WCBR Program 02

Welcome to the Thirty-Sixth Annual Winter Conference on Brain Research

The Winter Conference on Brain Research (WCBR) was founded in 1968 to promote free exchange of information and ideas within neuroscience. It was the intent of the founders that both formal and informal interactions would occur between clinical and laboratory-based neuroscientists. During the past thirty years neuroscience has grown and expanded to include many new fields and methodologies. This diversity is also reflected by WCBR participants and in our program. A primary goal of the WCBR is to enable participants to learn about the current status of areas of neuroscience other than their own. Another objective is to provide a vehicle for scientists with common interests to discuss current issues in an informal setting. On the other hand, WCBR is not designed for presentations limited to communicating the latest data to a small group of specialists; this is best done at national society meetings. The program includes panels (reviews for an audience not neces- sarily familiar with the area presented), workshops (informal discussions of current issues and data), and a number of posters. The annual conference lecture will be presented at the Sunday breakfast on January 26. Our guest speaker will be Dr. Michael E. Phelps, Professor and Chair, Department of Molecular and Medi- cal Pharmacology, University of California, Los Angeles. The title of his talk will be Molecular Imaging of Biology in vivo from Mouse to Patient and from Metabolism to Gene Expression. On Tuesday, January 28, a town meeting will be held for the Salt Lake City community, at which Dr. Glen Hanson, Acting Director of the National Institute on Drug Abuse, will give a talk entitled Drug Abuse: Morality versus Medicine: A Proper Perspective. WCBR participants Bill Carlezon, Bryan Yamamoto, Marina Picciotto, Kyle Frantz, Kristin Anstrom, and Marc Laruelle will respond and answer questions as part of an expert panel. Also, participants in the WCBR School Outreach Program will present sessions at local schools throughout the week to pique students’ interest in science.

1 Finally, the banquet, including a special program, music, and dancing, will be held on Friday evening. Generous donations from sponsors have permitted us to continue the WCBR Fellowship Award Program. These awards are given to young neuroscientists who are on the program and who are newcomers to WCBR. Congratulations and a warm welcome to this year’s fellows: Sara Becker-Catania, Victor Chaban, David Devilbiss, Suzanne Guenette, Robert Jinks, Catherine Krull, Birgit Liss, Ewan McNay, Paul Mermelstein, Vladimir Parpura, Susan Patterson, Ruth Perez, Amir Raz, Nicole Sanders, Eric Schwartz, Jeremy Seamans, Uri Shalev, Kevin Sinchak, Laura Stone, Ai Yamamoto, and Venetia Zachariou. Please plan to attend the business meeting at 6:30 PM on Wednes- day, January 29. We will elect a Conference Chair Elect and three members of the Board of Directors. Other important matters will be discussed, including the selection of future conference sites.

Don’t forget to visit the exhibit area.

2 Conference Chair Michael Levine Program Committee Elizabeth Abercrombie, Katherine Kalil Chair Kristen A. Keefe Monte Westerfield, Irwin Lucki Chair Elect David J. Perkel Marjorie Ariano Kent Shellenberger Valina L. Dawson Ralph M. Siegel Janet Finlay Celia Sladek Robert Foehring Mark A. Smith Gerald F. Gebhart William Spain Herbert M. Geller Oswald Steward Thomas Hyde George Wilcox Treasurer Suzanne Haber Facilities Committee Monte Westerfield, Chris Lee Chair Simona Neumann Kim Topp, Facilities Melinda Piper Chair Elect Josh Plotkin Carolyn Byl Amaal Starling Board of Directors Jill Becker Barbara Lipska Michael Egan Bruce Ransom Karen Gale Thomas Swanson David Goldman Claude Westerlain Teresa Hastings

Fellowship Program James Surmeier, Chair Paul Letourneau Elizabeth Abercrombie Michael Levine R. Bartus Irwin Levitan Allan Basbaum Peter R. MacLeish Martha C. Bohn P. Skolnick Robert Burke Judith R. Walters Beth Fischer Michael Zigmond E. Hall

3 Exhibits Wendy B. Macklin

School Outreach Karen Greif, Chair John Mendelson Paula Dore-Duffy Hooly Moore Helen Ensellem Vladimir Parpura Anne Etgen Marina Picciotto Judy Garner Mark Smith Karen Greif Brad Stokes Jim Joseph Tom Swanson Kristen Keefe Kimbery Topp Hugh McIntyre Frank Welsh Marsha Melnick Michael Zigmond

Town Meeting Patricio O’Donnell 2003 Fellowship Awardees Sara Becker-Catania Ruth Perez Victor Chaban Amir Raz David Devilbiss Nicole Sanders Suzanne Guenette Eric Schwartz Robert Jinks Jeremy Seamans Catherine Krull Uri Shalev Birgit Liss Kevin Sinchak Ewan McNay Laura Stone Paul Mermelstein Ai Yamamoto Vladimir Parpura Venetia Zachariou Susan Patterson

Conference Arrangements Scott C. Miller, Assistant Head Conferences & Institutes Office of Continuing Education University of Illinois at Urbana-Champaign 302 East John Street, Suite 202 Champaign, IL 61820 Phone toll free 877-455-2687 Fax 217-333-9561 E-mail [email protected]

4 Winter Conference on Brain Research Fellowship Sponsors

Public Constance Atwell, National Institute for Neurological Diseases and Stroke Beth-Anne Sieber, National Institute for Mental Health. Private Abbott Laboratories Alkermes Alzheimer's Association Cephalon Cortex DOV Pharmaceutical Dupont Dystonia Foundation Élan Eli Lilly & Company Fine Science Tools Merck Research Laboratories Novartis Pharmaceutical Corporation Pfizer Pharmacia & Upjohn Company

Don’t forget to visit the exhibit area.

5 Exhibitors Association Book Exhibit 8728-A Cooper Road Alexandria, VA 22309 Contact: Mark Trocchi Phone 703-619-5030 Fax 703-619-5035 E-mail: [email protected]

Carl Zeiss One Zeiss Drive Thornwood, NY 10594 Contact: Julie Zellar Phone 914-681-7855 Fax 914-681-7445 E-mail: [email protected]

CHEMICON International, Inc. 28820 Single Oak Drive Temecula, CA 92590 Contact: Customer Service Phone 800-437-7500 Fax 909-676-9209 e-mail: [email protected]

CMA/Microdialysis 73 Princeton Street North Chelmsford, MA 01863 Contact: Kathleen Gariepy Phone 978-251-1940 Fax 978-251-1950 e-mail: [email protected]

ESA Inc. 22 Alpha Road Chelmsford, MA 01824-4171 Contact: Helmer Korb Phone 978-250-7000 Fax 978-250-7090 E-mail: [email protected]

6 Fine Science Tools 373-G Vintage Park Drive Foster City, CA 94404 Contact: Jeff Wiley Phone 650-349-1636 Fax 650-349-3729 E-mail: [email protected]

S. Karger AG Allschwilerstrasse 10 CH-4009 Basel, SWITZERLAND Contact: Corina Maetzler Phone 41-61-306-1364 Fax 41-61-306-1234 E-mail: [email protected]

MED Associates, Inc. PO Box 319 St. Albans, VT 05478 Tel 802-527-2343 Fax 802-527-5095 Contact: Karl Zurn E-mail: [email protected]

Division of Neuroscience and Basic Behavioral Science National Institute of Mental Health 6001 Executive Boulevard, Room 7168 Bethesda, MD 20892-9641 Contact: Beth-Anne Sieber Phone 301-443-5288 Fax 301-402-4740 E-mail: [email protected]

Don’t forget to visit the exhibit area.

7 Nikon Inc. PO Box 2464 Evergreen, CO 80437 Contact: Gerald Benham Colorado Office Phone and Fax 303-674-1569 E-mail: [email protected]

Olympus America Two Corporate Center Drive Melville, NY 11797 Contact: Kathleen Karmel Phone 800-645-8100 Box 6462 Fax 435-615-8350

8 General Information

Headquarters is the Cliff Lodge and Conference Center. All scientific activities will be held there. WCBR Information Desk and Message Center are in the Cliff Lodge and Conference Center Level B – Ballroom Lobby. The desk hours are as follows: Morning Afternoon Evening Saturday 1/25 9:00–11:00 AM 3:30–5:30 PM 6:30–10:00 PM Sunday 1/26 7:00–8:00 AM 3:30–6:30 PM Monday 1/27– 7:00–8:00 AM 3:30–4:30 PM Friday 1/31

The telephone number for messages is 801-742-2222. The Cliff Lodge and Conference Center Fax number is 801-933-2119. The person sending or receiving faxes is responsible for all charges. Registration packets containing conference badge, registration receipt, tickets for breakfasts, mid-week lunch and banquet, and program book should be picked up at the WCBR Information Desk. PLEASE NOTE that your housing reservation must be shown before these items can be issued. Conferees who do not accept WCBR-assigned accommodations are charged a facilities supple- ment of $100 as stated in the WCBR announcement. No excep- tions can be granted. Attendance at this conference is strictly limited to PREREGISTERED participants. On-site registration is not available. Posters will be available for viewing in two different sessions during the week in Ballroom 2-3: Poster Session 1, Sunday– Tuesday and Poster Session 2, Wednesday–Friday. Poster presenters will be by their posters for discussion from 3:30–4:30 PM according to the schedule listed on pages 23–28. Presenters may put up their posters after 9:30 AM on the day their session starts. Presenters should take down their posters by 10 PM on the final day of their session. Please see Poster Sessions section in program for titles and names of presenters.

9 Exhibits and Lounge are in the Ballroom 2-3. Coffee is available there from 7:30–10:30 AM Monday through Friday. Refreshments are provided by the exhibitors at 3:30–4:30 PM, Sunday through Friday. Exhibits close after 10:30 AM on Friday. Friday’s afternoon break will be in the ballroom lobby. Breakfast is served to all registrants on Sunday 7:30–8:30 AM, in the Ballroom of the Cliff Lodge and Conference Center, and on Monday through Friday, 6:30–7:30 AM, in the Golden Cliff. (Social guests may breakfast until 10 AM in the Aerie Restaurant.) The tickets in your registration packet are required for admission. On Saturday morning (February 1) before departure, a continental breakfast is available in the Ballroom of the Cliff Lodge and Conference Center. Ski Lift Tickets will be available from the WCBR Information Desk. Daily tickets can be purchased or prepaid tickets can be picked up during desk hours.

Don’t forget to visit the exhibit area.

10 Special Events

Saturday, January 25 Welcome Wine and Cheese Party • 7–10 PM, Cliff Lodge Ballroom

Sunday, January 26 Conference Breakfast and Opening Address • 7:30 AM, Cliff Lodge Ballroom (Your required ticket is in your registration packet.) The plenary keynote speaker will be Dr. Michael E. Phelps. Meeting of Panel and Workshop Organizers • 9:30–10:30 AM, Cliff Lodge Ballroom, immediately after breakfast. The meeting will be brief but important. Organizers and WCBR staff please attend.

Monday, January 27 First Meeting of Board of Directors • 6:30–8:30 AM, White Pine room of the Cliff Lodge

Tuesday, January 28 Town Meeting • 7 PM, Albion Middle School, Salt Lake City, Utah

Wednesday, January 29 Smitty Stevens Memorial (NASTAR) Ski Race • 10–11:30 AM, Gad Valley Race Hill NASTAR registration cards to be completed no later than Monday, January 27, 8 AM at WCBR Information Desk. Mountain Lunch • 12 Noon–2 PM, Base of Gad Valley Required lunch ticket is in your registration packet. Non-skiers requiring transportation should sign up at the WCBR Information Desk. Business Meeting • 6:30 PM, Ballroom 1 Election of Chair Elect and Three Members of the Board of Directors.

Friday, January 31 Second Meeting of Board of Directors • 6:30–7:30 PM, White Pine room of the Cliff Lodge Banquet and Dance • 7:30 PM, Cliff Lodge Ballroom Required ticket is in your registration packet. Cash bar open at 6:30 PM in the Ballroom Lobby.

11 Preamble to the Program

The 2003 WCBR Program consists of panels, workshops, and posters. Please consult the program booklet and posted announcements for details regarding the scientific presentations as well as information regarding the School Outreach program and the town meeting.

12 Sunday, January 26

7:30 AM PANEL • The Development and Patterning of the Vertebrate PLENARY BREAKFAST • Molecular Spinal Cord Imaging of Biology in vivo from E. Carpenter, C. Krull, Mouse to Patient and from C. Lance-Jones, P. Phelps, Metabolism to Gene Expression G. Schoenwolf Guest Speaker: Dr. Michael E. Maybird Phelps, Professor and Chair, Department of Molecular and PANEL • APP Function: New Medical Pharmacology, Insights from APP C-Terminal University of California, Los Binding Proteins and Notch Angeles Signaling Ballroom R. Perez, L. Goldstein, F. LaFerla, S. Guenette 3:30– 4:30 PM Superior A PANEL • Magnetic Resonance EXHIBITS Microimaging—A Non-Invasive Ballroom 2–3 Tool for Monitoring Spinal Cord Repair 4:30–6:30 PM M. Murray, A. Flanders, M. Selzer, E. Schwartz PANEL • Steroids, Catecholamines, and Sex: Working Together in Superior B the Brain? G. Snyder, J. Becker, S. Mani, 8:30–10 PM A. Etgen, R. Meisel PANEL • Cellular Basis of Persis- Ballroom 1 tent Activity PANEL • Diverse Roles of Calcium J. Seamans, J. Surmeier, Signaling in CNS Growth Cones I. Timofeev, P. O’Donnell and Synapses Ballroom 1 K. Kalil, T. Gomez, S. Smith, PANEL • Attention—Locus P. Mermelstein Coeruleus Magpie J. Williams, V. Alvarez, PANEL • The Role of Metabotropic G. Aston-Jones, C. Chow, Glutamate Receptors in Drug E. Van Bockstaele Dependence and Schizophre- Magpie nia A. Markou, P. Kalivas, F. Conquet, M. Geyer Wasatch

13 Sunday, January 26, continued

WORKSHOP • Conditioned Drug WORKSHOP • Black Diamond Effects: Mechanisms and Technique in Knock-Down, Potential Role in Relapse to Knock-Out, Sequestration, and Addiction Synergism Studies C. O’Brien, B. Hoebel, C. Fairbanks, L. Stone, P. De Witte , F. Weiss J. Zadina, D. Paul Wasatch Superior A WORKSHOP • Serotonin as a WORKSHOP • The Anterior Trophic Factor Cingulate and Orbitofrontal A. Andrews, M. Blue, Cortices and Goal-Directed B. Hoffman, J. Lauder, Behavior L. Mamounas, J. Lakoski L. Peoples, B. Richmond, Maybird J. Parkinson, H. Barbas, E. Koechlin Superior B

Monday, January 27

7:30–9:30 AM PANEL • Cell Death in the CNS: How Does Oligodendrocyte PANEL • Genetic Models and Death Impact Neurons? Behavioral Modifications W. Macklin, J. de Vellis, N. Marks, O. Arancio, I. Duncan, P. Knapp, R. Skoff R. Bourtchouladze, R. Hen, Maybird A. Yamamoto PANEL • GAD Gene Therapy for Ballroom 1 the Treatment of CNS Disease PANEL • Estrogen-State Modulates L. Jasmin, S. Rabkin, M. During Neurotransmitter Action Superior A P. Micevych, E. Wagner, K. Sinchak, C. Bethea, PANEL • Neuronal Circuitry of the V. Chaban Mammalian Retina Magpie S. Massey, M. Iuvone, S. Bloomfield, R. Taylor PANEL • Who is the Boss? Prefron- tal Cortical Interaction with Superior B Subcortical Limbic Systems B. Moghaddam, A. Grace, 3:30–4:30 PM D. Weinberger, M. Laruelle POSTER SESSION and EXHIBITS Wasatch Ballroom 2–3

14 4:30–6:30 PM 6:30 PM PANEL • Nicotinic Acetylcholine MINI-COURSE • Microarray: To Do Receptors in the 21st Century: or Not To Do; If So, How To Genetic Manipulations of D. Geschwind, K. Mirnics, nAChRs in Mice C. Barlow, S. Ginsberg M. Picciotto, J. Dani, Ballroom 1 S. Heinemann, H. Lester Ballroom 1 8:30–10 PM PANEL • The Mesolimbic System and Reward—There’s More PANEL • Decisions and Emotions Than Dopamine to the Story in the Context of Free Will and Suggestion S. Rayport, S. Sesack, D. van der Kooy, P. O’Donnell, R. Wise P. Churchland, A. Raz, R. Adolphs, D. Tranel Magpie Ballroom 1 PANEL • Relationship Between BOLD-fMRI and Behavioral PANEL • The Influence of Glucose Performance and Lipids on Brain Functions M. Corbetta, D. Heeger, S. Leibowitz, B. Levin, M. D’Esposito, L. Pessoa, E. McNay, N. Salem G. Shulman Magpie Wasatch WORKSHOP • Changing Their PANEL • Atypical PKC—Neuronal Minds: Enduring Effects of Survival, Synaptic Plasticity, Early Stimulant Exposure and Memory Formation K. Frantz, G. Laviola, H. Steiner, J. Yin, M. Wooten, M. Sutton, W. Carlezon T. Sacktor Wasatch Maybird WORKSHOP • Patterning of PANEL • So Many Areas, So Little Sensory Cortical Areas: Nature Time: Transformations of Visual and Nurture? Information in Extrastriate S. Pallas, E. Grove, J. Hebert, Cortex R. Erzurumlu D. Tso, V. Casagrande, D. Tsao, Maybird G. DeAngelis WORKSHOP • Mortally Wounded Superior A and Still Talking? Protection PANEL • Food Deprivation and and Rescue from Insult- Drug-Taking Behavior: New Induced Delayed Insights to an Old Question Neurodegeneration Y. Shaham, P. Piazza, M. Bennett, K. Gale, V. Dawson, D. Lattemann, M. Dallman, E. Aizenman U. Shalev Superior A Superior B

15 Monday, January 27, continued

WORKSHOP • Protein Indigestion in Neurodegenerative Diseases: How Do Neurons Spell Relief? R. Nixon, A. Cuervo, D. Sulzer, J. Keller Superior B

Tuesday, January 28

7:30–9:30 AM PANEL • The Development of the Embryonic Nervous System: PANEL • Exercise Is Not Just for From Global To Local Organiza- Fun! Influences on Health and tion Disease D. Chambers, U. Nordström, M. Zigmond, C. Cotman, C. Kiecker, J. Gilthorpe W. Greenough, T. Schallert, Superior A M. Melnick PANEL • NMDA-mGluR Inter- Ballroom 1 actions: Mechanisms and PANEL • BIRNing Down the Potential Therapeutic Implica- House: Biomedical Informatics tions and the Structure of the Brain J. Krystal, S. Zukin, P. J. Conn, D. Kennedy, G. McCarthy, W. B. Moghaddam Wells, A. Toga, B. Rosen Superior B Magpie PANEL • Plasticity of Intrinsic 3:30–4:30 PM Neuronal Excitability POSTER SESSION and EXHIBITS G. Turrigiano, D. Johnston, R. Harris-Warrick, L. Griffith Ballroom 2–3 Wasatch PANEL • Cannabinoid CB1 4:30–6:30 PM Receptors: Molecular Insights PANEL • DRIPs and Other Cellular and Therapeutic Potential Plumbing P. Iredale, D. Kendall, B. Martin, M. Ariano, R. Levenson, F. Liu, M. Abood D. Sibley Maybird Ballroom 1

16 PANEL • GABAA Receptor 7 PM Synapses: Exciting Developments in Inhibition TOWN MEETING R. Olsen, J. Nymann-Andersen, Drug Abuse: Morality versus B. Luscher, J. Kittler, W. Wisden Medicine: A Proper Perspective Magpie G. Hanson PANEL • What Controls Albion Middle School, Salt Lake Neurogenesis? City, UT F. Crews, M. Rao, J. Joseph, S. Goldman 8:30–10 PM Wasatch PANEL • When Life Is Not Sweet: PANEL • Molecular Mechanisms of Brain Responses to Low Blood Cellular Feedback and Sugar Pulsatility in Neuroendocrine B. Levin, D. Lattemann, Systems B. Ransom, N. Sanders, G. Aguilera, S. Lightman, I. Simpson E. Teresawa, D. Klein Ballroom 1 Maybird PANEL • Emerging Ideas on PANEL • Galanin as a Multi- Synaptic Function in the functional Neuropeptide: Peripheral Nervous System Pharmacological and Genetic J. Horn, A. Fox, D. Weinreich Approaches Magpie V. Zachariou, C. Wrenn, PANEL • Stress, Endogenous T. Bartfai, D. Wynick Opioids, and Relapse Behavior Superior A F. Henn, M. Kreek, K. Mann, PANEL • Intracellular Recording in Y. Shaham, R. Spanagel vivo: A Window to Observe Wasatch Neural Computation in Action WORKSHOP • Indices of Neuronal D. Jaeger, S. Nelson, R. Sachdev, Function: Just Because You G. Arbuthnott Believe It Doesn’t Make It So Superior B K. Keefe, J. McGinty, B. Yamamoto, P. O’Donnell 6:30 PM Maybird Special Issues WORKSHOP • Small WORKSHOP • Strategies for Science? The Facts and Myths Recovery of Function after about Research in Liberal Arts Nervous System Injury Colleges H. Geller, J. Fawcett, D. Stein, K. Greif, P. Dickinson, B. Stokes, A. Schwartz S. Devoto, R. Jinks Superior A Magpie

17 Tuesday, January 28, continued

WORKSHOP • Columnar Interac- tions in Neural Computation A. Wang Roe, N. Swindale, M. Tanifuji, C. Hung, L. Cohen Superior B

Wednesday, January 29

7:30–9:30 AM PANEL • Cellular Mechanisms of Pathogenesis in Models of PANEL • Used and Improved: Huntington’s Disease Activity and Its Role in Growing E. Schweitzer, V. Wheeler, New Connections in the S. Finkbeiner, L. Ellerby Developing and Adult CNS Superior A M. Chesselet, H. Cline, J. Goldberg, L. Boulanger, PANEL • Understanding Pain: New T. Carmichael Mechanisms and Novel Therapies Ballroom 1 D. Fink, T. Morrow, L. Sorkin, PANEL • Novel Presynaptic Actions M. Pohl␣ of Drugs of Abuse and Neuromodulators Superior B J. Weiner, C. Valenzuela, A. Bonci, C. Lupica 3:30–4:30 PM Magpie POSTER SESSION and EXHIBITS PANEL • New Technologies for an Ballroom 2–3 Integrated Investigation of the Human Genome, Transcriptome, and Proteome 4:30–6:30 PM T. Hyde, W. Freed, T. Vasicek, PANEL • Modulation and Expres- N. Dovichi, C. Colantuoni sion of Long and Short-Term Plasticity of CNS Synapses Wasatch D. Madison, J. Montgomery, PANEL • How Do Persistent Inward L. Dobrunz, L. McMahon Currents Affect the Motor System’s “Final Common Path”? Ballroom 1 M. Binder, R. Brownstone, PANEL • The Role of Inhibition in C. Heckman, R. Powers Striatal Function Maybird D. Plenz, P. Bolam, A. Blackwell, J. Tepper, J. Wickens Magpie

18 PANEL • Intraneuronal PANEL • The Secret Life of Mito- Cytoskeletal Inclusions: Cause chondria or Consequences? Good or V. Dawson, G. Fiskum, Bad? I. Reynolds, G. Rintoul␣ K. Topp, J. Garner, M. Smith, Superior B S. Gunawardena Wasatch 6:30–7:30 PM PANEL • Mood Disorders: The Search for Candidate Genes BUSINESS MEETING and and Pathways ELECTIONS S. Potkin, W. Bunney, Ballroom 1 E. Gershon, T. Young, J. Kelsoe Maybird 8 PM PANEL • Processing of Afferent (after business meeting) Information in a Circadian SPECIAL PANEL • Setting the Clock Nation’s Research Priorities: E. Albers, C. Colwell, Neuroscience’s Piece of the Pie D. Earnest, L. Morin K. Olsen, C. Atwell, A. Leshner, Superior A M. Rasenick Ballroom 1

Thursday, January 30

7:30–9:30 AM PANEL • The Many Faces of Protein Kinase Modulation of PANEL • Evaluation of Addiction NMDA Receptors and Depression Phenotypes M. Salter, M. Browning, Resulting from Single Gene J. MacDonald Mutations Wasatch J. Blendy, R. Maldonado, S. Heinrichs, B. Caldrone PANEL • Functional Roles of Identified Kv Potassium Ballroom 1 Channel Subunits in Neurons PANEL • To Turn or Not to Turn: R. Foehring, A. Ribera, Extrinsic and Intrinsic Regula- J. Surmeier, L. Kaczmarek, tors of Stem-Cellness J. Trimmer S. Levison, S. Goldman, Maybird D. van der Kooy, G. Fishell, S. Becker-Catania Magpie

19 Thursday, January 30, continued

PANEL • Trophic Factor Therapy: PANEL • Spatial and Dynamic What Works and What Does Influences on Coincidence Not? Detection of Synaptic Inputs D. Gash, B. Hoffer, M. Traub, W. Spain, M. Scanziani, M. Tuszynski M. Hausser, D. Heck Superior A Maybird PANEL • Glomeruli: Dynamic PANEL • When Bad Things Happen Portals into the Olfactory Brain to Good Brains: The Contribu- M. Ennis, L. Cohen, R. Friedrich tion of Mitochondrial Dysfunc- tion to Neural Cell Injury Superior B Following Hypoxic/Ischemic Events 3:30–4:30 PM E. Jonas, L. Dugan, S. Hewett, POSTER SESSION and EXHIBITS D. Nicholls Ballroom 2–3 Superior A PANEL • AMPA and NMDA 4:30–6:30 PM Receptors: From Synaptic Plasticity to Drug Abuse PANEL • Molecular Mechanisms A. Bonci, D. Ron, J. Gutlerner, for Postsynaptic Plasticity at C. Paladini Excitatory Synapses Superior B D. Bredt, K. Roche, P. Worley, V. Maricq Ballroom 1 8:30–10 PM PANEL • Neurobiology of ADHD: PANEL • CREB, Plasticity, and What Do We Know, What Do We Behavior Need to Know? D. Ron, S. Finkbeiner, C. Berridge, M. Solanto, W. Carlezon, S. Patterson, X. Castellanos, R. Kuczenski, P. Janak B. Waterhouse Ballroom 1 Magpie PANEL • The Role of Ventral PANEL • Hot Acid, Triple Phos- Striatum in Goal-Directed phate and Chronic Pain: Behavior and Response Vanilloid, ATP- and Voltage- Selection Gated Cation Channels in G. Schoenbaum, A. Kelley, Nociception J. Parkinson, S. Floresco, G. Wilcox, J. Wood, B. Setlow A. Oaklander, S. Lawson, Magpie M. Iadarola Wasatch

20 WORKSHOP • Distributed Neural WORKSHOP • Hemichannels in Coding: Facts and Fiction glia? Fishing for Function E. Keller, A. Schwartz, L. Young, R. Dermietzel, D. Spray, D. Guitton B. Ransom, M. Nedergaard Wasatch Superior A WORKSHOP • A Requiem for WORKSHOP • All Species Are Not Amyloid Beta? Created Equal: Differential J. Joseph, M. Smith, D. Morgan, Responses to Neural Damage A. Butterfield, P. Coleman G. Meredith, K. Gale, Maybird G. Arbuthnott, T. Napier, P. Sullivan Superior B

Friday, January 31

7:30–9:30 AM PANEL • CNS Zn2+: New Insights into Physiologic and Patho- PANEL • The Serotonin-2C physiologic Roles Receptor: Structure, Function, J. Weiss, S. Sensi, I. Reynolds, and Interactions with Dopam- C. Frederickson, X. Huang ine Systems Maybird E. Pehek, K. Herrick-Davis, L. Mignon, K. Cunningham, PANEL • Nonlinear Integration of L. Tecott Synaptic Input in Cortical Neurons Ballroom 1 H. Robinson, S. Williams, PANEL • Blue to White Collar: M. Larkum, M. Häusser The Evolving Role of Glia in Neurotransmission Superior A P. Kalivas, V. Parpura, R. PANEL • Gene Expression Analyses Bergeron, R. Schwarcz in the Mammalian Brain: Technologies and Objectives Magpie B. Meurers, F. Kamme, B. Liss, PANEL • Signaling Life and Death G. Eichele in NGF-Dependent Neurons Superior B R. Freeman, P. Barker, M. Deshmukh, M. Wooten Wasatch 4:30–6:30 PM PANEL • The Biological Clock: A Timely Update R. Baler, M. Rollag, D. Virshup, M. Reick Ballroom 1

21 Friday, January 31, continued

PANEL • From Phenotype to PANEL • Locus Coeruleus Efferent Function: The Role of GABA in Actions: Recent Findings, New CNS Development Hypotheses B. Sieber, S. Anderson, J. B. Waterhouse, K. Simpson, Huang, S. Tobet, J. Nunez D. Devilbiss, C. Berridge Magpie Superior A PANEL • The Role of Experience on PANEL • Expanding Beyond Gut Recovery of Function Feelings F. Gomez-Pinilla, T. Schallert, G. Gebhart, M. Gold, T. Jones, J. Kleim K. Westlund-High, G. Wilcox Wasatch Superior B PANEL • Glutamate Transporters: From Pharmacology to 7:30 PM Physiology BANQUET AND DANCE M. Robinson, R. Bridges, Ballroom M. Kavanaugh, A. Brooks-Kayal Maybird

Don’t forget to visit the exhibit area.

22 Poster Session 1 • Ballroom

Posters will be available for viewing from Sunday afternoon through Tuesday. Poster presenters with odd numbers will be available at their posters on Monday from 3:30–4:30 PM. Poster presenters with even numbers will be available at their posters on Tuesday from 3:30–4:30 PM. 1. Sharon Anderson Antagonism of Dopamine Receptors in the Nucleus Accumbens Shell Attenuates Cocaine-Priming Induced Reinstatement of Drug-Seeking Behavior 2. Ausaf Bari The Role of Nucleus Accumbens Dopamine Receptor Subtypes in Processing Cocaine Reward 3. Michael Brenner GFAP Mutations in Alexander Disease 4. Linda Bristow In vitro Characterization of a Selective, Metabotropic Glutamate Receptor 2 (mGluR2) Positive Modulator 5. Robert Burke Simulation of Short-Term Synaptic Depression in Two Different Synaptic Systems 6. Idil Cavus Modulation of Hippocampal Neurochemistry and Synchrony with Cognitive Tasks 7. Elena Chartoff Effect of D1 Dopamine Receptor Activation During Withdrawal from Chronic Morphine: Enhanced Camp-Mediated Signaling in vitro and Decreased Conditioned Place Aversion in vivo 8. James Chou Racial Differences in Pharmacokinetics of Risperidone: Genetic and Environmental Factors 9. Duff Davis In vivo Calcium Oscillations in the Rat Striatum Are Regulated by Nigrostriatal Dopamine Inhibitory and Prefrontal Cortical Excitatory Inputs

23 10. Michael Egan The BDNF val66met Polymorphism Affects Activity-Dependent Secretion of BDNF and Human Memory and Hippocampal Function 11. Greg Gerhardt GDNF Increases Stimulus-Evoked Dopamine Release and Motor Speed in Aged Rhesus Monkeys 12. Roland Ghanem Serotonin as Likely Mediator in Human Asthma 13. Greta Ann Herin Evidence for an Interaction Between N-terminal Redox Sensitive Cysteines and a Polyamine Modulatory Site of the NR1/NR2A NMDA Receptor 14. Henry Holcomb Visual Encoding Dysfunction in Schizophrenic Patients Before and After Perceptual Training 15. Bruce Hope Fos as a Marker of Sensitized Neurons in the Rat Accumbens Following Behavioral Sensitization to Cocaine or Amphetamine 16. Satoshi Ikemoto

Microinjections of the GABAA Antagonists Picrotoxin or Bicuculline into the Posterior Hypothalamus Are Rewarding 17. Hank Jedema Direct Action of Corticotropin-Releasing Hormone on Locus Coeruleus Neurons Recorded in vitro 18. Claudia Kappen A Unique Enhancer in Midbrain Stem Cells and its Transcriptional Regulation: Implications for the Fate and Specification of Dopaminergic Neurons 19. Ingo Kleppe Changes in the Input-Output Relationships of Cortical Synaptic Connections During Natural Patterns of Activation Following STDP 20. Scott Krahl Identification of a Satisfactory Animal Model to Study Radiosurgery for Epilepsy 21. Christopher Lapish Fast Neurotransmission in the VTA to PFC Pathway

24 22. Christian Lee Pallidal Control of Nigral Dopaminergic Neuron Firing Pattern and Its Relation to Extracellular Striatal Dopamine 23. Daniel Leszkiewicz A Role for the Redox Site in the Modulation of the NMDA Receptor by Light 24. Stephanie Licata Ionotropic Glutamate Receptors, L-type Calcium Channels and Calcium/ Calmodulin-Dependent Protein Kinase II in the Ventral Tegmental Area Are Critical for the Initiation of Cocaine-Induced Behavioral Sensitization 25. John Mendelson Selegiline Blocks Cocaine-Induced Increases in Urinary MHPG-Sulfate Excretion 26. Kim Neve Critical Factors in D1/D2 Receptor Selective Binding of Ligands 27. Emmanuel Pothos The Cholecystokinin-B Receptor is Expressed on and Regulates Quantal Size in Catecholamine Releasing Cells 28. Gabriele Schilling Role of Nuclear Aggregates in the Pathogenesis of Huntington’s Disease in Transgenic Mouse Models 29. Judith Siuciak The Activity of Pramipexole in the Mouse Forced Swim Test is Mediated by D2 Rather Than D3 Receptors 30. Heather Trantham-Davidson Dose Responsiveness of DA Modulation of Inhibition in Prefrontal Cortex: Differential Activation of D1 and D2 Receptors 31. Erica Unger Decreased Serotonin Transporter Expression Prevents Age-Related Serotonergic Fiber Loss in the Forebrain 32. Clifford O. James Novel Method of Interrogating Brain Function Independent of Instruction or Overt Response Applied to Non- and Clinical Populations

25 Poster Session 2• Ballroom

Posters will be available for viewing from Wednesday through Friday morning. Poster presenters with odd numbers will be available at their posters on Wednesday from 3:30–4:30 PM. Poster presenters with even numbers will be available at their posters on Thursday from 3:30–4:30 PM.

1. Gary Bassell The Localization of b-ACTIN mRNA in Dendrites Is Dependent on Zip Code Binding Protein-1 and Provides a Mechanism to Regulate Filopodial and Spine Growth in Cultured Hippocampal Neurons

2. Margery Beinfeld The Distribution and Co-Localization of Cholecystokinin with the Prohormone Convertase Enzymes PC1, PC2, and PC5 mRNA in Rat Brain

3. Brook Brouha Active L1 Retrotransposons in the Human Genome

4. David Carr G-Protein Coupled Receptors Modulate Na+ Channel Gating by Promoting Entry into a Slow Inactivated State: A Novel Form of Activity- Dependent Plasticity

5. David Chapman Differential Incorporation of NR2 Subunits into Striatal NMDARs: Different Biophysic and Pharmacologic Properties across Striatal Subregions and Development

6. A. D. (Bud) Craig Lamina I Provides “Labeled Lines” for First Pain, Second Pain, Cool, Warm, Itch, and Muscle Sensations

7. Jason Dictenberg mRNA Localization in Neurons Involves Formation of a Putative mRNP Complex with Two RNA-Binding Proteins and Kinesin

8. Robert Donahoe Monkey Studies Indicate Bidirectional Regulation of AIDS Progression by Opiates

9. Denson Fujikawa Spontaneous Neuronal Apoptosis in the Adult Rat Brain

26 10. Ronald L. Hayes CSF Accumulation of Calpain-Specific αII-Spectrin Breakdown Products Correlate with Injury Magnitude and Lesion Volume after Traumatic Brain Injury in Rats

11. Shraga Hocherman Quantitative Relationship between Visuo-Motor Coordination and Dopaminergic Innervation of the Striatum Is Revealed by SPECT Imaging

12. Kristen Horner Neuropeptide mRNA Expression in Striatum, Psychostimulants, and Serotonin

13. George Jaskiw Tyrosine Availability Affects Haloperidol-Induced Catalepsy and Striatal Dopamine Release: Studies in Tyrosine Augmentation and Depletion

14. Thomas Jerrells Activation of the HPA Axis with the Resulting Production of Corticosterone Provides Protection of FAS and TNF-Mediated Liver Damage

15. Sergei Kirov The Homeostatic Regulation of Dendritic Spine Number by Synaptic Transmission is Age-Dependent

16. Paul Kullmann A Fast Dynamic Clamp Built with LabVIEW-RT

17. Antonieta Lavin Stimulation of the VTA Evokes Depolarizing States in the PFC

18. Kanghyun Leem Protective Effect of New Medicinal Decoction on Focal Cerebral Ischemia of Rat

19. Bruce MacIver Enhanced GABA-Mediated Inhibition is Necessary for IV Agents but Not for Inhalation Anesthetics

20. David Marcus A New Model for Alzheimer’s Disease: Activation of Apoptosis by Brain c-Fos and c-Jun by Beta Amyloid Employing the Acute Slice Explant Technique

27 21. Mark Mennemeier Bridging Neuroscience and Psychophysics: Heteromodal Association Cortex Is a Critical Component of S.S. Stevens’ Power Law.

22. Ronald Meyer In vivo Imaging of Regenerating Optic Fibers in Adult Goldfish: Adverse Effect of Low Density and BDNF

23. Paul E. Phillips Subsecond Dopamine Release Promotes Cocaine Seeking

24. Charles Pluto The Role of Development in Cortical Reorganization of Rats That Sustained Forelimb Removal

25. Jung-Chul Seo Apo-1/Fas Promoter Polymorphism in Korean Stroke Patients

26. Ralph Siegel Independent Component Analysis of Intrinsic Optical Signals for Gain Fields in Inferior Parietal Cortex of Behaving Monkey

27. Heinz Steiner Repeated Methylphenidate Treatment During Rat Adolescence: Effects on Gene Regulation by Cocaine in the Striatum

28. Ramon Trullas Signal Transduction Pathways Involved in Programmed Cell Death and Neuronal Pentraxin 1 Overexpression in Cerebellar Granule Cells

29. Gary Wenk Inflammation in Alzheimer’s Disease: Its Role and an Opportunity for Therapy

30. Diek Wheeler Dynamic-Clamp Tests of a Theory of Synaptic Gain

31. Byron Yoburn Regulation of Trafficking Proteins and µ Opioid Receptors in the Mouse Spinal Cord

32. Elmer Yu An In-Patient Phase I/II Study of Lofexidine (Alpha-2 Adrenergic Agonist) for Opiate Detoxification

28 Poster Abstracts

Abstracts are in alphabetical order by the presenter’s last name. Presenters are signified by an *

Antagonism of Dopamine Receptors in the Nucleus Accumbens Shell Attenuates Cocaine-Priming Induced Reinstatement of Drug-Seeking Behavior S. M. Anderson*, A. A. Bari and R. C. Pierce A growing literature indicates that increased dopamine transmission in the nucleus accumbens contributes to priming-induced reinstatement of cocaine-seeking behavior. However, some evidence suggests that D1 and D2- like dopamine receptors differentially mediate reinstatement to drug-seeking behavior. The present experiments were designed to assess the role of D1 dopamine receptors in the nucleus accumbens core and shell in cocaine priming-induced reinstatement of cocaine-seeking behavior. Rats were trained to lever press for cocaine using a fixed ratio 5 schedule of reinforcement. After stable responding of cocaine self-administration was achieved, the animals underwent an extinction phase during which saline was substituted for cocaine. Following the extinction period, the ability of systemically administered cocaine to induce reinstatement of drug seeking behavior was assessed. Cocaine dose-dependently reinstated cocaine seeking, with robust drug seeking at 10 mg/kg cocaine. Administration of the D1 dopamine receptor antagonist, SCH-23390 (0.1-1.0 µg), directly into the medial nucleus accumbens shell dose-dependently attenuated drug seeking induced by 10 mg/kg cocaine. In contrast, microinjection of 1.0 µg SCH- 23390 into either the nucleus accumbens core or lateral septum had no influence on drug-seeking behavior. These results indicate that dopamine D1 receptors in the accumbal shell, but not the accumbal core, contribute to cocaine-induce reinstatement of drug-seeking behavior.

The Role of Nucleus Accumbens Dopamine Receptor Subtypes in Processing Cocaine Reward A. A. Bari*, R. C. Pierce An important role for nucleus accumbens dopamine receptors in cocaine reinforcement is supported by previous studies showing that microinjections of dopamine antagonists into the nucleus accumbens decrease responding for cocaine on fixed ratio schedules of reinforcement. Here, we used intracerebral microinjection and a progressive ratio schedule to study the role of dopamine receptors and a second messenger associated with these receptors in cocaine reinforcement. We microinjected adult, male

29 Sprague Dawley rats with dopamine receptor antagonists or the MAP kinase inhibitor PD98059 using a counterbalanced repeated measures experimental design. We found that, relative to saline, microinjection of the dopamine D1 receptor antagonist SCH-23390, the D2/3 receptor antagonist sulpiride or the D2 receptor antagonist eticlopride into the nucleus accumbens lowered the breakpoint on a progressive ratio schedule for intravenous cocaine. Intra-accumbal microinjection of the MAP kinase inhibitor PD98059 lowered the breakpoint to a lesser extent than the dopamine receptor antagonists. These results indicate that both D1- and D2-like dopamine receptors in the nucleus accumbens mediate the reinforcing efficacy of cocaine. The present findings also suggest that the MAP kinase second messenger pathway is involved in nucleus accumbens reward circuitry.

The Localization of b-ACTIN mRNA in Dendrites is Dependent on Zip Code Binding Protein-1 and Provides a Mechanism to Regulate Filopodial and Spine Growth in Cultured Hippocampal Neurons T.Eom, H.L.Zhang, R.H. Singer, G.J. Bassell* The regulated transport of b-actin mRNA in developing dendrites of hippocampal neurons may influence spine and synapse growth. Using double label fluorescence in situ hybridization and immunofluorescence, b-actin mRNA and ZBP1 were colocalized in granules within dendrites, filopodia and spines. To investigate the molecular mechanism of b-actin mRNA localization in hippocampal dendrites, we have cloned and sequenced the rat homolog of chicken Zipcode Binding Protein, ZBP1, that was previously shown to bind the b-actin mRNA zipcode in cultured fibroblasts and forebrain neurons from chick embryos. ZBP1 from rat hippocampus has 95% homology to chick ZBP1. Transfection of rat ZBP1 fused to EGFP revealed granules that exhibited fast, bi-directional movements within dendrites. Transfections of truncated rZBP1 constructs demonstrated that RNA binding domains were necessary but not sufficient for granule transport. ZBP1 from hippocampal neurons was shown to bind the b-actin zipcode in vitro and in vivo. Knockdown of rZBP1 in cultured hippocampal neurons using antisense oligonucleotides decreased b-actin mRNA localization and impaired filopodial growth. Over-expression of EGFP/b-actin resulted in growth of spines that was dependent on the b-actin zipcode. These results suggest a novel mechanism to influence actin dynamics and spine development that involves the dendritic transport of a RNA-protein complex.

30 The Distribution and Co-Localization of Cholecystokinin with the Prohormone Convertase Enzymes PC1, PC2 and PC5 mRNA in Rat Brain B. M. Cain, K. Connolly, A. Blum, D. Vishuvardhan, J. Marchand, M. C. Beinfeld* During post-translational processing, pro-CCK undergoes endoproteolytic cleavage. The enzyme(s) responsible for the processing of CCK in the brain have not been definitively identified, but a number of studies suggest that the subtilisin/kexin-like enzymes prohormone convertase (PC) 1, PC2 and PC5 are good candidates. Analysis of PC2 knockout mice indicated that PC2 is important for normal CCK processing, but in its absence, substantial amounts of processed CCK were detected. The degree to which CCK levels were altered was regionally-specific. It is likely that PC2 is not the only enzyme that is involved. In order to evaluate whether PC1 and PC5 are possible candidates for the other enzymes involved in CCK processing, double label in situ hybridization for CCK and the enzymes was performed in rat brain. PC2 is the most abundant of these enzymes in terms of its mRNA content and was widely co-localized with CCK. PC1 and PC5 mRNA was less abundant, but they were also widely co-localized with CCK. It is clear that PC1 and PC5 could be participating in CCK processing the rat brain and may be able to substitute for PC2 in its absence. These enzymes may represent a redundant system to insure production of biologically active CCK.

GFAP Mutations in Alexander Disease M. Brenner*, R. Li, J. Goldman, V. Hsiao, A. Messing Alexander disease is a rare but usually fatal neurological disorder. In its most common, infantile form, it presents with impaired physical and mental development, seizures and megalencephaly. The pathological hallmark of the disease is the widespread presence in astrocytes of protein aggregates, termed Rosenthal fibers. We have discovered that mutations in the coding region of the GFAP gene are responsible for most cases of the infantile form of Alexander disease, and we and others have extended these findings to cases with later onset. This is the first description of a disease due to mutations in GFAP, as well as the first example of a disorder arising from a primary defect in astrocytes. All the GFAP mutations are heterozygous missense changes. Alexander disease apparently results from a dominant gain of function, as GFAP null mice are fully viable. This is in contrast to other intermediate filament diseases, which have been attributed to a dominant loss of function. Nevertheless, many of the GFAP mutations are homologous to ones found in these other diseases, suggesting a shared causality due to defective filament assembly. In addition to sequencing studies, we are investigating the functional consequences of the GFAP mutations. The properties of one of the most com-

31 mon and severe GFAP mutations, R239C, have been examined by transfect- ing intermediate filament-negative SW13Vim- cells with vectors expressing either the wild type or mutant GFAP. Whereas the wild type GFAP formed normal appearing filaments, the R239C mutant yielded only diffuse and ir- regular patterns of GFAP staining.

In vitro Characterization of a Selective, Metabotropic Glutamate Receptor 2 (mGluR2) Positive Modulator L.J. Bristow*, H. Schaffhauser, L.E. Chavez-Noriega, B. Rowe, R. Yin, A. Pinkerton, J.M. Vernier, M.A. Varney The group II mGlu receptor agonist, LY354740, is a constrained glutamate analog which binds with similar affinity to the glutamate recognition site on both the mGluR2 and mGluR3 receptors. In preclinical animal models LY354740 has a profile suggestive of antipsychotic and anxiolytic activity although the group II mGlu receptor subtype mediating these effects is unclear. Recently the selective mGluR2 positive modulator N-(3-(2- methoxyphenoxy)-phenyl-N-(2,2,2-trifluoroethylsulfonyl)pyrid-3-ylmethylamine (LY487379) was identified and we have characterized this compound in vitro. LY487379 had no intrinsic agonist activity but potentiated glutamate-stimulated [35S]-GTPgammaS binding to recombinant hmGlu2 receptors (EC50 = 1.5 micromolar) and rat brain membranes (EC50 = 3 micromolar), shift- ing the glutamate dose response curve leftward by 3 fold and increasing the maximum levels of [35S]-GTPgammaS stimulation. In rat hippocampal slices, co-application of LY487379 potentiated the DCG-IV-mediated inhibition of medial perforant path-evoked fEPSPs with an EC50 of 4.2 micromolar. Furthermore, co-application of LY487379 (3 micromolar) shifted the DCG-IV concentration response curve 3 fold to the left (IC50 = 32 nanomolar versus 92 nanomolar for DCG-IV alone) and the effects of combined application of LY487379 + DCG-IV were blocked by the mGluR2/3 antagonist LY341495. These data confirm that, in both recombinant cell lines and na- tive tissue preparations, LY487379 selectively potentiates the effects of glutamate at mGluR2 receptors.

Active L1 Retrotransposons in the Human Genome B. L. Brouha*, R. M. Badge, J. A. Schustak, J. V. Moran1, H. H. Kazazian Though most are inactive, L1 retrotransposons comprise 17% of the human genome. There are 14 known cases of an insertion causing disease. Full-length L1s are ~6kb and move by a copy and paste mechanism. Ac- cording to Boissinot et al, (2000), the non-Ta category, characterized by GAG at L1 positions 5926-8, is the oldest L1 family. The pre-Ta family, with ACG at these positions, is the next oldest and the Ta family, with ACA, is the youngest. The Ta family is subdivided, from oldest to youngest, into Ta-0, Ta-1nd, and Ta-1d subfamilies. We isolated all 89 potentially active L1s (full length with 2 intact ORFs) from the sequenced human genome. Three of the 89

32 elements were non-Ta, 26 were pre-Ta, 60 were Ta, and 2 did not fall into any category. Of Ta elements, 17 were Ta-0 elements, 1 was a Ta-0/Ta-1 intermediate, 3 were Ta-0 elements with the Ta-1d deletion, 16 were Ta-1nd, and 21 were Ta-1d. We tested 81 of the 89 elements for presence in 23 individuals from 5 ethnic groups and found 37 were not fixed in the population, making them useful phylogenetic markers. Putative younger elements tended to be rarer than older ones. To date, 46 of the 89 have been cloned and assayed in cell culture for retrotransposition activity relative to L1RP (a highly active element). We found activity for 4 of 13 pre-Ta elements (average activity 2.6% of L1RP); 6 of 11 Ta-0 (1.9% of L1RP); 4 of 9 Ta-1nd (3.4% of L1RP); and 9 of 12 Ta-1d (24.75% of L1RP). Putative younger elements had higher average activities and greater variation in activity. Extrapolation by category indicates that 45 of the 89 elements will be active. With a finished genome we expect about 48 active elements per haploid genome or 96 in the diploid genome. This work triples the number of known active human L1s from 10 to 34. Upon completion, we will know the number, genomic location, activity level, and polymorphism information content of all active L1s in the sequenced human genome. The data provide further evidence that L1s continue to retrotranspose, causing genomic expansion and inser- tional mutagenesis.

Simulation of Short-Term Synaptic Depression in Two Different Synaptic Systems R. E. Burke*, Y. Li, S. Oleskevich, and B. Walmsley We have compared short-term in vitro synaptic depression in two anatomically different systems in neonatal mice: 1) whole-cell recordings of glutamatergic EPSCs produced in AVCN bushy cells in mouse (P13) brainstem by giant endbulb of Held synapses; and 2) monosynaptic glutamatergic EPSPs in motoneurons in mouse (P2-12) lumbar spinal cord by dorsal root (group Ia) afferents. We examined paired-pulse and steady- state depression, as well as post-depression recovery curves. Data from both types of synapse were well fitted with a quantitative model of neurotransmitter release which assumes that there are two depleting presynaptic compartments (readily-releasable transmitter: RRT; and release-ready release sites: RRRS) with independent renewal time constants, plus two processes that enhance transmitter release (Li and Burke, J. Neurophysiol. 85:2047, 2001). Both synaptic systems exhibit large baseline release fractions (0.2– 0.5) and relatively slow time constants (2–7 s) of RRT renewal. However, the time constants for RRRS renewal were very different: 15 to 250 ms for the end bulb versus 1.5–4 s for group Ia synapses. The parameters for the two enhancement processes were similar in the two systems. The ability of the model to predict release properties in two very different synaptic systems suggests that it may have general applicability to short-term modulation at central synapses.

33 G-Protein Coupled Receptors Modulate Na+ Channel Gating by Promoting Entry into a Slow Inactivated State: A Novel Form of Activity-Dependent Plasticity D. Carr* We have shown that 5HT2 stimulation reduces both rapidly inactivating and persistent Na+ currents in PFC pyramidal neurons. This effect was partly mediated by a negative shift in the voltage dependence of fast inactivation, however another mechanism was also involved. In addition to fast inactivation, Na+ channels undergo an inactivation process with much slower development and recovery kinetics. We have investigated whether 5HT stimulation enhances entry of Na+ channels into this slow inactivated state. Recovery of Na+ currents from inactivation following prolonged depolarizations (5 s) exhibited both fast (~ 20 ms) and slow (~ 5 s) components. 5HT2 receptor stimulation (1) accelerated entry of Na+ channels into the slow inactivated state (2) shifted the voltage dependence of slow inactivation toward more negative potentials and (3) increased the maximal fraction of Na+ channels entering into this state. To examine whether enhanced entry into slow inactivation is the mechanism responsible for the attenua- tion of Na+ currents by 5HT2 receptors, cells were held at potentials that were either permissive (-70 mV) or non-permissive (-100 mV) for entry into slow inactivation. When cells were held at ˆ100 mV 5HT2 stimulation did not significantly affect either rapidly inactivating or persistent Na+ currents. When the same cells were held at ˆ70 mV, both components were significantly reduced by 5HT2 stimulation. We obtained similar results by stimulation of PKC or PKA indicating that enhancing entry of Na+ channels into slow inactivation may be a ubiquitous mechanism of action for suppres- sion of Na+ currents by these signaling pathways.

A Microdialysis and Depth Electrode Study of Awake Behaving Humans I. Cavus*, W. M. Abi-Saab, H. Zavery, M.Cassaday, D.D.Spencer, J.Krystal Evidence from animal research indicates that cognitive processing is associated with increased release of certain neurotransmitters, turnover of energy substrates and modulation of the brain oscillatory activity. In this study we used in vivo microdialysis and simultaneous depth electrode recordings in the hippocampi of awake behaving humans to study the effect of cognitive stimulation on the neurochemical efflux and electrophysiological activity. Methods: Sixteen patients with medically intractable temporal lobe epilepsy undergoing invasive intracerebral EEG evaluation prior to surgical treatment were studied. Microdialysis probes attached to depth electrodes were placed in the hippocampus. Samples were collected every 2 min during the performance of cognitive tasks (the complex figure task, CFT and the verbal selective response task, VSRT). The dialysates were analyzed for glutamate, GABA, glucose and lactate levels with HPLC.

34 Intrahippocampal EEG (iEEG) recordings from contacts adjacent to the microdialysis probes were analyzed for total power, theta and gamma band responses. The results from the epileptic focus and the relatively healthy tissue were also compared. Discussion: We used in vivo microdialysis in conscious epileptic subjects to measure the changes in the extracellular neurotransmitter (glutamate and GABA), energy metabolite (glucose and lactate) levels and the iEEG recordings to analyze the changes in the EEG power spectrum during performance of a visuospatial (CFT) and verbal memory task (VSRT). In the non-epilep- togenic hippocampal areas, cognitive stimulation with either tasks resulted in increase in the glutamate efflux. The glutamate efflux was largest during the copy (information encoding) phase of the CFT. Glucose increased with the immediate recall phase, followed by an increase in the lactate, during the delayed recall phase. GABA levels remained unchanged. In parallel, the total and theta band hippocampal EEG power decreased during the copy phase of the task, suggesting a neuronal activation related- desynchronization in the EEG. The increase in glutamate during this phase was inversely correlated with the performance success in the task. In the epileptic hippocampal focus the cognitive stimulation resulted in much larger and prolonged glutamate and lactate elevations, coupled with glucose decrease and impaired hippocampal EEG modulation. During VSRT test, successful performance in the task was strongly correlated with a drop in the intrahippocampal EEG power, which was seen during the information encoding phase but not in the recall phase of the task. To our knowledge, this is the first study to provide us with unique information on the neurochemical and electrophysiological changes in the healthy and epileptic hippocampi in conscious human brain during information processing. Such information will be critical in our understanding of the neuronal substrates of cognition in the normal and diseased human brain.

Differential Incorporation of NR2 Subunits into Striatal NMDARs: Different Biophysic and Pharmacologic Properties Across Striatal Subregions and Development D. E. Chapman*, K. A. Keefe, K. S. Wilcox N-methyl-D-aspartate receptors (NMDARs) are comprised of different subunits. NR2 subunits confer different functional properties to NMDARs. Al- though NR2B subunit expression is uniform throughout striatum, NR2A subunit expression increases shortly after birth, and achieves greater levels laterally. To test the hypothesis that functional properties of NMDA receptor-mediated EPSCs (NMDAR-EPSCs) vary as a function of location in striatum and development, we recorded synaptic NMDAR-EPSCs using local minimal stimulation and whole-cell patch clamping of neurons in the dorsolateral and ventromedial striatum of postnatal day (P) 4-6 rat pups, and P40 and P100 adults. We observed that the decay-time kinetics of NMDAR- EPSCs were significantly slower in pups irrespective of cell location. In both

35 older groups, decay-time kinetics of NMDAR-EPSCs were faster in dorsolateral than in ventromedial striatum. Furthermore, NMDAR-EPSC kinetics were significantly faster in the P100 group than the P40 group. The NR2B-selective antagonist ifenprodil did not differentially affect NMDAR- EPSCs in striatal subregions at any timepoint, but it did more potently block NMDAR-EPSCs in P4-6 rats. However, in striatal slices from P40 rats, application of either glycine or D-serine increased the peak current of NMDAR- EPSCs selectively in dorsolateral striatum. These data suggest that spiny efferent neurons in dorsolateral and ventromedial striatum express pharmacolgically and biophysically distinct subtypes of NMDA receptors. These different NMDA receptors may contribute to differences in information processing in the dorsolateral (sensorimotor) and ventromedial (limbic) striatum.

Effect of D1 Dopamine Receptor Activation during Withdrawal from Chronic Morphine: Enhanced cAMP-Mediated Signaling in vitro and Decreased Conditioned Place Aversion in vivo E.H. Chartoff*, C. Konradi, W.A. Carlezon Chronic morphine exposure causes supersensitivity of adenylate cyclase activity in several brain regions, including the ventral striatum (nucleus accumbens [NAc]). Naloxone-precipitated morphine withdrawal is associated with increased cAMP levels and reduced dopamine release in the NAc, each of which may contribute to somatic and affective signs of morphine withdrawal. We hypothesized that selective stimulation of D1 receptors during morphine withdrawal would enhance cAMP-mediated signaling and increase withdrawal-associated behaviors. We tested this hypothesis using both in vitro and in vivo models of morphine withdrawal. First, we measured activation of cAMP response element binding protein (CREB) and induction of c-fos by the D1 receptor agonist, SKF 82958, in primary cultures of striatal neurons. As expected, we found each of these markers increased during naloxone-precipitated morphine withdrawal. Next, we tested the effects of systemic SKF 82958 on naloxone-induced conditioned place aversion in morphine-dependent rats. Surprisingly, we found that place aversions associated with low doses of naloxone were reversed to place pref- erences in the presence of SKF 82958. Considering that systemic SKF 82958 would be expected to have significant actions within the NAc, these results suggest that elevated CREB activity within this region is not always associated with states of dysphoria and anhedonia. As such, activation of D1 receptors during precipitated morphine withdrawal may counteract negative affective states under some circumstances.

36 Racial Differences in Pharmacokinetics of Risperidone: Genetic and Environmental Factors J. C.-Y. Chou*, Y. Choy, M. Serper, N. Richardson, A. DiCastro, R. Suckow Risperidone is the most commonly prescribed antipsychotic in the U.S, and it is often used for psychotic brain disorders including schizophrenia. The majority of clinical studies of this drug have used Caucasian subjects. Ra- cial differences in the pharmacokinetics and clinical response to risperidone have been little studied. One report of Chinese schizophrenic subjects in Taiwan found that the Chinese have a mean steady-state blood level/dose ratio 32% higher than that found in the North American pivotal random- ized clinical trials. The blood level dose ratio is important because while physicians prescribe a drug dose, the brain is only exposed to the available plasma concentration of the drug. In this report we treated 30 consenting acute schizophrenic inpatients at Bellevue Hospital in New York with risperidone. The subjects included 15 African-American patients and 15 Chinese-born patients now living in New York (American-Chinese). Risperidone was titrated according to a protocol identical to that used in the Taiwan report. Clinical symptoms were measured with the Positive and Negative Syndrome Scale (PANSS) and steady-state blood levels of risperidone and 9-OH risperidone were measured weekly. The optimal blood level of risperidone and 9-OH risperidone was determined based on maximal improvement on the PANSS. Two sets of analyses will be presented. First the optimal blood level/dose ratio for the African-American subjects will be compared to the North American data to identify potential genetic effects. Second, the optimal blood level/dose ratio for the American-Chi- nese will be compared to the Chinese in Taiwan to examine for environmental factors. The American-Chinese (living in NY) will also be compared to the North American data to examine for principally genetic effects.

Lamina I Provides “Labeled Lines” for First Pain, Second Pain, Cool, Warm, Itch, and Muscle Sensations A.D. (Bud) Craig* Work in this laboratory over the past decade has identified distinct classes of spinal lamina I neurons that receive input from specific subsets of small- diameter primary afferents and display different stimulus-response characteristics, morphological shapes, ascending projections, descending controls, ongoing discharge rates and axonal conduction velocities. The response properties of these cell classes match the psychophysical characteristics of the distinct sensations of pain, temperature, itch and other feelings that relate the physiological condition of the material body. The projection of these sensory channels in the lateral spinothalamic tract to posterolateral thalamus and thence to the dorsal posterior insular cortex matches clinical lesion and human functional imaging data. These findings recommend a re-definition of “interoception” as the sensory representa-

37 tion of the state of the entire body, not just the viscera, and they provide a new view of the neural representation of pain sensations. An overview of these functional anatomical findings will be presented.

In vivo Calcium Oscillations in the Rat Striatum are Regulated by Nigrostriatal Dopamine Inhibitory and Prefrontal Cortical Excitatory Inputs M. D. Davis* Schizophrenia may arise as a consequence of increased dopamine tone and/ or decreased glutaminergic tone. In the striatum, dopamine imposes a predominantly inhibitory influence on medium spiny neurons (MSNs), while glutaminergic input promotes MSN cell firing. We studied these opposing systems in vivo by monitoring striatal [Ca+2]i flux in vivo as an index of MSN activity following cortical and NSP stimulation and pharmacological challenge. Male Sprague Dawley rats were intra-striatally implanted with a 200µm diameter fiber-optic probe (optrode). The calcium indicator, Oregon- Green (OG)-AM, was infused to load intrinsic cells and the fluorescence due to Ca+2 binding with OG was captured by back-reflectance. A stimulating electrode placed in the MFB or cortex delivered 100µA current pulses for 0.5msec at 0.1-100Hz. Recordings revealed both stable [Ca+2]i baseline values as well as recurrent oscillations of about 1.5Hz, most probably originat- ing from GABAergic medium spiny neurons (MSNs). Stimulation of the MFB (1-10Hz) for 10sec resulted in a complete, reversible cessation of the oscillations. This stimulation-induced inhibition was blocked by fluphenazine (2m/kg iv) and enhanced following apomorphine (0.1mg/kg iv). In contrast, 10-100Hz stimulation of the frontal cortex initiated or potentiated the generation of calcium oscillations. Cortical stimulation effects were suppressed after MK-801 (0.1mg/kg iv) administration, or subsequent MFB stimulation. These results demonstrate an inhibitory action of dopamine, and an excitatory glutaminergic control over striatal MSNs. mRNA Localization in Neurons Involves Formation of a Putative mRNP Complex with Two RNA-Binding Proteins and Kinesin J.B. Dictenberg*, R. Afroz, J. Goldman, L. Antar, R.H. Singer, G.J. Bassell Subcellular localization of mRNAs and local protein synthesis are important mechanisms for process outgrowth and plasticity in neurons. Recent data suggests the function of RNA-binding proteins in mRNA transport may be linked to translational regulation. Beta-actin mRNA contains a 3‚UTR sequence (zipcode) that is bound by Zipcode Binding Protein (ZBP1) and translocates into neurites becoming concentrated at growth cones. We characterized a complex associated with beta-actin that contains ZBP1 and surprisingly, the Fragile-X Mental Retardation Protein (FMRP), an RNA-binding protein involved in localized mRNA translation. Sucrose gradients showed ZBP1 and FMRP co-sedimenting in polyribosomes, and by immunofluorescence both proteins colocalized in punctate granules within processes.

38 FMRP and ZBP1 association in vitro with taxol-stabilized microtubules was enhanced by AMP-PNP and released by ATP. FMRP and ZBP1 co-precipitated in a complex associated with kinesin heavy chain. Beta-actin was contained in kinesin light chain immunoprecipitates by RT-PCR, which could be competed away by the zipcode. Treatment of hippocampal cultures with antisense oligonucleotides directed against kinesin heavy chain disrupted ZBP1 and FMRP translocation into neurites and decreased levels of several dendritic mRNAs including beta-actin. As a result the normal organization of filamentous actin was disrupted in these cells, possibly accounting for the previously observed inhibition of neurite outgrowth.

Monkey Studies Indicate Bidirectional Regulation of AIDS Progression by Opiates R. M. Donahoe*, H. M. McClure, S. O’Neil, F. Novembre, P. Turner, Y. Wang AIDS virus infections represent an archetype psychoneuroimmune infection. Since intravenous opiate users are one of the largest risk groups for contraction and spread of AIDS, there has been considerable interest in knowing whether opiates influence progression of AIDS. Clinical and epidemiological data, and data from several pilot monkey studies equivocate on this issue. Examination of this matter in an ongoing, large, well-controlled monkey-study is showing that well-maintained opiate-dependency retards the progression of AIDS—in terms of both viral and immune parameters; and in the context of both somatic and neural aspects of progression. Evi- dence suggests that this retarding effect relates to the ability of homeostatically delivered opiates to reduce the levels of stress and stress hormone fluxes in SIV-infected monkeys. Preliminary data further suggest that withdrawal from opiates leads to exacerbation of stress, diminution of immune control, and enhancement of AIDS virus expression. Taken together, this information is indicative of potential bi-directional effects of opiates on AIDS progression. As such, these findings support the homeostatic hypothesis regarding the neuroimmune effects of opiates in AIDS while helping to explain why equivocal findings on the role of opiates in AIDS have been reported to date. Such data also offer promise for pharmacological manipulation of the neuroimmune system to combat AIDS and to intervene in other types of infectious processes caused by latent DNA- integrating viruses.

The BDNF val66met Polymorphism Affects Activity-Dependent Secretion of BDNF and Human Memory and Hippocampal Function M. F. Egan*, M. Kojima, J. H. Callicott, T. E. Goldberg, B. S. Kolachana, A. Bertolino, E. Zaitsev, B. Gold, D. Goldman, M. Dean, B. Lu, D. R Weinberger Animal studies suggest that brain derived neurotrophic factor (BDNF) regulates hippocampal-dependent memory. Here we investigated the effects of a human polymorphism producing a valine (val) to methionine (met) sub-

39 stitution in the 5‚ pro-region of the BDNF protein. Subjects with the met/ met genotype exhibited poorer performance in tests of episodic memory. Functional magnetic resonance imaging of two separate cohorts both revealed abnormal hippocampal activation during a cognitive task in subjects with a met allele. Furthermore, levels of n-acetyl aspartate (NAA), a putative in vivo measure of neuronal integrity and synaptic abundance, were lower in the hippocampal formation of subjects with met alleles. Rodent hippocampal neurons transfected with val-BDNF-GFP exhibited a punctate distribution pattern throughout the soma and dendrites, while those with met-BDNF-GFP showed large clusters in the peri-nucleus region. De- polarization-induced secretion of met-BDNF was significantly reduced while its constitutive secretion was unchanged. These results represent the first demonstration of a role for BDNF and its val/met polymorphism in human memory and hippocampal function, and suggest val/met exerts these effects by impacting activity-dependent BDNF secretion.

Spontaneous Neuronal Apoptosis in The Adult Rat Brain D. G. Fujikawa* Postnatal neuronal apoptosis in rats becomes negligible by the third postnatal week. In the adult rat brain, neuronal apoptosis has been induced by adrenalectomy and olfactory bulbotomy, but there is little information about spontaneous neuronal apoptosis. In postnatal day 7 rats, apoptotic neurons become diffusely TUNEL-positive, except for the large chromatin clumps. This is easily recognized by brighfield light microscopy, is caused by disruption of the nuclear membrane, and is contrary to the widespread belief that only nuclei are TUNEL-positive. We determined if similarly appearing apoptotic neurons are found in adult rat brain. Adult Wistar rats (n=7) underwent transcardiac brain perfusion-fixation, their brains were removed and left hemispheric slices were embedded in paraffin, sectioned coronally and stained with H & E, TUNEL, NeuN and TUNEL/NeuN. Sec- tions at the level of anterior olfactory nuclei (+5.20 mm from bregma), caudate-putamen (-0.3 mm), dorsal hippocampus (-3.3 mm), ventral hippocampus (-5.6 mm) and pons/cerebellum (-10.52 mm) were examined. Apoptotic neurons with the same appearance as in P7 rats were found in (in descending numbers of apoptotic neurons): neocortex, thalamus, anterior olfactory nuclei, caudate-putamen, amygdala, septal nucleus, entorhinal cortex, pons, hippocampal hilus, perirhinal cortex, piriform cortex, cerebellum and hippocampal CA1, with about 31% of the total (16 ± 1) in neocortex. The total number of apoptotic neurons were relatively few in number (51 ± 1, mean ± SEM, n=7, or 35 sections). Thus, apoptotic neurons with the same morphological characteristics as in P7 rats appear spontaneously in adult rat brain, with 31% in neocortex, suggesting that this form of neuronal death continues into adulthood.

40 GDNF Increases Stimulus-Evoked Dopamine Release and Motor Speed in Aged Rhesus Monkeys R. Grondin, W. A. Cass, Z. Zhang, J. A. Stanford, D. M. Gash, G. A. Gerhardt* Changes in the functional dynamics of dopamine release and regulation in the basal ganglia have been posited to contribute to age-related slowing of motor functions. Here, we report the effects of glial cell line-derived neurotrophic factor (GDNF) on stimulus-evoked release of dopamine and motor speed in aged monkeys (21-27 years old, n=10). While no changes were observed in the vehicle controls (n=5), chronic infusions of 7.5 mg GDNF/ day into the right lateral ventricle initially increased upper limb movement speed up to 40%, on an automated hand-reach task. These effects were maintained for at least two months after replacing GDNF with vehicle, and further increased up to 50% following reinstatement of GDNF treatment for one month. In comparison, upper limb motor performance times of the aged GDNF-treated animals (n=5) recorded at the end of the study were similar to those of five young adult monkeys (8-12 years old). Stimulus- evoked release of dopamine was significantly increased up to 130% in the right caudate nucleus and putamen, and up to 116% in both the right and left substantia nigra of the aged GDNF recipients compared to vehicle controls. Also, basal extracellular levels of dopamine were bilaterally increased up to 163% in the substantia nigra of the aged GDNF-treated animals. The data suggest that the effects of GDNF on the release of dopamine in the basal ganglia may be responsible for the improvements in motor functions, and support the hypothesis that functional changes in dopamine release may contribute to motoric dysfunctions characterizing senescence.

Serotonin as Likely Mediator in Human Asthma R. Ghanem* Patients with active asthma experience significant decrease in asthma symptoms associated with increased FEV1 values following immunovaccine treatment because plasma serotonin levels decrease rapidly during immunovaccine, it is postulated that serotonin may be playing a role in human asthma; I could find no confirmation of theses findings by other groups nor much mention, reported or published paper of serotonin as likely mediator. We followed patients in our clinic for a period of thirty years, and we monitored clinical symptoms related to change in plasma serotonin level following treatment with immunovaccine and compared the results to patients who were treated with different regimens. The signs we have checked include: very high and very low mood swings, anxiety/depression, hospi- talization, psychatricunits admittance, antidepressant/antihistamine Rx. among all the patients checked we found decrease of the level of mood swings, decreased depression/anxiety episodes, none needed hospitaliza- tion and improved quality of live. Compared to no change of the behavior of patients who choose different treatments. We concluded that

41 immunovaccine reduces plasma serotonin level which is thought to be increase serotonin uptake in platelets. It may function as antidepressant by lowering serotonin levels available to the CNS. Accordingly this finding might make serotonin a unique marker abd it is worth exploring.

CSF Accumulation of Calpain-Specific αII-Spectrin Breakdown Products Correlate with Injury Magnitude and Lesion Volume after Traumatic Brain Injury in Rats R.L. Hayes, N.C. Ringger*, X. Silver, B. O‚Steen, J.G. Brabham, S.M. DeFord, B.R. Pike, J. Pineda There are no definitive diagnostic tests of traumatic brain injury (TBI) to determine the magnitude of injury, the mechanisms of cellular pathology, or to guide appropriate therapeutic administration. We recently reported that calpain-specific αII-spectrin breakdown products (SBDPs) accumulate in CSF after TBI (J. Neurochem. 78: 1297-1306, 2001). However, correlations of SBDP levels with injury magnitude and outcome are not known. This study examined SBDP accumulation in brain and CSF at two levels of lateral controlled cortical impact TBI (1.0 mm and 1.6 mm) in rats at 2, 6, and 24 hours after injury. In addition, SBDP levels at each injury magnitude were correlated with rotarod performance on days 1-5 post-TBI, and with lesion volume at 28 days post-TBI (by T2-weighted MRI). Accumulations of SBDPs in brain and CSF were highest after 1.6 mm injury at all time points. Both 1.0 mm and 1.6 mm groups had significantly greater CSF levels of SBDPs than the uninjured control group. SBDP levels correlated with both rotarod performance and with lesion volume where each was greater after 1.6 mm injury than 1.0 mm injury. These data indicate that CSF levels of calpain-specific SBDPs are sensitive to injury severity and that acute levels of SBDPs in CSF correlate with more delayed measures of behavioral outcome and lesion volume. Thus, protease-specific SBDPs could have considerable utility as biochemical markers of acute CNS injury.

Evidence for an Interaction between N-terminal Redox Sensitive Cysteines and a Polyamine Modulatory Site of the NR1/NR2A NMDA Receptor G. A. Herin*, F. Zheng, P. Le, E. Aizenman The NMDA subtype of glutamate receptor is sensitive to reducing and oxi- dizing agents in a subtype specific-manner. Cysteines 744 and 798 on NR1a are responsible for most of the redox sensitivity of NR1a/NR2B and NR1a/ NR2C receptors. However, NR1a(c744a/c798a)/NR2A receptors remain sensitive to redox modulation. This has been attributed to cysteines in the amino terminal domain (ATD) of NR1 and NR2A. We have previously shown that 30uM spermine blocks the effects of DTT in NR1a(c744a,c798a)/NR2A receptors, in a tricine-insensitive manner. This suggests a zinc-independent effect of spermine on redox modulation at the N-terminal redox-sensitive cysteines. Evidence exists that spermine alone modulates NR1a/NR2B (but

42 not NR1a/NR2A) receptors via the N-terminal regulatory domain of NR1a. We hypothesized that spermine block of DTT potentiation in NR1a(c744a/ c798a)/NR2A could be modified by alterations of the ATD of NR1a. Muta- tion of cys79 in NR1a(c744a/c798a)/NR2A receptors resulted in a decrease of DTT potentiation of NMDA-induced currents, as reported earlier. In support of our hypothesis, the inhibitory actions of spermine on DTT potentiation were markedly attenuated in this construct. These results suggest an interaction between cys79 of NR1a and a spermine modulatory site in NR1a/ NR2A receptors.

Quantitative Relationship between Visuo-Motor Coordination and Dopaminergic Innervation of the Striatum is Revealed by SPECT Imaging S. Hocherman*, M. Schwartz, D. Groshar It is long known that visuo-motor coordination (VMC) is impaired in patients with Parkinson‚s disease. We have shown that this impairment involves a reduction in the ability to control the direction of visually instructed hand movement and independently, a reduction in the ability to produce persistent tracking speed. We have also shown that these deficits are ame- liorated by treatments that increase dopaminergic activity in the basal ganglia. In the present study we have correlated the VMC capabilities of neurological patients with the striatal volume within which significant binding of a labeled ligand for the dopamine transporter occurred. We found a significant linear correlation between striatal ligand-uptake volume and a global measure of VMC for both the right striatum / left hand performance (R2=0.55, p=0.001) and for the left striatum / right hand performance (R2=0.37, p=0.01). Detailed analysis revealed exclusive correlation between ligand uptake in left striatum and directional control of visually guided hand movements. Both right and left striatal ligand-uptake volumes were found to correlate with the ability to produce persistent tracking, with a somewhat greater involvement of the right striatum. These findings are viewed in the context of the demonstrated premotor ˆ putamen ˆ GPi loop, and a similar parietal ˆ basal ganglia loop. They confirm that disruption of such loops at the basal ganglia level has similar effects as disruption at the cortical level, but add a quantitative aspect to this understanding.

Visual Encoding Dysfunction in Schizophrenic Patients Before and After Perceptual Training H. H. Holcomb*, L. Beason- Held, M. Tagamets, C. Tamminga When making perceptual judgments, patients with schizophrenia, SZ, rou- tinely fail to perform with the precision or modulated response times characteristic of NV. We have used event related fMRI to assess how SZ (n=10) and NV (n=9) encode a visual target in a visual delayed-match-to-sample-

43 task (DMST).The DMST required the subject to make a judgment, indicated by button press in right or left hand, as to whether two consecutively presented black rectangles, separated by 6 seconds, were the same height. Con- trol trials required the subject to match his hand button with the side to which the rectangle was displaced. Functional MRI data were acquired before and after a rigorous 2-week training period. NV and SZ responded similarly to training by becoming faster and more accurate. A random effects model (SPM99) was used to assess signals associated exclusively with the encoding of the first stimulus. Pre-training Task Encode signals for NV were significant for parietal and caudate regions. NV revealed no positive BOLD responses for Control Encode measures. Post-training Task Encode signals in NV were significant in hippocampal, thalamic, insula, and medial frontal / cingulate regions. Pre-training Task Encode responses for the SZ group were confined to the parietal cortex. Identical responses were found in SZ Pre-training Encode Control trials. Post-training Task Encode responses for SZ participants were confined to the visual cortex; Post-training Control Encode signals were also similar to the Task Encode trials. The SZ Task En- code abnormalities are consistent with an „early‰ defect in their perceptual information processing.

Fos as a Marker of Sensitized Neurons in the Rat Accumbens Following Behavioral Sensitization to Cocaine or Amphetamine B.T. Hope*, B.J. Mattson, H.S. Crombag, J.D. Kreuter Behavioral sensitization to psychostimulants, such as cocaine or amphetamine, involves a form of associative learning. The learning of specific associations between the drug-state and the animal‚s environment is thought to involve molecular and cellular alterations that change the neural activity of relatively small subsets of widely distributed synapses and neurons selected by stimuli in the animal‚s environment. We are developing techniques to identify neurons and synapses in the accumbens that are selectively altered and regulated by the environment during behavioral sensitization. Seven days following repeated administrations of cocaine or amphetamine versus repeated administrations of the saline vehicle in novel locomotor activity boxes, we challenged independent groups of rats with different doses of cocaine (0-30 mg/kg, i.p.) or amphetamine (0-4 mg/kg, i.p.). We monitored locomotor activity or stereotyped behaviors for 2 hours and processed the brains for Fos immunohistochemistry. For both drugs, there was a leftward shift in the dose-response curves for the induction of Fos in the accumbens, but not in the caudate, that corresponded with a leftward shift in the dose-response curves for drug-induced psychomotor activity. In a separate experiment, we observed a complete inhibition of cocaine-induced Fos induction in the caudate and accumbens while the rats were anesthetized with chloral hydrate or urethane. From these experiments, we infer that behavioral sensitization involves sensitization of neural activity in the accumbens. Using Fos as a marker of sensitized neurons, we are currently

44 characterizing these neurons for sensitized activation of signal transduction pathways involved in the induction of Fos protein.

Neuropeptide mRNA Expression in Striatum, Psychostimulants, and Serotonin K.A. Horner*, D.H. Adams, C. Xochime, G.R. Hanson, K.A. Keefe Psychostimulants induce dramatic changes in behavior and monoamine systems. The molecular mechanisms underlying these changes have yet to be elucidated. Recent studies suggest that neuropeptide changes may contribute to the effects of methamphetamine (METH) and cocaine (COC) exposure. We examined the effects of a single high dose of METH or COC on the expression of preprodynorphin (PPD) and neurotensin (NT) in striatum. METH increased PPD mRNA selectively in the patch division of rostral striatum, whereas COC increased PPD mRNA in patch and matrix. In caudal striatum, METH increased PPD mRNA expression in both patch and matrix; COC increased it in dorsal striatum. COC increased NT mRNA throughout rostral striatum and dorsal caudal striatum. METH did not affect NT mRNA expression in rostral striatum, yet an increase in caudal striatum was observed. The COC-induced changes in neuropeptides in the rostral matrix were blocked by lesion of striatal serotonin with para- chloroamphetamine. Serotonin loss did not affect neuropeptide induction by either drug in the rostral patch or in caudal striatum. These studies indicate that METH and COC differentially induce neuropeptide expression in the striatum and that serotonin systems are involved in COC-induced changes in the rostral matrix. The differential expression of neuropeptides induced by METH and COC may underlie the drug-specific molecular cascades that contribute to stimulant-induced behavioral and neuronal changes.

Microinjections of the GABAA Antagonists Picrotoxin or Bicuculline into the Posterior Hypothalamus are Rewarding S. Ikemoto* While the hypothalamus has long been associated with reward function, it is fibers of passage rather than intrinsic cells that have been thought to carry reward signals. Our recent discovery that microinjections of AMPA into the supramammillary or posterior hypothalamic nuclei induce reward provides the first evidence implicating specific hypothalamic nuclei and neurotransmitters with reward. Here we examined the role of GABA neurotransmission in these nuclei. Rats learned quickly to lever-press for microinjections of the GABAA antagonist picrotoxin into the supramammillary or posterior hypothalamic nuclei, but not the lateral hypothalamic area or medial mam- millary nucleus. Additional experiments support that the blockade of GABAA receptors mediates reward signals. First, when picrotoxin was co-infused with the GABAA agonist muscimol, self-administration was disrupted. More- over, animals did self-administer another GABAA antagonist bicuculline into

45 the supramammillary nucleus, while the same animals did not self-administer the GABAB antagonist 2-hydroxysaclofen into the same site. Pretreat- ment with the D1 dopamine antagonist SCH 23390 led to extinction of picrotoxin self-administration in the supramammillary nucleus, suggesting that supramammillary picrotoxin reward is dependent on intact dopamine neurotransmission. These findings suggest that supramammillary and posterior hypothalamic neurons involved in reward function are tonically inhibited by GABAA, but not GABAB, neurotransmission.

Novel Method of Interrogating Brain Function Independent of Instruction or Overt Response Applied to Non- and Clinical Populations Clifford O. James* Signal detection tasks (SDTs) are often used to interrogate brain function within and between non- and clinical human and non-human populations. This method uses instruction to direct attention towards specific stimuli, which are determined to evoke specific behaviors. Occurrence of these behaviors serves to scale integrity of brain functions intervening between stimulus presentation and response. While this method is an important component of most diagnostic tests, its reliance on instruction and behavior limits its application in human populations where comprehension and movement may be compromised (i.e. Attention deficit disorders, Alzheimer’s Disease), where ability to sense and respond has been intentionally compromised (i.e. clinical anesthesia and paralysis), and in non-human animals. Proper brain interrogation requires stimulating the same intervening events as during SDTs independent of instruction or overt behavior. The present study used a novel method of recording brain activity over time in 3-D during controlled stimulus presentation designed to evoke brain activity related to information processing in subjects not- and instructed to detect the same stimulus. Specific stimulus manipulations without instruction present varied the occurrence, position, and magnitude of brain activity similar to when instruction was present, while others showed that instruction may confound measurement of attention and memory functions during SDTs. These confounds can be accounted for using this non-instructed method as a control. This technique was applied to various clinical populations. These results suggest the non-instructed method can serve as a sur- rogate for instruction when assessing non-cooperative populations. Lastly, this method was applied to animal groups during various clinical manipulations. Without need for prior learning this method scaled the effect of various manipulations on information processing. Clinical application of this non-instructed method of brain interrogation may broaden diagnostics currently used in non- and human populations, while non-clinical application may further understanding of how the brain directs processing when instruction is absent.

46 Tyrosine Availability Affects Haloperidol-Induced Catalepsy and Striatal Dopamine Release: Studies in Tyrosine Augmentation and Depletion G. E. Jaskiw*, R. Bongiovanni Questions persist about the functional significance and reproducibility of studies showing that tyrosine availability influences striatal dopamine (DA) transmission. Our current data may explain previous inconsistencies and demonstrate that changes in brain tyrosine levels have behavioral as well as neurochemical effects. Male Sprague-Dawley rats (200-250gr) had a uni- lateral cannula inserted into the striatum; 2 days later, a microdialysis probe was lowered (AP + 1.2, ML ± 3.2, VD–7.2) and 16 hrs later, microdialysate collection began (1.0µl/min). Exp 1–Haloperidol 1mg/ml IP increased striatal DA release to 196 % of baseline (1.5 hr post dose). Different concentrations of tyrosine were then infused through the probe. Tyrosine 25µg/ml increased (240% of baseline) whereas tyrosine 150 µg/ml inhibited (135% of baseline) haloperidol-induced DA release. Exp 2—Some animals received a tyrosine and phenylanine free neutral amino acid mixture (NAA-) (two IP injections (1g/kg) 1 hr apart). NAA- reduced striatal tyrosine levels by 50%. Haloperidol (0.25mg/kg IP) induced striatal DA release (195% of baseline) was significantly attenuated (125% of baseline) by NAA(-) pretreatment; the latter was completely reversed by administration of tyrosine (100mg/kg IP). In a parallel study, NAA(-) pretreatment significantly increased haloperidol-induced catalepsy. These data are the first demonstration that tyrosine levels can enhance or inhibit striatal DA transmission. Furthermore, they show that tyrosine availability can affect behavioral indices of striatal DA transmission. Manipulation of brain tyrosine levels may prove useful in the treatment of and development of research probes for conditions in which abnormal striatal DA transmission has been implicated.

Direct Action of Corticotropin-Releasing Hormone on Locus Coeruleus Neurons Recorded in vitro H. P. Jedema*, A. A. Grace The noradrenergic neurons of the locus coeruleus are potently activated by corticotropin-releasing hormone (CRH). Evidence has been presented that this excitatory effect of CRH is exerted within or proximal to the LC although the exact site of the action on LC neurons has been debated. CRH immunoreactive terminals contact both TH-immunoreactive processes and presynaptic elements. CRH receptors have been clearly demonstrated but mRNA for either CRH1 or CRH2 receptors has been difficult to detect in the LC of rodents. We have previously characterized the excitatory effect of CRH on LC neurons recorded in vitro using intracellular recording techniques. In the present studies we demonstrate that the effect of CRH persists when synaptic activity is prevented using tetrodotoxin (TTX 2µM) or cadmium (CdCl2 100µM). In the presence of TTX, spontaneously active LC neurons

47 continued to discharge spontaneous spikes with a smaller amplitude, and CRH administration continued to cause an increase in the rate of spike discharge. Administration of CdCl2 increased the discharge rate LC neurons, most likely through inhibition of calcium-activated potassium conductances (IK(Ca)). Consistent with a cadmium-mediated inhibition of IK(Ca), we observed a decrease in the magnitude and duration of the afterhyperpolarization following action potential discharge during cadmium bath application. Again, in the presence of cadmium CRH administration continued to cause an increase in the rate of action potential discharge. These data strongly suggest that CRH activates LC neurons via a direct mechanism and also indicate that calcium influx is not essential for the spontaneous activity of LC neurons.

Activation of the HPA Axis with the Resulting Production of Corticosterone Provides Protection of FAS and TNF-Mediated Liver Damage T.R. Jerrells*, L. Sosa, D. Hoerman Withdrawal from alcohol by dependent mice is a model for severe stress and produces HPA axis activation and high levels of corticosterone (Cort). Alcohol-fed mice infected with a hepatotropic virus showed less liver damage early in the infection than control mice. Because the liver damage in this model is mostly mediated byFAS ligation and tumor necrosis factor [TNF]), we hypothesized that the stress response, through Cort, protected the liver. To model this, alcohol-fed mice were injected with anti-FAS (Jo2 mAb) or given TNF to induce hepatocyte apoptosis. The alcohol-fed mice showed significantly less liver damage, by TUNEL stains and caspase activation, than control mice. To definitive show that this was mediated by Cort, adrenalectomized (ADX) mice were provided Cort in the drinking water. To produce Cort levels similar to control mice, ADX mice were provided water with 30 ug Cort per ml; to produce Cort levels similar to the alcohol-fed mice, the ADX mice were provided water with 300 ug/ml cort. The mice provided water with 30ug cort showed significant levels of apoptosis and mortality where the group given 300 ug/ml were essentially protected. The high level of Cort in the water was also shown to protect against TnF-mediated liver damage. These data show that activation of the HPA axis by production of Cort has a direct protective effect on hepatic apoptosis induced by ligation of FAS and by TNF.

A Unique Enhancer in Midbrain Stem Cells and its Transcriptional Regulation: Implications for the Fate and Specification of Dopaminergic Neurons C. Kappen* Nestin is a marker for neural stem cells, and is expressed in the developing brain by neuroepithelial cells prior to overt differentiation. Using a transgenic approach, we have identified, within the second intron of the rat

48 nestin gene, two distinct CNS progenitor-specific gene regulatory elements. Each of these transcriptional enhancers requires for its activity the interaction of at least two independent regulatory sites. One enhancer is active throughout the developing CNS, while the other regulatory element is active only in ventral midbrain cells. These experiments indicate that neuroepithelial cells in the embryo have different transcriptional competence, depending on their anatomical location, and that stem cells in the ventral midbrain are a unique subpopulation by virtue of their ability to activate the midbrain enhancer. Comparative sequence analyses identified evolu- tionarily conserved regions in both of the enhancers. By mutagenesis experiments, we have shown that one of these conserved sequences, with similarity to DNA binding sites for nuclear receptors, is required for activation of the midbrain enhancer. From these results, we postulate that a nuclear receptor-type transcription factor is involved in the transcriptional regulation of the midbrain-specific enhancer. The implications of our results are several-fold: 1) The midbrain enhancer is the earliest marker available, a unique reagent for mapping origin, fate, lineage, migration, differentiation, and projections of cells that originate in the ventral midbrain. 2) The ventral midbrain is the major source of dopaminergic cells affected in Parkinson’s disease. The identification of a specific enhancer provides new strategies to manipulate gene expression in progenitors for the dopaminergic lineage. 3) The conservation of the enhancer in mammals suggests that transcription factor(s) regulating it may be functionally involved in specification and differentiation of dopaminergic cells. The identification of such transcription factors offers new targets for neurodegenerative diseases.

The Homeostatic Regulation of Dendritic Spine Number by Synaptic Transmission is Age-Dependent S. A. Kirov*, L. J. Petrak, C. A. Goddard, K. M. Harris Mature neurons respond to blockade of synaptic transmission by increasing the number of dendritic spines, apparently compensating for the diminished synaptic input. It is unsettled whether blockade of synaptic transmission will also elevate spine number during development. To address this question synaptic transmission was blocked in rat hippocampal slices during critical developmental stages of spine formation at postnatal days (P) 5–P22 and compared to adults. As revealed by confocal microscopy of CA1 cells labeled with DiI spine density increased during blocked synaptic transmission at P20, but was not changed during blockade at younger ages. When extracellular calcium was nominally zero, spine density increased further along P20 dendrites in a way similar to adult dendrites, but decreased along P11-12 dendrites. Thus developmental changes in mechanisms regulating postsynaptic calcium may be responsible for the age dependent changes in the ability of hippocampal neurons to regulate

49 homeostatically synapse number during altered synaptic transmission. The sequence of synaptogenesis on mature neurons during blockade of synaptic transmission recapitulates development, as revealed by the serial electron microscopy. The neuron responds to a large-scale loss of input by attempting to induce filopodia that guide axons to the dendritic shafts, and spines arise from those shaft synapses

Changes in the Input-Output Relationships of Cortical Synaptic Connections During Natural Patterns of Activation Following STDP I. C. Kleppe*, H. P. C. Robinson The dynamics of synaptic transmission in the neocortex depends strongly on the history of presynaptic activity, such that the magnitude of a single postsynaptic response is not entirely stochastic but can be forecast by nonlinear prediction: matching of recent input and response history to similar sequences arising at other times. Each response therefore carries information not only about the temporal structure of the preceding presynaptic input spike train but also about the actual release history, which is stochastic. The relevant length of the activation history can amount to several minutes during natural stimulation. We have investigated how this history-dependence changes at synapses between layer 2/3 neurons after induction of spike-timing-dependent plasticity (STDP). We drive presynaptic cells with spike trains patterned with a variety of natural statistics for over 30 minutes, at average rates of 1-30 Hz. We then induce potentiating STDP with a paired pulse protocol (Markram et al. 1997, Science 275:213–215) and record for another 30 minutes using the same stimulus train. Using nonlinear prediction of the response to characterize the input-output relationship, we show that long-term enhancement shifts reliably transmitted patterns to a more rapid time scale (1-5 s), increasing the influence of the more recent history on each EPSP amplitude. Spike-timing-dependent potentiation therefore not only raises the impact of a particular synaptic input on spike initiation in the postsynaptic neuron by raising the average amplitude of response, but also changes the time frame over which synapses are reliable, to produce a more accurate image of recent presynaptic activity.

Identification of a Satisfactory Animal Model to Study Radiosurgery for Epilepsy S. Krahl*, A. De Salles, A. Mazarati, N. Bezrukiy, T. Solberg, C. Wasterlain Despite the remarkable efficacy demonstrated in refractory epilepsy patients treated by stereotactic radiosurgery, the mechanism by which radiosurgery suppresses seizures and the dose range necessary to control epilepsy and yet maintain normal function of the target structure have yet to be elucidated. The first step in answering these questions is to find a suitable animal model of clinically refractory seizures that responds to low-dose

50 radiosurgery. The present study evaluated the efficacy of stereotactic radiosurgery in rats using the self-sustaining status epilepticus (SSSE) model. SSSE was produced by giving 30 minutes of intermittent electrical perforant path stimulation. This technique produces, after a latent period, recurrent spontaneous seizures which are quite consistent over time. Seizures were quan- tified with automated seizure detection software using around-the-clock EEG and video monitoring. Using a custom stereotactic frame and the Novalis Shaped Beam Radiosurgery System, the hippocampus was irradiated with 30-Gy. Control rats were not irradiated. Irradiated rats became seizure-free as compared to their baseline rate of more than seven seizures per day. No rate changes were observed in control rats during this same period. These data confirm that this animal model, already known to accurately mimic clinically refractory seizures, is well suited to study the mechanisms of low-dose radiosurgery for epilepsy.

A Fast Dynamic Clamp Built with LabVIEW-RT P. H.M. Kullmann*, D. W. Wheeler , J. P. Horn A dynamic clamp enables current injection into living neurons, thereby mimicking the existence of ionic conductances in the cell membrane. Add- ing such virtual ion channels to a cell requires a feedback loop that con- tinually measures membrane potential, computes current through the virtual conductance and generates a signal that drives the current command input of a recording amplifier. In many cases, mimicking the gating kinetics of a conductance requires a system in which the feedback loop operates accurately at speeds of >10 kHz. This cannot be readily achieved with common multi-tasking operating systems like Windows and Unix. Our goal was to develop a dynamic clamp that would employ a real-time operating system and be easy to install and to adapt to new experiments. Our dynamic clamp software is called G-clamp. G-clamp uses the real-time extension of the LabVIEW graphical programming environment (LabVIEW-RT) in combination with an embedded Pentium III processor from National Instru- ments. This approach offers several advantages: 1) the software and hardware are easy to install and to upgrade, 2) programming, debugging and button pushing are done on a host-computer running under the familiar Windows OS, and 3) execution of the feedback loop on the embedded processor guarantees real-time performance. G-clamp can calculate voltage-dependent conductances on the fly and use pre-defined conductance waveforms. For the initial development of G-clamp, we implemented 5 virtual conductances: gNa(V), gK(delayed rectifier), gK(M), g-leak and g-synaptic. The three voltage-dependent G’s are calculated using standard Hodgkin-Huxley-style equations. G-synaptic waveforms were computed in advance and read from template files. Under these conditions, the feedback loop can run at 24 kHz with simultaneous data acquisition (Vm and Im) for >6 min.

51 Fast Neurotransmission in the VTA to PFC Pathway C. Lapish*, L. Nogueira, A. Lavin, J. K. Seamans The ventral tegmental area (VTA) is the primary source of dopaminergic innervation to the medial Prefrontal Cortex (PFC) yet DA has not been shown to have transient effects in PFC, making it difficult to envisage how information about transient rewards could be effectively communicated by DA (Schultz 2002). On the other hand glutamate is well suited for extremely transient signaling. Here we tested whether DA neurons co-release glutamate. In vivo microdialysis in anesthetized animals showed that VTA stimulation (5x20Hzx60s) increased glutamate levels in the PFC. This increase was still present even after reverse dialysis of glutamate, DA and GABA antagonists into the PFC, indicating the signal was not due to activation of local circuits in the PFC. The glutamate signal was eliminated in VTA 6-OHDA lesioned animals, indicating it was derived from DA neurons. A similar glutamate signal was also evoked in the PFC when NMDA was infused into the PFC, thereby eliminating the possibility that the effect was due to stimulation of fibers of passage or antidromic activation of descending PFC fibers. In vivo intracellular recordings revealed that VTA stimulation evoked epsp-ipsp sequences that were abolished in 6-OHDA lesioned animals or by i.v. administration of the glutamatergic antagonist NBQX. These data suggest that 1) cortical responses evoked by the VTA are not solely mediated by DA. 2) The fast acting response is consistent with glutamate signaling. These data raise the possibility that the “phasic” error prediction encoded by VTA neurons could potentially be communicated by glutamate.

Stimulation of the VTA evokes Depolarizing States in the PFC A. Lavin*, L. Nogueira, J. K. Seamans Many studies have shown that the pathway from the ventral tegmental area (VTA) to the prefrontal cortex (PFC) is crucial in regulating normal cognitive and motivational processes. In order to assess the role of the VTA in the modulation of cortical threshold and subtrehsold events, we performed intracellular current clamp recordings in vivo in deep layers of the PFC of anesthetized male rats, and assessed the effects of delivering electrical stimulation to the VTA in single or trains (20 Hz) pulses. Single pulse stimulation delivered to the VTA evoked fast epsp’s-ipsp’s sequences in the great majority of the cells tested. Systemic administration of DAergic antagonist did not block the responses. In contrast, the responses were abolished by systemic injections of selective glutamate antagonist. Stimulation of the VTA with trains of pulses (20 Hz) evoked Up states in the majority of the cortical cells tested. Again, systemic administration of specific glutamatergic antagonist abolished the membrane bistability and the evoked Up states. In animals with 6-OHDA lesions of the VTA, electrical stimulation did not evoke synaptic responses or bistability on cortical neurons.

52 These data suggest that: 1) The cortical response evoked by VTA stimulation is not mediated by dopamine 2) The VTA-evoked response is blocked by glutamatergic antagonist and 3) The VTA-evoked response is abolished by destruction of DAergic cells.

Pallidal Control of Nigral Dopaminergic Neuron Firing Pattern and Its Relation to Extracellular Striatal Dopamine C.R. Lee*; J.M. Tepper; E.D. Abercrombie The firing pattern of dopaminergic (DAergic) neurons in vivo is strongly influenced by afferent modulation. The effect of burst firing induced by disinhibition of the globus pallidus with local bicuculline infusion (1000 uM, 200 nl) on extracellular striatal DA was examined using single unit extracellular recordings of DAergic neurons in the substantia nigra and simultaneous in vivo microdialysis in the striatum of adult male Sprague-Dawley rats. Disinhibition of the globus pallidus caused a slight but significant increase in the firing rate of DAergic neurons (4.29±0.26 to 4.63±0.26 Hz; t=2.13, p=0.04, n=29). More importantly, following drug infusion the majority (58.6%) of DAergic neurons discharged in the burst firing pattern corresponding to a significant shift in the distribution of the firing patterns compared to control (X2=13.11, df=2, p<0.01). The coefficient of variation also increased significantly (0.44±0.05 to 0.71±0.06; t=4.41, p<0.01, n=29) as did the overall percentage of total spikes fired in bursts (10.5±3.2% to 27.3±4.5%; t=4.50, p<0.01, n=29). Striatal DA efflux was measured in either 8 or 5 minute sampling intervals. In either case striatal DA increased significantly (8 min F(7, 77)=3.90, p=0.02, n=12; 5 min F(7, 112)=8.03, p<0.01, n=17) corresponding to absolute increases of 29.0±4.8% and 45.9±7.5% respectively. These data suggest that afferent-induced burst firing of DAergic neurons that is accompanied by only modest increases in firing rate leads to a greater level of extracellular DA in the striatum compared to that which is observed when firing pattern is less bursty.

Protective Effect of New Medicinal Decoction on Focal Cerebral Ischemia of Rat K. Leem*, J-H. Choi, Y. Boo, H-M. Kim, M-Y. Kim, S-J. Park, J-C. Seo, S. Y. Kim, H. Kim Many herbal medicines have been used to treat stroke and coma in Korea. This novel decoction was made on the basis of our preliminary data and traditional medicinal theory. We studied the neuroprotective effects of the decoction on the middle cerebral artery occlusion (MCAO) model of rat. The decoction significantly reduced the brain damage and the behavioral defect. It reduced the induction of cyclo-oxygenase 2 (COX-2) and inducible nitric oxide synthase (iNOS) in ischemic region of brain. The decoction may possess many mechanisms that might account for its high degree of efficacy. A number of factors including free radicals, glutamate, calcium

53 overload, NO, and various cytokines have been proposed to have an important role in causing neuronal death after ischemia. In this study, we found out that the effect of the decoction is closely related with the regulation of COX-2 and iNOS induction. Further studies are needed to know the neuroprotective mechanisms of the decoction.

A Role for the Redox Site in the Modulation of the NMDA Receptor by Light D. Leszkiewicz* Light has been shown to modulate NMDA receptor function. In this study, we have performed experiments aimed at elucidating the putative site of action of light within the receptor structure. Whole-cell recordings were performed in Chinese hamster ovary cells expressing various combinations of NMDA receptor subunits. Although there was no apparent difference in the actions of light between wildtype NR1/NR2A and NR1/NR2B subunit configurations, the light enhancement of NMDA-induced currents was either completely abolished or substantially diminished in the redox site mutants NR1a (C744A, C798A) / NR2B and NR1a (C744A, C798A) / NR2A. Further studies demonstrated that chemical reduction of NR1a / NR2B NMDA receptors decreased its sensitivity to light. In addition, sodium (2- sulfonatoethyl) methanethiosulfonate (MTSES), used to irreversibly bind free sulfhydryl groups and inactivate the redox site, abolished the effects of light on wildtype receptors. In contrast, no free sulfhydryls were available for MTSES following light stimulation, suggesting that light itself could not reduce the redox modulatory site. Our results suggest that a functionally intact, oxidized redox site is necessary for light induced potentiation. Hence, light and redox modulation of the NMDA receptor may share a common intramolecular pathway for altering the function of this ion channel.

Ionotropic Glutamate Receptors, L-type Calcium Channels and Calcium/Calmodulin-Dependent Protein Kinase II in the Ventral Tegmental Area Are Critical for the Initiation of Cocaine-Induced Behavioral Sensitization S. C. Licata* , R. C. Pierce Ionotropic glutamate receptors and L-type calcium channels play critical roles in the initiation of behavioral sensitization to cocaine. Although the ventral tegmental area (VTA) is the nucleus primarily associated with the initiation of behavioral sensitization, the effect of the modulation of ionotropic glutamate receptors and L-type calcium channels in this brain region during a sensitizing regimen of cocaine injections has not been evaluated comprehensively. Therefore, in the present experiments we administered an AMPA receptor antagonist (CNQX), NMDA receptor antagonist (AP-5), or L-type calcium channel blocker (diltiazem) directly into the VTA

54 prior to each of four daily systemic cocaine injections in order to assess their influence on the initiation phase of behavioral sensitization. Results indicated that all three pretreatments impaired the initiation of cocaine- induced behavioral sensitization. Because the AMPA and NMDA receptors as well as L-type calcium channels are permeable to calcium, we investigated the role of calcium signaling molecules such as calcium/calmodulin- dependent protein kinase II (CaM-KII). An inhibitor of CaM-KII (KN-93) also prevented behavioral sensitization when administered directly into the VTA prior to repeated cocaine injections. Consistent with this finding ho- mozygous a-CaM-KII knockout mice failed to develop behavioral sensitization. Although their cocaine-induced hyperactivity was increased relative to wild-type controls, this behavioral response did not augment further with repeated injections. Collectively, these results suggest that calcium influx through AMPA receptors, NMDA receptors, and L-type calcium channels on dopamine neurons in the VTA amplifies calcium signaling through CaM- KII during the initiation of behavioral sensitization to cocaine.

Enhanced GABA-Mediated Inhibition is Necessary for IV Agents but Not for Inhalation Anesthetics B. MacIver* General anesthetics have long been known to enhance synaptic inhibition in the mammalian central nervous system. A major target for this increase in inhibition is thought to be GABA-A receptors which couple to chloride channels. The present study investigated the degree of effect produced by four general anesthetics on GABA-mediated inhibition. Two intravenous (IV) and two inhalational anesthetics were investigated. Anesthetic-induced depression of population spike discharge was used as an overall measure of effect recorded from rat hippocampal brain slices. Anesthetic concentrations which produced a comparable degree of population spike depression were compared. To determine the extent of enhanced GABA-mediated inhibition produced by each anesthetic, the depressant effects were reversed using a GABA receptor antagonist (bicuculline) or chloride channel blocker (picrotoxin). The depression produced by IV anesthetics (pentobarbital and propofol) was strongly reversed by the GABA antagonist, and by picrotoxin; indicating that most of the depression of synaptically evoked discharge produced by these agents occurs via enhanced GABA-mediated inhibition. In contrast, the depression produced by the inhalational agents (halothane and isoflurane) was only partly reversed by bicuculline or picrotoxin. These results indicate that IV anesthetics act mainly via GABA-A receptors but that inhalational agents act at additional sites to depress hippocampal neuron synaptic transmission.

55 A New Model for Alzheimer’s Disease: Activation of Apoptosis by Brain c-fos and c-jun by beta Amyloid Employing the Acute Slice Explant Technique D. Marcus* Alzheimer’s Disease (AD) appears to be mediated by apoptosis or programmed cell death, which involves the activation of the immediate early genes c-Fos and c-Jun. The appearance of the p-53 protein suggests entry of the neuronal cells into the apoptotic pathway. The cascade thus activated leads to the production of neurofibrillary tangles and neuritic plaques, the neuropathological hallmarks of this disease. We tested the hypothesis that apoptosis and AD may be induced in the rat hippocampal tissue using beta Amyloid and the acute slice explant technique (ASE) and an artificial CSF. The appearance of c-Fos, c-Jun, and p-53 were detected by immunofluorescense and quantitated by the Metamorph Image Analysis System. Beta Amyloid incubation in the ASE produced a 475% increase in c-Jun, a 375% increase in c-Fos, and a 215% increase in p-53. This process took 2 hours to develop, while the same results in man took 75 years. Our results suggest that the apoptotic cascade is activated very rapidly in the presence of beta Amyloid, leading to neuronal apoptosis and Alzheimer’s Disease. In addition, the ASE model can provide an interesting window to test a variety of compounds for their ability to inhibit caspace-3, a commit- ted step in neuronal apoptosis.

Selegiline Blocks Cocaine-Induced Increases in Urinary MHPG- Sulfate Excretion J. Mendelson*, P. Jacob, III, P. Shwonek, R.T. Jones The acute CNS effects of cocaine are mediated by inhibition of dopamine (and norepinephrine) reuptake in the nucleus accumbens. Selegiline is a selective MAO-B inhibitor that is undergoing clinical trials for treatment of cocaine dependence. Even if selegiline is efficacious for cocaine addiction, some are likely to take cocaine during selegiline treatment. Therefore, we performed a phase 1 safety interaction trial with cocaine and a new transdermal formulation of selegiline. This study assessed the effects of cocaine and selegiline on CNS norepinephrine turnover. In many species, including man, CNS-derived norepinephrine is metabolized to 3-methoxy-4-hydroxyphenylglycol (MHPG) and conjugated to MHPG-sulfate that is ultimately excreted in the urine. In contrast, peripheral norepinephrine is conjugated to MHPG-glucuronide. Therefore, we estimated CNS norepinephrine turnover by measuring urinary MHPG-Sulfate excretion. In the 12-subject inpatient study we used a constant rate intravenous infusion of 2.5 mg/kg hour of cocaine to safely deliver relatively large cocaine doses that are similar to those taken by active abusers. Cocaine challenges were performed before and after 1 week of 20 mg/day transdermal selegiline

56 using a fixed order open label design. Urine was collected and MHPG-Sul- fate determined by LC-MS. Cocaine increased urinary MHPG-Sulfate from 0.95 ± 0.31 g/24h to 1.48 ± 0.43, with peak increases occurring 4 days after cocaine. Cocaine is rapidly cleared, suggesting that these noradrenergic effects were not due to cocaine per se but represent a subtler chronic effect of cocaine (withdrawal, homeostatic regulation, metabolite effects). The brief period of selegiline treatment abolished the effects of cocaine. This suggests that cocaine (or a metabolite) can increase CNS norepinephrine turnover for at least 4 days and that alterations in noradrenergic tone may be responsible for some of the long-term effects of cocaine. Based on these data we will assess urinary MHPG-Sulfate excretion in our proposed studies.

Bridging Neuroscience and Psychophysics: Heteromodal Association Cortex is a Critical Component of S.S. Stevens’ Power Law M. Mennemeier*, G. Jewell, T. Kretzmer, H.L. Murphy, A. Woods, T. Nunn, S. Liem Abstract: S.S. Stevens established perception of stimulus intensity, or magnitude estimation (ME), is a power function (a log-log relationship) of objective stimulus intensity (the Power Law). The consistency of this observation across a wide range of perceptual continua (brightness, loud- ness, etc?) suggests that the Power Law is an organizing principle of sensory-neural function. Initially, the transduction rate of sensory receptors in the peripheral nervous system was deemed the neural basis of the Power Law. However, we observed that power functions are altered by brain lesions, specifically, those associated with a disorder of attentional and arousal known as neglect. Neglect follows damage to a cortical system comprised of tertiary, or heteromodal association areas (HAAs), in posterior-parietal, dorsolateral-frontal, and anterior-cingulate cortex. We hypothesized that these HAAs are a cortical component of Stevens‚ Power Law. We tested groups of ischemic stroke patients and normal subjects to determine how brain damage alters ME across 12 perceptual continua. We analyzed MR images of brain lesions, coded in Talaraich coordinates, to identify critical brain regions. Finally, we examined how attention (spatial cueing) and arousal (cold presser stimulation) influence ME. The data support a cortical component for the Power Law. Power functions are consistently altered in patients with both neglect and damage to the above mentioned HAAs but not in other patients. Manipulations of arousal, rather than attention, can actually normalize power function parameters in affected patients. Thus, the Power Law may reflect a principle by which mental representations of sensory stimulation are constructed to match afferent information arising in the peripheral receptors.

57 In vivo Imaging of Regenerating Optic Fibers in Adult Goldfish: Adverse Effect of Low Density and BDNF␣ R. Meyer* When the optic nerve of an adult goldfish is severed, optic fibers grow back to the optic tectum to reestablish orderly connections. To understand the dynamic behavior underlying this successful regeneration, we have been using in vivo imaging to examine DiI labeled regenerating fibers in living goldfish. Since recent reports in mammals suggest that it is possible to stimulate the regeneration of a small number of optic fibers, we asked how the behavior of optic fibers might be affected if only a few were allowed to regenerate in goldfish. To do so, the normal optic innervation of one tectum was eliminated by removing its corresponding eye and a few percent of optic fibers from the opposite eye were surgically induced to grow into this denervated tectum. We found that in this “low-density” projection, optic fibers formed branches upon entering tectum and failed to translocated across tectum to their proper targets. In contrast, in a normal-density projection, invading fibers were unbranched and showed large translocations. To further test whether this premature branching might be due to reduced competition for a target derived trophic factor, BDNF was administered to ganglion cells following simple nerve crush. In this normal density projection, BDNF caused premature branching and reduced translocation. These results suggest that having and sufficient number of fibers may be important for forming ordered connections during regeneration.

Critical Factors IN D1/D2 Receptor Selective Binding of Ligands K.A. Neve*, H. Lan, C.J. DuRand, M.M. Teeter D1 and D2 dopamine receptors have opposite biochemical effects on adenylate cyclase but similar topology. Explication of the structural determinants of D1/D2-specific binding is an important problem. Based on a homology model of the dopamine D2 receptor and on amino acid identi- ties in the D1/D2 subfamilies, we predicted the primary residues that direct subtype-specific ligand binding to dopamine receptors. These residues are located principally near the primary ligand-binding site between TM2, TM3, and TM7, where they form a hydrophobic pocket called the ancillary pocket. We present mutagenesis results and the docking of the tested ligands into binding sites of the respective receptors. In particular, mutation of W99 in the D1 receptor to its corresponding residue in the D2 receptor, Phe, dra- matically increased the affinity of the mutant D1 receptor for several D2 antagonists, including spiperone, domperidone, and YM-09151-02. The re- ciprocal mutation in the D2 receptor caused modest decreases in affinity for D2-selective ligands and modestly increased affinity for the D1-selective ligand SCH23390. These results elucidate some D1/D2 differences for the drugs studied, particularly for the butyrophenones spiperone and haloperidol and for domperidone, each with varying rigidity. This testing per-

58 mits a refinement of D1/D2 binding determinants in a rhodopsin-based model of the dopamine D1 and D2 receptor.

Subsecond Dopamine Release Promotes Cocaine Seeking P. E. M. Phillips*, G. D. Stuber, M. L.A.V. Heien, R. M. Wightman, R. M. Carelli The dopaminergic projection from the ventral tegmental area to the nucleus accumbens is critically involved in mediating the reinforcing properties of cocaine. Although these neurons respond to rewards on a subsecond timescale, neurochemical studies have only addressed dopamine’s role in drug addiction by examining changes in the tonic (minute-to-minute) levels of extracellular dopamine. To investigate the role of phasic (subsecond) dopamine signaling, we measured dopamine every 100 ms in the nucleus accumbens using state-of-the-art electrochemical technology. Rapid changes in the extracellular dopamine concentration were observed at key aspects of drug-taking behavior. Before lever presses for cocaine, there was an increase in dopamine that coincided with the initiation of drug-seeking behaviors. Remarkably, these behaviors could be reproduced by electrically evoking dopamine release on this timescale. After lever presses there were further increases in dopamine concentration at the concurrent presentation of cocaine-related cues. These cues alone also elicited similar rapid dopamine signaling, but only in animals where it had previously been paired to cocaine delivery. These findings reveal an unprecedented role for dopamine regulating drug taking in real time.

The Role of Development in Cortical Reorganization of Rats that Sustained Forelimb Removal C.P. Pluto*, R.D. Lane, N.L. Chiaia, A.S. Stojic, R.W. Rhoades Rats which undergo forelimb removal (FLX) on the day of birth possess numerous (44%) multi-unit recording sites in the forelimb-stump representation of primary somatosensory cortex (S-I) that respond to cutaneous stimulation of both the stump (ST) and the hindlimb (HL) when cortical GABA(A+B) receptors are antagonized (J. Neurophysiol. 77:2723-35, 1997). A major source of these inappropriate HL inputs is the medially located S-I hindlimb representation (J. Neurophysiol. 81:625-33, 1999). These findings led to the question of why do nearly half of the neurons in the S-I stump region of neonatal amputees become additionally receptive to HL stimulation, but not to stimulation of the mystacial vibrissae (V) or lower jaw (LJ), which also have cortical representations located adjacent, but lateral to, that of the stump? As evidence suggests that S-I cortex develops in a lateral to medial gradient (McClandish et al., Exp. Brain Res. 92(3):369-74, 1993), we mapped the cortices of adult rats amputated at either fetal, neonatal, or adult periods to test whether the developmental stage at the time of injury affected reorganization. Fetal amputees (FLX on embryonic day 16) exhibited 10% ST+HL, 34% ST+V/LJ, and 22% with triple ST+HL+V/LJ receptivity during GABA receptor blockade. Neonatal ampu-

59 tees showed 38% ST+HL, 10% ST+V/LJ, and 14% ST+HL+V/LJ. Adult amputees showed fewer than 10% of either dual field, and no triple fields. These results support a developmental dependence of cortical reorganization in response to forelimb amputation.

The Cholecystokinin-B Receptor is Expressed on and Regulates Quantal Size in Catecholamine Releasing Cells E.N. Pothos*, M. Haburcak, J. Pratt and M.C. Beinfeld The neuroactive peptide cholecystokinin (CCK) is known for its physiological functions in the intestine, pancreas, gallbladder and the CNS. Its neuroanatomical profile implicates CCK in the regulation of food intake and certain catecholamine-related disorders including schizophrenia, drug addiction and Parkinson’s disease. However, the CCK-catecholamine interactions at the cellular level are still not well understood. We studied the effects of sulfated cholecystokinin octapeptide (CCK-8S) and selective CCK-A and CCK-B receptor antagonists on the evoked release of catecholamines in single quanta from mouse adrenal chromaffin granules. Exposure of adrenal chromaffin cultures to 100 nM CCK-8S for 45 minutes significantly decreased catecholamine quantal size from 680000±61000 (mean±SEM) to 520000±75000 molecules per vesicle (25 % reduction). No significant changes were observed after CCK-8S exposure for 5 and 30 minutes. The CCK-B antagonist L-365,260 (1 µM) significantly increased quantal size by 50% after 30 min, while the CCK-A antagonist L-364,718 (1 µM) did not have any effect. Therefore, any effects of CCK-8S on quantal size appear to be CCK-B receptor mediated. Both CCK-A and CCK-B receptors are present on adrenal chromaffin cultures as established by RT-PCR and immunofluorescence. We also found that both types of CCK receptors are expressed on dopaminergic terminals of cultured midbrain dopamine neurons, suggesting that direct regulation of neuronal dopamine quantal size by the CCK-B receptor is a distinct possibility. The results suggest that catecholamine quantal size is regulated by the CCK-B receptor through a “slow” but direct CCK-receptor-to-catecholamine-cell interaction.

60 Role of Nuclear Aggregates in the Pathogenesis of Huntington’s Disease in Transgenic Mouse Models G. Schilling*, A. Klevytska, S. Fangmark, M. Coonfield, D. R. Borchelt Huntington’s disease is a progressive autosomal dominant disease that is caused by expansion of polyglutamines in the N-terminus of htt (Htt, the HD protein). In vitro, htt fragments with expanded polyglutamine tracts aggregate when reaching a threshold of 35-40 consecutive glutamines (the threshold for human disease). Neuronal intranuclear inclusions (NII‚s) and cytoplasmic aggregates (CA) have been described in several HD transgenic mouse models and HD postmortem brains. We have developed HD-N171- 82Q transgenic mice that show a neurologic phenotype including progressive incoordination, hypoactivity, subtle tremors, loss of weight and premature death. The brains of HD-N171-82Q transgenic mice display a widespread distribution of NII‚s and CA consisting of apparently aggregated htt. Nuclear aggregates of polyQ proteins are a common neuropathological feature of polyglutamine diseases. However, for HD, cytoplasmic aggregates are as frequent as nuclear aggregates. We would have investigated the role of CA in vivo, by engineering a functional Nuclear Localization Signal (taken from atrophin-1) into the N-terminus of our HD-N171-82Q construct. Sev- eral lines of transgenic mice expressing high levels of NLS-N171-82Q fragments have been identified and are being characterized both behaviorally and neuropathologically. Preliminary studies of these mice have demonstrated abundant NII is cerebellar granule cells. Supported by grants from the Huntington’s Disease Society of America; Coalition for the Cure.

Apo-1/Fas Promoter Polymorphism in Korean Stroke Patients J-C. Seo*, K-H. Leem Stoke is somewhat a genetic disorder, which has more risk of occurrence in the family of stroke patients. Apoptosis has been implicated in the pathogenesis of neurodegenerative diseases such as stroke and Alzheimer’s disease. Apo-1/Fas gene is one of the mediator of apoptosis in stoke. MvaI polymorphism is the first polymorphic marker identified in the Apo-1/Fas gene promoter, which was typed by polymerase chain reaction and followed by MvaI digestion and gel electrophoresis. DNA was isolated from peripheral blood collected from 91 stroke patients and 103 healthy blood donors. The genotypes of GG, GA and AA were determined by sequence specific primer polymerase chain reactions. This study investigated an MvaI polymorphism based on Fas gene promotor region by restriction fragment length polymorphism (RFLP). The Fas-GG genotype was the least frequent in patients with stroke and healthy controls (p=0.57). In normal Korean controls the MvaI polymorphism GA, AA and GG were 48.6%, 34.9% and 16.5%. In stroke patients were 56.2%, 29.6% and 14.2% respectively. And the allelic

61 frequencies of MvaI*2 (G) alleles were less frequent than MvaI*1 (A) alleles in patients with stoke and healthy controls (p—0.76). In normal Korean controls MvaI*1 (A) and MvaI*2 (G) alleles were 59.2% and 40.8%. In stroke patients were 57.6% and 42.4%, respectively. Our results, pending confirmation in a larger study, indicate that the Fas genotype may not be a risk factor for stroke.

Independent Component Analysis of Intrinsic Optical Signals for Gain Fields in Inferior Parietal Cortex of Behaving Monkey R.M. Siegel*, J.R. Duann, T.P. Jung, T.J. Sejnowski The distribution of neuronal activity across the inferior parietal lobule (IPL) can be imaged using the reflection of 605 nm light to indicate the level of deoxyhemoglobin. Maps of the eye position gain fields are found across the IPL such that area 7a is tuned for lower eye positions and DP for upper eye fixations. Often definable blood vessels are observed to carry signals tuned similarly to the nearby tissue. Were these vascular changes related to the surrounding cortex? Independent component analysis (Bell and Sejnowski, 1995) utilizes the time-dependent characteristics to parcellate spatial signals into subsets. The independent components define small (~1-2mm) regions of IPL cortex, or individual branches of blood vessels, that have similar time dependent characteristics. There are time lags between these components that suggest that signal occurs first in cortical tissue and follows in the blood vessels that drained that region. Furthermore these signals depend on both the position of the eye in the orbit and time. A plausible mechanism is that the incoming neural activity first activates cortex and a trace is found in the draining veins. The different time courses with position in the image may indicate the strength of the inputs, local circuits, vascular inho- mogeneities, and may carry the information for slow changes in blood flow. In standard fMR studies in primates, these changes are likely low-pass fil- tered. That there is a relationship between the ICA blood flow defined regions and specific anatomically defined functional boundaries is a tantalizing possibility

The Activity of Pramipexole in the Mouse Forced Swim Test is Mediated by D2 Rather than D3 Receptors R. A. Fujiwara, J. A. Siuciak* Recent studies have reported antidepressant-like activities of the dopamine D2/D3 agonist pramipexole in the chronic mild stress model and in the forced swim test (Willner et al., 1994; Maj et al., 1997), suggesting that D3 receptor agonists may represent a new class of antidepressant drugs. How- ever, the relative contribution of D2 or D3 receptors in the activity of pramipexole in these models is unclear. The aim of the current studies was to explore the role of the D2 and D3 receptor in the activity of pramipexole

62 in the mouse forced swim test using both D3 receptor knockout mice as well as the D2 and D3 receptor antagonists, haloperidol and LU-201640, respectively. D3 receptor knockout mice were obtained on two different background strains (C57BL6 and B6/129) and activity was assessed in both locomotor activity and the forced swim test. No baseline differences were observed between knockout and wild-type mice of either background strain in locomotor activity or in the forced swim test. Knockout and wild-type mice from both background strains responded similarly to amitriptyline, a standard antidepressant, in the forced swim test. Furthermore, in the forced swim test, pramipexole showed similar efficacy in both KO and WT mice. The D3 selective antagonist LU-201640 failed to block the antidepressant- like effects of pramipexole. In contrast, the efficacy of pramipexole in the forced swim test was completely blocked by the D2 antagonist, haloperidol. Taken together, these studies suggest that the D2 receptor rather than the D3 receptor is important for the antidepressant-like activity observed in the mouse forced swim test.

Repeated Methylphenidate Treatment During Rat Adolescence: Effects on Gene Regulation by Cocaine in the Striatum. H. Steiner*, C. L. Brandon Psychostimulants such as cocaine produce changes in gene expression in striatal projection neurons, effects that are related to excessive stimulation of dopamine receptors. Methylphenidate (Ritalin) is a psychostimulant that is widely prescribed in the therapy of Attention Deficit Hyperactivity Disor- der and is also increasingly used for recreational purposes. Similar to cocaine, methylphenidate causes increased extracellular levels of dopamine in the striatum. In a previous study, rats treated with methylphenidate during adolescence showed increased self-administration of cocaine as adults, indicating that methylphenidate produced enduring neuronal changes. Using in situ hybridization histochemistry, we investigated the effects of acute and repeated methylphenidate treatment on gene expression in the striatum. Acute administration of methylphenidate (0-10 mg/kg, i.p.) induced immediate-early gene expression (c-fos, zif 268) in a dose-dependent manner. Following repeated methylphenidate treatment (10 mg/kg, 7 days) in adolescent rats, cocaine-induced expression of immediate-early genes and substance P was significantly attenuated throughout the striatum. In contrast, minimal changes were seen for enkephalin expression. These effects of acute and repeated methylphenidate mirror those of acute and repeated cocaine treatment. Our findings thus demonstrate that methylphenidate can produce molecular changes similar to other psychostimulants. Such neuronal changes may contribute to an increased risk of psychostimulant use and dependence following methylphenidate exposure.

63 Dose Responsiveness of DA Modulation of Inhibition in Prefrontal Cortex: Differential Activation of D1 and D2 Receptors H. Trantham-Davidson*, J.K. Seamans, A. Lavin A putative inverted U-shape dose response relationship exists for DA modulation of working memory functions in PFC. At a cellular level, dopaminergic (DAergic) modulation of pyramidal cells in the deep layers of the medial prefrontal cortex (mPFC) appear to show dose-dependent modulation of NMDA currents, with low DA activating D1 receptors and enhancing NMDA currents and high DA activating D2 receptors and reducing NMDA currents (Zheng, et al., 1999). We investigated whether a similar situation holds for GABAA currents based on the differential modulation of IPSCs by D1 and D2 receptors (Seamans, et al., 2001). The present study investigated the concentration of dopamine at which the shift between a D1 mediated enhancement and a D2 mediated reduction of IPSCs may occur. Excitatory synaptic transmission and action potentials were blocked, and voltage was clamped at around ˆ40 mV so that deep layer GABAA IPSC’s could be isolated. IPSC amplitude followed a shift from an increase in IPSC amplitude to a decrease with increasing DA concentrations (1nM-30uM). We also tested the effects of picomolar tonic DA levels that occur in vivo. These low endogenous concentrations of DA appeared to modulate GABA currents as DA receptor antagonists altered IPSC amplitudes in ventral tegmental area-PFC co-cultures that possesed endogenous DA tone that was in the in vivo picomolar range. These findings have important implications for DA modulation of cortical inputs and cortical networks that are essential for proper function of working memory.

Signal Transduction Pathways Involved in Programmed Cell Death and Neuronal Pentraxin 1 Overexpression in Cerebellar Granule Cells R. Trullas*, M. Enguita, N. DeGregorio-Rocasolano We have previously shown that treatment of cerebellar granule cells with low potassium induces overexpression of Neuronal Pentraxin (NP1) that leads to cell death . The increased expression of NP1 protein starts immediately after treatment and peaks after 4 h of exposure to low potassium. This up-regulation of NP1 precedes cytoplasmic membrane damage by at least 4 h, and the peak of NP1 protein corresponds approximately to the period when cerebellar granule cells commit to die. NP1 is a glycoprotein of an apparent molecular mass of ~50 kDa that has been proposed to mediate the uptake of synaptic material during synapse remodeling. We have now investigated the regulation of NP1 expression by signaling pathways known to mediate neuronal survival and death. Activation of the phosphatidylinositol 3-kinase/AKT pathway with IGF-1 inhibits cell death evoked by low potassium. Likewise, inhibition of stress activated protein kinase pathways p38 and c-jun-N-terminal kinase blocks cell death induced

64 by nondepolarizing conditions. However none of these treatments alters the increase in NP1 expression induced by low potassium. In contrast, inhibition of GSK3b activity prevents both cell death and NP1 overexpression evoked by low potassium. These results indicate that each one of these different signal transduction pathways contribute to cell death evoked by low potassium and show that NP1 overexpression is regulated by GSK3b activity.

Decreased Serotonin Transporter Expression Prevents Age- Related Serotonergic Fiber Loss in the Forebrain E.L. Unger*, B.A. Luellen, O. Lee, W.E. Lyons, M.E. Blue, L.A. Mamounas, A.M. Age-dependent loss of serotonin axons may contribute to an increased in- cidence of late life neuropsychiatric disorders, age-related decreases in cognitive function and late onset neurodegenerative disorders. Mice engineered to lack the serotonin transporter (SERT) show changes in serotonin forebrain arborization and behavior associated with reduced SERT expression. Serotonin axons were visualized with an antibody against serotonin at 3 or 19 months of age. In 3 month-old female wildtype mice, hippocampal serotonin fiber densities in subregions CA1, CA3 and dentate gyrus were 6.54, 9.78 and 11.2 axon-area/region-of-interest-area/% (AA/ROI/%), respectively. A significant age-related loss of axon density in 19 month-old wildtype mice was evident in fiber counts of 2.73, 5.70 and 6.01 AA/ROI/% in subregions CA1, CA3 and dentate gyrus. However, fiber densities in these same brain regions in 19 month-old SERT knockout mice was similar to or exceeded that observed in young wildtype and SERT knockout mice. The results were similar but less striking in aged male mice. Elevated plus-maze and locomotor activity also have been studied at both ages, and these data will be presented. Overall, the data suggest that decreased SERT expression is associated with a reversal or prevention of normal age-related degeneration of serotonergic axons and that these changes may have a beneficial effect on anxiety-related behavior or locomotor activity in advanced age. Further research will allow formulation of strategies aimed at preventing neurodegeneration and its adverse behavioral effects.

Inflammation in Alzheimer’s Disease: Its Role and an Opportunity for Therapy G. L. Wenk* Alzheimer’s disease (AD) is associated with a distinct pattern of neuropathological changes and a dense distribution of highly activated astrocytes and microglia. Due to glial activation, AD is associated with increased levels of the proinflammatory cytokines. Increased cytokine expression in the AD brain tends to occur at sites of pathology, e.g. temporal lobe structures, and not to occur in brain regions that demonstrate little or no neurodegeneration. Activated microglia are present in diffuse amyloid de-

65 posits and may drive the conversion of the diffuse plaques into compacted senile plaques. Chronic neuroinflammation produced by infusion of li- popolysaccharide (LPS) into the 4th ventricle of rats reproduces many of the behavioral, neurochemical, neurophysiological and neuropathological changes associated with AD. Epidemiological evidence suggests that conventional non-steroidal anti-inflammatory drugs (NSAIDs) can slow the progress, or delay the onset, of AD. The therapeutic use of most NSAIDs is limited by their poor gastrointestinal tolerability. Nitric oxide (NO)-donating NSAIDs, such as NitroFlurbiprofen (NFP, HCT1026), have excellent gastrointestinal tolerability and can significantly attenuate the consequences of chronic neuroinflammation. The consequences of chronic neuroinflammation, and the usefulness of NO-donating NSAIDs to attenuate these effects, will be presented. In addition, the effectiveness of NFP in the presence of the acetylcholinesterase inhibitor galantamine was also investigated. These findings demonstrate the critical role of inflammation in the distribution of the pathology associated with AD and the usefulness of combined therapies for the treatment of the symptoms

Dynamic-Clamp Tests of a Theory of Synaptic Gain D. W. Wheeler*, P.H.M. Kullmann, J. P. Horn Synaptic computation is the process by which a neuron converts an input sequence of spikes into an output sequence. The pattern of synaptic con- nectivity in sympathetic ganglia suggests that neurons can be computational amplifiers. As a quantitative measure of amplification, we define synaptic gain as the rate of postsynaptic output divided by the rate of presynaptic input. Our mathematical and computer models predict that synaptic gain is determined by the number of converging synapses and the strength of those synapses. In addition, synaptic gain depends on the frequency of presynaptic activity. Our simulations predict a peak synaptic gain of 2.66 at a mean presynaptic frequency of 2.8 Hz. To test these predictions experimentally, we are now using the dynamic clamp technique while recording from dissociated sympathetic neurons. With the dynamic clamp we are able to provide a neuron with virtual nicotinic synapses, and we can control the number and strength of virtual synapses that converge on a neuron. To quan- tify synaptic strength, we determine the threshold synaptic conductance required to elicit postsynaptic spiking at the start of every experiment. We then normalize our predefined patterns of synaptic activity with respect to the firing threshold, thereby keeping the stimulation parameters identical from one neuron to the next. Our dynamic clamp experiments produce a peak synaptic gain of 3.04 ± 0.04 (SEM, n = 16) at a mean presynaptic firing rate of 1.4 Hz. These results suggest that further refinement of the model is necessary to better understand the mechanisms of synaptic computation in living cells.

66 Regulation of Trafficking Proteins and µ Opioid Receptors in the Mouse Spinal Cord B.C. Yoburn*, C. Patel, M.Patel, V. Rajashekara, K. Patel Chronic treatment with opioid antagonists can increase µ-opioid receptor density, while some opioid agonists can decrease receptor density. Cell culture studies have implicated trafficking proteins including β arrestin, dynamin (DYN) and G-protein receptor kinases (GRK) in the internaliza- tion and regulation of opioid receptors. In the present studies, mice were treated chronically with opioids that differentially regulate µ-opioid receptor density. Changes in protein and mRNA abundance of DYN 2, GRK 2 and β arrestin 2 in spinal cord were determined in mice infused (sc osmotic pump) with etorphine (200ug/kg/day) or morphine (40mg/kg/day + 25mg morphine implant pellet) for 7 days. Other mice were implanted sc with a 15mg naltrexone (NTX) pellet for 8 days. Controls were implanted sc with a placebo pellet. After treatment, spinal cord was removed and trafficking proteins assayed and µ-opioid receptor saturation binding studies conducted. Chronic NTX-induced µ-receptor upregulation (+145%) in spinal cord was accompanied by decreased GRK2 (-36%, -48%) and DYN2 (-30%, - 29%) protein and mRNA abundance, respectively. Etorphine-induced µ-receptor downregulation (-38%) in spinal cord was correlated with increased protein abundance of DYN2 (70%) and decreased DYN2 mRNA (-31%). Etorphine had no effect on GRK2 protein or mRNA. Morphine had no effect on µ receptor density, trafficking proteins or mRNA. In other studies, NTX, etorphine, and morphine, decreased (-29%), increased (+21%) and had no effect, respectively on β arrestin 2 protein abundance. In summary, changes in spinal cord µ-opioid receptor density are associated with regulation of trafficking proteins. These data suggest that opioid-induced µ receptor regulation may be mediated by differential alteration of trafficking proteins.

An In-patient Phase I/II Study of Lofexidine (alpha-2 adrenergic agonist) for Opiate Detoxification E. Yu*, B.H. Herman, K. Miotto, A. Montgomery, P.J. Fudala, C.N. Chiang, C. Fisher, K. Kampman, V. Dhopesh, J. Cornish, B. Walsh, K. Davies, F. Vocci, P. Bridge, W. Ling, C.P. O’Brien Lofexidine HCl appears to be effective for the clinical management of opiate detoxification. Lofexidine also appears to produce less hypotension than clonidine. This study was conducted to assess the safety of lofexidine and to obtain information related to its potential efficacy. Opiate-dependent individuals were admitted to the hospital and stabilized on morphine 100 mg/day (subcutaneously) for 1 to 8 days. Morphine was then discontinued and lofexidine was administered daily for 5 or 10 days followed by no medication for 2 days. Nine subjects took lofexidine in the 1.6 mg/day dosage group, 23 in the 2.4 mg/day group, 12 in the 3.2 mg/day group and 3 in the 4.0 mg/day group. There were transient, orthostatic systolic BP changes with

67 the systolic BP < 85 mmHg: 1.6 mg (n=2), 2.4 mg (n=19), 3.2 mg (n=7), 4.0 mg (n=3). There were also apparent dose-dependent decreases in the Modi- fied Himmelsbach Opiate Withdrawal Scale. The Himmelsbach opiate withdrawal mean scores were: 1.6 mg = 30.3, 2.4 mg = 22.0, 3.2 mg = 18.3, 4.0 mg = 15.7. No serious adverse events were observed. Overall, lofexidine appeared to have minimal hypotensive effects up to up to 4.0 mg/day and clinically attenuated opiate withdrawal signs and symptoms.

68 Session Abstracts

Panel • Sunday, January 26 • 4:30–6:30 PM • Ballroom 1 G. Snyder, J. Becker, S. Mani, A. Etgen, R. Meisel Steroids, Catecholamines, and Sex: Working Together in the Brain? Ovarian steroid hormones, estradiol and progesterone, modulate neuroendocrine physiology and reproductive behavior in female mammals. It is increasingly clear that sex hormones exhibit significant cross talk with catecholamine signaling pathways. This panel will explore the cellular mechanisms and signaling molecules that may underlie the hypothalamic actions of sex hormones impacting sexual behavior. We also will consider evidence that sex hormones and sexual activity, in turn, exert profound and divergent effects on other motivated behaviors by activating midbrain dopamine systems. Shaila Mani will discuss a dopamine-signaling pathway that converges with a steroid hormone-initiated, receptor-mediated pathway regulating reproductive behavior. This effect involves cross talk between membrane receptors for dopamine and intracellular progestin receptors. Anne Etgen will show that hormonal background modulates signaling pathways stimulated by another catecholamine, norepinephrine. She will show that estrogen, progesterone, and IGF-1 regulate a-1B adrenergic receptors and their signaling cascades in the hypothalamus to affect female reproductive function. Jill Becker will discuss the temporal relations between dopamine in nucleus accumbens and coital stimulation during sexual behavior, and discuss possible mechanisms mediating the effect of estrogen in these brain regions. Her recent work using adenoassociated viral vectors suggests that the classical estrogen receptor can modulate behaviors mediated by the striatum. Robert Meisel will discuss how female sexual behavior sensitizes accumbens dopamine release to further sexual interactions and to an initial administration of amphetamine. Together, these presentations emphasize the diverse interactions between catecholamines and estrogen that likely regulate specific female reproductive behaviors and global aspects of motivated behavior.

69 Panel • Sunday, January 26 • 4:30–6:30 PM • Magpie K. Kalil, T. Gomez, S. Smith, P. Mermelstein Diverse Roles of Calcium Signaling in CNS Growth Cones and Synapses Calcium signaling controls important aspects of neuronal development and synaptic physiology. The panel will describe varied effects of calcium elevations, emphasizing the role of different influx mechanisms and downstream targets for calcium ions in growth cones and synapses. Kalil will demonstrate that, through L-type VGCCs, spontaneous calcium elevations regulate cortical growth cone pausing and axon branching. These effects may be through phosphorylation of the cAMP response element binding protein (CREB) and GAP-43 expression. Gomez will show that filopodia of Xe- nopus spinal neuron growth cones exhibit local calcium transients that regulate filopodial stability and growth cone guidance. These calcium signals locally activate calpain, which promotes repulsive turning from the site of increased filopodial adhesion and stability. Smith will discuss the importance of a novel ion channel in determining the shape of the presynaptic action potential and extent of calcium entry. Patch-clamp recording from intact neocortical nerve terminals revealed a non-specific cation channel sensitive to the concentration of extracellular calcium. His results demonstrate that the presynaptic terminal can detect and respond to reductions in cleft calcium, which may be important for the nerve terminal during periods of high activity. Mermelstein will show that, following brief periods of heightened stimulation, calcium entry through L-type calcium channels leads to activation of the transcription factor CREB and CRE-dependent transcription. The PDZ interaction sequence contained within the last four amino acids of the calcium channel a1C (CaV1.2) subunit (Val-Ser-Asn-Leu, VSNL) is critical in localizing L-type channels proximal to the signaling machinery that triggers activity-dependent gene expression.

Panel • Sunday, January 26 • 4:30–6:30 PM • Wasatch A. Markou, P. Kalivas, F. Conquet, M. Geyer The Role of Metabotropic Glutamate Receptors in Drug Dependence and Schizophrenia The purpose of this panel will be to discuss recent findings about the function of metabotropic glutamate receptors (mGluRs) in rodent behaviors that have relevance to drug dependence and schizophrenia. Peter Kalivas will present data indicating that repeated administration of the psychomotor stimulant cocaine has effects on mGluR5 function in the frontal cortex and the associated scaffolding protein Homer1. Francois Conquet will present additional data suggesting a role of mGluR5 receptors in cocaine dependence by showing that mGluR5 knockout mice do not exhibit cocaine-in-

70 duced hyperactivity and do not self-administer cocaine, while their responding for food and their ability to learn an operant response is at the same level as that of wildtype mice. Further, a relative selective mGluR5 antagonist decreased cocaine self-administration in wildtype mice providing pharmacological validation of the effects observed in the genetically modified mice. In addition, a relative selective mGluR5 antagonist decreased nicotine self-administration and drug-seeking behavior. Athina Markou will further discuss the role of mGluR receptors in nicotine dependence. She will present data showing that blockade of mGluR5 receptors that belong to Group I decreases nicotine self-administration in both rats and mice without affecting responding for food in rats. Interesting, however, mGlu5 receptors do not exhibit altered function after the development of nicotine dependence. By contrast, Group II and AMPA/kainate receptors exhibit increased sensitivity in nicotine-dependent rats. It was shown that the ventral tegmental area is the site of this effect. Mark Geyer will present new data about mGluR receptors, and their interactions with NMDA receptors in behaviors with relevance to both drug dependence and schizophrenia. Data will be shown demonstrating the influences of mGluR5 receptors on prepulse inhibition (PPI) of startle in both mice and rats. In mice, the deletion of the mGluR5 gene leads to marked and enduring deficits in PPI that are observed in two background strains and are independent of maternal influences. These are the same knockout mice that Francois Conquet used. In rats, an mGluR5 antagonist potentiates the PPI-disruptive effects of the NMDA antagonist phencyclidine in both startle and locomotor activity, while a Group II agonist showed no interactions with phencyclidine.

Panel • Sunday, January 26 • 4:30–6:30 PM • Maybird E. Carpenter, C. Krull, C. Lance-Jones, P. Phelps, G. Schoenwolf The Development and Patterning of the Vertebrate Spinal Cord The adult spinal cord is a highly ordered, complex structure, yet during early embryonic development it begins as a tube of actively dividing, progenitor cells. After neurons undergo their final cell division, they migrate out to the location where they will reside throughout life and subsequently extend their axons toward their synaptic targets. This panel will consider the molecular control of the early developmental events that establish the overall organization of the vertebrate spinal cord. Initially, Gary Schoenwolf will present an overview of spinal cord formation and new insights into mechanisms underlying formation of the neural tube, the rudiment of the spinal cord. Cynthia Lance-Jones will discuss the role of Hox genes in patterning the regional identity of the chick posterior spinal cord and will include recent results of the effects of in vivo electroporation of Hoxd10. Patty Phelps will examine the expression of Reelin, a large extracellular matrix protein associated with errors in cell migration. The defects in the migrations of both sympathetic and parasympathetic preganglionic neurons in the reeler spinal cord will be discussed as well as possible mechanisms leading to these

71 aberrant migrations. Cathy Krull will focus on the function of members of the Eph family of receptor tyrosine kinases and their ephrin ligands in guiding somatic motor neuron axons to their target muscles. Results from gene manipulation experiments suggest that subsets of motor neurons that express the same Eph receptor exhibit distinct responses to ephrins. Together this panel will explore recent advances in the understanding of the processes and molecules that are critical for normal embryonic spinal cord development. preganglionic neurons in the reeler spinal cord will be discussed as well as possible mechanisms leading to these aberrant migrations. Cathy Krull will focus on the function of members of the Eph family of receptor tyrosine kinases and their ephrin ligands in guiding somatic motor neuron axons to their target muscles. Results from gene manipulation experiments suggest that subsets of motor neurons that express the same Eph receptor exhibit distinct responses to ephrins. Together this panel will explore recent advances in the understanding of the processes and molecules that are critical for normal embryonic spinal cord development.

Panel • Sunday, January 26 • 4:30–6:30 PM • Superior A R. Perez, L. Goldstein, F. LaFerla, S. Guenette APP Function: New Insights from APP C-Terminal Binding Proteins and Notch Signaling Amyloid precursor protein (APP), the parent molecule to the b-amyloid (Ab) found in Alzheimer’s brain senile plaques, is a transmembrane protein that is processed by various “secretases”. APP processing has been found to be similar to that of Notch, a protein that regulates cell fate, pattern formation, and neuronal development. New data indicate that, just like Notch, APP can signal by releasing the APP intracellular domain (AICD). APP interacts with several proteins, predominantly by their association with the GYENPTY motif within the APP C-terminus. This panel discussion will explore the role of the APP C-terminus and these interacting proteins on protein processing, trafficking, signal transduction, transcriptional regulation, and apoptosis. Ruth Perez will present an introduction including her mutagenesis data defining the APP endocytic signal as YENP. Suzanne Guenette will discuss data on the role of the FE65 proteins, key APP interacting proteins, in AICD generation. Frank LaFerla will discuss the effects of Presenilin, a potential g-secretase, on AICD formation and the impact of AICD on calcium signaling. Lawrence Goldstein will discuss the role of APP in Kinesin- based axonal transport highlighting work suggesting that APP loss or overexpression interferes with axonal transport, that Ab is generated during APP axonal transport, and that amyloidogenic processing of APP may produce signals that induce neuronal cell death. Afterward, the speakers and members of the audience will join in a spirited discussion regarding the implications of the findings on both normal and aberrant APP function.

72 Panel • Sunday, January 26 • 4:30–6:30 PM • Superior B M. Murray, A. Flanders, M. Selzer, E. Schwartz Magnetic Resonance Microimaging: A Non-Invasive Tool for Monitoring Spinal Cord Repair. This panel will review recent advances in the use of high resolution MRI to assess regeneration in the injured spinal cord. Adam Flanders will review the fundamentals of MRI and discuss the MRI findings in human spinal cord injury. Various interventions have been reported to promote spinal cord repair through regeneration and neuroprotection. Some of these repair strategies are associated with recovery of function. Marion Murray will review the success of these strategies. The stage is set for translation to clinical settings. Clinical application will require that we be able to follow the survival and maturation of transplanted cells and to identify correlates of axonal regeneration using non-invasive methods. Axons in the lamprey spinal cord regenerate after transection. Because of its favorable geometry, the lamprey spinal cord can be imaged with resolutions down to 9mm. Mickey Selzer will describe MR imaging of individual axons in the lamprey spinal cord and the measurement of water diffusion by MRI to study degeneration and regeneration of axons. Eric Schwartz will describe MR imaging of grafts that elicit regeneration and those that don’t when placed into spinal cord lesions in the rat. Discussion will be focused on the present limitations and the future development of MRI technology and its application to treatment for spinal cord injury.

Panel • Sunday, January 26 • 8:30–10 PM • Ballroom 1 J. Seamans, J. Surmeier, I. Timofeev, P. O’Donnell Cellular Basis of Persistent Activity Persistent self-sustained activity has been observed in a variety of cortical and subcortical regions throughout the natural sleep-wake cycle and may underlie the active maintenance of information in working memory as well as aspects of selective attention. One form of persistent activity is a rhythmic oscillation in membrane potential from a hyperpolarized down-state to a depolarized up-state where spikes are fired. Persistent activity of this type may occur spontaneously or be evoked by a variety of inputs and while it requires sufficient network activity to be generated and maintained, it is shaped by intrinsic membrane currents. In spite of the ubiquity of persistent activity and its relevance to the sleep-wake cycle, attention and short- term memory functions, we are just beginning to understand the cellular mechanisms involved. This panel will discuss recent advances towards describing the cellular and synaptic mechanisms underlying persistent activ-

73 ity and how such mechanisms might inform us about the functions of persistent activity states in the brain. Igor Timofeev will describe how up- and down-states in cortical neurons recorded intracellularly in vivo are influenced by synaptic and intrinsic ionic currents during phases of the sleep- wake cycle. Jim Surmeier will provide a biophysical description of ionic conductances implicated in generating up and down states in striatal and prefrontal cortical neurons. Jeremy Seamans will discuss data derived from in vivo recordings and organotypic cultures about the synaptic mechanisms involved in evoking persistent activity in prefrontal cortex by various afferents including the ventral tegmental area and hippocampus. Patricio O’Donnell will present data on dopamine-glutamate interactions involved in sustaining up states in the prefrontal cortex and nucleus accumbens.

Panel • Sunday, January 26 • 8:30–10 PM • Magpie J. Williams, V. Alvarez, G. Aston-Jones, C. Chow, E. Van Bockstaele Attention–Locus Coeruleus The locus coeruleus (LC) is a tightly packed group of neurons that send noradrenergic projections throughout the central nervous system. In the absence of afferent input, these neurons are spontaneously active. The activity of individual neurons measured both in vivo and in brain slice preparations is highly synchronous under some conditions. This synchronous activity is thought to result from the presence of electrotonic coupling. The roles of electrotonic coupling and afferent input in the generation of synchronous activity are the subjects of this panel. The primary question is, what mechanisms underlie the transitions between periods of synchrony and asynchrony in the LC. Veronica Alvarez will describe the activity of LC neurons in brain slices, centering on the conditions that favor and disrupt synchronous activity. This analysis will include the use of paired recordings in both neonatal and adult animals. Elisabeth Van Bockstaele will present anatomical evidence for electrotonic connections using electron micro- scopic examination of immunoreactive connexin proteins. Carson Chow will present a mathematical model of coupled LC neurons based on the intrinsic membrane properties. The effects of firing rate and the strength of electrotonic coupling on synchrony will be addressed. Gary Aston-Jones will describe two modes of LC activity found in behaving monkeys: a phasic mode associated with selective attention, and a tonic mode corresponding to high behavioral flexibility. A computational model indicated a relationship between these two modes, the amount of synchrony present in the LC and task performance.

74 Workshop • Sunday, January 26 • 8:30–10 PM • Wasatch C. O’Brien, B. Hoebel, P. De Witte, F. Weiss Conditioned Drug Effects: Mechanisms and Potential Role in Relapse to Addiction The essence of addiction appears to be the learning that persists long after the drug has disappeared from the body. This accounts for the frequently life-long duration of this illness. Drugs of abuse produce direct (unconditioned) effects but with repetition, cues associated with drug administration produce learned (conditioned) effects in the absence of the drug. Drug withdrawal phenomena can also be conditioned to formerly neutral environmental cues when chronic drug use is suddenly stopped. Hoebel will discuss dopaminergic and cholinergic opposing mechanisms involved in both unconditioned and conditioned withdrawal responses from a variety of drugs. DeWitt will discuss conditioned adaptations to the presence of drug in terms of glutaminergic mechanisms. These adaptations result in tolerance to the effects of the drug, but when conditioned, result in withdrawal reactions when the subject is no longer receiving the drug. Weiss will report the effects of withdrawal on extra hypothalamic corticotrophin- releasing factor (CRF) in acute withdrawal and during protracted abstinence. The protracted abstinence state makes the subject more susceptible to stress and thus relapse. O’Brien will discuss human data showing the manifestations of conditioned withdrawal in former opiate and cocaine addicts using functional brain imaging. The entire group will discuss the potential for new relapse prevention medications that block or diminish these conditioned drug effects.

Workshop • Sunday, January 26 • 8:30–10 PM • Maybird A. Andrews, M. Blue, B. Hoffman, J. Lauder, L. Mamounas, J. Lakoski Serotonin as a Trophic Factor Serotonin is thought to promote neuronal plasticity during the treatment of mood and anxiety disorders and during development or following neurodegenerative insult. Important adaptations potentially occuring in response to changes in serotonergic neurotransmission include alterations in presynaptic and postsynaptic function and subsequent changes in the expression of critical genes. One of the most promising gene targets identified to date is brain derived neurotrophic factor (BDNF), however, the mechanisms by which serotonin and BDNF interact to potentially influence neuronal plasticity are unclear. This workshop will serve as a forum to discuss the role of serotonin as a trophic factor and to more precisely define the nature of the relationship between serotonin and BDNF. The workshop

75 will address the following questions: Does serotonin function as an autocrine or paracrine trophic factor, especially with regard to its interactions with BDNF? By what pre- and/or postsynaptic receptor mechanism(s) and second messenger system(s) does this occur? How does serotonergic signaling influence the phenotypic differentiation or survival of serotonergic or other postsynaptic neuronal populations? Does reduced reuptake enhance the ability of serotonin to act as a trophic factor by increasing extracellular serotonin and what effect does this have on BDNF? What are the critical periods during which serotonin can act as a trophic factor? And finally, which in vitro findings hold-up in in vivo models and which require further investigation? Additional questions posed by audience participants will be addressed. The overarching goal is to provide a clearer understanding of serotonin’s ability to function as a trophic factor and direction for future research efforts.

Workshop • Sunday, January 26 • 8:30–10 PM • Superior A C. Fairbanks, L. Stone J. Zadina, D. Paul Black Diamond Technique in Knock-Down, Knock-Out, Sequestration, and Synergism Studies Various techniques for reduction of protein/peptide levels or activation are increasingly incorporated into neuroscientific investigations. When applied appropriately, these methods enable the determination of mechanisms underlying central nervous system processing. Application of these techniques to in vivo models of CNS dysfunction (e.g. pain, nerve injury, drug addiction, tolerance) increases the complexity of such experiments. Each member of this workshop has extensive experience with developing best practice standards with respect to four such techniques in in vivo models of nociception and analgesia, including antisense knock-down, gene knockout, antisera sequestration of peptides, and statistically determined synergism. When conducted appropriately these strategies (applied individually or in combination) are experimentally powerful. Laura Stone will describe strategies for identifying effective antisense sequence targets, selection of control oligomers, and pharmacologic characterization of antisense sequences in vivo. Carolyn Fairbanks will illustrate the importance of con- ducting complete pharmacological characterization of agonists and antagonists in genetically modified mice prior to interpretation of study results. James Zadina will describe the best methods for using IgGs raised against endogenous peptides (e.g. endomorphins) to sequester the peptides and inactivate them in vivo. Dennis Paul will rigorously and statistically define the term “synergism” as well as describe the methods for determining interactions between two to three separate treatments. The objective of this workshop is to generate dialogue with attendees regarding the utility of these specific techniques (used either individually or in combination), and

76 to work toward consensus as to how they might be best applied to in vivo models of CNS dysfunction.

Workshop • Sunday, January 26 • 8:30–10 PM • Superior B L. Peoples, B. Richmond, J. Parkinson, H. Barbas, E. Koechlin The Anterior Cingulate and Orbitofrontal Cortices and Goal- Directed Behavior Animal and human studies show that the anterior cingulate and the orbitofrontal cortices are involved in the anticipation of future events of emotional significance, learning and executive control of instrumental behavior. Abnormalities in each structure have additionally been implicated in a range of human disorders involving emotions and behavioral control, including obsessive-compulsive disorder, drug addiction, and anxiety–mood disorders. The brain areas have, for the most part, been considered in isolation. However, as the data related to each area grows, it is clear that the proposed functions of these two cortical regions overlap significantly. The present workshop will bring together researchers that have studied these structures using electrophysiological and anatomical approaches in primates and neuro-imaging in humans to address questions regarding the relationship between the two structures. We will focus the discussion specifically on the acquisition and regulation of goal directed-behavior. Helen Barbas will discuss anatomical evidence that the two structures may cooperate functionally but additionally are in a position to make distinct contributions to goal-directed behavior. Barry Richmond and Wolfram Schultz will discuss electrophysiological recordings conducted in the anterior cingulate and orbitofrontal cortex, respectively, in an effort to delineate the unique contribution that the two structures may make to encoding of goal- related information and goal-related learning. Etienne Koechlin will discuss parallel neuro-imaging studies in humans aiming to identify the role of both structures in relation to other functionally associated brain regions including the ventral striatum and lateral prefrontal cortex.

Panel • Monday, January 27 • 7:30–9:30 AM • Ballroom 1 N. Marks, O. Arancio, R. Boutrchouladze, R. Hen, A. Yamamoto Genetic Models and Behavioral Modifications Genetic manipulation while providing useful models to demonstrate pathological counterparts of human disease have been less successful in terms of reproducing behavioral deficits. This becomes a critical issue for the rational drug discovery using animal models involving gene deletion or overexpression to replicate movement disorders (Parkinson’s, Huntington’s

77 and other CAG repeat diseases), neurodegeneration (familial Alzheimer’s disease, FAD) and changes in mood. Neville Marks will comment on the mismatch between pathology and neuronal deficits that lead to questions on design of the appropriate behavioral or other tools to judge the validity of animal models. Rusiko Boutrchouladze will focus on the genetic and pharmacological dissection of memory in mice including the role of cAMP/ PKA/MAPK-signaling, CaMKIV and CREB in plasticity and long-term memory. Ai Yammoto will discuss the reversibility of neurological deficits based on insights from a conditional model of Huntington’s disease. Ottavio Arancio will examine the progression of cognitive disorders in FAD following overexpression of factors enhancing beta amyloid toxicity, including RAGE (Receptor for Advanced Glycation Endproducts) and ABAD (Amyloid- beta-Binding-Alcohol-Dehydrogenase) in relation also to electrophysiology and histochemistry. Rene Hen will discuss genetic models for creating anxiety and depression using tissue specific and knockout models for serotonin 1A receptors to evaluate effects of drugs using classical tests for conflict as- sessment, or fear and anxiety.

Panel • Monday, January 27 • 7:30–9:30 AM • Magpie P. Micevych, E. Wagner, K. Sinchak, C. Bethea, V. Chaban Estrogen-State Modulates Neurotransmitter Action The estrogen environment influences the response of neuropeptide circuits involved in the regulation of reproduction. Novel results indicate, that estrogen-state determines the function of a large number of neurotransmitter circuits that have a profound impact on behavior. This panel will present evidence of estrogen modulation of four neurotransmitter systems: GABA receptors, endogenous opioid peptides, serotonin and purinergic receptors that influence physiology and behavior, as diverse as, reproduction, pain perception and depression. Ed Wagner will discuss the estrogen modulation of GABAB receptors on GABAnergic neurons that involves activation of an inwardly-rectifying K+ channel. Estrogen increases excitability of preop- tic area GABAergic neurons leading to an enhanced inhibitory tone. Kevin Sinchak will discuss estrogen activation of mu-opioid receptors in the pre- optic area and progesterone activation of opioid-receptor-like orphanin receptor in the ventromedial hypothalamus that accounts for an inhibition and subsequent facilitation of sexual receptivity. Cynthia Bethea will present data that 5-HT neurons containing estrogen receptor-ß are differentially regulated by the selective estrogen receptor modulators (SERM), tamoxifen and raloxifene. The ability of estrogens (and progestins) to alter serotonin function provides a cellular mechanism whereby ovarian hormones can impact mood, cognition, pain, and numerous other autonomic functions. Victor Chaban will discuss the estrogen inhibition of dorsal root ganglion (DRG) cells to the putative pro-nociceptive signal ATP. The estrogen inhibition of ATP activation of intracellular calcium concentration is dependent

78 on estrogen receptor-a which is associated with the plasma membrane. These data help explain the sex difference in pain perception.

Panel • Monday, January 27 • 7:30–9:30 AM • Wasatch B. Moghaddam, A. Grace, D. Weinberger, M. Laruelle Who Is the Boss? Prefrontal Cortical Interaction with Subcortical Limbic Systems As components of the limbic system, the amygdala, prefrontal cortex and ventral striatum are involved in interdependent functional modalities that coordinate emotional and cognitive behavior. In addition to the relevance of this circuit to basic brain function, characterizing the interaction between the corticolimbic regions has important implications for our understanding of the physiological basis of affective and cognitive disorders. In particular, these regions have been implicated extensively in the pathophysiology of schizophrenia and addictive disorders. The mechanism for the interaction between these regions is not clear but several ideas have been proposed. In particular, the PFC modulation of input from amygdala to the ventral striatum (nucleus accumbens) is thought to provide a mechanism where cognitive processes specialized to PFC, such as on-line reten- tion of internalized information, can influence the regulation of motor behavior by emotional, spatial and contextual inputs. There has been a surge of exciting basic and clinical research on this subject in the past few years. These studies have led to novel mechanisms suggesting that the prefrontal cortex may exert both excitatory and inhibitory influences on subcortical limbic systems and goal-directed behavior. The aim of this panel is to present these latest basic (Grace and Moghaddam) and clinical (Weinberger, Laruelle) findings, and to discuss the relevance of these new data to normal and abnormal cognitive and affective functioning.

Panel • Monday, January 27 • 7:30–9:30 AM • Maybird W. Macklin, J. de Vellis, I. Duncan, P. Knapp, R. Skoff Cell Death in the CNS: How Does Oligodendrocyte Death Impact Neurons? Oligodendrocyte cell death occurs during development and in pathological conditions, and this has significant impact on neuronal function, both developmentally and in the adult. This session will focus first on factors that induce oligodendrocyte cell death, and then on the consequences of oligodendrocyte survival or death for neurons. Dr. Macklin will provide an overview of factors that alter oligodendrocyte survival/death, and some of the clinical manifestations of axonal pathology following oligodendrocyte loss. Dr. Knapp will discuss “atypical” pro-apoptotic factors, including opiate peptides and perforin. These factors appear to have differential toxicity towards mature vs immature OLs and thus may differentially affect the

79 phases of demyelination and remyelination. In vivo studies focus on programmed cell loss after spinal cord injury and traumatic brain injury. Dr. de Vellis will discuss the role of 3 non-myelin genes (aspartoacylase, transfer- rin and glycerol phosphate dehydrogenase), whose expression is restricted to oligodendrocytes but which impact neuronal/oligodendrocyte function and pathology in animal models of Canavan disease, dysmyelination, and seizures. The myelin proteolipid protein (PLP) has long been studied as a myelin protein, but Dr. Skoff will present new findings on secreted factors from non-myelinating cells that express PLP, which contribute to neuronal death. Thus, these studies will discuss how PLP gene products may directly modulate neuron viability. Dr. Duncan will focus on the impact of PLP mutations on oligodendrocyte and axonal survival. He will discuss recent longterm studies on a PLP mutant, in which oligodendrocyte survival is impacted and axonal pathology results.

Panel • Monday, January 27 • 7:30–9:30 AM • Superior A L. Jasmin, S. Rabkin, M. During GAD Gene Therapy for the Treatment of CNS Disease Viral vector-mediated gene transfer is an efficient way to deliver specific transgenes to targeted groups of cells, resulting in the synthesis of a transgene product that will ultimately alter cell function. Epilepsy, Parkinson‚s disease and pain are common disorders that respond favorably to increasing the inhibitory neurotransmitter GABA in selected areas of the CNS. We will report how defective herpes simplex virus (HSV) vectors or adeno-associated viral (AAV) vectors expressing the two isoforms of the GABA synthesizing enzyme glutamic acid decarboxylase (GAD-65 and GAD- 67) are used as therapeutic tools by direct brain administration. Matthew During will show how, in Parkinson’s disease, AAV vectors are used to increase GAD expression in neurons of the subthalamic nucleus (STN) and shift the phenotype of these glutamatergic, excitatory cells to inhibitory. The resulting increase in GABA release in the outflow of the STN in the substantia nigra pars reticulata (SNpr) is associated with partial recovery in chronically parkinsonian rats, as well as neuroprotection to dopaminergic insults. The development of a clinical Parkinson’s Disease protocol based on this data will be presented. In epilepsy, increased GABA could decrease seizure threshold or inhibit seizure activity. Samuel Rabkin will show that defective HSV delivery of GAD65 to acute rat cortical slices results in focal inhibition of evoked epileptiform activity as determined by optical imaging methods. Luc Jasmin will show that modulating GABAergic neurotransmission in the cerebral cortex with locally administered GAD65 defective HSV vectors and GABA antagonists, bi-directionally alters the pain threshold of freely moving rats.

80 Panel • Monday, January 27 • 7:30–9:30 AM • Superior B S. Massey, M. Iuvone, S. Bloomfield, R. Taylor Neuronal Circuitry of the Mammalian Retina This is a time of unprecedented progress for retinal research. A new consensus is emerging on several key issues and for the first time, using a variety of new imaging, recording and molecular methods, we are close to identifying all the individual classes of retinal neurons. Steve Massey will show that rod and cone pathways are served by different circuits in the mammalian retina. Using triple label confocal microscopy, it has become possible to locate synaptic receptors and gap junctions at contact points between neurons and thus build up evidence for functional circuits in the retina. Mike Iuvone will focus on the genetic analysis of dopamine D4 receptors, which are expressed on photoreceptor cells in the mammalian retina. Pharmacological studies and experiments on knockout mice with a targeted deletion of the D4 receptor gene illustrate the roles of D4 receptors in retinal adaptation and in the regulation of photoreceptor biochemistry and gene expression. Stewart Bloomfield will report on correlated spike activity in dual recordings from alpha ganglion cells (a-GCs). The difference between the correlated spike activities of on- and off-center a-GCs reflects their different coupling patterns: neighboring off-center a-GCs are electrically coupled, whereas on-center a-GCs are not. Rowland Taylor will present patch recordings from directionally selective ganglion cells in the retina to illustrate the synaptic mechanisms involved. Extracellular recordings indicate that the key mechanism underlying direction selectivity is spatially asymmetric GABA inhibition, which counteracts excitation for motion in the null direction but not in the preferred direction.

Panel • Monday, January 27 • 4:30–6:30 PM • Ballroom 1 M. Picciotto, J. Dani, S. Heinemann, H. Lester Nicotinic Acetylcholine Receptors in the 21st Century: Genetic Manipulations of nAChRs in Mice The family of nicotinic acetylcholine receptors (nAChRs) has been a model for ligand-gated ion channels since Langley first described the “receptive substance” almost 100 years ago. These receptors are also notable because they are the molecular targets for nicotine in the brain and are involved in behaviors related to addiction, cognition and affect. The use of gene targeting in mice has identified physiological and behavioral properties of individual nAChR subtypes. Recently, the next generation of gene targeting techniques, including knockin, localized knockout and inducible expression, have been used to identify molecular, anatomical and temporal bases

81 for the actions of nAChRs in the brain. This symposium brings together laboratories applying these techniques to identify physiological and behavioral roles for nAChRs. John Dani will speak about nicotinic mutant mice as tools for neurophysiology experiments. Stephen Heinemann will discuss his approach for developing regional nAChR knockouts and will focus on analysis of mice lacking the beta3 subunit. Henry Lester will discuss lines of knock-in mice with graded gain of nAChR function due to point mutations in the M2 region of the alpha4 subunit resulting in neonatal death of dopaminergic neurons, altered nicotine-induced analgesia and hypersensitivity to ethanol. Marina Picciotto will discuss localized, conditional expression of high affinity nAChRs containing the beta2 subunit that have tetracycline- regulated expression of high affinity nAChRs in brain regions involved in different behavioral actions of nicotine. Use of these genetic techniques can unite the fields of molecular biology, biochemistry and physiology with the behavioral pharmacology of nicotine.

Panel • Monday, January 27 • 4:30–6:30 PM • Magpie S. Rayport, S. Sesack, D. van der Kooy, P. O’Donnell, R. Wise The Mesolimbic System and Reward — There’s More than Dopamine to the Story Dopamine dominates thinking about the mesolimbic projections and reward. However, the projections are not exclusively dopaminergic. GABAergic neurons—intermingled with dopaminergic neurons in the ventral tegmental area (VTA) of the midbrain—make up a significant minority of mesolimbic neurons, convey critical information, and undergo profound changes in responsiveness in drug dependence. Not only is there a significant GABAergic mesolimbic projection, but dopaminergic neurons themselves appear to corelease glutamate. The aim of the present panel is to review the evidence for these GABAergic and glutamatergic mesolimbic components and to discuss their role in the circuitry of reward. Susan Sesack will describe the morphology of VTA GABAergic neurons. In the VTA, these neurons receive different afferentation but project to the same regions as receive dopamine innervation, forming connections similar to those made by dopaminergic neurons. Derek van der Kooy will describe how during opiate deprivation, there appears to be a molecular switch in GABAa receptors on VTA GABAergic neurons from inhibitory to excitatory. In naïve rats, opiates injected into the VTA act through a non-dopaminergic projection from GABAergic neurons to the tegmental pedunculopontine nucleus in the brainstem, while during opiate withdrawal, opiates in the VTA cause reward via dopaminergic mesolimbic projection to the nucleus accumbens. Patricio O’Donnell and Stephen Rayport and will each present their data from intracellular recordings on the responses of n. accumbens neurons to ventral tegmental area stimulation. Together this work reveals both dopaminergic and glutamatergic components to the mesolimbic signal, which have potent implications for reward. The session will be chaired by Roy Wise.

82 Panel • Monday, January 27 • 4:30–6:30 PM • Wasatch M. Corbetta, D. Heeger, M. D’Esposito, L. Pessoa, G. Shulman Relationship Between BOLD-fMRI and Behavioral Performance Functional neuroimaging methods have been traditionally used to determine where‚ task-related activity is localized in the brain. However, more recently the development of event-related fMRI has allowed researchers to measure the response of the brain to single sensory, motor, or cognitive events. This opens the possibility of using neuroimaging as a way to understand how‚ a task is represented in the brain. Specifically, several laboratories are now focusing on whether bold deoxygenation level dependent (BOLD) signals measured with fMRI correlate or predict task performance. David Heeger will present data demonstrating that BOLD signals in human visual cortex are correlated with perception and performance accuracy. Gordon Shulman will present a quantitative model of visual search that accounts for a large fraction of BOLD signal variance over the brain, and will show that complex tasks in which the timing of cognitive operations depend on behavior can be accurately modeled with fMRI. Luiz Pessoa will show that fMRI signal amplitude during the delay interval of a visual working memory task predicted successful performance on a trial-by-trial basis in a network of fronto-parietal regions. Finally, Mark D’Esposito will address the relationship between individual differences in RT and accuracy and BOLD signals as a way to dissect different type of working memory operations supported by the human prefrontal cortex.

Panel • Monday, January 27 • 4:30–6:30 PM • Maybird J. Yin, M. Wooten, M. Sutton, T. Sacktor Atypical PKC: Neuronal Survival, Synaptic Plasticity and Memory Formation The PKC superfamily of protein kinases has long been implicated in a variety of neuronal processes, including synaptic plasticity and memory formation. In mammals, there are at least 10 family members that are subdivided into three subgroups (conventional, novel and atypical) based on structural motifs and co-factor requirements for activation. This molecular complexity has probably hampered previous efforts to ascribe function, since the pharmacological compounds and antibodies may not have been specific. The atypical subfamily does not require either calcium or phorbol ester for its activation. Work in a number of developmental and cellular contexts suggest that phosphorylation and protein:protein interactions may regulate activation of atypical PKC kinase activity. Marie Wooten will discuss the role of atypical PKC in NGF-mediated neuronal differentiation and survival in PC12 cells, linking “upstream” signaling to nuclear responses. Mike Sutton will describe the role that PKC, particularly the

83 truncated PKM form, has in intermediate phases of memory formation in Aplysia. This role in Aplysia is very similar to the role that aPKM activity plays in Drosophila memory formation, and Jerry Yin will discuss possible conserved cellular functions. Todd Sacktor will describe recent work demonstrating that aPKM activity is necessary and sufficient for the maintenance of long-term potentiation. These talks will highlight the emerging view that this kinase subtype plays critical roles in neuronal survival, plasticity and memory formation.

Panel • Monday, January 27 • 4:30–6:30 PM • Superior A D. Tso, V. Casagrande, D. Tsao, G. DeAngelis So Many Areas, So Little Time: Transformations of Visual Information in Extrastriate Cortex A long-standing question in systems neuroscience has been why there are so many visual cortical areas. More specifically, how do these extrastriate areas elaborate upon the receptive field properties and functional segrega- tions that begin in V1 (or earlier) and what is their raison d’etre? The current textbook description of the primate visual system depicts an arrangement in which specific types of visual neurons, neuronal pathways and cortical areas are specialized to handle particular visual attributes such as form, color, depth and motion. Within this framework, the processing of complex visual features is built upon the analysis of more basic features, a strategy that begins in the retina. Perhaps due to real-world time constraints, the visual system apparently accomplishes the processing required via parallel pathways, across multiple visual areas. At present, there is considerable debate and controversy over how specifically these computational tasks are accomplished and the contributions of the many extrastriate areas. New findings, however, including recent studies using modern functional imaging methods as well as standard recording techniques are beginning to reveal how higher order visual areas cooperate to yield visual perception and visually guided behaviors. This panel will present recent results on the role of extrastriate cortex, with a focus on the functional properties and organization of the extrastriate areas V2, V3/V3A and MT (V5), areas that all receive direct input from primary visual cortex (V1). We will begin with a short overview of the background and basic questions in the field to provide a backdrop for the recent findings that will be presented. We will then compare the functional organizations in visual areas V1 and V2 for orientation, color and disparity processing in Old World primates (Ts’o). Of particular interest is the transformation of the representation of color and disparity information between V1 and V2 and its implications for the concept of the cortical hypercolumn. Casagrande will explore these same themes in the prosimian as well as the New World primate, adding the insights that stud-

84 ies in V2 and V3 in these species provide on the segregation of the processing of object form and surface information. Tsao and DeAngelis will then examine in more detail how different extrastriate areas (V3/V3A and MT) contribute to the analysis of a particular attribute: binocular disparity processing for depth perception (stereopsis). Tsao will present comparisons of disparity processing in V1 and V3/V3A in both monkeys and humans, including an examination of the responses of these areas to zero vs non-zero disparities and absolute vs relative disparities. DeAngelis will discuss the role of disparity processing in area MT, in comparison to V1, including differences in the tuning properties of neurons in these areas, their functional organization and the possibility of a representation for 3D surface orientation. The presentations and discussions should provide an up-to-date sampling of the progression of functional properties between primary visual cortex and the extrastriate areas, and the interactions and cooperativity that leads ultimately to visual perception. however, including recent studies using modern functional imaging methods as well as standard recording techniques are beginning to reveal how higher order visual areas cooperate to yield visual perception and visually guided behaviors.

Panel • Monday, January 27 • 4:30–6:30 PM • Superior B Y. Shaham, P. Piazza, D. Lattemann, M. Dallman, U. Shalev Food Deprivation and Drug-Taking Behavior: New Insights to an Old Question It has long been established that food deprivation increases drug-taking behavior in laboratory animals. However, the neurobiological substrates involved in this effect are largely unknown. Our panel, which comprises of experts from the feeding and addiction fields, will present data on (1) new developments in the understanding of the CNS and peripheral physiological changes induced by food deprivation and how they may affect neuronal systems known to be involved in the rewarding effects of opioid and stimulant drugs, and (2) the neuronal and hormonal mechanisms underlying food deprivation-induced drug-taking behavior in rats and mice. Mary Dallman (UCSF) will provide a general overview of the physiological changes associated with food deprivation and how they affect the functioning of brain reward circuits. Dianne Lattemann (U of Washington) will discuss evidence for the effects of insulin and leptin on the function of the mesolimbic dopamine system. Her data suggest that these hormones, which vary dynamically during food deprivation, may serve as endogenous modulators of brain reward circuitry. Uri Shalev (NIDA/IRP) will present recent data on the involvement of the stress hormone corticosterone and of leptin in food deprivation-induced reinstatement of heroin and cocaine seeking following periods of withdrawal. P.V. Piazza (INSERM, France) will present recent

85 data indicating that an interaction between food deprivation and genetic background profoundly alters the rewarding effects of psychostimulant drugs in mice. These data will be put in the perspective of changes induced in the activity of the DA system and of glucocorticoid hormones by food deprivation.

Mini-Course • Monday, January 27 • 6:30 PM • Ballroom 1 D. Geschwind, K. Mirnics, C. Barlow, S. Ginsberg Microarray: To Do or Not To Do; If So, How To This mini-course course is a distillation of the microarray short course offered at the Society for neuroscience, but which is not being offered this year at SFN. The mini-course does not cover the entire field, but instead focuses on critical issues in experimental design and analysis so as to provide a practical foundation for those considering microarrays or those currently performing array experiments. The speakers and talks are designed to be complementary. Dr. Geschwind will provide a brief introduction, including an overview of the 3 NINDS/NIMH microarray centers which will serve as resource centers for the neuroscience community (he is a co-PI of the UCLA site). Dr. Mirnics will focus on basic issues of experimental design and analysis using cDNA microarrays (hybridizations and replicates, etc). Dr. Barlow will focus on the use of the Affymetrix plaftorm and its application to studying regional differences in gene expression within the brain. Other issues of great importance to neuroscientists, such as RNA amplification, tissue micro-dissection and the use of post-mortem tissues also will be covered by Dr. Ginsberg. The course would include the following faculty and presentations: D. Geschwind, Introduction K. Mirnics, Experimental Design from A to Z C. Barlow, Oligonucleotide Arrays, Regional and Cross Species Gene Expres- sion in the Brain (Affymetrix) D. Geschwind, Array Analysis and Bio-Informatics: After the List S. Ginsberg, Microdissection and RNA amplification

Panel • Monday, January 27 • 8:30–10 PM • Ballroom 1 P. Churchland, A. Raz, R. Adolphs, D. Tranel Decisions and Emotions in the Context of Free Will and Suggestion Philosophy and neuroscience intersect on questions concerning the causal antecedents of decision-making. Important issues include the role of emo-

86 tions in rational choice, the brain-regions involved in impulse control, the development of a neuroconscience, and top-down effects such as suggestion. Raz will begin the discussion by describing experiments showing that hypnotic suggestion can modulate reading Stroop words. He will present converging data from behavioral, optical and neuroimaging assays indicating that hypnotic and posthypnotic suggestion can exert top-down effects on attention and cognition. Tranel will discuss recent research concerning decision-making deficits in patients with ventromedial frontal cortex lesions. Adolphs will complement Tranel’s presentation with a discussion on the role of cortical structures in the right hemisphere on social judgments. Churchland will discuss these results in the broader framework of free will and responsibility, addressing the implications of a neural perspective on conscience, self, and self-control on issues in the criminal justice system.

Panel • Monday, January 27 • 8:30–10 PM • Magpie S. Leibowitz, B. Levin, E. McNay, N. Salem The Influence of Glucose and Lipids on Brain Functions This panel will present important research advances on the relationship of circulating metabolites to brain function. Recent findings support the possibility that dietary glucose and fatty acids may impact directly on gene expression and specific neural systems. This is illustrated by the work of Sarah Leibowitz, which demonstrates that dietary lipids, in particular triglycer- ides and fatty acids, as well as glucose alter the expression of hypothalamic peptides involved in controlling eating and body weight. Barry Levin will describe his research showing that hypothalamic glucosensing neurons actually sense a broader range of metabolic signals and are integral components of effector systems that regulate energy homeostasis. Ewan McNay will discuss his recent work showing how decreases in extracellular glucose levels in brain occur at times of increased cognitive demand. These changes are localized to brain areas involved in responding to such demand and may be reflective of limits on the cognitive function of these areas. Norman Salem, Jr., will demonstrate that dietary deficiency of sources of omega-3 fatty acids leads to a loss of brain docosahexaenoic acid, which in turn leads to decreased cell size in the hippocampus and cortex, decreased dendritic arborization, and a decrement in performance on spatial tasks and olfactory-cued discriminations. Collectively, these presentations will summarize the current status of research on mechanisms through which circulating nutrients alter central neural processes and function. This information may provide insight into the etiology of certain motivational and cognitive abnormalities.

87 Workshop • Monday, January 27 • 8:30–10 PM • Wasatch K. Frantz, G. Laviola, H. Steiner, W. Carlezon Changing Their Minds: Enduring Effects of Early Stimulant Exposure Recreational drug use peaks during adolescence and early exposure to drugs is a strong predictor of later drug use and dependence. To what extent do these trends reflect developmental changes in vulnerability to drugs such as psychomotor stimulants? Also what risks are inherent in childhood exposure to prescription stimulants such as methylphenidate? This workshop will address laboratory research on the acute and long-term consequences of early stimulant exposure. Giovanni Laviola (Italian National Institute of Health) will describe peculiarities in the behavioral repertoire of adolescent rodents, including risk-taking, impulsivity, and novelty-seeking. He will also report on behavioral and neuroendocrine responses to psychostimulants. Kyle Frantz (Georgia State University) will focus on an adolescent-specific dissociation between hyposensitivity to the motor effects of cocaine and adult-like sensitivity to its neurochemical and reinforcing effects. She will also discuss the effects of early MDMA (Ecstasy) exposure on cocaine self-administration in adulthood. Heinz Steiner (The Chicago Medical School) will analyze altered gene regulation by cocaine in the striatum of adult rats after repeated methylphenidate treatment during adolescence. His data corroborate behavioral cross-sensitization between methylphenidate and cocaine. Bill Carlezon (Harvard Medical School) will compare pre-adolescent (juvenile) with adolescent or adult exposure to methylphenidate. Juvenile-exposure increased aversive responses to cocaine and elevated expression of the transcription factor CREB in the nucleus accumbens. Taken together, these studies indicate that the enduring effects of stimulant drugs depend critically on age at exposure. Heinz Steiner (The Chicago Medical School) will analyze altered gene regulation by cocaine in the striatum of adult rats after repeated methylphenidate treatment during adolescence.

Workshop • Monday, January 27 • 8:30–10 PM • Maybird S. Pallas, E. Grove, J. Hebert, R. Erzurumlu Patterning of Sensory Cortical Areas: ␣ Nature AND Nurture? The most obvious organizing principle of mammalian cerebral cortex is its subdivision into multiple anatomically and functionally distinct areas. But how do these areas arise during development? There is apparently conflicting evidence on the relative roles of intrinsic genetic factors and extrinsic, activity-dependent factors in the gradual specification of individual corti-

88 cal areas such as somatosensory, visual, and auditory cortex. For example, transplants of presumptive visual cortex into presumptive somatosensory cortex have been reported by one group to induce somatosensory cortical specializations termed whisker barrels and by another group not to produce barrels. Cortical areas are always produced in the same location in normal cortex, and are reportedly shifted in predictable directions in certain gene knockout backgrounds, but when a portion of cortex is removed early in development, the entire cortical sheet apparently respecifies along with its thalamocortical input. Complicating the situation is a difference in the definition of an “area” between cortical researchers using genetic versus physiological/anatomical approaches. In this workshop, Elizabeth Grove will present her data on FGF8-induced functional respecification of somatosensory cortex. Jean Hebert will discuss his fgf8 and bmp4 knockout results showing that these factors can specify regional cortical patterning. Reha Erzurumlu will discuss the role of neural activity in patterning of thalamocortical projections and their target cells in the somatosensory cortex. Sa- rah Pallas will review evidence that changing the spatiotemporal pattern of activity during a critical period can change the functional identity of cortical areas, and discuss new evidence from deafened ferrets that activity can control the projection targets of thalamocortical afferents, and thus possibly respecify cortical areas. In the spirit of a workshop format, the focus will be on identifying areas of controversy, attempting to resolve conflicting evidence, and with audience input, developing a strategy for future experiments.

Workshop • Monday, January 27 • 8:30–10 PM • Superior A M. Bennett, K. Gale, V. Dawson, E. Aizenman Mortally Wounded and Still Talking? Protection and Rescue from Insult-Induced Delayed Neurodegeneration Neurological insults can cause delayed neurodegeneration, in that neurons recover from the initial insult but degenerate days later. Analyses of mechanism provide promise of rescue by post-insult intervention and of protection when an insult can be anticipated. Mechanisms for which there is evidence are embarrassingly many; our panel will address the members’ favorite candidates but acknowledge (and perhaps disparage) the candidates of others. A contrapuntal motif is apoptosis versus necrosis. Bennett will address global ischemia which causes downregulation of GluR2, formation of Ca2+-permeable AMPA receptors and excitotoxicity of endogenous glutamate through Ca2+ influx. Early activation of caspase-3, a supposed apoptotic death enzyme, is also observed. Ischemic precondi- tioning is protective and blocks GluR2 downregulation but not formation of activated caspase-3. Conversely, estrogen pretreatment is protective and blocks caspase-3 activation but not GluR2 mRNA downregulation. Gale will

89 consider the role of AMPA receptors in delayed death following seizures, in contrast to NMDA mediated death in in vitro models. Dawson will present evidence for the involvement of PARP in delayed degeneration in the pen- umbra of focal ischemic lesions, evaluated with high resolution MRI. She will also discuss death following formation of aggregates of abnormal proteins that appear to overwhelm the ubiquitin/proteasome pathway. Aizenman will regale us with the actions of methylisothiazolinone. This common ingredient of shampoos and cosmetics is bacteriosidal and neurotoxic. It acts via 12-lipoxygenase, ERK, PARP activation and DNA damage. Action on IQ of long-haired teenagers who keep their hair clean is uncertain.

Workshop • Monday, January 27 • 8:30–10 PM • Superior B R. Nixon, A. Cuervo, D. Sulzer, J. Keller Protein Indigestion in Neurodegenerative Diseases: How Do Neurons Spell Relief? Central to the pathogenesis of many late-age onset neurodegenerative diseases is an accumulation of mutant or abnormally folded polypeptides in neurons. While loss of protein function may be pathogenic in some cases, more often a gain of toxic function of the accumulated polypeptide seems more critical. In these cases, survival of the neuron may depend on how well it can mobilize its proteolytic defenses to degrade the offending polypeptide. Success, however, must be measured in terms of the neuron’s effectiveness not only in eliminating the polypeptide but also in keeping in check the potential for activated proteolytic systems to affect cells adversely. This workshop will review the mechanisms available to neurons to elimi- nate defective polypeptides and protein aggregates, emphasizing the importance of the proteasome and lysosomal systems. The influence of age- and disease-related alterations of these proteolytic systems on pathogenesis will also be considered. Jeff Keller will address changes in the proteasome proteolytic pathway that contribute to aging and neurodegeneration, emphasizing the role of heat shock proteins and protein aggregates in altering proteasome function. Ana Maria Cuervo will describe the handling of abnormal proteins by the lysosomal system and how aging alters the efficiency of these processes. Ralph Nixon will discuss how the pathways of autoph- agy and heterophagy are mobilized in Alzheimer’s disease in response to diminished proteasome function but, in doing so, create conditions favorable to b-amyloidogenesis. David Sulzer will present findings on the role of macroautophagy as a neuroprotective mechanism against dopamine protein adducts and pathogenic alpha-synuclein in neuronal culture models of Parkinson’s disease and methamphetamine-induced neurodegeneration.

90 Panel • Tuesday, January 28 • 7:30–9:30 AM • Ballroom 1 M. Zigmond, C. Cotman, W. Greenough, T. Schallert, M. Melnick Exercise is Not Just for Fun! Influences on Health and Disease Exercise has probably been associated with increased “brain power” since the ancient Greeks and even long before. Yet, it is only recently that neuroscience has begun to turn its attention to a systematic examination of this assumption and, finding it to often be correct, to understanding the underlying biology. Bill Greenough will begin by talking about the impact of exercise and enriched environments on synaptogenesis in cerebral cortex and the implications for cognition. Carl Cotman will then discuss the evidence that exercise can increase the levels of trophic factors in brain, particularly of BDNF in the hippocampus, and relate that to Alzheimer’s disease. Next, Tim Schallert will review studies on the impact of exercise on brain injury, with particular attention to stroke and Parkinson’s disease. Michael Zigmond will then discuss both cell culture and microarray studies that are helping us to uncover the mechanism by which trophic factors act to reduce the vulnerability of brain to injury. Finally, Marsha Melnick will act as a discus- sant, talking about the role that exercise and physical therapy can play in a program designed to promote health and avoid disease. Ample time will be provided for discussion.

Panel • Tuesday, January 28 • 7:30–9:30 AM • Magpie D. Kennedy, G. McCarthy, W. Wells, A. Toga, B. Rosen BIRNing Down the House: Biomedical Informatics and the Structure of the Brain Technological advances in neuroimaging have revolutionized the biomedical investigation of brain structure. In the past decade, this revolution has seen the ‘localized’ development of a wealth of critical data acquisition and analysis techniques. The next decade presents the challenge of how to ‘glo- balize’ these successes in order to realize the as yet unfulfilled potential of this revolution in the area of advanced diagnostic, prognostic and treatment monitoring capabilities in neurological and neuropsychiatric disorders. The NCRR-sponsored BIRN (Biomedical Informatics Research Network, http:// birn.ncrr.nih.gov/) initiative has established a federated neuroimaging database and the attendant infrastructure to serve as a test-bed for explora- tion of the technical, scientific, and sociological factors related to the conduct of clinical imaging studies across multiple sites, using the most powerful image analysis software regardless of development site, and to test new hypotheses on large collections of subjects with well characterized image and clinical data. Success in this effort will have a demonstrable and positive impact on progress in this field. In this session we explore current

91 issues in this effort which span from data acquisition, database structure, image analysis, to clinical applications. First, Bruce Rosen (Massachusetts General Hospital), will address issues related to data acquisition, including optimization and callibration, as well as surface based analysis of the cerebral cortex. Second, William Wells (Brigham and Women’s Hospital) will address issues related to database design, as well as mutual information- based tools for image registration and segmentation. Third, Arthur Toga (UCLA) will discuss large population tools for atlas creation and probabilis- tic analysis of brain morphometry in the normal brain as well as in patient populations such as Schizophrenia and Alzheimer’s disease. Finally,Gregory McCarthy (Duke) will focus on clinical applications areas such as depression and Alzheimer’s disease as exemplars of the power of the federated approach to the elucidation of the altered brain circuitry in these disorders. Discussion will be encouraged regarding development of a consensus on structural neuroimaging data collection and analysis procedures that will enable the global realization of the neuroimaging revolution.

Panel • Tuesday, January 28 • 7:30–9:30 AM • Wasatch G. Turrigiano, D. Johnston, R. Harris-Warrick, L. Griffith Plasticity of Intrinsic Neuronal Excitability Most neurons express a wide variety of voltage-dependent conductances that shape neuronal firing properties, the boosting of synaptic inputs, and the ability of somatic spikes to propagate into dendritic compartments. Sev- eral recent studies have shown that these conductances are an important locus of long-term plasticity, and that regulation of the balance of voltage dependent conductances can influence neuronal responsiveness and, ultimately, synaptic plasticity. In this panel Turrigiano will discuss both adaptive and non-adaptive changes in neuronal excitability in cortical pyramidal neurons, which may allow neurons to match their responsiveness to the frequency characteristics of their inputs. Johnston will discuss a mechanism that acts to globally depress neuronal excitability as a result of the potentiation of some inputs, which might help to selectively enhance the EPSP-spike coupling of the potentiated synapses. Many of these changes in voltage- dependent conductances rely on postsynaptic calcium influx. Griffith will discuss her use of in vivo recordings from identified Drosophila neurons to study the role of calcium/calmodulin-dependent protein kinase II (CaMKII) in intrinsic plasticity. She has found that both inhibition of CaMKII and expression of constitutively active CaMKII alter intrinsic excitability, and im- pair activity-dependent modulation of excitability. Finally, Harris-Warrick will discuss a novel, activity-independent mechanism by which increased expression of an A-type potasium channel is compensated for by increased expression of a functionally antagonistic Ih channel. Together these discussions will highlight the importance of intrinsic plasticity in the activity-dependent regulation of neuronal circuit properties.

92 Panel • Tuesday, January 28 • 7:30–9:30 AM • Maybird P. Iredale, D. Kendall, B. Martin, M. Abood Cannabinoid CB1 Receptors: Molecular Insights and Therapeutic Potential CB1 receptors are members of the GPCR superfamily and were first cloned in 1990. Since then their molecular characteristics have been extensively studied and links to numerous disease states investigated. The general aim of this panel is to review some of the understanding of how these receptors function and how this knowledge might be exploited to develop novel phar- macotherapies. Phil Iredale will begin by giving a brief overview of the CB1 field and the potential that exists for therapeutic intervention as well as some insights into receptor regulation. Debbie Kendall will continue by discussing the role that intracellular loop 3 plays in coupling the CB1 receptor to G proteins. This will include some NMR studies that provide evidence on the bound receptor state and provide a structural basis for distinguishing pref- erences for Gi and Gs association. This will be followed up by a presentation from Mary Abood describing the use of mutation studies to distinguish the binding site for aminoalklyindoles from other classes of cannabinoid agonists. In addition she will show evidence suggesting that pyrazole antagonists (typified by SR 141716A) and aminoalklyindoles may share a binding region, consistent with their structural similarities. Furthermore, modeling studies indicate that aromatic-aromatic stacking interactions in CB1 receptor helixes 3-4-5-6 may form this region. Billy Martin will move downstream of receptor activation to discuss the role that the endocannabinoid system plays in memory storage and how this knowledge might be applied to the development of cognition enhancers. He will describe studies using both the SR 141716A and mice lacking the CB1 receptor (CB1-/- mice). Data gath- ered from both models suggests that disruption of endocannabinoid signaling reduces how quickly a task is forgotten, but has no effect on initial learning. Furthermore, under certain circumstances this augmentation of memory may interfere with the learning of new information. The relationship between these two phenomena and the clinical utility of cannabinoid antagonists as cognitive enhancers will be further discussed.

Panel • Tuesday, January 28 • 7:30–9:30 AM • Superior A D. Chambers, U. Nordström, C. Kiecker, J. Gilthorpe The Development of the Embryonic Nervous System: From Global to Local Organization The CNS arises from a sheet of epithelial cells, the neural plate, which folds along its anteroposterior (AP) axis to form the neural tube. Subsequent morphogenetic events segment the CNS and define the fore, mid and hind-

93 brain and the spinal cord. This patterning process is accompanied by the refined commitment of neuronal precursor pools, firstly to distinct regions of the CNS and subsequently to distinct cell fates within those regions resulting in the complex but stereotypical neuronal architecture observed in the mature CNS. David Chambers will present a brief review of the general principles that are employed during AP patterning of the embryonic CNS. Clemens Kiecker and Ulrika Nordström will present novel data indicating that the Wnt/B-catenin signaling pathway acts in a graded fashion to im- part a crude AP pattern to the early neural plate. David Chambers will build upon these findings and describe studies that have elucidated the role of FGF-signaling mechanisms, positioned at the isthmus by earlier signaling events in the neural plate, in refining the specification of neuronal identity. Emphasis will be placed upon the characterization of the molecular effec- tors that define the positional identity of rhombomere1, which generates the cerebellum at later stages of development and is reliant on signals from the isthmus for its maintenance. Jonathan Gilthorpe will describe exciting new data that further refine our knowledge of cerebellar formation. Using a combination of cell labeling, co culture and time-lapse microscopy Jonathan will present evidence that details the origins and migratory behavior of rhombomere1-derived cells in the formation of the cerebellum. The panel will thus draw together some of the major molecular patterning events that are employed in the progression from a relatively homogenous sheet of neural cells to a complex structure of the adult CNS.

Panel • Tuesday, January 28 • 7:30–9:30 AM • Superior B J. Krystal, S. Zukin, P. J. Conn, B. Moghaddam NMDA-mGluR Interactions: Mechanisms and Potential Therapeutic Implications Our understanding of the neurobiology and psychopharmacology of glutamate systems is rapidly evolving. One feature of this evolution is a growing appreciation of the interrelatedness of ionotropic, particularly NMDA receptor-related, and metabotropic glutamate receptor function. The purpose of this panel is to examine NMDA-mGluR interactions from a translational neuroscience perspective. This perspective may help to link molecular and physiologic studies to medications development for neuropsychiatric disorders associated with disturbances in glutamate receptor function. The first presentation will be from Dr. Suzanne Zukin. Her presentation, titled “Molecular and cellular interactions between NMDA and mGlu receptors” will describe recent research related to physiologic function and receptor trafficking. The second presentation will be from Dr. Jeffrey Conn. His presentation, titled “Physiologic interactions between NMDA and mGlu receptors” will emphasize recent work on the interplay of group I mGlu and NMDA receptor function. The third presentation, by Dr. Bita Moghaddam, will

94 present, “NMDA-mGlu glutamate receptor interactions: from physiology to behavior.” This talk will describe the modulation of NMDA antagonist effects on cortical and limbic glutamate release and working memory in rats following pretreatment with agents that modulate mGluR function. Lastly, Dr. John Krystal will address possible clinical implications of the interplay between NMDA and mGlu receptors in a presentation titled, “Ef- fects of pretreatment with the group II mGluR agonist LY354740 upon ketamine-induced working memory deficits in healthy human subjects.

Panel • Tuesday, January 28 • 4:30–6:30 PM • Ballroom 1 M. Ariano, R. Levenson, F. Liu, D. Sibley DRIPs and Other Cellular Plumbing DRIPs are a growing list of Dopamine Receptor Interacting Proteins that have been identified using a variety of protein interaction screens. Many DRIPs are structural or cytoskeletal elements that contribute to the cellular “plumbing” and delivery of receptors to intracellular compartments. Actin, filamin, and spinophilin have been identified and their roles are to disperse the receptors intracellularly and anchor them in specific subcellular areas at or near the synapse. DRIPs may function in an analogous way to previously reported AMPA and NMDA receptor chaperones, e.g., GRIPs, but there are also unique associations between dopamine receptors and alternative receptor ionophores that confer a unique dimension to dopaminergic signaling. This panel will focus on DRIPs and their potential role in diseases with dopaminergic components by presenting the newest available data from leading researchers in this growing field. Dr. Levenson will describe various D2 and D3 DRIPs and their potential importance in the etiology of schizophrenia. Dr. Liu will provide evidence for the direct protein-protein interactions between D1/ D5 and NMDA/GABA receptors and their impact on synaptic signaling. Dr. Sibley will discuss the association of D1 with the intermediate sized neurofilament M DRIP and its role regulating D1 receptor sensitization, and D3/GRIP associations. Dr. Ariano will present work on the expression patterns of various striatal DRIPs in experimental Huntington’s disease mice models that show alterations in dopamine signaling. There will be ample opportunity for audience discussion of other potential DRIPs that may have roles in dopamine-based diseases.

Panel • Tuesday, January 28 • 4:30–6:30 PM • Magpie R. Olsen, J. Nymann-Andersen, B. Luscher, J. Kittler, W. Wisden

GABAA Receptor Synapses: Exciting Developments in Inhibition This panel of four speakers will describe new information about the role of associated proteins and subunit specificity in GABAA receptor (GABAR) synapse formation and stabilization. After a brief introduction by Richard Olsen,

95 Bill Wisden (Heidelberg) will talk about his use of gene-targeted mice to analyze GABAR targeting to synaptic and extrasynaptic membranes, in particular the difference between a synaptic subunit gamma 2 and a nonsynaptic subunit delta. Steve Moss (London) will discuss studies on the regulation of GABAR cell surface expression. He has found new proteins or implicated known proteins in GABAR synaptic plasticity: PLIC1, NSF, and adaptins. Jesper Nymann-Andersen (Los Angeles [YOUNG INVESTIGATOR]) will discuss the role of GABARAP in GABAR trafficking, surface expression, synaptic clustering, and turnover, as well as the difference in channel properties between clustered vs. non-clustered GABAR. Bernhard Luscher (Uni- versity Park, Pennsylvania) will talk about proteins involved in GABR cell surface expression and synaptic clustering, including gephyrin, GABARAP- like proteins, and GRAMP (GABA receptor-associated membrane protein). These presentations will give the audience an introduction to the established as well as hot new work on a topic, inhibitory synapses, increasingly appreciated as equally important with excitatory synapses in neuronal plasticity and CNS function.

Panel • Tuesday, January 28 • 4:30–6:30 PM • Wasatch F. Crews, M. Rao, J. Joseph, S. Goldman What Controls Neurogenesis? The formation of CNS cells throughout life provides new and exciting opportunities to understand plasticity in the brain, to understand the basic elements of environment brain structure interaction and to develop potential new therapies for brain disease. This panel will explore factors that regulate neurogenesis, e.g. stem cell mitogenesis, and the subsequent migration and differentiation of these cells into functional components of the CNS. Dr. Mahendra Rao will present studies on the regulation of fetal rodent and human stem cell integration, migration and differentiation in the adult brain. In vivo and in vitro studies using cell surface markers and treatment with growth factors and other agents that modulate cellular fate will be presented. Dr. S. Goldman will present studies examining methods of isolation of neural stem and progenitor cells and the behavior of these cells after transplan- tation in a model of demyelination. Dr. F. T. Crews will present studies investigating the effects of environmental enrichment, stress and ethanol on endogenous neurogenesis in rats. Hippocampal responses will be compared with those in the subventricular zone and frontal cortical areas. Dr. Jim Joseph will present studies investigating the effects of diet on neurogenesis and relate this to age related changes in cognition. He will discuss mechanisms that are involved in the effects of polyphenolics in dietary supplements that can increase neurogenesis and the relationship to improve cognitive behavior in senescence.␣ Together these studies cover a broad range of factors that control neurogenesis.

96 Panel • Tuesday, January 28 • 4:30–6:30 PM • Maybird G. Aguilera, S. Lightman, E. Teresawa, D. Klein Molecular Mechanisms of Cellular Feedback and Pulsatility in Neuroendocrine Systems Neuroendocrine secretion from the hypothalamus and pineal gland is responsible for controlling metabolic activity, reproduction, growth, and adaptation to internal and external environmental stimuli. An important characteristic of neuroendocrine systems is the presence of both diurnal and ultradian rhythms, which are essential for normal development and function of the organism. This panel will explore neuroendocrine pulsatility and molecular mechanisms responsible for generation of rhythmycity. Stafford Lightman will describe the characteristics of ultradian variations of the hypothalamic pituitary adrenal (HPA) axis, and how this pulsatile activity serves as a powerful mechanism to regulate tissue exposure to circulating corticosteroids. Greti Aguilera will show mechanisms including biphasic effects of glucocorticoids and sequential action of transcriptional activators and repressors capable to limit activation of corticotropin-releasing hormone expression and responses to stress. Ei Terasawa will describe how integration of neuronal and non-neuronal cells, can mediate synchro- nization of calcium oscillations and pulse generation in gonadotropin releasing hormone (GnRH) neurons, which is essential for synthesis and secretion of pituitary gonadotropins and normal reproductive function. Fi- nally, David Klein will describe a novel mechanism by which cAMP-mediated phosphorylation of serotonin N acetyl transferase promotes the formation of a protein complex, which enhances production of melatonin, a key mediator of circadian rhythmicity, by protecting the enzyme from protease activity and immediate degradation. Discussion of these topics will provide new insight on the multiple mechanisms mediating pulsatily and rhythmicity in neuroendocrine secretion, as well as opening novel perspectives for the development of diagnostic and therapeutic tools for neuroendocrine disorders.

Panel • Tuesday, January 28 • 4:30–6:30 PM • Superior A V. Zachariou, C. Wrenn, T. Bartfai, D. Wynick Galanin as a Multifunctional Neuropeptide: Pharmacological and Genetic Approaches Galanin is a neuropeptide with wide distribution and many functions in the nervous and endocrine system. A number of recent studies have shown that the galanin system is involved in Alzheimers disease, depression and neuropathic pain, but also modulates physiological processes such as ap- petite and neuroendocrine functions. In addition this peptide has poten-

97 tial therapeutic properties, such as analgesia or anticonvulsant actions. Galanin mediates its effects via activation of at least 3 different receptors with distinct pattern of distribution. Galanin receptors activate different second messenger pathways depending on the cell type and receptor subtype. This symposium will focus on pharmacological and transgenic approaches to elucidate the role of galanin in learning and memory, epilepsy, peripheral nerve injury and drug addiction. Dr. Crawley has examined the role of galanin in cognition using transgenic animal models. Dr. Bartfai will present studies on the anticonvulsant properties of non-peptidergic galanin analogues. Dr. Wynick will discuss his work on galanin knockout mice in studies of peripheral nerve injury and regeneration and Dr. Zachariou will describe work on the role of galanin in morphine dependence using both pharmacological and mouse genetic techniques. These studies provide evidence for potential therapeutic manipulation of the galaninergic system, a novel drug target.

Panel • Tuesday, January 28 4:30–6:30 PM Superior B D. Jaeger, S. Nelson, R. Sachdev, G. Arbuthnott Intracellular Recording in vivo: A Window to Observe Neural Computation in Action Intracellular recordings in vivo give a unique opportunity to follow the subthreshold membrane potential of neurons embedded in the network of the intact brain. In most cases a rich behavior indicating constant processing of thousands of synaptic inputs each second can be observed and analyzed for such events as input synchronicity or correlation to external events. This panel will present data showing how cortical and subcortical information processing can be examined using this method. Ed Stern will present about nonlinear integration of information from different synaptic sources in auditory cortex, and how that relates to processing of “natural” auditory stimuli. Sacha Nelson will describe in vivo whole cell recordings, which demonstrate that short-term synaptic depression at thalamocortical synapses plays an important role in rapid adaptation of whisker-evoked sensory responses in rat barrel cortex. Robert Sachdev will talk about how subthreshold fluctua- tions in membrane potential of somatosensory cortical neurons modifies their response to sensory stimuli. Dieter Jaeger will examine the question how the subthreshold membrane potential of medium spiny neurons in striatum is related to global cortical activity.

98 Special Issues Workshop • Tuesday, January 28 • 6:30 PM • Magpie K. Greif, P. Dickinson, S. Devoto, R. Jinks Small Science? The Facts and Myths about Research in Liberal Arts Colleges Interest in alternative careers in science has blossomed in recent years, among them academic careers in primarily undergraduate liberal arts institutions. A rich and active professional life in teaching and research is open to those who choose this career path. This workshop is intended to give a candid overview of what life is like as teacher/scholars at small liberal arts colleges. The speakers, all active neuroscientists in leading liberal arts institutions, will discuss both the challenges and rewards of balancing teaching and research. The characteristics of the range of liberal arts colleges will be described, from “mini” universities to purely undergraduate institutions. The benefits and limitations of working with undergraduates, as well as special funding opportunities for those in liberal arts colleges will be described. In addition, we will discuss the particular skills that make job candidates especially attractive in a competitive job market. We hope to clarify many misperceptions about the liberal arts environment, while honestly addressing the inevitable trade-offs inherent in a career in a small institution. This workshop will be useful both for mentors of graduate students and for those actively considering a career in a liberal arts college. small institution.

Panel • Tuesday, January 28 • 8:30–10 PM • Ballroom 1 B. Levin, D. Lattemann, B. Ransom, N. Sanders, I. Simpson When Life is Not Sweet: Brain Responses to Low Blood Sugar Hypoglycemia (low blood sugar) has become increasingly recognized as a serious clinical problem in the treatment of diabetes which has major detrimental effects on cognitive and neural function. The brain serves to both integrate information about the development of hypoglycemia and to activate the corrective, counterregulatory behavioral (feeding) and neuroendocrine responses. In this panel we will present current knowledge of how the brain senses and responds to changes in blood glucose, from the level of brain circuitry, to the cellular level (neurons and glia), to the molecular level (glucokinase and glucose transporters). Barry Levin will provide a brief clinical overview as introduction. Dianne Lattemann will describe brain circuitry critical to specific components of the neuroendocrine response to single or multiple bouts of hypoglycemia. Bruce Ransom will discuss the role of astrocyte glycogen stores in brain function during normo- and hypoglycemia, and will present new evidence regarding mechanisms of CNS axonal injury following hypoglycemia. Nicole Sanders will present data on

99 the role of glucokinase-containing (i.e. “glucose sensing”) CNS neurons in activating the feeding but not the neuroendocrine response to glucoprivation and low blood sugar. Ian Simpson will review the roles of the monocarboxylate and glucose transporters in the metabolic switching from lipids to glucose which occurs during normal postnatal development. To- gether, the speakers will summarize adaptive and maladaptive changes in the brain to physiological and pathological changes of glycemia.

Panel • Tuesday, January 28 • 8:30–10 PM • Magpie J. Horn, A. Fox, D. Weinreich Emerging Ideas on Synaptic Function in the Peripheral Nervous System Autonomic and sensory neurons provide simple systems for understanding the molecular basis of synaptic function and the consequences for circuit dynamics. This panel will outline complementary results that have recently emerged from three different model systems. First, Aaron Fox will discuss how chromaffin cells can be used to study the activity dependent modulation of calcium currents and will discuss the consequences for models of neurotransmitter release. Then, Danny Weinreich will present evidence for chemical communication between sensory neuronal cell bodies in dorsal root ganglia. Finally, John Horn will describe dynamic-clamp experiments using sympathetic neurons. In this system, one can examine how metabotrobic mechanisms modulate synaptic gain arising from the con- vergence of nicotinic synapses. The panel will then speculate on the consequences for systems function.

Panel • Tuesday, January 28 • 8:30–10 PM • Wasatch F. Henn, M. Kreek, K. Mann, Y. Shaham, R. Spanagel Stress, Endogenous Opioids and Relapse Behavior The complex relationship between stress and relapse behavior will be reviewed from a clinical perspective by M.J. Kreek. Here special emphasis will be given on HPA system activity and the involvement of endogenous opoid systems. K. Mann will describe the measurement of central µ-opiate receptors with [C-11]carfentanil and PET in human alcoholics. In his studies obsessive craving for alcohol correlated with a high availability of µ-opioid receptors in the bilateral orbitofrontal cortex and putamen. Time-dependent changes in stress- and cue-induced reinstatement of heroin and cocaine seeking along with long-lasting molecular correlates will be reported by Y. Shaham. R. Spanagel will describe different neurochemical and molecular pathways which result into alcohol relapse behavior. Data from these findings can be used for an individual adapted pharmacotherapy of alco- holism.

100 Workshop • Tuesday, January 28 • 8:30–10 PM • Maybird K. Keefe, J. McGinty, B. Yamamoto, P. O’Donnell Indices of Neuronal Function: Just Because You Believe It, Doesn’t Make It So Investigators interpret data using standard guidelines; but as new information becomes available, SOPs need to be re-evaluated. This workshop will explore assumptions and guidelines used to evaluate results obtained with different experimental approaches, and debate how these assumptions and guidelines affect the validity of different approaches as measures of “neuronal function”. The methodological approaches to be discussed will en- compass gene expression, neuropeptide transmission, extracellular sampling of biogenic amines and amino acids, and in vivo electrophysiology. Jakie McGinty and Kristen Keefe will address changes in gene expression as an index of neuronal function. Jakie will argue for the “standard” interpretation that increases in gene expression reflect neuronal activation, transmitter release, and compensatory increases in synthesis. Kristen will cite evidence from in vivo microdialysis studies of extracellular neuropeptides suggesting that this may not be so. Bryan Yamamoto will then discuss changes in extracellular neurotransmitters as measured with in vivo neurochemical approaches as indices of neuronal function. In particular, he will discuss how assumptions about synaptic vs. extrasynaptic sampling, uptake vs. release, and the importance of extrasynaptic events influence the interpretation of such changes as reflective of altered neuronal function. Patricio O’Donnell will provide the perspective of an in vivo electrophysi- ologist, addressing considerations needed to interpret changes in neuronal firing frequency or pattern as a measure of neuronal function. Presenters will each be limited to 5 min in which to make main points, with the re- maining time used for active discussions of alternative viewpoints provided by the audience.

Workshop • Tuesday, January 28 • 8:30–10 PM • Superior A H. Geller, J. Fawcett, D. Stein, B. Stokes, A. Schwartz Strategies for Recovery of Function after Nervous System Injury Nervous system function after injury, whether due to trauma or disease, is normally irreversibly altered. While certain kinds of insults are followed by spontaneous recovery of function, traumatic insults or certain diseases result in permanent damage. The objective of this blackboard-oriented workshop is to develop strategies for improving function after different kinds of brain injury/disease. Dr. Geller will act as a discussion facilitator. The other designated participants will contribute to outlining a general strategy for

101 improving recovery of function, including identification of the major issues that need to be addressed as well as potential therapeutic strategies, ranging from pharmacological to neuroprosthetics. Attendees will be expected to participate in refining the strategy. The overall result is intended to be a road map for future investigations.

Workshop • Tuesday, January 28 • 8:30–10 PM • Superior B A. W. Roe, N. Swindale, M. Tanifuji, C. Hung, L. Cohen Columnar Interactions in Neural Computation Optical imaging of olfactory bulb and somatosensory and visual cortex have revealed focal (<500 um) patterns of activation that are stimulus specific. What are the implications of these patterns for neural computation? Nicho- las Swindale will show how feature maps in V1 appear to be spatially orga- nized to ensure optimal and uniform representation of each possible combination of feature variables. Manabu Tanifuji will show how complex objects appear to be represented in IT cortex by a combination of feature columns. Lawrence Cohen will will provide contrasting views with optical imaging data from olfactory bulb. Chou Hung will present a model of how neuronal responses may be affected by the local spatial organization within these feature maps. The model suggests how differences in recurrent excitation and inhibition may result in boolean concepts such as AND, OR, and NOT functions and is proposed to explain such columnar interactions. The usefulness of these logical constructs will be evaluated and considered against a backdrop of experimental findings from primary visual cortex, inferotemporal cortex, and olfactory bulb. Participants are encouraged to suggest alternative models and interpretations of optically imaged results. Discussions are expected to draw interest from both experimentalists and modelers.

Panel • Wednesday, January 29 • 7:30–9:30 AM • Ballroom 1 M. Chesselet, H. Cline, J. Goldberg, L. Boulanger, T. Carmichael Used and Improved: Activity and Its Role in Growing New Connections in the Developing and Adult CNS Neuronal activity is critical for synaptic refinement; however, its role in the growth of neuronal processes has only been recently recognized. Further- more, molecular mechanisms linking neuronal activity and neuronal development are being identified. This panel will bring together investigators who have pioneered the notion that neuronal activity is critical for neuronal growth during development and after CNS lesions, and have elucidated new molecular mechanisms for the growth-promoting role of activity.

102 Holly Cline will report on the mechanisms by which activity regulates dendritic growth in vivo through glutamate receptors and Rho GTPase signaling (Li et al. Neuron 2002). Jeff Goldberg, from Ben Barres‚ lab, will show that physiological levels of neuronal activity profoundly affect axonal growth of retinal ganglion cells (Goldberg et al. Neuron, 2002). Lisa Boulanger, from Carla Shatz’s laboratory will discuss how members of the class I MHC gene cluster, which are expressed in an activity-dependent manner in CNS neurons, are required for normal activity-dependent modification of the strength and pattern of synaptic connections (Huh et al. Science, 2000 and unpub- lished data). Tom Carmichael will show that patterns of activity similar to those observed during phases of axonal growth during development are critical for axonal sprouting after ischemic cortical lesions in adults (J. Neurosci, in press). Together the panel members will present a set of complementary and provocative studies delineating new roles for neuronal activity in the growth and shaping of the nervous system during development, and the reactivation of similar mechanisms after lesions in the adults.

Panel • Wednesday, January 29 • 7:30–9:30 AM • Magpie J. Weiner, C. Valenzuela, A. Bonci, C. Lupica Novel Presynaptic Actions of Drugs of Abuse and Neuromodulators It is generally recognized that presynaptic mechanisms play a major role in regulating synaptic transmission and plasticity. However, the contribution of presynaptic mechanisms to the effects of drugs of abuse and endogenous neuromodulators is not as well understood. Many recent studies have demonstrated that a number of neuromodulators that were believed to act solely via postsynaptic mechanisms, also exert their actions by altering neurotransmitter release from presynaptic terminals. The goal of this panel is to bring together researchers that have discovered novel presynaptic effects of drugs and endogenous neuromodulators and to stimulate a discussion regarding the potential in vivo significance of these findings. Dr. Valenzuela will present evidence that memory-enhancing neurosteroids exert a potent facilitatory effect on quantal glutamate release in hippocampal neurons and that this effect requires activation of G protein-coupled receptors and an elevation in [Ca2+]i. Dr. Lupica will focus on the complex presynaptic effects of can- nabinoids on excitatory and inhibitory synaptic transmission. He will describe effects of CB1 receptor activation on GABAergic and glutamatergic synapses onto different classes of interneurons and principal cells in the hippocampus. Dr. Weiner will present recent evidence of a novel interaction between ethanol and presynaptic GABAB receptors in the hippocampus that serves to regulate the ethanol sensitivity of GABAergic synapses. Finally, Dr. Bonci will demonstrate that a single exposure to ethanol results in significant neuroadaptive changes in presynaptic GABAB receptor func-

103 tion at GABAergic synapses onto dopamine cells in the ventral tegmental area.

Panel • Wednesday, January 29 • 7:30–9:30 AM • Wasatch T. Hyde, W. Freed, T. Vasicek, N. Dovichi. C. Colantuoni New Technologies for an Integrated Investigation of the Human Genome, Transcriptome, and Proteome In recent years a myriad of new technologies have emerged which enable researchers to investigate biological systems like never before. In this session we will present a number of these technologies and describe how they can be used in combination to interrogate specific neurobiological questions. Dr. Thomas Hyde will open the session with an overview of basic issues in molecular biology as they relates to human disease research. Dr. William Freed will detail methods for the construction of and issues in the experimental use of custom cDNA arrays for gene expression analysis. Dr. Tom Vasicek will introduce a novel, open-architecture technology for RNA expression analysis: Massively Parallel Signal Sequencing (MPSS). MPSS is sequence and species independent, and can achieve a depth of mRNA characterization not attainable by conventional, or even microarray methods. Dr. Norman Dovichi will bring the discussion into the realm of proteomics. He will present the details of his newly developed protein detection and identification system: a two dimensional electrophoresis system with the power to resolve thousands of distinct protein components from a tissue sample, and sensitive enough to detect hundreds of such components from a single cell sample. Dr. Carlo Colantuoni will present general computational approaches and specific algorithms for the integration and analysis of these diverse data. Additionally, he will discuss the notion of hypothesis- driven functional genomics in neuropsychiatry: the integration of genomic DNA data with extensive RNA and protein expression data to yield basic insights into the impact of genetic variation on the molecular dynamics and higher functioning of the human brain.

Panel • Wednesday, January 29 • 7:30–9:30 AM • Maybird M. Binder, R. Brownstone, C. Heckman, R. Powers How Do Persistent Inward Currents Affect the Motor System’s “Final Common Path”? The capacity of mammalian motoneurons to generate persistent inward currents and the presence of a full array of voltage-gated conductances on motoneuron dendrites has prompted a re-evaluation of virtually every facet of motoneuron behavior. Much of the attention has been focussed on the

104 capacity of persistent inward currents in motoneuron dendrites to generate “plateau potentials” bistable discharge and self-sustained firing. How- ever, a number of other functions have been ascribed to persistent inward currents in motoneurons including sustaining repetitive firing, amplifying and “actively integrating” synaptic inputs, enhancing inhibitory control, and providing a major source of depolarizing drive to generate high firing rates. This panel will review what is presently known about the types and spatial distributions of membrane channels mediating persistent inward currents in motoneurons and describe how these currents shape motoneuron input-output functions. Rob Brownstone will discuss the potential contribution of non-inactivating dendritic calcium currents to integration in mouse spinal motoneurons. C.J. Heckman will describe the self-sustained firing and bistable behavior of cat spinal motoneurons, as well as the contribution that persistent sodium currents make to repetitive firing. Marc Binder will show how persistent calcium currents in the dendrites of rat hypoglos- sal motoneurons enhance the transfer of synaptic currents to the soma. Randy Powers will explore the various roles that persistent inward currents may make to motoneuron function using multi-compartmental motoneuron models with active dendritic conductances.

Panel • Wednesday, January 29 • 7:30–9:30 AM • Superior A E. Schweitzer, V. Wheeler, S. Finkbeiner, L. Ellerby Cellular Mechanisms of Pathogenesis in Models of Huntington’s Disease Huntington’s disease (HD) is a progressive neurodegenerative disease caused by an expansion of polyglutamines near the amino terminus of the huntingtin protein. Animal and cell culture models of HD are providing a wealth of clues about the cellular and molecular steps that accompany the disease process. These early events may serve as markers to monitor disease progression and to evaluate the effectiveness of therapeutic intervention prior to overt neurodegeneration, as well as to provide specific insight into mechanisms of pathogenesis. In some cases, identification of early steps in disease progression will provide targets for drug treatment. We will present data about early cellular events that antedate the appearance of overt pathology in knock-in mice (Wheeler). We will describe the intracellular dynamics of normal and expanded repeat huntingtin in cultured striatal neurons observed over days to weeks in the fluorescence microscope, and discuss the relationship between soluble huntingtin, aggregated huntingtin, and cell dysfunction (Finkbeiner). We will explore the importance of caspases in the cleavage of huntingtin and in disease progression in Htt YAC72 transgenic mice (Ellerby). We will describe the importance of proteasome-mediated degradation in both the removal of huntingtin and in the derangement of other cellular functions regulated by rapidly turned

105 over cytoplasmic proteins (Schweitzer). We will attempt to indicate how these various cellular phenomena may come together to cause dysfunction and eventual death of striatal neurons, and how the information provided by these studies may aid in the search for effective drug treatments for HD.

Panel • Wednesday, January 29 • 7:30–9:30 AM • Superior B D. Fink, T. Morrow, L. Sorkin, M. Pohl Understanding Pain: New Mechanisms and Novel Therapies Pain caused by damage to peripheral structures is a complex phenomenon, but recent advances have begun to elucidate mechanisms and suggest novel treatments. Tom Morrow (Michigan) will discuss supraspinal changes in brain activation that parallel the alterations in nociception in a model of painful diabetic neuropathy. Linda Sorkin (UCSD) will present evidence implicating tumor necrosis factor (TNF) in the pathogenesis of neuropathic pain, not only in the cell bodies of ligated axons but also in the DRG adjacent to the injury. David Fink (Pittsburgh) will present data showing that gene transfer of proenkephalin with HSV vectors can provide an anti- allodynic effect in the rodent model of neuropathic pain, and will discuss the results of recent experiments using a similar vector expressing the TNF- alpha soluble receptor in neuropathic pain. Finally Michel Pohl (INSERM, Paris) will present data demonstrating that targeted overexpression of proenkephalin from an HSV vector in sensory neurons of polyarthritic rats produces an analgesic effect and results in a long-term improvement of polyarthritis-associated disability suggesting a synergistic action of enkephalin on both inflammatory and painful aspects of the disease.

Panel • Wednesday, January 29 • 4:30–6:30 PM • Ballroom 1 D. Madison, J. Montgomery, L. Dobrunz, L. McMahon Modulation and Expression of Long and Short-Term Plasticity of CNS Synapses The mechanisms by which plastic changes in synaptic transmission are induced, expressed and regulated have become increasingly clear over the past few years. Both long-term forms of synaptic plasticity, such as LTD and LTP, and short-term forms such as facilitation and depression result from complex interactions between inducing synaptic activity, modulatory influences and intracellular expression mechanisms. What has become apparent is that much of the confusion in the understanding of plastic changes is that the kind of plasticity that is induced, and the mechanisms invoked depend strongly on the type of stimulus applied, the modulatory influences present at the time and the recent history of the synapses. This panel will

106 examine the latest findings in the regulation and expression of three forms of short- and long-term synaptic plasticity. Lori McMahon will discuss the modulatory influences of muscarinic activation on the induction of long- term depression in the hippocampus. Johanna Montgomery will describe the regulation of the trafficking of AMPA and NMDA receptors during the induction of long-term depression and how this depends on the plastic history of the synapse. Daniel Madison will describe new evidence that the movement of AMPA receptors in and out of the synaptic membrane is regulated by interactions between synaptic activity and PDZ-domain proteins in the postsynaptic spine. Lynn Dobrunz will provide new evidence on how the nature of the stimulus pattern dictates the direction and nature of subsequent plastic changes in synaptic transmission. Together, these presentations will provide a coherent picture of how synaptic activity interacts with the mechanisms inducing plasticity, and how these interactions can be modulated by the nature of the activity and external modulatory factors.

Panel • Wednesday, January 29 • 4:30–6:30 PM • Magpie D. Plenz, P. Bolam, A. Blackwell, J. Tepper, J. Wickens The Role of Inhibition in Striatal Function The role of inhibition in striatal function has always been controversial. Even though 98% of striatal neurons use GABA as the neurotransmitter, electrophysiological evidence for local inhibition has been surprisingly sparse. In particular, the absence of detectable inhibition between spiny projection neurons led to the view that local striatal GABAergic transmission was car- ried mainly by striatal interneurons. However, the specificity and overall function provided by striatal interneurons has been questioned because these interneurons comprise only 1–2 % of striatal neurons. The precise function of GABAergic transmission in the striatum remains difficult to understand because the reversal potential of GABAA synaptic currents in most striatal neurons is located between resting potential and spike threshold. Several recent findings have forced a reevaluation of our views on striatal inhibition. After a brief introduction by Dietmar Plenz into characteristics of GABAergic transmission and the concepts of lateral inhibition, Paul Bolam will provide an anatomical overview on GABAergic circuits in the striatum. Avrama Blackwell will present findings on the frequency and characteristics of glutamatergic and GABAergic inputs during Up- and Down-states in spiny projection neurons and fast spiking interneurons, and the contribution of GABAergic transmission to Up-state dynamics. Jeff Wickens will present findings on the probability of detecting inhibitory interactions between spiny projection neurons in brain slices, and their properties, and influence of these interactions on spiny neuron activity. Jim Tepper will discuss the role of fast spiking interneurons in the context of temporal modulation of spiking in striatal neurons through feed-forward networks. The

107 significance of these findings will be discussed in relation to current theo- ries of striatal function in basal ganglia disorders.

Panel • Wednesday, January 29 • 4:30–6:30 PM • Wasatch K. Topp, J. Garner, M. Smith, S. Gunawardena Intraneuronal Cytoskeletal Inclusions: Cause or Consequences? Good or Bad? The neuronal cytoskeleton plays a role in control of neuronal shape, axonal transport, neurotransmitter release, cell signaling and responses to cell injury. The accumulation of neuronal neurofilaments and/or associated cytoskeletal proteins is a hallmark of pathophysiology in several human neurodegenerative diseases and CNS injuries, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis and delayed neuronal degeneration following traumatic brain injury. Neurofilament phosphorylation appears to regulate the axonal transport of neurofilaments, and disease states may alter signal transduction mechanisms and thus neurofilament phosphorylation levels. There is debate concerning whether these cytoskeletal alterations represent a protective response of the cell or a sign of impending cell death. This panel will discuss cytoskeletal alterations that accompany disease and injury. TOPP will discuss alterations in neuronal intermediate filaments induced by systemic exposure to neurotoxic agents, including chemotherapeutic drugs. GARNER will discuss the cytoskeletal alterations that occur following viral infection of the neuron. GUNAWARDENA will discuss the disruption of axonal transport and neuronal viability by mutants in huntingtin and expression of polyglutamine repeats in Drosophila. SMITH will discuss the role of oxidative stress in the accumulation of neurofibrillary tangles in brains of individuals afflicted with Alzheimer’s disease. The panel will end with a discussion of whether the cytoskeletal alterations represent neuroprotective or neurodegenerative responses to cell injury.

Panel • Wednesday, January 29 • 4:30–6:30 PM • Maybird S. Potkin, W. Bunney, E. Gershon, T. Young, J. Kelsoe Mood Disorders: The Search for Candidate Genes and Pathways This panel will review the recent differences in gene expression revealed in cDNA array analysis in postmortem brain tissue of bipolar disorder patients using a variety of novel strategies. Bunney will present functional genomic differences, suggesting specific candidate genes and neuronal system pathways involved in bipolar disorder through contrasts in matched normal controls. RT-PCR and in situ hybridization data will be presented which

108 confirms differential expression patterns of specific genes observed by microarrays. Initial studies of 12,600 transcripts suggest specific pathways consistently altered in the anterior cingulate, in accord with brain imaging studies implicating cingulate dysfunction in mood disorders. Young, in the first recently published cDNA expression array study, observed a decrease in transforming growth factor beta1 (TGF-b1) and an increase in caspase-8 precursor (casp-8) expression in bipolar disorder. These results suggest down regulation of neural protective inhibitory cytokines could lead to neurotoxic insults etiologically related to mood disorders. In addition, Young has identified gene expression changes associated with lithium treatment response in transformed lymphoblasts. Animal models with differential expression can be used to generate candidate genes for bipolar disorder. Kelsoe will present results from microarray expression profiling studies of acute and chronic amphetamine treatment in rats, and a convergent approach that cross-indexes these results to linkage studies to identify candidate genes. Thus, G protein receptor kinase 3 gene on 22q11 was identified and mutations in the promoter associated with bipolar disorder discovered. Gershon will present a novel meta-analysis technique, Multiple Scan Prob- ability, which can be applied to whole genomic scans. Strong evidence for a susceptibility locus was found on 13q and 22q for bipolar disorder. The panel will summarize the power of these new approaches and recent data suggesting novel neural circuits underlying bipolar disorder.

Panel • Wednesday, January 29 • 4:30–6:30 PM • Superior A E. Albers, C. Colwell, D. Earnest, L. Morin Processing of Afferent Information in a Circadian Clock In mammals, the suprachiasmatic nucleus (SCN) functions as a circadian clock that generates rhythms in nearly all behavioral and physiological events. The 24 hr light-dark cycle synchronizes the circadian clock so that the rhythms under its control express a 24 hr rhythm. The light-dark cycle is able to synchronize the clock because light resets the timing of the clock on a daily basis. While light appears to be the most important agent for resetting the clock a variety of other stimuli (e.g. locomotor activity) are also capable of resetting the clock and altering the response of the clock to light. Several different afferent projections communicate these time cues to the SCN. How neurons within the SCN process afferent information is not well understood. The SCN is composed of a heterogenous population of neurons with complex synaptic relationships. The aim of this panel is to review current knowledge about the afferent input to the SCN and how this information is processed within the SCN. Larry Morin will discuss recent anatomical data on the terminal fields of afferent projections of the SCN. David Earnest will review the role of members of the neurotrophin family in modulating afferent input to the SCN. Elliott Albers will address the role of GABA

109 in processing afferent information within the SCN and Chris Colwell will discuss how vasoactive intestinal peptide modulates GABA-induced signaling pathways in the SCN.

Panel • Wednesday, January 29 • 4:30–6:30 PM • Superior B V. Dawson, G. Fiskum, I. Reynolds, G. Rintoul The Secret Life of Mitochondria The classic view of mitochondria is that of a bullet shaped remnant of a prokaryotic organism in a symbiosis with Eukarya, an event that occurred early in the evolution of life on earth. The “primary” function of mitochondria is energy metabolism within the cell. Recently our static view of mitochondria has been challenged by exciting new revelations that mitochondrial are physically active and mobile organelles with a highly dynamic, continuous reticulum that constantly undergoes fusions and fis- sions. The driving forces behind these behaviors are unknown. Ian Reynolds will present observations linking key proteins that promote either the fis- sion or fusion of mitochondria and discuss how this activity may impact on the viability of neurons. Gordon Rintoul will discuss the effect of glutamate activation of NMDA receptors on mitochondrial movement and shape. Other emerging data place mitochondria in a key position in the cell death process as gate-keepers and reliquaries of cell executioners, rather then just contributing to cell death by energy impairment. The role of mitochondria as judge, jury and executioner will be addressed by Gary Fiskum and Valina Dawson. Gary Fiskum will address activities of bcl-2 family members, mitochondrial free radical production, and mitochondrial heterogeneity. Valina Dawson will discuss PARP, PAR and AIF as key players in the cross-talk between the nucleus and mitochondria in the final execution phase of glutamate excitotoxicity.

Special Panel • Wednesday, January 29 • 8 PM • Ballroom 1 K. Olsen, C. Atwell, A. Leshner, M. Rasenick Setting the Nation’s Research Priorities: Neuroscience’s Piece of the Pie Over thousands of bills are introduced during each congressional session but only about 3% pass and become enacted into laws. The one thing that is certain in Washington is that each year Congress will “eventually” pass 13 appropriation bills that include the budget and written guidance to each federal agency. In a “McLaughlin-like” setting, this group will focus on the budget process and science policy formation and enactment from several perspectives including federal agencies ((NIH), professional scientific soci-

110 eties (AAAS), the White House (OSTP, OMB) and Congress (Appropriation and Authorization). Did you know that setting research priorities can require years of development and/or can happen what seems to be almost overnight? Do you know the role that you, as neuroscientists, can play in helping neuroscience get a bigger piece of the federal R&D pie and influencing priorities vital to your interests? Do you know all (or any) of the appropriate acronyms? There will be plenty of opportunity for interchange among the panelists and the workshop participants to discuss what goes on “inside the beltway” and anything else of interest.

Panel • Thursday, January 30 • 7:30–9:30 AM • Ballroom 1 J. Blendy, R. Maldonado, S. Heinrichs, B. Caldarone Evaluation of Addiction and Depression Phenotypes Resulting from Single Gene Mutations Gene targeting is a powerful approach to investigate gene function in the whole animal. Behavioral analysis of subsequent knock-out mice has identified phenotypes related to a variety of neuropsychiatric disorders including addiction and depression. The clinical co-morbidity of these disorders is well known, however few pre-clinical studies are aimed at investigating the overlap of addiction/depression phenotypes resulting from single gene mutations. Alterations in phenotypes associated with addiction and depression models in the same knock-out mouse could indicate a common molecule that links these behaviors. In support of this idea, it has been found that knock-out mice for the transcription factor CREB, display defects in motivational aspects of drug reward, as well as alterations in behaviors associated with antidepressant drug efficacy. The goal of this panel is to discuss recent research which evaluates overlapping phenotypes associated with addiction and depression in the same animal model. Dr. Julie Blendy will describe studies in CREB deficient mice, Dr. Rafael Madonado will discuss findings in mu-opiate mice, Dr. Stephen Heinrichs will describe the phenotype of CRH mutants in relation to addiction/depression processes and Dr. Barbara Caldarone will discuss effects of antidepressant drugs in neuronal nicotine receptor knock-out mice.

Panel • Thursday, January 30 • 7:30–9:30 AM • Magpie S. Levison, S. Goldman, D. van der Kooy, G. Fishell, S. Becker-Catania To Turn or Not to Turn: Extrinsic and Intrinsic Regulators of Stem-Cellness Understanding how stem cells are maintained as stem cells rather than dif- ferentiating into progenitors is a fundamental problem confronting devel-

111 opmental neurobiologists as well as neurobiologists interested in exploit- ing stem cells for cell replacement therapy. Whereas it was once postulated that stem-cellness was an intrinsic property of the stem cell, it recently has become evident that maintaining a precursor as a stem cell, perse, requires extrinsic and intrinsic signals. The experts on this panel will discuss new data on the mechanisms underlying the normal maintenance of neural stem cells and the signals that regulate their differentiation.␣ Dr. Gord Fishell will present data from in vitro and in vivo gain of function experiments that demonstrate that the Notch and FGF signaling pathways contribute to the formation and maintenance of neural stem cells. Continuing on this theme, Dr. Derek van der Kooy will present data that null mutations of the intracellular Notch signaling intermediates presenilin 1 and RBP-Jk decrease the capacity of neural stem cells within the embryonic mouse forebrain to self- renew.␣ Dr. Sara Becker-Catania will present data from in vitro studies using growth factors and small molecules, as well as environmental factors such as substrate to understand how these affect lineage determination during differentiation of rodent neural stem cells. Finally, Dr. Steve Goldman will discuss the roles of extrinsic signals in regulating the differentiation of neural stem cells into neurons vs glia, and will describe how these may be used to induce neurogenesis in otherwise non-regenersative regions in vivo.

Panel • Thursday, January 30 • 7:30–9:30 AM • Wasatch M. Salter, M. Browning, J. MacDonald The Many Faces of Protein Kinase Modulation of NMDA Receptors NMDA receptors play critical roles in development, plasticity and degeneration in the central nervous system. These receptors are targets for a variety intracellular signal transduction pathways, and protein phosphorylation has emerged as a principal convergent modulatory. Protein kinases may modulate the function of NMDARs through altering the channel gating properties. On the other hand, protein kinases may regulate the cell-surface expression of NMDARs and receptor trafficking to and from the cell surface. NMDA receptor subunits, postsynaptic density proteins and the kinases themselves form physically associated signaling complexes. In some in- stances, a signaling cascade involving the sequential activation of several kinases may be required for modification of receptor function. Phosphory- lation may also alter physical interactions between receptor subunits and other members of the signaling complex (i.e. PSD proteins) or alternatively modify the association of the complex with the cytoskeleton. The purpose of this panel is to bring together various investigators to discuss current issues in the regulation on NMDA channel function by kinases. John MacDonald will give a brief overview of the area and will discuss how G- protein coupled receptors link to NMDARs and synaptic plasticity via signal transduction pathways. Mike Browning will discuss the relationship

112 between NMDAR delivery and synaptic plasticity. Mike Salter will discuss the role of the mitochondrially-encoded protein, NADH dehydrogenase subunit 2 in the control of NMDA channel regulation by Src and its role in synaptic plasticity.

Panel • Thursday, January 30 • 7:30–9:30 AM • Maybird R. Foehring, A. Ribera, J. Surmeier, L. Kaczmarek, J. Trimmer Functional Roles of Identified Kv Potassium Channel Subunits in Neurons A major challenge is to relate the diversity of genes and molecules to neuronal functions. Potassium channels are particularly difficult because of staggering diversity and inadequate pharmacological tools. This panel presents diverse approaches to determining correspondence between specific Kv channel subunits and neuronal currents and functions. Dr. Trimmer will describe immunocytochemical and biochemical approaches to channel subunit expression and correspondence between Kv2 subunits and delayed rectifier currents in pyramidal neurons. He will also discuss the regulation of functional characteristics and localization of Kv2.1 channels by phosphorylation. Dr. Ribera will talk about developmental regulation of potassium channels containing Kv1.1 and Kv2.2 subunits in embryonic Xenopus spinal neurons. She will also discuss molecular mechanisms that maintain stable potassium current density in mature neurons. Dr. Kaczmarek will speak about pharmacological and genetic knockout experiments in mice, which indicate that the Kv3.1 subunit is required for auditory (MNTB) neurons to follow high frequency stimulation. Elimination of the Kv3.1 gene results in neurons that respond normally at lower frequencies, but are un- able to follow stimuli of > ~300 Hz. Short- and long-term mechanisms (phosphorylation, altered gene expression) adjust the amplitude of Kv3.1 currents to the pattern of synaptic stimulation received by the cell. Dr. Surmeier will discuss molecular, electrophysiological and pharmacological studies which suggest that a splice variant of the Kv3.4 subunit co-assembles with Kv3.1 subunits in fast spiking brain neurons. Co-expression of this splice variant with Kv3.1 subunits in HEK293 cells yield K+ currents that mimic those in neurons.

Panel • Thursday, January 30 • 7:30–9:30 AM • Superior A D. Gash, B. Hoffer, M. Traub, M. Tuszynski Trophic Factor Therapy: What Works and What Does Not Because of their potent neuroprotective and neurorestorative actions, trophic factors hold great promise for treating injuries and diseases effect-

113 ing the brain and spinal cord. However, this potential has yet to be realized, with no applications progressing beyond phase 3 clinical trials. Now, converging evidence from a number of laboratories suggests that targeted delivery to specific brain sites is necessary for efficacious effects. This session will review past and current strategies for trophic factor administration in the CNS of rodents, nonhuman primates and humans. Barry Hoffer will present an overview of trophic factors and their application in treating animal models of Parkinson’s disease, spinal cord injury and stroke. Michael Traub will focus on the lessons learned from clinical trials that have not demonstrated efficacy, including BDNF for the treatment of amyotrophic lateral sclerosis, NGF for the treatment of peripheral diabetic neuropathy and intraventricular GDNF for the treatment of Parkinson‚s disease. He will be followed by Don Gash, who will review new therapeutic approaches for GDNF treatment of Parkinson’s disease, including direct intraputamenal infusion. Mark Tuszynski will discuss trophic factor gene therapy and its application to treating spinal cord injury and Alzheimer’s disease. The new approaches of direct intraparenchymal infusion and gene therapy are in the early stages of clinical testing and promise to help realize the enormous potential of trophic factor therapy.

Panel • Thursday, January 30 • 7:30–9:30 AM • Superior B M. Ennis, L. Cohen, R. Friedrich Glomeruli: Dynamic Portals into the Olfactory Brain Main olfactory bulb glomeruli are the first site of synaptic integration in the olfactory system. Molecular studies suggests that each olfactory receptor neuron expresses only one type of receptor and that the ~10,000 scattered receptor neurons that express the same receptor send convergent axons to a single glomerulus on each side of each bulb. The basic circuit of the olfactory bulb is well known, but the role of glomeruli in odor processing is poorly understood. New work demonstrates that the glomeruli are not simple re- lay stations for transfer of odor signals, but instead, play an active role in shaping output of the bulb via mitral and tufted cells. Ennis will first provide an overview of bulbar circuitry emphasizing current understanding of the glomeruli. Cohen will then summarize new work from his group using functional imaging approaches to map glomerular odor responses, and data suggesting that glomerular neurons actively presynaptically regulate odor input. Ennis presents new electrophysiological data on intraglomerular synaptic interactions suggesting that interneurons of the same glomerulus are highly synchronous in a manner that “binds” the output of projection neurons of that glomerulus. Friedrich presents imaging and electrophysiology data illustrating the spatio-temporal oscillatory network dynamics and odor responses of mitral cells, which arise from dendrodendritic interactions between mitral cells and bulbar interneurons. Participants will pose their

114 work with a perspective for a new synthesis of olfactory bulb circuit function. The session concludes with a general discussion.

Panel • Thursday, January 30 • 4:30–6:30 PM • Ballroom 1 D. Bredt, K. Roche, P. Worley, V. Maricq Molecular Mechanisms for Postsynaptic Plasticity at Excitatory Synapses Excitatory neurotransmission in brain occurs primarily at glutamatergic synapses. Communication at these synapses participates in all aspects of higher brain function. In addition, use-dependent changes in strength of glutamatergic synapses provide an important mechanism for information storage and likely underlie aspects of learning and memory. Recent studies suggest that changes in the number of glutamate receptors at the synaptic membrane play a primary role in controlling postsynaptic plasticity. The importance of receptor trafficking has motivated intensive studies of the molecular mechanisms that control clustering of glutamate receptors at the synapse. This work has identified a variety of proteins “cytoskeletal, transmembrane and extracellular “ that interact with glutamate receptors. These associated proteins regulate many aspects of glutamate receptor cell biology such as promoting receptor biogenesis, anchoring receptors at the postsynaptic density, and controlling activity-dependent receptor cycling. Presentations in this panel will describe recent studies concerning the molecular underpinning of activity-dependent synaptic plasticity. David Bredt will describe recent work describing roles for the postsynaptic density protein, PSD-95, and the transmembrane protein stargazin in regulating AMPA receptor trafficking. Villu Maricq will discuss experiments using the power of invertebrate genetics to identify genes essential for glutamate receptor function and trafficking in C. elegans. Katherine Roche will present her lab’s work on cellular and molecular mechanisms that regulate clustering, stability and endocytosis of synaptic NMDA receptors. Paul Worley will discuss how activity-regulated gene expression can control synaptic function and plasticity.

Panel • Thursday, January 30 • 4:30–6:30 PM • Magpie C. Berridge, M. Solanto, X. Castellanos, R. Kuczenski, B. Waterhouse Neurobiology of ADHD: What Do We Know, What Do We Need to Know? Attention Deficit Hyperactivity Disorder (ADHD) was first described in 1901. Conservative estimates suggest a prevalence rate in the range of 2-5%. Cur- rently, the most effective treatment of ADHD is pharmacological, with am-

115 phetamine (AMPH)-like stimulants being the most widely prescribed. Be- tween 1990 and 1995 use of methylphenidate (Ritalin) for the treatment of ADHD increased 2.5-fold with approximately 1.5 million children aged 5- 18 receiving prescriptions for this drug in 1995. Despite its long history and high prevalence rate, our understanding of the neural bases of both the disorder and the therapeutic actions of AMPH-like stimulants has been extremely limited. This situation is changing with a number of recent observations from both human and animal studies providing new insight into both the origin of this disorder and the mechanisms underlying the therapeutic actions of AMPH-like stimulants. This panel will provide an overview of the clinical features and clinical pharmacology of ADHD (MS) and summarize recent findings from non-invasive imaging studies that point to possible neural mechanisms associated with this disorder, including possible frontostriatal dysfunction (FXC). Following this, recent observations regarding the actions of clinically-effective doses (e.g. low-dose) of methylphenidate on: 1) monoaminergic neurotransmission, as assessed by microdialysis (RTK); and, 2) thalamic and cortical information processing assessed using multiple-electrode electrophysiological recordings will be reviewed (BDW). Combined, these studies provide critical information for positing neural circuitry associated with the symptoms and treatment of this disorder. Additionally, these studies provide a roadmap for additional work essential for gaining a complete understanding of the neurobiology of ADHD.

Panel • Thursday, January 30 • 4:30–6:30 PM • Wasatch G. Wilcox, J. Wood, A. Oaklander, S. Lawson, M. Iadarola Hot Acid, Triple Phosphate and Chronic Pain: Vanilloid, ATP- and Voltage-Gated Cation Channels in Nociception Painful peripheral neuropathies are a serious problem for individuals with diabetes, cancer, and idiopathic neuropathy. Whereas mechanisms of acute pain transduction are well understood, the causes of neuropathic pain remain poorly characterized, making medical control of the pain difficult. Investigation of cutaneous sensory nerve endings has advanced clinical diagnosis and scientific understanding of normal and abnormal sensori-neural function. Recent molecular biological evidence from animal models strongly suggests the participation at least three distinct cation channels in abnormal sensitivity of neuropathic nerve terminals. This panel will profile those proteins from molecular definition to clinical implication of the role of sodium, ATP, and VR1 channels in development and maintenance of chronic pain. Anne Louise Oaklander will present compelling evidence that cutaneous denervation or dys-innervation accompanies most painful peripheral neuropathies. Sally Lawson will present neuroanatomical and functional descriptions of sensory neurons that express three voltage-gated sodium channels, NaV 1.7, 1.8 and 1.9. John Wood will define the contribu-

116 tion of ATP-gated channels (P2X receptors) in spontaneous pain accompa- nying normal pressure, thermal and tissue-damaging stimuli as well as address the possibility that they participate in neuropathic hypersensitivity. Michael Iadarola will discuss the role of vanilloid receptors (VR1) in chronic pain and the therapeutic sequelae of transient removal of VR1+ terminals or permanent deletion of VR1+ neurons. The objective of the panel will be to follow a full-circle pathway from clinical diagnosis through neuronal structure and function in the context of genomic expression back to therapies directed to cation channels expressed by nociceptors.

Panel • Thursday, January 30 • 4:30–6:30 PM • Maybird W. Spain, M. Scanziani, M. Hausser, D. Heck Spatial and Dynamic Influences on Coincidence Detection of Synaptic Inputs Coincidence detection (CD) is the operation performed by a neuron when it responds maximally to simultaneous inputs. Examples of functions, where CD is proposed as the primary mode of rapid signaling, include sound localization and pattern recognition. Postsynaptic membrane properties, circuitry and synaptic properties set limits on the ability of a neuron to perform CD vs. temporal integration and thus determine whether a neuron will primarily code information about the timing vs. the intensity of its inputs. The limiting mechanisms are not stationary and thus a neuron may use different coding strategies under different conditions. Bill Spain will provide a brief introduction and discuss work contrasting synaptic integration in cortex vs. the auditory brainstem focusing on the neuron’s average output spike rate as a code for input timing. For firing rate to be an effective CD signal it must represent the relative timing of inputs both sensitively and specifically. He will discuss mechanisms that allow for this sensitivity and specificity under a wide range of input intensities. Massimo Scanziani will show how the operating mode of a neuron depends on the characteristics of the network it belongs to. He has found that incoming monosynaptic excitation of hippocampal neurons is followed by precisely timed inhibition. This standard EPSP/IPSP sequence effectively reduces the integration time window of pyramidal neurons down to few milliseconds, thus transforming these neuron into precise coincidence detectors. Mike Hausser will discuss experiments using a combination of dendritic patch-clamp recordings and two-photon imaging to investigate CD in dendrites of cerebellar Purkinje neurons during conjunctive activation of climbing fiber and parallel fiber input. Detlef Heck will discuss the influence of background activity on CD by neocortical pyramidal neurons in vivo. He will describe the interaction of background activity and intrinsic membrane properties in determining CD, and how these interactions influence receptive field dynamics in sensory cortex.

117 Panel • Thursday, January 30 • 4:30–6:30 PM • Superior A E. Jonas, L. Dugan, S. Hewett, D. Nicholls When Bad Things Happen to Good Brains: The Contribution of Mitochondrial Dysfunction to Neural Cell Injury Following Hypoxic/Ischemic Events As we are all taught in grade school, the chief function of the mitochondria is to create energy for cellular activity by the process of aerobic respiration. Over the past decade, however, there has been a dramatic increase in our understanding of the central role that defective mitochondria play in a variety of human diseases. This is especially true of conditions affecting the nervous system, where mitochondrial dysfunction may be a key pathophysi- ological process in both acute and chronic disorders. With respect to the former, studies on mitochondria isolated from ischemic brain and from in vivo metabolic imaging studies reveal that ischemia-reperfusion can cause alterations in mitochondrial function with impairment lasting for hours- to-days after the ischemic insult. This panel will address the numerous ways by which hypoxic-ischemic insults could result in mitochondrial dysfunction and an exacerbation of neuronal injury. Sandra Hewett will begin the session by providing an historical perspective on the heretofore proposed/ purported and published mechanisms by which mitochondrial dysfunction contribute to hypoxic-ischemic and excitotoxic insults. Laura Dugan will discuss the differential responses of astrocytic and neuronal mitochondria to hypoxic-hypoglycemic insults with respect to changes in mitochondrial membrane potential and reactive oxygen species generated. Elizabeth Jonas will discuss the role of hypoxia-induced mitochondrial ion channels, including those of the BCL-2 family, and discuss their contribution to the decline in synaptic function that follows hypoxic insults. Finally, David Nicholls will tackle the general question of bioenergetic supply and demand during glutamate excitotoxicity describing the critical steps at which a lack of ATP becomes cytotoxic. Knowledge of these events may contribute to the development of strategies to target the mitochondrial component of ischemia to limit cell damage.

Panel • Thursday, January 30 • 4:30–6:30 PM • Superior B A. Bonci, D. Ron, J. Gutlerner, C. Paladini AMPA and NMDA Receptors: From Synaptic Plasticity to Drug Abuse AMPA and NMDA receptors play a key role in mediating addictive behaviors produced by drugs of abuse that have quite different pharmacological properties, such as ethanol, cocaine and amphetamine. The speakers on

118 the panel will present data that elucidate the effect of different drugs of abuse on AMPA and NMDA currents. Dr. Dorit Ron (Gallo Center UCSF) will describe a molecular mechanism that accounts for the brain region specificity in ethanol’s actions on the NMDA receptor. Dr. Ron will present evidence in slice preparations and in vivo to suggest that the brain region specific compartmentalization of the tyrosine kinase Fyn by the scaffolding protein RACK1 determines NMDA receptor sensitivity to ethanol. Dr. Johanna Gutlerner, (Brown University) will present data to clarify the mechanism of the block of LTD by amphetamine in the VTA dopamine cells. Specifically, Julie will provide evidence that elucidate the role of the cAMP-PKA signaling pathway in the VTA on the modulation of LTD. Dr. Antonello Bonci (Gallo center, UCSF) will present data regarding the characterization of the mechanism through which exposure to cocaine induces LTP. Antonello will present evidence that in the VTA cocaine increases NMDA current through activation of post-synaptic D1-like receptors. Such an effect is cAMP and PKA- dependent, and might represent the initial change that might enable VTA dopamine neurons to express LTP after exposure to cocaine. Finally, Dr. Carlos Paladini (Vollum Institute) will show that activation of a1-receptors produced an inward current, while brief exposure to an a-1 agonist, mimicking normal synaptic transmission, resulted in an outward current. This work demonstrates that a-adrenergic receptors can mediate very diverse, even opposing, cellular responses depending on the duration of noradrena- line exposure.

Panel • Thursday, January 30 • 8:30–10 PM • Ballroom 1 D. Ron, S. Finkbeiner, W. Carlezon, S. Patterson, P. Janak CREB, Plasticity, and Behavior Neuronal plasticity underlies adaptive behavior, such as learning, as well as detrimental disease states, like addiction. Neurobiological and behavioral studies indicate that such long-term changes in neuronal function depend upon induction of gene expression. Calcium is an important second messenger that mediates changes in gene expression. Activation of ligand- and voltage-gated ion channels increases intracellular levels of calcium, which in turn leads to the activation Ca2+/calmodulin-dependent kinase IV and/ or Ras/MAP kinase pathways leading to the phosphorylation and activation of the transcription factor, cAMP response element binding protein (CREB). CREB in turn mediates the induction of genes (Prodynorphin, BDNF, etc.) that regulate activity within neurons and neural circuits through a variety of mechanisms. For example, the CREB-induced neurotrophic factor, BDNF, is an important player in synaptic functions such as long-term potentiation (LTP). In this session, the four speakers will present molecular, physiological and behavioral studies that reveal the importance of CREB and CREB-mediated genes on plasticity and behavior. Dorit Ron (Gallo Cen-

119 ter/UCSF) will start by providing a brief overview. Steve Finkbeiner (Gladstone Institute/UCSF) will describe mechanisms of NMDA-receptor mediated changes in CREB-dependent gene expression. William Carlezon (McLean Hospital/Harvard Med. School) will describe the relationship between CREB activation in a specific brain region, the nucleus accumbens, and reward-related behavior. Susan Patterson (Columbia University) will focus on the role of BDNF in late-phase LTP. Finally, Patricia Janak (Gallo Center/UCSF) will describe how changes in BDNF alter ethanol‚s behavioral effects. The goal of this panel is to bring together exciting new work from different disciplines on the detailed mechanisms whereby CREB and CREB-associated genes plasticity lead to changes in cell function and behavior.

Panel • Thursday, January 30 • 8:30–10 PM • Magpie G. Schoenbaum, A. Kelley, J. Parkinson, S. Floresco, B. Setlow The Role of Ventral Striatum in Goal-Directed Behavior and Response Selection While the ventral striatum (VS) is involved in behavior guided by motivational information, the critical role of this region has yet to be clearly defined. For example, is VS critical for encoding associative information, or is its role limited to its use, and does VS serve a more general role in instrumental performance? This panel will consider these and other issues. Ann Kelley will begin by discussing the role of corticostriatal networks in guiding instrumental responding. Data will be presented on the effects of neu- ropharmacological manipulations of corticolimbic systems on the acquisition of instrumental responding. These data indicate that plasticity in VS may serve a fundamental role in selecting adaptive responses. John Parkinson will expand on this idea, discussing the role of cortical input to VS in instrumental and Pavlovian settings. These data suggest that VS se- lects among multiple convergent inputs to determine the appropriate response. Next, Stan Floresco will discuss electrophysiological data on the integration of limbic and dopaminergic inputs in the VS and prefrontal cortex. These data reveal that dopamine may gate neural activity in both VS and prefrontal cortex. The similarity between this function and the putative role of VS in response selection will be considered. Finally Barry Setlow will discuss the role of VS and input from basolateral amygdala in guiding responses based on motivational information. These data suggest that representations of value in basolateral amygdala are critical during learning, whereas representations in VS may be more important for the use of this information.

120 Workshop • Thursday, January 30 • 8:30–10 PM • Wastch E. Keller, A. Schwartz, L. Young, D. Guitton Distributed Neural Coding: Facts and Fiction It is now widely accepted that both sensory and motor functions in the central nervous system are represented by distributed systems of neurons. Nev- ertheless, this recognition provides little understanding of the actual mechanisms involved in information transmission or decoding. Indeed, is it even necessary that the brain decode its distributed activity to accom- plish behavioral results? What advantages are gained from a distributed representation beyond that which could be had with single exemplar neurons? The goal of this workshop will be to generate a discussion on these and other questions about distributed neural coding. Andy Schwartz will start the discussion with a brief presentation of the population vector algorithm (PVA), which has provided a successful explanation of motor cortex control of limb movement. Although the method gives observers a way to decode brain activity, it may not be the way the brain works. Instead a distributed representation may be maintained even at the level of the spinal motoneurons. Larry Young will consider the topic of noise reduction that may be gained by population processing and use data from semicircular canal neurons to start the discussion. If neural noise reduction is one goal of population processing, how is it that only a handful of neurons in cortical area MT are needed to explain visual motion encoding? Ed Keller will focus the discussion on vector averaging versus vector summation processing of distributed information. Do the results obtained following lesions in distributed motor maps prove that vector averaging is used by the nervous system to decode motor commands? Dan Guitton will raise the issue of how feedback about gaze dynamics can be implemented in distributed motor maps. Does this process lead to motor control by dynamic shifts of population activity during movements?

Workshop • Thursday, January 30 • 8:30–10 PM • Maybird J. Joseph, M. Smith, D. Morgan, A. Butterfield, P. Coleman A Requiem for Amyloid Beta? Much like the old science fiction movies of the ‘50s it appears that amyloid beta is “The Peptide That Wouldn’t Die.” We all know the drill, for it is the stuff of legends. Scientist is trying to do something good for the world, creates monster. The MONSTER CANNOT BE KILLED. Monster eats its cre- ator, as well as San Francisco or Tokyo. Scientists finally figure out how to destroy the monster. Well in this case the monster is amyloid beta and the

121 concept that it is necessary for AD has been created by scientists presumably for the good of mankind who tell us to “study its signaling, processing and the toxicity and you will develop a ‘cure’ for this terrible disease”. The Monster is created and dominates the Alzheimer literature, eating virtually all of the AD research funds available. IT CANNOT BE KILLED. Can clever scientists kill this monster? Given the lack of progress toward an AD treatment by this focus, can we finally have a requiem for amyloid beta, and explore other research options or should we? The purpose of this workshop is to discuss these possibilities. Paul Coleman will serve as moderator Mark Smith will discuss the protective role of amyloid beta in this disease. Allan Butterfield will discuss the oxidative stress and neurotoxic properties of amyloid beta. Jim Joseph will provide evidence showing that the major factor involved in AD is aging and Dave Morgan will describe data to show the importance of amyloid beta in behavioral deficits in AD transgenic mouse models. Presentation times will be kept to a minimum to facilitate a lively discussion and idea exchange.

Workshop • Thursday, January 30 • 8:30–10 PM • Superior A R. Dermietzel, D. Spray, M. Bennett, B. Ransom, M. Nedergaard Hemichannels in glia? Fishing for Function Gap junctions form electrical and metabolic avenues between adjoining cells for direct signal propagation and exchange of metabolites. Macroglial cells, and particularly astrocytes, are extensively coupled by gap junctions, thus creating a functional syncytium which allows buffering and dissipa- tion of ions as well as signal transmission. The classical functions of glial gap junctions have now been challenged by findings which support physiological clues for gap junction hemichannels. This workshop will focus on recent data which speak in favor of hemichannel prevalance in glia attributing new vistas to gap junction function. To give an introductionary overview of the biophysical properties of hemichannels we will first describe the electrophysiology and pharmacology of hemichannels as evidenced by expression in Xenopus oocytes (Michael Bennett). Thereafter, structural evidence is presented indicating direct visualizing of hemichannels in glia cells (Dermietzel). Finally, experimental data on hemichannel expression in astroglia and their relevance for cell survival (Ransom) and ATP release through hemichannels as a novel signaling pathway of intercellular communication in astrocytes will be discussed (Nedergaard). The session will end with a critical overview by the session co-chair (Dave Spray) question- ing the funcitonal existence of hemichannels.

122 Workshop • Thursday, January 30 • 8:30–10 PM • Superior B G. Meredith, K. Gale, G. Arbuthnott, T. Napier, P. Sullivan All Species are not Created Equal: Differential Responses to Neural Damage There is now abundant evidence that across species and across strains (within species), there is differential susceptibility to neuronal damage. Not all animals are alike in terms of the damage induced by specific neurotox- ins, such as MPTP, 6-OHDA, kainic acid or psychostimulants, or the functional responses to these agents (e.g., seizures). This creates difficulty in making comparisons across animal models and poses limitations in the applicability of specific models across animals and to humans. What are the major differences between strains or species? How do different systems (limbic, basal ganglia, spinal cord) respond functionally to neurodegenerative processes induced by toxic agents? On what basis should a strain be selected for studies of neurodegeneration? What are the mechanisms underlying the differential responses to neurotoxic agents? The fact that a mouse strain that is sensitive to MPTP toxicity is especially insensitive to excitotoxic injury indicates that variations in vulnerability may be mechanism-specific, intrinsic differences in mitochondrial resistance to Ca2+ overload will be discussed as a novel candidate mechanism for the divergence in excitotoxic sensitivity seen in different strains of mice as well as in the differential sensitivity of immature vs mature rats. Overall, we will focus on rodent-primate and mouse-rat differences, as well as on differences between specific mouse strains. We will challenge the audience to look at the degree to which their own work is “species bound” and share observations of inconsistencies across models using different animals.

Panel • Friday, January 31 • 7:30–9:30 AM • Ballroom 1 E. Pehek, K. Herrick-Davis, L. Mignon, K. Cunningham, L. Tecott The Serotonin-2C Receptor: Structure, Function and Interactions with Dopamine Systems The goal of this panel is to provide an overview of current research on the structure and function of the serotonin-2C (5-HT2C) receptor. This receptor is interesting because it has been implicated in the control of motor function, anxiety, and the actions of antipsychotic and psychostimulant drugs. The panel will begin with Kathy Herrick-Davis, who will provide a brief overview of receptor structure, brain distribution, function, and pharmacology. She will discuss how RNA editing regulates receptor constitutive activity and the effect of atypical antipsychotic drugs as 5-HT2C inverse agonists. Laurence Mignon will then discuss the role of the 5-HT2C receptor in regulating movement control in a normal and a dopamine-depleted state, as

123 seen in Parkinson’s disease. Data will be presented showing changes in gene expression following stimulation of 5-HT2C receptors. Lastly, she will discuss behavioral data showing the effects of administration of a 5-HT2C agonist on orofacial dyskinesias. Subsequently, Kathy Cunningham will share work from her laboratory. Pharmacological analyses suggest that 5-HT2A and 5-HT2C receptors provide a balanced excitatory and inhibitory influence on the expression of psychostimulant behaviors, respectively, that is based upon their specific regional and cellular localization in mesocorticolimbic pathways. Kathy will discuss the research (pharmacological, molecular, anatomical, behavioral) in support of this hypothesis and the implications for our understanding of addictive processes. Larry Tecott will then conclude the panel with a summary of his work in mice with a targeted mutation of the 5-HT2C receptor. These mice display multiple phenotypes including late-onset obesity, enhanced psychostimulant responses and enhanced neuronal network excitability. Larry will discuss the implications of his work for neuropsychiatric conditions such as eating disorders, and drug abuse. It is hoped that the multidisciplinary approach of the panel will generate vigorous discussion.

Panel • Friday, January 31 • 7:30–9:30 AM • Magpie P. Kalivas, V. Parpura, R. Bergeron, R. Schwarcz Blue to White Collar: The Evolving Role of Glia in Neurotransmission The view that glia exist to service the metabolic needs of neurons is transforming into an understanding that glia are collaborating with neurons to define the quality and content of communication within the CNS. It has long been known that glia scavenge the extracellular space of amino acid transmitters, providing a mechanism for metabolic recycling. Recent studies demonstrate that not only do glia express receptors for many classic neurotransmitters, but glia have mechanisms for releasing glutamate and kynurenate to regulate glutamatergic receptors. In the proposed panel, all speakers will emphasize the ‘active’ role played by glia in neurotransmission. Dr Bergeron introduces glial physiology, emphasizing a role in excitatory neurotransmission and the impact this may have on neuropathologies. Dr Schwarcz will discuss the regulation of kynurenic acid by glia and the capacity of kynurenate to regulate both NMDA and alpha7 nicotinic receptors. Dr Kalivas will discuss glial cystine/glutamate exchange as the primary source of extracellular glutamate, and present evidence that glutamate derived from cystine/glutamate exchange regulates presynaptic glutamate and dopamine release. Finally, Dr Parpara will discuss calcium-dependent release of glutamate from astrocytes in light of studies using fluorescence energy resonance transfer to examine the spatio-temporal dynamics of SNARE interactions during astrocytic glutamate secretion. Together, these speakers will provide a contemporary understanding of glial regulation of

124 neurotransmission and challenge the audience to consider the role of glia from neurotransmission to neuropathology.

Panel • Friday, January 31 • 7:30–9:30 AM • Wasatch R. Freeman, M. Deshmukh, P. Barker, M. Wooten Signaling Life and Death in NGF-Dependent Neurons A delicate balance between cell death and cell survival is essential for proper development of the nervous system. Neuronal survival is controlled by an intricate network of signaling pathways initiated when neurotrophic factors, such as nerve growth factor (NGF), bind their receptors. An equally complex cascade of events is set in motion to trigger cell death in neurons that receive inadequate trophic support. The intracellular pathways that transduce cell death and cell survival signals and the role of the p75 neurotrophin receptor (p75NTR) in these disparate processes have been the focus of intense research. This panel will highlight key biochemical events that transduce the life and death cues generated by the presence and absence of neurotrophic factors. Recent results concerning the mechanism by which caspases are activated during cell death after NGF withdrawal, with particular focus on events that regulate cytochrome c release and the function of the inhibitor of apoptosis family of proteins, will be spoken on by Dr. Deshmukh. Dr. Freeman will talk about new insights into the function of genes that are upregulated in NGF-deprived neurons and how these molecules act to propagate the cell death program. Dr. Barker will discuss recent findings that have identified novel p75NTR-interacting proteins, re- vealing downstream signaling mechanisms that allow p75NTR to carry out its diverse physiological functions ranging from induction of apoptosis to mediating survival. Dr. Wooten will speak on newly discovered mechanisms involving the interleukin 1-receptor associated kinase (IRAK), which link a multimeric p75NTR-signaling complex to the activation of pro-survival molecules including NF-kB.

Panel • Friday, January 31 • 7:30–9:30 AM • Maybird J. Weiss, S. Sensi, I. Reynolds, C. Frederickson, X. Huang CNS Zn2+: New Insights into Physiologic and Pathophysiologic Roles Neurons that release Zn2+ along with glutamate are among the most numerous of all forebrain neurons. Synaptic release of Zn2+ may contribute to selective degeneration in epilepsy, ischemia and Alzheimer’s disease (AD). The last few years have witnessed dramatic progress on all frontiers of Zn2+ neurobiology. While, until recently there has been little understanding of its effects, powerful tools (transgenic models, fluorescent probes, selective chelators etc) have enabled an explosion in our understanding of its physi-

125 ologic and patho-physiologic roles. Indeed, given the rapid pace of recent advances and compelling evidence of its role in brain disease, it may not be imprudent to suggest that the zinc ion will soon rival calcium in perceived importance in cell biology. This symposium will describe the neurobiology, and basic physiology of the Zn2+-containing system. John Weiss will chair the symposium and provide a brief overview of recent findings regarding the physiologic and patho-physiologic roles of Zn2+ in the CNS. Stefano Sensi will discuss findings suggesting that mitochondria play key roles in Zn2+ dependent neurotoxicity. Ian Reynolds will discuss novel intracellular targets for the toxic actions of zinc. Chris Frederickson will describe the anatomy and synaptology of Zn2+-containing neuronal systems, and discuss evidence that synaptic Zn2+ contributes not only to brain disease, but is likely to have roles in synaptic plasticity and LTP as well. Xudong Huang,will present data concerning how Zn2+ may mediate the assembly of amyloid plaques in Alzheimer’s disease and discuss how these findings may provide new therapeutic approaches to the disease. It is of course expected that each member of the panel will give a squeaky clean and fluff- free talk; as incentive, the most provocative presentation will be rewarded with a one-year supply of Zn2+-pyrithione fortified anti-dandruff shampoo.

Panel • Friday, January 31 • 7:30–9:30 AM • Superior A H. Robinson, S. Williams, M. Larkum, M. Häusser Nonlinear Integration of Synaptic Input in Cortical Neurons Cortical neurons and their dendrites have a rich nonlinear dynamics. The “decision” of cortical neurons to spike depends not only on the pattern of inputs received, but on how the voltage-dependent gating of channels and the spatial flow of current in the dendritic tree actively boosts or suppresses the input. Recently, much experimental progress in unraveling this complex phenomenon has been made by dendritic whole-cell recording and the use of realistic stimulation methods in vitro. In this panel, Matthew Larkum will describe spatial interactions in spike initiation in layer 5 cortical pyramidal neurons, during integration of inputs mimicking asynchro- nous synaptic activity. He will show measurements of the current:frequency gains and of the mutual influences of different electrical compartments in the dendritic tree. Stephen Williams will discuss temporal windows of integration, in layer 5 neurons, measured using random patterns of excitatory current or conductance inputs, at distal apical dendritic and somatic sites, showing how distal dendrites operate as coincidence detectors, while the soma behaves as a temporal integrator. Michael Häusser will describe experiments on how the encoding of synaptic input by neocortical pyramidal cells changes during postnatal development. He will focus on how development affects precision of encoding and the time window for synaptic integration, as well as the link between subthreshold boosting of synaptic input

126 and action potential output. Hugh Robinson will present measurements of how quickly NMDA receptors, in nucleated patches of layer 2/3 pyramidal neurons, unblock in response to fast depolarizations–this determines their nonlinear contribution to excitability. Unblock has both a submillisecond component and a slower component taking tens of milliseconds, while reblock is effectively instantaneous.

Panel • Friday, January 31 • 7:30–9:30 AM • Superior B B. Meurers, F. Kamme, B. Liss, G. Eichele Gene Expression Analyses in the Mammalian Brain: Technologies and Objectives The mammalian central nervous system is one of the most complex biological structures. It contains an estimated 100 billion cells and expresses the highest proportion of the genome among all organ systems within the body. At the molecular level its functional organization and regulatory mechanisms are reflected by different temporo-spatial gene expression patterns. Exploring these transcriptional programs has recently been made possible through DNA microarray and high throughput in situ hybridization technologies. Data generated with both technologies are amenable to computational analysis and manipulation providing further functional information through meta-analyses such as gene clustering. The sensitivity and specificity of microarray experiments can be greatly increased by using a combination of laser based cellular microdissection techniques and T7- RNA amplification. Besides using morphological criteria cells can also be selected based on the expression of specific genes or their projection area. The sensitivity of the method allows single cell analyses. This part of the panel will be presented by Fredrik Kamme and Bernd Meurers. One of the shortcomings of the array technology is that it does not provide detailed information about the anatomical distribution of the genes analyzed. This can be achieved by high throughput, automated in situ hybridization. Gregor Eichele will discuss the technical details of the method including automated slide scanning and digitalization of the expression patterns. Programs for automated annotation and quantitative analyses are also available. Comple- mentary to these techniques are fluorescence based quantitative PCR analyses. Particular advantages of this method are its reproducibility and sensitivity allowing single cell transcript analysis. Birgit Liss will illustrate how single cell real time RT-PCR in combination with brain slice patch clamp techniques provides a link between gene expression profiles and functional properties of individual neurons. The panel will provide an introductory overview of different technologies for generating gene expression patterns in the CNS, compare their advantages and disadvantages and give examples of their potential applications.

127 Panel • Friday, January 31 • 4:30–6:30 PM • Ballroom 1 R. Baler, M. Rollag, D. Virshup, M. Reick The Biological Clock: A Timely Update The biological clock houses the signal transduction pathway that keeps track of circadian time. This system is responsive, recursive and robust, three features that underlie its ability to entrain to photic stimuli and independently sustain rhythmic output for literally hundreds of cycles. Equally remarkable is the capacity of the clock in the brain to remotely orchestrate the vast number of circadian functions playing out in peripheral organs. Until very recently, these faculties presented a formidably complex biological puzzle. But today, a massive effort across multiple disciplines has finally, and rather explosively, converged to produce a rich picture, albeit certainly incomplete, of the molecular gears, feedback loops, and outgoing signals that make up the central oscillator. The four speakers will bring the non-initiated up to speed in the most active areas of molecular chronobiology research. We will follow a logical progression, with discussions covering the full range of topics from light input to transcription output. Rollag will describe the studies that uncovered the best candidate so far for mediating circadian photore- ception. Virshup and Reick will introduce the identity of the core clock components and recently discovered regulatory events that control their activities in the cytoplasm and nucleus. Finally, Baler will discuss novel aspects of the interaction between circadian transcription factors and the pro- moters of clock controlled genes. During the course of each presentation, attendants will be treated to a thorough discussion of both relevant background and unresolved issues.

Panel • Friday, January 31 • 4:30–6:30 PM • Magpie S. Anderson, J. Huang, S. Tobet, J. Nunez From Phenotype to Function: The Role of GABA in CNS Development Abnormalities in GABAergic function during development have been linked to a variety of psychiatric and neurological disorders, including schizophrenia, mood disorders and epilepsy. The molecular means by which these neurons are specified, migrate, integrate into functional circuits and direct postnatal brain development are the topics of this panel presentation. Stewart Anderson will focus on molecular mechanisms of GABAergic interneuron migration and specification in the developing cerebral cortex, including spatial and temporal factors influencing interneuron fate. Josh Huang will highlight recent findings from the versatile conditional transgenic system with which he is examining how neuronal activity and sensory experience influence the development of different classes of cortical GABA

128 interneurons. Stuart Tobet will discuss GABAergic function in the mechanisms by which neural cells aggregate to form functional nuclei during development; specifically, he will discuss pharmacological and transgenic approaches to the elucidation of the molecular link between GABAergic phenotype and formation of brain nuclei. Joseph Nunez will present his work on mechanisms by which GABAergic neurotransmission switches from excitatory to inhibitory during development, focusing on steroid hormone/ GABA interactions as a molecular basis for sex-related differences in the developing CNS. Together, these presentations will provide a survey of recent, critical studies on GABAergic function during CNS development, including implications for treatment of postnatal brain injury and of psychiatric disorders with developmental etiologies.

Panel • Friday, January 31 • 4:30–6:30 PM • Wasatch F. Gomez-Pinilla, T. Schallert, T. Jones, J. Kleim The Role of Experience on Recovery of Function In response to injury or degeneration the brain launches molecular and cellular mechanisms to repair the damage and to provide the potential for optimal synapse selection, reorganization of circuits, and restoration of function. Among the events that may contribute are dendritic growth, synapse formation, and neurogenesis, via the action of trophic factors. There is an emerging consensus that reactive plasticity sometimes depends in part, or entirely, on behavior-related signals, which can initiate or maintain these neural events. Without behavior, key use-dependent neural or glial adaptations may never get underway, and others may be retracted or rendered nonfunctional. There may be optimal windows of opportunity for plasticity and neuroprotection, as well as hazardous periods where intense motor training can cause cells to die. Theresa Jones will describe interactions between neurons and glial which enhance some types of learning as well as use-dependent structural plasticity in the motor cortex, in models of focal ischemia and transcallosal denervation. Jeff Kleim will show how differential motor experience following motor cortex infarcts influences both recovery of skilled motor behavior and the organization of cortical movement representations. Tim Schallert will describe time-dependent and use-dependent neural and functional protection in parkinsonian models of degeneration, as well as use dependent exaggeration of cortical injury. Fernando Gómez-Pinilla will describe experience-dependent molecular and cellular mechanisms for the formation and maintenance of neural circuits. He will describe the influence of exercise, learning, and diet on neurotrophin expression and neural function, and activity-dependent compensatory events after traumatic brain injury.

129 Panel • Friday, January 31 • 4:30–6:30 PM • Maybird M. Robinson, R. Bridges, M. Kavanaugh, A. Brooks-Kayal Glutamate Transporters: From Pharmacology to Physiology A family of homologous Na+-dependent transporters fine tunes excitatory synaptic transmission and limits the toxicity of glutamate in the CNS. The goal of this panel will be to provide an overview of four areas of study of these transporters. Dr. Bridges will describe recent efforts to understand the chemical properties that influence subtype -specific activity and delineate substrates from non-substrate inhibitors. In addition, he will discuss the potential utility of such analogues in elucidating transporter function under physiological and pathological conditions. Dr. Kavanaugh will provide an overview of the biophysical properties of the transporters, including a discussion of the ion channel properties. Dr. Robinson will provide an overview of the mechanisms that regulate these transporters. These mechanisms range from transcriptional control through identification of motifs required for assembly and signals that control cell surface expression of the transporters. Dr. Brooks-Kayal will present evidence that the expression of these transporters is altered in animals and humans with temporal lobe epilepsy. Each of the presenters will describe how these approaches provide tools and insights into the biology and pathophysiology of these transporters.

Panel • Friday, January 31 • 4:30–6:30 PM • Superior A B. Waterhouse, K. Simpson, D. Devilbiss, C. Berridge Locus Coeruleus Efferent Actions: Recent Findings, New Hypotheses The locus coeruleus (LC) efferent projection system originates in the brainstem and distributes broadly to forebrain structures. Phasic or tonic activation of the system results in widespread, presumably simultaneous, release of norepinephrine (NE) in multiple, functionally diverse forebrain regions. Over the years a number of different influences of NE on spontaneous and stimulus evoked neuronal activity have been demonstrated. Re- cent evidence further indicates co-localization of neuroactive peptides, e.g. galanin, in LC-NE-containing fibers, thus prompting speculation regarding the physiological actions of synaptically released peptides from LC-NE fibers. The postsynaptic influences of NE and co-localized peptides in efferent targets of the LC projection are the focus of this panel. The goal is to review new data that have modified our view of how output from the LC modulates behavioral state and state dependent cognitive processes. Kim Simpson will present anatomical evidence of the galininergic projection

130 from LC to sensory (trigeminal somatosensory system) and motor (cerebellum) regions of the rat brain. Barry Waterhouse will review afferent inputs to LC and describe simulated actions of NE in a computational model of rat thalamocortical circuitry. This experiment makes predictions regarding the operation of the circuit and responsiveness of single neurons to synaptic input as a function of LC-NE output. David Devilbiss will describe the effects of tonic vs phasic activation of the LC on spontaneous and stimulus- evoked activity of single neurons and arrays of single neurons in vibrissa-responsive regions of thalamus and cortex in awake, quietly resting rats. Craig Berridge will present data implicating the LC in regulation of behavioral state and will also offer a new integrated view of LC function that accounts for the broad array of experimental findings regarding LC activity states and actions of NE in LC projection fields.

Panel • Friday, January 31 • 4:30–6:30 PM • Superior B G. Gebhart, M. Gold, K. Westlund-High, G. Wilcox Expanding Beyond Gut Feelings The principal sensations that arise from the viscera are discomfort and pain. Mechanisms of acute visceral events are well understood and acute visceral problems are generally not medically problematic. Chronic visceral pain, however, is common, is the main type of pain that causes people to seek medical attention, and is medically difficult to control. Because many such chronic visceral pain problems are associated with inflammation, hyperalgesia (decreased response thresholds and/or increased responses) is present, although the mediators of increased responses to visceral stimuli are poorly understood. This panel will discuss models of stomach, pancreas and colon insult and consequent hyperalgesia. The contributions of changes in excitability of visceral afferent and spinal neurons will be considered and effects of organ insult on a principal contributor to neuron excitability, sodium channels, discussed. Pancreatitis is a serious problem and a model will be described, as will consequences of acute and persistent pancreatitis (Westlund-High). Similarly, irritable and inflammatory bowel disorders con- stitute a common problem and models of each will be presented (Wilcox) as will the consequences of such insult. Evidence that sodium currents in sensory spinal dorsal root and nodose ganglion cells are affected after gas- tric or colon inflammation will be presented (Gebhart and Gold, respectively). It is anticipated that the panel will conclude with suggestions for research directions to enhance our understanding of mechanisms that contribute to visceral hyperalgesia.

131 Town Meeting • Tuesday, January 28 • 7 PM • Albion Middle School, Salt Lake City G. Hanson Drug Abuse: Morality versus Medicine: A Proper Perspective As with many other diseases such as cancers and diabetes, we now know that drug addiction is a consequence of poor life-style selection, genetic predisposition and deterioration of a critical organ’s function (i.e., the brain). Based on this knowledge, we know that in order for society to be successful in dealing with drug abuse-related problems, it must take into consider- ation that addiction truly is a “brain disease” which requires aggressive and persistent treatment. However, just like other therapeutic strategies, effective treatment for substance addiction often requires a combination of medication to correct compromised brain function and behavior modification to facilitate recovery. Dr. Glen Hanson’s talk will discuss the research that has helped experts in addiction medicine to come to these conclusions and the implications.

Don’t forget to visit the exhibit area.

132 133 134 135 136 137 138 Participant List/Index

Elizabeth Abercrombie Gordon Arbuthnott, 98, 123 Rutgers University University of Edinburgh [email protected] [email protected]

Mary Abood, 93 Marjorie A. Ariano, 95 California Pacific Medical Center Finch University of Health Sciences/ [email protected] Chicago Medical School [email protected] Greti Aguilera National Institutes of Health Gary Aston-Jones, 74 [email protected] University of Pennsylvania [email protected] Michael Ahlijanian Pfizer, Inc. Constance Atwell, 110 [email protected] National Institute of Neurological Disorders and Stroke Elias Aizenman, 89 [email protected] University of Pittsburgh [email protected] Ruben Baler, 128 National Institutes of Health Elliott Albers, 109 [email protected] Georgia State University [email protected] Helen Barbas, 77 Boston University Veronica Alvarez, 74 [email protected] Harvard Medical School [email protected] Ausaf Bari, 29 Boston University School of Medicine Sharon Anderson, 29 [email protected] Boston University School of Medicine [email protected] Phil Barker, 125 McGill University Stewart Anderson, 128 [email protected] Cornell University Medical College [email protected] Carrolee Barlow, 86 Merck Research Laboratories, San Anne Andrews, 75 Diego Penn State University [email protected] [email protected] Tamas Bartfai, 97 Kristin Anstrom The Scripps Research Institute Wake Forest University School of [email protected] Medicine [email protected] Gary Bassell, 30 Albert Einstein College of Medicine Ottavio Arancio, 77 [email protected] New York University [email protected]

139 Jill Becker, 69 Stewart Bloomfield, 81 University of Michigan New York University [email protected] [email protected]

Sara Becker-Catania, 111 Mary Blue, 75 University of California, Los Angeles Kennedy Krieger Institute [email protected] [email protected]

Margery Beinfeld, 31 Martha C. Bohn Tufts University School of Medicine Northwestern University Medical [email protected] School [email protected] Mike Bennett, 89, 122 Albert Einstein College of Medicine J. Paul Bolam, 107 [email protected] Medical Research Council Anatomical Neuropharmacology Unit Richard Beresford [email protected] University of Rochester School of Medicine Antonello Bonci, 103, 118 [email protected] University of California, San Francisco [email protected] Richard Bergeron, 124 Ottawa Health Research Institute Stephen Bondy [email protected] University of California, Irvine [email protected] Craig Berridge, 115, 130 University of Wisconsin Lisa Boulanger, 102 [email protected] Harvard Medical School [email protected] Cynthia Bethea, 78 Oregon National Primate Research Rusiko Boutrchouladze, 77 Center Helicon Therapeutics, Inc. [email protected] [email protected]

Llewellyn Bigelow David Bredt, 115 National Institute of Mental Health University of California, San Francisco [email protected] [email protected]

Marc Binder, 104 Michael Brenner, 31 University of Washington University of Alabama, Birmingham [email protected] [email protected]

Kim Blackwell, 107 Richard Bridges, 130 George Mason University University of Montana [email protected] [email protected]

Julie Blendy, 111 Linda Bristow, 32 University of Pennsylvania Merck Research Laboratories, San [email protected] Diego [email protected] Jim Bloedel Iowa State University no e-mail on record

140 Amy Brooks-Kayal, 130 Ellen Carpenter, 71 University of Pennsylvania University of California, Los Angeles [email protected] [email protected]

Brook Brouha, 32 David Carr, 34 University of Pennsylvania Northwestern University [email protected] [email protected]

Mike Browning, 112 Vivien Casagrande, 84 University of Colorado Health Sciences Vanderbilt Medical School Center [email protected] [email protected] Francisco Xavier Castellanos, 115 Rob Brownstone, 104 New York University Dalhousie University [email protected] [email protected] Idil Cavus, 34 Vivian Budnik Yale University University of Massachusetts [email protected] [email protected] Victor Chaban, 78 William Bunney, 108 University of California, Los Angeles University of California, Irvine [email protected] [email protected] David Chambers, 93 Robert Burke, 33 King’s College London National Institutes of Neurological [email protected] Disorders and Stroke David Chapman, 35 [email protected] University of Utah Allan Butterfield, 121 [email protected] University of Kentucky Elena Chartoff, 36 [email protected] Harvard Medical School Carolyn Byl [email protected] University of California, San Francisco Marie-Francoise Chesselet, 102 [email protected] University of California, Los Angeles Barbara Caldarone, 111 [email protected] Yale University School of Medicine James Chou, 37 [email protected] New York University School of Medicine Angela Cantrell [email protected] University of Tennessee Carson Chow [email protected] University of Pittsburgh Bill Carlezon, 88, 119 [email protected] Harvard Medical School Anne Churchland [email protected] University of California, San Francisco Tom Carmichael, 102 [email protected] University of California, Los Angeles [email protected]

141 Patricia Churchland, 86 Fulton Crews, 96 University of California, San Diego University of North Carolina at Chapel [email protected] Hill [email protected] Paul Clarke McGill University Ana Maria Cuervo, 90 [email protected] Albert Einstein College of Medicine [email protected] Hollis Cline, 102 Cold Spring Harbor Laboratory Kathryn Cunningham, 123 [email protected] University of Texas Medical Branch [email protected] Larry Cohen102, 114 Yale University Mark D’Esposito, 83 [email protected] University of California, Berkeley [email protected] Carlo Colantuoni, 104 National Institute of Mental Health Mary Dallman, 85 [email protected] University of California, San Francisco [email protected] Paul Coleman, 121 University of Rochester Medical Center John A. Dani, 81 [email protected] Baylor College of Medicine [email protected] Carol Colton Duke University Duff Davis, 38 [email protected] Pfizer Global Research & Development [email protected] Christopher Colwell, 109 University of California, Los Angeles Ted Dawson [email protected] Johns Hopkins University [email protected] P. Jeffrey Conn, 94 Merck & Co., Inc. Valina Dawson, 89, 110 [email protected] Johns Hopkins University [email protected] Francois Conquet, 70 Addex Pharmaceuticals Philippe De Witte, 75 [email protected] University of Louvain [email protected] Maurizio Corbetta, 83 Washington University Greg DeAngelis, 84 [email protected] Washington University, St. Louis [email protected] Carl Cotman, 91 University of California, Irvine Rolf Dermietzel, 122 [email protected] Ruhr University Bochum [email protected]

Mohanish Deshmukh, 125 University of North Carolina at Chapel Hill [email protected]

142 Jean deVellis, 79 David Earnest, 109 University of California, Los Angeles Texas A&M University Health Science [email protected] Center [email protected] David Devilbiss, 130 University of Wisconsin–Madison Gregor Eichele, 127 [email protected] Max Planck Institute Hannover [email protected] Stephen Devoto, 99 Wesleyan University Burr Eichelman [email protected] University of Wisconsin-Madison [email protected] Patsy Dickinson, 99 Bowdoin College Lisa Ellerby, 105 [email protected] Buck Institute for Age Research [email protected] Lynn Dobrunz, 106 University of Alabama at Birmingham Helene Emsellem [email protected] George Washington University [email protected] Robert Donahoe, 39 Emory University Matt Ennis, 114 [email protected] University of Maryland School of Medicine Sylvain Dore [email protected] Johns Hopkins University [email protected] Reha Erzurumlu, 88 Louisiana State University Health Paula Dore-Duffy Sciences Center Wayne State University [email protected] [email protected] Anne Etgen, 69 Norman Dovichi, 104 Albert Einstein College of Medicine University of Washington [email protected] [email protected] Alan Faden Kelly Drew Georgetown University University of Alaska, Fairbanks [email protected] [email protected] Carolyn Fairbanks, 76 Laura Dugan, 118 University of Minnesota Washington University [email protected] [email protected] David Farb Ian Duncan, 79 Boston University School of Medicine University of Wisconsin-Madison [email protected] [email protected] James Fawcett, 101 Matthew During, 80 Cambridge University University of Oakland [email protected] [email protected]

143 David Fink, 106 Curt Freed University of Pittsburgh University of Colorado Health Sciences [email protected] Center [email protected] Steven Finkbeiner, 105, 119 University of California, San Francisco William Freed, 104 [email protected] National Institute on Drug Abuse [email protected] Gordon Fishell, 111 New York University Medical Center Robert Freeman, 125 [email protected] University of Rochester [email protected] Gary Fiskum, 110 University of Maryland School of Rainer Friedrich, 114 Medicine Max Planck Institute for Medical [email protected] Research Rainer.Friedrich@mpimf- Adam Flanders, 73 heidelberg.mpg.de Thomas Jefferson University Hospital [email protected] J. James Frost Johns Hopkins University Stan Floresco, 120 [email protected] University of Pittsburgh [email protected] Denson Fujikawa, 40 University of California, Los Angeles Robert Foehring, 113 [email protected] University of Tennessee [email protected] Remie Fujiwara Pfizer, Inc. Aaron Fox, 100 [email protected] University of Chicago [email protected] Karen Gale, 89, 123 Georgetown University Peter Fox [email protected] University of Texas Health Science Center Judy Garner, 108 [email protected] University of Southern California [email protected] Kyle Frantz, 88 Georgia State University Don Gash, 113 [email protected] University of Kentucky [email protected] Donald Franz University of Utah Jerry Gebhart, 131 c/o [email protected] University of Iowa [email protected] Alan Frazer University of Texas Health Science Herbert Geller, 101 Center National Heart, Lung and Blood [email protected] Institute [email protected] Christopher Frederickson, 125 NeuroBioTex, Inc. [email protected]

144 Greg A. Gerhardt, 41 Karen Greif, 99 University of Kentucky Medical Center Bryn Mawr College [email protected] [email protected]

Elliot Gershon, 108 Leslie Griffith, 92 University of Chicago Brandeis University [email protected] [email protected]

Daniel Geschwind, 86 Ellinor Grinde University of California, Los Angeles Albany Medical College [email protected] [email protected]

Mark Geyer, 70 Elizabeth Grove, 88 University of California, San Diego University of Chicago [email protected] [email protected]

Jonathan Gilthorpe, 93 Gary Gudelsky King’s College London University of Cincinnati [email protected] [email protected]

Stephen D. Ginsberg, 86 Suzanne Guenette, 72 Nathan Kline Institute Massachusetts General Hospital [email protected] [email protected]

Michael Gold, 131 Daniel Guitton, 121 University of Maryland, Baltimore McGill University [email protected] [email protected]

Jeffrey Goldberg, 102 Shermali Gunawardena, 108 Stanford University University of California, San Diego [email protected] [email protected]

Steven Goldman, 96, 111 Johanna Gutlerner, 118 Cornell University Medical College Brown University [email protected] [email protected]

Lawrence Goldstein, 72 Edward Hall University of California, San Diego University of Kentucky Medical Center [email protected] [email protected]

Timothy Gomez, 70 Glen Hanson, 132 University of Wisconsin—Madison National Institute on Drug Abuse [email protected] [email protected]

Fernando Gomez-Pinilla, 129 Sami Harik University of California, Los Angeles University of Arkansas College of [email protected] Medicine [email protected] Anthony Grace, 79 University of Pittsburgh Ronald Harris-Warrick, 92 [email protected] Cornell University [email protected] Bill Greenough, 91 University of Illinois [email protected]

145 Annette Harsch Sandra Hewett , 118 University of Cambridge University of Connecticut Health no e-mail on record Center [email protected] Michael Häusser, 117, 126 University College London Bart Hoebel, 75 [email protected] Princeton University [email protected] Ronald Hayes, 42 University of Florida Barry Hoffer, 113 [email protected] National Institutes of Health [email protected] Jean Hebert, 88 Stanford University Beth Hoffman, 75 [email protected] Eli Lilly and Company [email protected] C.J. Heckman, 104 Northwestern University Gregg Homanics [email protected] University of Pittsburgh [email protected] David Heeger, 83 New York University John P. Horn, 100 [email protected] University of Pittsburgh [email protected] Stephen Heinemann, 81 Salk Institute Kristen Ashley Horner, 45 [email protected] University of Utah [email protected] Stephen Heinrichs, 111 Boston University Richard Howells [email protected] University of Medicine and Dentistry of New Jersey Johannes Hell [email protected] University of Iowa [email protected] Paul Huang, 128 Massachusetts General Hospital Rene Hen, 77 [email protected] Columbia University [email protected] Xudong Huang Massachusetts General Hospital Fritz Henn, 100 [email protected] University of Heidelberg [email protected] Z. Josh Huang Cold Spring Harbor Laboratory Steven Henriksen [email protected] The Scripps Research Institute [email protected] Chou Hung, 102 Massachusetts Institute of Technology Katharine Herrick-Davis, 123 [email protected] Albany Medical College [email protected] Thomas Hyde, 104 National Institute of Mental Health [email protected]

146 Michael Iadarola, 116 Thomas Jerrells, 48 National Institute of Dental and University of Nebraska Medical Center Craniofacial Research [email protected] [email protected] Robert Jinks, 99 Satoshi Ikemoto, 45 Franklin and Marshall College Charles River Lab [email protected] [email protected] Daniel Johnston, 92 Philip Iredale, 93 Baylor College of Medicine Pfizer, Inc. [email protected] [email protected] Elizabeth Jonas, 118 John Isaac Yale University University of Bristol [email protected] [email protected] Theresa Jones, 129 Michael Iuvone, 81 University of Texas at Austin Emory University [email protected] [email protected] James Joseph, 96, 121 Russell E. Jacobs Tufts University California Institute of Technology [email protected] [email protected] Leonard K. Kaczmarek, 113 Mark Jacquin Yale University School of Medicine Washington University School of [email protected] Medicine Katherine Kalil, 70 [email protected] University of Wisconsin-Madison Dieter Jaeger, 98 [email protected] Emory University Peter Kalivas, 70, 124 [email protected] Medical University of South Carolina Patricia Janak, 119 [email protected] University of California, San Francisco Fredrik Kamme, 127 [email protected] Johnson & Johnson PRD George Jaskiw, 47 [email protected] Louis Stokes Cleveland VA Medical Claudia Kappen, 48 Center University of Nebraska Medical Center [email protected] [email protected] Luc Jasmin, 80 Paul Katz University of California, San Francisco Georgia State University [email protected] [email protected] Hank Jedema, 47 Michael Kavanaugh, 130 University of Pittsburgh Vollum Institute [email protected] [email protected] Seo Jeong-Cheol Kyungsan University [email protected]

147 Kristen Keefe, 101 David C. Klein, 97 University of Utah National Institutes of Health [email protected] [email protected]

Hans Keirstead Joel Kleinman University of California, Irvine National Institute of Mental Health [email protected] [email protected]

Edward Keller, 121 Ingo Kleppe, 50 Smith-Kettlewell Eye Research Institute University of Cambridge [email protected] [email protected]

Jeff Keller, 90 Pamela Knapp, 79 University of Kentucky University of Kentucky [email protected] [email protected]

Ann Kelley, 120 Etienne Koechlin, 77 University of Wisconsin—Madison INSERM [email protected] [email protected]

John Kelsoe, 108 George Koob University of California, San Diego The Scripps Research Institute [email protected] no e-mail on record

John Kemp Conan Kornetsky Evotec Neurosciences GmbH Boston University School of Medicine [email protected] [email protected]

Debra Kendall, 93 Stephen H. Koslow University of Connecticut National Institute of Mental Health [email protected] [email protected]

David Kennedy, 91 Catherine Kotz, 50 Massachusetts General Hospital Minneapolis VA Medical Center [email protected] [email protected]

Andrew Kertesz Scott Krahl, 50 University of Western Ontario University of California, Los Angeles/ [email protected] VA Greater Los Angeles [email protected] Clemens Kiecker, 93 Deutsches Krebsforschungszentrum Mary Jeanne Kreek, 100 [email protected] The Rockefeller University [email protected] Sergei Kirov, 49 Boston University Catherine Krull, 71 [email protected] University of Missouri-Columbia [email protected] Jeffrey Kleim, 129 Canadian Center for Behavioral John Krystal, 94 Neuroscience Yale School of Medicine [email protected] [email protected]

148 Ron Kuczenski, 115 Christian Lee, 53 University of California, San Diego Rutgers University [email protected] [email protected]

Paul Kullmann, 51 Michael Lee University of Pittsburgh Johns Hopkins University [email protected] [email protected]

Frank LaFerla, 72 Charles Leffler University of California, Irvine University of Tennessee [email protected] [email protected]

Joan M. Lakoski, 75 Sarah Leibowitz, 87 University of Pittsburgh The Rockefeller University [email protected] [email protected]

Joseph C. LaManna Alan Leshner, 110 Case Western Reserve University American Association for the [email protected] Advancement of Science [email protected] Cynthia Lance-Jones, 71 University of Pittsburgh School of Henry Lester, 81 Medicine California Institute of Technology [email protected] [email protected]

Matthew Larkum, 126 Daniel Leszkiewicz, 54 Max Planck Institute for Medical University of Pittsburgh Research [email protected] [email protected] Paul Letourneau Marc Laruelle, 79 University of Minnesota Columbia University [email protected] [email protected] Robert Levenson, 95 Dianne Lattemann, 85, 99 Penn State University University of Washington [email protected] [email protected] Barry Levin, 87, 99 Jean Lauder, 75 VA Medical Center University of North Carolina at Chapel [email protected] Hill Michael Levine [email protected] University of California, Los Angeles Antonieta Lavin, 52 [email protected] Medical University of South Carolina Steve Levison, 111 [email protected] Penn State University Giovanni Laviola, 88 [email protected] Istituto Superiore Sanità Irwin Levitan [email protected] University of Pennsylvania Sally Lawson, 116 [email protected] University of Bristol [email protected]

149 Anita Lewin Ken Mackie RTI International University of Washington [email protected] [email protected]

Stephanie Licata, 54 Wendy Macklin, 79 Boston University School of Medicine Cleveland Clinic Foundation [email protected] [email protected]

Stafford Lightman, 97 Daniel Madison, 106 University of Bristol Stanford University [email protected] [email protected]

Barbara Lipska Nigel Maidment National Institute of Mental Health University of California, Los Angeles [email protected] [email protected]

Birgit Liss, 127 Rafael Maldonado, 111 Oxford University University Pompeu Fabra [email protected] [email protected]

Fang Liu, 95 Laura Mamounas Centre for Addiction & Mental Health National Institutes of Neurological [email protected] Disorders and Stroke [email protected] Ronald Lukas Barrow Neurological Institute Shaila Mani, 69 [email protected] Baylor College of Medicine [email protected] Carl Lupica, 103 National Institutes of Health Karl Mann, 100 [email protected] Central Institute of Mental Health [email protected] Bernhard Luscher, 95 Penn State University Olivier Manzoni [email protected] INSERM [email protected] Ernie Lyons National Institutes of Neurological David Marcus, 56 Disorders and Stroke New York University Medical Center [email protected] [email protected]

John MacDonald, 112 Andres Maricq, 115 University of Toronto University of Utah [email protected] [email protected]

Marcy MacDonald, 105 Athina Markou, 70 Massachusetts General Hospital The Scripps Research Institute [email protected] [email protected]

Bruce MacIver, 55 Neville Marks, 77 Stanford University Nathan Kline Institute [email protected] [email protected]

150 Billy Martin, 93 John Mendelson, 56 Virginia Commonwealth University California Pacific Medical Center [email protected] [email protected]

Stephen Massey, 81 Mark Mennemeier, 57 University of Texas Medical School University of Alabama at Birmingham [email protected] [email protected]

Tyler McCabe Gloria Meredith, 123 Medtronic, Inc. Finch University of Health Sciences/ [email protected] Chicago Medical School [email protected] Una McCann Johns Hopkins University Paul Mermelstein, 70 no e-mail on record University of Minnesota [email protected] Gregory McCarthy, 91 Duke University Bernd Meurers, 127 [email protected] Johnson & Johnson PRD [email protected] Jakie McGinty, 101 Medical University of South Carolina Ronald Meyer, 58 [email protected] University of California, Irvine [email protected] Hugh McIntyre Harbor-UCLA Medical Center Paul Micevych, 78 [email protected] University of California, Los Angeles [email protected] Lori McMahon, 106 University of Alabama, Birmingham Laurence Mignon, 123 [email protected] University of California, Los Angeles [email protected] F. Arthur McMorris The Wistar Institute Karoly Mirnics, 86 [email protected] University of Pittsburgh [email protected] Ewan McNay, 87 Yale School of Medicine Bita Moghaddam, 79, 94 [email protected] Yale University [email protected] Robert Meisel, 69 Purdue University Johanna Montgomery, 106 [email protected] Stanford University [email protected] Synthia Mellon University of California, San Francisco Holly Moore [email protected] Columbia University [email protected] Marsha Melnick, 91 NeuroClin2 Dave Morgan, 121 [email protected] University of South Florida [email protected]

151 Larry Morin, 109 Jesper Nymann-Andersen, 95 State University of New York at Stony University of California, Los Angeles Brook [email protected] [email protected] Charles O’Brien, 75 A. Leslie Morrow University of Pennsylvania University of North Carolina at Chapel [email protected] Hill Patricio O’Donnell, 73, 82, 100 [email protected] Albany Medical College Thomas Morrow, 106 [email protected] University of Michigan Anne Louise Oaklander, 116 [email protected] Harvard Medical School Marion Murray , 73 [email protected] Drexel University College of Medicine Kathie Olsen, 116 [email protected] Executive Office of the President T. Celeste Napier, 123 [email protected] Loyola University Chicago Richard Olsen, 110 [email protected] University of California, Los Angeles Maiken Nedergaard, 122 [email protected] New York Medical College Jim Olson [email protected] Fred Hutchinson Cancer Center Sacha Nelson, 98 [email protected] Brandeis University Carlos Paladini, 118 [email protected] Oregon Health Sciences University Kim Neve, 58 [email protected] Portland VA Medical Center Sarah Pallas, 88 [email protected] Georgia State University David Nicholls, 118 [email protected] Buck Institute for Age Research John Parkinson, 77, 120 [email protected] University of Cambridge Ralph Nixon, 90 [email protected] New York University School of Medicine Vladimir Parpura, 124 [email protected] University of California Ulrika Nordström, 93 [email protected] Umea University Susan Patterson, 119 [email protected] Columbia University Joseph Nunez, 128 [email protected] University of Maryland, Baltimore Dennis Paul, 76 [email protected] Louisiana State University Health Sciences Center [email protected]

152 Christina Paxson Joshua Plotkin Princeton University University of California, Los Angeles [email protected] [email protected]

Betsy Pehek, 123 Michel Pohl, 106 Louis Stokes Cleveland VA Medical INSERM Center [email protected] [email protected] Emmanuel Pothos, 60 Dale Pelligrino Tufts University School of Medicine University of Illinois at Chicago [email protected] [email protected] Steven Potkin, 108 Laura Peoples, 77 University of California, Irvine University of Pennsylvania [email protected] [email protected] Randall Powers, 104 Ruth Perez, 72 University of Washington University of Pittsburgh [email protected] [email protected] Remi Quirion Luiz Pessoa, 83 McGill University National Institute of Mental Health [email protected] [email protected] Samuel Rabkin, 80 Michael Phelps Massachusetts General Hospital University of California, Los Angeles [email protected] [email protected] Bruce Ransom, 99, 122 Patty Phelps, 71 University of Washington University of California, Los Angeles [email protected] [email protected] Mahendra Rao, 96 Pier Vincenzo Piazza, 85 National Institute on Aging INSERM [email protected] [email protected] Mark Rasenick, 110 Marina Picciotto, 81 University of Illinois at Chicago Yale University [email protected] [email protected] Stephen Rayport, 82 Chris Pierce Columbia University Boston University School of Medicine [email protected] [email protected] Amir Raz, 86 Melinda Piper Cornell University University of California, San Francisco [email protected] [email protected] Martin Reick, 128 Dietmar Plenz, 107 University of Texas Southwestern National Institute of Mental Health Medical Center [email protected] [email protected]

153 Maarten Reith Suzanne Roffler-Tarlov University of Illinois College of Tufts University School of Medicine Medicine no e-mail on record [email protected] Mark Rollag, 128 Ian Reynolds, 110, 125 Uniformed Services University of the University of Pittsburgh Health Sciences [email protected] [email protected]

Angie Ribera Dorit Ron, 118, 119 University of Colorado Health Sciences University of California, San Francisco Center [email protected] [email protected] Bruce Rosen, 91 George Ricaurte Massachusetts General Hospital Johns Hopkins University [email protected] no e-mail on record Elliott Ross Steve Richardson University of Oklahoma Health Science University of Saskatchewan Center [email protected] [email protected]

George Richerson Shelley Russek Yale University Boston University School of Medicine [email protected] [email protected]

Barry Richmond, 77 Robert Sachdev, 98 National Institute of Mental Health University of Texas, San Antonio [email protected] [email protected]

Gordon Rintoul, 110 Ishmael Sackey University of Pittsburgh University of Cape Coast [email protected] no e-mail on record

Hugh Robinson, 126 Todd Sacktor, 83 University of Cambridge State University of New York at [email protected] Brooklyn [email protected] Michael Robinson, 130 University of Pennsylvania J. Michael Salbaum [email protected] University of Nebraska Medical Center [email protected] Katherine Roche, 115 National Institute of Neurological Norman Salem, 87 Disorders and Stroke National Institutes of Health [email protected] and [email protected] [email protected] Mike Salter, 112 Anna Roe, 102 Hospital for Sick Children Yale University School of Medicine [email protected] [email protected] Nicole Sanders, 99 University of Medicine and Denstistry of New Jersey [email protected] 154 Massimo Scanziani, 117 Michael Selzer, 73 University of California, San Diego University of Pennsylvania [email protected] [email protected]

Timothy Schallert, 91, 129 Stefano Sensi, 125 University of Texas at Austin University of California, Irvine [email protected] [email protected]

Stephen Scheff Susan Sesack, 82 University of Kentucky University of Pittsburgh [email protected] [email protected]

Gabriele Schilling, 61 Barry Setlow, 120 Johns Hopkins University Johns Hopkins University [email protected] [email protected]

Geoffrey Schoenbaum, 120 Yavin Shaham, 85, 100 Johns Hopkins University National Institute on Drug Abuse [email protected] [email protected]

Gary Schoenwolf, 71 Uri Shalev, 85 University of Utah D-Pharm [email protected] [email protected]

Joe Schwab Kent Shellenberger Novartis NeuroClin2 [email protected] [email protected]

Robert Schwarcz Gordon Shulman, 83 University of Maryland, Baltimore Washington University School of [email protected] Medicine [email protected] Andrew Schwartz, 101, 121 University of Pittsburgh David Sibley, 95 [email protected] National Institutes on Neurological Disease and Stroke Eric Schwartz, 73 [email protected] University of Pennsylvania [email protected] Beth-Anne Sieber National Institute of Mental Health Roy Schwarz, 124 [email protected] Pfizer Global Research & Development [email protected] Eric J. Simon New York University School of Medicine Erik Schweitzer, 105 [email protected] University of California, Los Angeles [email protected] Ian Simpson, 99 Penn State University Jeremy Seamans, 73 [email protected] Medical University of South Carolina [email protected] Kimberly Simpson, 130 University of Mississippi Medical Center [email protected]

155 Kevin Sinchak, 78 Heinz Steiner, 63, 88 University of California, Los Angeles Finch University of Health Sciences/ [email protected] Chicago Medical School [email protected] Robert Skoff, 79 Wayne State University School of Nephi Stella Medicine University of Washington [email protected] [email protected]

Phil Skolnick Laura Stone, 76 DOV Pharmaceutical, Inc. University of Minnesota [email protected] [email protected]

Mark A. Smith, 108, 121 Patrick Sullivan, 123 Case Western Reserve University University of Kentucky [email protected] [email protected]

Stephen Smith, 70 David Sulzer, 90 Oregon Health Sciences University Columbia University [email protected] [email protected]

Gretchen Snyder, 69 Dalton James Surmeier, 73, 113 Drexel University College of Medicine Northwestern University Medical [email protected] School [email protected] Mary Solanto, 115 Mount Sinai School of Medicine Michael Sutton, 83 [email protected] University of California, Irvine [email protected] Linda Sorkin, 106 University of California, San Diego Thomas Swanson [email protected] Midwest Neuroscience Inc. [email protected] William Spain, 117 University of Washington Nicholas Swindale, 102 [email protected] University of British Columbia [email protected] Rainer Spanagel, 100 Central Institute of Mental Health Manabu Tanifuji, 102 [email protected] RIKEN [email protected] David Spray, 122 Albert Einstein College of Medicine Rowland Taylor, 81 [email protected] Oregon Health Sciences University [email protected] Amaal Starling University of California, Los Angeles Laurence Tecott, 123 [email protected] University of California, San Francisco [email protected] Donald Stein, 101 Emory University [email protected]

156 James Tepper, 107 Daniel Tso, 84 Rutgers University State University of New York at Syracuse [email protected] [email protected]

Ei Terasawa, 97 Gina Turrigiano, 92 University of Wisconsin–Madison Brandeis University [email protected] [email protected]

Igor Timofeev, 73 Mark Tuszynski, 113 Laval University University of California, San Diego [email protected] [email protected]

Stuart Tobet, 128 Erica Unger, 65 The Shriver Center at the University of Penn State University Maryland Medical System [email protected] [email protected] C. Fernando Valenzuela, 103 Arthur Toga, 91 University of New Mexico University of California, Los Angeles [email protected] [email protected] Olga Valverde Kimberly Topp, 108 University Pompeu Fabra University of California, San Francisco [email protected] [email protected] Elisabeth Van Bockstaele, 74 Daniel Tranel, 86 Thomas Jefferson University University of Iowa [email protected] [email protected] Derek van der Kooy, 82, 111 Heather Trantham-Davidson, 64 University of Toronto Medical University of South Carolina [email protected] [email protected] Mariana Vargas-Caballero Michael Traub, 113 University of Cambridge Amgen [email protected] [email protected] Thomas Vasicek, 104 James Trimmer, 113 Lynx Therapeutics, Inc. State University of New York at Stony [email protected] Brook David Virshup, 128 [email protected] University of Utah Mark Trocchi [email protected] Association Book Exhibit Michael Vitek [email protected] Duke University Ramon Trullas, 64 [email protected] IIBB/CSIC Edward Wagner, 78 [email protected] Western University of Health Sciences Doris Tsao, 84 [email protected] Harvard Medical School [email protected]

157 Judith Walters George Wilcox, 116, 131 National Institutes of Health University of Minnesota [email protected] [email protected]

Barry Waterhouse, 115, 130 John Williams, 74 Drexel University College of Medicine Oregon Health Sciences University [email protected] [email protected]

Daniel Weinberger, 79 Stephen Williams, 126 National Institute of Mental Health University of Freiburg [email protected] [email protected]

Jeff Weiner, 103 William Wisden, 95 Wake Forest University School of University of Heidelberg Medicine [email protected] [email protected] Roy Wise, 82 Danny Weinreich, 100 National Institute on Drug Abuse University of Maryland School of [email protected] Medicine Marina Wolf [email protected] Finch University of Health Sciences/ Friedbert Weiss, 75 Chicago Medical School The Scripps Research Institute [email protected] [email protected] John Wood, 116 John Weiss, 125 University College London University of California, Irvine [email protected] [email protected] Terri Wood William Wells, 91 Penn State University Brigham and Women’s Hospital [email protected] [email protected] Marie Wooten, 83, 125 Frank Welsh Auburn University University of Pennsylvania [email protected] [email protected] Paul Worley, 115 Gary Wenk, 65 Johns Hopkins University University of Arizona [email protected] [email protected] Craige Wrenn, 97 Karin Westlund High, 131 National Institute of Mental Health University of Texas Medical Branch [email protected] [email protected] David Wynick, 97 Diek Wheeler, 66 Bristol University University of Pittsburgh [email protected] [email protected] Ai Yamamoto, 77 Jeffery Wickens, 107 Memorial Sloan Kettering Cancer University of Otago Center [email protected] [email protected]

158 Bryan Yamamoto, 101 Elmer Yu, 67 Boston University School of Medicine University of Pennsylvania [email protected] [email protected]

F. Eugene Yates Venetia Zachariou, 97 University of California, Los Angeles University of Texas Southwestern [email protected] Medical Center [email protected] Jerry Yin, 83 Cold Spring Harbor Laboratory James Zadina, 76 [email protected] Tulane University School of Medicine/ VA Medical Center Byron Yoburn, 67 [email protected] St. John’s University [email protected] Michael Zigmond, 91 University of Pittsburgh L. Trevor Young, 108 [email protected] Centre for Addiction & Mental Health [email protected] Suzanne Zukin, 94 Albert Einstein College of Medicine Laurence Young, 121 [email protected] Massachusetts Institute of Technology [email protected] Karl Zurn MED Associates Inc. Michael Young [email protected] Schepen’s Eye Research Institute [email protected]

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