BornsteinG.,and Ilin Y. and Richter-levin G.: The interplay between Ebstein R. P.:Association between the oxytocin Juvenile stress and Enriched Environment on receptor (OXTR) gene and pro-social behavior behavior and L1-CAM, 56 in two economic games: the Dictator and Social Inbar D. (with Grinvald Y., Zach N., and Vaadia E.): Value Orientations, 57 Movement parameters are related to inter-trial Itsykson P. (with Cohen M. A. and Reubinoff B. E.): The variability of single units activity in motor molecular mechanism of neural induction of cortex, 47 human embryonic stem cells, 22 142 Neural Plasticity

J June G. L. (with Hairston I. S., Talbot L. S., Polina E., and Jacob M. and Hochstein S.: Comparing Eye Movements to Harvey A. G.): Sensory gating in primary Detected vs. Un-detected Stimuli, 57 insomnia: A potential objective measure of Jacobi S. (with Eckmann J., Moses E., Zbinden C., and reduced sleep quality, 51 Marom S.): Leaders of Activity in Dissociated Neural Cultures, 30 K Jacobson G. (with Shapira A. and Nelken I.): The Kahan R. (with Haddad R., Harel D., and Sobel N.): A Ectosylvian Sulcal Audiotory Field (FAES) and Method for Odorant Comparison, 50 Localization of Sounds, 100 Kahana R. (with Tsuriel S., Stern M., and Ziv N.): Jacobson-Pick S. and Richter-Levin G.: Short and long Maintaining the presynaptic site–questions term consequences of exposing rats to stressors arising from live imaging experiments, 112 during juvenility, 58 Kaisman T. (with Karol N., Hershfinkel M., Forberg M., Jaffard R. (with Kaouane N., Calandreau L., Esclassan F., Fishman D., Sekler I., and Silverman W.): The Tronel S., Mons N., Abrous N., Piazza P., and correlation of intracellular zinc, zinc Desmedt A.): Boundary conditions of homeostatic proteins and apoptosis, 60 corticosterone-dependent enhancement or KaitzM.(withShalevI.,MeronY.,LaibeG.,LererE., alteration of memory consolidation, 60 Laiba E., Raz Y., Israel S., Bachner-Melman R., Javitt D. C. (with Levin R., Elran S., Ermilov M., Edelman Uzefovsky F., Dina C., and Ebstein R. P.): The S., and Heresco-Levy U.): Emotion recognition role of BDNF Val66Met and stress response in vs. non-effective visual processing deficits in smoking cessation in young women, 99 schizophrenia, 67 Kaizerman I. (with Tomkins O., Shelef I., and Friedman A.): Computer-Assisted Diagnosis of Jazayeri M. (with Dinstein I., Gardner J., and Heeger Blood-Brain Barrier Disruption, 112 D. J.): Classification of executed movements Kaizerman I. (with Tomkins O., Shelef I., Zumsteg D., and from fMRI response patterns in primary motor Friedman A.): Blood-Brain Barrier Disruption cortex, 27 in Post-Traumatic Epilepsy, 111 Joel D. (with Arad M. and Albelda N.): The effects of Kalcheim C. (with Groysman M.): RHO/ROCK signaling withdrawal from chronic administration of negatively modulates delimination of neural estradiol on “compulsive” lever-pressing of crest cells downstream of BMP and G1/S female rats–A preliminary study, 5 transition, 47 Joel D. (with Ben-Mair E., Schonberg T., and Inzelberg Kamber D. (with Hai A., Dormann A., Shappir J., R.): Evaluation of the interplay between Yitzchaik S., and Spira M.): Novel spine-like procedural learning and declarative learning gold structures as a three dimensional substrate systems revealed in a double-dissociation for neuro-electronic hybrids, 50 experiment among Alzheimer disease and Kamber D. and Spira M. E.: On the mechanism that Parkinson disease patients, 13 promote controlled and targeted regrowth of an Joel D. (with Brimberg L., Benhar I., and Cunningham injured axonal branch out of many, 59 M.): The possible association between Kamber D., Erez H., and Spira M. E.: Failure of neurons to streptococcus group A infection and the regenerate after axotomy stems from the emergence of obsessive compulsive disorder, 18 assembly of an endbulb rather than a competent ff Joel D. (with Klavir O. and Winter C.): The e ects of high agrowthcone,59 frequency stimulation and temporary Kanyas K. (with Alkelai A., Kohn Y., Hamdan A., Lancet inactivation of the globus pallidus in the signal D., and Lerer B.): Fine mapping of a attenuation rat model of obsessive compulsive schizophrenia susceptibility locus on disorder, 62 chromosome 10q23-q26: Significant evidence Joel D. (with Schonberg T., Daw N., Inzelberg R., and for linkage and a reduced linkage interval, 3 O‘Doherty J.): An fMRI study of striatal activity Kaouane N., Calandreau L., Esclassan F., Tronel S., Mons during reinforcement learning in Parkinson’s N., Jaffard R., Abrous N., Piazza P., and Disease, 96 Desmedt A.: Boundary conditions of Joel D., Klavir O., and Winter C.: Mapping regions for corticosterone-dependent enhancement or high frequency stimulation in two rat models of alteration of memory consolidation, 60 obsessive-compulsive disorder, 58 Kaphzan H. (with David O., Anderson C., Grant S., and Jorquera I. (with Goldin M., Epsztein J., Represa A., Rosenblum K.): Dopamine induces tyrosine Ben-Ari Y., Cre’pel V., and Cossart R.): A phosphorylation of the NR2A subunit (PY1325) specific processing of afferent theta inputs via in mature rat hippocampus, 24 synaptic kainate receptors in O-LM neurons, 45 Kaphzan H., Doron G., and Rosenblum K.: Novel Jubran M. and Richter-Levin G.: Local circuit plasticity in Environment and Co-application of NMDA and the dentate gyrus induced by a week titanic Dopamine Induce Rapid Translation of RSK2 in stimulation, 59 the Mature Hippocampus, 60 Author Index 143

Kaplan-Louzone V. (with Golan H. M., Zuckerman M., Kimchi T., Xu J., and Dulac C.: A functional circuit and Perez-Polo R. J.): Impaired migration underlying male sexual behavior uncovered in signaling in the hippocampus following the adult female mouse brain, 61 prenatal hypoxia, 44 Kipervasser S. (with Fisch L., Privman E., Kramer U., Kapon J. (with Bloch-Shiderman E., Rabinovitz I., Egoz I., AndelmanF.,NeufeldM.,FriedI.,andMalach Raveh L., Grauer E., and Allon N.): Integrating R.): Neural correlates of visual recognition telemetry data in toxicological studies: The revealed through backward masking and effect of chronic exposure of rats to low doses of intracranial electrode recordings, 36 VX, 16 Kipervasser S. (with Privman E., Fisch L., Kramer U., ff Kapur S. (with Ge en Y., Appel L., and Davidson M.): Andelman F., Neufeld M. Y., Yehezkel Y., Fried BL-1020, First in Class GABA Enhanced I., and Malach R.): Sustained image Antipsychotic Candidate: Results of a D2 presentation supports a role for gamma LFP in Receptor Occupancy Study in Humans, 41 object perception, 88 Karniel A. (with Nisky I.): Perceptuo-motor transparency Kisliouk T. (with Yossifoff M. and Meiri N.): Dynamic in bilateral teleoperation, 80 changes in DNA CpG dinucleotide methylation Karol N., Hershfinkel M., Forberg M., Kaisman T., in the brain-derived neurotrophic factor Fishman D., Sekler I., and Silverman W.: The (BDNF) promoter area during thermal control correlation of intracellular zinc, zinc establishment, 118 homeostatic proteins and apoptosis, 60 Kastner S. (with Magen H. and Treisman A.): Attentional Kisliouk T. and Meiri N.: A critical role for histone 3 demands predict short-term memory load methylation in thermal control development, 62 response in posterior parietal cortex, 70 Klapper L. (with Nisemblat Y., Geffen Y., Winkler I., Katsarava Z. (with Sensen K., Obermann M., Yoon M., Savitsky K., Nudelman A., Rephaeli A., Gilad I., Maschke M., and Diener H.): Pregabalin in the and Weizman): BL-1021: A New Chemical treatment of trigeminal neuralgia: a prospective Entity for Treatment of Naturopathic and Acute open-label clinical trial, 98 Pain, 80 Katz B. (with Parnas M., Lev S., Tzarfaty V., Klar A. (with Golan-Lev T., Nissim-Eliraz E., Mansour A., Gordon-Shaag A., and Minke B.): Membrane Zisman S., Schatz O., and Ben-Arie N.): The lipids modulation removes divalent open transcription factor Nato3 is implied as a novel channel block of TRPL and NMDA channels, 84 regulator of floor plate and spinal cord Katz O. (with Gonen G., Ferdman N., Even B., Maroun C., development, 44 Pershin L., Schulkin J., and Leshem M.): Klar A. (with Hadas Y. and Shkolnik N.): Transcriptional Influence on offspring behavior of stress to the control of commissural neuron cell fate, 49 ff rat dam before she becomes pregnant: e ects of Klar A. (with Zisman S., Marom K., and Avraham O.): cross-fostering, 45 Proteolysis and membrane capture of Katz Y. (with Ganmor E., Mazig V., Heiss J., and Lampl I.): F-spondin generates combinatorial guidance Sensory Adaptation to Different Stimulus cues from a single molecule, 121 Strengths in Rat Whisker to Barrel Pathway, 39 ff Klavir O. (with Joel D. and Winter C.): Mapping regions Katz Y. A. and Lampl I.: E ect of anesthesia and breathing for high frequency stimulation in two rat on the receptive field size of thalamic cells in the models of obsessive-compulsive disorder, 58 somatosensory system, 61 Klavir O., Winter C., and Joel D.: The effects of high Kelly S. P. (with Barnett K. J., Fox J. J., Molholm S., Shalgi frequency stimulation and temporary S.,MitchellK.J.,andNewellF.N.):Differences inactivation of the globus pallidus in the signal in Early Visual Processing in Synesthesia: an attenuation rat model of obsessive compulsive ERP study, 9 disorder, 62 KerenA.S.,GevaA.B.,andDeouellL.Y.:ERPSource Estimation by MRI Constrained Linear Klein E. (with Brenner-Lavie H. and Ben-Shachar D.): DA Solutions, 61 Inhibits Mitochondrial Membrane Potential Keren N. and Korngreen A.: Constraining compartmental Possibly through its Interaction with Complex I: models using a parameter peeling procedure, 61 Implications to DA related Pathologies, 18 Kilner J. (with Litvak V., Penny W., Eusebio A., Chen Klein E. (with Chertkow-Deutsher Y., Ben-Shachar D., C. C., Oostenveld R., Limousin P., Zrinzo L., and Cohen H.): Epigenetic Factors in the Hariz M., Friston K., and Brown P.): Vulnerability to PTSD; The Role of DNA Simultaneous MEG and subthalamic local field Methylation, 21 potential recordings in Parkinson patients reveal KleinE.(YanivS.P.andBen-ShacharD.):AComplex the frequency-specific spatial pattern and Norepinephrine and Glucocorticoid directionality of subthalamo-cortical Intercellular Interaction: Relevance to Plasticity interactions, 69 Hypothesis of Depression, 116 144 Neural Plasticity

Klein M. (with Shomrat T., Feinstein N., and Hochner B.): in female triple transgenic AD mice treated with Serotonin is a neuromodulator of short- and lipophilic metal chelators is associated with long term synaptic plasticity in the octopus reduced astrocyte activation, amyloid-Beta and vertical lobe, 104 p-tau pathology, 38 KnafoA.(withIsraelS.,ReiboldM.,LererE.,Bornstein Kozminsky-Atias A. and Zilberberg N.: Characterization G., and Ebstein R. P.):Association between the of the first anti-Shaker specific toxin from the oxytocin receptor (OXTR) gene and pro-social venom of the Israeli scorpion Buthus occitanus behavior in two economic games: the Dictator israelis, 63 and Social Value Orientations, 57 Kramer U. (with Fisch L., Privman E., Kipervasser S., Knutsen P. M. (with Horev G., Pietr M., and Ahissar E.): AndelmanF.,NeufeldM.,FriedI.,andMalach Stereotyped whisker and head movements are R.): Neural correlates of visual recognition associated with object localization in revealed through backward masking and unrestrained rats, 55 intracranial electrode recordings, 36 Koch C. (with Yaron-Jakoubovitch A., Segev I., and Yarom Kramer U. (with Privman E., Fisch L., Kipervasser S., Y.): Is conductance change involved in the shift Andelman F., Neufeld M. Y., Yehezkel Y., Fried between UP and DOWN states of rat I., and Malach R.): Sustained image neocortical neurons?, 116 presentation supports a role for gamma LFP in Kohen R. (with Numa R. and Yaka R.): Tempol object perception, 88 Diminishes Oxidative Damage and Attenuates Kravitz E., Davidson M., Gigi A., Orr G., Seidman S., Behavioral Sensitization Following Cocaine Weiser M., and Biegon A.: Testosterone Administration in Rats, 80 improves visual-spatial memory in Kohn Y. (with Alkelai A., Kanyas K., Hamdan A., hypogonadal men, 63 Lancet D., and Lerer B.): Fine mapping of a Kremer I. (with Amar S., Shamir A., Ovadia O., Blanaru schizophrenia susceptibility locus on M., Reshef A., Rietschel M., Maier W., Belmaker chromosome 10q23-q26: Significant evidence R., Ebstein R., Agam G., and Mishmar D.): for linkage and a reduced linkage interval, 3 ff Mitochondrial DNA HV lineage increases the Konan E. (with Deri Y., Miron S., Achiron A., Ho mann susceptibility to schizophrenia among Israeli C., and Biegon A.): Selective hippocampal Arabs, 4 atrophy in Multiple Sclerosis quantitave MRI Kremer I. (with Bloch B., Haliba Y., Vadas L., Ben Shitrit studies, 26 Y., Ehood Golz A., Shelahavich K., Tangi R., Kopel H. and Mizrahi A.: In vivo two-photon calcium Tavakuli H. R., Ziv N., and Haimov I.): The imaging of periglomerular neurons in the effects of music background on sleep efficiency, mouse olfactory bulb, 62 anxiety and depression in Schizophrenia Korngreen A. (with Almog M. and Gurkiewicz M.): patients, 15 Modeling voltage-gated Sodium conductances from cortical pyramidal neurons, 3 Kremer U. (with Elkana O., Ben Bashat D., Hendler T., Korngreen A. (with Bar-Yehuda D. and Ben-Porat H.): Fros R., and Schweiger A.): Patterns of brain Modulation of Dendritic Calcium Spike by language organization as a function of linguistic Extracellular Calcium Concentration, 9 performance following recovery from Korngreen A. (with Bugaisen J., Bar-Gad I.): Cellular childhood insults to the left hemisphere, 32 Mechanisms of Deep Brain Stimulation, 19 Kuba M. J. (with Gutnick T., Byrne R. A., and Hochner Korngreen A. (with Davidson K.): Dynamic Properties of B.): Where are my arms? An octopus visually Martinotti-Pyramidal Synapses in Layer 2/3 of controlling its arm movements, 49 the Rat Somatosensory Cortex, 24 Kuba M. J. (with Thonhauser K. E., Zullo L., Byrne R. A., Korngreen A. (with Keren N.): Constraining and Hochner B.): Learning to move an arm compartmental models using a parameter inside a maze, 110 peeling procedure, 61 Kuba M. J., Byrne R. A., Gutnick T., Zullo L., Thonhauser Korngreen A. (with Peled N.): Parameters distributions K. E., and Hochner B.: Modifications and and interrelations in compartmental models of adaptations of arm use in Octopus vulgaris, 64 neurons, 85 Kubota Y. (with Aslam N. and Shouval H.): A Kovalev E., Tal Z., Zimmermann G., Ben-Ari S., Soreq H., Self-sustaining Translational Switch for Yarom Y., and Shoham S.: Glutamatergic Regulating the Maintenance of Synaptic excitotoxicity in cerebellar stroke: contribution Plasticity, 7 of genetic background to neurological and Kugler W. (with Shandalov Y., Veenman L., Leschiner S., histopathological outcomes in a mouse Lakomek M., and Gavish M.): Translocator model, 63 Protein ligands attenuate the mitochondrial Kozak A. (with Friedman J. E., Eilam R., Madala membrane collapse normally induced by the Halagappa K. V., Mattson M. P., Bush A. I., antineoplastic agent Adlard P. A., and David Y.): Improved cognition Erucylphosphohomocholine, 100 Author Index 145

Kugler W., Veenman L., Gavish M., and Lakomek M.: Role Lampl I. (with Okun M.): Synchronized excitation and of the 18 kDa Translocator protein and the inhibition during spontaneous and sensory adenine nucleotide transporter in evoked responses in the rat barrel cortex, 83 erucylphosphohomocholine-induced cell death Lamprecht R. (with Mantzur L.): Actin polymerization in in human glioma cells, 64 lateral amygdala is essential for fear memory Kushnir M. (with Dresner E. and Gozes I.): Advanced formation, 74 molecular genetic tools to further investigate the Lamy D. (with Salomon R. and Malach R.): Is That Me in essential protein ADNP and its family member the Mirror? The neural correlates of self ADNP2, 28 recognition through movement, 96 Kushnir R. (with Hanani M. and Cherkas P. S.): Lamy D., Salti M., and Bar-Haim Y.: Neural correlates of Purinergic signaling in satellite glial cells in subjective and objective awareness: An ERP sensory ganglia is enhanced in mouse models of study, 65 chronic pain, 51 Lancet D. (with Alkelai A., Kohn Y., Kanyas K., Hamdan Kutas M. (with Zion Golumbic E. and Bentin S.): Do you A., and Lerer B.): Fine mapping of a remember me? Retrieving Memories for schizophrenia susceptibility locus on Faces–Evidence from Theta (4–8 Hz) and chromosome 10q23-q26: Significant evidence > Gamma Band ( 30 Hz) Activity, 121 for linkage and a reduced linkage interval, 3 Lancet D. (with Slonimsky A., Alkelai A., L Amann-Zalcenstein D., Olender T., LaibaE.(withShalevI.,MeronY.,LaibeG.,LererE.,Raz Ben-Asher E., and Lerer B.): Sequence structure Y., Israel S., Bachner-Melman R., Uzefovsky F., identification and characterization of C6orf217: Dina C., Kaitz M., and Ebstein R. P.): The role A positional candidate gene for schizophrenia, of BDNF Val66Met and stress response in 105 smoking cessation in young women, 99 Landau A., Esterman M., Robertson L., Bentin S., and LaibeG.(withShalevI.,MeronY.,LererE.,LaibaE.,Raz Prinzmental W.: Different Effects of Voluntary Y., Israel S., Bachner-Melman R., Uzefovsky F., and Involuntary Attention on EEG Activity in Dina C., Kaitz M., and Ebstein R. P.): The role the Gamma Band, 65 of BDNF Val66Met and stress response in Lanir A. (with Tilleman H., Hakim V., Liser K., Scheffner smoking cessation in young women, 99 O., Nashelsky L., Meir I., and Brodski C.): LakomekM.(withKuglerW.,VeenmanL.,andGavish Effects of mid-hindbrain organizer genes and M.): Role of the 18 kDa Translocator protein members of the Bmp 60A subgroup in the and the adenine nucleotide transporter in development of noradrenergic locus coeruleus erucylphosphohomocholine-induced cell death neurons, 110 in human glioma cells, 64 ff Lakomek M. (with Shandalov Y., Veenman L., Leschiner Lanir A. (with Tilleman H., Liser K., Sche ner O., S., Kugler W., and Gavish M.): Translocator Nashelsky L., Meir I., and Brodski C.): The role Protein ligands attenuate the mitochondrial of members of the BMP 60A subgroup in the membrane collapse normally induced by the development of catecholaminergic neurons and antineoplastic agent the anterior pituirary, 110 Erucylphosphohomocholine, 100 Lapid H., Harel D., and Sobel N.: Predicting pleasantness Lalazar H., Shahar M., and Vaadia E.: Shaping of tuning of binary mixtures in olfaction, 65 properties in Motor Cortex during Long Term Lebedev M. (with Zacksenhouse M. and Nicolelis M.): VisuoMotor Learning, 65 Capacity of binned neural channels during Lampl I. (with Cohen E.): Exacerbated Subthreshold experiments with Brain-Machine-Interfaces, Oscillatory Activity in Rat Model of Essential 119 Tremor Revealed by In-Vivo Intracellular Lefler Y., Belenky M., and Yarom Y.: Reconstructing the Recordings of Inferior Olivary Neurons, 23 olivo-cerebellar system in a dish, 66 Lampl I. (with Dothan D. J.): Interbarrel synaptic Leker R. (with Hayon Y., Varon D., and Brill A.): connections in the rat barrel cortex, 28 Cell-driven angiogenesis and neurogenesis after Lampl I. (with Ganmor E., Katz Y., Mazig V., and Heiss J.): stroke with platelet derived microparticles, 53 Sensory Adaptation to Different Stimulus Leker R. (with Yeshurun-Cohen A., Alexandrocivh A., Strengths in Rat Whisker to Barrel Pathway, 39 Mechoulam R., and Shohami E.): The Lampl I. (with Heiss J., Oron E., and Grinvald A.): Endocannabinoid-Like Adaptation to repetitive whisker stimulation is N-Arachidonoyl-L-Serine Improves Outcome highly correlated among neurons in the rat after Traumatic Brain Injury, 117 barrel cortex, 53 Leker R. R. (with Thau-Zuchman O., Shohami E., and Lampl I. (with Katz Y. A.): Effect of anesthesia and Ovadia H.): Vascular Endothelial Growth Factor breathing on the receptive field size of thalamic Increases Neurogenesis Following Traumatic cells in the somatosensory system, 61 Brain Injury, 109 146 Neural Plasticity

Lerer B. (with Alkelai A., Kohn Y., Kanyas K., Hamdan A., neurodegeneration resulting in marked and Lancet D.): Fine mapping of a cognitive deficits, 10 schizophrenia susceptibility locus on Lev M. and Polat U.: Collinear facilitation at the chromosome 10q23-q26: Significant evidence periphery: does it differ from the fovea?, 66 for linkage and a reduced linkage interval, 3 Lev S. (with Parnas M., Katz B., Tzarfaty V., Lerer B. (with Lifschytz T., Shalom G., Golzer T., Segman Gordon-Shaag A., and Minke B.): Membrane R. H., and Newman M. E.): Biochemical and lipids modulation removes divalent open behavioral effects of triiodothyronine (T3) may channel block of TRPL and NMDA channels, 84 provide a basis for the antidepressant attributes Lev-Tov A. (with Etlin A., Shamir B., Mor Y., Sasson D., this compound, 68 and Zeilig G.): Myoclonic bursting of the ankle Lerer E. (with Edelman S., Paz A., Zeev-Ben-Mordehai T., joint musculature in spinal cord injury patients IsraelS.,NemanovL.,SussmanJ.L.,SilmanI., is attenuated by activation of crossed-inhibitory LeviS.,SalomonS.,YirmiyaN.,andEbstein pathways, 33 R. P.): Association between DLG4 (PSD-95) Lev-Tov A. (with Finkel E., Blivis D., Etlin A., and Scaffolding Protein and Autism: Relations to Anglister L.): Cholinergic involvement in Adaptive Behavior and Cognition, 30 sensory-induced activation of locomotor Lerer E. (with Israel S., Knafo A., Reibold M., Bornstein networks in the mammalian spinal cord, 35 G., and Ebstein R. P.):Association between the Lev-Tov A. (with Mor Y.): Statistical analysis of rhythmic oxytocin receptor (OXTR) gene and pro-social motor patterns produced by the spinal cord, 78 behavior in two economic games: the Dictator Levav T., Blumkin E., and Golan H.: Gender dependent ff and Social Value Orientations, 57 behavioral e ects of perinatal Lerer E. (with Shalev I., Meron Y., Laibe G., Laiba E., Raz gamma-aminobutyric acid (GABA) Y., Israel S., Bachner-Melman R., Uzefovsky F., potentiation and methylenetetrahydrofolate Dina C., Kaitz M., and Ebstein R. P.): The role reductase (MTHFR) deficiency in mice, 66 of BDNF Val66Met and stress response in Levi I. (with Eskira Y., Almog O., and Agam G.): Novel smoking cessation in young women, 99 approach to inhibit inositol monophosphatase as an alternative to Lithium as a mood Lerer B. (with Slonimsky A., Alkelai A., stabilizer, 33 Amann-Zalcenstein D., Olender T., Levi I., Shamir A., Cryns K., Steckler T., Moechars D., Ben-Asher E., and Lancet D.): Sequence Belmaker R., and Agam G.: Characterization of structure identification and characterization of the IMPA1 deficient mouse, 67 C6orf217: A positional candidate gene for Levi M. (with Nahum M. and Ahissar M.): Limitations of schizophrenia, 105 stimulus-anchoring mechanisms: evidence from Leschiner S. (with Maniv I., Veenman L., Spanier I., behavioral and ERP data, 78 Marek I., Shterenberg A., Hadad E., and Gavish Levi S. (with Edelman S., Lerer E., Paz A., M.): Novel TSPO ligands as neuroprotective Zeev-Ben-Mordehai T., Israel S., Nemanov L., agents, 73 Sussman J. L., Silman I., Salomon S., Yirmiya Leschiner S. (with Shandalov Y., Veenman L., Kugler W., N., and Ebstein R. P.): Association between Lakomek M., and Gavish M.): Translocator DLG4 (PSD-95) Scaffolding Protein and Protein ligands attenuate the mitochondrial Autism: Relations to Adaptive Behavior and membrane collapse normally induced by the Cognition, 30 antineoplastic agent Levin N. (with Raz N., Dotan S., Zohary E., Arkadir D., Erucylphosphohomocholine, 100 and Chokron S.): Behavioral and cortical Leschiner S. (with Zeno S., Veenman L., Zaarur M., and activation patterns following an optic neuritis Gavish M.): The correlation between the episode, 88 Translocator Protein (TSPO) and apoptosis in Levin R., Elran S., Ermilov M., Edelman S., Javitt D. C., human glioma cells under hypoxia, 120 and Heresco-Levy U.: Emotion recognition vs. Leshem (with Shachar-Dadon A., Even B., Maroun C., non-effective visual processing deficits in Galon I., and Schulkin J.): Effects of weanling schizophrenia, 67 stress and acute pre-mating shock on affect in Levine J. (with Bromberg A., Nemetz B., Belmaker R., and progeny in rats, 98 Agam G.): Global leukocyte DNA methylation Leshem M. (with Gonen G., Ferdman N., Even B., in schizophrenia patients, 18 Maroun C., Katz O., Pershin L., and Schulkin Levit-Binnun N. and Moses E.: The importance of being J.): Influence on offspring behavior of stress to stable and balanced-a therapy inspired network the rat dam before she becomes pregnant: approach, 68 effects of cross-fostering, 45 Levkovitz Y. (with Gruberger M., Hendler T., and Zangen Lev D. (with Belinson H., Dolev I., Masliah E., and A.): The Restless Mind–A relation between rest Michaelson D. M.): Activation of the Amyloid and the self in the brain–A deep-TMS Cascade in ApoE4 transgenic mice induces study-Presentation of preliminary results, 48 Author Index 147

Levkowitz G. (with Russek-Blum N., Gutnick A., dyskinetic movements in Nabel-Rosen H., Blechman J., Staudt N., Dorsky 6-hydroxydopamine-lesioned rats, 34 R., and Houart C.): Dopaminergic Neuronal Loewenstein Y. (with Gavornik J. and Shouval H.): Cluster Size is Determined During Early Learning temporal representations through Forebrain Patterning, 94 reward dependant expression of synaptic Levy R. (with Rolls A., Shechter R., London A., Ziv Y., eligibility traces in recurrent networks, 41 Ronen A., and Schwartz M.): Toll-like receptors Loewenstein Y. (with Neiman T.): A dynamic model for regulate adult neurogenesis, 92 matching behavior that is based on the Libersat F. (with Gal R.): Venomous wasp targets different covariance of reward and action, 79 head ganglia to manipulate specific behaviors of London A. (with Rolls A., Shechter R., Ziv Y., Ronen A., its cockroach prey, 39 Levy R., and Schwartz M.): Toll-like receptors Libersat F. (with Gavra T. and Gal R.): Involvement of the regulate adult neurogenesis, 92 opioid system in the decreased responsiveness London M. (with Gidon A. and Segev I.): Stochastic induced in cockroaches stung by a parasitoid synaptic transmission is advantageous for wasp, 41 learning complex temporal firing patterns in Lifschytz T., Shalom G., Golzer T., Segman R. H., Lerer B., neurons, 43 and Newman M. E.: Biochemical and Lottem E. and Azouz R.: Variable Processing of Texture behavioral effects of triiodothyronine (T3) may Signals by Whisker Vibrations, 69 provide a basis for the antidepressant attributes Lourbopoulos A. (with Boimel M., Grigoriadis N., this compound, 68 Abramsky O., and Rosenmann H.): Limousin P. (with Litvak V., Penny W., Eusebio A., Chen Immunotherapy targeting pathologically C. C., Oostenveld R., Kilner J., Zrinzo L., Hariz phosphorylated tau conformers in a tangle M., Friston K., and Brown P.): Simultaneous mouse model, 17 MEG and subthalamic local field potential Lovinger D. M. (with Sheinin A.): Endocannabinoid- and recordings in Parkinson patients reveal the mGluR5-dependent Short-Term Synaptic frequency-specific spatial pattern and Depression in an Isolated Neuron/Bouton directionality of subthalamo-cortical Preparation from the Hippocampal CA1 interactions, 69 Region, 102 Liraz-Zaltsman S., Fishbein I., Greeneberger V., Shohami Luques L., Shoham S., and Weinstock M.: Chronic E., and Biegon A.: Regional sensitivity to inhibition of brain cytochrome oxidase in rats Neuroinflammation: In vivo and in vitro induces memory deficits and associated with studies, 68 oxidative stress and alterations in cholinergic ff Liser K. (with Tilleman H., Hakim V., Sche ner O., transmission, 70 Nashelsky L., Meir I., Lanir A., and Brodski C.): Effects of mid-hindbrain organizer genes and members of the Bmp 60A subgroup in the M development of noradrenergic locus coeruleus Madala Halagappa K. V. (with Friedman J. E., Eilam R., neurons, 110 Mattson M. P., Bush A. I., Adlard P. A., David Y., Liser K. (with Tilleman H., Scheffner O., Nashelsky L., and Kozak A.): Improved cognition in female Meir I., Lanir A., and Brodski C.): The role of triple transgenic AD mice treated with members of the BMP 60A subgroup in the lipophilic metal chelators is associated with development of catecholaminergic neurons and reduced astrocyte activation, amyloid-Beta and the anterior pituirary, 110 p-tau pathology, 38 Litvak V., Penny W., Eusebio A., Chen C. C., Oostenveld Magen H., Kastner S., and Treisman A.: Attentional R., Kilner J., Limousin P., Zrinzo L., Hariz M., demands predict short-term memory load Friston K., and Brown P.: Simultaneous MEG response in posterior parietal cortex, 70 and subthalamic local field potential recordings Magen I., Avraham Y., Berry E., Ackerman Z., and in Parkinson patients reveal the Mechoulam R.: Cannabidiol (CBD) ameliorates frequency-specific spatial pattern and cognitive impairments associated with a model directionality of subthalamo-cortical of chronic liver disease in mice, 70 interactions, 69 MagidovichH.,OrrI.,FassD.,AbduU.,andYifrachO.: Livneh Y., Raday G., and Mizrahi A.: Synaptogenesis of The role of intrinsically-disordered protein adult-born neurons in the mouse olfactory segments in mediating Kv channel clustering: bulb, 69 implications for synapse assembly, maintenance Loboda Y. (with Feld Y., Finberg J. P., Gluzman Z., and function, 71 Mohsen O., Reshef M., and Marom S.): Maier W. (with Amar S., Shamir A., Ovadia O., Blanaru Transplanted fibroblasts reduce neuronal M., Reshef A., Kremer I., Rietschel M., Belmaker synchronised bursting discharge and correct R., Ebstein R., Agam G., and Mishmar D.): Parkinsonian asymmetry and L-Dopa-induced Mitochondrial DNA HV lineage increases the 148 Neural Plasticity

susceptibility to schizophrenia among Israeli Mandel Y. (with Doron R., Meshulam A., Rosner M., Arabs, 4 Belkin M., and Polat U.): Less is more: The Makin T., Holmes N. P., Brozzoli C., Rossetti Y., and Farne perceptual advantage of being color blinded, 27 A.: Rapid modulation of motor cortex Mandel Y. (with Meshulam A., Yehezkel O., Rosner M., excitability–TMS evidence for hand-centered Belkin B., and Polat U.): Visual processing visual representations of space, 72 under limiting visual conditions, 76 Makin T., Vax M., and Zohary E.: Towards behavioural Mandelblat-Cerf Y. and Vaadia E.: Dynamics of neuronal measures of action space–manipulability vs. variability in motor cortical areas during and ff compatibility in objects affordances, 71 switching between di erent tasks. What may it reflect?, 73 Malach R. (with Fisch L., Privman E., Kramer U., Maniv I., Veenman L., Leschiner S., Spanier I., Marek I., Kipervasser S., Andelman F., Neufeld M., and Shterenberg A., Hadad E., and Gavish M.: Novel Fried I.): Neural correlates of visual recognition TSPO ligands as neuroprotective agents, 73 revealed through backward masking and Mann L., Heldman E., Belmaker R. H., and Agam G.: The intracranial electrode recordings, 36 Inhibitory Effect of Mood Stabilizers on Malach R. (with Gelbard-Sagiv H., Mukamel R., Harel M., Adenylyl Cyclase Isoforms, 73 and Fried I.): Neural correlates of free recall in Mansour A. (with Golan-Lev T., Nissim-Eliraz E., Zisman the human medial temporal lobe, 42 S., Schatz O., Klar A., and Ben-Arie N.): The Malach R. (with Gotthilf-Nezri D., Gilaie-Dotan S., Perry transcription factor Nato3 is implied as a novel A., Bonneh Y., Bentin S., and Polat U.): Does regulator of floor plate and spinal cord abnormal binocular experience during critical development, 44 period limit normal development of visual Mantzur L. and Lamprecht R.: Actin polymerization in cognitive functions?, 46 lateral amygdala is essential for fear memory Malach R. (with Nir Y., Dinstein I., Mukamel R., Fisch L., formation, 74 Gelbard-Sagiv H., Arieli A., and Fried I.): Slow Maor M., Dangoor D., and Gozes I.: The interaction of the modulations of spontaneous firing rates and drug candidate NAP with microtubules in the LFP Gamma power in human auditory cortex presence of tau, 74 during wakefulness and sleep, 79 Marek I. (with Maniv I., Veenman L., Leschiner S., Malach R. (with Privman E., Fisch L., Kramer U., Spanier I., Shterenberg A., Hadad E., and Kipervasser S., Andelman F., Neufeld M. Y., Gavish M.): Novel TSPO ligands as Yehezkel Y., and Fried I.): Sustained image neuroprotective agents, 73 presentation supports a role for gamma LFP in Markram H. (with Druckmann S., Gidon A., Schuermann object perception, 88 F., and Segev I.): Constraining Neuron Models Malach R. (with Salomon R. and Lamy D.): Is That Me in by Experimental Data, 29 the Mirror? The neural correlates of self Marmor O. (with Rivlin-Etzion M., Rosin B., Slovik M., recognition through movement, 96 and Bergman H.): Low-pass filter properties of Malkinson G. and Spira M. E.: Watching Synapses Form: basal ganglia (BG) networks and possible Live Imaging of the Formation of Presynaptic mechanisms of action of high-frequency deep Boutons by Growth Cones of Cultured Aplysia brain stimulation (DBS), 91 Neurons, 72 Marom K. (with Zisman S., Avraham O., and Klar A.): Proteolysis and membrane capture of Mandel S. (with Fishman T. and Youdim M. B. H.): F-spondin generates combinatorial guidance Silencing plus over-expression of selected genes cues from a single molecule, 121 as a novel model of sporadic Parkinson’s MaromS.(withEckmannJ.,JacobiS.,MosesE.,Zbinden disease, 37 C.): Leaders of Activity in Dissociated Neural Mandel S. (with Gozes I., Pinhasov A., Pikman R., Cultures, 30 Grigoriadis N., Touloumi O., Pittel Z., and Marom S. (with Feld Y., Finberg J. P., Loboda Y., Gluzman Vulih-Shultzman I.): NAP reduces TAU Z., Mohsen O., and Reshef M.): Transplanted hyperphosphorylation and enhances learning in fibroblasts reduce neuronal synchronised a novel transgenic mouse model, 46 bursting discharge and correct Parkinsonian Mandel S. and Gozes I.: Activity–dependent asymmetry and L-Dopa-induced dyskinetic neuroprotective protein constitutes a novel movements in 6-hydroxydopamine-lesioned element in the SWI/SNF chromatin remodeling rats, 34 complex and modulates neural shape, 72 Marom S. (with Gal A. and Eytan D.): Recruitment Order Mandel S. A. (with Reznichenko L. and Youdim M. B. H.): Coding in Large-Scale Recurrent Networks of The Neurorestorative Effect of the Green Tea Cortical Neurons, 38 Polyphenol (-)-Epigallocatechin-3-Gallate Maroun C. (with Gonen G., Ferdman N., Even B., Katz O., Combined With the Selective MAO-B Inhibitor, Pershin L., Schulkin J., and Leshem M.): Rasagiline in MPTP Mice Model, 90 Influence on offspring behavior of stress to the Author Index 149

rat dam before she becomes pregnant: effects of component, elicits psychoactivity by activating cross-fostering, 45 TRPV3 channels, 78 Maroun C. (with Shachar-Dadon A., Even B., Galon I., Mechoulam R. (with Yeshurun-Cohen A., Leker R., Schulkin J., and Leshem): Effects of weanling Alexandrocivh A., and Shohami E.): The stress and acute pre-mating shock on affect in Endocannabinoid-Like progeny in rats, 98 N-Arachidonoyl-L-Serine Improves Outcome Maroun M. (with Bareni A. and Rosenblum K.): Akt is after Traumatic Brain Injury, 117 differently activated in the amygdala-prefrontal Meir I. (with Tilleman H., Hakim V., Liser K., Scheffner cortex-insular cortices circuit in acquisition and O., Nashelsky L., Lanir A., and Brodski C.): extinction of CTA, 9 Effects of mid-hindbrain organizer genes and Maroun M. (with Motanis H.): Alterations in members of the Bmp 60A subgroup in the hippocampal long-term potentiation following development of noradrenergic locus coeruleus fear conditioning, 78 neurons, 110 ff Maschke M. (with Bultmann U., Frings M., Pierscianek Meir I. (with Tilleman H., Liser K., Sche ner O., D., Fritsche N., Gizewski E. R., and Timmann Nashelsky L., Lanir A., and Brodski C.): The D.): Reorganisation of motor deficits in patients role of members of the BMP 60A subgroup in with acute cerebellar stroke, 19 the development of catecholaminergic neurons Maschke M. (with Pierscianek D., Frings M., Bultmann and the anterior pituirary, 110 U., Fritsche N., Gizewski E. R., Flossdorf A., and Meir R. (with Barak E., Eytan D., and Zeevi Y. Y.): Timmann D.): Rehabilitation of cognitive Topology Regulates Source Separation in impairment in patients with acute cerebellar Biologically Realistic Neural Networks, 8 stroke, 86 Meir R. (with Bobrowski O. and Eldar Y. C.): Optimal Maschke M. (with Sensen K., Obermann M., Yoon M., multi-modal state estimation by neural Diener H., and Katsarava Z.): Pregabalin in the networks based on recursive spike train treatment of trigeminal neuralgia: a prospective decoding, 16 open-label clinical trial, 98 Meiri N. (with Kisliouk T.): A critical role for histone 3 methylation in thermal control development, 62 Masliah E. (with Belinson H., Dolev I., Lev D., and Meiri N. (with Yossifoff M. and Kisliouk T.): Dynamic Michaelson D. M.): Activation of the Amyloid changes in DNA CpG dinucleotide methylation Cascade in ApoE4 transgenic mice induces in the brain-derived neurotrophic factor neurodegeneration resulting in marked (BDNF) promoter area during thermal control cognitive deficits, 10 establishment, 118 Materna S., Dicke P. W., and Thier P.: Neuronal substrates Melamed E. (with Barzilay R., Ben-Zur T., Bulvik S., and of head gaze following in monkeys: an fMRI Offen D.): Lentiviral delivery of LMX1a into study, 74 human Mesenchymal Stem Cells directs towards Mattson M. P. (with Friedman J. E., Eilam R., Madala dopaminergic differentiation, 9 Halagappa K. V., Bush A. I., Adlard P. A., David Melamed E. (with Shemesh N., Sadan O., Offen D., and Y., and Kozak A.): Improved cognition in female CohenY.):MRIdetectsinvivomigrationof triple transgenic AD mice treated with rat’sbonemarrowderivedmesechymalstem lipophilic metal chelators is associated with cells towards quinolinic acid lesion, 102 reduced astrocyte activation, amyloid-Beta and Mendelssohn A. (with Siman-Tov T., Schonberg T., p-tau pathology, 38 Avidan G., Pessoa L., Gadoth N., Ungerleide L., Matuzany-Ruban A. and Teichberg V. I.: Blood glutamate Podlipsky I., and Hendler T.): Hemispace- scavenging in the prevention of glioma rather than hemisphere-superiority as the basis invasiveness, 75 for visuospatial attention asymmetry: new Mazig V. (with Ganmor E., Katz Y., Heiss J., and Lampl I.): insights from fMRI, 104 Sensory Adaptation to Different Stimulus MeronY.(withShalevI.,LaibeG.,LererE.,LaibaE.,Raz Strengths in Rat Whisker to Barrel Pathway, 39 Y., Israel S., Bachner-Melman R., Uzefovsky F., McCairn K., Bronfeld M., and Bar-Gad I.: The Dina C., Kaitz M., and Ebstein R. P.): The role neurophysiological correlates of abnormal of BDNF Val66Met and stress response in behavior in a primate model of Tourette smoking cessation in young women, 99 syndrome and their response to high frequency Meshulam A. (with Doron R., Mandel Y., Rosner M., stimulation, 75 Belkin M., and Polat U.): Less is more: The Mechoulam R. (with Magen I., Avraham Y., Berry E., and perceptual advantage of being color blinded, 27 Ackerman Z.): Cannabidiol (CBD) ameliorates Meshulam A., Yehezkel O., Mandel Y., Rosner M., Belkin cognitive impairments associated with a model B., and Polat U.: Visual processing under of chronic liver disease in mice, 70 limiting visual conditions, 76 Mechoulam R. (with Moussaieff A.,FrideE.,and MeyerU.(withSpoerriE.,YeeB.K.,andFeldonJ.): Shohami E.): Incensole acetate, an incense Evaluating early preventive antipsychotic drug 150 Neural Plasticity

treatment during the prodromal phase in a learning: A study of forebrain neuronal glycine neurodevelopmental animal model of transporter 1 (GlyT1) deletion, 105 schizophrenia, 107 Mohsen O. (with Feld Y., Finberg J. P., Loboda Y., Mezer A., Yovel Y., Pasternak O., Gorfine T., and Assaf Y.: Gluzman Z., Reshef M., and Marom S.): The Anatomical Basis of Functional MRI, 76 Transplanted fibroblasts reduce neuronal Michaeli A. and Yaka R.: Acute dopamine exposure synchronised bursting discharge and correct attenuates GABAA receptor currents in the VTA Parkinsonian asymmetry and L-Dopa-induced through D1 and D2 dopamine receptors, 76 dyskinetic movements in MichaelsonD.M.(withBelinsonH.,DolevI.,LevD.,and 6-hydroxydopamine-lesioned rats, 34 Masliah E.): Activation of the Amyloid Cascade Molholm S. (with Barnett K. J., Fox J. J., Kelly S. P., Shalgi in ApoE4 transgenic mice induces S., Mitchell K. J., and Newell F. N.): Differences neurodegeneration resulting in marked in Early Visual Processing in Synesthesia: an cognitive deficits, 10 ERP study, 9 Michailovici I., Dangoor D., and Gozes I.: ADNP Mongillo G. (with Barak O. and Tsodyks M.): Working messenger RNA knock down–a novel approach memory: somatic spikes or synaptic calcium?, 8 for cancer therapy, 77 Mongillo G., Barak O., and Tsodyks M.: Facilitating Micheau J. (with Boucard A. and Nogues` X.): Training synapses mediate working memory, 77 and behavioral recovery after hippocampal Mons N. (with Kaouane N., Calandreau L., Esclassan F., lesion are coupled with changes in the pattern Tronel S., Jaffard R., Abrous N., Piazza P., and of connectivity, 17 Desmedt A.): Boundary conditions of Minke B. (with Parnas M., Katz B., Lev S., Tzarfaty V., and corticosterone-dependent enhancement or Gordon-Shaag A.): Membrane lipids alteration of memory consolidation, 60 modulation removes divalent open channel Mor Y. (with Etlin A., Shamir B., Sasson D., Zeilig G., and block of TRPL and NMDA channels, 84 ff Lev-Tov A.): Myoclonic bursting of the ankle Miron S. (with Deri Y., Achiron A., Ho mann C., Konan joint musculature in spinal cord injury patients E., and Biegon A.): Selective hippocampal is attenuated by activation of crossed-inhibitory atrophy in Multiple Sclerosis quantitave MRI pathways, 33 studies, 26 Mor Y. and Lev-Tov A.: Statistical analysis of rhythmic Mishmar D. (with Amar S., Shamir A., Ovadia O., Blanaru motor patterns produced by the spinal cord, 78 M., Reshef A., Kremer I., Rietschel M., Maier Moran T. H. (with Schroeder M., Shbiro L., and Weller W., Belmaker R., Ebstein R., and Agam G.): A.): Gender differences in coping with “lean” Mitochondrial DNA HV lineage increases the and “obese” postnatal environments in a rat susceptibility to schizophrenia among Israeli model of obesity, 97 Arabs, 4 Mitchell K. J. (with Barnett K. J., Fox J. J., Molholm S., MoranT.H.(withShbiroL.,SchroederM.,andWeller Kelly S. P., Shalgi S., and Newell F. N.): A.): Maternal obesity levels at the time of Differences in Early Visual Processing in weaning are influenced by the strain of the Synesthesia: an ERP study, 9 pups: insights from a cross-fostering study in Mitelman R. (with Rosin B., Slovik M., Rivlin-Etzion M., the OLETF rat model of obesity, 101 and Bergman H.): The contribution of forced Moses E. (with Eckmann J., Jacobi S., Zbinden C., and oscillations of the arm to the discharge pattern Marom S.): Leaders of Activity in Dissociated of primary motor cortex (M1) and globus Neural Cultures, 30 pallidus (GP) neurons, 92 Moses E. (with Levit-Binnun N.): The importance of Mitelman R. and Bergman H.: Is it possible to learn with being stable and balanced-a therapy inspired asymmetry between the ‘good teacher’ and the network approach, 68 ‘bad teacher’?, 77 Moses E. (with Rotem A.): Magnetic stimulation of living Mizrahi A. (with Kopel H.): In vivo two-photon calcium and dissociated brains, 93 imaging of periglomerular neurons in the Moses E. (with Soriano-Fradera J., Rodriguez Martinez mouse olfactory bulb, 62 M., and Tlusty T.): Development of Input Mizrahi A. (with Livneh Y. and Raday G.): Synaptogenesis Connections in Neural Cultures, 106 of adult-born neurons in the mouse olfactory Moss C. F. (with Ulanovsky N.): Hippocampal neural bulb, 69 activity in freely moving echolocating bats, 113 Moechars D. (with Levi I., Shamir A., Cryns K., Steckler Motanis H. and Maroun M.: Alterations in hippocampal T., Belmaker R., and Agam G.): long-term potentiation following fear Characterization of the IMPA1 deficient conditioning, 78 mouse, 67 Moussaieff A., Fride E., Shohami E., and Mechoulam R.: Mohler H. (with Singer P., Yee B. K., Boison D., and Incensole acetate, an incense component, elicits Feldon J.): To freeze or not to freeze? Cognitive psychoactivity by activating TRPV3 enhancement in the modulation of associative channels, 78 Author Index 151

Mukamel R. (with Gelbard-Sagiv H., Harel M., Malach R., Nelken I. (with Shapira A. and Jacobson G.): The and Fried I.): Neural correlates of free recall in Ectosylvian Sulcal Audiotory Field (FAES) and the human medial temporal lobe, 42 Localization of Sounds, 100 Mukamel R. (with Nir Y., Dinstein I., Fisch L., Nelken I. (with Ta‘aseh N. and Yaron A.): Gelbard-Sagiv H., Arieli A., Fried I., and Malach Context-dependent Stimulus-Specific R.): Slow modulations of spontaneous firing Adaptation in Rat Auditory Cortex, 108 rates and LFP Gamma power in human Nemanov L. (with Edelman S., Lerer E., Paz A., auditory cortex during wakefulness Zeev-Ben-Mordehai T., Israel S., Sussman J. L., and sleep, 79 Silman I., Levi S., Salomon S., Yirmiya N., and Ebstein R. P.): Association between DLG4 (PSD-95) Scaffolding Protein and Autism: N Relations to Adaptive Behavior and Nabel-Rosen H. (with Russek-Blum N., Gutnick A., Cognition, 30 Blechman J., Staudt N., Dorsky R., Houart C., Nemetz B. (with Bromberg A., Levine J., Belmaker R., and and Levkowitz G.): Dopaminergic Neuronal Agam G.): Global leukocyte DNA methylation Cluster Size is Determined During Early in schizophrenia patients, 18 Forebrain Patterning, 94 Neufeld M. (with Fisch L., Privman E., Kramer U., Nahum M. (with Daikhin L. and Ahissar M.): Fast Kipervasser S., Andelman F., Fried I., and switching from computation based to memory Malach R.): Neural correlates of visual based perception–evidence from ERP, 23 recognition revealed through backward masking Nahum M., Levi M., and Ahissar M.: Limitations of and intracranial electrode recordings, 36 stimulus-anchoring mechanisms: evidence from Neufeld M. Y. (with Privman E., Fisch L., Kramer U., behavioral and ERP data, 78 Kipervasser S., Andelman F., Yehezkel Y., Fried I., and Malach R.): Sustained image Najami N. (with Gnatek Y., Bitan Y., and Friedman A.): presentation supports a role for gamma LFP in Altered Cholinergic Gene Expression in object perception, 88 Pilocarpine-Treated Mice, 44 Newell F. N. (with Barnett K. J., Fox J. J., Molholm S., Naor Z. (with Dobkin-Bekman M. and Seger R.): A Kelly S. P., Shalgi S., and Mitchell K. J.): preformed signaling complex mediates GnRH Differences in Early Visual Processing in activated ERK phosphorylation of paxillin and Synesthesia: an ERP study, 9 FAK at focal adhesions in LfiT2 gonadotrope Newman M. E. (with Lifschytz T., Shalom G., Golzer T., cells, 27 Segman R. H., and Lerer B.): Biochemical and Nashelsky L. (with Tilleman H., Hakim V., Liser K., behavioral effects of triiodothyronine (T3) may Scheffner O., Meir I., Lanir A., and Brodski C.): ff provide a basis for the antidepressant attributes E ects of mid-hindbrain organizer genes and this compound, 68 members of the Bmp 60A subgroup in the Nicolelis M. (with Zacksenhouse M. and Lebedev M.): development of noradrenergic locus coeruleus Capacity of binned neural channels during neurons, 110 experiments with Brain-Machine-Interfaces, ff Nashelsky L. (with Tilleman H., Liser K., Sche ner O., 119 Meir I., Lanir A., and Brodski C.): The role of Nir Y., Dinstein I., Mukamel R., Fisch L., Gelbard-Sagiv members of the BMP 60A subgroup in the H., Arieli A., Fried I., and Malach R.: Slow development of catecholaminergic neurons and modulations of spontaneous firing rates and the anterior pituirary, 110 LFP Gamma power in human auditory cortex Nefussy B. (with Ben Bashat D., Drory V. E., Artzi M., during wakefulness and sleep, 79 Zachor T., Assaf Y., and Aizenstein O.): White Nisemblat Y., Geffen Y., Winkler I., Klapper L., Savitsky matter impairment in Amyotrophic Lateral K.,NudelmanA.,RephaeliA.,GiladI.,and ff Sclerosis (ALS): Di usion tensor imaging and Weizman: BL-1021: A New Chemical Entity for high b-value DWI study, 11 Treatment of Naturopathic and Acute Pain, 80 Neiman T. and Loewenstein Y.: A dynamic model for Nisky I. and Karniel A.: Perceptuo-motor transparency in matching behavior that is based on the bilateral teleoperation, 80 covariance of reward and action, 79 Nissim-Eliraz E. (with Golan-Lev T., Mansour A., Zisman Nelken E. (with Shayevitz O.): Towards a characterization S., Schatz O., Klar A., and Ben-Arie N.): The of natural sounds, 101 transcription factor Nato3 is implied as a novel Nelken I. (with De Hoz L. and Raizel H.): Effect of regulator of floor plate and spinal cord exposure to a behaviourally relevant tone on development, 44 auditory cortex responses to the same tone in Nogues` X. (with Boucard A. and Micheau J.): Training mice, 25 and behavioral recovery after hippocampal Nelken I. (with Hershenhoren I.): Tone Detection in lesion are coupled with changes in the pattern Noise in the Mouse Auditory Cortex, 54 of connectivity, 17 152 Neural Plasticity

Novick I. (with Arce F., Shahar M., Ghez C., and Vaadia Eren R.): Immunotherapies for Alzheimer’s E.): Modalities of feedback induce differential Disease, 11 reaching strategies in adaptations to Okon-Singer H., Podlipsky I., Yovel G., Siman-Tov T., and force field, 6 Hendler T.: Knowing Left from Right: A Nudelman A. (with Nisemblat Y., Geffen Y., Winkler I., Combined ERP-fMRI Study of Visuospatial Klapper L., Savitsky K., Rephaeli A., Gilad I., Attention, 82 and Weizman): BL-1021: A New Chemical Okun M. and Lampl I.: Synchronized excitation and Entity for Treatment of Naturopathic and Acute inhibition during spontaneous and sensory Pain, 80 evoked responses in the rat barrel cortex, 83 Nudelman A. (with Rephaeli A., Gil-Ad I., Trasenko N., Olender T. (with Slonimsky A., Alkelai A., Tarasenko I., Aharoni A., Geffen Y., Savitsky K., Amann-Zalcenstein D., Ben-Asher E., Lancet D., and Weizman A.): Amidic GABA derivatives of and Lerer B.): Sequence structure identification antidepressants display improved pain and characterization of C6orf217: A positional suppressing activity, 89 candidate gene for schizophrenia, 105 Numa R., Kohen R., and Yaka R.: Tempol Diminishes Omer D. B., Rom L., Ulchin Y., and Grinvald A.: Oxidative Damage and Attenuates Behavioral Comparing the dynamics of ongoing activity in Sensitization Following Cocaine Administration awake and anesthetized monkey, 83 in Rats, 80 Oostenveld R. (with Litvak V., Penny W., Eusebio A., Chen Nussinovitch I. (with Ben-Zeev G.): Cone-shaped C. C., Kilner J., Limousin P., Zrinzo L., Hariz lysophospholipids modulate voltage-gated M., Friston K., and Brown P.): Simultaneous calcium channel currents in pituitary cells, 14 MEG and subthalamic local field potential recordings in Parkinson patients reveal the O frequency-specific spatial pattern and O‘Connell R. G. (with Shalgi S., Deouell L. Y., and directionality of subthalamo-cortical RobertsonI.H.):AbsentMindedbutAccurate: interactions, 69 Delaying responses increases Accuracy but Oron E. (with Heiss J., Grinvald A., and Lampl I.): decreases Error Awareness, 99 Adaptation to repetitive whisker stimulation is O‘Doherty J. (with Schonberg T., Daw N., Inzelberg R., highly correlated among neurons in the rat and Joel D.): An fMRI study of striatal activity barrel cortex, 53 during reinforcement learning in Parkinson’s Orr G. (with Kravitz E., Davidson M., Gigi A., Seidman S., Disease, 96 Weiser M., and Biegon A.): Testosterone Obermann M. (with Sensen K., Yoon M., Maschke M., improves visual-spatial memory in Diener H., and Katsarava Z.): Pregabalin in the hypogonadal men, 63 treatment of trigeminal neuralgia: a prospective open-label clinical trial, 98 Orr I. (with Magidovich H., Fass D., Abdu U., and Yifrach Ofek E. and Reiner M.: Haptics and subjective emotional O.): The role of intrinsically-disordered protein significance, 81 segments in mediating Kv channel clustering: Ofen N., and Gabrieli J. D.: Development of declarative implications for synapse assembly, maintenance memory systems in the human brain, 81 and function, 71 Offen D. (with Barzilay R., Ben-Zur T., Bulvik S., and Ovadia H. (with Thau-Zuchman O., Shohami E., and Melamed E.): Lentiviral delivery of LMX1a into Leker R. R.): Vascular Endothelial Growth human Mesenchymal Stem Cells directs towards Factor Increases Neurogenesis Following dopaminergic differentiation, 9 Traumatic Brain Injury, 109 Offen D. (with Shemesh N., Sadan O., Melamed E., and Ovadia O. (with Amar S., Shamir A., Blanaru M., Reshef Cohen Y.): MRI detects in vivo migration of A., Kremer I., Rietschel M., Maier W., Belmaker rat’sbonemarrowderivedmesechymalstem R., Ebstein R., Agam G., and Mishmar D.): cells towards quinolinic acid lesion, 102 Mitochondrial DNA HV lineage increases the Oged A. and Gutfreund Y.: Effects of early auditory susceptibility to schizophrenia among Israeli experience on the auditory space map in the Arabs, 4 barn owl’s brain, 82 Oz S. and Gozes I.: The influence of NAP treatment on the Ogran A. (with Feder Y., Zinn A., Yadid G., and Pinhasov severity of experimental autoimmune A.): Establishment of a Dominant Submissive encephalomyelitis, 83 Relationships Model in Sabra Outbred mice, 34 Ohayon S., Harmening, Wagner H., and Rivlin E.: Through a barn owl’s eyes: interactions between P scene content and visual attention, 82 Panarsky R. and Weinstock M.: Ladostigil reduces release Ohayon T. (with Ben Porata J., Terkieltaub D., Goren O., of NO from activated microglia and oxidative Yakov N., Abrameto J., Sharon N., Zaretsky I., stress in neuronal cells by different Shaki-Loewenstein S., Hazum S., Gopher J., and mechanisms, 84 Author Index 153

Pannasch U., Ezan P., Willecke K., Giaume C., and Rouach rat dam before she becomes pregnant: effects of N.: Synaptic strength regulated by astrocytic gap cross-fostering, 45 junctions, 84 Pertzov Y., Avidan G., and Zohary E.: The representation Papathomas T. V. (with Wagner M. and Ehrenstein of saccadic eye movements in human cortical W. H.): Vergence in reverspective: Effects of real regions, 86 and virtual depth cues, 114 Pessoa L. (with Siman-Tov T., Mendelssohn A., Schonberg Papo D. (with Ben Simon E., Podlisky I., Zhdanov A., and T., Avidan G., Gadoth N., Ungerleide L., Hendler T.): Exploring Alpha Correlates In The Podlipsky I., and Hendler T.): Hemispace- Brain–An EEG-fMRI Study, 12 rather than hemisphere-superiority as the basis Parnas M., Katz B., Lev S., Tzarfaty V., Gordon-Shaag A., for visuospatial attention asymmetry: new and Minke B.: Membrane lipids modulation insights from fMRI, 104 removes divalent open channel block of TRPL Piazza P. (with Kaouane N., Calandreau L., Esclassan F., and NMDA channels, 84 Tronel S., Mons N., Jaffard R., Abrous N., and Pasternak O. (with Mezer A., Yovel Y., Gorfine T., and Desmedt A.): Boundary conditions of Assaf Y.): The Anatomical Basis of Functional corticosterone-dependent enhancement or MRI, 76 alteration of memory consolidation, 60 Pasternak O., Sochen N., Intrator N., and Assaf Y.: Pick C. G. (with Benaroya-Milshtein N., Hollander N., Mapping and Eliminating Free Water in the Apter A., Yaniv I., Haberman Y., Halpert H.): ff Brain by Di usion Imaging, 85 Acutestressinmice;alterationinbehavior, Pavlovskaya M. and Hochstein S.: Does the Right Side immunity and cancer development, 12 Remember what the Left Side Learned? Pick C. G. (with Defrin R., Dror A., and Yulzari L.): Hemispheric Transfer of Perceptual Learning ff ff Habituation to pain: the e ect of absolute vs E ects, 85 relative stimulation intensity, 26 Paz A. (with Edelman S., Lerer E., Zeev-Ben-Mordehai T., Pick C. G. (with Edut S., Rubovitch V., Schreiber S., and IsraelS.,NemanovL.,SussmanJ.L.,SilmanI., Feldon J.): Deficits in spatial learning in mice LeviS.,SalomonS.,YirmiyaN.,andEbstein after minimal traumatic brain injury R. P.): Association between DLG4 (PSD-95) demonstrated by a novel dry maze test, 31 Scaffolding Protein and Autism: Relations to Pierscianek D. (with Bultmann U., Frings M., Fritsche N., Adaptive Behavior and Cognition, 30 Gizewski E. R., Timmann D., and Maschke M.): Pehter I. (with Garion L., Azouz R., and Schiller J.): Single Reorganisation of motor deficits in patients cell resolution network dynamics in the rat with acute cerebellar stroke, 19 barrel cortex using calcium imaging two-photon microscopy in-vivo, 40 Pierscianek D., Frings M., Bultmann U., Fritsche N., Peled N. and Korngreen A.: Parameters distributions and Gizewski E. R., Flossdorf A., Timmann D., and interrelations in compartmental models of Maschke M.: Rehabilitation of cognitive neurons, 85 impairment in patients with acute cerebellar Penny W. (with Litvak V., Eusebio A., Chen C. C., stroke, 86 Oostenveld R., Kilner J., Limousin P., Zrinzo L., Pietr M. (with Horev G., Knutsen P. M., and Ahissar E.): Hariz M., Friston K., and Brown P.): Stereotyped whisker and head movements are Simultaneous MEG and subthalamic local field associated with object localization in potential recordings in Parkinson patients reveal unrestrained rats, 55 the frequency-specific spatial pattern and Pikman R. (with Gozes I., Pinhasov A., Mandel S., directionality of subthalamo-cortical Grigoriadis N., Touloumi O., Pittel Z., and interactions, 69 Vulih-Shultzman I.): NAP reduces TAU Perez-Polo J. (with Haramati O., Chalifa-Caspi V., and hyperphosphorylation and enhances learning in Golan H.): Prenatal hypoxia influences a novel transgenic mouse model, 46 cerebellum gene expression, 52 Pinhasov A. (with Feder Y., Ogran A., Zinn A., and Yadid Perez-Polo R. J. (with Golan H. M., Kaplan-Louzone V., G.): Establishment of a Dominant Submissive and Zuckerman M.): Impaired migration Relationships Model in Sabra Outbred mice, 34 signaling in the hippocampus following Pinhasov A. (with Gozes I., Mandel S., Pikman R., prenatal hypoxia, 44 Grigoriadis N., Touloumi O., Pittel Z., and Perry A. (with Gotthilf-Nezri D., Gilaie-Dotan S., Bonneh Vulih-Shultzman I.): NAP reduces TAU Y., Bentin S., Malach R., and Polat U.): Does hyperphosphorylation and enhances learning in abnormal binocular experience during critical a novel transgenic mouse model, 46 period limit normal development of visual Pinhasov A. (with Reichenstein M. and Rehavi M.): Effect cognitive functions?, 46 of antidepressants on PACAP and its receptors PershinL.(withGonenG.,FerdmanN.,EvenB.,Maroun in rat primary neurons, 89 C., Katz O., Schulkin J., and Leshem M.): Pinhasov A. (with Schneider J., Feder Y., and Reichenstein Influence on offspring behavior of stress to the M.): Gene Expression Profile of Pac1 and 154 Neural Plasticity

Vpac1/2 Receptors in Developing and Adult Rat Poltyrev T., Bejar C., and Weinstock M.: Detection of Brain, 96 differences in learning strategy and reference Pinhasov A., Reichenstein M., Feder Y., and Schneider J.: memory in young and old rats: Prevention of Neuropeptides, Antidepressants and memory deficits by ladostigil, 87 Depression, 86 Prager O., David Y., and Friedman A.: Real-time Piontkewitz Y., Arad M., and Weiner I.: Effects of neonatal monitoring of blood-brain barrier disruption in administration of polyinosinic-polycytidilic the rat cerebral cortex, 88 acid (Poly I:C) on latent inhibition and Pratt H. (with Berkovich E. and Gur M.): Face discrimination reversal in adulthood, 87 Recognition Inspired by the Visual Cortex, 14 Pittel Z. (with Gozes I., Pinhasov A., Mandel S., Pikman Prinzmental W. (with Landau A., Esterman M., Robertson R., Grigoriadis N., Touloumi O., and L., and Bentin S.): Different Effects of Voluntary Vulih-Shultzman I.): NAP reduces TAU and Involuntary Attention on EEG Activity in hyperphosphorylation and enhances learning in the Gamma Band, 65 a novel transgenic mouse model, 46 Privman E. (with Fisch L., Kramer U., Kipervasser S., Podlipsky I. (with Okon-Singer H., Yovel G., Siman-Tov AndelmanF.,NeufeldM.,FriedI.,andMalach T., and Hendler T.): Knowing Left from Right: A R.): Neural correlates of visual recognition Combined ERP-fMRI Study of Visuospatial revealed through backward masking and Attention, 82 intracranial electrode recordings, 36 Podlipsky I. (with Sadeh B., Zhdanov A., Hendler T., and Privman E., Fisch L., Kramer U., Kipervasser S., Yovel G.): The reliability and validity of the Andelman F., Neufeld M. Y., Yehezkel Y., Fried face-specific N170 ERP component recorded I., and Malach R.: Sustained image presentation simultaneously with functional MRI, 94 supports a role for gamma LFP in object Podlipsky I. (with Siman-Tov T., Mendelssohn A., perception, 88 Schonberg T., Avidan G., Pessoa L., Gadoth N., Ungerleide L., and Hendler T.): Hemispace- R rather than hemisphere-superiority as the basis Rabinovitz I. (with Bloch-Shiderman E., Egoz I., Kapon J., for visuospatial attention asymmetry: new Raveh L., Grauer E., and Allon N.): Integrating insights from fMRI, 104 telemetry data in toxicological studies: The Podlisky I. (with Ben Simon E., Zhdanov A., Papo D., and effect of chronic exposure of rats to low doses of Hendler T.): Exploring Alpha Correlates In The VX, 16 Brain–An EEG-fMRI Study, 12 Raday G. (with Livneh Y. and Mizrahi A.): Synaptogenesis Polat U. (with Doron R., Meshulam A., Mandel Y., Rosner of adult-born neurons in the mouse olfactory M., and Belkin M.): Less is more: The bulb, 69 perceptual advantage of being color blinded, 27 Rahamimoff R. (with Valitsky M., Blank P., Raveh A., Polat U. (with Gotthilf-Nezri D., Gilaie-Dotan S., Perry Coorssen J., and Zimmerberg J.): Non A., Bonneh Y., Bentin S., and Malach R.): Does Stationary Fluctuation Analysis of Calcium in abnormal binocular experience during critical Secretory Vesicles, 113 period limit normal development of visual Raizel H. (with De Hoz L. and Nelken I.): Effect of cognitive functions?, 46 exposure to a behaviourally relevant tone on Polat U. (with Lev M.): Collinear facilitation at the auditory cortex responses to the same tone in ff periphery: does it di er from the fovea?, 66 mice, 25 Polat U. (with Meshulam A., Yehezkel O., Mandel Y., Raveh A. (with Valitsky M., Blank P., Coorssen J., Rosner M., and Belkin B.): Visual processing Zimmerberg J., and Rahamimoff R.): Non under limiting visual conditions, 76 Stationary Fluctuation Analysis of Calcium in Polat U. (with Sterkin A.): Functional architecture of Secretory Vesicles, 113 collinear interactions induce spatial and Raveh L. (with Bloch-Shiderman E., Rabinovitz I., Egoz I., temporal correlation as a basis for binding, 107 Kapon J., Grauer E., and Allon N.): Integrating Polat U. (with Tadmor S.): When noise can mask visual telemetry data in toxicological studies: The targets, 108 effect of chronic exposure of rats to low doses of Polat U. (with Yehezkel O.): Natural developmental optical VX, 16 astigmatism during childhood induces “cortical Raz N., Dotan S., Zohary E., Arkadir D., Chokron S., and astigmatism” in the adult visual cortex, 117 Levin N.: Behavioral and cortical activation Polat U. (with Zomet A. and Amiaz R.): Early perceptual patterns following an optic neuritis episode, 88 loss in depression, 121 RazY.(withShalevI.,MeronY.,LaibeG.,LererE.,Laiba Polina E. (with Hairston I. S., Talbot L. S., June G. L., and E., Israel S., Bachner-Melman R., Uzefovsky F., Harvey A. G.): Sensory gating in primary Dina C., Kaitz M., and Ebstein R. P.): The role insomnia: A potential objective measure of of BDNF Val66Met and stress response in reduced sleep quality, 51 smoking cessation in young women, 99 Author Index 155

Reches A. (with Gutfreund Y. and Zachar Y.): bursting discharge and correct Parkinsonian Visual-auditory integration in the barn owl: A asymmetry and L-Dopa-induced dyskinetic neuroethological approach, 48 movements in 6-hydroxydopamine-lesioned Reches A. and Gutfreund Y.: Auditory and visual rats, 34 responses in the tectofugal pathway of the barn Reubinoff B. E. (with Cohen M. A. and Itsykson P.): The owl, 89 molecular mechanism of neural induction of Rehavi M. (with Dror V., Assaf Y., and Eliash S.): human embryonic stem cells, 22 Neuronal rescue in thiamine deficiency, 29 Reuveni I., Saar D., and Barkai E.: Associative odor Rehavi M. (with Reichenstein M. and Pinhasov A.): Effect learning induces non uniform increase in the of antidepressants on PACAP and its receptors synaptic efficacy, 90 in rat primary neurons, 89 Revol P. (with Holmes N. P., Farne` A., Rode G., Spence C., ReiboldM.(withIsraelS.,KnafoA.,LererE.,Bornstein Calvert G., and Rossetti Y.): Recognising your G., and Ebstein R. P.):Association between the own hands: Attribution biases & brain oxytocin receptor (OXTR) gene and pro-social mechanisms, 54 behavior in two economic games: the Dictator Reznichenko L., Youdim M. B. H., and Mandel S. A.: The and Social Value Orientations, 57 Neurorestorative Effect of the Green Tea Reichenstein M. (with Pinhasov A., Feder Y., and Polyphenol (-)-Epigallocatechin-3-Gallate Schneider J.): Neuropeptides, Antidepressants Combined With the Selective MAO-B Inhibitor, and Depression, 86 Rasagiline in MPTP Mice Model, 90 Reichenstein M. (with Schneider J., Feder Y., and Pinhasov Richter-Levin G. (with Horovitz O. and Tsoory M. M.): A.): Gene Expression Profile of Pac1 and Individual differences in stress responsiveness Vpac1/2 Receptors in Developing and Adult Rat affect the consequences of juvenile stress on Brain, 96 coping with stress in adulthood, 55 Reichenstein M., Rehavi M., and Pinhasov A.: Effect of Richter-levin G. (with Ilin Y.): The interplay between antidepressants on PACAP and its receptors in Juvenile stress and Enriched Environment on rat primary neurons, 89 behavior and L1-CAM, 56 Reichert F. (with Gitik M. and Rotshenker S.): Rho/ROCK Richter-Levin G. (with Jacobson-Pick S.): Short and long signalling down-regulates myelin phagocytosis term consequences of exposing rats to stressors in microglia, 43 during juvenility, 58 Reichert F. (with Hadas S. and Rotshenker S.): Tyrosine Richter-Levin G. (with Jubran M.): Local circuit plasticity kinase Syk regulates differentially myelin and in the dentate gyrus induced by a week titanic pathogen phagocytosis mediated by stimulation, 59 Complement Receptor-3, Dectin-1 and Rietschel M. (with Amar S., Shamir A., Ovadia O., Mannose Receptor, 50 Blanaru M., Reshef A., Kremer I., Maier W., Reiner M. (with Ofek E.): Haptics and subjective Belmaker R., Ebstein R., Agam G., and Mishmar emotional significance, 81 D.): Mitochondrial DNA HV lineage increases Rephaeli A. (with Nisemblat Y., Geffen Y., Winkler I., the susceptibility to schizophrenia among Israeli Klapper L., Savitsky K., Nudelman A., Gilad I., Arabs, 4 and Weizman): BL-1021: A New Chemical Rimmerman N., Bradshaw H. B., Tan B., and Walker Entity for Treatment of Naturopathic and Acute J. M.: Microsomal Enzymes Metabolize the Pain, 80 Endogenous Lipid, N-arachidonoyl dopamine, Rephaeli A., Gil-Ad I., Trasenko N., Tarasenko I., Aharoni to Hydroxylated Metabolites Active at A., Geffen Y., Savitsky K., Weizman A., and Recombinant human TRPV1 Receptors, 91 Nudelman A.: Amidic GABA derivatives of Rivlin E. (with Ohayon S., Harmening, and Wagner H.): antidepressants display improved pain Through a barn owl’s eyes: interactions between suppressing activity, 89 scene content and visual attention, 82 Represa A. (with Goldin M., Epsztein J., Jorquera I., Rivlin-Etzion M. (with Rosin B., Slovik M., Mitelman R., Ben-Ari Y., Cre’pel V., and Cossart R.): A and Bergman H.): The contribution of forced specific processing of afferent theta inputs via oscillations of the arm to the discharge pattern synaptic kainate receptors in O-LM neurons, 45 of primary motor cortex (M1) and globus Reshef A. (with Amar S., Shamir A., Ovadia O., Blanaru pallidus (GP) neurons, 92 M., Kremer I., Rietschel M., Maier W., Belmaker Rivlin-Etzion M., Marmor O., Rosin B., Slovik M., and R., Ebstein R., Agam G., and Mishmar D.): Bergman H.: Low-pass filter properties of basal Mitochondrial DNA HV lineage increases the ganglia (BG) networks and possible susceptibility to schizophrenia among Israeli mechanisms of action of high-frequency deep Arabs, 4 brain stimulation (DBS), 91 Reshef M. (with Feld Y., Finberg J. P., Loboda Y., Gluzman Rizzolatti G. (with Caggiano V., Fogassi L., Giese M., Thier Z., Mohsen O., and Marom S.): Transplanted P., and Casile A.): Tuning of the point of view of fibroblasts reduce neuronal synchronised mirror neurons in monkey premotor cortex, 20 156 Neural Plasticity

RobertsonI.H.(withShalgiS.,O‘ConnellR.G.,and Dopamine Induce Rapid Translation of RSK2 in Deouell L. Y.): Absent Minded but Accurate: the Mature Hippocampus, 60 Delaying responses increases Accuracy but Rosenmann H. (with Boimel M., Grigoriadis N., decreases Error Awareness, 99 Lourbopoulos A., and Abramsky O.): Robertson L. (with Landau A., Esterman M., Bentin S., Immunotherapy targeting pathologically and Prinzmental W.): Different Effects of phosphorylated tau conformers in a tangle Voluntary and Involuntary Attention on EEG mouse model, 17 Activity in the Gamma Band, 65 Rosin B. (with Rivlin-Etzion M., Marmor O., Slovik M., Rode G. (with Holmes N. P., Revol P., FarneA.,SpenceC.,` and Bergman H.): Low-pass filter properties of Calvert G., and Rossetti Y.): Recognising your basal ganglia (BG) networks and possible own hands: Attribution biases & brain mechanisms of action of high-frequency deep mechanisms, 54 brain stimulation (DBS), 91 Rodriguez Martinez M. (with Soriano-Fradera J., Tlusty Rosin B., Slovik M., Mitelman R., Rivlin-Etzion M., and T., and Moses E.): Development of Input Bergman H.: The contribution of forced Connections in Neural Cultures, 106 oscillations of the arm to the discharge pattern Roebroeck A. (with Van Atteveldt N. M., Blau V., of primary motor cortex (M1) and globus Formisano E., Blomert L., and Goebel R.): pallidus (GP) neurons, 92 Multisensory integration of speech and script in Rosner M. (with Doron R., Meshulam A., Mandel Y., fluent and dyslexic readers, 113 Belkin M., and Polat U.): Less is more: The Rokni D. and Yarom Y.: Cerebellar cortical responses to perceptual advantage of being color blinded, 27 mossy fiber repetitive stimulation are enhanced Rosner M. (with Meshulam A., Yehezkel O., Mandel Y., by dissinhibition, 91 Belkin B., and Polat U.): Visual processing Rolls A., Shechter R., London A., Ziv Y., Ronen A., Levy under limiting visual conditions, 76 R., and Schwartz M.: Toll-like receptors regulate Rossetti Y. (with Holmes N. P., Revol P., FarneA.,Rode` adult neurogenesis, 92 G., Spence C., and Calvert G.): Recognising Rom L. (with Omer D. B., Ulchin Y., and Grinvald A.): your own hands: Attribution biases & brain Comparing the dynamics of ongoing activity in mechanisms, 54 awake and anesthetized monkey, 83 Rossetti Y. (with Makin T., Holmes N. P., Brozzoli C., and Ronen A. (with Rolls A., Shechter R., London A., Ziv Y., Farne A.): Rapid modulation of motor cortex Levy R., and Schwartz M.): Toll-like receptors excitability–TMS evidence for hand-centered regulate adult neurogenesis, 92 visual representations of space, 72 Rosenberg K., Fried I., and Hendler T.: Searching for Rotem A. and Moses E.: Magnetic stimulation of living anatomical based functional organization in the and dissociated brains, 93 human brain: The case of the Supplementary Rotem N., Sestieri E., Hounsgaard J., and Yarom Y.: Motor Area, 92 Differential postsynaptic efficiency of Rosenblum K. (with Bareni A. and Maroun M.): Akt is electrosensory afferents and parallel fibers in the differently activated in the amygdala-prefrontal principal neurons of the shark Dorsal cortex-insular cortices circuit in acquisition and Octavolateral Nucleus, 93 extinction of CTA, 9 Roth Y. (with Gelstein S. and Sobel N.): Can the effects of Rosenblum K. (with Cohen-Matsliah S. I., Brosh I., and putative human pheromones be attributed to Barkai E.): A novel role for ERK in maintaining chemical sensing?, 42 long-term memory relevant excitability Rotshenker S. (with Gitik M. and Reichert F.): Rho/ROCK changes, 23 signalling down-regulates myelin phagocytosis Rosenblum K. (with David O., Kaphzan H., Anderson C., in microglia, 43 and Grant S.): Dopamine induces tyrosine Rotshenker S. (with Hadas S. and Reichert F.): Tyrosine phosphorylation of the NR2A subunit (PY1325) kinase Syk regulates differentially myelin and in mature rat hippocampus, 24 pathogen phagocytosis mediated by Rosenblum K. (with Doron G.): Novel taste elevates c-fos Complement Receptor-3, Dectin-1 and expression in GABAergic neurons in the Mannose Receptor, 50 dysgranular Insular Cortex, 28 Rotshenker S.: Microglia activation is subject to Rosenblum K. (with Elkobi A., Belelovsky K., modulation in injury and disease, 93 Barki-Harrington L., and Ehrlich I.): The role of Rouach N. (with Pannasch U., Ezan P., Willecke K., and PSD-95 in consolidation of taste learning, 33 Giaume C.): Synaptic strength regulated by Rosenblum K. (with Inberg S. and Wagner S.): Molecular astrocytic gap junctions, 84 correlations following mating in the rodent Rubin N. (with Yu C., Haidarliu S., Derdikman D., and female olfactory bulb, 56 Ahissar E.): Coding selectivity of object location Rosenblum K. (with Kaphzan H. and Doron G.): Novel in the secondary somatosensory cortex during Environment and Co-application of NMDA and active vibrissal touch, 118 Author Index 157

Rubovitch V. (with Edut S., Schreiber S., Feldon J., and Savitsky K. (with Nisemblat Y., Geffen Y., Winkler I., Pick C. G.): Deficits in spatial learning in mice Klapper L., Nudelman A., Rephaeli A., Gilad I., after minimal traumatic brain injury and Weizman): BL-1021: A New Chemical demonstrated by a novel dry maze test, 31 Entity for Treatment of Naturopathic and Acute Ruff E. (with Slutsky I. and Abramov E.): The Pain, 80 physiological and pathological activities of Savitsky K. (with Rephaeli A., Gil-Ad I., Trasenko N., amyloid-beta peptide: From synaptic release to Tarasenko I., Aharoni A., Geffen Y., Weizman information processing in neuronal A., and Nudelman A.): Amidic GABA networks, 106 derivatives of antidepressants display improved Russek-Blum N., Gutnick A., Nabel-Rosen H., pain suppressing activity, 89 Blechman J., Staudt N., Dorsky R., Houart C., Schatz O. (with Golan-Lev T., Nissim-Eliraz E., Mansour and Levkowitz G.: Dopaminergic Neuronal A., Zisman S., Klar A., and Ben-Arie N.): The Cluster Size is Determined During Early transcription factor Nato3 is implied as a novel Forebrain Patterning, 94 regulator of floor plate and spinal cord development, 44 S Scheffner O. (with Tilleman H., Hakim V., Liser K., Saar D. (with Reuveni I. and Barkai E.): Associative odor Nashelsky L., Meir I., Lanir A., and Brodski C.): learning induces non uniform increase in the Effects of mid-hindbrain organizer genes and synaptic efficacy, 90 members of the Bmp 60A subgroup in the Sadan O. (with Shemesh N., Offen D., Melamed E., and development of noradrenergic locus coeruleus Cohen Y.): MRI detects in vivo migration of neurons, 110 rat’sbonemarrowderivedmesechymalstem Scheffner O. (with Tilleman H., Liser K., Nashelsky L., cells towards quinolinic acid lesion, 102 Meir I., Lanir A., and Brodski C.): The role of SadehB.,PodlipskyI.,ZhdanovA.,HendlerT.,andYovel members of the BMP 60A subgroup in the G.: The reliability and validity of the development of catecholaminergic neurons and face-specific N170 ERP component recorded the anterior pituirary, 110 simultaneously with functional MRI, 94 Schiller J. (with Garion L., Pehter I., and Azouz R.): Single Sader-Mazbar O. and Finberg J. P.: The role of cell resolution network dynamics in the rat monoamine oxidase subtypes in striatal barrel cortex using calcium imaging metabolism of dopamine produced from l-dopa two-photon microscopy in-vivo, 40 in the rat, 94 Schneider J. (with Pinhasov A., Reichenstein M., and Sagi D. (with Bonneh Y. S.): Asymmetric visual Feder Y.): Neuropeptides, Antidepressants and interactions across the boundary of Depression, 86 awareness, 17 Schneider J., Feder Y., Reichenstein M., and Pinhasov A.: Saig A., Arieli A., and Ahissar E.: The “human Gene Expression Profile of Pac1 and Vpac1/2 rat”–learning to use a new sense via sensory Receptors in Developing and Adult Rat Brain, substitution principles, 95 96 Salomon R., Malach R., and Lamy D.: Is That Me in the Mirror? The neural correlates of self recognition Schneidman E. (with Ganmor E. and Segev R.): through movement, 96 Robustness and Structure of 2nd Order Salomon S. (with Edelman S., Lerer E., Paz A., Maximum Entropy Models Describing the State Zeev-Ben-Mordehai T., Israel S., Nemanov L., Distribution of Neural Populations, 39 Sussman J. L., Silman I., Levi S., Yirmiya N., and Schonberg T. (with Ben-Mair E., Inzelberg R., and Joel Ebstein R. P.): Association between DLG4 D.): Evaluation of the interplay between (PSD-95) Scaffolding Protein and Autism: procedural learning and declarative learning Relations to Adaptive Behavior and systems revealed in a double-dissociation Cognition, 30 experiment among Alzheimer disease and Salomon S. and Weinstock M.: Maternal corticosterone Parkinson disease patients, 13 mediates anxiety but not learning deficits Schonberg T. (with Siman-Tov T., Mendelssohn A., induced by prenatal stress in rats, 95 Avidan G., Pessoa L., Gadoth N., Ungerleide L., Salti M. (with Lamy D. and Bar-Haim Y.): Neural Podlipsky I., and Hendler T.): Hemispace- correlates of subjective and objective awareness: rather than hemisphere-superiority as the basis An ERP study, 65 for visuospatial attention asymmetry: new Sasson D. (with Etlin A., Shamir B., Mor Y., Zeilig G., and insights from fMRI, 104 Lev-Tov A.): Myoclonic bursting of the ankle Schonberg T., Daw N., Inzelberg R., O‘Doherty J., and Joel joint musculature in spinal cord injury patients D.: An fMRI study of striatal activity during is attenuated by activation of crossed-inhibitory reinforcement learning in Parkinson’s pathways, 33 Disease, 96 158 Neural Plasticity

Schonfeld E. (with Fishbein I., Greenberger V., and Segal Segev I. (with Gidon A. and London M.): Stochastic M.): Physiological Mechanisms of synaptic transmission is advantageous for Neurodegeneration Induced by Activity learning complex temporal firing patterns in Deprivation, 36 neurons, 43 Schonfeld E., Fishbein I., Greenberger V., and Segal M.: Segev I. (with Yaron-Jakoubovitch A., Koch C., and Yarom Molecular correlates of TTX-induced cell death, Y.): Is conductance change involved in the shift 97 between UP and DOWN states of rat Schreiber S. (with Edut S., Rubovitch V., Feldon J., and neocortical neurons?, 116 Pick C. G.): Deficits in spatial learning in mice Segev R. (with Ganmor E. and Schneidman E.): after minimal traumatic brain injury Robustness and Structure of 2nd Order demonstrated by a novel dry maze test, 31 Maximum Entropy Models Describing the State Schroeder M. (with Shbiro L., Moran T. H., and Weller Distribution of Neural Populations, 39 A.): Maternal obesity levels at the time of Segev R.: Population code for moving target in the archer weaning are influenced by the strain of the fish retina, 98 pups: insights from a cross-fostering study in Segman R. H. (with Lifschytz T., Shalom G., Golzer T., the OLETF rat model of obesity, 101 Lerer B., and Newman M. E.): Biochemical and Schroeder M., Shbiro L., Moran T. H., and Weller A.: behavioral effects of triiodothyronine (T3) may Gender differences in coping with “lean” and provide a basis for the antidepressant attributes “obese” postnatal environments in a rat model this compound, 68 of obesity, 97 Seidman S. (with Kravitz E., Davidson M., Gigi A., Orr G., Schuermann F. (with Druckmann S., Gidon A., Markram Weiser M., and Biegon A.): Testosterone H., and Segev I.): Constraining Neuron Models improves visual-spatial memory in by Experimental Data, 29 hypogonadal men, 63 Schulkin J. (with Gonen G., Ferdman N., Even B., Maroun Sekler I. (with Karol N., Hershfinkel M., Forberg M., C., Katz O., Pershin L., and Leshem M.): Kaisman T., Fishman D., and Silverman W.): Influence on offspring behavior of stress to the The correlation of intracellular zinc, zinc rat dam before she becomes pregnant: effects of homeostatic proteins and apoptosis, 60 cross-fostering, 45 Sela L. (with Arzi A., Haddad R., Green A., Dagan Y., and Schulkin J. (with Shachar-Dadon A., Even B., Maroun C., Sobel N.): Using odors to treat sleep apnea: A Galon I., and Leshem): Effects of weanling stress test of feasibility, 6 and acute pre-mating shock on affect in Sensen K., Obermann M., Yoon M., Maschke M., Diener progeny in rats, 98 H., and Katsarava Z.: Pregabalin in the Schumann J. and Yaka R.: Repeated cocaine exposure treatment of trigeminal neuralgia: a prospective induces long term alterations in NMDAR open-label clinical trial, 98 subunits in the nucleus accumbens (NAc), 97 Sestieri E. (with Rotem N., Hounsgaard J., and Yarom Y.): Schwartz M. (with Rolls A., Shechter R., London A., Ziv Differential postsynaptic efficiency of Y., Ronen A., and Levy R.): Toll-like receptors electrosensory afferents and parallel fibers in the regulate adult neurogenesis, 92 principal neurons of the shark Dorsal Schweiger A. (with Elkana O., Ben Bashat D., Kremer U., Octavolateral Nucleus, 93 Hendler T., and Fros R.): Patterns of brain Shachar-Dadon A., Even B., Maroun C., Galon I., language organization as a function of linguistic Schulkin J., and Leshem: Effects of weanling performance following recovery from stress and acute pre-mating shock on affect in childhood insults to the left hemisphere, 32 progeny in rats, 98 Segal M. (with Fishbein I., Schonfeld E., and Greenberger Shahar M. (with Arce F., Novick I., Ghez C., and Vaadia V.): Physiological Mechanisms of E.): Modalities of feedback induce differential Neurodegeneration Induced by Activity reaching strategies in adaptations to Deprivation, 36 force field, 6 Segal M. (with Schonfeld E., Fishbein I., and Greenberger Shahar M. (with Lalazar H. and Vaadia E.): Shaping of V.): Molecular correlates of TTX-induced cell tuning properties in Motor Cortex during Long death, 97 Term VisuoMotor Learning, 65 Seger R. (with Dobkin-Bekman M. and Naor Z.): A Shaki-Loewenstein S. (with Ben Porata J., Terkieltaub D., preformed signaling complex mediates GnRH Goren O., Yakov N., Abrameto J., Sharon N., activated ERK phosphorylation of paxillin and Zaretsky I., Hazum S., Gopher J., Ohayon T., FAK at focal adhesions in LfiT2 gonadotrope and Eren R.): Immunotherapies for Alzheimer’s cells, 27 Disease, 11 Segev I. (with Druckmann S., Gidon A., Schuermann F., ShalevI.,MeronY.,LaibeG.,LererE.,LaibaE.,RazY., and Markram H.): Constraining Neuron Israel S., Bachner-Melman R., Uzefovsky F., Models by Experimental Data, 29 Dina C., Kaitz M., and Ebstein R. P.: The role of Author Index 159

BDNF Val66Met and stress response in smoking Shbiro L. (with Schroeder M., Moran T. H., and Weller cessation in young women, 99 A.): Gender differences in coping with “lean” Shalgi S. (with Barnett K. J., Fox J. J., Molholm S., Kelly and “obese” postnatal environments in a rat S.P.,MitchellK.J.,andNewellF.N.): model of obesity, 97 Differences in Early Visual Processing in Shbiro L., Schroeder M., Moran T. H., and Weller A.: Synesthesia: an ERP study, 9 Maternal obesity levels at the time of weaning Shalgi S., O‘Connell R. G., Deouell L. Y., and Robertson are influenced by the strain of the pups: insights I. H.: Absent Minded but Accurate: Delaying from a cross-fostering study in the OLETF rat responses increases Accuracy but decreases model of obesity, 101 Error Awareness, 99 Shechter R. (with Rolls A., London A., Ziv Y., Ronen A., Levy R., and Schwartz M.): Toll-like receptors Shalom G. (with Lifschytz T., Golzer T., Segman R. H., regulate adult neurogenesis, 92 Lerer B., and Newman M. E.): Biochemical and Shein N. A., Horowitz M., and Shohami E.: Identification behavioral effects of triiodothyronine (T3) may of Neuroprotective Pathways in Brain Trauma provide a basis for the antidepressant attributes Using Heat Acclimation Preconditioning, 101 this compound, 68 Sheinin A. and Lovinger D. M.: Endocannabinoid- and Shamir A. (with Amar S., Ovadia O., Blanaru M., Reshef mGluR5-dependent Short-Term Synaptic A., Kremer I., Rietschel M., Maier W., Belmaker Depression in an Isolated Neuron/Bouton R., Ebstein R., Agam G., and Mishmar D.): Preparation from the Hippocampal CA1 Mitochondrial DNA HV lineage increases the Region, 102 susceptibility to schizophrenia among Israeli Shelahavich K. (with Bloch B., Haliba Y., Vadas L., Ben Arabs, 4 Shitrit Y., Ehood Golz A., Tangi R., Tavakuli Shamir A. (with Levi I., Cryns K., Steckler T., Moechars H. R., Ziv N., Kremer I., and Haimov I.): The D., Belmaker R., and Agam G.): effects of music background on sleep efficiency, Characterization of the IMPA1 deficient anxiety and depression in Schizophrenia mouse, 67 patients, 15 Shamir B. (with Etlin A., Mor Y., Sasson D., Zeilig G., and Shelef I. (with Tomkins O., Kaizerman I., and Friedman Lev-Tov A.): Myoclonic bursting of the ankle A.): Computer-Assisted Diagnosis of joint musculature in spinal cord injury patients Blood-Brain Barrier Disruption, 112 is attenuated by activation of crossed-inhibitory Shelef I. (with Tomkins O., Kaizerman I., Zumsteg D., and pathways, 33 Friedman A.): Blood-Brain Barrier Disruption Shandalov Y., Veenman L., Leschiner S., Kugler W., in Post-Traumatic Epilepsy, 111 Lakomek M., and Gavish M.: Translocator Shemesh N., Sadan O., Offen D., Melamed E., and Cohen Protein ligands attenuate the mitochondrial Y.: MRI detects in vivo migration of rat’s bone membrane collapse normally induced by the marrow derived mesechymal stem cells towards antineoplastic agent quinolinic acid lesion, 102 Erucylphosphohomocholine, 100 Shemesh O. A., Erez H., Ginzburg I., and Spira M. E.: Shani-Hershkovich R. and Arieli A.: The effects of Tau-induced microtubules polarity stimulus expectation on perception and the reorientation leads to axonal trafficjamsand dynamics of cortical activity, 100 neurodegeneration, 103 Shapira A., Jacobson G., and Nelken I.: The Ectosylvian Shetreet E., Friedmann N., and Hadar U.: Syntactic Sulcal Audiotory Field (FAES) and Localization Processing and Lexical Retrieval during of Sounds, 100 Sentence Comprehension: An fMRI study, 103 Shkolnik N. (with Hadas Y. and Klar A.): Transcriptional Shapiro M. (with Bahar A.): Reorganized prospective and control of commissural neuron cell fate, 49 retrospective hippocampal memory coding after Shmuelof L. (with Eisenberg M., Vaadia E., and Zohary switching the start and goal of a journey, 7 E.): Inferring the representation of arm Shappir J. (with Hai A., Kamber D., Dormann A., movements in the human motor cortex from Yitzchaik S., and Spira M.): Novel spine-like the fMRI signal, 32 gold structures as a three dimensional substrate Shmuelof L., Hertz U., and Zohary E.: Viewpoint for neuro-electronic hybrids, 50 dependent representation of observed Sharon N. (with Ben Porata J., Terkieltaub D., Goren O., actions, 103 Yakov N., Abrameto J., Zaretsky I., Shoham S. (with Kovalev E., Tal Z., Zimmermann G., Shaki-Loewenstein S., Hazum S., Gopher J., Ben-Ari S., Soreq H., and Yarom Y.): Ohayon T., and Eren R.): Immunotherapies for Glutamatergic excitotoxicity in cerebellar Alzheimer’s Disease, 11 stroke: contribution of genetic background to Shayevitz O. and Nelken E.: Towards a characterization of neurological and histopathological outcomes in natural sounds, 101 a mouse model, 63 160 Neural Plasticity

Shoham S. (with Luques L. and Weinstock M.): Chronic Relations to Adaptive Behavior and inhibition of brain cytochrome oxidase in rats Cognition, 30 induces memory deficits and associated with Silver H. (with Danovich L., Weinreb O., and Youdim oxidative stress and alterations in cholinergic M. B. H.): The molecular mechanism of transmission, 70 pharmacodynamic interactions between Shohami E. (with Liraz-Zaltsman S., Fishbein I., antipsychotic drugs and SSRI antidepressants, Greeneberger V., and Biegon A.): Regional 24 sensitivity to Neuroinflammation: In vivo and Silverman W. (with Karol N., Hershfinkel M., Forberg M., in vitro studies, 68 Kaisman T., Fishman D., and Sekler I.): The Shohami E. (with Moussaieff A., Fride E., and Mechoulam correlation of intracellular zinc, zinc R.): Incensole acetate, an incense component, homeostatic proteins and apoptosis, 60 elicits psychoactivity by activating TRPV3 Siman-Tov T. (with Okon-Singer H., Podlipsky I., Yovel channels, 78 G., and Hendler T.): Knowing Left from Right: Shohami E. (with Shein N. A. and Horowitz M.): A Combined ERP-fMRI Study of Visuospatial Identification of Neuroprotective Pathways in Attention, 82 Brain Trauma Using Heat Acclimation Siman-Tov T., Mendelssohn A., Schonberg T., Avidan G., Preconditioning, 101 Pessoa L., Gadoth N., Ungerleide L., Podlipsky Shohami E. (with Thau-Zuchman O., Ovadia H., and I., and Hendler T.: Hemispace- rather than Leker R. R.): Vascular Endothelial Growth hemisphere-superiority as the basis for Factor Increases Neurogenesis Following visuospatial attention asymmetry: new insights Traumatic Brain Injury, 109 from fMRI, 104 Shohami E. (with Tsenter J., Beni-Adani L., Assaf Y., Simony E., Ahissar E., and Golomb D.: Role of Sensory Alexandrovitch A. G., and Trembovler V.): Feedback in determining the Firing Patterns of Dynamic Changes in the Recovery after Vibrissa Motoneurons, 105 Traumatic Brain Injury in Mice: Effect of Injury Singer P., Yee B. K., Boison D., Mohler H., and Feldon J.: Severity on T2-Weighted MRI and functional To freeze or not to freeze? Cognitive recovery, 112 enhancement in the modulation of associative Shohami E. (with Yeshurun-Cohen A., Leker R., learning: A study of forebrain neuronal glycine Alexandrocivh A., and Mechoulam R.): The transporter 1 (GlyT1) deletion, 105 Endocannabinoid-Like Slonimsky A., Alkelai A., Amann-Zalcenstein D., N-Arachidonoyl-L-Serine Improves Outcome Olender T., Ben-Asher E., Lancet D., and after Traumatic Brain Injury, 117 Lerer B.: Sequence structure identification and Shomrat T., Feinstein N., Klein M., and Hochner B.: characterization of C6orf217: A positional Serotonin is a neuromodulator of short- and candidate gene for schizophrenia, 105 long term synaptic plasticity in the octopus vertical lobe, 104 Slovik M. (with Rivlin-Etzion M., Marmor O., Rosin B., Shore D. I.: Work Better in the Dark: Close your eyes, 104 and Bergman H.): Low-pass filter properties of Shouval H. (with Aslam N. and Kubota Y.): A basal ganglia (BG) networks and possible Self-sustaining Translational Switch for mechanisms of action of high-frequency deep Regulating the Maintenance of Synaptic brain stimulation (DBS), 91 Plasticity, 7 Slovik M. (with Rosin B., Mitelman R., Rivlin-Etzion M., Shouval H. (with Gavornik J. and Loewenstein Y.): and Bergman H.): The contribution of forced Learning temporal representations through oscillations of the arm to the discharge pattern reward dependant expression of synaptic of primary motor cortex (M1) and globus eligibility traces in recurrent networks, 41 pallidus (GP) neurons, 92 Shterenberg A. (with Maniv I., Veenman L., Leschiner S., Slutsky I. (with Vertkin I. and Bettler B.): Optimal activity Spanier I., Marek I., Hadad E., and Gavish M.): level of presynaptic GABAB receptors Novel TSPO ligands as neuroprotective agents, maximizes the capacity of synapses for 73 correlation-based plasticity, 114 Sicsic C. (with Wald H., Irony-Tur-Sinai M., Akkawi S., Slutsky I. (with Abramov E.): Amyloid-beta peptide Higazi A. E., and Brenner T.): Involvement of modulates the pattern of transmitter release in plasminogen activator system in hippocampal synapses, 2 immunomoudulation of experimental Slutsky I., Abramov E., and Ruff E.: The physiological and autoimmune myasthenia gravis, 114 pathological activities of amyloid-beta peptide: Silman I. (with Edelman S., Lerer E., Paz A., From synaptic release to information processing Zeev-Ben-Mordehai T., Israel S., Nemanov L., in neuronal networks, 106 Sussman J. L., Levi S., Salomon S., Yirmiya N., Sobel N. (with Arzi A., Sela L., Haddad R., Green A., and and Ebstein R. P.): Association between DLG4 Dagan Y.): Using odors to treat sleep apnea: A (PSD-95) Scaffolding Protein and Autism: test of feasibility, 6 Author Index 161

Sobel N. (with Gelstein S. and Roth Y.): Can the effects of SpoerriE.,MeyerU.,YeeB.K.,andFeldonJ.:Evaluating putative human pheromones be attributed to early preventive antipsychotic drug treatment chemical sensing?, 42 during the prodromal phase in a Sobel N. (with Haddad R., Kahan R., and Harel D.): A neurodevelopmental animal model of Method for Odorant Comparison, 50 schizophrenia, 107 Sobel N. (with Lapid H. and Harel D.): Predicting Staudt N. (with Russek-Blum N., Gutnick A., pleasantness of binary mixtures in olfaction, 65 Nabel-Rosen H., Blechman J., Dorsky R., Sobel N. (with Yeshurun Y. and Dudai Y.): Working Houart C., and Levkowitz G.): Dopaminergic memory across nostrils, 117 Neuronal Cluster Size is Determined During Sochen N. (with Pasternak O., Intrator N., and Assaf Y.): Early Forebrain Patterning, 94 Mapping and Eliminating Free Water in the Steckler T. (with Levi I., Shamir A., Cryns K., Moechars Brain by Diffusion Imaging, 85 D., Belmaker R., and Agam G.): Solomon B. (with Arbel M.): A novel approach for Characterization of the IMPA1 deficient treatment of Alzheimer’s disease: antibodies mouse, 67 against beta-secretase cleavage site of APP, 5 Sterkin A. and Polat U.: Functional architecture of Sompolinsky H. (with Fisher D. and Tsodyks M.): collinear interactions induce spatial and Unsupervised learning in network of temporal correlation as a basis for binding, 107 temportrons, 36 Stern M. (with Tsuriel S., Kahana R., and Ziv N.): Sompolinsky H. (with Guetig R.): The conductance-based Maintaining the presynaptic site–questions tempotron: a model for time warp invariant arising from live imaging experiments, 112 auditory processing, 48 Stewart M. G.: Synaptic and dendritic plasticity in aged Soreq H. (with Kovalev E., Tal Z., Zimmermann G., mammalian hippocampus induced by a cell Ben-Ari S., Yarom Y., and Shoham S.): adhesion molecule mimetic, FGL peptide: a 3-D Glutamatergic excitotoxicity in cerebellar ultrastructural study, 108 stroke: contribution of genetic background to Sussman J. L. (with Edelman S., Lerer E., Paz A., neurological and histopathological outcomes in Zeev-Ben-Mordehai T., Israel S., Nemanov L., a mouse model, 63 Silman I., Levi S., Salomon S., Yirmiya N., and Soriano-Fradera J., Rodriguez Martinez M., Tlusty T., and Ebstein R. P.): Association between DLG4 Moses E.: Development of Input Connections in (PSD-95) Scaffolding Protein and Autism: Neural Cultures, 106 Relations to Adaptive Behavior and Sourani D. and Goelman G.: The involvement of the Cognition, 30 raphe nuclei in parkinson’s disease, 106 Szechtman H. (with Eilam D., Zor R., and Hermesh H.): Spanier I. (with Maniv I., Veenman L., Leschiner S., Obsessive-Compulsive Disorder: Practical Marek I., Shterenberg A., Hadad E., and Gavish application of animal behavior as a conceptual M.): Novel TSPO ligands as neuroprotective model in studying compulsive rituals in agents, 73 humans, 31 Spence C. (with Holmes N. P., Revol P., FarneA.,RodeG.,` Calvert G., and Rossetti Y.): Recognising your T own hands: Attribution biases & brain Ta‘aseh N., Yaron A., and Nelken I.: Context-dependent mechanisms, 54 Stimulus-Specific Adaptation in Rat Auditory Spira M. (with Hai A., Kamber D., Dormann A., Shappir Cortex, 108 J., and Yitzchaik S.): Novel spine-like gold Tadmor S. and Polat U.: When noise can mask visual structures as a three dimensional substrate for targets, 108 neuro-electronic hybrids, 50 Tal Z. (with Kovalev E., Zimmermann G., Ben-Ari S., Spira M. E. (with Kamber D. and Erez H.): Failure of Soreq H., Yarom Y., and Shoham S.): neurons to regenerate after axotomy stems from Glutamatergic excitotoxicity in cerebellar the assembly of an endbulb rather than a stroke: contribution of genetic background to competent a growth cone, 59 neurological and histopathological outcomes in Spira M. E. (with Kamber D.): On the mechanism that a mouse model, 63 promote controlled and targeted regrowth of an Tal Z. and Yarom Y.: State dependant modification in the injured axonal branch out of many, 59 waveform of the complex spikes, 109 Spira M. E. (with Malkinson G.): Watching Synapses Talbot L. S. (with Hairston I. S., Polina E., June G. L., and Form: Live Imaging of the Formation of Harvey A. G.): Sensory gating in primary Presynaptic Boutons by Growth Cones of insomnia: A potential objective measure of Cultured Aplysia Neurons, 72 reduced sleep quality, 51 Spira M. E. (with Shemesh O. A., Erez H., and Ginzburg Taler M. (with First M., Tarasenko I., Grunbaum-Novak I.): Tau-induced microtubules polarity N., Weizman R., Gil-ad I., and Weizman A.): reorientation leads to axonal trafficjamsand Effect of chronic stress and fluoxetine therapy neurodegeneration, 103 on IGF-1 receptor expression in the brain and 162 Neural Plasticity

on behavioral and cognitive parameters of rats, ThierP.(withMaternaS.andDickeP.W.):Neuronal 35 substrates of head gaze following in monkeys: Tamayev L. (with Durrant A. R. and Anglister L.): an fMRI study, 74 Endocrine regulation of serum Thonhauser K. E. (with Kuba M. J., Byrne R. A., Gutnick butyrylcholinesterase activity: a study using T., Zullo L., and Hochner B.): Modifications and dystrophin deficient mdx mice, 29 adaptations of arm use in Octopus vulgaris, 64 Tan B. (with Rimmerman N., Bradshaw H. B., and Walker Thonhauser K. E., Zullo L., Byrne R. A., Hochner B., and J. M.): Microsomal Enzymes Metabolize the Kuba M. J.: Learning to move an arm inside a Endogenous Lipid, N-arachidonoyl dopamine, maze, 110 to Hydroxylated Metabolites Active at TillemanH.,HakimV.,LiserK.,Scheffner O., Nashelsky Recombinant human TRPV1 Receptors, 91 L., Meir I., Lanir A., and Brodski C.: Effects of Tangi R. (with Bloch B., Haliba Y., Vadas L., Ben Shitrit Y., mid-hindbrain organizer genes and members of Ehood Golz A., Shelahavich K., Tavakuli H. R., the Bmp 60A subgroup in the development of Ziv N., Kremer I., and Haimov I.): The effects of noradrenergic locus coeruleus neurons, 110 ffi music background on sleep e ciency, anxiety Tilleman H., Liser K., Scheffner O., Nashelsky L., Meir I., and depression in Schizophrenia patients, 15 Lanir A., and Brodski C.: The role of members Tanzer M., Goodale M. A., and Ganel T.: Dissociable of the BMP 60A subgroup in the development ff e ects of real and illusory size on perception of catecholaminergic neurons and the anterior and visuomotor control , 109 pituirary, 110 Tarasenko I. (with First M., Taler M., Grunbaum-Novak Timmann D. (with Bultmann U., Frings M., Pierscianek N., Weizman R., Gil-ad I., and Weizman A.): ff D., Fritsche N., Gizewski E. R., and Maschke E ect of chronic stress and fluoxetine therapy M.): Reorganisation of motor deficits in on IGF-1 receptor expression in the brain and patients with acute cerebellar stroke, 19 on behavioral and cognitive parameters of rats, Timmann D. (with Pierscianek D., Frings M., Bultmann 35 U., Fritsche N., Gizewski E. R., Flossdorf A., and Tarasenko I. (with Rephaeli A., Gil-Ad I., Trasenko N., ff Maschke M.): Rehabilitation of cognitive Aharoni A., Ge en Y., Savitsky K., Weizman A., impairment in patients with acute cerebellar and Nudelman A.): Amidic GABA derivatives of stroke, 86 antidepressants display improved pain Tlusty T. (with Soriano-Fradera J., Rodriguez Martinez suppressing activity, 89 M., and Moses E.): Development of Input Tavakuli H. R. (with Bloch B., Haliba Y., Vadas L., Ben Connections in Neural Cultures, 106 Shitrit Y., Ehood Golz A., Shelahavich K., Tangi R., Ziv N., Kremer I., and Haimov I.): The Tomer O. (with Yuval-Greenberg S. and Deouell L. Y.): effects of music background on sleep efficiency, Induced Gamma in the Eye of the Beholder: anxiety and depression in Schizophrenia Single Trial Analysis of Induced Gamma Band patients, 15 Responses in Human Observers, 119 Teichberg V. I. (with Matuzany-Ruban A.): Blood Tomer O., Yuval-Greenberg S., and Deouell L. Y.: Keeping glutamate scavenging in the prevention of an eye on induced Gamma activity: a study of glioma invasiveness, 75 combined EEG and eye-tracking, 111 Terkieltaub D. (with Ben Porata J., Goren O., Yakov N., Tomkins O., Shelef I., Kaizerman I., and Friedman A.: Abrameto J., Sharon N., Zaretsky I., Computer-Assisted Diagnosis of Blood-Brain Shaki-Loewenstein S., Hazum S., Gopher J., Barrier Disruption, 112 Ohayon T., and Eren R.): Immunotherapies for Tomkins O., Shelef I., Kaizerman I., Zumsteg D., and Alzheimer’s Disease, 11 Friedman A.: Blood-Brain Barrier Disruption in Thau-Zuchman O., Shohami E., Ovadia H., and Leker Post-Traumatic Epilepsy, 111 R. R.: Vascular Endothelial Growth Factor Toth E. (with Gersner R. and Zangen A.): The Increases Neurogenesis Following Traumatic antidepressant effect of repeated subconvulsive Brain Injury, 109 electrical stimulation of reward related brain Thier P. (with Caggiano V., Fogassi L., Giese M., Rizzolatti sites in a rat model for depressive behavior: A G., and Casile A.): Tuning of the point of view of comparison to the effect of electroconvulsive mirror neurons in monkey premotor cortex, 20 therapy, 42 Thier P. (with Catz N. and Dicke P. W.): The Touloumi O. (with Gozes I., Pinhasov A., Mandel S., compensation of oculomotor fatigue is based on Pikman R., Grigoriadis N., Pittel Z., and the adjustment of a Purkinje cell simple spike Vulih-Shultzman I.): NAP reduces TAU population signal, 20 hyperphosphorylation and enhances learning in Thier P. (with Ignashchenkova A., Dash S., Dietrich H., a novel transgenic mouse model, 46 Haarmeier T.): Lesions of the posterior vermis Trasenko N. (with Rephaeli A., Gil-Ad I., Tarasenko I., in the rhesus monkey cause deficits in visual Aharoni A., Geffen Y., Savitsky K., Weizman A., motion perception, 55 and Nudelman A.): Amidic GABA derivatives of Author Index 163

antidepressants display improved pain Uzefovsky F. (with Shalev I., Meron Y., Laibe G., Lerer E., suppressing activity, 89 Laiba E., Raz Y., Israel S., Bachner-Melman R., Treisman A. (with Magen H. and Kastner S.): Attentional Dina C., Kaitz M., and Ebstein R. P.): The role demands predict short-term memory load of BDNF Val66Met and stress response in response in posterior parietal cortex, 70 smoking cessation in young women, 99 Trembovler V. (with Tsenter J., Beni-Adani L., Assaf Y., Alexandrovitch A. G., and Shohami E.): V Dynamic Changes in the Recovery after Vaadia E. (with Arce F., Novick I., Shahar M., and Ghez Traumatic Brain Injury in Mice: Effect of Injury C.): Modalities of feedback induce differential Severity on T2-Weighted MRI and functional reaching strategies in adaptations to force field, recovery, 112 6 Tronel S. (with Kaouane N., Calandreau L., Esclassan F., Vaadia E. (with Eisenberg M., Shmuelof L., and Zohary Mons N., Jaffard R., Abrous N., Piazza P., and E.): Inferring the representation of arm Desmedt A.): Boundary conditions of movements in the human motor cortex from corticosterone-dependent enhancement or the fMRI signal, 32 alteration of memory consolidation, 60 Vaadia E. (with Grinvald Y., Inbar D., and Zach N.): Tsenter J., Beni-Adani L., Assaf Y., Alexandrovitch A. G., Movement parameters are related to inter-trial Trembovler V., and Shohami E.: Dynamic variability of single units activity in motor Changes in the Recovery after Traumatic Brain cortex, 47 Injury in Mice: Effect of Injury Severity on Vaadia E. (with Inbar D., Grinvald Y., and Zach N.): T2-Weighted MRI and functional recovery, 112 Correlated neuronal activity in Primary and Pre Tsodyks M. (with Barak O. and Mongillo G.): Working motor cortices of monkeys during performance memory: somatic spikes or synaptic calcium?, 8 of different visuomotor association tasks, 56 Tsodyks M. (with Fisher D. and Sompolinsky H.): Vaadia E. (with Lalazar H. and Shahar M.): Shaping of Unsupervised learning in network of tuning properties in Motor Cortex during Long temportrons, 36 Term VisuoMotor Learning, 65 Tsodyks M. (with Mongillo G. and Barak O.): Facilitating Vaadia E. (with Mandelblat-Cerf Y.): Dynamics of synapses mediate working memory, 77 neuronal variability in motor cortical areas Tsoory M. M. (with Asbe M. and Berger B. D.): Exposing during and switching between different tasks. rats to stressors during juvenility increases What may it reflect?, 73 morphine intake in adulthood, 6 Vaadia E. (with Zach N., Inbar D., and Grinvald Y.): Tsoory M. M. (with Horovitz O. and Richter-Levin G.): Circuitry underlying perceptual learning in Individual differences in stress responsiveness behaving monkeys, 119 affect the consequences of juvenile stress on Vadas L. (with Bloch B., Haliba Y., Ben Shitrit Y., Ehood coping with stress in adulthood, 55 Golz A., Shelahavich K., Tangi R., Tavakuli Tsuriel S., Stern M., Kahana R., and Ziv N.: Maintaining H. R., Ziv N., Kremer I., and Haimov I.): The the presynaptic site–questions arising from live effects of music background on sleep efficiency, imaging experiments, 112 anxiety and depression in Schizophrenia Tzarfaty V. (with Parnas M., Katz B., Lev S., patients, 15 Gordon-Shaag A., and Minke B.): Membrane Valitsky M., Blank P., Raveh A., Coorssen J., Zimmerberg lipids modulation removes divalent open J., and Rahamimoff R.: Non Stationary channel block of TRPL and NMDA channels, 84 Fluctuation Analysis of Calcium in Secretory Vesicles, 113 U Van Atteveldt N. M., Blau V., Formisano E., Roebroeck A., Ulanovsky N. and Moss C. F.: Hippocampal neural Blomert L., and Goebel R.: Multisensory activity in freely moving echolocating bats, 113 integration of speech and script in fluent and Ulchin Y. (with Omer D. B., Rom L., and Grinvald A.): dyslexic readers, 113 Comparing the dynamics of ongoing activity in Varon D. (with Hayon Y., Leker R., and Brill A.): awake and anesthetized monkey, 83 Cell-driven angiogenesis and neurogenesis after Ungerleide L. (with Siman-Tov T., Mendelssohn A., stroke with platelet derived microparticles, 53 Schonberg T., Avidan G., Pessoa L., Gadoth N., Vax M. (with Makin T. and Zohary E.): Towards Podlipsky I., and Hendler T.): Hemispace- behaviouralmeasuresofaction rather than hemisphere-superiority as the basis space–manipulability vs. compatibility in for visuospatial attention asymmetry: new objects affordances, 71 insights from fMRI, 104 Veenman L. (with Kugler W., Gavish M., and Lakomek Ungerleider L. (with Zhdanov A., Hendler T., and Intrator M.): Role of the 18 kDa Translocator protein N.): Inferring Cognitive States From and the adenine nucleotide transporter in Magnetoencephalographic (MEG) Signals: erucylphosphohomocholine-induced cell death Feature Selection Framework, 120 in human glioma cells, 64 164 Neural Plasticity

Veenman L. (with Maniv I., Leschiner S., Spanier I., Weinreb O. (with Danovich L., Youdim M. B. H., and Marek I., Shterenberg A., Hadad E., and Gavish Silver H.): The molecular mechanism of M.): Novel TSPO ligands as neuroprotective pharmacodynamic interactions between agents, 73 antipsychotic drugs and SSRI antidepressants, Veenman L. (with Shandalov Y., Leschiner S., Kugler W., 24 Lakomek M., and Gavish M.): Translocator Weinshall D. (with Hammer R., Diesendruck G., and Protein ligands attenuate the mitochondrial Hochstein S.): The Role of Object Comparison membrane collapse normally induced by the in Category Learning and the Emergence of antineoplastic agent Expertise, 51 Erucylphosphohomocholine, 100 Weinstein N. and Finberg J. P.: ARTS structure and Veenman L. (with Zeno S., Leschiner S., Zaarur M., and expression in rat cortical neurons, 115 Gavish M.): The correlation between the Weinstock M. (with Luques L. and Shoham S.): Chronic Translocator Protein (TSPO) and apoptosis in inhibition of brain cytochrome oxidase in rats human glioma cells under hypoxia, 120 induces memory deficits and associated with Vertkin I., Bettler B., and Slutsky I.: Optimal activity level oxidative stress and alterations in cholinergic of presynaptic GABAB receptors maximizes the transmission, 70 capacity of synapses for correlation-based Weinstock M. (with Panarsky R.): Ladostigil reduces plasticity, 114 release of NO from activated microglia and Vulih-Shultzman I. (with Gozes I., Pinhasov A., Mandel oxidative stress in neuronal cells by different S., Pikman R., Grigoriadis N., Touloumi O., and mechanisms, 84 Pittel Z.): NAP reduces TAU Weinstock M. (with Poltyrev T. and Bejar C.): Detection hyperphosphorylation and enhances learning in of differences in learning strategy and reference a novel transgenic mouse model, 46 memory in young and old rats: Prevention of memory deficits by ladostigil, 87 Weinstock M. (with Salomon S.): Maternal corticosterone W mediates anxiety but not learning deficits Wagner H. (with Ohayon S., Harmening, and Rivlin E.): induced by prenatal stress in rats, 95 Through a barn owl’s eyes: interactions between Weiser M. (with Kravitz E., Davidson M., Gigi A., Orr G., scene content and visual attention, 82 Seidman S., and Biegon A.): Testosterone Wagner M., Ehrenstein W. H., and Papathomas T. V.: improves visual-spatial memory in Vergence in reverspective: Effects of real and hypogonadal men, 63 virtual depth cues, 114 Weizman (with Nisemblat Y., Geffen Y., Winkler I., Wagner S. (with Inberg S. and Rosenblum K.): Molecular Klapper L., Savitsky K., Nudelman A., Rephaeli correlations following mating in the rodent A., and Gilad I.): BL-1021: A New Chemical female olfactory bulb, 56 Entity for Treatment of Naturopathic and Acute Wald H., Sicsic C., Irony-Tur-Sinai M., Akkawi S., Higazi Pain, 80 A. E., and Brenner T.: Involvement of Weizman A. (with First M., Tarasenko I., Taler M., plasminogen activator system in Grunbaum-Novak N., Weizman R., and Gil-ad immunomoudulation of experimental I.): Effect of chronic stress and fluoxetine autoimmune myasthenia gravis, 114 therapy on IGF-1 receptor expression in the Walker J. M. (with Rimmerman N., Bradshaw H. B., and brain and on behavioral and cognitive Tan B.): Microsomal Enzymes Metabolize the parameters of rats, 35 Endogenous Lipid, N-arachidonoyl dopamine, Weizman A. (with Rephaeli A., Gil-Ad I., Trasenko N., to Hydroxylated Metabolites Active at Tarasenko I., Aharoni A., Geffen Y., Savitsky K., Recombinant human TRPV1 Receptors, 91 and Nudelman A.): Amidic GABA derivatives of Weiner I. (with Arad M.): Amphetamine and ovariectomy antidepressants display improved pain induced disruption of latent inhibition in suppressing activity, 89 female rats can be reversed by haloperidol only Weizman R. (with First M., Tarasenko I., Taler M., in the presence of estrogen, 5 Grunbaum-Novak N., Gil-ad I., and Weizman Weiner I. (with De Levie A.): Neonatal nitric oxide A.): Effect of chronic stress and fluoxetine synthase inhibition leads to impaired reversal therapy on IGF-1 receptor expression in the performance which is alleviated by clozapine: a brain and on behavioral and cognitive neurodevelopmental model of negative parameters of rats, 35 symptoms, 25 Weller A. (with Schroeder M., Shbiro L., and Moran Weiner I. (with Piontkewitz Y. and Arad M.): Effects of T. H.): Gender differences in coping with “lean” neonatal administration of and “obese” postnatal environments in a rat polyinosinic-polycytidilic acid (Poly I:C) on model of obesity, 97 latent inhibition and discrimination reversal in Weller A. (with Shbiro L., Schroeder M., and Moran adulthood, 87 T. H.): Maternal obesity levels at the time of Author Index 165

weaning are influenced by the strain of the Ohayon T., and Eren R.): Immunotherapies for pups: insights from a cross-fostering study in Alzheimer’s Disease, 11 the OLETF rat model of obesity, 101 Yakubovich D. and Dascal N.: Expression level-dependent Wiesmann M. (with Ishai A.): Neural correlates of changes in GIRK1/2 activity in Xenopus laevis recollection- and familiarity-based memory oocytes: a modeling study, 115 decisions, 57 Yaniv I. (with Benaroya-Milshtein N., Hollander N., Apter Willecke K. (with Pannasch U., Ezan P., Giaume C., and A., Haberman Y., Halpert H., and Pick C. G.): Rouach N.): Synaptic strength regulated by Acutestressinmice;alterationinbehavior, astrocytic gap junctions, 84 immunity and cancer development, 12 Winkler I. (with Nisemblat Y., Geffen Y., Klapper L., Yaniv S. P., Klein E., and Ben-Shachar D.: A Complex Savitsky K., Nudelman A., Rephaeli A., Gilad I., Norepinephrine and Glucocorticoid and Weizman): BL-1021: A New Chemical Intercellular Interaction: Relevance to Plasticity Entity for Treatment of Naturopathic and Acute Hypothesis of Depression, 116 Pain, 80 Yarom Y. (with Kovalev E., Tal Z., Zimmermann G., Winter C. (with Joel D. and Klavir O.): Mapping regions Ben-Ari S., Soreq H., and Shoham S.): for high frequency stimulation in two rat Glutamatergic excitotoxicity in cerebellar models of obsessive-compulsive disorder, 58 stroke: contribution of genetic background to Winter C. (with Klavir O. and Joel D.): The effects of high neurological and histopathological outcomes in frequency stimulation and temporary a mouse model, 63 inactivation of the globus pallidus in the signal Yarom Y. (with Lefler Y. and Belenky M.): Reconstructing attenuation rat model of obsessive compulsive the olivo-cerebellar system in a dish, 66 disorder, 62 Yarom Y. (with Rokni D.): Cerebellar cortical responses to Wolosker H. (with Foltyn V. N., Balan L. F., and Dumin mossy fiber repetitive stimulation are enhanced E.): A novel mechanism regulating the synthesis by dissinhibition, 91 of the NMDA receptor coagonist D-serine: Yarom Y. (with Rotem N., Sestieri E., and Hounsgaard J.): implications for NMDA receptor activation, 37 Differential postsynaptic efficiency of electrosensory afferents and parallel fibers in the X principal neurons of the shark Dorsal Xu J. (with Kimchi T. and Dulac C.): A functional circuit Octavolateral Nucleus, 93 underlying male sexual behavior uncovered in Yarom Y. (with Tal Z.): State dependant modification in the adult female mouse brain, 61 the waveform of the complex spikes, 109 Yarom Y. (with Yaron-Jakoubovitch A., Koch C., Segev I.): Y Is conductance change involved in the shift Yaari Y. (with Benninger F., Ekstein D., and Becker A.): between UP and DOWN states of rat Zinc-induced Upregulation of T-type Calcium neocortical neurons?, 116 Currents in the Hippocampus, 13 Yaron A. (with Ta‘aseh N. and Nelken I.): Yaari Y. (with Caspi A. and Benninger F.): Osmotic Context-dependent Stimulus-Specific modulation of neuronal excitability is mediated Adaptation in Rat Auditory Cortex, 108 by KV7/M channels, 20 Yaron-Jakoubovitch A., Koch C., Segev I., and Yarom Y.: Is Yadid G. (with Feder Y., Ogran A., Zinn A., and Pinhasov conductance change involved in the shift A.): Establishment of a Dominant Submissive between UP and DOWN states of rat Relationships Model in Sabra Outbred mice, 34 neocortical neurons?, 116 Yaka R. (with Beltsov S.): Secreted factor from mutant Yaski O. and Eilam D.: The impact of geometry in shaping PC12 cells as a potential element for neuronal exploratory behavior in rats: Interpretation in survival, 10 terms of urban planning, 116 Yaka R. (with Michaeli A.): Acute dopamine exposure Yee B. K. (with Singer P., Boison D., Mohler H., and attenuates GABAA receptor currents in the VTA Feldon J.): To freeze or not to freeze? Cognitive through D1 and D2 dopamine receptors, 76 enhancement in the modulation of associative Yaka R. (with Numa R. and Kohen R.): Tempol learning: A study of forebrain neuronal glycine Diminishes Oxidative Damage and Attenuates transporter 1 (GlyT1) deletion, 105 Behavioral Sensitization Following Cocaine YeeB.K.(withSpoerriE.,MeyerU.,andFeldonJ.): Administration in Rats, 80 Evaluating early preventive antipsychotic drug Yaka R. (with Schumann J.): Repeated cocaine exposure treatment during the prodromal phase in a induces long term alterations in NMDAR neurodevelopmental animal model of subunits in the nucleus accumbens (NAc), 97 schizophrenia, 107 Yakov N. (with Ben Porata J., Terkieltaub D., Goren O., Yehezkel O. (with Meshulam A., Mandel Y., Rosner M., Abrameto J., Sharon N., Zaretsky I., Belkin B., and Polat U.): Visual processing Shaki-Loewenstein S., Hazum S., Gopher J., under limiting visual conditions, 76 166 Neural Plasticity

Yehezkel O. and Polat U.: Natural developmental optical Yovel G. (with Okon-Singer H., Podlipsky I., Siman-Tov astigmatism during childhood induces “cortical T., and Hendler T.): Knowing Left from Right: A astigmatism” in the adult visual cortex, 117 Combined ERP-fMRI Study of Visuospatial Yehezkel Y. (with Privman E., Fisch L., Kramer U., Attention, 82 Kipervasser S., Andelman F., Neufeld M. Y., Yovel G. (with Sadeh B., Podlipsky I., Zhdanov A., and Fried I., and Malach R.): Sustained image Hendler T.): The reliability and validity of the presentation supports a role for gamma LFP in face-specific N170 ERP component recorded object perception, 88 simultaneously with functional MRI, 94 Yeshurun Y., Dudai Y., and Sobel N.: Working memory Yovel Y. (with Mezer A., Pasternak O., Gorfine T., and across nostrils, 117 Assaf Y.): The Anatomical Basis of Functional Yeshurun-Cohen A., Leker R., Alexandrocivh A., MRI, 76 Mechoulam R., and Shohami E.: The Yu C., Haidarliu S., Derdikman D., Rubin N., and Ahissar Endocannabinoid-Like E.: Coding selectivity of object location in the N-Arachidonoyl-L-Serine Improves Outcome secondary somatosensory cortex during active after Traumatic Brain Injury, 117 vibrissal touch, 118 Yifrach O. (with Ben Abou Y. and Zilberberg N.): Distinct Yulzari L. (with Defrin R., Dror A., and Pick C. G.): ff pore properties of leak and voltage-activated Habituation to pain: the e ect of absolute vs potassium channels underlie their unique roles relative stimulation intensity, 26 in electrical signaling, 11 Yuval-Greenberg S. (with Tomer O. and Deouell L. Y.): Yifrach O. (with Magidovich H., Orr I., Fass D., and Abdu Keeping an eye on induced Gamma activity: a U.): The role of intrinsically-disordered protein study of combined EEG and eye-tracking, 111 segments in mediating Kv channel clustering: Yuval-Greenberg S., Tomer O., and Deouell L. Y.: Induced implications for synapse assembly, maintenance Gamma in the Eye of the Beholder: Single Trial and function, 71 Analysis of Induced Gamma Band Responses in Human Observers, 119 Yirmiya N. (with Edelman S., Lerer E., Paz A., Zeev-Ben-Mordehai T., Israel S., Nemanov L., Z Sussman J. L., Silman I., Levi S., Salomon S., Zaarur M. (with Zeno S., Veenman L., Leschiner S., and and Ebstein R. P.): Association between DLG4 Gavish M.): The correlation between the (PSD-95) Scaffolding Protein and Autism: Translocator Protein (TSPO) and apoptosis in Relations to Adaptive Behavior and Cognition, human glioma cells under hypoxia, 120 30 Zach N. (with Grinvald Y., Inbar D., and Vaadia E.): Yitzchaik S. (with Hai A., Kamber D., Dormann A., Movement parameters are related to inter-trial Shappir J., and Spira M.): Novel spine-like gold variability of single units activity in motor structures as a three dimensional substrate for cortex, 47 neuro-electronic hybrids, 50 Zach N. (with Inbar D., Grinvald Y., and Vaadia E.): Yoon M. (with Sensen K., Obermann M., Maschke M., Correlated neuronal activity in Primary and Pre Diener H., and Katsarava Z.): Pregabalin in the motor cortices of monkeys during performance treatment of trigeminal neuralgia: a prospective of different visuomotor association tasks, 56 open-label clinical trial, 98 Zach N., Inbar D., Grinvald Y., and Vaadia E.: Circuitry ff Yossifo M., Kisliouk T., and Meiri N.: Dynamic changes underlying perceptual learning in behaving in DNA CpG dinucleotide methylation in the monkeys, 119 brain-derived neurotrophic factor (BDNF) Zachar Y. (with Gutfreund Y. and Reches A.): promoter area during thermal control Visual-auditory integration in the barn owl: A establishment, 118 neuroethological approach, 48 Youdim M. B. H. (with Danovich L., Weinreb O., and Zachor T. (with Ben Bashat D., Drory V. E., Artzi M., Silver H.): The molecular mechanism of Nefussy B., Assaf Y., and Aizenstein O.): White pharmacodynamic interactions between matter impairment in Amyotrophic Lateral antipsychotic drugs and SSRI antidepressants, Sclerosis (ALS): Diffusion tensor imaging and 24 high b-value DWI study, 11 Youdim M. B. H. (with Fishman T. and Mandel S.): Zacksenhouse M. and Beiser K.: Adaptive motor control Silencing plus over-expression of selected genes during experiments with Brain Machine as a novel model of sporadic Parkinson’s Interfaces, 120 disease, 37 Zacksenhouse M., Lebedev M., and Nicolelis M.: Capacity Youdim M. B. H. (with Reznichenko L. and Mandel S. A.): of binned neural channels during experiments The Neurorestorative Effect of the Green Tea with Brain-Machine-Interfaces, 119 Polyphenol (-)-Epigallocatechin-3-Gallate Zangen A. (with Gersner R. and Toth E.): The Combined With the Selective MAO-B Inhibitor, antidepressant effect of repeated subconvulsive Rasagiline in MPTP Mice Model, 90 electrical stimulation of reward related brain Author Index 167

sites in a rat model for depressive behavior: A Stationary Fluctuation Analysis of Calcium in comparison to the effect of electroconvulsive Secretory Vesicles, 113 therapy, 42 Zimmermann G. (with Kovalev E., Tal Z., Ben-Ari S., Zangen A. (with Gruberger M., Hendler T., and Levkovitz Soreq H., Yarom Y., and Shoham S.): Y.): The Restless Mind–A relation between rest Glutamatergic excitotoxicity in cerebellar and the self in the brain–A deep-TMS stroke: contribution of genetic background to study-Presentation of preliminary results, 48 neurological and histopathological outcomes in Zaretsky I. (with Ben Porata J., Terkieltaub D., Goren O., a mouse model, 63 Yakov N., Abrameto J., Sharon N., Zinn A. (with Feder Y., Ogran A., Yadid G., and Pinhasov Shaki-Loewenstein S., Hazum S., Gopher J., A.): Establishment of a Dominant Submissive Ohayon T., and Eren R.): Immunotherapies for Relationships Model in Sabra Outbred mice, 34 Alzheimer’s Disease, 11 Zion Golumbic E., Kutas M., and Bentin S.: Do you Zbinden C. (with Eckmann J., Jacobi S., Moses E., and remember me? Retrieving Memories for Marom S.): Leaders of Activity in Dissociated Faces–Evidence from Theta (4–8 Hz) and Neural Cultures, 30 Gamma Band (>30 Hz) Activity, 121 Zeev-Ben-Mordehai T. (with Edelman S., Lerer E., Paz A., Zisman S. (with Golan-Lev T., Nissim-Eliraz E., Mansour IsraelS.,NemanovL.,SussmanJ.L.,SilmanI., A., Schatz O., Klar A., and Ben-Arie N.): The LeviS.,SalomonS.,YirmiyaN.,andEbstein transcription factor Nato3 is implied as a novel R. P.): Association between DLG4 (PSD-95) regulator of floor plate and spinal cord Scaffolding Protein and Autism: Relations to development, 44 Adaptive Behavior and Cognition, 30 Zisman S., Marom K., Avraham O., and Klar A.: Zeevi Y. Y. (with Barak E., Eytan D., and Meir R.): Proteolysis and membrane capture of Topology Regulates Source Separation in F-spondin generates combinatorial guidance Biologically Realistic Neural Networks, 8 cues from a single molecule, 121 Zeilig G. (with Etlin A., Shamir B., Mor Y., Sasson D., and Ziv N. (with Bloch B., Haliba Y., Vadas L., Ben Shitrit Y., Lev-Tov A.): Myoclonic bursting of the ankle Ehood Golz A., Shelahavich K., Tangi R., Tavakuli H. R., Kremer I., and Haimov I.): The joint musculature in spinal cord injury patients ff ffi is attenuated by activation of crossed-inhibitory e ects of music background on sleep e ciency, pathways, 33 anxiety and depression in Schizophrenia patients, 15 Zeno S., Veenman L., Leschiner S., Zaarur M., and Gavish Ziv N. (with Tsuriel S., Stern M., and Kahana R.): M.: The correlation between the Translocator Maintaining the presynaptic site–questions Protein (TSPO) and apoptosis in human glioma arising from live imaging experiments, 112 cells under hypoxia, 120 Ziv Y. (with Rolls A., Shechter R., London A., Ronen A., Zhdanov A. (with Ben Simon E., Podlisky I., Papo D., and Levy R., and Schwartz M.): Toll-like receptors Hendler T.): Exploring Alpha Correlates In The regulate adult neurogenesis, 92 Brain–An EEG-fMRI Study, 12 Zohary E. (with Eisenberg M., Shmuelof L., and Vaadia Zhdanov A. (with Sadeh B., Podlipsky I., Hendler T., and E.): Inferring the representation of arm Yovel G.): The reliability and validity of the movements in the human motor cortex from face-specific N170 ERP component recorded the fMRI signal, 32 simultaneously with functional MRI, 94 Zohary E. (with Makin T. and Vax M.): Towards Zhdanov A., Hendler T., Ungerleider L., and Intrator N.: behaviouralmeasuresofaction Inferring Cognitive States From space–manipulability vs. compatibility in Magnetoencephalographic (MEG) Signals: objects affordances, 71 Feature Selection Framework, 120 Zohary E. (with Pertzov Y. and Avidan G.): The Zilberberg N. (with Ben Abou Y. and Yifrach O.): Distinct representation of saccadic eye movements in pore properties of leak and voltage-activated human cortical regions, 86 potassium channels underlie their unique roles Zohary E. (with Raz N., Dotan S., Arkadir D., Chokron S., in electrical signaling, 11 and Levin N.): Behavioral and cortical Zilberberg N. (with Cohen A., Chen S., and Ben Abou Y.): activation patterns following an optic neuritis Protonation of extracellular histidine residues episode, 88 facilitates C-type gating of the human Zohary E. (with Shmuelof L. and Hertz U.): Viewpoint potassium leak channel K2P2.1, 22 dependent representation of observed actions, Zilberberg N. (with Kozminsky-Atias A.): 103 Characterization of the first anti-Shaker specific Zomet A., Amiaz R., and Polat U.: Early perceptual loss in toxin from the venom of the Israeli scorpion depression, 121 Buthus occitanus israelis, 63 Zor R. (with Eilam D., Szechtman H., and Hermesh H.): Zimmerberg J. (with Valitsky M., Blank P., Raveh A., Obsessive-Compulsive Disorder: Practical Coorssen J., and Rahamimoff R.): Non application of animal behavior as a conceptual 168 Neural Plasticity

model in studying compulsive rituals in humans, 31 Zrinzo L. (with Litvak V., Penny W., Eusebio A., Chen C. C., Oostenveld R., Kilner J., Limousin P., Hariz M., Friston K., and Brown P.): Simultaneous MEG and subthalamic local field potential recordings in Parkinson patients reveal the frequency-specific spatial pattern and directionality of subthalamo-cortical interactions, 69 Zuckerman M. (with Golan H. M., Kaplan-Louzone V., and Perez-Polo R. J.): Impaired migration signaling in the hippocampus following prenatal hypoxia, 44 ZulloL.(withKubaM.J.,ByrneR.A.,GutnickT., Thonhauser K. E., and Hochner B.): Modifications and adaptations of arm use in Octopus vulgaris, 64 Zullo L. (with Thonhauser K. E., Byrne R. A., Hochner B., and Kuba M. J.): Learning to move an arm inside a maze, 110 Zumsteg D. (with Tomkins O., Shelef I., Kaizerman I., and Friedman A.): Blood-Brain Barrier Disruption in Post-Traumatic Epilepsy, 111 Stroke International Journal of Depression Research Schizophrenia Sleep Disorders Research and Treatment Alzheimer’s Disease and Treatment Research and Treatment Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014

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