University of Toronto Neuroscience Program

ANNUAL POSTER DAY Collaborative Program in Neuroscience

Stone Lobby, Medical Sciences Building, University of Toronto Wednesday April 14, 2010

The 2010 University of Toronto Neuroscience Annual Poster Day was held Wednesday April 14, 2010 in conjunction with David Brooks’ Distinguished Lecture "Imaging inflammation in neurodegenerative diseases"

Congratulations to the five top posters:

Graeme Schwindt

David Wasserman

Monika Janus

Ava Elahipanah

Adelaide Yiu

Each was awarded a $100 gift certificate to the UofT Bookstore and a certificate. Thank you to all those students who presented and attended. A very special thank you to the faculty and postdocs who volunteered to judge the presentations: Susanne Benseler, JonathanDostrovsky, Zhong-Ping Feng, Zheng-Ping Jia, John Kennedy, Myriam Lafreniere-Roula, William MacKay, Jose Nobrega, Ian Rogers, Joanne Rovet, Lorelei Silverman Gavrila, Frances Skinner, Margot Taylor, Vincent Tropepe, Alexander Velumian, Lu-Yang Wang, Jerry Warsh, John Yeomans

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Schedule Location | Medical Sciences Building, University of Toronto

9:30 – 10:00am Registration, Poster Setup | Stone Lobby

10:00am – 1:00pm Poster viewing | Stone Lobby

10:30am -12:00pm Poster judging | Stone Lobby

12:00 - 1:00pm Pizza Lunch | Stone Lobby

1:00-2:00pm Distinguished Lecture: David Brooks | Rm 3153

2:00pm Announcement of Top Posters | Rm 3153

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Poster List by Submitting Author

1. Abi-Jaoude E; Sandor P 1Institute of Medical Science; 2Department of Psychiatry, University of Toronto; 3Tourette Syndrome Neurodevelopmental Clinic, Toronto Western Hospital, UHN; 4Youthdale Institute for Paediatric Neuroscience; BRAIN ACTIVATION RELATED TO URGES IN TOURETTE SYNDROME DETECTED BY FMRI – A STUDY IN PROGRESS

2. Acton BA1; Ivakine EA2; McInnes RR2; Woodin MA1 1Department of Cell & Systems Biology, University of Toronto, 25 Harbord Street, Toronto, M5S 3G5; 2Program in Stem Cell and Developmental Biology, Hospital for Sick Children Research Institute, Toronto, M5G1L7; NETO2 IS A NOVEL REGULATOR OF THE POTASSIUM CHLORIDE CO-TRANSPORTER KCC2 AND GABA-MEDIATED SYNAPTIC INHIBITION

3. Adusei DC1; Pacey LK1; Chen D1; Hampson DR1 1Department of Pharmaceutical Sciences, University of Toronto; ALTERED GABA RECEPTOR EXPRESSION AND FUNCTION IN FRAGILE X KNOCKOUT MICE

4. Arruda-Carvalho M1,3; Sakaguchi M1,2; Frankland PW1,2,3 1Hospital for Sick Children, Toronto, ON, Canada; 2Department of Physiol.,; 3Inst. of Med. Sci., Univ. of Toronto, Toronto, ON, Canada; VISUALIZATION OF ADULT BORN NEURONS INCORPORATED IN THE MEMORY NETWORK USING NESTIN TRANSGENIC MICE

5. Arshad SA1,5; Anderson NA3,4,5; Polatajko HP1,2; Dawson DD1,2,5 1Graduate Department of Rehabilitation Science, Departments of; 2Occupational Science & Occupational Therapy; 3Psychology, and; 4Medicine, University of Toronto; 5Kunin-Lunenfeld Applied Research Unit, Baycrest; NATURALISTIC ASSESSMENT OF EXECUTIVE DYSFUNCTION: THE VALUE OF EVENT RECORDING

6. Ballios BG1; Cooke MJ2; Shoichet MS1,2,3; Van der Kooy D1,4 1Institute of Medical Science, University of Toronto; 2Chemical Engineering and Applied Chemistry, University of Toronto; 3Institute of Biomaterials and Biomedical Engineering, University of Toronto; 4Molecular Genetics, University of Toronto; DEVELOPMENT OF A STEM CELL DELIVERY SYSTEM TO TREAT RETINAL DEGENERATIVE DISEASES

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7. Barr MS1; Farzan F1; Arenovich T2; Chen R3; Fitzgerald PB4; Daskalakis ZJ1 1Schizophrenia Program, Centre for Addiction and Mental Health, Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada; 2Biostatistical Consultant, Centre for Addiction and Mental Health, Toronto, Ontario, Canada; 3Division of Neurology, Toronto Research Institute, University of Toronto, Toronto, Ontario, Canada; 4Alfred Psychiatry Research Centre, The Alfred and Monash University Department of Psychological Medicine, Commercial Rd Melbourne, Victoria, Australia; THE EFFECT OF REPETITIVE TRANSCRANIAL MAGNETIC STIMULATION ON GAMMA OSCILLATORY ACTIVITY IN SCHIZOPHRENIA

8. Barszczyk AM1,2; Li R2,3; Tymianski M1,2,3 1Department of Physiology, University of Toronto; 2Toronto Western Hospital Research Institute; 3NoNO Inc.; DETERMINATION OF THE NADH DEHYDROGENASE SUBUNIT 2 BINDING DOMAIN FOR SRC40-49 AND ITS ATTENUATION OF INFLAMMATORY PAIN

9. Brown ZJ1; Tribe E1; D’Souza NA1; Erb S1 1Centre for the Neurobiology of Stress, Department of Psychology, University of Toronto at Scarborough; INTERACTION BETWEEN NORADRENALINE AND CORTICOTROPHIN-RELEASING FACTOR IN THE REINSTATEMENT OF COCAINE SEEKING

10. Brunello ME1; Hunter JP2; Popovic M3; Dostrovsky J1 1Department of Physiology, University of Toronto, Toronto, Canada; 2Department of Physical Therapy, University of Toronto, Toronto, Canada; 3Rehabilitation Engineering Laboratory, University of Toronto, Toronto, Canada; EFFECTS OF BODY LOCATION ON THE THERMAL GRILL ILLUSION OF PAIN

11. Chee J1; Tung J1; Gage W2; McIlroy W1,3; Zabjek K1 1Graduate Department of Rehabilitation Science, University of Toronto; 2School of Kinesiology and Health Science, York University; 3Department of Kinesiology, University of Waterloo; CHARACTERIZING FOOT PLACEMENT PATTERNS DURING REAL-WORLD ROLLATOR USE: INITIAL DEVELOPMENT AND VALIDATION

12. Clarke L; Van der Kooy D Institute of Medical Science, University of Toronto; THE ADULT MOUSE DENTATE GYRUS CONTAINS A POPULATION OF PROGENITOR CELLS WHICH IS DISTINCT FROM SUBEPENDYMAL ZONE STEM CELLS

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13. Cole CJ1,2; Ross PJ1; Han J-H1; Pekar T1; Vetere G1; Neve RL3; Frankland PW1,2,4; Josselyn SA1,2,4 1Program in Neurosciences & Mental Health, The Hospital for Sick Children, Toronto, ON, Canada M5G 1X8; 2Department of Physiology, University of Toronto, Toronto, ON, Canada; 3Brain and Cognitive Sciences, MIT, Cambridge, MA, USA; 4Institute of Medical Sciences, University of Toronto, Toronto, ON, M5G 1X8; THE TRANSCRIPTION FACTOR MEF2 NEGATIVELY REGULATES LONG-TERM MEMORY FORMATION AND SPINE DENSITY IN MICE.

14. Coppin PW1; Hockema SA1 1Faculty of Information University of Toronto; AN ATTENTION BASED THEORY TO EXPLORE THE COGNITIVE AFFORDANCES OF DIAGRAMS RELATIVE TO TEXT

15. Creed MC1,2; Hamani C1,3; Nobrega JN1,2,4 1Neuroimaging Research Dept., Center for Addiction and Mental Health; 2Dept. of Pharmacology & Toxicology, University of Toronto; 3Toronto Western Hospital; 4Dept. of Psychiatry, University of Toronto; DEEP BRAIN STIMULATION ALLEVIATES MOTOR SYMPTOMS IN AN ANIMAL MODEL OF TARDIVE DYSKINESIA.

16. Diaconescu AO1,2; McIntosh AR1,2 1Rotman Research Institute, Baycrest Center; 2Department of Psychology, University of Toronto; THE COSTS OF SWITCHING BETWEEN “WHAT” AND “WHERE” PROCESSING IN AUDITION AND VISION

17. Ehsani S1,2; Watts JC3; Huo H2; Westaway D4; Wille H3; Schmitt-Ulms G1,2 1Department of Laboratory Medicine and Pathobiology, University of Toronto; 2Centre for Research in Neurodegenerative Diseases, University of Toronto; 3Institute for Neurodegenerative Diseases, University of California San Francisco; 4Centre for Prions and Protein Folding Diseases, University of Alberta; EVOLUTIONARY DESCENT OF PRION FAMILY GENES FROM A ZIP METAL ION TRANSPORT ANCESTOR

18. Elahipanah A1,2; Christensen BK1,3; Reingold EM4 1Institute of Medical Science, University of Toronto; 2Centre for Addiction and Mental Health; 3Department of Psychiatry and Behavioural Neurosciences, McMaster University; 4Department of Psychology, University of Toronto; MEASURING VISUAL SPAN SIZE AMONG PATIENTS WITH SCHIZOPHRENIA USING THE GAZE-CONTINGENT MOVING WINDOW PARADIGM

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19. Elbert A1,2; Gomez L2; Cate-Carter T3; Wigg K2; Feng Y2; Archibald J3; Anderson B3; Kerr E3; Lovett M3; Humphries T3; Barr C1,2,3 1University of Toronto; 2Toronto Western Research Institute; 3Sick Kids Hospital; INVESTIGATION OF DCDC2 (A DYSLEXIA CANDIDATE GENE) FOR ASSOCIATION TO ADHD AND RD

20. Ferguson KA3,1; Skinner FK1,2,3,4 1Toronto Western Research Institute, University Health Network; 2Department of Medicine (Neurology), University of Toronto; 3Department of Physiology, University of Toronto; 4Institute of Biomaterials and Biomedical Engineering, University of Toronto; MATHEMATICAL NETWORK MODELS OF THETA RHYTHMS IN THE HIPPOCAMPUS

21. Findlater J1; Xiao S1; Robertson J1 1Centre for Research in Neurodegenerative Diseases, University of Toronto; PERIPHERIN-28 AS A BIOMARKER OF ALS: A METHODOLOGICAL STUDY

22. Gardezi SR1; Taylor P2; Khanna R3; Stanley EF1 1Department of Physiology, Genetics and Development, Toronto Western Hospital; 2Advanced Protein Technology Centre, Hospital For Sick Children, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8; 3Stark Neurosciences Research Institute, Department of Pharmacology and Toxicology, 950 W. Walnut St., Indianapolis, IN 46202; LONG C TERMINAL SPLICE VARIANT CAV2.2 IDENTIFIED IN PRESYNAPTIC MEMBRANE BY MASS SPECTROMETRIC ANALYSIS

23. Goncharenko K1,2; Eftekharpour E1; Velumian A1,2; Carlen PL1,2; Fehlings MG1 1Divisions of Neurosurgery, Cell and Molecular Biology, Toronto Western Research Institute, Krembil Neuroscience Centre, & University of Toronto, Toronto ON, Canada; 2Department of Physiology, University of Toronto, Toronto ON, Canada; GAP JUNCTION FUNCTION AND EXPRESSION IN SECONDARY SPINAL CORD WHITE MATTER INJURY.

24. Green S1; Keightley ML1,3; Chen JK1,3; Ptito A2; Johnston K3; Saluja R2 1Rehabilitation Science, University of Toronto; 2Montreal Neurological Institute; 3Toronto Rehab; CHANGES TO BRAIN ACTIVATION AND TASK PERFORMANCE DURING A VISUAL WORKING MEMORY TASK IN YOUTH POST-MTBI: AN FMRI STUDY

25. Han HA1,3; Wu Y3; Cortez MA2,3; Shen L3; Snead OC III1,2,3 1Institute of Medical Science, University of Toronto, Toronto, ON, Canada; 2Department of Paediatrics, Faculty of Medicine, University of Toronto, Toronto, ON, Canada; 3Program in Neuroscience and Mental Health., Hosp. for Sick Children, Toronto, ON, Canada; BEHAVIORAL CHARACTERIZATION OF TRANSGENIC MICE WITH OVER-EXPRESSION OF GABA(B) RECEPTORS

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26. Hawryluk G1,2; Mothe A1; Tator C1,2; Fehlings MG1,2 1Toronto Western Research Institute; 2Division of Neurosurgery, Department of Surgery, University of Toronto; CELL-BASED REPAIR STRATEGIES FOR SPINAL CORD INJURY: EXAMINATION OF TROPHIC FACTOR EXPRESSION IN VIT

27. Ho KT1,4; Lam EMILY1; Griffin J4; Mac J5; Brown M4; Mclaurin J2,4; Mount HT1,3,4 Departments of; 1Physiology; 2Laboratory Med. and Pathobiology; 3Med., Univ. of Toronto, Toronto, ON, Canada; 4Ctr. for Res. in Neurodegenerative Dis., Toronto, ON, Canada; 5Humberside Collegiate, Toronto, ON, Canada; BEHAVIOURAL PHENOTYPES OF DJ-1-DEFICIENT MICE IMPLICATE ALTERED TRANSMISSION IN MULTIPLE BRAIN AREAS AND ARE DIFFERENTIALLY AFFECTED BY ATM EXPRESSION

28. Ho ECY1,2; Zhang L1,3; Skinner FK1,2,3,4 1Toronto Western Research Institute, University Health Network, Toronto, Ontario, Canada Departments of; 2Physiology; 3Medicine (Neurology); 4Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada.; INDIVIDUAL NEURON CHARACTERISTICS AND THE CONTROL OF SLOW POPULATION ACTIVITIES

29. Hodgson N1; Lewis MD2 1,2Human Development and Applied Psychology, University of Toronto; BRAIN AND BEHAVIOUR INDICES OF SELF-MONITORING IN CHILDREN WITH BEHAVIOURAL PROBLEMS

30. Hung Y1,3; Smith ML2,3; Taylor MJ1,3 1Diagnostic Imaging, Hospital for Sick Children; 2Psychology, Hospital for Sick Children; 3Department of Psychology, University of Toronto; FUSIFORM LATERALITY AND LIMBIC-FRONTAL ACTIVITY DURING EMOTIONAL FACE PROCESSING

31. Janus MK1; Lewis MD1 1Human Development and Applied Psychology, University of Toronto; NEUROPHYSIOLOGICAL CORRELATES OF SELF-MONITORING DIFFERENTIALLY MODERATE THE RELATION BETWEEN MATERNAL DEPRESSION AND CHILDREN’S BEHAVIOUR PROBLEMS

32. Johnson SA1; Sediqzadah S1; Erb S1,2 1Department of Psychology, U of T Scarborough; 2Centre for the Neurobiology of Stress, U of T Scarborough; RECENT COCAINE EXPERIENCE RENDERS CONDITIONED LOCOMOTOR RESPONSES RESISTANT TO EXTINCTION

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33. Jordao JF1,2; Ayala-Grosso CA3,2; Huang Y2; Chopra R1,2; McLaurin J1,4; Hynynen K1,2; Aubert I1,2 1University of Toronto; 2Sunnybrook Research Institute; 3Unidad de Biología Molecular, Universidad Central de Venezuela; 4Centre for Research in Neurodegenerative Disease; RAPID REDUCTION OF AΒ PLAQUE LOAD IN THE BRAIN OF TGCRND8 MICE FOLLOWING ULTRASOUND-ENHANCED IMMUNOTHERAPY

34. Kanawaty AK1; Van der Kooy D2; Henderson JT1 1Faculty of Pharmaceutical Sciences, University of Toronto; 2Department of Medical Biophysics, University of Toronto; ROLE OF EPHB2 IN REGULATING MORPHINE DEPENDENT RESPONSE

35. Karpova A1; Sooyong C1; Rabin D1; Craciunas S1; Smith SR1; Fehlings MG1,2 1Department of Surgery, Division of Neurosurgery, University of Toronto, Toronto, Ontario, Canada; 2Spinal Program, Krembil Neuroscience Centre, Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada; 3Department of Radiology, Division of Neuroimaging, University of Toronto, Toronto Western Hospital, Toronto,Ontario, Canada.; INTER-RATER AND INTRA-RATER RELIABILITY OF RATINGS OF FOUR QUANTITATIVE METHODS TO ASSESS SPINE STENOSIS ON MAGNETIC RESONANCE IMAGING IN PATIENTS WIT

36. Kirshenbaum G1,2; Clapcote S5; Roder J1,2,3,4 1Institute of Medical Science, University of Toronto; 2Samuel Lunenfeld Research Institute, Mount Sinai Hospital; 3Department of Physiology, University of Toronto; 4Department of Medical Genetics, University of Toronto; 5Institute of Membrane and Systems Biology, University of Leeds; MANIC BEHAVIOUR IS ATTENUATED IN A MOUSE MODEL OF MANIA BY REDUCTION OF AGRIN AND ERK SIGNALING.

37. Koshimori Y1,2; Turner G3; Crawley A4; Mikulis DR4; Bradbury CL2; Green REA2 1Graduate Department of Rehabilitation Science, University of Toronto; 2Toronto Rehabilitation Institute; 3Sunnybrook Health Sciences Centre; 4Toronto Western Hospital; DIFFUSION TENSOR IMAGING (DTI) VS CONVENTIONAL MRI FOR SINGLE CASE DIAGNOSIS OF MILD TRAUMATIC BRAIN INJURY (MTBI)

38. Kostelecki W1,2; Perez Velazquez JL1,2 1Institute of Medical Science, University of Toronto; 2Neurosciences and Mental Health Program, Hospital for Sick Children; CLASSIFICATION OF BRAIN STATES FROM MEASURES OF DIRECTED CORTICAL PROCESSING

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39. Krakowski A1,2; Frankland P1,2 1Institute of Medical Science, University of Toronto; 2Department of Neurosciences and Mental Health, Hospital for Sick Children; FUNCTIONAL INTEGRATION OF ADULT-BORN GRANULE CELLS INTO DENTATE GYRUS CIRCUITRY

40. Kuipers MJ1; Popovic MR3,4,5; Verrier MC1,2,3,5 Departments of; 1Physiology; 2Physical Therapy; 3Rehabilitation Science, Faculty of Medicine; 4Institute of Biomaterials and Biomedical Engineering, University of Toronto; 5Toronto Rehabilitation Institute, Lyndhurst Center, Toronto, Ontario, Canada.; TRUNK NEUROPROSTHESIS FOR SPINAL CORD INJURY: RELATIONSHIP BETWEEN POSTURAL CONTROL AND RESPIRATORY CAPACITY

41. Kupferschmidt DA; Wang T; Erb S Centre for the Neurobiology of Stress, Department of Psychology, University of Toronto Scarborough.; THE CANNABINOID-1 RECEPTOR ANTAGONIST, AM251, BLOCKS THE EFFECTS OF CRF ON ANXIETY AND REINSTATEMENT OF COCAINE SEEKING

42. Lam JJ1; Hunter JP2; Dostrovsky JO1 1Department of Physioglogy, University of Toronto; 2Toronto Rehab Institute, Toronto, ON, Canada; INTENSITY OF THE THERMAL GRILL ILLUSION DEPENDS ON CONFIGURATION OF GRILL ELEMENTS

43. Lecker I1; Chen X1; Mazer CD1,3,4; Orser BA1,2,3 1Department of Physiology, University of Toronto; 2Sunnybrook Health Sciences Centre, University of Toronto; 3Department of Anesthesia, University of Toronto; 4Cara Phelan Centre for Trauma Research, Keenan Research Centre in the Li Ka Shing Knowledge Institute, St. Michael's Hospital; TRANEXAMIC ACID PREFERENTIALLY TARGETS EXTRASYNAPTIC GABAA RECEPTORS

44. Lee DH1; Susskind JM1; Anderson AK1 1Psychology, University of Toronto; EFFECTS OF FEAR EXPRESSIONS ON EYE GAZE PERCEPTION

45. Lindvere L1; Sun J1; Dorr A1; Van Raaij M1; Foster S1; Stefanovic B1 1Imaging Research, Sunnybrook Research Inststitute; HIGH FREQUENCY ULTRASOUND IMAGING OF CEREBRAL BLOOD FLOW

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46. Ljubojevic V1; De Rosa E1 1Department of Psychology, University of Toronto; DOES THE NEUROCHEMICAL ACEYLCHOLINE MODULATE BOTH VISUAL AND OLFACTORY ATTENTION?

47. Luu P1; Becker3; Smith DM2; Wojtowicz JM1 1Department of Physiology, University of Toronto, 1 King’s College Circle, Toronto, Ontario, Canada; 2Department of Psychology, Cornell University, 252 Uris Hall, Ithaca, New York, New York; 3Department of Psychology, McMaster University, 1280 Main St. W., Hamilton, Ontario, Canada.; EFFECTS OF ADULT NEUROGENESIS ON CONTEXTUAL LEARNING AND MEMORY INTERFERENCE

48. Malik A1; Buck LT1,2 1Cell and Systems Biology, University of Toronto; 2Ecology and Evolutionary Biology, University of Toronto; SEASONAL PLASTICITY OF GABAERGIC SYNAPTIC TRANSMISSION IN LYMNAEA STAGNALIS

49. McFarlane MT1,2; Mirabella G1; Wright T1; Westall CA1,3 1Ophthalmology and Vision Sciences, The Hospital for Sick Children, Toronto, ON, Canada; 2Institute of Medical Science; 3Ophthalmology and Vision Sciences, University of Toronto, Toronto, ON, Canada.; CONE PATHWAY ABNORMALITIES IN ADOLESCENTS WITH TYPE 1 DIABETES AND NO CLINICALLY EVIDENT DIABETIC RETINOPATHY

50. McIlveen-Brown E1; Tannock R1,2 1Ontario Institute for Studies in Education (OISE), University of Toronto, Toronto, Canada; 2Ontario Institute for Studies in Education (OISE), Hospital for Sick Children, Toronto, Canada; MOTOR SKILLS IN ADOLESCENT ATTENTION DEFICIT/HYPERACTIVITY DISORDER (ADHD): GENDER SPECIFIC PROFILES OF FINE AND GROSS MOTOR PERFORMANCE

51. Moxon-Emre I1,2; Schlichter LC1,2 1Toronto Western Research Institute University Health Network; 2Department of Physiology, University of Toronto; EVOLUTION OF INFLAMMATION AND WHITE MATTER INJURY IN A MODEL OF TRANSIENT FOCAL ISCHEMIC STROKE

52. Nahirny A1,3; Fong J1,3; Mills LR1,2,3 1Department of Physiology; 2Faculty of Medicine; 3University of Toronto, Division of Genetics and Development TWRI University Health Network.; ELEVATED CA(I) INCREASES MITOCHONDRIAL PROTEIN IMPORT AND ACCUMULATION OF MITOCHONDRIAL PROTEINS IN DIFFERENTIATED PC12 CELLS AND RAT CORTICAL NEURONS

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53. Nejatbakhsh N1; Guo CH1; Lu TZ1; Van Kesteren R2; Feng ZP1 1Department of Physiology, University of Toronto, Toronto, Canada; 2Department of Molecular and Cellular Neurobiology, Free University, Amsterdam, Netherlands; REGULATION OF LOCAL CYSKELETAL ELEMENTS BY A NOVEL LYMNAEA PROTEIN PROMOTES NEURITE EXTENSION FOLLOWING AXOTOMY

54. Ng E1,2,3; Marziali E1,2; Polatajko H1; Dawson D1,2,3 1University of Toronto; 2Baycrest Centre; 3Toronto Rehab Institute; USING TELE-REHABILITATION TO ADDRESS EXECUTIVE DYSFUNCTION AND COMMUNITY INTEGRATION AFTER TRAUMATIC BRAIN INJURY

55. Ng TS1; Trubiani G1; Lovejoy DA1 1Cell and Systems Biology, University of Toronto; THE EFFECT OF TENEURIN C-TERMINAL ASSOCIATED PEPTIDES-1 (TCAP-1) ON BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) AND REACTIVE OXYGEN SPECIES (ROS)

56. Nguyen DH1,2; Cho N1,2; Wang J2; Fehlings M1,2,3,4,5 1Institute of Medical Science, Faculty of Medicine, University of Toronto; 2Division of Genetics and Development, Toronto Western Research Institute; 3Krembil Neuroscience Center, University Health Network; 4Division of Neurosurgery, University of Toronto; 5University of Toronto Neuroscience Program.; NEUROPROTECTIVE EFFECTS OF INTRAVENOUS IMMUNOGLOBULIN G (IVIG) AFTER SPINAL CORD INJURY

57. Rizvi, SJ1,2; Sproule BA3,4; Kennedy SH2,5; Usoa BUSTO3,4 1Departments of Pharmaceutical Sciences and Neuroscience, University of Toronto; 2Department of Psychitary, University Health Network; 3Centre for Addiction and Mental Health; 4Faculty of Pharmacy, University of Toronto; 5Department of Psychiatry, University of Toronto; DOPAMINERGIC FUNCTIONING IN TREATMENT RESISTANT DEPRESSION: THE EFFECT OF DEEP BRAIN STIMULATION

58. Roedding AS1,2,3; Au-Yeung W1,2; Gao AF1,2; Li PP1,2,4; Warsh JJ1,2,3,4,5 1Cellular & Molecular Pathophysiology, Centre for Addiction and Mental Health; 2Pharmacology and Toxicology, University of Toronto; 3Univeristy of Toronto Neuroscience Program; 4Psychiatry, Univeristy of Toronto; 5Institute of Medical Sciences,University of Toronto; CHRONIC OXIDATIVE STRESS REGULATES TRP CHANNEL EXPRESSION: RELEVANCE TO BIPOLAR DISORDER

59. Rosenzweig S; Czerwinska E; Orser BA; Wojtowicz JM Department of Physiology, Faculty of Medicine, University of Toronto.; AN IMPORTANT ROLE FOR GABA(A)R-DELTA IN THE REGULATION OF ADULT NEUROGENESIS.

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60. Rudy KM1; Yunusova Y1,2 1Speech Language Pathology,University of Toronto; 2Sunnybrook Health Sciences Center; THE EFFECT OF PALATAL GEOMETRY ON CONSONANT ARTICULATION

61. Saverino C1,2; Grady C1,2,3; Hasher L1,2 1Department of Psychology, University of Toronto; 2Rotman Research Institute, Baycrest Geriatric Centre; 3Department of Psychiatry, University of Toronto; AGING AND IMPLICIT MEMORY FOR EMOTIONAL WORDS

62. Schwindt GC1,2; Graham NL3,4; Rochon E3,4; Tang-Wai D5; Black SE1,2,6 1Institute of Medical Science, University of Toronto; 2Brain Sciences Research, Sunnybrook Research Institute; 3Department of Speech-Language Pathology, University of Toronto; 4Toronto Rehabilitation Institute; 5Department of Medicine, University of Toronto; 6Brill Chair in Neurology, Dept of Medicine, Sunnybrook HSC and University of Toronto; DIFFUSION TENSOR IMAGING METRICS REVEAL WHITE MATTER ABNORMALITIES IN PRIMARY PROGRESSIVE APHASIA

63. Sekeres MJ1,2; Neve RL4; Frankland PW1,2,3; Josselyn SA1,2,3 1The Hospital for Sick Children, Toronto, ON, Canada; 2Department of Physiology, University of Toronto; 3Institute of Medical Science, University of Toronto, Toronto, ON, Canada; 4Department of Brain and Cognitive Science, MIT, Cambridge, MA, USA; INCREASING CREB IN THE DORSAL HIPPOCAMPUS IS SUFFICIENT TO INDUCE SPATIAL MEMORY

64. Shulyakova N1,2; Mills LR1,2 1Division of Genetics and Development, TWRI, TWH, UHN; 2Department of Physiology, University of Toronto.; PROTEASOME INHIBITION AND MITOCHONDRIAL PROTEIN IMPORT: THEIR ROLE IN MITOCHONDRIAL PROTEIN HOMEOSTASIS

65. Silverman LB; Praver M; Charlton MP Department of Physiology, Faculty of Medicine, University of Toronto; PROTEOMICS OF PRESYNAPTIC DIFFERENTIATION

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66. Sinai L1,2; Ivakine EA3; Dida J4; Aubin JE5; Yeomans J4; Ralph M4; McInnes RR3,5; Roder R2,5 1Institute of Medical Science, University of Toronto; 2Samuel Lunenfeld Research Institute, Mount Sinai Hospital; 3Hospital for Sick Children Research Institute; 4Department of Psychology, University of Toronto; 5Department of Molecular and Medical Genetics, University of Toronto; BEHAVIORAL PHENOTYPE OF SRC SPONTANEOUS MUTATION IN MICE

67. Srejić LR1; Aarts MR1,4; Hutchison WD2,3 1Cell and Systems Biology, University of Toronto; 2Physiology, University of Toronto; 3Surgery, Division of Neurosurgery, Toronto Western Research Institute; 4Biological Sciences, Univ. of Toronto at Scarborough; HIGH-FREQUENCY CORTICAL ACTIVITY ASSOCIATED WITH POST-ISCHEMIC EPILEPTIFORM DISCHARGES IN A RAT FOCAL STROKE MODEL IN VIVO

68. Stevens SA1,2; Nash K1,3; Greenbaum R4; Koren G1,2; Rovet J1,2 1Psychology Department, University of Toronto; 2The Hospital for Sick Children; 3Ontario Institute for Studies in Education of the University of Toronto; 4Children’s Mental Health Team, Surrey Place Centre; CAPTURING THE SOCIOEMOTIONAL PROFILES IN CHILDREN EXPOSED TO PRENATAL TERATOGENS

69. Sun X1; Hoque T1; Gunraj, C1; Nelson AJ2; Chen R1 1Division of Neurology and Krembil Neuroscience Centre, Toronto Western Research Institute, University of Toronto; 2Department of Kinesiology, University of Waterloo; SOMATOSENSORY PROCESSING IN PARKINSON’S DISEASE

70. Tan LA1,2; Al Chawaf A1; Xu K2; Vaccarino, FJ2,3; Lovejoy DA1; Rotzinger S3,4 Departments of; 1 Cell and Systems Biology; 2Psychology; 3Psychiatry; 4Institute of Medical Science, University of Toronto; NEWLY-ELUCIDATED NEUROPEPTIDES IN THE HIPPOCAMPUS: THE ROLE OF THE TENEURIN C-TERMINAL ASSOCIATED PEPTIDES (TCAPS) ON STRESS-RELATED PATHWAYS

71. Teitelbaum A1; Perez Velazquez JL2 1Institute of Medical Science, University of Toronto; 2The Hospital for Sick Children, Neuroscience and Mental Health.; BRAIN COORDINATION DYNAMICS AND AUTISM

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72. Titley HK1; Heskin-Sweezie R1; Broussard DM1,2,3 1Department of Physiology, University of Toronto; 2Division of Neurology, Department of Medicine, University of Toronto; 3Division of Fundamental Neurobiology, Toronto Western Research Institute, University Health Network; LEARNING OF GAIN INCREASES IN THE VESTIBULO-OCULAR REFLEX REQUIRES MGLUR1 AND GABAB RECEPTORS IN THE CEREBELLAR CORTEX

73. Tong R1; Zai C1,2; Freeman N1,2; Tampakeras1,2; Shaikh S1,2; Casey D3; Hodgins D3; Smith G4; Williams R5; Schopflocher D6; Wood R7; El-Guebaly N8; Lobo D1,2; Kennedy J1,2 1Neurogenetics Section, neuroscience Department, Centre for Addiction and Mental Health; 2Department of Psychiatry, University of Toronto; 3Department of Psychology, University of Calgary; 4Faculty of Extension, University of Alberta; 5School of Health Sciences, university of Lethbridge; 6Faculty of Nursing, University of Alberta; 7Department of Sociology, University of Lethbridge; 8Division of Addiction, Department of Psychiatry, University of Calgary NO ASSOCIATION BETWEEN THE SEROTONIN TRANSPORTER PROMOTER POLYMORPHISM (5HTTLPR) AND GAMBLING BEHAVIOUR SEVERITY

74. Tsang EW1,2; Hamani C3; Elena MORO2; Mazzella F2; Saha U2; Lozano AM1,3; Hodaie H3; Chen R1,2 1Institute of Medical Science, University of Toronto; 2Division of Neurology, 3Division of Neurosurgery,Toronto Western Research Institute, University Health Network, Toronto, Ontario Canada.; MOVEMENT RELATED POTENTIALS AND OSCILLATORY ACTIVITIES IN THE HUMAN INTERNAL GLOBUS PALLIDUS DURING VOLUNTARY MOVEMENTS

75. Schlichter LC; Kaushal V; Vincent C; Moxon-Emre I; Sivagnanam V Toronto Western Research Institute, University Health Network and Department of Physiology, University of Toronto, Canada; THE SK3 (KCA2.3/KCNN3) CHANNEL IS EXPRESSED IN MICROGLIA IN VIVO AND IN VITRO AND CONTRIBUTES TO MICROGLIAL ACTIVATION AND NEUROTOXICITY

76. Wasserman D1; Lee E2; Wang H1; Rashid A3; Josselyn S3; Yeomans J1,2,4 1Department of Psychology, University of Toronto; 2Department of Cell & Systems Biology, University of Toronto; 3The Hospital for Sick Children Research Institute; 4Centre for Biological Timing and Cognition, University of Toronto; MORPHINE INDUCED LOCOMOTION AND ULTRASONIC VOCALIZATIONS IN M5 KO MICE RESCUED BY VIRAL TRANSFECTION OF M5 MUSCARINIC RECEPTORS IN VENTRAL TEGMENTUM

77. West GL1; Anderson AK1,2; Ferber S1,2; Pratt J1 1Department of Psychology, University of Toronto; 2Roman Research Institute, Baycrest Hosptial; ATTENUATION OF THE DORSAL-ACTION PATHWAY SUPPRESSES FEAR PRIORITIZATION: AN EVOLUTIONARY LINK BETWEEN EMOTION AND ACTION

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78. Wilkinson AA1; Keightley ML1,2,3,4,5; Agnihotri S2; Dick T3; Schwartz D6; Reed, NP1,2; Green S1,2

1Department of Psychology, University of Toronto; 2Graduate Department of Rehabilitation Science, University of Toronto; 3Department of Occupational Science and Occupational Therapy, University of Toronto; 4Toronto Rehabilitation Institute; 5Bloorview Kids Rehab Research Institute; 6Department of Psychology, Ryerson University; VERBAL LEARNING AND MEMORY FOLLOWING MILD TRAUMATIC BRAIN INJURY IN YOUTH: A LONGITUDINAL STUDY

79. Chao H1; Kennedy JM2; Wnuczko M2 1Department of Architecture, National Taiwan University of Science and Technology; 2Department of Psychology, University of Toronto at Scarborough; ELEVATION JUDGED EASIER THAN PLAN BY THE SIGHTED AND BLIND ON PERSPECTIVE TAKING TASKS

80. Yilmaz Z1,3; Kaplan AS2,3; Levitan RD2,3; Kennedy JL2,3 1Institute of Medical Science, University of Toronto; 2Department of Psychiatry, University of Toronto; 3Centre for Addiction and Mental Health; ASSOCIATION OF THE DRD4 GENE WITH COMORBID CHILDHOOD ADHD IN WOMEN WITH BULIMIA NERVOSA

81. Yiu AP1,2; Neve RL3; Hill M4; McLaurin J4,5; Josselyn SA1,2,6 1Program in Neurosciences & Mental Health, Hospital for Sick Children, Toronto, ON, M5G 1X8 Canada; 2Institute of Medical Sciences, University of Toronto, Toronto, ON, M5S 1A8 Canada; 3Dept. of Brain and Cognitive Sciences, MIT, Cambridge, MA 02139 USA; 4Centre for Research in Neurodegenerative Diseases; 5Laboratory Medicine and Pathobiology; 6Dept. of Physiology, University of Toronto, Toronto, ON, M5S 1A8 Canada; ACUTE EXPRESSION OF ALZHEIMER’S DISEASE LINK MUTATIONS LEAD TO SPATIAL MEMORY FORMATION BUT NOT RETRIEVAL DEFICITS IN MICE

82. Zurek AA1; Aydin B1; Orser BA1,2 1Department of Physiology, University of Toronto; 2Department of Anesthesia, Sunnybrook Health Sciences Centre; POST-ANESTHETIC MEMORY IMPAIRMENT IS MEDIATED BY Α5GABAAR ACTIVITY DURING ANESTHESIA

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1. Abi-Jaoude E; Sandor P 1Institute of Medical Science; 2Department of Psychiatry, University of Toronto; 3Tourette Syndrome Neurodevelopmental Clinic, Toronto Western Hospital, UHN; 4Youthdale Institute for Paediatric Neuroscience; BRAIN ACTIVATION RELATED TO URGES IN TOURETTE SYNDROME DETECTED BY FMRI – A STUDY IN PROGRESS Tourette Syndrome (TS) is a neuropsychiatric condition characterized by motor and vocal tics. Tics are sudden, rapid, repetitive motor movements or vocalizations. Tics are under ‘partial voluntary’ control, since these are done in response to an urge. In other words, while the tics do not occur completely independently of one’s control, a person with TS will have a mounting urge such that he/she is compelled to eventually carry out the tic. In addition to tics, people with TS usually have difficulty with self-control in a number of other domains, including thoughts and emotions. The purpose of this study is to understand the development and control of urges in the brain of people with TS, in comparison to healthy controls without TS. We will examine 2 different urges: the urge to blink, which is the most common tic in TS; and the urge to drink water during moderate thirst. This will be done using functional magnetic resonance imaging (fMRI), which allows us to view brain activity in a non-invasive manner. In the MRI scanner, subjects will be asked to refrain from blinking for 1 minute at a time, which will be interleaved with 1 minute periods during which they can blink normally. In addition, subjects will view enticing images of potable water, which will be interleaved with images of random objects. Subjects will be scanned for brain activity during these tasks. The brain activity during the urge to blink and during the urge to drink water in TS subjects will be compared to that of control subjects. Subjects will be also scanned during resting state in order to examine their so-called default mode activity, a now well-recognized network of activity that has been found to be disrupted in several neuropsychiatric conditions. In addition, structural scans will include diffusion tensor imaging (DTI), which provides a measure of connectivity, and high resolution anatomical scans. Further, an exhaustive list of behavioral measures and diagnostic scales are carried out on the subjects. For analysis, the brain activations during the different tasks will be compared will be compared across the groups. Moreover, the brain activity leading up to blinks during the periods of attempted blink suppression will be compared to such activity during periods where subjects are blinking normally. This project will increase our knowledge of the brain structures underlying tic symptomatology. This could guide the development of more targeted treatment options not only in TS, but also in other conditions that involve difficulty controlling impulses. Our study will help to elucidate the neuro-anatomical substrates of the inhibition of internally generated urge in addition to extending our understanding of neuropathophysiology underlying TS. These observations will have implications for other disorders in which inhibitory mechanisms of internal urge appear to be impaired, such as substance abuse. Finally, the findings will contribute our understanding of the influence of urges in seemingly deliberate, voluntary actions.

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2. Acton BA1; Ivakine EA2; McInnes RR2; Woodin MA1 1Department of Cell & Systems Biology, University of Toronto, 25 Harbord Street, Toronto, M5S 3G5; 2Program in Stem Cell and Developmental Biology, Hospital for Sick Children Research Institute, Toronto, M5G1L7; NETO2 IS A NOVEL REGULATOR OF THE POTASSIUM CHLORIDE CO-TRANSPORTER KCC2 AND GABA-MEDIATED SYNAPTIC INHIBITION The objective of the current study was to define the role of the homologous protein, Neto2, in GABA-mediated synaptic inhibition. The strength of GABA-mediated synaptic inhibition is determined by KCC2; Neto2 is a neuronal single pass transmembrane protein that is a putative KCC2 interactor. Experiments were performed on low-density dissociated cultured hippocampal neurons prepared from wild-type and Neto2-/- mice (on a C57Bl/6 genetic background). We used electrophysiogical recordings to examine GABAergic transmission. Specifically, by making gramicidin perforated patch clamp recordings we found that Neto2-/- neurons had significantly reduced GABA-mediated synaptic inhibition. The strength of synaptic inhibition is determined by both the synaptic GABA receptor conductance and by the reversal potential for GABA (EGABA). Our experiments demonstrate that Neto2-/- mice have decreased GABA-mediated synaptic inhibition due to a significant depolarization of EGABA, compared to wild type mice (-53.74 ± 2.43 mV vs. -75.22 ± 2.05 mV; p < 0.001). The depolarization of EGABA suggests a decrease in KCC2 activity. This depolarized EGABA could be completely rescued by reintroducing a full length Neto2 into Neto2-/- neurons; EGABA in rescued cultures was -73.12 ± 3.07 mV (p < 0.001). We further examined whether the decreased synaptic inhibition in Neto2 -/- hippocampal neurons was due to a change in spontaneous neuronal activity during synapse formation and maturation. Overall spontaneous activity of wild type and Neto2 -/- hippocampal neurons in culture (DIC 3-12) was examined using fluorescence imaging. Neurons were loaded with the fluorescence calcium indicator Fluo-4AM; increased calcium fluorescence (> 2000 units/within 2ms) indicated an action potential. We found no significant differences in spontaneous activity between wild type and Neto2 -/- hippocampal neurons throughout their development (DIC 3-12), suggesting that the decreased synaptic inhibition of Neto2 -/- hippocampal neurons is not due to altered neuronal activity. In conclusion, the novel protein Neto2 mediates the strength of GABA-mediated synaptic inhibition by regulating the neuron specific Cl- transporter KCC2.

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3. Adusei DC1; Pacey LK1; Chen D1; Hampson DR1 1Department of Pharmaceutical Sciences, University of Toronto; ALTERED GABA RECEPTOR EXPRESSION AND FUNCTION IN FRAGILE X KNOCKOUT MICE Fragile X syndrome (FXS) is the most common heritable form of mental retardation. The disorder is caused by a trinucleotide repeat expansion in the 5’ UTR region of the Fmr1 gene, resulting in the loss of the Fragile X Mental Retardation Protein (FMRP). The metabotropic glutamate receptor (mGluR) theory of Fragile X posits that Group I mGluRs are overactive in the disorder. However, other receptors are implicated in the disorder, including GABAA (ligand-gated ion channels) and GABAB receptors (G-protein coupled receptors). GABA receptors are involved in several processes that are perturbed in FXS patients, such as controlling the excitability of the brain, modulating anxiety, cognition, memory and learning. Previous studies in Fmr1 knockout mice have focused on GABAergic expression at the mRNA level, while validation with protein expression studies has been comparatively limited. Furthermore, studies have only examined adult Fmr1 knockout mice for alterations in GABAergic transmission. Thus, it is possible that GABAergic alterations occur in Fmr1 knockout mice during the critical periods of development when synaptogenesis and neuronal maturation occurs. To address this, we chose three time points (postnatal days 5, 12 and adulthood) to investigate the global protein expression of GABA receptor subunits and GABA metabolic enzymes in the brains of Fmr1 knockout mice. Using quantitative western blotting analysis, we found that the GABAA receptor α1, β2, and δ subunits as well as the enzymes GABA transaminase and succinic semialdehyde dehydrogenase are down-regulated during postnatal development in knockout mice. In addition, we found that glutamic acid decarboxylase (GAD-65) was expression was increased in adult Fmr1 knockout mice. We also assessed the effects of diazepam, phenobarbital, and loreclezole on the suppression of motor activity and seizures in light of our finding that GABAA receptor expression is altered in knockout mice. Although all three drugs reduced seizures and motor activity, the suppressive effect of the GABAA β2/3-selective drug loreclezole on motor activity was impaired in the knockout mice. Similarly, we examined the effects of GABAB receptor drugs on audiogenic seizures. The GABAB agonist R-baclofen significantly reduced seizures in knockout mice, while seizures could be induced in wild-type mice with a combination of a GABAB antagonist (CGP46381) and an mGluR5 agonist (CDPPB). This result demonstrates that increased audiogenic seizure susceptibility in Fmr1 knockout mice is in part associated with decreased GABAB receptor signaling. Overall, our data suggests that GABA receptors and GABA metabolic enzymes display complex patterns of changes during brain development which likely play a role in the behavioural phenotype of FXS.

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4. Arruda-Carvalho M1,3*; Sakaguchi M1,2*; Frankland PW1,2,3 1Hospital for Sick Children, Toronto, ON, Canada; 2Department of Physiol.,; 3Inst. of Med. Sci., Univ. of Toronto, Toronto, ON, Canada; VISUALIZATION OF ADULT BORN NEURONS INCORPORATED IN THE MEMORY NETWORK USING NESTIN TRANSGENIC MICE New neurons are continuously added to the dentate gyrus (DG) in the adult brain and may become incorporated in spatial memory networks. However, the overall contribution of new neurons to the spatial memory trace is unknown. Previously, retroviral or thymidine-analogue (e.g., BrdU) labeling techniques have been used to visualize newborn neurons in adult mouse brain. Because these methods are relatively inefficient in labeling new neurons, it makes it difficult to estimate the total contribution of newborn neurons to an entire memory network. To address this limitation, we took advantage of a pNestin-CREERT2/RosaLacZ mouse line (Imayoshi et al, 2006, 2008). In these mice Tamoxifen (TMX) treatment induces the permanent expression of a LacZ reporter only in nestin-positive cells allowing for the stable labeling of adult-generated cells. We compared different TMX injection protocols in order to optimize labeling efficiency. We found that injecting TMX in younger mice (P28) and maximizing the number of injections led to a 10-fold increase in labeling efficiency compared to BrdU-based approaches. We also confirmed that the vast majority of the labeled cells were NeuN-positive, indicating that the cells had differentiated into neurons. Using this protocol, we then trained mice in the Morris water maze and at different delays following TMX treatment and examined expression of immediate early-genes (e.g., c-fos) in the LacZ+ cells. By quantifying the number of Fos+ cells that are also LacZ+, these methods will make it possible to reliably estimate the contribution of adult-generated neurons to spatial memory networks in the dentate gyrus. *The first two authors contributed equally to this work.

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5. Arshad SA1,5; Anderson NA3,4,5; Polatajko HP1,2; Dawson DD1,2,5 1Graduate Department of Rehabilitation Science, Departments of; 2Occupational Science & Occupational Therapy; 3Psychology, and; 4Medicine, University of Toronto; 5Kunin-Lunenfeld Applied Research Unit, Baycrest; NATURALISTIC ASSESSMENT OF EXECUTIVE DYSFUNCTION: THE VALUE OF EVENT RECORDING Background/Objective: The goal of rehabilitation is to improve everyday functioning, yet human behavior in the real world is remarkably complex and difficult to assess. Several researchers have started using event recorders to make data collection and analysis easier during naturalistic assessments. However, to the best of our knowledge this methodology has not been used in relation to naturalistic assessment of executive dysfunction following acquired brain injury (ABI). The purpose of this study is to use an event recorder to expand our characterization of errors and thus allow for a better discrimination between people with ABI and matched controls as they complete the Multiple Errands Test (MET). The MET is a real-world measure of executive function which requires participants to complete a series of tasks and collect specific pieces of information within the constraints of a set of rules. To date the focus of investigation related to this task has been on understanding the errors people make in terms of inefficiencies or interpretation failures that interfere with achieving tasks and following task rules. To further our understanding of participants’ performance problems, we are undertaking a more rigorous characterization of behaviors with the help of an event recorder. We hypothesize that this will allow more sensitive and specific discrimination between participants with ABI and healthy controls. Materials/Methods: Twenty-seven participants with ABI (n= 14 stroke survivors, 13 traumatic brain injury survivors) and 25 healthy controls matched for age, gender and education were videotaped as they completed the Baycrest MET. The Baycrest MET is a site-specific version of the MET that has good reliability and validity. An event recorder was then used to codify the occurrence, frequency and duration of behaviors occurring as participants attempted to complete tasks. We coded the time it took participants to complete each task, including the route they chose and the amount of time they spent at each location. Results: The event recorder allowed coding of multiple behaviors previously not analyzed including the amount of time participants spoke to staff and whether they changed direction in order to arrive at a certain location. We were also able to identify some interesting social rule breaks that were performed. Anticipated results are that we will identify additional behaviors that discriminate between the ABI population and healthy controls. Conclusion: The study illustrates the utility of event recorders in documenting multiple real-world behaviors as they occur in a test situation. We anticipate that the data will highlight real-world behaviors that are particularly problematic for people with executive dysfunction as they attempt to achieve tasks on the MET and allow for a better understanding of the impact of executive dysfunction on real-world behaviors.

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6. Ballios BG1; Cooke MJ2; Shoichet MS1,2,3; Van der Kooy D1,4 1Institute of Medical Science, University of Toronto; 2Chemical Engineering and Applied Chemistry, University of Toronto; 3Institute of Biomaterials and Biomedical Engineering, University of Toronto; 4Molecular Genetics, University of Toronto; DEVELOPMENT OF A STEM CELL DELIVERY SYSTEM TO TREAT RETINAL DEGENERATIVE DISEASES Purpose: The therapeutic potential of adult retinal stem cells (RSCs) – multipotent cells capable of differentiating into any retinal cell type – avoids ethical concerns surrounding the transplantation of embryonic/fetal tissue. Subretinal cell transplantation is limited by poor cell survival, distribution and integration into host tissue. To overcome this, a stem cell delivery system was developed, taking advantage of the minimally-invasive, injectable and biodegradable properties of a blend of hyaluronan (HA) and methylcellulose (MC) – HAMC. Methods: Natural polymer hydrogels were screened in vitro for desired physical properties (flow and gelation time) and biological properties (cell growth and survival). Agarose, collagen, chitosan/glycerol-phosphate, and HAMC were included based on literature precedent for injectability and simple gelation mechanisms. Adult stem cell growth and survival was analyzed in vitro by RSC sphere diameter and live-dead assays. HAMC was pursued in adult mouse subretinal transplantation studies to investigate biodegradability and potential as a cell delivery vehicle by injection of GFP+ RSC progeny. Results: In the screen, several hydrogels were eliminated: chitosan/glycerol-phosphate based on long gelation time, collagen because of retarded cell growth relative to media controls, and agarose based on cell spreading and morphological differentiation. A blend of 0.5/0.5 wt% HA/MC supported in vitro stem cell growth and survival as spheres and single cells similar to control media over 6 days. HAMC maintained 3D cellular distribution at physiological temperature in vitro, and prevented cellular aggregation. The blend was a viscous solution on injection with physical properties ideal for subretinal delivery, and degraded over 7 days in vivo. Transplanted RSC progeny integrated into the retinal pigment epithelium layer. When delivered in HAMC, cells were more contiguously distributed over larger areas of retina compared to delivery in saline, which showed restricted, patch-like integration and cellular aggregation. Conclusions: HAMC is a promising vehicle for cellular delivery to the degenerating retina, overcoming previously reported barriers to tissue integration such as cellular aggregation and non-contiguous distribution.

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7. Barr MS1; Farzan F1; Arenovich T2; Chen R3; Fitzgerald PB4; Daskalakis ZJ1 1Schizophrenia Program, Centre for Addiction and Mental Health, Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada; 2Biostatistical Consultant, Centre for Addiction and Mental Health, Toronto, Ontario, Canada; 3Division of Neurology, Toronto Research Institute, University of Toronto, Toronto, Ontario, Canada; 4Alfred Psychiatry Research Centre, The Alfred and Monash University Department of Psychological Medicine, Commercial Rd Melbourne, Victoria, Australia; THE EFFECT OF REPETITIVE TRANSCRANIAL MAGNETIC STIMULATION ON GAMMA OSCILLATORY ACTIVITY IN SCHIZOPHRENIA Background: Gamma (γ) oscillations (30-50 Hz) have been shown to be excessive in patients with schizophrenia (SCZ) during working memory (WM). WM is a cognitive process that involves the online maintenance and manipulation of information that is mediated largely by the dorsolateral prefrontal (DLPFC). Repetitive transcranial magnetic stimulation (rTMS) represents a non-invasive method to stimulate the cortex that has been shown to enhance cognition and γ oscillatory activity during WM. Methods: We examined the effect of 20 Hz rTMS administered to the DLPFC on γ oscillatory activity elicited during the N-back task in 24 patients with SCZ compared to 22 healthy subjects. Results: Prior to rTMS, patients with SCZ elicited excessive γ oscillatory activity compared to healthy subjects across WM load. Active rTMS resulted in the inhibition of γ oscillatory activity in patients with SCZ, while potentiating activity in healthy subjects that was most pronounced in the 3-back condition, the condition of the greatest task difficulty. The differential regulation of rTMS on γ oscillations in patients with SCZ compared to healthy subjects may be related to the interaction between GABA receptors that have been shown to support γ oscillations. Conclusions: These findings provide important insights into the neurophysiological mechanisms underlying WM and demonstrate how rTMS can inhibit excessive γ oscillatory activity in SCZ, a potential finding that may ultimately translate into a better understanding of the mechanisms leading to cognitive improvement.

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8. Barszczyk AM1,2; Li R2,3; Tymianski M1,2,3 1Department of Physiology, University of Toronto; 2Toronto Western Hospital Research Institute; 3NoNO Inc.; DETERMINATION OF THE NADH DEHYDROGENASE SUBUNIT 2 BINDING DOMAIN FOR SRC40-49 AND ITS ATTENUATION OF INFLAMMATORY PAIN NADH dehydrogenase subunit 2 (ND2) is one of several proteins that interacts with the unique domain of the Src tyrosine kinase. Acting as an adapter protein, ND2 anchors Src to the N-methyl-d-aspartate (NMDA) receptor complex in post synaptic densities (PSDs), allowing it to regulate NMDA receptor activity. While the peptide sequence comprising the ND2 interaction domain of Src has been characterized (Src40-49) and has been used as a cell-permeant peptide to treat pain (Src40-49Tat), the Src interaction domain of ND2 has not yet been determined, though it is known to reside in an ND2 segment known as ND2.1. To identify the Src interacting domain of ND2, four Glutathione-S-transferase (GST) fusion proteins containing 4 overlapping sequence fragments of ND2.1 were constructed (ND2.1.1 through ND2.1.4). ND2.1.4–GST was observed to bind directly to the biotinylated domains of Src 40-49. Dot blot and competitive ELISA assays demonstrated that the interaction of Src 40-49Tat with ND2 or ND2.1 is blocked by ND2.1.4–GST. Next, eight peptides containing different segments of ND2.1.4 were synthesized and used in binding assays for Src 40-49Tat. One segment of ND2 (ND2.1.4-7) demonstrated a strong dose-response relationship on binding to Src 40-49-Tat. The interaction of ND2 with Src 40-49 was significantly reduced by pre-incubation with the ND2.1.4-7 peptide in competitive ELISA assays and dot blot assays. Additionally, endogenous colocalization of ND2 with Src was significantly reduced in primary cultures of hippocampal neurons treated with ND2.1.4-7. It was also determined that ND2.1.4-7, when affixed to the cell-permeating HIV1 Tat domain, alleviated the reduction in paw withdrawal threshold induced by the Complete Freund’s Adjuvant model of inflammatory pain. This suggests that inhibiting the interaction between Src and ND2 with the Src-interacting domain of ND2 can alleviate the NMDAR-mediated central sensitization that contributes to inflammatory and neuropathic pain.

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9. Brown ZJ1; Tribe E1; D’Souza NA1; Erb S1 1Centre for the Neurobiology of Stress, Department of Psychology, University of Toronto at Scarborough; INTERACTION BETWEEN NORADRENALINE AND CORTICOTROPHIN-RELEASING FACTOR IN THE REINSTATEMENT OF COCAINE SEEKING Corticotropin-releasing factor (CRF) and noradrenaline (NA) systems, acting within the extended amygdala circuitry, have been shown independently to play a critical role in stress-induced reinstatement of cocaine seeking. Despite considerable neuroanatomical evidence indicating interactions between these systems within the extended amygdala, no direct functional studies have been conducted to determine whether, and in what direction, NA and CRF interact to mediate the reinstatement of cocaine seeking. METHODS: In a series of experiments, rats were trained to self-administer cocaine (1.0 mg/kg per infusion) for 8-10 days. Subsequently, responding for drug was extinguished and tests for reinstatement were conducted, utilizing pharmacological agents to activate NA or CRF cell populations while simultaneously antagonizing the activity of the alternate system. Specifically, at time of test in Experiment 1, animals were pre-treated with CRF receptor antagonist, D-Phe CRF12-41 (0, 0.3, 1µg; i.c.v) prior to tests for NA (0, 10 µg; i.c.v.)-induced reinstatement. In Experiment 2, animals were pre-treated with the alpha-2 adrenceptor agonist clonidine (0, 40µg/kg; i.p.), which acts to block NA cell firing and release, prior to tests for CRF (0, 0.5µg; i.c.v.)-induced reinstatement. In Experiment 3, animals were pre-treated with the CRF receptor antagonist, D-Phe (0, 0.3, 1µg; i.c.v) prior to tests for yohimbine (0, 1.25 mg/kg, i.p.)-induced reinstatement. Yohimbine is an alpha-2 adrenceptor antagonist, acts to facilitate NA cell firing and release. RESULTS: Antagonism of CRF receptors blocked NA-induced reinstatement (Exp. 1). In contrast, interference in NA release did not attenuate CRF-induced reinstatement (Exp. 2). The CRF receptor antagonist, D-Phe failed to interfere in the reinstatement of cocaine seeking induced by yohimbine. However, subsequent studies revealed that yohimbine induces reinstatement primarily via its action on D1-receptors. CONCLUSION: Our findings are consistent with the idea that NA-CRF interactions mediate the reinstatement of cocaine seeking and, moreover, that the effect involves activation of CRF receptors subsequent to the release of NA.

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10. Brunello ME1; Hunter JP2; Popovic M3; Dostrovsky J1 1Department of Physiology, University of Toronto, Toronto, Canada; 2Department of Physical Therapy, University of Toronto, Toronto, Canada; 3Rehabilitation Engineering Laboratory, University of Toronto, Toronto, Canada; EFFECTS OF BODY LOCATION ON THE THERMAL GRILL ILLUSION OF PAIN Purpose: The simultaneous application of interlaced warm (40°C) and cool (20°C) temperature bars (a thermal grill, TG) is known to elicit reports of paradoxical pain when applied to the hand or forearm (termed the thermal grill illusion, TGI). In a previous study, we found that participants report more pain and unpleasantness when the TG is applied to the palm vs. the forearm. There have been no further reports on whether the TGI is elicited at other body sites. In this study, we extended the testing of this phenomenon to the back, calf, and foot. Methods: Thermal stimuli were produced by a 1x6 matrix of Peltier-controlled thermodes. Three bar configurations were tested: all bars 40°C (warm), all bars 20ºC and alternating bars 20°C/40°C (TG) at four sites (palm, back, calf, and plantar surface of the foot). Stimulus duration was 60s. Two runs were conducted for each condition at every location. Presentation of stimuli was pseudo-randomized by location and condition. After completion of each run, subjects rated the pain intensity and the unpleasantness of the primary thermal sensation on an 11 point numeric rating scale (0 - 10). Pain and unpleasantness ratings obtained at the four locations were compared for each bar configuration (ANOVA). Results: Pain and unpleasantness ratings obtained during the TG condition were significantly higher than when the bars were all warm or all cool (p<0.001, for all comparisons). The main effect of location was also significant (p<0.05 for pain, p<0.001 for unpleasantness). For the TG condition, the back elicited the highest pain and unpleasantness ratings (3.3,± 0.6, and 4.3, ±0.6, respectively), followed by the palm (3.3±0.8 and 3.9±0.7), calf (2.3±0.6 and 2.9±0.5), and foot (1.8±0.4 and 2.1±0.4). We also observed a significant (p<0.001) main effect of repetition on pain ratings, in that scores obtained during the second run were consistently lower across all locations and conditions. Conclusions: An illusion of pain in response to the TG was evoked from all four body sites tested. Furthermore, there are significant differences in the magnitude of the TG across the body sites, possibly due to differences in peripheral innervation, and/or central processing.

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11. Chee J1; Tung J1; Gage W2; McIlroy W1,3; Zabjek K1 1Graduate Department of Rehabilitation Science, University of Toronto; 2School of Kinesiology and Health Science, York University; 3Department of Kinesiology, University of Waterloo; CHARACTERIZING FOOT PLACEMENT PATTERNS DURING REAL-WORLD ROLLATOR USE: INITIAL DEVELOPMENT AND VALIDATION Introduction: Mobility impairments often become manifested during gait as changes in step width or step width variability[1]. Assistive mobility devices are commonly prescribed to enhance medio-lateral stability and prevent falls in patients with poor lateral balance control. Through quantifying rollator-assisted gait characteristics, without using a laboratory-based motion capture system, we may enhance our understanding of how these devices influence their user’s gait patterns in a real-world environment. Aim: The purpose of this study was to assess the validity of a novel algorithm to extract step width from video data recorded directly on-board an instrumented walker (i.e. iWalker). Methods: Five able-bodied young adults (mean: 27±3 years) were recruited to ambulate across an in-laboratory walkway at their preferred step width and walking speed. Step width was quantified using both an Archos 404 digital video camera (Archos, CO, U.S.A.), mounted on-board the iWalker (i.e. the footcam), and a 7-camera Vicon MX Motion Capture System (Vicon, CO, U.S.A.). The footcam was oriented backwards towards the user’s feet to capture the position of toe markers. Matlab code was applied to correct for parallax error in the video image and the 2-D marker position was extracted using Peak Motus software (Vicon, CO, U.S.A.). Step widths were calculated and compared to those obtained using Vicon. Results: The average step widths calculated by the iWalker and Vicon systems were 14.9 ± 4.7 cm and 14.2 ± 4.4 cm respectively, with an average root mean square (RMS) difference of 0.70 cm. As such, there was a strong correlation between the two methods (R^2=0.9817). Discussion and Conclusions: Due to the high agreement between the Vicon and iWalker systems, we believe that our camera-based process of calculating step width provides an accurate assessment of foot placement during rollator use. Future work will be conducted to characterize the real-world step width patterns of balance-impaired patient populations, such as individuals with multiple sclerosis, traumatic brain injury, stroke, and THA. References: [1] Brach, J.S. et al. (2008). Stance time and step width variability have unique contributing impairments in older persons. Gait & Posture 27(3); p. 431-9. Acknowledgments: CIHR Pilot Projects in Aging grant awarded to Dr. Zabjek & Dr. McIlroy.

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12. Clarke L; Van der Kooy D Institute of Medical Science, University of Toronto; THE ADULT MOUSE DENTATE GYRUS CONTAINS A POPULATION OF PROGENITOR CELLS WHICH IS DISTINCT FROM SUBEPENDYMAL ZONE STEM CELLS Neural stem cells are proposed to exist in 2 areas of the adult brain: the subependymal zone (SEZ) of the lateral ventricle and the subgranular zone of the dentate gyrus (DG). The properties of the cells which support neurogenesis in each region are proposed to be similar. We find that clonal sphere colonies from both areas form exclusively from cells which are nestin-positive and that like the SEZ, DG colonies form from cells with a long cell cycle time (long-term histone-GFP label-retaining cells). Clonal cultures from these two regions however, are strikingly different. The adult SEZ yields large colonies which self-renew and are multipotential, while the adult DG produces only small, unipotent and nonself-renewing colonies. Clonal colonies from the embryonic and early postnatal hippocampus retain some ability to produce both neurons and glia, however, the proportion of neuronal progeny is significantly less than from the SEZ. Long-term self-renewing colonies can be isolated only from the hippocampus early in its development, before the formation of the DG. When spheres from the adult DG are cocultured with slices of adult brain, clonal secondary spheres can be derived from slice cultures, however, the ability to self-renew is not maintained. When adult spheres are cultured in contact with embryonic tissue, we find that clonal self-renewal is restored and maintained for several passages off of slices. Adult DG spheres grown on adult or embryonic brain slices did not give rise to beta-III tubulin-positive neurons. We find that self-renewal and differentiation can be dissociated in the DG, and that the SEZ and DG lineages are distinct.

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13. Cole CJ1,2; Ross PJ1; Han J-H1; Pekar T1; Vetere G1; Neve RL3; Frankland PW1,2,4; Josselyn SA1,2,4 1Program in Neurosciences & Mental Health, The Hospital for Sick Children, Toronto, ON, Canada M5G 1X8; 2Department of Physiology, University of Toronto, Toronto, ON, Canada; 3Brain and Cognitive Sciences, MIT, Cambridge, MA, USA; 4Institute of Medical Sciences, University of Toronto, Toronto, ON, M5G 1X8; THE TRANSCRIPTION FACTOR MEF2 NEGATIVELY REGULATES LONG-TERM MEMORY FORMATION AND SPINE DENSITY IN MICE. The transcription factor myocyte enhancer factor-2 (MEF2) was originally identified and characterized in muscles. MEF2 is also highly expressed in the brain, but the function of neural MEF2 is virtually unexplored. Recent findings suggest that MEF2 negatively regulates dendritic spine formation and spine density. As the growth and restructuring of spines and synapses are thought to underlie memory formation, we examined the effects of manipulating MEF2 function on memory formation in mice. We assessed two type of memory that critically depend on different brain regions. Spatial memory involves the hippocampus, including the dentate gyrus whereas auditory fear conditioning involves the lateral amygdala. To increase MEF2 function in a region- and temporally-specific manner, we overexpressed a constitutively active form of MEF2 using a viral-mediated in vivo expression system. Increasing MEF2 function in dentate gyrus region before training in the Morris water maze disrupted spatial memory formation. This deficit was accompanied by a reduction in dendritic spine density. Conversely, expressing a dominant negative MEF2 repressor in the dentate gyrus increased spatial memory formation. The effects of MEF2 manipulation also generalized to the lateral amygdale where increasing MEF2 similarly disrupted the formation of long-term memory for auditory and contextual fear conditioning. Our findings suggest that MEF2 is important for the formation of two distinct forms of long-term memory perhaps by repressing new spine formation.

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14. Coppin PW1; Hockema SA1 1Faculty of Information University of Toronto; AN ATTENTION BASED THEORY TO EXPLORE THE COGNITIVE AFFORDANCES OF DIAGRAMS RELATIVE TO TEXT Why are most geometric proofs usually “non-visual” (e.g., textually based)? Exploring this question exposes issues that could inform the design of notation systems to increase abilities to conceptualize, comprehend, and communicate ideas in education, public policy, and beyond. For example, Shimojima and Katagiri (Shimojima & Katagiri, 2008) demonstrated that diagrams reduce “inferential load” during reasoning by scaffolding visual-spatial aspects of memory and attention (cf. (Ballard, Hayhoe, Pook, & Rao, 1995; Spivey & Geng, 2001)). But if diagrams reduce inferential load, then it would seem to follow that a diagrammatic notation system would emerge as an important ergonomic paradigm for proofs. However, as (Tennant, 1986) described: “[The diagram] is only an heuristic to prompt certain trains of inference…it has no proper place in a proof…the proof is a syntactic object consisting only of sentences arranged in a finite and inspectable array.” (as quoted in (Barwise & Etchemendy, 1991)). Thus, we sought to explore ergonomic affordances of text (relative to diagrams) that may encourage their use in proofs by examining the role of text and diagrams in Proposition 35 of Euclid’s elements. A better understanding of text relative to diagrams could enable more effective communication in math, logic, science, education, engineering, public policy, and beyond. By building on prior work in attention (Scholl, 2001; Treisman & Gelade, 1980), we claimed that textual notations may focus a reasoner’s “spotlight” of attention through serialized sequential chunks, enabling the methodical presentation of a rational argument in a way that is not possible (or is very difficult given current understandings and practices) when using a diagrammatic notation that may “diffuse” attention; such notations may enable a reasoner to discern how elements fit together holistically, but place less focus on individual steps in the argument, or on reifying and explicitly representing connections/relationships between steps. Ballard, D. H., Hayhoe, M. M., Pook, P. K., & Rao, R. P. N. (1995). Deictic Codes for the Embodiment of Cognition. Behavioral and Brain Sciences, 20, 723--767. Barwise, J., & Etchemendy, J. (1991). Visual information and valid reasoning. In Visualization in teaching and learning mathematics (pp. 9-24). Mathematical Association of America. Retrieved June 27, 2009, from http://portal.acm.org/citation.cfm?id=115667. Scholl, B. J. (2001). Objects and attention: the state of the art. Cognition, 80(1-2), 46. Shimojima, A., & Katagiri, Y. (2008). An Eye-Tracking Study of Exploitations of Spatial Constraints in Diagrammatic Reasoning. In Diagrammatic Representation and Inference (pp. 74-88). Retrieved June 14, 2009, from http://dx.doi.org/10.1007/978-3-540-87730-1_10. Spivey, M. J., & Geng, J. J. (2001). Oculomotor mechanisms activated by imagery and memory: Eye movements to absent objects. Psychological Research, 65(4), 235–241. Tennant, N. (1986). The Withering Away of Formal Semantics? Mind & Language, 1(4), 302-318. doi: 10.1111/j.1468-0017.1986.tb00328.x. Treisman, A. M., & Gelade, G. (1980). A feature-integration theory of attention. Cognitive psychology, 12(1), 97-136.

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15. Creed MC1,2; Hamani C1,3; Nobrega JN1,2,4 1Neuroimaging Research Dept., Center for Addiction and Mental Health; 2Dept. of Pharmacology & Toxicology, University of Toronto; 3Toronto Western Hospital; 4Dept. of Psychiatry, University of Toronto; DEEP BRAIN STIMULATION ALLEVIATES MOTOR SYMPTOMS IN AN ANIMAL MODEL OF TARDIVE DYSKINESIA. Deep brain stimulation (DBS) of the subthalamic nucleus (STN) and internal globus pallidus (GPi) has been recently shown to alleviate symptoms of tardive dyskinesia (TD)(e.g., Damier et al., 2007, Arch Gen Psychiatry, 64:107-176), a subcortical motor disorder induced by typical antipsychotics in an estimated 30% of chronically exposed patients. The mechanisms underlying this alleviation remain to be elucidated and there is disagreement over the optimal stimulation parameters and anatomical target for DBS. In rats, chronic haloperidol (HAL) administration induces vacuous chewing movements (VCMs), which are analogues to orofacial dyskinesias observed in TD. The objective of this study was to model the alleviation of TD by DBS in the rodent VCM model and to examine the effects of varying current frequency and target. Ninety male Sprague Dawley rats were treated with 21mg/kg HAL (i.p.) every three weeks, with 2 minute VCM assessments occurring weekly. Monopolar electrodes were then implanted in either the STN or entopeduncular nucleus (EPN), the rodent homologue of the GPi. DBS was applied to freely moving rats, permitting the assessment of VCMs during stimulation. In HAL-treated rats, bilateral DBS of either the STN and EPN applied at 130Hz, 60Hz and 30Hz attenuated VCMs. There was a frequency-dependent effect of stimulation to the STN, whereas all frequencies were equally effective in attenuating VCMs when applied to the EPN. When DBS was applied acutely, bilateral 130Hz DBS attenuated VCMs to a greater extent than did unilateral DBS applied to either hemi-nucleus at the same frequency. Over 60 minutes of continuous 130Hz DBS applied to the STN or EPN, VCMs were reduced at all time points. 130Hz DBS did not induce VCMs in HAL-treated rats when applied acutely to either the STN or EPN. In both HAL and VEH-treated rats, VCMs recovered to levels not different than baseline in the two minutes following cessation of both acute and prolonged DBS. To ensure that the motor effects of DBS were specific to VCMs, locomotor activity (LMA) was assessed using an open field arena. HAL treatment decreased LMA in sham-operated rats and in rats undergoing bilateral 130Hz DBS of the STN. However during DBS of the EPN, LMA of HAL-treated rats was restored to levels equal to controls. This is the first demonstration of DBS effects in the VCM model. These findings suggest that DBS of both targets specifically attenuates HAL-induced VCMs and that this model will permit the further study of mechanisms underlying the efficacy of DBS in TD.

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16. Diaconescu AO1,2; McIntosh AR1,2 1Rotman Research Institute, Baycrest Center; 2Department of Psychology, University of Toronto; THE COSTS OF SWITCHING BETWEEN “WHAT” AND “WHERE” PROCESSING IN AUDITION AND VISION Switching from one task-set to another relies on cognitive control processes. We proposed that the efficacy of control processes is proportional to the extent of overlap between the neural circuits mediating those task-sets. Functional magnetic resonance imaging (fMRI) studies revealed the existence of segregated “what” and “where” processing streams in audition and vision with “where” processes exhibiting commonalities across the two modalities. A cue-target paradigm and fMRI recordings (Siemens 3.0T; TR=2s) were employed in a group of 17 healthy volunteers (mean age 25) who responded to the location or identity of lateralized targets as signalled by a preceding cue. Cue-driven response rules (location vs. identity) alternated while target modality was blocked, and vice versa. Switch costs were observed in both modalities with largest costs when switching from location to identity task-sets in the visual modality. Activity in the dorsal anterior cingulate (BA 24) and dorsolateral prefrontal cortices (BA 46) as well as modality-specific areas, such as the superior temporal cortex, and V1, accounted for the largest switch costs in the two modalities. This study provides insight into the extent of overlap between “what” and “where” processing streams and the modality-independence of prefrontal cortex activity. Work was supported by NSERC and the JS McDonnell Foundation.

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17. Ehsani S1,2; Watts JC3; Huo H2; Westaway D4; Wille H3; Schmitt-Ulms G1,2 1Department of Laboratory Medicine and Pathobiology, University of Toronto; 2Centre for Research in Neurodegenerative Diseases, University of Toronto; 3Institute for Neurodegenerative Diseases, University of California San Francisco; 4Centre for Prions and Protein Folding Diseases, University of Alberta; EVOLUTIONARY DESCENT OF PRION FAMILY GENES FROM A ZIP METAL ION TRANSPORT ANCESTOR Prion diseases are fatal neurodegenerative diseases of humans and animals which, in addition to sporadic and familial modes of manifestation, can be acquired via an infectious route of propagation. Prion diseases include sporadic and variant forms of Creutzfeldt-Jakob disease in humans. In sheep and cattle, prion diseases manifest as scrapie and bovine spongiform encephalopathy, respectively. In the more than 20 years since its discovery, both the phylogenetic origin and cellular function of the prion protein (PrP) have remained enigmatic. Insights into the function of PrP may be obtained through a characterization of its molecular neighbourhood. Following a 'guilt-by-association' logic, we set out to identify the function of the cellular prion protein through a comprehensive interactome investigation. Investigations of this kind often result in long lists of candidate interactors. The challenge then remains to discriminate specific from unspecific binding partners. Here we incorporated quantitative mass spectrometry based on isotopic tagging of peptides into the workflow to overcome this limitation. Furthermore, investigations were extended to all three members of the mammalian prion protein family to further facilitate discrimination of potential interactors by differential interactome comparison. Quantitative interactome data revealed the spatial proximity of a subset of metal ion transporters of the ZIP family to mammalian prion proteins. A subsequent bioinformatic analysis revealed the presence of a prion-like protein sequence within the N-terminal, extracellular domain of a phylogenetic branch of ZIPs. Additional structural threading and ortholog sequence alignment analyses consolidated the conclusion that the prion protein gene family is phylogenetically derived from a ZIP-like ancestor molecule. Our data explain structural and functional features found within mammalian prion proteins as elements of an ancient involvement in the transmembrane transport of divalent cations. The connection to ZIP proteins is expected to open new avenues to elucidate the biology of the prion protein in health and disease.

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18. Elahipanah A1,2; Christensen BK1,3; Reingold EM4 1Institute of Medical Science, University of Toronto; 2Centre for Addiction and Mental Health; 3Department of Psychiatry and Behavioural Neurosciences, McMaster University; 4Department of Psychology, University of Toronto; MEASURING VISUAL SPAN SIZE AMONG PATIENTS WITH SCHIZOPHRENIA USING THE GAZE-CONTINGENT MOVING WINDOW PARADIGM Patients with Schizophrenia (SCZ) are less efficient on visual search tasks (i.e., identifying a target item among non-target items). However, the mechanism underlying this deficit is unknown. We propose that SCZ-related visual search impairment is mediated, in part, by a smaller visual span. “Visual span” is the region of the visual field from which one can extract information during an eye fixation. A narrower visual span would necessitate a greater number of eye movements in order to process the whole visual display, and would, therefore, lead to a less efficient search. In a previous study, we found indirect evidence of a narrower visual span among patients with SCZ, that is, patients’ search times were disproportionately slower and their visual search impairment was more salient when the target was placed farther away from the centre of the search display (Elahipanah, Christensen, & Reingold, 2010). The current study aims to more directly investigate visual span size differences between patients with SCZ and healthy controls by using the gaze-contingent moving window paradigm. It also investigates visual span flexibility among patients with SCZ compared to healthy individuals. Previous research has shown that healthy individuals modulate the size of their visual span as a function of visual search factors such as distractor familiarity, that is, search among familiar distractors is more efficient and yields wider visual spans compared to searches among unfamiliar distractors (Greene & Rayner, 2001). This finding is referred to as the familiarity effect. The current study also investigates the familiarity effect among patients with SCZ. A group of patients with SCZ (n=26) and a group of healthy controls (n=22) completed a visual search task with two conditions of distractor familiarity while their eye movements were being recorded by an EyeLink eyetracker. Using the gaze-contingent moving window paradigm and an iterative algorithm for adjusting the size of the window, each participant’s visual span size was estimated in each of the two conditions. Response times and eye movement indices were also recorded. Compared to healthy controls, patients with SCZ demonstrated slower search times, a greater number of eye fixations and narrower visual spans across both conditions. Healthy controls’ visual span size increased as distractor familiarity increased. However, this modulation of visual span size as a function of distractor familiarity was not observed among patients. These results support the hypothesis that patients with SCZ have a narrower visual span. Results also suggest that, unlike healthy individuals, patients with SCZ do not modulate their visual span size as a function of distractor familiarity.

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19. Elbert A1,2; Gomez L2; Cate-Carter T3; Wigg K2; Feng Y2; Archibald J3; Anderson B3; Kerr E3; Lovett M3; Humphries T3; Barr C1,2,3 1University of Toronto; 2Toronto Western Research Institute; 3Sick Kids Hospital; INVESTIGATION OF DCDC2 (A DYSLEXIA CANDIDATE GENE) FOR ASSOCIATION TO ADHD AND RD Introduction: Attention Deficit/ Hyper-Activity Disorder (ADHD) is a learning disability affecting 2-18% of school-aged children (Rowland 2002). DCDC2, a well-supported risk gene for Reading Disabilities (RD), was recently reported as a new candidate ADHD risk gene (p= 0.000038; Couto et al., 2009). RD often co-occurs with ADHD, and there is evidence for shared genetic etiology. The purpose of this project was to investigate DCDC2 as a risk gene for ADHD and RD, with a specific focus on DNA variants present in DCDC2 regulatory elements. Hypothesis: Risk alleles will be significantly associated with ADHD or RD and function by altering the expression level of DCDC2. Therefore, I expect that the functionally relevant polymorphisms will be within putative regulatory elements of DCDC2, and that the risk alleles will alter the binding sites of transcription factors. Methods: The putative regulatory elements of DCDC2 were identified by ChIP-on-chip of histone-3 acetylation (Couto et al., 2009), and ChIP-sequencing of p300 and phosphorylated RNA polymerase II (Barr et al., unpublished) in brain-relevant cell lines. Histone-3 acetylation and p300 peaks mark active chromatin and enhancer elements, respectively. These regions were screened for polymorphisms in 48 affected ADHD probands. The allele frequencies in the probands were compared with the frequencies reported in public databases. Polymorphisms with skewed allele frequencies from those reported were tested for association in ADHD and RD families (~300 families per sample) by Transmission Disequilibrium Test (TDT). Transcription Factor Binding sites were predicted in silico using Transcription Element Search Software, and sorted for brain-relevant transcription factors. Results and Conclusions: One histone-3 acetylated peak (intron 7), and three p300 binding regions (two in intron 3, one in intron 9) were identified in the DCDC2 gene. Within these regions, six known and 2 new polymorphisms were tested by TDT in ADHD and RD samples. No significant results (p< 0.05) were obtained. Therefore, we found no support for functionally relevant polymorphisms in these putative regulatory elements of DCDC2 that affect ADHD or RD risk. The linkage disequilibrium in the surrounding region is high; one possibility is that the association signal from the past study supporting DCDC2 may be coming from a risk allele in a nearby gene called Vesicular Membrane Protein (VMP).

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20. Ferguson KA3,1; Skinner FK1,2,3,4 1Toronto Western Research Institute, University Health Network; 2Department of Medicine (Neurology), University of Toronto; 3Department of Physiology, University of Toronto; 4Institute of Biomaterials and Biomedical Engineering, University of Toronto; MATHEMATICAL NETWORK MODELS OF THETA RHYTHMS IN THE HIPPOCAMPUS Theta oscillations are potentially one of the most significant and well-studied rhythms occurring in the mammalian brain. These rhythms, oscillating between 3-12 Hz, may play a lead role in spatial navigation and episodic memory. In an attempt to understand the mechanisms behind the theta activity, a mathematical network model has been developed. The model is composed of four types of cells: pyramidal cells, O-LM interneurons, fast-firing parvalbumin (PV) basket cells, and slow-firing cholecystokinin (CCK) basket cells. The CCK basket cells have not been included in this type of network model before, but may be essential to the generation of theta rhythms, as distinct phase relationships have been found between PV and CCK cells during these rhythms recorded in vivo. Also different from existing models is that our network model includes only synaptic connections for which there is empirical evidence. Each cell is represented with a conductance based model, composed of one compartment for each of the interneurons, and two compartments for the pyramidal neuron. This network model successfully produces theta activity in the pyramidal neuron. Future work will involve using direct synaptic constraints obtained from experimental data, and the development of more appropriate cellular neuronal models and larger networks.

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21. Findlater J1; Xiao S1; Robertson J1 1Centre for Research in Neurodegenerative Diseases, University of Toronto; PERIPHERIN-28 AS A BIOMARKER OF ALS: A METHODOLOGICAL STUDY The neuronal intermediate filament protein, Peripherin, has previously been shown to have several splice-variant isoforms with probable disease relevance in Amyotrophic Lateral Sclerosis (ALS). This is particularly true of an isoform which retains introns 3 and 4 resulting in a 28 kDa protein named Per28. This isoform has been shown to be up regulated in ALS spinal cord tissue and also to cause protein aggregation. These traits have made Per28 an excellent biomarker candidate of ALS. ALS is a neurodegenerative disease, which affects the peripheral nervous system and in most cases results in fatality within 3 to 5 years of diagnosis. The fact that this horrific disease can only be detected at such a late stage makes the need for new biomarkers essential. In this study, we attempt to design an assay capable of quantifying Per28 levels from cerebrospinal fluid, which would be suitable for use in a clinical setting, as well as design a standard procedure for the creation of similar assays. This was accomplished through a multi-step procedure. First, Per28 DNA was subcloned into a BL21 bacterial line and column purification of the resultant protein was carried out to produce a representative standard protein. Following this a Sandwich ELISA was designed using a previously characterized capture antibody, which is selective for the unique epitope caused by Per28’s intron retention, and a commercial detection anti-peripherin antibody, which was characterized to show it’s recognition of the Per28 isoform. Third and currently the resultant ELISA was tested for sensitivity and, to date, has been shown capable of detecting a minimum of 1ng/ml of Per28. Future directions for this project will take the final step of characterizing the assay’s accuracy in detecting Per28 from CSF and also the creations of new antibodies against other candidate biomarkers to be used in future assays.

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22. Gardezi SR1; Taylor P2; Khanna R3; Stanley EF1 1Department of Physiology, Genetics and Development, Toronto Western Hospital; 2Advanced Protein Technology Centre, Hospital For Sick Children, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8; 3Stark Neurosciences Research Institute, Department of Pharmacology and Toxicology, 950 W. Walnut St., Indianapolis, IN 46202; LONG C TERMINAL SPLICE VARIANT CAV2.2 IDENTIFIED IN PRESYNAPTIC MEMBRANE BY MASS SPECTROMETRIC ANALYSIS Cav2.2 voltage gated calcium channels play a key role in the gating of transmitter release at presynaptic terminals. Recently we used mass spectrometry (MS) to analyze the protein complex associated with Cav2.2 in purified presynaptic terminal membranes (Khanna et al., J Biochem Mol Biol 40: 302, 2007). A number of known and new Cav2.2-associated proteins were identified, but not the channel itself. Objective: We set out to explore the above mentioned anomaly and tested the hypothesis that the channel was missed due to high concentrations of co-precipitated proteins. As previously, antibody Ab571 was used to capture the channel from purified synaptosome membrane lysate. Materials and Methods: Cav2.2 specific antibody, Ab571, was immobilized onto the Protein A agarose gel and incubated with purified synaptosome membrane lysates. Protein complexes captured by the immobilized Ab571 were subjected to a high salt treatment and the remaining proteins were eluted with high concentration urea. Urea eluted protein complexes were analyzed by Liquid chromatography tandem mass spectrometry (LC MS/MS). Results: LC MS/MS analysis of protein complexes that remained bound after the high salt treatment identified 12 distinct Cav2.2 peptides. These peptides were all from intracellular domains of the protein but otherwise their origins span almost the full-length of the protein, including 2 in the N terminus, 4 in the II-III loop, and 6 in the C terminus. One Cav2.2 peptide heralded from the alternatively spliced, long C terminal, region. Conclusions: This finding is the first conclusive detection of a presynaptic Cav2-family calcium channel by mass spectrometry and the first detection of this particular channel type in any analysis. Furthermore, one peptide derived from the alternatively spliced, long-C terminal region, confirmed that this Cav2.2 splice variant is targeted to the presynaptic terminal.

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23. Goncharenko K1,2; Eftekharpour E1; Velumian A1,2; Carlen PL1,2; Fehlings MG1 1Divisions of Neurosurgery, Cell and Molecular Biology, Toronto Western Research Institute, Krembil Neuroscience Centre, & University of Toronto, Toronto ON, Canada; 2Department of Physiology, University of Toronto, Toronto ON, Canada; GAP JUNCTION FUNCTION AND EXPRESSION IN SECONDARY SPINAL CORD WHITE MATTER INJURY. Introduction: Axonal dysfunction after spinal cord injury (SCI) is associated with hypoxia/ischemia, which can be modeled in vitro as oxygen-glucose deprivation (OGD) . Under such conditions axonal ionic mechanisms undergo changes, whereby the reversal of the Na+/Ca2+ exchanger leads to increased intracellular levels of calcium, followed by cell death from second messenger cascades. Previous attempts at reducing such excitotoxic damage by blocking the exchanger provided only partial axonal protection, foreshadowing the involvement of other channels in propagation of axonal injury. Gap junctions are widely present in the spinal cord white matter; however, their role in post-injury axonal dysfunction remains largely unexplored. The purpose of the present study was to explore the role of gap junctions in exacerbating the deleterious effects of OGD on spinal cord white matter. Hypothesis: We hypothesized that inhibition of gap junctions would improve axonal conduction in spinal cord white matter during OGD. Methods: The functional role of gap junctions in normal and ischemic spinal cords was assessed by electrophysiological recordings of compound action potentials (CAP) in rat spinal cord slices using the sucrose-gap technique. To model secondary SCI, in vitro slices were subjected to 30 min oxygen-glucose deprivation. Gap junction connexin mRNA expression was determined using qPCR and normalized to β-Actin. Localization of connexins in white matter spinal cord tissue was performed using immunohistochemistry. Results: In response to 30 min OGD, there was a rapid and reversible decline in the amplitude of the CAP compared to pre-injury. Carbenoxolone (100µM), a gap junction blocker, significantly delayed both the rate and the extent of the CAP decline, suggesting that blocking gap junctions reduces conduction loss during OGD. Carbenoxolone alone did not change the amplitude of CAP in non-injured tissue and thus does not seem to interfere with intrinsic axonal conduction. The results show no difference in mRNA expression of connexins 32, 36 and 43 following OGD injury and one hour recovery periods. However, upon application of carbenoxolone, astrocytic connexin 43 expression appears to be downregulated exclusively during OGD (p<0.005), compared to non-injured carbenoxolone treated cord. Overall, carbenoxolone appears to upregulate connexin mRNA. Immunohistochemistry showed that both connexins 36 and 43 are present in longitudinal spinal cord slices and connexin 43 overlaps with astrocytic marker GFAP, confirming its location in astrocytic gap junctions. Conclusions: Preliminary results confirm the presence of gap junctions in spinal cord white matter, propose dynamic changes in mRNA expression resulting from alterations to their open states and suggest that blocking gap junctions improves axonal conduction during ischemia modeling secondary SCI.

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24. Green S1; Keightley ML1,3; Chen JK1,3; Ptito A2; Johnston K3; Saluja R2 1Rehabilitation Science, University of Toronto; 2Montreal Neurological Institute; 3Toronto Rehab; CHANGES TO BRAIN ACTIVATION AND TASK PERFORMANCE DURING A VISUAL WORKING MEMORY TASK IN YOUTH POST-MTBI: AN FMRI STUDY Purpose: To explore what changes occur to task performance and brain activation during a visual working memory task in youth after mild Traumatic Brain Injury (mTBI) compared to non-injured age-matched peers. Subjects: 16 youth between the ages of 10-17 years, 8 post-mTBI and 8 non-injured youth (6 male, 2 female per group). At time of testing, the 8 post-mTBI youth were less than 6 months post-mTBI still experiencing symptoms as determined by the Post-Concussion Symptom Scale. Methods: A cross-sectional study design using functional Magnetic Resonance Imaging (fMRI) and a visual working memory task with post-mTBI and non-injured age-matched youth. fMRI data was collected on a Siemens 3T MRI scanner to determine Blood oxygen level dependent (BOLD) activation patterns associated with the working memory task. Working memory responses were recorded and measured for accuracy. Results: Both post-mTBI and non-injured youth showed significant bilateral activation in the dorsolateral and ventrolateral prefrontal cortices and dorsal cingulate cortex, although activation in the prefrontal cortices of the injured group was weak. A significant difference in working memory performance was found between post-mTBI and non-injured youth (F=5.24, p= 0.04). Post-mTBI youth averaged 63 percent correct responses while non-injured youth averaged 74 percent. Conclusion: While symptomatic post-mTBI, youth demonstrated both behavioural and physiological changes during a visual working memory task.

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25. HAN HA1,3; Wu Y3; Cortez MA2,3; Shen L3; Snead OC III1,2,3 1Institute of Medical Science, University of Toronto, Toronto, ON, Canada; 2Department of Paediatrics, Faculty of Medicine, University of Toronto, Toronto, ON, Canada; 3Program in Neuroscience and Mental Health., Hosp. for Sick Children, Toronto, ON, Canada; BEHAVIORAL CHARACTERIZATION OF TRANSGENIC MICE WITH OVER-EXPRESSION OF GABA(B) RECEPTORS Functional GABA(B) receptors exist endogenously as heterodimers consisting of R1 and R2 subunits. Wu et al (2007) and Stewart et al (2009) showed respectively that over-expression of either the GABA(B)R1a or R1b receptor subtype in mouse forebrain neurons induces an atypical absence seizure phenotype whereas mice with over-expression of GABA(B)R2 receptors display no seizure phenotype. When GABA(B)R1b and R2 receptor subtypes (GABA(B)R1b/R2) are over-expressed together, the seizure phenotype becomes more robust than the over-expression of R1b receptors alone. However, little is known about other behavioral manifestations consequential to the expression of the GABA(B) transgenes. Mice of 4 different genotypes (over-expression of GABA(B)R1b, R2, R1b/R2 & littermate controls) were subjected to behavioral testing paradigms examining anxiety and motor coordination. No differences were observed between all 4 genotypes in terms of the percentage time spent and the number of entries to the open or closed arms of the elevated plus maze. Similarly, there were no significant differences in the performance on the Rotarod apparatus across all 4 groups. Chronic depth electrode implantations in GABA(B)R1b/R2 mice revealed the presence of slow spike-and-wave discharges (SSWDs) within the dentate gyrus and CA1 regions of the hippocampus as well as in the thalamus, confirming the “atypical” nature of the SSWDs. Pharmacologically, treatment with ethosuximide (100mg/kg, i.p.) did not significantly reduce the SSWDs in the GABA(B)R1b/R2 mice while treatment with CGP35348 (100mg/kg), a GABA(B) antagonist, did. Taken together, these studies suggest that mice with over-expression of GABA(B)R1b/R2 receptors in the forebrain neurons represent a novel animal model of medically refractory atypical absence seizures.

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26. Hawryluk G1,2; Mothe A1; Tator C1,2; Fehlings MG1,2 1Toronto Western Research Institute; 2Division of Neurosurgery, Department of Surgery, University of Toronto; CELL-BASED REPAIR STRATEGIES FOR SPINAL CORD INJURY: EXAMINATION OF TROPHIC FACTOR EXPRESSION IN VIT Hypothesis: Cells transplanted to repair the injured spinal cord produce trophic factors or induce their expression in host tissue. Purpose: Diverse cell transplantation approaches to repair the injured spinal cord have shown benefit. Trophin augmentation may thus underlie this benefit, but this has been insufficiently explored. Methods: RNA was extracted from bone marrow stromal cells (BMSCs), and different passages of neural precursor cells (NPCs) extracted from the adult mouse brain, the E16 rat spinal cord and the adult rat spinal cord before and after induced differentiation in vitro. RNA was also extracted from experimental and control tissue from three transplantation paradigms - two involving NPCs and one involving BMSCs. Quantitation of candidate trophic factor gene expression was performed via qPCR with SYBR Green chemistry. Results: NPCs and BMSCs express detectable levels of trophic factors in vitro. All NPCs demonstrate a similar expression profile which changes little with passaging. NPCs from all sources markedly upregulate their expression of the neurotrophins, GDNF, CNTF, GGF2, IGF-1, LIF, and TGF-B1 following differentiation in vitro. Tissue transplanted with NPCs shows relatively little change in trophin expression, but when EGF, FGF and PDGF are co-administered via an osmotic minipump there is a marked and statistically significant increase in the expression of the neurotrophins, GDNF, FGF and LIF. Further, BMSC transplantation led to significantly higher levels of NGF, IGF-1, LIF and TGF-B1 relative to control tissue. Conclusions: Trophic factors may contribute to the benefits noted with cellular transplantation for spinal cord injury. Assays on undifferentiated cells in vitro cannot be extrapolated to the post-transplant environment.

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27. Ho KT1,4; Lam EMILY1; Griffin J4; Mac J5; Brown M4; Mclaurin J2,4; Mount HT1,3,4 Departments of; 1Physiology; 2Laboratory Med. and Pathobiology; 3Med., Univ. of Toronto, Toronto, ON, Canada; 4Ctr. for Res. in Neurodegenerative Dis., Toronto, ON, Canada; 5Humberside Collegiate, Toronto, ON, Canada; BEHAVIOURAL PHENOTYPES OF DJ-1-DEFICIENT MICE IMPLICATE ALTERED TRANSMISSION IN MULTIPLE BRAIN AREAS AND ARE DIFFERENTIALLY AFFECTED BY ATM EXPRESSION Mutations in the DJ-1 gene result in a loss of functional DJ-1 protein and cause early-onset familial Parkinson’s disease. DJ-1-knockout (DJ-1-KO) mice exhibit hypersensitivity to MPTP, a dopaminergic neurotoxin, as well as progressive disruption of gait and impaired corticostriatal and hippocampal synaptic activity. Thus, it appears that DJ-1 is involved in the function of brain regions beyond the dopaminergic nigrostriatal neurons that are targeted in Parkinson’s disease. Increases in DJ-1 expression are associated with certain cancers and have been observed in p53 mutant tumour lines. Ataxia telangiectasia (AT) is a neurodegenerative disorder caused by loss of functional ATM, the kinase that phosphorylates p53 in response to genotoxic stress. In human patients, AT is characterized by an increased risk of cancer as well as Purkinje and granule cell death in the cerebellum. In an Atm-KO mouse model of AT, we discovered increased expression of DJ-1 in Purkinje neurons following exposure to genotoxic stress. Intriguingly, these neurons do not degenerate, suggesting a possible neuroprotective role for DJ-1 expression in the ATM/p53-dependent genotoxic stress response. Collectively, these findings led us to test whether and how deficiencies in the two proteins might regulate murine behavioural phenotypes. In this study, we subjected DJ-1-KO mice on wild type and Atm-KO backgrounds to tests of cognition, neuromotor function and affect. DJ-1-KO mice were impaired in cortically-encoded novel object recognition memory and in a Morris water maze test of hippocampal spatial memory. In a test of forelimb incoordination that has been shown to be sensitive to disrupted nigrostriatal dopamine, and in a test of gait symmetry, DJ-1-KO mice exhibited progressive impairment. Similarly, in a test of behavioural despair, DJ-1-KO mice exhibited increased immobility, a measure that is inversely correlated with synaptic noradrenaline turnover. Exploration of open quadrants in the zero-maze, a measure of anxiety that is sensitive to serotonin transmission, was reduced in DJ-1-deficient mice. Combined deficiencies in Atm and DJ-1 abrogated the forelimb impairment, gait asymmetry and behavioural despair of DJ-1-KO mice. Conversely, DJ-1-KO anxiety in the zero maze was exacerbated by Atm-deficiency. We suggest that reciprocal putative effects of DJ-1 and Atm deficiencies on expression of the transporters for dopamine and noradrenaline, but not serotonin, could underlie the phenotype-canceling effect of combined deficiencies in these proteins.

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28. Ho ECY1,2; Zhang L1,3; Skinner FK1,2,3,4 1Toronto Western Research Institute, University Health Network, Toronto, Ontario, Canada Departments of; 2Physiology; 3Medicine (Neurology); 4Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada.; INDIVIDUAL NEURON CHARACTERISTICS AND THE CONTROL OF SLOW POPULATION ACTIVITIES Objectives: Slow oscillations (SOs) are population activities of frequencies from 0.5 to 5 Hz occurring in many areas of the brain. Examples of SOs include the cortical EEG K-complex during NREM sleep and the large irregular activities in the hippocampus. While SOs are believed to play a major role underlying synaptic plasticity, many aspects of SOs are still unknown. For instance, is it possible for SOs to emerge if long time scales are not present in individual neurons and synaptic connections? Our aim here is to achieve a general mechanistic understanding of SOs by studying a specific in vitro example of SOs in the hippocampus. Materials and Methods: We use a combination of data extraction, simulation and mathematical analysis to pursue our goal of understanding how SOs are generated. We first extract relevant synaptic quantities from an experiment on 1mm thick mice hippocampal slices in which a form of spontaneous inhibitory-based SO occurred. We then use these quantities as parameter constraints in our inhibitory network simulations. The network size (120 cells) is constrained to represent the approximate number of fast-spiking interneurons in the hippocampal slice preparation. The largest explicit time scale used in the network is the GABA time constant (10ms). We vary the input-output characteristics (i.e. f-i curve) of the constituent inhibitory neurons and the inhibitory coupling constant (gsyn) as parameters of simulation. Finally, in order to explain the trends and make predictions from our simulation results, we approximate the network with a set of low-dimensional mean field equations and perform mathematical analysis through these equations. Results: Population SOs are observed in our network simulation with the determined experimental constraints. However, simulated networks with differing input-output characteristics of constituent neurons exhibit diverging SO behaviour. In general, we see a strong SO response (defined as having a high ratio of activity in "high activity" states to "low activity" states) for networks with a more-linear f-I curve for their constituent neurons. In contrast, a network with its neurons having a high curvature f-I curve has a weaker SO response, although the response can be observed for a larger set of gsyn values. Subsequent mathematical analysis concludes that solutions for SO tend to "clump" together in a narrow region of gsyn values for a more linear f-I curve of constituent neurons, thus explaining the strong SO response for those networks. However, SO solutions tend to "spread out" for networks with a high curvature f-I curve for their neurons--the underlying reason for the weaker response (but more easily observable for a wider range of gsyn values) of these networks. Conclusions: Intrinsic properties of individual neurons are a critical component in determining the overall network characteristics of SOs. In order to have a robust SO response, a tradeoff has to be made between a strong response that only occurs in a narrow range of gsyn values and a weaker response that can be observed for a wider range of gsyn values. This tradeoff is facilitated by the curvature of f-I curves. We believe that our results may generalize to population slow activities occurring in other brain areas.

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29. Hodgson N1; Lewis MD2 1,2Human Development and Applied Psychology, University of Toronto; BRAIN AND BEHAVIOUR INDICES OF SELF-MONITORING IN CHILDREN WITH BEHAVIOURAL PROBLEMS The error-related negativity (ERN) is an event-related potential (ERP) thought to originate in the anterior cingulate cortex (ACC). This phenomenon provides the opportunity to study the neural processes involved in error monitoring. Significant ERNs have been reported when participants commit errors on cognitive tasks. Although many studies have now investigated the ERN, limited research has examined this phenomenon in children. However, research focusing on this demographic is crucial in understanding the development of cognitive skills such as error monitoring, which are being consolidated in childhood. Furthermore, very few studies have investigated the connection between individuals? ERNs to performance on behavioural tasks. Clinical subjects with impaired self-monitoring make an ideal population for studying these connections, as variations will be more noticeable in such a group. We first evaluated 31 children 7-11 years of age diagnosed with behavioural problems for performance on the Iowa Gambling Task, a task that is facilitated by the exercise of self-control. We then used dense-array (128-channel) electroencephalography (EEG) to record the ERN component while the children engaged in a go/no-go task, which taps self-monitoring. IGT performance significantly correlated with ERN amplitudes: Better performance on the IGT was associated with larger ERN amplitudes. These findings suggest that children who are better able to recruit self-monitoring, as indexed by larger ERN amplitudes, will perform better on tasks requiring self-control, as indicated by performance on the IGT.

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30. Hung Y1,3; Smith ML2,3; Taylor MJ1,3 1Diagnostic Imaging, Hospital for Sick Children; 2Psychology, Hospital for Sick Children; 3Department of Psychology, University of Toronto; FUSIFORM LATERALITY AND LIMBIC-FRONTAL ACTIVITY DURING EMOTIONAL FACE PROCESSING Neurocognitive models of emotional face processing involve fusiform specialisation and the interaction between the limbic and frontal systems, yet the temporal information of this processing is still not understood. Here we investigated the timing of emotional face processing with particular attention to the lateral asymmetries of brain activations in the fusiform and the relation between amygdala and frontal activity. We recorded neuromagnetic field generated from the brain using magnetoencephalography (MEG) in 14 adults during a target-detection task presented with emotional faces. Source analyses identified brain activations in the visual, fusiform, and amygdale-ACC (anterior cingulate) areas. Examination of the time courses of the activated brain areas revealed that at 100 ms, fearful faces elicited activations in the amygdala and the dorsal ACC regions but deactivations in the ventral ACC areas compared to the neutral faces. Lateralised fusiform activations responded to faces in contralateral visual fields at 150 ms, involving an early right and later left hemispheric dynamic.. Our results suggest that afferent visual inputs modulate cortical processing associated with hemispheric laterality and also identified an early and automatic fear-related network within the limbic and frontal systems.

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31. Janus MK1; Lewis MD1 1Human Development and Applied Psychology, University of Toronto; NEUROPHYSIOLOGICAL CORRELATES OF SELF-MONITORING DIFFERENTIALLY MODERATE THE RELATION BETWEEN MATERNAL DEPRESSION AND CHILDREN’S BEHAVIOUR PROBLEMS Research in developmental psychopathology has advanced our understanding of emotional dysregulation underlying children’s behavioural problems and their association with maternal depression. Neurophysiological measures may further clarify these relations. The ERN (error-related negativity) is an event-related potential commonly used to assess self-monitoring, with large amplitudes reflecting internalizing and small amplitudes reflecting externalizing symptoms. The present study investigated the effect of ERN amplitude on the relation between maternal depression and internalizing and externalizing problems in a sample of children referred for aggressive behaviour. ERN amplitudes were recorded while 50 children (8-10 years of age) engaged in a go/no-go emotion induction task. Results indicated an association between high ERN amplitudes and internalizing behaviour and between small ERN amplitudes and externalizing behaviours for children with depressed mothers. These findings suggest that the degree of self-monitoring (indexed by ERN amplitude) moderates the relation between maternal depression and psychopathological outcomes in children.

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32. Johnson SA1; Sediqzadah S1; Erb S1,2 1Department of Psychology, U of T Scarborough; 2Centre for the Neurobiology of Stress, U of T Scarborough; RECENT COCAINE EXPERIENCE RENDERS CONDITIONED LOCOMOTOR RESPONSES RESISTANT TO EXTINCTION In rats trained to self-administer cocaine, return to the self-administration context elicits drug-seeking behaviour. The magnitude of this response increases after extended drug-free periods, suggesting that associations formed between the context and instrumental responding for drug reward are maintained and strengthen over time. Similarly, we have shown that the conditioned locomotor response elicited by non-contingent cocaine administration in a specific context is maintained after an extended drug-free period. In the present experiment, we asked whether this drug-context association might also become more resistant to extinction after extended drug-free periods. We then asked whether conditioned locomotion could be reinstated by a cocaine challenge, and whether this response would spontaneously recover following re-extinction of the drug-context association. Male rats received injections of cocaine (30 mg/kg, i.p.) or saline once daily for 6 days in activity monitoring chambers. The presence of a conditioned locomotor response was confirmed both 1 day and 6 weeks after the last injection, and was fully extinguished with 5 additional sessions. The following day, rats were tested for locomotor sensitization by administering a single cocaine challenge (10 mg/kg, i.p.). The recovery of conditioned locomotion was monitored 24 hours later, and this test was followed by 2 additional extinction sessions. Six weeks later, rats were tested for spontaneous recovery. Conditioned locomotion did not become resistant to extinction after a 6-week drug-free period. In fact, the conditioned locomotor response was slower to extinguish in rats tested 1 day after cocaine pre-exposure. After a cocaine challenge, locomotor sensitization was evident in rats that had undergone either 1 day or 6 weeks of abstinence; however, this re-pairing of the drug with context did not prompt recovery of the conditioned locomotor response. Our results suggest that while drug-context associations resulting in conditioned locomotor activity are maintained after extended drug-free periods, prolonged abstinence renders these associations less resistant to extinction. This is in contrast to associations formed during drug self-administration that promote drug-seeking behaviour, which become more resistant to extinction over time.

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33. Jordao JF1,2; Ayala-Grosso CA3,2; Huang Y2; Chopra R1,2; McLaurin J1,4; Hynynen K1,2; Aubert I1,2 1University of Toronto; 2Sunnybrook Research Institute; 3Unidad de Biología Molecular, Universidad Central de Venezuela; 4Centre for Research in Neurodegenerative Disease; RAPID REDUCTION OF AΒ PLAQUE LOAD IN THE BRAIN OF TGCRND8 MICE FOLLOWING ULTRASOUND-ENHANCED IMMUNOTHERAPY Passive immunotherapy approaches for Alzheimer’s disease (AD) rely on antibodies directed against toxic amyloid-beta peptides (Aβ), which circulate in the bloodstream and pull Aβ away from the brain. In animal models of AD, the administration of anti-Aβ antibodies directly in the brain, in comparison to the bloodstream, clears Aβ more effectively, minimizes cerebral amyloid angiopathy, and reduces the associated risk of microhemorrhages. Thus, it may be ideal to deliver anti-Aβ antibodies to the brain of AD patients, as non-invasively as possible. The use of focused ultrasound (FUS) in the presence of a microbubble ultrasound contrast agent is known to cause localized and transient permeability of the blood-brain barrier. We propose that low doses of anti-Aβ antibodies administered in the bloodstream can efficiently enter the brain and target Aβ following FUS treatment. Our aims were two-fold; first, to deliver anti-Aβ antibodies injected into the peripheral bloodstream to targeted areas of the brain using FUS. Secondly, we evaluated the effectiveness of the anti-Aβ antibodies for reducing the Aβ-plaque load by 4 days following this drug delivery approach. Definity microbubbles, MRI contrast agent and BAM-10, anti-Aβ antibody were injected into the tail vein of 4 month old TgCRND8 mice at the onset of FUS application. FUS was applied over cortical areas to 4 spots in a line along the right hemisphere of the brain. TgCRND8 mice were sacrificed at several time points post-treatment and their brains processed for biochemical analyses and quantitative imaging. Our study showed that FUS delivered anti-Aβ antibody to the right hemisphere of the brain. By 4 days post-treatment, anti-Aβ antibody significantly reduced Aβ plaque load in the right hemisphere compared to the left. In conclusion, the administration of a low dose of anti-Aβ antibodies in the peripheral bloodstream, combined with FUS, significantly reduced Aβ plaque pathology in targeted cortical areas of TgCRND8 mice within 4 days of a single treatment. This novel approach shows promise for the improvement of current immunotherapy treatments by providing a more targeted delivery strategy, allowing a rapid reduction of Aβ plaque load in the brain with a concentration of anti-Aβ antibodies that is 10-fold lower than that used in previous mouse immunization studies.

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34. Kanawaty AK1; Van der Kooy D2; Henderson JT1 1Faculty of Pharmaceutical Sciences, University of Toronto; 2Department of Medical Biophysics, University of Toronto; ROLE OF EPHB2 IN REGULATING MORPHINE DEPENDENT RESPONSE Eph receptors and their ligands comprise the largest family of axon guidance signaling molecules in mammals. Receptors can be segregated into two fundamental classes (A or B) depending upon the nature of their ligands. EphB receptors interact with transmembrane ligands which themselves possess intracellular signaling properties. We have previously shown that in addition to regulating several forms of axon guidance in the central nervous system (Ho et al., Neuroscience 2009), EphB receptors regulate activity-dependent neuronal signaling through the stabilization of active postsynaptic NMDA receptors (Henderson et al. Neuron 2001). Recently I have begun to delve into an entirely new aspect of EphB receptor function, the potential of these receptors to influence pain-related behaviors. Using a Lac-Z knockin of the EphB2 locus, I have determined that the temporal and spatial expression of this receptor in vivo is strongly correlated with neural loci which express the mu opioid receptor, a well established mediator of morphine-induced analgesia. Despite demonstrating wild-type levels of motor activity, and showing normal baseline responses to a variety of nociceptive, thermoceptive and mechanoceptive stimuli, EphB2 knockouts exhibit a significantly lower pain threshold following prolonged morphine exposure compared to controls. The results indicate that EphB2 plays a critical role in regulating opiate tolerance. Specifically, it appears that EphB2 regulates the learned component of opiate tolerance. In this respect it is interesting to note that several Eph-family receptors/ligands map proximal to putative schizoaffective loci in man, a disorder in which altered opiate responses are a known outcome. Using induced mutations of the endogenous EphB2 locus, I have demonstrated that the opiate effects observed are dependent upon ectodomain function of the EphB2 receptor. These studies thus provide insight into both the mechanisms and new potential treatments for opiate addiction in man.

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35. Karpova A1; Sooyong C1; Rabin D1; Craciunas S1; Smith SR1; Fehlings MG1,2 1Department of Surgery, Division of Neurosurgery, University of Toronto, Toronto, Ontario, Canada; 2Spinal Program, Krembil Neuroscience Centre, Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada; 3Department of Radiology, Division of Neuroimaging, University of Toronto, Toronto Western Hospital, Toronto,Ontario, Canada.; INTER-RATER AND INTRA-RATER RELIABILITY OF RATINGS OF FOUR QUANTITATIVE METHODS TO ASSESS SPINE STENOSIS ON MAGNETIC RESONANCE IMAGING IN PATIENTS WIT Design: Retrospective study. Objective: To measure the intraobserver and interobserver reliability of transverse area (TA), compression ratio (CR), maximum canal compromise (MCC) and maximum spinal cord compression (MSCC) in assessing the degree of spine stenosis in population with CSM (Cervical Spondylotic Myelopathy). Background: Earlier studies have demonstrated inconsistencies in predicting surgical outcomes for patients who demonstrate myelopathy; most notably, due to lack of standardized approach to assess severity of CSM. These variations may reflect inconsistency of degree of spinal cord and canal stenosis in MR image diagnosis. The extent of TA, CR, MCC and MSCC is of clinical and prognostic value in the setting of CSM. However, concerns remain regarding the accuracy of these measurements. Hypothesis: We hypothesized that the interrater and intrarater reliability of these assessments would be enhanced using T2-weighted imaging and midsagittal view - based measurements using digitized/magnified images and written instructions. Methods: Four spine surgeons examined mid-sagittal and axial T1-/T2 MR weighted images from 17 patients with spine stenosis who were clinically diagnosed with CSM. Spine surgeons examined images on four occasions to assess stenotic changes, while blinded to the clinical status of the patients. The degree of spine stenosis were evaluated by measuring TA and CR on axial T2WI, MCC on mid-sagittal T1WI and MSCC on mid-sagittal T2WI using digitized/magnified images and written instructions. Analyses included interclass correlation coefficients (ICCs) assessment of intraobserver and interobserver reliability. Results: The repeated measures analysis of variance indicated intra- and inter-reliability for TA, CR, MCC and MSCC with ICCs of 0.97, 0.95, 0.94, 0.93 and 0.76, 0.80, 0.64, 0.84 respectively. Those coefficients were calculated using Shrout-Fleiss models for random effects (Model 2) and fixed effects (Model 3) (Fleiss, 1979). Conclusion: For four measurement tools, the degree of accuracy in reproducing similar results was moderately high, with more precision noted in T2-weighted image, especially in mid-sagittal planes. This supports the common use of mid-sagittal T2WI image in the clinical and research settings. This is the first study to examine, in a large cohort of observers, the intra-/interobserver reliability of objective, quantifiable methods to assess spinal canal and cord stenosis. This study demonstrated that the consistency is high enough to confirm the validity of these radiologic parameters.

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36. Kirshenbaum G1,2; Clapcote S5; Roder J1,2,3,4 1Institute of Medical Science, University of Toronto; 2Samuel Lunenfeld Research Institute, Mount Sinai Hospital; 3Department of Physiology, University of Toronto; 4Department of Medical Genetics, University of Toronto; 5Institute of Membrane and Systems Biology, University of Leeds; MANIC BEHAVIOUR IS ATTENUATED IN A MOUSE MODEL OF MANIA BY REDUCTION OF AGRIN AND ERK SIGNALING. The lack of a valid animal model for Bipolar disorder has been hindering the discovery of the underlying neurobiology of the disease and the development of novel treatments. By ENU mutagenesis, my lab has created a mouse called Myshkin that has a point mutation in the alpha-3 sodium potassium ATPase pump causing haploinsufficiency. Myshkin is a compelling new mouse model of bipolar mania as it demonstrates construct validity, face validity and predictive validity. Myshkin demonstrate many symptoms of mania found in humans including hyperactivity, increased risk taking behaviour, circadian disturbances and abnormal sleep patterns. Here we show that manic behaviour is attenuated by decreasing Na+,K+ ATPase inhibition by agrin and by decreasing intracellular ERK signaling.

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37. Koshimori Y1,2; Turner G3; Crawley A4; Mikulis DR4; Bradbury CL2; Green REA2 1Graduate Department of Rehabilitation Science, University of Toronto; 2Toronto Rehabilitation Institute; 3Sunnybrook Health Sciences Centre; 4Toronto Western Hospital; DIFFUSION TENSOR IMAGING (DTI) VS CONVENTIONAL MRI FOR SINGLE CASE DIAGNOSIS OF MILD TRAUMATIC BRAIN INJURY (MTBI) Mild traumatic brain injury (mTBI) is a major public health issue, with the annual incidence ranging from 100 to 550 per 100,000 people worldwide, and estimates of up to 30% reporting persisting symptoms. However, diagnosis of mTBI is challenging because conventional neuroimaging tools are not sensitive to microscopic axonal injury. More recently, diffusion Tensor Imaging (DTI) shows sensitivity to mTBI due to the axonal injury, but most research has been done in group studies and there is limited data on individual cases. However, it is important to determine whether DTI can detect mTBI in individual cases because this is what is needed for clinical diagnosis. We examined DTI-derived fractional anisotropy [FA] in five individuals who: (1) had sustained a traumatic injury (resulting in spinal cord injury) due to motor vehicle related accidents or falls, and were therefore at risk of mTBI, but (2) whose conventional MRI findings were considered normal by two expert neuroradiologists. Five “clean” patients (aged 35.4±14.9) who had no history of neurological or psychiatric illnesses, substance abuse or prior trauma were selected from a larger sample of 43. Ten group-matched controls were also included. Whole brain conventional MRI including structural MRI, T2*-weighted gradient-echo, (GRE) and fluid-attenuated inversion recovery (FLAIR) as well as DTI of all subjects were acquired on a GE 3 Tesla MRI scanner equipped with an eight-channel head-coil. DTI data were processed offline using FSL tools from the FMRIB software library (FSL, http://www.fmrib.ox.ac.uk/). A region of interest (ROI) analysis was conducted using 28 ROI masks created based on the International Consortium of Brain Mapping-DTI-81 (ICBM-DTI-81). FA of patients was individually compared with the control mean FA for each of the 28 brain regions. FA data for each patient and region were classified into 3 bands (1.5 to 1.99 SDs, 2 to 2.49 SDs, and < 2.5 SDs below controls). Two of the five patients had normal conventional MRI findings while the rest had non-specific white matter hyperintensities (NWMH) found on FLAIR. All five patients showed at least one area of FA reduction at <-2.5SDs; four of five had multiple areas of reduced FA. Patients had an average of 8.6 of 28 (30.71%) reduced regions. The most frequently affected regions were cingulum, uncinate fasciclus, tapetum, corpus callosum, and anterior limb of the internal capsule. In contrast, there was no FA reduction for any patient in the body of the corpus callosum, and fornix (column and body) and retrolenticular part of the internal capsule. DTI was more sensitive in detecting brain changes than conventional neuroimaging in these cases, suggesting that DTI holds promise for mTBI single case diagnosis. We are continuing to investigate the utility of this novel imaging methodology as a diagnostic tool in this population.

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38. Kostelecki W1,2; Perez Velazquez JL1,2 1Institute of Medical Science, University of Toronto; 2Neurosciences and Mental Health Program, Hospital for Sick Children; CLASSIFICATION OF BRAIN STATES FROM MEASURES OF DIRECTED CORTICAL PROCESSING The brain is a complex system that can only be understood through the simultaneous consideration of many interacting and evolving processes. As a result, multivariate data acquisition techniques have become useful tools in many aspects of brain research. One such technique is magnetoencephalography (MEG) which detects the neuromagnetic activity being produced by the brain. MEG has become a popular tool in neuroscience research because it allows for a high degree of temporal resolution which provides improved insight into the brain processes that constitute cognitive and behavioural brain states. Although used abundantly, MEG recordings are notoriously difficult to interpret due to the complex anatomical and functional origins of the signals being measured. There are many methods, however, with which researchers are approaching the analysis of these recordings. One framework – termed Granger causality – is a concept in multivariate time series analysis defined by the presence of a time-lagged linear mapping between two time series. Specifically, if consideration of past values of time series, X, provides predictive insight for another time series, Y, then X is said to Granger cause Y. This formulation of causality has been useful because it provides access to directed relationship between time series and offers insight into possible cortical processes that underlie various brain states. In this study, I applied the definition of Granger causality to human MEG recordings in order to uncover the transient cortical interactions that occur during the performance of a cognitive task. This task required that a subject press a button with their left or right finger in response to a cue that either, 1) specifies the finger with which the button should be pressed or 2) instructs the subject to choose the finger with which to press the button. Using this experimental paradigm, I identified cortical structures that differentially contribute to chosen and forced behaviour. Linear classification of single-trial measures of Granger causality provided useful insight into cortical structures supporting the mental states underlying chosen and forced behaviour. Among notable differences is an increase in anteriorly directed measures of causality over much of the parietal and temporal cortices immediately preceding a chosen button press. This suggests a role for these regions in generating behaviour that requires a decision, and demonstrates the utility of linear classification of single-trial Granger causality measures for the discrimination of cognitive states.

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39. Krakowski A1,2; Frankland P1,2 1Institute of Medical Science, University of Toronto; 2Department of Neurosciences and Mental Health, Hospital for Sick Children; FUNCTIONAL INTEGRATION OF ADULT-BORN GRANULE CELLS INTO DENTATE GYRUS CIRCUITRY It is recognized that new neurons are generated throughout adulthood in specific regions of the brain, including the dentate gyrus of the hippocampus. As adult-generated neurons mature they undergo significant morphological changes, including dendritic growth and spine formation and are eventually integrated into dentate gyrus circuitry. The aim of the current study was to address whether differences in rates of morphological development affect the integration of new-born cells into dentate gyrus circuitry. A CAG-retrovirus was stereotaxically injected into the dentate gyrus of mice to selectively label proliferating cells with GFP and allow us to define morphological features of dendrites and spines. Either 10, 20, 40, or 80 days following viral infection, mice were injected with pentylenetetrazol (PTZ), and expression of the immediate early gene c-fos was used as a marker of activated neurons. Morphological features of neurons among groups and of Fos+ and Fos- new-born neurons within groups were then compared. As expected, between group differences in neuronal morphology were seen at 10, 20, 40, and 80 days post-infection. The greatest increases in dendritic length and spine density were seen from 10 to 20 days post-infection. Interestingly, between 20 to 40 days post-infection there was a reduction in both dendritic branch number and length, suggesting that maturation of adult-generated neurons is associated with an active pruning process. Consistent with previous observations, the proportion of new-born cells expressing Fos depended on cell age. The percentage of infected neurons increased markedly between 10 and 20 days post-infection and was highest 40 and 80 days post-infection. Fos+ neurons also had a greater spine density at 20 days than Fos - neurons suggesting an association between spine density and integration of adult-generated neurons into hippocampal circuitry. Our results suggest that an increase in spine density promotes integration of adult-generated neurons into hippocampal networks. Furthermore, our results suggest that as adult-generated neurons mature they undergo a pruning mechanism, similar to developmentally-generated neurons.

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40. Kuipers MJ1; Popovic MR3,4,5; Verrier MC1,2,3,5 Departments of; 1Physiology; 2Physical Therapy; 3Rehabilitation Science, Faculty of Medicine; 4Institute of Biomaterials and Biomedical Engineering, University of Toronto; 5Toronto Rehabilitation Institute, Lyndhurst Center, Toronto, Ontario, Canada.; TRUNK NEUROPROSTHESIS FOR SPINAL CORD INJURY: RELATIONSHIP BETWEEN POSTURAL CONTROL AND RESPIRATORY CAPACITY Following spinal cord injury (SCI), the musculature of the trunk that provides support to the spine is compromised by paralysis and atrophy. When injury occurs at or above the first lumbar vertebra, some degree of paralysis to the lumbar musculature is usually present that diminishes voluntary postural control. This is especially relevant during sitting where individuals with SCI at levels above L1 tend to assume a kyphotic posture with a posteriorly tilted pelvis to maintain sitting balance1. Consequences of assuming this suboptimal posture include reduced respiratory capacity2, limitations in functional ability3, and secondary health problems4. Interventions available for corrective postural control are invasive (i.e. internal fixation or implanted stimulating electrodes) or external (i.e. abdominal binders), which are functionally restrictive. We are testing the efficacy of a non-invasive (transcutaneous) functional electrical stimulation (FES) neuroprosthetic system to determine whether trunk muscle activation alters seated posture and respiratory capacity in SCI using the Toronto Rehabilitation Neuroprosthesis for Sitting. We hypothesize that achieving vertebral alignment with transcutaneous FES will result in improved respiration as measured by lung capacity. In addition, the expected improvements in postural control may translate to increased arm function as measured by functional task performance. Simultaneous stimulation applied to trunk muscles of the back and abdomen causes anterior rotation of the pelvis and reduction of kyphotic curvature of the spine to gain vertebral alignment, and an increase in muscle stiffness of the abdominal wall, achieving a position that is known to facilitate gains in respiratory capacity5 and functional work space6. Using a multiple single case study design, subjects will serve as their own controls and be tested using the following paradigm. Transcutaneous FES is being administered to the lumbar erector spinae (longissimus thoracis), the rectus abdominus, and the external obliques of individuals with paresis due to SCI between levels C5-T12. Lung capacity, postural alignment, and functional task performance are being measured in both experimental conditions (with and without FES). Lung capacity [vital capacity (VC), forced vital capacity (FVC), and forced expiratory volume in one second (FEV1)] is being measured with a SpiroPro® spirometer (VIASYS Healthcare, USA). Postural alignment (pelvic tilt, spinal curvature, and head position) coupled with a functional task (forward reaching) is being measured kinematically using Optotrak motion capture system (NDI, Germany). To determine meaningful clinical important difference, subjects will be asked about their perceptions of sitting straighter, breathing deeper, experiencing less fatigue, and a feeling of well being during both quiet sitting and forward reaching using relevant questionnaires. Results will be used to develop a protocol for testing the relationship between postural control and respiratory capacity, arm function, and health status during rehabilitation in a SCI population. Secondary benefits of improved postural control include changes in pressure distribution during sitting and a reduction in the incidence of pressure sores. 1 Hobson, D.A. and R.E. Tooms, Seated lumbar/pelvic alignment. A Comparison between Spinal Cord Injured and Noninjured groups. Spine (Phila Pa 1976), 1992. 17(3):293-8.

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2 Winslow, C., and J. Rozovsky, Effect of Spinal Cord Injury on the Respiratory System. Am J Phys Med Rehabil, 2003. 82(10):803–814. 3 Gagnon, D., et al., Movement patterns and muscular demands during posterior transfers toward an elevated surface in individuals with spinal cord injury. Spinal Cord, 2005. 43(2): p. 74-84. 4 Kirchberger, I., et al., Identification of the most common problems in functioning of individuals with spinal cord injury using the International Classification of Functioning, Disability and Health. Spinal Cord, 2009. 5 Triolo, R.J., et al., Implanted Electrical Stimulation of the Trunk for Seated Postural Stability and Function after Cervical Spinal Cord Injury: A Single Case Study. Arch Phys Med Rehabil, 2009. 90(2): 340-347. 6 Kukke, S.N. and R.J. Triolo, The Effects of Trunk Stimulation on Bimanual Seated Workspace. IEEE Trans Neural Syst Rehabil Eng, 2004. 12(2):177-85.

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41. Kupferschmidt DA; Wang T; Erb S Centre for the Neurobiology of Stress, Department of Psychology, University of Toronto Scarborough.; THE CANNABINOID-1 RECEPTOR ANTAGONIST, AM251, BLOCKS THE EFFECTS OF CRF ON ANXIETY AND REINSTATEMENT OF COCAINE SEEKING OBJECTIVES: The endocannabinoid (eCB) system is recognized as an important regulator of the stress response, and has been implicated in the mediation of several stress-related behaviours. Although there is anatomical evidence that eCBs interact with the principle stress peptide, corticotropin-releasing factor (CRF), there are relatively few data addressing functional interactions between these systems. Accordingly, in the present series of experiments, we examined the effects of a CB1 receptor antagonist, AM251, on two CRF-induced behaviours: anxiety and reinstatement of cocaine seeking. MATERIALS AND METHODS: Male Long-Evans rats were pretreated with AM251 (0, 100, 200 μg, i.c.v.) followed by CRF (0, 0.5 μg, i.c.v.), prior to testing for anxiety on the elevated plus maze (EPM). In a separate experiment, male Long-Evans rats were trained to self-administer cocaine for 8-10 days. Upon extinction of cocaine-seeking behaviour, rats were pretreated with AM251 (0, 100, 200 μg, i.c.v.) and tested for reinstatement in response to injections of CRF (0, 0.5 μg, i.c.v.) or footshock stress (0, 0.9 mA; 20 min). RESULTS: Pretreatment with AM251 was itself mildly anxiogenic in the EPM, but interfered with the increased behavioural anxiety induced by CRF. AM251 also blocked CRF-, though not footshock-induced reinstatement of cocaine seeking. CONCLUSION: The present findings provide some of the first evidence that eCB transmission is importantly involved in the behavioural effects of CRF.

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42. Lam JJ1; Hunter JP2; Dostrovsky JO1 1Department of Physioglogy, University of Toronto; 2Toronto Rehab Institute, Toronto, ON, Canada; INTENSITY OF THE THERMAL GRILL ILLUSION DEPENDS ON CONFIGURATION OF GRILL ELEMENTS The thermal grill (TG) illusion (TGI) of pain occurs in response to simultaneous application of interlaced warm (40 °C) and cool (20 °C) bars. The illusion is proposed to reflect the integration of the relative activity of innocuous cool and cold responsive nociceptive (termed HPC cells) spinal neurons. Previous studies of the TGI used multiple alternating warm and cool bars delivered to the hand and forearm. We evaluated the effect of different arrangements of warm vs. cool bars on perceived pain and unpleasantness at the forearm and calf. Thermal stimuli (duration, 30s) were produced by an array of 5 Peltier-controlled bars, arranged in four control and two TG conditions as follows: all bars 20 °C, all bars 40 °C, center bar 20 °C /outer bars 33 °C (normal skin temperature), center bar 40 °C /outer bars 33 °C, and two TG conditions: center bar 20 °C /outer bars 40 °C (TG1), and center bar 40 °C /outer bars 20 °C (TG2); presented in randomized order. Subjects continuously rated either pain or unpleasantness intensity on an electronic visual analogue scale. Preliminary data from 7 subjects revealed that the intensity of pain and unpleasantness in the forearm and calf evoked by the TG1 array were higher than for any of the four control stimuli and were higher in the calf vs. the forearm. Unexpectedly, the intensity of TG-induced pain and unpleasantness were perceived as much weaker when induced by TG2 vs. TG1. In conclusion, these data suggest that a single cool bar surrounded by warm bars produces a more intense TGI compared to the opposite configuration and that illusions in the calf are more intense than in the forearm. Additional studies are required to elucidate the mechanisms underlying these phenomena. Acknowledgments: NSERC/CIHR CHRP Grant 350980

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43. Lecker I1; Chen X1; Mazer CD1,3,4; Orser BA1,2,3 1Department of Physiology, University of Toronto; 2Sunnybrook Health Sciences Centre, University of Toronto; 3Department of Anesthesia, University of Toronto; 4Cara Phelan Centre for Trauma Research, Keenan Research Centre in the Li Ka Shing Knowledge Institute, St. Michael's Hospital; TRANEXAMIC ACID PREFERENTIALLY TARGETS EXTRASYNAPTIC GABAA RECEPTORS Tranexamic acid (TXA) is an antifibrinolytic drug that is widely used to reduce blood loss during surgery. Unfortunately, TXA causes a 4-6 fold increase in the incidence of post-operative seizures. Since TXA is the only antifibrinolytic drug available in Canada, there is an urgent need to identify the mechanisms underlying TXA-induced seizures. Previous studies showed that TXA blocks synaptic -aminobutyric acid type A receptors (GABAARs), albeit at high, clinically-irrelevant concentrations. The GABAARs are the main inhibitory receptors in the mammalian brain and are responsible for producing two forms of inhibition: phasic (generated by synaptic GABAARs) and tonic (generated by extrasynaptic GABAARs). Presently it is not clear whether TXA acts on synaptic and/or extrasynaptic GABAARs. We tested the hypothesis that: 1) TXA preferentially inhibits a tonic inhibitory conductance generated by high affinity extrasynaptic GABAARs and, 2) GABergic drugs that preferentially increase extrasynaptic GABAAR function reverse TXA-induced inhibition and neuronal hyperexcitability. Whole-cell voltage clamp techniques were used to record the tonic and GABA-evoked currents in mouse cortical neurons grown in culture. Results: 1) TXA could inhibit both tonic and GABA-evoked currents. However the sensitivity of tonic conductance, to TXA mediated inhibition, was 3 fold-greater than GABA evoked conductance (IC50: 205 μM, n=4 versus IC50: 773 μM, n=3). These results indicate that the potency of TXA at extrasynaptic receptors is greater than at postsynaptic receptors. 2) GABAergic drugs that preferentially target extrasynaptic GABAARs (e.g. propofol) fully reversed TXA blockade of the tonic conductance. Taken together, these results provide the first evidence for a population of GABAARs that is sensitive to a clinically-relevant concentration of TXA and a plausible strategy to reverse neuronal hyperexcitability.

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44. Lee DH1; Susskind JM1; Anderson AK1 1Psychology, University of Toronto; EFFECTS OF FEAR EXPRESSIONS ON EYE GAZE PERCEPTION Evidence suggests that our facial expressions originated for sensory regulatory function (Susskind et al., 2008). For example, wider eye-opening in fear expressions is associated with a subjectively larger visual field and enhanced peripheral stimulus detection. Here we examined the Functional Action Resonance hypothesis (Susskind et al., 2008), which predicts that fear expressions’ direct benefits for the sender have parallel indirect consequences for how receivers perceive and respond to their environment. Using schematic eye gazes that represent actual wider “fear” and narrower “disgust” eyes, without the remainder of the emotional expression, we examined the effects of eye aperture on gaze perception and target detection. Participants making forced-choice response judgments of left vs. right gaze direction responded more accurately with the increasing eye aperture characteristic of fear expressions. In a Posner-cuing paradigm where gaze matched or mismatched the location of a target, participants responded faster to the eccentric target when viewing fear eyes. These benefits appear due to the enhanced physical signals emitted by wider fear eyes, independent of emotional content, as similar effects were found with schematic boxes that were not perceived as eyes. Consistent with the Functional Action Resonance hypothesis, these results demonstrate a link between how emotions are expressed on the face and their influences on an observer’s behavioural and perceptual processes.

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45. Lindvere L1; Sun J1; Dorr A1; Van Raaij M1; Foster S1; Stefanovic B1 1Imaging Research, Sunnybrook Research Inststitute; HIGH FREQUENCY ULTRASOUND IMAGING OF CEREBRAL BLOOD FLOW The study of brain development, its function, and its compromise in the course of neurodegeneration can profoundly benefit from quantitative data on microvascular architecture and hemodynamics. Current imaging modalities for investigating in vivo brain function are challenged to provide the spatial resolution needed to image brain microvessels on the time scale of neuronal events. High frequency ultrasound has the spatial resolution (40-150 um) to resolve individual microvessels throughout the rodent cerebrum (depth of field ~ 10mm) at frame rates as high as 1000 fps. The present study was carried out to investigate the potential of high frequency ultrasound in neuroimaging of rodents. Adult Sprague-Dawley rats (120 – 250 g) were anesthetized with isoflurane, tracheotomized and mechanically ventilated. Stereotaxic surgery was done to prepare a small (~8mm in diameter) cranial window, allowing interrogation of 3 regions of interest; the forelimb representation in the primary somatosensory cortex (S1FL), primary motor cortex (M1), and the thalamus. Ultrasound contrast agent (Micromarker, VisualSonics) was infused (40uL/min at 2x109 microbubbles/mL concentration) through the tail vein. A functional response was induced with 10% inhaled CO2 and electrical stimulation of the forelimb (180s-off 90s-on 180s-off blocks, with each 90s stimulation interval made of 270 0.3-ms, 2-mA pulses, played out at a frequency of 3 Hz). Ultrasound imaging was performed with a high frequency linear array probe (Vevo2100, VisualSonics), with a 20-MHz center frequency. The imaging was done using non-linear (pulse inversion and amplitude modulation) contrast mode. When signal intensity reached steady state, a contrast disruption pulse was delivered. Average signal intensity from regions of interest were fit to a monoexponential model to estimate the slope (indicates rate of flow) and plateau (indicates blood volume) values for the reperfusion curves. An increase in both slope and plateau of the reperfusion curve were observed in the S1FL (but not in M1) during the electrical stimulation to the forepaw (P<0.01) and in both S1FL and M1 during the CO2 inhalation (P<0.05). As expected, the electrical stimulation and CO2 inhalation was found to result in a transient increase in cerebral blood flow and volume. These data confirm the potential of high frequency ultrasound for functional brain imaging in rodents. High frequency ultrasound allows for fine spatiotemporal imaging with depth penetration sufficient to enclose the entire cerebrum. This provides a unique window for investigating cerebral hemodynamics, both in the cortex and in the deep grey matter.

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46. Ljubojevic V1; De Rosa E1 1Department of Psychology, University of Toronto; DOES THE NEUROCHEMICAL ACEYLCHOLINE MODULATE BOTH VISUAL AND OLFACTORY ATTENTION? Background: The basal forebrain (BF) is a collection of nuclei, located at the anterior ventral portion of the brain; it is typically defined by its magnocellular cholinergic neurons. The anterior portion of the BF, consisting of the medial septum and vertical limb of the diagonal band of Broca, sends ACh to the hippocampus and related areas, while its posterior portion (nucleus basalis magnocellularis; NBM) sends ACh to neocortical regions that are involved in higher cognitive processing. Cholinergic function of the BF was initially thought to play an exclusive role in learning and memory, but subsequent investigations have shown that ACh from the NBM specifically plays a more direct role in modulating attentional processes (McGaughy, Kaiser, & Sarter, 1996). This advancement in our understanding of cholinergic function came with the more recent use of immunotoxin 192 IgG-saporin which allows for the selective removal of cholinergic neurons from a brain region(s). The present study will also use 192 IgG-saporin in the NBM to remove the cholinergic innervation from the neocortical mantle to allow an examination of ACh’s role in attention. Using the 5-CSRTT, the rodent analog of the continuous performance task of sustained attention in the human cognitive literature, it has been shown that the loss of cholinergic NBM neurons, due to an infusion of 192 IgG-saporin, causes impaired attentional performance in rats (Lehmann, Grottick, Cassel, et al., 2003; McGaughy, Dalley, Morrison, et al., 2002), but this has never been tested with an olfactory version of the task. Methods: The present study is to train a new cohort of male adult Long-Evans rats on both the visual and olfactory 5-CSRT tasks consecutively, then perform cholinergic lesions of the NBM to examine cholinergic contributions to both visual and olfactory attention. The rat survival surgeries will be performed under aseptic conditions. In the operant chamber, there are 5 apertures at the front of the chamber that can be briefly illuminated via light-emitting diodes or briefly filled with odors. The rats will be trained to attend and react to the briefly presented visual or odor stimuli until a behavioral criterion, after which they will undergo either a cholinergic immunotoxic or sham lesion surgery. Loss of cortical cholinergic input will be accomplished by injecting the 192 IgG-saporin, into the NBM bilaterally. The 192 IgG-saporin will be dissolved in 0.1M phosphate-buffered saline in 0.2 μg/μl concentration. After the two week post-surgical recovery period, we will compare the attentional performance of the saporin-lesioned animals to that of the sham-lesioned group on these 5-CSRT tasks. Further, acetylcholinesterase (AChE) histochemistry and choline acetyltransferase (ChAT) immunohistochemistry will be carried out in order to determine the extent of the loss of cholinergic afferents in fronto-parietal target cortical areas and the loss of cholinergic cell bodies in the NBM, respectively. It is hypothesized that the lack of cortical cholinergic modulation will lead to comparable attentional difficulties in the saporin-lesioned rats with both visual and olfactory stimuli.

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47. Luu P1; Becker3; Smith DM2; Wojtowicz JM1 1Department of Physiology, University of Toronto, 1 King’s College Circle, Toronto, Ontario, Canada; 2Department of Psychology, Cornell University, 252 Uris Hall, Ithaca, New York, New York; 3Department of Psychology, McMaster University, 1280 Main St. W., Hamilton, Ontario, Canada.; EFFECTS OF ADULT NEUROGENESIS ON CONTEXTUAL LEARNING AND MEMORY INTERFERENCE New neurons are continually produced throughout adult life in the dentate gyrus (DG) of the hippocampus. These new neurons have been shown to play a role in learning; however their specific functional significance is not well understood. A recent model of adult neurogenesis assigns newly generated neurons with the ability to distinctly encode highly similar episodes in memory to prevent them from interfering. Specifically the model indicates that newborn cells allow for the integration of an event and associated context into a unique episode. We postulate that by selectively disrupting neurogenesis in the DG, the ability to encode context and consequently to learn interfering information will be impaired. In order to address this hypothesis, rats were trained on a novel memory-interference task in which two interfering lists of odours were taught to irradiated and non-irradiated rats under simliar or different environmental context. Sections of the hippocampus and olfactory-system were stained using immunohistochemistry for markers of neurogenesis to characterize the effect of irradiation on neurogenesis. Analysis of the olfactory-system revealed no significant reduction in neurogenesis. Analysis of the DG revealed reduced neurogenesis by approximately 79±3% in irradiated animals compared to control. As expected, performance on the first odour list (first episode) was unaffected by irradiation. An ANOVA of the performance of animals learning the second list (second episode) however, demonstrated a main effect of group (F[3,32]=3.99, p=.016). Control rats that had learned the second list under different context performed significantly better than irradiated rats learning the list under same and different context (p<0.01). These results suggest that animals with reduced neurogenesis could not link context with an episode in memory and as a result failed to distinctly encode each odour list resulting in memory-interference. These results indicate that neurogenesis plays a role in integrating contextual information into learned events to allow for interference free representation of simliar episodes.

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48. Malik A1; Buck LT1,2 1Cell and Systems Biology, University of Toronto; 2Ecology and Evolutionary Biology, University of Toronto; SEASONAL PLASTICITY OF GABAERGIC SYNAPTIC TRANSMISSION IN LYMNAEA STAGNALIS To examine the effect of γ-aminobutyric acid (GABA) on neuronal activity, we conducted intracellular recordings from isolated central ring ganglia of the hypoxia-tolerant pond snail Lymnaea stagnalis. GABA decreased neuronal activity by hyperpolarizing the resting membrane potential (Vm) and inhibiting electrical firing, while bicuculline methiodide, an antagonist of GABAA receptors, blocked the GABA-induced inhibition and excited “silent” cells. To determine the contributions of the K/Cl co-transporter KCC2 to setting EGABA below action potential (AP) threshold and rendering GABA inhibitory, we used a pharmacological inhibitor of KCC2, furosemide. Similar to bicuculline perfusion, this manipulation blocked the GABA-induced inhibition. Contrary to the inhibitory response observed in “summer” animals, in the majority of neurons harvested during the winter months (Dec-Mar) GABA excited “silent” cells and increased neuronal activity by depolarizing Vm and increasing AP frequency, while bicuculline blocked this response. GABAA receptor-mediated excitation failed to occur when intracellular chloride homeostasis was perturbed with the Na/K/2Cl (NKCC1) antagonist bumetanide. These data indicate that environmental stimuli regulate the activity of transmembrane co-transporters, leading to changes in anionic gradients that determine the polarity of GABAergic transmission.

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49. McFarlane MT1,2; Mirabella G1; Wright T1; Westall CA1,3 1Ophthalmology and Vision Sciences, The Hospital for Sick Children, Toronto, ON, Canada; 2Institute of Medical Science; 3Ophthalmology and Vision Sciences, University of Toronto, Toronto, ON, Canada.; CONE PATHWAY ABNORMALITIES IN ADOLESCENTS WITH TYPE 1 DIABETES AND NO CLINICALLY EVIDENT DIABETIC RETINOPATHY BACKGROUND Diabetic retinopathy is a common complication of diabetes and the leading cause of acquired blindness in the developed world. Twenty-five percent of individuals with young-onset or type 1 diabetes (T1D) develop retinopathy after five years. This increases to 90% 15-20 following T1D diagnosis. Diabetic retinopathy that is clinically observable chronically progresses and is characterized by pathology to the vascular structures of the retina. To reduce the impact of retinopathy on adolescents with T1D, it is therefore essential to improve methods for detection and monitoring before the development of sight-threatening, vascular changes. A previous report has shown that short-wavelength visual pathways are dysfunctional in adolescents with T1D but no clinically evident diabetic retinopathy. This dysfunction may be attributed to a defect in the function of cone photoreceptors in the retina that process short-wavelength light (S-cones). This study strives to identify whether S-cone function can be used as a biomarker of diabetic retinopathy before it becomes clinically observable. OBJECTIVE To determine if the function of S-cone photoreceptors in the retina is altered in adolescents with T1D before clinically observable diabetic retinopathy. HYPOTHESIS Functional defects in S-cone photoreceptors are present in adolescents with T1D but no clinically observable diabetic retinopathy. RESEARCH PLAN & APPROACH To assess visual pathway function, visual evoked potentials (VEPs) were recorded to black-white luminance as well as isoluminant short-and long-medium- vertical, sinusoidal gratings (1cyc/deg) in 50 patients with T1D (15 ± 1.88 years old) and 42 controls (16 ± 3.64 years old). VEP latencies were evaluated in response to pattern onset-offset gratings (2Hz) presented at 40, 20 and 10% contrasts. Short-wavelength electroretinograms (sERGs) were recorded using blue flashes (peak 410nm) against an amber (594 nm) background in 17 of the patients with T1D (16 ± 1.53 years old) and 18 controls (18 ± 3.88 years old) to preferentially stimulate S-cones. The outcome measures were timing to the S-cone response. Visual acuity, contrast sensitivity, and colour vision were tested in all participants to detect pre-existing pathology. All patients with T1D underwent stereoscopic photography assessing the central 30° of the retina to detect retinal pathology. Patients with any retinal pathology were excluded from analysis. Ambient blood glucose was monitored and maintained within 4-10mmol/L before and during testing. PRELIMINARY RESULTS VEP latencies to short-wavelength stimuli were delayed in those with T1D compared with controls at all contrasts (repeated measures regression, p=0.004). Responses to long-medium wavelength and achromatic stimuli were not delayed significantly in those with T1D.Timing to the S-cone dominated response was significantly delayed in adolescents with T1D (46.0 ms ± 3.72) in comparison to controls (40.9ms ± 3.35, p<0.001). RELEVANCE The global incidence of T1D in children and adolescents shows an annual increase of around 3%. With this, the number of people at risk for developing diabetic retinopathy is expected to double over the next 30 years. A suitable biomarker for retinopathy will help to reduce its impact on a young population at increasing risk for this sight-threatening condition.

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50. McIlveen-Brown E1; Tannock R1,2 1Ontario Institute for Studies in Education (OISE), University of Toronto, Toronto, Canada; 2Ontario Institute for Studies in Education (OISE), Hospital for Sick Children, Toronto, Canada; MOTOR SKILLS IN ADOLESCENT ATTENTION DEFICIT/HYPERACTIVITY DISORDER (ADHD): GENDER SPECIFIC PROFILES OF FINE AND GROSS MOTOR PERFORMANCE Introduction and Objectives: Across a wide age range, questionnaire measures indicate that motor coordination abnormalities are more pronounced in girls than boys with ADHD (Fliers et al., 2008). The current study investigates fine and gross motor coordination skills in an adolescent, ADHD sample. Methods: 90 participants (24% female), aged 13 to 18 years, with a confirmed, DSM-IV ADHD diagnosis completed fine (Beads in a Box, Nut and Bolt) and gross (Heel-Toe Walk, Standing on one Foot) motor tasks from the McCarron Assessment of Neuromuscular Development – Revised (MAND). Results: Compared to standardized norms, males preformed poorly on fine motor tasks whereas females performed poorly on both fine and gross motor tasks. While motor performance was unrelated to ADHD symptoms in males, performance on the Beads in a Box task predicted inattentive symptoms in females. Discussion: ADHD-related motor pathology was wider-ranging in females than in males and was differentially correlated with ADHD symptoms. Conclusion: Measures of motor coordination and their brain-based correlates can be used to provide suggestive explanations of gender differences in the ADHD clinical profile.

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51. Moxon-Emre I1,2; Schlichter LC1,2 1Toronto Western Research Institute University Health Network; 2Department of Physiology, University of Toronto; EVOLUTION OF INFLAMMATION AND WHITE MATTER INJURY IN A MODEL OF TRANSIENT FOCAL ISCHEMIC STROKE After an ischemic stroke, there is a prolonged inflammatory response and secondary phase of injury that is more amenable to treatment than acute neurotoxicity. Surprisingly little is known about temporal and spatial relationships between inflammation and white matter injury. Thus, we quantified development of white matter damage, inflammation and a ‘glial limitans’ at 1, 3 and 7 days after transient ischemia in the rat striatum. Quantitative analysis showed that myelin damage—decreased staining for myelin basic protein (MBP) and increased damaged MBP—began in the core, coincided with neutrophil infiltration, and progressed outward with time. Axon damage (accumulation of amyloid precursor protein) began at the edge of the lesion, coinciding with substantial microglia/macrophage activation, and progressed into the core. Over the 7 days, activated microglia/macrophages dramatically increased in the core and edge of the lesion only. Detailed spatial analyses revealed that activated microglia/macrophages that surrounded undamaged axon bundles did not express ED1, a marker of phagocytic cells, while those inside damaged bundles expressed ED1. These results imply different contributions of neutrophils and microglia/macrophages to white matter injury after ischemic stroke, and complex signals regulating migration of activated microglia/macrophages; they are excluded from undamaged myelinated bundles and only infiltrate damaged bundles.

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52. Nahirny A1,3; Fong J1,3; Mills LR1,2,3 1Department of Physiology; 2Faculty of Medicine; 3University of Toronto, Division of Genetics and Development TWRI University Health Network.; ELEVATED CA(I) INCREASES MITOCHONDRIAL PROTEIN IMPORT AND ACCUMULATION OF MITOCHONDRIAL PROTEINS IN DIFFERENTIATED PC12 CELLS AND RAT CORTICAL NEURONS >99% of mitochondrial proteins are nuclear-encoded and imported into mitochondria. Deficits in mitochondrial protein import (MPI) impact every aspect of mitochondrial function, but little is known about how it is regulated in neurons. We hypothesized that a sustained increase in basal iCa2+ will increase MPI. To increase iCa2+ we used the Ca ionophore A23187 and measured the import of 4 proteins; (a) mtGFP, an inducible GFP fusion protein targeted to mitochondria, (b) mtHSP70, a mitochondrial matrix chaperone, (c) mtTFA, a mitochondrial transcription factor, and (d) Tom20, a key MPI receptor. MPI and intramitochondrial mtGFP turnover was measured by western blot of mitochondrial fractions and flow cytometry in live cells (Sirk et al 2003; 2007). iCa2+ levels were measured using Fluo3, ROS by DCF, mitochondrial mass by mitotracker green FM, cell viability by MTT reduction and cell death by PI. Results: Sublethal 0.15uM A23187 for 24h decreased MTT reduction by 26% +/-3 compared to control however higher doses of A23187 caused cell swelling and death. Exposure to 0.15uM A23187 for 24h significantly increased iCa2+ levels as did a 24h pulse of A23187 (followed by 24h normal media). Sublethal 24h 0.15uM A23187 increased mtGFP fluorescence by 20% +/-1, while a 24h pulse increased mtGFP by 78% +/-3. In PC12 cells, western blots of mitochondrial fractions showed increased mtGFP and mtHsp70 protein versus controls but mtTFA and Tom20 were unchanged. In cortical neurons 0.15uM A23187 increased mtHsp70 but levels of mtTFA and Tom20 were unaffected. Interestingly, intramitochondrial mtGFP half-life increased with A23187 treatment, indicating slowed mtGFP turnover. A23187 also increased mitochondrial mass significantly, however other markers of mitochondrial biogenesis (mtTFA and PGC1a) were unchanged. These findings demonstrate that sustained increases in iCa2+ not only upregulate MPI but also slow degradation of mitochondrial proteins in neurons. (This study was funded by CIHR, NSERC to LRM, OGSST to AN and OGS to JF)

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53. Nejatbakhsh N1; Guo CH1; Lu TZ1; Van Kesteren R2; Feng ZP1 1Department of Physiology, University of Toronto, Toronto, Canada; 2Department of Molecular and Cellular Neurobiology, Free University, Amsterdam, Netherlands; REGULATION OF LOCAL CYSKELETAL ELEMENTS BY A NOVEL LYMNAEA PROTEIN PROMOTES NEURITE EXTENSION FOLLOWING AXOTOMY Regulation of cytoskeletal dynamics is a key target mechanism for neuronal development and regeneration. In response to growth or regenerative cues, local microtubule protein regulation occurs in growth cones of neurites to direct neurite behaviour. Multiple mechanisms are thought to be involved in this process, including up-regulation of gene transcription and mRNA translation, stabilization/polymerization of existing proteins, and reduction in protein degradation. In this study, we identify a novel Lymnaea protein, LCaBP, which is ubiquitously expressed in central neurons of the animal. The transcripts of LCaBP are localized in various regions of cells, including neurites and growth cones, indicating a possible role for locally synthesized LCaBP. Our objective was to study the role of local LCaBP translation in neurite outgrowth and regeneration and to elucidate possible mechanisms of local LCaBP action. To investigate the role of local LCaBP transcripts in growth cones, we studied isolated neurite behaviour by severed the communication between the soma and growth cones of cells in vitro, using either mechanical transaction or pharmaceutical agents which block axonoplasmic transport. We probed for binding partners of LCaBP using co-immunoprecipitation analysis and tested the distribution pattern of LCaBP using immunocytochemical staining in combination with laser confocal microscopy. Our results indicate that local translation of LCaBP is essential for neurite regeneration. LCaBP colocalizes with tubulin in the same spatial region in neurites and growth cones of cultured cells. Further test revealed that that LCaBP directly interacts with both α and β-tubulin. Reduction of LCaBP leads to a subsequent decrease in tubulin protein expression. Our data suggest that LCaBP is crucial for neurite outgrowth and regeneration in the central neurons of Lymnaea and that these effects are mediated, in part, via direct manipulation of local microtubule expression. (This study is funded by a CIHR grant to ZPF and NSERC-CGSD to NN)

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54. Ng E1,2,3; Marziali E1,2; Polatajko H1; Dawson D1,2,3 1University of Toronto; 2Baycrest Centre; 3Toronto Rehab Institute; USING TELE-REHABILITATION TO ADDRESS EXECUTIVE DYSFUNCTION AND COMMUNITY INTEGRATION AFTER TRAUMATIC BRAIN INJURY Objectives: Executive dysfunction resulting from frontal and prefrontal lobe injuries has been shown to affect community integration in adults with traumatic brain injuries (TBI). Recent evidence supports direct training of problem-solving strategies in real-life situations as a rehabilitation intervention for executive dysfunction. However, access to health services to receive this training is often limited especially in rural communities. It is therefore important to explore ways to deliver rehabilitation services when face-to-face intervention is not feasible while ensuring that the intervention provided is supported by research. One intervention approach that has been successfully used in a face-to-face format with adults with TBI is the Cognitive Orientation to daily Occupational Performance (CO-OP) approach. The CO-OP approach explicitly teaches the use of problem-solving strategies applied to self-identified goals related to real-life situations. The objective of the study is to investigate whether the CO-OP approach can be used effectively in a tele-rehabilitation format to promote community integration post-TBI. No previous study has used a tele-rehabilitation approach to deliver the CO-OP training. Method: A case study of an adult male, more than 20 years post-TBI, will be presented. Neuropsychological tests of attention, memory, and executive function were used to characterize the participant. Three outcome measures were used: the Canadian Occupational Performance Measure (COPM), the Dysexecutive Questionnaire (DEX), and the Mayo-Portland Adaptability Inventory-4 Participation Index (MPAI-P). The COPM, a standardized interview, guided the participant to identify his occupational performance issues, enabled him to develop 5 goals of which 3 were addressed in the CO-OP training, and captured changes in the his self-perception of occupational performance related to his goals at pre- and post-intervention and at 3-month follow-up. The untrained goals were used to examine the generalizability of the approach. The training sessions were video recorded and analyzed to examine the integrity of the CO-OP approach when applied in a tele-rehabilitation format. Participant’s feedbacks on the approach and the delivery format were gathered through an interview post-intervention. The intervention was composed of 10 weeks of biweekly 1-hour videoconference sessions that were completed through the internet at the participant’s home using commercially available softwares. Results: Webcam and headset were provided to the participant for the study. The participant required technical support to setup the computer for videoconferencing but few technical issues were experienced that interfered with the sessions. The participant’s selected goals for the CO-OP training were related to his mobility, organizational skills, and leisure participation. Positive changes were found in the COPM ratings and the community measures. He often commented that the global strategy taught in the CO-OP training was applicable to almost everything he did. Conclusions: Tele-rehabilitation shows promise as a way of delivering the CO-OP approach and can have implications to promote community integration of individuals with TBI.

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55. Ng TS1; Trubiani G1; Lovejoy DA1 1Cell and Systems Biology, University of Toronto; THE EFFECT OF TENEURIN C-TERMINAL ASSOCIATED PEPTIDES-1 (TCAP-1) ON BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) AND REACTIVE OXYGEN SPECIES (ROS) BDNF is one of the most abundant and widely distributed neurotrophins in the central nervous system and is recognized for its involvement in mediating survival, differentiation, and proliferation. There is a great necessity to identify agents involved in upregulating BDNF transcription and translation. TCAP-1 is a recently characterized peptide that has been shown to regulate a number of stress-associated behaviours in rodents and confer neuroprotective actions on cells. Our recent studies indicated that TCAP-1 can reduce superoxide radical formation in immortalized brain cells by an upregulation of the superoxide dismutase-catalase pathway. This study also indicates that acute TCAP-1 can regulate BDNF expression in embryonic immortalized hypothalamic N38 cells. Since BDNF can also regulate ROS activity, TCAP-1 may act, in part, via BDNF to provide neuroprotection.

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56. Nguyen DH1,2; Cho N1,2; Wang J2; Fehlings M1,2,3,4,5 1Institute of Medical Science, Faculty of Medicine, University of Toronto; 2Division of Genetics and Development, Toronto Western Research Institute; 3Krembil Neuroscience Center, University Health Network; 4Division of Neurosurgery, University of Toronto; 5University of Toronto Neuroscience Program.; NEUROPROTECTIVE EFFECTS OF INTRAVENOUS IMMUNOGLOBULIN G (IVIG) AFTER SPINAL CORD INJURY Objective: Spinal cord injury (SCI) is characterized by a biphasic pathophysiology: the initial mechanical injury and the secondary damage during which the acute neuroinflammatory response plays a significant role. More specifically, neutrophils and macrophages have been shown to exacerbate SCI via the release of cytokines, free radicals, and proteases that cause neuronal and glial toxicity and loss of function. As a result, the attenuation of neuroinflammation is a promising strategy for preventing extensive damage following SCI. In this regard, immunoglobulin G (IgG) from pooled human serum is a promising treatment candidate. Clinically, IgG, because of its immunomodulatory effects, has been used to treat many autoimmune diseases, but never SCI. The purpose of this study is to characterize the potential neuroprotective effects of IgG in terms of functional recovery and the molecular mechanisms of IgG in SCI. Methods: Female Wistar rats were subject to a 35-g clip compression injury at the C7-T1 level. To assess the effects of IgG, IgG (0.4g/kg), bovine serum albumin (BSA) (0.4g/kg), or saline was injected intravenously to randomly selected animals at 15 minutes post-SCI. Neutrophil infiltration at 24 hours post-SCI was measured via myeloperoxidase (MPO) activity. MMP-9 expression, another measure of neutrophil infiltration, was also analyzed by western blotting. Results: Fluorescence microscopy demonstrated that IgG localized mainly in the grey matter. We found significant reductions in MPO activity after IgG treatment by 50% and 65%, compared with saline and BSA treatments, respectively. In addition, we found significant reductions in MMP-9 expression after IgG treatment by 43% and 55%, compared with saline and BSA treatments, respectively. Conclusion: Together, these data suggest that IgG actually enters the grey matter at the injury epicenter and attenuates neuroinflammation potentially by acting on neutrophils.

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57. Rizvi, SJ1,2; Sproule BA3,4; Kennedy SH2,5; Usoa BUSTO3,4 1Departments of Pharmaceutical Sciences and Neuroscience, University of Toronto; 2Department of Psychitary, University Health Network; 3Centre for Addiction and Mental Health; 4Faculty of Pharmacy, University of Toronto; 5Department of Psychiatry, University of Toronto; DOPAMINERGIC FUNCTIONING IN TREATMENT RESISTANT DEPRESSION: THE EFFECT OF DEEP BRAIN STIMULATION Background: The dopamine system has important effects on anhedonia, a primary symptom of major depressive disorder (MDD), as well as on motor abilities, sexual function, reward and motivation. Current available treatments that largely target the serotonin and norepinephrine systems do not result in remission for the majority of patients. Deep brain stimulation (DBS) is a promising neurosurgical procedure for treatment resistant depression. Preliminary evidence suggests that the “dopaminergic symptoms” (anhedonia, psychomotor retardation, libido) are almost fully resolved in patients that remit or respond to DBS, whereas mood and other physical symptoms are still present to some degree, indicating a potential dopamine regulation with DBS treatment. Method: In this double-blind randomized-controlled trial, 40 patients with MDD will undergo DBS surgery and be randomized to receive either active DBS treatment or sham treatment for 3 months. Pre-surgery and 3 months post-surgery, a dextroamphetamine challenge and dopamine receptor ligand binding PET scan will be used to test the dopaminergic effects of DBS treatment, which will elucidate DBS mechanisms and provide further support for a “dopamine subtype” of depression. Results and Conclusions: It is expected that patients with greater symptom severity in mood, psychomotor retardation and anhedonia will exhibit a hypersensitive response to the challenge, and greater receptor binding potential, which will be predictors of positive outcome with DBS. Outcome measures and the statistical plan to test the study hypotheses will be discussed.

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58. Roedding AS1,2,3; Au-Yeung W1,2; Gao AF1,2; Li PP1,2,4; Warsh JJ1,2,3,4,5 1Cellular & Molecular Pathophysiology, Centre for Addiction and Mental Health; 2Pharmacology and Toxicology, University of Toronto; 3Univeristy of Toronto Neuroscience Program; 4Psychiatry, Univeristy of Toronto; 5Institute of Medical Sciences,University of Toronto; CHRONIC OXIDATIVE STRESS REGULATES TRP CHANNEL EXPRESSION: RELEVANCE TO BIPOLAR DISORDER Objective: Recent findings have implicated the non-selective calcium-permeable ion channels, transient receptor potential (TRP) melastatin subtype 2 (TRPM2) and canonical subtype 3 (TRPC3), in the pathogenesis of bipolar disorder (BD). As both are involved in calcium and oxidative stress signalling thought to be disrupted in BD, we sought to determine the effects of elevated oxidative stress on their expression. Methods: Primary rat cortical neurons and astrocytes, and human B lymphoblast cell lines (BLCLs) were treated with oxidative stressors (rotenone and paraquat) for 1 day (acute) and 4 days (chronic). Protein and mRNA expression of TRPC3/TRPM2 and appropriate housekeeping genes were determined by immunoblotting and real-time PCR, respectively. TRPC3-mediated calcium fluxes were measured in BLCLs using the calcium-sensitive dye, Fluo-4 and the TRPC3 activator, 1-oleoyl-2-acetyl-sn-glycerol (OAG). Results: Neurons treated with rotenone (15-30 nM) for 4 days but not 24 hours showed dose dependent and statistically significant decreases in TRPC3 mRNA (31% ±12, p<0.001) and protein levels (60% ±28, p<0.001). In contrast, TRPM2 mRNA but not protein levels increased (47% ±49, p=0.017) also only at 4 days of treatment. Exposure of rat cortical neurons for 4 days to paraquat (1-2 µM), an alternate stressor that is known to produce mitochondrial oxidative stress, caused similar decreases in TRPC3 expression (mRNA: 41% ±19, p=0.003; protein: 61% ±26, p=0.001), supporting the validity of the findings. As with rotenone, acute paraquat treatment had no effect on TRPC3 mRNA and protein levels. The stress-induced alterations in TRPM2 channel expression were more variable than for TRPC3, with the greatest magnitude of change observed at 1 µM paraquat (1 day, protein level: ↑24% ±23, p=0.018; 4 day, protein level: ↓12% ±10, p=0.042; 4 day, mRNA level: ↑36% ±19, p=0.012). In rat cortical astrocytes, no change in protein levels of TRPC3 was observed after 4 days of rotenone (600-1200 nM) treatment; TRPM2 protein expression in these cells was too low to reliably quantify. To investigate the human relevance of these findings, the effect of oxidative stressors on TRPC3 expression in human BLCLs was examined. A dose-dependent decrease in TRPC3 protein expression (45% ±25, p=0.001) was observed after chronic, but not acute, rotenone (2.5-10 µM) treatment similar to rat cortical neurons. To examine whether stress-induced decreases in TRPC3 protein levels translates into altered channel function in BLCLs, the rate and magnitude of calcium entry upon TRPC3 agonist addition was determined. Chronic rotenone (10 µM) treatment resulted in significant reductions in the rate and magnitude of calcium influx in comparison to acutely treated cells (48% ±25, p<0.001). Conclusion: These findings support a novel mode of regulation for TRPC3/TRPM2, in which their expression is altered only after chronic exposure to oxidative stress in both human and rat models. Moreover, we have demonstrated functional consequences of stress-induced reductions in TRPC3 levels in BLCLs. This provides a link between observations of altered oxidative stress markers and dysfunction of these TRP channels in BD.

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59. Rosenzweig S; Czerwinska E; Orser BA; Wojtowicz JM Department of Physiology, Faculty of Medicine, University of Toronto.; AN IMPORTANT ROLE FOR GABA(A)R-DELTA IN THE REGULATION OF ADULT NEUROGENESIS. During adult neurogenesis, new cells are born in the Sub-granular zone (SGZ) of the dentate gyrus (DG) and undergo differentiation, migration and maturation. Many factors are known to affect these developmental stages, and a particularly important one is the neurotransmitter GABA, which depolarizes young DG neurons before they become responsive to glutamate. This early depolarization initially occurs extrasynaptically. As most extrasynaptic GABAA receptors in the DG contain the delta subunit, we hypothesized that this type of receptor (GABAAR-delta) is involved in the early depolarization and developmental regulation of young DG neurons. Our initial experiments demonstrated that normal neurogenesis was disrupted in the DG of delta-subunit knockout mice when compared to wild type mice, thus confirming the importance of GABAAR-delta to this process. In subsequent experiments, we administered THIP, a selective GABAA-receptor agonist with a preference for GABAAR-delta, to rats in vivo. Three months old rats were injected with the mitotic indicator BrdU, and a week later administered seven daily injections of either saline (in control animals) or THIP (4mg/kg). The rats were sacrificed two weeks after the last injection. Hippocampal sections were immunostained for BrdU and calbindin, a marker for mature DG neurons, and analyzed using confocal microscopy. We found a significant increase in the survival and maturation rate of adult born DG neurons in response to the administration of THIP, evident by a 33% increase in the number of BrdU-positive cells (p<0.005, n=3), and a 36% increase in the portion of BrdU positive cells that were also positive for calbindin (p<0.005, n=3). Taken together, these results suggest that GABAAR-delta play a role in the normal regulation of adult neurogenesis, and that neurogenesis can be influenced by targeting this receptor with selective drugs.

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60. Rudy KM1; Yunusova Y1,2 1Speech Language Pathology,University of Toronto; 2Sunnybrook Health Sciences Center; THE EFFECT OF PALATAL GEOMETRY ON CONSONANT ARTICULATION Rationale: There is a great deal of individual variability in articulation of speech sounds; however, the sources of such variability are not well understood. One of the potential factors influencing articulatory variability is differences in vocal tract sizes/shapes between talkers. The goal of this study is to investigate the influence of size and shape of the hard palate (e.g., height, width, length, curvature) on the size and location of consonant target regions across healthy talkers. It is anticipated that the hard palate geometry will account for some of the observed variability in consonant articulation. Palate size and shape has previously been associated with articulatory variability in vowels and sibilants (Fuchs, Perrier, Geng, and Mooshammer, 2006; Brunner, Fuchs and Perrier, 2004; 2009). These studies found that dome-shaped palates have a tendency for larger articulatory variability than flat-shaped palates. These studies used electropalatography as a method for obtaining articulatory data which requires the use of an artificial palate that constrains speech articulation. In the present work we used electromagnetic articulography, which preserves the natural shape of the vocal tract. Articulatory variability will be defined through the concept of target regions (Guenther, 1995). However, for the purpose of this study, target regions will be operationally defined as regions in the vocal tract where specific lingual consonants are produced. Measures of the size and location of these target regions will be related to the measures of palatal size and shape. Consonant articulation is not well understood and motor control theories are lacking in data for this sound class. The results of this study provide significant information to bridge the gap in our knowledge of consonant articulation. Establishing a normal range of articulatory variability can serve as a comparison for the deterioration of articulation in neurodegenerative diseases, for example amyotrophic lateral sclerosis (ALS). This information can be used to investigate potential diagnostic markers in articulatory decline of speech in ALS, and in determining subcategories of ALS. Furthermore, this research can be used in the development of visual biofeedback programs to treat motor speech disorders resulting from acquired brain injury. Method: 5 (1 male, 4 female) healthy adult talkers of Canadian English produced a series of symmetrical VCV sequences containing the corner vowels /a, i, u/ and the consonants /t, d, k, g, tch, sh, s, y/. 3 dimensional tongue blade and dorsum movement were recorded with Aurora (NDI). Acoustic recordings were obtained simultaneously. The maximum displacement of the tongue in Z (vertical dimension) during a consonant were identified and X, Y, and Z coordinates of this point were recorded for each syllable. Using a point-digitizer, important landmarks on each dental impression were identified between which measurements illustrating hard palate size and shape were made. Additional anthropometric measurements of cranio-facial features were collected to make additional inferences about the vocal tract size Results: Palate curvature and height was correlated with articulatory variability in consonants. Conclusion: Individual variability in articulation is influenced by the size and shape of the hard palate.

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61. Saverino C1,2; Grady C1,2,3; Hasher L1,2 1Department of Psychology, University of Toronto; 2Rotman Research Institute, Baycrest Geriatric Centre; 3Department of Psychiatry, University of Toronto; AGING AND IMPLICIT MEMORY FOR EMOTIONAL WORDS The present study investigated age differences in implicit memory for positive, negative and neutral words. We also explored how cognitive control influence emotional memory. Participants completed a one-back picture comparison task with superimposed distracting emotional and neutral words. Memory for distracting words was tested using an implicit memory test and cognitive control by an arrow flanker task. Priming was significant for negative but not for positive and neutral words. A high level of cognitive control was related to greater priming for negative words in young adults and lower priming in older adults. Priming for positive words, however, was not influenced by participants’ level of cognitive control, suggesting that different mechanisms may underlie memory for positive and negative items.

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62. Schwindt GC1,2; Graham NL3,4; Rochon E3,4; Tang-Wai D5; Black SE1,2,6 1Institute of Medical Science, University of Toronto; 2Brain Sciences Research, Sunnybrook Research Institute; 3Department of Speech-Language Pathology, University of Toronto; 4Toronto Rehabilitation Institute; 5Department of Medicine, University of Toronto; 6Brill Chair in Neurology, Dept of Medicine, Sunnybrook HSC and University of Toronto; DIFFUSION TENSOR IMAGING METRICS REVEAL WHITE MATTER ABNORMALITIES IN PRIMARY PROGRESSIVE APHASIA Introduction: Primary progressive aphasia (PPA) shows early selective language impairment, and relative sparing of other cognitive domains. Cortical atrophy is noted in the left perisylvian language areas, though different PPA subtypes may have additional areas involved. To date, little work has examined the integrity of white matter tracts in PPA, but there is some suggestion that the arcuate region of the left superior longitudinal fasciculus (SLF) may be involved. The present study uses diffusion tensor imaging (DTI) and tract-based spatial statistics (TBSS) to examine differences in fractional anisotropy (FA), radial (DR), and axial diffusivity (DA) between a group of PPA patients and healthy controls. Methods: 10 patients with PPA (3 non-fluent, 7 semantic dementia) were recruited from two clinical sites in Toronto. 17 healthy controls were matched to patients for age and education. Diffusion weighted images were collected on a 3.0T GE Signa scanner with 23 directions and two repetitions. Analysis was carried out using TBSS within the FSL package. FA, DA, and DR images were calculated for each individual. Images were transformed into MNI space using the FMRIB58 FA template and nonlinear registration. FA images were skeletonised to define a search space for voxel-wise comparisons. 2-sample t-tests compared FA, DR, and DA between groups, with randomise for non-parametric estimation and threshold-free cluster enhancement for multiple-comparisons correction. Results: FA values were higher in controls across a number of territories, including left SLF, bilateral inferior longitudinal fasciculi (ILF) and uncinate fasciculi (UF). Patients showed higher DR overlapping these changes in FA, while DA was not reduced in patients. DA was higher in patients than controls within voxels contributing to the left UF and forceps major. Conclusions: Results suggest white matter disruption is widespread in PPA, but includes left-hemisphere SLF/arcuate involvement. This disruption is marked by an increase in radial diffusivity without loss of axial diffusivity and may reflect demyelination in multiple tracts. Increased DA and DR in left UF may represent a unique degenerative process in this tract which could relate to loss of semantic memory in PPA. Future work will examine differences between PPA subtypes and clinical correlates of these findings.

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63. Sekeres MJ1,2; Neve RL4; Frankland PW1,2,3; Josselyn SA1,2,3 1The Hospital for Sick Children, Toronto, ON, Canada; 2Department of Physiology, University of Toronto; 3Institute of Medical Science, University of Toronto, Toronto, ON, Canada; 4Department of Brain and Cognitive Science, MIT, Cambridge, MA, USA; INCREASING CREB IN THE DORSAL HIPPOCAMPUS IS SUFFICIENT TO INDUCE SPATIAL MEMORY The CREB (cAMP/Ca2+ responsive element binding protein) family of transcription factors is critical for memory in many species from Aplysia and Drosophila to mice and rats (Bourtchuladze et al., 1994; Yin et al., 1994; Guzowski and McGaugh, 1997; Bartsch et al., 1998). In rodents, disrupting CREB function in the brain typically impairs memory formation, whereas increasing CREB function enhances the formation of several simple forms of memory. Here we examine whether acutely increasing CREB levels in the dorsal hippocampus is sufficient to enhance the formation of a more complex form of memory, spatial memory as measured by the water maze. Increasing CREB function using viral vectors specifically enhanced the acquisition, but not retrieval, of a robust spatial memory produced by strong training of wild-type (WT) mice. Moreover, increasing hippocampal CREB levels was sufficient to induce a strong spatial memory under weak training conditions that do not normally support spatial memory formation in WT mice. Importantly, we demonstrate that CREB is necessary to support memory formation observed in mutant mice with a brainwide deficit in CREB function (CREBαδ −/− mice), and that acute CREB replacement in the dorsal hippocampus is sufficient to support formation of a robust memory for the spatial watermaze in these CREB deficient mice which otherwise show a severe memory deficit for the task. Together with previous reports, these findings indicate that CREB in the dorsal hippocampus is both necessary and sufficient for the formation of spatial memory, a higher-order type of memory.

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64. Shulyakova N1,2; Mills LR1,2 1Division of Genetics and Development, TWRI, TWH, UHN; 2Department of Physiology, University of Toronto.; PROTEASOME INHIBITION AND MITOCHONDRIAL PROTEIN IMPORT: THEIR ROLE IN MITOCHONDRIAL PROTEIN HOMEOSTASIS Increasing evidence suggests mitochondrial deficits contribute to the pathogenesis of neurodegenerative diseases. Since more then 99% of mitochondrial proteins are nuclear encoded mitochondrial structure and function depend upon mitochondrial protein import (MPI). Under conditions where mitochondrial protein import is inhibited mitochondrial proteins accumulate in cytoplasm. Evidence also implicates proteasome dysfunction and the excessive and/or “ectopic” accumulation of proteins in variety of neurodegenerative diseases. These findings link proteasome dysfunction and mitochondrial protein import. We hypothesized that inhibiting MPI causes the accumulation of mitochondrial proteins in the cytoplasm, which over time results in proteasome overload/dysfunction. Conversely, inhibiting proteasome function (and the consequent accumulation of mitochondrial proteins) triggers changes in MPI and activation of retrograde (mitochondria to nucleus) signalling. In differentiated PC12 cells sublethal CCCP (2µM) caused a decrease in the import of mitochondrially targeted GFP (mtGFP) and a concomitant accumulation of mtGFP in the cytoplasm. These findings indicate that inhibiting mitochondrial protein import creates conditions that favour proteasome overloading. Inhibition of proteasome function with MG115 (5µM) decreased mtGFP, mtHSP70, Tom20 and mtTFA import to mitochondria in PC12 cells, and import of mtHSP70, Tom20 and mtTFA in primary cortical neurons. In conjunction with decreased MPI, a massive accumulation of mtGFP and Tom20 was observed in cytoplasmic cellular fractions of PC12 cells. Proteasome inhibition induced non-reversible changes in mitochondrial morphology: mitochondria were punctate, and appeared to form aggregates at one pole of the cell. These results indicate that proteasome inhibition is associated with deficits in MPI, and suggest that proteasome dysfunction may disrupt mitochondrial to nuclear signalling pathways, that normally serve to coordinate changes in the expression of nuclear-encoded mitochondrial proteins and MPI.

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65. Silverman LB; Praver M; Charlton MP Department of Physiology, Faculty of Medicine, University of Toronto; PROTEOMICS OF PRESYNAPTIC DIFFERENTIATION The synapses of Crustacean neuromuscular junctions provide an extraordinary opportunity to study presynaptic differentiation. For instance, at individual fibres of the crayfish leg extensor muscle, the phasic motor neuron makes synapses that have a high probability of transmitter release and depress easily with low-frequency stimulation. On the same muscle fiber, the tonic motoneuron makes synapses that have a probability of transmitter release hundreds of times lower than that of the phasic synapses, but the probability increases dramatically with repetitive stimulation (Bradacs et al., 1997; Atwood and Karunanithi, 2002). Low frequency depression (LFD) of phasic synapses was observed by recording from both leg extensor preparations and intact leg stimulated at 0.2 Hz. Calpain inhibition abolished LFD in both preparations. Our long term goal was to determine the molecular basis of this differentiation using a proteomic approach in both crayfish and Drosophila synapses at various locations as well as at cerebelar co-culture between granule cells and Purkinje cells (phasic) and inferior olivary-Purkinje cells (tonic). Since dephosphorylation of the cytoskeleton is involved in low frequency depression (Silverman-Gavrila and Charlton, 2009) we wanted first to determine if there are any differences in the cytoskeleton between the phasic and tonic terminals. Using double immunostaining and confocal imaging of actin and tubulin we found that tubulin is more abundant in tonic than phasic axons trunks, while actin seems to be more concentrated in phasic axons. We isolated and dissociated the phasic and the tonic terminals using enzymatic and mechanical manipulation. Once enough material is collected, proteins from the two terminals are extracted. Next the phasic proteins are stained with Cy3 dye and the tonic proteins with Cy5 dye, then are submitted to 2D DIGE (two dimensional differential in gel electrophoresis) for separation. Next, the gel is simultaneously scanned and protein spots analyzed for differential expression. Protein spots whose expression is different for samples from phasic and tonic synapses are digested and then identified by mass spectromety. Next these proteins will be further investigated for their specific function. The identification of proteins that are differentially expressed will advance the identification of molecular basis of synaptic plasticity. Acknowledgements: NSERC fellowship to LBSG and CIHR grant to Milton Charlton. Special thanks to Rene Prashad for his continuous technical assistance and helpful discussions.

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66. Sinai L1,2; Ivakine EA3; Dida J4; Aubin JE5; Yeomans J4; Ralph M4; McInnes RR3,5; Roder R2,5 1Institute of Medical Science, University of Toronto; 2Samuel Lunenfeld Research Institute, Mount Sinai Hospital; 3Hospital for Sick Children Research Institute; 4Department of Psychology, University of Toronto; 5Department of Molecular and Medical Genetics, University of Toronto; BEHAVIORAL PHENOTYPE OF SRC SPONTANEOUS MUTATION IN MICE Src is a non-receptor protein tyrosine kinase that is expressed widely throughout the central nervous system and is involved in diverse biological functions such as cell growth, differentiation and signalling. Despite the well documented role of Src in synaptic plasticity its role in social behaviour, motor function and cognition remains elusive. Here we generate mice with a point mutation within the kinase domain of Src leading to a premature stop codon. This mutation predicts a deletion of ½ of the kinase domain. At birth, Srcthl/thl mice are indistinguishable from their littermates, but by 12 days of age can be easily identified by their small size, lack of incisors and variable numbers of molar teeth. A truncated Src protein is present in the brain identified by western blots. We show that Srcthl/thl null mice exhibit hyper sociability and hyperactivity in the open field. These mice have impaired visio-spatial learning, amygdala dependent learning, and motor learning. The period of the circadian rhythm of wheel-running activity in constant dark conditions is significantly shorter and the ability to synchronize by external signals is impaired during the light dark period in Srcthl/thl null mice. Src mutant mice show increased ultrasonic vocalization during social interaction. Src is known to be involved in regulating several proteins directly linked to Williams Beurens syndrome (WBS). WBS is a multisystem dysfunction manifested as hyper sociability, cognitive defects, and supravalvar aortic stenosis. Here we suggest a new role of Src activity in the molecular pathway associated with the phenotype observed in WBS. Protein analysis is in progress to prove the direct correlation of Src activity with several molecules involved in the pathophysiology of WBS.

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67. Srejić LR1; Aarts MR1,4; Hutchison WD2,3 1Cell and Systems Biology, University of Toronto; 2Physiology, University of Toronto; 3Surgery, Division of Neurosurgery, Toronto Western Research Institute; 4Biological Sciences, Univ. of Toronto at Scarborough; HIGH-FREQUENCY CORTICAL ACTIVITY ASSOCIATED WITH POST-ISCHEMIC EPILEPTIFORM DISCHARGES IN A RAT FOCAL STROKE MODEL IN VIVO Ischemic injury is the leading cause of epileptiform activity in the adult patient population. While epileptiform discharges may exacerbate normal neurological function after stroke, their genesis and association with high frequency activity has not been extensively studied in either human or animal stroke models. We used a parasagittal 8-channel intracortical microelectrode array to obtain high resolution recordings of cortical oscillations in urethane anaesthetized rats following partial middle and anterior cerebral artery occlusion. Upon ischemia, non-convulsive epileptiform theta runs (TR) ranging from 5 s to 5 min in duration were observed in 75% of the animals within 1 h of occlusion. TRs were confined to a single electrode in 6 rats and spread across electrodes in 3 animals. High frequency oscillations (HFOs) in the high gamma range (80 – 120 Hz) were initiated 5 – 15 s before each TR and terminated at the onset of the discharge. Non-convulsive periodic epileptiform discharges (PEDs) were detected in 58% of the rats following ischemia. The PED consisted of an early negative slow wave, a high amplitude positive spike and a short negative slow wave. Transient HFOs in the low gamma range (30 – 70 Hz) occurred on the first negative wave and the rising phase of the positive spike of the PED. The occurrence of HFOs with both types of epileptiform activity suggests an involvement of gamma activity in epileptogenesis.

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68. Stevens SA1,2; Nash K1,3; Greenbaum R4; Koren G1,2; Rovet J1,2 1Psychology Department, University of Toronto; 2The Hospital for Sick Children; 3Ontario Institute for Studies in Education of the University of Toronto; 4Children’s Mental Health Team, Surrey Place Centre; CAPTURING THE SOCIOEMOTIONAL PROFILES IN CHILDREN EXPOSED TO PRENATAL TERATOGENS Ongoing work in our lab has shown significant deficits in socioemotional processing and functioning in children with Fetal Alcohol Spectrum Disorders (FASDs). However, we do not know if the severity of these deficits is similar to those of children prenatally exposed to other teratogens. In order to address this question, the present study compared social cognitive and emotional processing skills in children with FASDs and children with prenatal cocaine exposure (PCE) versus normal controls (NC). Participants: 16 children with a FASDs (mn age: 8.9 yrs), 16 with PCE (mn age: 10.9 yrs), and 16 NC (mn age: 8.5years) were matched for socioeconomic status and gender. Methods: All children underwent an extensive neuropsychological evaluation, which included the Social Skills Rating Scales (SSRS) completed by both parents and teachers. To assess social cognition, three subtests were used from a Social Cognitive measure (Saltzman, 2007). To assess emotion processing, four subtests were used from the Minnesota Test of Affective Processing (MNTAP). Multivariate analyses of variance served to identify group differences on social and behavioral rating scales, as well as social cognitive and emotional processing measures. Results: On the SSRS, parents indicated marked impairments in the FASD group relative to PCE and NC on Social Skills (p<0.01 and p<0.001, respectively) and Behavioral Problems scales (p<0.05; p<0.001) while children with PCE showed deficits relative to NC only on Behavioral Problems (p<0.001); teachers indicated impairments in the FASD and PCE groups relative to NC on both Social Skills (p<0.001, p<0.01,) and Behavioral Problems scales (p<0.001 for both). Regarding the Social Cognitive measure, FASDs showed marked impairment compared to NC on the False-belief subtest (p<0.01), which measured children’s ability to detect false-beliefs, deceptions and sarcasm in a story. The FASD group also performed more poorly than NC and PCE (p<0.05) on the Display Rules. On the MNTAP, FASDs and PCE groups performed significantly below NC on Affect Match subtest (p<0.05) measuring child’s ability to determine whether faces convey same or different emotions. The FASD group also performed more poorly than NC on the Prosody Content subtest (p<0.06). Conclusions: This research provides insight into the different behavioural and social skill profiles of children with FASDs versus PCE. These results aid in discerning the socioemotional processing factors between these two groups, suggesting unique profiles as a result of prenatal exposure to different teratogens. Overall, the specific socioemotional processing abilities of children with FASDs are not adequately developed compared to children exposed to other prenatal teratogens.

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69. Sun X1; Hoque T1; Gunraj, C1; Nelson AJ2; Chen R1 1Division of Neurology and Krembil Neuroscience Centre, Toronto Western Research Institute, University of Toronto; 2Department of Kinesiology, University of Waterloo; SOMATOSENSORY PROCESSING IN PARKINSON’S DISEASE Arm and hand movements are frequently affected in Parkinson’s Disease (PD). Given the remarkable connectivity between somatosensory and motor networks and the dependence on sensory feedback to guide movements, maladaptive changes in sensory regions may contribute to the motor impairments in PD. The goal of the present research is to characterize somatosensory representation of the digits of the hands in patients with PD. Based on previous studies in patients with focal hand dystonia, we hypothesize that cortical representations of digits are abnormal in PD patients. We studied 10 PD patients 10 healthy age-matched controls. Functional magnetic resonance imaging (fMRI) was used to quantify the representation of digits in the brain. Digits 2 and 5 and the median nerve on each hand were stimulated. fMRI activation was examined in the primary and secondary somatosensory cortices (S1 & S2), and in the insula. In addition, sensory acuity was measured using techniques of psychophysics and intracortical inhibition was studied with transcranial magnetics stimulation (TMS). In healthy subjects, vibrotactile stimulation of digits 2 and 5 elicited activation in contralateral S1, bilateral S2 and contralateral insular cortex. In contrast, smaller and inconsistent activations were observed in the S1 area for PD patients, which may be due to dysfunction of the basal ganglia. In some patients, activity also occurred in the ipsilateral S1 area, which could represent compensatory recruitment. PD patients had lower spatial acuity and TMS studies suggest that they had reduced long-latency afferent inhibition. These results suggest that cortical sensory system in PD patients has reduced activation with vibrotactile stimuli, which may partially account for their sensory deficits.

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70. Tan LA1,2; Al Chawaf A1; Xu K2; Vaccarino, FJ2,3; Lovejoy DA1; Rotzinger S3,4 Departments of; 1 Cell and Systems Biology; 2Psychology; 3Psychiatry; 4Institute of Medical Science, University of Toronto; NEWLY-ELUCIDATED NEUROPEPTIDES IN THE HIPPOCAMPUS: THE ROLE OF THE TENEURIN C-TERMINAL ASSOCIATED PEPTIDES (TCAPS) ON STRESS-RELATED PATHWAYS The teneurin C-terminal associated peptides (TCAPs) are a novel family of four bioactive neuropeptides that are expressed in the brain. In situ hybridization studies have indicated that TCAPs are expressed in areas of the brain associated with the behavioural responses to stress, including the hippocampus, an area associated with stress, spatial reasoning, and memory. The following studies investigated the role of TCAP-1 in hippocampal stress-related pathways, and TCAP-1’s role in the regulation of stress and anxiety. Rats were injected with acute intracerebroventricular (ICV) synthetic TCAP-1 and corticotropin-releasing factor (CRF). The brains were processed using c-Fos immunohistochemistry and quantified to determine how acute or repeated TCAP-1 affects CRF-induced c-Fos expression. TCAP-1 modulates CRF-induced c-Fos expression in areas associated with stress, such as the hippocampus, amygdala, medial prefrontal cortex, dorsal raphe nucleus, and septum. However, TCAP-1 did not affect all areas, as TCAP-1 did not attenuate the effects of CRF in the paraventricular nucleus of the hypothalamus, which is the main source of CRF to the hypothalamic-pituitary-adrenal axis. Next, rats were injected with ICV-administered TCAP-1 and subjected to chronic restraint stress (CRS). The brains were stained using the Golgi-stain method and neurons in the hippocampus were analyzed for morphological characteristics. TCAP-1 caused a remodelling of neuron morphology in the pyramidal cells of the hippocampus, specifically in the stratum oriens and the stratum radiatum of the dendritic trees, depending on if the rats were treated with or without CRS. Finally, rats were injected with ICV-administered TCAP and CRF, and tested on the elevated plus maze and open field behavioural tests. TCAP-1 potentiated the effect of CRF in the elevated plus maze and open field tests. These results suggest that TCAP-1 has a role in the regulation of CRF-related pathways in the hippocampus. One such pathway may include the modulation of immediate-early gene expression, such as c-Fos, which produces downstream effects such as remodelling of neuronal morphology and ultimately modification of CRF-induced anxiety-like behaviour. TCAPs therefore represent a novel regulatory pathway which may provide a new therapeutic target in the treatment of stress and anxiety disorders.

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71. Teitelbaum A1; Perez Velazquez JL2 1Institute of Medical Science, University of Toronto; 2The Hospital for Sick Children, Neuroscience and Mental Health.; BRAIN COORDINATION DYNAMICS AND AUTISM The following work applies biophysical measurements to autism spectrum disorder. Specific conceptual pieces include brain coordination as phase synchronization and rate of fluctuation, assessed through MEG signal transformation, and additionally, autism spectrum disorder itself as a group hypothesized to show differences in this coordination when compared to non-ASD participants. An auditory-attention task requiring children to press a button in response an auditory tone showed differences in synchronization and desynchronization. Moreover, intraparietal phase coordination within ASD was much larger than intrafrontal or mixed frontal-parietal interactions across frequencies from 8 through 42 Hz, whereas within non-ASD this pattern only maintained itself through about 8 to 14 Hz and at a smaller magnitude. The rates of fluctuation across the midline tended to be much lower within the parietal lobe of participants with ASD, even where the aforementioned pattern overlaps, and this effect was not found within the frontal lobe at all.

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72. Titley HK1; Heskin-Sweezie R1; Broussard DM1,2,3 1Department of Physiology, University of Toronto; 2Division of Neurology, Department of Medicine, University of Toronto; 3Division of Fundamental Neurobiology, Toronto Western Research Institute, University Health Network; LEARNING OF GAIN INCREASES IN THE VESTIBULO-OCULAR REFLEX REQUIRES MGLUR1 AND GABAB RECEPTORS IN THE CEREBELLAR CORTEX The horizontal rotatory vestibulo-ocular reflex (VOR) exhibits motor learning, which is thought to depend on synaptic plasticity at the parallel fiber-Purkinje cell synapses in the cerebellar flocculus. It has been suggested that learned gain increases are a result of long-term depression (LTD) at the synapses, while gain decreases depend on long-term potentiation (LTP). Parallel-fiber LTD is thought to involve the activation of type 1 metabotropic glutamate receptors (mGluR1), resulting in a signaling cascade that leads to the internalization of AMPA receptors from the post-synaptic membrane. B-type γ-aminobutyric acid receptors (GABAB) are thought to interact with mGluR1, enhancing its signaling cascade. To determine whether mGluR1 and GABAB are necessary for VOR gain changes, 1 µl of either the mGluR1 antagonist (YM 298198, 50 µM), or agonist (S-DHPG, 1µM), or the GABAB receptor antagonist (CGP 52432, 1 – 10 µM), or vehicle alone was injected bilaterally into the flocculi of an alert cat. We then attempted to induce learning by rotating the cat in the light for 60 minutes using a sum-of-sines velocity profile, while the cat wore either miniaturizing (X0.25) telescopes (to decrease the gain of the VOR) or magnifying (X2) telescopes (to increase it). The VOR gain was measured after 30 and 60 minutes, in darkness, using sinusoidal rotation at 0.5, 2 and 8 Hz. The injection of the YM 298198 not only prevented learned gain increases, but resulted in a decrease in VOR gain when the cat wore X2 telescopes. Injection of CGP 52432 also prevented VOR gain increases, and caused a decrease in the VOR gain in the higher concentration. Injections of (S)-DHPG increased the gain of the VOR to above normal levels during gain up learning. The results were similar across frequencies. There were no consistent effects on the phase of the VOR. Neither the mGluR1 nor the GABAB antagonists or agonist had any effect on normal VOR function or cancellation. The injections of drugs did not affect gain down learning as compared to injections of the vehicle alone. We conclude that both the mGluR1 and GABAB receptors are required for VOR gain increases, but these receptors are not involved in learned gain decreases.

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73. Tong R1; Zai C1,2; Freeman N1,2; Tampakeras1,2; Shaikh S1,2; Casey D3; Hodgins D3; Smith G4; Williams R5; Schopflocher D6; Wood R7; El-Guebaly N8; Lobo D1,2; Kennedy J1,2 1Neurogenetics Section, neuroscience Department, Centre for Addiction and Mental Health; 2Department of Psychiatry, University of Toronto; 3Department of Psychology, University of Calgary; 4Faculty of Extension, University of Alberta; 5School of Health Sciences, university of Lethbridge; 6Faculty of Nursing, University of Alberta; 7Department of Sociology, University of Lethbridge; 8Division of Addiction, Department of Psychiatry, University of Calgary NO ASSOCIATION BETWEEN THE SEROTONIN TRANSPORTER PROMOTER POLYMORPHISM (5HTTLPR) AND GAMBLING BEHAVIOUR SEVERITY Objective: Problem gambling (PG) is an impulse-control disorder with a life-time prevalence of 5% in adults and its heritability has been estimated to be 50-60%. Serotonin (5-HT) dysregulation has been associated with PG. The 5-HT transporter is highly expressed in brain regions that regulate impulse control, such as the amygdala and prefrontal cortex. Additionally, the functional polymorphism (5-HTTLPR) has been associated with greater risk-taking in financial investments. Here, we investigate the effect of the 5-HTTLPR polymorphism on gambling behavior severity. Materials and Methods: A sample of 1154 subjects (580 males, mean age = 42.2 14.3) and each subject was assessed by the

Canadian Problem Gambling Index (CPGI) or the South Oaks Gambling Screen (SOGS) to be assigned into gambling severity groups (non-PG, low-risk, moderate-risk, and problem gambler). The effect of gender and age on gambling behaviour severity was assessed to determine whether the inclusion of the factors as covariates in the genetic analysis would be appropriate. All participants were genotyped for the 5-HTTLPR functional polymorphism and an allelic and genotypic analysis was performed to analyze the association between the polymorphism and the gambling severity groups. For further examination, the sample was stratified by ethnicity (Caucasian (C), African(AF), and Asian(AS)) and the genetic analysis was again performed. Results: Male gender was significantly associated with greater gambling severity (Total: p ≤0.001, C: p≤0.001; AF: p=0.013; AS: p=0.009) while age was not significantly associated with gambling severity (Total: p>0.05, all ethnicity groups: p>0.05). Therefore, gender was included as a covariate in the genetic analysis. The 5-HTTLPR polymorphism alleles and genotypes were not significantly associated with gambling severity in the total sample and across the different ethnic groups (Total: p>0.05, all ethnicity groups: allelic= p>0.05; genotypic= p>0.05). Conclusion: Results from our study suggest that the 5-HTTLPR polymorphism does not significantly influence gambling severity in subjects of Caucasian, African, and Asian descent. Additionally, the findings corroborate that of previous research showing that male gender is associated with increased gambling severity, which can be used to modify and improve prevention strategies. Further study should investigate whether other polymorphisms in the 5-HTT gene are associated with gambling behaviour. Efforts should be taken to replicate the findings of this study as well.

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74. Tsang EW1,2; Hamani C3; Elena MORO2; Mazzella F2; Saha U2; Lozano AM1,3; Hodaie H3; Chen R1,2 1Institute of Medical Science, University of Toronto; 2Division of Neurology, 3Division of Neurosurgery,Toronto Western Research Institute, University Health Network, Toronto, Ontario Canada.; MOVEMENT RELATED POTENTIALS AND OSCILLATORY ACTIVITIES IN THE HUMAN INTERNAL GLOBUS PALLIDUS DURING VOLUNTARY MOVEMENTS Objective: The internal globus pallidus (GPi) is used as a target for deep brain stimulation (DBS) for treatment of dystonia and related disorders. We aim to study GPi activities and its interaction with the cortex during voluntary movements. Methods: We studied six cervical dystonia (CD) patients with bilateral GPi DBS electrode implantations. Local field potentials from the DBS electrodes and EEG were recorded while CD patients performed unilateral externally-triggered and self-initiated wrist movements. Results: Movement-related potentials (MRP) at the bilateral GPi prior to electromyography onset were found in self-initiated but not in externally-triggered movements. In all movements studied, frequency analysis revealed a ~10-24 Hz event related desychronization (ERD) and a contralateral ~64-68 Hz gamma event related sychronization (ERS) at the GPi. The onset latencies of the 10-24 Hz ERD and 64-68 Hz ERS were ~1s earlier in the self-initiated than the externally-triggered movements. A ~5-18 Hz coherence was found between the bilateral GPi in CD patients. During movements, this coherence attenuated for ~1 s between the bilateral GPi in CD patients. Interpretation: These results showed that the cortico-basal ganglia circuit is active during preparation and execution of voluntary movements. Attenuation of 5-18 Hz coherence in the bilateral GPi may be associated with voluntary movements.

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75. Schlichter LC; Kaushal V; Vincent C; Moxon-Emre I; Sivagnanam V Toronto Western Research Institute, University Health Network and Department of Physiology, University of Toronto, Canada; THE SK3 (KCA2.3/KCNN3) CHANNEL IS EXPRESSED IN MICROGLIA IN VIVO AND IN VITRO AND CONTRIBUTES TO MICROGLIAL ACTIVATION AND NEUROTOXICITY Objectives: To examine expression of KCNN3/SK3 in CNS microglia in vivo and in vitro, and to use an established in vitro model to determine if this channel contributes to the neurotoxic capacity of activated microglia. Methods: KCNN3 mRNA (real-time RT-PCR) and SK3 immunoreactivity were examined in rat microglia. Lipopolysaccharide was then used to activate microglia (monitored by iNOS, nitric oxide, activation of NF-kB and p38 MAPK) and transform them to a neurotoxic state. Microglia-mediated neuron damage (TUNEL, activated caspase-3, tyrosine nitration) was assessed using a two-chamber system that allowed microglia to be treated with channel blockers, washed and then added to neuron/astrocyte cultures. Contributions of SK3 to these processes were discriminated using a subtractive pharmacological approach with apamin and tamapin. ANOVA and post-hoc tests were used to assess the statistical significance of differences between treatment groups. SK3 immunoreactivity was then compared in the normal and damaged adult rat striatum, by injecting collagenase (a hemorrhagic stroke) or endothelin-1 (a transient ischemic stroke). Results: KCNN3 mRNA was prevalent in cultured microglia and increased after lipopolysaccharide-induced activation; SK3 channel blockers inhibited microglia activation and reduced their ability to kill neurons. SK3 immunoreactivity was prevalent in cultured microglia and throughout the adult rat striatum (except white matter tracts). After strokes, SK3 was highly expressed in activated microglia/macrophages within the lesions and reduced in other cells. Discussion: SK3 is expressed in microglia in both the healthy and damaged adult striatum, and mechanistic in vitro studies show it contributes to transformation of microglia to an activated neurotoxic phenotype. Thus, SK3 might be a therapeutic target for reducing inflammation-mediated acute CNS damage. Moreover, its roles in microglia must be considered when targeting this channel for CNS diseases, disorders and reducing neuron hyper-excitability.

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76. Wasserman D1; Lee E2; Wang H1; Rashid A3; Josselyn S3; Yeomans J1,2,4 1Department of Psychology, University of Toronto; 2Department of Cell & Systems Biology, University of Toronto; 3The Hospital for Sick Children Research Institute; 4Centre for Biological Timing and Cognition, University of Toronto; MORPHINE INDUCED LOCOMOTION AND ULTRASONIC VOCALIZATIONS IN M5 KO MICE RESCUED BY VIRAL TRANSFECTION OF M5 MUSCARINIC RECEPTORS IN VENTRAL TEGMENTUM Mesopontine cholinergic neurons activate tegmental dopamine neurons via nicotinic and M5 muscarinic receptors. In rats, ventral tegmental area (VTA) muscarinic receptors are needed for brain-stimulation reward or food reward sensitivity, and for morphine-induced dopamine output. M5 knockout mice emit fewer ultrasonic vocalizations (USVs) during mating, and show less locomotion or dopamine output in response to morphine than wild-type mice. Using a Herpes simplex virus, the M5 receptor gene was transfected into the VTA or rostromedial tegmentum (RMT) of M5 knockout mice along with a green fluorescent protein (GFP) marker gene (HSV-M5-GFP). M5 transfection into VTA dopamine and non-dopamine neurons fully restored mating-induced USVs and increased morphine-induced locomotion and stereotypy. M5 transfection into RMT inhibited USVs and morphine-induced locomotion, consistent with activation of RMT GABA neurons that inhibit VTA dopamine neurons. These M5 transfection studies help identify which tegmental neurons are responsible for deficits in M5 knockout mice, and show that these deficits are reversed in adult mice with a single localized transfection.

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77. West GL1; Anderson AK1,2; Ferber S1,2; Pratt J1 1Department of Psychology, University of Toronto; 2Roman Research Institute, Baycrest Hosptial; ATTENUATION OF THE DORSAL-ACTION PATHWAY SUPPRESSES FEAR PRIORITIZATION: AN EVOLUTIONARY LINK BETWEEN EMOTION AND ACTION It is widely thought that emotional facial expressions receive privileged neural status compared to their non-affective counterparts. This prioritization, however, comes at a cost, as the neural capacity of the human brain is finite; the prioritization of any one object comes at the processing expense of other concurrent objects in the visual array competing for awareness (Desimone & Duncan, 1995). Despite this reality, little work has examined the functional benefit derived from the perceptual prioritization of affective information. Why do we preferentially attend to emotional faces? According to evolutionary accounts, emotions originated as adaptations towards action, therefore acting to prepare the organism for locomotion (Darwin, 1872; Frijda, 1986). To directly examine this relationship, we reasoned that the prioritization of affective events may occur via two parallel pathways originating from the retina - a parvocellular (P) pathway projecting to ventral stream structures responsible for object recognition, or a faster and phylogenetically older magnocellular (M) pathway projecting to dorsal stream structures responsible for localization and action. It has previously been demonstrated that retinal exposure to red diffuse light suppresses M cell neural activity. Here we tested whether the fast propagation along the dorsal-action pathway drives an accelerated conduction of fear-based content. Using a visual prior entry procedure, accelerated stimulus perception was assessed while either suppressing the M pathway with red diffuse light, or leaving it unaffected with green diffuse light. We show that that the encoding of a fearful face is accelerated, but not when M-channel activity is suppressed. Additional control experiments confirmed that this affective prioritization is driven by coarse low spatial frequency information, and that red diffuse uniquely affects dorsal competition but not top-down ventral competition. Together, our results reveal a dissociation that implicates a privileged neural link between emotion and action that begins at the retina.

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78. Wilkinson AA1; Keightley ML1,2,3,4,5; Agnihotri S2; Dick T3; Schwartz D6; Reed, NP1,2; Green S1,2 1Department of Psychology, University of Toronto; 2Graduate Department of Rehabilitation Science, University of Toronto; 3Department of Occupational Science and Occupational Therapy, University of Toronto; 4Toronto Rehabilitation Institute; 5Bloorview Kids Rehab Research Institute; 6Department of Psychology, Ryerson University; VERBAL LEARNING AND MEMORY FOLLOWING MILD TRAUMATIC BRAIN INJURY IN YOUTH: A LONGITUDINAL STUDY BACKGROUND: Concussion, or mild traumatic brain injury (mTBI), is the most commonly reported injury in youth participating in organized sports. Competitive sports, such as hockey, provide us with the rare opportunity to utilize a pre-post design, which allow us to obtain pre-injury data on youth characteristics and functioning before mTBI occurs and then relate this to outcome following injury. Memory has been described as the psychological function that is potentially the most vulnerable to brain trauma. Despite growing public interest in mTBI and the understanding that children and adolescence are in a time of dramatic neural reorganization, what remains to be explored is the effect of developmental maturation on recovery from mTBI. OBJECTIVES: To document the recovery of verbal learning and memory in children following mild traumatic brain injury (mTBI). METHODS: 126 youth hockey players were followed for two years with 13 instances of mTBI (~10%). The mTBIs occurred in 11 male athletes aged 10-11, with one youth sustaining 3 separate injuries. Post-concussion symptoms were measured using a 21-item checklist adapted from the Postconcussive Symptom Scale–Revised (PCS). Recovery is defined as a return to a PCS score of ≤ 6. The Rey Auditory Verbal Learning Test (RAVLT) was administered as a baseline measure at the beginning of the season and again once post-concussion symptoms resolved. The RAVLT assesses a number of memory domains (i.e. learning, immediate recall, delayed recall, recognition and serial position) at once allowing for an efficient way to assess verbal learning and memory, as well as allowing the examination of relations between the different domains in the same sample. Reliable Change-Index (RCI) scores were calculated to determine clinical significance of the index scores of the RAVLT. An RCI of +/- 1.96 is considered to be clinically significant. RESULTS: PCS scores at initial follow-up were found to vary from 7-89. A higher score on the PCS at initial follow-up was generally found to coincide with a longer recovery time. A significant RCI score was found for 4/13 participants on the immediate recall trial, 4/13 on the recognition trial, 7/13 for serial position of words 10-12 in the list, and 5/13 for words in the 13th-15th position in the list. A significant RCI was found for 2/13 participants on delayed recall; however, 2 more participants each had an RCI of -1.95. CONCLUSIONS: The verbal learning trials and recall of words from the beginning of the word list (i.e. primacy) do not appear to be affected by mTBI. Immediate and delayed recall, delayed recognition, and recalling words from the end of the word list (i.e. recency) appear to be affected by mTBI. These results suggest a decline in verbal memory following mTBI. Children in this developmental period are in an active learning environment, and the use of verbal learning and memory is needed to retain and manage new information, the disruption of these skills may have detrimental effects on their education and daily activities.

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79. Chao H1; Kennedy JM2; Wnuczko M2 1Department of Architecture, National Taiwan University of Science and Technology; 2Department of Psychology, University of Toronto at Scarborough; ELEVATION JUDGED EASIER THAN PLAN BY THE SIGHTED AND BLIND ON PERSPECTIVE TAKING TASKS Elevations are visual angles,showing the vertical shapes of objects, with the objects arranged from left to right. Plans are maps, showing the shapes of the objects plus the left-right and the order in distance of objects, that is from near to far. Plans, having more spatial information, should be more difficult for subjects to construct. Results of difficulty judgments from sighted and blindfolded, and blind participants on Piaget's 3- mountains task supported this hypothesis. The plan task was judged as more difficult than the elevation task even when participants performed with the same level of accuracy on both tasks.

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80. Yilmaz Z1,3; Kaplan AS2,3; Levitan RD2,3; Kennedy JL2,3 1Institute of Medical Science, University of Toronto; 2Department of Psychiatry, University of Toronto; 3Centre for Addiction and Mental Health; ASSOCIATION OF THE DRD4 GENE WITH COMORBID CHILDHOOD ADHD IN WOMEN WITH BULIMIA NERVOSA Rationale: Bulimia nervosa (BN) is a psychiatric disorder that predominantly affects women, and is characterized by regular binge eating, purging and characteristic psychopathology. Past research has shown that up to one third of patients with BN report a history of attention deficit/hyperactivity disorder (ADHD) symptoms, and the dopaminergic genes, especially the dopamine receptor D4 (DRD4), have been associated independently with both BN and ADHD. Objectives: The purpose of this study is to explore the possible role of DRD4 genetic variants in predicting childhood ADHD comorbidity in women with BN. Methods: 109 women with current or past BN purging subtype were genotyped for the presence or absence of the hypofunctional 2-repeat and 7-repeat alleles of DRD4. Patients also completed the Wender Utah Rating Scale (WURS) for the assessment of childhood ADHD history and the Brown Adult ADD Scale for current ADHD symptoms. Results: The presence of the 2-repeat or 7-repeat alleles was associated with comorbid childhood ADHD in BN patients, as assessed by the WURS. There was no relationship between the Brown scores and the DRD4 genotype. Conclusion: To our knowledge, this is the first study to look at the role of the DRD4 gene in comorbid ADHD in women with BN. The pathophysiology of both BN and ADHD may in part be related to underlying dopaminergic abnormalities, and these finding may have implications for treatment, especially with dopaminergic agents, for bulimic women with significant symptoms of ADHD.

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81. Yiu AP1,2; Neve RL3; Hill M4; McLaurin J4,5; Josselyn SA1,2,6 1Program in Neurosciences & Mental Health, Hospital for Sick Children, Toronto, ON, M5G 1X8 Canada; 2Institute of Medical Sciences, University of Toronto, Toronto, ON, M5S 1A8 Canada; 3Dept. of Brain and Cognitive Sciences, MIT, Cambridge, MA 02139 USA; 4Centre for Research in Neurodegenerative Diseases; 5Laboratory Medicine and Pathobiology; 6Dept. of Physiology, University of Toronto, Toronto, ON, M5S 1A8 Canada; ACUTE EXPRESSION OF ALZHEIMER’S DISEASE LINK MUTATIONS LEAD TO SPATIAL MEMORY FORMATION BUT NOT RETRIEVAL DEFICITS IN MICE Alzheimer’s disease (AD) is a neurodegenerative disorder that is initially characterized by mild memory impairments that progress to more global cognitive deficits, behavioral impairment and eventually death. Several genes have been implicated in familial Alzheimer’s disease (FAD). Transgenic mouse models chronically expressing these FAD genes recapitulate many of the AD cognitive deficits. However, the effects of acute expression of these mutant genes is unknown. Here we used viral vectors to acutely express FAD genes in adult mice. Genes encoding the Swedish mutation, Indiana mutation, Swedish and Indiana double mutation of amyloid precursor protein (APP) and a Presenilin 1 (PS1) mutation were expressed in the CA1 region of the dorsal hippocampus for 5 days and the effect on spatial memory was examined. Acute expression of the FAD genes produced deficits in the formation but not retrieval of spatial memory, as assessed by the Morris water maze. These behavioral deficits occurred in the absense of amyloid plaques or cell death. As changes in spine structures are thought to contribute to synaptic plasticity, we also examined the effects on spine density. Acute expression of these FAD genes had no effect on the structure (dendritic length, number of intersections, surface area, etc.) of CA1 neurons but decreased the total number of dendritic spines as well as spine density in infected neurons. Therefore, acute localized expression of these FAD genes in the CA1 region of the hippocampus produce deficits in spatial memory formation that may be mediated by impairments in dendritic spine plasticity.

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82. Zurek AA1; Aydin B1; Orser BA1,2 1Department of Physiology, University of Toronto; 2Department of Anesthesia, Sunnybrook Health Sciences Centre; POST-ANESTHETIC MEMORY IMPAIRMENT IS MEDIATED BY Α5GABAAR ACTIVITY DURING ANESTHESIA Postoperative memory deficit is a common adverse outcome associated with surgery and anesthesia, yet the mechanisms underlying this deficit remain poorly understood. α5 subunit-containing γ-Aminobutyric acid type A receptors (α5GABAARs) have been implicated in modulating normal memory performance and the acute amnestic effects of anesthetics. We hypothesized that activation of α5GABAARs causes undesirable post-anesthetic memory deficits. We sought to determine whether these deficits can be prevented or treated with the α5GABAAR selective inverse agonist L-655,708. C57Bl6/SV129 male mice were exposed to isoflurane (1.3%; 1 MAC) or vehicle (30% O2) for 1 h in a heated, air-tight chamber. Mice received L-655,708 (0.7 mg/kg, i.p.) or vehicle (90% saline, 10% DMSO) either prior to anesthesia [prevention] or prior to behavioural training [treatment]. Memory performance was assessed using the object recognition paradigm. In comparison to vehicle-treated mice, mice exposed to isoflurane exhibited a memory deficit 1 h and 24 h after anesthesia (Student’s t tests, P < 0.05, n = 8 per group). L-655,708 failed to reverse the memory deficit 1 h and 24 h after isoflurane (P > 0.05). However, the deficit could be prevented by L-655,708 administration prior to anesthesia (P < 0.05). Hence, α5GABAAR activity during anesthesia is important in mediating post-anesthetic memory impairment. The injurious process leading to memory impairment can be prevented by decreasing α5GABAAR activity during anesthesia.