WCBR Program 00

Home , Angela Vincent, Jean Loring, Suzanne Zukin

Welcome to the Thirty-Third 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.

The program includes panels (reviews for an audience not necessarily familiar with the area presented), workshops (informal discussions of current issues and data), a minicourse, and posters. The annual conference lecture will be presented at the breakfast on Sunday, January 23. Our guest speaker will be Dr. Carla Shatz. On Tuesday, January 25, a town meeting will be held for the Breckenridge community. Finally, the banquet, including a special program, music, and dancing, will be held on Friday evening. The continued 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: Kristin Anstrom, Michael Costigan, Sylvain Dore, Douglas J. Epstein, Sarah Gibbs, Robert E. Gross, Kurt Haas, David Johns, Rolf Karlstrom, Robert Mihalek, Patricio O Donnell, Amir Rezvani, Lisa Schrott, David Self, Benjamin R. Walker, Val J. Watts, David Wells, Austin Yang, Konrad Zinsmaier.

Please plan to attend the business meeting at 6:30 p.m. on Wednesday, January 26. We will elect a new Conference Chair Elect, Program Chair Elect, and three members of the Board of Directors. Other important matters will be discussed including the selection of future conference sites. 1 2 Conference Chair Irwin Levitan Allan Basbaum, Chair Elect Program Committee Paul Letourneau, Chair Elizabeth Abercrombie Christine Konradi Allan Basbaum Paul Letourneau Jill Becker Michael Levine Marc Binder Joseph Lipinski Marie-Francoise Cheselet David Perkel Joseph Coyle Bruce Ramson Thomas Dunwiddie Suzanne Roffler-Tarlov Neil Harrison Oswald Steward Karl Herrup James Surmeier Paul Katz George Wilcox Treasurer Elizabeth Abercrombie Facilities Committee Karen Greif, Chair Monte Westerfield, Chair Elect Murray Blackmore Stas Kholmanskikh Gianluca Gallo Sujatha Narayan Scott Gehler Board of Directors Elizabeth Abercrombie Joel Kleinman Marjorie Ariano Paul Letourneau Allan Basbaum Michael Levine Martha Bohn Irwin Levitan William Bunney Marsha Melnick Karen Greif Eric Simon Bart Hoebel James Surmeier Thomas Hyde Monte Westerfield Harvey Karten Don Woodward Kristen Keefe Michael Zigmond

3 Fellowship Program Donald Stein, Chair James Surmeier, Chair Elect Raymond Bartus Gene Palmer Exhibits Michael Levine School Outreach Victor Denenberg Chris Ransom Paul Dore-Duffy Suzanne Roffler-Tarlov Helene Emsellem Kent Schellenberger Karen Greif Harald Sontheimer A. Chistina Grobin Brad Stokes Hugh McIntyre Thomas Swanson Marsha Melnick Kimberly Topp Gene Palmer Frank Welsh Bruce Ransom Town Meeting Kristen Keefe Conference Arrangements Scott C. Miller, Program Director Nancy Mulvany, Program Secretary Conferences and Institutes University of Illinois at Urbana-Champaign Suite 202 University Centre 302 East John Street Champaign, IL 61820

4 2000 Fellowship Awardees Kristin Anstrom Michael Costigan Sylvain Dore Douglas J. Epstein Sarah Gibbs Robert E. Gross Kurt Haas David Johns Rolf Karlstrom Robert Mihalek Patricio O Donnell Amir Rezvani Lisa Schrott David Self Benjamin R. Walker Val J. Watts David Wells Austin Yang Konrad Zinsmaier Winter Conference on Brain Research Fellowship Sponsors Benefactor: $1000+ Alzheimer s Association Amgen Astra Zeneca Dupont Pharmaceuticals Co. Elan Pharmaceuticals, Inc. Eli Lilly and Co. Pfizer, Inc. Pharmacia & Upjohn Co. Schering Plough Research Institute Synthelabo Recherche Warner-Lambert Co. WCBR Board of Directors

5 Patron: $500-$999 Alkermes, Inc. Cephalon, Inc. Paralyzed Veterans of America WCBR Former Fellows Wyeth-Ayerst Pharmaceuticals Sponsor: up to $500 Children s Memorial Institute Exhibitors Advanced Bioconcept Co. 5375 Rue Par Montreal, QC H4P 1P7 CANADA Contact: Jonathan Suk Email: [email protected] Assocation Book Exhibit 639 South Washington St. Alexandria, VA 22314 Contact:Mark Trocchi Tel: 703-519-3909 Fax: 703-519-7732 Email:[email protected] Biorad Laboratories 2000 Alfred Nobel Drive Hercules, CA 94547 Contact:Phil Cyr Tel: 800-876-3425 x1560 Email:[email protected] Carl Zeiss One Zeiss Drive Thornwood, NY 10594 Contact:Edward Mancini Tel: 800-982-6493 Fax: 914-681-7446 Chemicon International 28835 Single Oak Drive Temecula, CA 92590 Contact:Carol Birmingham Tel:909-676-8080 x223 Fax: 909-676-9209 Email:[email protected]

6 Elsevier Science London/Neuroscion The Online Community of Neuroscientists Middlesex House 34-42 Cleveland Street London, W1P 6LE, ENGLAND Contact:Samar Syed Tel: 44--020-7611-4362 Fax: 44-020-7611-4201 Email: [email protected] Instrutech Corporation 20 Vanderventer Ave. Suite 101E Port Washington, NY 11050-3752 Contact:Milan Kesler / Telly Galiatsatos Tel: 616-829-5942 Fax: 616-829-0934 Email:[email protected]

S. Karger AG Allschwilerstrasse 10 Postfach 4009 Basel, SWITZERLAND Contact:Angela Gasser Tel: 41 61 306 1264 Fax: 41 61 306 1234 Email:[email protected] Leica Microsystems Inc. 111 Deer Lake Road Deerfield, Illinois 60015 Contact:Wayne A. Buttermore Tel: 847-317-7217 Fax: 847-405-0030 Email:wayne.buttermore@ leica-microsystems.com The MIT Press Exhibits 5 Cambridge Center, 4th Floor Cambridge, MA 02142 Contact:John Costello Tel: 617-258-5764 Fax: 617-253-1709 Email: [email protected]

7 National Research Council/ National Academy of Sciences 2101 Constitution Ave. NW (TJ 2114) Washington, DC 20418 Contact:Judith Nyquist Tel: 202-334-2202 Fax: 202-334-2759 Email: [email protected]

Nikon Inc. PO Box 2464 Evergreen, CO 80437 Contact:Gerald Benham Tel&Fax:303-674-1569 N.Y. Tel: 516 -547-8596 Fax: 516-547-4033 Email:[email protected] Noldus Information Technology, Inc. 6 Pidgeon Hill Drive, Suite 180 Sterling, VA 20165 Contact: Bart van Roekel Tel: 703-404-5506 Fax: 703-404-5507 Email: [email protected]

Olympus America Two Corporate Center Drive Melville, NY 11747 Contact: Angela Goodacre / Kathleen Karmel Tel: 800-446-5967 x5091 Fax: 631-844-5112 Email:[email protected] Oxford University Press 198 Madison Avenue New York, NY 10016 Contact: Fiona Stevens Tel: 212-726-6063 Fax: 212-726-6441 Email:[email protected]

8 Pacer Scientific 5649 Valley Oak Drive Los Angeles, CA 90068 Contact:Richard and Kathy Bellamy Tel: 323-462-0636 Fax: 323-462-1430 [email protected] PerkinElmer Wallac 9238 Gaither Rd Gaithersburg, MD 20877 Contact:Peter Franklin/Michael Smith Tel: 301-963-3200 Voicemail: x241 Fax: 301-963-7780 Email:[email protected] Trends in Neuroscience Elsevier Sceince London Theobalds Road London WC1X 8RR Contact: Stephanie Walsh Tel: 44-020-7611-4449 Fax: 44-020-7611-4463 Email: [email protected]

9 General Information

Headquarters is the Beaver Run Resort and Conference Center. All scientific activities will be held there.

WCBR Information Desk and Message Center are in the Beaver Run Resort and Conference Center Floor 3 Foyer. The desk hours are as follows: Morning Afternoon Evening Saturday 1/22 9:00—11:00 AM 3:30—5:30 PM 7:30—10:00 PM Sunday 1/23 7:00—8:00 AM 3:30—6:30 PM Monday 1/24— 7:00—8:00 AM 3:30—4:30 PM. Friday 1/28 The telephone number for messages is 970-453-7859. The Beaver Run Resort and Conference Center FAX number is 970-453-2454. The person receiving or sending 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 did not accept WCBR-assigned accommodations are charged a facilities supplement of $100 as stated in the WCBR announcement. No exceptions can be granted. Attendance at this conference is strictly limited to PREREG- ISTERED participants. On-site registration is not available. Posters will be available for viewing throughout the week. Poster presenters will be with their posters on the day and time indicated.

Exhibits and Lounge are in Peak 5. Coffee is available there from 7:30—10:30AM Monday through Friday. Refreshments are provided by the exhibitors 3:30—4:30PM, Sunday through Friday.

10 Breakfast is served to all registrants on Sunday 7:30—8:20AM, in Peaks 1—5 of the Beaver Run Resort and Conference Center, and on Monday through Friday, 6:30—7:30AM, in both the Coppertop Restaurant and Spencer s Restaurant. Both will feature the same menu items. (Social Guests may breakfast until 10:00 AM). The tickets in your registration packet are required for admission. On Saturday morning (January 29) before departure, continental breakfast is available in Peaks 1—4 of the Beaver Run Resort and Conference Center.

Ski Lift Tickets will be available from the WCBR Information Desk at the Beaver Run Resort and Conference Center Floor 3 Foyer located opposite 3rd Floor Ballroom overlooking Coppertop Deck and chairlift. Daily tickets can be purchased or prepaid tickets can be picked up on: Early Mid-Morning Late Saturday 1/22 9:00—11:00 AM 7:30—10:00 PM Sunday 1/23 7:00—8:00 AM 9:30—10:30 AM 3:30—4:30 PM Monday 1/24— Thursday 1/27 7:00—8:00 AM 9:30—10:30 AM 3:30—4:30 PM Friday 1/28 7:00—8:00 AM

Don’t forget to visit the exhibit area.

11 Special Events Saturday, January 22: Newcomers Reception ¥ 6:30—7:30 PM, Peaks 1—5. Welcome Wine and Cheese Party • 7:30—10:30 PM, Peaks 1—5. Sunday, January 23: Conference Breakfast and Opening Address • 7:30 AM, Peaks 1—5 (Your required ticket is in your registration packet). Our plenary keynote speaker will be Carla Shatz. Meeting of Panel and Workshop Organizers • Peaks 1—5, immediately after breakfast. The meeting will be brief but important. Organizers and WCBR staff please attend. Monday, January 24: First Meeting of Board of Directors • 6:30 AM, Peaks 6—8. Tuesday, January 25: Town Meeting ¥ 7:30—9:30 PM, Summit High School Auditorium 16201 Highway 9, Breckenridge, CO. Wednesday, January 26: Smitty Stevens Memorial (NASTAR) Ski Race • 10:00 AM—11:30AM, Peak 9. NASTAR registration cards to be completed no later than Monday, January 24, 8:00 AM at WCBR Information Desk. Mountain Lunch • 12:00 PM—2:00 PM. 3rd Floor of Vista Haus at Peak 8. (Required lunch ticket is in your registration packet). Non-skiers, requiring transportation, should sign up at he WCBR Information Desk. Business Meeting: Election of Conference Chair Elect, Program Chair Elect, and 3 Directors • 6:30 PM, Peaks 1—4. Friday, January 28: Second Meeting of Board of Directors. 6:30 AM, Peaks 6—8. Banquet and Dinner • 7:30 PM Peaks 1—5. (Required ticket is in your registration packet). Cash bar open at 6:30 PM in the Beaver Run Conference Center lobby.

12 Preamble to the Program

The 2000 WCBR Program consists of a Minicourse, Panels, Workshops, and Posters. Please consult the Program Booklet and posted announcements for details regarding the School Outreach, Town Meeting, and special presentations by NIH personnel.

13 Sunday, January 23 7:30 AM 8:00–10:00 PM BREAKFAST ADDRESS PANEL ¥ Sleep ... and Yet To Guest Speaker: Carla Shatz Breathe: A Neuroscientific Exploration of Sleep Apnea Peaks 1—5 H. Emsellem, L. Kubin, R. Lydic, I. Colrain, J. Black 4:30–6:30 PM Peak 11 PANEL Psychostimulant-induced • PANEL ¥ Causes and Effects of Sensitization: Behavioral and Irregularity in Neural Firing Cellular Models C. Canavier, H. Braun, P. , C. Pierce, A. Janowsky, K. Neve Steinmetz, C. Chow K. Merchant, V Watts Peak 12 Peaks 9—10 PANEL ¥ Regulation of Endogenous PANEL Oscillatory and Synchro- • Adenosine: How, When, and nized Activities in Cortex-basal Why? Ganglia Circuits S. Masino, T. White, R. Greene, , H. Bergman, M. D. Plenz J. Williams, T. Dunwiddie Bevan, J. Surmeier, T. Wichman Peaks 6—8 Peaks 6—8 PANEL ¥ DNA Repair in the WORKSHOP ¥ Dont Count Your Nervous System Chicks Neurons or Behavior Only After They Hatch P. Hanawalt, S. Ledoux, G. Kisby, P. Brooks, T. Nouspikel S. Sparber, R. Hughes, H. Karten, P. Letourneau, L. Schrott Peaks 9—10 Peak 11 PANEL • Approaching Gene Transfer To the Nervous System WORKSHOP ¥NMDA Receptors from the Inside and Out and the Nr2 Subunit. 2b, or Not 2b: That Is the Question and D. Fink, H. Federoff, W. I. Many More Lipkin, B. Davidson S. Donevan, R. Wenthold, G. Peak 4 Westbrook, J. Kemp, D. Rock PANEL • Genetic Basis of Neural Peak 4 Tube Defects and Their Preven- tion by Vitamins PANEL ¥ Regulation and Gene Expression of Opioid Peptides J.Nye, M. Speer, M.E. Ross, A. Copp E. Simon, L. Devi, L. Fricker, C. Konradi, J. Zadina Peaks 1—3 Peaks 1—3

14 Monday, January, 24 7:30–9:30 AM 3:30–4:30 PM PANEL ¥ Mitochondria and the POSTER SESSION ¥ See Poster Potentiation of Neurotransmitter Session section for detailed listing Release of poster titles, dates and times. E. Jonas, E. Kaftan, R. Rizzuto, Peak 5 K. Kinnally Peaks 9—10 4:30–6:30 PM WORKSHOP ¥Addiction and the PANEL ¥ Synaptic Plasticity Signal Medium Spiny Neuron by Calcium and Calmodulin R. Wise, B. Moghaddam, T. C. Kinases Napier, J. Surmeier T.R. Soderling, J. Hell, D. Wells, Peak 12 R.W. Tsien PANEL • Retinal Circadian Physiol- Peaks 1—3 ogy: Keeping Time in the Eye PANEL ¥ Moving To the Next M. Iuvone, J. Besharse, R. Millenium — Cloning Novel Barlow, S. Mangel Neuronal Genes Peak 11 M. Costigan, D. Chambers, K. PANEL • How Glial Cells Navigate Befort, S. Tate A Slippery Slope Peak 4 H. Sontheimer, C. ffrench- PANEL ¥ Stuttering: A Neurobiologi- Constant, J. Goldman, S. cal Perspective Hockfield P. F o x , J. Costello, R. Ingham, Peaks 6—8 C.˚Ludlow PANEL • Murine Models of Hd: Peak 12 What Have We Learned About PANEL ¥ Brain Real Estate: When the Cellular Etiology and Function Doesn t Follow Location Progression of the Disease? A. Schwartz, E. Keller, G. M. Ariano, M. DiFiglia, D. Tononi, K. Hoffmann Goldowitz, D. Tagle Peak 11 Peak 4 PANEL ¥ Nociceptive Dorsal Horn PANEL • Preclinical and Clinical Neurons-the Gateway To Pain Bases for Agonist Approaches to , A. Light, F. Nagy, C. Cocaine Dependence. Anne King Woolf C. Bradberry, J. Glowa, R. Peaks 6—8 Rothman, J. Grabowski Peaks 1—3

15 PANEL ¥ Exploring Cell Death in PANEL • From Arousal To Cogni- Parkinson s Disease: What Can tion —The Role of Basal Fore- Different Approaches Teach Us brain Corticopetal Systems M. Zigmond, R. Burke, S. J.P. Bruno, T. C. Napier, D. Roffler-Tarlov, D. Sulzer Rasmusson, M. Sarter, R. Peaks 9—10 Szymusiak Peaks 6—8 8:00–10:00 PM WORKSHOP • A Healthy Mind in A Healthy Body: Can in Vivo WORKSHOP Up or Down? • Neuroimaging Techniques Cortical Glutamate in Schizo- Provide Insights For Research, phrenia Preclinical Detection, and S. Bachus, J. Coyle, S. Zukin, B. A. Lewin, D. Choi, A. Basile, J. Moghaddam, J. Kleinman Gatley, K. Leenders Peak 11 Peak 4 PANEL ¥ Norepinephrine Crosstalks: PANEL • Mechanisms of Brain Functional Implications and Inflammation After Injury Speculations J.K. Relton, G.J. del Zoppo, J.M. , L. K.M. Merchant Hallenbeck, N.J. Rothwell Matuszewich, C. de Montigny, S. Birnbaum, E.H.F. Wong Peaks 1—3 Peak 12 PANEL ¥ Regulation of Neuronal Protein Tyrosine Phosphoryla- tion: the Next Step S. Vannucci, P. Lombroso, J. Naegele, M. Salter, J. Gurd Peaks 9—10

Tuesday, January 25

7:30–9:30 AM WORKSHOP • Thalamocortical Dynamics of Interactions PANEL ¥ GABA-A receptor Between the Senses of Touch and diversity: why, where and how Pain W. Wisden, R. Olsen, H. A. Apkarian, M. Tommerdahl, Monyer, B. Luscher, S. Moss D. Katz, V. Galhardo Peaks 9—10 Peak 11

16 PANEL • The Uses of Saporin PANEL • Dopamine: Is It Excitatory, Conjugates in Neuroscience Inhibitory, Neither, or Both? L. Jasmin, J. Krum, D. Lappi, P. O’Donnell, M.S. Levine, R.C. A.˚Basbaum Malenka, G. L. Snyder Peaks 6—8 Peaks 1—3 PANEL • Promoting axon regenera- PANEL • To Be or Not To Be: Basic tion in the CNS and Clincial Investigations of J. Fawcett, H. Geller, R. Meyer, Suicide M. Maden W. Bunney, S. Potkin, J. A. Peak 4 Fawcett, J. Lopez, J. Mann PANEL • Fatty Acid Amides: Peak 11 Greasing Neural Circuits WORKSHOP • Do LTP and Visual B. Cravatt, A. Basile, C. Felder, Developmental Plasticity Really B. Martin Share A Common Mechanistic Basis? Peak 12 S. Pallas, E. Debski, K. Haas, R. PANEL Genetic Vulnerability in • Rhoades Psychiatric and Neurological Disorders Peaks 9—10 H.I. Hanbauer, R. Greenspan, PANEL ¥ Columnar Organization in H. Caruncho, E. Costa the Olfactory Bulb Circuit? Peaks 1—3 M. Meredith, W. Chen, M. Ennis, C. Greer, J. Kauer 3:30–4:30 PM Peak 12 PANEL ¥ Intervention in POSTER SESSION Neurodegenrative Disease: See Poster Session section for Lessons from the Aging Brain detailed listing of poster titles, J. Joseph, M. Smith, R. Perez- dates and times. Polo, S. Griffin, D. Ingram Peak 5 Peaks 6—8 4:30–6:30 PM 7:30–9:30 PM MINICOURSE ¥ Practical Method- TOWN MEETING ¥ Summit High ologies for the in Vivo, On-line School Auditorium, 16201 Measurement of Neurochemical Highway 9, Breckenridge, CO Activity in the Brain Using (Transportation provided.) Miniaturized Biosensors D.M. Davis, A. Michael, E.˚Isacoff, G. Gerhardt 8:00–10:00 PM Peak 4 PANEL ¥Biomarkers of Pain A. L. Oaklander, J. Mogil, C. Woolf Peaks 6—8

17 PANEL ¥Re wards of Food, Sex and PANEL ¥ Current Ethical and Drugs: How Does the Brain Tell Regulatory Issues in the Conduct the Difference? of Clinical Research B. Hoebel, M. Carroll, P. De L. Bigelow, T. Sunderland, D. Witte, E. Hull, S. Leibowitz Shore Peaks 1—3 Peak 11 PANEL ¥In Vivo, in Vitro and in PANEL ¥R oles of the Serotonin 5- Computo Evidence That ht(3) Receptor in Brain Function Membrane Potential Fluctuations and Embryogenesis A. Destexhe, F. Amzica, S. J. Yakel, Spier, J. Lauder, A. Hestrin, P. Steinmetz Allan Peak 12 Peaks 9—10 PANEL ¥Glutamine Repeat Proteins & Formation of Toxic Aggregates in Neurodegeneration N. Marks, D. Bredesen, G. Salvesen, L. Ellerby, A. Yang Peak 4

Wednesday, January 26 7:30–9:30 AM WORKSHOP ¥ Does Drug Sensitiza- tion Contribute To Relapse To PANEL ¥GABA-go-round: Make It, Heroin and Cocaine? Shake It, Update Y. Shaham, J. Neisewander, D. A. Schousboe, K. Gale, H. Self, T. De Vries, P. Piazza Waagepetersen, K. Keefe Peak 12 Peaks 6—8 PANEL • Organization, Function PANEL • Lack of Self-Respect Can and Plasticity At the Synapse: Lead to Neurological Disease The View From the Fly A. S. Basile, P. Usherwood, C. I. Levitan, K. Zinsmaier, V. Genain, A. Vincent Budnik, L. Griffith Peak 11 Peaks 9—10 PANEL • Microarrays and Neurobi- PANEL • Excitotoxicity: Modulation ology by Natural Brain Consituents J. Loring, D. Barker, R. H. Scharfman, R. Schwarcz, C. Somogyi, J. Eberwine Zorumski, A. Schurr Peak 4 Peaks 1—3

18 PANEL • Functional Brain Imaging 3:30–4:30 PM in Disease: Problems and POSTER SESSION Potential Solutions See Poster Session section for F. Henn, P. Fletcher, C. Weiller, detailed listing of poster titles, C. Buechel dates and times. Peak 4 Peak 5 PANEL • Electrophysiological Correlates of Neuropathology in 4:30–6:30 PM Transgenic Models of WORKSHOP ¥ Dollars for Schol- Alzheimer s Disease ars W here Will My Next Grant J. Larson, P. Chapman, G. Come From? Seabrook, R. Nicoll C. Atwell, NINDS/NIH, M. Peaks 1—3 Martin, NIH, K. Olsen, NASA, PANEL • Scavenging Free Radicals D. Shore, NIMH and Preventing Apoptosis, How CopperTop Restaurant Far Can We Go? PANEL • Anesthetic Actions at R. Quirion, M.P. Mattson, S. GABA and Glutamate Synapses Dore, D.W. Nicholson B. MacIver, N. Harrison, H. Peaks 9—10 Hemmings, F. Weight, R. Pearce Peak 11 6:30–7:30 PM PANEL • Addiction and Behavior: BUSINESS MEETING AND Cellular & Molecular Correlates ELECTIONS and Determinants Peaks 1—4 B. Kosofsky, W. Carlezon, D. Self, T. Shippenberg, J. Coyle Peaks 6—8 WORKSHOP • Circadian Regulation of Arousal: Role For A Suprachiasmatic-locus Coeruleus Link G. Aston-Jones, R. Moore, C. Berridge, D. Edgar Peak 12

19 Thursday, January 27 7:30–9:30 AM WORKSHOP ¥The Contribution of Astrocytes To Cns Pathophysiol- PANEL ¥ Migraine 2000: Beyond the ogy Triptans B. MacVicar, H. Kimelberg, H. S. Peroutka, G. Gebhart, R. Sontheimer, M. Chesler McCall, P. Mermelstein Peaks 9—10 Peak 11 PANEL ¥ Modulation of Sonic Hedgehog in Anterior CNS 3:30–4:30 PM Patterning POSTER SESSION J. Kohtz, M. Hynes, D. Epstein, See Poster Session section for R. Karlstrom detailed listing of poster titles, dates and times. Peaks 6—8 Peak 5 PANEL Cross-talk Between Map/Erk Kinase and Tyrosine Kinase Cascades 4:30–6:30 PM and G-protein Coupled Recep- WORKSHOP ¥ Does Synchroniza- tors: A New Direction For Drug tion of Neuronal Firing Play A Abuse Research Role in CNS Catecholamine E. Simon, P. Stork, C. Coscia, K. System Function? Kramer, H. Gutstein J. Walters, G. Aston-Jones, J. Peak 4 Williams, H. Bergman PANEL ¥ BetterThan Sliced Bread! Peak 11 Slice Cultur es:As Close To in PANEL ¥˚Do NMDA channels have Situ As in Vitro Can Get a kinase complex? T. Lanthorn, T. Wieloch, D. J. MacDonald, M. Browning, I. Turner, G. Murphy, S. Mody, M. Salter Moskowitz Peaks 6—8 Peaks 1—3 PANEL ¥ Bending Light To the PANEL ¥The Search For A Salty Neuroscientist s Will or Taste: Gustatory and Biological Watching the Brain Think: Bases Optical Imaging At Multiple F. Flynn, D. Hill, R. Lundy, A. Scales Spector, A. Schulkin R. Siegel, F. Helmchen, B. Peak 12 Salzberg, A. Roe Peaks 1—3

20 PANEL ¥When and How To Just PANEL • Supraspinal nociceptive Say No During facilitating mechanisms Neurodevelopment D. Lima, G. Gebhart, M. P. Letourneau, V. Rehder, R. Morgan, K. Ren Mize, G. Gallo, S. Gibbs Peak 11 Peaks 9—10 PANEL • From Neuron To Song: PANEL ¥ Can in-vivo Transfer of Diverse Approaches To Vocal Genes Be Therapeutic? Non- Production and Learning human Primate Experience D. Perkel, A. Doupe, M. K. Bankiewicz, M. Bohn, J. Schmidt, F. Goller Kordower, M. Tuszynski Peaks 1—3 Peak 4 PANEL • Seizure Control From A PANEL ¥ ExtendedAmygdala, Distance: The Power and Incentive Motivation, and Potential of Vagus Nerve Relapse To Drug-taking Behavior Stimulation E. Gardner, G. Alheid, G. N. Rodgers-Neame, S. Krahl, Phillips, T. Robinson, S. Vorel D.˚Ko, B. Walker Peak 12 Peak 12 WORKSHOP • Deep Brain Stimula- 8:00–10:00 PM tion: Turn on, Tune in, Find out WORKSHOP • §-Amyloid and K. Gale, M. DeLong, R. Gross, Alzheimer Disease: The X-Files A. Benabid of Brain Research Peaks 6—8 M.A. Smith, S. Griffin, J. PANEL • New Insights Into GABAa Joseph, R. Neve, J. Loring Receptor Function Revealed by Peak 4 Gene Knockout G. Homanics, J. Huguenard, T. DeLorey, D. Hammond, R. Mihalek Peaks 9—10

21 Friday, January 28

7:30–9:30 AM C. Fairbanks, S. Carlton, M.˚Max, P. Mantyh PANEL ¥ Divide and Conquer: Peaks 6—8 Using Local Activity Regulation To Study the Brain Andrew King, A. Smith, 3:30–4:30 PM R.˚Rhoades, A. Ramoa POSTER SESSION Peaks 1—3 See Poster Session section for PANEL • Is the Reactive Oxygen detailed listing of poster titles, Species Peroxynitrite the Holy dates and times. Grail of Neurodegeneration? Peak 5 E. Hall, J. Beckman, M. A. Smith, D. Pelligrino 4:30–6:30 PM Peaks 9—10 PANEL ¥Ta rgeted Tinkering: PANEL ¥Tr anscritpional Regulation Manipulating Gene Expression in and Tissue-specific Expression of the Brain Neuroendocrine Genes R. Baler, M. Kelz, H. Gainer, D. G. Aguilera, S. Lightman, R. Johns, R. Martin Dorin, T. Insel, S. Radovick Peaks 1—3 Peak 4 PANEL • Multiple Sclerosis: WORKSHOP ¥ Serotonin Receptors Pathogenesis and Regulation That Regulate Dopamine H. Offner, P. Dore-Duffy, R.E. Systems: What Sub-types Are Jones, G. Konat, Vanderbark They and Where Are They Located? Peaks 9—10 PANEL Taster s Choice: B. Pehek, S. Sesack, L. Parsons, • K. Cunningham Mesocorticolimbic Memories Driving Goal-Directed Behavior Peak 11 P.H. Janak, A.E. Kelley, K. WORKSHOP ¥ Right Hemisphere Anstrom, G. Schoenbaum Language: An Oxymoron? Peak 11 S. Small, A. Kertesz, E. Ross, A.˚Hillis PANEL • Redox Fuse Box: Wiring That Juices the System During Peak 12 Stroke PANEL Controlling Spinal • M. Espey, C. Colton, Plasticity in the New Millen- E.˚Aizenman, D. Harder nium: New Targets and New Tools Peak 12

22 PANEL • Combination Pharmaco- therapy: Implications For Drug 7:30 PM Addiction BANQUET A. Rezvani, J. Rose, L. Reid, C. Peaks 1—5 Farren Peaks 6—8 PANEL Dendritic/Synaptic Protein Synthe- sis: A Mechanism of Synaptic Tagging With Implications For Clinical Problems and Synaptic Plasticity W. Greenough, O. Steward, A. Scheetz, J. Eberwine Peak 4

Don’t forget to visit the exhibit area.

23 Poster Sessions Poster Session 1 • Monday-Tuesday Posters will be available for viewing from Sunday to Tuesday. Presenters will be with their posters on the days and times indicated.

Monday • 3:30-4:30 PM • Peak 5 TGF-beta-1 Modulates Kir 2.3 Currents Via a PLC-PKC Dependent Mechanism In Reactive Astrocytes from Adult Brain ¥ E.A. Potts Novel Anti-stress Neuromodulators ¥ M. A. Gingras Evaluation of the Ability of Neocortical Neurons to Perform Coincidence Detection On Coherent Inputs ¥ G. A. Kinney The Role of CRH In the Regulation of Conditioned Defeat ¥ K.L. Huhman Patterns of Brain Activation Associated with Different Forms of Motor Learning ¥ M. F. Ghilardi Differential Effects of Ethanol On Kainate Receptor-Gated Inhibition of Gabaergic and Glutamatergic Synaptic Transmission ¥ .J L. Weiner A Selective D1 Dopamine Receptor Antagonist Reverses the Potentiation of Grooming Behavior Produced by the Selective CB1 ¥ D. Lin Communication Between the Lateral Septal Area and Lateral Hypothalamus In Feeding Control Communication Between the Lateral Septal Area and the Lateral Hypothalamus In the Control of Feeding C ¥ M. Kotz Testosterone Regulation of Vasopressin Receptors (V1a) In Hamster Brain ¥ E. Albers Sustained Cocaine Exposure of 12 Or 24 Hours Can Decrease Cocaine Self- administration and Desire For Cocaine But Increases Plasma ¥ .J Mendelson

Tuesday • 3:30-4:30 PM • Peak 5 Role of CRF-r1 In Opiate Withdrawal ¥ P. A. Iredale Comparison of Halothane Effects On CA1 Pyramidal Cells and Interneurons ¥ K. Nishikawa A New Method For Quantal Analysis: Deconvolution of Postsynaptic Responses ¥ M. Bykhovskaia NMDA Receptor Mediated Inhibition of Phosphatidylcholine Synthesis Precedes Excitotoxic But Not Serum Deprivation-induced ¥ R. Trullas 3-alpha-hydroxy-5alpha-pregnan-20-one Neurosteroid Brain Levels Vary Across Development In Rat and Alters GABAa Receptor ¥A.C. Grobin

24 Modulation of Intracranial Self-Stimulation Threshold by Drug Associated Contextual Cues ¥ R. J. Hayes Ethanol Elevates Cerebral Cortical Allopregnanolone Levels That Contribute to Its Pharmacological Actions ¥A. L. Morrow Possible Age-related Loss of Synapses In the Human Brain: Will We Be Disconnected In the New Millenium ¥ S. Scheff Changes In Rat CNS Metabolic Activity In the Course of a Chronic Monoarthritis ¥ .M.J Castro-Lopes Baseline Plasma HVA and Drug Response In Mania ¥ .J Chou

Activation of 5-HT1b Receptors In the Vta Potentiates Cocaine-induced Elevations of DA Levels In the NAcc ¥ L. E. O Dell Wednesday-Thursday Posters will be available for viewing from Wednesday to Friday. Presenters will be with their posters on the days and times indicated.

Wednesday • 3:30-4:30 PM • Peak 5 Alcoholism and Immunity: Disease Marker Or Secondary Effect? ¥ S. Schleifer Heritability of Independent Domains of Cognitive Dysfunction In Schizophrenia ¥ M. F. Egan APOPTOSIS—CASPASE OR POLY (ADP-RIBOSE) POLYMERASE? ¥ .J Adams Evidence For a Distinct Light-induced Calcium-dependent Potassium Current In Hermissenda Crassicornis ¥ K. Blackwell Purification and Analysis of In Vivo Differentiated Oligodendrocytes Expressing the Green Fluorescent Protein ¥W. B. Macklin Localization of Receptors of the Calcitonin Gene-related Peptide Family In the Central Nervous System ¥ K. R. Oliver Cocaine and Other Inhibitors of Dopamine Uptake Promote Different Conformational Changes In the Dopamine Transporter ¥ M.E.A. Reith Axons, Dendrites and the Ganglioside Enigma: the Crucial Role of Ca2+ and Nuclear GM1 In Neuronal Differentiation ¥ R.W. Ledeen Synaptic and Inherent Mechanisms of Temperature Sensitivity In Hypothalamic Neurons ¥ .A.J Boulant Chronic Hypercortisolemia Inhibits Dopaminergic Activity In the Nucleus Accumbens But Not In the Prefrontal Cortex ¥ K. Pacak Tau Distribution In a Transgenic That Expresses the Entire Tau Gene On a Knockout Background, a Potential Model For Neurofibrillary Tangle Formation ¥ M. P. Vitek

25 Thursday • 3:30-4:30 PM • Peak 5 Chronic PCP Administration as a Model of Schizophrenia: Effects On Cortical and Subcortical Dopaminergic Function ¥A. Balla Neurotrophin Regulation of CaMKIIa mRNA Localization to Dendritic Filopodia and Spines ¥ M.M. Martinez Plasticity In Barrel Cortex Over the Lifespan ¥ F. Ebner Attention Modulates Synchronized Neuronal Firing In Primate Somatosensory Cortex ¥˚P. Steinmetz Abnormalities of Neuronal Endocytosis As a Basis For Increased ß- amyloidogenesis In Sporadic Alzheimer’s Disease ¥˚A. M. Cataldo Identification of Transcription Factors Developmentally Regulated In Embryonic Cerebral Cortex ¥ D.B. Campbell A Putative 5-HT6 Receptor Antagonist Facilitates Amphetamine-induced Locomotion ¥ K.J. Frantz A Functional Dopamine D2 Receptor Modulator with Potential Unique Antipsychotic Properties ¥ K.A.Svensson

Behavioral Pharamcology of Selective Dopamine D3 Receptor Antagonists ¥ S. R. Haadsma-Svensson Catecholaminergic Modulation of Calcium Currents in Rat Amygdaloid Pyramidal Neurons ¥ R.C.Foehring Modulation of Localization and Function of PKC Targeting Protein RACK1 by Ethanol and cAMP ¥D. Ron Spatially Distant Neurons in the Basal Ganglia Can Demonstrate Corre- lated Multisecond Periodicities in Firing Rate in Vivo ¥ D. N. Ruskin

Don’t forget to visit the exhibit area.

26 Abstracts

PANEL • Sunday, 4:30-6:30 PM • Peaks 9-10 Psychostimulant-induced Sensitization: Behavioral and Cellular Models Organizer: K. Neve ¥ Participants: C. Pierce, A. Janowsky, K. Merchant, V. Watts Administration of psychostimulant drugs produces adaptive responses such as tolerance and sensitization. Sensitization refers to the enhanced response to psychostimulants that persists after drug withdrawal, and has been proposed to be a central component of drug craving and addiction. Potential mechanisms of sensitization include presynaptic or postsynaptic changes in the function of the mesotelencephalic dopamine system, or changes in the activity of other neurotransmitter systems that interact with the dopamine system to mediate behavioral responses to psychostimulant drugs. These mechanisms are not mutually exclusive, and there is experimental evidence for all of them. The aim of this panel is to present experimental data that explore four models of psychostimulant- induced sensitization. Chris Pierce will outline the roles of mitogen-activated and calcium/calmodulin-dependent protein kinases in the sensitized increase in accumbal dopamine associated with the expression of behavioral sensitization to cocaine. Aaron Janowsky will present work comparing the effects of passive treatment with cocaine vs. cocaine self-administration on expression, assembly, and phosphorylation of NMDA receptors and associated proteins. Kalpana Mer- chant will discuss the role of dopamine D2 receptor subtypes in behavioral sensitization to amphetamine, PCP, and cocaine, and will also show results of DNA microarray analyses of changes in gene expression that are associated with behavioral sensitization. Val Watts will describe mechanisms of heterologous sensitization of recombinant adenylate cyclase by Gi/o-coupled receptors, a cellular model of psychostimulant-induced sensitization.

PANEL • Sunday, 4:30-6:30 PM • Peaks 6-8 Oscillatory and Synchronized Activities in Cortex-basal Ganglia Circuits Organizer: D. Plenz ¥ Participants: H. Bergman, M. Bevan, J. Surmeier, T. Wichman The anatomical connections between cortex and basal ganglia set up an intri- cately complicated structure of coupled brain regions predominantly involved in movement control. Whereas cortical activity is organized into spatio-temporal domains that show both oscillatory and synchronized activities over a wide frequency range, neuronal activity in the basal ganglia, has largely been considered

27 lacking such organization. A possible linkage in temporal organization of cortical and basal ganglia activity might occur through the subthalamic nucleus. Sub- thalamic neurons discharge vigorously in bursts upon cortical inputs and they excite several other basal ganglia nuclei, including globus pallidus and substantia nigra. Synchronized oscillatory activity in the cortex, globus pallidus and thalamus correlates with tremor in Parkinson s patients that can be relieved by deep brain stimulation or lesioning of the subthalamic nucleus. Furthermore, the subthalamic nucleus by recurrent connections with the external pallidum was recently shown to generate synchronized oscillatory burst activity. This panel reviews new findings on the temporal organization of neuronal activity in the cortex- basal ganglia system. Hagai Bergman will present data on cortical ~1 Hz activity and oscillation and synchronization in the basal ganglia before and after MPTP treatment in the behaving monkey. Mark Bevan will report on synchronization of cortical ~1 Hz activity with subthalamic and pallidal activity in the anesthetized rat and burst characteristics of subthalamic neurons in the acute slice. Dietmar Plenz will present data on the generation of ~1 Hz activity in the subthalamic nucleus g lobus pallidus pacemaker in organotypic cultures. Jim Surmeier, at the single cell level using RT-PCR, will discuss afferent regulation of potassium channel populations in pallidal neurons that modifies their responsiveness to synchronized inputs. Finally, Thomas Wichmann, in the behaving monkey, will present comparative data on oscillatory activity in the substantia nigra pars reticulata, the internal pallidal segment and the subthalamic nucleus in normal and MPTP-treated animals.

WORKSHOP Sunday, 4:30-6:30 PM Peak 11 Don’t Count Your Chicks’ Neurons or Behavior Only After They Hatch Organizer: S. Sparber ¥ Participants: R. Hughes, H. Karten, P. Letourneau, L. Schrott The organizer will present a short historical perspective on the use of the developing chick as a tool to study developmental neuroscience, in the broadest terms and will discuss its utility for basic and applied neurobehavioral teratology research. During relatively recent times the chick embryo has proven useful as an experimental subject for studying cir cuit design , from a structural and neurochemical viewpoint. Letourneau and Karten will present examples of its utility, in this regard, for basic developmental neuroscience research. Hughes and Schrott will present some examples of its utility for applied research related to developmental effects of drugs of abuse and how it may be possible to study interactions between the CNS, endocrine and immune systems and effects of drugs or withdrawal from them during development. The discussions between the participants and the audience are expected to include lively debates related to problems of experimental design, data analyses and interpretation, and the relevance of such research to mammalian species, especially primates, including Homo sapiens.

28 WORKSHOP • Sunday, 4:30-6:30 PM • Peak 4 NMDA Receptors and the NR2 Subunit. 2B, or Not 2B: That Is the Question…and Many More Organizer: S. Donevan ¥ Participants: R. Wenthold, G. Westbrook, J. Kemp, D. Rock NMDA receptors have received a great deal of interest because of their involvement in synaptic plasticity, neuronal development, and in neurological disease. Cloning studies have identified 6 cDNAs that encode NMDA receptor subunits: NR1, NR2A-NR2D, and NR3. The NR2 subunits, in particular, show markedly different developmental profiles and distributions. While it is clear from studies of recombinant receptors that NR2 subunits can affect the pharmacology and kinetics, and perhaps the localization, of diheteromeric receptors (NR1 and a single NR2 species), the impact of this diversity for native receptors is still not well defined. We will explore the role of the NR2 subunit in determining the pharmacological and physiological phenotype of NMDA receptors. Specific issues to be discussed are: 1) What is the subunit composition of NMDA receptors in situ? Is subunit composition different at synaptic versus non-synaptic receptors and is it static or can it be dynamically regulated? Do NMDA receptors contain more than one NR2 subunit, and if so how does this affect the NMDA receptor phenotype? 2) What underlies the favorable in vivo profile of CP101,606 and other phenylethanolamines? Is it related to NR2 subunit selectivity? More- over, are these compounds truly NR2B selective or do they also act at receptors that incorporate both NR2B and other NR2 subunits? Alternatively, is their favorable behavioral profile related to their unique allosteric mechanism of action? These questions will be addressed by 1) biochemical and immunocytochemi- cal [Wenthold], 2) electrophysiological [Westbrook and Kemp] and 3) imaging [Rock] techniques. It is anticipated that the speakers will not all arrive at the same conclusions, which should provide for lively discussion and debate.

PANEL • Sunday, 4:30-6:30 PM • Peaks 1-3 Regulation and Gene Expression of Opioid Peptides Organizer: E. Simon ¥ Participants: L. Devi, L. Fricker, C. Konradi, J. Zadina. The panel will discuss current knowledge concerning novel and widely studied opioid peptides, placing emphasis on their regulation and function, using multiple techniques including studies of transgenic animals. Dr. Lakshmi Devi (New York University School of Medicine) will discuss the analysis of opioid peptide processing in mice lacking various peptide-processing enzymes. Dr. Lloyd Fricker (Albert Einstein College of Medicine) will discuss a novel technique to identify forms of opioid and other neuroendocrine peptides in mouse tissue. Dr. Chris- tine Konradi (Harvard University Medical School) will present information on the regulation of proenkephalin gene expression by L-type calcium channels in

29 the striatum. Finally, Dr. James Zadina (Tulane University Medical Center) will summarize the growing body of knowledge on the neurobiology of endomorphins and on the current evidence supporting the idea that they are endogenous peptides.

PANEL • Sunday, 8-10 PM • Peak 11 Sleep ... and Yet To Breathe: A Neuroscientific Exploration of Sleep Apnea Organizer: H. Emsellem ¥ Participants: L. Kubin, R. Lydic, I. Colrain, J. Black Obstructive sleep apnea (OSA) is a state-dependent, nocturnal disorder characterized by loss of tone in the airway musculature during inspiration, resulting in obstruction to airflow. Gasping and arousals with the restitution of airflow dis- rupt sleep continuity and result in non-restorative sleep, functional sleep deprivation and overt daytime sleepiness. This panel will explore recent multi-disci- plinary advances in our understanding of control of respiration and upper airway musculature. Emsellem will moderate the session and provide a brief clinical overview, stressing the prevalence of OSA, significant morbidity in terms of alertness, productivity, cognitive function and co-morbidity with hypertension and depression. Kubin will discuss lessons learned from various carbachol models of control of upper airway muscle activity, emphasizing sleep-related changes in the central aminergic excitatory drive to upper airway motoneurons and cellular basis of these changes. Lydic will discuss recent evidence suggesting that M2/ M4 muscarinic cholinergic receptors and their associated G proteins within the pontine brainstem contribute to sleep and respiratory control. The relationship between brainstem and cortical respiratory function to changes in EEG frequency during the sleep onset period and changes in upper airway resistance and chemical respiratory drive will be discussed by Colrain. Black will discuss quantitative analysis of the EEG spectrum during periods surrounding respiratory events in OSA and the changes in cortical activity coincident with sleep-related respiratory events. Meaningful quantification of these changes may provide better correlates with reductions in daytime performance in patients with OSA than con- ventional methods.

PANEL • Sunday, 8-10 PM • Peak 12 Causes and Effects of Irregularity in Neural Firing Organizer: C. Canavier ¥ Participants: H. Braun, P. Steinmetz, C. Chow Sources of apparent randomness in the firing pattern of neurons and their effects on signal transduction will be examined. These sources can be stochastic (such as thermal noise or channel noise) or deterministic (such as chaos). Hans Braun will present evidence supporting chaotic dynamics occuring in experimental data from different types of sensory receptors and hypothalamic neurons as well as in computer simulations. The chaotic dynamics were detected using a search algorithm for the detection of unstable periodic orbits, and in addition, fluctions of

30 spike activity were observed that could only result from cooperative effects between the nonlinear dynamics and noise. Carmen Canavier will present an analysis of interspike intervals from midbrain dopamine neurons in vitro. The data were transformed into a continuous spike density function, then analysed using nonlinear forecasting. This technique quantifies the loss of predictive efficiency with increasing prediction interval in order to differentiate between different kinds of nonlinear structure observed, including chaos and correlated noise. Peter Steinmetz will present theoretical studies quantifying the degradation of temporal coding under signal estimation and detection paradigms due to the effects of thermal noise, channel noise, and synaptic background noise. He will also present studies of how these noise levels are related to the excitability of underlying channel kinetic schemes. On the other hand, Carson Chow will present theoretical studies of how noise can enhance rather than degrade signal processing by several methods. One is boosting sub-threshold signals via stochastic resonance enabling detection. Another is desynchonizing the firing of a population of neurons in order to allow encoding as a population firing average rather than as a temporal average, resulting in faster responses.

PANEL • Sunday, 8-10 PM • Peaks 6-8 Regulation of Endogenous Adenosine: How, When, and Why? Organizer: S. Masino ¥ Participants: T. White, R. Greene, J. Williams, T. Dunwiddie Levels of adenosine sufficient to tonically activate adenosine receptors are present throughout the nervous system, and in most brain regions the primary effect of endogenous adenosine is a presynaptic inhibition of excitatory transmission. However, the role and regulation of this ongoing inhibition is not well understood. While pathological situations such as hypoxia and ischemia have long been recognized to increase extracellular adenosine, recent studies have demonstrated other physiologically relevant and non-neuropathic circumstances that transiently or chronically alter adenosine levels. Tom Dunwiddie will chair this panel which will outline findings relating adenosine in the central nervous system to immune system activation, brain temperature, behavioral state transitions, and withdrawal from drug addiction. Tom White will discuss cellular mechanisms, including excitatory amino acid receptor activation, which are able to regulate adenosine levels, and will also present data on immunogen-evoked release of adenosine and other neurotransmitters from the cerebral cortex. Susan Masino will present data obtained in the hippocampus suggesting that endogenous adenosine levels may be influenced in an ongoing basis by small changes in temperature. Robby Greene will discuss the evidence for adenosine as a fa- tigue factor in cholinergic arousal centers to increase the likelihood of a transi- tion to sleep. Finally, John Williams will present a role for adenosine in the long term cellular consequences of drug withdrawal in the ventral tegmental nucleus. Taken together, these studies begin to elucidate a broad yet diverse role for ongoing endogenous adenosine levels, suggest situations which alter these levels, and demonstrate some functional consequences of altered endogenous adenosine.

31 PANEL • Sunday, 8-10 PM • Peaks 9-10 DNA Repair in the Nervous System Organizer: P.Hanawalt ¥ Participants: S. Ledoux, G. Kisby, P.J. Brooks, T. Nouspikel Deficiencies in DNA repair have been proposed as a cause of neuronal senes- cence and some forms of dementia. The characteristic neurological deficiencies in Cockayne s syndrome may be the consequence of excessive cell death resulting from unrepaired oxidative damage in expressed genes. DNA repair modes that operate in the nuclei and mitochondria of human cells will be outlined. Then we will focus upon recent advances in our understanding of DNA repair in the nervous system. Susan Ledoux will describe studies to evaluate repair in normal diploid cells of the CNS. Repair of both alkylation and oxidative damage to DNA in primary cultures of astrocytes is more efficient than that in oligodendrocytes, microglia, or neurons. Inefficient repair is correlated with induction of apoptosis. Glen Kisby will consider neurodegeneration due to damage from exogenous chemicals, as studied using neuronal and astrocyte cell cultures prepared from mice with targeted mutations in different DNA repair genes. PJ. Brooks will focus on the question of why some xeroderma pigmentosum patients have progressive neurological degeneration. A novel DNA lesion, 8,5’ cyclodeoxyadenosine, generated by oxygen radical attack, is a substrate for nucle- otide excision repair, but cannot be removed by base excision repair, the main pathway for oxidative DNA damage. This lesion is a strong block to transcription and that may lead to neuronal death and subsequent neurodegeneration. Thierry Nouspikel has demonstrated modulation of DNA repair during neuronal differentiation. Comparative studies with human NT2 neuroteratoma cells and their differentiated hNT neurons have revealed that global repair efficiency is strikingly reduced while both DNA strands in expressed genes are still profi- ciently repaired in the terminally differentiated cells. Strong induction of several essential DNA repair enzymes, also occurs during neuronal differentiation. The studies to be described are highly relevant to an understanding of neurodegenerative disease and aging.

PANEL • Sunday, 8-10 PM • Peak 4 Approaching Gene Transfer To the Nervous System From the Inside and Out Organizer: D. Fink ¥ Participants: H. Federoff, W. I. Lipkin, B.Davidson Advances in the technology of gene transfer have increased the options available for the delivery of genes into neurons for experimental and therapeutic applications. Dr. Davidson will compare recombinant adenoviral and lentiviral vectors, with specific reference to experimental studies of lysosomal storage disease. Dr. Fink will discuss the use of genomic herpes simplex virus vectors to deliver antinociceptive peptides to the peripheral nervous system, and anti-apoptotic gene products to the central nervous system. Dr. Federoff will present data on

32 the use of a herpes-packaged amplicon for somatic gene transfer of cre recombinase to alter brain function in mature transgenic mice. Finally, Dr. Lipkin will describe Borna Disease Virus, the prototype of a new family of nonsegmented negative-strand RNA viruses with a tropism for highly conserved circuits in brain, which may be useful as a vector for targeted gene delivery within the CNS. The discussion will explore: (1) comparison of different vector types for specific applications; (2) potential risks to the use of viral vectors for gene transfer; and (3) remaining hurdles to be overcome before such vectors can be used for therapeutic gene transfer in humans.

PANEL • Sunday, 8-10 PM • Peaks 1-3 Genetic Basis of Neural Tube Defects and Their Prevention by Vitamins Organizer: J.Nye ¥ Participants: M. Speer, M.E. Ross, A. Copp Neural tubes defects (NTDs) are common congenital malformations whose etiology is multifactorial. Familial clustering implies that inherited factors are important, and the existence of dozens of genetic lines of mice with NTDs suggests that a similar number of genes can contribute to the etiology of NTDs. Environmental factors also play important etiologic and preventative roles as evidenced by the observation that folic acid supplementation reduces the incidence of NTDs in humans by as much as 75%. In this symposium we present recent studies on the genetic etiology and developmental mechanisms of NTDs in humans and mice. Marcy Speer will discuss how a statistical genetic approach is used for disease gene identification in a complex disorder such as NTDs. She will also examine the evidence that variant forms of folic acid metabolizing enzymes contribute to the risk of NTDs. Jeffrey Nye will discuss how human NTDs resemble the murine lines both in heterogeneity of etiology and in associated malformations. He will show examples of humans that have NTDs and genetic mutations homologous to mouse lines such as Splotch. M. Elizabeth Ross will discuss the semidominant murine line, crooked tail (Cd), which is a model of both anencephaly and spinal defects. She will show mapping of the Cd locus to 0.4 cM and give evidence that Cd responds to folic acid supplementation in a manner similar to human NTDs. Andrew Copp will discuss the genetic and developmental basis of neurulation and NTDs in humans and mice. He will examine recent work on mouse genetic models showing digenic modes of inheritance, epistatic mechanisms, and reveal how the folate-sensitive and folate-resistant murine models suggest methods for preventing the human disorder.

PANEL • Monday, 7:30-9:30 AM • Peaks 9-10 Mitochondria and the Potentiation of Neurotransmitter Release Organizer: E. Jonas ¥ Participants: E. Kaftan, R. Rizzuto, K. Kinnally Intracellular calcium stores, including those of mitochondria, have been found to be important in the function of excitable cells. Calcium uptake into mitochon-

33 dria followed by rapid re-release from the mitochondrial matrix shape the time course of calcium transients during synaptic activity and cause the prolonged elevation of intracellular calcium ( r esidual calcium ) tha t underlies post-teta- nic potentiation (PTP). In this session, we will address the topic of the function of mitochondria in management of cytosolic calcium in excitable cells. E.J. Kaf- tan will describe his studies on simultaneous imaging of calcium in the cytosol and mitochondria in pituitary gonadotropes, and show that mitochondria se- quester calcium rapidly after its release from IP3-sensitive stores during calcium oscillations. R. Rizzuto will demonstrate the spatial relationship between endo- plasmic reticulum and mitochondria revealed by using two differently colored, specifically targeted green fluorescent proteins. He will show that a large, interconnected, rapidly changing network of mitochondria exists, and that close contacts between organelles play a role in calcium signaling. K.W. Kinnally will discuss different types of mitochondrial ion channels and what role they might play in calcium signaling. E.A. Jonas will show recordings of mitochondrial conductances in an intact presynaptic terminal and discuss the changes seen in these conductances upon calcium influx into the terminal during synaptic transmission.

WORKSHOP • Monday, 7:30-9:30 AM • Peak 12 Addiction and the Medium Spiny Neuron Organizer: R. Wise ¥ Participants: B. Moghaddam, T.C. Napier, J. Surmeier Amphetamine, cocaine, nicotine, heroin, and PCP have habit-forming actions involving nucleus accumbens (NAS). Amphetamine, cocaine, and nicotine are habit-forming because they elevate NAS dopamine, which inhibits NAS medium spiny output neurons. Morphine elevates NAS DA and is rewarding when injected into VTA; it is also habit-forming when microinjected into NAS, where it directly inhibits medium spiny s. PCP blocks NMDA-type excitatory input to these neurons. Thus it has been suggested that decreases in the output of medium spiny s may be a common denominator of several addictions. This workshop will explore the weaknesses of this hypothesis. Wise will introduce the problem. Napier will discuss the multiple efferent targets of medium spiny s and raise the question of how indiscriminate depression of multiple GABAergic outputs of NAS could have a simple non-disruptive outcome. Surmeier will discuss evidence that dopamine is not simply inhibitory for medium spiny s; it can be excitatory or inhibitory depending on the momentary membrane potential of the medium spiny, and it can modulate the effectiveness of other inputs to the medium spiny. Moghaddam will argue that non-competitive NMDA antagonists such as PCP increase Glu efflux leading to stimulation of non-NMDA (e.g. AMPA/kainate) receptors, which should result in activation rather than inhibition of medium spiny neurons. After these and other subtleties of NAS function are discussed, we will return to the question of whether these various drugs could have common actions on medium spiny neurons that could account for their shared addiction liability.

34 PANEL • Monday, 7:30-9:30 AM Peak 11 Retinal Circadian Physiology: Keeping Time in the Eye Organizer: M. Iuvone ¥ Participants: J. Besharse, R. Barlow, S. Mangel In order to see under starlit skies and in bright sunlight, vertebrate animals must adapt to more than a 1,000,000-fold change in illumination. This adaptation is attributable in part to the presence of two types of photoreceptors, rods for vision in dim light and cones for bright light. This adaptation occurs at several levels in the phototransduction machinery of rods and cones and in plasticity of the synaptic organization of the retina. In many species, this latter form of adaptation is organized on a daily basis, regulated by a retinal circadian clock. Thus, the retina anticipates changes in ambient illumination, particularly at dawn and dusk. A circadian clock has been localized in vertebrate eyes, specifically to pho- toreceptor cells. This clock regulates adaptation and other important aspects of retinal physiology. The panel will review recent progress in understanding the molecular mechanisms of the retinal circadian clock and the functional consequences of its action. The first two speakers will discuss circadian aspects of gene expression, with an emphasis on clock genes (per 2) and clock-controlled genes (nocturnin, tryptophan hydroxylase, and serotonin N-acetyltransferase). Circadian regulation and light sensitivity will be compared, as will transcriptional vs. post-transcriptional mechanisms. The other two speakers will focus on the physiological actions of the circadian clock. Their topics include how the clock uses neuromodulators (dopamine, melatonin, and adenosine) and protons to regulate plasticity in rod and cone pathways, and the mechanisms whereby the clock regulates visual sensitivity. Thus, the topic of circadian retinal physiology will be covered from genes to vision.

PANEL • Monday, 7:30-9:30 AM • Peaks 6-8 How Glial Cells Navigate A Slippery Slope Organizer: H. Sontheimer ¥ Participants: C. ffrench-Constant, J. Goldman, S. Hockfield In the developing brain neurons and glial cells migrate over large distances. Glial migration extends well into postnatal life. Migrating cells interact in complex ways with other cells, fibers, extracellular matrix and diffusible signals. Diseases and injury can induce migration of glial cells in the adult brain. Thus, gliosis causes migration of astrocytes towards an injury site. Glial neoplasms, gliomas, are highly motile and invasive and rapidly spread throughout the CNS. This panel will discuss anatomical pathways of glial migration and mechanisms involved in guidance, motility and cell shape changes in migrating cells. Goldman will talk about pa tterns and dynamics of glial progenitor migration visualized in living slice preparations . He will show how glial progenitor cell migration can be visualized in real time in slices of developing rodent forebrain and cerebellum

35 using a green fluorescent protein-expressing retrovirus. ffrench-Constant will examine inte grin function and signaling in the regulation of neural precursor behavior . He will show how different integrins regulate modes of progenitor cell migration and the timing of migration. He will discuss mechanisms of integrin signaling during migration and the interaction with growth factors mediated responses. Hockfield will present recent work on BEHAB/brevican, a brain-specific extracellular matrix protein. She will discuss possible roles of BEHAB in glioma cell migration, and show how this novel extracellular matrix molecule, may increase the motility and growth kinetics of glioma cells. Sontheimer will discuss shape and cell volume changes that occur during migration of glia and glioma cells. He will provide evidence that ion and water fluxes across glial membranes are dynamically regulated by the cells cytoskeleton and provide an opportunity to interfere with the uncontrolled migration of glioma cells.

PANEL • Monday, 7:30-9:30 AM • Peak 4 Murine Models of HD: What Have We Learned About the Cellular Etiology and Progression of the Disease? Organizer: M. Ariano ¥˚Participants: M. DiFiglia, D. Goldowitz, D. Tagle Huntington s Disease (HD) is an autosomal dominant disorder that demonstrates progressive motor and cognitive symptoms. The genetic defect is produced by an unstable expanded CAG triplet repeat within the coding region of the huntingtin gene on the short arm of chromosome 4. HD neuropathology shows selective neuronal losses in the striatum and deep layers of the cerebral cortex. The striatal degeneration exhibits an organized progression beginning in the dorsomedial nucleus, targeting medium spiny projection neurons with the enkephalin phenotype. End stage HD displays further loss of substance P efferent neurons in the dorsal striatum, near normal anatomy in the ventral striatum, and sparing of the striatal interneuron populations. The cellular events contributing to these disease sequelae are unknown. The recent developments of transgenic animals that express different portions of the mutated human gene have provided information on the mechanism of neuronal death in HD. DiFiglia will present the distribution of neuronal internuclear inclusions, protein trafficking and phenotypic characterization of a murine mutant expressing the human transgene that includes a caspase 3 cleavage site. Tagle will present data on the use of a second transgenic to study HD pathogenesis using cDNA microarrays to evaluate early molecular markers/targets for the disease; screening and evaluation of therapeutic strategies; and identification of neurochemical and cellular changes in presymptomatic mice. Goldowitz will discuss a chimeric analysis of the cellular target for HD in a third transgenic mouse. Ariano will demonstrate DA receptor expression patterns and physiological differences of striatal neuron populations in these three mouse models, before and after the onset of motor symptoms.

36 PANEL • Monday, 7:30-9:30 AM • Peaks 1-3 Preclinical and Clinical Bases for Agonist Approaches to Cocaine Dependence Organizer: C. Bradberry ¥ Participants: J. Glowa, R. Rothman, J. Grabowski There are currently no effective pharmacotherapies to assist in treatment of cocaine dependence. An approach that has achieved some success with dependence on other substances such as tobacco and opiates is agonist treatment. This panel will present both preclinical and clinical speakers addressing such an approach. Charles Bradberry will present data on the behavioral and neurochemical effects of cocaethylene, a close analog of cocaine formed as a metabolite of combined alcohol and cocaine consumption. While equipotent to cocaine at the dopamine uptake site, it is less potent at the noradrenergic and serotonergic uptake sites. It appears to result in a more rapid acute tolerance to its behavioral and neurochemical effects than cocaine, and because it is formed in humans, can readily be tested in humans. Jase Glowa will present data on the behavioral effects of GBR 12909 and phentermine in a monkey self-administration model comparing the effects of agonists on cocaine and food self-administration. Rich- ard Rothman will review the clinical signs and symptoms of stimulant withdrawal, as well as relevant animal studies, to highlight a dual deficit model of stimulant withdrawal. This model emphasizes the notion that stimulant withdrawal is associated with neurochemical deficits of serotonin and dopamine. A prediction of this hypothesis is that reversing the neuronal deficits of dopamine and serotonin with substrates of the biogenic amine transporters, i.e. stimulants, may be a viable treatment strategy. Neurochemical and behavioral data obtained which test his hypothesis will be presented. John Grabowski will present results from clinical studies using agonists d-amphetamine, l-dopa/carbidopa, and desoxyamphetamine for stimulant dependence, including safety data from the human lab studies.

PANEL • Monday, 4:30-6:30 PM • Peaks 1-3 Synaptic Plasticity Signal by Calcium and Calmodulin Kinases Organizer: T.R. Soderling ¥˚Participants: J. Hell, D. Wells, R.W. Tsien Many forms of neuronal synaptic plasticity, such as long-term potentiation (LTP) and depression, are initiated by elevations of postsynaptic calcium. There are multiple targets for postsynaptic Ca2+ including several CaM-kinases. In this panel presentation, the following issues will be addressed. 1) Activation of the NMDA receptor in hippocampal neurons with resultant Ca2+ influx triggers binding of CaM-Kinase II to the NMDA-R. This activated CaM-kinase II is now localized at the postsynaptic density to phosphorylate critical substrates. 2) Induction of LTP triggers prolonged activation of CaM-kinase II which phos- phorylates the GluR1 subunit of the AMPA-R. Phosphorylation by CaM-kinase II of Ser831 in GluR1 potentiates AMPA-R current by stabilizing higher con-

37 ductance states. 3) Induction of LTP can also cause increased dendritic synthesis of CaM-kinase II, and hippocampal dendrites contain significant amount of the mRNA for CaM-kinase II as well as all the machinery for localized protein synthesis. Recent studies show that localized synthesis of CaM-Kinase II in the dendrites might be mediated by the cytoplasmic polyadenylation element binding protein (CPEB). 4) Late-stage LTP requires new gene expression mediated by CREB phosphorylation, and multiple signaling pathways, including CaM-kinase IV, are involved. Ca2+/CaM signaling from the synapse to the nucleus will be discussed. These presentations will provide a broad but cohesive hypothesis for multiple roles of Ca2+ signaling and CaM-kinases in synaptic plasticity.

PANEL • Monday, 4:30-6:30 PM • Peak 4 Moving To the Next Millenium—Cloning Novel Neuronal Genes Organizer: M. Costigan ¥˚Participants: D. Chambers, K. Befort, S. Tate In recent years much effort in neuroscience has been devoted to isolating previously unknown genes which are regulated in a particular etiology or specifically expressed within a given tissue. In other cases defined gene targets have been sought, for instance, specific receptors or ion channels. These methods are on the leading edge of the molecular revolution, which has marked neuroscience within the past decade. This panel will analyze several of these techniques in turn and is made up of young scientists with extensive hands on experience in these emerging fields. Michael Costigan will discuss the development and application of PCR-based subtractive hybridization with particular reference to the production of representative PCR generated libraries and their subsequent subtraction. Examples of clones regulated within the dorsal root ganglion following sciatic nerve section will be given with reference to subsequent functional analysis of these clones. David Chambers will discuss the use of differential display PCR to find genes switched on and off in early vertebrate brain development and follow with functional analysis of these genes. Katia Befort will describe cloning the d-opioid receptor using an expression cloning strategy and then describe structure-function studies using site-directed mutagenesis and binding assays. Simon Tate will discuss, first, more traditional methods of PCR based homology screening, used to isolate a novel sodium channel specific to the peripheral nervous system. Then follow with a discussion of the fast emerging field of insilico-cloning, which is set to transform the way many of us perform molecular biology within the next millennium.

PANEL • Monday, 4:30-6:30 PM • Peak 12 Stuttering: A Neurobiological Perspective Organizer: P. Fox ¥˚Participants: J. Costello, R. Ingham, C. Ludlow Stuttering is a common (1% incidence), often disabling speech disorder. Neuro- biological theories of stuttering have been put forward for many years, but have relied heavily on indirect evidence. Over the past 3-5 years, advanced neuroimaging

38 techniques (i.e., PET, fMRI, TMS) have been brought to bear on this disorder, with remarkable success. Fluency inductions a f amily of behavioral techniques able to decrease or eliminate stuttering ha ve played a prominent role in this breakthrough, by allowing fluent and non-fluent speech to be acquired in the same imaging session. Fluency inductions include: prolonged speech, rhythmic speech, and speaking in chorus with others. Using imaging and fluency induction, abnormal regional activations have been identified by several laboratories in areas including the SMA (activations), lateral premotor cortex (activations), and posterior temporal cortex (inhibitions). These regional abnormalities are presently being modeled as neural systems/circuits underlying stuttering, using inter-regional co-variance and structural equation modeling. This workshop will review stuttering from a neurobiological perspective, placing the recent neuroimaging findings in the context of the disorder as a whole. Dr. Janis Costello will review the epidemiology, symptomatology and pre-imaging studies of developmental stuttering, emphasizing findings implicating specific regions of the nervous system. Dr. Roger Ingham will review fluency inductions in three con- texts: as a clue to the etiology; as a treatment; as an experimental strategy. Dr. Peter Fox will review imaging studies of stuttering and their modeling. Dr. Christy Ludlow will review the neurobiology of acquired stuttering (e.g., post stroke) and its relationship with aphasia, by way of comparison with the neurobiology of developmental stuttering revealed through neuroimaging and developmental risk factors.

PANEL • Monday, 4:30-6:30 PM • Peak 11 Brain Real Estate: When Function Doesn’t Follow Location Organizer: A. Schwartz ¥ Participants: E. Keller, G. Tononi, K. Hoffmann The theme of neuroanatomy is to define brain regions based on similarities and differences of projection pathways and cytoarchitectonics. As anatomical methods have advanced, the number of defined brain areas and their subdivisions have mushroomed. On the other hand, many areas are interconnected with reciprocal loops suggesting that information is largely shared throughout the brain. This has great implications for mapping function to location with methods such as functional imaging and raises the question as to whether there is a separate function for each anatomical entity. Recent physiological studies in behaving animals have generated a converging line of evidence showing that brain processing is carried out by large populations of neurons. Not only does each cell participate in different processes, but there is great similarity between distant brain regions in their single-cell activity within a given behavior. Giulio Tononi will describe a theory based on mutual information that will demonstrate how processing within and between groups of cells can be identified with changes in behavioral state. Ed Keller will show how cells in the superior colliculus and frontal eye fields have the same latency, visual responsiveness and sensitivity to targets/distractors in a visual search task. Klaus-Peter Hoffmann will show how a different set of cells in the superior colliculus have activity related to arm movements with specific correlation to arm muscle activity in a reaching task. An-

39 drew Schwartz will show how populations of cells in premotor and primary cortices are inter-related and how motor cortical cells are similar to those in superior colliculus in their muscle correlations during reaching. These examples will show how cells in the same structure code for different movements while cells in different structures seem to have similar codes for the same movement.

PANEL • Monday, 4:30-6:30 PM • Peaks 6-8 Nociceptive Dorsal Horn Neurons-the Gateway To Pain Organizer: Anne King ¥ Participants: A. Light, F. Nagy, C. Woolf Much progress has been made towards a more complete understanding of the organization and operation of dorsal horn circuitry that underpins transmission of peripheral noxious stimuli. This panel is made up of international experts who will present an overview of developments in some key areas. Anne King (Leeds, UK) will discuss stimulation-transcription coupling and neurokinin- mediated activation of protein kinase-dependent second messenger cascades in dorsal horn neurons in vitro. These intracellular signaling pathways offer routes to the nucleus for initiation of gene transcription and may be relevant to post- injury neuroplasticity. Clifford Woolf, (Harvard, USA) will consider prostanoids and sensory processing in the dorsal horn. He will address the question To what extent do classical non-steroidal anti-inflammatory drugs produce their analgesic actions within spinal cord? . The distribution, regulation and function of cyclooxygenases and the EP receptor class within the dorsal horn will be discussed. Alan Light (UNC, USA) will present unique electrophysiological data obtained from patch clamp studies of lamina I/II neurons in vivo. The morphology of a subset of neurons, revealed using biocytin as an intracellular marker, and neuronal responsiveness to opioid agonists will be described. Frederic Nagy (Bordeaux, France) will describe intrinsic membrane regenerative properties and their role in nociceptive integration and wind-up in the dorsal horn. The expression of voltage-dependent plateaus that rely on activation of an L-type calcium channel could provide a link between short- and long-term modification of neuronal excitability and central sensitization. In summary, we will draw together knowledge of the dorsal horn that impacts on our future efforts to manage acute and chronic pain states.

PANEL • Monday, 4:30-6:30 PM • Peaks 9-10 Exploring Cell Death in Parkinson’s Disease: What Can Different Approaches Teach Us Organizer: M. Zigmond ¥ Participants: R. Burke, S. Roffler-Tarlov, D. Sulzer We may know more about Parkinson s disease than any other neurodegenerative disorder. For example, we know that the symptoms can be attributed primarily to dopamine (DA) neuron loss in the nigrostriatal projection. Yet, we do not

40 know what causes the disease, how to arrest its progression, or how to prevent it. In this panel we explore these issues using a variety of model systems. After a brief introduction to the neuropathology of Parkinson s disease, Bob Burke will focus on an in vivo rat model in which programmed cell death in DA neurons is examined during development and as a result of the administration of the neu- rotoxin 6-hydroxydopamine. Suzanne Roffler-Tarlov will then discuss her work on the weaver mouse, an animal in which the DA neurons of the nigrostriatal projection die during the first few weeks of life because of a mutation the G- protein-gated inwardly rectifying potassium channel Girk2. She will also describe her recent work on the impact of the weaver mutation in immortalized tyrosine hydroxylase-positive CNS neurons. Next, David Sulzer will discuss the role of the vesicular monoamine transporter (VMAT) on the intracellular oxidation or DA in cells prepared from VMAT knock-out animals. He also will discuss the use of substantia nigra melanosomes as model systems. Finally, Michael Zigmond will present his work on the impact of overexpression of wild type and mutant synuclein on cell death in primary neurons from both ventral mesencephalon and cerebellum. He also will discuss the use of organotypic slice cultures for studies of DA neuron cell death. Audience members will be encouraged to participate actively in discussions about these studies and about the relative merits of the different approaches.

WORKSHOP • Monday, 8:00-10:00 PM • Peak 11 Up or Down? Cortical Glutamate in Schizophrenia Organizer: S. Bachus ¥ Participants: J. Coyle, S. Zukin, B. Moghaddam, J. Kleinman A great deal of convergent evidence, including neuropharmacological, in vivo imaging, neuropathological, molecular biological, and animal psychopharma- cological findings, implicates cortical glutamate dysfunction in schizophrenia. Controversy abounds about the interpretation of these data however, since many of the same observations have been cited in support of two apparently diametri- cally opposed hypotheses, namely that either cortical glutamate hypo- or hyper- function contributes to schizophrenia. Joseph Coyle will argue from postmortem studies of cortical glutamate and NAALADase levels that cortical glutamate function is reduced in schizophrenia. Steve Zukin will review animal and human effects of NMDA antagonists, as well as evidence for therapeutic amelioration of NMDAR hypofunction in schizophrenia by glycine-site agonists. Bita Moghaddam will present the case gleaned from animal models that excess cortical glutamate is responsible for schizophrenia. Joel Kleinman will suggest from postmortem studies of expression of glutamate transporters that aberrant connections between glutamate neurons and their targets, rather than glutamate levels per se, pose the problem. Since both glutamate agonists and antagonists are being proposed for clinical trials for pharmacotherapy in schizophrenia, there is a critical need to examine the seeming contradictions head on.

41 PANEL • Monday, 8:00-10:00 PM • Peak 12 Norepinephrine Crosstalks: Functional Implications and Speculations Organizer: K.M. Merchant ¥ Participants: L. Matuszewich, C. de Montigny, S. Birnbaum, E.H.F. Wong Recent availability of genetically engineered tools and phamacological agents that selectively modify central norepinephrine neurotransmission have revived an interest in the role of this neurotransmitter in the normal functioning and pathophysiology of the CNS. This panel will address how norepinephrine inter- acts with classical neurotransmitters, dopamine, serotonin and glutamate, as well as stress hormones to regulate neural functions. K.M. Merchant will begin with a brief introduction of neuroanatomical organization of central norepinephrine systems and clinical literature implicating this neurotransmitter in a number of psychiatric diseases. Using in vivo microdialysis, B.K. Yamamoto has demonstrated norepinephrine transporter (NET) mediated regulation dopamine neurotransmission in the prefrontal cortex and the nucleus accumbens-shell. He will discuss the implications of these data with respect to regulation of CNS functions. C. de Montigny will present new data showing interactions between norepinephrine and serotonin neurons in the hippocampus and the possible implications of these interactions in the treatment of major depression. S. Birnbaum will present data from her doctoral research on alpha-1 and alpha-2 adrenoreceptor mediated regulation of cognitive functions mediated by the prefrontal cortex. Finally, E.H.F. Wong will present data that demonstrate an interaction of norepinephrine with stress hormones and glutamate receptors that may have implications for novel drug therapies. Together, this panel will show that through the varied neural interactions, central norepinephrine systems regulate critical neural functions.

PANEL • Monday, 8:00-10:00 PM • Peaks 9-10 Regulation of Neuronal Protein Tyrosine Phosphorylation: The Next Step Organizer: S. Vannucci ¥ Participants: P. Lombroso, J. Naegele, M. Salter, J. Gurd Tyrosine phosphorylation regulates many aspects of neuronal development, as well as synaptic function in mature cells. Tyrosine phosphorylation is involved in the modification of synaptic activity, such as during depolarization, long-term potentiation or depression, and cerebral ischemia. The Striatal Enriched Protein Tyrosine Phosphatase family of protein tyrosine phosphatases (PTPs) were the first group of PTPs to be described that are exclusively expressed within the CNS. STEP proteins are enriched within neurons of the striatum and to a lesser extent within the hippocampus and other regions of the telencephalon. The family members comprise both higher and lower molecular weight (Mr) isoforms which

42 result from alternative splicing of a single STEP gene. The purpose of this panel is to bring together the various investigators who have been most involved in analyzing this interesting family to help elucidate the role(s) of tyrosine phosphorylation in the regulation of normal synaptic function and the response to ischemia. Paul Lombroso will provide an overview of STEP and discuss the three pertinent mechanisms of regulation: alternative splicing, phosphorylation by PKA and PKC and upstream neuromodulatory agents, and proteolytic cleavage of high Mr STEP to yield active STEP isoforms. The expression of the STEP isoforms is developmentally regulated and Janice Naegele will discuss the ontog- eny of STEP in the rat striatum. Mike Salter will present recent evidence that STEP associated with NMDA receptors results in depressed channel function, likely due to dephosphorylation of protein(s) in the complex. Finally, Jim Gurd and Susan Vannucci will discuss the effects of cerebral hypoxia-ischemia (H/I) in neonatal and young rat brain on the expression of STEP family members and the potential contribution to neuroprotection.

PANEL • Monday, 8:00-10:00 PM • Peaks 6-8 From Arousal To Cognition— The Role of Basal Forebrain Corticopetal Systems Organizer: J.P. Bruno ¥ Participants: T. C. Napier, D. Rasmusson, M. Sarter, R. Szymusiak There is substantial evidence for the vital role of basal forebrain corticopetal projections in the gating of information throughout the neocortex. This gating ranges from determining the more general levels of information processing as reflected by arousal states to the mediation of more specific information such as plasticity of cortical sensory fields and attentional processing. As such, dysfunctions in the regulation of these basal forebrain cholinergic and GABAergic projections may contribute to a variety of cognitive disorders and neuropsychiatric diseases. This panel will discuss data, using electrophysiological, biochemical, neuropharmacological and behavioral techniques, related to functions and dysfunctions associated with basal forebrain corticopetal systems. Dr. Napier will discuss reciprocal transmitter interactions between basal forebrain neurons and their afferent inputs and the significance of these parallel loops to motivated behavior. Dr. Szymusiak will discuss comparative data demonstrating the reciprocal modulations of basal forebrain neurons and sleep-waking states. Dr. Rasmusson will discuss the extent to which the basal forebrain is necessary for different forms of neurobehavioral plasticity and the relative contributions of cholinergic and non-cholinergic basal forebrain neurons to such plasticity. Dr. Sarter will discuss the accumulating evidence linking changes in cortical acetylcholine to attentional processes and the implications of abnormal regulation of the excitability of basal forebrain corticopetal systems for the development of cognitive disorders.

43 WORKSHOP • Monday, 8:00-10:00 PM • Peak 4 A Healthy Mind in A Healthy Body: Can in Vivo Neuroimaging Techniques Provide Insights For Research, Preclinical Detection, and Organizer: A. Lewin ¥ Participants: D. Choi, A. Basile, J. Gatley, K. Leenders Novel HIV-1 therapies reduce circulating viral load and reconstitute immune function, but their effectiveness in preventing, arresting, or reversing the progressive development of HIV-associated dementia (HAD), which occurs in up to 50- 60% of infected individuals, is questionable. Postmortem CNS tissue exhibits astrocytosis, microgliosis, and neuronal loss. Animal models and in vitro studies have implicated unincorporated viral protein-fragments, oxidative processes, overactivation of glutamate receptors, and apoptosis in HAD-associated neurodegeneration. Neuroimaging provides an opportunity to detect preclinical CNS changes and to track the effects of treatment agents. This workshop will examine mechanisms of neurodegeneration and the contribution of neuroimaging techniques to research, detection and treatment. To introduce the subject Dennis Choi will discuss chronic neurodegenerative processes with emphasis on specific known and potential triggers. Next, Anthony Basile will argue that glutamate is the r oot of all evil in the brain. Challenges and successes in development of receptor-specific ligands suitable for in vivo neuroimaging will be discussed by Maria Maccecchini. Use of neuroimaging for preclinical detection and for the tracking of neurodegenerative processes in living brain will be described by John Gatley and Nick Leenders. Examples will include the use of available indicators to: (a) follow attempts to slow the neurodegenerative process in Parkinson s and Huntington s disease in humans by use of dopamine agonists or antiglutamatergic substances; and (b) identify candidates for experimental putative neuroprotective and restorative effects (e.g. neurotrophic factors or apoptosis inhibitors) in animal models. Discussion will be directed to the connection between specific neurodegenerative processes and the application of neuroimaging to disease detection and treatment.

PANEL • Monday, 8:00-10:00 PM • Peaks 1-3 Mechanisms of Brain Inflammation After Injury Organizer: J.K. Relton ¥ Participants: G.J. del Zoppo, J.M. Hallenbeck, N.J. Rothwell The concept that inflammatory processes play a significant role in the pathogenesis of brain injury after cerebral ischemia has gained increasing importance in recent years. It is also clear that mechanisms once thought unique to the immune system now appear integral to injury responses in the brain. The aim of this session is to present data supporting a role for non neuronal immuno-competent cells and inflammatory mediators in focal cerebral ischemia, further challenging the view that the brain is an immunologically privileged site. Inflammation is typified by leukocyte infiltration into damaged brain, which requires receptor

44 expression on microvascular endothelial cells and circulating inflammatory cells. These processes are mediated, at least in part, by cytokines. This session will explore 1) the involvement of infiltrating inflammatory cells in brain injury after stroke, 2) the contribution of peripherally generated cytokines to cerebral ischemia, 3) the effects of cytokines in the brain after stroke, and 4) the consequences of ischemia on microvascular integrity. These settings provide new insight into the evolution of ischemia to inflammation during experimental ischemic brain injury, which may offer targets for therapy.

PANEL • Tuesday, 7:30-9:30 AM • Peaks 9-10 GABA-A Receptor Diversity: Why, Where and How Organizer: W. Wisden ¥ Participants: R. Olsen, H. Monyer, B. Luscher, S. Moss GABA-A receptors are involved in all aspects of brain function. The receptors differ in their GABA sensitivity, activation and desensitization rates, channel conductance, and pharmacology. Genes encoding the receptor subunits (alpha1- 6, beta1-3, gamma1-3, delta, epsilon and pi) are differentially transcribed in the brain and other organs and the subunits assembled into pentamers of variable composition. What are the functions of these different receptor subtypes? Why are there so many? Wouldn t the brain work just as well with an e.g. alpha1beta2gamma2 receptor at every synapse? In vivo, the answer seems to be no . Different subunits target GABA-A receptors to different parts of the cell, and provide binding platforms for different effector signaling molecules such as kinases. The session will start with R. Olsen reviewing GABA-A receptor diversity. H. Monyer will illustrate the specific contribution of the alpha1 subunit to GABAergic interneurons in the hippocampus. S. Moss will show that the beta- subunits are non-equivalent: different beta-subunits are used for recruiting different kinases and to bind other signaling molecules. B. Luscher will show that the gamma2 subunit is required for synaptic targeting of the receptor and that the gamma3 subunit can only partly substitute for gamma2 in vivo. Small deficits in GABA-A receptor clustering may underlie the pathology of anxiety disorders.

WORKSHOP • Tuesday, 7:30-9:30 AM • Peak 11 Thalamocortical Dynamics of Interactions Between the Senses of Touch and Pain Organizer: A. Apkarian ¥ Participants: M. Tommerdahl, D. Katz, V. Galhardo Within the central nervous system, the sensory representations for touch and pain are usually treated as independent systems, and as a result they are studied as such. Recently a number of groups have studied the interplay between these two senses at the thalamocortical level. The purpose of this workshop is to bring these groups together to begin a dialogue on the dynamics of the interplay between touch and pain at the level of populational coding at different scales from small local networks to the whole body map. The four speakers use differ-

45 ent methodologies to examine the interaction and short term reorganizational effects between the two senses. Apkarian will present thalamic population data in the squirrel monkey thalamus. By using a novel multi-tip multi-unit recording approach, he will describe network organizational differences between nociceptive and non-nociceptive groups of neurons that anatomically may correspond to distinct rods in VPL. Tommerdahl will describe cortical interactions between touch and pain in the squirrel monkey. Using intrinsic signal optical imaging the temporal dynamics of the primary somatosensory cortex will be described for innocuous and noxious somatic stimuli. Galhardo and Katz will describe the dynamics of the above networks within minutes after perturbing the peripheral input. Katz will demonstrate immediate reorganization of thalamocortical networks in the rat following either whisker ablations or injections of capsaicin around the mouth. Galhardo will describe the reorganization of thalamic nociceptive networks immediately following partial ligation of the sciatic nerve. The purpose of the workshop is to stimulate discussion in search for common principles that must underlie these studies.

PANEL • Tuesday, 7:30-9:30 AM • Peaks 6-8 The Uses of Saporin Conjugates in Neuroscience Organizer: L. Jasmin ¥ Participants: J. Krum, D. Lappi, A. Basbaum The use of saporin conjugates represents a versatile new approach to remove selected cell populations in the adult CNS. When conjugated to a carrier, the ribosome-inactivating protein saporin acquires the ability to be internalized and thus destroy the cell population that binds the carrier. To date a variety of conjugates have been synthesized and several routes of administration have been used. This panel will present an overview of the current and potential uses of saporin conjugates in neuroscience. Dr. Lappi will describe the presently available saporin conjugates, review the mechanisms of action of saporin, and discuss possible strategies in designing new saporin conjugates. Dr. Krum will describe how OX7- saporin was used to demonstrate in vivo that the blood-brain barrier remains functionally intact after surrounding neurons and astrocytes are removed. Dr. Basbaum will show how anti-dopamine beta-hydroxylase-saporin conjugates are used to selectively remove brainstem noradrenergic neurons. This strategy has allowed his laboratory to study the contribution of noradrenergic systems to pain generating and control systems and to the development of antinociceptive tolerance to morphine. Dr. Jasmin will report how the B fragment of cholera toxin conjugated to saporin is used in the rat to produce a reversible ascending paraplegia (over 2 months) caused by an acute inflammatory demyelination of the spinal cord.

46 PANEL • Tuesday, 7:30-9:30 AM • Peak 4 Promoting Axon Regeneration in the CNS Organizer: J. Fawcett ¥ Participants: H. Geller, R. Meyer, M. Maden Axon regeneration following CNS injuries fails because the CNS environment is inhibitory, and because most CNS axons have poor regenerative potential. Re- generation can occur if the balance is tipped by increasing the ability of axons to regrow, making the environment more permissive, or ideally both. In this session novel ways of achieving these objectives will be presented. Malcolm Maden will discuss the role of retinoids and their receptors in regulating neuronal survival and axon growth potential. Recent results show that transfection of adult spinal cord neurons with retinoic acid receptors can make them able to regenerate their axons, and that there are interactions between retinoic acid and neurotrophin effects on neuronal survival. Retinal ganglion cells are one of the very few adult neurons that will survive and regenerate their axons in vitro. Ron Meyer will discuss the factors that regulate and promote regeneration, and the differences between the growth of axons from embryonic neurons and their regeneration in adulthood. Much of the inhibition of axon regeneration in the CNS is due to molecules in the extracellular matrix. Herb Geller will present work on tenascin, a large multifunctional alternatively spliced molecule with direct positive and negative effects on axon growth, and a key role in binding to and modulating the function of many of the molecules that make up the CNS matrix. Some of the most potent inhibitory molecules in the injured CNS are chondroitin sulphate proteoglycans. James Fawcett will talk about which proteoglycans are expressed in CNS injuries, which cells make them, what upregulates their production, and the effects on axon regeneration of disrupting them.

PANEL • Tuesday, 7:30-9:30 AM • Peak 12 Fatty Acid Amides: Greasing Neural Circuits Organizer: B. Cravatt ¥ Participants: A. Basile, C. Felder, B. Martin Fatty acids are known for their role as structural molecules in cell membranes and as inflammatory mediators, making the discovery of the neurotransmitter for the cannabinoid receptor family, a fatty acid amide (anandamide), all the more remarkable. Unlike classical neurotransmitters, lipid neurotransmitters and modulators are too hydrophobic to be stored in synaptic vesicles. Therefore, they must be synthesized and released on demand, whereupon they readily cross membrane bilayers to act in an autocrine or paracrine fashion. Other related fatty acid amides, such as oleamide, have been recently identified and, in contrast to anandamide, they may serve a neuromodulator role. The fatty acid amides are known to play important roles in regulating such physiological processes such as pain, sleep, mood, and locomotion. This session will review the discovery of anandamide, and its novel mechanism of formation, release, and re-uptake. The role of anandamide as a neurotransmitter will be presented, based on

47 its interaction with cannabinoid receptors. Discussions will follow, reviewing the discovery and biology of oleamide and its interactions with serotonin, GABA, and possibly other receptor families.

PANEL • Tuesday, 7:30-9:30 AM • Peaks 1-3 Genetic Vulnerability In Psychiatric and Neurological Disorders Organizer: I. Hanbauer ¥ Participants: R. Greenspan, H. Caruncho, E. Costa The identification of disease vulnerability genes is a key to clarify the genetically based susceptibility to psychosis and neurodegenerative diseases. Mechanisti- cally, this vulnerability may evolve from polyploidism, haploinsufficiency, abnormal expression of antioxidant enzymes, or transmitter-induced gene abnormalities. In this panel, we will discuss the potential of: 1. fly/human gene homology, 2. oxidative stress-induced susceptibility, 3. haploinsufficiency of het- erozygous reeler mice, and 4. extracellular matrix-dependent decrease of glutamic acid decarboxylase (GAD)67 gene. R. Greenspan will introduce the fly/human gene homologies in relation to Alzheimer Disease, Huntington Disease, amyotrophic lateral sclerosis, and alcoholism. I. Hanbauer will discuss studies in the trisomy 16 mouse that relate oxygen radical-induced neuronal damage to increased gene dosage of SOD-1, GluR5, amyloid precursor protein, and cytokine receptors. H. Caruncho will talk on anatomical and behavioral phenotypic features of reelin haploinsufficiency in reelin (+/-) mice. E.Costa will relate the findings in the reelin (-/+) mouse to schizophrenia and bipolar depression with psychosis. He will discuss the correlation between the decrease in reelin tran- script and protein expression to that of GAD 67 gene in double blind studies on postmortem brain of nonpsychiatric, schizophrenic, monopolar depression without psychosis, and bipolar depression with psychosis patients.

MINICOURSE • Tuesday 4:30-6:30 PM • Peak 4 Practical Methodologies For the in Vivo, On-line Measurement of Neurochemical Activity in the Brain Using Miniaturized Biosensors Organizer: D.M. Davis ¥ Participants: A. Michael, E. Isacoff, G. Gerhardt The measurement of neurochemical activity in the brain was originally attained by taking relatively large post-mortem tissue sections followed by time consum- ing and rather laborious off-line extraction, separation by HPLC and quantitation by fluorometric or other means. Microdialysis has offered a large increment in our ability to sample the extracellular milieu in living animals, but suffers draw- backs in that the probes are relatively large, sampling intervals are long and the perfusates are analyzed off-line. While the ultimate in biochemical sensing devices may be tricor der -lik e units ala Star Trek (the next generation fMRI and PET scanners), significant advances in the fabrication of miniature biosensors is now to the stage of practical application. This minicourse seeks to provide the audience with a background on the current state of several biosensor based technologies in a ho w-to format so that the uninitiated investigator can incorpo-

48 rate similar approaches into his/her own in vivo research program. Dr. Michael will present on immobilized enzyme sensors for the detection of choline and glutamate release from neuronally-relevant acetylcholinergic and EAA neurotransmitter pools. Dr. Gerhardt will talk on novel nitric oxide, biogenic amine and glutamate amperometric microsensors. Dr. Isacoff will describe how gene delivery can be used to express, in a cell specific and non-invasive manner, protein-based detector probes in the mammalian brain to monitor physiological signal processing events. Finally, Dr. Davis will discuss subcortical fiber-optic fluo- rescence measurements of intrinsic cells loaded with ion- and pH-sensitive indicators as well as the use of extrinsic, single receptor expressing cells for the selective recording of neurotransmitter overflow. These approaches offer enhanced temporal and spatial resolution of brain neurochemical dynamics.

PANEL • Tuesday 4:30-6:30 PM • Peaks 1-3 Dopamine: Is It Excitatory, Inhibitory, Neither, or Both? Organizer: P. O Donnell ¥ Participants: M.S. Levine, R.C. Malenka, G. L. Snyder The actions of dopamine (DA) in the brain have been intensively studied over the past four decades given its involvement in Parkinson s disease and schizophrenia. Yet, from a physiological perspective, very little consensus has come from this enormous body of work. Fundamental questions like whether DA is excitatory or inhibitory continue to be debated. Some recent developments, however, are converging toward a possible synthesis in which apparently conflicting pieces of evidence could be integrated in a single conceptual framework. This panel has the objective of bringing together some of these new ideas and findings in presentations combining biophysical and molecular studies, DA receptor gene targeting, whole-cell patch recordings and in vivo intracellular recordings. Dr. Levine will present work indicating that the direction of DA modulation of glutamate receptor responses in striatum and cortex is a function of both the subtype of glutamate receptor and the subtype of DA receptor activated. Dr. Malenka will present work suggesting that D1-like DA receptors presynaptically inhibit transmitter release at both excitatory and inhibitory synapses in the nucleus accumbens. Dr. O Donnell will present data obtained using in vivo intracellular recordings, in which activation of the source of DA afferents, the ventral tegmental area, elicits different responses depending on whether the neuron is in the up or down state of its membrane potential at the time of stimulation. Dr. Snyder will present biochemical evidence for the idea that D1 receptors modulate NMDA and AMPA glutamate receptors via regulation of a protein kinase A/protein phosphatase 1 cascade. Overall, the findings converge remarkably; together, they may provide a basis to understand the current confusion regarding the actions of DA receptors. DA can subserve both inhibitory and excitatory actions, depending on the excitatory or inhibitory nature of the synapses it affects, the glutamate receptor subtype involved in them, and the membrane potential state of target cells, which present different subsets of active ion currents. In short, attempting to frame the nature of DA actions within an inhibitory vs. excitatory question may not be appropriate.

49 PANEL • Tuesday 4:30-6:30 PM • Peak 11 To Be or Not To Be: Basic and Clincial Investigations of Suicide Organizer: W. Bunney, Jr. ¥ Participants: S. Potkin, J. A. Fawcett, J. Lopez, J. Mann This panel will review clinical and neurobiological aspects of suicide. In the last half decade, the number of reported suicides in the United States has significantly exceeded the number of homicides. While suicide s association with depression has been well-studied, its association with schizophrenia has been less appreciated. Ninety-percent of the suicides in this country are associated with schizophrenia and depressive disorders. Fawcett will review clinical characteristics of suicide in depressive illness. A great deal of new information has been acquired concerning the identification of risk factors and their potential importance in the prevention of suicide. Fawcett will also review new studies on modi- fiable risk factors that may decrease the incidence of suicide. Potkin will describe the incidence and characterization of suicidal behavior in schizophrenia. Nine to 13% of schizophrenic patients commit suicide. Antipsychotic treatment has improved symptoms and cognition but not altered the suicide rate in schizophrenia. New data, however, suggest clozapine lowers the suicide rate. A general scientific consensus now supports low functional serotonin and the dysregulation of the HPA axis as critical in the neurobiology of suicide. These two fields will be reviewed by Mann and Lopez. Mann will discuss new data on the role of serotonin in suicidal behavior. Diffuse abnormalities of the serotonergic system in the prefrontal cortex are observed in major depression while focal abnormalities in the orbital cortex are observed in suicide in general. Reduced serotonin transporter binding and gene expression in the brainstem and orbital cortex provide support for the hypothesis that an impairment in behavioral inhibition mediated by the orbital cortex places individuals at greater risk for suicide. Finally, Lopez will review evidence suggesting that dysregulation of stress circuits are critical in the pathophysiology of suicide. He will review animal data and human data that dysregulation of CRH and glucocorticoids may be correlated with clinical symptoms of anxiety and depression in man and may explain critical aspects of the pathogenesis of suicide.

WORKSHOP • Tuesday 4:30-6:30 PM • Peaks 9-10 Do Ltp and Visual Developmental Plasticity Really Share a Common Mechanistic Basis? Organizer: S. Pallas ¥ Participants: E. Debski, K. Haas, R. Rhoades Similarities between NMDA receptor-dependent LTP in adult animals and visual system plasticity in developing animals have led to the popular view that synaptic plasticity is controlled by similar mechanisms throughout life. What is the current support for this view? The goal of this workshop will be to critically evaluate previous evidence, and to report on recent contributions from studies of

50 developmental plasticity in the retinotectal pathway. Dr. Pallas will discuss the role of NMDA receptors in mammalian retinotectal map plasticity and population matching. Dr. Debski will discuss neuromodulatory influences of serotonin and acetylcholine on NMDA receptor-dependent plasticity. Dr. Haas will discuss the relationship between maturation of retinotectal glutamatergic synapses and tectal cell dendritic morphology, and present preliminary data on the development of LTP and LTD at these synapses. Dr. Rhoades will discuss how biogenic amines acting through receptors on retinotectal axons may alter retinocollicular axon development and the physiology of tectal neurons. Together we will compare the results of our studies on retinotectal development to results from other model systems, and discuss the potential for developing a unified view of the mechanistic basis for developmental plasticity.

PANEL • Tuesday 4:30-6:30 PM • Peak 12 Columnar Organization in the Olfactory Bulb Circuit? Organizer: M. Meredith ¥ Participants: W. Chen, M. Ennis, C. Greer, J. Kauer The basic circuit of the olfactory bulb is well known, but its function in discrimination of olfactory stimuli is not. Molecular-level analysis of olfactory receptors suggests that each olfactory receptor neuron expresses only one receptor molecule and that scattered neurons of each type send convergent axons to a single glomerulus on each side of each olfactory bulb esta blishing a columnar organization of 1000-2000 glomerular columns per bulb (depending on species). Electro-physiological recordings from bulbar relay (Mitral/Tufted, M/T) neurons in intact animals suggests that each odor activates many glomeruli and that neighboring glomeruli are activated by related odors, despite evidence for independent targeting of receptor neuron types. Meredith will chair and introduce the session, including a brief outline of the circuit and some expectations for its function. Greer will summarize work from his own lab and others on glomerular development and organization, including sub- and inter-glomerular connections; outlining important functional features. John Kauer will summarize work from his group including in vivo electrophysiology and voltage sensitive dye recordings. New data from olfactory-bulb slice recordings from Gordon Shepherd s group, and from Michael Shipley s group, give us a new understanding of individual M/T neuron responses to glomerular input, and the pharmacology of potential interactions between M/T and other cells, both within a glomerular column , and between neighboring columns. These findings will be summarized by Chen and by Ennis. The presence of dendritic spikes and Ca++/NMDA dependent transmitter release, together with multiple recurrent and lateral pathways, inhibitory and excitatory, and via ionotropic and metabotropic receptors, complicates the traditional picture. Participants will attempt to put all in perspective for a new synthesis of olfactory bulb circuit function. The session will conclude with a general discussion.

51 PANEL • Tuesday 4:30-6:30 PM • Peaks 6-8 Intervention in Neurodegenrative Disease: Lessons From the Aging Brain Organizer: J. Joseph ¥ Participants: M. Smith, R. Perez-Polo, S. Griffin, D. Ingram Statistics indicate that the number people who are alive today who are 65 years of age or older represent over 50% of all those who have lived throughout human history who have achieved this age. There is a high probability that the incidence of neurodegenerative diseases, most notably, Alzheimer s and Parkinson s diseases (AD, PD, respectively) will increase in this group and become even more prevalent as the numbers in this group grow larger in the next century. Even in the absence of these diseases, there is a high likelihood that many of these individuals will be exhibiting alterations in neuronal (e.g., signal transduction) and behavioral (e.g., memory) function that occur in aging. Given these considerations, it is important to ask what factors might pre-dispose the aged brain to express these deficits and ultimately, to sensitize it to the development of neurodegenerative disease. To attempt to answer these questions the panel will: a) elucidate the changes in neuronal signaling, (e.g., ERK, Nf kappaB), membrane micro-environmental (e.g., fluidity), and receptor (subtype) properties that can enhance vulnerability to oxidative stress and sensitivity to inflammation in the brain b) specify possible changes in cell cycling or synaptogenesis in aging that could become aberrant in neurodegenerative diseases and c) examine putative cellular or nutritional/pharmacological interventions which can be employed to forestall the appearance of these neuronal changes and perhaps prevent the development of AD or PD.

PANEL • Tuesday, 8:00-10:00 PM • Peaks 6-8 Biomarkers of Pain Organizer: A. L. Oaklander ¥ Participants: J. Mogil, C. Woolf Chronic pain is a global medical problem, but pain research was slowed by its subjectiveness. This changed as it was discovered that pain can be studied inde- pendently of underlying diseases and animal models were developed. Identifica- tion of objective correlates, or biomar kers of pain is advancing pain research and development of new therapies. This panel will review ongoing studies of markers of pain and pain-related molecules and cells. Jeffrey Mogil will discuss the genetics of pain including heritability, genetic complexity, correlations among nociceptive assays and analgesic effects, gender, and linkage mapping of nociceptive and analgesic sensitivity using inbred strains of mice. His work demonstrates strong genetic influences on susceptibility to pain in mice, and augurs the development of genetic testing for susceptibility to chronic pain and analgesic responsiveness. Clifford Woolf will discuss the distribution and regulation of the

52 TTX-resistant sensory-neuron-specific voltage-gated sodium channels SNS1 and SNS2. SNS2 is found in various sensory neurons while SNS2 is found only in cells with unmyelinated axons, most of which are nociceptors. Michael Caterina will discuss two heat-gated ion channels expressed in the pain pathway: VR1 is activated by capsaicin, protons or temperatures > 43C. VRL-1 is insensitive to capsaicin or protons and activates at temperatures >50C. These types of channels may serve both as markers for subsets of nociceptive neurons and as targets for the development of novel analgesics. Anne Louise Oaklander will discuss the pathology of neuropathic pain, with an emphasis on human pain patients. Her data from punch skin biopsies, and measurements of the density of cutaneous nerve endings in painful skin have implications for development of diagnostic tests for neuropathic pain.

PANEL • Tuesday, 8:00-10:00 PM • Peaks 1-3 Rewards of Food, Sex and Drugs: How Does the Brain Tell the Difference? Organizer: B. Hoebel ¥ Participants: M. Carroll, P. De Witte, E. Hull, S. Leibowitz Studies of homeostatic behavior suggest a degree of interchangeability between eating food, engaging in mating and self-administering drugs. All three behavior patterns can involve dependency, abuse and possible addiction. It becomes essential to understand the commonalties and differences in neural control of eating, mating and drug taking if we are to find therapies that will be suitably selective. Marilyn Carroll will lead off with studies of the behavioral economics of drug abuse focusing on the interchangeability of dietary items, e.g. saccharin, with drugs of abuse. Stress, sex and hormonal status are important in this interaction. Philippe De Witte studies alcohol, which is at the same time a food and a drug. He will focus on the progressive impairment induced by successive with- drawals, probably leading to neurodegenerative processes. Sarah Leibowitz will describe a dangerous positive feedback loop between the intake of palatable fat- rich foods and hypothalamic galanin. Studies suggest that a high-fat meal inhibits the release of hormones, insulin and leptin, that normally control galanin expression. Elaine Hull shows that hypothalamic serotonin, or local injection of a serotonin uptake blocker, slows male copulation and ejaculation and decreases female-stimulated dopamine release in the accumbens. Because accumbens dopamine contributes to numerous motivated behaviors, the inhibition of its release by hypothalamic serotonin may inhibit motivation for other goals as well. Bart Hoebel will show that hypothalamic norepinephrine or galanin can release accumbens dopamine; whereas serotonin, combined with CCK, releases accumbens acetylcholine, in a system for eating and its inhibition. This reward- aversion system is involved in starting and stopping eating, mating, and cocaine intake.

53 PANEL Tuesday, 8:00-10:00 PM Peak 12 In Vivo, in Vitro and in Computo Evidence That Membrane Potential Fluctuations Organizer: A. Destexhe ¥ Participants: F. Amzica, S. Hestrin, P. Steinmetz The membrane potential (V_m) of neocortical neurons displays fluctuations due to various sources, such as the ongoing activity of the network in vivo, miniature synaptic events and noise intrinsic to ion channels. However, how the presence of V_m fluctuations impacts the response of these neurons is unknown. This panel is organized such as to provide an overview of different sources of noise in cortical neurons, and how could noise be useful for neuronal encoding. Florin Amzica will present results of intracellular recordings from neocortical pyramidal neurons and local-circuit interneurons in vivo during activated states with desynchronized EEG obtained by stimulating the brain stem (PPT-LDT). These states are characterized by continuous synaptic bombardment responsible for high-amplitude V_m fluctuations and tonic firing activity. Shaul Hestrin will describe how synaptic inputs impact spiking activity in cortical neurons main- tained in vitro. Here, V_m fluctuations are induced by injection of noisy current waveforms and the response is analyzed for additional synaptic stimulation. Pe- ter Steinmetz will describe how channel kinetics determine subthreshold membrane noise and the trade-off between excitability and noise imposed by channel kinetics using monte-carlo methods. Finally, Alain Destexhe will present biophysical models of neocortical pyramidal neurons which were constrained by intracellular recordings in awake animals. The model shows that the presence of V_m fluctuations lowers the detection threshold and allows the cell to discrimi- nate synaptic inputs more efficiently. Collectively, the experiments and models presented in this panel lead to the counter-intuitive view that V_m fluctuations are not detrimental to information processing, but they actually enhance the computational efficiency of neocortical neurons.

PANEL • Tuesday, 8:00-10:00 PM • Peak 4 Glutamine Repeat Proteins & Formation of Toxic Aggregates in Neurodegeneration Organizer: N. Marks ¥ Participants: D. Bredesen, G. Salvesen, L. Ellerby, A. Yang CAG trinucleotide expansion disorders coding for Gln repeats occur in HD, Kennedy s (spinal and bulbar muscular atrophy), Machado-Joseph disease (MJD), and spinocerebellar ataxias among others. Recent advances show mutant forms of the Androgen Receptor, huntingtin, ataxins, and atrophin contain one or more caspase-3 cleavage sites leading to production of peri-and intranuclear deposits. A common feature of these proteins that are otherwise are unrelated structurally is the generation of a truncated protein containing the polyglutamine repeat ca-

54 pable of forming peri- and intranuclear deposits. Contributors will describe mu- tational analysis and physical chemistry of triplet repeat proteins as related to their cytotoxicity, and potential metabolism by death effector-proteases acting as etiological agents. This has lead to renewed interest in pathways available for procaspase-3 conversion in post-mitotic neurons lacking normal receptor mediated events. Recent advances in processing zymogens will be described in relation to apoptosis associated factors (Apafs 1-3) and their roles in brain development and pathology using knockouts as models. Formation and translocation of toxic aggregates will be discussed also in relation to other neurodegenerative disorders including familial and sporadic Alzheimer s. This includes fragmenta- tion of amyloid or presenilins by caspases, uptake and targeting of fibrillar aggregates to lysosomes or other compartments, and the toxicological consequences in terms of upregulation of proteases or release of secondary effectors for neuronal damage.

PANEL • Tuesday, 8:00-10:00 PM • Peak 11 Current Ethical and Regulatory Issues in the Conduct of Clinical Research Organizer: L. Bigelow ¥ Participants: T. Sunderland, D. Shore In recent months there has been intense media interest in the participation of mentally ill persons in research. The National Bioethics Advisory Committee (NBAC) has just issued its report and recommendations suggesting many procedural changes which will, if adopted, significantly impact the conduct of clinical research. Perhaps the most controversial recommendations are for the establish- ment of a national Special Standing P anel to review any research classified as having greater than minimal risk and the introduction of a requirement that an independent person evaluate each subject s capacity for giving informed consent This panel will explore some of the background history of the development of the ethical principles and procedures that have until now guided the conduct of clinical research on the mentally ill and will also review the reported events that have stimulated the current reevaluation of clinical research procedures. (Dr. Bigelow). Dr. Sunderland is Chairperson of the NIMH Intramural Institutional Review Board and will discuss recent changes in intramural program procedures responsive to the current concerns. Dr. Shore is the NIMH Associate Director for Clinical Research (extramural) and will discuss the NIMH response to the issues that have been raised. Audience discussion will be encouraged with a focus on the issues involved as well as the most constructive possible response to the public s concerns. The discussion will also focus on the merits and draw- backs of pharmacological challenge studies and of protocols that involve medication free (placebo) periods.

55 PANEL • Tuesday, 8:00-10:00 PM • Peaks 9-10 Roles of the Serotonin 5-HT(3) Receptor in Brain Function and Embryogenesis Organizer: J. Yakel ¥ Participants: A. Spier, J. Lauder, A. Allan The 5-HT3 receptor (5-HT3R) is a ligand-gated ion channel gated by the neurotransmitter serotonin (5-HT) and belonging to the superfamily of ligand-gated ion channels, a group that includes nicotinic acetylcholine (ACh), GABA, and glycine receptor channels. The activation of the 5-HT3R opens a cationic ion channel that depolarizes the membrane, thereby activating a rapid excitatory response. The 5-HT3R is widely distributed within the CNS and PNS, functions both pre- and postsynaptically, and is thought to control a diffuse array of diverse physiological responses, including possibly cognition, pain reception, motor neuron activity, and sensory processing. The 5-HT3R is believed to play a role in the development of neural and non-neural tissues. Recently a second 5- HT3R subunit has been cloned which may help to explain some of the functional diversity observed in the properties of native 5-HT3Rs. Dr. Yakel will discuss the distribution, molecular makeup, and function of the 5-HT3R in the nervous system, Dr. Spier will discuss the characterization of the 5-HT3R ligand- binding site, Dr. Lauder will discuss the prenatal expression of 5-HT3Rs in the mouse and the possible role in craniofacial development, and Dr. Allan will discuss the 5-HT3R overexpressing mouse as a possible animal model for alcoholism.

PANEL • Wednesday, 7:30-9:30 AM • Peaks 6-8 GABA-Go-round: Make It, Shake It, Update Organizer: A. Schousboe ¥ Participants: K. Gale, H. Waagepetersen, K. Keefe GABA is the major inhibitory transmitter in the brain. The te xtbook version of the biosynthesis, release, and inactivation of GABA is relatively simple and straightforward. However, the rule that nothing is as simple as it seems has now come to govern the making and use of GABA. The purpose of this panel is to provide an overview and update of the comings and goings of presynaptic and synaptic GABA, and insights into the regulation of GABA synthesis, release and uptake. Inadequacies of the te xtbook models will be discussed in the light of new information concerning the significance of the different pools or compartments of GABA. Moreover, we will take a new look at the role that inter- mediary metabolism plays in generating the glutamate needed to produce GABA. We will challenge traditional (and boring) notions of the TCA cycle and its relationship to cytoplasmic and vesicular GABA. Emerging evidence from microdialysis studies of the basal ganglia will help to put the regulation of GABA release into the dynamic context of the intact organism; from which pools does the released GABA come? how do the various GABA transporters play a role in both release and inactivation? The importance of these issues to understanding GABA-related diseases and therapy will also be highlighted.

56 PANEL • Wednesday, 7:30-9:30 AM • Peak 11 Lack of Self-Respect Can Lead to Neurological Disease Organizer: A. S. Basile ¥ Participants: P. Usherwood, C. Genain, A. Vincent. Autoimmune damage to the central and peripheral nervous system is classically seen as mediated by the cellular components of the immune system, such as cytotoxic T-cells, activated microglia and macrophages. These cells can damage or destroy neurons by releasing pro-inflammatory cytokines, reactive oxygen species, or excitotoxic concentrations of glutamate, among other agents. The second component consists of the humoral factors, antibodies and B-cells. Re- cent evidence indicates that antibodies play a significant role in the full development of autoimmune neurological diseases, and have great potential for altering the signaling properties of neurons as well as contributing to their death in multiple sclerosis, seizure disorders and possibly HIV-1 dementia. In this panel, A. Basile and P. Usherwood will present evidence for the presence of auto-antibodies against the AMPA receptor in mice with retrovirus induced immunodefi- ciency. These antibodies can activate the AMPA receptor, altering neurotransmission and potentially killing the neuron. The roles of antibodies to proteins in the myelin sheath, including the newly discovered anti-myelin/oligodendrocyte glycoprotein in multiple sclerosis will be elucidated by C. Genain. A. Vincent will discuss the role of antibodies to K+ channels and the nAChR in myasthenia gravis.

PANEL • Wednesday, 7:30-9:30 AM • Peak 4 Microarrays and Neurobiology Organizer: J. Loring ¥ Participants: D. Barker, R. Somogyi, J. Eberwine As the human and other genome projects proceed at an accelerating pace, the reagents for the next revolution in biology are being created. These reagents are the genes themselves. DNA microarrays are tools to exploit these reagents, by allowing assays of the expression of thousands of genes in parallel. Measuring the differences in gene expression extends our knowledge of biological processes to the systems level and presents new technical and philosophical challenges. Most of us are unused to being showered with such a large mass of data. How can we be certain that microarray data are reliable? What can microarrays tell us, and more importantly, what are their limitations? Should experiments with microarrays be designed differently; for example, is a lot of things will change an acceptable hypothesis? Finally, how can we extract a higher level of information from the observed dynamic changes in thousands of genes? This panel fo- cuses on using microarrays of PCR products derived from cDNAs. David Barker will describe methods for fabricating, hybridizing and analyzing cDNA microarrays and will describe the important factors for obtaining reproducible arrays and quantitative expression data. Jeanne Loring will report microarray results on differentiating embryonic stem cells and a survey of Alzheimer s disease gene expression. Roland Somogyi will describe his methods for extracting

57 meaningful data from microarrays, and for discovering higher-level clusters of genes that interact through as yet undiscovered mechanisms. Finally, Jim Eberwine will describe methods for linear amplification of mRNA samples that allow differential expression experiments on single cells using microarrays. The panel will provide an overview of the joys and difficulties of launching this new technology, and will address the problems of making sense of 10,000 data points obtained from a single experiment.

WORKSHOP • Wednesday, 7:30-9:30 AM • Peak 12 Does Drug Sensitization Contribute to Relapse to Heroin and Cocaine? Organizer: Y. Shaham ¥ Participants: J. Neisewander, D. Self, T. De Vries, P. Piazza Repeated exposure to opioid and stimulant drugs or stress results in sensitized behavioral and neurochemical responses upon reexposure to these stimuli. Pre- exposure to drugs and stressors also facilitates the acquisition of drug self-administration in rats. Several influential theories have argued that processes involved in drug sensitization contribute to relapse to drug use but data to support or refute this view are lacking. We will present data from studies using animal models of relapse on the degree to which sensitization processes contribute to relapse to drug seeking in rats. Neisewander will show that enhancement of drug seeking induced by cocaine reexposure after prolonged drug-free periods is associated with increased cocaine-induced dopamine release in the amygdala. De Vries will show data on strong correspondence between cocaine and heroin seeking behavior and behavioral sensitization induced by dopaminergic agents. Pi- azza will show that long periods of cocaine self-administration result in shift to the left in the dose response curve for cocaine-induced relapse to drug seeking, indicating sensitization to the incentive effects of cocaine. Self, however, will show that animals that exhibit escalating drug intake show a propensity for relapse to cocaine-seeking, while high locomotor responses to amphetamine and the capacity to develop behavioral sensitization are not correlated with relapse to drug seeking. Shaham will summarize the data and discuss the degree to which sensitization processes contribute to relapse to drug seeking induced by drug reexposure, drug related cues and stressors. The organizer also has asked Wise (Psychomotor theory of addiction) and Robinson (Incentive-sensitization theory of addiction) to discuss the degree to which the present data are in agreement with their theories.

PANEL • Wednesday, 7:30-9:30 AM Peaks 9-10 Organization, Function and Plasticity At the Synapse: The View From the Fly Organizer: I. Levitan ¥ Participants: K. Zinsmaier, V. Budnik, L. Griffith The power of Drosophila genetics has long been exploited to investigate various features of development. More recently a combination of genetic, molecular and

58 electrophysiological approaches has been used to characterize genes and molecules that participate in synaptic transmission in the fly. The astonishing degree of evolutionary conservation of many of the key molecular players allows the extrapolation of results from this simple and experimentally amenable system to higher organisms as well. This panel will summarize recent work on molecules that are critical for the formation and function of the glutamatergic neuromuscular synapse in the fly. Levitan will give a brief overview and then summarize work on signaling protein complexes associated with ion channels in presynaptic nerve terminals. Zinsmaier will describe studies on cysteine string proteins, synaptic vesicle-associated proteins that contain an unusual cysteine motif. These proteins play an essential role in depolarization-dependent exocytosis, possibly by coordinating sequential interactions of calcium channels with SNARE proteins to mediate fast synchronous neurotransmitter release. Budnik will discuss the tumor suppressor gene discs-large, the protein product of which (DLG) is essential for normal development of both the pre- and post-synaptic elements of the neuromuscular synapse. DLG is involved in the clustering and targeting of ion channels and neurotransmitter receptors at the synapse, and its function is subject to dynamic regulation by protein phosphorylation. Griffith will continue with the theme of phosphorylation, and will describe work from her laboratory on the calcium/calmodulin-dependent protein kinase type II (CaMKII), another molecule that plays key roles both pre- and post-synaptically.

PANEL Wednesday, 7:30-9:30 AM Peaks 1-3 Excitotoxicity: Modulation by Natural Brain Consituents Organizer: H. Scharfman ¥ Participants: R. Schwarcz, C. Zorumski, A. Schurr Abnormal glutamatergic neurotransmission is believed to be causally involved in acute and chronic neurodegenerative diseases and in several psychiatric disorders. Mechanisms capable of correcting glutamatergic dysfunction are therefore of both theoretical and therapeutic interest. This panel will provide evidence that ordinary cellular energy metabolites, alone or in conjunction with kynurenate, a quantitatively minor endogenous excitatory amino acid receptor antagonist, can help restore normal glutamatergic activity. The theme will be introduced by A. Schurr, who will review the beneficial effects of lactate in cerebral ischemia and in other situations of glutamaterigc compromise. His presentation will be followed by C. Zorumski, who will describe the ability of pyruvate to convey substantial neuroprotection against excitotoxic insults in the hippocampus and in the retina. Interestingly, as will be discussed by R. Schwarcz, both lactate and pyruvate, along with other 2-oxoacids, promote the formation of kynurenate in the mammalian brain. Functional follow-up studies, which will be summarized by H. Scharfman, have demonstrated that newly produced kynurenate has profound anticonvulsant effects, and that these effects are potentiated by pyruvate. The electrophysiological, microscopic and biochemical data described by the four speakers will converge to support the concept that glutamate receptor function and dysfunction is controlled by common brain constituents. Consequently,

59 the panelists will promote the idea that these endogenous modulatory agents should be exploited for the development of novel therapeutic strategies in neurological and psychiatric diseases.

WORKSHOP • Wednesday, 4:30-6:30 PM CopperTop Restaurant Dollars for Scholars—Where Will My Next Grant Come From? Organizer: C. Atwell, NINDS, NIH ¥ Participants: K. Olsen, NASA, D. Shore, NIMH, M. Martin, NIH Last year s budgetary bonanza was great for neuroscience, but will it continue? What happens at the federal agencies when there is a sudden infusion of money? Do we just increase funding rates generally, or do we initiate large scale targeted programs? Are the days of the individual investigator working only with a small staff in her own lab truly numbered? Senior staff from NIH, NSF, and NASA will discuss their strategies and priorities. There will be plenty of opportunity for interchange among the panelists and the workshop participants to discuss the proposed evaluation and extramural oversight groups for the new neuroscience study sections at NIH, infrastructure needs, modular grant applications, elec- tronic grant submission (FastLane and the NIH Commons), and anything else of interest.

PANEL Wednesday, 4:30-6:30 PM Peak 11 Anesthetic Actions At GABA and Glutamate Synapses Organizer: B. MacIver ¥ Participants: N. Harrison, H. Hemmings, F. Weight, R. Pearce Recent advances regarding anesthetic actions at inhibitory GABA-mediated and excitatory glutamate-mediated synapses will be compared and contrasted. Anes- thetic actions at these synapses will be presented with emphasis placed on molecular sites of action informed from molecular/genetic approaches together with electrophysiological patch clamp investigations. We hope to convey the high degree of selectivity which is exhibited by anesthetics for protein targets essential for function at these two amino acid-mediated synapses; and will discuss physiological consequences resulting from anesthetic effects on these proteins. Harrison Selecti ve and agent-specific anesthetic actions can be accounted for, at least in part, by discrete binding sites on postsynaptic GABA-A receptor/ chloride ionophores. Point mutations indicate separate binding sites for several anesthetic agent classes which can interact allosterically to alter channel function and enhance synaptic inhibition. Hemmings Detailed studies of anesthetic effects on neurotransmitter release from hippocampal synaptosomes indicate that agent specific effects result from selective interactions with proteins associated with excitation-release coupling in nerve terminals. Weight Anesthetics and ethanol also appear to have selective postsynaptic actions at glutamate-mediated

60 synapses. Actions on NMDA, AMPA and Kainate-mediated ligand gated ion channels will be compared and contrasted with effects seen at GABA-mediated inhibitory synapses. Pearce P arallel inhibitory circuits that target somatic and dendritic regions of hippocampal pyramidal neurons operate on different time scales and produce functionally distinct effects on postsynaptic targets. The inhibitory interneurons that comprise these circuits interact with each other, producing oscillations that are thought to contribute to network processing. Recent advances in understanding inhibitory circuit organization, with particular emphasis on interactions between parallel inhibitory circuits, have clarified the consequences of altering the time course of synaptic inhibition with anesthetic agents. Taken together, panel members will provide a comprehensive view of the variety of synaptic targets with which general anesthetics can act.

PANEL • Wednesday, 4:30-6:30 PM • Peaks 6-8 Addiction and Behavior: Cellular & Molecular Correlates and Determinants Organizer: B. Kosofsky ¥ Participants: W. Carlezon, D. Self, T. Shippenberg, J. Coyle Drug addiction in humans is characterized by escalating drug intake during self- administration, and a propensity for relapse to drug-seeking during abstinence. Studies in animals attempting to simulate components of these behaviors have included Drug Self-administration, Brain Stimulation Reward, and Conditioned Place Preference. Utilizing these paradigms, certain intracellular neuroadaptations induced by chronic (prenatal or postnatal) or repeated (self-or investigator-administered) drug exposure have been identified, which may contribute to, and perhaps be the determinants of aspects of these corefeatures of addiction. The focus of this panel will be to present behavioral data from different rodent models which suggest that exposure to cocaine alters the set point for the drug s rewarding effects. Evidence will be presented that prior exposure to cocaine acts presynaptically to attenuate the efficacy of cocaine-induced DA release, and postsynaptically to blunt the coupling of DA signal transduction. Data will be presented that direct stimulation of the cAMP system (through PKA) counter- acts cocaine s rewarding effects, and that a sequence of intracellular events, cul- minating in dynorphin gene expression underlie this process. Some of the associated molecular neuroadapations including cocaine-induced increases in the activity of the transcription factors *FosB and CREB in the nucleus accumbens, and behavioral consequences of genetic manipulation of these transcription factors will be reviewed. One goal of this panel will be to identify the extent to which drug-induced cellular and molecular neuroadaptations are causal in altering drug-taking and drug-seeking behaviors in ways that contribute to aspects of behavioral changes described in experimental studies in animals, and perhaps to the addicted state in humans.

61 WORKSHOP Wednesday, 4:30-6:30 PM Peak 12 Circadian Regulation of Arousal: Role For A Suprachiasmatic-locus Coeruleus Link Organizer: G. Aston-Jones ¥ Participants: R. Moore, C. Berridge, D. Edgar The suprachiasmatic nucleus (SCN) is the master clock of the brain. Among other rhythms, the SCN is responsible for the pronounced circadian regulation of the sleep-waking cycle. Although this has been known for over 20 years, and the circuitry responsible for sleep and waking has been well elaborated in the same time, the link between the SCN and arousal has not been specified. This workshop will integrate and summarize new evidence that circuits linking the SCN to the locus coeruleus (LC), and from the LC to the forebrain, may underlie circadian regulation of arousal. Robert Moore will describe the classical evidence for the SCN being the brain s circadian pacemaker, as well as recent exten- sions and challenges to this view. Dale Edgar will review his studies revealing that the SCN may provide circadian control of the sleep-waking cycle by selectively increasing arousal and waking. Gary Aston-Jones will describe recent anatomical data with transsynaptic transport techniques that reveal the SCN to be a major indirect afferent to the noradrenergic locus coeruleus (LC), a system strongly implicated in arousal. He will also present evidence that specific hypothalamic and preoptic nuclei are important relays in the SCN-LC circuit. Craig Berridge will review his work demonstrating that selective activation and inhibition of the locus coeruleus elicits increases and decreases, respectively, in EEG and behavioral indices of arousal. These arousal-modulatory actions of the locus coeruleus involve beta and alpha-1 adrenoceptors, located within distinct subregions of the medial basal forebrain. This symposium is unusually integrated, as data from each speaker are relevant to those presented by other speakers. We will encourage input and interaction from the audience to elaborate the hypothesis that circadian regulation of arousal involves an SCN-LC circuit.

PANEL • Wednesday, 4:30-6:30 PM • Peak 4 Functional Brain Imaging in Disease: Problems and Potential Solutions Organizer: F. Henn ¥ Participants: P. Fletcher, C. Weiller, C. Buechel Among the possible confounds in using functional imaging to understand the pathophysiology of CNS illnesses are the effects of performance, the difficulty in determining the sequential connectivity in a circuit and the effects of the pathology itself on the signal. Fritz Henn will present data in schizophrenic patients illustrating the use of a simple sensory paradigm that minimizes the effect of performance. This also allows one to determine a pathological circuit and analyze the effects of both typical and atypical anti-psychotic medications on

62 this circuit. Paul Fletcher will present PET data on schizophrenia and will illustrate how by using a parametric design one can determine differences between patients and controls without using a subtraction design. Cornelius Weiller will discuss the use of imaging to document neuronal reorganization following a stroke and discuss the effects of brain pathology on the coupling between neuronal activity and blood flow measurements commonly used in functional imaging. Christian Buechel will present a new approach in analyzing fMRI data. Here instead of analyzing differences in activity between single regions, one develops inferences concerning the effective connectivity between brain regions. This allows one to assess the differences in connectivity between areas in disease states, compared to that found in normal controls. Taken together these presentations open new avenues for the study of CNS pathology and provide interesting data on neuroplasticity in the CNS following injury or pharmacological treatment.

PANEL • Wednesday, 4:30-6:30 PM • Peaks 1-3 Electrophysiological Correlates of Neuropathology in Transgenic Models of Alzheimer’s Disease Organizer: J. Larson ¥ Participants: P. Chapman, G. Seabrook, R. Nicoll The alterations in neural network operations that result from the neuropathological manifestations of Alzheimer s disease (AD) and that result in its cognitive and memory disturbances can only be identified in studies of animal models of the disease. Familial forms of AD are associated with mutations in the amyloid precursor protein (APP) and presenilin (PS) genes that lead to accumulation of the amyloid-beta (A-beta) peptide, a major component of senile plaques. Sev- eral genetically-engineered mouse models have been developed in the last several years that reproduce various aspects of the neuropathology of AD. This panel will describe and discuss electrophysiological studies of neuronal and synaptic function in these mouse models. John Larson will describe age-dependent alterations in synaptic function and plasticity in the PDAPP mouse which overexpresses a human mutant APP. Paul Chapman will describe selective alterations in long-term potentiation (LTP) in mice overexpressing the Sw edish APP mutation. Guy Seabrook will describe neuronal properties and plasticity in APP knockout mice, PS1, and double transgenic mice. Roger Nicoll will discuss studies that reveal that overexpression of certain human mutant APP results in a loss of synapses and neurons well before the development of amyloid plaques. Issues for discussion will include: (1) similarities and differences between the models; (2) the relative importance of A-beta accumulation/plaque formation, synaptic/neuronal degeneration, and gliosis; (3) possible functions of APP in the normal brain; (4) changes in network populations versus changes in plasticity mechanisms (LTP).

63 PANEL • Wednesday, 4:30-6:30 PM • Peaks 9-10 Scavenging Free Radicals and Preventing Apoptosis, How Far Can We Go? Organizer: R. Quirion ¥ Participants: M.P. Mattson, S. Dore, D.W. Nicholson Oxidative stress is believed to be involved in numerous physiological mechanisms; from development to normal aging. It is also the hallmark of the pathogenesis of a variety of acute (stroke and traumatic injury) and chronic (Alzheimer s, Parkinson s, Huntington s diseases and amyotrophic lateral sclerosis) neurodegenerative diseases. It acts on a variety of cellular events such as neuronal plasticity, mitochondrial depolarization, calcium influx, excitatory amino acid toxicity, lipid peroxidation, DNA damage, energy depletion, and cell death,. It is involved in many signaling pathways from transcription factors to growth factors. Several known toxins are believed to act through generation of reactive oxygen species (i.e. amyloid beta peptides, metals, mitochondrial inhibitors, etc). MPM will detail the crucial role played by the transcription factor NFkB. SD will discuss the action of heme oxygenase in the brain and the importance of bilirubin as an endogenous antioxidant. RQ will look at the putative action of new classes of radical scavengers from natural extracts. DWN will focus on potential therapeutic factors regulating caspase activation in order to limit apoptosis-related cell death. From in vitro to in vivo experiments, we will describe the ability of radical scavengers to control damage caused by oxyradicals thus maintaining cellular homeostasis.

PANEL • Thursday, 7:30-9:30 AM • Peak 11 Migraine 2000: Beyond the Triptans Organizer: S. Peroutka ¥ Participants: G. Gebhart, R. McCall, P. Mermelstein The treatment of migraine was transformed in the 1990s by the introduction of the triptan class of 5-HT1 agonists. The tremendous initial enthusiasm that accompanied the clinical introduction of these drugs was based on the possibility that high therapeutic efficacy and minimal side effects could be obtained. How- ever, reality has demonstrated that, while effective in many people, the oral triptans are only effective in approximately 60% of people at 2 hours after ingestion, while placebo rates at this time point average 30%. This net ef ficacy of only 30% is simply not acceptable and can clearly be improved. In addition, important concerns have been raised about the cardiovascular effects of these drugs. Therefore, significant activity exists in the attempt to define more efficacious and safer therapeutic approaches to migraine. This Panel will focus on ways to im- prove migraine therapy from both the basic and clinical sciences points of view. Dr. Jerry Gebhart will discuss basic pain mechanisms that are likely to be involved in migraine. Dr. Paul G. Mermelstein will discuss the role of calcium channels in genetic forms of migraine and the relevance of this information for therapeutic interventions. Dr. Bob McCall will review the development of selec-

64 tive 5-HT1D agonists in migraine as an attempt to decrease the cardiovascular side effects of less selective 5-HT1 agonists. Finally, Dr. Steve Peroutka will discuss the concept of rational polytherapy in migraine as it relates to the concur- rent use of 5-HT1 agonists, dopamine antagonists and fast acting non-steroidal anti-inflammatory agents.

PANEL • Thursday, 7:30-9:30 AM • Peaks 6-8 Modulation of Sonic Hedgehog in Anterior CNS Patterning Organizer: J. Kohtz ¥ Participants: M. Hynes, D. Epstein, R. Karlstrom The hh gene was originally identified in Drosophila as a segment polarity gene. Since its discovery in flies, members of the Hedgehog family, all of which are secreted signaling molecules, have been implicated in a variety of vertebrate developmental processes. One Hedgehog family member, sonic hedgehog (Shh), is known to specify ventral neurons along the anterior-posterior extent of the neuraxis. Consistent with this is the demonstration that deletion of the Shh gene in mice results in the loss of ventral structures throughout the nervous system, including the brain. In the absence of Shh, mice exhibit cyclopia and holoprosencephaly, reinforcing the importance of this gene in the developing forebrain. Thus, the question of how this single molecule generates a diversity of ventral neuronal phenotypes is central to our understanding of how the brain is patterned. It has been shown that in the posterior neuraxis, ventral neuronal subtypes are produced in a concentration-dependent manner. In this region, high level exposure to Shh results in the formation of floor-plate cells, whereas lower levels result in motor neurons. Using analyses in rodents and zebrafish, members of this panel will present experiments that identify different mechanisms responsible for modulating the effects of Shh signaling in more anterior regions of the neuraxis. These will include showing that fatty-acylation of Shh enhances ventral forebrain induction, and that cooperativity with FGF-8 is responsible for the ability of Shh to generate midbrain dopaminergic neurons. In addition, experiments describing factors which act upstream of Shh to control its expression at the transcriptional level, and zebrafish forebrain patterning defects which result from mutations in Shh downstream targets (gli-1 and gli-2) will be presented.

PANEL • Thursday, 7:30-9:30 AM • Peak 4 Cross-talk Between Map/ERK Kinase and Tyrosine Kinase Cascades and G-protein Coupled Receptors: A New Direction For Drug Abuse Research Organizer: E. Simon ¥ Participants: P. Stork, C. Coscia, K. Kramer, H. Gutstein Neuronal cells receive signals from multiple extracellular molecules including hormones, transmitters, and growth factors, as well as intrinsic signals reflecting the electrical activity of the neuron itself. These various signals are integrated and conveyed to the nucleus through the action of mitogen-activated protein kinase (MAP)/extracellular signal-regulated protein kinase (ERK) kinase cas-

65 cades. Signals that activate the MAP kinase cascade control diverse processes from the regulation of neuronal survival to synaptic function and gene expression. In addition, MAP kinase signals are regulated by cross-talk with other signaling pathways, most notably those mediated by G protein-couple receptors. Many of these mechanisms of cross-talk appear to be unique to neuronal cells and provide neurons the ability to mediate long-term changes in gene expression in response to a complex array of extracellular and intracellular signals. In this panel, we will explore the relationship between MAP/ERK kinase cascades and G-protein-coupled receptor signaling in greater detail. After a brief introduction, evidence from a wide variety of experimental paradigms will be presented that begins to delineate the mechanistic and functional roles ERK may play in the nervous system and in clinical problems such as drug tolerance, dependence, and addiction. Dr. Philip Stork (The Vollum Institute) will discuss how multiple distinct G protein-coupled pathways provide both inhibitory and stimulatory inputs into the MAP kinase cascade, involving both G-alpha and G-beta/gamma subunits. These studies have identified novel levels of modulation of intracellular signaling cascades, involving both cAMP and calcium second messengers in the regulation of novel small G proteins as well as identifying new roles for the cytoplasmic tyrosine kinases in G protein signaling. Dr. Kenneth Kramer (New York University Medical Center) will discuss how agonist stimulation of the delta opioid receptor activates members of the Src-family of protein tyrosine kinases, and suggests how this action modulates both opioid receptor function and subsequent MAP kinase activity in transfected cell lines.

PANEL • Thursday, 7:30-9:30 AM • Peaks 1-3 Better Than Sliced Bread! — Slice Cultures: As Close To in Situ As in Vitro Can Get Organizer: T. Lanthorn ¥ Participants: T. Wieloch, D. Turner, G. Murphy, S. Moskowitz The slice culture technique is now about ten years old, but recent advances have allowed the full potential of this powerful platform to become clear. Those who attend this session will leave determined to set up, or expand their uses of, slice cultures in their own lab! The panel members will excite the audience with data from a wide range of studies that can be carried out using slice cultures. Slice cultures are viable and retain much of their organotypic structure for weeks or months. This allows the clear identification of specific cell types and the study of interneuronal fiber tracts. Reactive cells like microglia take on a resting, ramified morphology as they do in vivo. They respond to stimuli by activation, change in morphology and location, perform phagocytosis or trophic activities, followed by a return to the resting state. In models of acute insult, such as ischemia, insults of physiologically-relevant duration (e.g., 10 min) induce organotypic, de- layed degeneration of selective neurons, which can be monitored by a number of techniques, from confocal and videomicroscopy to electrophysiology, from insult to degeneration and phagocytosis and beyond. Chronic diseases like Alzheimer s disease can be studied by long-term monitoring of the responses of,

66 and interactions between, cells to beta-amyloid, applied exogenously or endogenously. Neuronal pathways can be visualized while they form, and reform after damage. Biolistic transfection and viral vectors can be used to knock-in or -out specific gene products to determine their importance in functioning neuronal circuits. Slice cultures can be used with tissue from mice, rats, and other animals, with tissue coming from embryonic, adolescent, and, in a very exciting recent advance, adult animals. Slice cultures will revolutionize cell biology and physiology.

PANEL • Thursday, 7:30-9:30 AM • Peak 12 The Search For A Salty Taste: Gustatory and Biological Bases Organizer: F. Flynn ¥ Participants: D. Hill, R. Lundy, A. Spector, A. Schulkin Salt has been referred to as the 5th element, as essential as air, water, fire, and earth. The response to salt taste is mediated by specific afferent pathways and salt taste signals are modified by developmental factors and need state. These factors will be covered by the participants. Dr. Hill will discuss the role that early embryonic environment plays in the normal development of electrophysiological and behavioral responses to salt taste. Dr. Spector will discuss the contribution of specific peripheral cranial nerves and salt taste transduction pathways (amiloride [an epithelial Na+ channel antagonist] sensitive and amiloride insensitive) to salt taste function as psychophysically assessed in the rat. The neurophysiological basis for amiloride s effects on salt taste will be presented by Dr. Lundy. He will discuss results showing that lingual application of amiloride selectively inhibits the response of a subpopulation of geniculate ganglion neurons. Sodium need alters electrophysiological and behavioral responses to salt taste. Dr. Flynn will discuss the effects of sodium deficiency on salt taste and that these effects involve brain tachykinin NK3 receptors. Unlike the specificity of blocking Na+ channels in the periphery on NaCl taste, the central application of NK3 receptor agonists modify responses to several sodium and non sodium salts that comprise a perceptual category of salty . Dr. Schulkin will discuss the evolutionary significance of salt appetite and how the recruitment of specific salt cravings may serve other mineral needs. Specific taste transduction mechanisms may operate to promote the recognition and ingestion of several different mineral appetites.

WORKSHOP • Thursday, 7:30-9:30 AM • Peaks 9-10 The Contribution of Astrocytes To CNS Pathophysiology Organizer: B. MacVicar ¥ Participants: H. Kimelberg, H. Sontheimer, M. Chesler The participants of this workshop will debate the contributions of astrocytes to several pathophysiologies of the brain. We will focus on chloride channels, pH regulation and novel forms of glutamate release. We will evaluate evidence for their roles in both the normal functioning of astrocytes and their possible roles in

67 several CNS diseases. The astrocyte chloride channel is thought to be important in regulating the volume of astrocytes during conditions of cellular swelling. The release of excitatory amino acids through astrocyte chloride channels has been postulated to be neurotoxic in some conditions. Evidence will be presented on the involvement of chloride channels and other release mechanisms in the release of excitatory amino acids from astrocytes in cell culture and in brain slices (Kimelberg and MacVicar). Chesler will discuss the roles for pH regulation in astrocytes is controlling the propagation of spreading depression which is postulated to underlie migraines. Morphological changes are important in developmental migration of astrocytes and in the invasion of gliomas in the brain. Sontheimer will discuss the role of Cl- channels in cell shape changes during development and disease. Using a combination of electrophysiological and imaging techniques Sontheimer s lab has shown that Cl- channels are upregulated in highly motile astrocytes and invading glioma cells and their inhibition leads to arrest of cell migration.

WORKSHOP • Thursday, 4:30-6:30 PM • Peak 11 Does Synchronization of Neuronal Firing Play A Role in CNS Catecholamine System Function? Organizer: J. Walters ¥ Participants: G. Aston-Jones, J. Williams, H. Bergman An area of current debate in systems neuroscience is the possibility that the degree of synchrony in firing patterns of neurons within or between different brain regions is a critical factor in the functional performance of the CNS. It has long been recognized that catecholamine systems play important modulatory roles in the CNS, affecting attention and cognitive and motor performance. This workshop will discuss the hypothesis that an important, and perhaps critical, aspect of catecholaminergic modulation of behavior involves changes in the degree of synchronization of neuronal activity, either at the level of catecholamine neurons themselves, or at the level of systems receiving catecholaminergic input. Attention will also be paid to the possibility that gap junction formation may, in a dynamic sense, play a role in mediating some effects of catechomines on neuronal synchrony. John Williams will discuss evidence for electrotonic coupling among LC neurons and the functional significance of coupling as a mechanism for facilitating synchrony in catecholaminergic systems, and Gary Aston-Jones will discuss evidence for such coupling in monkey LC cells and the functional role of coupling in attentional modulation. Hagai Bergmann will discuss effects of dopamine depletion on the functional coupling of neurons in the primate globus pallidus and the significance of this phenomena with respect to the role of dopamine in movement and the symptomatology of Parkinson s disease. Judith Walters will moderate the discussion and discuss the view that dopamine receptor stimulation affects the frequency and degree of synchrony of periodic multisecond oscillatory activity in several basal ganglia nuclei with a focus on the potential functional significance of this effect.

68 PANEL • Thursday, 4:30-6:30 PM • Peaks 6-8 Do NMDA Channels Have A Kinase Complex? Organizer: J. MacDonald ¥ Participants: M. Browning, I. Mody, M. Salter NMDA receptors play critical roles in development, plasticity and degeneration in the central nervous system. These receptors are convergent targets for intracellular signal transduction pathways, and protein phosphorylation is known to be a major mechanism for regulating the function of NMDA channels. Some kinases appear to directly phosphorylate NMDA receptor subunits and thereby alter their gating properties. However, NMDA receptor subunits, postsynaptic density proteins and the kinases themselves likely form physically associated signaling complexes. In some instances, a signaling cascade involving the sequential activation of several kinases may be required for modification of receptor function. Phosphorylation 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 an overview of the area and present recent evidence on the regulation of NMDA channels by protein kinase C. Mike Browning will discuss the role of phosphorylation in regulating surface expression of NMDA receptors. Istvan Mody will describe regulation of NMDA channels by casein kinase II and an interaction with beta-amyloid peptides. Mike Salter will discuss NMDA channel regulation by Src and its role in synaptic plasticity.

PANEL • Thursday, 4:30-6:30 PM • Peaks 1-3 “Bending Light To the Neuroscientist’s Will” or “Watching the Brain Think: Optical Imaging At Multiple Scales” Organizer: R. Siegel ¥ Participants: F. Helmchen, B. Salzberg, A. Roe One of the more challenging aspects of understanding brain function is the how activity is distributed spatially. Difficulties begin with the collection of spatial data to understanding and specifying the underlying spatial organizational principles. Light affords the neuroscientist a particularly efficient means to observe distributed activity and affords the capability to observe changes in both space and time. Fritjof Helmchen will discuss how two-photon imaging can measure the finest scale of the spread of dendritic excitation in pyramidal neurons in rat barrel cortex in vivo. These signals can be modulated by sub-cortical inputs and may serve as a substrate for plasticity and learning. Spatiotemporal changes in up to five ganglia of the enteric plexus have been analyzed by Brian Salzberg using voltage-sensitive dyes and a fast imaging system. nAChRs reversibly de- sensitize after exposure to nicotine and may be responsible for the enhancement of activity that is observed across the population. Anna Roe will describe the spatial representations of early visual processing using intrinsic signals in the

69 monkey cortex. Intrinsic optical signals are also used to examine how association cortex of the parietal lobule is organized to represent extrapersonal space and such physiological results are contrasted to modeling predictions by Ralph Siegel. In all the presentations, the highly technical, quantitative and computationally intensive methods that are used both the identification of the neuronal activity with light and its analysis will be explained simply. Most of the work so far has been limited to two-dimensional imaging. The panel will discuss future directions for the development of three-dimensional imaging of the elements of the brain during behavior.

PANEL • Thursday, 4:30-6:30 PM • Peaks 9-10 When and How To Just Say No During Neurodevelopment Organizer: P. Letourneau ¥ Participants: V. Rehder, R. Mize, G. Gallo, S. Gibbs Nitric oxide (NO) is produced by the enzymatic activity of nitric oxide synthase and has been implicated in a number of important processes such as neuronal plasticity, neurodevelopment, and neuropathology. This panel will discuss the role and cellular mechanisms of NO in shaping the pattern of connections between neurons and their targets during neurodevelopment in vertebrates and in- vertebrates, using both in vivo and in vitro approaches. Dr. R. Mize will discuss the role of NO in refining axonal projections during neurodevelopment of the mouse. Using both pharmacological and genetic approaches to inhibit NO production, Dr. Mize s laboratory has generated data implicating NO in mediating aspects of the refinement of glutamateric, but not cholineric pathways in the central nervous system. Dr. S. Gibbs will present data from her studies of the developing Drosophila visual system, demonstrating that NO mediates patterning of retinal projections through a cGMP-mediated mechanism. Dr. V. Rehder will describe his laboratory s finding on the effects and mechanisms of NO on filopodial behavior at the neuronal growth cone of snail neurons in vitro. NO causes the collapse of vertebrate retinal and dorsal root ganglion growth cones in vitro. Dr. G. Gallo will present data demonstrating that neurotrophins (e.g., BDNF and NGF) can inhibit NO-induced growth cone collapse and that the protective effects of neurotrophins are mediated by a cAMP-protein kinase A- mediated mechanism. Collectively, the data presented by these researchers strongly indicate that NO is an important mediator of activity-dependent processes during neurodevelopment and suggest novel avenues of inquiry.

PANEL • Thursday, 4:30-6:30 PM • Peak 4 Can in Vivo Transfer of Genes Be Therapeutic? Non-human Primate Experience Organizer: K. Bankiewicz ¥ Participants: M. Bohn, J. Kordower, M. Tuszynski Direct transfer of genes into CNS provides a way for introducing therapeutic molecules locally. This approach might play an essential role in treatment of neurodegenerative disorders, such as Parkinson s and Alzheimer s diseases. Lo-

70 cal administration of either neurotransmitter and/or growth factors appears to be potentially therapeutic, however, large areas of human brain need to be safely infected which present a significant limitation of this approach. For gene therapy approach to work a mechanism for safe and efficient gene transfer into human brain and a way to monitor in-vivo gene expression is essential. We will discuss efficient delivery for introduction of several viral vectors and/or genes using con- vection-enhanced delivery and cellular methods in parkinsonian and aged mon- keys. in-vivo properties of these vectors will be discussed for delivery of growth factors and use of pro-drug approach for controlling levels of neurotransmitters in the brain. Current methods for evaluation of gene transfer and gene expression, including neuroimaging, stereological cell counting, biochemical and molecular methods will be discussed.

PANEL • Thursday, 4:30-6:30 PM • Peak 12 Extended Amygdala, Incentive Motivation, and Relapse To Drug- Taking Behavior Organizer: E. Gardner ¥ Participants: G. Alheid, G. Phillips, T. Robinson, S. Vorel The extended amygdala, incentive motivation, and relapse to drug-taking have each been topics of past WCBR programs; but never before brought together in an integrated fashion. Recent developments now permit this, yielding insights into brain mechanisms underlying relapse to drug addiction. George Alheid will discuss the anatomical concept of the extended amygdala, and why it may rea- sonably be involved in incentive motivation. Gavin Phillips will discuss recent findings of enhanced dopamine (DA) efflux in amygdala by predictive but not non-predictive stimuli, and facilitation of same by prior amphetamine. and, more generally, evidence of a role for meso-accumbens DA in conditioned approach behavior and facilitation of associative learning. Terry Robinson will present recent data on the ability of environmental context to alter cocaine- and amphetamine-induced c-fos in the amygdala. and, more generally, the role of incentive sensitization in relapse to drug abuse, and the view that meso- accumbens DA is more involved in encoding incentive salience rather than hedonic tone or reward learning. Stanislav Vorel will present recent data that discrete electrical stimulation of extended amygdala triggers relapse to drug- taking behavior, and the anatomical and neurochemical substrates underlying this. Goaded by the organizer, participants will attempt a synthesis of views. Audience participation will be invited from WCBR regulars familiar with anatomical, electrophysiological, neurochemical, and behavioral work relevant to this topic, several of whom have agreed in advance to participate. We anticipate that a clearer role of the extended amygdala in the incentive motivation that underlies relapse to drug addiction will emerge, together with clinical implications for drug abuse treatment and anti-addiction medication development.

71 WORKSHOP • Thursday, 8:00-10:00 PM • Peak 4 ß-Amyloid and Alzheimer Disease: The X-Files of Brain Research Organizer: M.A. Smith ¥ Participants: S. Griffin, J. Joseph, R. Neve, J. Loring Although there is a relatively long history of attempting to correlate §-amyloid deposition and toxicity with the neural and behavioral degeneration seen in Alzheimer disease, there is still considerable controversy. Is the §-amyloid hypothesis still valid or, like the Titanic, is this once unsinkable hypothesis about to crash into an iceberg of reality? Is §-amyloid deposition both a necessary and sufficient condition for the neuronal degeneration to take place? Does the almost total domination of research by this hypothesis overshadow other avenues of exploration? This panel will explore these questions by having an interchange between members of the Amyloid Organization (Jean Loring and Sue Griffin) and those who believe that the tr uth is still out there (Mark A. Smith and Rachel Neve). Government Operative, James Joseph, will assure a fair fight.

PANEL • Thursday, 8:00-10:00 PM • Peak 11 Supraspinal Nociceptive Facilitating Mechanisms Organizer: D. Lima ¥ Participants: G. Gebhart, M. Morgan, K. Ren Pain transmission at the spinal level is under the influence of supraspinal actions, which are believed to modulate nociceptive signaling as a function of autonomic, attentional, emotional and cognitive processing. Supraspinal inhibitory effects have been thoroughly demonstrated and earned a great deal of attention due to the expectation of improving pain treatment through local manipulation. However, it is clear from recent research that descending inputs can either inhibit or facilitate spinal nociceptive transmission, suggesting that it is the balance of various descending effects that determines the attributes of pain percep- tion and reactions. The pain control effect triggered in the RVM has a biphasic nature, as revealed by the switching from facilitation to inhibition of dorsal horn nociceptive neurons activity as a function of the intensity of local stimulation and of the doses of neurotransmitters applied to the nucleus. Facilitation of nociceptive spinal neuronal activity following RVM stimulation can occur simultaneously with inhibition of nociceptive reflexes, whereas spinal nociceptive inhibition may be accompanied by facilitation of nociceptive reflexes. The dorsal reticular nucleus appears to be primarily involved in facilitation of acute and tonic pain through a reciprocal reverberating medullary-spinal circuit. Facilitat- ing and inhibitory actions are selectively elicited from different supraspinal nuclei during chronic pain, although in the two models investigated the net effect seemed to be inhibition of neuronal activity and depression of hyperalgesia. These findings prompt the evaluation of the functional complexity of the endogenous pain control system and its contribution to the development of chronic pain.

72 PANEL • Thursday, 8:00-10:00 PM • Peaks 1-3 From Neuron To Song: Diverse Approaches To Vocal Production and Learning Organizer: D. Perkel ¥ Participants: A. Doupe, M. Schmidt, F. Goller Vocal learning in songbirds is a rapidly growing area in neuroscience because it provides an accessible system in which to study the neural bases of a complex behavior at a variety of levels. Song is learned in two phases: an early sensory phase during which a young bird memorizes the song of a tutor; and a later sensorimotor phase during which he uses auditory feedback to refine his vocal- izations to match the memorized song. Two major circuits containing discrete forebrain nuclei mediate song production and learning: a motor pathway and a pathway essential for song learning, but not required for production of previously learned song. This circuitry ultimately permits the stereotyped production of a complex motor pattern involving the finely tuned coordination between respiratory centers and muscles of the vocal organ and tract. The speakers in this panel will address their work on song at four levels. David Perkel will begin with an overview of song learning and recent data on the functional connectivity of an avian basal ganglia circuit essential for song learning. Allison Doupe will describe the effects of social context on neural activity in this pathway during singing. Marc Schmidt will describe the hierarchical organization of the song motor system by talking about the interhemispheric synchronization and coordination of vocal motor commands. Finally, Franz Goller will discuss his work on the physical mechanisms of vocal production in birds

PANEL • Thursday, 8:00-10:00 PM • Peak 12 Seizure Control from a Distance: The Power and Potential of Vagus Nerve Stimulation Organizer: N. Rodgers-Neame ¥ Participants: S. Krahl, D. Ko, B. Walker Vagus nerve stimulation (VNS) to treat intractable epilepsy is an enticing concept in that a purely peripheral event can be used to treat a disease localized in the brain. The main advantages to the therapy over anti-epileptic drugs (AEDs), are appreciated in the adverse events most commonly associated with AEDs : impaired cognition, ataxia, and somnolence. None of these side effects are associated with VNS to any degree. VNS suppresses seizures by activation of endogenous seizure suppressing neuronal circuitry in the brain. What is this circuitry and how is it accessed by VNS? Answers to these questions will be discussed in the context of how they provide new insights into the treatment of epilepsy. In our panel, we will present new findings on the basic science of VNS in both well defined animal models and in humans already utilizing the device; starting in the periphery and ending in central networks. Which vagus nerve fibers and branches mediate the anti-epileptic effects? Can these events be mimicked by peripherally acting drugs? What is the endogenous seizure suppressing circuitry

73 activated by VNS in animal models? What have we discovered from clinical imaging studies in patients receiving VNS? What is the clinical experience? How are the clinical stimulation parameters selected? This panel will address these questions and provide a well balanced presentation of VNS mechanisms, span- ning peripheral to cortical effects, animal models to human subjects, showing how basic science has been translated into improved clinical methods.

WORKSHOP • Thursday, 8:00-10:00 PM • Peaks 6-8 Deep Brain Stimulation: Turn on, Tune in, Find out Organizer: K. Gale ¥ Participants: M. DeLong, R. Gross, A. Benabid Stimulation of specific subcortical nuclei, through chronically indwelling elec- trodes, is an emerging new clinical treatment. Although in a highly formative and experimental stage, this exciting approach is now being tested clinically in several centers as a treatment for patients with Parkinson s disease, Huntington s disease, dystonia and epilepsy; examples of successes and failures will be presented. Thalamus, subthalamic nucleus, and globus pallidus are some of the more promising targets of the stimulation. However, as is often the case with novel therapies, the underlying mechanisms are mysterious at best, and highly conten- tious at second best. This workshop will brainstorm about br ainstim and generate hypotheses about underlying mechanisms. We will try to relate the basic and preclinical animal data (especially from nonhuman primates) to the clinical findings. Several questions about mechanisms will be tackled: Is the brain stimulation acting as a functional lesion? What are we really doing to the regions of stimulation? Is the effect distant or local? orthodromic or antidromic? inhibitory or excitatory? mediated by fibers or cells? How does the stimulation interact with the side effects and therapeutic effects of drugs such as L-DOPA? What insights can we gain from bloodflow measurements and neuroimaging studies? Have we made some unfounded assumptions about the disorders that we are treating? about the models that we are using? Dogma will be challenged and cross-species differences will be highlighted, especially between rodent and primate. The experience of the audience will be broadly solicited to help disentangle the neuroanatomy, electrophysiology, behavior and pathophysiology of diencephalic and basal ganglia circuitry as they relate to a host of neurological disorders.

PANEL • Thursday, 8:00-10:00 PM • Peaks 9-10 New Insights Into GABAa Receptor Function Revealed by Gene Knockout Organizer: G. Homanics ¥ Participants: J. Huguenard, T. DeLorey, D. Hammond, R. Mihalek GABA is the main inhibitory neurotransmitter in the central nervous system. Most of the effects of GABA are mediated by the GABAa receptor, of which at least 19 different subunits are now known to exist. The physiologic functions of the various subunits are unknown. Recently, gene knockout technology has been

74 employed to genetically dissect the contribution of specific subunits to various physiologic and pathophysiologic functions. Homanics will briefly introduce the session by providing an overview of GABAa receptor biology and knockout technology. Huguenard will discuss the specific involvement of the beta3 and delta subunits in the reverberant thalamocortical circuits that control sleep and epilepsy, and how knockout of receptor subunits can result in functional circuit rearrangements. DeLorey will describe sleep patterns and epilepsy in beta3 and delta deficient animals. Hammond will describe dramatic alterations in nociceptive sensitivity and the actions of analgesic drugs in beta3 knockout mice. Lastly, Mihalek will present novel results detailing the intimate involvement of the delta and gamma 2 long subunits in behavioral responses to neuroactive steroids and benzodiazepines, respectively.

PANEL • Friday, 7:30-9:30 AM • Peaks 1-3 Divide and Conquer: Using Local Activity Regulation To Study the Brain Organizer: Andrew King ¥ Participants: A. Smith, R. Rhoades, A. Ramoa How do individual brain areas, neurotransmitter systems or signaling pathways contribute to brain function and plasticity? To address this question, various methods have been developed for either up- or down-regulating neuronal activity in a specific, long-term, and reversible manner. This session brings together researchers who are applying these techniques to investigate diverse questions in the field of sensory processing. Using methods ranging from polymeric delivery to antisense knockdown, they are studying the molecular, anatomical and functional consequences of locally and reversibly modifying brain activity. Adam Smith will describe how polymer implants can be used to inactivate visual cortex in developing ferrets, allowing segregation of the effects of intrinsic and extrinsic activity in patterning neurotransmitter receptor development. Bob Rhoades will discuss potential influences of peptide up-regulation after neonatal nerve injury and how antisense technology has been used to assess the effects of galanin and NPY in the rodent trigeminal system. Ary Ramoa will show how antisense DNA can be used to produce a selective suppression of NMDA receptor function without affecting the responsiveness and stimulus selectivity of visual neurons; these experiments shed new light on the controversial role of NMDA receptor function in visual cortex plasticity. Finally, Andrew King will describe how polymer implants that produce a localized, reversible blockade of cortical activity that lasts for months can be used to study the role of the ferret auditory cortex in spatial hearing and in the learning and plasticity of localization behavior. To- gether, these presentations will provide a critical overview of the various approaches that are being used to modify activity and a detailed analysis of their effects on neuronal function.

75 PANEL • Friday, 7:30-9:30 AM • Peaks 9-10 Is the Reactive Oxygen Species Peroxynitrite the Holy Grail of Neurodegeneration? Organizer: E. Hall ¥ Participants: J. Beckman, M. A. Smith, D. Pelligrino Peroxynitrite (ONOO-) is a highly reactive oxygen species formed from the combination of nitric oxide and superoxide radical. It is capable of producing oxidative damage to lipids, proteins and nucleic acids (DNA, RNA). The latter leads to the activation of the DNA repair enzyme poly-ADP ribose polymerase (PARP) which can contribute to cellular injury via severe NADH depletion. Peroxynitrite has been increasingly implicated in the pathogenesis of chronic neurodegenerative diseases and acute neurological injury. However, a clear definition of a role for ONOO- as a principal mediator of cellular damage in these disorders has been somewhat controversial. This is due to the difficulty of measuring neuronal damage markers that are specifically associated with ONOO-. One approach to cir- cumventing this problem is to track ONOO- induced nitration of tyrosine resi- dues (i.e. nitrotyrosine). J. Beckman will review the chemistry of ONOO- in vivo and mechanisms of apoptosis resulting from endogenous ONOO- formation. Additionally, he will discuss the evidence of ONOO- importance in amyotrophic lateral sclerosis. M. Smith will discuss the role of ONOO- in Alzheimer s disease and how it is integrated with other neurodegenerative mechanisms. However, despite his demonstration of widespread nitrotyrosine immunostaining in Alzheimer s brain, he will take a skeptical view of its relative importance in the disease. D. Pelligrino will consider the importance of ONOO- damage mechanisms in acute cerebral ischemia paradigms. Lastly, E. Hall will examine the role of ONOO- in traumatic brain and spinal cord injury. He will also discuss the design and neuroprotective efficacy of peroxynitrite scavenging compounds in animal models of acute and chronic neurodegeneration.

PANEL • Friday, 7:30-9:30 AM Peak 4 Transcritpional Regulation and Tissue-specific Expression of Neuroendocrine Genes Organizer: G. Aguilera ¥ Participants: S. Lightman, R. Dorin, T. Insel, S. Radovick Hypothalamic neuropeptides are vital mediators not only of classical neuroendocrine functions but also of autonomic and behavioral responses to the environment. Appropriate regulation of the expression of these neuropeptides is therefore essential for survival. This panel will explore recent progress in the molecular mechanisms which underlie the neuron-specific expression and differential activation of discrete neuropeptides within the same neuron or of single neuropeptides and receptors at different sites in the brain. After an introduction to recent advances in this area by Greti Aguilera, Stafford Lightman will present studies which analyze the differential expression of corticotropin releasing factor (CRF) and vasopression transcription in hypothalamic neurons in vivo. Rich-

76 ard Dorin will follow with analysis of cis- and trans- activating elements which can influence the differential regulation of CRH expression, and the possible role of differential promoter utilization. Next Thomas Insel will show that differences in neural distribution of vasopression and oxytocin receptors between species are due to variations in sequences in the promoter, and will demonstrate the functional consequences of altering the distribution of these receptors, using transgenes which encode the promoter from a different species. Lastly, Sally Radovick will present data obtained in transgenic mice bearing gonadotropin releasing hormone (GnRH)-luciferasae transgenes that confer neuron-specific expression of the GnRH gene, and will discuss transcription factors that control GnRH gene expression. Discussion of the multiple mechanisms capable of regulating the expression of these key regulatory neuropeptides and receptors will integrate current knowledge and identify critical questions for future research in this important field.

WORKSHOP • Friday, 7:30-9:30 AM • Peak 11 Serotonin Receptors That Regulate Dopamine Systems: What Sub- types Are They and Where Are They Located? Organizer: B. Pehek ¥ Participants: S. Sesack, L. Parsons, K. Cunningham For many years, there have been indications that serotonin (5-HT) regulates dopamine (DA) neurochemistry and behavior. However, investigations into this regulation have been hampered by the large number of 5-HT receptor sub-types (some of which have only been recently discovered) and the lack of selective ligands for these sub-types. Finally, within the last few years, specific ligands have been developed for some of these receptors. Additionally, the development of selective antibodies has generated immunohistochemical data that addresses the cellular localization of some of these receptors. The aim of this workshop is to utilize a multidisciplinary approach to examine and discuss recent data to see if a consensus can be reached as to the roles of the 5-HT1B, 5-HT2A, 5-HT2C, and 5-HT4 in the regulation of mesocorticolimbic DA function. Susan Sesack will lead a discussion that addresses the question: What is the anatomical relationship between prefrontal cortex (PFC) and nucleus accumbens (NA) 5-HT and DA neurons? Betsy Pehek will focus on an examination of the 5-HT2A receptor in the mesocortical DA system: Where are these receptors and do they regulate DA release? Loren Parsons will discuss 5-HT1B receptor modulation of DA and amino acid neurochemistry in the mesolimbic system and how this changes after cocaine exposure. Kathryn Cunningham will lead an examination of the brain localization of 5-HT2A, 5-HT2C, and 5-HT4 receptors that modulate DA-mediated behaviors. This workshop will probably generate more questions than answers, as this field is largely unexplored. However, the hope is that it will generate testable hypotheses.

77 WORKSHOP • Friday, 7:30-9:30 AM • Peak 12 Right Hemisphere Language: An Oxymoron? Organizer: S. Small ¥ Participants: A. Kertesz, E. Ross, A. Hillis Most patients with focal lesions to the right hemisphere do not show any obvi- ous language disturbances, whereas patients with similarly placed lesions of the left hemisphere show tremendous interruptions of normal language function (aphasia). Nonetheless, most neuroimaging studies of language processing show either symmetrical activation of left and right hemispheres, or at least, asym- metrical activation that still includes a significant right hemispheric component. Many studies have suggested that this right hemisphere activation is not linguistic , attributing it to other factors important in language processing. These include the processing of the basic auditory signal itself, the melody (prosody) of auditory language, the spatial aspects of written language, emotional content, working memory, attention, or motor function. But to what extent are these so- called non-linguistic factors theoretically distinct from the processing of language itself? To what extent does the experimental design determine the results, and how do these results differ from what we really want to know, i.e., the organization of ecologically valid use of language? Discussion in this workshop will focus on the role of right hemisphere structures in language processing. Data that bear on this question come from multiple sources, including patients with focal brain lesions, patients with diffuse brain dysfunction, functional MRI, PET, scalp electrical and magnetic recording, and direct cortical stimulation and recording. Controversies surrounding hemispheric specialization, differences between acti vation (e.g., imaging) versus subtr active (e.g., lesions) approaches, and the roles of non-linguistic processing in language will form the crux of the discussion.

PANEL • Friday, 7:30-9:30 AM • Peaks 6-8 Controlling Spinal Plasticity in the New Millennium: New Targets and New Tools Organizer: C. Fairbanks ¥ Participants: S. Carlton, M. Max, P. Mantyh Long term potentiation or plasticity has been implicated in the mechanisms gov- erning inflammatory and neuropathic pain. However, side effects have limited extension of NMDAR/NOS modulators into clinical use. Therefore, identification of novel targets for controlling spinal plasticity remains an area of intense investigation. This panel will present three novel approaches to address this challenge. Susan Carlton will summarize information from behavioral, electrophysiological, and anatomical studies that used clinically available NMDA receptor antagonists (ketamine, memantine, dextrorphan) and subsequently focus on 5,7 dichlorokynurinic acid, which selectively modulates the glycine site on NMDA receptors. The latter will illustrate a rationale for design of NMDA receptor modula tors that remain confined to the periphery. Mitchell Max will review

78 the clinical data from multiple investigations of NMDA, kainate, and NK1 and NK2 receptor antagonists; this presentation will facilitate an interface between basic science and clinical research in plasticity-mediated pain. Carolyn Fairbanks will introduce the recently identified endogenous compound agmatine (decar- boxylated arginine) which antagonizes/inhibits both NMDAR/NOS and demonstrates anti-plasticity effects when delivered exogenously to the CNS. Patrick Mantyh will describe the potential for profound plasticity interruption by SP- saporin toxin-mediated and targeted spinal neuron cell death. Collectively, the panel will integrate the following: an evaluation of previous studies of plasticity in pain, examination of the relationship of preclinical to clinical data, future direction of application of these novel basic science approaches, and consider- ation of how these investigations might be uniquely informative to other areas of plasticity-related neuroscience.

PANEL • Friday, 4:30-6:30 PM • Peaks 1-3 Targeted Tinkering: Manipulating Gene Expression in the Brain Organizer: R. Baler ¥ Participants: M. Kelz, H. Gainer, D. Johns, R. Martin The swift pace of genetic data accumulation may sometimes obscure the fact that biologically meaningful knowledge is derived from the painstakingly slow process of functionally testing target genes. Fortunately, our ability to interro- gate these genes is constantly expanding, and today there is a plethora of methods that enable investigators to tinker with their expression. Neuroscience research poses many challenging questions that can be addressed with the help of these emerging techniques. The remarkable ability of discrete regulatory DNA fragments to recreate delicate patterns of tissue and temporal distribution, together with an increasing array of devices to establish them in vivo provides some powerful tools with which to fill the information gap between databases and complex behaviors. In this panel we will explore the potential for synergistic interactions between the use of highly specific promoter regions and selected ongoing efforts aimed at crafting novel, versatile and efficient modes of gene delivery and induction. Promoter-mediated targeting will be illustrated using the serotonin N-acetyltransferase (Baler) and Oxytocin-Vasopressin (Gainer) genes. On the other hand, a modified tetracycline system (Kelz), the administration of microencapsulated recombinant cells (Ralph) and an ecdysone-madiated elec- tric silencing method (Johns) will be presented to exemplify promising modes of in vivo delivery and control.

PANEL • Friday, 4:30-6:30 PM • Peaks 9-10 Multiple Sclerosis: Pathogenesis and Regulation Organizer: H. Offner ¥ Participants: P. Dore-Duffy, R.E. Jones, G. Konat, A. Vanderbark This session will focus on new approaches to define inflammatory and regulatory elements that contribute to CNS myelin destruction and clinical signs in

79 multiple sclerosis. Dr. Richard Jones will evaluate unique interactions between antigen presenting cells and T cells in an EAE model involving transfer of T cells and antigen presenting cells (APC) into immunodeficient (SCID) mice. Dr. Konat will present new data demonstrating the formidable inhibitory effects of oxi- dants produced by inflammatory leukocytes on expression of myelin proteins and the function of cultured oligodendrocytes. Dr. Dore-Duffy will talk about blood-brain barrier and role of CNS microvascular pericyte in experimental autoimmune encephalomyelitis (EAE) and MS. Dr. Offner will explore gender differences in susceptibility to EAE, and in efficacy of treatments for EAE. Dr. Vandenbark will evaluate regulatory mechanisms involved in T cell receptor (TCR) peptide therapy in MS patients.

PANEL • Friday, 4:30-6:30 PM • Peak 11 Taster’s Choice: Mesocorticolimbic Memories Driving Goal- Directed Behavior Organizer: P.H. Janak ¥ Participants: A.E. Kelley, K. Anstrom, G. Schoenbaum How does a particular smell or taste guide current and future behavior? New electrophysiological and pharmacological tools and sophisticated behavioral paradigms allow the exploration of the role of cognition and learning in goal- directed behavior. Janak will introduce the panel with a review of the anatomy and a presentation of the issues. Kelley will address how taste cues, particularly conditioned taste cues, influence behavior, with an emphasis on opioid mechanisms of the accumbens shell. Anstrom will provide electrophysiological evidence for reinforcer-specific neural coding obtained from rats self-administering differently-flavored solutions, including ethanol, within n.accumbens and two of its important afferents, the lateral insular and medial prefrontal cortical regions. Schoenbaum will continue the exploration of prefrontal cortex, by providing evidence from olfactory learning that the orbitofrontal cortex and the basolateral amygdala may form a working memory system for encoding the motivational value of cues. Together, these talks will provide the springboard for a discussion on the notion that the mesocorticolimbic system is the neural substrate for conditioned chemosensory stimulus effects on goal-directed behavior.

PANEL • Friday, 4:30-6:30 PM • Peak 12 Redox Fuse Box: Wiring That Juices the System During Stroke Organizer: M. Espey ¥ Participants: C. Colton, E. Aizenman, D. Harder Although redox mechanisms are clearly involved in numerous neurological disease processes, differences in experimental approaches have resulted in conflicting viewpoints. The goal of this panel will be to discuss the complex interplay between nitrosative and oxidative mechanisms that affect neuronal survival during ischemia/reperufusion injury toward developing a better understanding of excitotoxicity. Topics were chosen that connect redox molecules of notable or emerging importance with their actions at the receptor, cellular and system (e.g.,

80 blood flow) levels. Attendees will gain an overview of redox concepts and will have the opportunity to load-test several novel schemes. Michael Espey will dia- gram the NOS isozymes in the system with an emphasis on detailing the relevant chemical interactions arising from each source. Carol Colton will provide insight into the influence of nitrogen monoxides on the status of the NMDA receptor. New concepts on nitroxyl anion (NO-) will be discussed. Elias Aizenman will charge a provocative session with the presentation of a redox-based mechanism for the release of zinc from intracellular stores and its role in apoptosis. The regulation of vascular tone by P450 metabolites of arachidonic acid and the dynamics of redox-active lipid-second messenger pathways will be discussed by David Harder. These topics will provide a framework for a lively debate on the relative contribution of metals, ecosinoids, reactive nitrogen oxide and oxygen species etc. in the neuropathology of stroke.

PANEL • Friday, 4:30-6:30 PM • Peaks 6-8 Combination Pharmacotherapy: Implications For Drug Addiction Organizer: A. Rezvani ¥ Participants: J. Rose, L. Reid, C. Farren Addiction is a major health problem. In spite of large and intense efforts devoted to the treatment of this devastating disease, remediation of drug dependence remains a great challenge. It is common to treat some medical diseases with more than one medication simultaneously. There is considerable evidence that addiction is a multi-factorial disease that may involve central seratonergic, dopaminergic, opiodergic, GABAergic and NMDA systems. If deficits in more than one of these systems additively or synergistically contribute to drug seeking behavior, theoretically, a therapeutic approach that targets more than one system should be more effective than one addressing a single system. Recently, combination pharmacotherapy has been studied in animal models of addiction and human alcoholics. The main objective of this panel is to present findings and discuss strategies for the treatment of alcohol, nicotine and cocaine dependence. Amir Rezvani will open the panel by giving an introduction to combina tion pharmacotherapy and the rational behind it. L.D. Reid will present his research on the combination pharmacotherapy of cocaine addiction and alcoholism in animal model, J. Rose will present his findings on nicotine addiction, and finally, C. Farren will present and discuss his findings on the combination pharmacotherapy for human alcoholism.

PANEL • Friday, 4:30-6:30 PM • Peak 4 Dendritic/Synaptic Protein Synthesis: A Mechanism of Synaptic Tagging With Implications For Clinical Problems and Synaptic Plasticity Organizer: W. Greenough ¥ Participants: O. Steward, A. Scheetz, J. Eberwine Several different forms of dendritic and synaptic-level regulation of local protein synthesis have been recently reported. Clear links to clinical disorders and to

81 synaptic plasticity have been demonstrated. These findings have raised interesting new questions about mRNA transport and targeting, local regulatory control mechanisms, functional purposes of localized protein synthesis regulation and the cellular and system-level processes in which the proteins are involved. In this panel, members of four leading research laboratories in this area will review the history and latest findings in this field at a level appropriate to a diverse scientific audience. Topics to be covered include NMDA receptor dependent regulation of protein synthesis via phosphorylation of the protein synthesis regulator elonga- tion factor 2, metabotropic glutamate receptor dependent regulation of translation of the Fragile X Mental Retardation Protein (FMRP), regulation of synthesis of CREB and homeobox proteins in isolated cultured dendrites, mechanisms that appear to bypass substantial components of previously described signaling pathways, synaptic activity-dependent regulation of the synthesis, transport and local translation of mRNA for a cytoskeletally-associated protein, and a role for FMRP in synaptically upregulated protein translation.

Don’t forget to visit the exhibit area.

82 Poster Abstracts

TGF-beta-1 Modulates Kir 2.3 Currents Via a PLC-PKC Dependent Mechanism in Reactive Astrocytes From Adult Brain Potts E.A., Perillan, P. R., Li, X., Simard, J.M. Department of Neurosurgery, University of Maryland, Baltimore MD Reactive astrocytosis is a constant feature following CNS injury. Processes regulating this, however, are not well understood. The most striking histological feature of gliosis is the cellular response of reactive astrocytes. Transforming growth factor beta-1 (TGFbeta-1) secreted by astrocytes in both paracrine and autocrine fashion, plays a critical role in brain injury. We have previously characterized inward rectifier (KIR) currents in reactive astrocytes. We believe this channel plays an important role in proliferative control and pathophysiology of reactive astrocytosis. Here we report the identification of the KIR 2.3 protein via fluorescent immunohistochemistry. Individual cells were studied using nystatin perfo- rated whole cell technique in both current and voltage clamp protocols. Electro- physiological recordings revealed depolarization due to TGFbeta-1, which we hypothesized was associated with a block of potassium channel conductance. After application of TGFbeta-1 (0.1,1.0,10 ng/mL) KIR currents (n=28) were decreased 20%-90% in a dose dependent fashion. Selective inhibition of the PLC- PKC second messenger system with neomycin (n=4), staurosporine (n=4) and calphostin C (n=4) prevented the decrement of KIR currents. This report demonstrates, for the first time, control of an ion channel by an immuno-mediating growth factor. TGFbeta-1 modulation of KIR 2.3 currents is mediated by a PLC- PKC dependent second messenger signal transduction pathway. We believe this link plays a crucial role in the pathogenesis of brain injury.

Novel Anti-Stress Neuromodulators MA Gingras,(2) RH Purdy,(1) GF Koob,(1) and KT Britton(2).The Scripps Research Institute, La Jolla, CA; San Diego, Veterans Administration Medical Center and University of California, San Diego,CA Stress and depression are intimately linked clinically and pre-clinical studies on novel stress mechanisms may provide insight into depression and novel anti- depressants. Work using a Geller-Seifter conflict procedure has shown that the neuroactive steroids such as allopregnanolone when administered systemically to rats produce significant anxiolytic-like effects. These anxiolytic-like effects appear to be similar to those observed with the synthetic steroid alphaxolone and appear to be at least partially mediated by actions at the GABA-A receptor[Brot et al., European J. Pharmacol 325 (1997) 1-7]. The purpose of the present series of studies was to examine the effects of other steroids related to allopregnanolone and the effects of neuropeptide Y on the conflict test by themselves and in combination with alcohol. Results show effective anti-conflict ac-

83 tions of a series of neuroactive steroids and of NPY and potential additive or synergistic actions when combined with ethanol. These powerful anxiolytic-like actions may involve modulation of the GABA-A receptor but also interactions with other stress neurotransmitters such as corticotropin releasing factor and norephinephrine.

Evaluation of The Ability of Neocortical Neurons To Perform Coincidence Detection On Coherent Inputs Kinney, G. A., Spain, W.J., Department of Physiology and Biophysics, University of Washington, Seattle WA It is unclear whether cortical neurons extract information carried in the rate or timing of action potentials. Constraints on the type of information that can be extracted are dependent on a number of factors, including the properties the circuit and synapses, as well as neuronal membrane properties. Neurons in the auditory brain stem provide an excellent example of the specializations utilized to convert precisely timed action potentials from two sets of inputs into a rate code (coincidence detection (CD). The auditory neurons are notably different from neocortical neurons in that they do not fire repetitively to depolarizing DC inputs, which may enable them to extract timing information from inputs firing at high frequencies. However, neocortical neurons may be able to perform CD under certain circumstances. We asked whether cortical neurons are capable of decoding coherent information at frequencies relevant to the neocortex (40 Hz). Experiments were done in whole cell recordings from visualized neurons in neocortical slices. Using evoked synaptic potentials recorded from layer 5 pyramidal neurons as a template, we stimulated these neurons with simulated EPSPs at various input strengths and frequencies. We also systematically varied EPSP time course to evaluate its impact on CD. Our results indicate that neocortical pyramidal neurons can perform CD on coherent information when they receive relatively few excitatory synaptic inputs. However, when the input strength increases the pyramidal neurons act primarily as temporal integrators, extracting rate information. When pyramidal neurons were stimulated with simulated EPSPs with a shorter time-course (a situation that may simulate the higher membrane conductance that is observed in vivo) they showed only a modest increase in the range of input strengths where they could act as coincidence detectors. (Sup- ported by a VA merit review & NIH grants CD02254 & NS07395).

The Role of CRH in The Regulation of Conditioned Defeat Huhman, K. L., Jasnow, A. Department of Psychology. Georgia State University. Atlanta GA Social conflict is a major source of stress, and perhaps disease, in a variety of species including humans. Profound and long-lasting changes in behavior and physiology can be produced by exposure to social conflict particularly if an individual loses . For example, when Syrian hamsters are defeated during a brief encounter in the home cage of a larger, aggressive opponent, the defeated ham-

84 sters subsequently fail to display normal territorial aggression in their own home cages even when the intruder is a docile, younger animal. We have called this dramatic behavioral change conditioned defeat. To investigate the duration of conditioned defeat, hamsters were tested for territorial aggression every 3-5 days for 33 days following a single defeat experience. All experimental animals showed conditioned defeat for at least 16 days (5th test) and 57% of the animals still exhibited conditioned defeat on Day 33 despite the fact that they were never again attacked by their opponents. Since corticotropin releasing hormone (CRH) plays an important role in anxiety and stress, we examined whether CRH may be involved in modulating the response of animals to defeat. Conditioned defeat was significantly reduced following intracerebroventricular injections of the CRH receptor antagonist, D-Phe CRH(12-41) as compared to control animals injected with saline. In summary, conditioned defeat is a long lasting, biologically relevant paradigm within which behavioral responses to stress can be studied. These data demonstrate that CRH is an important component of the circuit that modulates the response of hamsters to stress.

Patterns of Brain Activation Associated With Different Forms of Motor Learning Ghilardi, M.-F Center for Neurobiology & Behavior, Columbia University, New York NY We examined the variations in regional cerebral blood flow during different types of motor learning with a series of kinematically and dynamically controlled motor tasks in which cognitive, mnemonic and executive features of performance were differentiated and characterized quantitatively. During 15O-labeled water positron emission tomography (PET) scans, twelve right-handed subjects moved their dominant hand on a digitizing tablet from a central location to equidistant targets displayed with a cursor on a computer screen in synchrony with a tone. In the preceding week, all subjects practiced three motor tasks: 1) movements to a predictable sequence of targets; 2) learning of new visuomotor transformations in which screen cursor motion was rotated by 30°-60°; 3) learning new target sequences by trial and error, by using previously acquired routines in a task placing heavy load on spatial working memory. The control condition was observing screen and audio displays. Subtraction images were analyzed with Statistical Parametric Mapping to identify significant brain activation foci. Execution of predictable sequences was characterized by a modest decrease in movement time and spatial error. The underlying pattern of activation involved primary motor and sensory areas, cerebellum, basal ganglia. Adaptation to a rotated reference frame, a form of procedural learning, was associated with decrease in the imposed directional bias. This task was associated with activation in the right posterior parietal cortex. New sequences were learned explicitely. Significant activation was found in dorsolateral prefrontal and anterior cingulate cortices.We conclude that explicit and implicit types of motor learning require the activation of different brain networks.

85 Differential Effects of Ethanol On Kainate Receptor-gated Inhibition of GABAergic and Glutamatergic Synaptic Transmission Weiner, J. L., Crowder, T., Ariwodola, Segun, J. Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem NC We recently demonstrated that intoxicating concentrations of ethanol inhibit kainate receptor-gated synaptic transmission in rat hippocampal CA3 pyramidal neurons (Mol Pharm, 56: 85-90, 1999). In addition to their role as postsynaptic mediators of excitatory synaptic transmission, presynaptic kainate receptors have also been identified. Activation of these presynaptic kainate receptors results in inhibition of GABAergic and glutamatergic synaptic transmission at a number of synapses. In this study, we assessed the ethanol sensitivity of the presynaptic kainate receptors that depress synaptic inhibition and excitation in rat hippocampal CA1 pyramidal neurons. Brain slices were prepared from 4-6 week old male Sprague-Dawley rats and synaptic currents were recorded from CA1 pyramidal cells using the whole cell patch clamp technique. Pharmacologically isolated GABAa- or AMPA receptor-mediated synaptic currents were evoked every 20 seconds using a concentric bipolar stimulating electrode. Under these recording conditions, bath application of 1 uM kainate, a concentration that primarily activates kainate but not AMPA receptors, significantly depressed the amplitude of GABAa and AMPA receptor-mediated synaptic currents. Pretreating slices for 10 minutes with 20, 40, or 80 mM ethanol significantly antagonized kainate- mediated inhibition of GABAa receptor-gated synaptic currents. In contrast, ethanol pretreatment had no effect on kainate inhibition of AMPA receptor-dependent synaptic currents, even at the highest concentration tested. These results are consistent with the known inhibitory effects of ethanol in this brain region and suggest that presynaptic kainate receptors that regulate GABA release may contribute to some of the behavioral and cognitive effects associated with ethanol intoxication and abuse. Supported by NIH Grants AA 12251 and AA 11997.

A Selective D1 Dopamine Receptor Antagonist Reverses The Potentiation of Grooming Behavior Produced by The Selective CB1 D. Lin, L.H. Parsons. Department of Neuropharmacology, The Scripps Research Institute, La Jolla, CA 92037 The high density of cannabinoid CB1 receptors in the basal ganglia and its associated output nuclei, the globus pallidus and substantia nigra reticulata, suggests an intimate involvement of endogenous cannabinoid neurotransmission in the regulation of motor functions. Recent evidence indicates that activation of CB1 cannabinoid receptors functionally antagonizes the motor effects of both D1 and D2 dopamine receptor agonists. A preliminary study in our laboratory revealed a potentiation of grooming behavior following systemic administration of the selective cannabinoid CB1 receptor antagonist SR 141716A. Since the expres-

86 sion of grooming behavior has been closely linked to D1 dopamine receptor function in the dorsal striatum and its output targets, we hypothesized that an- tagonism of endogenous cannabinoid neurotransmission may alter the regulation of D1 receptor-mediated processes. To investigate this hypothesis, animals were administered 0, 0.3, 1 and 3 mg/kg SR 141716A (i.p.) with the dose order randomized across repeated tests in a latin-square design. After a 15 min. pretreatment interval grooming behavior was continuously monitered for 30 minutes by an experimenter blind to the drug treatments. SR 141716A dose-depen- dently increased the time spent grooming with the highest dose producing approximately a two-fold increase relative to veh-treated controls. Pretreatment with the D1 dopamine receptor antagonist SCH 23390 (0.1 mg/kg) reversed the potentiation of grooming behavior produced by SR 141716A (3 mg/kg). These data provide initial evidence of a role for endogenous cannabinoids in the regulation of D1 dopamine receptor-mediated motor behavior.

Communication Between The Lateral Septal Area and Lateral Hypothalamus in Feeding Control Communication Between The Lateral Septal Area and The Lateral Hypothalamus in The Control of Feeding C. M. Kotz and C. F. Wang, Minnesota Obesity Center, V.A. Medical Center and University of Minnesota, St. Paul and Minneapolis, MN The lateral septal area (LS) and the lateral hypothalamus (LH) have historical roles in the regulation of feeding. The LS sends projections to the LH, and elec- trolytic damage to the LS enhances feeding induced by LH stimulation, whereas stimulation of the LS decreases feeding induced by LH stimulation, implicating inhibitory control of the LH by the LS. To determine potential neurochemical signaling pathways involved in the interaction between these two sites, we performed feeding studies in 20 male Sprague Dawley rats prepared with double cannulas: one placed in the intermediate lateral septal area (LSi) and one placed into the LH. All LSi injections were performed 15 min prior to the LH injections in a repeat measure design, and food intake was measured 2 h later. Lidocaine (4%/0.5 µl) injected into the LSi significantly enhanced the feeding produced by LH hypocretin 1 (1000 pmol/0.5 µl, orexigenic neuropeptide) administration, indicating that temporary freezing of the LSi with lidocaine may prevent communication of inhibitory messages received by the LH. Conversely, urocortin (30 pmol/0.5 µl, anorectic neuropeptide) administration into the LSi significantly inhibited deprivation-induced feeding and feeding stimulated by hypocretin 1 (1000 pmol/0.5 µl) injection into the LH, implying that urocortin stimulation of the LSi may transmit feeding inhibitory signals to the LH. These data suggest LSi inhibition of LH feeding signals, and implicate urocortin and hypocretin 1 as potential neuromodulators permitting communication between the LSi and the LH in the control of feeding.

87 Testosterone Regulation of Vasopressin Receptors (V1a) in Hamster Brain Albers, E., Department of Biology, Georgia State University, Zuoxin, W., Young, L. Emory University School of Medicine, Atlanta GA Arginine vasopressin (AVP)is important in the regulation of social behavior in many species. In the Syrian hamster, AVP acts on V1a AVP receptors in a zone from the posterior medial preoptic area to the posterior anterior hypothalamus (MPOA-AH) to stimulate scent marking and aggression. Since these behaviors are also influenced by androgens, we examined whether testosterone regulates V1a binding and mRNA levels in hamster brain. The distribution of V1a binding was similar to that observed previously which included a significant concentration of binding distributed homogeneously in the MPOA-AH. Like V1a binding, V1a receptor mRNA was abundant in several areas involved in scent marking and aggression such as the lateral septum. However, it was interesting that the V1a receptor mRNA was anatomically more restricted in several areas when compared to the pattern of ligand binding. For example, although binding was distributed throughout the AVP-responsive zone, V1a mRNA within this region was found primarily in the medial preoptic nucleus (MPN). Comparison of V1a binding and mRNA levels on alternate sections in sham-castrated, castrated, and castrated-testosterone treated animals indicated that castration significantly reduced the levels of V1a binding in the MPOA-AH but not in other sites compared to sham-castrates and castrates given testosterone. Castration nearly abol- ished V1a receptor mRNA in the MPN but had no effect on V1a mRNA levels in any other sites examined. In summary, these data confirm that V1a binding in the AVP-responsive zone of the MPOA-AH but not other CNS sites is testosterone-dependent. In addition, these data indicate that the levels of V1a receptor mRNA are also testosterone-dependent in the MPN, suggesting that the V1a receptor within the MPOA-AH is transcriptionally regulated by testosterone.

Sustained Cocaine Exposure of 12 or 24 Hours Can Decrease Cocaine Self-administration and Desire For Cocaine But Increases Plasma J. Mendelson, D. Harris, E. Fernandez, M. Baggott, and R.T. Jones Drug Dependence Research Center, Univ. of Calif., San Francisco, CA 94143 We tested the hypothesis that cocaine could be effective as a substitution pharmacotherapy, analogous to nicotine and opiate substitution therapies. The efficacy of cocaine substitution therapy was defined as decreased cocaine self-administration, cocaine craving, or subjective effects. Six cocaine abusers were administered constant rate infusions of deuterated cocaine (6 mg/kg or placebo) for 12 or 24 hr periods. Effects of and craving for cocaine were measured with probe doses of smoked cocaine (2-100 mg pipeloads) available 1 hr before and 25 hr after the start of infusions. Heart rate and blood pressure were increased during the 12 but not 24 hr infusions when compared with placebo. Four of 6 Ss decreased the number of self-administered cocaine inhalations (vs 1 of 6 Ss with placebo) after cocaine infusions. Self-ratings of desire for cocaine decreased in

88 all 6 Ss after 1 or both infusions (vs 2 of 6 with placebo). Cocaine craving was variable with both infusion conditions. Although cocaine agonist therapy may diminish cocaine use, it could increase cardiovascular toxicity. Endothelin-1, an endogenous asocostrictor peptide synthesized in vascular endothelial cells, may be a key mediator in cardiovascular disease. Endothelin-1 increased with plasma cocaine concentration, suggesting cocaine has direct peripheral vascular vaso- constrictor effects in humans. Continuous but brief exposures to cocaine may decrease cocaine self-administration or desire for cocaine. Because cocaine increases endothelin-1, a less vasoactive compound than cocaine should be used for agonist substitution therapy. Supported by NIDA grant DA10939.

Role of CRF-R1 in Opiate Withdrawal Iredale, P. A. Department of Neuroscience, Pfizer Central Research, Groton CT Previous studies indicate that corticotropin releasing factor (CRF) contributes to the anxiety-like and aversive states associated with drug-induced withdrawal. The present study extends this work by analyzing the CRF receptor subtype involved in withdrawal responses. First, the influence of a selective CRF-R1 anatgonist, CP-154,526, on opiate withdrawal behavior was examined. Pretreat- ment with the CRF-R1 antagonist significantly attenuated several behavioral signs of naltrexone-induced morphine withdrawal, including writhing, chewing, weight loss, lacrimation, salivation, and irritability, measured during the first hour of withdrawal. Next the expression of CRF-R1 was determined as a second measure of the involvement of this receptor in opiate withdrawal. Naltrexone-induced morphine withdrawal resulted in down-regulation of CRF-R1 mRNA in several brain regions, including frontal cortex, parietal cortex, striatum, nucleus accumbens, and amygdala, but not in hypothalamus or periaqueductal gray. Ex- pression of CRF-R2, the other major CRF receptor subtype, was not significantly down-regulated by withdrawal in any of the regions examined, although morphine alone significantly increased levels of this receptor subtype. Taken together, the behavioral and receptor regulation findings indicate that CRF-R1 is the primary mediator of the actions of the CRF system on opiate withdrawal, although it is possible that CRF-R2 contribute to the response.

Comparison of Halothane Effects On CA1 Pyramidal Cells and Interneurons Nishikawa K., Department of Anesthesia, Stanford University School of Medicine, Stanford CA Inhibitory interneurons are thought to play an important role for the synchronization of neural activity of the hippocampus and other cortical regions. Thus, anesthetic modulation of GABAergic interneurons could play an important role during anesthesia. The purpose of this study was to investigate the effects of a general anesthetic, halothane, on membrane and synaptic properties of inhibitory interneurons. Inhibitory postsynaptic currents (IPSCs) were recorded with whole cell patch clamp techniques in visually identified rat hippocampal CA1 interneurons and pyramidal cells (voltage-clamped at -60 mV). Halothane (0.35

89 mM) slightly but significantly depressed the amplitude of stimulus-evoked IPSCs recorded from both interneurons (75.8 ± 5.9 % of control, n = 5, p<0.01) and pyramidal neurons (81.2 ± 9.8 % of control, n = 6, p<0.05). Also, halothane significantly prolonged the decay time constant of evoked IPSCs in interneurons (225.6 ± 35.0% of control, n = 8, p<0.001). The frequency of spontaneous IPSCs recorded from interneurons and pyramidal cells was also increased by halothane (2-3 fold). On the other hand, halothane effects on resting membrane potentials of interneurons were variable from cell to cell, but generally small (< 2 mV) in about 70 % of interneurons examined. Halothane depressed excitatory postsynaptic potential (EPSP) amplitudes and slightly increased inhibitory postsynaptic potential (IPSP) amplitudes recorded from interneurons in current clamp mode. In addition, halothane increased the failure rate of stimulus-evoked action potentials in interneurons. Taken together, these data provide evidence that halothane facilitates GABA-mediated inhibitory synaptic transmission between interneurons and depresses excitatory transmission, similar to effects observed in pyramidal neurons.

A New Method For Quantal Analysis: Deconvolution of Postsynaptic Responses Bykhovskaia, M., O. N. Vorobieva , E. Polagaeva, and J. T. Hackett. Dept. of Molular Physiology, UVA; Charlottesville VA 22906-0011 Release of neurotransmitter packages from nerve terminals can be detected by recording of postsynaptic quantal responses. Quantal analysis of postsynaptic responses allows quantitative investigation of neurosecretion and synaptic plasticity at many preparations. A major problem of quantal analysis is that when many neurosecretory quanta are released synchronously, unique quantal components are not discernable in the resulting postsynaptic response. We developed a new deconvolution algorithm for evaluation of quantal content and its vari- ability in synchronous multiquantal postsynaptic responses. The algorithm is based on the method of ridge regression. The distribution of the number of neurosecretory quanta is derived from the sizes of evoked postsynaptic responses and from quantal sizes obtained by measuring of miniature postsynaptic potentials. The method was tested by the analysis of simulated multiquantal responses and succeeded to reproduce the imposed distribution of quantal content within the calculated confidence limits. The main advantage of our algorithm is that it does not rely on any models for neurotransmitter release. Therefore, the obtained distribution of quantal content can be used to test different models employing release probabilities and the number of releasable vesicles. We apply our method to quantify facilitation at the lobster neuromuscular junction under conditions of hyperosmolarity.

90 NMDA Receptor Mediated Inhibition of Phosphatidylcholine Synthesis Precedes Excitotoxic But Not Serum Deprivation-induced Trullas, R., Neurobiology Unit, IIBB/CSIC, Rossello 161, Barcelona 08036 Spain N-methyl-D-aspartate (NMDA) receptor overactivation has been proposed to induce excitotoxic neuronal death by enhancing membrane phospholipid degradation. In previous studies we have shown that NMDA releases choline (Cho) and reduces membrane phosphatidylcholine in vivo. We now observed that glutamate and NMDA induce Cho release in primary neuronal cortical cell cultures. This effect is Ca2+-dependent and is blocked by MK-801. In cortical neurons, the NMDA-receptor mediated Cho release precedes excitotoxic cell death but not neuronal death induced by either osmotic lysis or serum deprivation. Glutamate, at concentrations that release arachidonic acid, does not release Cho in cerebellar granule cells, unless these cells are rendered susceptible to excitotoxic death by energy deprivation. The NMDA-evoked release of Cho is not mediated by phospholipases A2 or C. Moreover, NMDA does not activate phospholipase D in cortical cells. However, NMDA inhibits incorporation of [3H]Cho into both membrane phosphatidylcholine and sphingomyelin. These results show that the increase in extracellular choline induced by NMDA receptor activation is directly related with excitotoxic cell death and indicate that choline release is an early event of the excitotoxic process produced by inhibition of phosphatidylcholine synthesis and not by activation of membrane phospholipid degradation.

3-alpha-hydroxy-5alpha-pregnan-20-one Neurosteroid Brain Levels Vary Across Development in Rat and Alters GABAa Receptor Grobin, A. C., Bowles Center for Alcohol Studies. University of North Carolina at Chapel Hill, Thurston Bowles Rm 3027, CB# 7178, Chapel Hill NC 27599 Neuroactive steroids are endogenously produced potent modulators of GABA- A receptor function. Given the trophic role proposed for stimulation of GABA- A receptors during early development, we determined cortical levels of 3-alpha- hydroxy-5-alpha-pregnan-20-one (allopregnanolone, ALLO) at several time points during embryonic (E) and post-natal (P) development of the rat. Using a RIA with a sheep-derived polyclonal antibody we found that brain levels of ALLO vary dramatically across development. As predicted, high levels of ALLO were found in fetal brain during gestation, reaching a maximum on embryonic day 18 (18.76±1.25 ng/g). On E20, ALLO levels in rat brain declined to 1.1±0.03 ng/g; however, prior to parturition brain ALLO rebounded to 4.5±0.4 ng/g. Follow- ing birth, ALLO levels in the cerebral cortex remain low (~2 ng/g). At post-natal day 7, cortical ALLO levels were 0.65±0.4 ng/g. Elevated cortical levels of ALLO were observed on P10 (3.3±0.8 ng/g) and P14 (3.8±1.5 ng/g), returning to normal adult levels by P21. It is possible that the variation in neurosteroid levels, particularly the elevated levels observed at P14 could affect cortical organizational events. To examine the effects of neurosteroids on GABA-A receptor expression, we exposed developing neuronal cells (P19 cells) in vitro to varying

91 concentrations (0.01-1 µM) of ALLO for 4 days. Using quantitative RT-PCR analysis we observed 42.7±6.3% to 58.5±7.2% decreases in GABA-A receptor alpha4 subunit mRNA expression. However, six hours following withdrawal of ALLO alpha4 subunit mRNA expression had returned to control levels. These data suggest that variations in neurosteroid levels regulate the pattern of GABA- A receptor subunit expression. These signals may alter the trophic effects of GABA and play an important role in susceptibility to neurodevelopmental disorders. Supported by NIH grants.

Modulation of Intracranial Self-stimulation Threshold by Drug Associated Contextual Cues Robert J. Hayes, Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461 Learning and memory appear to be critical aspects of drug abuse phenomena; presumably playing an especially important role in craving and relapse. There- fore, it becomes important to understand how learning and memory systems may interact with classical reward circuitry. As a step in this direction, the ability of drug-associated environmental cues to modulate electrical intracranial self- stimulation (ICSS) behavior was assessed. Because medial forebrain bundle ICSS sensitivity is indicative of the level of activation of classical reward circuits, the ability of environmental cues to affect ICSS sensitivity would suggest that learning and memory centers can modulate activity within classical reward circuits. We have developed a method in which animals can be tested within the same apparatus with differing sets of environmental cues. This allows the establish- ment of baseline behavior, the pairing of drug exposure with unique cues, and finally testing of the effect of cue exposure on behavior within the same apparatus. ICSS thresholds were decreased by morphine (5mg/kg, IP) or cocaine (10 mg/kg, IP) during five days of paired drug-cue training sessions. Presentation of the environmental cues previously paired with drug exposure decreased thresholds when presented in the absence of drug. Control animals treated with vehicle-paired cue presentation showed no change from baseline behavior. These results are suggestive of a Pavlovian conditioning phenomenon in which the functioning of brain reward circuitry is directly modulated by drug-associated environmental cues. The observed modulation is of a proponent nature, suggesting that drug-associated environmental cues affect brain reward mechanisms in a similar manner to acute drug administration itself.

Ethanol Elevates Cerebral Cortical Allopregnanolone Levels That Contribute To Its Pharmacological Actions Morrow, A. L., Center for Alcohol Studies, University of North Carolina School of Medicine, CB#7178, Thurston Bowles Bldg.Chapel Hill NC 27599 Ethanol is a physiological stressor. Since stress induces the formation of GABAa receptor active neurosteroids, we investigated the effect of acute ethanol administration on cerebral cortical 3alpha-hydroxy-5alpha-pregnan-20-one

92 (allopregnanolone, allo). Ethanol (1.3-3.5 g/kg; i.p.) elevates cerebral cortical concentrations of allo with a maximal effect at 2.5g/kg. The elevation of allopregnanolone is time dependent with a maximal response between 40-80 minutes after ethanol administration. Allo is synthesized in brain by reduction of progesterone via 5alpha-reductase and 3alpha-hydroxysteroid-oxidoreductase. We found that pretreatment with the irreversible 5alpha-reductase inhibitor, finasteride (25 mg/kg, s.c. 4 hrs and 1.5 hrs prior to ethanol administration), reduces the effect of ethanol (2g/kg) on cerebral cortical allo levels by 45±15% (p<0.05). This suggests that ethanol induction of allo involves de novo biosynthesis. Following finasteride pretreatment, the anticonvulsant effects of ethanol (2g/kg) on bicuculline-induced seizures are completely reversed. Moreover, there is a good correlation (r=0.59; p<0.0001) between cerebral cortical allo levels and ethanol sleep-time, measured by duration of the loss of righting reflex. Acute systemic ethanol administration substantially reduces spontaneous neural activity in medial septal neurons. Finasteride (50mg/kg) pretreatment completely blocked the effect of ethanol (1.5g/kg) on spontaneous firing rate 15-60 min following ethanol administration (p<0.05). These data suggest that induction of brain allo contributes to the behavioral and electrophysiological effects of ethanol and may explain GABAmimetic effects of ethanol where direct ethanol interactions with GABAa receptors are absent.

Possible Age-related Loss of Synapses in The Human Brain: Will We Be Disconnected in The New Millenium Stephen Scheff, Sanders-Brown Center on Aging, University of Kentucky, Center on Aging, 233 Sanders-Brown, University of Kentucky, Lexington KY 40536-0230 Patients with Alzheimer s disease manifest a significant loss of synaptic contacts is several key cortical structures. The most notable of these structures is the frontal cortex (Brodmann area 9) and the hippocampal formation. It is unclear how much of this loss is the result of normal aging or if in fact these brain regions show age-related changes. We sought to examine possible changes in the synaptic numbers in these two regions throughout the human life span. Tissue was obtained at autopsy from neurologically normal individuals within thirteen hours of death ranging in age from 20 to 90 years of age. Tissue was examined with the electron microscope and unbiased stereologic estimates were obtained of the density of synaptic contacts. Contrary to what many individuals may believe, no significant age-related declines in synaptic numbers were observed in either lamina III or V of the frontal cortex. However, the CA1 regio superior synaptic field of the hippocampus and the dentate gyrus outer molecular layer showed highly significant age-related changes. There were no significant changes in the width of the these structures. The age-related changes appeared to be initiated by the fifth decade of life and continued to decline. These results may provide an anatomical substrate for the progressive decline in memory tasks which often accompany normal aging.

93 Changes in Rat CNS Metabolic Activity in the Course of a Chronic Monoarthritis J.M. Castro-Lopes1, F. Neto1, J. Schadrack2, A. Ableitner2, W. Zieglg nsber ger2, T.R. T lle 3 1Inst. Histology & Embryology, Faculty of Medicine of Oporto, Portugal; 2Dept. Neuropharmacology, Max-Planck Institute of Psychiatry, Munich, Germany; 3Dept. of Neurology, Technical University of Munich, Germany Pain is a multi-dimensional experience with sensory-discriminative and affec- tive-motivational components. The attribution of such components to a neuronal substrate is based on electrical brain stimulation, lesion studies, topographic mappings and metabolic imaging. In the present study we have mapped the CNS structures which showed increased metabolic activity during ongoing monoarthritic pain at 2, 4, and 14 days of the disease using the the quantitative autoradiographic 2-deoxyglucose technique. Bilateral increases of glucose utilization, ranging from 20% to 65% above controls, were seen in all spinal laminae and in several brainstem, thalamic, limbic and cortical regions at 2 and 14 days of monoarthritis. Maximum values were detected in the spinal cord, anterior pretectal nucleus, anterior cingulate cortex and nucleus accumbens. Interestingly, at 4 days of monoarthritis, and in monoarthritic rats receiving an additional noxious stimulation, the glucose utilization values were in the control range in almost all regions studied. The data evidence not only a general increase of CNS metabolic activity during the development of a chronic pain state, but show a region specific non-linear time profile. This may reflect the complexity of trans- ducing and modulating transmitter systems involved in the central processing of chronic pain.

Baseline Plasma HVA and Drug Response in Mania Chou, J., C.Y. Department of Psychiatry, Nathan Kline Institute, 140 Old Orangeburg Rd., Bldg. 35, Orangeburg NY 10962, Dacpano, G. S., New York University Sch.of Medicine, Czobor, P., Cooper T. B., Nathan Kline Institute, Chang, W.-H., Taipei City Psychiatric Center Bipolar disorder is a severe and persistent brain disease afflicting over 1% of the general population. The clinical hallmark of this brain disease is the acute manic episode in which brain dysfunction can lead to severely aberrant hyperactive behavior. While no clear brain mechanisms have been conclusively identified as the cause of mania, abnormalities in dopamine function have been considered to potentially be important, and antipsychotics have been the class of medication used most often for treatment. Pretreatment plasma homovanillic acid (HVA) levels have been reported to be a correlate of clinical response to typical antipsychotics for schizophrenic, bipolar manic, and mixed psychotic groups of patients. Biological markers of clinical response to antipsychotics could be useful for optimizing drug treatment. Method: Thirty-one consenting acute inpa- tient subjects between ages 19-66 years with a DSM-IIIR clinical diagnosis of bipolar disorder, manic with psychotic features were entered into this double-

94 blind study and were randomly assigned to receive either haloperidol 25 mg/d or haloperidol 5 mg/ for the 3-week study. Subjects also received one of the following concomitant medications: standard lithium, lorazepam 4 mg/d, or placebo. Results: The primary multiple regression analysis, including all subjects on both haloperidol doses, yielded a significant main effect for pretreatment plasma HVA (n=31, F=5.7, p = .025), indicating that higher pretreatment plasma HVA was predictive of better clinical response. In addition, the interaction between haloperidol dose and pretreatment plasma HVA was also significantly associated with clinical response (F=12.59, p = .0015). When the two haloperidol doses were analyzed separately, we found that pretreatment plasma HVA was only correlated with clinical response in the LOW haloperidol 5 mg/d group (n=18, F=11.73, p = .0038) and was unrelated to clinical response to the HIGH haloperidol 25 mg/d group. Limitations: The sample size was small. Results may have been confounded by prior antipsychotic treatment and concomitant use of lithium or lorazepam. Discussion: These results suggests that pretreatment plasma HVA could be useful for dosing

Alcoholism and Immunity: Disease Marker or Secondary Effect? Schleifer, S. J., Keller, S. E., Benton, T. Department of Psychiatry, UMDNJ-New Jersey Medical School, 185 South Orange Avenue, Newark NJ 07103 Altered immunity, reportedly common in alcoholism, may relate to disease-associated state or trait CNS alterations(including neuroendocrine), comorbid psychiatric disorders (e.g., depression), toxic effects of alcohol exposure, or secondary effects of organ (e.g., liver) dysfunction. Studies investigating immune effects of alcoholism per se vs its medical sequelae are needed. We compared in vitro immune measures from 44 exclusively alcohol dependent (SCID-DSM-III-R) subjects without medical disorders (AWLDs) with that of 34 healthy non-abus- ing community subjects (NCSs) and 11 alcoholics excluded from initial analyses due to (mild) liver disease (ALDs). AWLDs included 66% males, 89% African- Americans, 27% homeless, 88% unemployed, averaged 12 drinks/day over the preceding 5 yrs, and a mean of 19 yrs of alcohol abuse. ALDs were similar, but consumed a mean of 22 drinks/day. Controlling age and gender, ANCOVA revealed no differences between AWLDs and NCSs in lymphocyte subsets, responses to the mitogens PHA, ConA, or PWM, or NK cell activity (NKCA) (p>.1). Decreased phagocytosis of S. aureus was found in male alcoholics only (p<0.04); phagocytic killing did not differ between groups. ALDs, however, additionally showed decreased CD45RA+ inducer-suppressor/naive cells (p <.03), decreased activated T-cells (p<.04), increased CD56+ (NK) cells (p<.02), and possibly lower phagocytic killing (p<.1). ALDs higher alcohol consumption accounted statistically only for their decreased activated T cells. The data suggest that alcoholism and chronic alcohol use per se are not associated with substantial intrinsic immune changes and that immune alterations in alcoholics may relate primarily to secondary effects of hepatic or other organ dysfunctions.

95 Heritability of Independent Domains of Cognitive Dysfunction in Schizophrenia Egan, M. F. CBDB, NIMH, NIH, Bldg Bldg 10, Center Drive, Rm 4S 241; MSC1377 Bethesda MD 20814-9692 Patients with schizophrenia have impairments in executive function, memory, language, psychomotor speed, and general intelligence. Impairments in some of these domains have also been observed in unaffected sibs, suggesting they could be heritable. To assess the suitability of impaired cognition for use as phenotypes in genetic studies, we estimated relative risk (l) in a large cohort of sibs. One hundred and forty seven patients, 193 sibs, and 47 controls were given a test battery including IQ, WRAT reading, WCST, Wechsler Memory Scale (WMS), CVLT, CPT, Trails A and B, and Verbal and Category Fluency. Relative risk was estimated using cutoff scores of 1 and 2 standard deviations below the control mean to define af fected probands and siblings. Patients performed markedly worse than controls on all tests except WRAT reading. Siblings had worse scores relative to controls WCST (categories), WMS, and letter fluency, with trends for reductions on Trails A and B. Relative risk for siblings was significantly increased for WCST (categories), WMS, CVLT, letter fluency, Trails B, and CPT. Relative risk for various tests ranged from 1.8 (Letter Fluency) to over 7 (WMS and Trails B). Correlations between domains were weak to moderate, indicating relative independence. These data suggest that impaired cognition is familial and possibly genetic. Using these relatively independent dimensions of cognitive impairment as biological phenotypes may be a practical solution for dissecting the genetic heterogeneity of schizophrenia and improving the power of linkage studies.

Apoptosis—Caspase or Poly(adp-ribose) Polymerase? Adams, James, D. Molecular Pharmacology and Toxicology, USC School of Pharmacy, 1985 Zonal Avenue, PSC 508, Los Angeles CA 90089 Caspase-3 is activated early in the apoptotic program and hydrolyzes PARP. This leaves DNA susceptible to endonuclease or caspase activated DNase attack. Caspase knock out mice are resistant to ischemia and reperfusion. This may show that caspase-3, and not PARP, is important in apoptosis. PARP is activated when it attaches to DNA breaks that are induced by oxygen radicals as a primary step in the apoptotic program. Excessive PARP activity leads to NAD and ATP depletion. PARP that is attached to DNA is not a good substrate for caspase-3. Therefore, caspase-3 activation may not cleave all nuclear PARP. PARP knock out mice are resistant to ischemia and reperfusion. This may show that PARP, and not caspase-3, is important in apoptosis. Which pathway leads to apoptosis, the caspase-3 pathway or the PARP pathway? Are these pathways mutually exclusive? Are these pathways separate but equal?

96 Evidence For A Distinct Light-induced Calcium-dependent Potassium Current in Hermissenda Crassicornis Blackwell, Kim, T. Department of Conputational Sciences & Informatics, George Mason University, Krasnow Institute, MS 2A1, Fairfax VA 22030 Hermissenda can be classically conditioned using light as the Conditioned Stimu- lus (CS) and turbulence as the Unconditioned Stimulus (US). Cellular correlates of the associative learning behavior include an increase in input resistance, a long-lasting depolarization (LLD) in response to light, and an increase in the spikes elicited by depolarizing current (Crow and Alkon, 1980, Farley and Alkon 1982, West et al. 1982) measured in Type B photoreceptors. A model of phototransduction is developed as a first step toward a model for investigating the critical interaction of light and turbulence that leads to the change in cell properties. The model includes equations describing production and degradation of the relevant enzymes and second messengers, release of calcium from intracellular stores and other calcium regulatory mechanisms, equations describing ligand-gating of a rhabdomeric sodium current and previously characterized somatic voltage-dependent currents. The model is used to determine the sources of calcium in the soma, whether calcium or IP3 is a plausible ligand of the light- induced sodium current, and whether the light-induced potassium current is equivalent to the calcium-dependent potassium current activated by light-induced calcium release. Simulations show that the early light-induced calcium elevation is due to influx through voltage-dependent channels, whereas the later calcium elevation is due to release from intracellular stores. Simulations suggest that the ligand of the fast, light-induced sodium current is IP3, but that there is a smaller, prolonged component of the light-induced sodium current which is activated by calcium. The calcium-dependent potassium current, located in the soma, is activated only slightly by light-induced calcium elevation, leading to the prediction that a calcium-dependent potassium current, active at resting potential, is located in the rhabdomere, and is responsible for the light-induced potassium current.

Purification and Analysis of in Vivo Differentiated Oligodendrocytes Expressing The Green Fluorescent Protein Wendy B. Macklin1, Babette Fuss2, Barbara Mallon1, Tom Phan1, Carsten Ohlemeyer3, Frank Kirchhoff 3 1Dept. of Neurosciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195; 2Dept. of Anatomy, Virginia Commonwealth University, Richmond, VA 23298; 3Dept. of Cellular Neurosciences, Max-Delbrueck-Center for Molecular Medicine, D-13092 Berlin. A complete understanding of the molecular mechanisms, involved in the formation and repair of the CNS myelin sheath, requires unambiguous identification and characterization of in vivo differentiated, myelin-forming oligodendrocytes. Recent studies rely on the use of differentiation stage-specific antibodies recog- nizing oligodendrocyte surface antigens. However, differences in antibody speci-

97 ficities, both in vivo and in different species, make it difficult to obtain a comprehensive picture of the characteristics of mature oligodendrocytes. We have generated a novel tool for the analysis of in vivo differentiated oligodendrocytes, i.e., transgenic mice expressing a red-shifted variant of the green fluorescent protein (GFP) under the control of the PLP promoter. We demonstrate here that GFP expression in the CNS of 3 to 7-week-old mice is restricted to mature oligodendrocytes, as determined by their spatio-temporal appearance and by immunocy- tochemical as well as electrophysiological criteria. These GFP-positive oligodendrocytes could easily be visualized in live and fixed CNS tissue. The conve- nient and reliable identification of these cells in live tissue allows detailed physiological analyses of differentiated oligodendrocytes in situ. In these studies, we have found that mature oligodendrocytes in gray matter have similar electrophysiological characteristics to those in white matter. In addition, we developed a novel tissue culture system for in vivo differentiated oligodendrocytes. Initial data using this system indicate that these cells can be cultured, but that their survival and/or the reappearance of the mature phenotype of in vivo differentiated oligodendrocytes requires astrocyte-conditioned medium. This suggests the existence of yet ill-defined factors secreted by astrocytes that could be important for remyelination in vivo. This work was supported by a grant from the NIH (NS25304, WBM) and a fellowship from the National Multiple Sclerosis Society (BF).

Localization of Receptors of The Calcitonin Gene-related Peptide Family in The Central Nervous System K. R. Oliver & N. Keyvan-Fouladi. Merck, Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex CM20 2QR, UK. Calcitonin gene-related peptide (CGRP) is a member of a family of neuropeptides that includes calcitonin, amylin and adrenomedullin. Historically, CGRP receptors have been pharmacologically characterized as CGRP 1 and CGRP 2 receptors. However, the molecular basis of receptor function has until recently been very unclear. Recent cloning studies isolated receptors that confer specific responsiveness to CGRP. These were named calcitonin receptor-like receptor (CRLR), RDC-1 and CGRP-receptor component protein (CGRP-RCP). The molecular basis of CGRP function was further elucidated upon the identification of the receptor-activity-modifying proteins (RAMPs). These data showed that CRLR in association with RAMP1 bound CGRP, whilst CRLR-RAMP2 preferentially bound adrenomedullin. CRLR-RAMP3 bound CGRP and adrenomedullin. More recently, RAMP1 or RAMP3 were shown to associate with calcitonin receptor to bind amylin. In the present series of studies we demonstrate the CNS distribution of [125I]-CGRP binding sites and compare this with detailed neuroanatomical studies on the molecular localization of CGRP peptide receptors as determined by ISH, and CGRP by immunohistochemistry. These data have important implications for our understanding of this neuropeptide family and its neurophysiological activities.

98 Cocaine and Other Inhibitors of Dopamine Uptake Promote Different Conformational Changes in The Dopamine Transporter M.E.A. Reith, J.L. Berfield, J.V. Ferrer and J.A. Javitch, University of Illinois, College of Medicine, Department of Biomedical and Peoria, IL Differences in the abilities of various dopamine uptake inhibitors and substrates to protect the dopamine transporter (DAT) from alkylation by sulfhydryl reagents have led to the hypothesis that the binding sites for these compounds do not sterically overlap, in turn spurring attempts to develop a cocaine antagonist that does not inhibit dopamine uptake. The recent observation, however, that cocaine increases the reactivity of Cys90 with sulfhydryl reagents and that reaction of this cys potentiates [3H]WIN 35,428 binding fosters caution in the interpretation of protection experiments. We have determined the effects of reaction of DAT with methanethiosulfonate ethyltrimethyl ammonium (MTSET), a posi- tively charged sulfhydryl reagent that reacts preferentially with water-accessible cys. Membrane preparations of HEK-293 cells stably expressing the human DAT were pretreated with various compounds before addition of MTSET; the reagents were removed by multiple centrifugation, and residual ligand binding was determined. With the cocaine analog [3H]WIN 35,428 as radioligand, cocaine and WIN 35,428 protected potently with PC50 s (concentration for half-maximal protection) smaller than their IC50 values for competitive binding. This is consistent with cocaine-induced increased reactivity of Cys90, the reaction of which with MTSET potentiated binding and led to an apparent enhancement in protection. This could explain the increased binding (150-300% of that without cocaine and MTSET) consistently observed at high concentrations of cocaine (3-10 x PC50) sufficient to protect the cys at which MTSET causes a reduction in binding. In the Cys90Ala mutant, the PC50 for cocaine was increased ~200-fold, consistent with loss of the potentiating reaction of Cys90. Other blockers (mazindol, benztropine, BTCP) and substrates (DA, d-amphetamine) were weak protectors of wild type DAT, suggesting that the binding of these compounds does not induce the same conformational changes in Cys90 as do cocaine analogs.

Axons, Dendrites and The Ganglioside Enigma: The Crucial Role of Ca2+ and Nuclear GM1 in Neuronal Differentiation R.W. Ledeen, G. Wu, X. Xie, and Z.-H. Lu, Department of Neuroscience, New Jersey Medical School, Newark NJ Of the several functions attributed to nervous system ganliosides, their role in neuronal differentiation has posed a special enigma. GM1 was shown to be promi- nently expressed in both the nuclear and plasma membranes of primary neurons and neuroblastoma cells undergoing neuritogenesis (Wu et al., J. Neurosci. 15:3739, 1995; Dev. Brain Res. 115:201, 1999). With neuroblastoma cells, upregulation of GM1 in nuclear and plasma membranes was shown to accompany axon-like but not dendrite-like outgrowth (Kozireski-Chuback et al., J. Neurosci. Res. 55:107, 1999). Such axonogenesis is triggered by agents such as KCl and cholera toxin B subunit that elevate cytosolic Ca2+, whereas dendritogenic agents, such as retinoic acid and dibutyryl-cAMP do not affect Ca2+. GM1 modulates Ca2+ flux across

99 the nuclear membrane by facilitating efflux, thus contributing to the reduced level of nuclear Ca2+ that characterizes differentiated neurons. A mutated subclone of NG108-15 (NG-CR72), which lacks GM1 in its plasma and nuclear membranes, was found to extend neurites similar to wild type in response to dendritogenic agents. However, axonogenic agents, which elevate intracellular Ca2+, induced apotosis due to unregulated elevation of nuclear Ca2+. Such apototis could be greatly diminished by treatment of the cells with LIGA-20, a derivative of GM1 that penetrates the plasma membrane and inserts into the nuclear membrane.

Synaptic and Inherent Mechanisms of Temperature Sensitivity in Hypothalamic Neurons J.A. Boulant and P.W. Burgoon. Department of Physiology, Ohio State University, Columbus, OH 43210 The rostral hypothalamus contains both temperature sensitive and insensitive neurons. In the preoptic nucleus (PO), these neurons control several thermoregu- latory responses; and in the nearby suprachiasmatic nucleus (SCN), these neurons may play a role in temperature compensation (and thermosensitivity) of the circadian clock. To understand mechanisms of neuronal thermosensitivity, whole- cell patch clamp recordings examined intracellular activity in PO & SCN neurons in rat hypothalamic tissue slices. Both temperature sensitive and insensitive neurons contain depolarizing prepotentials that determine the interspike interval between action potentials. In temperature sensitive neurons, warming increases the rate of prepotential depolarization; and this shortens the interspike interval, increases firing rate, and is a primary mechanism of neuronal thermosensitivity. A secondary mechanism is associated with GABA synaptic inhibition of temperature sensitive neurons. Warming decreases the resistance of the postsynaptic membrane, and this reduces the amplitude of inhibitory postsynaptic potentials (IPSPs). The resulting increase in firing rate contributes to neuronal thermosensitivity. In some SCN neurons, however, temperature also affects IPSP frequencies. An increase in IPSP frequency with warming allows some neurons to maintain a relatively constant firing rate during changes in temperature. This thermally-adjusted change in synaptic frequency may provide a mechanism for temperature compensation in the SCN control of circadian rhythm. (Supported by NIH grant NS14644.)

Chronic Hypercortisolemia Inhibits Dopaminergic Activity in The Nucleus Accumbens But Not in The Prefrontal Cortex K. Pacak, O. Turmina, M. Palkovits, D. S. Goldstein, C. A. Koch, P. Goldsmith, G. P. Chrousos, National Institutes of Health, Bethesda, Maryland 20892 Substantial clinical evidence supports a strong link between chronic hypercortisolemia and depression. Over 60% of patients with Cushing syndrome suffer from depression, while over 50% of patients with depression have hypercortisolism. Dopamine (DA) depletion in the nucleus accumbens and caudate nucleus occurs in animals with learned helplessness, an animal model of

100 depression. This study examined whether chronic (7 days) hypercortisolemia inhibits dopaminergic activity in the nucleus accumbens and the prefrontal cortex. Microdialysis was used to measure interstitial concentrations of DA and its metabolites. By measuring dialysate concentrations of dihydroxyphenylalanine (DOPA) after local perfusion with 3-hydroxybenzylhydrazine dihydrochloride (NSD-1015), we also assessed whether chronic hypercortisolemia decreased dopamine biosynthesis. Cortisol (25 mg/kg/day) was infused s.c. for 7 days via osmotic minipump. Chronic hypercortisolemia markedly decreased extracellular levels of dopamine in the nucleus accumbens but not in the prefrontal cortex. DOPA accumulation after NSD-1015 was markedly decreased in the nucleus accumbens in cortisol-treated than in saline-treated animals. The present study suggests that chronic hypercortisolemia inhibits DA activity in the nucleus accumbens and influences, thus, a major component of the reward system. This may explain the depression observed in Cushing syndrome and normalization of the affect after correction of hypercortisolism.

TAU Distribution in A Transgenic That Expresses The Entire TAU Gene On A Knockout Background, A Potential Model For Neurofibrillary Tangle Formation M. P. Vitek, L. I. Binder* and H. N. Dawson, OSV and Duke University Medical Center, Durham, NC and *Northwestern University Medical Center, Chicago, IL Neurofibrillary tangles (NFTs) are significantly associated with neuronal loss in Alzheimer s disease. These tangles consist of bundles of twisted pairs of helical filaments (PHFs). Filaments consist of the microtubule associated protein known as TAU, which has aggregated into an ordered fibrillar structure. Patients with Frontal Lobe Dementia display massive numbers of NFTs which are associated with the presence of mutated TAU genes. Since wild type mice fail to spontane- ously display NFT pathology, we have created TAU knockout mice. Since transgenic mice expressing single human Tau protein isoforms fail to spontane- ously display NFT pathology, we have created a transgenic mouse that includes the entire 200 kBp human TAU gene. By combining these two, we have generated a human TAU gene-transgenic on a homozygous TAU knockout background. Our preliminary characterizations show that at least 6 human Tau mRNA isotypes are expressed in the brains of these animals. Using a variety of antibodies, multiple Tau protein isoforms are also expressed. Using a variety of anti-Tau antibodies, we are currently evaluating the distribution of Tau epitopes in wild-type, homozgyous knockout and gene-transgenic/homozygous knockout mouse brains. Additional efforts are ongoing to characterize transgenics expressing mutated TAU genes in a combined effort to generate a mouse that displays neurofibrillary tangle pathology.

101 Chronic PCP Administration As A Model of Schizophrenia: Effects On Cortical and Subcortical Dopaminergic Function A. Balla, H. Sershen and D.C. Javitt Nathan S. Kline Institute, Orangeburg, NY 10962 Phencyclidine (PCP) and other NMDA receptor antagonists cause cognitive impairments and perceptual changes in humans similar to those observed in schizophrenia. In rodents, PCP induces cognitive disruptions, stereotypy and impairments in social behavior, along with locomotor hyperactivity which are mediated at least in part via dysregulation of mesolimbic/mesocortical dopamine systems. The majority of studies with PCP have analyzed effects following acute administration. The present study was performed to evaluate changes in dopaminergic functioning in rodents following chronic PCP administration. Sprague-Dawley rats were treated with PCP (5, 10, 15, 20 mg/kg/day) via ALZET osmotic pumps for 2-3 weeks. Spontaneous (night-time) and amphetamine (1 mg/kg s.c.)-induced activity was measured prior to and following chronic PCP administration. Dopamine and dopamine metabolite levels were determined by in vivo microdialysis and LC-EC. The spontaneous night-time activity was not altered by PCP. Amphetamine (1 mg/kg.)-induced locomotor activity was significantly enhanced in a dose-dependent fashion following PCP. Significant potentiation of amphetamine-induced effects on DA and DOPAC levels were observed in frontal cortex and striatum. In accumbens shell, no increase in dopamine release was observed. However, amphetamine-induced reductions in DOPAC levels were significantly enhanced. Schizophrenia has been shown to be associated with increased striatal responsivity to amphetamine challenge. The present study demonstrates that similar effects are observed following chronic PCP administration, supporting PCP/NMDA models of the disorder.

Neurotrophin Regulation of CaMKIIa mRNA Localization To Dendritic Filopodia and Spines M.M. Martinez, A.L. Byrd, S.M. Shenoy, M.P. Plociniak, R. H. Singer, and G. J. Bassell, Albert Einstein College of Medicine, New York, NY The localization of specific mRNAs near synapses is believed to play a major role in synaptogenesis and synaptic plasticity. This hypothesis is based on observations that polyribosomes are concentrated at synapses and that new protein synthesis is required for various forms of long term plasticity. However, there has been no direct evidence for the subsynaptic localization of specific mRNAs which encode proteins that mediate long term plasticity. Part of the difficulty has been the lack of suitable methods to visualize specific mRNAs at high resolution within dendrites. We have applied high resolution fluoresence in situ hybridization and digital imaging methods, which were developed in our laboratory (J. Neuroscience 1998, 18:251; J. Cell Biology 1999, 147:59), to visualize dendritic mRNAs. Spe- cific dendritic mRNAs were observed to have distinct distribution patterns, with some mRNAs showing an enrichment within spines. Calcium/calmodulin dependent protein kinase IIa (CaMKIIa) mRNAs were localized to spines and subsynaptic sites in the form of RNA granules. The localization of CaMKIIa

102 mRNA granules into dendrites and spines was stimulated by the neurotrophins, NT-3 and BDNF. The rapid localization of CaMKIIa mRNAs occurred prior to an increase in CaMKIIa mRNA levels suggesting a change in the distribution of pre-existing mRNA. At the ultrastructural level, NT-3 stimulated the localization of polyribosomes to both dendritic filopodia and spines. NT-3 treatment also induced the formation of filopodia and synaptic contacts suggesting that local synthesis of synaptic components may stabilize newly formed synapses and provide a regulated mechanism to influence synaptic architecture and strength.

Plasticity in Barrel Cortex Over The Lifespan F. Ebner. Kennedy Center-IDN. Vanderbilt University. GPC. Box 152. Nashville TN The rate of activity-dependent synaptic plasticity can be measured in rat S1 cortex by short periods of whisker trimming from roughly 1 week after birth to the end of the natural life span. The rate at which plasticity occurs is altered by many events, esp. 1) age and 2) environmental stimulation. We assay plasticity by quantifying the changes in cortical cell discharge induced by trimming all but 2 whiskers on one side of the face (called whisker pairing or WP). After trimming whiskers for 3 to 7 days the changes are assayed under urethane anesthesia by recording single cell responses to test stimuli. The baseline for the effect of WP on the principal (PW) and surround (SW) whiskers is taken at 2-3 months after birth when cortical development is complete in rats, and at this time SW plasticity occurs in <1 day and PW plasticity by 3 days. At 1 year of age the rate of plasticity does not change significantly, but after 2 years of standard lab conditions SW plasticity requires >3 days. A similar failure to develop normal plasticity rates is seen after sensory deprivation produced by trimming all whiskers on one side from P0 to P30 and then letting them regrow for the next 2 months. Several lines of evidence suggest that this type of delay in plasticity is strongly correlated with decreases in NMDA receptor function and/or decreased cholinergic modulation of cortical excitability, both of which raise the threshold for activity-dependent synaptic modification. (supported by NS 25907)

Attention Modulates Synchronized Neuronal Firing in Primate Somatosensory Cortex P. Steinmetz. Computation & Neural Systems. Caltech. MS 139-74. 1200 E. California Blvd. Pasadena CA A. Roy, P. Fitzgerald, S. Hsaio, E. Niebur, Zanvyl Krieger Mind/ Brain Institute. Johns Hopkins University. 3400 N. Charles St., Baltimore MD Temporal patterns of neuronal firing, such as oscillations or synchrony, have been reported in cortical and subcortical parts of the brain. These patterns have been interpreted as representing sensory input or motor output; for instance, it has been proposed that synchronized oscillations bind different sensory components of an odorant or different parts of a visual object. Here we report two findings concerning synchronous firing between pairs of neurons in rhesus somatosensory cortical area SII. The first is that a majority of such neuron pairs fire synchronously while the animal performs a tactile or visual discrimination

103 task. The second, and more important finding, is that the degree of synchrony of many neuron pairs covaries with the animal s focus of attention. Of three tactile tasks examined, the task with a random change of target is accompanied by a greater change in the degree of synchrony (32% of pairs change) than are two other tasks which require performance of a fixed set of discriminations on each trial (10% of pairs change). For the task with a random target change, 81% of pairs with a change in synchrony increase the level of synchrony when attention is directed to the tactile task. These changes in synchrony are consistent with previous computational models and suggest that synchronous neural firing plays a role in attention.

Abnormalities of Neuronal Endocytosis As A Basis For Increased ß- amyloidogenesis In Sporadic Alzheimer’s Disease Anne M. Cataldo, Paul M. Mathews, Panaiyur Mohan, Carolyn B. Guerra, Ying Jiang, Corrinne Peterhoff, Ralph A. Nixon.* Nathan Kline Institute, New York University School of Medicine, Orangeburg, NY, USA 10962 The fate or function of etiologically important molecules in AD pathogenesis, including amyloid precursor protein (APP), A§, and apolipoprotein E (Apo E)are closely tied to the process of endocytosis. We showed that neuronal endocytosis is specifically altered in AD brain as reflected in marked enlargement of rab5- positive early endosomes (EE) and increased expression of positive effectors of endocytosis. We now find that endocytic alterations precede any other AD-related neuropathologic lesions, are prominent at preclinical stages of disease, and, appear in juvenile Down syndrome decades before §-amyloid deposition. Inher- itance of an Apo E4 allele accentuates the endocytic response. Trafficking of l ysosomal proteases to EE is also increased in AD brain as a result of elevated expression of these proteases and the cation-dependent mannose-6-phosphate receptor (CD-MPR). To determine whether increased levels of lysosomal hydrolases in EE alters APP processing, we overexpressed APP alone and in combination with CD-MPR in cell lines. We also expressed CD-MPR constructs with modified carboxy-termini that preferentially traffic hydrolases to EE (CD- MPRendo) or to the plasma membrane (CD-MPRpm). Secretion into the growth media of A§ 1-40 and A§1-42 was increased 3-fold in the lines expressing CD- MPR and CD-MPRendo when compared to the parental APP or CD-MPRpm lines. These results are consistent with a model in which changes in the expression and delivery of lysosomal hydrolases to EE contribute to A§ generation in SAD and DS. Supported by NIA (AG05134,AG08278).

Identification of Transcription Factors Developmentally Regulated in Embryonic Cerebral Cortex D.B. Campbell and P. Levitt; University of Pittsburgh School of Medicine. The mammalian cerebral cortex develops from a mass of apparently homog- enous proliferative cells in the embryonic ventricular zone into a structure with numerous distinct functional regions in the adult. How such functional diversity is established in the adult neocortex is as yet unclear. To identify genes differen-

104 tially expressed in developing cerebral cortex, we used subtractive differential display on late embryonic cortex divided into three regions: frontal, somatosensory, and occipital. This approach succeeded in identifying four known genes expressed either more or less abundantly in somatosensory cortex compared to frontal and occipital regions. The identified genes encode three transcription factors: Net, Rho GTPase-activating protein (RhoGAP) p190, and c-myc intron 1 binding protein (MIBP1). The differential expression of transcription factors is particularly interesting due to the central role of these proteins in establishing gene expression patterns during development. In situ hybridization experiments revealed: (1) a dramatic peak of cortical mRNA expression of all three transcription factors at embryonic day (E) 11.5; (2) frontal- and occipital cortex-specific expression of RhoGAP p190 mRNA at E15.5; and (3) somatosensory cortex- specific expression of MIBP1 mRNA at E16.5. Extra-cortical signaling appears to be required for the E11.5 peak of MIBP1 expression as cortical explants cultured at E10.5 did not express MIBP1 mRNA after 24 hours in vitro. Further manipulation of the expression of these transcription factors promises to elucidate fundamental processes involved in the development of the mammalian cerebral cortex.

A Putative 5-HT6 Receptor Antagonist Facilitates Amphetamine-Induced Locomotion Frantz, K. J., Hansson, K. J., Parsons, L. H.Department of Neuropharmacology, The Scripps Research Institute, 10550 N. Torrey Pines Rd. La Jolla, CA 92037. Serotonin 6 receptors have recently received a good deal of attention based on the high affinity of atypical antipsychotic agents for this site. The high density of markers for 5-HT6 receptors in the nucleus accumbens, frontal cortex, hippocampus, olfactory tubercle, caudate-putamen and substantia nigra suggests the involvement of 5-HT6 receptors in psychotic disorders, as well as reward-related behaviors and motor activity. Yet little is known about this receptor subtype and its actual behavioral function. The present study was designed to characterize the effects of a novel 5-HT6 receptor antagonist on motor behavior, including amphetamine-induced locomotion, rearing, and grooming. Male Wistar rats were injected with SB 258510A (0, 1 or 3 mg/kg, i.p.), and placed immediately into a novel environment. Thirty min later, rats were injected with amphetamine (0 or 1 mg/kg, i.p.) and placed back into the same cages. Each rat was tested only once. Locomotor activity was recorded as the interruption of photocell beams and was analyzed in 10 min intervals during a 2.5 h session. Rearing and grooming were recorded by an observer who was blind to the drug condition. The high dose of this 5-HT6 receptor antagonist dramatically increased the duration of amphetamine-induced locomotion. SB 258510A alone did not alter any recorded motor behavior. Nor did any of the drug conditions induce motor stereotypies. These data indicate that 5-HT6 receptors may normally serve as a negative feedback mechanism on psychostimulant-induced behaviors. Investigations of the role of the 5-HT6 receptor in psychostimulant self-administration are in progress.

105 A Functional Dopamine D2 Receptor Modulator With Potential Unique Antipsychotic Properties K.A.Svensson, N. Waters*, K. M. Merchant, M.F.Piercey, C. Sonesson*, L.Svensson*, J. Tedroff#, J.A. Engel* and A. Carlsson Neurobiology Research, Pharmacia & Upjohn, Kalamazoo, MI. *Dept of Pharmacololgy Univ. of Goteborg and #Dept of Neurology Univ of Uppsala, Sweden S-(-)-3-(3-methylsulphonyl-phenyl)-N-n-propylpiperidine, OSU6162, is a dopamine D2 receptor ligand (Ki = 447 nM) with unique behavioral stabilizing properties. In contrast to most antipsychotics, OSU6162 fails to alter normal explor- atory activity in rats while it readily antagonizes the hyperactivity induced by d- amphetamine. When administered to animals that are habituated to their environment, OSU6162 will increase motor activity to about 400% of controls. Thus, OSU6162 appears to possess behavioral stabilizing properties which strongly depend upon the animal s baseline activity. Additional support for antipsychotic potential include a preferential elevation of c-fos expression in the medial prefrontal cortex. Also, OSU6162 clearly antagonized the increase in 2-deoxyglucose utilization produced by both d-amphetamine and phencyclidine (PCP), particularly in the prefrontal cortex area of the rat brain. OSU6162 also blocked PCP- induced disruption of prepulse-inhibition; another indication of potential antipsychotic action. In vivo neurochemical studies with OSU6162 in the rat reveal antagonistic properties with increases in both synthesis release and metabolism of dopamine. In summary, our data suggests that OSU6162 may possesses unique antipsychotic properties with minimal side effect potential.

Behavioral Pharamcology of Selective Dopamine D3 Receptor Antagonists Susanne R. Haadsma-Svensson, Kerry A. Cleek, William H. Darlington, J. Neil Duncan, C.A. Haber, Rita M. Huff, Jeffery A. Leiby, Robert .B. McCall, Nan.F. Nichols, Arthur G. Romero, Martin W. Smith, Kjell A. Svensson, Chiu-Hong Lin. Pharmacia & Upjohn, Kalamazoo, MI 49007.

The dopamine D3 receptor is a target for the development of novel antipsychotics with improved efficacy and side-effect profile. The recent interest in this receptor is related to the role the neurotransmitter dopamine plays in the etiology of schizophrenia and the localization of this receptor in brain areas associated with cognitive and emotional functions. The selective dopamine D3 receptor antagonist PNU-99194A (5,6-dimethoxy-2-dipropylaminoindan) produces behavioral activation in habituated rats at doses that do not affect dopamine synthesis or release. This, and other findings, has led to the hypothesis that the functional D3 receptor is postsynaptically located where it exerts an inhibitory function on psychomotor activity. We have recently studied a series of structural analogs of PNU- 99194A and the results confirm our initial findings. These compounds differ pro- foundly in their behavioral effects in rodents when compared to classical D2 receptor antagonists. Our findings indicate that these compounds may treat schizophrenia, in particular negative symptoms.

106 Catecholaminergic Modulation of Calcium Currents in Rat Amygdaloid Pyramidal Neurons R.C.Foehring. Dept. of Anatomy and Neurobiology,Univ. of Tenn., Memphis, TN 38163 The amygdaloid nuclei comprise a forebrain structure important inthe regulation of emotions (especially fear), including the emotional aspects of learning and memory. Through connections with the nucleus accumbens and striatum, the amygdaloid nuclei may also influence the emotional aspects of tics and vo- calizations characteristic of Tourette Syndrome. Catecholamines (dopamine: DA; norepeineprine: NE) are also implicated in fear learning and Tourette syndrome. We are studying the effects of DA and NE on ion channels in amygdaloid pyramidal neurons to gain insight into the role of intrinsic biophysical properties in the regulation of pyramidal cell activity, and thus amygdaloid output. Due to the Ca2+-dependence of pyramidal cell firing behavior, our initial studies are of Ca2+ currents. We found that both NE and DA reduced current through high-voltage activated (HVA) Ca2+ channels in a biphasic manner. Both transmitters modulated currents elicited with action potential waveforms or voltage steps. For NE, the initial rapid component of the modulation was mediated by a2 receptors, involved N- and P/Q-type channels, and was voltage-dependent. The slower component was mediated by b receptors and was voltage-independent. DA also reduced current via fast and slow pathways. The fast pathway was voltage-dependent and the slow pathway was not. Supported by NS33579 and a grant from the Tourette Syndrome Foundation.

Activation of 5-HT1b Receptors in The VTA Potentiates Cocaine- Induced Elevations of DA Levels in The NAcc O Dell L.E. and Parsons L.H. The Scripps Research Institute, Department of Neuropharmacology, 10550 N. Torrey Pines Rd., La Jolla, CA 92037

Recent work from our laboratory suggests that serotonin1B (5-HT1B) receptor stimulation enhances both the reinforcing properties of cocaine and cocaine- induced increases in dopamine (DA) levels in the nucleus accumbens (NAcc). Moreover, preliminary evidence suggested that these effects are mediated in part by 5-HT1B receptors in the A10 DA cell body region (VTA). The present study was designed to directly test the involvement of 5-HT1B receptors in the VTA in modulating DA levels in the NAcc. Microdialysis probes were implanted into the NAcc and ipsilateral VTA. The next day, dialysate samples were collected every 10 min from both probes during 1) a 60-min baseline period, 2) a 20-min period during which either vehicle or the selective 5-HT1B agonist CP 93,129 (100 _M) was delivered through the VTA probe, and 3) a 90-min period following systemic administration of cocaine (10 mg/kg). Preliminary results indicate that cocaine-induced elevations in NAcc DA levels are potentiated by 5-HT1B receptor activation in the VTA. Ongoing analyses are examining dialysate GABA levels from the VTA to determine whether activation of 5-HT1B receptors in the VTA inhibits GABA transmission in this region, thereby producing the facilitation of DA release in the NAcc.

107 Modulation of Localization and Function of PKC Targeting Protein RACK1 by Ethanol and cAMP D. Ron, A.J. Vagts, R. Yaka, The Ernest Gallo Clinic and Research Center and Department of Neurology, University of California San Francisco, San Francisco, CA 94100 USA Compartmentalization of signaling proteins such as kinases is important for their function. Targeting proteins are involved in compartmentalization of signaling proteins and play an important role in the regulation of signal transduction cascades. Protein kinase C (PKC) is a family of ten isozymes that translocate upon activation from one intracellular site to another. Targeting of the translocated isozymes is mediated at least in part by RACKs (Receptors for Activated C Ki- nase). RACK1 is the targeting protein for activated betaIIPKC. We recently found that RACK1 is a translocating protein that shuttles betaIIPKC to its appropriate site. Here we show that ethanol and cAMP induce RACK1 to move to the nucleus in three cells lines. This nuclear localization of RACK1 is different from the site to which RACK1 translocates upon PKC activation. betaIIPKC localization is not affected by ethanol or cAMP. In contrast, we found that when RACK1 is localized to the nucleus, activation-induced betaIIPKC translocation is inhibited, presumably because RACK1 is not available for shuttling betaIIPKC. Simi- lar results were obtained in vivo. We found that in the CA2/CA3 region of the hippocampus, chronic ethanol treatment induced an increase in RACK1 localization to the nucleus, whereas neither treatment affected the localization of betaIIPKC. Supported by funds from the State of California.

Spatially Distant Neurons in the Basal Ganglia Can Demonstrate Correlated Multisecond Periodicities in Firing Rate in Vivo David N. Ruskin, Debra A. Bergstrom and Judith R. Walters, Experimental Therapeutics Branch, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD Previous studies from our laboratory have shown that many neurons in the basal ganglia have multisecond (<0.5 Hz) periodicities in firing rate in awake rats. The period and power of these oscillations are modulated by systemically-injected dopamine (DA) agonists. Since oscillatory activity should have greater functional effects if shared by many neurons, we assessed the correlation of multisecond periodicities by recording spatially distant pairs of neurons in pallidal basal ganglia nuclei (globus pallidus, entopeduncular nucleus, substantia nigra). Both inter- and intrahemispheric pairs were recorded. Cross-correlation (90—180 s lag) and spectral analysis were used to characterize coincident slow activity. 21 neuron pairs were recorded during normal (baseline) conditions. 8 of these pairs (38%) had cross-correlograms indicating coincident slow periodicities. Oscilla- tory periods ranged from 7 to 48 s in different pairs. These 8 neuron cases included both inter- and intrahemispheric pairs. DA agonists (e.g. apomorphine or quinpirole) were injected systemically during the recording of 9 neuron pairs. Of

108 these cases, coincident multisecond oscillations were found in 5 pairs (56%). Phase relationships of multisecond periodicities varied between cases and conditions, but most were near 0 or 180 degrees. The data demonstrate that multisecond oscillatory activity in the basal ganglia can be correlated even in widely sepa- rated neurons, suggesting that correlation arises from distributed network mechanisms. The data also suggest that DA agonists increase the level of correlation of slow oscillations, and modulate their period and power. Coincident slow oscillations in basal ganglia neurons should strongly impact firing patterns of neurons in target nuclei. Changes in the parameters of slow oscillations may relate to the abnormal behaviors produced by systemic DA agonist treatment.

Don’t forget to visit the exhibit area.

109 110 111 112 113 114 115 116 117 118 119 120 Index/Participant List Elizabeth Abercrombie Neil Aronen Rutgers University University of Massachusetts Medical [email protected] Center [email protected] James Adams — 96 USC School of Pharmacy David Arthur [email protected] Duke University Medical Center [email protected] Greti Aguilera — 76 National Institutes of Health Gary Aston-Jones — 62, 68 [email protected] University of Pennsylvania [email protected] Elias Aizenman — 80 University of Pittsburgh School of Susan Bachus — 41 Medicine CBDB NIMH NIH [email protected] [email protected]

Elliott Albers — 88 Ruben Baler — 79 Georgia State University National Institutes of Health [email protected] [email protected]

George F. Alheid — 71 Andrea Balla — 102 Northwestern University Nathan S. Kline Institute [email protected] [email protected]

Andrea Allan — 56 Krzysztof Bankiewicz — 70 University of New Mexico-HSC National Institutes of Health [email protected] [email protected]

Florin Amzica — 54 David Barker — 57 Laval University Molecular Dynamics-AP Biotech [email protected] [email protected]

Rodrigo Andrade Robert Barlow — 35 Wayne State University School of Suny Health Science Center Medicine [email protected] [email protected] George Bartcokis Kristin Anstrom — 80 CAUHS Wake Forest University [email protected] [email protected] Raymond Bartus A. Vania Apkarian — 45 Alkermes, Inc. SUNY Health Science Center at Syracuse [email protected] [email protected] George Bartzokis Margie Ariano — 36 University of Arkansas for Medical UCLA Sciences [email protected] [email protected]

121 Allan Basbaum — 46 Shari Birnbaum — 42 University of California San Francisco Yale University [email protected] [email protected]

Anthony Basile — 44, 47, 57 Jed Black — 30 National Institute Health Stanford University [email protected] [email protected]

Gary Bassell Murray Blackmore Albert Einstein College University of Minnesota [email protected] [email protected]

Steven L. Bealer Kim Blackwell — 97 University of Tennessee George Mason University [email protected] not available

Joseph Beckman — 76 Danny Bodeker University of Alabama at Birmingham Pharmacia & Upjohn,Inc. [email protected] [email protected]

Katia Befort — 38 Martha Bohn — 70 Massachusetts General Hospital Children s Memorial Institute for [email protected] Education [email protected] Margery Beinfeld Tufts University School of Medicine Stephen Bondy [email protected] University of California, Irvine [email protected] Alim Louis Benabid — 74 Joseph Fourier University Jack Boulant — 100 [email protected] Ohio State University [email protected] Michael V.L. Bennett Albert Einstein College of Medicine Charles Bradberry — 37 [email protected] Yale School of Medicine [email protected] Hagai Bergman — 27, 68 The Hebrew University Hans Albert Braun — 30 [email protected] University of Marburg [email protected] Craig Berridge — 62 University of Wisconsin Dale Bredsen — 54 [email protected] Buck Center for Research in Aging [email protected] Joseph Besharse — 35 Medical College of Wisconsin P. J. Brooks — 32 [email protected] NIAAA-NIH [email protected] Mark Bevan — 27 [email protected] Gerald Brown University of Virginia Llewellyn Bigelow — 55 [email protected] National Insitute of Mental Health [email protected]

122 Michael Browning — 69 William A. Catterall University of Colorado Health Sciences University of Washington Center [email protected] [email protected] Leo Chalupa John Bruno — 43 University of California Davis The Ohio State University [email protected] [email protected] David Chambers — 38 Vivian Budnik — 58 King s College London University of Massachusetts [email protected] [email protected] Paul Chapman — 63 Christian Buechel — 62 Cardiff University Wellcome Department of Cognitive [email protected] Neurology Wei Chen — 51 [email protected] Yale University William Bunney, Jr. — 50 [email protected] University of California, Irvine Mitchell Chesler — 67 [email protected] New York University School of Medicine Robert Burke — 40 [email protected] Columbia University Dennis Choi — 44 [email protected] Washington University School of Maria Bykhovskaia — 90 Medicine University of Virginia [email protected] [email protected] Michael Chopp Carmen Canavier — 30 Henry Ford Hospital University of New Orleans [email protected] [email protected] James C-Y Chou — 94 Bill Carlezon — 60 Nathan Kline Institute Harvard Medical School [email protected] [email protected] Carson Chow — 30 Susan Carlton — 78 University of Pittsburgh University of Texas Medical Branch [email protected] [email protected] Julius Cinque Marilyn Carroll — 53 National Institutes of Health University of Minnesota [email protected] [email protected] Vicki Coffin Hector Juan Caruncho — 48 CNS CV Phar macological University of Santiago De Compostela [email protected] [email protected] Ian Colrain — 30 Jos Castr o-Lopes — 94 Stanford University University of Porto [email protected] [email protected]

123 Carol Colton — 80 Claude de Montigny — 42 Georgetown University Medical School McGill University [email protected] [email protected]

Jeffrey Conn Jean de Vellis Emory University School of Medicine University of California Los Angeles [email protected] [email protected]

Andrew Copp — 33 Taco De Vries — 58 University of London Research Institute Neurosciences Vrije [email protected] University [email protected] Carmine Coscia — 65 St. Louis University School of Medicine Philippe De Witte — 53 [email protected] University of Lourain [email protected] Erminio Costa — 48 Psychiatric Institute University of Illinois Elizabeth Debski — 50 at Chicago University of Kentucky [email protected] [email protected]

Michael Costigan — 38 Gregory Del Zoppo — 44 MGH and Harvard Medical School Scripps Research Institute costigang.helix.mgh.harvard.edu [email protected]

Joseph Coyle — 41, 61 Mahlon DeLong — 74 Harvard Medical School Emory University [email protected] [email protected]

Benjamin Cravatt — 47 Timothy DeLorey — 74 The Scripps Research Institute Molecular Research Institute [email protected] [email protected]

Fulton Crews Victor Denenberg University of North Carolina at Chapel University of Connecticut Hill [email protected] [email protected] Rolf Dermietzel Kathryn Cunningham — 77 University of Bochum University of Texas Medical Branch [email protected] [email protected] Alain Destexhe — 54 Mauro Dal Canto Laval University Northwestern University Medical School [email protected] [email protected] Lakshmi Devi — 29 Beverly Davidson — 32 New York University School of Medicine Univeresity of Iowa [email protected] [email protected] Marian Difiglia — 36 Duff Davis — 48 Massachusetts General Hospital Parke-Davis Co. [email protected] [email protected]

124 Dennis Dixon Matthew Ennis — 51 Mayo Clinic University of Maryland School of [email protected] Medicine [email protected] Sean Donevan — 29 Parke-Davis Research Douglas Epstein — 65 [email protected] University of Pennsylvania [email protected] Sylvain Dore — 64 Johns Hopkins University/ School Michael Espey — 80 Medicine National Institutes of Health [email protected] [email protected]

Paula Dore-Duffy — 79 Carolyn Fairbanks — 78 Wayne State University School of University of Minnesota Medicine [email protected] [email protected] Conor Farren — 81 Richard Dorin — 76 Mount Sinai School of Medicine Alburquerque VA Medical Center [email protected] [email protected] James Fawcett — 47, 50 Daniel Dorsa University of Cambridge University of Washington School of [email protected] Medicine Jan Fawcett [email protected] Rush-Presbyterian-St. Luke s Medical Tom Dunwiddie — 31 Center University of Colorado [email protected] [email protected] Howard Feit Linda Dwoskin Henry Ford Hospital University of Kentucky [email protected] [email protected] Christian Felder — 47 Jim Eberwine — 57, 81 Eli Lilly and Company Univ. of Pennsylvania Med. School [email protected] [email protected] Charles ffrench-Constant — 35 Ford Ebner — 103 University of Cambridge Vanderbilt University [email protected] [email protected] David Fink — 32 Dale Edgar — 62 University of Pittsburgh Stanford University [email protected] [email protected] Paul Fletcher — 62 Lisa Ellerby — 54 Heinrich-Heine Universitat Buck Center for Research in Aging [email protected] [email protected] Francis Flynn — 67 Helene Emsellem — 30 University of Wyoming The Center for Sleep & Wake Disorders [email protected] [email protected]

125 Bob Foehring — 107 Don Gash University of Tennessee-Memphis University of Kentucky [email protected] [email protected]

Peter Fox — 38 Samuel Gatley — 44 University of Texas Health Science Ctr Brookhaven National Laboratory [email protected] copy: [email protected] [email protected] G.F. Gebhart — 64, 72 Donald Franz University of Iowa University of Utah [email protected] [email protected] Scott Gehler Nigel Fraser University of Minnesota U. Penn Med School [email protected] [email protected] Herbert Geller — 47 Curt Freed Robert Wood Johnson Medical School University of Colorado Health Sciences [email protected] Center Claude Genain — 57 [email protected] Univeresity of California San Francisco Lloyd Fricker — 29 claudeg@ Albert Einstein College of Medicine Greg Gerhardt — 48 [email protected] University of Kentucky Denson Fujikawa [email protected] VA Greater IA Healthcare System/UCLA M. Felice Ghilardi — 85 [email protected] Columbia University Harold Gainer — 79 [email protected] NIH Sarah Gibbs — 70 [email protected] University of California Karen Gale — 56, 74 [email protected] Georgetown University John Glowa — 37 [email protected] LSUMC-S Vasco Galhardo — 45 [email protected] University of Porto James Goldman — 35 [email protected] Columbia University Telly Galiatsatos [email protected] Instrutech Corp Daniel Goldowitz — 36 [email protected] University of Tennessee Gianluca Gallo — 70 [email protected] U. of Minnesota Franz Goller — 73 [email protected] University of Utah Eliot Gardner — 71 [email protected] Albert Einstein College of Medicine John Grabowski — 37 [email protected] Univ of TX Houston Health Sci Ctr [email protected]

126 Irwin Greenberg Edward Hall — 76 Pharmacia & Upjohn Parke-Davis Pharmaceutical Research [email protected] [email protected]

Robert Greene — 31 John Hallenbeck — 44 Harvard Medical School VA Medical NINDS Center [email protected] [email protected] Mark Hamblin Bill Greenough — 81 U. Washington, Seattle VAMC Univ. Illinois, Urbana-Champaign [email protected] [email protected] Donna Hammond — 74 Ralph Greenspan — 48 University of Chicago The Neurosciences Institute [email protected] [email protected] Philip Hanawalt — 32 Charles Greer — 51 Stanford University Yale University School of Medicine [email protected] [email protected] Ingeborg Hanbouer — 48 Karen Greif National Institute of Health Bryn Mawr College [email protected] [email protected] David R. Harder — 80 Sue Griffin — 52, 72 Medical College of Wisconsin UAMS/Central Ark Veterans Healthcare [email protected] System Sami Harik [email protected] University of Arkansas, College of Leslie C. Griffith — 58 Medicine Brandeis University [email protected] [email protected] Neil Harrison — 60 Chistina Grobin — 91 Cornell University University of North Carolina at Chapel [email protected] Hill Teresa Hastings [email protected] University of Pittsburgh Robert Gross — 74 [email protected] University of Utah Robert Hayes — 92 [email protected] Albert Einstein College of Medicine Jim Gurd — 42 [email protected] University of Toronto at Scarborough Johannes Hell — 37 [email protected] University of Wisconsin Susanne Haadsma-Svensson — 106 [email protected] Pharmacia & Upjohn Fritjof Helmchen — 69 [email protected] Lucent Technologies, Bell-Labs Kurt Haas — 50 [email protected] Cold Spring Harbor Labs [email protected]

127 Hugh Hemmings — 60 Kim Huhman — 84 Cornell University Georgia State University [email protected] [email protected]

Fritz Henn — 62 Elaine Hull — 53 Central Institute of mental Health SUNY at Buffalo [email protected] [email protected]

Neal Hessler Thomas Hyde University of California at San Francisco National Institute of Mental Health [email protected] [email protected]

Shaul Hestrin — 54 Mary Hynes — 65 University of Tennessee, Memphis Genertech Inc [email protected] [email protected]

David Hill — 67 Janis Ingham University of Virginia University of California, Santa Barbara [email protected] jcingham

Argye Hillis — 78 Roger Ingham — 38 Johns Hopkins Hospital University of California, Santa Barbara [email protected] jcingham

Susan Hockfield — 35 Donald Ingram — 52 Yale University National Institute on Aging [email protected] [email protected]

Bart Hoebel — 53 Thomas Insel — 76 Princeton University Emory University [email protected] [email protected]

Klaus-Peter Hoffmann — 39 Philip Iredale — 89 Ruhr-Universtity Bochum Pfizer [email protected] [email protected]

Gregg Homanics — 74 Ehud Isacoff — 48 University of Pittsburgh UC Berkeley [email protected] [email protected]

Paul Huang Michael Iuvone — 35 Massachusetts General Hospital Emory University [email protected] [email protected]

Richard A. Hughes — 28 Russell Jacobs Iowa State University California Institute of Technology [email protected] [email protected]

John Huguenard — 74 Mark Jacquin Stanford University Washington University School of [email protected] Medicine [email protected]

128 Patricia Janak — 80 Rolf Karlstrom — 65 National Institute on Drug Abuse University of Massachusetts [email protected] [email protected]

Aaron Janowsky — 27 Harvey Karten — 28 V. A. Medical Center University of California San Diego [email protected] [email protected]

George Jaskiw Donald Katz — 45 Cleveland Veterans Affairs Medical Duke University Center [email protected] gxj52PO.CWRU.EDU Paul Katz Luc Jasmin — 46 Georgia State University Georgetown University [email protected] [email protected] Kristen Keefe — 56 David Johns — 79 Univ. of Utah Johns Hopkins School of Medicine [email protected] [email protected] Edward Keller — 39 Alan Kim Johnson Smith Kettlewell Eye Research Institute University of Iowa [email protected] [email protected] Ann Kelley — 80 Elizabeth Jonas — 33 University of Wisconsin-Madison Yale University [email protected] [email protected] Max Kelz — 79 Reese Jones Yale University University of California San Francisco [email protected] [email protected] Andrew Kertesz — 78 Richard Jones University of W Ontario Portland VA Medical Center [email protected] [email protected] Milan Kesler James Joseph — 52, 72 Instrutech Corp USDA Human Nutrition Res. Ctr on [email protected] Aging James Kew [email protected] F. Hoffmann-La Roche Ltd. Leonard Kaczmarek [email protected] Yale University School of Medicine Stanislav Kholmanskikh [email protected] University of Minnesota Edward Kaftan — 33 [email protected] University of Washington Harold Kimelberg — 67 [email protected] Albany Medical College Katherine Kalil [email protected] University of Wisconsin Madison [email protected]

129 Andrew King — 75 Jeffrey Kordower — 70 University of Oxford Rush Presbyterian Medical Center [email protected] [email protected]

Anne King — 40 Conan Kornetsky University of Leeds Boston University School of Medicine [email protected] [email protected]

Kathleen Kinnally — 33 Barry Kosofsky — 60 Wadsworth Center Massachusetts General Hospital- East [email protected] [email protected]

Gregory Kinney — 84 Catherine Kotz — 87 University of Washington Minneapolis VA Medical Center [email protected] [email protected]

Glen Kisby — 32 Scott Krahl — 73 Oregon Health Sciences University VA Greater Los Angeles Healthcare [email protected] System [email protected] David Klein NIH Ken Kramer — 65 [email protected] New York University School of Medicine [email protected] Joel Kleinman — 41 National Mental Health Institute Janette Krum — 46 [email protected] George Washington University Medical Center David Ko — 73 [email protected] University of Southern California [email protected] Leszek Kubin — 30 University of Pennsylvania Jhumku Kohtz — 65 [email protected] Children s Memorial Institute for Research Joseph LaManna [email protected] Case Western Reserve University [email protected] Gregory Konat — 79 West Virginia University School of Thomas Lanthorn — 66 Medicine Astra Zeneca R & D Boston [email protected] [email protected]

P Eric Konicki Douglas Lappi — 46 Louis Stokes Cleveland Veterans Affairs Advanced Targeting Systems Med Ctr [email protected] [email protected] John Larson — 63 Christine Konradi — 29 University of Illinois at Chicago College Massachusetts General Hospital of Medicine [email protected] [email protected]

Dianne Lattemann VA Medical Center/University of Washington [email protected] 130 Jean Lauder — 56 Deolinda Lima — 72 Univ. NC Sch. Med. Institute of Histology and Embryology [email protected] [email protected]

Matthew J. LaVoie Iris Lindberg University of Pittsburgh LSU Med Ctr [email protected] [email protected]

Robert Ledeen — 99 W. Ian Lipkin — 32 New Jersey Medical School University of California-Irvine [email protected] [email protected]

Susan LeDoux — 32 Barbara Lipska University of South Alabama NIMH [email protected] [email protected]

Klaus Leonhard Leenders — 44 Paul Lombraso — 42 University Hospital Groninger Yale University [email protected] [email protected]

Sarah Leibowitz — 53 Juan Lopez — 50 The Rockefeller University University of Michigan [email protected] [email protected]

Paul Letourneau — 28, 70 Jeanne Loring — 57, 72 University of Minnesota Arcos BioScience and Incyte [email protected] Pharmaceuticals [email protected] Barry Levin VA Medical Center Christy Ludlow — 38 [email protected] NINDS, NIH [email protected] Michael Levine — 49 UCLA Robert Lundy — 67 [email protected] Penn State College of Medicine [email protected] Steve Levison Penn State College of Medicine Carl Lupica [email protected] Nih,Nida-Irp [email protected] Irwin Levitan — 58 Brandeis University Bernhard Luscher — 45 [email protected] Penn State University [email protected] Anita Lewin — 44 Research Triangle Institute Ralph Lydic — 30 [email protected] University of Michigan [email protected] Alan Light — 40 UNC-Chapel Hill William Lyman [email protected] Wayne State University School of Medicine Stafford Lightman — 76 [email protected] University of Bristol,UK [email protected]

131 Maria Maccecchini Billy Martin — 47, 79 Annovis Inc Virginia Commonwealth University [email protected] [email protected]

John MacDonald — 69 Susan Masino — 31 University of Toronto University of Colorado [email protected] [email protected]

Bruce MacIver — 60 Mark Mattson — 64 Stanford University Medical School University of Kentucky [email protected] [email protected]

Ken Mackie Mitchell Max — 78 University of Washington NIH [email protected] [email protected]

Wendy Macklin — 97 John Mazziotta Cleveland Clinic Foundation UCLA [email protected] [email protected]

Brian MacVicar — 67 Bob McCall — 64 University of Calgary Pharmacy & Upjohn [email protected] [email protected]

Malcolm Maden — 47 Hugh McIntyre King s College London Harbor-UCLA Medical Center [email protected] [email protected]

Robert Malenka — 49 F.Arthur McMorris Stanford University School of Medicine The Wistar Institute [email protected] [email protected]

Stuart Mangel — 35 Marsha Melnick University of Alabama—Birmingham UCSF/SFSU [email protected] [email protected]

J. John Mann — 50 John Mendelson — 88 Columbia University University of California at San Francisco [email protected] [email protected]

Robert Mansbach Kalpana Merchant — 27, 42 Pfizer Inc Pharmacia & Upjohn, Inc. [email protected] [email protected]

Patrick Mantyh — 78 Michael Meredith — 51 University of Minnesoata Florida State University (On sabbat. U [email protected] MD Balt.) [email protected] Neville Marks — 54 Nathan Kline Institute Paul Mermelstein — 64 [email protected] Stanford University [email protected]

132 Ronald Meyer — 47 Shaye Moskowitz — 66 University of California Irvine State University of New York- Brooklyn [email protected] [email protected]

Adrian Michael — 48 Stephen Moss — 45 University of Pittsburgh University College [email protected] [email protected]

Elena Mihailova Greer Murphy — 66 National Mental Health Research Center Stanford University [email protected] [email protected]

Robert Mihalek — 74 Marion Murray University of Pittsburgh MCP Hahnemann Univeristy [email protected] [email protected]

Neil Millar Janice Naegele — 42 University College London Wesleyan University [email protected] [email protected]

Richard Mize — 70 N Eric Naftchi Louisiana State Univ Medical Center New York University Medical Center [email protected] [email protected]

Istvan Mody — 69 Frederic Nagy — 40 UCLA School of Medicine INSERM [email protected] [email protected]

Bita Moghaddam — 34, 41 T. Celeste Napier — 34, 43 Yale University Loyola University Chicago Stritch School [email protected] of Medicine [email protected] Jeffrey Mogil — 52 University of Illinois Sujatha Narayan [email protected] Bryn Mawr College [email protected] Hannah Monyer — 45 Max-Planck-Institute Medical Research Janet Neisewander — 58 [email protected] Arizona State University [email protected] Robert Moore — 62 University of Pittsburgh Kim Neve — 27 [email protected] Portland VA Medical Center [email protected] Michael Morgan — 72 Washington State University, Vancouver Rachael Neve -72 [email protected] Harvard Medical School [email protected] A. Leslie Morrow — 92 Univ. of North Carolina at Chapel Hill Roger Nicoll — 63 [email protected] University of California [email protected]

133 Thierry Nouspikel — 32 Larry (Loren) Parsons — 77, 86 Stanford University Scripts Research Dept [email protected] [email protected]

Jeffrey Nye — 33 Hemai Parthasarathy Northwestern University Nature [email protected] [email protected]

Patricio O Donnell — 49 Robert Pearce — 60 Albany Medical College University of Wisconsin patricio.o [email protected] [email protected]

Anne Louise Oaklander — 52 Betsy Pehek — 77 Harvard Medical School-Mass General Cleveland DVA Medical Center [email protected] [email protected]

Charles O Brien Dale Pelligrino — 76 University of Pennsylvania University of Illinois at Chicago [email protected] [email protected]

Halina Offner — 79 Regino Perez-Polo — 52 Oregon Health Sciences University UTMB [email protected] [email protected]

Kevin Oliver — 98 David Perkel — 73 Merck Sharp & Dohme University of Pennsylvania [email protected] [email protected]

Kathie Olsen — 60 Stephen Peroutka — 64 NASA Analgesic Technologies, Inc. [email protected] [email protected]

Richard Olsen Gavin Phillips — 71 UCLA School of Medicine University of York [email protected] [email protected]

Karel Pacak — 100 Piazza Pier Vincenzo — 58 National Institute of Health I.N.S.E.R.M. unit 259 [email protected] [email protected]

Terry Painter Chris Pierce — 27 Pharmacia & Upjohn Boston University School of Medicine [email protected] [email protected]

Sarah Pallas — 50 Dietmar Plenz — 27 Georgia State University Unit of Neural Network Physiology [email protected] [email protected]

Gene Palmer Steven Potkin — 50 AstraZeneca R&D Boston University of California, Irvine [email protected] [email protected]

134 Eric Potts — 83 Amir Rezani — 81 University of Maryland Duke University Medical Center [email protected] [email protected]

Herbert Proudfit Robert Rhoades — 50, 75 Univ. of Illinois at Chicago Medical College of Ohio [email protected] [email protected]

Remi Quirion — 64 Steve Richardson Douglas Hospital Research Centre McGill University of Saskatchewan Iniversity [email protected] [email protected] George Richerson Sally Radovick — 76 Yale University Children s Hospital [email protected] [email protected] Rosario Rizzuto — 33 Martin Ralph University of Padeva University of Toronto [email protected] [email protected] Terry Robinson — 71 Ary Ramoa — 75 University of Michigan Medical College of Virginia, VCU [email protected] [email protected] David Rock — 29 Bruce Ransom Parke-Davis Research [email protected] [email protected]

Douglas Rasmusson — 43 Nancy Rodgers-Neame — 73 Dalhousie University Suncoast Comprehensive Epilepsy Center [email protected] [email protected]

Vincent Rehder — 70 Anna Roe — 69 Georgia State University Yale University School of Medicine [email protected] [email protected]

Larry Reid — 81 Suzanne Roffler-Tarlov — 40 Rensselaer Polytechnic Institute Tufts University School of Medicine [email protected] [email protected]

Maarten Reith — 99 Jed Rose — 81 Univ. Illinois, Coll. Med. Duke University [email protected] [email protected]

Jane Relton — 44 Elliott Ross — 73 Biogen OUHSC/VA [email protected] [email protected]

Ke Ren — 72 M Elizabeth Ross — 33 University of Maryland University of Minnesota [email protected] not available

135 Richard Rothman — 37 Jay Schulkin — 67 DHHS/PHS/NIR/NIDA/ARC/IRP ACOG [email protected] [email protected]

Nancy Rothwell — 44 Avital Schurr — 59 University of Manchester University of Louisville [email protected] a@schu@[email protected]

Michael Salter — 42, 69 Joe Schwab Hospital for Sick Children Pharmacia & Upjohn [email protected] [email protected]

Brian Salzberg — 69 Robert Schwarcz University of Pennsylvania School of University of maryland School of Medicine Medicine [email protected] [email protected]

Martin Sarter — 43 Andrew Schwartz — 39 The Ohio State University The Neurosciences Institute [email protected] [email protected]

Eliana Scemes Roy Schwarz — 59 Albert Einstein College of Medicine Parke-Davis Pharmaceutical Research [email protected] [email protected]

Helen Scharfman — 59 Guy Seabrook — 63 Helen Hayes Hospital and Columbia Merck Sharp & Dohme University [email protected] [email protected], Peter Seeburg [email protected] Max-Planck-Institute Medical Research Stephen Scheff — 93 [email protected] University of Kentucky David Self — 58, 61 [email protected] Yale University Steven Schleifer — 95 [email protected] umdnj-new jersey med school Henry Sershen [email protected] Nathan S. Kline Institute Marc Schmidt — 73 [email protected] University of Pennsylvania Susan Sesack — 77 [email protected] University of Pittsburgh Geoff Schoenbamm — 80 [email protected] Johns Hopkins University Yavin Shaham — 58 [email protected] NIDA/IP Arne Schousboe — 56 [email protected] Royal Danish School Pharmacy Carla Shatz [email protected] HHMI-University of California Berkeley Lisa Schrott [email protected] University of Minnesota schro@[email protected]

136 M. Kent Shellenberger Thomas Soderling — 37 Elam Pharmaceuticals Oregon Health Science University not available [email protected]

Toni Shippenberg — 61 Roland Somogyi — 57 NIDA Incyte Pharmaceuticals [email protected] [email protected]

David Shore — 55, 60 Harald Sontheimer — 35, 67 National Institute of Mental Health University of Alabama at Birmingham [email protected] [email protected]

Ralph Siegel — 69 William Spain Rutgers University University of Washington [email protected] [email protected]

Eric Simon — 29, 65 Shelton Sparber — 28 NYU Medical School University of Minnesota [email protected] Alan Spector — 67 Ian Simpson University of Florida Penn State University College of [email protected] Medicine Marcy Speer — 33 [email protected] Duke Medical Center Phil Skolnick [email protected] Eli Lilly and Company Avron Spier — 56 [email protected] Scripps Research Institute Celia Sladek [email protected] Chicago Medical School David Spray [email protected] Albert Einstein College of Medicine John Sladek [email protected] Chicago Medical School [email protected] David Standaert Massachusetts General Hospital Steven Small — 78 [email protected] The University of Chicago [email protected] Barry Stein Wake Forest Univ. School of Medicine Adam Smith — 75 [email protected] University of Oxford [email protected] Donald Stein Emory University Mark A. Smith — 52, 72, 76 [email protected] Case Western Reserve University [email protected] Peter Steinmetz — 30, 54, 103 California Institute of Technology Gretchen Snyder — 49 [email protected] The Rockefeller University [email protected]

137 Fiona Stevens Mark Tommerdahl- 45 Oxford University Press University of North Carolina [email protected] [email protected]

Oswald Steward — 81 Giulio Tononi — 39 Univ of CA Irvine The Neurosciences Institute [email protected] [email protected]

Bradford Stokes Kimberly Topp Ohio State University University of California San Francisco [email protected] [email protected]

Philip Stork — 65 Ramon Trullas — 91 Oregon Health Sciences University IIBB/CSIC/IDIBAPS [email protected] [email protected]

David Sulzer — 40 Richard Tsien — 37 Columbia University Stanford University [email protected] [email protected]

Trey Sunderland — 55 Dennis Turner — 66 NIMH Duke University [email protected] [email protected]

James Surmeier — 27, 34 Mark Tuszynski — 70 Northwestern University University of California, San Diego [email protected] [email protected]

Kjell Svensson — 106 Peter Usherwood — 57 Pharmacia & Upjohn The University of Nottingham [email protected] [email protected]

Ronald Szymusiak — 43 Arthur Vandenbark — 79 V. A. Greater Los angeles Healthcare Portland VA Medical Center System [email protected] [email protected] Susan Vannucci — 42 Danilo Tagle — 36 Penn State University College of NHGRI, NIH Medicine [email protected] [email protected]

Simon Tate — 38 Angela Vincent — 57 Glaxo-Wellcome University of Oxford [email protected] [email protected]

Evelyn Thoman Mike Vitek — 101 University Connecticut DUMC/OSV [email protected] [email protected]

Arthur Toga S.R. Vorel — 71 UCLA School of Medicine Albert Einstein College of Medicine [email protected] [email protected]

138 Helle Waagepetersen — 56 Tadeusz Wieloch — 66 Royal Danish School of Pharmacy Lund University Hospital [email protected] [email protected]

Benjamin Walker — 73 Clayton Wiley Georgetown University Medical Center University of Pittsburgh [email protected] [email protected]

Judith Walters — 68 John Williams — 31, 68 NIH NINDS Oregon Health Sciences Unviersity [email protected] [email protected]

Val Watts — 27 William Wisden — 45 Purdue University Medical Research Council [email protected] [email protected]

Forrest Weight — 60 Roy Wise — 34 NIH/NIAAA NIDA/IRP [email protected] [email protected]

C. Weiller — 62 Erik Wong — 42 Florida State University Pharmacia & Upjohn [email protected] [email protected]

Jeff Weiner — 86 Terri Wood Wake Forest University School of PSU/College of Medicine Medicine [email protected] [email protected] Donald Woodward David Wells — 37 Wake Forest University School of Brown University Medicine [email protected] [email protected]

Frank Welsh Clifford Woolf — 40, 52 University of Pennsylvania Massachusetts General Hospital [email protected] [email protected]

Robert Wenthold — 29 Doug Wright NIH University of Kansas Medical Center [email protected] [email protected]

Gary Westbrook — 29 Jerrel Yakel -56 Vollum Institute NIEHS/NIH [email protected] [email protected]

Thomas D. White — 31 Austin Yang — 54 Dalhousie University Nathan Kline Institute [email protected] [email protected]

Thomas Wichmann — 27 F Eugene Yates Emory University School of Medicine UCLA [email protected] [email protected]

139 Laurence Young Konrad Zinsmaier — 58 Massachusetts Institute of Technology University of Pennsylvania School of [email protected] Medicine [email protected] Elmer Yu University of Pennsylvania/Philadelphia Charles Zorumski — 59 VAMC Washington University Medical School [email protected] [email protected]

James Zadina — 29 R. Suzanne Zukin VA Med Ctr/Tulane University School of Albert Einstein College of Medicine Medicine [email protected] [email protected] Stephen Zukin — 41 Michael Zigmond — 40 National Institute on Drug Abuse University of Pittsburgh [email protected] [email protected]

140