NEUROSCIENCE POSTER DAY - Friday, April 22, 2005

SCHEDULE 10:00 – 11:00: Registration (free), Poster set up and viewing Medical Sciences Building, Stone Lobby 11:00 - 1:00pm: Poster viewing and judging and Pizza lunch

Medical Sciences Building, Stone Lobby 1:00 -2:00pm: DR. MIRCEA STERIADE, Laval University

"Corticothalamic oscillations in normal and paroxysmal states: neurons and networks" Medical Sciences Building, Rm 2172

2:00 – 5:00pm: Symposium: Brain Oscillations: From Neuron to Behaviour

Medical Sciences Building, Rm 2172

Poster Day Organizers: Jonathan Dostrovsky, Program in Neuroscience Director Pat Reed, PIN Program Administrator Martin Ralph, Undergraduate Neuroscience Program Coordinator Peter Carlen, Symposium organizer

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GRADUATE POSTERS

1. Abdelmalik PA.1. Department of Pharmacology, University of Toronto, Toronto, Canada.

*1,2,3, Yiu A. 1, Burnham WM 1,2 and Carlen PL 2,3.

2. University of Toronto Epilepsy Research Program (UTERP), Toronto, Canada. 3. Toronto Western Research Institute, University Health Network, Toronto, Canada. SEIZURE-LIKE ACTIVITY INDUCED BY HYPOGLYCEMIA FACILITATES HYPOGLYCEMIC CELL DEATH. 2. Aoki Cynthia,Departments of Medicine and Physiology, University of Toronto

* Liu Hattie, Horner Richard. L

FOCAL MANIPULATION OF CAMP AT MEDULLARY RESPIRATORY MOTONEURONS INCREASES RESPIRATORY MUSCLE ACTIVITY IN VIVO 3. Arunachalam, LakshmananDepartment of Physiology, University of Toronto

*, Wang, Li.

Division of Cell & Molecular Biology, Toronto Western Research Institute ANALYSIS OF THE ROLE OF MUNC18-1 IN DENSE CORE VESICLE RELEASE USING RNAi 4. Austin, James W*Institute of Medical Science and Department of Surgery, University of Toronto

and Fehlings, Michael G.

Division of Cellular and Molecular Biology, Toronto Western Research Institute IN VITRO PROTECTION AGAINST OLIGODENDROCYTE CELL DEATH USING TAT-FUSION PEPTIDE THERAPEUTICS 5. Bega, S*1,2

1Institute of Medical Sciences, University of Toronto. , Wright, T2, Nobile, R2, Buncic, RJ2, Westall, CA1,2.

2Department of Ophthalmology, Sick Kids. PREDICTOR VARIABLE ANALYSIS TO DETERMINE ONSET OF RETINAL TOXICITY IN CHILDREN ON VIGABATRIN THERAPY 6. Behl, Pearl1-4

1 Cognitive Neurology Unit, 2Sunnybrook and Women’s, 3Institute of Medical Science, 4University of Toronto, 5Department of Medicine/(Neurology), 6Department of Psychiatry, 7Rotman Research Institute, Toronto, ON, Canada.

* Black, Sandra1-5,7 Streiner, David3,4,6-7 Lanctot, Krista2-4,6,7

OVERALL AND SELECTIVE COGNITIVE TREATMENT EFFECTS OF CHOLINESTERASE INHIBITORS OVER ONE YEAR IN ALZHEIMER’S DISEASE (AD) 7. Bonin RobertDepartments of 1Physiology, 2Pharmaceutical Sciences, and 3Anesthesia, University of Toronto, Toronto, ON, Canada; 4Department of Anesthesia, Sunnybrook & Women’s College HSC, Toronto, ON, Canada

1*, MacDonald John1,2, and Orser Beverley1,4,5

TONIC GABA-ERGIC CONDUCTANCE REGULATES NEURONAL EXCITABILITY IN HIPPOCAMPAL CA1 PYRAMIDAL NEURONS

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8. Borkowski, Sarah1

Departments of 1Psychology and 2Pediatrics, University of Toronto, *, Westall, Carol3, and Rovet, Joanne2,4

3Department of Ophthalmology and 4Brain & Behaviour Program, The Hospital for Sick Children, Toronto, Canada THE EFFECTS OF AN EARLY LIFE TRANSIENT THYROID HORMONE DEFICIENCY ON THE SUBSEQUENT COLOUR VISION CAPABILITIES OF CHILDREN 9. Botly, LeighDepartment of Psychology, University of Toronto

*, Jonathan Lee, Vicky Bamberger, Wojtek Grabski & Eve De Rosa

TOUCHSCREEN-BASED VISUAL LEARNING IN RATS: AN INVESTIGATION OF THE ROLE OF ACETYLCHOLINE IN VISUAL FEATURE BINDING 10. Boudreau, S.*(aFaculty of Dentistry, University of Toronto, Canada, bSensory for Motor Interaction (SMI), Denmark, cFaculty of Dentistry, University of Åarhus, Denmark)

a, b, B. Sesslea, L. Arendt-Nielsonb, P. Svenssonc, K. Wangb

INTRA-ORAL PAIN EFFECTS AND NEUROPLASITICITY IN THE TONGUE MI AREA 11. Bulos, AndrewUniversity of Toronto, Department of Zoology

* and Stephenson, Richard.

THE RELATIONSHIP BETWEEN METABOLIC RATE AND DELTA WAVE ACTIVITY IN NREM SLEEP. 12. Burgess, AlisonProgram in Neuroscience, Department of Laboratory Medicine and Pathobiology, University of Toronto.

* and Aubert, Isabelle

Neuroscience Research, Sunnybrook and Women’s College Health Sciences Centre POLYSIALIC ACID REGULATES THE EFFECTS OF BRAIN-DERIVED NEUROTROPHIC FACTOR ON CHOLINERGIC NEURONS 13. Carmichael N*University of Toronto, Department of Physiology

., Charlton M.P. and Dostrovsky J.O.

EFFECT OF THE 5-HT1B/D AGONIST, SUMATRIPTAN, ON NEUROGENIC INFLAMMATION. 14. Cheng Victor*

1Institute of Medical Science, Depts. 2Physiology, 3Pharmaceutical Sciences, and 4Anesthesia, University of Toronto, Toronto, ON, Canada; 5Dept. Anesthesia, Sunnybrook & Women’s College HSC, Toronto, ON, Canada

, MacDonald John2,3, and Orser Beverley1,2,4,5

GABAPENTIN INCREASES GABAERGIC TONIC INHIBITION IN HIPPOCAMPAL NEURONS 15. Chin, Gordon D.1Dept. of Physiology, Faculty of Medicine, University of Toronto,

1*; Hutchison, William D.1,2

Toronto, Ontario, Canada, M5S 1A8 2Toronto Western Research Institute and Krembil Neuroscience Centre, The Toronto Western Hospital, 399 Bathurst St., Toronto, Ontario, Canada, M5T 2S8 INVESTIGATION OF THE MECHANISMS OF DEEP BRAIN STIMULATION: BICUCULLINE INJECTION AND MICROSTIMULATION IN THE PALLIDUM AND STN OF THE RAT

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16. Chiu Alan W.L.Institute of Biomaterials and Biomedical Engineering, Department of Electrical and Computer Engineering, Department of Physiology, Toronto Western Research Institute, University of Toronto

, Kang Eunji E., Derchansky Miron, Carlen Peter L. and Bardakjian Berj L.

ONLINE PREDICTION OF SEIZURE ONSETS USING WAVELET ARTFICIAL NEURAL NETWORKS 17. Chiu, Mary W.Y. Departments of *Physiology, ^Pharmaceutical Sciences, and †Anesthesia, *Institute of Medical Science, University of Toronto, Canada, M5S 1A8; #Department of Anesthesia, Sunnybrook & Women’s College Health Science Center, Toronto, Canada, M4N 3M5.

*, Robert P. Bonin*, John F. MacDonald*^ and Beverley A. Orser*†#

EVIDENCE FOR A NOVEL POPULATION OF TONICALLY CONDUCTING GABAA RECEPTORS IN THE HIPPOCAMPAL CA1 REGION 18. Christie, Lori-Ann

1. Institute of Medical Science, University of Toronto, Toronto, ON, Canada. 2. Laboratory of Neuropsychology, National Institute of Mental Health / National Institute of Health, Bethesda, MD, USA. 3. Department of Neurophysiology, Nencki Institute of Experimental Biology, Warsaw, Poland 4. Institute for Brain Aging and Dementia, University of California, Irvine, CA, USA. 5. Life Sciences Division, University of Toronto at Scarborough, Scarborough, ON, Canada. † - deceased

1*; Saunders, Richard C.2; Kowalska, Danuta M.3†; Head, Elizabeth4; Cotman, Carl W.4; MacKay, William A.1; Milgram, Norton W.5

RHINAL CORTEX LESIONS DISRUPT OBJECT RECOGNITION WHILE SPARING VISUOSPATIAL MEMORY IN DOGS. 19. Chu, Gordon K. T.,Division of Neurosurgery, Department of Surgery, Toronto Western Research Institute, Krembil Neuroscience Center

* Michael G. Fehlings

INHIBITION OF THE P75 NEUTROPHIN RECEPTOR DOES NOT PROTECT AGAINST CELL DEATH AT THE INJURY SITE AND WORSENS FUNCTIONAL OUTCOME AFTER A CLINICALLY RELEVANT COMPRESSION MODEL OF SPINAL CORD INJURY 20. Chung, Ji-Yeon Jenni 1*

1Dept. of Physiology, University of Toronto; 2Division of Cellular and Molecular Biology, Toronto Western Research Institute, University Health Network; 3Division of Neurology, Dept of Medicine, University of Toronto

, Charles D. Kassardjian2, Yao-Fang Tan2, Raquel Heskin1, Michael J. Peterson1 and Dianne M. Broussard1,2,3

THE ROLE OF THE CEREBELLAR CORTEX IN MOTOR MEMORY 21. DaSilva, K.A.Program in Neuroscience

* and McLaurin, J.

Department of Laboratory Medicine and Pathobiology, University of Toronto Centre for Research in Neurodegenerative Diseases CYTOKINE-IN-ADJUVANT STEERING OF THE IMMUNE RESPONSE TO ALZHEIMER’S IMMUNOTHERAPY 22. Dason Jeffrey SDepartment of Physiology, University of Toronto

*, Charlton Milton P, Atwood Harold L

EFFECTS OF ALTERED FREQUENIN EXPRESSION ON SYNAPTIC TRANSMISSION

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23. Farb, Norman*,University of Toronto, Toronto, Ontario, Canada

William Cunningham & Adam K. Anderson

PHYSIOLOGICAL RESPONSE TO POSITIVE AND NEGATIVE EVENTS IS MODERATED BY REGULATORY FOCUS 24. Gelinas DavidLaboratory Medicine and Pathobiology, University of Toronto

*, JoAnne McLaurin

ROLE OF THE PPAR SYSTEM IN NEUROINFLAMMATION 25. Glaholt, M. GRotman Research Institute, Baycrest Center, University of Toronto, Ontario, Canada.

.*, Itier, R. J., McIntosh, A. R.

EVENT-RELATED POTENTIALS REFLECTING RESPONSE COMPATIBILITY AND RULE SWITCHING IN A CUED REACTION TIME TASK. 26. Gonzalez, Andrea*1 Department of Psychology, University of Toronto. 2 Department of Psychiatry & Behavioural Neurosciences, McMaster University. 3 Women’s Health Concerns Clinic & Father O’Suillvan Research Centre, St. Joseph’s Healthcare, Hamilton, ON.

1, Dawn Zinga1, Marg Coote, Meir Steiner2 3, Alison S. Fleming1.

POSTPARTUM DEPRESSION IS RELATED TO SALIVARY CORTISOL, MATERNAL RESPONSIVENESS, AND EARLY CHILDHOOD FAMILY INSTABILITY 27. Harrison, Angela S.1Cellular and Molecular Pathophysiology, Centre for Addiction and Mental Health, 2Psychiatry, University of Toronto, 3Institute of Medical Science, University of Toronto, 4Pharmacology, University of Toronto

1,4*, Li, Peter P.1,2,4, Warsh, Jerry J.1,2,3,4

ALTERED AGONIST-STIMULATED TRANSIENT RECEPTOR POTENTIAL CHANNEL RESPONSES SUGGESTS DYSFUNCTION [A1]IN BIPOLAR DISORDER 28. Hong, Hyunwook.

, Li, Yan Mei., Duffin, James., and Peever, John. Laboratory for Sleep Research, Departments of Zoology and Physiology, University of Toronto, Toronto, Canada. EPISODIC HYPOXIA INDUCES LONG-TERM FACILITATION OF RESPIRATORY MOTOR OUTPUT IN IMMATURE RATS.

29. Joshi, MeenalCAMH and University of Toronto

, Ph.D.; Miksys Sharon, Ph.D.; and Tyndale Rachel, Ph.D.

CYTOCHROME CYP2E1 IN MONKEY BRAIN: CONSTITUTVE EXPRESSION AND INDUCTION BY CHRONIC NICOTINE 30. Kadis, D.S.

TITLE: INTRAHEMISPHERIC REORGANIZATION OF LANGUAGE IN EARLY ONSET EPILEPSY

, MA * 1, 2, ML Smith, PhD 1, 2, 3, A Crawley, PhD 2, I Elliott, MSc 2, 3, K Iida, MD 3, E Kerr, PhD 1, W Logan, MD 2, 3, MP McAndrews, PhD 2, 5, A Ochi, MD 3, H Otsubo, MD 3, J Rutka, MD 2, 4, OC Snead, MD 2, 3 and S Weiss, MD 2, 3. 1 Psychology, Hospital for Sick Children, Toronto, ON, Canada, M5G 1X8; 2 University of Toronto; 3 Neurology, Hospital for Sick Children; 4 Neurosurgery, Hospital for Sick Children; and 5 Applied and Interventional Research, Toronto Western Hospital.

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31. Kanisek Marijana.1Collaborative Progam in Neuroscience, 2Department of Physiology, University of Toronto

3Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Canada, 4Department of Molecular and Medical Genetics, 5The Research Institute, Hospital for Sick Children, Toronto,

*1,2,3, Ng, David 4,5, McInnes, R. Roderic4,5, Roder, C. John 1,4

Canada ROLE OF NETO 1 IN NMDA RECEPTOR DEPENDENT LEARNING AND MEMORY 32. Kim, A.Rotman Research Institute, Baycrest Centre for Geriatric Care WORKING MEMORY OF AUDITORY STIMULI

, He, Y., Alain, C., Grady, C.

33. Kong, M.M.C. 1Departments of Pharmacology and 2Medicine, University of Toronto; 3Centre for Addiction and Mental Health, Toronto, Ontario, Canada

1*, G.Varghese1,3, T.Fan1,3 B.F. O’Dowd1,3, S.R. George1,2,3

AGONIST-SPECIFIC RESCUE OF AN INTRACELLULARLY SEQUESTERED D1 DOPAMINE RECEPTOR OLIGOMER TO THE CELL SURFACE 34. Krpan, Katherine M.,1, 3*and Dawson, Deirdre R. 1, 4, 5

, Levine, Brian, 2, 3, 6, Stuss, Donald T., 2, 3, 5, 6,

1 Kunin-Lunenfeld Applied Research Unit, Baycrest Centre for Geriatric Care

2 The Rotman Research Institute, Baycrest Centre for Geriatric Care

3 Department of Psychology, 4 Department of Occupational Therapy, 5 Graduate Department of Rehabilitation Science, and 6 Department of Medicine (Neurology), University of Toronto EXECUTIVE FUNCTION AND COPING AT ONE-YEAR-POST TRAUMATIC BRAIN INJURY 35. Labrie Viviane1Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Canada; 2Institute of Medical Science and Collaborative Program in Neuroscience, University of Toronto, Canada

*12, Duffy Steve1, Roder John12

REGULATION OF HIPPOCAMPAL LONG-TERM POTENTIATION AND HIPPOCAMPUS-DEPENDANT SPATIAL LEARNING BY D-SERINE AND GLYCINE 36. Lafoyiannis, Dina1*

THE EFFECT OF MATERNAL THYROID

, Lara Rosenberg1, Carol Westall2,3, Laura Kenton3,4, & Joanne Rovet3,4. 1Institute of Medical Science, University of Toronto, 2Ophthalmology, 3Brain & Behaviour Program, 4The Hospital for Sick Children, Toronto, Canada.

HORMONE DEFICIENCIES ON OFFSPRING VISUAL DEVELOPMENT 37. Lovic, Vedran1*

1Department of Psychology, University of Toronto at Mississauga , Fleming, Alison1 & Fletcher, Paul J.1, 2

2Centre for Addiction and Mental Health, Toronto, Canada ARTIFICIALLY REARED RATS SHOW INCREASED SENSITIVITY TO AMPHETAMINE REVERSAL OF EFFECTS WITH TACTILE STIMULATION

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38. Mahabir, Megan BSc*1,4,6

Department of Pharmaceutical Sciences1; Department of Medical Biophysics2, Department of Public Health Sciences3, University of Toronto4, Centre for Addiction and Mental Health5, Sunnybrook and Women’s College Health Sciences Centre6.

, Laurie Zawertailo PhD1., Simon Graham PhD 1,2,4,6, Peter Selby MBBS3-5, Usoa Busto Pharm.D

FMRI BOLD SIGNAL ACTIVATION DURING CUE-ELICITED CRAVING IN FORMER SMOKERS 39. McCall, Martha

A MODIFIED CONSTRAINT INDUCED MOVEMEMNT THERAPY PROGRAM WITH THE GERIATRIC SUB ACUTE STROKE POPULATION

*, Department of Rehabilitation Science; Dawson, Dr. Deirdre, Department of Occupational Therapy, Graduate Department of Rehabilitation Science; Colantonio, Dr. Angela, Department of Occupational Therapy, Graduate Department of Rehabilitation Science; Streiner, Dr. David, Department of Medicine, University of Toronto

40. Ngo, L1Graduate Department of Rehabilitation Science, University of Toronto

*123., Green, R.E.A.123 & Melo, B.3

2Collaborative Program in Neuroscience, University of Toronto 3Toronto Rehabilitation Institute ENHANCEMENT OF COGNITIVE FUNCTIONING IN HEALTHY YOUNG INDIVIDUALS THROUGH BRIEF AND INTENSIVE COGNITIVE STIMULATION 41. Pamenter, Matthew*Department of Zoology, University of Toronto, 25 Harbord St. Toronto, ON M5S 3G5

, Shin, Damian, Buck, L.T.

NMDA RECEPTOR REGULATION BY MITOCHONDRIAL KATP CHANNELS AND ADENOSINE RECEPTORS IN CORTICAL NEURONS OF THE ANOXIA-TOLERANT WESTERN PAINTED TURTLE (CHRYSEMYS PICTA BELLII) 42. Parr, AnnCellular and Molecular Biology/Neurosurgery, Toronto Western Hospital

*, Kulbatski, Iris, and Tator, Charles

TRANSPLANTATION OF ADULT RAT SPINAL CORD EPENDYMAL REGION PRECURSOR CELLS INTO THE INJURED ADULT RAT SPINAL CORD 43. Peever, John.

GLUTAMATERGIC CONTROL OF AIRWAY MOTONEURONS DURING SLEEP IN RATS.

, Lai, Diane., and Siegel, Jerome. Laboratory of Sleep Research, Department of Zoology and Physiology, University of Toronto, Toronto, ON, Canada; and Department of Psychiatry and Biobehavioral Science, University of California, Los Angeles, North Hills, CA, USA.

44. Perova, Tatiana1Cellular and Molecular Pathophysiology, Centre for Addiction and Mental Health, Departments of 2Psychiatry,and 3Pharmacology, and 4Institute of Medical Science, University of Toronto,

1,4*, Warsh, Jerry J1,2,3,4, Li, Peter P1,2,4

MOOD STABILIZERS LITHIUM AND LAMOTRIGINE DIFFERENTIALLY AFFECT INTRACELLULAR CALCIUM MOBILIZATION IN B LYMPHOBLASTS 45. Phan, Nam*Cell and Molecular Division, Toronto Western Research Institute,

, Natasha Shulyakova, Linda Mills

University Health Network Department of Physiology, University of Toronto THE ROLE OF TOM20 IN MITOCHONDRIAL PROTEIN IMPORT IN DIFFERENTIATED PC12 CELL AND PRIMARY NEURONS

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46. Placenza, Franca M.Departments of Psychology1 and Psychiatry2, University of Toronto, Toronto, Canada; Division of Life Sciences3, University of Toronto, Scarborough, Canada; Centre for Addiction and Mental Health4, Toronto, Canada

1*, Erb, Suzanne3, Fletcher, Paul J. 1,2,4 and Vaccarino, Franco J.1,2,4

BLOCKADE OF CENTRAL NEUROKININ-1 RECEPTORS HAS DIFFERENTIAL EFFECTS ON OPIATE- AND COCAINE-INDUCED LOCOMOTOR ACTIVITY AND SELF-ADMINISTRATION BEHAVIOUR 47. Podkowa Monika

1Dept. of Biochemistry, 2Dept. of Medical Biophysics, 4Dept. of Medical Genetics and Microbiology, University of Toronto

1, Lee-Hoeflich Si Tuen2, Causing Carrie3, Zhao Xin1, Wrana Jeffrey L.3,4, Attisano Liliana1,2

3Program in Molecular Biology and Cancer, Mount Sinai Hospital, Toronto, CANADA LIMK1 BINDS TO THE BMP RECEPTOR, BMPRII TO REGULATE BMP-DEPENDENT DENDRITOGENESIS 48. Robins, SherriInstitute of Medical Sciences, University of Toronto; Dept of Cellular and Molecular Biology, Toronto Western Research Institute; Division of Neurosurgery, Department of Surgery, University of Toronto

* and Fehlings, Michael G.

CHARACTERIZATION OF SOLUBLE FAS RECEPTOR AS A POTENTIAL NEUROPROTECTIVE AGENT FOLLOWING ACUTE SPINAL CORD INJURY

49. Roy, FrancoisInstitute of Biomaterials and Biomedical Engineering, University of Toronto

; Popovic, Milos

NEUROMUSCULAR SIGNALS IMPROVE PERFORMANCE IN FORCE TRACKING TASK 50. Saab, Béchara1Collaborative Program in Neuroscience, Molecular & Medical Genetics Department, University of Toronto, 2Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Canada

1,2*, Georgiou, John2, Bechard, Allison2. & Roder, John1,2

NCS-1 MODULATES SYNAPTIC PLASTICITY & POTENTIALLY LEARNING AND MEMORY. 51. Seif, GamalInstitute of Medical Science, University of Toronto

*. Tator, Charles

QUANTITATIVE MEASUREMENT OF RETROGRADE DEGENERATING OF THE RAT CORTICOSPINAL TRACT: A CONFOCAL IMAGING STUDY 52. Setiawan E*

EFFECTS OF PRENATAL GLUCOCORTICOID EXPOSURE ON HIPPOCAMPAL LONG-TERM POTENTIATION AFTER BIRTH

, MacDonald JF, Matthews SG. Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, Canada

53. Shaikh KamalDepartment of Psychology, University of Toronto

*, Kooshesh Sam, Wong Karen, De Rosa Eve

LEARNED IRRELEVANCE: SELECTIVE ATTENTION AS AN INHIBITORY PROCESS. 54. Silverman LoreleiDepartment of Physiology, Faculty of Medicine, University of Toronto

and Charlton Milton

DEPRESSION AND PHOSPHORYLATION AT PHASIC SYNAPSES

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55. Skov-Rackette*, Shannon I., Miller*, NoamDepartment of Psychology, University of Toronto

& Shettleworth, Sara.J.

EPISODE BASED RESPONDING IN THE PIGEON 56. So, Christopher H.1*

Departments of Pharmacology1 and Medicine2, University of Toronto; Centre for Addiction and Mental Health3.

, Varghese, George1,3, Curley, Kevin J.1, Kong, Michael M.C.1 , O'Dowd, Brian F.1,3 and George, Susan R.1,2,3

DOPAMINE D1 AND D2 RECEPTORS EXIST AS HETEROOLIGOMERS ON THE CELL SURFACE AND ARE CO-INTERNALIZED UPON SELECTIVE ACTIVATION BY D1 OR D2 AGONISTS 57. Soleimani, L1 Institute of Medical Sciences, University of Toronto, Toronto, Ontario.

.*1, Dennis, J. W.2, Roder, J. 1,2

2 Department of Molecular and Medical Genetics, University of Toronto, Toronto, Ontario. BEHAVIOURAL CHARACTERIZATION OF THE MGAT5 KNOCKOUT MICE 58. Steidl, StephanDepartments of Psychology and Zoology, University of Toronto

, Ng, Karen, Bhattacharyya, Moni, Wang, Haoran, Yeomans, John

IN VIVO ELECTROPORATION OF THE M5 MUSCARINIC RECEPTOR GENE INTO VENTRAL TEGMENTAL AREA FACILITATES BRAIN-STIMULATION REWARD IN RATS. 59. Todorovski, ZarkoDepartment of Physiology and Program in Neuroscience, University of Toronto

* and Zhengping Jia

THE ROLE OF LIM KINASE IN SYNAPTIC PLASTICITY 60. Wan, Yudi*Institute of Medical Science, University of Toronto

; Lu, Wei-Yang; Xiang, Yun-Yan; Yang, Burton.

VERSICAN G3-DOMAIN REGULATES GLUTAMATERGIC SYNAPTIC FORMATION AND TRANSMISSION 61. Wang HaoranDepartments of Psychology and Zoology, University of Toronto

, Butt Zareen, Chui Gary, Madden Aileen, Steidl Stephan, Yeomans John.

IN VIVO ELECTROPORATION OF M5 MUSCARINIC RECEPTOR GENES IN THE RAT VENTRAL TEGMENTAL AREA WITH IRES HR-GFP VECTORS 62. Ypsilanti, Athéna*Program in Neuroscience, Department of Laboratory Medicine and Pathobiology, University of Toronto - Neuroscience Research Program,

& Aubert, Isabelle

Sunnybrook and Women’s College Health Sciences Centre CHOLINERGIC DEGENERATION DURING NORMAL AGING AND IN A TRIPLE-TRANSGENIC MOUSE MODEL OF ALZHEIMER’S DISEASE 63. Zamir O.Department of Physiology, University of Toronto

* and Charlton M.

THE ROLE OF CHOLESTEROL DEPLETION IN NEUROTRANSMITTER RELEASE

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UNDERGRADUATE POSTERS 64. Bostan, Andreea CDepartment of Psychology, University of Toronto

., Zelazo, Philip D.

COGNITIVE FUNCTION CORRELATES OF AGE-RELATED CHANGES IN EEG POWER SPECTRA 65. Bowles, BDepartment of Psychology, University of Toronto

., Ferber, S., & Pratt, J.

LETTER PROCESSING INTERFERES WITH INHIBITION OF RETURN (IOR): EVIDENCE FOR CORTICAL INVOLVEMENT IN IOR 66. Chiew, KDepartment of Psychology, University of Toronto

., Schwindt, G., Fatima, Z., & Anderson, A.K.

NEURAL ACTIVATIONS UNDERLYING THE EXPERIENCE OF MIXED FEELINGS 67. Cusi, AndréeDepartment of Psychology, University of Toronto

, Grabski, Wojtek, & Anderson, Adam K.

RESPIRATORY AND VISUAL RESPONSES DURING VOLUNTARY FACIAL ACTION: AN EXAMINATION OF FACIAL EXPRESSIONS AS EVOLUTIONARY ADAPTATIONS FOR SENSORY INTAKE 68. Hau, M.Rotman Research Institute, Department of Neuroscience, University of Toronto

, Fujiwara, E., Schwartz, M.L., Miller, B.M., Black, S.E., Levine, B.

THE FRONTAL LOBES AND AUTOBIOGRAPHICAL RECOLLECTION: EVIDENCE FROM TRAUMATIC BRAIN INJURY, FOCAL FRONTAL LOBE LESIONS AND FRONTOTEMPORAL DEMENTIA 69. Leung, GraceDepartment of Psychology, University of Toronto; Rotman Research Institute

. Supervised by Dr. J.D. Ryan

INVESTIGATION OF COGNITIVE PROCESSING IN OLDER ADULTS USING EYE MOVEMENT MONITORING 70. MacLean, DavidDepartment of Physiology, University of Toronto

; Baker, Chris; and MacDonald, John F.

SLOW INACTIVATION OF THE LURCHER MUTATION IN THE GLUR1 SUBUNIT 71. Purzner, Jamie

1 Department of Neuroscience, University of Toronto

1; Paradiso, Guillermo2,3; Cunic, Danny2; Saint-Cyr, Jean A.2,4; Hoque, Tasnuva2,4; Mahant, Neil3; Lozano, Andres M.2,4; Lang, Anthony E.2,3; Chen Robert2,3

2 The Krembil Neuroscience Centre and Toronto Western Research Institute 3 Division of Neurology, University of Toronto 4 Division of Neurosurgery, University of Toronto MOVEMENT RELATED POTENTIALS AND OSCILLATORY ACTIVITY IN THE SUBTHALAMIC NUCLEUS AND VENTRAL LATERAL THALAMUS DURING SELF-PACED AND CUED MOVEMENTS 72. Rick, John T., Shirin JaliniDepartment of Physiology, University of Toronto

& Peter L. Carlen

EFFECT OF AMPAKINES ON NEOCORTICAL PAIRED-PULSE RATIOS

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73. Schoen, Tanya1Department of Neuroscience, Faculty of Arts and Science, University of Toronto

1 & Tremblay, Luc2

2Faculty of Physical Education and Health, University of Toronto EFFECT OF STRESS ON IMPLICIT LEARNING 74. Schwindt, GraemeG Schwindt, K Chiew: Undergraduate Neuroscience Program, University of Toronto

, Kimberly Chiew, Zainab Fatima, & Anderson, Adam K

Z Fatima, AK Anderson: Department of Psychology, University of Toronto THE NEURAL MECHANISMS OF AFFECTIVE PRIMING 75. Wettlaufer, P.Department of Psychology, University of Toronto

Ralph, M., & Anderson, Adam K.

REACTIONS TO DEFORMITY AND DISFIGUREMENT: AN EVOLUTIONARY PERSPECTIVE 76. Yassa, MarilynDepartment of Pharmacology, University of Toronto

, Kong, Michael, George, Dr. Susan R

LOCALIZATION OF HUMAN D1 DOPAMINE RECEPTORS IN CAVEOLAE AND PHARMACOLOGICAL CHARACTERIZATION OF D1 CAVEOLIN-BINDING RECEPTOR MUTANTS

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GRADUATE POSTER ABSTRACTS 1. Abdelmalik PA.1. Department of Pharmacology, University of Toronto, Toronto, Canada.

*1,2,3, Yiu A. 1, Burnham WM 1,2 and Carlen PL 2,3.

2. University of Toronto Epilepsy Research Program (UTERP), Toronto, Canada. 3. Toronto Western Research Institute, University Health Network, Toronto, Canada. SEIZURE-LIKE ACTIVITY INDUCED BY HYPOGLYCEMIA FACILITATES HYPOGLYCEMIC CELL DEATH. The threat of severe hypoglycemia makes the goal of tight glycemic control in patients suffering from type-one diabetes mellitus very difficult. Severe hypoglycemia, which can result in seizures and coma, has been shown to have irreversible consequences on neuronal function and survival. Areas that are especially vulnerable are areas of the dentate gyrus and CA1 of the hippocampus. This may explain some of the cognitive deficits associated with severe hypoglycemia. Using extracellular field recordings in the immature, intact mouse hippocampus, we have devised an in vitro model of hypoglycemic seizures. In this model neuronal-specific cell death is confined to CA1 and dentate gyrus areas of the hippocampus. This is similar to what has been described in vivo. NMDA and AMPA/kainate antagonists prevented both hypoglycemic cell death and hypoglycemic seizure activity. The anticonvulsants phenytoin (50 ?M) and valproate (1 mM) did little to prevent hypoglycemic seizures and cell death. However, the GABAergic agonist midazolam (10 nM) was effective in preventing both hypoglycemic seizures and cell death. These data support the hypothesis that hypoglycemic neuronal damage is greatly exacerbated by seizure-like activity and excessive glutamatergic activation. The authors would like to acknowledge funding from the Canadian Institutes of Health Research, the Hospital for Sick Children Foundation and the Juvenile Diabetes Research Foundation.

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2. Aoki Cynthia,Departments of Medicine and Physiology, University of Toronto

* Liu Hattie, Horner Richard. L

FOCAL MANIPULATION OF CAMP AT MEDULLARY RESPIRATORY MOTONEURONS INCREASES RESPIRATORY MUSCLE ACTIVITY IN VIVO The cAMP signal transduction pathway is ubiquitous in the central nervous system and is involved in modulating various types of cellular processes including integrative physiological functions such as breathing. The hypoglossal motor nucleus in the medulla innervates the genioglossus (GG) muscle of the tongue, which is important in maintaining an open airway for effective breathing. However in sleep, especially rapid-eye-movement (REM) sleep, powerful neural mechanisms are recruited that suppress GG muscle activity. These effects predispose humans to common and serious sleep-related breathing problems. Several receptors that are directly associated with cAMP have been found both post-synaptically and pre-synaptically at the hypoglossal motor nucleus. Some of these when activated inhibit the effector enzyme adenylyl cyclase, which lowers cAMP and subsequently protein kinase A leading to neuronal hyperpolarization. We have recently developed an animal model allowing focal manipulation of brainstem motor nuclei using in-vivo microdialysis in freely behaving rats. Accordingly, we examined the role of cAMP at the hypoglossal motor nucleus in modulating GG muscle activity across sleep and awake states to test the hypothesis that increasing cAMP will increase GG motor activity. Under sterile surgical conditions approximately 7 days before the experiments, the animals were implanted with electrocortical and neck muscle electrodes to record sleep and awake states, and GG and diaphragm electrodes for respiratory muscle recordings. On the day of the experiments, microdialysis probes were inserted into the hypoglossal motor nucleus for application of artificial cerebrospinal fluid (ACSF) either alone or in combination with a cAMP analogue (500 μM) or a water soluble derivative of forskolin (500 μM), an adenylyl cyclase activator, to increase endogenous cAMP. Compared to ACSF controls, local application of the cAMP analogue to the hypoglossal motor nucleus significantly increased respiratory related GG activity during non-REM sleep (P < 0.001) and quiet wakefulness (P = 0.015) but not during REM sleep (P = 0.850). Application of forskolin, which increases endogenous cAMP, also increased respiratory-related GG activity during non-REM sleep (P = 0.022) and quiet wakefulness (P = 0.004). However activity in REM sleep after forskolin administration was not different than control (P = 0.478) showing that it also could not prevent the major suppressant effects of REM sleep on GG activity. This is the first demonstration that focal manipulation of downstream components of a signal transduction pathway can be used to determine the mechanisms modulating motor control of important breathing muscles in a freely behaving preparation in-vivo. These results are also relevant to understanding basic physiological processes underlying respiratory muscle control in sleep, with clinical relevance to the pathogenesis and potential pharmacological treatment of sleep-related breathing disorders.

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3. Arunachalam, LakshmananDepartment of Physiology

*, Wang, Li.

Division of Cell & Molecular Biology, Toronto Western Research Institute ANALYSIS OF THE ROLE OF MUNC18-1 IN DENSE CORE VESICLE RELEASE USING RNAi Munc18-1 is a 67kDa mammalian orthologue to unc18 in C.Elegans and was first identified as a syntaxin binding protein. Deletion of Munc18-1 has been shown to result in complete block of exocytosis in neurons and ~90% reduction of dense core vesicle (DCV) secretion from chromaffin cells, indicating that Munc18-1 is critically involved in neurotransmitter exocytosis. The neurons of Munc18-1 knockout mice degenerate and the rescue of the knockouts by re-introducing the Munc18-1 gene has not been successful. As a result the mechanism by which this protein plays an important role in exocytosis has been unclear. Malfunctions in neurotransmitter release lead to numerous neurological disorders including depression and schizophrenia. Through the use of RNA interference techniques, we have established PC12 cells in which munc18-1 is stably knocked down by ~90%. Our secretion assays reveal that the knockdown of munc18-1 in PC12 cells result in a 40-80% reduction in Ca dependent DCV exocytosis of norepinephrine. Electrophysiological studies will also be conducted to show more precisely the extent of reduction in DCV exocytosis in Munc18-1 knockdown cells. We also seek to identify specific domain(s) of Munc18-1 that are absolutely required for DCV exocytosis through conducting rescue studies on stably knocked down PC12 cells. The interaction of Munc18-1 with syntaxin1 has been considered to be essential to the process of exocytosis, but the functional significance of this interaction has not been clearly understood. We postulate that munc18-1 acts as a molecular chaperone to syntaxin1a to facilitate the transport of syntaxin to the cell membrane. We are analyzing the localization of syntaxin in Munc18-1 knockdown PC12 cells and comparing it with that in control cells. Our preliminary results suggest that syntaxin is localized in a dispersed manner in Munc18-1 knockdown cells compared with a more cell membrane localization in control cells, suggesting that Munc18-1 is essential for the correct localization of syntaxin 1. Our study will identify the domain(s) of Munc18-1 essential to the process of DCV exocytosis in PC12 cells and in addition characterize the functional importance of the Munc18-1 - syntaxin 1 interaction. This study is in progress and a manuscript is in the process of being constructed.

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4. Austin, James W*Institute of Medical Science and Department of Surgery, University of Toronto

and Fehlings, Michael G.

Division of Cellular and Molecular Biology, Toronto Western Research Institute IN VITRO PROTECTION AGAINST OLIGODENDROCYTE CELL DEATH USING TAT-FUSION PEPTIDE THERAPEUTICS Introduction: Neurotrauma is an important cause of mortality and neurological morbidity particularly in children and young adults. Although methylprednisolone or GM-1 ganglioside results in modest neurological improvement after SCI, the overall impact of these treatments remains minimal. Improved therapeutic interventions for neurotrauma are therefore required. Cell death including apoptosis of oligodendrocytes is a significant component of secondary damage following spinal cord injury (SCI) and other neurodegenerative disorders. Identified mechanisms of apoptosis responsible for oligodendrocyte loss include generation of reactive oxygen species (ROS), glutamate excitotoxicity and death receptor meditated apoptosis. Previous studies in our lab have shown that oligodendroglial and neuronal apoptosis, through activation of the Fas death receptor pathway, is implicated in white and grey matter degeneration following spinal cord injury (SCI). Moreover, Fas knockout mice have decreased cell death after SCI and application of soluble Fas receptor (sFasr) is neuroprotective following SCI. Based on these promising data, we hypothesize that using peptide inhibition of apoptotic protein to protein interactions which are critically important after neurotrauma will be neuroprotective. Current approaches to inhibit initiation and execution of apoptosis in vivo have significant limitations, thus peptides were attached to the HIV-1 Tat protein translocation domain to aid in cellular transduction. Methods: Peptides were tested in vitro using an oligodendroglial cell line, MO3.13 (generous gift of Neil Cashman, University of Toronto) and in oligodendrocyte primary cultures. Small Tat-fusion peptides were produced using an automated peptide synthesizer at the Advanced Protein Technology Centre, Hospital for Sick Children in Toronto. Larger Tat-fusion peptides were generated using pTat plasmids (generous gift from Steve Dowdy, UC San Diego) in bacteria. Cells were pre-incubated with the Tat-fusion peptides and subsequently challenged with various insults such as solube Fas ligand (sFasL), various ROS, and glutamate. Flow cytometric analysis, immunohistochemistry and immunoblotting were used to determine efficacy of peptides to prevent against apoptosis and cell death. Results: Cells were sufficiently killed upon exposure to ROS, sFasL, and glutamate insults. Peptides were internalized into cells in culture as demonstrated by fluorescent labeling studies. Protection against various molecular hallmarks of apoptosis and cell death was compared to pre-incubation with the general caspase inhibitor z-VAD-fmk, which significantly reduced cell death and apoptotic marker activation. Conclusions: The use of Tat-fusion peptides to protect against oligodendroglial cell death following SCI, although in its infancy, shows a great deal of promise and can translate well into a clinical setting. Anti-apoptotic Tat-fusion peptides might also show promise in the treatment of other neurological conditions due to overlapping pathophysiological mechanisms.

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5. Bega, S*1,2

1Institute of Medical Sciences, University of Toronto. , Wright, T2, Nobile, R2, Buncic, RJ2, Westall, CA1,2.

2Department of Ophthalmology, Sick Kids. PREDICTOR VARIABLE ANALYSIS TO DETERMINE ONSET OF RETINAL TOXICITY IN CHILDREN ON VIGABATRIN THERAPY Purpose: Infantile spasms (IS) is a rare form of childhood epilepsy affecting 2-5 children in 10,000. The prognosis is very poor; seizure activity arrests neuro and psycho-motor development and may be associated with mental retardation, cerebral palsy and a high mortality rate. Vigabatrin is an anti-epileptic drug that is effective in the treatment of IS. It works by increasing the levels of GABA in the cerebral cortex. Vigabatrin also increases the levels of GABA in the retina and has been associated with a retinal toxicity presenting as bilateral concentric constrictions of the visual fields in 40% of the adult population being prescribed the drug.. In the infant population, it is difficult to diagnose visual field constriction because the infants cannot undergo the same visual field tests that are done on adults. Therefore, to determine the onset of vigabatrin toxicity in infants, other measures of visual aptitude must be performed. Previous research has shown electroretinogram (ERG) changes with vigabatrin therapy. If visual changes can be discovered at an early stage then there is potential for minimizing or avoiding visual loss. It is therefore of prime importance to determine which variables can be used to predict early onset of toxicity. Hypothesis: Monitoring variables associated with a prediction of toxicity will allow clinicians to carefully screen for the progression of retinal toxicity within the pediatric population prescribed vigabatrin. Methods: We are using Bayesian analysis to incorporate three groups of variables associated with toxicity into a predictive model. Those are: ERG variables that show change with VGB treatment, subject variables such as age and sex, and VGB variables such as cumulative dosage, days on drug, and mean daily dosages. The importance of each variable is conditional on what is known about the other variables and its direct relationship to toxicity. Data collected from 172 patients on Vigabatrin therapy at Sick Kids was used for the analysis. Models reflecting change over 6 months, 12 months, 18 months and 24 months were analyzed. Results: The models were able to correctly predict toxicity in the majority of the cases. This was done using cross-validation and a leave-one-out analysis. Conclusions: Employing these predictive models we are able to determine which children are most likely to develop retinal toxicity. We will be implementing these predictive models into clinical practice so that children with higher toxicity predictions may be monitored more closely throughout their Vigabatrin therapy.

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6. Behl, Pearl1-4

1 Cognitive Neurology Unit, 2Sunnybrook and Women’s, 3Institute of Medical Science, 4University of Toronto, 5Department of Medicine/(Neurology), 6Department of Psychiatry, 7Rotman Research Institute, Toronto, ON, Canada.

* Black, Sandra1-5,7 Streiner, David3,4,6-7 Lanctot, Krista2-4,6,7

OVERALL AND SELECTIVE COGNITIVE TREATMENT EFFECTS OF CHOLINESTERASE INHIBITORS OVER ONE YEAR IN ALZHEIMER’S DISEASE (AD) Background and Purpose: Despite widespread use of second-generation cholinesterase inhibitors (CHIs) for the symptomatic treatment of Alzheimer’s Disease (AD), surprisingly little is known about possible effects in different cognitive domains. To assess overall and selective cognitive treatment effects of CHIs over one year in a cohort matched to untreated controls in the same longitudinal observational study. Methods: Participants (Untreated=65, Treated=65) meeting NINCDS-ADRDA criteria for mild (MMSE 20-30) or moderate (MMSE 10-19) AD were recruited from the Cognitive Neurology Clinic at Sunnybrook & Women’s, a large academic healthcare institution. Patients underwent standardized neuropsychological, functional, and behavioral assessments at baseline and 12 months later (mean follow-up=14.4 months; range 11 to 17 months). Groups were matched on education and baseline MMSE and received an extensive evaluation on comorbid illnesses, use of concomitant medications, and presence of vascular risk factors. Results: There were no significant differences between the two groups in the prevalence of comorbid illnesses, concomitant medication use and vascular risk factors (hypertension, hyperlipidemia, diabetes mellitus) except for a greater number of patients in the treated group with a previous history of smoking. Repeated measures ANOVA on the Mini Mental State Examination (MMSE), the Mattis Dementia Rating Scale (DRS) total score, and similar analyses with Bonferroni correction on its 5 subscores, standardized tests of memory, language, visuospatial and executive functioning, and activities of daily living revealed a significant group by time interaction (p=0.042) with post-hoc comparisons showing significantly less decline in treated patients in overall MMSE, overall DRS total score and all domains of the DRS (attention, initiation, construction and conceptualization) except memory, and in the additional measures, namely, phonemic fluency, backward digit span, Rey copy and Boston naming. Furthermore, less decline was seen in the treated group in overall function and in the instrumental and basic activities of daily living as measured with the Disability Assessment for Dementia Scale (effect sizes 0.4-0.8). Conclusions: Treated patients declined more slowly in several cognitive domains over one year. More specifically, they showed less decline in attention, working memory, verbal fluency, concept formation, and copying graphomotor designs. These tasks entail executive functioning, in addition to visuoconstructive and language components. Its noteworthy that executive functions, rather than memory, were particularly responsive to cholinesterase inhibitor treatment in AD patients treated for one year. It may be that these so-called “memory enhancers” may not benefit mnemonic functions because they are already severely compromised by the time of diagnosis with little ability to recover, whereas frontally mediated functions may be relatively less affected and still allow for relative improvement. Therefore, future studies should incorporate tests that can better assess attention and executive dysfunction in patients with AD.

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7. Bonin RobertDepartments of 1Physiology, 2Pharmaceutical Sciences, and 3Anesthesia, University of Toronto, Toronto, ON, Canada; 4Department of Anesthesia, Sunnybrook & Women’s College HSC, Toronto, ON, Canada

1*, MacDonald John1,2, and Orser Beverley1,4,5

TONIC GABA-ERGIC CONDUCTANCE REGULATES NEURONAL EXCITABILITY IN HIPPOCAMPAL CA1 PYRAMIDAL NEURONS Synaptically located GABAA receptors are capable of transiently responding to the local release of GABA from presynaptic neurons. In contrast, extrasynaptic GABAA receptors may be activated by low, ambient concentrations of GABA to generate a persistent or ‘tonic’ inhibitory conductance (Trends Neurosci 2004; 27: 262-269). We previously demonstrated that in hippocampal CA1 pyramidal neurons this tonic conductance is generated by α5 subunit-containing GABAA receptors (PNAS 2004; 101: 3662-3667). A functional role for tonic GABAergic conductance in the hippocampus is suggested by observations of enhanced performance on hippocampal-dependent learning tasks by mice lacking the α5 GABAAR subunit (J Neurosci 2002; 22: 5572-5580), although this role remains unknown. The aim of this study was to determine the effect of α5 subunit-mediated tonic inhibition on neuronal excitability. Cultured hippocampal pyramidal neurons from α5 knockout (KO) and wildtype (WT) mice were examined using whole-cell voltage- and current-clamp techniques. The amount of current injected required to evoke action potentials was significantly less in the α5 KO mice compared to α5 WT. This decrease was not due to strain differences in cell size, membrane potential, or action potential threshold. Action potential amplitude, half width, and 10-90% rise-time was similar between strains. Also, action potential frequency, and amplitude and frequency accommodation during sustained depolarization was similar between the α5 WT and KO mice. These data demonstrate that α5-mediated tonic GABAergic conductance reduces neuronal excitability by necessitating greater excitatory drive to elicit an action potential rather than changing the gain of the input-output relationship. As the timing of action potential firing is considered a key source of information in hippocampal function, this observed role of tonic GABAergic inhibition may have important consequences for neuronal network behaviour.

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8. Borkowski, Sarah1

Departments of 1Psychology and 2Pediatrics, University of Toronto, *, Westall, Carol3, and Rovet, Joanne2,4

3Department of Ophthalmology and 4Brain & Behaviour Program, The Hospital for Sick Children, Toronto, Canada THE EFFECTS OF AN EARLY LIFE TRANSIENT THYROID HORMONE DEFICIENCY ON THE SUBSEQUENT COLOUR VISION CAPABILITIES OF CHILDREN

Animal research has shown that within the visual system, thyroid hormone (TH) is necessary for the differentiation of cone photoreceptor subtypes. In humans, cones are responsible for colour vision and since it is possible that TH plays a similar role in human cone differentiation as it does in animals, it is therefore possible that children who experienced a lack of TH during development have colour vision deficits. In order to ascertain the role of TH in the development of human colour vision, the colour vision of children who experienced a TH deficiency during pregnancy or early life was assessed. Results indicated that children who experienced a third trimester or early life TH deficiency had deficits relative to controls on measures of the blue-yellow visual pathway. This deficit was related to some indices of TH levels during development and also to performance on behavioural tasks where colour was a salient feature.

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9. Botly, LeighDepartment of Psychology, University of Toronto

*, Jonathan Lee, Vicky Bamberger, Wojtek Grabski & Eve De Rosa

TOUCHSCREEN-BASED VISUAL LEARNING IN RATS: AN INVESTIGATION OF THE ROLE OF ACETYLCHOLINE IN VISUAL FEATURE BINDING Visual feature binding involves the integration of the perceptual features (e.g. colour, shape, size) of a stimulus to form a unified percept. Human studies have implicated selective spatial attention in feature binding, and acetylcholine’s (ACh) capacity to boost neural activity in attention-related structures of the brain may provide a neural mechanism for such binding. The nucleus basalis magnocellularis in the basal forebrain has been identified as the primary source of cholinergic input to the neocortex, particularly the frontal and parietal lobes, and lesions to this region result in an impairment in attentional processing in human and nonhuman animals. Previous studies examining perceptual binding have been limited to behavioural studies using human subjects; this experiment will use rats to examine neuromodulatory influences on perceptual binding. We used operant chambers equipped with touchscreens to train rats to perform a visual go/no-go task with water reinforcement. Black-and-white computer-generated stimuli that varied in shape, pattern, and orientation were used as target and distractor stimuli. Each distractor stimulus resembled its target on one of its stimulus dimensions. Go/no-go training forced rats to use both features of the target stimuli to discriminate it from its distractors, as rats were rewarded for nose-poking targets (go trials), and rewarded for not nose-poking distractors (no-go trials). After successful learning of the go/no-go task, pharmacological manipulations will be undertaken to systemically block cholinergic neurotransmission using the central cholinergic muscarinic antagonist, scopolamine. Saline and the peripheral cholinergic muscarinic antagonist, methylscopolamine, will be used as controls in a within-subjects design. Under the three different pharmacological conditions, rats will perform the previously learned go/no-go task as well as receive novel distractor stimuli (foils) periodically during the go/no-go task. Cholinergic blockade is expected to impair the ability of rats to bind features, resulting in the formation of illusory conjunctions. Thus, scopolamine-injected rats are expected to recombine the features of the distractor and foil stimuli to form targets, and nose-poke distractor and foil stimuli more often than controls. The goals of this study are to provide insight into the neuromodulatory role of acetylcholine in perceptual binding, as well as to provide support for the utility of touchscreens and computer-generated stimuli for training rats on visual tasks.

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10. Boudreau, S.*(aFaculty of Dentistry, University of Toronto, Canada, bSensory for Motor Interaction (SMI), Denmark, cFaculty of Dentistry, University of Åarhus, Denmark)

a, b, B. Sesslea, L. Arendt-Nielsonb, P. Svenssonc, K. Wangb

INTRA-ORAL PAIN EFFECTS AND NEUROPLASITICITY IN THE TONGUE MI AREA Background: The reorganization of neuronal connections, and the associated changes in their excitability, is characteristic of cortical neuroplasticity. Previous studies have shown that neuroplastic changes of the human tongue motor area during learning of a novel tongue-protrusion task can occur over one week of 60 minute daily training. Objectives: To determine if neuroplasticity of the tongue motor area occurs following 15 minutes of novel tongue-protrusion task training and whether the neuroplasticity is modulated by intra-oral pain. Methods: 10 healthy volunteers aged 24±3.2 years participated in two training sessions in which the application to the tongue of the algesic chemical capsaicin (1%) or placebo cream was randomized. Transcranial magnetic stimulation (TMS) was applied in each session to evoke motor potentials (MEPs) recorded in tongue musculature, and TMS stimulus – MEP response curves were constructed. MEPs were recorded at baseline, and again immediately after 15 minutes of tongue-task training. Pain intensity was recorded on a visual analogue scale (VAS) and tongue-training performance measures were also obtained. Results: Neuroplasticity of the tongue motor area, as reflected in an enhanced stimulus – response curve, was observed in both sessions; however the placebo session demonstrated a greater enhancement than that of the capsaicin session. Subjects reported an average capsaicin pain score of 5.5±2.5 on VAS and performance scores were significantly lower in the capsaicin sessions (p<0.009). Conclusion: Rapid learning and cortical neuroplasticity occur following 15 minutes of novel tongue-protrusion training, but intra-oral pain may limit these effects. Acknowledgements: Danish Research Council, CIHR STP 53877 CellSignals.

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11. Bulos, AndrewUniversity of Toronto, Department of Zoology

* and Stephenson, Richard.

THE RELATIONSHIP BETWEEN METABOLIC RATE AND DELTA WAVE ACTIVITY IN NREM SLEEP.

Sleep is mainly a mammalian-defined behaviour, as the electrophysiological data used to define it is much easier to access in mammals than in non-mammalian species. However, sleep or sleep-like behaviour has been shown to exist in non-mammalian research models such as fruit flies and crustaceans. It is defined behaviourally by the following criteria when electrophysiological data is not available: 1) a species-specific posture 2) immobility 3) an increased arousal threshold and 4) homeostatic regulation. Homeostatic regulation implies that that if a subject is sleep deprived for a significant period of time, a rebound will occur to compensate for sleep loss, during which recovery sleep is either longer, more intense, or a mixture of the two.

The question of sleep intensity is an issue that has yet to be clearly answered. If it can in fact become deeper, or more intense, one would expect correlates of sleep to become more profound as this progression occurs. One such correlate that may serve as a candidate to answer this question is metabolic rate. Mammalian subjects have consistently exhibited a decrease in overall metabolic rate as the transition from wakefulness to sleep is made.

When rats undergo short-term (6-24 hours) total sleep deprivation (TSD), a recovery period follows where the sleep stages, rapid-eye-movement (REM) sleep and non-rapid-eye-movement (NREM) sleep are longer in duration with respect to pre-TSD values. Furthermore, assessment of EEG activity during NREM sleep reveals large increases in the amount of activity in the delta frequency range (1.5-6Hz). This regular occurrence of delta increase during sleep recovery has led many to believe that it represents a dimension of intensity in sleep. In this study, we attempt to further elucidate this idea of delta intensity by investigating the relationship between delta wave amplitude in NREM and the fall in metabolic rate from wakefulness to sleep. Male Wistar rats underwent TSD for 16 hours enforced via the modified multiple platform method (MMPM) starting at ZT12 (6pm EST). The purpose of utilizing TSD was to initiate an increase in delta wave activity during subsequent recovery period. Immediately following TSD, metabolic rate of the subject was evaluated at ZT4 (10am EST) using plethysmography for several hours. Our subjects showed the expected changes during the experiment; a decrease in metabolic rate as a subject makes the transition from wakefulness to sleep and an increase in delta wave activity during NREM sleep following TSD with respect to non-TSD subjects. However, insofar as this study has been completed, the decrease in metabolic rate has not been shown to increase or decrease significantly regardless of the change in delta wave activity. In other words, the metabolic rate decrease during the wake-to-sleep transition was consistently the same between sleep deprived and control groups. These findings may represent a stumbling block for advocates of the delta-wave intensity theory, although it is unlikely that these results provide the only possible perspective on this issue, as there are likely several ways with which to approach the question. However, these preliminary results seem to indicate that there is no correlation between metabolic rate decreases and delta wave activity during NREM sleep. Experimentation needs to continue before conclusions can be deduced from the data.

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12. Burgess, AlisonProgram in Neuroscience, Department of Laboratory Medicine and Pathobiology, University of Toronto.

* and Aubert, Isabelle

Neuroscience Research, Sunnybrook and Women’s College Health Sciences Centre POLYSIALIC ACID REGULATES THE EFFECTS OF BRAIN-DERIVED NEUROTROPHIC FACTOR ON CHOLINERGIC NEURONS Polysialic acid (PSA) is a carbohydrate linked to neural cell adhesion molecule (NCAM). Removal of PSA has been shown to increase the activity of choline acetyltransferase (ChAT; enzyme synthesizing acetylcholine) in sympathetic ganglion cells (Acheson and Rutishauser, J Cell Biol (1988)). Recently, PSA was suggested to present brain-derived neurotrophic factor (BDNF) to its receptor tyrosine kinase (TrkB) in a manner which potentiates BDNF’s biological actions (Vutskits et al., Eur. J. Neurosci. (2001) ; Muller et al., Proc. Natl Acad. Sci. USA (2000)). ChAT activity is increased by NGF and BDNF in neurons of the septal nuclei. The objective of this study is to evaluate the influence of PSA on ChAT activity in embryonic septal neurons in vitro. Remarkably, the removal of PSA drastically increased ChAT activity, only in presence of BDNF, and without affecting the number of cholinergic neurons. ChAT activity induced by BDNF and PSA removal was abolished with K252a, a Trk receptor inhibitor, implying that TrkB signaling is involved. Binding assays indicated the number of [125I]BDNF receptor sites increased in the absence of PSA. Current experiments are assessing the phosphorylation states of TrkB receptors in each culture condition. Taken together, these results demonstrate a novel role for PSA in the regulation of ChAT activity by BDNF. PSA may prevent maximal TrkB activation by masking the receptor sites, changing receptor conformations or sequestering BDNF away from TrkB receptors. Relating to the in vivo situation, as cholinergic neurons mature, the normal loss of PSA may coincide with greater TrkB activation and increases in ChAT activity.

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13. Carmichael N*University of Toronto, Department of Physiology

., Charlton M.P. and Dostrovsky J.O.

EFFECT OF THE 5-HT1B/D AGONIST, SUMATRIPTAN, ON NEUROGENIC INFLAMMATION. The aim of this study was to determine if sumatriptan, which binds to peripheral 5-HT1B/D receptors can inhibit capsaicin-induced neurogenic inflammation (NI) in the rat paw. NI was assessed by measuring plasma extravasation (PEV) and changes in blood flow in the rat paw. A video camera and digital image analysis were used to measure changes in reflectance (pixel intensity, PI) of rat skin due to accumulation of extravasated EB dye and a laser Doppler flowmeter was used to measure changes in blood flow. Adult male SD rats were pre-treated with sumatriptan (20uL, 0.1uM, s.c.) in the dorso-medial region of one hind paw. The other paw was pre-treated with vehicle (20ul of 0.9% saline), which served as a control. Capsaicin (15uL, 1%) was injected into each paw 10 minutes following treatment with sumatriptan/vehicle. To confirm that sumatriptan’s effects were mediated by the 5-HT1B/D receptor, a subset of animals was pretreated with the selective 5-HT1B/D receptor antagonist, GR127935 (GR; 15uL, 1uM, s.c.), 10 minutes before receiving an injection of sumatriptan and 15 minutes prior to capsaicin injection. EB was injected i.v. 1 minute after capsaicin. The capsaicin-induced PEV was significantly reduced (ANOVA, Post-hoc Tukey, P < 0.05, n = 7) in paws pretreated with sumatriptan (38+/-0.9 SD PI) compared to control (79+/-1.6 SD PI). GR pretreatment significantly reduced the inhibitory effect of sumatriptan. In vehicle treated paws, capsaicin induced a significant increase (ANOVA, Post-hoc Tukey, P < 0.05, n = 9) in blood flow (80 +/- 18% of baseline), which was almost completely blocked by sumatriptan (7 +/- 3%). GR pretreatment completely blocked this sumatriptan effect. This study has revealed that sumatriptan reduces NI in the skin. Thus, in addition to inhibiting cerebrovascular NI we propose that 5-HT1B/D agonists also inhibit NI in other areas of the body by blocking the release of the inflammatory mediators substance P and calcitonin-gene related peptide. Supported by CIHR and Astra Zeneca. NC is a CIHR Strategic Training Fellow in Pain: Molecules to Community.

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14. Cheng Victor*

1Institute of Medical Science, Depts. 2Physiology, 3Pharmaceutical Sciences, and 4Anesthesia, University of Toronto, Toronto, ON, Canada; 5Dept. Anesthesia, Sunnybrook & Women’s College HSC, Toronto, ON, Canada

, MacDonald John2,3, and Orser Beverley1,2,4,5

GABAPENTIN INCREASES GABAERGIC TONIC INHIBITION IN HIPPOCAMPAL NEURONS Gabapentin (GBP) is used to treat epilepsy and neuropathic pain with relatively few side effects. Despite widespread clinical use, the molecular mechanisms of GBP remain poorly understood. The GABAA receptor (GABAAR) has been implicated in mediating the effects of GBP (Epilepsy Res 29:233); however, GBP does not directly bind to GABAARs (Eur. J. Pharmacol. 244:293). Here, we investigate the effect of GBP on a tonic form of GABAergic inhibition that we previously showed is generated by α5 subunit-containing GABAARs in hippocampal pyramidal neurons (PNAS USA 101:3662). We test the hypothesis that GBP increases the tonic inhibition and compare the effects of GBP to those of vigabatrin (VIG), a GABA transaminase inhibitor. Whole-cell currents were recorded from cultured murine hippocampal neurons (-60 mV) that were pre-treated with GBP, VIG or VIG + GBP for 24 hours. The amplitude of the tonic current was calculated as a reduction in the holding current during an application of the GABAAR antagonist, bicuculline (100 µM). GBP and VIG caused a concentration-dependent increase in the tonic current. Saturating concentrations of VIG (100 µM) and GBP (300 μM) increased the tonic current to 274% and 402% of control, respectively. In neurons pre-treated with a saturating concentration of both GBP (300 µM) and VIG (100 µM), the tonic current was increased to 910% of control. Thus, the tonic inhibition in hippocampal neurons is a novel target for GBP. Further, VIG and GBP act by different mechanisms to increase the tonic current suggesting that they may interact synergistically for the treatment of epilepsy and pain. Supported by the CIHR to J.F.M, B.A.O.; the Ontario Ministry of Health.

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15. Chin, Gordon D.1Dept. of Physiology, Faculty of Medicine, University of Toronto,

1*; Hutchison, William D.1,2

Toronto, Ontario, Canada, M5S 1A8 2Toronto Western Research Institute and Krembil Neuroscience Centre, The Toronto Western Hospital, 399 Bathurst St., Toronto, Ontario, Canada, M5T 2S8 INVESTIGATION OF THE MECHANISMS OF DEEP BRAIN STIMULATION: BICUCULLINE INJECTION AND MICROSTIMULATION IN THE PALLIDUM AND STN OF THE RAT Deep brain stimulation (DBS) is a proven surgical treatment for individuals with Parkinson’s disease. Chronic stimulation of the subthalamic nucleus (STN) and the internal segment of the globus pallidus (GPi) alleviate many of the symptoms associated with the disease. Several contrasting hypotheses regarding the mechanism of action of DBS have been proposed, including inhibition of neuronal firing via pre synaptic gamma-aminobutyric acid (GABA) release, and neuronal excitation of efferent output. To investigate these hypotheses, 14 neurons in the globus pallidum (GP) and 4 in the STN of anesthetized rats were stimulated and modulated by local microinjections (0.2 – 1 µl) of bicuculline (a GABAA receptor antagonist). Trains of high frequency of stimulation (HFS) were administered in the pallidum (~300 Hz, event interval 1-2s, pulse width 300µs, train duration 500 ms) either directly through the recording electrode or through an adjacent electrode. Paired-pulses were delivered in the STN through an adjacent electrode (event interval 10 ms, event delay 5 ms). HFS was performed prior to and following injections of bicuculline, resulting in two phases of inhibition. The early phase of post stimulus inhibition was attenuated but not absent following bicuculline, but the second phase of inhibition was not noticeably affected. These results suggest that GABAA receptors mediate HFS induced inhibition, but are not solely responsible. In 2 neurons, one in the GP and STN, stimulation induced excitation rather than inhibition. In summary, our results of in vivo single unit recordings suggest that DBS acts by inducing GABA mediated inhibition and efferent excitation.

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16. Chiu Alan W.L.Institute of Biomaterials and Biomedical Engineering, Department of Electrical and Computer Engineering, Department of Physiology, Toronto Western Research Institute, University of Toronto

, Kang Eunji E., Derchansky Miron, Carlen Peter L. and Bardakjian Berj L.

ONLINE PREDICTION OF SEIZURE ONSETS USING WAVELET ARTFICIAL NEURAL NETWORKS Wavelet artificial neural networks (WANNs) have been previously shown to be able to classify the different states of epileptiform activity and predict the onsets of seizure-like events (SLEs) in offline analysis [Chiu et al., 2005] of the electrical data from the in-vitro hippocampal slice model of recurrent spontaneous seizures. The WANN design entails the assumption that time-varying frequency information in the extracellular electrical field recordings from in-vitro rat hippocampal slices can be used to compute the times at which onsets of SLEs are most likely to occur in the future. Progressions of different frequency components are captured by the ANN, after the initial wavelet transforms in the appropriate frequency bands. The training of the WANN has been established using 102 SLE episodes in 14 slices from 14 rats [Chiu et al., 2005] offline. Non-preictal bursts (NPBs), or interictal bursts, in the duration of 500 seconds are included as part of the training to help distinguish between dynamical difference in bursting activities between the preictal-type and interictal-type. In this paper, we present the results of online application of the WANN in 20 in-vitro rat hippocampal slices from 7 rats having 82 SLE episodes and over 3000 seconds of NPBs. We demonstrated that the network is able to classify the different states of the system, namely, interictal, preictal and ictal activities with an accuracy of 86.6%, 72.6% and 84.5% respectively. Prediction of state transitions to the SLEs occurred up to 36.4 seconds ahead of their onsets with an error of 15.8 ± 48.0 seconds. [1] Chiu, A.W.L., Khosravani, H., Carlen, P.L. and Bardakjian, B.L., “Predicting the Seizure Onset in an In-Vitro Hippocampal Slice Model of Epilepsy Using Gaussian-based and Wavelet-based Artificial Neural Networks”, Annals of Biomedical Engineering, 2005 (in press for June publication).

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17. Chiu, Mary W.Y. Departments of *Physiology, ^Pharmaceutical Sciences, and †Anesthesia, *Institute of Medical Science, University of Toronto, Canada, M5S 1A8; #Department of Anesthesia, Sunnybrook & Women’s College Health Science Center, Toronto, Canada, M4N 3M5.

*, Robert P. Bonin*, John F. MacDonald*^ and Beverley A. Orser*†#

EVIDENCE FOR A NOVEL POPULATION OF TONICALLY CONDUCTING GABAA RECEPTORS IN THE HIPPOCAMPAL CA1 REGION Two forms of GABAergic inhibition coexist: fast synaptic neurotransmission and tonic activation of GABA receptors due to ambient GABA. Our lab previously demonstrated that tonic inhibition in mouse CA1 pyramidal neurons is predominantly mediated by α5 subunit-containing GABAARs (Caraiscos et al. 2004. PNAS; 101:3662). However, a tonic conductance can also be detected in neurons from α5 knockout (KO) mice, albeit reduced in amplitude. This implies either compensatory upregulation of other GABAAR subunits known to mediate tonic conductance, such as the δ subunit, or that a heterogeneous population of GABAAR is responsible for tonic conductance in these cells. In the present experiment, we combined biochemical and electrophysiological analyses of the δ subunits in KO and wildtype (WT) hippocampal tissue to determine if the level of δ subunit is altered in the absence of the α5 subunit. At low concentrations, the directly acting agonist 4,5,6,7-tetrahydroisoxazolo[5,4-c] pyridin-3-ol (THIP) displays functional selectivity for extrasynaptic δ containing GABAARs (Brown et al. 2002; Br J Pharmacol; 136: 965). Potentiation of tonic inhibition by 0.1-10 mM THIP was similar in hippocampal CA1 neurons from α5 subunit KO and WT mice, suggesting no upregulation of δ-containing GABAARs in the α5 KO mice. Western blot analysis confirmed that α5 subunit deletion does not lead to a concomitant upregulation in hippocampal δ subunit levels. Thus, the residual tonic current in hippocampal CA1 pyramidal neurons from α5 KO mice is likely mediated by non-δ, non-α5 subunit-containing GABAARs not yet associated with tonic inhibitory conductance.

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18. Christie, Lori-AnnCotman, Carl W.4; MacKay, William A.1; Milgram, Norton W.5

1*; Saunders, Richard C.2; Kowalska, Danuta M.3†; Head, Elizabeth4;

1. Institute of Medical Science, University of Toronto, Toronto, ON, Canada . 2. Laboratory of Neuropsychology, National Institute of Mental Health / National Institute of Health, Bethesda, MD, USA 3. Department of Neurophysiology, Nencki Institute of Experimental Biology, Warsaw, Poland 4. Institute for Brain Aging and Dementia, University of California, Irvine, CA, USA. 5. Life Sciences Division, University of Toronto at Scarborough, Scarborough, ON, Canada . † - deceased RHINAL CORTEX LESIONS DISRUPT OBJECT RECOGNITION WHILE SPARING VISUOSPATIAL MEMORY IN DOGS. To assess the role of the rhinal cortex in object recognition and visuospatial memory, beagle dogs were trained using a unique protocol involving daily testing on both a delayed non-matching to sample (DNMS) task and a complex delayed non-matching to position (DNMP) task. Once the tasks were acquired at a short, 5-second delay, dogs were tested at progressively increasing delays to obtain estimates of maximal working memory. After completing the baseline protocol, bilateral rhinal cortex lesions were made by aspiration (N = 4). Another N = 4 animals served as unoperated controls. Two weeks following surgery, the dogs were re-tested on the same protocol. Rhinal cortex lesions severely disrupted retention of the object recognition task. One animal was unable to relearn the task, two could not perform accurately at delays longer than 5 seconds, and one was successful only up to the 10-second delay. Control animals showed robust retention of the DNMS task at the 5-second delay, and obtained maximal memory scores ranging from 20 to 70 seconds. By contrast, rhinal cortex lesions did not affect retention of the DNMP task at short or long delays, establishing a dissociation in the role of the rhinal cortex in object recognition and visuospatial function in the dog. Impaired retention of the DNMS task at short delays suggests that the canine rhinal cortex mediates high-level perceptual representation or encoding of object information. Supported by: National Institute on Aging AG12694

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19. Chu, Gordon K. T.,Division of Neurosurgery, Department of Surgery, Toronto Western Research Institute, Krembil Neuroscience Center

* Michael G. Fehlings

INHIBITION OF THE P75 NEUTROPHIN RECEPTOR DOES NOT PROTECT AGAINST CELL DEATH AT THE INJURY SITE AND WORSENS FUNCTIONAL OUTCOME AFTER A CLINICALLY RELEVANT COMPRESSION MODEL OF SPINAL CORD INJURY Biomedical Science Introduction: Apoptotic cell death plays an important role in spinal cord injury (SCI). Recent studies show that deletion of the p75 neurotrophin receptor may protect against apoptosis after a partial transection SCI. However, transection injuries are not common in humans compared to compression injuries. Therefore, we tested if p75 inhibition is neuroprotective after a clinically relevant compressive SCI. Methods: SCI was induced in p75 knockout and wild type mice using a clip (Fejota) calibrated to a closing force of 8.4g. The cord was compressed at the T6 level for one minute. Three and seven days after injury, the cord was extracted for immunoblotting of caspase-9, and caspase-3. Animals were sacrificed at 7 days for TUNEL counts at the injury site. For functional recovery, the animals were assessed with a modified Basso, Beattie, and Breshnahan (BBB) locomotor rating scale. Results: The knockout mice had decreased levels of cleaved caspase-9. However, at seven days, there was no difference in the levels of cleaved caspase-3 between either group. In contrast, the wild types had a greater BBB scores (8.75) than the knockouts (6.42) at 8 weeks. Similarly, the wild types had a decreased number of TUNEL positive cells compared to knockouts (12.1 ± 5.8 vs 36.8 ± 10.3) Conclusions: Surprisingly, our results indicate that inhibition of the p75 receptor is not neuroprotective after a compressive SCI. In fact, it is detrimental to recovery as indicated by the BBB scores. It is possible that alternate cell death pathways (Fas) may take precedence if p75 is inhibited or perhaps the prosurvival aspects of p75 are more important than the proapoptotic aspects after SCI. In conclusion, it appears that the role of the p75 receptor after SCI may be multi-faceted and cell death or survival may depend on the type of injury sustained.

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20. Chung, Ji-Yeon Jenni 1*

1Dept. of Physiology, University of Toronto; 2Division of Cellular and Molecular Biology, Toronto Western Research Institute, University Health Network; 3Division of Neurology, Dept of Medicine, University of Toronto

, Charles D. Kassardjian2, Yao-Fang Tan2, Raquel Heskin1, Michael J. Peterson1 and Dianne M. Broussard1,2,3

THE ROLE OF THE CEREBELLAR CORTEX IN MOTOR MEMORY The vestibulo-ocular reflex (VOR), which stabilizes gaze so that we can move and see simultaneously, is widely used as a model system to investigate the site of motor learning. Although it is well established that the cerebellar cortex (specifically the flocculus) is necessary for motor learning in the VOR, it is not known whether it is the site of storage of the motor memory. Our hypothesis is that memory for short periods of motor learning is stored in the cerebellar cortex, but after a longer period, the memory becomes distributed among sites in the cerebellar cortex and vestibular nuclei as a process of consolidation. In order to test this hypothesis, we blocked excitatory synaptic input to the flocculus bilaterally after learning was induced in cats. In short-term motor learning, cats were passively rotated for one hour while wearing miniaturizing spectacles. For long-term learning, cats wore the spectacles continuously for 3 days, and passive rotation was applied for one hour daily. Immediately after motor learning, bilateral injections of CNQX, a glutamate antagonist, were made into the flocculus or/and ventral paraflocculus. The VOR gain changes in the short term were completely abolished by bilateral floccular inactivation. However, bilateral CNQX injections after a longer period of motor learning had a smaller effect on the adapted gain. These results suggested that short-term VOR gain changes take place in the cerebellar cortex, but that consolidated motor memory is stored in a distributed fashion.

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21. DaSilva, K.A.Program in Neuroscience

* and McLaurin, J.

Department of Laboratory Medicine and Pathobiology, University of Toronto Centre for Research in Neurodegenerative Diseases CYTOKINE-IN-ADJUVANT STEERING OF THE IMMUNE RESPONSE TO ALZHEIMER’S IMMUNOTHERAPY Alzheimer’s disease (AD) is a neurodegenerative disease characterized by the formation of senile plaques composed of amyloid-beta (Abeta) peptide. Recent studies with transgenic models of AD have demonstrated that vaccination with Abeta not only reduces Abeta deposition but also protects these mice from memory deficits and cognitive decline seen in control mice. However, Phase IIa clinical trials were halted when a number of patients presented with symptoms consistent with meningoencephalitis. Follow-up studies showed that an effective immune response was generated, which resulted in clearance of Abeta deposits and slower rates of cognitive decline in immunized patients over unimmunized controls. However, neuropathological analysis revealed extensive infiltration of T-lymphocytes. Several investigators have suggested that the adjuvant QS-21 may have promoted a cytotoxic inflammatory response (Th1). In designing a vaccine for AD, it is essential that a potent humoral response (Th2) be generated. This can be accomplished by administering cytokines in conjunction with the vaccine, thereby activating specific subsets of T-cells, shifting the Th1/Th2 balance in favour of the humoral response. Two of the most studied cytokines, granulocyte macrophage-colony stimulating factor (GM-CSF) and interleukin-4 (IL-4), have been shown to direct the immune response towards a Th2 phenotype, while increasing the number of dendritic cells and influencing their activation state. IL-4 has also been shown to reverse Th1 autoimmune disease by diverting the immune response towards a Th2 phenotype. Thus, I propose that co-administration of the cytokines GM-CSF and IL-4 will be sufficient to mount an immune response to Abeta, devoid of the inflammatory response observed in human clinical trials. Antibody titres were found to increase in all groups examined with each subsequent boost, with the highest titres observed in the Abeta/GM-CSF/IL-4 treated group. Sera from Abeta-immunized mice stained plaques in brain sections from transgenic mice. These antibodies decreased amyloid burden in transgenic mice by as much as 38% (in Abeta/GM-CSF/IL-4 and Abeta/IL-4 immunized mice), which is equivalent to reductions seen in studies employing Complete Freund’s adjuvant. Plaque load was reduced by 18% in mice immunized with Abeta/GM-CSF. There also appears to be a reduction in plaque-associated microgliosis with cytokine treatment. T-cells from all immunized mice exhibited proliferative responses to their respective antigens, with the highest stimulation index seen in Abeta/GM-CSF/IL-4 immunized mice. T-cells from Abeta/GM-CSF/IL-4 immunized mice were also found to secrete increased amounts of IL-4 over IFN-gamma, suggesting a Th2-biased immune response. Thus, GM-CSF and IL-4 appear to be effective adjuvants for AD immunotherapy.

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22. Dason Jeffrey SDepartment of Physiology, University of Toronto

*, Charlton Milton P, Atwood Harold L

EFFECTS OF ALTERED FREQUENIN EXPRESSION ON SYNAPTIC TRANSMISSION Frequenin (Frq) and its mammalian homologue, neuronal calcium sensor 1 (NCS-1), are calcium-binding proteins, which are reported to enhance neurotransmitter release. Since NCS-1 and Frq are highly conserved, the Drosophila nervous system can be used to gain a better understanding of Frq's effects. Most studies of the Drosophila larval neuromuscular junction focus on the nerve terminals innervating the ventral longitudinal muscles 6 and 7, which are innervated by two axons: axon 1 which generates type 1b boutons, and axon 2 which generates 1s boutons. In Drosophila, Frq can be over- or under-expressed in response to genetic intervention. Recently, a second Frq gene (Frq 2) was found in Drosophila. The purpose of this study was to define the physiological consequences of genetic alteration of Frq 1 and Frq 2 expression. We found, using whole-cell recordings, that nerve-evoked excitatory junction potentials recorded from Frq 1 and Frq 2 overexpressers were significantly larger than those recorded from wild-type and Frq underexpressers. Surprisingly, we also found a significant reduction in the number of synaptic boutons of Frq 1 and Frq 2 overexpressers compared to wild type and Frq underexpressers. This reduction was specific for type 1s boutons. Extracellular recordings were done to assess synaptic transmission from individual boutons and determine if Frq’s effects were specific to 1s or 1b boutons. Overexpression of Frq 1 or Frq 2 caused an almost 2- fold increase in quanta released by single 1b boutons and an approximately 1.4-fold increase in quanta released by a single 1s bouton. Therefore, it appears that Frq overexpressers have enhanced transmitter release, despite having fewer boutons, because they have more release of transmitter per bouton than controls, whereas underexpressers may have less. We also found that at low external calcium concentrations, overexpression of Frq enhances paired-pulse facilitation, whereas underexpression of Frq reduces it.

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23. Farb, Norman*,University of Toronto, Toronto, Ontario, Canada

William Cunningham & Adam K. Anderson

PHYSIOLOGICAL RESPONSE TO POSITIVE AND NEGATIVE EVENTS IS MODERATED BY REGULATORY FOCUS Traditional hedonic models of emotion associate any emotional experience with an increase in physiological arousal, a prediction which seems at odds with homeostatic self-regulatory models, which predict that individuals will seek to avoid high levels of arousal regardless of the type of valence accompanying such arousal. One avenue for resolving the conflict between these models may lie in the regulatory focus model of motivation, which suggests that people tend to focus alternatively on maximizing goal rewards (promotion orientation) or minimizing threats to these goals (prevention orientation), with differing values of arousal between the two orientations. Regulatory focus may therefore act as a moderating factor in determining the optimal peripheral nervous system response to evoked affective states. The present study evaluated the effects of state regulatory focus on physiological arousal in response to positive and negative feedback. State regulatory focus was experimentally manipulated through a behavioural task that consisted of either potential gains/non-gains (promotion condition) or losses/non-losses (prevention condition). Participant affect was then manipulated through a fixed feedback categorization task that alternately provided positive and negative feedback so that physiological arousal could be monitored under positive and negative affective states. To measure physiological arousal skin conductance, cardiac output, and vascular constriction were recorded throughout the categorization task. An interaction between regulatory focus and arousal to specific goal relevant stimuli supported our hypothesis that goal achievement style is associated with changes within a peripheral nervous system control system, and that flexibility in goal orientation may be an important component in maintaining homeostasis.

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24. Gelinas DavidLaboratory Medicine and Pathobiology, University of Toronto

*, JoAnne McLaurin

ROLE OF THE PPAR SYSTEM IN NEUROINFLAMMATION Ciglitazone, rosiglitazone and pioglitazone belong to a relatively new class of antidiabetic agents referred to as thiazolidinediones (TZDs). Later, TZDs were found to be peroxisome proliferator-activated receptor (PPAR)-g agonists and to elicit anti-inflammatory effects in both in vitro and in vivo models in response to stimuli such as lipopolysaccharide (LPS) and phorbol 12-myristate 13-acetate (PMA). In the present study we sought to investigate the effects of oral administration of ciglitazone on basal inflammatory cytokine expression in healthy adult rats. The analysis of cytokine expression in the spleen revealed a reduction in IL-4 production after ciglitazone treatment. In contrast, in the brain, ciglitazone administration increased IL-1b synthesis at the protein and mRNA level, while TNF-a protein expression was also increased. To ensure that the latter findings were not an indirect effect originating from the periphery, we delivered ciglitazone intracerebrally for a 7-day period using an osmotic pump, which confirmed the increase in IL-1b and TNF-a expression. Our results show that despite anti-inflammatory effects described for ciglitazone in "primed" models, ciglitazone can positively modulate basal inflammatory mediators within the central nervous system (CNS) of healthy adult rodents.

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25. Glaholt, M. GRotman Research Institute, Baycrest Center, University of Toronto, Ontario, Canada.

.*, Itier, R. J., McIntosh, A. R.

EVENT-RELATED POTENTIALS REFLECTING RESPONSE COMPATIBILITY AND RULE SWITCHING IN A CUED REACTION TIME TASK. The relationship between response compatibility and response rule switching was examined in a cued reaction time task. In each trial of this paradigm a tone preceded a lateralized visual target. In 'mixed' blocks of trials, participants were cued to respond on the same (compatible) or different (incompatible) side as the visual target depending on the pitch of the preceding tone. In 'pure' blocks the response rule remained constant on each trial. Brain activity was measured using a 64-electrode EEG array, allowing us to ask whether the factors of response compatibility and response rule switching engaged the same neural processes. Event-related potential (ERP) analysis exposed large differences between the mixed and pure conditions. This difference appeared as a slow sustained potential between the auditory cue and visual target, at frontal and parietal electrodes. To better understand the contributions of rule switching and response compatibility to this difference, we divided the mixed block into trials where the rule had switched since the previous trial, and trials where the rule had repeated. A Partial Least Squares analysis allowed us to quantitatively compare the pure, repeat and switch ERPs, for compatible and incompatible trials. This analysis identified a pattern of scalp potentials that matched the spatial and temporal appearance of the original pure/mixed difference. This pattern was sensitive to both response compatibility and rule sequence. It was most expressed in the high demand cases where the rule had switched from the compatible rule to the incompatible rule, and least expressed in the low demand cases where the compatible response rule was constant for the whole block. In this paradigm, response demands incurred by rule switching and response compatibility appear to contribute to the same variations in EEG signal. (Supported by NSERC & CIHR grants to A.R.M.)

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26. Gonzalez, Andrea*1 Department of Psychology, University of Toronto. 2 Department of Psychiatry & Behavioural Neurosciences, McMaster University. 3 Women’s Health Concerns Clinic & Father O’Suillvan Research Centre, St. Joseph’s Healthcare, Hamilton, ON.

1, Dawn Zinga1, Marg Coote, Meir Steiner2 3, Alison S. Fleming1.

POSTPARTUM DEPRESSION IS RELATED TO SALIVARY CORTISOL, MATERNAL RESPONSIVENESS, AND EARLY CHILDHOOD FAMILY INSTABILITY

Depression or dysphoria among new mothers can have profound effects on both the new

mother and infant. While interacting with their new babies depressed mothers are known to show reduced contingent responding or ‘sensitivity’ to their infants. The present project was designed to determine whether depression postpartum is also related to alternations in mother’s hormonal , autonomic, and hedonic responses to recorded infant cues (especially cries) and the relationship of these outcome measures to the mother’s earlier childhood experiences.

Preliminary results indicate that the more depressed mothers exhibited significantly higher levels of salivary cortisol, were more annoyed and irritated by an infant pain cry and felt less positively towards interacting with infants or children. As well, the more depressed mothers experienced greater instability in their family of origin (more changes in family composition) and expressed more negative attitudes towards their own parents. We speculate that one mechanism through which early experience being cared for may affect later maternal responsiveness is through alterations in mothers’ affective state.

Supported by CIHR grant to A.S.Fleming

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27. Harrison, Angela S.1Cellular and Molecular Pathophysiology, Centre for Addiction and Mental Health, 2Psychiatry, University of Toronto, 3Institute of Medical Science, University of Toronto, 4Pharmacology, University of Toronto

1,4*, Li, Peter P.1,2,4, Warsh, Jerry J.1,2,3,4

ALTERED AGONIST-STIMULATED TRANSIENT RECEPTOR POTENTIAL CHANNEL RESPONSES SUGGESTS DYSFUNCTION [A1]IN BIPOLAR DISORDER Altered 1-oleoyl-lysophosphatidic acid (LPA, 100 μM)-stimulated calcium responses occur in B-lymphoblast cell lines (BLCLs) from bipolar disorder (BD) patients, but the mechanism(s) involved is uncertain. BLCLs were used in this study as a surrogate, non-excitable cell model that may "report" cellular disturbances, related to those causing glial cell changes, implicated in the pathophysiology of BD. LPA shares a structurally similar fatty acid side chain with the cell permeable diacylglycerol analogue, 1-oleoyl-2-acetyl-sn-glycerol (OAG), which is a known agonist of subtypes 3, 6 and 7 of the canonical transient receptor potential (TRPC) cation channel subfamily. Accordingly, the objective of this study was to characterize the involvement of this TRPC channel subfamily in the LPA-stimulated calcium response of BLCLs. Bivalent cation (barium versus calcium) selectivity of thapsigargin (200 nM), LPA (100 μM), OAG (100 μM) and the phospholipase C (PLC) activator, m-3M3FBS (50-100 μM) was used to distinguish the TRPC-like character of the calcium responses to these agents in BLCLs. Gadolinium (5-150 μM) sensitivity was used to determine the store-operated versus non-store-operated nature of the responses. The PLC inhibitor, U73122, demonstrated the PLC dependence of agonist responses. Western immunoblotting and PCR techniques were used to identify the TRPC isoforms present in BLCLs. Minimal barium influx in calcium free media was observed following thapsigargin stimulation, a classical activator of store-operated calcium entry. However, significant barium influx occurred in response to OAG and LPA. m-3M3FBS did not affect barium influx. Thapsigargin-provoked calcium influx was completely inhibited by gadolinium (15 μM), whereas the LPA-stimulated response was minimally inhibited. Furthermore, the OAG-activated calcium response was potentiated when pre-treated with gadolinium (≤100 μM). This profile of responses is consistent with the finding of TRPC1, 3 and 5 expression in these BLCLs. The results suggest that 100 μM LPA stimulates calcium entry through channels with characteristics similar to the TRPC3 subfamily in BLCLs. Thus, findings of enhanced LPA-stimulated calcium responses from BD compared with healthy subjects may implicate dysfunction of TRPC3-like calcium entry in the pathophysiology of BD.

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28. Hong, Hyunwook.

, Li, Yan Mei., Duffin, James., and Peever, John. Laboratory for Sleep Research, Departments of Zoology and Physiology, University of Toronto, Toronto, Canada. EPISODIC HYPOXIA INDUCES LONG-TERM FACILITATION OF RESPIRATORY MOTOR OUTPUT IN IMMATURE RATS.

Neuroplasticity allows the brain to adapt. The neural network that generates breathing exhibits considerable functional plasticity, one form of which is long-term facilitation – a persistent, long-lasting (>1 hour) increase in respiratory motor output resulting from episodic, but not continuous hypoxia. While long-term facilitation has been characterized in intact, adult animals, it has not been well demonstrated in the immature respiratory system. The aim of this study was to determine if episodic hypoxia evokes long-term facilitation of respiratory motor output in immature rats (11-30 days old). To do this, we exposed the endogenously active respiratory network contained in the in-situ, perfused working-heart brainstem preparation to either episodic or continuous hypoxia. Phrenic nerve activity served as an index of respiratory motor output and was recorded before, during and for 60 min after both episodic and continuous hypoxic exposure. After exposure to episodic hypoxia (three 5-min periods of 10% 02 / 5% CO2 separated by 5-min periods of 95% O2 / 5% CO2) respiratory frequency transiently returned to baseline, and over the next 60 min progressively increased to 226% above baseline values (n = 6; P=0.01). However, exposure to continuous hypoxia (15-min period of 10% O2 / 5% CO2) had no such effect (n = 4; P=0.87). We conclude that exposure to episodic hypoxia induces long-term facilitation of the endogenously active respiratory network in-situ. We suggest that this form of plasticity is an adaptive respiratory behaviour that may occur in disease states involving intermittent exposures to hypoxia, such as, obstructive sleep apnea. Supported by: Parker B. Francis Family Foundation, CFI, OIT, CIHR.

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29. Joshi, MeenalCAMH and University of Toronto

, Ph.D.; Miksys Sharon, Ph.D.; and Tyndale Rachel, Ph.D.

CYTOCHROME CYP2E1 IN MONKEY BRAIN: CONSTITUTVE EXPRESSION AND INDUCTION BY CHRONIC NICOTINE We found that CYP2E1 increases after chronic nicotine treatment in monkey brain in a region- and cell-specific manner. CYP2E1 can metabolically inactivate drugs (ethanol, acetaminophen) and bioactivate procarcinogenic tobacco-specific nitrosamines and neurotoxins; it can also metabolize endogenous substrates (arachidonic acid). Nicotine, obtained while smoking, is also used to treat smoking and neurological diseases such as Alzheimer’s disease. We have shown that CYP2E1 is increased by nicotine in rat brain and is higher in smoker’s brains. CYP2E1 expression patterns differ between rat and human brain probably due to species (rat vs. human) and/or inducer (cigarette smoke vs. nicotine) differences. Therefore we developed a model whereby African green monkeys were treated for 22 days bid s.c. with saline or nicotine (0.3 mg/kg). In saline treated monkeys, the immunostaining patterns were more similar to human non-alcoholic non-smokers than to rat (e.g. the cerebellar Purkinje cells and frontal cortex pyramidal neurons were stained strongly). Staining was also seen in CA1, CA2 regions of hippocampus, substantia nigra, subthalamic nuclei and caudate. Brain CYP2E1 increased after chronic nicotine in a region- and cell-specific manner (e.g. cerebellar Purkinje cells, CA3 region of hippocampus, subthalamic nuclei and substantia nigra). Immunoblotting showed increased CYP2E1 (p<0.05) in cerebellum (1.4-fold) and frontal cortex (1.5-fold) but no overall change in hippocampus. In monkey brain, basal expression of CYP2E1 and the increases in immunoreactivity after nicotine treatment appear more like human than rat brain. This indicates that species differences likely contribute to the variation between rat and human data. Supported by CIHR-MT14173; CSCP (MJ) and CR Chair (RFT)

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30. Kadis, D.S.

TITLE: INTRAHEMISPHERIC REORGANIZATION OF LANGUAGE IN EARLY ONSET EPILEPSY

, MA * 1, 2, ML Smith, PhD 1, 2, 3, A Crawley, PhD 2, I Elliott, MSc 2, 3, K Iida, MD 3, E Kerr, PhD 1, W Logan, MD 2, 3, MP McAndrews, PhD 2, 5, A Ochi, MD 3, H Otsubo, MD 3, J Rutka, MD 2, 4, OC Snead, MD 2, 3 and S Weiss, MD 2, 3. 1 Psychology, Hospital for Sick Children, Toronto, ON, Canada, M5G 1X8; 2 University of Toronto; 3 Neurology, Hospital for Sick Children; 4 Neurosurgery, Hospital for Sick Children; and 5 Applied and Interventional Research, Toronto Western Hospital.

RATIONALE: Study of individuals with epilepsy suggests a period of increased functional plasticity of language within the first few years of life, in that those with early seizure onset demonstrate increased right- and bilateral language representation. Historically, research has focused on interhemispheric shifts in language representation, without systematically assessing intrahemispheric effects. In this study, we developed a novel 2D-to-3D coregistration technique to assess findings from invasive language mappings. This study is the first to investigate the extent of intrahemispheric reorganization in the context of paediatric epilepsy. METHODS: Eight children, aged 5.7-17.8 years underwent extraoperative stimulation mapping (ESM) to localize language within the left hemisphere. All had left-hemisphere seizure foci with onset before 6 years. ESM permitted direct cortical stimulation and precise determination of language areas using subdural grids. Capture of digital images at the time of implant facilitated development of detailed functional maps, sensitive to each patient’s unique cortical morphology. ESM data were co-registered with 3D brain representations compiled from thin-slice MRIs, spatially normalized, and assessed in standard stereotactic space. Language sites were compared to structural probability maps of the frontal operculum, or Broca’s area. RESULTS: Language areas were observed both within and outside of canonical language regions (Broca’s area and Wernicke’s area). In the frontal lobe, language sites were observed in regions substantially anterior and superior to classical Broca’s area, to an extent not previously described. Language sites were observed inside, bordering, and outside of epileptogenic regions. CONCLUSION: In addition to interhemispheric shifts in language, individuals with early onset epilepsy experience intrahemispheric reorganization of language. Neurosurgical teams must consider the potential for language representation anterior to Broca’s area; abnormal cortex may support language. Extensive functional mapping within and beyond canonical language areas is necessary for comprehensive characterization of the language cortex prior to resective surgery.

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31. Kanisek Marijana.1Collaborative Progam in Neuroscience, 2Department of Physiology, 3Samuel Lunenfeld

*1,2,3, Ng, David 4,5, McInnes, R. Roderic4,5, Roder, C. John 1,4

Research Institute, Mount Sinai Hospital, Toronto, Canada, 4Department of Molecular and Medical Genetics, 5The Research Institute, Hospital for Sick Children, Toronto, Canada ROLE OF NETO 1 IN NMDA RECEPTOR DEPENDENT LEARNING AND MEMORY Neto 1 is a novel neuronal transmembrane protein, discovered by in silico screening of a human retinal cDNA library for known protein motifs, including the CUB domain. Expression of Neto 1 begins as early as embryonic day 12.5 (E12.5) and is maintained into adulthood. Neto 1 expression is neural-specific; however, it is most prominent in hippocampal CA3 pyramidal cells. Neto 1 has an identical C-terminal TRV binding ligand to that found in the synaptic proteins neuroligin and SynGap that bind to the third PDZ domain of post-synaptic density protein of 95 kDa (PSD-95). PSD-95 is a major postsynaptic scaffolding protein that mediates binding of receptor proteins like the NMDA receptor, to intracellular signaling molecules and cytoskeletal proteins. NMDA receptors are of considerable interest because their disruption in the hippocampus impairs long-term potentiation (LTP), and hippocampus dependent spatial learning and memory.

Initial findings have shown that Neto 1, like neuroligin, interacts with PSD-95 at the third PDZ domain. More importantly Neto 1 was also found to bind directly to the NR2 subunit of the NMDA receptor and indirectly through the scaffold protein PSD-95. The dual binding of Neto 1 to the NMDA receptors and recent findings that Neto 1-/- mice are impaired in maintaining LTP (Late-LTP) at the Schaffer collateral-CA1 pathway lead us to investigate hippocampus dependent spatial learning and memory using the Morris water maze (MWM) test. We hypothesized that Neto 1 knockouts may have impaired spatial learning and memory. Neto1 mice were trained in a series of MWM tests, including acquisition of a hidden platform location and subsequent reversal learning and memory and Delayed Matching-to-Place (DMP) tests. There was no difference in acquisition when the platform was hidden from view, or in the number of crossings over the former platform location in a probe trial. These results demonstrate that the absence of Neto1 does not impair spatial reference memory. However, in a test of reversal learning, with the platform relocated to the opposite quadrant a prominent deficit in Neto 1-/- mice was observed. This would suggest that Neto 1-/- mice have difficulty in flexible use of the spatial map. This deficit in reversal learning was further demonstrated during DMP (switching of the hidden platform location daily) tests in which Neto 1-/- mice were unable to selectively retrieve the most recent platform location against the interference of the long-term memories encoded by previous locations. Consistent with the earlier findings that Neto1-/- mice cannot maintain long-term potentiation and present findings that show Neto 1-/- mice are impaired in the MWM test when faced with platform “reversals”, would suggest that Neto 1 has an important role in rapid hippocampal encoding of novel information.

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32. Kim, A.Rotman Research Institute, Baycrest Centre for Geriatric Care WORKING MEMORY OF AUDITORY STIMULI

, He, Y., Alain, C., Grady, C.

In order to ascertain whether working memory utilizes two segregated, specialized pathways to process spatial and non-spatial auditory stimuli, functional magnetic resonance imaging (fMRI) and three categories of auditory stimuli were used to study working memory for sound location and sound category in seven young adults (21 - 32 years old). The auditory stimuli consisted of sounds produced by humans, animals and musical instruments, which were presented in random order at three equiprobable locations (90◦ left of center, center, or 90◦ right of center). The subjects performed a one-back task in which they responded to repetitions of sound category or sound location. There was no difference in accuracy between responses for the sound location and sound category tasks: the percentage of hits, false alarms and misses for the sound location task was 87%, 10% and 3%, respectively, and for the location task, 81%, 12% and 7%, respectively. Similarly, the reaction times for the sound location judgments (912 + 250 ms) and the sound category judgments (959 + 208 ms) did not significantly differ. The fMRI results for this study are pending. However, greater activation is expected in the ventral brain region for the sound category task and greater activation in the dorsal brain region for the sound location task. Moreover, activation in the dorsolateral prefrontal cortex is expected to be found across both sound tasks. The findings of this study will provide substantive evidence to either support or counter the two domain-specific, spatial and nonspatial, processing streams that have been proposed for the organization of the auditory system and will thereby lay firm grounds upon which future related studies can be conducted.

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33. Kong, M.M.C. 1Departments of Pharmacology and 2Medicine, University of Toronto; 3Centre for Addiction and Mental Health, Toronto, Ontario, Canada

1*, G.Varghese1,3, T.Fan1,3 B.F. O’Dowd1,3, S.R. George1,2,3

AGONIST-SPECIFIC RESCUE OF AN INTRACELLULARLY SEQUESTERED D1 DOPAMINE RECEPTOR OLIGOMER TO THE CELL SURFACE The objective of this study was to determine how oligomerization modulates the trafficking of the wild-type D1 dopamine receptor. We mutated the conserved aspartic acid in transmembrane domain 3 of the D1 receptor (D103A). Although this receptor was unable to bind ligand, it was present at the cell surface as oligomers and exhibited higher basal cAMP levels than wild-type receptor (WT). Co-expression of D103A with WT reduced WT cell surface expression as detected by radioligand binding and cell surface fluorometry. Co-immunoprecipitation of D103A with WT from cell lysates suggested that the two receptors interacted and that the oligomeric complex was not trafficked. To determine if the dominant negative effect of D103A was due to its conformation consistent with an activated receptor state, we incubated cells co-expressing D103A and WT with cell permeable agonists to determine whether a conformational shift of the WT could be achieved. This resulted in cell surface rescue of the WT, suggesting that the agonist-induced change in conformation of the WT permitted cell surface trafficking of the D103A/WT receptor oligomeric complex from an intracellular compartment. The cell surface rescue of the oligomeric complex was confirmed by FRET studies in which cell surface energy transfer between D103A and WT was increased with prolonged agonist treatment. No energy transfer was observed when both receptors were co-expressed suggesting the D103A/WT oligomer was not present at the plasma membrane in the absence of ligand. Therefore, we propose a model in which the oligomeric configuration of the D1 receptor is under cellular quality control and that an oligomer can be pharmacologically induced to assume the preferred “homogenous” conformation that allows cell surface trafficking. This study was supported by grants from the Canadian Institutes of Health Research and the National Institute on Drug Abuse to B.F.O and S.R.G

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34. Krpan, Katherine M.,1, 3*and Dawson, Deirdre R. 1, 4, 5

, Levine, Brian, 2, 3, 6, Stuss, Donald T., 2, 3, 5, 6,

1 Kunin-Lunenfeld Applied Research Unit, Baycrest Centre for Geriatric Care

2 The Rotman Research Institute, Baycrest Centre for Geriatric Care

3 Department of Psychology, 4 Department of Occupational Therapy, 5 Graduate Department of Rehabilitation Science, and 6 Department of Medicine (Neurology), University of Toronto EXECUTIVE FUNCTION AND COPING AT ONE-YEAR-POST TRAUMATIC BRAIN INJURY

Persons with traumatic brain injury (TBI) often have poor outcome. Poor outcome has been related to a number of factors, including executive dysfunction and the use of maladaptive coping behaviours. To date, the relationship between these two factors has not been investigated in a TBI sample. The purpose of this study was to examine the relationship between executive dysfunction and coping at one-year post TBI. TBI and matched sociodemographic control groups completed the Ways of Coping Questionnaire- Revised, and were administered a set of neuropsychological tests, with an emphasis on executive functions. Within the TBI group, high executive performance was related to the use of problem focused coping (considered more adaptive), and decreased executive performance was related to the use of emotion focused coping (considered more maladaptive). These relationships were not found in the control group. Hierarchical regression showed that executive function contributed significantly to the use of both problem and emotion focused coping behaviours above and beyond pre-morbid intelligence and injury severity. These results suggest a link between executive function and coping following TBI, which may have implications for rehabilitation.

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35. Labrie Viviane1Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Canada; 2Institute of Medical Science and Collaborative Program in Neuroscience, University of Toronto, Canada

*12, Duffy Steve1, Roder John12

REGULATION OF HIPPOCAMPAL LONG-TERM POTENTIATION AND HIPPOCAMPUS-DEPENDANT SPATIAL LEARNING BY D-SERINE AND GLYCINE The NR1 subunit of the NMDA receptor contains a high affinity glycine-binding site at which either glycine or D-serine can act as an obligatory co-agonist. We examined the unique roles of D-serine and glycine in modulating NMDA-dependent hippocampal long-term potentiation (LTP) and hippocampus-dependent spatial learning. In hippocampal slices from adult C57BL/6J mice a high concentration of exogenous D-serine (100µM) did not alter LTP, suggesting that synaptic D-serine is saturating during LTP induction. The Grin1D481N mutation confers a 4-5 fold lower glycine affinity, and Grin1D481N/ D481N mice demonstrated a deficiency in LTP that was rescued by exogenous D-serine, but not by the GLYT-1 blocker ALX-5407. Pre-injection of D-serine did not alter spatial learning in wild-type mice (Grin1+/+) as measured by the Morris water maze memory task. D-serine did rescue spatial learning in Grin1D481N/ D481N mice, while ALX-5407 was without effect. Spatial learning was correlated with hippocampal LTP under all conditions. We propose that exogenous D-serine did not alter hippocampus-dependent learning in Grin+/+ mice because the NR1 glycine site was saturated by D-serine and so NMDA-dependent plasticity was unaffected. In constrast, exogenous D-serine rescued poor spatial learning in Grin1D481N/ D481N mice by restoring NMDA-dependent plasticity in the hippocampus. D-serine is an effective cognitive enhancer when D-serine is deficient, as may occur in schizophrenia.

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36. Lafoyiannis, Dina1*

THE EFFECT OF MATERNAL THYROID

, Lara Rosenberg1, Carol Westall2,3, Laura Kenton3,4, & Joanne Rovet3,4. 1Institute of Medical Science, University of Toronto, 2Ophthalmology, 3Brain & Behaviour Program, 4The Hospital for Sick Children, Toronto, Canada.

HORMONE DEFICIENCIES ON OFFSPRING VISUAL DEVELOPMENT Thyroid hormone (TH) is essential for normal neurodevelopment and plays an important role in fetal and early infant development. Recent studies have demonstrated that TH is essential at specific time periods during gestation, in order for primary visual system development. In particular, animal studies have shown that TH is involved in the development of the retina, thalamus, and visual cortex, all of which are important for contrast detection and colour vision. Infants of women who had hypothyroidism and hyperthyroidism during pregnancy are being examined as distinct models of different time windows of TH deficiency in gestation. Infants of mothers with hypothyroidism do not receive enough maternal TH in early and mid gestation because the fetal thyroid is undeveloped. Infants of mothers with hyperthyroidism experience TH deficiencies later in gestation because the antithyroid medication used to treat their mothers’ condition can block the fetus’s own thyroid functioning in later gestation. In this ongoing study, we have currently examined 22 infants of women diagnosed and treated for hypothyroidism (HYPO) prior to or during pregnancy, 7 infants of hyperthyroid women (HYPER) exposed to antithyroid medications during pregnancy, and 20 control infants. All children are being tested at 6-8 months using electrophysiological techniques. Contrast sensitivity and visual acuity are assessed using sweep visual evoked potential (VEP) technique in which infants view black and white bars that change rapidly in contrast and width of bars. Colour vision is assessed using a transient VEP technique in which red-green, yellow-blue, or black-white bars change rapidly in an onset-offset mode. All infants also receive an ophthalmology examination for refractive errors and ocular health. To date, there have been no group differences on ocular examinations or visual acuity. However, HYPO and HYPER are demonstrating reduced contrast sensitivity at both low and moderate temporal frequencies. In addition, HYPO are showing more abnormal responses to blue-yellow stimuli than controls while both HYPO and HYPER have a greater incidence of abnormal VEP responses to red-green stimuli. These findings support the view that the developing human visual system is vulnerable to a lack of TH, and the type of deficit will reflect the timing of TH deficiency. However, further study is needed before any definite conclusions and clinical inferences can be made.

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37. Lovic, Vedran1*

1Department of Psychology, University of Toronto at Mississauga , Fleming, Alison1 & Fletcher, Paul J.1, 2

2Centre for Addiction and Mental Health, Toronto, Canada ARTIFICIALLY REARED RATS SHOW INCREASED SENSITIVITY TO AMPHETAMINE REVERSAL OF EFFECTS WITH TACTILE STIMULATION Mammalian brain and behaviour plasticity is particularly evident during early stages of development while the young organism is in the care of its mother. Previously we have found that total maternal deprivation of rat pups, achieved through artificial rearing (AR), leads to a number of behavioural and neurophysiological changes, suggesting a change in the dopamine system. The purpose of this study was to further investigate changes in the dopamine system, associated with AR, using two indirect dopamine agonists, d-amphetamine (dopamine releaser) and methylphenidate (Ritalin – dopamine reuptake inhibitor). Rats were raised with or without mothers (AR, ‘pup-in-a-cup’ paradigm) and some of those raised without mothers were provided with tactile, maternal-licking like stimulation. Rats’ locomotion was measured after an injection of d-amphetamine (0, 0.25, 0.5 and 1.0mg/kg) or methylphenidate (0, 2, 5, 10 mg/kg). While the AR produced increased sensitivity to d-amphetamine in a dose-response fashion, as exemplified by increased locomotion, there were no group differences in sensitivity to methylphenidate. Furthermore, AR animals that were provided with maternal-licking like stimulation were not different from the control, mother-reared animals. These data show that motherless rearing can produce increased sensitivity to amphetamine and that this increase in sensitivity can be reversed by providing motherless pups with tactile stimulation.

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38. Mahabir, Megan BSc*1,4,6

Department of Pharmaceutical Sciences1; Department of Medical Biophysics2, Department of Public Health Sciences3, University of Toronto4, Centre for Addiction and Mental Health5, Sunnybrook and Women’s College Health Sciences Centre6.

, Laurie Zawertailo PhD1., Simon Graham PhD 1,2,4,6, Peter Selby MBBS3-5, Usoa Busto Pharm.D

FMRI BOLD SIGNAL ACTIVATION DURING CUE-ELICITED CRAVING IN FORMER SMOKERS Nicotine-induced neuroadaptations and drug-cue exposure are important predictors of craving and relapse. Functional magnetic resonance imaging (f-MRI) demonstrates hyper-activation in the mesocorticolimbic system [amygdala, dorsolateral prefrontal cortex (DLPFC), anterior cingulate (AC), ventromedial prefrontal cortex (VMPFC)] during cued craving in nicotine-deprived smokers (NDs). However, the neurobiology of cue-induced craving in recent ex-smokers who are at high relapse-risk is unknown. We tested the hypothesis that neural activation during cued craving is similar in early-remitted past-nicotine dependent subjects (PNDs), and NDs. Control (<100 cigarettes/lifetime); overnight NDs (10-25 cigarettes/day; Fagerstrom score > 3); and PNDs (quit < 6 months) underwent f-MRI during visual smoking vs. neutral cue exposure; and smoking vs. neutral auditory scripts. Craving was self-reported before and after cues. Preliminary analyses (n=4/group) of smoking vs. neutral cues for each group suggests increased BOLD signal activity in: a) amygdala, parahippocampal gyri, AC and DLPFC in NDS; and b) AC, DLPFC and VMPFC in PNDs following visual and auditory smoking cues. Direct limbic activation was not observed in PNDs. Cues did not alter limbic or prefrontal activity in controls. Increased self-reports of desire and intention to smoke followed smoking cues, in NDs and PNDs. This study corroborates reports of increased limbic and frontal responses to smoking cues in NDs, and provides first evidence of increased frontal activity during cued craving in PNDs. Our results provide preliminary support for the hypothesis that specific long-term, nicotine-induced neuroadaptations may mediate cue-reactivity; and predict relapse to smoking. This study is ongoing and additional data will be presented. Supported by NIH DA-13630.

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39. McCall, Martha

A MODIFIED CONSTRAINT INDUCED MOVEMEMNT THERAPY PROGRAM WITH THE GERIATRIC SUB ACUTE STROKE POPULATION

*, Department of Rehabilitation Science; Dawson, Dr. Deirdre, Department of Occupational Therapy, Graduate Department of Rehabilitation Science; Colantonio, Dr. Angela, Department of Occupational Therapy, Graduate Department of Rehabilitation Science; Streiner, Dr. David, Department of Medicine

Objective: To determine if constraint induced movement therapy (CIMT) is an effective upper extremity intervention to use with the geriatric stroke population in the sub-acute rehabilitation phase. Design: Interrupted time series (ITS) design using a single participant. An ITS design is proposed as a rigorous vehicle for addressing such questions as, “Is the intervention effective?”; “When is the intervention most effective?”; “What is the pattern of the intervention effect through time?” Setting: Outpatient rehabilitation setting. Participant: 91 year old female who sustained a large right MCA (middle cerebral artery) ischemic stroke two months before study entry exhibiting upper-limb hemiparesis on the non-dominant (left) side. Inclusion criteria were: (1) Age 65 and older; (2) Functional written and spoken English; (3) Ischemic and/or hemorrhagic stroke; (4) Hemiparesis as defined by successful completion of at least one of the three tasks at Stage 3 of 7 (with 7 being normal movement) on the Chedoke McMaster Stroke Assessment for the arm and/or hand; (5) Able to give informed consent as indicated by 22/30 on the Mini Mental Status Examination (MMSE) or a lower score with confirmation by the unit physician that the patient is competent; (6) Willing and able to participate in daily therapy for two weeks. Procedure: The participant was assessed five times prior to the intervention and five times after the intervention on four measures. Immediately after discharge from an inpatient rehabilitation setting, the participant returned as an outpatient to participate in a 2-week CIMT program. The participant received 2 hours of occupational therapy 5 days a week for 2 weeks. There are two standard components to CIMT: restraint and shaping. The restraint component includes the use of a padded mitt on the unaffected side for 6 hours a day. Use of the padded mitt requires the concentrated and repetitive use of the more affected upper extremity that leads to overcoming the strongly learned habit of nonuse and to inducing use-dependent cortical reorganization. The shaping component is the participation in progressively more difficult forms of tasks. This approach allows subjects to experience rewards for successful gains with relatively small amounts of motor improvement. The sessions emphasized activities of daily living. Throughout the session the patient’s direct attention and effort was redirected to the use of the affected upper extremity, even if the less-affected extremity would normally be used for that activity. Results: Preliminary analyses indicate a positive effect of CIMT on motor recovery. The differences between the pre and post intervention slopes on assessments of basic activities of daily living, recovery of upper extremity movement, and performance of unilateral and bilateral daily tasks and self-reported changes in performance and satisfaction with performance of the participant’s goals in activities of daily living indicate that CIMT had an effect significantly greater than that of natural recovery. Scores on the self-report measure improved between 2 and 5 points out of 10. A change score of two or more on this measure is considered clinically significant. Conclusions: Participation in CIMT may increase a stroke patient’s use of his/her more affected limb. These results emphasize the potential beneficial effect of therapeutic intervention for the geriatric hemiplegic arm and lend themselves to future research regarding learned non-use, cortical re-organization and neural plasticity in the geriatric stroke population.

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40. Ngo, L1Graduate Department of Rehabilitation Science, University of Toronto

*123., Green, R.E.A.123 & Melo, B.3

2Collaborative Program in Neuroscience, University of Toronto 3Toronto Rehabilitation Institute ENHANCEMENT OF COGNITIVE FUNCTIONING IN HEALTHY YOUNG INDIVIDUALS THROUGH BRIEF AND INTENSIVE COGNITIVE STIMULATION BACKGROUND. Based on anecdotal reports of healthy individuals, there is some suggestion that cognitive functioning may transiently improve or decline as a function of ‘cognitive environment’, that is, whether the environment provides cognitively demanding stimulation, or a lack thereof. People report feeling mentally sharper after periods of intensive stimulation, such as studying for exams; whereas they report feeling less sharp after periods of inactivity or cognitive deprivation, such as being on summer holidays. Studies of Environmental Enrichment (EE) in animals and human elderly subjects provide compelling evidence to suggest that there are cognitive benefits associated with participating in a stimulating environment over periods of months to years. To date, there is only one pilot study (from the principal author’s lab) in healthy young adults that examined empirically the cognitive benefits of a brief period of intensive cognitive stimulation. The findings from that study revealed that two weeks of intensive cognitive stimulation increased cognitive capacity. OBJECTIVE. To replicate the initial pilot study and to demonstrate that cognitive capacity in healthy young adults can be transiently enhanced through a brief period of intensive cognitive stimulation. METHODS. Twenty-four healthy young adults were assigned to either the “Intervention Group” or the “Sham-Intervention Group” (matched control group). Both groups were administered neuropsychological (NP) assessments before and after a 2-week intervention period. NP measures were counterbalanced between subjects and made use of alternate forms. NP tests assessed attention, speed of processing, verbal memory and working memory. The Homework Group was required to engage in very effortful 'homework' daily (e.g. memorization of poetry passages and facts from ‘Guinness World Records’; speeded oral-mental arithmetic) while the Sham-Intervention Group was asked to perform brief periods (5 minutes) of light reading on alternate nights. Compliance in the Homework Group was assessed by the experimenter via phone testing on alternate nights. The dependent variable was performance on neuropsychological tests. Based on pilot results, we hypothesized that the Homework Group would show greater improvement in pre- vs. post-intervention NP testing compared to the Sham-Intervention Group on tests of working memory and verbal learning. ANALYSES. All test scores were converted to Z-scores. Pre-post intervention difference scores were calculated for each group. The relative improvement from pre- to post-intervention was compared between the two groups using effect size calculations (Cohen’s d). These allow for detection of changes independent of sample size. RESULTS. Moderate to high effect size differences between the two groups were shown in working memory (d = 0.56) and long-term verbal learning and retention (from d = 0.48 to 0.72) in favour of the Homework Group. This finding is consistent with previous pilot study findings. Interestingly, moderate to high effect sizes were shown on speed of processing tests in favour of the Sham-Intervention Group (from d = -0.43 to -0.68). The relative increase in speed in the sham group was also associated with an increase in error rates, suggesting a speed-error trade-off. CONCLUSIONS. Cognitive performances in long-term verbal learning and memory and working memory were enhanced by a brief period of intense mental stimulation. Interestingly, on speed of processing tests, the Homework Group spontaneously slowed down relative to the Sham Intervention Group, but made fewer errors, suggestive of a strategic and conservative decision to favour accuracy over speed. These findings provide preliminary evidence that intensive cognitive stimulation can enhance cognitive capacity. As opposed to skill-based training that is not generalizable, the ability to enhance cognitive capacity has significant implications for rehabilitation after brain injury.

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41. Pamenter, Matthew*Department of Zoology, University of Toronto, 25 Harbord St. Toronto, ON M5S 3G5

, Shin, Damian, Buck, L.T.

NMDA RECEPTOR REGULATION BY MITOCHONDRIAL KATP CHANNELS AND ADENOSINE RECEPTORS IN CORTICAL NEURONS OF THE ANOXIA-TOLERANT WESTERN PAINTED TURTLE (CHRYSEMYS PICTA BELLII) Unlike anoxia-sensitive mammals the western painted turtle survives prolonged periods of anoxia. Key is the ability to acutely decrease N-methyl-D-aspartate receptor (NMDAR) activity with the onset of anoxia. Adenosine (ADO) and mitochondrial ATP-sensitive K+ channels (mKATP) are neuroprotective in mammalian brain and impact NMDAR activity. To examine their role in attenuating NMDAR activity in turtle brain, whole-cell NMDAR currents were measured from cortical neurons undergoing a normoxic to anoxic transition. After 40 min of anoxia NMDAR whole-cell currents decreased 56%. Normoxic application of ADO or the ADO A1 receptor (A1R) agonist cyclopentyladenosine (CPA) resulted in a similar 42% decrease in NMDAR currents. The A1R antagonist 8-cyclopentyl-1,3-dimethylxanthine (DPCPX) abolished the ADO-mediated but not the anoxia-mediated decrease in NMDAR activity. The mKATP channel activator diazoxide (DZX) decreased normoxic NMDAR currents by 44% after 40 minutes while the mKATP blocker 5 hydroxydecanoic acid (5HD) abolished the anoxia-induced decrease in NMDAR activity as well as the ADO and DZX mediated decreases. Taken together with the inability of DPCPX to abolish anoxic changes in NMDAR activity, these data suggest that A1R activation is one of potential multiple cellular activators of mKATP channels, and that these channels mediate NMDAR activity in the anoxic turtle cortex. Supported by an NSERC Grant to LTB.

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42. Parr, AnnCellular and Molecular Biology/Neurosurgery, Toronto Western Hospital

*, Kulbatski, Iris, and Tator, Charles

TRANSPLANTATION OF ADULT RAT SPINAL CORD EPENDYMAL REGION PRECURSOR CELLS INTO THE INJURED ADULT RAT SPINAL CORD Hypothesis: Adult rat spinal cord precursor cells transplanted into the injured adult rat spinal cord survive and differentiate for at least 28 days. Methods: Spinal cord precursor cells were harvested and cultured from adult male Wistar rats expressing enhanced green fluorescent protein (eGFP). Neurospheres were generated and then transplanted at the time of clip compression injury (35g force) into the injury site (n=9), or 1mm rostral and caudal to the injury site (n=9). Rats were sacrificed at 7, 14, and 28 days after injury and transplantation (n=6 at each time point). Results: Live transplanted cells were identified in the injured rat spinal cord after 28 days post injury. Cell survival was improved in the rats receiving rostral and caudal injections as compared to injection directly into the site of injury, where live cells were only seen at the periphery of the lesion near healthier tissue. Cells became more homogeneously distributed over time, probably due to migration into the injury site. Immunohistochemistry was performed to identify the phenotypic fate of the cells. Conclusions: Adult rat spinal cord precursor cells transplanted into the injured adult rat spinal cord survive and differentiate for at least 28 days. Survival is improved with injection rostral and caudal to the injury site. Cellular differentiation will be discussed.

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43. Peever, John.

GLUTAMATERGIC CONTROL OF AIRWAY MOTONEURONS DURING SLEEP IN RATS.

, Lai, Diane., and Siegel, Jerome. Laboratory of Sleep Research, Department of Zoology and Physiology, University of Toronto, Toronto, ON, Canada; and Department of Psychiatry and Biobehavioral Science, University of California, Los Angeles, North Hills, CA, USA.

One of the hallmarks of sleep is a potent suppression of skeletal muscle activity that occurs in a stereotypical pattern across the sleep cycle. Understanding the physiological processes that regulate motor activity during sleep is important because most of the major sleep disorders are caused by dysregulation of muscle activity. The neurophysiological mechanisms that mediate muscle activity during sleep are unclear. It is hypothesized that muscle activity is suppressed during sleep because motoneurons are passively disfacilitated by sleep-related neurons in the brainstem. While glutamate is the major excitatory neurotransmitter in the brain, its role in mediating motoneuron excitability during sleep is unknown. This study aims to understand the role that glutamate plays in regulating airway motoneuron excitability across the sleep-wake cycle in rats. To do this, glutamate was focally applied onto trigeminal motoneurons while masseter muscle activity was monitored in behaving rats. Male, Sprague-Dawley rats (n=6) were implanted with EEG and EMG (masseter and neck muscles) electrodes to record sleep states. Microdialysis probes were implanted in the left trigeminal motor nucleus for dialysis of artificial cerebral spinal fluid (ACSF) or 25mM glutamate. Application of ACSF onto trigeminal motoneurons had no effect on masseter muscle activity (P=0.548); however, glutamate application caused a significant increase in masseter muscle activity (P=0.01). Compared to baseline conditions, glutamate application increased masseter muscle activity during wakefulness by 176% (P<0.001) and during NREM sleep by 691% (P<0.001). However, glutamate application during REM sleep had no effect on tonic masseter muscle activity (P=0.91). While glutamate potently facilitated trigeminal motoneurons excitability and hence masseter muscle activity during waking and NREM sleep, its excitatory effects were abolished during REM. These results suggest that the excitatory effects of glutamate are nullified by powerful inhibitory processes (e.g. glycine) during REM sleep. Supported by: Parker B. Francis Family Foundation National Sleep Foundation, CFI, OIT, NIH.

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44. Perova, Tatiana1Cellular and Molecular Pathophysiology, Centre for Addiction and Mental Health, Departments of 2Psychiatry,and 3Pharmacology, and 4Institute of Medical Science, University of Toronto,

1,4*, Warsh, Jerry J1,2,3,4, Li, Peter P1,2,4

MOOD STABILIZERS LITHIUM AND LAMOTRIGINE DIFFERENTIALLY AFFECT INTRACELLULAR CALCIUM MOBILIZATION IN B LYMPHOBLASTS Intracellular calcium abnormalities have been implicated in the pathophysiology of bipolar I disorder (BD-I). Chronic lithium treatment ex vivo attenuates stimulated intracellular calcium (Ca2+) responses in B lymphoblast cell lines (BLCLs) from BD I patients and healthy controls (Wasserman et al. Neuropsychopharmacology 2004, 29:759) and differentially decreased levels of the type 3 canonical transient receptor potential calcium permeable channels (TRPC3) in BLCLs from BD patients (Andreopoulos et al. Pharmacogenomics J . 2004, 4:365). To determine whether the effects on intracellular Ca2+ homeostasis are common to clinically efficacious mood stabilizers in general, we compared the effects of acute and chronic ex vivo treatment of BLCLs from BD-I and healthy controls (HC) with therapeutically relevant concentrations of lithium, lamotrigine, or respective vehicle. BLCLs from BD-I patients, and age and sex-matched HC were treated with lithium (0.75 mM), lamotrigine (0.015 mM) or vehicle for 24 hours (acute) or 7 days (chronic). Lysophosphatidic acid (LPA, 100µM)- and thapsigargin (TG, 200nM)-stimulated Ca2+ responses were determined using ratiometric fluorometry with Fura-2. TRPC1 and TRPC3 protein levels were quantified by Western immunobloting. Compared with vehicle, chronic lithium exposure produced a small but significant decrease in peak LPA-stimulated [Ca2+]influx and delta [Ca2+]influx ( absolute difference between stimulated [Ca2+]influx and basal [Ca2+]B intracellular Ca2+ levels) in BLCLs from BD-I patients and HC (F=4.8; df=1,21; p=0.04 and F=4.7; df=1,21; p=0.04 respectively). In contrast, chronic lamortigine treatment did not affect LPA- or TG-induced Ca2+ responses (F=0.31; df=1,20; p=0.81 and F=1.21; df=1,20; p=0.34 respectively). At the therapeutically relevant concentrations, chronic treatment with lithium modulated receptor- and capacitance mediated Ca2+ flux in BLCLs. Unlike lithium, lamotrigine had no effect on Ca2+ mobilization. The differential effects of lithium as compared with lamotrigine on Ca2+ homeostasis may reflect the distinctive clinical profiles of these mood stabilizers. Western immunolabeling of TRPC1 and TRPC3 proteins will provide further insight on the differences in action of these two mood stabilizers. Supported by a grant from the CIHR

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45. Phan, Nam*Cell and Molecular Division, Toronto Western Research Institute,

, Natasha Shulyakova, Linda Mills

University Health Network Department of Physiology, University of Toronto THE ROLE OF TOM20 IN MITOCHONDRIAL PROTEIN IMPORT IN DIFFERENTIATED PC12 CELL AND PRIMARY NEURONS

Although mitochondria contain their own DNA, 99% of proteins are nuclear-encoded and imported into mitochondria. Previous studies from our lab on differentiated PC12 cells have shown that prolonged exposure to sub-lethal beta amyloid (Aβ1-42) inhibits protein import resulting in functional mitochondrial deficits and ultimately increased vulnerability to secondary insults. There are no known pharmacological agents that can selectively increase (or decrease), mitochondrial protein import. Consequently we elected to modify protein import by targeting Tom20 an integral component of the protein import machinery. We hypothesized that overexpression of Tom20 would increase protein import and wholly or partially prevent the changes in mitochondria and cell survival associated with the Aβ1-42 mediated decline in import. To test this hypothesis we are transfecting differentiated PC12 cells and primary rat hippocampal neurons with the full length human Tom20 using Lipofectamine 2000 or biolostic transfection with the Helios Gene Gun. Results with Tom20 and other test plasmids indicate that both transfection methods are effective but in primary neurons the gene gun is associated with higher transfection rates and less toxicity; primary neurons in dissociated cultures or in hippocampal slice cultures survive for up to 28 days post-transfection. In PC12 cells transfection with Tom20 increased the import of a GFP fusion protein targeted to mitochondria by 10% by 24hrs and 17% by 48hrs as assessed by flow cytometry. A similar increase was evident when live cells were imaged by confocal microscopy. Western blot confirmed that transfection with Tom20 increased Tom20 expression and increased Tom20 levels in mitochondria. Ongoing experiments are confirming that overexpression of Tom20 increases the import of endogeneous mitochondrial proteins, and determining if increases in Tom20 alter mitochondrial function and cell viability in PC12 cells under conditions where import is been inhibited by sub-lethal beta amyloid Aβ1-42.

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46. Placenza, Franca M.Departments of Psychology1 and Psychiatry2, University of Toronto, Toronto, Canada; Division of Life Sciences3, University of Toronto, Scarborough, Canada; Centre for Addiction and Mental Health4, Toronto, Canada

1*, Erb, Suzanne3, Fletcher, Paul J. 1,2,4 and Vaccarino, Franco J.1,2,4

BLOCKADE OF CENTRAL NEUROKININ-1 RECEPTORS HAS DIFFERENTIAL EFFECTS ON OPIATE- AND COCAINE-INDUCED LOCOMOTOR ACTIVITY AND SELF-ADMINISTRATION BEHAVIOUR Substance P (SP) is a neuropeptide that has been implicated in the mediation of opiate reinforcement. Studies have shown that the reinforcing effects of morphine are absent in mice lacking the SP-preferred receptor, the neurokinin-1 (NK-1) receptor. A role for SP and NK-1 receptors in psychostimulant reinforcement has also been shown, at least for amphetamine. However, studies indicate that while NK-1 knockout mice show impairments in opiate and amphetamine reinforcement, the reinforcing effects of cocaine remain intact in these animals. The aim of the present study was to directly compare the effects of pharmacological manipulations of central NK-1 receptors on reward-related behaviours induced by opiates and cocaine. Specifically, we assessed the effects of intracerebroventricular (ICV) administration of the selective NK-1 receptor antagonist, GR82334, on the locomotor activating effects of morphine and cocaine, as well as on heroin and cocaine self-administration behaviour. In addition, because SP itself has been shown to have reinforcing properties, we further assessed whether activation of NK-1 receptors is capable of augmenting the reinforcing effects of opiates and cocaine. To this end, we examined the effects of the selective NK-1 receptor agonist, [Sar9Met(O2)11]-SP, on heroin and cocaine self-administration. Unilateral guide cannulae aimed above the lateral ventricle and indwelling intravenous catheters were surgically implanted into male Wistar rats. In tests for locomotor activity, rats were given ICV infusions of the selective NK-1 receptor antagonist, GR82334 (0, 10, 50pmol), prior to systemic injections of morphine (5mg/kg) or cocaine (10 or 20mg/kg). In self-administration experiments, rats were trained to self-administer heroin or cocaine on a fixed-ratio 5 (FR5) schedule of reinforcement. Following acquisition of stable responding, animals were pre-treated with GR82334 (0, 2, 10, 50pmol; ICV) prior to subsequent self-administration sessions. In addition, we tested the effects of pre-treatment with the selective NK-1 receptor agonist, [Sar9Met(O2)11]-SP (0, 3μg; ICV), on FR5 responding for heroin or cocaine. Results showed that ICV administration of GR82334 attenuated the locomotor activating effects of morphine, but not cocaine. Similarly, GR82334 increased heroin, but not cocaine self-administration, suggesting an attenuation in the reinforcing effects of heroin but not cocaine. In contrast, [Sar9Met(O2)11]-SP decreased both heroin and cocaine self-administration, suggesting an increase in the reinforcing effects of both drugs. These findings suggest that NK-1 receptors play an important role in mediating the behavioural activating and reinforcing effects of opiates, but that activation of these receptors is not a necessary, but rather sufficient, condition for the modulation of cocaine reinforcement. Supported by: Canadian Institutes of Health Research Grant to FJV.

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47. Podkowa Monika

1Dept. of Biochemistry, 2Dept. of Medical Biophysics, 4Dept. of Medical Genetics and Microbiology, University of Toronto

1, Lee-Hoeflich Si Tuen2, Causing Carrie3, Zhao Xin1, Wrana Jeffrey L.3,4, Attisano Liliana1,2

3Program in Molecular Biology and Cancer, Mount Sinai Hospital, Toronto, CANADA LIMK1 BINDS TO THE BMP RECEPTOR, BMPRII TO REGULATE BMP-DEPENDENT DENDRITOGENESIS The growth and morphological differentiation of dendrites are critical events in the establishment of proper neuronal connectivity and neural function. One extrinsic factor, BMP7, has been shown to specifically affect dendritic morphogenesis, however, the underlying mechanism by which this occurs is unknown. Here we show that LIM Kinase 1 (LIMK1), a key downstream effector of Rho GTPases, colocalizes with the BMP receptor, BMPRII in the tips of neurites and binds to BMPRII. This interaction is required for BMP-dependent induction of the dendritic arbor in cortical neurons. Furthermore, we demonstrate that the physical interaction of LIMK1 with BMPRII synergizes with the Rho GTPase, Cdc42, to activate LIMK1 catalytic activity. These studies thus directly link the BMP receptor to regulation of actin dynamics and provide insights into how extracellular signals modulate LIMK1 activity to permit fine spatial control over cytoskeletal remodeling during dendritogenesis.

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48. Robins, SherriInstitute of Medical Sciences, University of Toronto; Dept of Cellular and Molecular Biology, Toronto Western Research Institute; Division of Neurosurgery, Department of Surgery, University of Toronto

* and Fehlings, Michael G.

CHARACTERIZATION OF SOLUBLE FAS RECEPTOR AS A POTENTIAL NEUROPROTECTIVE AGENT FOLLOWING ACUTE SPINAL CORD INJURY

Spinal cord injury (SCI) is a devastating form of neurotrauma, effecting any population, and is a major cause of morbidity and mortality in children and young adults. The pathophysiology of SCI consists of a primary mechanical insult that triggers a secondary cascade of cellular damage. A key event in this pathology is delayed apoptotic cell death at and adjacent to the injury site, leading to progressive neurodegeneration. Several molecular pathways have been attributed to apoptosis after SCI. The Fas receptor pathway plays an integral role in the initiation of apoptosis through receptor-ligand binding of target cells and has been observed after CNS trauma and in several neurodegenerative diseases. Previous work in our lab has shown that subarachnoid infusion of a soluble form of the Fas receptor (sFasR) can be neuroprotective, as shown by long term behavioral evaluation and neuronal tracing. We hypothesize that inhibition of the Fas receptor pathway is neuroprotective in the acutely injured spinal cord and results in reduction of neuronal and oligodendroglial cell death, and enhanced axonal integrity across the lesion site. In this study, we used a 35g and 50g clip compression injury model at C7-T1 followed by intrathecal adminstration of sFasR using osmotic minipumps. Using Western Blotting and Immunohistochemistry at 5 and 7 days following injury, our results revealed enhanced axonal preservation in sFasR treated animals at the lesion epicenter. These results indicate that disruption of the Fas pathway in acute injury can lead to enhanced axonal and tissue preservation, which mirrors well with the improved long-term recovery observed previously in our lab. Moreover, this work shows the potential of soluble Fas receptor administration to be a therapeutic option for individuals suffering from acute SCI.

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49. Roy, FrancoisInstitute of Biomaterials and Biomedical Engineering

; Popovic, Milos

NEUROMUSCULAR SIGNALS IMPROVE PERFORMANCE IN FORCE TRACKING TASK Introduction: The purpose of this research is to determine if neuromuscular signals recorded using surface electromyography (EMG) can improve an individual’s ability to control forces in a visually guided tracking task. This study compares the use of visual feedback from two real-time controllers: 1) the actual measured force and 2) an EMG-based predictive controller. This study tests the feasibility of using an EMG-based predictive controller to improve the ability of minimizing the difference between the target and actual response. This study has direct applications for developing man-machine interfaces involving biomechanical movements and force control. Methods: The experiment required a subject to track force profiles displayed on a screen by generating isometric finger movements with the index finger of the dominant hand. The experiment was performed on one trained able-bodied subject. Finger force was measured using a load cell placed under the tip of the index finger. Five EMG electrodes were placed on accessible sites of the hand and arm to capture the muscular activity involved in the finger response including the extensor digitorum superficialis, extensor digitorum profundus, extensor indicis, flexor digitorum, and first dorsal interosseous. An EMG-based model was developed using the Laguerre expansion technique to predict finger force from the five EMG signals. This technique involves using an orthogonal set of Laguerre functions to develop finite-impulse digital filters (i.e. one per muscle) which effectively filter the rectified EMG signals to predict the force. Since muscular activity is a necessary precursor to motor movements, the EMG-based model was tweaked to respond faster than the actual finger movements. The model was calibrated to predict finger forces 50 ms before its onset. A predictive controller was developed in an attempt to improve force control during the tracking task. The predictive controller uses 1) the measured forces from the load cell and 2) the predicted forces calculated from the EMG-based predictive model. For the experiment, the subject tracked different force profiles using the two different visual feedback controllers: 1) the measured force, and 2) the predictive controller. The experiments were performed using real-time feedback working at 2000 Hz. The subject performed a total of twelve trials. To assess the performance of each trial, the error was calculated between the target force and the response. Results: For n = 12 trials, and p = 0.00001, the one-tailed t-test indicates that the performance error using the predictive controller was significantly lower than the traditional force feedback. This result reveals that the neuromuscular signals improve the overall tracking response. The predictive controller improved the dynamic responses by providing a 14% performance enhancement (p = 0.000002, for a one-tailed t-test). During static finger forces (1-2.5 s after stimulus onset), there was no significant difference between the two controllers (p = 0.78, for a two-tailed t-test). This result suggests that both controllers performed equally well during the stable holding phase of the tracking task. Conclusion: It was found that the predictive controller enhances the ability to control forces in a visually guided tracking task. The predictive EMG-based model has direct advantages over velocity commands (i.e. changes in force) since the model provides a direct estimate of the finger force, merely shifted in time, as opposed to using an entirely different signal. As a result, the tracking response does not significantly overshoot the target force. The predictive model merely provides a faster response while being equally capable of providing finer touch control. These results provide evidence that an individual’s ability to control a device via a man-machine interface is augmented by combining neuromuscular signals with traditional mechanical sensors. These findings provide direct insight on how to bridge the gap between EMG activity and force control, and may be of importance for improving the control of a neuroprosthesis for grasping.

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50. Saab, Béchara1Collaborative Program in Neuroscience, Molecular & Medical Genetics Department, University of Toronto, 2Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Canada

1,2*, Georgiou, John2, Bechard, Allison2. & Roder, John1,2

NCS-1 MODULATES SYNAPTIC PLASTICITY & POTENTIALLY LEARNING AND MEMORY. Synaptic plasticity, including learning and memory, is thought to be regulated by changes in calcium concentrations at nerve terminals. Resulting calcium-dependent cascades are mediated by proteins of the calcium-binding protein (CBP) superfamily. The most sensitive CBP, neuronal calcium sensor-1 (NCS-1), is believed to have a prominent role in synaptic plasticity and underlie thought processes used in learning and memory. I have generated double transgenic mice to overexpress NCS-1 specifically in the dentate gyrus of the hippocampus. Here we show the C-terminal peptide of NCS-1 fused to the HIV-1 protein transduction domain (TAT) sequence modulates synaptic plasticity and could be enhancing NCS-1 activity. Our data suggest mice containing elevated NCS-1 in the dentate gyrus will also have altered synaptic plasticity and may even be superior learners as a result.

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51. Seif, GamalInstitute of Medical Science

*. Tator, Charles

QUANTITATIVE MEASUREMENT OF RETROGRADE DEGENERATING OF THE RAT CORTICOSPINAL TRACT: A CONFOCAL IMAGING STUDY Retrograde degeneration of injured spinal cord axons (dieback), is a process in which axons in the proximal stump of descending spinal tracts retract away from the initial site of injury. Previous studies have attempted to quantify the degree of dieback using histochemical staining and light microscopy; however, the disparity of their results, even with similar experimental conditions, suggest deficiencies in their quantifying techniques. The development of confocal microscopy, in association with fluorescent neuronal tracers (i.e. DiI) has increased the depth at which labeled axons and their terminal ends can be analyzed to levels previously unattainable without an electron microscope. The purpose of this study is to test the utility of the confocal imaging system to study the morphology and physiology of the dieback phenomenon. We hypothesis that more reliable dieback measurements will be obtained at various times delays, using this system in comparison to results obtained in previous studies. Thirty female rats (Charles River) received transection injuries at the T8 spinal levels, and where sacrificed at different time periods (1, 2, 4, 8, & 16 wks, N=5 or 6 per group). Three weeks prior to sacrifice, DiI crystals were implanted in the sensorymotor cortex of each rat, allowing for complete corticospinal tract labeling to the tips of injured axons. Preliminary results indicate a non-significant trend showing greater dieback in groups with longer injury delays. These results are based on data with limited number of samples. More finite conclusions will be obtained upon completion of this study.

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52. Setiawan E*

EFFECTS OF PRENATAL GLUCOCORTICOID EXPOSURE ON HIPPOCAMPAL LONG-TERM POTENTIATION AFTER BIRTH

, MacDonald JF, Matthews SG. Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, Canada

Synthetic GCs (sGCs) are routinely used to treat pregnant women at risk of preterm labour. Administration of sGCs during late gestation results in permanent effect on molecular and endocrine aspects of the stress axis. However, the consequence for cognitive development of the offspring remains uncertain. Human studies show a higher incidence of neurodevelopmental abnormalities in children exposed in utero or treated neonatally with the sGC, dexamethasone. Currently, nothing is known about prenatal exposure to sGCs on synaptic function with respect to the mechanisms underlying learning and memory. The current study hypothesizes that there will be negative postnatal effects of prenatal exposure to sGCs in a guinea pig model with respect to synaptic plasticity in the hippocampus. Pregnant guinea pigs were injected subcutaneously with Betamethasone (1mg/kg) or Saline on gestational days 40/41(neurogenesis), 50/51 (peak brain growth) and 60/61 (myelination; term=68d). On post-natal day 21 (±2) offspring were euthanized and hippocampal slices taken for electrophysiological recording. Hippocampal function in treated and control animals was assessed using field potential techniques according to a synaptic model for learning and memory, long-term potentiation (LTP). Subsequently, the GR and MR-dependent effects of cortisol on synaptic plasticity were examined by applying concentrations of 0.1uM, 1.0uM or 10uM to the slice 30 mins before LTP induction. Preliminary results indicate that there is no difference in LTP between Beta and Saline exposed offspring in either the control, 0.1uM or 1uM concentrations of cortisol. However, LTP after exposure to 10uM cortisol results in augmented baseline EPSPs and a facilitated LTP in female Beta offspring, while male Beta offspring show an opposite trend. This study may reveal sex specific effects of prenatal glucocorticoid exposure on mechanisms underlying learning and memory, particularly in the presence of elevated cortisol. This work was generously supported by the CIHR and the Genesis Research Foundation.

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53. Shaikh KamalDepartment of Psychology

*, Kooshesh Sam, Wong Karen, De Rosa Eve

LEARNED IRRELEVANCE: SELECTIVE ATTENTION AS AN INHIBITORY PROCESS. Selective attention is a cognitive mechanism that is thought to increase the signal-to-noise ratio for behaviorally-relevant information; this can be achieved by increasing signal (i.e., selecting for relevant information) or reducing noise (i.e., suppressing irrelevant information). We examined the capacity for the selective attention mechanism to suppress noise associated with behaviorally-irrelevant information. Invoking the principle of Learned Irrelevance (LI) (Mackintosh, 1973) from animal studies, we hypothesized that inhibition to irrelevant information would accumulate during learning. We created a simultaneous discrimination paired-associate paradigm where subjects learned color discriminations consisting of four stimuli (A, B, C, and D) paired into the following three contingencies: A+B-, C+B-, and B+D-. The letters represent the two colors in a color pair and "+" signifies the relevant stimulus while "-" signifies its paired-associate. Subjects indicated, with a key press, the left or right location of the relevant stimulus. A+B- served as baseline learning, C+B- served as a second baseline during which inhibition to B was accrued, and B+D- was the index of LI. There was no change in performance when subjects acquired the second baseline. In contrast, during the LI condition when the previously irrelevant stimulus (B) became relevant, there was a significant decrease in mean accuracy and a significant increase in median response time. LI induced a robust behavioral decrement that had an extended time course and accordingly can serve as a measurable index of inhibition. The LI phenomenon reveals that even though the irrelevant stimulus was “ignored”, it acquired inhibitory significance.

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54. Silverman LoreleiDepartment of Physiology, Faculty of Medicine, University of Toronto

and Charlton Milton

DEPRESSION AND PHOSPHORYLATION AT PHASIC SYNAPSES Modulation of synaptic transmission is involved in learning and memory. As a model system for studying the role of protein phosphorylation in one form of synaptic plasticity- low-frequency depression (LFD) at phasic synapses we use the crayfish leg extensor neuromuscular junctions because it allows electrophysiological and pharmacological access to both pre and post synaptic sites. In a previous study we implicated protein phosphatase 2B (calcineurin) in LFD at crayfish phasic synapses (Silverman Gavrila, Orth and Charlton, 2005, J. Neuroscience). We showed that calcineurin is present in phasic synaptic terminals using immuno-staining. Western blot analysis identified bands at appropriate MW in both presynaptic axons and neuromuscular junctions. Inhibition of calcineurin with membrane permeant inhibitors FK-506 and calcineurin autoinhibitory peptide abolished LFD. LFD at phasic synapse is a presynaptic phenomenon that involves changes in the probability of transmitter release, but it might be mediated by a postsynaptic retrograde messenger. To determine if the site of action of calcineurin is pre or/and postsynaptic we pressure injected calcineurin autoinhibitory peptide into pre-synaptic axons or post-synaptic muscle cells. We assessed its effect on neurotransmitter release by measuring the amplitude of the excitatory postsynaptic potential recorded intracellularly from the muscle and evoked by stimulating the phasic axons at 0.2 Hz. Action potential from the phasic nerve was recorded simultaneously. LFD was inhibited only when calcineurin was inhibited by injecting the peptide into the axon and not in the muscle fiber. FK-506 added to the bath after 30 min of depression in the presence of calcineurin autoinhibitory peptide injected in the muscle, recovered the depression suggesting that calcineurin act on presynaptic site to cause LFD. To determine the difference in phosphoprotein levels before and after LFD we employed a combined proteomic and electrophysiological approach. Phosphoproteins extracted before and after LFD from the neuromuscular junction or from axons were separated by SDS-PAGE and detected using ProQ diamond/SYPRO Ruby protein gel staining technique and identified by mass spectrometry.

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55. Skov-Rackette*, Shannon I., Miller*, NoamDepartment of Psychology

& Shettleworth, Sara.J.

EPISODE BASED RESPONDING IN THE PIGEON An animal that simultaneously encodes the identity, location, and time of an event should be able to respond correctly to any of the three questions, “what was it?”, “where was it?”, or “when was it?” when it cannot anticipate which will be asked. We developed a novel approach to testing “episodic-like” memory based on this assumption. Pigeons were trained to match the identity of a 3 second sample on a touchscreen, to match its location, and to report on the length of the retention interval (2 or 6 seconds). The three tasks were trained in separate, interleaved, sessions until the birds reached a criterion level of performance at both retention intervals. Then blocks of “what”, ‘when”, and “where” trials were intermixed within each session. Performance on “when”, but not “what” or “where” initially decreased dramatically in the blocked sessions, suggesting that the birds do not spontaneously encode all three features as a solitary unit. With extensive training, some pigeons recover performance on all tasks and even when the three questions are randomly intermixed. Consistent with Clayton & Dickinson (1998), these findings suggest that although episodic-like memory in the pigeon may not be a single entity, the identity and location of the stimulus and how long ago it was presented are all encoded in memory and can be recalled.

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56. So, Christopher H.1*

Departments of Pharmacology1 and Medicine2, University of Toronto; Centre for Addiction and Mental Health3.

, Varghese, George1,3, Curley, Kevin J.1, Kong, Michael M.C.1 , O'Dowd, Brian F.1,3 and George, Susan R.1,2,3

DOPAMINE D1 AND D2 RECEPTORS EXIST AS HETEROOLIGOMERS ON THE CELL SURFACE AND ARE CO-INTERNALIZED UPON SELECTIVE ACTIVATION BY D1 OR D2 AGONISTS While dopamine D1 and D2 receptors belong to structurally and biochemically distinct subfamilies of dopamine receptors, several lines of evidence indicate that they are functionally linked as seen by their synergism in certain behavioural and electrophysiological studies. We provide evidence to demonstrate that D1 and D2 receptors are heterooligomeric on the cell surface as indicated by co-immunoprecipitation of D1 receptors with D2 receptors and vice versa, and cell surface fluorescence resonance energy transfer studies from cells co-expressing the human D1 and D2 receptors. D1 receptor internalization occurred in response to the D1-specific agonist SKF 81297 when the receptor was expressed alone or co-expressed with the D2 receptor. D2 receptor internalization by SKF 81297 was not observed when the receptor was expressed alone but was observed when D2 was co-expressed with the D1 receptor. Similarly, the D1 receptor did not internalize in response to the D2-selective agonist quinpirole when expressed alone but internalized when co-expressed with the D2 receptor. The D2 receptor did not internalize on activation by quinpirole when expressed alone but did so upon co-expression with the D1 receptor. The formation of the D1-D2 receptor complex also enabled cross-modulation of receptor function. The D2 receptor, when co-expressed with a D1 receptor lacking its primary agonist-induced GRK2 phosphorylation site (D1-E359A), was phosphorylated upon selective activation of the mutated D1 receptor. These results indicate that the D1 and D2 receptors physically interacted at the cell surface to form a novel signaling unit and co-internalized upon agonist activation of either receptor. This study was supported by grants from the National Institute on Drug Abuse and from the Canadian Institutes of Health Research to B.F.O and S.R.G.

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57. Soleimani, L1 Institute of Medical Sciences, University of Toronto, Toronto, Ontario.

.*1, Dennis, J. W.2, Roder, J. 1,2

2 Department of Molecular and Medical Genetics, University of Toronto, Toronto, Ontario. BEHAVIOURAL CHARACTERIZATION OF THE MGAT5 KNOCKOUT MICE Mgat5 (UDP-N-acetylglucosamine: α-6-D Mannoside ß 1,6 N-acetylglucosaminyl transferase 5), a trans-membranous enzyme in the medial Golgi, belongs to the family of N-acetylglucosaminyl transferases. This enzyme promotes the substitution of N-glycans with poly-N-lactosamine, which adds considerable heterogeneity to the structure of glyco-proteins. It is well known that the bulky Mgat5 products present on adhesion molecules (such as Integrins and N-Cadherins) affect the cell-cell interaction. In the immune synapse, they tend to modulate the Tcell and the cytokine activation. These products are over-expressed in malignancies through activation of RAS-RAF-MAPK pathway, interfere with the action of adhesion molecules and therefore facilitate the metastasis of the tumoral cells. Genetic defects of N-glycosylation affect the central nervous system. Knocking out Mgat5 gene in mouse was shown to induce behavioural abnormalities such as nurturing deficits. Moreover, a linkage study recently implicated a role for Mgast5 in mental retardation and schizophrenia in Scottish family. Our knowledge about the role of the enzyme in the brain is quite limited. Its activity can be detected from the embryonic day (E9.5) in the dividing and differentiating cells in the mouse brain. It is also widely expressed in adulthood, especially in cortical cells and hippocampus. Due to the structural complexity of the glycans, study of the targeted mutated mice offers a powerful tool for studying the structure-function relationship. The main objective of our study is to characterize these mice behaviourally in order to investigate the probable role of the glycans in brain. Mgat5 knockout mice and their littermate controls on C57BL/6 background were screened through a battery of tests, which included locomotor activity (open-field, rota-rod), startle and sensori-motor gating (pre-pulse inhibition (PPI) and latent inhibition (LI)), hippocampal-dependent learning and memory (Morris water maze), and depression screen (forced swim test, and tail suspension test). Our results show that the knockouts are not different in locomotor activity, hippocampal dependent learning, and PPI. However, they show lower startle level as well as less immobility time in both depression tests. The latter indicates a “less depressed” phenotype in the Mgat5 knockout mice. In order to suggest a probable role for the gene in depression, we will investigate whether these changes can be attributed to the differences in the metabolic state or the anxiety.

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58. Steidl, StephanDepartments of Psychology and Zoology, University of Toronto

, Ng, Karen, Bhattacharyya, Moni, Wang, Haoran, Yeomans, John

IN VIVO ELECTROPORATION OF THE M5 MUSCARINIC RECEPTOR GENE INTO VENTRAL TEGMENTAL AREA FACILITATES BRAIN-STIMULATION REWARD IN RATS. M5 muscarinic receptors, which are expressed on dopaminergic cell bodies of the ventral tegmental area (VTA), are needed for brain-stimulation reward (BSR), and sustained dopamine release in response to mesopontine cholinergic stimulation (Yeomans et al., 2000; Forster et al., 2001). Here, we used the method of Inoue et al. (2003) to electroporate the M5 muscarinic receptor gene, along with the gene for green fluorescent protein (GFP), into the VTA of rats. Animals were trained to bar press for lateral hypothalamic BSR. The sensitivity of animals to BSR was assessed by rate-frequency curves tested for 3 days before and up to 14 days after electroporation. In 8 VTA sites, electroporation of the M5 gene facilitated BSR, reducing thresholds between 15 and 20% between 3 and 14 days after electroporation. Electroporation sites in the rostral VTA were most effective in reducing BSR thresholds. Electroporation in sites that were outside the VTA area, such as substantia nigra, led to no change or an increase in BSR thresholds. Anodal electroporation led to greater facilitation than cathodal electroporation. Electroporation of control plasmids in 5 sites raised BSR thresholds for the first 2 days, perhaps due to lesions, followed by recovery to baseline. Adding M5 receptor genes to the VTA, then, appears to facilitate dopamine-mediated reward. Supported by Canadian Institutes of Health Research grants to JY, a NSERC PGSA to SS, and a NSERC summer fellowship to MB.

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59. Todorovski, ZarkoDepartment of Physiology and Program in Neuroscience, University of Toronto

* and Zhengping Jia

THE ROLE OF LIM KINASE IN SYNAPTIC PLASTICITY The Lim Kinase family of proteins (LIMK) is known to play an important role in actin dynamics through its regulation of ADF/coffilin. A subtype of LIMK, LIMK1, is only expressed in the neuronal tissues with high levels in the mature synapse. Previous studies from this lab have shown that LIMK1 knockout mice exhibit abnormal spine morphology as well as altered hippocampal LTP. A recent study has found that LIMK1 phosphorylates the cyclic AMP Response Element Binding Protein (CREB) in hippocampal progenitor cells. CREB is a transcription factor that can be activated by a number of stimuli. However, one mechanism that is relevant when dealing with synaptic plasticity is the CREB activation through NMDA receptors in facilitating late long-term potentiation (L-LTP). Increased levels of phosphorylated CREB are found after L-LTP as well as after memory training tasks. This suggests that CREB is important in facilitating the changes necessary for long-term memory. We propose that LIMK1 is able to phosphorylate CREB in response to a stimulus. LimK is thereby able to induce changes in L-LTP. We propose that LIMK knockout mice will have depressed L-LTP and those mice will have lower levels of p-CREB. Very preliminary results suggest that LIMK1 knockout mice have increased LTP as shown in previous studies in this lab. However, LIMK1 knockout mice do not exhibit altered L-LTP. Western analysis shows that there is no significant change in p-CREB levels between slices where L-LTP was induced and controls. Yet, LIMK1/K2 double knockout mice show severely depressed L-LTP. These results suggest that perhaps LIMK2 is capable of phosphorylating CREB and compensates for the absence of LIMK1 in the knockout mice

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60. Wan, Yudi*Institute of Medical Science, University of Toronto

; Lu, Wei-Yang; Xiang, Yun-Yan; Yang, Burton.

VERSICAN G3-DOMAIN REGULATES GLUTAMATERGIC SYNAPTIC FORMATION AND TRANSMISSION The large chondroitin sulfate proteoglycan (CSPG) versican is one of the major extracellular matrix (ECM) molecules that are highly expressed in the brain. During brain development, ECM molecules, including versican, are proteolyzed into small domains, thus adjusting tissue reorganization. The G3 domain of versican (G3), which contains two epidermal growth factor (EGF)-like sequences, naturally exists in growing brain tissues, but its role remains unknown. Given that G3 is involved in non-neuronal cell adhesion, and synapses are specialized adhesion sites among neuronal cells, we hypothesize that G3 regulates central synaptic formation. Glutamate is the major excitatory neurotransmitter in the mammalian brain. The purpose of this study is to examine the effect of G3 on neurite growth and glutamatergic synaptic functions. Using methods of patch-clamp recording, Western blot and immunocytochemistry in cultured embryonic hippocampal neurons, we obtained following results. 1). Coating culture dishes with G3, but not a G3 mutant that lacks EGF repeats (G3EGF), enhanced neurite growth, glutamate-evoked currents, as well as miniature excitatory postsynaptic currents (mEPSCs) of the cultured neurons. 2). Treat the neurons with the G3-conditioned medium not only increased the surface expression of GluR2 subunits of glutamate receptors (GluRs), but also elevated the levels of synaptic proteins, including synaptophysin, PSD-95 and the NR1 subunits. 3). Effects of G3 on neurite growth and glutamate-currents were significantly reduced by adding the selective EGF receptor antagonist AG1478 to the culture medium. We conclude that the G3 domain of versican plays regulatory roles in synaptic formation and transmission via an EGF receptor-mediated signaling pathway.

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61. Wang HaoranDepartments of Psychology and Zoology, University of Toronto

, Butt Zareen, Chui Gary, Madden Aileen, Steidl Stephan, Yeomans John.

IN VIVO ELECTROPORATION OF M5 MUSCARINIC RECEPTOR GENES IN THE RAT VENTRAL TEGMENTAL AREA WITH IRES HR-GFP VECTORS Removal of M5 muscarinic receptors reduces brain-stimulation reward and prolonged striatal dopamine release in response to mesopontine cholinergic stimulation, and improves latent inhibition in mice (Yeomans et al.; Forster et al., 2001; Wang et al., 2004). It is believed that M5 muscarinic receptors on dopamine neurons in the ventral tegmental area (VTA) play essential roles in these dopamine-mediated functions. Electrotransfer is an efficient way of gene delivery. Several studies reported in vivo micro-electroporation of genes into local brain sites leading to functional changes (Inoue et al., 2003; Zhuo et al., 2003). Here, we used 10 mA, 2 ms electric pulses to deliver M5 genes directly into VTA cells. To avoid interference of the M5 receptor by the reporter, we chose the CMV-IRES vector, and used the less toxic hrGFP instead of EGFP. For maximal translation of M5 mRNA, a strong Kozak sequence was added prior to the start codon. Expression of GFP was better near the anode than the cathode, reached a peak 4 days after electroporation, and lasted at least 3 weeks. GFP-positive cells in VTA as large as 23 microns were observed, suggesting successful M5 gene expression in dopamine neurons. Further double-labeling work with tyrosine hydroxylase and M5 (or flag) antibodies is needed to show whether the GFP-positive cells are dopamine neurons. Improved brain-stimulation reward was observed in M5-IRES-hrGFP electroporated rats (Steidl et al., 2004). This study helps understand the molecular and cellular bases of the M5-gene mediated behavioral change. Support Contributed By: Canadian Institutes for Health Research

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62. Ypsilanti, Athéna*Program in Neuroscience, Department of Laboratory Medicine and Pathobiology, University of Toronto - Neuroscience Research Program,

& Aubert, Isabelle

Sunnybrook and Women’s College Health Sciences Centre CHOLINERGIC DEGENERATION DURING NORMAL AGING AND IN A TRIPLE-TRANSGENIC MOUSE MODEL OF ALZHEIMER’S DISEASE Pathological aging is associated with a decrease in cell number in several brain areas. The situation in normal aging differs; suggesting that age-related decline in cognitive functions is related to neuronal dysfunction, and perhaps axonal degeneration, rather then neuronal death. This study will use novel stereological tools to provide quantitative data on the status of cholinergic neurons during normal and pathological aging, exemplified in a mouse model of Alzheimer’s disease (AD) which overexpresses mutants of presenilin 1 (PS1), human amyloid precursor protein (APP), and tau. This PS1/APP/tau line develops both beta-amyloid plaques and neurofibrillary tangles, which are the main neuropathological characteristics of AD. In addition to estimating cell numbers, we will evaluate the size of the cell bodies in the medial septal nuclei (MS) and the axonal length density in the hippocampal formation (HF). The activity of choline acetyltransferase (ChAT) and the levels of nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) will also be measured. Current results indicate that, in aging, the total number of cell bodies and their size, as well as the levels of ChAT activity, NGF and BDNF in the HF and the MS are maintained at 24 months of age. We are currently focusing on the analysis of axonal length densities in aging. Initial neurochemical data obtained in young (2 months-old) PS1/APP/tau mice reveal normal levels of neurotrophic factors and ChAT activity. We are pursuing these analyses in 12 months-old PS1/APP/tau mice. These results will provide a comprehensive understanding of the impact of normal aging on the status of cholinergic neurons, both at the level of the cell bodies in the MS and of their distant axons in the HF. Furthermore, the use of PS1/APP/tau mice will allow, for the first time, to test the spatio-temporal influence of the combined pathology of beta-amyloid and tau on the cholinergic septohippocampal pathway.

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63. Zamir O.Department of Physiology, University of Toronto

* and Charlton M.

THE ROLE OF CHOLESTEROL DEPLETION IN NEUROTRANSMITTER RELEASE The lipid composition of membranes affects their physical properties as well as the function of membrane proteins. While many proteins are known to be essential for exocytosis, the role of membrane lipids in the regulation of synaptic transmission is unclear. Cholesterol controls membrane fluidity and is found in higher concentrations in the synaptic vesicle membrane than in the plasma membrane. Cholesterol depletion produced opposite results on evoked exocytosis in pancreatic beta and PC12 cells. We tested the effects of cholesterol depletion on synaptic transmission at the crayfish neuromuscular junction. Cholesterol depletion reduced the level of evoked synaptic transmission to 10% of the initial value but increased the frequency of spontaneous quantal release 6 fold. The increase in spontaneous release is independent of the calcium concentration as a comparable increase occurred with the removal of extracellular or intracellular calcium. Both responses recovered when cholesterol was reintroduced; eliminating the possibility that cholesterol depletion causes irreversible damage. The amplitude of spontaneous events did not change, suggesting a presynaptic mechanism. We conclude that altering cholesterol levels in the presynaptic membrane modulates several key properties of synaptic transmission. Further work must be done to determine whether the change in cholesterol content affects lipid fusion events directly or works by altering protein function.

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UNDERGRADUATE POSTER ABSTRACTS

64. Bostan, Andreea C.Department of Psychology

, Zelazo, Philip D.

COGNITIVE FUNCTION CORRELATES OF AGE-RELATED CHANGES IN EEG POWER SPECTRA During the neonatal period, human waking electroencephalographic (EEG) rhythms consist of mainly slow frequency waves (delta, <4 Hz, and theta, 4 7 Hz), whereas activity in the higher frequency bands (alpha, 8 12 Hz, and beta, 13 30 Hz) has been observed to increase in relative power with age (Harmony, Marosi, Diaz de Leon, Becker, & Fernandez, 1990). The changes in relative power in the EEG frequency bands take place at different rates in different areas of the brain (Wada, Ogawa, Sonoda, & Sato, 1996). It has been suggested that the changes in the power of EEG frequency bands with maturation may be reflective of development of higher cognitive functions (Case, 1992). However, there is currently no empirical evidence to support these suggestions. The prefrontal cortex provides the neural basis for executive function, a complex array of cognitive processes that allow for cognitive control (Zelazo, Carter, Reznick, & Frye, 1997) and its development throughout childhood is very well documented (Giedd, Blumenthal, Heffries, Castellanos, Liu, Zijdenos, et al., 1999). The present research explores the relation between performance on executive function tasks and the demonstrated increase in gamma band oscillations (3070 Hz, centered at 40 Hz) in the frontal region (Takano and Ogawa, 1998) in 3 to 5 year olds.

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65. Bowles, B.Department of Psychology

, Ferber, S., & Pratt, J.

LETTER PROCESSING INTERFERES WITH INHIBITION OF RETURN (IOR): EVIDENCE FOR CORTICAL INVOLVEMENT IN IOR Inhibition of return (IOR) refers to the finding that when the time lag between a cue and a target is prolonged, the reaction to the target, when it eventually appears, is actually slower than with no cue. This phenomenon is thought to make visual search more efficient and it is subserved by the left inferior parietal cortex and the supramarginal gyrus bilaterally. Interestingly, the very same brain structures are also involved in letter processing. Accordingly, we asked whether the two mental processes interfere with each other when simultaneously probed. The first experiment used a typical IOR procedure but the cue/target placeholders were either simple geometric shapes or English letters. The results show that although IOR is approximately the same across visual fields when shape placeholders are used, it is significantly lessened in the right visual field when letters are used as cue and target placeholders. To examine if this finding was due to potential spatial frequency differences between the placeholders, a second experiment using shapes and Japanese letters was conducted and no differences in IOR were found. The supramarginal gyrus appears to be the most likely locus for the letter-IOR interference effect because it is active bilaterally in IOR, but only in the left hemisphere during letter processing. These findings provide support for the notion that IOR is not simply due to subcortical processes but also involves processing from cortical structures.

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66. Chiew, KDepartment of Psychology, University of Toronto

., Schwindt, G., Fatima, Z., & Anderson, A.K.

NEURAL ACTIVATIONS UNDERLYING THE EXPERIENCE OF MIXED FEELINGS Evidence for mixed feelings, or concurrent experiences of pleasure and displeasure, has been recently demonstrated using the paired-picture paradigm (Schimmack & Colcombe, 1999), which explores participants’ reactions to different valence combinations of emotional stimuli via self-report. In this study participants reported mixed feelings to combinations of positive and negative stimuli. With the current study we aimed to explore the neural systems underlying the experience of mixed feelings using the paired-picture paradigm, investigating activation associated with reported mixed feelings via event-related fMRI imaging. In particular, we explored dissociation between the medial and lateral orbitofrontal cortex, previously noted to be involved in representations of reward and punishment (O’Doherty et al., 2001). This study involved three experimental stages. 24 subjects participated in Stage 1, a stimulus-selection study where subjects emotionally rated individually-presented positive, negative, and neutral stimuli to select pictures that resulted in pure positive, negative or neutral affect. In Stage 2, 24 subjects performed a paired-picture behavioural test, where emotional ratings of pairs of these positive and negative stimuli confirmed prior results of subjective report of mixed feelings. Mixed feelings ratings from Stage 2 were utilized to select stimuli resulting in greatest mixed feelings for Stage 3, completion of the full paired-picture paradigm during fMRI scanning. We hypothesize that simultaneous activation of the medial and lateral orbitofrontal cortices will be observed in association with reported concurrent pleasure and displeasure: such activation may be interpreted as the neural basis of the experience of mixed feelings. Lack of such coactivation would suggest that mixed feelings are an artifact of labelling emotional experience rather than a direct result of simultaneous engagement of appetitive and defensive motivational systems.

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67. Cusi, AndréeDepartment of Psychology, University of Toronto

, Grabski, Wojtek, & Anderson, Adam K.

RESPIRATORY AND VISUAL RESPONSES DURING VOLUNTARY FACIAL ACTION: AN EXAMINATION OF FACIAL EXPRESSIONS AS EVOLUTIONARY ADAPTATIONS FOR SENSORY INTAKE In his book, The Expression of Emotions in Man and Animals

, Darwin proposed that the expressions that characterize certain emotions are patterns of movement that served adaptive functions. While some facial configurations are actions to modify sensory intake (e.g., opening or closing the eyes or nostrils), others are parts of approach and withdrawal movements (e.g., wincing). However, these notions have gone untested in over a century since they were proposed. Recently, researchers have extended this theory by stating that human facial expressions express action tendencies, states of readiness to respond to the environment or rather to establish, maintain, or disrupt a relationship with the environment, placing special emphasis on the communicative rather than functional value of facial expressions. To examine Darwin’s proposed functional role of facial expressions, the present study was designed to assess the effects of voluntarily produced emotional facial configurations on respiration and visual field size. The basic technique of these studies was to measure respiration via three convergent measures (respiratory effort over the chest and abdomen, inspiration through the nasal passages by means of pressures changes via a pneumotach and nasal temperature via a nasal thermistor) during an instructed breathing cycle while participants pose various facial practiced expressions (neutral, disgust, and fear) presented to them. Following the instructed breathing cycle trials, while positioned in front of a large grid filling their visual field, participants were asked to pose the disgust and fear facial configurations, and to indicate changes in their visual field while posing each expression. In addition, ratings of subjective difficulty in generating each expression were obtained.

We hypothesize that the nose wrinkling present in facial configurations of disgust (an expression of nasal-oral irritation) serves the function of reducing the ability to inspire air through the nasal passages, thus respiration through the nasal passages should be decreased for disgust relative to other expressions, such as fear. We also propose that the correlations between reported difficulty and respiratory changes for each configuration will not be significant. Finally, we hypothesize that the raising of one’s eyelids in fear configurations (an expression of attack related threat) will result in an increase in the size of one’s visual field, but posing the disgust facial expression will not produce such an effect. Taken together, the results of this study would provide evidence for the biomechanical properties associated with human facial expressions and suggest that their social communicative value is secondary to their primary functional role in moderating sensory interactions with the environment.

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68. Hau, M.Rotman Research Institute, Department of Neuroscience

, Fujiwara, E., Schwartz, M.L., Miller, B.M., Black, S.E., Levine, B.

THE FRONTAL LOBES AND AUTOBIOGRAPHICAL RECOLLECTION: EVIDENCE FROM TRAUMATIC BRAIN INJURY, FOCAL FRONTAL LOBE LESIONS AND FRONTOTEMPORAL DEMENTIA Much of an individual’s identity is based upon the events that have occurred in his or her lifetime. Retrieval of such personal events can occur by activating one of two separate recognition processes: “remember” (retrieval accompanied by a sense of reliving the event) or “know” (recall without re-experiencing event details). To date, the Remember/Know (R/K) distinction has not been studied in depth with respect to autobiographical memory; the goal of this project is to determine how these subjective retrieval experiences may be affected after damage to frontal and temporal lobe regions. Jacoby’s (1991) independent model of R/K for recognition memory was adopted for this study. A novel, one-step recognition memory test was used to compare R/K performance of autobiographical memories among traumatic brain injury (TBI) patients of varying severities and healthy control participants, as well as among frontotemporal dementia (FTD) patients, focal frontal lesion (FL) patients and older, healthy controls. Participants selected a memory associated with each cue given by the experimenter, and reported whether the retrieval experience was Type A (“remember”), Type B (“know”), or Type N (“no memory” or “never occurred”). Proportions of each response type were compared; as stipulated by the independence view, Jacoby’s adjusted familiarity formula (1996) was used to correct for “know” responses. FTD and FL patients produced significantly fewer “remember” responses compared to older controls, while no differences were seen in corrected “know” responses. No significant differences in R/K were found among TBI severity groups and healthy controls. However, correlations between response types and brain volume data in severe TBIs indicate “remember” responses are associated with damage to left inferior and middle frontal lobe regions, as well as temporal and occipital regions. “Know responses” are correlated with left inferior parietal and posterior temporal damage in severe TBIs. Results support findings from other memory studies which also implicate frontal and temporal lobe regions’ involvement in conscious retrieval with the ability to relive the experience. Results from FTD, FL and healthy control comparisons also appear to support the independence R/K model proposed by Jacoby (1991).

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69. Leung, GraceDepartment of Psychology, University of Toronto; Rotman Research Institute

. Supervised by Dr. J.D. Ryan

INVESTIGATION OF COGNITIVE PROCESSING IN OLDER ADULTS USING EYE MOVEMENT MONITORING This paper examined two prevalent theories associated with age-related deficits in memory: the inhibition deficit theory and the binding deficit theory. The inhibition deficit theory proposes that impaired inhibition processing in older adults leads to encoding of irrelevant information which competes with relevant information during memory retrieval. Binding deficit theory accounts for age-related memory impairment as a failure to successfully encode information. Eye movement monitoring was used to assess attention and encoding processes. Differences in the pattern of allocation of attentional resources and evidence of stored memory representations were observed in younger and older adults.

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70. MacLean, DavidDepartment of Physiology

; Baker, Chris; and MacDonald, John F.

SLOW INACTIVATION OF THE LURCHER MUTATION IN THE GLUR1 SUBUNIT Heterozygous Lurcher mice exhibit ataxia due to the apoptotic death of cerebellar Purkinje neurons and homozygous Lurcher mice die shortly after birth owing to wide-spread mid- and hindbrain cell loss. These phenotypes result from a single amino acid change near the putative second trans-membrane region of the GluRδ2 receptor. The point mutation occurs in a region highly conserved among ionotropic glutamate receptors and renders the GluRδ2 channel constitutively active and Ca2+-permeable. This region is highly conserved among glutamate receptor subunits and previous studies have examined the effects of the Lurcher mutation in these receptors. In GluR1 recombinant receptors, the Lurcher mutation (GluR1-Lc) significantly increases the potency of glutamate and kainic acid, converts the glutamate receptor antagonist CNQX into an agonist and reveals a novel form of slow inactivation. GluR1 wild-type receptors (GluR1-wt) completely inactivate in 2-3 ms, while GluR1-Lc inactivate incompletely and over a period of 10 to 25 minutes. To investigate the mechanism of this slow inactivation, GluR1-Lc and GluR1-wt mRNA was microinjected into Xenopus laevis oocytes and recordings made using two-electrode voltage-clamp. Slow inactivation was shown to be Ca2+-dependant and enhanced by the PKC inhibitor, chelerythrine. Conversely, PKC stimulation via the phorbol ester, PMA, reduced inactivation of the receptor. Our results suggest that Ca2+-dependant dephosphorylation of the PKC site in GluR1 promotes inactivation, and that the slow inactivation of the GluR1-Lc may be due to a structural change favoring phosphorylation by PKC.

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71. Purzner, Jamie

1 Department of Neuroscience, University of Toronto

1; Paradiso, Guillermo2,3; Cunic, Danny2; Saint-Cyr, Jean A.2,4; Hoque, Tasnuva2,4; Mahant, Neil3; Lozano, Andres M.2,4; Lang, Anthony E.2,3; Chen Robert2,3

2 The Krembil Neuroscience Centre and Toronto Western Research Institute 3 Division of Neurology, University of Toronto 4 Division of Neurosurgery, University of Toronto MOVEMENT RELATED POTENTIALS AND OSCILLATORY ACTIVITY IN THE SUBTHALAMIC NUCLEUS AND VENTRAL LATERAL THALAMUS DURING SELF-PACED AND CUED MOVEMENTS Oscillatory activity has been reported in cortical and basal ganglia motor regions. In this study, local field potentials were recorded from deep brain stimulating (DBS) electrodes in the subthalamic nucleus (STN) and ventral lateral thalamic nuclei (VL) to compare how these regions are involved in movement preparation. We studied 7 patients with Parkinson’s disease (PD) and 5 patients with tremor who had been treated with DBS. Potentials were recorded from DBS electrodes and scalp electrodes simultaneously during self-paced movement and during an externally cued (ready, go/no-go) movement. The electrodes were implanted within the STN for patients with PD and within the VL for patients with tremor. During self-paced movement a pre-movement related potential (pMPR) was observed in all patients from cortical, STN and VL electrodes. The average onset for the pMPR recorded from the STN (-2299 ± 762 ms) and the cortex (2067 ± 585 ms) were not significantly different. However, the onset of the VL pMPR (-1494 ± 811 ms) occurred significantly later then both cortical and STN potentials. During externally cued movements an expectancy potential was observed soon after the ready signal in cortical and STN electrodes but not in the VL electrodes. The contact with maximum amplitude or phase reversal was localized to be within the STN or VL using post surgical MRI verification. The average power spectrum of patients with PD and tremor revealed peaks at alpha (10 Hz) and beta (20 Hz) frequencies in cortical, STN and VL electrodes. Time-frequency distribution was determined using a continuous wavelet transform. The baseline frequency content was subtracted and changes in frequency content were observed over time. Significant event related desynchronization (ERD) throughout alpha and beta frequencies was observed in the cortex, STN and VL prior to self-paced movements. Between the ready and go/no-go signal, significant beta desynchronization was observed in the STN but not in the VL. The findings suggest the STN is involved in both cued and self-paced movements while the VL is only involved in self-paced movement. In addition, decreasing beta power appears to be significant not only in movement preparation but also movement expectancy.

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72. Rick, John T., Shirin JaliniDepartment of Physiology

& Peter L. Carlen

EFFECT OF AMPAKINES ON NEOCORTICAL PAIRED-PULSE RATIOS

Abnormalities in AMPA receptor function and/or distribution have been implicated in numerous developmental and degenerative neurological disorders. Previous work has suggested that Ampakine drugs, a specific class of AMPA receptor agonists, might serve to ameliorate cognitive deficits associated with these disorders by enhancing synaptic transmission. We recorded field potentials from neocortical slices of normal adult mice in the presence of low, medium, or high concentration of Ampakine CX516. Efficacy of synaptic transmission was assessed using paired-pulse tests administered before, during, and after drug infusion. At the high dose, Ampakine significantly increased the amplitude of the transynaptic excitatory components of the neocortical response. In paired-pulse tests, the drug significantly decreased the response to the second pulse in a dose-dependent manner, with responses at short interpulse intervals being the most depressed. We believe that this effect is a consequence of increased GABA-mediated feedforward and feedback inhibition resulting from enhanced AMPA response at excitatory synapses upon inhibitory interneurons. The increase in efficacy of excitatory transmission suggests that Ampakines may be beneficial in improving some aspects of synaptic functions, but the implied suppression of burst mode communication argues against their potential utility as a general enhancer of cognitive function.

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73. Schoen, Tanya1Department of Neuroscience, Faculty of Arts and Science

1 & Tremblay, Luc2

2Faculty of Physical Education and Health EFFECT OF STRESS ON IMPLICIT LEARNING

Does stress arousal interfere with the performance of learned motor skills? In this experiment, implicit learning processes will be used to examine the effect of stress on the demonstration of learned motor skills. Participants will perform a visuo-motor tracking task, which will require them to keep a cursor superimposed on a central target using key presses. Both experimental groups will be submitted to 100 acquisition trials of fifteen (15) seconds each, either without (i.e., Control Group) or with (i.e., Implicit Learning Group) a fixed sequence for the middle five (5) seconds. It has been shown that individuals cannot reliably detect the consistency of the perturbations during the middle five (5) seconds between trials (Pew, 1966). Following a 24 hour period, there will be a retention condition as well as a condition designed to elicit a stress arousal response. The stress response will be monitored through Galvanic Skin Response (GSR) and Heart Rate (HR). The tracking task performance will be assessed using the Root Mean Squared Error (RMSE) taken from the distance between the cursor and the central target every 10 ms. We expect to find significantly less RMSE in the experimental group compared to the control group in the retention phase due to implicit learning. If stress does interfere with performance of learned motor skills, we expect no group differences in the stress condition.

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74. Schwindt, Graeme,G Schwindt, K Chiew: Undergraduate Neuroscience Program, University of Toronto

Kimberly Chiew, Zainab Fatima, & Anderson, Adam K

Z Fatima, AK Anderson: Department of Psychology, University of Toronto THE NEURAL MECHANISMS OF AFFECTIVE PRIMING Affective priming occurs when an emotionally salient stimulus presented at a degraded level of awareness influences subsequent cognitive processing. Murphy and Zajonc (1993) showed that the rapid presentation of an emotional prime face (happy or angry) followed by an emotionally neutral symbol (Chinese Ideograph) resulted in subjective “liking” ratings of the symbols that were congruent with the valence of the prime face (i.e., more negative following presentation of an angry face, and more positive following presentation of a happy face). This priming effect disappeared when the emotional prime faces were presented such that participants had explicit awareness of them. This finding suggests that separate consciously and unconsciously operating mechanisms influence preference. However, the neural mechanisms supporting these two putative mechanisms are largely unexplored. The present study uses event-related functional MRI to record cerebral blood flow associated with changes in subjective awareness of an emotional prime in an affective priming paradigm. Face primes are presented for 33ms and are either immediately masked (suboptimal awareness) or partially masked with a 100ms delay (optimal awareness). The two condition manipulations of awareness were shown to significantly reduce both an objective and subjective measure of prime awareness in a psychophysical experiment. Following primes, participants then make a preference rating on the ideographs. Based on previous research, it is hypothesized that imaging data will show unique functional associations between the amygdala and ventromedial prefrontal cortex (vmPFC) during suboptimal priming conditions with emotionally relevant (i.e., fearful) primes. Previous research has shown that the amygdala is an important structure for processing of fearful faces, while the vmPFC is implicated in preference judgments. It is further expected that these interactions are disrupted during more optimal prime presentation under conditions of greater prime awareness. By contrast, during these optimal presentations, more reflective and conscious processes supported by the lateral prefrontal cortices will control ideograph preference. Additionally, we predict that the magnitude of amygdala activation and vmPFC connectivity will predict behavioural responses (liking judgments) more strongly in suboptimal than optimal prime conditions. These findings would provide evidence of the neural mechanisms supporting affective priming and further support for the notion that separable neural processes support unconscious and conscious influences on choice preference behaviour.

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75. Wettlaufer, P.Department of Psychology, University of Toronto

Ralph, M., & Anderson, Adam K.

REACTIONS TO DEFORMITY AND DISFIGUREMENT: AN EVOLUTIONARY PERSPECTIVE Evolutionary Psychology captured public attention when researchers found positive correlations between attractiveness, fertility, longevity, and “averageness”. Although research regarding the human ideal is informative, psychology has much to benefit from study of physical deviation. Human rejection of physically unacceptable others can be so powerful that many parents leave their own children to die of neglect if they possess physical deformities. As such, sensitivity to physical deviation strongly influences social relations. This series of studies explores the nature of differential rejection based on the acquired or genetic status of deviation. The present study compared participant reactions to the physical deviations of injury (acquired during ones lifetime) and deformity (congenital genetic anomalies) through three experiments. In all three experiments, photographs of injured, deformed and normal hands served as independent variables. In experiment one, participants viewed a series of hand photographs presented on a computer screen, and rated whether they believed the hands were deformed, injured, or normal. Participants then rated the hands for perceived functionality. Participants clearly distinguished between injured and deformed hands. Despite recognizing the genetic vs. acquired origin of deviation, participants rated hands of each type as equally functional. Thus any perceived difference in social fitness was not due to unequal function. In experiment two, subjective assessments of socio-biological fitness were assessed by examining participants’ ratings of pleasantness/unpleasantness, and indicated which emotion (e.g., disgust, fear, surprise) they experienced most strongly when viewing each hand image. In Experiment 3, an objective measure of the special significance of genetic anomaly detection was employed by examining differences in reflexive attentional orienting to disfigured and deformed hands when subjects performed a concurrent simple line detection task. These studies will shed light on whether humans have evolved to support a bias towards experiencing subjective aversion and detection of genetic anomaly to prevent transmission of genetic defects to their offspring.

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76. Yassa, Marilyn,Department of Pharmacology, University of Toronto

Kong, Michael, George, Dr. Susan R

LOCALIZATION OF HUMAN D1 DOPAMINE RECEPTORS IN CAVEOLAE AND PHARMACOLOGICAL CHARACTERIZATION OF D1 CAVEOLIN-BINDING RECEPTOR MUTANTS The 21-24 kDa integral membrane protein caveolin-1 (cav-1) is the primary component of caveolae, which are 50-100 nm nonclathrin-coated flask-shaped plasma membrane invaginations. Caveolin has been found in most mammalian tissues, including astroglial cells, cerebral cortex and cerebellum of the rat brain. Caveolin has been implicated in the compartmentalization and functional modulation of various cytosolic signaling proteins and G-protein coupled receptors (GPCR’s) through a proposed aromatic caveolin-binding motif - ΚXΚXXXXΚ or ΚXXXXΚXXΚ or combined- ΚXΚXXXXΚXXΚ, where Κ is an aromatic residue (Trp, Phe, or Tyr). The D1 dopamine receptor is a GPCR that is widely expressed in the brain’s neuronal cells, as well as in astrocytes. Here, it has been proposed that through its proposed caveolin-binding domain the D1 dopamine receptor interacts with cav-1, and various D1 receptor point mutants have been used to characterize the proposed function of this domain in D1 receptor function. Detergent-free sucrose gradient fractionation was used to purify caveolin-rich membrane domains using c-myc tagged cav-1 and HA tagged human D1 receptor (hD1R) transiently expressed in COS-7 cells. Immunoblotting was performed and cav-1 was found to cofractionate with hD1R. Agonist-induced translocation of the D1R into caveolae was observed by using the D1 specific agonist SKF81297 and the techniques mentioned previously. Saturation binding experiments performed with the putative caveolin-binding mutants F313A, W318A and W321A transfected in COS-7 cells using [3H] SCH23390 antagonist, indicated that the W321A mutant did not bind ligand, whereas the other two mutants bound ligand with affinity similar to that of wild-type D1R. Competition binding experiments using SCH23390 and SKF81297, performed only on the F313A and W318A mutants, determined that both mutants bound to SKF81297. These results indicate that the hD1R may potentially interact with cav-1 with a potential role for modulation of receptor functioning, and assign a key role for the W321 residue in ligand-binding ability. Further studies with the ligand-binding F313A and W318A mutants can be used to measure their signal transduction ability, to determine the possible effect of these mutations on D1R signaling and effects on interaction with cav-1.