NEUROSCIENCE POSTER DAY - Thursday, April 29, 2004

SCHEDULE 11:00 - Noon: Registration (free), Poster set up and viewing Medical Sciences Building, Alumni Lounge

First Undergraduate Neuroscience Specialist’s Posters Separate undergraduate poster viewing area: MacLeod Auditorium Balcony

Noon - 1:00pm: Pizza lunch 1:00 - 3:00pm: Poster viewing and judging

Medical Sciences Building, Alumni Lounge and MacLeod Auditorium Balcony

3:00 -4:00pm: DR. JOE TSIEN, Department of Molecular Biology, Princeton

University "Integrated analysis of memory processes in the brain" Medical Sciences Building, Rm 2172 Co-sponsored by the Hospital for Sick Children

Poster Day Organizers: John Yeomans, Program in Neuroscience Acting Director Pat Reed, PIN Secretary Martin Ralph, Undergraduate Neuroscience Program Coordinator

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GRADUATE POSTERS

1 Asrar, SuhailDepartment of Physiology, University of Toronto; Program of Brain and Behaviour, Hospital for Sick Children

*

AMPA-DEPENDENT LTP: A LESSER KNOWN FORM OF PLASTICITY 2 Bagshaw, Rick D.

1. Dept. of Laboratory Medicine and Pathobiology; 2. Dept. of Biochemistry, University of Toronto; 3. Metabolism Programme, Research Institute, The Hospital for Sick Children, Toronto, Canada

*1,3, Callahan, John W.2,3, Mahuran, Don J.1,3

PROTEOMICS OF THE LYSOSOMAL MEMBRANE REVEALS DIVERSE ORIGINS OF THE LYSOSOME

3 Bedard, Anne-Claude

Institute of Medical Science & Program in Neuroscience, The University of Toronto * & Tannock, Rosemary

Brain & Behaviour Research Program, The Hospital for Sick Children BENEFICIAL EFFECTS OF METHYLPHENIDATE ON VERBAL WORKING MEMORY IN CHILDREN WITH ADHD

4 Behl, Pearl

Institute of Medical Science * & Black, Sandra - CANCELLED

EXAMINATION OF THE LONGITUDINAL EFFECTS OF CHOLINERGIC THERAPY ON ALZHEIMER’S DISEASE (AD)(ELECT-AD)

5 Bercovici, Eduard1. Institute of Medical Science, University of Toronto, Toronto, Canada; 2. Brain and Behaviour Program, Division of Neurology, The Hospital for Sick Children Department of Pediatrics, Faculty of Medicine, University of Toronto, Toronto, Canada

1,2*, Cortez, M.A.2, Snead III, O. Carter1,2

SEROTONIN DIRECTLY MODULATES AY-9944 INDUCED ATYPICAL ABSENCE SEIZURES

6 Bezchlibnyk, Yarema B.

1. Mood and Anxiety Program, Centre for Addiction and Mental Health, Department of Psychiatry, University of Toronto, Toronto, Ontario; 2. Department of Psychiatry and Behavioural Neuroscience, McMaster University, Hamilton, Ontario

1,2, Young, L. Trevor1,2 , Chen, Biao2, Wang, Jun-Feng1,2 and MacQueen, Glenda M.2

CREB PHOSPHORYLATION IN THE AMYGDALA OF SUBJECTS WITH MOOD DISORDERS

7 Blech-Hermoni, Yotam

University of Toronto Centre for the Study of Pain, Faculty of Dentistry * & Seltzer, Ze’ev

A LOCUS ON CHROMOSOME 7 PLAYS A ROLE IN NEUROPATHIC PAIN IN HA AND LA RATS AND IS ORTHOLOGOUS TO PUTATIVE PAIN QTL PAIN1 IN THE MOUSE

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8 Bollig, Carmen M. 1, Bressmann, Tim1, Uy, Catherine1, Thind, Parveen1, Irish, Jonathan C. 2

1Graduate Department of Speech-Language Pathology, University of Toronto; 2Department of Otolaryngology/Head and Neck Surgery, University Health Network, University of Toronto EVALUATION OF TONGUE SHAPES WITH 3-DIMENSIONAL ULTRASOUND IMAGING IN GLOSSECTOMY PATIENTS PRE- AND POST-SURGICALLY

9 Caraiscos, Valerie B.1*, You-Ten, Kong E.2, Newell, J. Glen3, Elliott, Erin M.1, Rosahl,

Thomas W.5, Wafford, Keith A.5, MacDonald, John F.3,4 and Orser, Beverley A.1,2,3,6 1Institute of Medical Science, Departments of 2Anesthesia, 3Physiology and 4Pharmaceutical Sciences, University of Toronto, Toronto, Ontario, Canada; 5Merck Sharp & Dohme Research Laboratories, Neuroscience Research Center, Terlings Park, Harlow, Essex, United Kingdom; 6Department of Anesthesia, Sunnybrook & Women’s College Health Sciences Centre, Toronto, Ontario, Canada ANESTHETICS SELECTIVELY MODIFY A NOVEL FORM OF GABAERGIC INHIBITION

10 Cheung, Joyce & Wojtowicz, J. Martin Department of Physiology, University of Toronto AGE-RELATED CHANGES IN THE PRODUCTION AND MIGRATION OF NEW NEURONS IN THE RAT OLFACTORY SYSTEM

11 Chiu, Mary* & Orser, Beverley

Department of Physiology, University of Toronto LOCALIZATION OF α5-CONTAINING GABAA RECEPTORS IN THE HIPPOCAMPUS

12 Cohn, Mélanie*1, Levine, Brian1,2,3, Black, Sandra E. 2,3,4, Richards, Brian5, Kaufman, Yakir6, Freedman, Morris2,6, and Moscovitch, Morris 1,3 Departments of 1Psychology/2Medicine (Neurology), University of Toronto; 3Rotman Research Institute at Baycrest Centre for Geriatric Care; 4Sunnybrook and Women’s College Health Sciences Centre; Departments of 5Psychology/6Behavioural Neurology, Baycrest Centre for Geriatric Care, Toronto, Ontario SEMANTIC AND EPISODIC MEMORY LOSS IN A CASE OF WHIPPLE’S DISEASE ENCEPHALOPATHY

13 Cunic, D.I.1,2*, Paradiso, G. 1,2, Kwan, C.2, Sailer, A.1,2, Moro, E.1,2, Poon, Y.1,2, Molnar, G.1,2, Gunraj, C.1,2, Lang, A.E.1,2, Lozano, A.M.2, 3, Chen, R.1,2

1 Division of Neurology, Toronto Western Hospital, Toronto, Ontario, Canada; 2Toronto Western Research Institute, Toronto, Ontario, Canada; 3 Division of Neurosurgery, Toronto Western Research Institute, Toronto, Ontario, Canada SOURCE GENERATORS OF EVOKED POTENTIALS FROM SUBTHALAMIC NUCLEUS DEEP BRAIN STIMULATION

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14 Elliott, Erin M. 1*, MacDonald, John F. 2,3, and Orser, Beverley A. 1,2,4,5

1Institute of Medical Science, Depts. of 2Physiology, 3Pharmacology, 4Anesthesia, Univ. of Toronto, Toronto, ON, Canada, M5S 1A8; 5Dept. of Anesthesia, Sunnybrook & Women’s College HSC, Toronto, ON, Canada, M4N 3M5 TONIC BUT NOT SYNAPTIC INHIBITORY CONDUCTANCE IN MURINE HIPPOCAMPAL NEURONS IS ENHANCED BY LOW CONCENTRATIONS OF THE β2/3 SUBUNIT SELECTIVE ANESTHETIC ETOMIDATE

15 Fawcett, A.P. 1*, Moro, E.2, Lang, A.E.2, Lozano, A.M.3, Hutchison, Wm.D.1,3 1. Dept. of Physiology 2. Dept. of Medicine, Division of Neurology 3. Dept. of Surgery, Div. of Neurosurgery, University of Toronto, Toronto, Ontario, Canada PALLIDAL DEEP BRAIN STIMULATION (DBS) INFLUENCES BOTH REFLEXIVE AND VOLUNTARY SACCADES IN HUNTINGTON’S DISEASE

16 Giannoylis, Irene*1, Nelson, Aimee J.3, Staines, Richard W.3,4, McIlroy, William E.2,3,4 1. Department of Physiology, University of Toronto; 2. Graduate Department of Rehabilitation Science, University of Toronto; 3. Sunnybrook & Women’s College Health Science Center, University of Toronto; 4. Kinesiology & Health Science, York University, Toronto, ON, Canada EFFECTS OF PERCEIVED EFFORT DURING A MOTOR TASK MEASURED USING FMRI

17 Glazer, P. M.* 1, Quant, S. 2, Maki, B. E. 2, 5, & McIlroy, W. E. 1,2,3,4 1Graduate Department of Rehabilitation Science, 2Institute of Medical Science, 3Department of Physical Therapy, 4Toronto Rehab Institute, University of Toronto; 5Centre for Studies in Aging, Sunnybrook and Women’s College Health Sciences Centre, University of Toronto THE EFFECT OF VERBAL FLUENCY TASK ON BALANCE CONTROL

18 Guy, Allison* & Broussard, Dianne Department of Physiology, University of Toronto, Canada Toronto Western Research Institute, University of Toronto, Canada INVESTIGATION OF THE ROLE OF IONOTROPIC GLUTAMATE RECEPTORS IN SHORT-TERM PLASTICITY IN THE MEDIAL VESTIBULAR NUCLEI

19 Ho, Stephanie K.Y.1*, Kovacevic, Natasha2, Chen, Josette X.2, Henkelman, Mark R.2, Henderson, Jeffrey T.1 1 Department of Pharmaceutical Sciences, University of Toronto, 2 Mouse Imaging Centre, Hospital for Sick Children, Toronto ROLE OF EPHB RECEPTORS IN MURINE CNS AXON GUIDANCE

20 Huang, Juan 1, Wu, Xihong 1, Yeomans, John 2, Li, Liang 1,2 1Department of Psychology, Speech and Hearing Research Center, Peking University, Beijing, China, 100871 2Department of Psychology, Centre for Research on Biological Communication Systems, University of Toronto, Toronto, Ontario, Canada M5S 3G3 EFFECTS OF TETANIC STIMULATION OF THE AUDITORY THALAMUS OR AUDITORY CORTEX ON ACOUSTIC STARTLE RESPONSES IN AWAKE RATS

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21 Hwang, Rudi 1*, Deluca, V.1, Masellis, M,1 Mueller, D.1, Czobor, P.2, Volavka, J. 2, Lieberman, J.A.3

, Meltzer, H.Y.4

, Kennedy, J.L.1

1. Neurogenetics Section, Centre for Addiction and Mental Health (CAMH), University of Toronto; 2. Nathan S. Kline Institute for Psychiatry Research; 3. University of North Carolina at Chapel Hill; 4. Case Western Reserve University INVESTIGATING THE EFFECT OF DOPAMINE D1 & D2 RECEPTOR GENE POLYMORPHISMS ON ANTIPSYCHOTIC TREATMENT RESPONSE

22 Labrie, Viviane*1,2,3, Lipina, Tatiana3, Roder, John1,2,3 1Collaborative Program in Neuroscience, 2Institute of Medical Science, 3Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Canada THE BRAIN GLUTAMATERGIC SYSTEM AS A TARGET FOR NOVEL CLASS OF NEUROLEPTICS

23 Lau, A.*, Arundine, M., Tymianski, M. Department of Physiology, University of Toronto, Toronto, Canada; Division of Cellular and Molecular Biology, Toronto Western Research Institute, Toronto, Canada SIN-1 INDUCED NITRATION INHIBITS CASPASE-3 ACTIVITY IN THE STAUROSPORINE MODEL OF CLASSICAL APOPTOSIS IN NEURONS

24 Levy, Naama 1,2,3*, Black, Sandra1-5, Caldwell, Curtis1,2, Lobaugh, Nancy1,2,4, Bocti, Christian1,4 - CANCELLED Cognitive Neurology Unit and Imaging Research, Sunnybrook and Women's College Health Sciences Centre1, Toronto, Ontario, Canada; Institute of Medical Science 2, Program in Neuroscience3, and Department of Medicine/Division of Neurology4, University of Toronto; Rotman Research Institute and Baycrest Centre for Geriatric Care5 IMPACT OF CEREBROVASCULAR COMORBIDITY ON SPECT PERFUSION IMAGING AND EXECUTIVE FUNCTION IN ALZHEIMER'S DISEASE

25 McDonald, Heather* & Wojtowicz, J. Martin Department of Physiology, University of Toronto AGE-RELATED DECREASE IN HIPPOCAMPAL NEUROGENESIS: POSSIBLE IMPLICATIONS FOR COGNITIVE DECLINE DURING AGING

26 Miller, R.C.*1,5, McIlroy, W.E.1,2,3,6, Mikulis, D.J.7, Jurkiewicz, M.T.*3,7, Popovic, M.R.4,5,6, and Verrier, M.C.1,2,3,6. 1. Department of Rehabilitation Science, 2. Physical Therapy, 3. Physiology, 4. Institute of Biomaterials and Biomedical Engineering, University of Toronto; 5. Rehabilitation Engineering Laboratory, 6. Toronto Rehabilitation Institute: Lyndhurst Center; 7. Medical Imaging, Toronto Western Hospital; Toronto, Ontario, Canada NEUROMUSCULAR RESTORATIVE THERAPY (NRT)

27 Moore, Kathryn J.1,2 & Shoichet, Molly S.1,2,3 Department of Chemical Engineering and Applied Chemistry1; Institute of Biomaterials and Bioengineering2; Department of Chemistry3 COMBINED GRADIENTS OF NEUROTROPHIC FACTORS WORK IN SYNERGY TO GUIDE NEURITE OUTGROWTH

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28 Niechwiej-Szwedo, E.* 1, Gonzalez, E. 2,3,4, Steinbach, M.J. 1,2,3,4 1Institute of Medical Science, 2Department of Ophthalmology and Vision Science, University of Toronto; 3Vision Science Research Program, Toronto Western Hospital; 4Centre for Vision Research, York University LOCALIZATION OF TARGETS IN DEPTH WITH ALTERED AFFERENT FEEDBACK

29 Rivkin, Elena* & Cordes, Sabine Department of Molecular and Medical Genetics FORWARD GENETIC RECESSIVE SCREEN TO IDENTIFY NOVEL MOUSE MUTANTS WITH DEFECTS IN HINDBRAIN PATTERNING

30 Saab, Béchara1,2*, Georgiou, John2, Roder, John1,2 1Collaborative Program in Neuroscience, Molecular & Medical Genetics Department, University of Toronto, 2Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Canada THE C-TERMINAL PEPTIDE OF THE CALCIUM SENSOR, NCS-1, MODULATES SHORT-TERM SYNAPTIC PLASTICITY IN THE MOUSE HIPPOCAMPUS

31 Seminowicz, D.A.*, Mikulis, D.J., Davis, K.D. Institute of Medical Science CORTICAL NOCICEPTIVE ACTIVITY IS ALTERED DURING COGNITIVE ENGAGEMENT

32 Setnik, Beatrice 1,2* & Nobrega, José N. 1,2

1 Neuroimaging Research Section, Centre for Addiction and Mental Health, Toronto, ON, Canada; 2 Department of Pharmacology, University of Toronto, Toronto, ON, Canada SEX-DEPENDENT UPREGULATION OF CORTICAL TrkB RECEPTOR mRNA LEVELS IN THE LEARNED HELPLESSNESS MODEL OF DEPRESSION

33 Shao, Li, Sun, Xiujun, Xu, Li, Young, L.Trevor and Wang, Junfeng Centre for Addiction and Mental Health, and Department of Psychiatry, University of Toronto, Ontario, Canada ENDOPLASMIC RETICULUM STRESS PROTEINS: A TARGET IN COMMON FOR MOOD STABILIZERS LITHIUM AND VALPROATE IN NEURONAL CELLS?

34 Sibley, K.M.*1, 3, Tang, A.1-3, Brooks, D.1-3, McIlroy, W.E.1-3 1. Graduate Department of Rehabilitation Science, 2. Department of Physical Therapy, University of Toronto, 3. Toronto Rehabilitation Institute, Toronto, Ontario NEUROMUSCULAR AND CARDIOVASCULAR RESPONSES TO NOVEL PEDALING STRATEGIES IN HEALTHY PARTICIPANTS

35 Stevens, W. Dale1*, Cron, Greg O.2, Pappas, Bruce A.3, Santyr, Giles E.2, Grady, Cheryl L.1

1. Rotman Research Institute, University of Toronto, Toronto, ON; 2. Department of Physics, Carleton University, Ottawa, ON; 3. Institute of Neuroscience, Carleton University, Ottawa, ON QUANTIFICATION OF CEREBRAL, RETINAL, AND VERTEBRAL BLOOD FLOW IN RAT MODELS OF ISCHEMIA: A MRI STUDY

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36 Vessal, Mani*1,2,3,4, Dugani, Chandrasagar B.4 , Solomon, Dianand A.4, Burnham, W. McIntyre 1,2,3,5, Ivy, Gwen O4. Institute of Medical Science1, Program in Neuroscience2, and Bloorview Epilepsy Research Program3, University of Toronto, Toronto; Centre for the Neurobiology of Stress4, University of Toronto at Scarborough, Scarborough; Department of Pharmacology5 GLIOGENESIS IN THE PIRIFORM CORTEX OF KINDLED SUBJECTS: A QUANTITATIVE ANALYSIS OF FULLY KINDLED BRAINS

37 Xu, J.*, Xue, S., Lei, G., Kwan, C.L., Yu, X.-M. Faculty of Dentistry, University of Toronto, Toronto, ON, Canada THE ROLE OF C-TERMINAL SRC KINASE (CSK) IN THE REGULATION OF NMDA RECEPTORS

38 Zai, Gwyneth*1,2, King, Nicole 2, Burroughs, Eliza 4, Barr, Cathy L. 1,3,5, Kennedy, James L. 1,2,3,5, Richter, Peggy 3,4

1Institute of Medical Science, University of Toronto; 2Neurogenetics Section, Centre for Addiction and Mental Health; 3Department of Psychiatry, University of Toronto; 4Anxiety Disorders Clinic, Centre for Addiction and Mental Health; 5The Toronto Hospital – Western Division, Department of Psychiatry, University of Toronto QUANTITATIVE TRAIT ANALYSIS OF THE GAMMA-AMINOBUTYRIC ACID BETA RECEPTOR 1 GENE IN OBSESSIVE-COMPULSIVE DISORDER

39 Zhao, Xiao-Han*1,2 , Xin, Wen-Kuan1,2 , Xu, Jindong1,2 , Kwan, Chun L.1,2, Zhu, Kang-Min1,2, Cho, Jae-Sung1,2, Duff, Missy1,2, Ellen, Richard P.1,3 , McCulloch, Christopher A.G.1,3 and Yu, Xian-Min1,2 1. Faculty of Dentistry, 2. Centre for Addiction and Mental Health, 3. The CIHR Group in Matrix Dynamics, University of Toronto, Toronto, ON, Canada CRITICAL CONTROL POINT: RECRUITING N-METHYL-D-ASPARTATE (NMDA) RECEPTOR-MEDIATED TOXICITY

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UNDERGRADUATE POSTERS 40. Capano, Lucia

Undergraduate Neuroscience Specialist Program INVESTIGATION OF DNA VARIANTS IN THE 5’-REGULATORY REGION OF THE DRD1 GENE IN ATTENTION DEFICIT/HYPERACTIVITY DISORDER

41. Chan, E.1, Kovačević, N.2, Henderson, J. T.3

1. Neuroscience Specialty, University of Toronto; 2. Department of Pharmceutical Sciences, University of Toronto; 3. Mouse Imaging Centre, Hospital for Sick Children THE DEVELOPMENT OF AN MRI BASED EXPERT SYSTEM AND 3D SURGICAL MRI/CT ATLAS FOR 129/SvImJ AND C57BL6 INBRED MOUSE STRAINS

42. Cheung, Joyce Department of Physiology AGE-RELATED CHANGES IN THE PRODUCTION AND MIGRATION OF NEW NEURONS IN THE RAT OLFACTORY SYSTEM

43. Clarke, Laura, Georgiou, John, Salter, Michael, Roder, John The Samuel Lunenfeld Research Institute ROLES OF Src TYROSINE KINASE IN HIPPOCAMPAL SYNAPTIC PLASTICITY

44. Ding, Hoi Ki, Ko, Shanelle, Shum, Fanny, Zhuo, Min Department of Physiology, Centre for the Study of Pain, University of Toronto A THERMAL-BASED ACTIVE ESCAPE/AVOIDANCE PARADIGM WITHOUT FEAR

45. Hirshhorn, Marnie Undergraduate Neuroscience Specialist Program ASSESSING THE PRESENCE OF OSCILLATORY ACTIVITY IN THE THALAMUS OF PARKINSON’S DISEASE PATIENTS

46. Ng, Karen Undergraduate Neuroscience Specialist Program INVESTIGATING THE ROLE OF THE m5 CHOLINERGIC RECEPTOR IN BRAIN STIMULATION REWARD USING PHAMACOLOGICAL AND ELECTROPORATION TECHNIQUES

47. Rizvi, Sakina Undergraduate Neuroscience Specialist Program MEMORY DEFICITS AMONG PERSONS WITH SCHIZOPHRENIA: UTILITY OF THE NINE-BOX MAZE TASK

48. Salmasi, Giselle Ghazal Neuroscience Research, Department of Laboratory Medicine and Pathobiology, Sunnybrook and Women’s College Health Sciences Centre, University of Toronto DRAINAGE OF CEREBROSPINAL FLUID INTO EXTRACRANIAL LYMPHATICS IN RATS AND MICE REVEALED BY INTRACISTERNAL INJECTION OF MICROFIL

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49. Watts, Jeff

Undergraduate Neuroscience Specialist Program CAN DIFFERENCES IN THE Ca2+ SENSOR EXPLAIN DIFFERENCES IN QUANTAL OUTPUT BETWEEN CRAYFISH TONIC AND PHASIC CELLS? A MONTE CARLO MODEL

50. Wong, Fiona

Undergraduate Neuroscience Specialist Program H1, A STABLE HEPOXILIN ANALOG, DOES NOT ENHANCE NEURITE OUTGROWTH OR REGENERATION AFTER INJURY IN RAT PHEOCHROMOCYTOMA CELLS OR PRIMARY HIPPOCAMPAL NEURONS IN VITRO

51. Wong, J.S., Hutchison, W.D.

Department of Physiology, Faculty of Arts and Science and Faculty of Medicine, University of Toronto, Ontario, Canada 6-HYDROXYDOMAPINE REDUCES MOTOR BEHAVIORS OF RATS AND INDUCES DISTINCT FIRING PATTERNS IN MULTI-UNIT RECORDINGS OF THE RODENT GLOBUS PALLIDUS

52. Yum, Jennie Undergraduate Neuroscience Program, University of Toronto, Toronto, Ontario, Canada, M5S 3G3 SHORT-TERM DEPRESSION AT THE DEVELOPING CALYX OF HELD SYNAPSE: EVIDENCE FOR HETEROSYNAPTIC INHIBITION MEDIATED BY PRESYNAPTIC GABAB RECEPTORS

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GRADUATE POSTER ABSTRACTS 1. Asrar, Suhail* Department of Physiology, University of Toronto; Program of Brain and Behaviour, Hospital for Sick Children AMPA-DEPENDENT LTP: A LESSER KNOWN FORM OF PLASTICITY A strong majority of studies conducted involving synaptic plasticity (which is thought to be important in learning and memory) revolve around NMDA-dependent forms of plasticity. However, certain studies have revealed that NMDA-independent forms of plasticity may be induced in the hippocampus of mice where the AMPA GluR2 subunit has been knocked out. Most AMPA receptors are normally not significantly permissive to calcium due to the activity of the GluR2 subunit, and the knocking-out of this subunit leads to the formation of AMPA receptors that are calcium permeable. The study of these mutant receptors is important for several reasons. Firstly, there are inter-neurons present in the hippocampus that are also permeable to calcium but are difficult to study, and research in calcium permeable AMPA receptors may shed more light on the way that these inter-neurons function. Secondly, under pathological conditions, calcium influx from calcium permeable AMPA receptors has shown to have an important role in the adverse mechanisms that ultimately lead to cell death. The precise mechanisms involved in this NMDA-independent form of plasticity remain unknown, and may involve a variety of signaling factors including PKA, PKC and CaMKII. The latter has shown to be particularly important in numerous studies implicating its role in NMDA-dependent forms of plasticity. Therefore, to test the possibility that CaMKII may play an important role in AMPA-dependent plasticity, we used the CaMKII inhibitor KN-62 in the presence of the NMDA blocker APV in electrophysiological studies where AMPA-dependent LTP (long term potentiation) was induced tetanically under field recordings measured in the CA1 region of the hippocampus. Surprisingly, our preliminary data suggests that CaMKII may not have a significant role in AMPA-dependent LTP induced in mutant mice. These results suggest that a distinct mechanism may operate for AMPA receptor-induced synaptic plasticity.

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2. Bagshaw, Rick D.*1,3, Callahan, John W.2,3, Mahuran, Don J.1,3 1. Dept. of Laboratory Medicine and Pathobiology; 2. Dept. of Biochemistry, University of Toronto; 3. Metabolism Programme, Research Institute, The Hospital for Sick Children, Toronto, Canada PROTEOMICS OF THE LYSOSOMAL MEMBRANE REVEALS DIVERSE ORIGINS OF THE LYSOSOME Lysosomes are dynamic, endocytic subcellular compartments which contribute to degradation and recycling of cellular material. From our proteomic model of lysosomes (rat liver Triton WR1339-filled lysosomes) we have identified 254 unique proteins thus far in the lysosomal membrane. We have used a combination of 2D-IPG-PAGE:mass spectrometry and Ion-exchange chromatography:LC-MS/MS as protein identification strategies. About half of the proteins identified are known constituents of the endosomal/lysosomal system and proteins involved in membrane trafficking, and 25% of proteins match to unknown cDNAs. The remaining proteins are those originally associated with other cellular compartments such as Golgi, ER, and Plasma membrane indicating diverse origins of the lysosomal membrane. The unexpected identification of the Alzheimer’s disease-associated γ-secretase complex (Nicastrin, Presenilin, and APP), allowed us to characterize its enrichment and acidic-pH optimum enzymatic activity in the lysosomal membrane. An unknown protein identified in the integral membrane protein fraction contains domains highly similar to those from the ARF family of G-proteins involved in protein trafficking. It localizes with lysosomal markers by immunofluorescence, and is expressed in all human tissues, suggesting that it has a fundamental role in the endosomal/lysosomal system. Characterizing novel lysosomal proteins will help elucidate the roles of the lysosome in cell biology.

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3. Bedard, Anne-Claude* & Tannock, Rosemary Institute of Medical Science & Program in Neuroscience, The University of Toronto Brain & Behaviour Research Program, The Hospital for Sick Children BENEFICIAL EFFECTS OF METHYLPHENIDATE ON VERBAL WORKING MEMORY IN CHILDREN WITH ADHD Objective: To investigate the effect of methylphenidate (MPH) on verbal working memory, as measured by the digit span subtests of the WISC-PI, in children with Attention-Deficit/Hyperactivity Disorder (ADHD). Verbal working memory is a core component of working memory that has been shown to be impaired in ADHD. Given the lack of precision in the behavioral phenotype of ADHD, we examined whether individual differences within the inattention dimension were associated with patterns of treatment response in verbal working memory. Methods: A clinic-referred sample of school-aged children with a confirmed DSM-IV diagnosis of ADHD (n=100) completed a test of verbal span and working memory in an acute, randomized, placebo-controlled, crossover trial with three single fixed doses of MPH. The sample was divided into mildly inattentive and severely inattentive subgroups. Results: MPH significantly improved performance on the verbal working memory task. Severely inattentive children were characterized by a positive cognitive response to stimulant medication compared to mildly inattentive children. Conclusions: These findings provide insight into potential mechanisms underlying individual differences in cognitive functioning and treatment response in ADHD, which in turn may facilitate more targeted treatments.

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4. Behl, Pearl * & Black, Sandra Institute of Medical Science EXAMINATION OF THE LONGITUDINAL EFFECTS OF CHOLINERGIC THERAPY ON ALZHEIMER’S DISEASE (AD)(ELECT-AD) Cholinergic neurons in the basal forebrain project diffusely to the cortical and limbic structures of the brain and are involved in many aspects of cognitive function. These nuclei have strong interconnections with the limbic system and are a major source of cholinergic output to the hippocampus and the cerebral cortex. The basal forebrain nuclei are targeted in AD and deterioration of these neurons leads to a progressive decline in the brain levels of Acetylcholine. Given this gradual cortical cholinergic denervation, therapy that would enhance the synaptic concentrations of Acetylcholine would seem rational and several cholinesterase inhibitors have now been on the market for symptomatic treatment of AD, some for over 10 years. No other effective treatments have yet emerged, although research into better therapeutics on AD continues. It is important therefore to better understand the effects of cholinergic therapy on cognitive and behavioral functioning over time. In order to appreciate the effects of these agents, it is necessary, however, to know about the natural history of the cognitive and behavioral impairments in AD. Only one study has compared the natural history of cognitive decline in untreated AD patients over one year to the progression seen in patients on cholinesterase inhibitors. Patients on cholinesterase inhibitors were better at one year both cognitively and functionally compared to those who had never had treatment. This is promising, but more studies, especially with more detailed assessments of cognitive domains are certainly needed, particularly longitudinal follow-up of executive functions that especially impact on instrumental activities of daily living. Given that AD has a mean duration of 8 to 9 years, it is essential to assess the potential of cholinesterase inhibitors over longer timer periods in order to evaluate whether these drugs really do make a lasting difference to patients. Most studies have only looked at short-term benefits in cognition, behavior and function within a 6-month, double blind, randomized placebo controlled design, since placebo-controlled trials are very difficult to do over periods longer than 6 months or one year in the AD population. In fact, the relative success of the cholinergic agents now means that a placebo group is unethical. Hence, case-control studies of patients in the untreated era compared to post-treatment era may realistically be the only design that is feasible to understand the longer-term effects of this new class of drug. Purpose: This study, therefore, aims to assess the longitudinal effects of treatment with cholinesterase inhibitors compared to no treatment in matched cohorts of patients with AD enrolled in a longitudinal observation study either prior to when treatment became available or after treatment became a common clinical option. Methods: Probable AD patients were recruited from the Cognitive Neurology Memory clinic at Sunnybrook and Women’s, where they underwent standardized neuropsychological, functional and behavioral assessments as well as neuroimaging. My study investigated potential differences in progression rates in different cognitive domains, such as memory, language, and visuospatial function, in relation to treatment status. I also investigated the sensitivity of behavioral measures to treatment effects as captured by the Neuropsychiatric Inventory (NPI) and the potential differences in the activities of daily living using the Disability Assessment for Dementia scores (DAD) Hypotheses: A) i) A slower rate of progression will be seen overall in the treated group compared to the untreated group based on the Mattis Dementia Rating scale, ii) some cognitive domains will be more responsive than others, specifically visuospatial/executive. B) Improvement or less decline will be seen in the treated group in behavior as captured by the Neuropsychiatric Inventory (NPI) and in function as measured by the Disability Assessment for Dementia scale (DAD). Results: analysis is in progress right now. Conclusion: This study hopes to answer questions concerning long term effects of a drug class, whose introduction to clinical use was based on 6-month pivotal studies. This will help clinicians to better evaluate the ongoing utility of these drugs, and will also help to understand their psychopharmacological effects.

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5. Bercovici, Eduard1,2*, Cortez, M.A.2, Snead III, O. Carter1,2 1. Institute of Medical Science, University of Toronto, Toronto, Canada; 2. Brain and Behaviour Program, Division of Neurology, The Hospital for Sick Children Department of Pediatrics, Faculty of Medicine, University of Toronto, Toronto, Canada SEROTONIN DIRECTLY MODULATES AY-9944 INDUCED ATYPICAL ABSENCE SEIZURES Administration of the cholesterol inhibitor AY-9944 (AY) produces chronic atypical absence seizures in Long Evans hooded rats. AY seizures are characterized as bilaterally synchronous 5-7 Hz slow spike and wave discharges (SSWD). In AY rats, SSWD are apparent during sleep, as are myoclonic jerks. We hypothesized that serotonin can modulate AY induced SWD by acting on the serotonin receptor subtypes 5-HT2A and 5-HT2C. The duration and frequency of SSWD that characterize the AY model as well as SSWD duration were measured using electrocorticographic (ECoG) recordings in freely moving animals. Using randomized counterbalanced dose response design, rats were treated with either the 5-HT2A agonist 1-[2,5-dimethoxy-4-iodophenyl]-2-aminopropane (DOI, 0.5, 1 or 2 mg/kg), the 5-HT2C preferring agonist m-chlorophenylpiperazine (mCPP, 1, 2, or 4 mg/kg), or vehicle. DOI significantly reduced the total duration and number of SSWD without affecting average burst duration. In contrast, mCPP had no effect on total duration or number of SSWD, but significantly reduced the average burst at 1 and 2 mg/kg. These data support the hypothesis that 5HT2A receptors are involved in the pathogenesis of experimental atypical absence seizures.

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6. Bezchlibnyk, Yarema B.1,2, Young, L. Trevor1,2 , Chen, Biao2, Wang, Jun-Feng1,2 and MacQueen, Glenda M.2 1. Mood and Anxiety Program, Centre for Addiction and Mental Health, Department of Psychiatry, University of Toronto, Toronto, Ontario; 2. Department of Psychiatry and Behavioural Neuroscience, McMaster University, Hamilton, Ontario CREB PHOSPHORYLATION IN THE AMYGDALA OF SUBJECTS WITH MOOD DISORDERS Signal transduction abnormalities have been identified in patients with bipolar disorder (BD) and major depressive disorder (MDD). In addition, components of these signaling cascades have been shown to be targets for mood stabilizers such as lithium, and antidepressant drugs. Since the transcription factor cAMP regulatory element binding protein (CREB) is critical in converting activity of signal transduction pathways to changes in cellular and molecular status, we measured the level of phosphorylated CREB (pCREB) in postmortem amygdala sections consisting of subjects with MDD, BD, schizophrenia and non-psychiatric, non-neurologic comparison subjects (n = 15 per group). This region is critical for emotional processing, and important in the pathophysiology of both BD and MDD. No significant differences were found between diagnostic groups - non-psychiatric controls, subjects with BD, MDD, or schizophrenia (SCZ) - but increased numbers of pCREB stained cells were identified in several amygdalar nuclei in subjects who had died by suicide. In contrast, patients treated with lithium at the time of death had significantly lower pCREB levels in the same region. These results may be important in understanding the neurobiology of suicide and the well-documented anti-suicidal effect of lithium.

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7. Blech-Hermoni, Yotam*, Seltzer, Ze’ev University of Toronto Centre for the Study of Pain, Faculty of Dentistry A LOCUS ON CHROMOSOME 7 PLAYS A ROLE IN NEUROPATHIC PAIN IN HA AND LA RATS AND IS ORTHOLOGOUS TO PUTATIVE PAIN QTL PAIN1 IN THE MOUSE Background: Nerve injury produces in some humans chronic neuropathic pain. The same variability is seen in animal models of chronic pain. In one model of chronic pain, a peripheral nerve is transected. As a result, a neuroma develops at the site of injury and spontaneous firing from this site, as well as from the cell bodies in the Dorsal Root Ganglia, begins shortly after. Within a similar time-course, some animals begin to exhibit abnormal behaviour of licking, biting, and scratching of the anesthetic foot. This abnormal behaviour is expressed postoperatively over a period of weeks, can be quantified using an acceptable scale and is used as a model of chronic pain. In previous studies, an outbred Sabra rat line was phenotypically isolated into two distinct inbred lines: One expresses high levels of the abnormal behaviour (HA) and one expresses no – or low – levels (LA). This phenotype was purported to be controlled by a single autosomal recessive gene, although no speculation was made at the time with respect to its possible identity (Devor & Raber, 1990). Subsequently, our group reported identifying a Quantitative Trait Locus (QTL) on chromosome 15 of mice, having a major effect on this phenotype. This QTL was named Pain1 (Seltzer et al., 2001). Aims of investigation: To examine whether a rat genomic region orthologous to Pain1 in the mouse plays a role in neuropathic pain in rats. Methods: In this comparative study DNA samples were used from HA, LA, and Sabra rat lines. 15 microsatellite markers were chosen, to genotype a section of the 7q34 region of 45 HA, 37 LA, and 6 Sabra rats. This region is orthologous to the location of the Pain1 QTL on mouse chromosome 15. An additional 6 markers were used to genotype other (control) regions on rat chromosomes 3, 5, and 20. Results: Six out of the 15 markers on chromosome 7 and 2 out of the 6 control markers were informative, showing dimorphism in the tested DNA samples. Significant linkage disequilibrium was found with these contrasting rat lines using the markers on chromosome 7, but not with the control markers. Significant differences were found between HA and LA rats, using the Chi Square test, examining the segregation of alleles of markers in the genotyped region of chromosome 7, ranging from p<0.00005 for D7Rat70 up to p<1.0*E-24 for D7Got98. Discussion and Conclusions: These results indicate that (1) Pain1, the mouse QTL for neuropathic pain, maps to the rat genome as well, (2) there are one or more genes for chronic pain in this region on rat chromosome 7, and (3) this QTL plays an important role in the contrasting neuropathic pain levels of HA and LA rat lines. Since in the original report on the production of the HA and LA lines the Mendelian crossing experiments suggested that the contrasting phenotype is determined by a single gene (Devor & Raber, 1990), we offer evidence from two species that this gene may be found in the Pain1 QTL, now also localized to the 7q34 region in the rat, near D7Got98. Experiments are underway to genotype this region in additional rat lines with known phenotypes for this model. This should further substantiate these conclusions and generalize the role this locus plays in chronic pain in rats. Our lab is also genotyping the orthologous region in humans, using DNA samples from women postmastectomy and men and women following leg amputation, 60-80% of whom developed neuropathic chronic pain. This work should indicate whether the same locus plays a role in human chronic pain as well.

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8. Bollig, Carmen M. 1, Bressmann, Tim1, Uy, Catherine1, Thind, Parveen1, Irish, Jonathan C. 2 1Graduate Department of Speech-Language Pathology, University of Toronto; 2Department of Otolaryngology/Head and Neck Surgery, University Health Network, University of Toronto EVALUATION OF TONGUE SHAPES WITH 3-DIMENSIONAL ULTRASOUND IMAGING IN GLOSSECTOMY PATIENTS PRE- AND POST-SURGICALLY The aim of the present study is to assess tongue shapes and speech outcome in glossectomy patients. Our data will enable us to investigate the quality of the surgical reconstruction technique chosen for an individual patient. To this end, we use ultrasound imaging to compare pre-operative and post-operative speech and tongue function in patients undergoing partial tongue resection surgery. The standard procedure for cancer of the tongue and adjacent structures is a partial glossectomy and defect reconstruction. Our goal is to ascertain which reconstruction method provides the best speech outcome and the most symmetrical tongue shapes for patients with different sites and sizes of tumor lesions. The outcome of our study will enable us to provide valuable phonetic information to oral surgeons in deciding which reconstruction method is most suitable for an individual patient. At this point we can present data of the first two patients, who were chosen for a comparison of two methods of reconstruction. The one patient who suffered of a relatively small tumor (T1) underwent a local defect closure and the other patient who had a severe in-cratered tumor (T3-4) underwent a free gracilis flap reconstruction. The assessments, which were made with non-invasive 3-dimensional ultrasound imaging, took place shortly before and after the surgical treatment, when the wound healing was completed. Using ultrasound we are able to investigate the shape, position, surface and volume of the tongue in a novel way during the production of speech sounds. The perceptual evaluation of the post-operative speech of both subjects was close to normal except for distortions mainly of alveolar consonants. Since ultrasound analysis allows for the detection and visualization of compensatory tongue gestures in the production of speech sounds, our data indicate that the tongue mobility of both subjects was decreased. The 3-dimensional ultrasound volume reconstruction enabled us to undertake a detailed analysis of the patients’ pre- and post-surgical tongue shapes. The ultrasound allowed us to validate that the tongue reconstruction methods used for our two patients were adequate for the sites and sizes of their tumors. The current paper offers a glimpse into the future perspectives our on-going research. The detailed quantitative analysis of tongue shapes and function using the ultrasound imaging will allow us to establish scientifically based guidelines for the surgical reconstruction of tongue defects.

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9. Caraiscos, Valerie B.1*, You-Ten, Kong E.2, Newell, J. Glen3, Elliott, Erin M.1, Rosahl, Thomas W.5, Wafford, Keith A.5, MacDonald, John F.3,4 and Orser, Beverley A.1,2,3,6 1Institute of Medical Science, Departments of 2Anesthesia, 3Physiology and 4Pharmaceutical Sciences, University of Toronto, Toronto, Ontario, Canada; 5Merck Sharp & Dohme Research Laboratories, Neuroscience Research Center, Terlings Park, Harlow, Essex, United Kingdom; 6Department of Anesthesia, Sunnybrook & Women’s College Health Sciences Centre, Toronto, Ontario, Canada ANESTHETICS SELECTIVELY MODIFY A NOVEL FORM OF GABAERGIC INHIBITION Background: Whole-cell recordings from hippocampal neurons show two distinct forms of GABAergic inhibition: 1) transient synaptic transmission or miniature inhibitory post-synaptic currents (mIPSCs) and 2) a persistent low-amplitude tonic current. Our lab has previously shown that the tonic current in cultured hippocampal neurons is preferentially enhanced by the intravenous anesthetic, propofol, compared to synaptic currents (Bai et al., 2001). We also showed that extrasynaptic α5 subunit-containing γ-aminobutyric acid subtype A receptors (α5GABAARs) generate a tonic current in hippocampal CA1 pyramidal neurons (Caraiscos et al., 2004). Here, we test the hypothesis that the volatile (inhaled) anesthetic, isoflurane, differentially enhances tonic versus synaptic currents by acting on α5GABAARs. Methods: The whole-cell voltage-clamp technique was used to examine tonic and synaptic GABAergic currents from wild type (WT) and GABAAR α5-/- cultured hippocampal neurons as well as GABA-evoked currents from recombinant GABAARs expressed in HEK 293 cells. Cells were voltage-clamped at a holding potential of –60 mV. Results: We observed that the GABAAR α5 subunit was necessary for enhancement of the tonic current by low concentrations (25 µM) of the volatile anesthetic, isoflurane, as potentiation was absent in α5-/- neurons. At this concentration, isoflurane had no effect on mIPSCs recorded from WT or α5-/- mice. Studies of recombinant human α5β3γ2L and α1β3γ2L GABAARs demonstrated that the α5 subunit confers a marked sensitivity and efficacy to potentiation of GABA-evoked currents by isoflurane. Discussion: Our results show that low, amnestic concentrations of isoflurane selectively act on tonic α5GABAARs in the hippocampus. The suppression of memory for traumatic surgical events is an essential effect of anesthetics. These results suggest that extrasynaptic α5GABAARs are primary targets for low concentrations of volatile anesthetics, thus providing the foundation for investigating an association between tonic inhibition in the hippocampus and effects of anesthetics on memory. (Supported by the CIHR to VBC, JGN, JFM, BAO; the CAS to KEY-T; a Career Scientist Award to BAO).

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10. Cheung, Joyce & Wojtowicz, J. Martin Department of Physiology, University of Toronto AGE-RELATED CHANGES IN THE PRODUCTION AND MIGRATION OF NEW NEURONS IN THE RAT OLFACTORY SYSTEM The subventricular zone (SVZ) is one area in the mammalian brain where neurogenesis continues into adulthood. Many of the cells generated in the SVZ are neuronal precursors that migrate sagittally along a pathway known as the rostral migratory stream (RMS) to the olfactory bulb (OB) where they differentiate into local interneurons. The goal of the present study was to identify age-related changes in neurogenesis in the SVZ. Young (1-2 months old) and middle-aged (12 months old) rats were injected with bromodeoxyuridine (BrdU) to label dividing cells that were subsequently quantified. The neuronal phenotype of the newly generated cells was confirmed by double-labeling the cells with doublecortin (DCX), a marker of young migrating neurons. It was found that in young rats, proliferation of new cells occurred in the SVZ and migrated via the RMS to the OB within 10 days. Middle-aged rats exhibited cell proliferation in the SVZ, RMS, and OB, but fewer of the newly divided cells differentiated into neurons. In both groups of animals, there appeared to be a second population of cells within the SVZ that was characterized by delayed proliferation and migration that occurred between 10 and 28 days. This study demonstrates novel mechanisms in the production and migration of new neurons from the SVZ via the RMS to the OB.

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11. Chiu, Mary* & Orser, Beverley Department of Physiology, University of Toronto LOCALIZATION OF α5-CONTAINING GABAA RECEPTORS IN THE HIPPOCAMPUS GABAA receptors (GABAAR) are hetero-pentameric ligand-gated chloride ion channels composed of subunits from at least seven different classes (α1-6, β1-3, γ1-3, δ, ε, θ, π). Different combinations of subunits confer diverse pharmacological and biophysical properties. α5-containing GABAAR represents one of the minor combinations in the brain, as they constitute less than 5% of the total GABAA receptor population. However, they are relatively highly expressed (constituting approximately 20% of the GABAAR population) in the hippocampus, the part of the brain that governs learning and memory. These α5-containing GABAARs have been shown to mediate tonic GABAergic inhibition, a form of GABAergic conductance that arises from activation of extrasynaptic receptors by low ambient concentrations of GABA in the extracellular space (Caraiscos et al., 2004). This tonic conductance may provide a background level of inhibition that regulates neuronal networks by mechanisms that are distinct from synaptic transmission. Immunocytochemical study has also shown α5-containing GABAARs to have an extrasynaptic localization (Brunig et al., 2002). In dissociated cultures of hippocampal neurons, the α5 subunit was shown to have no apparent colocalization with gephyrin, a selective marker of postsynaptic sites. There is also an almost complete lack of colocalization between α5 subunit and PSD95 and Synapsin-I terminals, suggesting extrasynaptic localization of α5 GABAAR. Given their relatively restricted expression in the brain and their potential physiological importance, we seek to better understand these extrasynaptic α5-containing GABAARs. Specifically, we propose to perform a subcellular fractionation protocol that allows us to investigate the localization of hippocampal α5-containing GABAARs at a subcellular level. By fractionating hippocampal neuron into its components, we may explore what other subunits and/or proteins may associate with extrasynaptic receptors. This information offer fundamental insights into the regulation of brain function and possible new strategies for developing target specific therapeutic drug.

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12. Cohn, Mélanie*1, Levine, Brian1,2,3, Black, Sandra E. 2,3,4, Richards, Brian5, Kaufman, Yakir6, Freedman, Morris2,6, and Moscovitch, Morris 1,3 Departments of 1Psychology/2Medicine (Neurology), University of Toronto; 3Rotman Research Institute at Baycrest Centre for Geriatric Care; 4Sunnybrook and Women’s College Health Sciences Centre; Departments of 5Psychology/6Behavioural Neurology, Baycrest Centre for Geriatric Care, Toronto, Ontario SEMANTIC AND EPISODIC MEMORY LOSS IN A CASE OF WHIPPLE’S DISEASE ENCEPHALOPATHY Background: Whipple's disease (WD) is a rare, chronic, multisystemic illness caused by the bacteria Tropheryma whippelii. While symptoms are typically gastrointestinal, in rare cases the central nervous system is affected. There are few descriptions of the cognitive symptoms associated with WD, and only one of formal neuropsychological test results and none of retrograde memory function.

Objectives: To investigate cognitive deficits, with an emphasis on episodic and semantic retrograde memory function, in a case of WD encephalopathy presenting with an amnestic syndrome, to relate these deficits to underlying brain abnormalities documented using MRI technique, and to evaluate the findings in reference to current neuropsychological theories of episodic and semantic.

Results: MS, a 49-year-old with WD encephalopathy, showed impaired visual spatial skills, smell identification, speed of information processing, executive functions and anterograde memory function on neuropsychological tests. In terms of retrograde memory, he showed impaired autobiographical episodic memory for all life periods preceding the onset of his amnesia without evidence of a temporal gradient. As for semantic memory, a temporal gradient of approximately 20 to 25 years was apparent in autobiographical and public knowledge domains. The pattern of his episodic and semantic memory loss is consistent with MRI findings, which showed severe atrophy in the medial temporal lobes bilaterally. Conclusion: WD encephalopathy can result in a typical amnestic syndrome affecting both semantic and episodic retrograde memory, but to different degrees, consistent with recent theories regarding the role of the medial temporal lobe.

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13. Cunic, D.I.1,2*, Paradiso, G. 1,2, Kwan, C.2, Sailer, A.1,2, Moro, E.1,2, Poon, Y.1,2, Molnar, G.1,2, Gunraj, C.1,2, Lang, A.E.1,2, Lozano, A.M.2, 3, Chen, R.1,2

1 Division of Neurology, Toronto Western Hospital, Toronto, Ontario, Canada; 2Toronto Western Research Institute, Toronto, Ontario, Canada; 3 Division of Neurosurgery, Toronto Western Research Institute, Toronto, Ontario, Canada SOURCE GENERATORS OF EVOKED POTENTIALS FROM SUBTHALAMIC NUCLEUS DEEP BRAIN STIMULATION Purpose and Hypothesis: High frequency deep brain stimulation (DBS) of the subthalamic nucleus (STN) alleviates the cardinal motor symptoms of advanced Parkinson’s Disease (PD), but its mechanism of action remains unclear. Evoked potentials recorded from scalp electrodes have been reported with STN DBS. However, their generator source and whether these potentials are specific to stimulation of clinically effective contacts are not known. It is hypothesized that generator sources of cortical potentials for clinically effective DBS will be similar in different patients. Methods: We studied 4 PD patients (mean age: 57 years; mean disease duration:15 years) with bilateral STN DBS. All patients were on their usual medications. The clinical effectiveness of the unilateral bipolar stimulation was verified by comparing UPDRS motor scores with the stimulator turned off and on at the high frequency stimulation rate the patients normally use. To record evoked potentials, high resolution EEG was recorded using a cap equipped with 58 scalp electrodes and 6 inferior face electrodes. The STN was stimulated at 10 Hz with both the optimal and other possible adjacent bipolar contact combinations (e.g. 0-1+, 1-2+, 2-3+, 2+3-) from the implanted quadripolar stimulating electrode. Regional dipoles (source generators) of the potentials evoked were calculated using Brain Electric Source Analysis (BESA) software, and their location was estimated using an averaged brain. Results: High frequency bipolar stimulation at the optimal contacts improved UPDRS motor scores in all patients (mean improvement: 21%). In all patients, a potential with latency of about 20 ms was consistently observed with stimulation at optimal contacts. In 3 patients this potential was positive (average peak latency:23ms; average amplitude:1.53μV) and was maximal over the medial-posterior frontal leads. In one patient, the potential was negative (19ms;-0.59μV) and was maximal over the parietal cortex. Regional dipole analysis localized the generator source of this potential (average time of peak regional dipole source activity: 22ms) in all patients to the ipsilateral medial premotor cortex . This regional source was not observed with stimulation of the lowest contacts (0-1+). Conclusions: STN stimulation at clinically effective contacts activates the ipsilateral premotor cortex at a latency of about 22 ms. This suggests that STN DBS may work in part through activation of the cortex.

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14. Elliott, Erin M. 1*, MacDonald, John F. 2,3, and Orser Beverley A. 1,2,4,5 1Institute of Medical Science, Depts. of 2Physiology, 3Pharmacology, 4Anesthesia, Univ. of Toronto, Toronto, ON, Canada, M5S 1A8; 5Dept. of Anesthesia, Sunnybrook & Women’s College HSC, Toronto, ON, Canada, M4N 3M5 TONIC BUT NOT SYNAPTIC INHIBITORY CONDUCTANCE IN MURINE HIPPOCAMPAL NEURONS IS ENHANCED BY LOW CONCENTRATIONS OF THE β2/3 SUBUNIT SELECTIVE ANESTHETIC ETOMIDATE Hippocampal neurons are regulated by two types of inhibitory conductances including a rapid phasic conductance generated by post-synaptic GABAA receptors (GABAARs) and a low amplitude, persistent tonic conductance putatively mediated by extrasynaptic GABAARs. We first reported that phasic and tonic conductances in the hippocampus are generated by pharmacologically distinct populations of GABAARs. Gabazine (Mol Pharmacol 2001; 59:814) and penicillin (Mol Pharmacol 2003; 63:2-8) selectively blocked the synaptic but not tonic conductance in CA1 pyramidal neurons and neurons grown in primary culture. Here we report that low concentrations of etomidate, an anesthetic that selectively modulates β2/3 subunit-containing GABAARs, enhanced the tonic current but not phasic conductance. Whole cell currents (–60 mV) were recorded from murine hippocampal neurons (E17) grown in dissociated cultures. Etomidate (100nM) enhanced the amplitude of the tonic conductance by 91.8 ± 23.7 % (n=7, p<0.05) whereas no change was detected in the amplitude or time course of miniature inhibitory postsynaptic currents (mIPSCs). Higher concentrations of etomidate (>1µM) further enhanced the tonic conductance (229.1 ± 57.0 % at 1µM, n=10, p< 0.05). Additionally, concentrations above 1 µM also prolonged decay (τw = 21.4 ± 3.7 vs 24.8 ± 2.9 msec; n=8, p<0.05) and increased charge transfer (641.9 ± 90.5 vs 1085.18 ± 94.6 pA msec; n=8, p< 0.05) of mIPSCs whereas no change was detected in the amplitude or frequency. Thus, etomidate selectively enhanced the tonic conductance suggesting that extrasynaptic GABAARs contain β2/3 subunits. Further, modulation of extrasynaptic GABAARs may contribute to behavioral changes associated with low concentrations of anesthetics such as impaired learning and memory. Supported by the Ontario Ministry of Health & CIHR

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15. Fawcett, A.P. 1*, Moro, E.2, Lang, A.E.2, Lozano, A.M.3, Hutchison, Wm.D.1,3 1. Dept. of Physiology 2. Dept. of Medicine, Division of Neurology 3. Dept. of Surgery, Div. of Neurosurgery, University of Toronto, Toronto, Ontario, Canada PALLIDAL DEEP BRAIN STIMULATION (DBS) INFLUENCES BOTH REFLEXIVE AND VOLUNTARY SACCADES IN HUNTINGTON’S DISEASE Introduction: Deep brain stimulation (DBS) of the globus pallidus internus (GPi) is being evaluated as a potential new therapy for patients with Huntington’s disease (HD). In addition to the skeletal movement disorders, HD patients have oculomotor deficits, including difficulty initiating voluntary saccades and difficulty in suppressing rapid saccades towards newly appearing stimuli. Purpose: This study measured changes in several saccade parameters, due to stimulation, in one of the first HD patients to be implanted with bilateral GPi DBS in the world. The aim of this study was to determine if oculomotor performance improved with stimulation in parallel with clinical scores. Methods: Oculomotor performance was assessed using three testing paradigms: pro- saccades, anti-saccades and memory-guided saccades. The data from the HD patient was also compared to that of two healthy controls. Results: Pallidal DBS decreased pro-saccade latency, total movement time and the number of correctly executed trials, as well as increasing saccade gain compared to values when stimulation was off (p<0.05). Rightward memory-guided saccade performance was adversely affected with stimulation: saccade gain decreased, latency increased and the patient’s ability to suppress unwanted saccades decreased in comparison to data when stimulation was off (p<0.05). Conclusions: Our data demonstrates a task-specific modulation of oculomotor deficits in this HD patient with mediodorsal pallidal DBS, supporting a role for GPi in oculomotor control.

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16. Giannoylis, Irene*1, Nelson, Aimee J.3, Staines, Richard W.3,4, McIlroy, William E.2,3,4 1. Department of Physiology, University of Toronto; 2. Graduate Department of Rehabilitation Science, University of Toronto; 3. Sunnybrook & Women’s College Health Science Center, University of Toronto; 4. Kinesiology & Health Science, York University, Toronto, ON, Canada EFFECTS OF PERCEIVED EFFORT DURING A MOTOR TASK MEASURED USING FMRI Studies revealing brain changes associated with motor learning and recovery of motor function following injury fail to account for the confounding effects of perceived effort on cortical activation. Previous work on sense of effort has typically altered the sensorimotor demands of a motor task by inducing muscle fatigue. We currently vary task difficulty without changing peripheral motor state to reveal changes in the underlying neural network associated with differences in perceived effort. We employed a motor task involving simultaneous abd/adduction of the 3rd and 4th digits. The task was performed when: 1) digit pairs (2nd/3rd) and (4th/5th) were taped (easy) and 2) when digit pairs were not taped (difficult). Twenty healthy young right-handed subjects were imaged using a 1.5 T GE echospeed MRI while performing the task with their dominant hand for 15 seconds interleaved with a 15 second rest condition for 10 epochs over a 5 minute period. Subjects were recruited who rated the task (without assistance from tape) as easy (n=10) or difficult (n=10). A 10-point rating scale for perceived effort was used to select subjects and to measure effort following the performance of each task during scanning. Overall, a greater sense of effort resulted in greater activation in primary, secondary, and association motor cortices. Our findings have implications for studies reporting brain changes associated with changes in motor function such as occur during stroke recovery or sensorimotor learning. This work reveals the importance of developing experimental designs to control and/or monitor not only the sensorimotor demands of a task but also the perceived effort. (Support Contributed By: OHSF & CIHR)

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17. Glazer, P. M.* 1, Quant, S. 2, Maki, B. E. 2, 5, & McIlroy, W. E. 1,2,3,4 1Graduate Department of Rehabilitation Science, 2Institute of Medical Science, 3Department of Physical Therapy, 4Toronto Rehab Institute, University of Toronto; 5Centre for Studies in Aging, Sunnybrook and Women’s College Health Sciences Centre, University of Toronto THE EFFECT OF VERBAL FLUENCY TASK ON BALANCE CONTROL The literature has well documented that the elderly are at an increased risk of falling and that this risk is exacerbated by decline in cognitive functioning. Over the past several years the relationship between cognitive status and postural stability has been extensively studied and resulted in evidence for direct association between posture and cognition. Despite these efforts the mechanism of cortical involvement in postural control still remains largely unknown. The purpose of this study was to provide basic understanding of the association between specific aspects of cognitive function and the control of stability, but more specifically to assess whether cortical areas believed to be involved in attention switching are involved in the control of posture. The novelty of this approach was to explore the influence on postural control of concurrent performance of cognitive tasks that have well described underlying cortical networks. The Verbal Fluency (FAS) task is a standard neuropsychological test involving activation of two different areas of the cortex in two separate tests. One of the subtests, the Phonemic Fluency (PF), assesses word generation and switching ability which is mediated by the frontal lobes, while the Semantic Fluency (SF) counterpart is believed to involve a temporally mediated lexical search. This dissociation between tests provides an opportunity to provide insight about localization of specific cortical areas involved in cognitive control of postural stability as well as gaining evidence for specific cognitive processes involved in postural control. Since the prefrontal cortex is believed to be involved in attention switching it was hypothesized that postural control would be disrupted when Phonemic Fluency but not Semantic Fluency is performed concurrently.

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18. Guy, Allison* & Broussard, Dianne Department of Physiology, University of Toronto, Canada Toronto Western Research Institute, University of Toronto, Canada INVESTIGATION OF THE ROLE OF IONOTROPIC GLUTAMATE RECEPTORS IN SHORT-TERM PLASTICITY IN THE MEDIAL VESTIBULAR NUCLEI Purpose. To investigate the role of ionotropic glutamate receptors in short-term plasticity at the synapses between primary vestibular afferents and second order vestibular neurons in the medial vestibular nuclei (MVN). Short-term plasticity at these synapses changes their strength, thus altering the information processing characteristics of these neurons. These changes may cause these neurons to act as frequency filters and may play a role in altering the vetibulo-ocular reflex in response to immediate changes in the environment. Methods. Using 600 mm coronal slices of mouse brainstem (P14-P32), we induced short-term plasticity in second order vestibular neurons by stimulating vestibular afferents with bipolar tungsten electrodes and currents of 20-100 mA. We were able to observe the effect of stimulation by recording from second order vestibular neurons with an Axoclamp 2A amplifier. Using paired pulses (IPI 5ms – 50 ms) and trains of various frequencies (10 Hz – 100 Hz) as stimuli, we were able to investigate the dynamics of these synapses in the MVN. Results. In three cells, we observed short-term facilitation at the synapses between primary vestibular afferents and second order vestibular neurons. An analysis of the peak amplitudes of the first and second peaks evoked by paired-pulse stimuli suggest that this phenomenon may be post-synaptic in these three synapses. Future Directions. We will continue to observe the synaptic dynamics between the primary vestibular afferents and the second order vestibular neurons in the MVN. We will also be applying ionotropic glutamate receptor antagonists, APV and NBQX, to observe the role of AMPA receptors and NMDA receptors respectively in short-term plasticity at these synapses.

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19. Ho, Stephanie K.Y.1*, Kovacevic, Natasha2, Chen, Josette X.2, Henkelman, Mark R.2, Henderson, Jeffrey T.1 1 Department of Pharmaceutical Sciences, University of Toronto, 2 Mouse Imaging Centre, Hospital for Sick Children, Toronto ROLE OF EPHB RECEPTORS IN MURINE CNS AXON GUIDANCE A crucial step in the proper assembly of mammalian central nervous system (CNS) is the guidance of axons to their appropriate synaptic targets. With respect to this, Eph receptors have been shown to play a key role in the formation of many neural structures. In order to gain a better understanding of these receptors and their role in axon guidance, wild-type and Eph mutant brains are analyzed by high-resolution MRI. A major advantage of high-resolution MRI over traditional histological methods is that it provides an accurate three-dimensional (3D) representation of CNS structures and allows analysis of morphological changes in a high throughput manner. As a first step to validate high-resolution MRI as a tool for examining axonal tracts and to determine the sensitivity of this system, Eph mutants previously shown to exhibit axon guidance defects in their anterior commissures were examined. The results obtained for EphB2 using this system compared favorably with those previously described using histology. At present, an extensive analysis of the EphA4 null mutants has been performed and compared to EphB2. The results demonstrated interesting similarities and differences between B2 and A4 mutants. Furthermore, these findings support the concept that EphB-family members delineate distinct zones of axon guidance cues.

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20. Huang, Juan 1, Wu, Xihong 1, Yeomans, John 2, Li, Liang 1,2 1Department of Psychology, Speech and Hearing Research Center, Peking University, Beijing, China, 100871 2Department of Psychology, Centre for Research on Biological Communication Systems, University of Toronto, Toronto, Ontario, Canada M5S 3G3 EFFECTS OF TETANIC STIMULATION OF THE AUDITORY THALAMUS OR AUDITORY CORTEX ON ACOUSTIC STARTLE RESPONSES IN AWAKE RATS The amygdala plays an important role in both emotional learning and fear potentiation of the startle reflex. The lateral nucleus of the amygdala (LA), which receives auditory inputs from both the auditory thalamus (medial geniculate nucleus, MGN) and the auditory association cortex (AAC), is a critical structure for auditory fear conditioning. The central nucleus of the amygdala, which has intra-amygdaloid connections with the LA, increases startle magnitude via midbrain connections to the startle circuits. Although tetanic stimulation of either the MGN or the AAC in vitro or in vivo can induce long-term potentiation (LTP) in the LA, the behavioral consequences of tetanization of each of these two auditory afferents have not been reported. In the present study, the startle reflex, elicited by either an intense noise or noise paired with transient electrical stimulation of MGN or AAC in awake rats, was enhanced by tetanic stimulation of MGN, but suppressed by that of AAC. The tetanization-induced changes of startle diminished within 24 hours. Transient electrical stimulation of the MGN, but not the AAC, either inhibited or enhanced startle, depending on the interval between the electrical stimulus and startling stimulus. Moreover, block of GABAB receptors in the LA reversed the effect of tetanic stimulation of the AAC on startle but did not change the effect of tetanic stimulation of the MGN. The results suggest that MGN and AAC afferents play a differential role in emotional modulation of startle. The AAC inputs to the LA are more dependent on the inhibitory GABAB transmission.

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21. Hwang, Rudi 1*, Deluca, V.1, Masellis, M,1 Mueller, D.1, Czobor, P.2, Volavka, J. 2, Lieberman, J.A.3

, Meltzer, H.Y.4

, Kennedy, J.L.1

1. Neurogenetics Section, Centre for Addiction and Mental Health (CAMH), University of Toronto; 2. Nathan S. Kline Institute for Psychiatry Research; 3. University of North Carolina at Chapel Hill; 4. Case Western Reserve University INVESTIGATING THE EFFECT OF DOPAMINE D1 & D2 RECEPTOR GENE POLYMORPHISMS ON ANTIPSYCHOTIC TREATMENT RESPONSE Hypothesis: Based on evidence that dopamine D1 receptors play a role improving cognitive and working memory deficits in schizophrenic patients and based on evidence that blockade of dopamine D2 receptors is the primary mechanism by which symptoms of psychosis are alleviated, we hypothesize that dopamine D1 and D2 receptor gene polymorphisms may play a role in predicting antipsychotic treatment response. Methods: Four single nucleotide polymorphisms (SNPs) in DRD1 and 11 SNPs spanning DRD2 were genotyped in three schizophrenic populations. These samples had a total number of about 280 patients. Treatment (clozapine, haloperidol, olanzapine, and risperidone) response data was evaluated using the Positive and Negative Syndrome Scale (PANSS) and the Brief Psychiatric Rating Scale (BPRS). Analysis of covariance and X2 were used to compare genotype group differences in treatment response. Linkage disequilibrium analysis was used to reveal haplotype blocks within the genes that was in turn used to perform haplotype analyses. Results: DRD2 –241 A/G SNP was associated with cognitive symptom scores from the PANSS in one sample as well as positive symptom scores from the BPRS in another sample. DRD2 –141 C Ins/Del polymorphism was associated with negative symptom subscale change scores in two different samples as well as being associated with overall BPRS response when two samples were combined. A trend was observed for DRD1 –48 A/G SNP in predicting negative symptom change scores as well as overall improvement. Conclusions: These exploratory results are interesting and suggest a possible role for DRD1 and DRD2 genes in prediction of subtypes of response to antipsychotic treatment. Replication in larger and independent samples is warranted.

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22. Labrie, Viviane*1,2,3, Lipina, Tatiana3, Roder, John1,2,3 1Collaborative Program in Neuroscience, 2Institute of Medical Science, 3Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Canada THE BRAIN GLUTAMATERGIC SYSTEM AS A TARGET FOR NOVEL CLASS OF NEUROLEPTICS Schizophrenia is frequently characterized by disturbances in sensorimotor gating and in attentional processes, which can be measured by pre-pulse inhibition (PPI) and latent inhibition (LI), respectively. Researchers have implicated dysfunction of the glutamatergic system to be involved in this disorder. Behaviours analogous to the symptoms of schizophrenia can be mimicked in both humans and rodents by inhibiting NMDA receptor neurotransmission. The pharmacologically-induced hypofunctional NMDA receptor model consequently provides a means of assessing the efficacy of putative neuroleptics. This study examines whether drugs that target the glutamate system; D-serine and ALX5407, have an effect on the PPI and LI of mice, in the presence or absence of an NMDA receptor antagonist; MK-801. Inbred C57Bl/6J mice were tested in a startle reactivity paradigm, following the administration of drugs. Latent inhibition compared the response animals had to a tone, after having received 0 or 40 tone pre-expositions, 4 tone-shock associations, and systemic drug treatments. Thus the ability of D-serine and ALX5407, to facilitate PPI, prevent disruption of latent inhibition, and reverse the effects of NMDA receptor inhibition was determined. A comparison of these drugs with the effects of the traditional atypical neuroleptic, clozapine, was equally completed to further identify their suitability as potential neuroleptics.

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23. Lau, A.*, Arundine, M., Tymianski, M. Department of Physiology, University of Toronto, Toronto, Canada; Division of Cellular and Molecular Biology, Toronto Western Research Institute, Toronto, Canada SIN-1 INDUCED NITRATION INHIBITS CASPASE-3 ACTIVITY IN THE STAUROSPORINE MODEL OF CLASSICAL APOPTOSIS IN NEURONS It has been shown that cells subjected to sublethal stretch followed by the application of an otherwise tolerated NMDA treatment leads to increased neuronal death. This mortality exhibits certain hallmarks of classical apoptosis, including irregular nuclear morphology and DNA fragmentation. In addition, the presence of ROS, ONOO-, and other free radicals were readily apparent in biochemical assays. However, these cells do not display an increased presence of active caspase-3 protease, a main effector protein of the apoptotic pathway. It is our hypothesis that the caspase-3 mediated pathway of cellular death is directly or indirectly inhibited by protein nitration. Our studies employed the use of staurosporine, a known initiator of classical apoptotic pathways; SIN-1, a nitration agent; or a combination of treatments. The stretch model was briefly re-characterised and was consistent with previous data. Staurosporine (1uM) treated cells showed increased active caspase-3 immunoreactivity starting at 3 h progressing to a least 24. Increased cellular death was demonstrated by the larger proportion of propidium iodide stained cells, though protein nitration was not observed. A titration curve of cell death versus SIN-1 concentration was also acquired. 1mM SIN-1 demonstrated sub-saturated levels of cell death compared to treatments of 3mM SIN-1 and 10mM SIN-1. Cells subjected to 1mM SIN-1 displayed no active caspase-3 immunoreactivity from 3h to 24h, but showed increased protein nitration beginning at 3h. Cotreatment of cells with 1uM staurosporine and 1mM SIN-1 or 3mM SIN-1 displayed no immunoreactivity with a pan-caspase-3 antibody. However, cells cotreated in this fashion still display increased cell death compared to controls. These results suggest that some pathways of delayed neuronal death may be independent of caspase-3 activity and that protein nitration is the key inhibitor.

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24. Levy, Naama 1,2,3*, Black, Sandra1-5, Caldwell, Curtis1,2, Lobaugh, Nancy1,2,4, Bocti, Christian1,4

Cognitive Neurology Unit and Imaging Research, Sunnybrook and Women's College Health Sciences Centre1, Toronto, Ontario, Canada; Institute of Medical Science 2, Program in Neuroscience3, and Department of Medicine/Division of Neurology4, University of Toronto; Rotman Research Institute and Baycrest Centre for Geriatric Care5 IMPACT OF CEREBROVASCULAR COMORBIDITY ON SPECT PERFUSION IMAGING AND EXECUTIVE FUNCTION IN ALZHEIMER'S DISEASE An important issue confronting differential diagnosis in dementia and a major source of heterogeneity is the frequent coexistence of Alzheimer's Disease (AD) and Cerebrovascular Disease (CVD). Although CVD is rarely the sole cause of dementia, small subcortical strokes increase the likelihood of expressing dementia in those with co-occurring AD pathology. Such facts have been shifting our understanding of how AD and CVD pathologies interact in the human brain. In the landmark NUN study, only 57% of elderly women meeting pathological criteria for AD were demented, whereas 93% with small vessel infarcts and AD were demented, suggesting synergistic effects of AD and subcortical CVD on cognition. Functional brain imaging techniques, such as Positron Emission Tomography (PET) and single photon emission computed tomography (SPECT), are currently used for examining deficits in regional cerebral blood flow and metabolism in several neurologic diseases, including stroke and dementia. Brain SPECT is usually less expensive and more widely available. Numerous studies have compared SPECT in AD, normal controls and/or other dementias; however few have concentrated primarily on the functional effects of subcortical CVD alone or in combination with AD. Hypothesis: 1.Patients with mixed AD and subcortical CVD evident as hyperintensities on MRI will show prefrontal perfusion deficits on SPECT. 2.Executive dysfunction will correlate with prefrontal perfusion deficits on SPECT and will be more common in patients with AD mixed with CVD. Methods: Subjects meeting NINCDS- ADRDA criteria for probable and possible AD, and DSM-IV criteria for dementia were recruited from the Cognitive Neurology Clinic and Stroke Unit at Sunnybrook and Women's College Health Sciences Centre. After a careful review of patient history by two independent clinicians, patients are classified into subgroups according to the degree of subcortical cerebrovascular disease on imaging and presence of focal signs. 50 AD patients with and 50 AD patients without subcortical CVD who have undergone standardized neurological assessment and who are matched for age, education, sex, and Mini-Mental State Exam score have been selected. The neuropsychological battery includes Mattis Dementia Rating Scale, Weschler Memory Scale - Visual Reproduction, Rey-Osterrieth Complex Figure Test, Benton Line Orientation and Boston Naming Test. Executive functions are assessed with phonemic fluency, Digit Span, Wisconsin Card Sorting Test, Trails A & B, and select subcategories of the Mattis Dementia Rating Scale. Structural MRI and SPECT perfusion imaging performed within 90 days of neuropsychological testing will also be analyzed. SPECT studies were acquired using our Picker 3000, triple-headed gamma camera, with ECD as the tracer. Reconstructions are performed using our in-house software for coregistration to a standardized MRI-derived Region of Interest anatomical template. Lesion load is assessed using a white matter hyperintensity rating scale in all subjects. Conclusion: This investigation of brain perfusion and behavior correlations aims to increase understanding of the cognitive profile and clinical course in mixed AD and subcortical CVD with particular attention to the impact of CVD on frontal perfusion and executive deficits.

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25. McDonald, Heather* & Wojtowicz, J. Martin Department of Physiology, University of Toronto AGE-RELATED DECREASE IN HIPPOCAMPAL NEUROGENESIS: POSSIBLE IMPLICATIONS FOR COGNITIVE DECLINE DURING AGING The hippocampal dentate gyrus is one of two adult brain regions to which neurons are added throughout life. Neurogenesis, the process by which new neurons are added to the brain, occurs in the dentate subgranular zone when neural progenitors give rise to new cells. Our goal was to investigate age-related changes in neurogenesis in order to understand if and how the new cells may relate to memory impairments seen in aging subjects. The production of new granule cells persists in aged and even senescent animals, but the rate of production declines steadily over the lifespan, becoming considerably reduced to less than 10% of young values by about one year, or middle age. The present study represents a quantitative comparison of neurogenesis in young and aged rats, taking into account the proliferation, survival, and differentiation of cells produced by a population of labeled progenitors. Thirty-eight day and 12-month-old Sprague-Dawley rats were injected with 5-bromo-2¡¦-deoxyuridine (BrdU), a thymidine analogue, in order to label cells dividing in the dentate gyrus over a 24-hr. period, and to follow their fates. Examined at several time points ranging from one day to two months following injection, aged rats showed a 90% decrease in cell proliferation, but similar patterns of cell survival (indicated by BrdU labeling), neuronal differentiation (indicated by doublecortin labeling), and maturation (indicated by CaBP labeling) relative to young. These results indicate that hippocampal neurogenesis, although it occurs on a drastically reduced scale relative to young levels, continues to proceed normally in aged rats. Based on previous results in our laboratory we suggest that the extreme reduction in neurogenesis could have profound consequences for memory loss in aging adults.

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26. Miller, R.C.*1,5, McIlroy, W.E.1,2,3,6, Mikulis, D.J.7, Jurkiewicz, M.T.*3,7, Popovic, M.R.4,5,6, and Verrier, M.C.1,2,3,6. 1. Department of Rehabilitation Science, 2. Physical Therapy, 3. Physiology, 4. Institute of Biomaterials and Biomedical Engineering, University of Toronto; 5. Rehabilitation Engineering Laboratory, 6. Toronto Rehabilitation Institute: Lyndhurst Center; 7. Medical Imaging, Toronto Western Hospital; Toronto, Ontario, Canada NEUROMUSCULAR RESTORATIVE THERAPY (NRT) PURPOSE: To determine the effect of NRT for individuals with cSCI. RELEVANCE: NRT uses functional electrical stimulation (FES), muscle strengthening, goal orientated functional training and stretching with the ultimate goal of increasing hand grasping abilities. Function, motor control, and cortical activation will be examined before and after participation in NRT to evaluate change. METHODS: A right handed male (age 46, C6-7 with a traumatic cSCI, 4 years post injury). Assessments [Spinal Cord Independence Measure (SCIM), standard neurological classification (ASIA), kinematic hand analysis (KHA), quadriplegic hand assessment tool (Q-HAT), standard electromyography, and functional magnetic resonance imaging (fMRI)] were conducted before and after NRT, which was delivered 3 X / week for 3 months. This is a single case repeated measures design. RESULTS: FMRI data suggested greater cortical involvement during right palmar grasp compared to normals. Pre NRT scores were: ASIA: motor - 19/50 right, 11/50 left; sensory: light touch - 23/56 right, 22/56 left and pinprick - 11/56 right, 17/56 left; SCIM 64/100; KHA wrist range of motion (ROM) of 48 degrees (right) and 2 degrees (left), finger ROM: PIP of 2.6 degrees (right) and 1.5 degrees (left), MIP of 1.5 degrees (right) and 1 degrees (left); Q-HAT 22/45 (right) and 12/45 (left). Post NRT scores will be reported. CONCLUSIONS: A five point increase in the Q-HAT score would be considered significant, (i.e. improved grasp performance) and should translate into an increase in force of 1.5 lbs/sq” for palmar grasp and 0.5 kg for pinch grasp, with a concurrent improvement in range of motion.

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27. Moore, Kathryn J.1,2 & Shoichet, Molly S.1,2,3 Department of Chemical Engineering and Applied Chemistry1; Institute of Biomaterials and Bioengineering2; Department of Chemistry3 COMBINED GRADIENTS OF NEUROTROPHIC FACTORS WORK IN SYNERGY TO GUIDE NEURITE OUTGROWTH Spinal cord injury is a devastating disorder. Early intervention with medicine prevents some secondary damage after injury, and physical therapy provides some relief for patients, but a cure likely requires regeneration of damaged axons in the spinal cord. Our research is focused on the development of a device capable of bridging the gap in an injured spinal cord and encouraging axons to regenerate within this device using peptides, drugs, and neurotrophic factors. Neurons extend neurites in response to growth factors such as nerve growth factor (NGF) and neurotrophin-3 (NT-3). Even more interesting is the fact that neurons, such as dorsal root ganglia (DRGs) and pheochromocytoma (PC12) cells, extend neurites up an NGF concentration gradient with a minimum gradient required for guidance. Our lab has demonstrated that DRGs and PC12 cells grow neurites in the direction of an immobilized gradient of neurotrophins.1 In an attempt to translate this fundamental research towards a device for clinical evaluation, our current research goals are to create a cell-adhesive, cell-invasive polymer scaffold to entrap NGF and NT-3 together in combined immobilized concentration gradients, and to look for synergism in the guidance of neurite extension along these combined gradients. NGF and NT-3 act on the cell through two tyrosine kinase receptors, TrkA and Trk C, respectively. These two receptors initiate neuronal responses through different signaling cascades2, thus allowing possible interactions between the cascades, resulting in synergistic responses. But for interactions to occur, the two receptors must be located on a single cell. We were able to show the presence of both receptors on E10 chick DRG cells through double immunolabelling. Crosslinked p(HEMA) scaffolds are cell-invasive at 15 wt%, and have been shown both to entrap NGF and NT-3 and maintain stable concentration gradients of these neurotrophins. Using this system, effective guidance of DRG neurites was achieved with a NGF concentration gradient of 310 ng/ml/mm alone. When combined NGF and NT-3 gradients of only 200 ng/ml/mm each were used, guidance was also observed; however, gradients of either NGF or NT-3 alone at 200 ng/ml/mm were unable to guide neurites and served as controls. Gradients of one neurotrophin at 200 ng/ml/mm with the second neurotrophin at a homogeneous concentration were also unable to guide neurite growth. This suggests that the mere presence of the second growth factor is insufficient to achieve synergism - the second neurotrophin gradient is required. We plan to test the efficacy of these gradient scaffolds in vivo to enhance regeneration following injury to the spinal cord. Acknowledgments: We are grateful to NSERC for funding.

1. Kapur T, Shoichet MS. Immobilizing a concentration gradient for neurite guidance. Submitted to Journal of Biomedical Engineering, September 2002.

2. Song HJ, Poo M. Signal transduction underlying growth cone guidance by diffusible factors. Current Opinion Neurobiology 9: 355-363, 1999.

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28. Niechwiej-Szwedo, E.* 1, Gonzalez, E. 2,3,4, Steinbach, M.J. 1,2,3,4 1Institute of Medical Science, 2Department of Ophthalmology and Vision Science, University of Toronto; 3Vision Science Research Program, Toronto Western Hospital; 4Centre for Vision Research, York University LOCALIZATION OF TARGETS IN DEPTH WITH ALTERED AFFERENT FEEDBACK Knowledge of eye position is important for the perception of visual direction and to maintain space constancy during eye movements. The central nervous system (CNS) can obtain non-visual information about eye position from two sources: outflow (efferent copy of the motor command) and inflow (afferent feedback from the eye muscles). Palisade Endings (PE), which are associated with the global layer of the eye muscles, might provide the proprioceptive information about eye position. Recent evidence suggests that the PE are innervated by a distinct set of non-twitch motor neurons found in the periphery of the oculomotor nuclei that control eye movements. Moreover, activity in the non-twitch motor neurons does not add to the force used to move the eye. It has been hypothesized that these non-twitch motor neurons could be involved in modulating the gain of sensory feedback, analogous to the gamma-efferent fibers which control the sensitivity of muscle spindles in the skeletal muscles. The purpose of this study was to examine the above hypothesis using behavioral methods. Specifically, it was hypothesized that altering the gain of the afferent feedback from eye muscles would result in misregistration of eye position and increased pointing errors with the arm. The Jendrassik maneuver (JM) was used to alter the afferent feedback by increasing the efferent activity of the non-twitch fibers that innervate the PE.

Healthy, young adults (n=8) were seated in total darkness and were asked to look and point to green lights which appeared at two distances in depth (25 and 45 cm). Eye movement data were collected using the El-Mar eye tracking system, and pointing responses were measured with an electromagnetic tracking device (Flock of Birds). Participants were tested in 3 experimental conditions, which were randomized as to order: 1. control (look and point to target); 2. look and point during JM (while performing a muscle contraction with the lower limbs); 3. look during JM and point after JM (point 2-3 sec after the contraction has been released). Data were analyzed using a custom software program and focused on the end-point accuracy of vergence eye movements and hand movements.

Results: Subjects systematically overshot the target with the hand, and converged beyond the target in all the conditions. Pointing responses were significantly less accurate (p<0.01) in condition 3, when subjects first localized the target while performing a muscle contraction, and then executed the pointing movement during a relaxed state. No significant difference was found between the other two conditions. Furthermore, there was no significant difference in the vergence angle of the eyes between any of the conditions. These results suggest that the registered eye position might be affected by the JM, possibly via increased activity in the non-twitch motor neurons. Since the increased pointing error was found in the condition when the eye movement was executed during the JM and the pointing movement was executed 2-3 sec after the JM was finished, it is possible that looking and pointing responses were executed under different afferent feedback conditions. No significant difference was found between the other two conditions because eye and hand movements were both executed concurrently based on the same afferent feedback from the eye muscles.

In summary, the study provides preliminary support for the hypothesis that the gain of the PE might be affected by the JM. Data also suggest that the afferent feedback from eye muscles is continuously monitored by the CNS and used to calculate the egocentric position of targets.

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29. Rivkin, Elena* & Cordes, Sabine Department of Molecular and Medical Genetics FORWARD GENETIC RECESSIVE SCREEN TO IDENTIFY NOVEL MOUSE MUTANTS WITH DEFECTS IN HINDBRAIN PATTERNING

Cranial nerves arise in a highly stereotypical manner in the embryonic hindbrain, and serve as landmarks for proper hindbrain development. The genetic hierarchy that governs specification and patterning of each individual cranial nerve is still largely unknown. To identify novel mouse mutations that affect cranial nerve development we performed a small-scale, recessive mutagenesis screen using the chemical mutagen N-ethyl-N-nitrosourea (ENU). As a phenotypical assay for mutant selection we performed immunohistochemical analysis using the 2H3 anti-neurofilament antibody. In total, the progeny of 41 carrier males were analyzed. From these, 6 had axon guidance defects, and 2 had ventral patterning defects. In one of the mutants, which we named gumby, anti-neurofilament staining of 10.5dpc revealed an abnormally sprouting facial nerve (cranial nerve VII). At embryonic days 11.5-12.5dpc, gumby homozygotes had severely reduced lower jaws (micrognathia), abnormally shaped heads, and lacked blood. The gumby mutation is embryonically lethal at day 13.5dpc. To localize the locus affected by the gumby mutation we used meiotic backcrosses that segregate the phenotype relative to known molecular markers. Interestingly, gumby is located in a region that is syntenic to a region of human chromosome that has been implicated in Cri du Chat Syndrome (CDCS). CDCS is one of the most common deletion disorders with an incidence of 1 in 20,000 live births. Hallmarks of this syndrome include severe mental retardation, speech delay, hypotonia, microcephaly, hypertelorism, epicanthal folds, micrognathia, and a high-pitched cry similar to the mewing of a cat. Therefore, our future analysis of gumby may provide biologic understanding of some of the clinical features of Cri Du Chat syndrome. Our results demonstrate the productivity of small-scale mutagenesis screens for identifying novel neurodevelopmental mouse mutations. Clearly, some novel mutations such as gumby, not only can provide insight into vertebrate neurodevelopment, but also allow us to model aspects of human neurodevelopmental disorders.

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30. Saab, Béchara1,2*, Georgiou, John2, Roder, John1,2 1Collaborative Program in Neuroscience, Molecular & Medical Genetics Department, University of Toronto, 2Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Canada THE C-TERMINAL PEPTIDE OF THE CALCIUM SENSOR, NCS-1, MODULATES SHORT-TERM SYNAPTIC PLASTICITY IN THE MOUSE HIPPOCAMPUS Synaptic plasticity, including learning and memory, is thought to be regulated by changes in calcium concentrations at nerve terminals. Calcium influx into both the pre- and post-synapse triggers a cascade of events to alter their physiology. These calcium-dependent cascades are likely mediated by certain proteins of the calcium-binding protein (CBP) superfamily (of which calmodulin is the best understood). The most sensitive CBP, the intriguing protein neuronal calcium sensor-1 (NCS-1), is believed to have a prominent role in synaptic plasticity and underlie the thought processes that lead to learning and memory. Here we shown that the C-terminal peptide of NCS-1 fused to the HIV-1 protein transduction domain (TAT) sequence modulates short-term synaptic plasticity. Paired pulse facilitation (PPF) and post-tetanic potentiation (PTP) are increased in the CA1 and dentate gyrus hippocampal regions of slices. These data suggest that mice containing the C-terminal NCS-1 peptide will have altered thought paradigms leading to behavioural differences from wild-type mice.

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31. Seminowicz, D.A.*, Mikulis, D.J., Davis, K.D. Institute of Medical Science CORTICAL NOCICEPTIVE ACTIVITY IS ALTERED DURING COGNITIVE ENGAGEMENT Interactions of pain and cognition have been studied in humans and animals previously, but a clear relationship of behavior and brain activity has not previously been shown. We aimed to show using functional MRI how a cognitively demanding task (Stroop) modulates pain-related brain activations and conversely, how pain modulates attention-related activity. Reaction time (RT) data indicated two types of pain responders: subjects in the A group had a faster Stroop reaction time when pain was concomitant to the task, while those in the P group had a slower Stroop performance during painful stimulation. Two region of interest analyses were performed. We first tested whether brain areas activated during painful median nerve stimulation were modulated by cognitive load. We next tested whether brain areas activated during the high conflict cognitive task were modulated by pain. Pain-related activity in three regions, primary (S1), and secondary (S2) somatosensory cortices, and anterior insula, was attenuated by cognitive engagement, but this effect was specific to the A group. Pain-related activity in the caudal and rostral anterior cingulate cortex (ACC) and ventroposterior thalamus were not modulated by cognitive load. None of the attention-related areas, including bilateral dorsolateral prefrontal and posterior parietal cortices, were modulated by pain, although a nonsignificant trend was noted. These findings suggest that pain networks can be modulated by cognitive strategies. Furthermore, the distinction of behavioral subgroups may relate to cognitive coping strategies taken by patients with chronic pain.

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32. Setnik, Beatrice 1,2* & Nobrega, José N. 1,2

1 Neuroimaging Research Section, Centre for Addiction and Mental Health, Toronto, ON, Canada; 2 Department of Pharmacology, University of Toronto, Toronto, ON, Canada SEX-DEPENDENT UPREGULATION OF CORTICAL TrkB RECEPTOR mRNA LEVELS IN THE LEARNED HELPLESSNESS MODEL OF DEPRESSION Neurotrophic factors have been recently recognized for their role in behavioural and plasticity-related alterations in patients with major depression. The biological activity of neurotrophic factors such as brain-derived neurotrophic factor (BDNF), which itself has been shown to exert antidepressant effects, are largely mediated by the receptor tyrosine kinase-B (TrkB). Since BDNF levels are decreased in animals exposed to both acute and chronic stress, this may potentially affect levels of the TrkB receptor in stress-dependent animal models of depression. Furthermore, BDNF levels fluctuate in response to hormonal changes in females. The learned helplessness animal model of depression was used in this study to determine how Trk B levels are affected according to depressive behaviour and sex. Male and female rats, in diestrus, were exposed to the learned helplessness paradigm and were classified as either learned helpless or non-learned helpless on the basis of escape performance. Quantitative in situ hybridization analysis was used to determine TrkB receptor mRNA levels in the frontal cortical regions of LH, nLH and normal control rats. In males, TrkB receptor mRNA expression was consistently higher in the LH group compared to control and nLH males in all 48 regions sampled, indicating an association with learned helplessness behavior. This upregulation was most prominent in specific regions including the primary somatosensory area (layer 4, +29.5%) and caudate putamen (+24.5%). Females in the diestrus phase showed a pattern of TrkB upregulation distinct to that of males. TrkB levels in females showed a trend towards upregulation in 81% of regions sampled. This upregulation was observed in both groups exposed to stress, LH and nLH collectively, relative to controls, reaching significance in 9 regions. Unlike males, females showed a generalized stress effect as opposed to a behavioural effect, despite the fact that there were no gender differences in vulnerability towards developing helplessness behaviour. These results suggest that TrkB may play a role in both stress and learned helpless behaviour, however these roles may be sex-dependent.

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33. Shao, Li, Sun, Xiujun, Xu, Li, Young, L.Trevor and Wang, Junfeng Centre for Addiction and Mental Health, and Department of Psychiatry, University of Toronto, Ontario, Canada ENDOPLASMIC RETICULUM STRESS PROTEINS: A TARGET IN COMMON FOR MOOD STABILIZERS LITHIUM AND VALPROATE IN NEURONAL CELLS? Lithium and valproate are highly effective treatments for bipolar disorder. Previous studies in our laboratory found that chronic treatment with valproate increased the expression of endoplasmic reticulum (ER) stress proteins GRP78, GRP94 and calreticulin in rat brain and C6 glioma cells. We report here that in primary cultured rat cerebral cortical cells, expression of GRP78, GRP94 and calreticulin are increased by chronic treatment with lithium and valproate at therapeutically relevant concentrations, but not increased by the other mood stabilizing drugs carbamazepine and lamotrigine. Both mRNA and protein levels are increased by lithium and valproate. In contrast to inhibitor of the ER Ca2+-ATPases thapsigagin, a classic GRP78 inducer, chronic treatment with lithium and valproate has no effects on cell damage, intracellular free Ca2+ concentration or GRP78 translocation. Our results suggest that lithium and valproate increase the expression of GRP78, GRP94 and calreticulin in primary cultured rat cerebral cortical cells without causing cell stress. This also suggests that the mechanism of GRP78 increase induced by lithium and valproate may be different from that of thapsigagin.

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34. Sibley, K.M.*1, 3, Tang, A.1-3, Brooks, D.1-3, McIlroy, W.E.1-3 1. Graduate Department of Rehabilitation Science, 2. Department of Physical Therapy, University of Toronto, 3. Toronto Rehabilitation Institute, Toronto, Ontario NEUROMUSCULAR AND CARDIOVASCULAR RESPONSES TO NOVEL PEDALING STRATEGIES IN HEALTHY PARTICIPANTS Recumbent seated pedaling has been proposed as a safe and effective form of neuromuscular and cardiovascular rehabilitation following stroke. Studies of pedaling in people following a stroke have shown that during pedaling the paretic limb performs significantly less work than the non-paretic limb, which is compensating for weakness on the paretic side.

Traditional models of seated bicycle pedaling use a linked-crank paradigm in which the pedals are mechanically coupled to one another. The mechanical constraints of the system are such that the pedals do not move independently, and accordingly when one pedal is pushed down during the extensor phase of the pedaling motion, the other pedal is rotated to the top of the cycle without any active contribution by the flexing leg. The result is that traditional seated pedaling is primarily extensor in nature with little active flexion. Patients with hemiparesis are able to successfully pedal in spite of asymmetries in sensori-motor control because of the bicycle design.

While traditional recumbent bicycle pedaling is a good choice for cardiovascular training following stroke, it does not optimally challenge the neuromuscular control pathways. To maximize recovery, an ideal training program must ensure that both legs contribute to the movement while maintaining the cardiovascular challenge. The purpose of this study was to investigate the neuromuscular and cardiovascular characteristics of three novel pedaling paradigms in young healthy participants for potential application to stroke rehabilitation.

Ten healthy males and females (mean age 28.7 +/- 1.1 years) were recruited for the study. All participants performed a maximal exercise test to determine the maximum workload achievable, which was used to determine exercise intensity for the study. A minimum of one week following the maximal exercise test, participants returned to pedal in three novel pedaling paradigms (single leg, visual feedback, spring-loaded CyclocentricTM) as well as traditional pedaling, which was the control condition. All participants performed all four conditions, pedaling for four minutes in each condition at 50% of the maximum workload achieved and at 70 revolutions per minute (25% of maximum workload for the single leg condition). Participants were given five minutes of rest in between conditions. Traditional pedaling was always performed twice: at the beginning and end of testing, while the order of the three novel paradigms was counterbalanced between participants. Sub-maximal oxygen uptake and surface electromyography of eight leg muscles were recorded in each condition.

Preliminary analysis indicates that there were task-specific differences in the timing and amplitude of muscle activation profiles and oxygen uptake characteristics. Ongoing work will continue to examine cardiovascular and underlying sensori-motor control characteristics of novel pedaling strategies in stroke patients with the goal of developing an optimized training program for stroke rehabilitation.

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35. Stevens, W. Dale1*, Cron, Greg O.2, Pappas, Bruce A.3, Santyr, Giles E.2, Grady, Cheryl L.1

1. Rotman Research Institute, University of Toronto, Toronto, ON; 2. Department of Physics, Carleton University, Ottawa, ON; 3. Institute of Neuroscience, Carleton University, Ottawa, ON QUANTIFICATION OF CEREBRAL, RETINAL, AND VERTEBRAL BLOOD FLOW IN RAT MODELS OF ISCHEMIA: A MRI STUDY A model for inducing acute global ischemia has been introduced recently wherein bilateral carotid artery occlusion (2VO) is combined with systemic hypotension (H2VO). Blood pressure is reduced and maintained below 50 mm Hg by controlled anaesthesia via a respirator. This model offers improvements as it has an extremely low mortality rate, yields consistent neural degeneration and the ischemia is completely reversible. In both 2VO and H2VO models, the extent to which the vertebral arteries compensate for reduced cerebral blood flow (BF), as well as the time course and means by which this occurs, are not well known. Further, the extent of retinal ischemia, a cause of ocular pathology in these models, is unknown. We used quantitative dynamic contrast-enhanced magnetic resonance imaging (MRI) to quantify changes in cerebral BF, vertebral artery BF, and retinal BF in adult male rats (N=10) during both 2VO and H2VO. Each rat was anaesthetised with halothane, then imaged during a control condition, immediately following 2VO, and in an H2VO condition respectively. An immediate and substantial increase in vertebral BF occurred after 2VO, which was positively correlated with retinal BF. BF reduction occurred in the retina, frontal cortex, temporal cortex, cerebellum, and midbrain, from most to least respectively. These results indicate that anterior cerebral regions and the retina are particularly vulnerable to ischemia in these models. As well, they indicate an immediate compensatory increase in vertebral BF when the carotid arteries are occluded. Variability of compensatory vertebral BF between rats may explain divergent effects of 2VO across studies using different strains of rats. Support Contributed By: CIHR and Ontario Heart and Stroke

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36. Vessal, Mani*1,2,3,4, Dugani, Chandrasagar B.4 , Solomon, Dianand A.4, Burnham, W. McIntyre 1,2,3,5, Ivy, Gwen O4. Institute of Medical Science1, Program in Neuroscience2, and Bloorview Epilepsy Research Program3, University of Toronto, Toronto; Centre for the Neurobiology of Stress4, University of Toronto at Scarborough, Scarborough; Department of Pharmacology5 GLIOGENESIS IN THE PIRIFORM CORTEX OF KINDLED SUBJECTS: A QUANTITATIVE ANALYSIS OF FULLY KINDLED BRAINS Complex partial epilepsy is a seizure disorder in which attacks frequently arise from foci located in the temporal lobes. The amygdala-kindling model is a widely used model of complex partial epilepsy with secondary generalization. This model is thought to mimic such seizures because brain regions such as piriform cortex (PC), amygdala, and hippocampus, which are in the human temporal lobes, are among brain regions that are the most prone to the development and maintenance of the seizure-prone state. This study was designed to quantitatively assess astrocytic proliferation in the rat-PC in the amygdala-kindling model of epilepsy in an attempt to understand the functional significance of astrocytes in the maintenance of the epileptic state. Five groups of male Wistar rats (n = 6 per group) were kindled to five stage 5 seizures. The kindled subjects and their corresponding sham-kindled controls (n = 6 per group) were then sacrificed after different survival periods: 1,7,18,30 or 90 days. Dividing astrocytes were identified by double labeling with bromodeoxyuridine (BrdU) and either glial fibrillary acidic protein (GFAP; expressed in mature astrocytes) or vimentin (Vim; expressed in immature astrocytes) and quantified using a confocal laser-scanning microscope. In addition to observing a significantly higher number of dividing astrocytes in kindled animals, we also noted differences in the numbers of dividing astrocytes in the ipsilateral versus contralateral-PC. Using one-way analysis of variance (ANOVA), we observed the highest number of proliferating astrocytes in the 18-day group and the lowest in the 90-day post-kindled group. Previous studies have demonstrated a significant role played by astrocytes in proper synaptic functioning. Thus, the increased number of astrocytes may be involved in synaptic reorganization and synaptogenesis, both of which have been observed in kindling. Furthermore, the differences observed among the kindled groups, as well as between the PCs in both hemispheres, may be suggestive of possible function(s) of astrocytes in facilitating neural networks necessary in maintaining the seizure prone state.

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37. Xu J.*, Xue S., Lei G., Kwan C.L., Yu X.-M. Faculty of Dentistry, University of Toronto, Toronto, ON, Canada THE ROLE OF C-TERMINAL SRC KINASE (CSK) IN THE REGULATION OF NMDA RECEPTORS The regulation of N-methyl-D-aspartate (NMDA) receptors by Src family protein tyrosine kinases has been implicated in a wide spectrum of physiological and pathological conditions in the central nervous system (CNS), such as learning and memory, epilepsy, chronic pain and neurodegenerative disorders. However, how Src kinase activity per se is regulated in the control of NMDA receptors is still an open question. Recently, we have demonstrated that protein tyrosine phosphatase alpha (PTPá), the activator of Src kinases, is necessary for the initiation and maintenance of the up-regulation of NMDA receptors by Src kinases (The EMBO J. 2002, 21, 2977-2989). Furthermore, we found that the Src kinase inhibitor, C-terminal Src kinase (Csk) may also complex with NMDA receptors in the brain. Specifically, Csk was found to associate with co-expressed NMDA NR2A subunits in heterologous cells, and the Csk-NR2A association could be enhanced by co-expression of constitutively active form of Src, but not the kinase dead form of Src, indicating that the Csk-NR2A subunit interaction may be regulated by Src kinase. Moreover, intracellular application of Csk (2nM) significantly inhibited the whole-cell currents mediated by either native NMDA receptors in cultured hippocampual neurons or recombinant NMDA (NR1-1a/NR2A) receptors in fibroblasts. In contrast, boiled Csk applied into cells had no such effect, suggesting that Csk may down-regulate NMDA receptor activity. Taken together, it was demonstrated that Csk, along with PTPá, may play important roles in finely regulating NMDA receptor function in the CNS.

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38. Zai, Gwyneth*1,2, King, Nicole 2, Burroughs, Eliza 4, Barr, Cathy L. 1,3,5, Kennedy, James L. 1,2,3,5, Richter, Peggy 3,4 1Institute of Medical Science, University of Toronto; 2Neurogenetics Section, Centre for Addiction and Mental Health; 3Department of Psychiatry, University of Toronto; 4Anxiety Disorders Clinic, Centre for Addiction and Mental Health; 5The Toronto Hospital – Western Division, Department of Psychiatry, University of Toronto QUANTITATIVE TRAIT ANALYSIS OF THE GAMMA-AMINOBUTYRIC ACID BETA RECEPTOR 1 GENE IN OBSESSIVE-COMPULSIVE DISORDER Background: Obsessive-compulsive disorder (OCD) is a severe neuropsychiatric illness. Genetic factors are believed to be important etiologically. Although genetic testing has focused on the serotonergic and dopaminergic systems, there is increasing evidence that the major inhibitory neurotransmitter, gamma-aminobutyric acid (GABA), may also be functionally involved. Furthermore the GABA beta receptor 1 (GABBR1) gene has been localized to chromosome 6p21.3 region, which has shown linkage to OCD. Purpose/Hypothesis: We hypothesize that variations within the GABBR1 gene might be a risk factor for developing OCD. Methods: We investigated five polymorphisms (–7265A/G substitution; 10497C/G substitution; 33795A/G substitution in the 3’-UTR; Ser491Ser-1473T→C transition; Phe659Phe-1977T→C transition) in the GABBR1 gene in a sample of 159 DSM-IV OCD probands and their families, using the transmission disequilibrium test. Results: A trend was observed with an over-transmission of allele 1 at the A-7265G polymorphism and OCD (χ2=3.270, P=0.071). Moreover, the TDT haplotype analysis using TRANSMIT showed a trend toward association with the haplotype of the five polymorphisms together [2.1.1.2.1 (A-7265G.C10-71G.Ser-491-Ser.Phe-659-Phe.A33795G)] with a chi-square value of 3.418, which corresponds to a p-value of 0.065 (overall χ2=6.353, 5 d.f., P=0.273). Moreover, a trend was observed for the total Yale-Brown obsessive-compulsive scale score in the Phe-659-Phe polymorphism (z=1.934, P=0.053) using the family-based association test, considering the diagnosis of OCD and then the clinically relevant quantitative phenotypes. Conclusion: The observed trends suggest that further investigations of the role of the GABBR1 gene in OCD are warranted.

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39. Zhao, Xiao-Han*1,2 , Xin, Wen-Kuan1,2 , Xu, Jindong1,2 , Kwan, Chun L.1,2, Zhu, Kang-Min1,2, Cho, Jae-Sung1,2, Duff, Missy1,2, Ellen, Richard P.1,3 , McCulloch, Christopher A.G.1,3 and Yu, Xian-Min1,2 1. Faculty of Dentistry, 2. Centre for Addiction and Mental Health, 3. The CIHR Group in Matrix Dynamics, University of Toronto, Toronto, ON, Canada CRITICAL CONTROL POINT: RECRUITING N-METHYL-D-ASPARTATE (NMDA) RECEPTOR-MEDIATED TOXICITY INTRODUCTION: Although NMDA receptor antagonists have shown clear benefit in protecting neurons in experimental stroke/trauma models, clinical treatment of stroke/trauma patients with NMDA receptor antagonists has not yielded promising results. OBJECTIVES: The purpose of this project was to characterize mechanisms of how NMDA receptor activity is recruited to cause toxicity in the central nervous system (CNS). METHODS: Cultured hypocampal neurons were prepared from E15-E19 rat embryos. Neuronal Image, NMDA single channel activity and [Na+]i and [Ca2+]i were recorded at 10-14 days after plating. Neuronal images were immediately (<1min) recorded after the culture medium was replaced with either the standard extracellular solution containing 2mM Ca2+ or low [Ca2+] as indicated, and henceforth continuously monitored and photographed every 3 or 5 minutes. NMDA single channel currents were evoked by including 10µM NMDA in recording pipettes and recorded through an AxoPatch 1D amplifier and analyzed with pClamp6 software. [Na+]i and [Ca2+]i were measured with the Na+- and Ca2+-sensitive fluorescent dyes, sodium-binding benzofuran isophthalate (SBFI) and Fura-2, respectively, using a 346/380 nm pair of excitation wavelengths from monochromators, and single-photon counting methods. RESULTS: We found that 19±2% and 46±12% of neurons showing swelling, beading and/or process disintegration after reperfusion of a standard extracellular solution to neurons following the pre-treatment with the same solution except containing 600 and 6M Ca2+, respectively. Interestingly, neuronal injury produced by Ca2+ reperfusion following the treatment of neurons with the solution containing 6M Ca2+ could be significantly reduced by NMDA receptor antagonist application concomitant to [Ca2+]e reduction. Otherwise, NMDA receptor antagonists could not produce protective effects. Furthermore, we found the depletion of extracellular [Ca2+]e from 2mM to 6M may significantly increase [Na+]i by 23±4mM and NMDA single channel gating: the overall channel open probability and mean open time of the channels increased to 155±24% and 126±4% of control levels. The increase of NMDA channel activity could be prevented by blocking Na+ influx. CONCLUSION: The enhancement of NMDA channel activity induced by depletion of extracellular Ca2+, associated with focal ischemia, can be a key event triggering the recruitment of NMDA receptor activity leading to pathological changes in neurons. (Supported by: CIHR, Ont. Neurotrauma Fnd.)

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UNDERGRADUATE POSTER ABSTRACTS 40. Capano, Lucia Undergraduate Neuroscience Specialist Program INVESTIGATION OF DNA VARIANTS IN THE 5’-REGULATORY REGION OF THE DRD1 GENE IN ATTENTION DEFICIT/HYPERACTIVITY DISORDER Attention Deficit/Hyperactivity Disorder (ADHD) is a prevalent childhood psychiatric disorder with a strong genetic basis. The Dopamine receptor D1 gene (DRD1) is a strong candidate for involvement in ADHD. A recent linkage study by Misener et al. (2003) tested for linkage of DRD1 to ADHD and in that study the Transmission/Disequilibrium Test (TDT) showed biased transmission of a particular DRD1 haplotype, designated Haplotype 3. This finding supports the hypothesis that the DRDI gene is involved in this disorder, and implicates Haplotype 3 in particular, as a risk factor. However, the polymorphic markers used in that study were not predicted to alter DRD1 gene function. Furthermore, a sequence screen of the coding region of the gene, with DNA from children who showed biased transmission of Haplotype 3, did not reveal any variants. The present study tests the hypothesis that a disorder-causing variant, associated with Haplotype 3, is in the 5'-regulatory region of this gene. We performed a sequence screen of 2468 bp of the 5'-regulatory region of the gene in 41 children who showed biased transmission of Haplotype 3. Sequence analysis revealed 3 nucleotide changes (variants) from the published sequence, at -2115, -2031, and -1785 upstream from the translation start site. A search for potential transcription factor (TF) binding sites showed that the change at -2115 resulted in the loss of a potential Pax-4 binding site, and the gain of a potential Oct-1 binding site. The change at -2031 resulted in the loss of a potential Pax-6 site and the gain of a potential CP2 site. The change at -1785 did not result in a change in potential TF binding sites. These findings suggest the possibility that changes at -2115 and -2031 might affect expression of the DRD1 gene, as a result of altered transcription factor binding.

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41. Chan, E.1, Kovačević, N.2, Henderson, J. T.3

1. Neuroscience Specialty, University of Toronto; 2. Department of Pharmceutical Sciences, University of Toronto; 3. Mouse Imaging Centre, Hospital for Sick Children THE DEVELOPMENT OF AN MRI BASED EXPERT SYSTEM AND 3D SURGICAL MRI/CT ATLAS FOR 129/SvImJ AND C57BL6 INBRED MOUSE STRAINS Mice are important animal models used to investigate the physiological and biochemical aspects of a number of human diseases. Improvements in magnetic resonance imaging (MRI) and computed tomography (CT) have progressed to the point where these techniques are applicable to the analysis of small rodent physiology and structural morphology. In order to efficiently utilize these tools for the analysis of structural perturbations in mice, one must first determine the levels of natural variation which exists within structures such as the central nervous system (CNS) in specific murine populations. In addition, one must develop a system for analyzing these data, in which specific CNS components are automatically recognized and compared for the presence of significant structural perturbations in terms of data obtained from control specimens. In order to achieve this, an averaged atlas composed of >9 brains from a genetically inbred strain of mice was produced (129/SvIMJ - N. Kovacevic). Neuroanatomic structures identifiable in each of the 9 composite brains (54) were then rendered in three dimensions by hand. These data were then used to "teach" the computational expert system to correctly identify and characterized each structure. This analysis system was then tested against several unknown (previously characterized mutant) data sets in order to determine its accuracy. The results demonstrate that this system reliably identified the indicated structures and correctly identified structural mutations in each case. This system is presently being employed as part of a system of analytic tools to examine the structure of the murine CNS in 3D at high throughput. The second objective of my study was to create a three-dimensional surgical stereotactic atlas for several mouse strains using data derived from MRI and computed tomography (CT). These spatially accurate 3D atlases exhibited a far more accurate spatial representation of the murine skull and brain than was previously possible using standard histologic techniques. The resulting atlases demonstrate, in and to the ability to render a number of important neural interactions within the CNS in 3D, the relative differences which exist between the brain and skull of 129Sv versus C57B1 mice. These atlases are currently being employed to more accurately plan and position stereotactic surgeries in the CNS. Data from these atlases has also been a key factor in the development of a new system of stereotactic coordinates for the murine brain.

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42. Cheung, Joyce Department of Physiology AGE-RELATED CHANGES IN THE PRODUCTION AND MIGRATION OF NEW NEURONS IN THE RAT OLFACTORY SYSTEM The subventricular zone (SVZ) is one area in the mammalian brain where neurogenesis continues into adulthood. Many of the cells generated in the SVZ are neuronal precursors that migrate tangentially along a pathway known as the rostral migratory stream (RMS) to the olfactory bulb (OB) where they differentiate into local interneurons. The goal of the present study was to identify age-related changes in neurogenesis in the SVZ. Young (1-2 months old) and middle-aged (12 months old) rats were injected with bromodeoxyuridine (BrdU) to label dividing cells that were subsequently quantified. The neuronal phenotype of the newly generated cells was confirmed by double-labeling the cells with doublecortin (DCX), a marker of young migrating neurons. It was found that in young rats, proliferation of new cells occurred in the SVZ and migrated via the RMS to the OB within 10 days. Middle-aged rats exhibited cell proliferation in the SVZ, RMS, and OB, but fewer of the newly divided cells differentiated into neurons. In both groups of animals, there appeared to be a second population of cells within the SVZ that was characterized by delayed proliferation and migration that occurred between 10 and 28 days. This study demonstrates novel mechanisms in the production and migration of new neurons from the SVZ via the RMS to the OB. Keywords: aging, cell proliferation, neurogenesis, subventricular zone, rostral migratory stream, olfactory bulb, bromodeoxyuridine, doublecortin

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43. Clarke, Laura, Georgiou, John, Salter, Michael, Roder, John The Samuel Lunenfeld Research Institute ROLES OF Src TYROSINE KINASE IN HIPPOCAMPAL SYNAPTIC PLASTICITY Src is a non-receptor protein tyrosine kinase that is highly expressed in the CNS. Previous work has suggested that Src plays an important role in the induction of long-term potentiation (LTP). In the present study, we use a protein transduction domain to deliver Src(40-49), a peptide inhibitor targeting the unique domain of Src, into intact cells, and show that late phase LTP in CA1 of the hippocampus is unimpaired, while short-term forms of plasticity manifested immediately post-tetanus are reduced. This deficit was not accompanied by changes in basal transmitter release. We also show that the Src family kinase inhibitors PP2 and SU6656 do not affect short-term forms of plasticity, suggesting that the role of Src in short-term plasticity is mediated by protein-protein interactions and not by its kinase activity. We propose several possible mechanisms through which Src(40-49) may act in presynaptic terminals to transiently depress synaptic transmission after the delivery of tetanic stimulation.

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44. Ding, Hoi Ki, Ko, Shanelle, Shum, Fanny, Zhuo, Min Department of Physiology, Centre for the Study of Pain, University of Toronto A THERMAL-BASED ACTIVE ESCAPE/AVOIDANCE PARADIGM WITHOUT FEAR Various analgesic tests measure the behavioural reactivity to different noxious sensations by applying different sensory stimuli. In experimental studies, the hotplate is a common thermal analgesic test for detecting both hyperalgesic and analgesic behavioural responses, while Pavlovian fear conditioning is used to measure aversive fear memory. Based on a modified hotplate test, we have developed an active escape/avoidance paradigm to test aversive memory without the properties of fear, by using a thermal stimulus instead of an electrical shock. C57B1/6 demonstrated full learning and extinction curve, and repeated exposure to the thermal stimulus did not alter pain reactivity. Escape latency was not altered when tested at 45°C, 35°C or at RT, but was impaired when tested under altered contextual cues. CaMKIV KO mice were tested to compare this paradigm with classic fear conditioning, and different types of receptors were blocked to examine their effects on the learning and memory of this paradigm. CaMKIV KO mice which were previously shown to have fear memory impairment have enhanced escape latency. Injection of SQ22536 to block adenylyl cyclase impaired Day 1 escape latency, while injection of MK801 to block NMDA receptors impaired acquisition of escaping behaviour. Overall, the present results indicated that this thermal based active escape/avoidance paradigm could be a simple method for studying aversive memories without the properties of fear, and could be a useful test to detect performance and memory deficits related to aversive stimuli.

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45. Hirshhorn, Marnie Undergraduate Neuroscience Specialist Program ASSESSING THE PRESENCE OF OSCILLATORY ACTIVITY IN THE THALAMUS OF PARKINSON’S DISEASE PATIENTS Parkinson's disease (PD) is a hypokinetic movement disorder characterized by difficulty in the initiation of willed movements, muscular rigidity, and tremor of the hands and jaw at rest (Kandel et al., 2000). Parkinson's patients are known to have a deficiency in the dopaminergic projection from the Substantia Nigra to the striatum in the basal ganglia (BG). How this deficiency of dopamine in the striatum contributes to the symptoms of PD remains unknown (Timmermmann et al., 2003). Much of previous research has focused on changes in the firing rate of BG nuclei, noting that the loss of dopamine in the striatum results in an increasing firing rate among the output neurons of the BG (Obeso et al., 1997). This increases the inhibition of thalamocortical neurons that facilitate movement, resulting in the hypokinetic symptoms characteristic of PD. More recent research has begun to focus on changes in the patterns of activity in the BG and how such changes relate to the symptoms of PD. A current hypothesis is that parkinsonian symptoms result from abnormal synchronization of the BG that leads to a breakdown in the functional segregation between parallel subcircuits of the BG-thalamocortical system (Levy et al., 2002). Microelectrode single unit recordings have demonstrated synchronized oscillatory activity in the subthalamic nucleus (STN) and the globus pallidus internus (GPi) at the frequency of parkinsonian tremor (4-6 Hz) (Lemstra et al., 1999, Levy et al., 2002) and in the frequency range of the beta band (11-30 Hz) (Levy et al., 2000). Based on these findings and the fact that the GPi sends output to the thalamus, one would expect to observe oscillations at similar frequencies in the thalamus (Niktarash, 2003). The present study analyzed microelectrode single unit recordings of 27 thalamic cells from seven patients undergoing stereotactic surgery for bilateral deep brain stimulation (DBS) to alleviate symptoms of PD. Autocorrelation histograms and spectral analysis showed that 86% of cells had rhythmic activity at a mean frequency of 3.16 Hz. These results do not support the hypothesis that thalamic cells should oscillate within a similar frequency range as cells in the STN and GPi.

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46. Ng, Karen Undergraduate Neuroscience Specialist Program INVESTIGATING THE ROLE OF THE m5 CHOLINERGIC RECEPTOR IN BRAIN STIMULATION REWARD USING PHAMACOLOGICAL AND ELECTROPORATION TECHNIQUES The M5 receptor is one of five cholinergic muscarinic receptor subtypes. It is associated with dopamine neurons in the brain. The dopaminergic system has, in the past, been linked to reward seeking behaviour. Therefore, in order to investigate the role of the M5 muscarinic receptor and dopamine neurons, the brain stimulation reward paradigm in rats is utilized as a behavioural measure for pharmacological manipulations and electrophysiological manipulations. The simultaneous nicotinic antagonist mecamylamine (30 ug/0.5 uL) and the muscarinic antagonist atropine (30 ug/0.5 uL) infusion and atropine (30 ug/0.5 uL) alone was injected into the VTA. M5 receptor expression was then increased in the ventral tegmental area by electroporation. The combination intracranial infusion of mecamylamine and atropine, as well as intracranial infusions of atropine did not significantly shift self-stimulation threshold. After M5 receptor expression was increased, self-stimulation threshold was not significantly increased compared to the control animal. Two animals, however, did demonstrate a significant change in self-stimulation frequency. After applying a Bonferonni correction, one animal displayed an increase in self-stimulation threshold (t =38.17, df=2, p>0.05), suggesting a VTA lesion, and another animal displayed a decrease in self-stimulation threshold (t=8.08, df=2, p>0.05). The results of these studies also suggest that further investigations should be conducted to reduce damage, and increase gene uptake in order to obtain more definitive results.

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47. Rizvi, Sakina Undergraduate Neuroscience Specialist Program MEMORY DEFICITS AMONG PERSONS WITH SCHIZOPHRENIA: UTILITY OF THE NINE-BOX MAZE TASK It is now well established that the hippocampus (HF) is a central site of pathology in schizophrenia (Nelson et al, 1998), and as such schizophrenic patients may exhibit a specific profile of memory loss that is associated with HF-damage. Namely, they may exhibit specific deficits in spatial, working and allocentric memory. In this study, we utilize the nine-box maze task (NBMT) to test the HF-related memory loss that occurs in schizophrenia. Though the NBMT has been used to effectively test memory deficits associated with HF pathology in humans (Abrahams, 1997), it has never been used to test memory impairment in schizophrenia. In addition, the NBMT is one of the few human paradigms that exist that can effectively test the three memory dimensions associated with HF-damage. As predicted, schizophrenia patients exhibited a specific memory loss on the NBMT component that required allocentric, spatial, and working memory. The present findings are relevant in that we have demonstrated that schizophrenia patients exhibit memory loss that is highly related to HF pathology.

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48. Salmasi, Giselle Ghazal Neuroscience Research, Department of Laboratory Medicine and Pathobiology, Sunnybrook and Women’s College Health Sciences Centre, University of Toronto DRAINAGE OF CEREBROSPINAL FLUID INTO EXTRACRANIAL LYMPHATICS IN RATS AND MICE REVEALED BY INTRACISTERNAL INJECTION OF MICROFIL Cerebrospinal fluid (CSF) drainage has conventionally been thought to occur through arachnoid granulations and villi into the superior sagittal sinus. However, the clinical experience and experimental data in animals suggests that this view is most likely incorrect. Numerous anatomical and quantitative physiological investigations into CSF transport have shown that extracranial lymphatics play a significant role in CSF absorption. A particularly well-documented route of CSF drainage relates to CSF transport through the cribriform plate in association with olfactory nerves. Lymphatics in the submucosa of the olfactory and respiratory epithelium absorb the CSF that has drained via this pathway. To date, the most convincing work on CSF drainage mechanisms (qualitative as well as quantitative) has been carried out in sheep. This work suggests the possibility that lymphatic vessels are involved in the pathogenesis of hydrocephalus. However, the existing genetic and induced hydrocephalus models are largely confined to rodents. In order to take advantage of these interesting animal correlates of disease it will be important to establish the connections between the CSF and lymph compartments in rats and mice. These models will allow us to test new and innovative ideas about how hydrocephalus may come about, namely through a possible impairment in the lymphatic drainage of CSF. The objective of my study was to visualize CSF-lymphatic linkages in wild-type rodents. To achieve this, yellow Microfil was injected post mortem into the cisterna magna of mice (n=15) and rats (n=5) to perfuse the cranial subarachnoid compartment and follow normal CSF drainage routes out of the cranial vault. Microfil was observed at numerous locations extracranially. In both the mouse and rat, there was extensive filling of lymphatics in the olfactory and respiratory submucosa and in the nasal mucosa. These included lymphatics covering the ethmoid turbinates, the nasal septum, and the lateral walls of the nasal cavity. Additionally, filling of lymphatic vessels in the vomeronasal organ was noted. Furthermore, Microfil was seen terminating at the retropharyngeal and cervical lymph nodes in the mouse and at the cervical lymph node in the rat. These results confirm the existence of CSF-lymph linkages in rodents and support the role of lymphatics in CSF drainage in many species. These results also indicate that additional investigation of the lymphatic CSF drainage pathways in various rodent models of hydrocephalus may reveal new insights into the pathogenesis of this disorder and could lead to new therapeutic approaches for the treatment of ventricular dilation in children and adults. Supported by the Canadian Institute of Health Research (CIHR)

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49. Watts, Jeff Undergraduate Neuroscience Specialist Program CAN DIFFERENCES IN THE Ca2+ SENSOR EXPLAIN DIFFERENCES IN QUANTAL OUTPUT BETWEEN CRAYFISH TONIC AND PHASIC CELLS? A MONTE CARLO MODEL Evoked neurotransmitter release requires Ca2+ entry into the presynaptic terminal. This increase in Ca2+ concentration is thought to be detected by several different sensors, the primary being synaptotagmin-1. Once Ca2+ binding to synaptotagmin-1 occurs at a vesicle that has been primed for release, the vesicle fuses with the presynaptic membrane, dumping its contents into the synaptic cleft. Different types of neurons display varying patterns of neurotransmitter release; tonic and phasic axons synapsing on the crayfish opener muscle show up to a 1000-fold difference in neurotransmitter release per action potential. A Monte Carlo model was constructed of a crayfish tonic active zone, and then differences in the binding properties of synaptotagmin-1 were examined to determine what is necessary to reproduce the difference in neurotransmitter release found in tonic and phasic cells. A fifteen-fold difference in Ca2+ binding affinity of synaptotagmin-1 was necessary to reproduce a 200-fold difference in neurotransmitter release. The current model did not take into account Ca2+ dependence of synaptotagmin-l-phospholipid interactions. If this fact were to be accounted for, it is possible that a four-fold difference in Ca2+ binding affinity would produce the same result.

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50. Wong, Fiona Undergraduate Neuroscience Specialist Program H1, A STABLE HEPOXILIN ANALOG, DOES NOT ENHANCE NEURITE OUTGROWTH OR REGENERATION AFTER INJURY IN RAT PHEOCHROMOCYTOMA CELLS OR PRIMARY HIPPOCAMPAL NEURONS IN VITRO Hepoxilins are 12(S)-lipoxygenase metabolites of arachidonic acid found in the CNS that have recently been implicated in growth factor-dependent neurite outgrowth and regeneration. We investigated the effects of a chemically synthesized stable hepoxilin analog, H1 (methyl 8-hydroxy-11,12-cyclopropyl HxA3), in in vitro models of spinal cord injury using rat pheochromocytoma (PC 12) cells and primary hippocampal neurons. 0.1 µM DMSO control and 0.28 µM H1 treatments to PC 12 cells and hippocampal neurons were compared in order to determine if H1 had any effects neurite outgrowth, regeneration, dendritic spine formation, and calcium dynamics. At a dose of 0.28 µM, Hl was non-toxic to cells but did not significantly enhance neurite outgrowth or regeneration 8 h or 48 h post-injury. DiIC12(3)-stained hippocampal neurons 48 h after H1 treatment failed to show any conclusive evidence for dendritic spine formation or growth due to floating debris and possible fixation artifacts. Optimized fluo-3 calcium imaging showed that H1 did not significantly increase intracellular calcium levels or dynamics. Overall, these results suggest that HI does not have any effect in enhancing neurite outgrowth and regeneration, or altering intracellular calcium levels in PC 12 cells and primary hippocampal neurons.

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51. Wong, J.S., Hutchison, W.D. Department of Physiology, Faculty of Arts and Science and Faculty of Medicine, University of Toronto, Ontario, Canada 6-HYDROXYDOMAPINE REDUCES MOTOR BEHAVIORS OF RATS AND INDUCES DISTINCT FIRING PATTERNS IN MULTI-UNIT RECORDINGS OF THE RODENT GLOBUS PALLIDUS Idiopathic Parkinson's disease is mainly attributed to the losses of dopaminergic neurons in the nigrostriatal pathway. It is widely accepted that the loss of dopamine in striatal synapses lead to paradoxical increases in firings of GABAnergic neurons projecting to the external globus pallidus, leading to inhibition of the nucleus and increasing activation of the indirect stop pathway ultimately. In this study, rodent Parkinsonian models are constructed by infusions of 6-hydroxydopamine into the medial forebrain bundle, causing lesions of nigrostriatal dopaminergic neurons. The open field test over the course of 40 days suggests progressive declines in motor behaviors of the rats after 6-hydroxydopamine administrations. Rotation test was employed to screen the efficacy of 6-hydroxydopamine on destroying the nigrostriatal dopaminergic neurons, and only two of the rats had sufficient contralateral rotations 20 minutes after apomorphine (D1, D2 nonselective agonist) injection for them to be considered satisfactory Parkinsonian models. Detailed multi-unit electrophysiological profile on 3 different sites of the globus pallidus (rodent homologue of external globus pallidus) produced several findings. Firing rates of some cells gradually decreased after apomorphine injection, which contradicts with the current pathological model of Parkinson's disease. β-bands with frequencies between 11 and 30 Hz were identified in cross-correlations of different sites in the globus pallidus, previously identified in subthalamic nuclei of Parkinsonian objects. Slow wave recordings suggest that they are possibly triggered by high amplitude spikes in the globus pallidus or the subthalamic nucleus. This study provides a novel approach to evaluate motor behaviors in pathological models of the motor system. Most importantly, electrophysiological analyses of firing patterns suggest that the current model of idiopathic Parkinson's disease may have undermined the role of interactions between the external globus pallidus and subthalamic nucleus. Keywords: apomorphine; external globus pallidus; motor behavior; multi-cell recording; Parkinson's disease; rat; 6-hydroxydopamine

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52. Yum, Jennie Department of Neuroscience, University of Toronto, Toronto, Ontario, Canada, M5S 3G3 SHORT-TERM DEPRESSION AT THE DEVELOPING CALYX OF HELD SYNAPSE: EVIDENCE FOR HETEROSYNAPTIC INHIBITION MEDIATED BY PRESYNAPTIC GABAB RECEPTORS Activity-dependent depression is an integral component of short-term plasticity at the calyx of Held synapse. We examined synaptic depression in postnatal day (P) 10-16 mice and found that depression may be induced by endogenous release of neurotransmitter in response to physiological patterns of stimuli. EPSCs were elicited by afferent fibre stimulation of 100Hz bursts for 30ms each, separated by varying inter-burst intervals (in the range of 0.25s to 10s). Successive bursts generated EPSCs that declined in amplitude. Depression was found to be frequency-dependent, increasing as the interval between bursts decreased from 10s to 0.25s. In order to examine the impact of stage of development, cells were divided into two age groups: those prior to hearing onset (P10-12) and those after (P13-16). Depression was further found to be age-dependent, being more robust at immature synapses. At P10-12, EPSC amplitudes declined to 44.6 ± 3.27% of initial levels, while at P13-16, amplitudes declined to 57.6 ± 3.14%. Finally, we have shown that the degree of depression was enhanced when stimulating at 3x the initial stimulation voltage (threshold) which recruits minor perisynaptic inputs. At P10-12, stimulating at 1x reduced EPSC amplitudes 85.3 ± 3.12% and stimulating at 3x reduced amplitudes to 77.5 ± 3.67%. At P13-16, the reduction was from 84.3 ± 3.26% to 79.6 ± 2.20%. P<0.05 in both cases, implying that heterosynaptic mechanisms may play a role in presynaptic inhibition. Application of GABABR antagonists CGP and SCH blocked the enhancement of depression observed at 3x, while mGluR antagonist CPPG did not have an appreciable effect. These findings suggest that stimulating at higher intensities induces spill-over of neurotransmitter from neighbouring synapses onto the calyx membrane and that this hetero-presynaptic inhibition may primarily be mediated by GABAB receptors. Keywords: calyx of Held-MNTB synapse; short-term depression; presynaptic inhibition; heterosynaptic inhibition; GABAB metabotropic receptor; developmental plasticity