welcome to the thirty-second annual winter conference on...

1

Welcome to the Thirty-Second AnnualWinter Conference on Brain Research

The Winter Conference on Brain Research (WCBR) was founded in1968 to promote exchange of information and ideas within neuro-science. It was the intent of the founders that both formal and informalinteractions would occur between clinical and laboratory basedneuroscientists. During the past thirty years neuroscience has grownand expanded to include many new fields and methodologies. Thisdiversity is reflected by WCBR participants and in our program. Aprimary goal of the WCBR is to enable participants to learn about thecurrent status of areas of neuroscience other than their own. Anotherobjective is to provide a vehicle for scientists with common interests todiscuss current issues in an informal setting.

The program includes panels (reviews for an audience not necessarilyfamiliar with the area presented), workshops (informal discussions ofcurrent issues and data), a minicourse, and posters. The annualconference lecture will be presented at breakfast on Sunday, January24. Our guest speaker will be Dr. Steve Hyman, Director of theNational Institute of Mental Health. On Tuesday, January 26, a townmeeting will be held for the Aspen/Snowmass community at whichDr. Steve Hyman and other WCBR participants will discuss theneurobiological basis of mental illness. Finally, the banquet, includinga special program, music, and dancing, will be held on Friday evening.

The continued generous donations from sponsors have permitted us tocontinue the WCBR Fellowship Award Program. These awards aregiven to young neuroscientists who are on the program and who arenewcomers to WCBR. Congratulations and a warm welcome to thisyear s fellows: Bruce Appel, Aldo Badiani, Jang-Ho John Cha, StevenC. Cramer, Gianluca Gallo, Edward Giniger, Michael H usser ,DiAnna L. Hynds, Daniel C. Javitt, Anna Y. Klintsova, Zachary F.Mainen, Michael Peter Matise, Lawrence P. Reagan, AlexanderDeJesus Reyes, Gunter Schumann, Angus Silver, Steven A. Thomas.

2

Please plan to attend the business meeting at 6:30 p.m. on Wednesday,January 27. We will discuss the new Conference Chairperson Elect,and elect three members of the Board of Directors. Other importantmatters will be discussed including changes in the WCBR corporationby-laws and the selection of future conference sites.

3

Conference ChairIrwin Levitan

Program CommitteeHarvey Karten, ChairPaul Letourneau, Chair ElectElizabeth Abercrombie Paul KatzSusan Amara Paul LetourneauAllan Basbaum Michael LevineJill Becker Irwin LevitanMarc Binder Suzanne Roffler-TarlovRobert Burke Edwin RubelMarie-Francoise Chesselet Oswald StewardDennis Choi D. James SurmeierJoseph Coyle Gregor SutcliffeThomas Dunwiddie Nancy ZahniserKarl Herrup

TreasurerAllan Basbaum

Facilities CommitteeMarsha Melnick, ChairKaren Greif, Facilities Chair ElectDan MajorSujatha NarayanAlex Straiker

Board of Directors and OfficersElizabeth Abercrombie Joel KleinmanMarjorie Ariano Paul LetourneauAllan Basbaum Barry LevinMartha Bohn Michael LevineWilliam Bunney Irwin LevitanWilliam Greenough Marsha MelnickKaren Greif Eric SimonFrances Grover Daniel WeinbergerMiles Herkenheim Donald WoodwardBart Hoebel Michael ZigmondHarvey Karten

4

Fellowship ProgramDonald Stein, ChairRaymond BartusEd HallGene Palmer

ExhibitsMichael LevinePamela Rawlins

School OutreachPaula Dore-DuffyAmy Butler Joseph LipinskiJill Delfs Gene PalmerVictor Denenberg Margaret RiceHelene Emsellem Harry SontheimerKaren Greif Bradford StokesSami Harik Thomas SwansonJoseph LaManna Frank Welsh

Web PagesDon WoodwardHarvey KartenElizabeth AbercrombieRalph Siegel

Town MeetingKristen Keefe

RegistrarJudith Shivak

WCBR StaffPaula ShelleyEllie Watelet

5

Sponsoring InstitutionsBeckman Institute

University of Illinois, Urbana-ChampaignGraduate Program in Physical Therapy

University of California, San Francisco/San Francisco State University

Department of AnatomyUniversity of California, San Francisco

Department of NeurosciencesUniversity of California, San Diego

Volen Center for Complex SystemsBrandeis University

Conference ArrangementsScott C. Miller, Program DirectorNancy Mulvany, Program SecretaryConferences and InstitutesUniversity of Illinois at Urbana-ChampaignSuite 202 University Centre302 East John StreetChampaign, IL 61820

1999 Fellowship AwardeesBruce Appel, Ph.D.Aldo Badiani, M.D.Jang-Ho John Cha, MD, Ph.D.Steven C. Cramer, MDGianluca Gallo, Ph.D.Edward Giniger, Ph.D.Michael H usser , D. PhilDiAnna L. Hynds, Ph.D.Daniel C. Javitt, MD, Ph.D.Anna Y. Klintsova, Ph.D.Zachary F. Mainen, Ph.D.Michael Peter Matise, Ph.D.Lawrence P. Reagan, Ph.D.Alexander DeJesus Reyes, Ph.D.Gunter Schumann, M.D.Angus Silver, Ph.D.Steven A. Thomas, M.D., Ph.D.

6

1999 Fellowship Fund ProgramSponsors

Benefactor: $1000+ALKERMESATHENA NEUROSCIENCESBRAIN INJURY ASSOCIATION INC.PARKE-DAVISPFIZER, INC.PHARMACIA & UPJOHN CO.

Patron: $500–$999ASTRA MERCKCEPHALON, INC.DUPONT MERCKFINE SCIENCE TOOLS, INC.GUILFORD PHARMACEUTICALS, INC.SCIOSSMITHKLINE BEECHAM PHARMACEUTICALSWCBR BOARD OF DIRECTORSWYETH-AYERST RESEARCHZENECA PHARMACEUTICALS

Sponsors: up to $500ASTRA/ARCUSLIST BIOLOGICAL LABSPROMEGA CORPORATION

ExhibitorsAcademic Press525 B Street, Suite 1900San Diego, CA 92101-4495Contact: Graham LeesTel (619) 699-6745 Fax (619) 699-6580

Alza Corporation—Alzet® Osmotic PumpsPO Box 10950950 Page Mill RoadPalo Alto, CA 94303Contact: Clarissa PeerTel (800) 692-2990 Fax (650) 962-2482Email: [email protected]

7

Association Book Exhibit639 South Washington St.Alexandria, CA 22314Contact: Mark TrocchiTel (703) 519-3909 Fax (703) 519-7732

Biorad4505 Maureen CircleLivermore, CA 94550Contact: Brendan YeeTel (925) 447-7774 Fax (925) 447-7114Email: [email protected]

Carl ZeissOne Zeiss DriveThornwood, NY 10594Contact: Edward ManciniTel (800) 982-6493 Fax (914) 681-7446

Elsevier Science LondonThe Online Community of NeuroscientistsMiddlesex House34-42 Cleveland StreetLondon W1P 6LE, ENGLANDContact: Steve LohnTel 44-171- 580-2588 Fax 44-171-631-0819Email: [email protected]

S. KargerAllschwilerstrasse 10Postfach4009 Basel, SWITZERLANDContact: Angela GasserTel 41-613-061264Email: [email protected]

Leica Microsystems Inc.111 Deer Lake RoadDeerfield, Illinois 60015Contact: Andy LeeTel (847) 317-7217 Fax (847) 405-0030Email: [email protected]

8

MED Associates Inc.PO Box 319St. Albans, VT 05478Tel (802) 527-5095 Fax (802) 527-5095Contact: Karl ZurnEmail: [email protected]

Micron Optics240 Cedar Knolls Road, Suite 208Cedar Knolls, NJ 07927Contact: Peter BurbockTel (973) 267-5799 Fax (973)267-6598

Mini-Mitter Co., Inc.PO Box 3386Sunriver, OR 97707Contact: David and Judy OsgoodTel (541) 593-8639 Fax (541) 593-5604Email: [email protected]

The MIT PressNE25-40935 Cambridge CenterCambridge, MA 02142Contact: Michael RutterTel (617) 253-1558 Fax (617) 258-6779Email: [email protected]

National Research Council/National Academy of Sciences2101 Constitution Ave NW (TJ2114)Washington, DC 20418Contact: Judith NyquistTel (202)334-2768 Fax (202) 334-2759

Ni Kon Inc.PO Box 2464Evergreen, CO 80437Contact: Gerald BenhamTel and Fax (303) 674-1569Email: [email protected]

9

Noran Instruments2551 West Beltline HighwayMiddleton, WI 53562Contact: Steve PfeifferPhone/Fax (503)642-9973Email: [email protected]

Olympus AmericaTwo Corporate Center DriveMelville, NY 11747Contact: Angela GoodacreEmail:[email protected] (800) 645-8100 Fax (972) 625-6439

Oxford University Press198 Madison AvenueNew York, NY 10016Contact: Fiona StevensTel (212) 726-6063 Fax (212) 726-6441

Pacer Scientific5649 Valley Oak DriveLos Angeles, CA 90068Contact: Richard and Kathy BellamyTel (323) 462-0636 Fax (323) 462-1430Email: [email protected]

10

General Information

Headquarters is the Snowmass Village Conference Center. All scien-tific activities will be held there.

WCBR Information Desk and Message Center are in the SnowmassVillage Conference Center lobby. The desk is open:

Morning Afternoon Evening

Saturday, 1/23 9:00—11:00 AM 3:30—5:30 PM 7:30—10:00 PM

Sunday, 1/24 7:00—8:00 AM 3:30—6:30 PM

Monday, 1/25—Friday, 1/29

7:00—8:00 AM 3:30—4:30 PM

The telephone number for messages is 970—923-2000, extension 278.The Snowmass Village Conference Center FAX number is 970—923-6785. FAX charges: To receive—$2.00/; To send—$3.00/1st page and$2.00/subsequent page. FAX numbers and charges for individualhousing properties are available by calling the individual properties.

Registration packets, containing conference badge, registrationreceipt, tickets for breakfasts, mid-week lunch and banquet, andprogram book should be picked up at the WCBR Information Desk.PLEASE NOTE that your housing reservation must be shown beforethese items can be issued. Conferees who did not acceptWCBR-assigned accommodations are charged a facilities supplementof $100 as stated in the WCBR announcement. No exceptions can begranted. 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. Posterpresenters will be with their posters on the day and time indicated.

Exhibits and Lounge are in the Anderson room. Coffee is availablethere from 7:30—10:30AM Monday through Friday. Refreshments areprovided by the exhibitors 3:30—4:30PM, Sunday through Friday.

Breakfast is served to all registrants on Sunday 7:30—8:20 AM, inAnderson/Hoaglund room of the Snowmass Village ConferenceCenter, and on Monday through Friday, 6:30—7:30 AM, in the Wild-

11

wood Lodge. (Social Guests may breakfast until 10:00 AM). Thetickets in your registration packet are required for admission. OnSaturday morning (January 30) before departure, a continental break-fast is available in the Anderson/Hoaglund room of the SnowmassVillage Conference Center.

Ski Lift Tickets will be available from the WCBR Information Desk atthe Snowmass Village Conference Center lobby. Daily tickets can bepurchased or prepaid tickets can be picked up on:

Early Mid-Morning Late

Saturday 1/23 9:00—11:00 AM 7:30—10:00 PM

Sunday 1/24 7:00—8:00 AM 9:30—10:30 AM 3:30—4:30 PM

Monday 1/25—Thursday 1/28

7:00—8:00 AM 9:30—10:30 AM 3:30—4:30 PM

Friday 1/29 7:00—8:00 AM

12

Special Events

Saturday, January 23:Newcomers Reception 6:30—7:30 PM, Anderson/Hoaglund rooms.WCBR Fellows and all others attending WCBR for the first time arecordially invited.

Welcome Wine and Cheese Party for all registered participants 7:30—10:30 PM, Anderson/Hoaglund rooms.

Sunday, January 24:Conference Breakfast and Opening Address 7:30 AM, Anderson/Hoaglund rooms (Your required ticket is in your registration packet). Ourplenary keynote speaker will be Steve Hyman, Director of the NationalInstitute of Mental Health and a WCBR veteran. Dr. Hyman s lecture willbe entitled Neur oscience at NIH: A Look Into the Crystal Ball.

Meeting of Panel and Workshop Organizers 9:30 AM, Anderson/Hoaglund rooms, immediately after breakfast. The meeting will be briefbut important. Organizers and WCBR staff please attend.

Monday, January 25:Minicourse on Digital Imaging A formal presentation of recent develop-ments will be presented on Monday afternoon, 4:30—6:30 PM. In addition,there will be two application Workshops on Tuesday and Thursday nightsto discuss special applications of these methods to various researchquestions. A number of confocal and digital imaging instruments will beavailable for use by members.

Tuesday, January 26:Town Meeting 8:30—10:30 PM, Aspen High School, Aspen 1 SchoolDistrict, 0235 High School Road, Aspen, CO 81611.

Wednesday, January 27:Smitty Stevens Memorial (NASTAR) Ski Race 10:00 AM—11:30 AM,Spider Sabich Race Arena. NASTAR registration cards to be completed nolater than Monday, January 25, 8:00 AM at WCBR Information Desk.

Mountain Lunch 12:00 PM—2:00 PM. Spider Sabich Race Arena PicnicArea. (Required lunch ticket is in your registration packet). Non-skiers,requiring transportation, should sign up at the WCBR Information Desk.

13

Business Meeting Election of Conference Chair Elect, Facility ChairElect, and 3 Directors. 6:30 PM, Hoaglund room.

Government Funding Update: Dollars for Scholars following theBuisness Meeting. Dynamic growth in research opportunities in theneurosciences and now, finally, federal budgets to match them! Here s youropportunity to hear the latest on funding initiatives at the NIH and NSF.Among the topics of interest to both junior and senior investigators will be:

¥ Modular grants: As of June 1, most grant applications to NIH will be in$25,000 chunks. Come hear how to construct your budget and justify it toreviewers.

¥ New study sections for neuroscience and the behavioral and socialsciences at NIH: Discussion of our experience so far with the newneuroscience study sections and plans for the newly integrated behavioraland social science study sections.

¥ NINDS Planning Process: First glimpse of some recommendations ofthe seven planning panels to set priorities for the NINDS over the next 2-5years.

¥ New initiatives at NSF and other funding agencies

Friday, January 29:Banquet and Dinner 7:30 PM, Anderson/Hoaglund rooms. (Requiredticket is in your registration packet). Cash bar open at 6:30 PM in theSnowmass Village Conference Center lobby.

14

Preamble to the Program

The 1999 WCBR Program consists of aMinicourse, Panels, Workshops, and Posters.Please consult the Program Booklet and postedannouncements for details regarding the Posters,Town Meeting, and special presentations by NIHpersonnel.

15

7:30 AMPLENARY BREAKFAST

Anderson/Hoaglund

Guest Speaker: Steve Hyman,Director of the National Instituteof Mental Health.

Neuroscience at NIH: A LookInto the Crystal Ball.

4:30–6:30 PMPANEL Ion Channels that Control

Behavior.

Abdel El Manira, Nicholas Dale,Sten Grillner, Ronald Harris-Warrick, Jorn Hounsgaard

Sinclair

PANEL Glutamatergic DysfunctionIn Schizophrenia: In VivoAssessment And Targets ForIntervention.

Daniel Javitt, Kelvin Lim,Daniel Weinberger, ChristianFibiger

Erickson

PANEL Do Common Pathways InThe Brain Mediate Food AndDrug-Motivated Behaviors?

Robin Kanarek, Allen Levine,Ann Kelley, Marilyn Carroll

Carroll

PANEL Potential Of EmbryonicAnd Adult Neural Stem AndProgenitor Cells.

Jean de Vellis, John Kessler,Fred Gage, Arthur McMorris

Janss

Sunday, January 24, 1999PANEL Transgenic Approaches To

Stroke Research Using Geneti-cally Engineered Mice.

Paul Huang, Ted Dawson,Constantino Iadecola, DavidPinsky

Hoaglund

8:30–10:00 PMWORKSHOP Why Iron Is Clinically

Relevant : A Necessity AndNemesis For Neurology.

James Connor, Steve Bondy,Fulton Crews, George Bartzokis,Christopher Earley

Sinclair

WORKSHOP New Anion ChannelsIn The Brain: Structure, Biophys-ics And Role In Cell VolumeRegulation.

Eliana Scemes, Kevin Strange,Harold Kimelberg, RolfDermietzel

Snobble

WORKSHOP What s So SpecialAbout The Development Of ThePrimate Visual System.

Leo Chalupa, VivienCasagrande, Henry Kennedy,Barry Stein

Janss

WORKSHOP˚ Apoptosis OrNecrosis: What s In A Name?

Claude Wasterlain, DennisChoi, Michael Chopp, DensonFujikawa

Erickson

16

Monday, January 25, 19997:30–9:30 AMPANEL Sensory Neuron Adaptation

During Inflammation: Dr. JekyllAnd Mr. Hyde.

Susan Carlton, Peter Reeh,Michael Vasko, Linda Sorkin

Sinclair

PANEL Cerebellar Long TermDepression (Ltd): Does ItOperate In The Real World?

James McElligott, Robert Baker,James Bloedel, Bernard Schreurs

Erickson

PANEL Notch Signaling In NeuralDevelopment AndNeurodegenerative Disease.

Jeffrey Nye, Raphael Kopan,Bruce Appel, Edward Giniger

Snobble

PANEL Cannabinoid Signaling InThe Retina And Brain.

Greg Maguire, Daniele Piomelli,Ken Mackie, Stanley Thayer

Carroll

PANEL Is Dopamine Over-Rated InNmda Model Of Psychosis?

Bita Moghaddam, Mark Geyer,John Krystal, Alan Breier

Janss

PANEL Global Efforts InNeuroinformatics.

Stephen Koslow, Jan Bjaalie,Jaap van Pelt, Sten Grillner, PaulVerschure

Hoaglund

4:30–6:30 PMPANEL Huntington s Disease and

Related Disorders: Lessons fromTransgenic Mouse Models.

John Penney, Jang-Ho, JohnCha, Gillian Bates, ChristopherRoss

Carroll

PANEL Neural Stopwatches:Implications For Normal AndPathological Cognitive Processes.

Aldo Badiani, Warren Meck,John Gibbon, Charles Gallistel

Erickson

PANEL Chondroitin SulfateProteoglycans: MultifacetedRegulators Of Growth ConeNavigation And NeuronalRegeneration.

Diane Jaworski, RobertMcKeon, David Muir, DiAnnaHynds

Janss

Sunday, January 24, 1999, continued

WORKSHOP Supraspinal Contribu-tions To Hyperalgesia.

Gerald Gebhart, KarinWestlund, Timothy Brennan,Frank Porreca

Carroll

17

PANEL Gap Junctions In The Cns:New Insights For Brain FunctionAnd Dysfunction.

Christian Naus, David Spray,Maiken Nedergaard, MichaelBennett, Roberto Bruzzone

Snobble

PANEL Pharmacogenetic Ap-proaches To Clinical Response,Side Effects And Brain Metabo-lism.

William Bunney, DavidGoldman, James Kennedy,Steven Potkin, Eric Reiman

Sinclair

MINI COURSE SESSION I NewOptical Imaging Methods InCellular Neuroscience

Stephen Smith, Stuart Thomp-son, Philip Haydon, MaikenNedergaard

Hoaglund

8:30–10:00 PMWORKSHOP A Little Daba Gaba:

Can We Measure Gaba Neu-rotransmission With In VivoMicrodialysis?

Kristen Keefe, Bryan Yamamoto,John Bruno, Janet Finlay, ArneSchousboe

Janss

WORKSHOP Experimentation ToAddiction: What Drives TheProgression?

Fulton Crews, George Koob,Agu Pert, Mary Kreek, CharlesO Brien

Carroll

WORKSHOP DelayedNeurodegeneration: ADam(N)Able Cascade.

Michael Bennett, Dennis Choi,Suzanne Zukin, Roger Simon

Sinclair

WORKSHOP˚ Sharing Reagents:The Dream And The Reality.

Michael Zigmond, Marie-Francoise Chesselet, StevenHyman, Gordon Shepherd

Erickson

Tuesday, January 26, 19997:30–9:30 AMPANEL Interactions Between The

Nigra And Pallidum ModulateBasal Ganglia Output.

Suzanne Haber, J. Paul Bolam, T.Celeste Napier, Hagai Bergman

Erickson

PANEL Transgenic Mice AndAlzheimer s Disease.

Jeanne Loring, Bruce Lamb, LisaMcConlogue, Steven Wagner,Karen Hsiao

Hoaglund

18

Tuesday, January 26, 1999, continued

PANEL Keeper Of The Gate: TheRole Of The Vagal Complex InThe Regulation Of The Auto-nomic Nervous System.

William Renehan, RenatoTravagli, David Mendelowitz,Richard Gillis

Snobble

PANEL Apoptosis In NervousSystem Development AndDisease H.

Robert Horvitz, HermannSteller, Pasko Rakic, JunyingYuan

Sinclair

PANEL Heavy Breathing InSnowmass: Serotonin And TheRespiratory Response ToAltitude.

George Richerson, Jan Ramirez,Jack Feldman, Gordon Mitchell

Carroll

PANEL Neurological ConsequencesOf Diabetes: Modulation ByGlucocorticoids.

Lawrence Reagan, AnthonyMcCall, Errol De Souza, StephenWoods

Janss

4:30–6:30 PMPANEL Cag Repeat Expansions:

How Do They Kill Neurons?

Marie-Francoise Chesselet,Diane Merry, Christopher Ross,Tim Greenamyre, MichaelLevine

Carroll

PANEL Glutamatergic MechanismsIn Sensory Information Process-ing.

Sue Kinnamon, Thomas Hughes,Charles Greer, NirupaChaudhari, Thomas Finger

Hoaglund

PANEL Serotonin And Behavior:Recent Findings And The LegacyOf Markku Linnoila.

J. Higley, Joseph Hibbeln,Gerald Brown, David Nielson

Janss

PANEL Intrinsic And ExtrinsicMechanisms Of Axon CollateralBranch Formation.

Paul Letourneau, Peter Baas,Gianluca Gallo, Katherine Kalil,Eduardo Macagno

Sinclair

PANEL Nonselective CationChannels: Emerging Targets ForG Protein Coupled Receptors.

Rodrigo Andrade, LeonardKaczmarek, Steven Siegelbaum,Yasuko Nakajima

Erickson

7:30–10:00 PMTOWN MEETING—Aspen High

School. (Transportation pro-vided.)

19

7:30–9:30 AMPANEL How The Brain Senses,

Utilizes And Regulates EnergySubstrates.

Barry Levin, Dianne Lattemann,Pierre Magistretti, BruceRansom, Ian Simpson

Hoaglund

PANEL Magnocellular Neurons:Bigger Is Better!

Celia Sladek, Steve Bealer,Gloria Hoffman, Alan Johnson

Carroll

PANEL Exploring The RelationshipsOf Mesenchyme To NervousSystem And CraniofacialDevelopment And Regeneration.

Daniel Marshak, Martha Bohn,Anthony LaMantia, Jean Lauder,Darwin Prockop

Janss

Wednesday, January 27, 1999

Tuesday, January 26, 1999, continued

8:30–10:00 PMWORKSHOP Cognitive Neuro-

science Investigations: Choice OfTechnique.

John Hart, Jr., Steven Small,Nathan Crone

Janss

WORKSHOP The Final Paradox:Neuronal Division, ProliferationOr Death?

Mark Smith, A. David Smith,Huntington Potter, Karl Herrup,Gregory Brewer

Carroll

WORKSHOP What RegulatesReceptor Channel Properties InDeveloping Sensory Cortex?

Sharon Juliano, Adam Smith,Hannah Monyer, ArnoldKriegstein

Sinclair

WORKSHOP Novel Preparations ToUntangle Brain Functions.

Sandra Pearl, Dietmar Plenz,Karen O Malley, Jay Hirsh,Steven Thomas

Erickson

MINI COURSE SESSION II NewOptical Imaging Methods InCellular Neuroscience


Hoaglund

20

Thursday, January 28, 19997:30–9:30 AMPANEL Have We Got Connections?

Mapping Inter-Regional Connec-tivity In The Human Brain.

Peter Fox, Christian Bueciel,Thomas Paus, David Kennedy,Jin-Hu Xiong

Janss

PANEL Cell Cycle Control InNeurobiology.

William Freed, RichardNowakowski, Herbert Geller,Karl Herrup

Erickson

PANEL Voltage-Dependent SodiumChannels: Molecular Determi-nants Of Normal And AbnormalFunction And Its Pharmacologi-cal Modulation.

Todd Scheuer, Alan Goldin, PaulBennett, Peter Ruben, RobertFrench

Erickson

WORKSHOP˚ Searching For NovelAnalgesics: Lessons FromSubstance P.

Allan Basbaum, Stephen Hunt,Patrick Mantyh, Clifford Woolf

Sinclair

4:30–6:30 PMPANEL Stroke Therapies From

Hibernating Squirrels.

Kelly Drew, John Hallenbeck,Kai Frerichs, Margaret Rice

Hoaglund

PANEL Mechanisms OfNeuromodulation Of Hippocam-pal Gabaergic Interneurons.

Carl Lupica, Daniel Madison,Jeff Weiner, Tom Dunwiddie

Erickson

PANEL Developmental PatterningOf The Anterior CNS.

Monte Westerfield, CaroleLaBonne, Michael Matise, JohnRubenstein

Sinclair

PANEL Signaling With SingleAxons.

Shaul Hestrin, Peter Jonas,Etienne Audinat, Scott Thompson

Janss

PANEL Neuronal Nicotinic Acetyl-choline Receptors From BindingSites To Behavior.

Edward Hawrot, Lorna Role,Marina Picciotto, Ellis Cooper,Gregory Grant

Carroll

6:30–7:30 PMBUSINESS MEETING AND

ELECTIONS

Hoaglund

21

PANEL Synaptic Integration In TheMammalian Cns.

Marc Binder, Robert Burke, AlexReyes, William Spain

Sinclair

PANEL Estrogen, Progesterone, AndBrain Protection: The Joy Of Sex(Steroids).

Dale Pelligrino, Edward Hall,Phyllis Wise, Donald Stein

Hoaglund

PANEL Dynamic Measures OfFunctional Properties OfMonoamine Transporters.

Alan Frazer, Greg Gerhardt,Sammanda Ramamoorthy, DavidSulzer

Carroll

PANEL From Receptor ActivationTo Creb Phosphorylation: AMechanism Of Neuroplasticity.

Christine Konradi, JacquelineMcGinty, David Ginty, RichardTsien

Snobble

4:30–6:30 PMPANEL Serotonin & Cocaine: It s

Just Not An Obsession AnyMore.

Scott Mackler, KathrynCunningham, Beth Hoffman,Loren Parsons

Erickson

PANEL STROKE—ReformattingBrain And Recapturing Youth.

Michael Chopp, Steven Cramer,Giora Feuerstein, SethFinklestein

Hoaglund

PANEL Neuronal Nicotinic Acetyl-choline Receptors: From FoldingTo Function.

Neil Millar, Darwin Berg, JonLindstrom, Ronald Lukas

Carroll

PANEL New Approaches ForEstimating Quantal Parameters.

Michael Häusser, Angus Silver,John Clements, Zachary Mainen

Snobble

PANEL Protein Tyrosine KinasesAnd Protein Tyrosine Phos-phatases In The Brain.

Fritz Henn, R dig er Klein,David van Vactor, Takeshi Yagi,Gunter Schumann

Sinclair

PANEL Mechanisms Of MotionDetection In The Visual SystemOf Invertebrates And Vertebrates.

Harvey Karten, Nick Strausfeld,Alexander Borst, RichardMasland

Janss

8:30–10:00 PMWORKSHOP Static Maps Vs.

Dynamic Networks: RevolutionIn Somatosensory Research.

John Chapin, Jon Kaas, FordEbner, Miguel Nicolelis

Erickson

WORKSHOP Probing GABAAReceptor Function And Regula-tion: Cut And Paste, Mix AndMatch, Delete .

Neil Harrison, Richard Olsen,Cynthia Czajkowski, GreggHomanics, Sheryl Smith

Sinclair

Thursday, January 28, 1999, continued

22

Thursday, January 28, 1999, continued

WORKSHOP Nucleus AccumbensPhysiology And Drug Abuse:Integration Across DivergentFindings.

Roy Wise, Francis White,Anthony Grace, WilliamCarlezon, Laura Peoples

Janss

WORKSHOP The Internal StructureOf Central Pattern Generators:How Big Can They Get WithoutBecoming Something Else?

Robert Burke, Ronald Harris-Warrick, Simon Giszter, JeffreySmith, Paul Katz

Snobble

WORKSHOP Trophic Factors AndThe Human Brain: Is SiteSpecific Delivery Important AndIs It Possible?

Greg Gerhardt, James Conner,Don Gash, Patrick Aebischer

Carroll

MINI COURSE SESSION III NewOptical Imaging Methods InCellular Neuroscience


Hoaglund

Friday, January 29, 19997:30–9:30 AMPANEL The Neurobiology Of

Incentive-Motivation.

Agu Pert, Wolfram Schultz,Donald Woodward, AnthonyPhillips

Hoaglund

PANEL Activation Of Microglia InAlzheimer s Disease: Cause OrConsequence?

Wolfgang Streit, DennisDickson, Sue Griffin, SteveBarger

Erickson

PANEL Cells To Systems: Can WeCreate A Cohesive Electrophysi-ology Of The Effects Of EthanolOn The Brain?

Patricia Janak, Forrest Weight,Richard Morrisett, BennettGivens

Carroll

PANEL What Has MutationalAnalysis Taught Us About DrugAction?

Phil Skolnick, Marina Strakhova,Heinrich Betz, Eric Moody,Jurgen Wess

Sinclair

PANEL Localization And FunctionsOf Metabotropic GlutamateReceptors In The Basal Ganglia.

Yoland Smith, P. Jeffrey Conn,David Standaert, David Lovinger

Janss

23

PANEL Astrocytic CommunicationSkills.

Maiken Nedergaard, AndyCharles, Eliah Scemes, PhilipHaydon, Stanley Kater

Snobble

4:30–6:30 PMPANEL Hippocampus, Prefrontal

Cortex And Dopamine: TheBermuda Triangle Of TheSchizophrenic Brain.

Barbara Lipska, Susan Sesack,Therese Jay, Patricio O Donnell,Alessandro Bertolino

Carroll

PANEL Novel Approaches ToSmoking Cessation: DifferentSmokes For Different Folks.

Linda Dwoskin, Edythe London,Rachel Tyndale, Michael Bardo,Robert Mansbach

Erickson

PANEL Glutamate Receptors AtEarly CNS.

Martha Constantine-Paton,Stefano Vicini, Ann Marie Craig ,Arnold Kriegstein

Snobble

PANEL Astrocytes, Axon GrowthAnd Brain Injury.

James Fawcett, Herb Geller, RonMeyer, Steven Levison

Janss

PANEL From Jogging To High WireAcrobatics: Brain Adaptation InResponse To Exercise And MotorSkill Learning.

Anna Klintsova, BrendaAnderson, Theresa Jones, JeffreyKleim, Rodney Swain

Hoaglund

PANEL Cellular And NetworkMechanisms Of ThalamocorticalFunction And Dysfunction: SleepAnd Epilepsy.

David McCormick, DiegoContreras, Alain Destexhe,Manuel Castro-Alamancos

Sinclair

7:30 PMBANQUET

Hoaglund

Friday, January 29, 1999, continued

24

Poster Sessions

Poster Session IMonday—Tuesday: Cellular and molecular physiology and drug abuse

Poster will be available for viewing from Sunday to Tuesday. Presenterswill be with their posters on the days and times indicated.

Monday • 3:30–4:30 PM • AndersonBeverley˚Clark˚˚¥ DIFFERENTIAL SYNAPTIC ACTIVATION OF AMPA

AND NMDA RECEPTORS IN MOLECULAR LAYER INTERNEU-RONS OF THE CEREBELLUM

Stuart˚Cobb˚˚¥ SYNAPTIC ACTIVATION OF NICOTINIC RECEPTORSREGULATES HIPPOCAMPAL OSCILLATORY STATES

Jill˚Delfs˚˚¥ NOREPINEPHRINE (NE) IN THE BED NUCLEUS OF THESTRIA TERMINALIS (BNST) IS CRITICALLY INVOLVED INOPIATE WITHDRAWAL

Mark˚Farrant˚˚¥ DIFFERENTIAL TARGETING OF GABA-A RECEPTORSUBTYPES REVEALED BY SINGLE-CHANNEL PROPERTIES OFSYNAPTIC AND EXTRASYNAPTIC RECEPTORS

Silvia˚Giraudo˚˚¥ EFFECTS OF PARAVENTRICULAR NUCLEUS (PVN)INJECTION OF MELANOCORTIN 4 RECEPTOR (MC4-R)LIGAND

Carol ˚Hamelink˚˚¥ UNABLE TO LINK GLUTAMATE EXCITOTOXICITYTO ALCOHOL INDUCED NEURODEGENERATION

Hank˚Jedema˚˚¥ ENHANCED CRH-EVOKED INCREASE IN ELECTRO-PHYSIOLOGICAL ACTIVITY OF NORADRENERGIC NEURONSOF THE LOCUS COERULEUS IN CHRONICALLY COLD EX-POSED RATS

Catherine˚Kotz˚˚¥ EFFECT OF MU-OPIOID RECEPTOR STIMULATIONIN THE NUCLEUS OF THE SOLITARY TRACT ON C-FOS IN THERAT

Joe˚LoTurco˚˚¥ A NEW MUTANT: EVIDENCE FOR A NOVEL GENEESSENTIAL TO NEOCORTICAL DEVELOPMENT AND NEU-RONAL EXCITABILITY

Tyler˚McCabe˚˚¥ THE CONANTOKIN FAMILY OF PEPTIDES ISO-LATED FROM PREDATORY MARINE SNAILS: UNIQUE NMDARECEPTOR SUBUNIT SELECTIVITY

Sujatha˚Narayan˚˚¥ PATTERN OF EXPRESSION OF SYNAPTIC VESICLEPROTEINS IN THE DEVELOPING RAT PINEAL GLAND

25

Tuesday • 3:30–4:30 PM • AndersonEric˚Nisenbaum˚˚¥ SEROTONERGIC MODULATION OF THE PERSIS-

TENT POTASSIUM CURRENT IN STRIATAL NEURONS

Betsy˚Pehek˚˚¥ COMPARISON OF AMPHETAMINE-INDUCED DOPAM-INE EFFLUX IN THE PRELIMBIC AND CINGULATE CORTICESOF THE RAT

Luc˚Pellerin˚˚¥ GLUTAMATE STIMULATES NA+/K+ ATPASE INASTROCYTES VIA ACTIVATION OF A SUBUNIT HIGHLYSENSITIVE TO OUABAIN

Pablo˚Perillan˚˚¥ STRONG INWARD POTASSIUM RECTIFICATION INADULT ASTROCYTES IN CNS INJURY

R. Christopher˚Pierce˚˚¥ THE ROLE OF THE NEUROTROPHINS IN THEINITIATION OF BEHAVIORAL SENSITIZATION TO COCAINE

Anjali˚Rajadhyaksha˚˚¥ DOPAMINE ACTIVATES CREB PHOSPHORYLA-TION AND GENE EXPRESSION IN AN NMDA RECEPTORDEPENDENT MECHANISM

Harald˚Sontheimer˚˚¥ HIGH GRADE HUMAN GLIOMA CELLS EX-PRESS Ca2+— ACTIVATED K+ CHANNELS

Peter˚Syapin˚˚¥ MOLECULAR MECHANISM FOR ALCOHOL SUPPRES-SION OF INNATE CNS IMMUNITY

Elizabeth˚Thomas˚˚¥ DOPAMINE-MEDIATED ADENYLATE CYCLASEACTIVITY IN RAT STRIATUM: SELECTIVE BLOCKADE BYANTISERA DIRECTED AGAINST VARIOUS G-PROTEIN SIGNAL-LING COMPONENTS

Anthony˚West˚˚¥ NITRIC OXIDE GENERATORS MODULATE THERESPONSIVENESS OF STRIATAL NEURONS TO ELECTRICALSTIMULATION OF THE PREFRONTAL CORTEX

Elmer˚Yu˚˚¥ AN OPEN LABEL PILOT SAFETY STUDY OFLOFEXIDINE FOR THE TREATMENT OF OPIATE WITH-DRAWAL

Poster Session IIWednesday—Thursday: Disease states, neuroprotection and aging

Poster will be available for viewing from Wednesday to Friday. Present-ers will be with their posters on the days and times indicated.

Wednesday • 3:30–4:30 PM • AndersonSusan˚Bachus˚¥ ELEVATED SUPERIOR TEMPORAL GYRUS GLYCINE

TRANSPORTER 1a mRNA LEVELS In SCHIZOPHRENIA

Joseph˚Callicott˚˚¥ RELATIONSHIP BETWEEN CORTICAL PATHOL-OGY AND NEGATIVE SYMPTOMATOLOGY IN SCHIZOPHRE-

26

NIA AS REVEALED BY PROTON MAGNETIC RESONANCESPECTROSCOPIC IMAGING

Michael˚Costigan˚˚¥ INJURY INDUCED EXPRESSION OF HSP27WITHIN THE DRG—THE UPREGULATION OF A NEURONALSURVIVAL FACTOR

Sylvain˚Dore˚˚¥ A ROLE FOR HEME OXYGENASE INNEUROPROTECTION

Michael˚Egan˚˚¥ HIPPOCAMPAL NAA AND COGNITIVE DYSFUNC-TION IN PATIENTS WITH SCHIZOPHRENIA AND WELL SIB-LINGS: DISTINCT PHENOTYPES?

Alan˚Faden˚˚¥ DEVELOPMENT OF NOVEL DIPEPTIDES WITHNEUROPROTECTIVE AND COGNITIVE ENHANCING PROPER-TIES

Susan˚Feldman˚˚¥ SOMATOSTATIN REGULATION OF C6 GLIOMACELL GROWTH

Francis ˚Flynn˚˚¥ EXPRESSION OF C-FOS IN RAT FOREBRAIN AFTERLATERAL VENTRICLE INJECTIONS OF THE TACHYKININAGONIST SENKTIDE

Mady Hornig ¥ REGIONAL AND SERIAL VARIATION IN SOLUBLEFACTORS FOLLOWING NEONATAL BORNA DISEASE VIRUSINFECTION OF LEWIS RATS

Luc˚Jasmin˚˚¥ ACTIVATION OF CNS CIRCUITS PRODUCING A NEU-ROGENIC CYSTITIS. EVIDENCE FOR CENTRALLY INDUCEDPERIPHERAL INFLAMMATION

Thursday: 3:30–4:30 PM AndersonJames˚Joseph˚˚¥ NUTRITIONAL MODULATION OF AGE RELATED

DECLINES IN BEHAVIORAL AND NEURONAL FUNCTION

Matthew˚La Voie˚˚¥ IMPLICATIONS OF NITRIC OXIDE IN THE SELEC-TIVE VULNERABILITY OF DOPAMINERGIC CELLS:PEROXYNITRITE- AND NITRITE- INDUCED DOPAMINEOXIDATION

Charles˚Leffler˚˚¥ CARBON MONOXIDE AND CEREBRAL MICROVAS-CULAR TONE IN NEWBORN PIGS

Anita˚Lewin˚˚¥ ALTERATIONS IN BRAIN RECEPTOR FUNCTION AS ARESULT OF GP120/BM5D

Wendy˚Macklin˚˚¥ A NEW PURKINJE CELL DEGENERATION MU-TANT EXHIBITS DETRIMENTAL EFFECTS ON OLIGODENDRO-CYTE DIFFERENTIATION

Matthew˚Matell˚˚¥ STRIATAL COINCIDENCE DETECTION MODEL OFINTERVAL TIMING

Christian˚Naus˚˚¥ THE ROLE OF GAP JUNCTIONS IN THE PATHO-PHYSIOLOGY OF STROKE

27

M. A.˚Ruda˚˚¥ NEONATAL PERSISTENT PAIN ALTERS SPINALNEURAL CIRCUITRY

Daniel H.˚Silverman˚˚¥ EFFECTS OF ANTICHOLINESTERASETHERAPY ON REGIONAL CEREBRAL ACTIVITY OF PATIENTSWITH ALZHEIMER S DISEASE

Rui-Man˚Xie˚˚¥ THE CLINICAL AND SPECT STUDIES OF PHOTICSTIMULATION THERAPY IN PATIENTS WITH HOMONYMOUSHEMIANOPIA

28

Abstracts

Panel • Sunday 1/24/99 • 4:30–6:30 PM • Sinclair

ION CHANNELS THAT CONTROL BEHAVIOR

Abdel El Manira, Nicholas Dale, Sten Grillner, Ronald Harris-Warrick, Jorn Hounsgaard

A complete understanding of how the nervous system generates different typesof behaviors requires identification of the neural circuit responsible; that is, thedifferent neural components involved, their connectivity, transmitters, the typesof channels they possess and their modulation by various receptors. Only in afew preparations has the neural network generating behavior been characterizedin a sufficient detail to account for full complement of the motor output. Therole of the various ion channels in the generation of rhythmic activity and theirmodulation by different transmitters/modulators will be discussed in severalexperimental models. In particular, the role of different ion channels in control-ling firing properties, synaptic transmission and operation of the locomotor net-work will be highlighted with data from experiments and biophysically realisticsimulations in lower vertebrates (lamprey and Xenopus). The involvement ofspecific types of channels in the generation of rhythmic motor patterns and theirmodulation in a small neuronal network (Crustacean stomatogastric system) willbe presented. Finally, the role of ion channels in controlling intrinsic membraneproperties and firing of motoneurons and their modulation by descending path-ways will be discussed in the turtle spinal cord. This panel will thus focus ondiscussing how modulation of specific ion channels modifies neuronal firing prop-erties and thereby produces changes in network pattern generation and motorbehavior.

Panel • Sunday 1/24/99 • 4:30–6:30 PM • Erickson

GLUTAMATERGIC DYSFUNCTION IN SCHIZOPHRENIA: IN VIVOASSESSMENT AND TARGETS FOR INTERVENTION

Daniel Javitt, Kelvin Lim, Daniel Weinberger, Christian Fibiger

Converging lines of evidence indicate a role for glutamatergic dysfunction inschizophrenia. Glutamate is the major excitatory neurotransmitter in cortex andhippocampus, and glutamatergic corticostriatal fibers innervate ascending dopam-inergic projections to striatum. Dysfunction of glutamatergic systems could thuslead to both the corticohippocampal underactivity and subcortical dopaminer-gic dysregulation that are associated with schizophrenia. Noncompetitive andcompetitive antagonists of N-methyl-D-aspartate (NMDA)-type glutamate re-ceptors induce schizophrenia-like psychosis in normal volunteers, while agentsthat potentiate NMDA receptor-mediated neurotransmission appear to be clini-cally beneficial in schizophrenia. Thus, deficits in NMDA functioning may be

29

particularly relevant to the pathophysiology of schizophrenia. Key issues regardingglutamate theories of schizophrenia are first, how to assess integrity ofglutamatergic neurons in vivo, and, second, how to intervene in schizophreniabased upon glutamatergic models. Dr. Lim will present data on use of MRS,combined with structural MRI, to evaluate mechanisms underlying reported re-ductions in brain levels of the amino acid N-acetylaspartate (NAA) in schizo-phrenia. Dr. Weinberger will discuss models of schizophrenia based upon theactions of ketamine in normal volunteers and effects of ventral hippocampallesions in developing primates. Dr. Javitt will report on results of recent studiesutilizing glycine and glycine transport inhibitors clinically and in animal modelsof schizophrenia. Finally, Dr. Fibiger will discuss the development of glycinetransport inhibitors and other novel compounds for the treatment of schizophre-nia. Overall, the panel will focus on neurochemical and neuroanatomical basesof glutamatergic dysfunction in schizophrenia and potential approaches for newtreatment development based upon gluamatergic models of the disorder.

Panel • Sunday 1/24/99 • 4:30–6:30 PM • Carroll

DO COMMON PATHWAYS IN THE BRAIN MEDIATE FOOD ANDDRUG-MOTIVATED BEHAVIORS?

Robin Kanarek, Allen Levine, Ann Kelley, Marilyn Carroll

Food and drug-motivated behavior may be mediated by common pathways inthe central nervous system. In support of this idea, it has been found that intakeof foods, particularly preferred or palatable items, can modify the activity ofendogenous neurotransmitter systems, and can alter the actions of psychoactivedrugs. Additionally, there is increasing evidence that areas of the brain, such asthe nucleus accumbens, are critical in mediating both food reward, and the rein-forcing efficacy of psychoactive drugs. This panel will discuss recent researchdemonstrating the physiological and behavioral importance of interactions be-tween food consumption and the actions of reinforcing drugs. A. Levine willconsider the role of the endogenous opioid system in mediating food intake andmacronutrient selection, and evidence that ingestion of rewarding substancessuch as sweet or high-fat foods leads to the release of endogenous opioid pep-tides. A. Kelley will review work on the importance of the nucleus accumbens inmodulating opioid-induced feeding and diet selection, and will contrast the ef-fects of opioid and GABAergic stimulation in the nucleus accumbens on subse-quent food selection. R. Kanarek will present data that indicate that ingestion ofpalatable sweet and high-fat foods, and increased energy output significantly al-ter a number of the behavioral consequences of opioids and other psychoactivedrugs. M. Carroll will report on recent studies with rats and monkeys self-ad-ministering cocaine and other drugs of abuse, demonstrating that intake of foodor palatable non-caloric substances 1) reduced the acquisition of drug self- ad-ministration; 2) decreased the demand for drug in experienced animals; and 3)reduced drug-primed reinstatement of drug-seeking behavior during drug absti-nence.

30

Panel • Sunday 1/24/99 • 4:30–6:30 PM • Janss

POTENTIAL OF EMBRYONIC AND ADULT NEURAL STEM ANDPROGENITOR CELLS

Jean de Vellis, John Kessler, Fred Gage, Arthur McMorris

Neural stem cells are multipotent cells that give rise to cells of the nervous sys-tem. Before differentiation into mature cells, stem cells generally generate pro-genitor cells that retain limited capacity to proliferate and limited phenotypicfate. Recent in vitro and in vivo research support the intriguing concept that theadult CNS retains quiescent stem/progenitor cells along the entire neuraxis, withinperiventricular zones as well as some areas of the cerebral cortex. These cellsundergo proliferation, progressive lineage restriction and commitment to glialand neuronal phenotypes in response to cascades of growth factors, cytokinesand the induction of transcriptional regulators. This knowledge is serving as thebasis of current strategies for activation of such cells in situ to effect regenerationwithout transplantation. Alternately, progenitors from adult brains could beamplified for genetic manipulation and transplantation. This session will focuson molecular regulation of stem cells and their potential use in therapy.

Panel • Sunday 1/24/99 • 4:30–6:30 PM • Hoaglund

TRANSGENIC APPROACHES TO STROKE RESEARCH USINGGENETICALLY ENGINEERED MICE

Paul Huang, Ted Dawson, Constantino Iadecola, David Pinsky

The stroke research community has recently begun to use transgenic anddeletionally mutant approaches to study the molecular events during cerebralischemia. This has necessitated the development of mouse models of focal andglobal ischemia, as well as physiologic monitoring capabilities and functionalbehavioral assessments of outcome. This panel will discuss several examples whereoverexpression or targeted disruption of single genes has led to new insights intothe pathophysiology of stroke. Dr. Iadecola will discuss the effects of focal is-chemia on transgenic mice overexpressing the Alzheimer s precursor protein,and the role of inducible NOS in mediating toxicity following stroke. Dr. Dawsonwill discuss the NMDA NO-dependent activation of p21ras and synaptic plas-ticity in nNOS knockout mice. Dr. Huang will discuss the vascular and meta-bolic effects of endothelial and neuronal NO generation on focal ischemia andischemic preconditioning in NOS mutant mice. Dr. Pinsky will discuss the patho-physiologic significance of ischemia-driven expression of leukocyte adhesionreceptor glycoproteins (P-selectin and ICAM-1) in the cerebral microvasculatureusing knockout mice. The panel will also discuss the limitations of transgenicapproaches, and the effects of physiologic compensation and genetic backgroundon mouse models of cerebral ischemia.

31

Workshop Sunday 1/24/99 • 8:30–10:00 PM • Sinclair

WHY IRON IS CLINICALLY RELEVANT: A NECESSITY AND NEM-ESIS FOR NEUROLOGY

James Connor, Steve Bondy, Fulton Crews, George Bartzokis, Christopher Earley

Iron is required for synthesis of neurotransmitters, myelin production and en-ergy metabolism. However, the high rate of oxidative metabolism and the abun-dance of lipids is an ideal environment for iron generated free radicals to causeoxidative stress. In some brain areas, substantia nigra, deep cerebellar nuclei andcorpus striatum iron deposition is considerable. Indeed the striatum, under nor-mal conditions, has iron concentrations that are similar to those in liver. In manydisease states, such as Alzheimer s, Parkinson s Huntington s, Frederich Ataxia,additional iron accumulates in basal ganglia. The goal of this workshop is topromote discussion of the pathobiology of iron in the brain with the hope ofunderstanding its contribution to the pathogenic process. S.C. Bondy will ini-tiate the discussion by presenting the pathological events in the brain associatedwith iron. These include generation of free radicals, promotion of deposition ofamyloid and accumulation in neurons and glia following brain injury. F. Crewswill provide insight into mechanisms suggesting that iron induced oxidation canaccelerate NMDA neuronal death, but that reactive oxygen species are not aninitial part of the delayed neuronal death cascade triggered by NMDA calciumflux. J. Connor will overview mechanisms for iron uptake into the brain withemphasis on a newly discovered receptor for ferritin. This receptor is found onlyon oligodendrocytes and is altered in Multiple Sclerosis (MS). The discussionwill center on whether the inability to remyelinate in MS could be associatedinadequate iron delivery to oligodendrocytes. G. Bartzokis will review findingson brain ferritin iron deposits in neurodegenerative diseases and normal agingusing magnetic resonance imaging and will present data on the relationship ofserum iron levels in schizophrenia and Tardive dyskinesia offering provocativeand novel insights into iron metabolism in these disorders. C. Earley will open adiscussion on the relationship of iron deficiency to Restless Legs Syndrome (RLS).RLS, although poorly understood, is relatively common and is the first evidenceof moderate iron deficiency in adults with neurological consequences. Connorwill conclude with a summary of the status of iron neurobiology.

Workshop Sunday 1/24/99 • 8:30–10:00 PM • Snobble

NEW ANION CHANNELS IN THE BRAIN: STRUCTURE, BIOPHYSICSAND ROLE IN CELL VOLUME REGULATION

Eliana Scemes, Kevin Strange, Harold Kimelberg, Rolf Dermietzel

Anion channels dramatically contribute to the maintenance of cell volume, acid-base balance and amino-acid exchange between intra- and extracellular com-partments in the brain. This workshop will bring together recent advances inunderstanding gene families encoding anion channels (Kevin Strange), proper-ties and pharmacological sensitivity of swelling-induced amino acid release inastrocytes (Harold Kimelberg) and activation of large conductance anion chan-

32

nels by glutamate isomers (Eliana Scemes). In addition, Rolf Dermietzel willpresent exciting and controversial results indicating that the gene encoding mito-chondrial voltage sensitive anion channels (VDAC) also encodes the large con-ductance anion channels in glial cells.

Workshop Sunday 1/24/99, 8:30–10:00 PM • Janss

WHAT S SO SPECIAL ABOUT THE DEVELOPMENT OF THE PRIMATEVISUAL SYSTEM

Leo Chalupa, Vivien Casagrande, Henry Kennedy, Barry Stein

The unique organizational features of the primate visual system have been well-characterized in the adult monkey brain. Recent studies on the development ofmonkey retino-geniculate projections, as well as those dealing with the visualcortex and superior colliculus, have revealed unexpected differences, as well asapparent similarities, between primates and other species. Chalupa will discussthe formation of projections from the two retinas to the eye-specific layers of thedorsal lateral geniculate nucleus in monkey embryos and show how this differsfrom what occurs in fetal cat. Casagrande will address the formation of afferent,efferent, and intrinsic connections in monkey visual cortex. She will considerevidence supporting and contradicting the idea that parallel LGN pathways tocortex mature at different times. Kennedy will focus on the early regionalizationof cell-cycle kinetics in the ventricular zone and show how their modulationgenerates area specific features in different cortical regions (e.g., areas 17 and18). Stein will talk about the remarkable specificity evident in the sensory re-sponse properties of superior colliculus neurons in the newborn monkey. Thespeakers will encourage discussion of the intriguing possibility that collectivelythese studies provide evidence that different strategies may have evolved to es-tablish some of the hallmark features characterizing the primate visual system.

Workshop Sunday 1/24/99 • 8:30–10:00 PM • Erickson

APOPTOSIS OR NECROSIS: WHAT S IN A NAME?

Claude Wasterlain, Steven Schreiber, Michael Chopp, Denson Fujikawa

How should we define neuronal necrosis and apoptosis? Barely a week goes bywithout the publication of work which questions the basic principles on whichthese definitions are founded, or points out that widely accepted methods usedto differentiate them lack specificity. The participants of this workshop have allencountered the problem of defining different types of neuronal death in theirresearch, and their individual answers represent a broad spectrum of opinions inthat field. They will briefly describe the factural basis for their cherished beliefs,then spend most of the session in an interactive debate which will tackle currentcontroversies. Is there a gold standard that defines apoptosis? Are there only twotypes of cell death? What is the relationship between apoptosis and programmedcell death? Do the various genetic programs that implement cell suicide haveanything in common? Can we identify sequences or patterns of gene expressionthat define a specific mode of neuronal demise? Are these sequences the same in

33

postmitotic cells and in cells which are still able to divide, in the adult and in theimmature brain? How often is expression of these genes triggered as a secondaryevent in a cell which is disintegrating? How common is secondary apoptosis,and how rare is secondary necrosis? Is the timing of biochemical and morpho-logical markers the key to their significance? What is the role of caspases and ofdeath-promoting or death-inhibiting genes in necrosis? Can we continue to de-fine necrosis by its negative properties, and if we insist on a positive definitionwill it swell and explode into a multitude of descriptively defined entities? Thiswill be a BYOD (bring you own definition) session in which the audience isencouraged to bring one slide, some verbal arrows and a suit of armor. The re-sulting interchanges will help us to understand our differences and limitations.

Workshop Sunday 1/24/99 • 8:30–10:00 PM • Carroll

SUPRASPINAL CONTRIBUTIONS TO HYPERALGESIA

Gerald Gebhart, Karin Westlund, Timothy Brennan, Frank Porreca

Tissue injury leads to development of hyperalgesia, an exaggerated response—typically pain—to applied stimuli after the injury. Most interesting is that undam-aged tissue adjacent to or even some distance from the site of primary injury alsobecomes hyperalgesic. This distant, secondary hyperalgesia is believed to repre-sent involvement of central spinal circuitry in consequence of increased inputfrom primary afferent fibers. Scant attention has been paid to other than spinalmechanisms of secondary hyperalgesia, commonly described as central sensiti-zation. Recent evidence suggests, however, that secondary hyperalgesia also in-volves brainstem circuitry, particularly the rostroventral medulla (rvm). Severalexperimental models—articular inflammation, bone injury, cutaneous/muscleincision, nerve ligation, and colonic inflammation—all illustrate an involvementof supraspinal sites in the generation/maintenance of secondary hyperalgesia.Lesions of the rvm or the dorsal columns and spinal cord transection all signifi-cantly attenuate or completely reverse the secondary hyperalgesia. Anatomicaldata will be provided for a new ascending pathway to the rvm through the dorsalcolumn and transmitters in the rvm that contribute to the hyperalgesia will bediscussed. The data suggest that amplification of pain after tissue injury involvescentral processing through an ascending projection to the brainstem and conse-quent bulbospinal contributions to the increased excitability of spinal neurons.

Panel • Monday 1/25/99 • 7:30–9:30 AM • Sinclair

SENSORY NEURON ADAPTATION DURING INFLAMMATION:DR. JEKYLL AND MR. HYDE

Susan Carlton, Peter Reeh, Michael Vasko, Linda Sorkin

Inflammation is a universal response to tissue injury. Positive aspects (Dr. Jekyll)of inflammation include control of infection and promotion of wound healing.Under certain conditions, however, the inflammatory response can be detrimen-tal (Mr. Hyde), causing enhanced pain sensations that may not resolve with woundhealing. Sensory neurons not only respond, but also contribute to inflammatory

34

conditions, playing a pivotal role in the regulation of this potentially construc-tive/destructive process. In this symposium we will elucidate the cellular mecha-nisms mediating sensory adaptations which contribute to the Jekyll/Hyde phe-nomenon of inflammation. Dr. Reeh will discuss primary afferent excitation/sensitization and the consequent neurosecretion of vasoactive peptides in in-flammation. These electrical and chemical signals usually change in parallel, butinteresting discrepancies shed light on the differential control of excitation ofperipheral terminals and neuronal exocytosis. Dr. Vasko will discuss how activa-tion of PKA and/or PKC pathways by inflammatory mediators can augmenttransmitter release from primary afferent neurons. Importantly, this enhancedrelease does not desensitize with long term activation of these transduction cas-cades. Dr. Carlton will discuss how inflammation results in an upregulation ofperipheral glutamate receptors on nociceptors and a consequent supersensitivityto peripheral glutamate. Dr. Sorkin will focus on the actions of immune cellproducts (e. g. cytokines) on peripheral nerves. These compounds can initiatepain behaviors, produce changes in peripheral receptor thresholds and promoteectopic discharges in peripheral axons. Understanding the various componentsregulating excitability of sensory neurons will elucidate the neurogenic contribu-tions to the positive and negative outcomes of inflammation.

Panel • Monday 1/25/99 • 7:30–9:30 AM • Erickson

CEREBELLAR LONG TERM DEPRESSION (LTD): DOES IT OPERATEIN THE REAL WORLD?

James McElligott, Robert Baker, James Bloedel, Bernard Schreurs

The cerebellum has been identified as a putative site of neuroplastic changesassociated with sensori-motor adaptation and motor learning. The conditionedeye blink response and adaptation of the vestibulo-ocular reflex (VOR) are twoof the simpler model systems that have been utilized to evaluate the cerebellum srole in sensori-motor learning. LTD has been postulated to be one of the under-lying neuronal mechanisms contributing to these behavioral changes and hasbeen extensively investigated in reduced preparations such as the brain tissueslice. However, this mechanism has not been shown to be present in the cerebel-lum under conditions that produce neuroplastic changes that underlie these be-haviors. Data obtained from experiments on these two model systems will beused to provide evidence either supporting or countering the view that LTD isresponsible for these behavioral changes. Bloedel will describe his work in therabbit on the conditioned eye blink response while recording simultaneously frommultiple individual neurons in the cortex and deep nucleus of the cerebellum.Schreurs will present data obtained from conditioned eye blink experiments inwhich both behavioral protocols and tissue slice recordings are used in a com-mon experiment. Baker will report on his work involving continuous Purkinjecell recordings during VOR adaptation in the goldfish. McElligott will presentevidence from his studies also involving goldfish VOR adaptation that was gath-ered using a behavioral neuropharmacological approach within the cerebellum.

35

Panel • Monday 1/25/99 • 7:30–9:30 AM • Snobble

NOTCH SIGNALING IN NEURAL DEVELOPMENT ANDNEURODEGENERATIVE DISEASE

Jeffrey Nye, Raphael Kopan, Bruce Appel, Edward Giniger

Notch signaling represents a novel system of cell-cell communication that hasimportant roles in development of the nervous system and other organs. Recentstudies have also indicated its relevance to two neurodegerative disorders,presenilin-linked familial Alzheimer s disease (FAD) and CADASIL (for cere-bral autosomal dominant arteriopathy with subcortical infarcts and leukoencepha-lopathy). This panel will present an introduction to Notch signaling in neuronaldevelopment and studies on the mechanism of Notch signal transduction thatinvolve dimerization, cleavage and nuclear localization of the Notch protein.We will present evidence that Notch has a dual function in neurogenesis. In earlyneurogenesis, we will examine the role of Notch signaling in cell fate decisionsduring primary neurogenesis in the zebrafish, and in regional and cellular fatesin the cerebral cortex of mammals. In late neurogenesis, we will present evi-dence that Notch signals are essential to axon formation and discuss presenilin-Notch interactions. I: Introduction to Notch, mammalian cortical neurogenesis,and presenilin-Notch interactions (Nye) II. Mechanism of Notch Signaling(Kopan) III. The role of Delta in Zebrafish Neurogenesis (Appel) IV. The role ofNotch in Axonal Development (Giniger)

Panel • Monday 1/25/99 • 7:30–9:30 AM • Carroll

CANNABINOID SIGNALING IN THE RETINA AND BRAIN

Greg Maguire, Daniele Piomelli, Ken Mackie, Stanley Thayer

Cannabinoid receptors are best known as the molecular targets for marijuanaand hashish, the widespread drugs of abuse, but also represent part of an endo-genous cannabinoid system that appears to be present in the brain. Two majortypes of cannabinoid receptor, CB1 and CB2, have been cloned and the recep-tors localized: CB1 in the brain, and CB2 primarily in the peripheral nervoussystem. Three proposed endogenous cannabinoid ligands, arachidonylethano-lamide (anandamide), palmitoylethanolamide (PEA), and 2-arachidonylgly-cerol (2-AG) have been found in brain. The receptors CB1 and CB2, and theligands PEA and 2-AG, but not anandamide, appear to be present in vertebrateretina. Cannabinoids have been shown to be released from neurons during elec-trical stimulation, and are inactivated by a set of mechanisms parallel to, butdistinct from, those utilized for the elimination of other establishedneurotransmitters.The physiological actions of these ligands at the CB1 and CB2receptors are diverse, including modulation of voltage-gated ion channels, inhi-bition of glutamate release, modulation of long-term potentiation, and a possi-ble neuroprotective role against glutamate insult. The rapidly emerging study ofthe endogenous cannabinoid system in brain and retina promises to bring a muchgreater understanding not only of cannabinoids as drugs of abuse, but also oftheir role in brain function, and the possible involvement of cannabinoids indisease and neuroprotection.

36

Panel • Monday 1/25/99 • 7:30–9:30 AM • Janss

IS DOPAMINE OVER-RATED IN NMDA MODEL OF PSYCHOSIS?

Bita Moghaddam, Mark Geyer, John Krystal, Alan Breier

Phencyclidine (PCP), ketamine, and other non-competitive antagonists of theNMDA receptor produce cognitive and motoric disruptions that mimic someaspects of schizophrenic symptomatology and are used routinely as animal andclinical models of schizophrenia. The psychotomimetic and cognitive-impairingeffects of these drugs are generally associated with their effects on dopamineneurotransmission. This is based on two lines of evidence: (1) PCP and ketamineincrease dopamine release, thus, producing a hyperdopaminergic state consis-tent with the status quo dopamine hypothesis of schizophrenia, and (2) dopam-ine antagonists and/or lesions of dopamine pathways reduce some of the behav-ioral effects of PCP and ketamine in the rodent. However, recent data suggestthat increases in the synaptic availability of dopamine may not be sufficient tosustain those behavioral effects of PCP that have relevance to schizophrenic symp-tomatology and that non-dopaminergic mechanisms are necessary for expres-sion of these behavioral disruptions. This panel will present recent animal andhuman research examining the impact of ketamine and PCP on dopamine neu-rotransmission and behavior. The animal data will include assessments of sev-eral behavioral disruptions by PCP and ketamine that have relevance to clinicalphenomenology, and the relationship of dopamine neurotransmission to thesebehaviors. The clinical data will include PET studies assessing the impact ofketamine on dopamine release as well as the effects of dopamine antagonists oncognitive and other behavioral consequences of ketamine in healthy individualsand schizophrenics.

Panel • Monday 1/25/99 • 7:30–9:30 PM • Hoaglund

GLOBAL EFFORTS IN NEUROINFORMATICS

Stephen Koslow, Jan Bjaalie, Jaap van Pelt, Sten Grillner, Paul Verschure

The field of Neuroinformatics(NI) is uniquely placed at the intersection of medi-cal, biological, neuro, behavioral, physical, computer sciences and engineering.NI combines neuroscience, informatics and computation research to to developand apply advanced tools and approaches to understanding brain structure andfunction. The United States Initiative began five years ago as the Human BrainProject. The aim of this panel is to present similar programs underway aroundthe world on NI. These presentations will demonstrate the opportunities andadvantages made possible through the construction of computer-based databasesand the insights gained through neurocomputational models. These presenta-tions include: 3-D reconstruction of anatomical tract-tracing data with visual-ization, cell distribution analyses, axon plexus, surfaces of brain regions for stud-ies LM and EM studies (Jan Bjaalie); modeling and computer simulation forstudying the neuron growth and the dynamic behavior of growth cones(Jaap van

37

Pelt); the lamprey brainstem-spinal cord of locomotor excitatory glutamatergicand inhibitory glycinergic neurons including synaptic connectivity and ion chan-nels along with biophysically realistic cell and network modeling in combinationwith experiments as well as 3-D neuromechanical models with sensory feedback(Sten Grillner); and, the use of synthetic simulation to explore principles under-lying different forms of learning, showing the structures involved in each form(Paul Verschure). Computational models are advantageous since it: (1) guidesdata collection in terms of the kind of data needed, and highlights missing data;(2) requires the user to make explicit their assumptions about the theory; (3)provides for new discoveries by supplementing intuition; (4) allows for the iden-tity of principles of neuronal function; and (5) provides a clear mechanism forcommunication with other scientists.

Panel • Monday 1/25/99 • 4:30–6:30 PM • Carroll

HUNTINGTON S DISEASE AND RELATED DISORDERS: LESSONSFROM TRANSGENIC MOUSE MODELS

John Penney, Jang-Ho John Cha, Gillian Bates, Christopher Ross

Huntington s Disease (HD) belongs to a family of neurologic diseases in whichthe abnormal gene is characterized by an abnormal expansion of a CAG repeatregion encoding an abnormally long polyglutamine stretch within the affectedprotein. CAG repeat diseases share many similarities autosomal dominant in-heritance, adult onset neurodegeneration, and genetic anticipation sug gestingthat these entities may share a common underlying pathogenic mechanism.However, the mechanism by which expanded polyglutamine stretches produceneuronal dysfunction in HD and other CAG repeat diseases remains unknown.Recently created transgenic mice for several CAG repeat diseases offer tremen-dous potential insight into the pathogenesis of CAG repeat diseases. This ses-sion will outline some of the important observations obtained from transgenicmouse models of human CAG repeat diseases. John Penney will offer an over-view of the clinical and neuropathologic aspects of HD. Gillian Bates will de-scribe her transgenic mice which express exon 1 of the human HD gene. Bateswill describe her group s observation of neuronal intranuclear inclusions andtheir relevance to neuronal degeneration. Christopher Ross will describe histransgenic mouse model for dentatorubropallidoluysian atrophy (DRPLA), an-other CAG repeat disease. Jang-Ho Cha will review neurotransmitter receptoralteration in human HD and in transgenic mouse models of HD. This sessionwill provide an overview of HD and related disorders, an introduction to someof the transgenic mouse models of CAG repeat diseases, and a demonstration ofhow such models can yield insights to the pathogenesis of human neurologicdiseases.

38

Panel • Monday 1/25/99 • 4:30–6:30 PM • Erickson

NEURAL STOPWATCHES: IMPLICATIONS FOR NORMAL ANDPATHOLOGICAL COGNITIVE PROCESSES

Aldo Badiani, Warren Meck, John Gibbon, Charles Gallistel

A number of neuropsychological phenomena ranging from rhythmic motor pat-terns (such as licking and tapping) to more complex psychological processes (suchas time discrimination and time estimation) are thought to be depend on internaltiming mechanisms. These interval clocks or stopwatches are very different fromthe better known periodic, circadian clocks. Recent animal and clinical researchhas shed new light on the neurobiological bases of these stopwatches . In par-ticular, there is increasing evidence for an important role of dopamine and ofbasal ganglia in temporal cognition. The goal of this panel is to discuss some ofthese developments and to emphasize the powerful implications that neural clockshave for theoretical models of cognition, reward, and motor performance, undernormal and pathological conditions. Meck will discuss the role of midbraindopaminergic neurons and cortico-striatal circuits in time computation. Gibbonwill report on the distortion of temporal memory in Parkinson patients and onits correction by medications that facilitate dopaminergic transmission. Gallistelwill discuss a time scale invariance model of conditioning as opposed to moretraditional associative learning models based on temporal pairing. Badiani willreport on the effect of repeated amphetamine on the speed of clock-driven lick-ing in the rat.

Panel • Monday 1/25/99 • 4:30–6:30 PM • Janss

CHONDROITIN SULFATE PROTEOGLYCANS: MULTIFACETEDREGULATORS OF GROWTH CONE NAVIGATION AND NEURONALREGENERATION

Diane Jaworski, Robert McKeon, David Muir, DiAnna Hynds

Chondroitin sulfate proteoglycans (CSPGs) are expressed following nervous sys-tem injury, where they play a complex role in regulating neuronal growth conenavigation. Numerous studies now demonstrate that CSPGs inhibit growth coneadvance and may lead to regenerative failure in the CNS. In this session, we willreport on CSPG-mediated inhibition and its role in neuronal regeneration. Fol-lowing an introductory overview by D. Jaworski, presentations will be given cov-ering varied but interrelated experimental approaches to the study of CSPGsand regeneration: 1) B. McKeon will report on factors that stimulate CSPG pro-duction following CNS injury, and will discuss data from his laboratory showingthat TGF-beta stimulates CSPG production by cortical astrocytes. In a model ofCNS injury in vivo, administration of anti-TGF-beta antibodies reduces CSPGexpression and gliosis, and may result in an attenuation of regenerative failure.2) D. Muir will present data using cryoculture demonstrating that the neurite-promoting potential of nervous system tissues is greatly increased by treatmentwith enzymes that degrade and inactivate inhibitory CSPGs, and by matrixmetalloproteinase-2, that is expressed by regenerating ganglionic neurons and

39

Schwann cells. Results of these treatments may provide a means by which to de-inhibit axonal regeneration in the CNS. 3) Growth cones of regenerating neuritesturn to avoid CSPG-rich territories in vivo and in vitro. D. Hynds will present real-time image analysis of neuronal cytoskeletal changes as growth cones contactCSPG, and will discuss associated changes that demonstrate an important rolefor second messenger systems in the detection and avoidance response to CSPG.Each of the above approaches to the study of CSPGs in the nervous system maylead to potential therapies for nerve regeneration.

Panel • Monday 1/25/99 • 4:30–6:30 PM • Snobble

GAP JUNCTIONS IN THE CNS: NEW INSIGHTS FOR BRAINFUNCTION AND DYSFUNCTION

Christian Naus, David Spray, Maiken Nedergaard, Michael Bennett, Roberto Bruzzone

Gap junctions are intercellular channels through which electrolytes, second mes-sengers and metabolites move directly between adjacent cells. In the brain, gapjunctions allow direct signaling between neurons, between glial cells or betweenneurons and glial cells. This interactive panel was designed to allow the discus-sion of recent innovative studies by pioneers in this field that have led to a moresophisticated understanding of what gap junctions actually can do in the CNS.Among the issues to be addressed are the identity, diversity and physiologicalproperties of gap junctions in the CNS (Spray), astrocyte-to-neuron signaling viagap junctions (Rozental and Nedergaard), gap junction-related genetic diseases(Bruzzone and Bennett) and glial gap junctions, tumors and gene therapy (Naus).A critical discussion of these studies may enhance knowledge of the role of gapjunctions in several human brain diseases and perspectives for pharmacologicalmanipulations and gene therapy.

Panel • Monday 1/25/99 • 4:30–6:30 PM • Sinclair

PHARMACOGENETIC APPROACHES TO CLINICAL RESPONSE, SIDEEFFECTS AND BRAIN METABOLISM

William Bunney, David Goldman, James Kennedy, Steven Potkin, Eric Reiman

This panel will review data demonstrating that normal allelic variations in genescan explain heterogeneity in clinical response to therapeutic medications and theoccurrence and severity of side effects. Such contributing differences in allelicvariations need not be causally related to the illness. This will be reviewed by D.Goldman in light of the progress of the human genome project. Two cognitivedisorders, Alzheimer s disease (AD) and schizophrenia, will be contrasted tohighlight the role that normal allelic variation can play in the age of onset, thera-peutic and brain metabolic response. Reiman will discuss FDG PET reductionsin regional brain glucose metabolism that precede the onset of AD in persons atgenetic risk. Those with one or two copies of the APO-E4 allele, a risk factor forAD, demonstrate decreased brain metabolism prior to the onset of any clinicalsymptoms in the same posterior cingulate, parietal, temporal and prefrontal re-gions as patients with Alzheimer s dementia. Potkin will discuss that clozapine,

40

a highly effective treatment for schizophrenia, binds with high affinity to D1,D4, and serotonin 2A receptors. Subjects homozygous for the type 2 D1 alleleclinically respond to clozapine and have a corresponding alteration in brain me-tabolism. In contrast, those without the 2-2 pattern fail to clinically respond toclozapine and do not exhibit significant changes in brain metabolism. Kennedywill present epidemiological data suggesting that improvement in psychotic symp-toms following clozapine is related to genetic variations in D4 and serotonin 2Areceptors. Further, he will present provocative new data strongly linking allelicdifferences in the D3 dopamine receptor to the development of tardive dyskine-sia.

Minicourse Session I • Monday 1/25/99 • 4:30–6:30 PM • Hoaglund

NEW OPTICAL IMAGING METHODS IN CELLULAR NEUROSCIENCE

Stephen Smith, Stuart Thompson, Philip Haydon, Maiken Nedergaard

New imaging instruments and new staining methods have transformed cellularneuroscience repeatedly ever since apochromatic microscope objectives and Golgistains led a century ago to the neuron doctrine. At present, two-photon, confocaland CCD-based digital imaging instruments along with a panoply of new syn-thetic and molecular biological stains are taking center stage. This minicoursewill provide a mix of tutorial introductions and cutting-edge research examplesof some of the most exciting new methods. Most speakers will emphasize ap-proaches suitable to the dynamic study of live neural specimens.

Workshop Monday 1/25/99 • 8:30–10:00 PM • Janss

A LITTLE DABA GABA: CAN WE MEASURE GABA NEUROTRANSMIS-SION WITH IN VIVO MICRODIALYSIS?

Kristen Keefe, Bryan Yamamoto, John Bruno, Janet Finlay, Arne Schousboe

Although in vivo microdialysis is frequently used to measure various transmit-ters, its validity for measuring neuronally released amino acid transmitters, inparticular GABA, is controversial. For example, at least one recent review hassuggested that extracellular GABA as measured with in vivo microdialysis is nota valid measure of GABA-mediated neurotransmission under many conditions.Since GABA is the main inhibitory neurotransmitter in the brain, the ability tomeasure its release in vivo is extremely important. The purpose of this workshoptherefore will be to address a number of fundamental, yet controversial, issuessurrounding the use of microdialysis to measure GABA neurotransmission. Theparticipants and audience will address the following questions in open debate,presenting data only to support the specific point being made. The questions tobe addressed and the participants who will lead the debate include: 1) Is it pos-sible to reliably derivatize GABA and to isocratically separate it from other aminoacids, especially at short retention times (Yamamoto, Keefe, Bruno)?; 2) Wheredoes extracellular GABA come from, if not the synapse, under basal and evokedconditions (Schousboe, Finlay)?; 3) Can we measure GABA release evoked by

41

circuitry-specific manipulations in the cortex (Finlay), basal ganglia (Keefe, Bruno,Yamamoto), and basal forebrain (Bruno)?; 4) Can we relate changes in GABAlevels in dialysate to behavior (Bruno; Schousboe)? Each participant will providean answer to their question and the data supporting their conclusion in 5 min.An additional 10 min will be provided for open discussion about each topic,during which time audience members will be invited to discuss their own dataand experience.

Workshop Monday 1/25/99 • 8:30–10:00 PM • Carroll

EXPERIMENTATION TO ADDICTION: WHAT DRIVES THE PROGRESSION?

Fulton Crews, George Koob, Agu Pert, Mary, Kreek, Charles O Brien

A significant percentage of the population experiments with alcohol and otheraddictive drugs, yet only a portion, approximately 10% become addicted. Thetransition from experimentation to addiction appears to be similar for all addic-tive drugs, often taking several years to develop and frequently involving polydruguse. Although the processes underlying the progression to addiction are not fullyunderstood, they appear to involve complex interactions among neurobiologi-cal, psychological and social factors. Recent preclinical conceptualizations haveemphasized both neuroadaptive changes and associative mechanisms (learning)as principal determinants behind the evolution of addiction. Dr. Crews will dis-cuss new data on chronic alcohol induced changes in gene expression and neuro-chemistry within the limbic and association cortex. Changes in the function ofthese cortical areas will be related to increases in alcohol consumption. Dr.Koobwill present new data on the progressive dysregulation of brain reward systemsby repetitive drug exposure and the implications of such alterations for under-standing the addictive process. Dr.Pert will discuss the relevance of associative(learning) mechanisms and their neurobiological substrates in the evolution ofdrug addiction. Dr.Kreek will focus on the importance of alterations in neuroen-docrine function following cocaine exposure as a determinant of cocaine addic-tion. Dr O Brien and Dr. Kreek will attempt to integrate these preclinical find-ings and conceptualizations with clinical observations in addicts. Dialogue amongparticipants and audience participation will be actively encouraged.

Workshop Monday 1/25/99 • 8:30–10:00 PM • Sinclair

DELAYED NEURODEGENERATION: A DAM(N)ABLE CASCADE

Michael Bennett, Dennis Choi, Suzanne Zukin, Roger Simon

A brief neurological insult, such as transient forebrain or global ischemia, maybe followed by apparently complete recovery, yet certain neurons are destined todie. The insult triggers a cascade of transcriptional and translational changes,providing numerous candidates for involvement in the ultimate cell death. Onewould like to know which, if any, are sufficient, and which, if not all, are neces-sary. Given that there is a sequence of changes prior to frank and irreversibledeath, one would expect there to be corresponding interventions in the course of

42

the maturation of the degenerative changes. One should distinguish betweenprotection, which by definition must be done before the sequence is initiated,and rescue, which may be possible at stages after the initiation. Rescue raises theissue of therapeutic window; how late can a given rescuing treatment be initi-ated and how long must the treatment be continued, if indeed it can ever beterminated. Given the unpredictability of stroke, rescue is of great clinical rel-evance. Dennis Choi will present evidence that zinc entry during ischemia trig-gers the subsequent steps leading to cell death. Michael Bennett will discusschanges in GluR2 mRNA and protein that leads to formation of GluR2 lackingand therefore Ca2+ permeable AMPA receptors and, apparently, increased patho-genicity of endogenous glutamate. Suzanne Zukin will describe the neurotoxiceffects of knock down of GluR2 by antisense oligonucleotides. Roger Simonwill address the role of caspases and apoptosis in the finale of delayedneurodegeneration.

Workshop Monday 1/25/99 • 8:30–10:00 PM • Erickson

SHARING REAGENTS: THE DREAM AND THE REALITY

Michael Zigmond, Marie-Francoise Chesselet, Steve Hyman, Bob McCall, and GordonShepherd

Many guidelines, including those from NIH and the Journal of Neuroscience,call for scientists to share materials used in published research that are not other-wise available. There are many good reasons for such a position. For example,research is of little value if the scientific community cannot adequately evaluate and attempt to replicate published results. Nonetheless, several concerns havebeen raised: (1) To which materials should these guidelines by applied? (2) Oncean investigator has stopped using a given reagent or animal, must a supply bemaintained for others? (3) How is the requirement for sharing to be enforced? (4)Can researchers working in private industry be expected to abide by this require-ment? And, (5) might the career of a junior scientist jeopardized by such a policy.Several individuals have been invited to make brief presentations to be followedby a round table discussion that will include the issues listed above. Marie-Francoise Chesselet has made use of many antibodies over the years, Steve Hymanhas both produced and used specialized reagents and, in addition, serves as di-rector of an NIH institute, Perry Molinoff is director of CNS pharmacology inprivate industry and Gordon Shepherd is the editor-in-chief of the Journal ofNeuroscience. The discussion will be moderated by Michael Zigmond, who hasserved as the chair of a committee drafting guidelines for responsible conduct inpublishing. Audience members will be encouraged to participate actively in thesediscussions.

43

Panel • Tuesday 1/26/99 • 7:30–9:30 AM • Erickson

INTERACTIONS BETWEEN THE NIGRA AND PALLIDUM MODULATEBASAL GANGLIA OUTPUT

Suzanne Haber, J. Paul Bolam, T. Celeste Napier, Hagai Bergman

The substantia nigra and globus pallidus are considered to be the main targets ofthe striatum. Recent studies have focused on the neural networks that allow inte-gration among sensorimotor, cognitive, and limbic functional domains of thestriatum, as determined by its cortical inputs. This panel addresses how the inter-play between the nigra and pallidum output influences communication amongthese domains. Two of the talks will examine these neural networks in rats andtwo in nonhuman primates. Dr. Paul Bolam will discuss the synaptology of neu-rons of the globus pallidus and the convergence of limbic and nonlimbic pallidalinputs onto both dopamine and nondopamine cells. Dr. Suzanne Haber will dis-cuss how pallidonigral/striatal pathways create an ascending integrative networkthat affects motor outcome through successive connections with different popu-lations of dopamine neurons. Dr. Celeste Napier will discuss how nigra outputsinfluence limbic-pallidal function through the subthalamic nucleus and how thisfunction is altered by A9 dopaminergic lesions. Dr. Hagai Bergman will discusshow the reward driven activity of dopaminergic neurons in the substantia nigraand striatal cholinergic interneurons influence pallidal output and synchronicityand how this system is altered with a large dopamine lesion. These discussionswill shed new light on the contribution of pallidal/nigral interplay in informa-tion processing that under lies complex behaviors.

Panel • Tuesday 1/26/99 • 7:30–9:30 AM • Hoaglund

TRANSGENIC MICE AND ALZHEIMER S DISEASE

Jeanne Loring, Bruce Lamb, Lisa McConlogue, Steven Wagner, Karen Hsiao

An animal model for Alzheimer s disease has been high on the wish list of basicresearchers and drug developers for many years. Without such an experimentaltool, all theoretical models of disease development, no matter how logical andexciting, remain untested and so cannot evolve. There has been rapid improve-ment in genetic engineering of animals in the last ten years, and several researchgroups have applied this new knowledge to building transgenic solutions to theproblem of understanding AD. There are now at least half a dozen mousetransgenic lines that develop one of the pathological characteristics of AD, amy-loid plaques. Thus, it seems as if the solution may have been found. Or has it?The speakers for this panel include researchers who have produced amyloid-accumulating transgenic mouse lines, and others whose primary goal is to testthe effects of AD drug candidates in an animal model. They will discuss theprogress in this field and address the question of whether the existing lines arethe long-awaited animal models that can be used to test the theories of AD patho-genesis. If they are, then what is the best course for their use? If they are not, thenwhat can be done to improve them?

44

Panel • Tuesday 1/26/99 • 7:30–9:30 AM • Snobble

KEEPER OF THE GATE: THE ROLE OF THE VAGAL COMPLEX IN THEREGULATION OF THE AUTONOMIC NERVOUS SYSTEM

William Renehan, Renato Travagli, David Mendelowitz, Richard Gillis

It could be argued that the vagal complex (VC) is one of the least understoodregions of the central nervous system. The VC receives inputs from numerousparts of the body, such as the cardiovascular and gastrointestinal systems, andsends projections to such diverse sites as forebrain nuclei and the respiratorytract. This abundance of connections has prompted many investigators to sug-gest that the VC must serve an important role in homeostasis, but the mecha-nisms underlying this function remain unclear. Recently, however, neuroscien-tists have gained a number of insights into the activity and purpose of vagalcircuits. The goal of this Panel Presentation is to illustrate our current under-standing of the assimilation, integration and dissemination of information bythe VC. Dr. Mendelowitz will discuss the brainstem circuits that regulate heartrate and rhythm. He will focus on the synaptic interactions between cardiac va-gal neurons and present evidence that central cholinergic pathways as well aspre- and post-synaptic nicotinic receptors are involved in modulating the sensi-tivity of the baroreflex and cardiac rhythm. Dr. Travagli will discuss the brainstemcircuits that regulate gastrointestinal vago-vagal reflexes, concentrating on theinterplay between sensory and motor neurons and presenting evidence that va-gal motor neurons can be distinguished based on their location, morphology,membrane properties and pharmacology. Dr. Gillis will focus on vagal neuronsinvolved in respiration and will introduce some very recent data regarding theresponse of these neurons to various receptor agonists and antagonists. He willdiscuss a number of apparent inconsistencies in the results obtained in theseinvestigations and illustrate the potential role of these receptors in the control ofrespiration. Dr. Renehan will moderate the session and present recent data re-garding the electrophysiology of vagal neurons that process information regard-ing noxious visceral stimuli.

Panel • Tuesday 1/26/99 • 7:30–9:30 AM • Sinclair

APOPTOSIS IN NERVOUS SYSTEM DEVELOPMENT AND DISEASE

H. Robert Horvitz, Hermann Steller, Pasko Rakic, Junying Yuan

Apoptosis or programmed cell death is a major feature of the normal develop-ment of the nervous system. The clinical features of a variety of neurologicaldisorders inc luding neurodegenerative diseases, stroke and traumatic braininjury ar e a consequence of excessive neuronal cell death, and one currenthypothesis is that much of this excessive cell death involves the same mecha-nisms as those used during normal nervous system development. We will discussnew findings concerning the mechanisms of apoptosis and implications of thesefindings for neurologic disease and for drug discovery. The theme of our session

45

is the finding that the molecular mechanisms responsible for programmed celldeath are broadly conserved among organisms as diverse as nematodes, fruitflies, mice and humans. H. Robert Horvitz will discuss the genetic pathway ofprogrammed cell death in the nematode Caenorhabditis elegans, describing therole of protective genes related to the human proto-oncogene bc1-2 and of killergenes, such as the ced-3 gene, which encodes a founding member of the caspasefamily of proteases. Hermann Steller will describe genes that regulate programmedcell death in the fruit fly Drosophila melanogaster and a Drosophila model forneurodegeneration that suggests that caspases could be an appropriate target forthe treatment of human retinal degeneration. Pasko Rakic will present findingsthat mutant mice lacking either of two mammalian caspases, caspase-3 andcaspase-9, generate supernumerary neurons and that a block in apoptosis cancause gross structural alterations in the murine nervous system, such as a convo-luted cortex. Junying Yuan will discuss studies of a mouse model for ischaemicstroke that has revealed that cell death in such mice is apoptotic in nature andcan be blocked by inhibiting caspase activity.

Panel • Tuesday 1/26/99 • 7:30–9:30 AM • Carroll

HEAVY BREATHING IN SNOWMASS: SEROTONIN AND THE RESPI-RATORY RESPONSE TO ALTITUDE

George Richerson, Jan Ramirez, Jack Feldman, Gordon Mitchell

Many lowlanders suffer from acute mountain sickness for the first couple days ataltitude, especially when coupled with vigorous exercise and dietary indiscre-tion: Sound familiar? Acclimatization, rather than simply being due to changesin acid/base status (a distinctly non-brain function), results in part from plastic-ity of the response of the central respiratory control system to hypoxia. Thishypoxia induced plasticity of ventilatory control is dependent upon serotonergicmechanisms in the CNS. We will present data pointing to potential mechanismsby which serotonin could mediate this response. George Richerson will discussfindings that raphe neurons sensitive to pH contain serotonin and project to res-piratory neurons. Jan (Nino) Ramirez will describe data from brain slices show-ing that hypoxia-induced responses in medullary respiratory neurons are seroto-nin dependent. Jack Feldman will discuss data from the rat in vitro brainstem /spinal cord preparation examining the role of raphe neurotransmitters in centralrespiratory control. Gordon Mitchell will discuss in vivo data indicating that se-rotonin plays a key role in the adaptation of the central respiratory response tohypoxia. The focus of this panel will be to discuss the role of serotonergic mecha-nisms in respiratory control, and in adaptation to hypoxia and exercise. Under-standing these mechanisms may help to find effective treatments to permit morerapid acclimatization to altitude, without curtailing activity.

46

Panel • Tuesday 1/26/99 • 7:30–9:30 AM • Janss

NEUROLOGICAL CONSEQUENCES OF DIABETES: MODULATION BYGLUCOCORTICOIDS

Lawrence Reagan, Anthony McCall, Errol De Souza, Stephen Woods

It is now recognized that diabetes mellitus produces damage in the central ner-vous system and potentiates neuronal damage mediated by stroke or ischemia.Glucocorticoid (GC) mediated neuronal damage and exacerbation of neuronalloss in pathophysiological settings also appears to involve decreases in glucoseutilization. Accordingly, this panel will examine our current understanding ofthe neurological changes mediated by diabetes, as well as discuss how GCs maycontribute to or modulate diabetes-induced changes in the brain. McCall willdescribe the deleterious neurological consequences of hypoglycemia observed inexperimental models of diabetes, as well as describe some of the consequencesof diabetes on the human brain. De Souza will describe insulin-like growth fac-tor binding protein (IGF-BP) regulation of IGF function, and also discuss thepotential therapeutic benefits of IGF-BP ligand inhibitors in the treatment ofneurodegenerative disorders. Woods will discuss leptin regulation of neuroen-docrine functions; in particular, leptin enhancement of hypothalamo-pituitary-adrenal axis activity. Reagan will discuss the molecular changes induced by stressin the hippocampus of diabetic rats; specifically, the stress/diabetes regulationof genes critically involved in glucose utilization. Collectively, this panel willdescribe molecular and physiological changes in the brain induced by diabetesand neuroendocrine activation in experimental paradigms, and relate these find-ings towards the development of therapeutic strategies to protect the brain dur-ing periods of hypoglycemia.

Panel • Tuesday 1/26/99 • 4:30–6:30 PM • Carroll

CAG REPEAT EXPANSIONS: HOW DO THEY KILL NEURONS?

Marie-Francoise Chesselet, Diane Merry, Christopher Ross, Tim Greenamyre, MichaelLevine

Expansion of CAG repeats in the coding region of different genes causes at least8 different late-onset neurodegenerative diseases. The last few years have seen anexplosion of information on the effects of expanded glutamine repeats in celland mouse models. A remarkable aspect of this research is the emergence ofparallels between pathological mechanisms in Alzheimer disease, Parkinson sdisease and triplet repeat expansion diseases. This panel will provide an over-view of state of the art knowledge in the field of CAG repeat disease and high-light the significance of these findings for other neurodegenerative diseases. DianeMerry will present data on aggregation of the mutated androgen receptor incellular models of Kennedy disease; Chris Ross will review data on protein-pro-tein interactions of huntingtin, the protein mutated in Huntingtin s disease,huntingtin aggregation in Huntingtin s disease and cell models of Huntingtin s

47

disease; Tim Greenamyre will present his findings on mitochondrial dysfunctionin cells from patients with Huntingtin s disease and Michael Levine will presentdata on altered sensitivity to glutamate of neurons from mouse models ofHuntingtin s disease.

Panel • Tuesday 1/26/99 • 4:30–6:30 PM • Hoaglund

GLUTAMATERGIC MECHANISMS IN SENSORY INFORMATIONPROCESSING

Sue Kinnamon, Thomas Hughes, Charles Greer, Nirupa Chaudhari, Thomas Finger

Glutamate plays a pivotal role in the transmission of information at early syn-apses for virtually every sensory modality. In addition, glutamate serves as adirect stimulus for taste receptor cells. This session will explore the role ofglutamate receptors in the detection and transmission of sensory information intaste, olfactory and visual modalities. Glutamate often serves as the transmitterbetween the receptor cell and subsequent neurons in a sensory system. For ex-ample in the retina, photoreceptors transmit signals to the bipolar neurons via aglutamatergic synapse. Thomas Hughes will describe the wide variety of differ-ent receptor subtypes expressed by retinal cells, and will discuss how we canbegin to dissect out the function of receptor subtypes at specific synapses. Simi-larly, olfactory receptor cells utilize glutamate as a transmitter at their synapsewithin the olfactory bulb. Charles Greer will describe the role of glutamate re-ceptors in mediating both primary afferent input into the olfactory bulb as wellas in modulating local circuit, dendrodendritic synapses during olfactory learn-ing and development. The gustatory system is unique in that glutamate is usedboth as a neurotransmitter and as a taste stimulus per se. Nirupa Chaudhari willpresent evidence for the presence of ionotropic and metabotropic glutamate re-ceptors in taste receptor cells and their possible interactions in detecting glutamateas a taste stimulus. Thomas Finger will discuss the role of NMDA and non-NMDA receptors in taste information processing in the primary gustatory nucleus.

Panel • Tuesday 1/26/99 • 4:30–6:30 PM • Janss

SEROTONIN AND BEHAVIOR: RECENT FINDINGS AND THE LEGACYOF MARKKU LINNOILA

J. Higley, Joseph Hibbeln, Gerald Brown, David Nielson

Dr. Brown will present a brief historical overview and recent work by Dr. Linnoilaand his colleagues investigating impaired CNS serotonin function and impulsivebehavior. He will present data demonstrating homicidal patients seen in the emer-gency room, who were committed for violent behavior (within 2 days) are likelyto have been prescribed serotonin enhancing drugs (Valproic acid, lithium, orcarbamazepine), and to be noncompliant with their medication at commissionof the violent behavior. Dr. Higley will discuss research from a collaborationwith Dr. Linnoila using nonhuman primates investigating CNS serotonin func-

48

tioning and impulsive behavior. He will show molecular genetic data from stud-ies investigating the relationship between serotonin transporter (5-HTT) geno-types, CSF 5-HIAA concentrations, and alcohol-related aggression. His data showthat monkeys with the s allele 5-HTT variant have low CSF 5-HIAA concentra-tions and are particularly aggressive when intoxicated. New SPECT data will beshown indicating a correlation between cisternal CSF 5-HIAA concentrationsand 5-HTT reuptake, particularly in the frontal region. Dr. Nielsen will presentdata from Finnish alcoholic offenders showing candidate allele and marker link-age studies. The role of gene expression in serotonergic function will also bepresented. One of the last areas of research Dr. Linnoila was involved in investi-gated the function of nutritional variables in serotonin functioning. Dr. Hibbelnwill show recent cross-national epidemiological data indicating a strong protec-tive role of fish consumption in major depression (r= -0.84). Consistent withthese findings, plasma docosahexaenoic acid (DHA) concentrations positivelypredicts CSF 5-HIAA concentrations. Such findings indicate that DHA maymodulate serotonergic neurotransmission.

Panel • Tuesday 1/26/99 • 4:30–6:30 PM • Sinclair

INTRINSIC AND EXTRINSIC MECHANISMS OF AXON COLLATERALBRANCH FORMATION

Paul Letourneau, Peter Baas, Gianluca Gallo, Katherine Kalil, Eduardo Macagno

The formation of collateral branches from axonal shafts is an important part ofboth the development of synaptic connections and axonal regeneration. Little isknown about the intrinsic mechanisms that generate collateral axonal branchesor the extrinsic signals that might induce the formation of collateral branches.This group of speakers will present information from in vitro and in vivo studiesof how collateral branches are formed in developing birds, mammals and leeches.Kate Kalil will discuss the formation of interstitial branches by cultured corticalneurons. The sites where axonal growth cones pause and undergo structural re-organization before advancing are locations where interstitial branches later sproutfrom the same axon. Peter Baas will present data on proteins that facilitate branch-ing by fragmenting axonal microtubules in the region where branches are formed,and on motors proteins that transport microtubules into a newly formed branch.Gianluca Gallo will describe the action of neurotrophins to induce filopodialsprouts along axons, which can lead to formation of stable collateral branches.Eduardo Macagno is studying the formation of a network of motor axon branchesaround the developing leech heart. Formation of this network is inhibited by anantibody against the extracellular portion of a receptor tyrosine phosphataseexpressed by the heart muscle. The induction of collateral branching may in-volve homophilic interactions with receptor tyrosine phosphatases on the axonalshafts.

49

Panel • Tuesday 1/26/99 • 4:30–6:30 PM • Erickson

NONSELECTIVE CATION CHANNELS: EMERGING TARGETS FOR GPROTEIN COUPLED RECEPTORS

Rodrigo Andrade, Leonard Kaczmarek, Steven Siegelbaum, Yasuko Nakajima

G protein coupled receptors regulate membrane excitability in neurons by regu-lating a variety of ion channels. Most work to date has focused on the regulationof calcium and potassium channels. However, it is now becoming clear that non-selective cation channels are also an important, but often overlooked, target forthese receptors. In this panel we will review some recent developments in ourunderstanding of nonselective cation channels and their role in mediating neu-rotransmitter actions in excitable cells. It is now clear that there are multipleclasses of nonselective cation channels. The best understood of these are thecyclic nucleotide gated channels, which play an important role in sensory trans-duction, and also probably in the life of neurons. Steve Siegelbaum will reviewthe molecular biology of these channels and present results illustrating how cy-clic nucleotides regulate these channels. Yasuko Nakajima will then describerecent studies on a different nonselective cation channel that is regulated byneurotensin in mammalian dopamine cells. Rodrigo Andrade will describe howmuscarinic responses in prefrontal cortex are mediated in large part by a voltage-and calcium- dependent nonselective cation current. Finally, Len Kaczmarekwill talk about the signaling mechanism regulating a voltage- and calcium-de-pendent cation channel in Aplysia bag cell neurons.

Workshop Tuesday 1/26/99 • 8:30–10:00 PM • Janss

COGNITIVE NEUROSCIENCE INVESTIGATIONS: CHOICE OFTECHNIQUE

John Hart, Jr., Steven Small, Nathan Crone

Recent advances in neuroimaging have challenged cognitive neuroscientists toconsider thoughtfully the choice of investigative technique for particular ques-tions. Two contrasting approaches, with different strengths and weaknesses, in-clude (1) subtractive or lesion studies, and (2) activation or metabolic studies.The activation studies, if properly designed, can delineate multiple brain regionsinvolved in the performance of a cognitive task, often without revealing howessential that region is to performing the task. Some investigators have claimedthat these studies can lead to an overestimation of the regions involved in a cog-nitive function, and that they require acceptance of a number of questionableassumptions (e.g., serial processing, subtractive logic) for interpretation of thedata. On the other hand, subtractive or lesion studies can delineate the brainregions essential to performing a cognitive function, but have different disadvan-tages. Human brain lesions are accidental in location, the premorbid status ofpatients is unknown, and functional interpretation is complicated by mechanismsof physiological recovery and possibly cerebral reorganization. Discussion inthis workshop will comprise two parts. Part one will focus on the virtues andshort-comings of these approaches including lesion studies, cortical electrical

50

interference, ERP/ECoG, PET, and fMRI. Part two will involve discussion ofthe investigative questions being asked, the factors that influence experimentaldesign, and how these issues may/should subsequently influence choice of in-vestigative techniques to be used, given their availability.

Workshop Tuesday 1/26/99 • 8:30–10:00 PM • Carroll

THE FINAL PARADOX: NEURONAL DIVISION, PROLIFERATION ORDEATH?

Mark Smith, Inez Vincent, Zsuzsanna Nagy, Peter Davies, Gregory Brewer

There is increasing evidence that post-mitotic, terminally differentiated neuronscan re-enter the cell cycle. Whether re-entry leads to cellular proliferation or deathis open to question, evidence supports both mechanisms. Indeed, while there isevidence that post-mitotic neurons are able to proliferate both in vitro and in vivo,exactly the same mechanism may result in cell death in animal models and inneurodegenerative disorders. In the latter, it is proposed that re-entry in the cellcycle leads to a cascade of biochemical events including oxidative stress andaberrant phosphorylation of cytoskeletal elements, i.e., exactly those featuresfound in such conditions as Alzheimer and Parkinson diseases. The goal of thisworkshop is to gather together experts from both sides of the fence to debatethese controversial issues. Drs. Gregory Brewer, Peter Davies, Zauzsanna Nagy,Huntington Potter, Mark A. Smith, and Inez Vincent will lead the discussions. Itis anticipated that the dichotomy of research findings will provide an ideal fo-rum for a lively debate.

Workshop Tuesday 1/26/99 • 8:30–10:00 PM • Sinclair

WHAT REGULATES RECEPTOR CHANNEL PROPERTIES IN DEVEL-OPING SENSORY CORTEX?

Sharon Juliano, Adam Smith, Hannah Monyer, Arnold Kriegstein

Neurotransmitter receptor channels change their properties during development,presumably to accommodate their changing functional roles as the brain ma-tures. By focussing on NMDA and GABAA receptors in developing sensory cor-tex, the participants present evidence that both intrinsic activity and sensory ex-perience regulate changes in receptor expression. NMDA receptor current laten-cies recorded during cortical development decrease; this latency reduction is atleast partly due to a switch in receptor subunit composition. Hannah Monyer(Heidelberg) shows that this switch is delayed in rat visual cortex by dark-rear-ing, implying that the change in receptor subunit composition is regulated bysensory experience. In neonatal ferret visual cortex, however, Adam Smith (Ox-ford) suggests that the switch is regulated by intrinsic cortical activity since thechange in subunit composition is inhibited by cortical activity blockade prior togeniculocortical invasion. GABAA receptor levels in primary sensory cortex arehigher than in surrounding areas, raising the possibility that afferent sensoryinformation may influence the pattern of GABAA receptor expression. By study-

51

ing ferrets in which the primary target of thalamic afferents (i.e., layer 4) is dis-rupted in somatosensory cortex, Sharon Juliano (Bethesda) reports that alteredthalamocortical connectivity coincides with changes in the laminar expressionpatterns of GABAA receptors. But during synaptogenesis in developing rat cor-tex, Arnold Kriegstein (New York) finds that changing receptor channel phar-macologies underlie the switch from non-synaptic to synaptic activation ofGABAA receptors, suggesting that GABAA receptor properties are also influ-enced by synaptic contacts before the onset of sensory experience.

Workshop Tuesday 1/26/99 • 8:30–10:00 PM • Erickson

NOVEL PREPARATIONS TO UNTANGLE BRAIN FUNCTIONS

Sandra Pearl, Dietmar Plenz, Karen O Malley, Jay Hirsh, Steven Thomas

During the past few decades, the function of monoamines within the basal gan-glia has been elucidated in tight connection with the introduction and improve-ment of in vitro and in vivo models such as synaptosomes, primary cell lines,acute slices, and in vitro vertebrate preparations. Recent progress has now madeit possible to combine both molecular manipulative strength and comparabilitywith the in vivo situation into new models which overcome some of the limita-tions of previous approaches. This workshop will focus on how novel prepara-tions may be used to examine neurotransmission, connectivity and developmentin discrete brain systems, in this case systems involving amines. Dr. Plenz willdescribe a technique of organotypic co-culture involving the striatum, cortex,sunstantia nigra and other related basal ganglia nuclei. These cultures retain theneuronal connections seen in situ and yet allow manipulations of specific nueronalpopulations never before possible. Dr. O Malley will detail a novel primary cellculture line which both synthesizes and releases dopamine, and the characteriza-tions of this line with regard to tyrosine hydroxylase and dopamine receptorregulation. Dr. Hirsh will discuss the role that invertebrate models may play inbasic aminergic research. His work with Drosophila demonstrates that behav-ioral effects induced by dopamine agonists and cocaine largely resemble thoseseen in vertebrates. And Dr. Thomas will describe the importance of targetedgene knockouts in understanding the role that enzymes and receptors may playin basal ganglia regulation. Specifically he has created a dopamine B-hydroxy-lase knockout mouse that conditionally lacks norepinephrine. The audience isinvited to discuss the relevance of these novel methods and determine futurestudies that may be particularly well addressed by these preparations.

Minicourse Session II • Tuesday 1/26/99 • 8:30–10:00 PM • Hoaglund

NEW OPTICAL AND IMAGING METHODS IN CELLULAR NEURO-SCIENCE

Stephen Smith, Stuart Thompson, D. Madison, A. Charles

SEE SESSION I MINICOURSE ABSTRACT PAGE 40.

52

Panel • Wednesday 1/27/99 • 7:30–9:30 AM • Hoaglund

HOW THE BRAIN SENSES, UTILIZES AND REGULATES ENERGYSUBSTRATES

Barry Levin, Dianne Lattemann, Pierre Magistretti, Bruce Ransom, Ian Simpson

Energy homeostasis is tightly regulated within the body. In part this reflects theneeds of the brain for a constant supply of substrate for normal functioning. Thispanel will discuss the mechanisms by which the brain senses the availability ofsubstrate, utilizes it for neuronal function and, in turn, regulates the availabilityof substrate both in the brain itself and in the periphery. Increasing evidencesuggests that astrocytes play a critical role in coupling synaptic activity to glu-cose utilization. In addition, astrocytes can store glucose as glycogen and releaselactate as an adequate substrate to meet the energetic demands of synaptic activ-ity and axon function.. Monocarboxylate transporters (MCT) provide a mecha-nism for entry of lactate into the neurons where it is converted into pyruvate foruse in the TCA cycle. Expression of both MCT and glucose transporters changewith alterations in glucose availability. Specialized neurons alter their firing rateswhen ambient glucose levels rise or fall. An ATP-sensitive K+ channel mediatesthis effect in those neurons whose firing rate rises with increasing glucose levels.This channel can be neuroprotective by hyperpolarizing the neuron when sub-strate availability becomes limited. Such neurons are integrated into the pitu-itary-sympathoadrenal counter-regulatory response mechanism which is activatedduring hypoglycemia. Repeated hypoglycemic bouts progressively dampen thisresponse through an unknown mechanism. Thus, the brain can sense, utilizeand, to some extent regulate substrate availability in both physiologic and patho-logic states.

Panel • Wednesday 1/27/99 • 7:30–9:30 AM • Carroll

MAGNOCELLULAR NEURONS: BIGGER IS BETTER!

Celia Sladek, Steve Bealer, Gloria Hoffman, Alan Johnson

The focus of this panel will be utilization of the hypothalamo-neurohypophy-seal system as a model for understanding neuronal mechanisms. Themagnocellular vasopressin and oxytocin neurons of this system are tightly clus-tered in the supraoptic and paraventricular nuclei, project to the neural lobe, andare specialized for secretion of large amounts of peptide. As a result of theseattributes, they have served as excellent model neurons for studies on neurose-cretion, electrophysiology of identified neurons, and morphological plasticity inthe CNS. The panelists will describe recent studies employing this system thatdemonstrates its continued efficacy as a model for studies on a variety of issues.C. D. Sladek will initiate the panel by reviewing research areas in which knowl-edge was significanly advanced as a result of use of the magnocellular neurohy-pophyseal system as a model system. She will also present recent studies demon-strating the ability of these neurons to utilize exogenous mRNA to synthsizepeptides and the unexpected importance of ongoing transcription and transla-tion in the release of the hormones. S.L. Bealer will describe recent studies utiliz-

53

ing in vivo dialysis to study neurotransmitter regulation of intranuclear peptiderelease during physiological stimulation. G.E. Hoffman will describe the devel-opment and utility of dual and triple labelling histological approaches to studydifferential regulation of co-localized peptides in the magnocellular neurons. Thefinale will be A.K. Johnson presenting evidence validating the use of adenoviralvectors for transfection of genes to the magnocellular neurons. Each presenta-tion will provide new information on the regulation of the neurohypophysealstytem as well as highlighting the importance of these findings to the rest of theCNS.

Panel • Wednesday 1/27/99 • 7:30–9:30 AM • Janss

EXPLORING THE RELATIONSHIPS OF MESENCHYME TONERVOUS SYSTEM AND CRANIOFACIAL DEVELOPMENT ANDREGENERATION

Daniel Marshak, Martha Bohn, Anthony LaMantia, Jean Lauder, Darwin Prockop

Mesenchymal cells differentiate to form various musculoskeletal and connectivetissue, including bone, cartilage, muscle, fat, marrow stroma, tendon and liga-ment. During development, mesenchymal cells derived from neural crest are foundin craniofacial tissues, and mesenchymal cells derived from mesoderm form thesomatic connective tissues. Participants in this session will discuss how mesen-chyme influences development of tissues in the nervous system and in craniofa-cial structures. Dr. LaMantia will discuss the role of mesenchyme in the induc-tion of embryonic forebrain development in mice. Dr. Lauder will discuss sero-tonergic regulation of mouse cranial neural crest migration, and proliferationand differentiation of crest-derived craniofacial mesenchyme cells. Dr. Prockopwill discuss the transplantation of mesenchymal cells of the bone marrow stromainto rat brain, and their differentiation in vivo. Dr. Bohn will discuss the use ofmesenchymal progenitor cells expressing the neurotrophic factor, GDNF, to sup-port survival of motoneurons in a mouse model of amyotrophic lateral sclerosis.Dr. Marshak will lead the panel and will make brief remarks on the phenotypeof human mesenchymal stem cells and their potential clinical use for tissue re-generation and gene therapy in the nervous system.

Panel • Wednesday 1/27/99 • 7:30–9:30 AM • Erickson

VOLTAGE-DEPENDENT SODIUM CHANNELS: MOLECULAR DETER-MINANTS OF NORMAL AND ABNORMAL FUNCTION AND ITS PHAR-MACOLOGICAL MODULATION

Todd Scheuer, Alan Goldin, Paul Bennett, Peter Ruben, Robert French

Properly functioning sodium channels are essential for normal neuronal func-tion. In addition to being responsible for the upstroke of the action potential, amaintained, non-inactivating component of sodium current plays important rolesin neuronal behavior. However, abnormally large non-inactivating sodium cur-rents produce pathological electrical behavior in the brain, as well as in otherelectrically excitable tissues. Blockers and modulators of ion channels are im-

54

portant tools for controlling such aberrant electrical activity as well as being im-portant tools for probing the molecular basis of ion channel function. This ses-sion will briefly introduce function and modulation of transient and maintainedsodium currents in the brain. Speakers will then discuss molecular mechanismsunderlying maintained sodium currents including effects of G protein beta gammasubunits (Scheuer), and expression of particular sodium channel isoforms(Goldin). Effects of sodium channels with abnormal inactivation and/or sloweddeactivation underlying abnormal physiological behavior expressed in transgenicmice or in heterologous systems will be considered (Goldin and Ruben). Focaland local interactions between an external peptide blocker, mu conotoxin, andcharges on and in the sodium channel and their implications for channel func-tion and mechanisms of drug block will be presented (French). Finally, sodiumchannels, as well as other ion channels as pharmacological targets in the nervoussystem will be discussed (Bennett).

Workshop Wednesday 1/27/99 • 7:30–9:30 AM • Sinclair

SEARCHING FOR NOVEL ANALGESICS: LESSONS FROMSUBSTANCE P

Allan Basbaum, Stephen Hunt, Patrick Mantyh, Clifford Woolf

Substance P (SP) is an eleven amino acid member that is synthesized in the nor-mal animal by small diameter primary afferent fibers. Although numerous phar-macological and electrophysiological studies have implicated SP in the transmis-sion of pain messages, its precise contribution to nociceptive processing is notclear. This workshop will highlight several new approaches that have been takento better understand the contribution that SP makes to signaling pain. Amongthe topics to be discussed are behavioral studies in mice with a deletion of thegene that encodes the preprotachykinin precursor of SP, or of the gene that en-codes the NK-1 receptor. These studies have revealed distinct deficits in painprocessing. Participants will also discuss the hypothesis that the involvement ofSP in signaling pain is changed in the setting of nerve or tissue injury. The possi-bility of using SP-toxin conjugates to selectively destroy spinal cord neurons thatexpress the NK-1 receptor will also be addressed. This workshop will also dis-cuss how animal data are best integrated with results from human studies indeciding which systems to target for the development of novel analgesics. Fi-nally, the lessons recent experiments with SP have taught us about the correctmodels to use in evaluating the contribution of other neurotransmitters to painprocessing will be examined.

Panel • Wednesday 1/27/99 • 4:30–6:30 PM • Hoaglund

STROKE THERAPIES FROM HIBERNATING SQUIRRELS

Kelly Drew, John Hallenbeck, Kai Frerichs, Margaret Rice

Hold a cold (3°C), but living hibernating squirrel in your hands; look at a nearlyblack autoradiograph of blood flow or protein synthesis in the brain; watch oxy-gen consumption drop 10 fold; examine blood that will not clot; count leuko-

55

cytes on one hand; or watch body temperature increase from near 0°C to 37°C ina matter of hours and you will begin to appreciate how a hibernating mammalsurvives prolonged (up to 8 months), of ischemic-like conditions and brief, peri-odic arousals. By contrast, non-hibernating mammalian species suffer severe,progressive neurological damage when blood flow to the brain is diminished. Inlight of the paucity of effective treatments to improve prognosis in stroke pa-tients, John Hallenbeck and Kai Frerichs proposed in 1994 that better under-standing of how hibernating mammals tolerate stroke-like conditions would di-rect research towards improved stroke therapies. In this panel discussion, Dr.Hallenbeck will provide an overview of how understanding hibernation strate-gies can guide efforts to develop effective therapies for stroke. Dr. Frerichs willpresent results dealing with protein synthesis suppression and tolerance to invitro ischemia in a hippocampal slice preparation. Dr. Rice will present evidencesuggesting that ascorbate may protect brain tissue from oxidative stress duringfrequent, periodic arousal from torpor. Finally Dr. Drew will show evidence thathibernating brain tissue is resistant to mechanical trauma based on quantitativemicrodialysis studies of glutamate release in striatum of hibernating ground squir-rels. These recently discovered physiological adaptations work in concert withdecreased metabolic demand in hibernating mammals to produce profound tol-erance to cerebral ischemia and trauma.

Panel • Wednesday 1/27/99 • 4:30–6:30 PM • Erickson

MECHANISMS OF NEUROMODULATION OF HIPPOCAMPALGABAERGIC INTERNEURONS

Carl Lupica, Daniel Madison, Jeff Weiner, Tom Dunwiddie

The GABAergic interneurons of the hippocampus constitute approximately only10% of the total neuronal population. However, each of these cells can exertwidespread control over hippocampal excitability and information processingdue to their synaptic interactions with hundreds of principal neurons. In addi-tion, these interneurons have been shown to be extremely heterogeneous withregard to their morphology, neuropeptide content, ion channel expression andpharmacological sensitivities. Recent developments in microscopy have madepossible the routine analysis of interneuron characteristics in the hippocampus,thus permitting the evaluation of their potential roles in modulating hippocam-pal function. The members of this panel will discuss the pharmacological sensi-tivity of various classes of hippocampal interneurons with particular emphasison the physiological mechanisms involved. Dr. Madison will discuss the modu-lation of interneuron function by cholinergic ligands acting at both nicotinic andmuscarinic receptors. Dr. Dunwiddie will discuss the synaptic modulation ofstratum radiatum and stratum oriens interneurons by acetylcholine acting at al-pha-7 nicotinic receptors. Dr. Weiner will present data suggesting that ethanolcan modulate isolated kainate receptor-mediated responses in stratum radiatuminterneurons via a direct postsynaptic action. Dr. Lupica will present data tosuggest that opioid receptors can modulate both potassium and cation channelsin the same interneurons. In addition, through the use of anatomical techniques,

56

Drs. Madison and Lupica will discuss their data with regard to patterns of axonarborization within the hippocampus. Together, these presentations will providea current assessment of the actions of several neuromodulators of interneuronactivity, as well as a description of the cellular mechanisms involved.

Panel • Wednesday 1/27/99 • 4:30–6:30 PM • Sinclair

DEVELOPMENTAL PATTERNING OF THE ANTERIOR CNS

Monte Westerfield, Carole LaBonne, Michael Matise, John Rubenstein

The vertebrate central nervous system (CNS) arises from the neural plate, anectodermal thickening on the dorsal side of the embryo that forms towards theend of gastrulation. Cells in this plate proliferate and undergo morphogenesis toform the CNS primordia. Cells at the lateral edge of the plate contribute to theneural crest which gives rise to most of the peripheral nervous system. The ge-netic mechanisms that control regional specification, morphogenesis, and differ-entiation of both the CNS and neural crest are starting to be understood. Recentstudies have suggested that developmental patterning of the anterior CNS beginsin the neural plate and is regulated by signals emanating from several discreteregions of the embryo, including the anterior neural ridge, the presumptive mid-brain/hindbrain junction, and the axial mesoderm/mesendoderm. Similar sig-nals may also pattern the neural crest. This panel will discuss experiments frommouse, chick, frog, and zebrafish that have identified 1) signaling centers, 2)members of the Hedgehog, Fibroblast Growth Factor and Wnt families that actas signals, 3) putative transcription factor families like Dlx, Nkx, and Gli that actdownstream of these signals, and 4) responses of anterior CNS and cranial crestcells to the signals.

Panel • Wednesday 1/27/99 • 4:30–6:30 PM • Janss

SIGNALING WITH SINGLE AXONS

Shaul Hestrin, Peter Jonas, Etienne Audinat, Scott Thompson

Unitary connections among individual neurons are the building blocks of neu-ronal circuits. The strength of these connections, their reliability, temporal preci-sion and regulation will be the focus of this panel which will present resultsobtained with simultaneous recordings from pairs of synaptically connected neu-rons. Peter Jonas will present an analysis of the mechanisms that underlie anexceptionally fast EPSP at an hippocampal synapse. At these synapses rapidkinetics of AMPA receptors coupled with the electrotonic properties of thepostsynaptic cell produce a synaptic response with a short integration time.Etienne Audinat will present data on unitary synaptic currents at fast-spikingneurons in the motor cortex and will compare these data to the properties of thepostsynaptic receptors at these excitatory synapses. Shaul Hestrin will discussexperimental results and the possible mechanisms that may determine the im-pact of excitatory and inhibitory synapses on spiking in pyramidal andnonpyramidal neurons in pairs of cortical neurons. Scott Thompson will discussthe importance of precise timing of presynaptic and postsynaptic action poten-

57

tials in the induction of LTP and LTD of excitatory synapses. Synchronous fir-ing of the pre- and postsynaptic cells produces long-term depression but if thepresynaptic cell fires prior to the postsynaptic action potential long-term poten-tiation is induced.

Panel • Wednesday 1/27/99 • 4:30–6:30 PM • Carroll

NEURONAL NICOTINIC ACETYLCHOLINE RECEPTORS FR OMBINDING SITES TO BEHAVIOR

Edward Hawrot, Mark Levandoski, Marina Picciotto, Ellis Cooper, Gregory Grant

Neuronal nicotinic acetylcholine receptors (nAChRs) are distributed through-out the peripheral and central nervous system (CNS) where they are believed tofunction both pre- and post-synaptically as ligand-gated ion channels. The ob-served responses to acetylcholine fall into two categories. One class is blocked bythe classic nicotinic antagonist, alpha-bungarotoxin, whereas the second groupis insensitive to this or other alpha-neurotoxins. The second group can be furthersubdivided into those receptors that are blocked by kappa-bungarotoxin and thosethat are not. Multiple receptor subunits have been identified and various combi-nations of these subunits can be expressed in the oocyte expression system. Theanalysis of these heterologously expressed receptors, together with detailed stud-ies of the channel properties of native nicotinic receptors in peripheral gangliasuggest a diverse array of possible subunit combinations within the proposedpentameric configuration of the functional receptor. Among the functions as-cribed to one or more of the neuronal nAChRs found in the CNS is the ability tobind nicotine with high affinity and to mediate its reinforcing effects on behav-ior. This panel will review and discuss recent advances in understanding the na-ture of nicotine gated ion channels and the role of different nAChR subtypes inCNS synaptic transmission(Role); will show how the study of knock-out micelacking the beta-2 subunit argues for an involvement of the receptors containingthis subunit in the performance of specific behavior tasks as examined with vari-ous cognitive and reinforcement paradigms (Picciotto); will explore some of thestructural determinants important in specifying whether a nicotinic receptor bindsalpha-bungarotoxin or not (Cooper); and will examine those structural featuresof kappa-bungarotoxin which allow it to recognize certain neuronal nAChRs(Grant).

Panel • Thursday 1/28/99 • 7:30–9:30 AM • Janss

HAVE WE GOT CONNECTIONS? MAPPING INTER-REGIONALCONNECTIVITY IN THE HUMAN BRAIN

Peter Fox, Christian Bueciel, Thomas Paus, David Kennedy, Jin-Hu Xiong

For over a decade, human neuroimaging has mapped brain functional organiza-tion by associating task-induced focal activations with specific mental opera-tions. The crucial step from functional-location mapping to neural-system mod-eling, however, has been impeded by the lack of a non-invasive means of estab-lishing the anatomical pathways by which task-activated sites communicate. The

58

purpose of this session is to present four new techniques which ostensibly imageanatomical pathways in humans, in vivo, thereby providing a basis for neuralsystem modeling. First, Christian Buechel (Functional Imaging Laboratory, Lon-don) will describe PET- and fMRI-based Effective Connectivity, a technique highlyanalagous to Effectivity Connectivity as computed from high-density arrays ofintracortical electrodes. Second, Thomas Paus (Montreal Neurological Institute,Montreal) will describe the use of transcranial magnetic stimulation during PET,a non-invasive version of neuronographic connectivity determinations used formany years in animal models. Third, Jin-Hu Xiong (University of Texas HealthScience Center at San Antonio) will describe an fMRI-derived measure of ana-tomical connectivity achieved at rest, rather than during task as with EffectiveConnectivity. Fourth, David Kennedy (MGH-NMR Center, Boston) will presentthe use of MRI diffusion anisotropy to image fibre pathways in vivo. The audi-ence will be encouraged to critique the techniques from two perspectives: 1) whatthey contribute to the field of human brain mapping (i.e., do they substantivelyadvance efforts at human neural-system modeling?); and 2) what they lack bycomparison to the invasive techniques currently used in animal models.

Panel • Thursday 1/28/99 • 7:30–9:30 AM • Erickson

CELL CYCLE CONTROL IN NEUROBIOLOGY

William Freed, Richard Nowakowski, Herbert Geller, Karl Herrup

The cell cycle is the name given to the sequence of biochemical and structuralprocesses associated with cell division. Although mature neurons are normallymitotically inactive, there are interactions between cell cycle regulation and pro-cesses of neuronal function and dysfunction. Proteins which influence the cellcycle may also serve multiple roles in regulating neuronal differentiation or initi-ating apoptosis. The speakers in this session will address various aspects of cellcycle regulation as related to neurogenesis, neurotoxicity, neurodegeneration andimmortalization of neurons. Nowakowski will describe cell cycle control duringneurogenesis in the developing mouse neocortex. This process includes 11 cellcycles which gradually increase in length, mainly due to lengthening of the G1phase, while an increasing proportion of daughter cells leave the cell cycle. Freedwill discuss possibilities for manipulating the cell cycle to produce immortal neu-rons, and will consider the ways in which classical methods for producing im-mortal cells may interfere with neuronal differentiation. Geller will discuss therole of cell cycle regulatory mechanisms in neuronal apoptosis due to trophicfactor withdrawal and neurotoxic insults. Herrup will discuss evidence that celldeath may be linked to ectopic expression of cell cycle components, and evi-dence that these mechanisms play a role in neurodegenerative changes inAlzheimer s disease. The session will provide an overview of relationships be-tween cell cycle regulation and normal and abnormal neuronal function.

59

Panel • Thursday 1/28/99 • 7:30–9:30 AM • Sinclair

SYNAPTIC INTEGRATION IN THE MAMMALIAN CNS

Marc Binder, Robert Burke, Alex Reyes, William Spain

The activity of a neuron in the mammalian CNS is influenced by transmitterrelease from thousands of presynaptic inhibitory and excitatory synaptic con-tacts distributed throughout its dendritic tree. The amount of synaptic currenttransferred to the spike-generating conductances in the soma from any set ofactivated synapses should be affected by concurrent transmitter release from othersynapses, which may alter the driving forces for synaptic current and increasemembrane conductance. It has generally been thought that both of these effectswill lead to sublinear summation of the currents produced by two separate setsof synapses. Surprisingly, the departures from linearity observed experimentallyare relatively small, and often completely absent. Two factors that appear to en-hance the summation of concurrently-active synaptic inputs are: (1) the spatialdistribution of synaptic terminals on the dendritic tree that may serve to isolatesynapses electrotonically; and (2) the activation of voltage-sensitive dendriticconductances carrying inward currents that enhance transfer of current to thesoma. This panel will first review the anatomical and theoretical framework forunderstanding how synaptic inputs may interact in the mammlian CNS. Subse-quently, the participants will present experimental results on the summation ofsynaptic inputs derived from studies of spinal motoneurons and neocortical py-ramidal neurons.

Panel • Thursday 1/28/99 • 7:30–9:30 AM • Hoaglund

ESTROGEN, PROGESTERONE, AND BRAIN PROTECTION:THE JOY OF SEX (STEROIDS)

Dale Pelligrino, Edward Hall, Phyllis Wise, Donald Stein

The peripheral cardiovascular protective effects of ovarian steroids, estrogen inparticular, have been known for a number of years. Evidence is beginning toemerge indicating a lower incidence of cerebrovascular disease and neuropa-thology in pre-menopausal women and women undergoing hormone replace-ment therapy-a treatment regimen which includes estrogen and progesteronecombinations. Additional findings in experimental animals, although limited,have indicated that estrogen and progesterone can provide neuroprotection inmodels of cerebral ischemia and brain trauma. The mechanisms responsible forovarian steroid-associated neuroprotection are poorly understood, but may verywell involve multiple processes and targets. The panelists will discuss currentknowledge regarding the mechanisms of ovarian steroid-related brain protec-tion. The information presented will be based, to a large degree, upon data ob-tained in the panelists own laboratories employing animal models of cerebralischemia and neurotrauma. The topics to be emphasized are: 1) sexual dimor-phism in ischemia-induced neuropathology and the antioxidant actions of ova-rian steroids (E. Hall); 2) Reduced apoptosis and other mechanisms of estrogen-related neuroprotection in focal ischemia (P. Wise); 3) Mechanisms of progester-

60

one-mediated functional recovery related to reductions in brain edema, lipidperoxidation and blood-brain barrier damage following cortical impact injury(D. Stein); and 4) Estrogen-associated protection in forebrain ischemia viaupregulation of endothelial nitric oxide synthase, improved vasodilating capac-ity, and reduced leukocyte adhesion (D. Pelligrino).

Panel • Thursday 1/28/99 • 7:30–9:30 AM • Carroll

DYNAMIC MEASURES OF FUNCTIONAL PROPERTIES OFMONOAMINE TRANSPORTERS

Alan Frazer, Greg Gerhardt, Sammanda Ramamoorthy, David Sulzer

Monoamine transporters are key targets for both psychotherapeutic drugs (e.g.,antidepressants) and drugs of abuse (e.g., cocaine). The regulatory properties ofboth plasma membrane transporters and the more recently cloned vesicle mem-brane transporters (VMATs) are receiving considerable attention. This issue willbe discussed by the participants who use approaches ranging from biochemicalstudies of transfected cells in vitro to knockout mice to voltammetric studies oftransporter function in rat and monkey brain in vivo. Dr. Ramamoorthy will showthat the human serotonin transporter (SERT) can be rapidly phosphorylated bymultiple cellular kinases and how this could control trafficking decisions for sur-face expression of the SERT. Dr. Frazer has used voltammetry to demonstrate,in the CA3 region of the hippocampus, that activation of terminal serotoninautoreceptors regulates SERT function in vivo as does chronic administration ofparoxetine. Dr. Gerhardt also uses electrochemical methods to measure the func-tioning of the dopamine transporter (DAT). He will report on the voltage depen-dence of the DAT, the coupling between it and D2/D3 autoreceptors, and age-related changes in DAT function in the striatum and nucleus accumbens of ratsand monkeys. Dr. Sulzer will discuss interrelationships between the DAT andthe brain VMAT2. His recent studies have shown that amphetamine still releasesDA in midbrain neurons from VMAT2 knockout mice, but that the release isdecreased. All these studies demonstrate that these are multiple processes ca-pable of regulating the function of these key neuronal proteins.

Panel • Thursday 1/28/99 • 7:30–9:30 AM • Snobble

FROM RECEPTOR ACTIVATION TO CREB PHOSPHORYLATION:A MECHANISM OF NEUROPLASTICITY

Christine Konradi, Jacqueline McGinty, David Ginty, Richard Tsien

Neuroplasticity is the spirit of the brain. Yet, what is the physical substrate forsuch an ethereal phenomenon? The transcription factor cyclic AMP responsiveelement binding protein (CREB) is a perfect candidate to mediate synaptic plas-ticity. In recent years, CREB activation has been linked to physical changes inneurons, including neuronal sprouting, and to more elusive events underlyingmemory formation. Phosphorylation of CREB at a single serine residue, Ser133,

61

promotes CREB-dependent transcription of genes whose protein products aresubstrates for neuroplasticity. The panel will focus on the elements in varioussecond messenger cascades that link extracellular stimuli, previously implicatedin regulation of neuroplasticity, to nuclear CREB phosphorylation and gene ex-pression. In particular, the involvement of kinases and phosphatases in neurotrans-mitter- and growth factor-induced phosphorylation of CREB will be addressed.Christine Konradi will illustrate pathways coupling dopamine-receptor activa-tion to CREB phosphorylation and gene expression in the striatum. David Gintywill focus on the mechanisms and function of growth factor-mediated CREBphosphorylation. Richard Tsien will discuss how Ca2+-dependent mechanismsdue to neuronal activity lead to CREB phosphorylation in the hippocampus.Jakie McGinty will speak about the role of PKA and CAM kinase as well asprotein phosphatase 1/2A in amphetamine-induced CREB phosphorylation instriatal neurons in vivo. The aim of the panel is to provide a forum for discussionof biochemical pathways that link events at neuronal membranes to changes ingene expression. By focusing on regulation of CREB phosphorylation in neu-rons, we hope to provide insight into the nature of neuronal signaling pathwaysthat influence neuroplasticity and neurodevelopment.

Panel • Thursday 1/28/99 • 4:30–6:30 PM • Erickson

SEROTONIN & COCAINE: IT S JUST NOT AN OBSESSION ANY MORE

Scott Mackler, Kathryn Cunningham, Beth Hoffman, Loren Parsons

Cocaine acts to block the re-uptake of biogenic amines. Inhibition of dopaminere-uptake is an important determinant of its rewarding properties. However, co-caine also blocks the re-uptake of serotonin (5-HT) and norepinephrine (NE)into nerve terminals that contain functional 5-HT and NE transporters. Accu-mulation of 5-HT in the synaptic cleft after cocaine administration may result inshort- and long-term changes in signaling through specific 5-HT receptors. Thegoal of this session is to review recent studies of the interactions between co-caine and serotonergic transmission, concentrating on both molecular and be-havioral findings. The molecular biology of the 5-HT transporter and the familyof 5-HT receptors will be reviewed, with an emphasis on regulation of 5-HTtransport by 5-HT2A and 5-HT2C receptors (Beth Hoffman). Cell culture studiesthat demonstrate an interaction between cocaine and 5-HT receptors on regula-tion of the Na/K ATPase pump in monoaminergic cells will be described; thephysiological consequences of altered pump function may help to explain howcocaine affects neurotransmission in the nucleus accumbens. (Scott Mackler).The regulation of dopamine mesoaccumbens circuits by 5-HT1B and 5-HT2Creceptors and the impact of this site-specific interaction on the behavioral effectsof cocaine will be discussed (Kathryn Cunningham). The final talk will high-light the effects of 5-HT receptor manipulation on cocaine self-administration inthe rat (Loren Parsons).

62

Panel • Thursday 1/28/99 • 4:30–6:30 PM • Hoaglund

STROKE—REFORMATTING BRAIN AND RECAPTURING YOUTH

Michael Chopp, Steven Cramer, Giora Feuerstein, Seth Finklestein

Patients exhibit a wide range of recovery of neurological function after stroke.The molecular basis and indices for this recovery are unknown. The participantsin this panel will present human and animal data demonstrating: functionalremapping of surviving penumbric tissue to compensate for cerebral infarct, ex-pression of developmental proteins and genes after experimental focal cerebralischemia indicating a vibrant process of cerebral tissue plasticity in ischemicbrain, and therapeutic interventions designed to promote and enhance functionalrecovery. Dr. Cramer will describe BOLD functional MRI studies on stroke pa-tients with good motor recovery after a single stroke. Stroke subjects tapping therecovered finger showed patterns of increased brain activation in the unaffectedhemisphere sensomotor cortex. Dr. Chopp will present data on the expression ofembryonic proteins (e.g. synaptophysin, neuro D, GAP-43, cyclin D1, VEGF)and the relationship between apoptosis and brain tissue plasticity in experimen-tal stroke in the rat. Dr. Feuerstein will present data on gene regulation that im-pact on brain tissue plasticity and focus on the expression and role of osteopontinand integrins in ischemic rat brain. Dr. Finklestein will describe his studies ontreatment of experimental stroke in rat with pharmacological agents that en-hance functional recovery. Treatment instituted out to 24 h reduced neurologicaldysfunction without necessarily reducing the volume of cerebral infarction. Thesepresentations revolve about the theme that brain returns to an early stage ofdevelopment after stroke and that therapeutic interventions should capitalize onthe inherent plasticity associated of this neoembryonic brain.

Panel • Thursday 1/28/99 • 4:30–6:30 PM • Carroll

NEURONAL NICOTINIC ACETYLCHOLINE RECEPTORS: FROMFOLDING TO FUNCTION

Neil Millar, Darwin Berg, Jon Lindstrom, Ronald Lukas

Neuronal nicotinic acetylcholine receptors (nAChRs) are complex oligomericion channels, expressed at both pre- and post-synaptic sites throughout the cen-tral and peripheral nervous system. Neuronal nAChRs have been implicated asplaying a role in addiction to tobacco and in conditions such as epilepsy andschizophrenia. In addition to the five muscle-type nAChR subunits (α, β, γ, δand ε) which are expressed at the vertebrate neuromuscular junction, eleven neu-ronal nAChR subunits (α2-α9 and β2-β4) have been identified by molecular clon-ing. In contrast to the relatively well characterised neuromuscular junctionnAChR, the precise subunit composition of the many of the various pharmaco-logically distinct neuronal nAChRs is still uncertain. Several areas of researchare beginning to provide a better insight into areas such as subunit co-assemblyand how this may influence the pharmacological and ion channel properties ofthese receptors. The speakers in this Panel session will discuss a variety of ex-periment approaches aimed at investigating issues such as folding, subunit as-

63

sembly, receptor distribution and functional properties of neuronal nAChRs. Datawill be presented from studies on defined combinations of cloned subunits ex-pressed in various heterologous expression systems and also on native nicotinicreceptors. Specific topics which will be discussed include 1) the folding and co-assembly of nicotinic receptor subunits and how this can be influenced by thehost cell type, 2) the cell-surface distribution of neuronal nAChRs and 3) theeffect of chronic nicotine exposure on both cell surface expression levels and thefunctional properties of these receptors.

Panel • Thursday 1/28/99 • 4:30–6:30 PM • Snobble

NEW APPROACHES FOR ESTIMATING QUANTAL PARAMETERS

Michael H usser , Angus Silver, John Clements, Zachary Mainen

Quantal analysis defines synaptic function in terms of three key parameters:number of release sites, release probability, and quantal size. To understand howthese parameters vary during synaptic plasticity and development it is crucial todetermine them accurately. The use of classical statistical analysis to extract theseparameters has been very successful at the neuromuscular junction, but applica-tion of these techniques at central synapses has proved to be much more chal-lenging. This is due not only to technical difficulties associated with recordingsfrom CNS neurons, but also because quantal parameters are not uniform acrosssynapses. To overcome these problems, the contributors to this session have useda variety of new approaches (optical, anatomical and electrophysiological) toinvestigate quantal parameters underlying excitatory synaptic transmission. An-gus Silver and John Clements will describe new statistical and experimentalmethods to reliably extract mean quantal parameters under conditions of non-uniformity in quantal size and release probability. They have used this method toinvestigate the locus of short- and long-term plasticity at cerebellar and hippoc-ampal synapses. Michael H usser will sho w simulations based on 3-dimensionalEM reconstructions of cerebellar synapses and kinetic models of receptors andtransporters to determine the relationship between synaptic structure and func-tion. Zach Mainen will present results obtained using two-photon imaging ofcalcium signals in pyramidal cell spines to make direct measurements of releaseprobability and quantal variability at individual synapses. This multidisciplinarypanel will discuss the merits and limitations of these novel methods and synthe-size the resulting new insights.

Panel • Thursday 1/28/99 • 4:30–6:30 PM • Sinclair

PROTEIN TYROSINE KINASES AND PROTEIN TYROSINEPHOSPHATASES IN THE BRAIN

Fritz Henn, R dig er Klein, David van Vactor, Takeshi Yagi, Gunter Schumann

Protein Tyrosine Phosphatases (PTP s) and Protein Tyrosine Kinases (PTK s)are gene families encoding important regulatory proteins in the brain.Geneticresearch in the developing central nervous system of various species has estab-lished the role of members of both gene families in the control of neurite out-

64

growth and axon guidance. Analysis of PTK-fyn knock-out mice revealed be-havioral abnormalities and decreased tolerance for alcohol, thus pointing towarda crucial regulatory role of this PTK in the adult mammalian system. Cytokine-induced transcription of PTP in human astrocytoma cells may suggest a contri-bution of PTP to the pathogenesis of inflammatory diseases of the central ner-vous system. The aim of this panel is to give an overview of recent results regard-ing various functional aspects of PTP s and PTK s in the brain, thus creating abase to stimulate further research about a possible role of these gene families indisease conditions. To this end, the following speakers will present their work:R dig er Klein, European Molecular Biology Laboratory (EMBL), Heidelberg,Germany: Biological functions of Eph receptors in the developing nervous sys-tem. David Van Vactor, Dep. of Cell Biology, Harvard Medical School, Boston,U.S.A.: Tyrosine kinases and tyrosine phosphatases control motor axon guid-ance in the drosophila embryo, Takeshi Yagi, National Institute of PhysiologicalSciences, Okazaki, Japan: Fyn can regulate NMDA-receptor activity and couplea novel cadherin (CNR) family in the mammalian synapse. Gunter Schumann,Dep. of Psychiatry, University of Freiburg, Germany: Cytokine-induced tran-scription of protein tyrosine phosphatases in human astrocytoma cells.

Panel • Thursday 1/28/99 • 4:30–6:30 PM • Janss

MECHANISMS OF MOTION DETECTION IN THE VISUAL SYSTEMOF INVERTEBRATES AND VERTEBRATES

Harvey Karten, Nick Strausfeld, Alexander Borst, Richard Masland

Detecting motion, direction and velocity are fundamental operations of the vi-sual system of all animals. David Marr, in his classic work, Vision, emphasizedthat there are two aspects to the problem: 1) primary recognition that an object ismoving, and 2) utilization of the motion signal. The neurobiological mechanismof initial detection of motion has long been considered to be the far more diffi-cult problem to solve. The problem is recognized as particularly complex as thereare several different motion detection systems in both retina and brain, depend-ing upon speed, object size and signal content. Parallel studies of motion detec-tion in insects and amniotic vertebrates have revealed a stunning extent of simi-larity in the anatomy and physiological mechanisms involved in detecting highspeed motion of small objects over a very large area. Alexander Borst and NickStrausfeld will decribe how motion is detected, categorized and used in insects.Richard Masland will present a summary of current models of motion detectionin the vertebrate retina, and Harvey Karten will summarize recent work on mo-tion detecting neurons in the tecto-pulvinar system of birds and mammals thatgenerate an initial motion signal. Evolutionary and computational comparisonsshould lead to a lively discussion.

65

Workshop Thursday 1/28/99 • 8:30–10:00 PM • Erickson

STATIC MAPS VS. DYNAMIC NETWORKS: REVOLUTION IN SOMA-TOSENSORY RESEARCH

John Chapin, Jon Kaas, Ford Ebner, Miguel Nicolelis

Though the somatosensory system is one of the oldest research areas in neuro-science, it is currently at the vanguard of a new wave, inspired by technologicaladvances. Classic notions emphasizing the static aspects of functional organiza-tion are being reexamined in light of mounting evidence showing a striking dy-namism in this system: its functional organization is in constant flux, exhibitingchanges over time scales from milliseconds to lifetimes. This workshop will bringtogether researchers from a variety of disciplines: Miguel Nicolelis will reportfindings in rats and monkeys that somatosensory stimulus features may be en-coded as spatiotemporal patterns of neuronal population activity which are widelydistributed through the thalamocortical circuitry in the SI, MI and parietal corti-ces. John Chapin will discuss dynamic, behavior and cognition related modifica-tion of sensory responses in multi-neuron ensembles recorded at multiple levelsof the somatosensory system during tactile discrimination tasks. Jon Kaas willdiscuss the range of plasticity which can be demonstrated in the mapping andconnectivity of this system in response to lesions of peripheral nerves or centralsomatosensory pathways such as the dorsal columns. Ford Ebner will discussthe importance of peri-natal experience on the development of this system, asrevealed in its receptive field organization in anesthetized and awake animals.For example, fetal alcohol syndrome may prevent normal development by inter-fering with activity-dependent plasticity.

Workshop Thursday, 1/28/99, 8:30–10:00 PM • Sinclair

PROBING GABAA RECEPTOR FUNCTION AND REGULATION: CUTAND PASTE, MIX AND MATCH, DELETE

Neil Harrison, Richard Olsen, Cynthia Czajkowski, Gregg Homanics, Sheryl Smith

The GABA-A receptor (GABAA-R) is the primary inhibitory neurotransmitterreceptor in the brain, and is a target for sedative-anxiolytic and anesthetic drugs,as well as endogenous neurosteroids. Harrison will introduce the session by ex-plaining how molecular techniques are revealing new aspects of GABAA-R func-tion. Czajkowski will describe the use of chimeric and mutant receptors to char-acterize benzodiazepine binding sites on the gamma subunit of the GABAA-R.Smith will discuss how variations in neurosteroid levels regulate the expressionof the GABAA-R alpha-4 subunit and thereby alter GABAA-R pharmacology,benzodiazepine sensitivity and animal behavior. Homanics will describe newgenetic techniques to probe the role of GABAA-R subunits in the mouse usingknockouts, conditional knockouts and knockins . Finally, Olsen will dicsuss thefascinating behavioral and neurobiological parallels between the beta-3 knock-out mouse and human sufferers of the genetically inherited Angelman syndrome.

66

Workshop Thursday 1/28/99 • 8:30–10:00 PM • Janss

NUCLEUS ACCUMBENS PHYSIOLOGY AND DRUG ABUSE: INTEGRA-TION ACROSS DIVERGENT FINDINGS

Roy Wise, Francis White, Anthony Grace, William Carlezon, Laura Peoples

Current theories of drug addiction posit an integral role of nucleus accumbens(NAcc) neurons in drug reinforcement and addiction. The neurophysiologymediating this role has been little investigated and available data are disparate.Extracellular recordings of accumbal neurons show that approximately one quar-ter of NAcc neurons exhibit excitatory phasic firing in association with operantbehavior reinforced by either heroin or cocaine. This observation suggests thatexcitatory events may contribute to accumbal control of drug-reinforced behav-ior. However, other data implicate inhibitory mechanisms. Drugs of abuse in-cluding psychomotor stimulants and opiates inhibit most accumbal neurons inboth anesthetized rat and brain slice preparations. Increased dopamine level inthe NAcc of rats, which is induced by most drugs of abuse, similarly disruptsfiring. Although a minority of NAcc neurons in the rat exhibit phasic and/ortonic increases in firing during cocaine self-administration sessions more thanhalf are tonically inhibited. Furthermore, microinjection studies show that oper-ant behavior of rats is reinforced by blockade of accumbal NMDA receptors.Procedural differences (e.g., recordings conducted in anesthetized versus behav-ing animals) may contribute to the incongruous findings. It is also possible thatexcitatory firing patterns of certain NAcc neurons contribute to drug self-admin-istration in conjunction with drug-induced tonic decreases in NAcc firing. Par-ticipants in the workshop will compare studies which implicate excitatory versusinhibitory mechanisms. Available data will be considered relative to other re-search findings regarding NAcc function. Such considerations may be useful inidentifying the mechanisms most likely to contribute to drug reinforcement anddrug addiction.

Workshop Thursday 1/28/99 • 8:30–10:00 PM • Snobble

THE INTERNAL STRUCTURE OF CENTRAL PATTERN GENERATORS:HOW BIG CAN THEY GET WITHOUT BECOMING SOMETHING ELSE?

Robert Burke, Ronald Harris-Warrick, Simon Giszter, Jeffrey Smith, Paul Katz

The subject of central pattern generators, or CPGs, has been discussed at severalrecent WCBR meetings. However, several critical issues about CPGs came intosharper focus during the final discussion session at a recent meeting sponsoredby the New York Academy of Sciences. All of the members of this workshoppanel were present at that meeting and all agreed that these issues deserved moreextensive exploration. The topics to be discussed in the workshop include thefollowing. (1) Is there, or can there be, fractionation of rhythm generation andpattern formation functions within a CPG? (2) Can a CPG be embodied in anorganization of hundreds or thousands of neurons that are not physically con-tiguous? (3) Can the neuronal elements of a CPG subserve additional functionsthat are not clearly related to the rhythms and patterns associated with that CPG?

67

These and other related topics will be discussed from the perspective of inverte-brate nervous systems by Ron Harris-Warrick and Paul Katz, who work on dif-ferent model systems (stomatogastric ganglion and swimming oscillators). Theperspective of vertebrate nervous systems will be taken up by Bob Burke and JeffSmith, who have data from locomotion and respiratory systems that produceorganized rhythms. Simon Giszter will speak to the relation between CPGs andCNS systems that generate coordinated, but non-rhythmic, movements but whichmay at times participate in rhythmic behaviors. The workshop format has beenchosen because the participants begin with differing views, which may or maynot be reconciled by the anticipated debate. On the basis of past experience, weexpect vigorous audience participation.

Workshop Thursday 1/28/99 • 8:30–10:00 PM • Carroll

TROPHIC FACTORS AND THE HUMAN BRAIN: IS SITE SPECIFIC DE-LIVERY IMPORTANT AND IS IT POSSIBLE?

Greg Gerhardt, James Conner, Don Gash, Patrick Aebischer

Numerous laboratories have reported studies supporting the use of nerve growthfactor (NGF) for the potential treatment of Alzheimer s disease, and glial-de-rived neurotrophic factor (GDNF) for the treatment of Parkinson s disease. How-ever, the question still remains whether these factors can be focally delivered tothe human brain, to decrease side effects and improve efficacy of these proteins.This workshop will focus on methods to focally deliver neurotrophic factors,such as NGF and GDNF, directly into the human brain. Dr. Pat Aebischer willlead discussion on the potential use of encapsulated genetically engineered cellsfor the delivery of trophic factors into the ventricle. Prior work in his lab hasinvolved successful delivery of GDNF into the ventricle of parkinsonian baboonsusing encapsulated cells. Dr. Greg Gerhardt will discuss data involving directdelivery of neurotrophic factors into specific brain sites in aged and parkinso-nian animal models using cannulae and infusion pump technologies. Previousstudies in his lab have shown great promise for direct infusion of GDNF intobrain parenchyma. Dr. James Conner will explore the effects of exogenous NGFdelivery by ex vivo gene therapy and direct intra-parenchymal infusions in ratsand nonhuman primates. He will lead discussions on the distribution of NGFdelivered by the two approaches, and the functional consequences to the basalforebrain cholinergic neurons in animal models of Alzheimer s disease. Finally,Dr. Don Gash will lead discussion on the use of infusion pump technologies todirectly deliver growth factors into the ventricle. His group has seen success fromthe pulsatile delivery of GDNF into the ventricles of parkinsonian Rhesus mon-keys.

Minicourse Session III • Thursday 1/28/99 • 8:30–10:00 PM • Hoaglund

NEW OPTICAL AND IMAGING METHODS IN CELLULAR NEURO-SCIENCE

Stephen Smith, Stuart Thompson, R. Tsien, E. Macagno

SEE SESSION I MINICOURSE ABSTRACT ON PAGE 40

68

Panel • Friday 1/29/99 • 7:30–9:30 AM • Hoaglund

THE NEUROBIOLOGY OF INCENTIVE-MOTIVATION

Agu Pert, Wolfram Schultz, Donald Woodward, Anthony Phillips

Incentive motivation refers to the process by which stimuli that are predictive ofreward increase arousal and direct behavior towards biologically significant events,such as feeding, copulation or drug seeking. Recent electrophysiological andneurochemical findings have begun to elucidate some of the neural circuitry ac-tivated by stimuli predictive of a variety of incentives including food, a sexualpartner or drugs of abuse. Electrophysiological studies in primates, for example,have revealed that the orbitofrontal cortex appears to be critically involved inassessing the motivational components of environmental stimuli associated withfood.A large fraction of task-related neuronal axtivity in this brain region wasfound to reflect the decoding of the type of reward expected.Phasic alterationsin spike activity have also been reported for a select population of neurons in thenucleus accumbens and prefrontal cortex preceding lever pressing responses forcocaine and heroin in rats. Studies utilizing electrochemical, microdialysis andin vivo autoradiographic procedures have further implicated basal forebrain andlimbic structures in incentive-motivational processes.Stimuli associated with avariety of primary incentives have been found to enhance mesoaccumbens dopam-ine release and activate various associated limbic structures.An attempt will bemade to integrate these diverse new and exciting findings in order to develop aworking outline of possible neural circuits involved in motivated behaviors drivenby incentive-motivation.

Panel • Friday 1/29/99 • 7:30–9:30 AM • Erickson

ACTIVATION OF MICROGLIA IN ALZHEIMER S DISEASE:CAUSE OR CONSEQUENCE?

Wolfgang Streit, Dennis Dickson, Sue Griffin, Steve Barger

A hallmark pathological feature of Alzheimer s disease (AD) is the persistentpresence of both activated microglia and astrocytes in and around senile plaqueswhich contain extracellular deposits of the beta-amyloid peptide. A key questionin understanding AD pathogenesis concerns the relationship between beta-amy-loid deposition and glial cell activation. Does gliosis develop and persist becausea shift in amyloid precursor protein (APP) metabolism causes excess productionof the insoluble beta-amyloid thereby providing an indelible, and thus, chroni-cally irritating stimulus? The organizer of this panel (Streit) will present this hy-pothesis in the context of the known functions and behavior of microglial cellsusing data from both experimental and human neuropathological studies. Dicksonwill address cellular details of senile plaque neuropathology and discuss a pos-sible relationship between the presence of amyloid peptides and glycated pro-teins causing activated microglia to produce proinflammatory cytokines and othernoxious agents that may result in bystander neuronal injury. Griffin will focusattention on glial- neuronal interactions in AD. Specifically, she will provide evi-dence that these interactions are associated with DNA damage, neurofibrillary

69

tangle formation, and with the dangerous neuritic plaque. Finally, Barger willpresent a discussion of experimental findings aimed at understanding the bio-logical activities of secreted forms of beta-APP and its role as a proinflammatoryfactor mediating the activation of microglia. Together, these presentations willprovide a sharply focused overview of current ideas regarding the relationshipbetween activated glial cells and the neurodegenerative features of AD.

Panel • Friday 1/29/99 • 7:30–9:30 AM • Carroll

CELLS TO SYSTEMS: CAN WE CREATE A COHESIVE ELECTROPHYSI-OLOGY OF THE EFFECTS OF ETHANOL ON THE BRAIN?

Patricia Janak, Forrest Weight, Richard Morrisett, Bennett Givens

The study of the interaction of ethanol and the brain proceeds along many levelsof analysis to address the unique cellular and behavioral actions of ethanol, witheach researcher using the system they believe is best suited to answer their ques-tions of interest. This interactive panel will attempt to integrate current knowl-edge regarding the electrophysiology of ethanol across these different levels ofanalysis. Each speaker will address the following ideas: How can results fromstudies of the cellular and synaptic actions of ethanol help us understand alcohol sacute and chronic effects at the level of circuits, as well as at the level of the intactbehaving animal? Are there fruitful points of interaction among these differentlevels of analysis of which we do not take advantage that would lead each of uscloser to a common goal? Where are the common goals (and potential dead-ends) in the electrophysiology of ethanol? The panel will review findings fromstudies of ethanol interactions at specific cellular and molecular sites using tech-niques of whole cell recording and site-directed mutagenesis in Xenopus oocytesand neuronal cultures, including studies of ethanol on 5-HT3, nicotinic ACH,and other receptors. (Weight). Also discussed will be chronic ethanol effects onsynaptic transmission and plasticity in brain slice and explant preparations, es-pecially in respect to NMDA-mediated currents within organotypic slices of hip-pocampus (Morrisett). In addition, behavioral neurophysiology of ethanol withinthe awake behaving rat will be reviewed. This discussion will include the effectsof ethanol on extracellular single-unit activity within cortical/hippocampal/septalsystems involved in attention (Givens), and effects on ensemble recordings withinthe mesolimbic system (Janak).

Panel • Friday 1/29/99, 7:30–9:30 AM • Sinclair

WHAT HAS MUTATIONAL ANALYSIS TAUGHT US ABOUT DRUGACTION?

Phil Skolnick, Marina Strakhova, Heinrich Betz, Eric Moody, Jurgen Wess

The use of molecular biological techniques to define loci of drug and transmitteraction has become widespread. Despite the apparent pivotal role of mutationaland chimeric strategies in understanding drug and transmitter actions, resultscan be misleading and the literature is replete with controversies. The purpose ofthis panel is to explore the uses of site directed mutagenesis in defining drug and

70

transmitter actions in the central nervous system. Studies performed on bothligand-gated ion channels and g-protein coupled receptor systems will be dis-cussed. Following a brief overview by P. Skolnick, H. Betz will present studieson the NMDA receptor system that delineate the structure of its binding sites forglutamate and glycine as well as provide information on its subunit stoichiom-etry. M. Strakhova will describe studies demonstrating the contribution of spe-cific amino acid residues to both ligand recognition and rectifying properties atspecific GABAA receptor subtypes. E. Moody will present data from a numberof mutations on the beta subunit of the GABAA receptor which likely representbinding sites for intravenous general anesthetics. Studies involving different mus-carinic acetylcholine receptors (which belong to the superfamily of G protein-coupled receptors) will be presented by J. Wess who will discuss mutagenesisapproaches to elucidate mechanisms governing receptor assembly and receptor/G protein coupling selectivity. Throughout these presentations, the commonthemes will be defining structure activity relationships, choice of amino acidsubstitutions and determining the basis for ligand selectivity at a specific site.The relationships between transmembrane regions and possible drug bindingsites in these regions will also be topics for discussion.

Panel • Friday 1/29/99 • 7:30–9:30 AM • Janss

LOCALIZATION AND FUNCTIONS OF METABOTROPIC GLUTAMATERECEPTORS IN THE BASAL GANGLIA

Yoland Smith, P. Jeffrey Conn, David Standaert, David Lovinger

Until recently, it was thought that all of the actions of glutamate were mediatedby activation of ionotropic glutamate receptors. However, it is now clear thatglutamate also activates receptors coupled to intracellular second messenger sys-tems through GTP-binding proteins. These receptors, referred to as metabotropicglutamate receptors (mGluRs), are widely spread throughout the central ner-vous system and play important roles in modulating cell excitability and synap-tic transmission. The goal of this panel is to review the current knowldege on thecellular and synaptic localization as well as functions of mGluRs in regulatingneuronal activity in the basal ganglia. Jeffrey Conn will first give an overview ofthe mGluRs family. He will briefly review the molecular biology, pharmacologyand localization of the three groups of mGluRs. He will then set the stage for theremaining talks by discussing the major physiological roles of the different mGluRsubtypes and their possible implications for the modulation of basal ganglia func-tion in normal and pathological conditions. David Standaert will then presentrecent data on the cellular localization of different subtypes of mGluRs in thebasal ganglia. He will first review in situ hybridization data showing strikingdifferential expression of mGluR subtype mRNAs both among the various nu-clei of the basal ganglia and among the distinct neuronal types found within thestriatum. This will be followed by the results of recent immunohistochemicalstudies showing that some of the mGluRs (Groups II and III) are found prima-rily at presynaptic sites, where they may act as autoreceptors (modulating their

71

own glutamate release) or heteroreceptors (modulating the release of GABA),while others (Group I) are localized at postsynaptic sites where they may regu-late a variety of effector mechanisms. Yoland Smith will then extend the local-ization studies of mGluRs to the synaptic level using immunogold techniques.He will show that the different subtypes of mGluRs display a highly specificpattern of synaptic and extra-synaptic localization in various structures of thebasal ganglia. Finally, David Lovinger will discuss the role of mGluRs in synap-tic modulation and plasticity in the striatum. He will present evidence that thepresynaptic Group II mGluRs inhibit transmission at corticostriatal synapsesvia a mechanism independent of pre-synaptic calcium. He will also show thatmGluRs activation is necessary for the induction, but not the maintained expres-sion, of long-term synaptic depression (LTD) at corticostriatal synapses ontostriatal projection neurones. This panel should provide a strong basis for stimu-lating interest and opening new research avenues for the role of mGluRs in regu-lating basal ganglia function.

Panel • Friday 1/29/99 • 7:30–9:30 AM • Snobble

ASTROCYTIC COMMUNICATION SKILLS

Maiken Nedergaard, Andy Charles, Eliah Scemes, Philip Haydon, Stanley Kater

Astrocytic calcium signaling has received considerable recent attention becauseof its possible role in brain function. Astrocytic calcium waves modulate neu-ronal calcium levels and astrocytes do thereby have the potential to regulate syn-aptic activity. Originally, it was believed that interastrocytic signaling was medi-ated by diffusion of IP3 and/or Ca2+ across gap junctions, but recent observa-tions suggest that an extracellular pathway may exist. Workshop participantswill discuss the alternative pathways that may participate in astrocytic commu-nication as well as in bidirectional signaling between astrocytes and neurons. Dr.Scemes will discuss the role of gap junctions versus release of a humoral factorin calcium signaling, including observations in astrocytes from Cx43 knockoutmice. Dr. Kater will consider the release of multiple compounds as a tool bywhich astrocytes can modulate signaling both among themselves but also to neigh-boring neurons. Dr. Charles will focus on complex patterns of intercellular cal-cium waves in astrocytes in hippocampal slice preparation, including spiral waves,and their potential roles in the modulation of neuronal activity in the hippocam-pus. Dr. Haydon will discuss the role of glutamate in astrocyte-neuronal signal-ing. Recent observations suggesting that astrocytic calcium waves reduce themagnitude of excitatory and inhibitory postsynaptic currents through activationof metabotropic glutamate receptors will be evaluated. Drs. Nedergaard andRozental will close by summarizing observations demonstrating that astrocytesfunctioning as a necessary intermediate in potentiation of inhibitory GABAergictransmission in hippocampus. This workshop will provide an overview of recentfindings in astrocytic calcium signaling and its possible role in synaptic modula-tion.

72

Panel • Friday 1/29/99 • 4:30–6:30 PM • Carroll

HIPPOCAMPUS, PREFRONTAL CORTEX AND DOPAMINE: THE BER-MUDA TRIANGLE OF THE SCHIZOPHRENIC BRAIN

Barbara Lipska, Susan Sesack, Therese Jay, Patricio O Donnell, Alessandro Bertolino

The prefrontal cortex (PFC) and the hippocampus (Hip) play an important rolein the organization of dopamine (DA)-related behaviors but the underlying mecha-nisms are elusive. Dysfunction in these regions and abnormal subcortical dopam-ine activity are implicated in the pathophysiology of schizophrenia. The mecha-nisms whereby the Hip regulates PFC function and modulates DA systems willbe the focus of this panel. We will provide an overview of potential anatomicalsubstrates for functional interactions between the PFC, the Hip, the nucleusaccumbens, and the DA innervation to these regions (Dr. Sesack). We will de-scribe the nature of the Hip/PFC connections and show that their plasticity ismodulated by DA (Dr. Jay). We will review electrophysiological data regardingthe role of the Hip input on the responses of PFC and nucleus accumbens neu-rons to DA afferent stimulation (Dr. O Donnell). We will also address the role ofthe Hip in the development of the PFC and the developmental regulation ofsubcortical DA in rodents and primates. We will show that neonatal excitotoxicdamage of the Hip in the rat alters behaviors related to subcortical DA and func-tion of the PFC. In the non-human primate, a developmental insult to the mesialtemporal limbic cortex results in neuronal pathology in the PFC as indicated byreduced NAA and in altered striatal DA activity (Dr. Bertolino). We will specu-late on the networks involved in the Hip modulation of PFC function and stri-atal DA activity and address the relevance of these phenomena for understand-ing the pathophysiology of schizophrenia.

Panel • Friday 1/29/99 • 4:30–6:30 PM • Erickson

NOVEL APPROACHES TO SMOKING CESSATION: DIFFERENTSMOKES FOR DIFFERENT FOLKS

Linda Dwoskin, Edythe London, Rachel Tyndale, Michael Bardo, Robert Mansbach

Tobacco smoking is the number one health problem accounting for more illnessand deaths in the US than any other factor. Elucidating the mechanism of actionof nicotine (NIC) is essential to understanding the initiation and maintenance oftobacco smoking behavior, as well as the development of effective smoking ces-sation therapies. The development of new selective receptor-subtype agents hasresulted from an increased understanding of the diversity of nicotinic receptorsat the molecular level. E.D. London will review studies using subtype-selectiveagents in noninvasive brain imaging to visualize brain nicotinic receptors with aview towards application in humans dependent upon NIC. Cytochrome P4502A6(CYP2A6) is the hepatic enzyme responsible for NIC metabolism to cotinine.R.F. Tyndale s studies have demonstrated that a common genetic deficit inCYP2A6 decreases an individual s risk of becoming dependent and decreasessmoking behavior of dependent individuals. These results will be discussed inlight of novel treatment strategies. M.T. Bardo s studies demonstrate that

73

nornicotine, a CNS metabolite of NIC, serves as a reinforcer that may substitutefor NIC. When rats were pretreated with nornicotine, self-administration of NICwas decreased for prolonged periods. R.S. Mansbach will discuss results indicat-ing the potential utility of partial agonists at the α4β2 site as a novel approach tosmoking cessation. This panel will discuss exciting results suggesting that noveland effective smoking cessation therapies are on the horizon.

Panel • Friday 1/29/99 • 4:30–6:30 PM • Snobble

GLUTAMATE RECEPTORS AT EARLY CNS

Martha Constantine-Paton, Stefano Vicini, Ann Marie Craig, Arnold Kriegstein

Early CNS synapses employ an array of receptors whose function is substan-tially different from that of the receptors for the same transmitters at the syn-apses in the mature nervous system. This panel will present evidence from bothprimary culture and slice work documenting these differences. The significanceof these differences in neurotransmission during the earlist phases ofsynaptogenesis will also be discussed. Stefano Vicini will present data on thedistribution, functional properties and pharmacology of NMDA receptor sub-types in developing cortical and cerebellar neurons in primary cultures followingtransfection of these cells with Green Fluorescent Protein to identify morpho-logical characteristics and anatomical compartments. Anne Marie Craig willpresent results, using antibodies to pre- and post-synaptic markers and antibod-ies to glutamate receptor subunits, detailing co-localization of receptor subunitsin isolated hippocampal neurons. Results of experiments in these cultures inwhich NMDA receptor blockade produces new synapses that lack GluR1 willalso be presented. Martha Constantine-Paton will discuss work on the structuraleffects of glutamate receptor activation in Xenopus tadpole tectal neurons inearly dissociated cell culture. In these cultures NMDA receptors function at earlycell-cell contacts in the absense of AMPA/KA receptors or voltage-dependentNa+ channels to supress neurite sprouting. Type I or II metabotropic glutamatereceptors appear to relieve the Mg++ block on the NMDA receptor in the major-ity of these neurons. Finally, Arnold Kreigstein will present the results of studieson GABAA mediated depolarization in neurons of young neocortical slices. Atthe immature glutamatergic synapses in these cultures NMDA receptor medi-ated currents are present in the absense of AMPA receptor mediated currents.GABA appears to mediate the depolarization necessary to remove the Mg++blockade from the NMDA receptor and allow these young contacts to function.

Panel • Friday 1/29/99 • 4:30–6:30 PM • Janss

ASTROCYTES, AXON GROWTH AND BRAIN INJURY

James Fawcett, Herb Geller, Ron Meyer, Steven Levison

When the adult mammalian CNS is damaged the cut axons will not regenerate.The three main reasons for this are the poor regenerative potential of most CNSneurons, inhibitory molecules made by oligodendrocytes and inhibition by theastrocytic glial scar that forms at injury sites. If axon regeneration is induced in

74

the CNS the axons have to grow through a predominantly astrocytic environ-ment. Understanding how astrocytes react to CNS damage, which inhibitoryand permissive molecules they produce, and how axons interact with them istherefore central to discovering how to repair the damaged CNS. This sessionlooks at in vivo, in vitro and molecular approaches to understanding and control-ling the astrocytic reaction to injury, and examines the interactions of regenerat-ing axons with astrocytes. We will be talking about the molecules that cause theastrocytic reaction in the damaged brain, the inhibitory and permissive moleculespresent on reactive astrocytes, and the ways in which these astrocytic moleculesinfluence axon behaviour. We will also cover the factors that make adult CNSaxons bad at regeneration in astrocyte environments, and the differences betweenembryonic axons which grow well, and adult axons which regenerate poorly.The aim of the session is to highlight molecules and strategies that are going tobe important in the repair of spinal cord and other CNS injuries.

Panel • Friday 1/29/99 • 4:30–6:30 PM • Hoaglund

FROM JOGGING TO HIGH WIRE ACROBATICS: BRAIN ADAPTATIONIN RESPONSE TO EXERCISE AND MOTOR SKILL LEARNING

Anna Klintsova, Brenda Anderson, Theresa Jones, Jeffrey Kleim, Rodney Swain

Historically, studies of motor learning have focused on changes in neuronal ac-tivity in association with simple reflex adaptation. Recent work examining thedevelopment of more complex motor behaviors has revealed a robust pattern ofneuroanatomical, neurophysiological and immunohistological changes withinseveral sensorimotor brain regions. Both the cerebellar and motor cortices ac-tively recruit new synapses and display physiological changes that are consistentwith altered neuronal connectivity. Further, immunohistological staining of syn-aptic and nonneuronal elements are increasingly contributing to our understand-ing of the mechanisms by which these morphological and functional adapta-tions are acquired. Participants on this panel will review this evidence in boththe intact and brain damaged animal. The role that these changes may play insupporting motor skill and facilitating recovery from brain damage will be dis-cussed. Swain will compare the onset of exercise-induced angiogenesis in cer-ebellum and motor cortex and their impact on behavior. Kleim will discuss howmotor skill learning affects the functional organization of the motor cortex andhow these changes may be supported by alterations in neuronal morphology.Anderson will discuss the effects of exercise on capillary density and cytochromeoxidase activity in the cerebellum and motor cortex. Jones will discuss behav-ioral experience effects on cerebellar structural plasticity following motor corti-cal damage. Klintsova will present evidence of rehabilitative effects of complexmotor task learning on cerebellar and neocortical neurons damaged by neonatalexposure to alcohol. Finally, the panel will compare and contrast learning-re-lated plasticity with that associated with repetitive motor activity (exercise).

75

Panel • Friday 1/29/99 • 4:30–6:30 PM • Sinclair

CELLULAR AND NETWORK MECHANISMS OF THALAMOCORTICALFUNCTION AND DYSFUNCTION: SLEEP AND EPILEPSY

David McCormick, Diego Contreras, Alain Destexhe, Manuel Castro-Alamancos

Thalamocortical networks can generate at least three distinct states of neuronalactivity: rhythmic oscillations during sleep, tonic activity during waking, andabnormal synchronized discharges during epileptic seizures. Prior investigationshave suggested that the generation of some forms of epileptic seizures may beexpressed as the perversion of normal sleep-related thalamocortical rhythms,such as spindle waves. However, the precise role of the thalamus and cerebralcortex in the generation of these seizures appears to vary in the different animalmodels of generalized epilepsy. D.A. McCormick will speak on the cellular mecha-nisms of generation of spindle waves, the conversion of these into abnormalseizure-like rhythms, and the pattern of activity generated during spike-and-waveseizures in behaving rats. Diego Contreras will present data on the importanceof the cortex in the generation of some rhythmic oscillations as well as thethalamocortical dialogue. Alain Destexhe will explore the hypothesis thatintrathalamic as well as intracortical GABAB-mediated mechanisms can explainthe genesis of spike-and-wave patterns in computational models of thalamocor-tical circuits. Finally, Manuel Castro-Alamancos will present work from in vivoand in vitro experiments on the response properties of different types of thalamo-cortical pathways, and their role in spreading seizures to the cortex. Together,these presentations will provide a detailed analysis of the basic mechanisms bywhich the thalamus and cerebral cortex generate both normal and abnormal ac-tivities.

76

Poster Abstracts

ELEVATED SUPERIOR TEMPORAL GYRUS GLYCINE TRANSPORTER1a mRNA LEVELS in SCHIZOPHRENIA

Susan Bachus

We have found abnormal glycine transporter 1a (GLYT1a) mRNA levels in in-termediate entorhinal and dorsolateral prefrontal cortices in schizophrenic pa-tients. We have extended this study to the superior temporal gyrus (STG), an-other multimodal association cortical area in the temporal lobe where we havefound evidence for aberrant glutamate synaptic function in schizophrenia. Insitu hybridization with an [35-S]-labeled ribonucleotide probe for human GLYT1amRNA was applied to postmortem STG sections from normal controls (n=16),schizophrenics (n=13), nonpsychotic suicides (n=8) and bipolar affective disor-der patients who received neuroleptic medications (n=6). Statistics were by 2way ANCOVA with layer (superficial, deep, and white matter) nested in diag-nostic group. Tissue pH was used as a covariate, since GLYT1a mRNA levelswere significantly positively correlated with pH. Schizophrenics had significantly(p< .05) elevated GLYT1a mRNA relative to both normals and suicides, reach-ing significance in the deep layers of the STG relative to normals, and both thesuperficial and deep layers of STG relative to suicides. Suicides had reducedlevels relative to the other 3 groups. Bipolars did not differ significantly fromnormals or schizophrenics.

These results extend the evidence for abnormalities in GLYT1a mRNA in thetemporal lobe in schizophrenia to the STG, and also implicate STG glutamatedysfunction in the neuropathology of suicide. However, we cannot as yet ex-clude the possibility that the elevation in schizophrenia is secondary to medica-tion history. SEB funded by NARSAD

RELATIONSHIP BETWEEN CORTICAL PATHOLOGY AND NEGA-TIVE SYMPTOMATOLOGY IN SCHIZOPHRENIA AS REVEALED BYPROTON MAGNETIC RESONANCE SPECTROSCOPIC IMAGING

Joseph Callicott

Patients with schizophrenia often present with cognitive, behavioral, and emo-tional deficits (so-called negative symptoms) that have often been attributed toprefrontal cortical pathology. Prior 1H- MRSI studies in schizophrenia have foundregionally specific reductions in relative NAA concentrations in the dorsolateralprefrontal cortex (Bertolino et al. 1996). We sought to demonstrate a relation-ship between an in-vivo measure of neuronal integrity in prefrontal cortex (N-acetyl aspartate or NAA) and negative symptoms using proton magnetic reso-

77

nance spectroscopic imaging (1H-MRSI). We studied 36 schizophrenic patientsusing 1H-MRSI as described elsewhere (Duyn et al. 1993) on a 1.5 Tesla GESigna scanner (Milwaukee, WI). After scanning, the patients were rated for posi-tive symptoms using the Psychiatric Symptom Assessment Scale (PSAS) andnegative symptoms using the Scale for the Assessment of Negative Symptoms(SANS). 1H MR spectra were analyzed using in-house software to calculate thearea beneath the metabolite peaks for NAA, choline containing moieties (CHO),and creatine/phosphocreatine (CRE). The 1H-MRSI results were averaged withinROIs drawn on anatomical scans and were converted to ratios (NAA/CRE,NAA/CHO, and CHO/CRE). We found a regionally specific negative correla-tion (Spearman rank correlation coefficient) between prefrontal NAA measures(NAA/CRE and NAA/CHO) and the SANS (rho = —0.58, p<0.0003 and rho =-0.38, p< 0.03, respectively). No significant correlations were found for prefron-tal CHO/CRE and SANS nor for any other regional NAA measure and SANS.Also, no regional NAA measures correlated with positive symptoms (PSAS) inthis sample. Although the exact interpretation of reduced NAA measures re-mains unclear, these results suggest that lower prefrontal NAA and b y infer-ence greater neuronal pathology ma y be predictive of more severe negativesymptoms in schizophrenia. 1H-MRSI may be a useful technique for identifyingschizophrenic patients at risk for more severe negative symptomatology.

DIFFERENTIAL SYNAPTIC ACTIVATION OF AMPA AND NMDARECEPTORS IN MOLECULAR LAYER INTERNEURONS OF THECEREBELLUM

Beverley Clark

At most central excitatory synapses glutamate activates both NMDA and non-NMDA receptors. The receptor subtypes present will influence the time-courseof excitatory postsynaptic currents (EPSCs). In this study the involvement ofdifferent glutamate receptors at parallel fibre to interneuron synapses was exam-ined. Spontaneous and evoked excitatory post-synaptic currents (EPSCs) wererecorded in molecular layer interneurons in cerebellar slices at 35°C under con-ditions of low extracellular magnesium. Asynchronous and delayed-release eventswere discarded in order to evaluate the EPSC time-course. At —70mV, spontane-ous EPSCs and those evoked with threshold stimulation decayed with meanweighted taus of 0.59ms and 0.62ms respectively and were not affected by theaddition of NMDA receptor antagonists. NMDA-activated channels are presentin somatic outside-out patches suggesting the exclusion of these receptors fromthe synapse. EPSCs evoked using higher stimulation intensity or high frequency(20-100Hz) revealed a slowly decaying component lasting for hundreds of milli-seconds that was partly blocked by NMDA receptor antagonists. Thus, EPSCsin interneurons have a submillisecond time-course and are mediated solely byAMPA receptors even in CE magnesium-free conditions. Activation of NMDAreceptors results only from bursts of parallel fibre activity or from recruitment oflarge numbers of synaptic inputs.

78

SYNAPTIC ACTIVATION OF NICOTINIC RECEPTORS REGULATESHIPPOCAMPAL OSCILLATORY STATES

Stuart Cobb

The hippocampus in vitro displays a variety of patterns of rhythmic activity inresponse to electrical or pharmacological stimulation which correlate with EEGactivity recorded in vivo during particular patterns of behaviour. Here we haveexamined the involvement of nicotinic acetylcholine receptors (nAChRs) in syn-chronous rhythmical states induced in hippocampal slices. Low concentrationsof the muscarinic AChR agonist oxotremorine-M (0.1-1mM) generated synchro-nized low frequency bursting activity in individual CA3 pyramidal cells and ad-jacent extracellular fields CE b urst mode. At higher agonist concentrations (10-50mM) the network displayed periodic episodes of theta frequency oscillations -CE theta mode. Both modes of activity were abolished by the mAChR antago-nist atropine (5mM). In contrast, a range of nAChR antagonists, but not the a7subunit specific antagonist methyllycaconitine (0.1-1mM), switched the networkfrom CE theta to CE burst mode in a reversible manner. Similar results wereobtained when presynaptic acetylcholine stores were disrupted usinghemicholinium-3 (20-50mM) and vesamicol (50mM). Taken together, these re-sults demonstrate that endogenous acetylcholine activating nAChRs is criticalfor switching the hippocampal network activity between oscillatory states.

INJURY INDUCED EXPRESSION OF HSP27 WITHIN THE DRGTHE UPREGULATION OF A NEURONAL SURVIVAL FACTOR.

Michael Costigan

We have identified the small heat shock protein HSP27 as an mRNA speciesmarkedly upregulated in the adult rat dorsal root ganglion (DRG) following sci-atic nerve section. Northern blot analysis shows HSP27 mRNA to be upregulatedapproximately tenfold 2 days post axotomy with levels persisting for at least 7days. In contrast, mRNA for HSP56, HSP60, HSP70 and HSP90 are not simi-larly regulated. HSP27 mRNA is constitutively expressed at low levels in me-dium/large A-fibre neurons. After peripheral axotomy high levels of expressionare seen in all cell types including nociceptive C-fibres. HSP27 protein isupregulated in the DRG cell bodies in a pattern which mimics that of the mRNA.In development, HSP27 mRNA levels within the DRG increase from very lowlevels at E15 to levels approaching that of the adult at P21. Consistent with invivo data, less than 5% of dissociated P0 DRG neurons in vitro express HSP27.After 4 days of culture in the absence of NGF, over 50% of P0 DRG neuronalcells die. However, greater than 80% of surviving cells are now highly positivefor HSP27, double labeling for HSP27 and Hoescht 33342 reveals that cells withapoptotic nuclei are not HSP27 positive. In the adult where all DRG cells areable to upregulate HSP27 no cell death occurs following axotomy, in neonateswhere only a small proportion of cells are able to upregulate HSP27, massive

79

cell death occurs, none of which is seen in those cells which upregulate HSP27.These results suggest that HSP27 acts as a nerve-injury induced survival factor inadult primary sensory neurons, preventing cell death after damage to the periph-eral axons.

NOREPINEPHRINE (NE) IN THE BED NUCLEUS OF THE STRIATERMINALIS (BNST) IS CRITICALLY INVOLVED IN OPIATEWITHDRAWAL

Jill Delfs

The BNST receives one of the densest NE projections in the forebrain, however,the involvement of this structure in the expression of opiate withdrawal (OW)behaviors has not been explored. This laboratory has previously reported that βadrenergic receptor antagonists attenuated both the somatic and aversive signsof OW (Harris & Aston-Jones, 1993). We now report that bilateral microinjec-tions of the selective β1 (betaxolol) plus the β2 (ICI 181555) antagonist (0.1 or1.0 nmol/0.5 ul per side) into the BNST dose-dependently decrease several so-matic signs as well as significantly reduce the OW-induced conditioned placeaversion (CPA). Injections of this cocktail 3 mm dorsal to the BNST had noeffect on OW behaviors. BNST injections of the non-selective β antagonist, pro-pranolol (5 nmol), resulted in a similar decrease in somatic and aversive OWsigns as seen with the beta antagonist cocktail. The behavioral effects of the inac-tive isomer of propranolol were not different from control animals. Current studiesare examining the effect of microinjections of the alpha adrenergic agonist, ST91,into the BNST on OW behaviors. Preliminary results indicate that a high dose (5nmol) had no significant effects on OW behaviors, while a lower dose (2.5 nmol)appeared to reduce the severity of OW. The BNST receives NE inputs from thelocus coeruleus (LC), A1 and A2 (NTS) cell groups. To determine the source ofthe BNST NE innervation that mediates these effects on OW, we treated animalswith the neurotoxin DSP-4 (50 mg/kg, i.p.), which selectively destroys NE-LCfibers, or lesioned the dorsal NE bundle with 6-OHDA. Neither of these treat-ments altered the somatic or aversive signs of OW, indicating that non-LC inputsto the BNST may be predominently involved. In support of this hypothesis, 6-OHDA lesions of the ventral NE bundle were found to attenuate some OWsomatic signs and significantly reduced the OW-induced CPA. Taken together,these data suggest that NE inputs to the BNST, arising from medullary sourcessuch as the A1 or A2 (NTS) NE cell groups, are importantly involved in mediat-ing OW behaviors.

A ROLE FOR HEME OXYGENASE IN NEUROPROTECTION

Sylvain Dore

Heme oxygenase (HO) mediates the conversion of heme to carbon monoxide,Fe2+, and biliverdin, which is immediately reduced to bilirubin (BR). Two major

80

HO isozymes, products of distinct genes, are well known. HO-1, a stress responseprotein is ubiquitously distributed. HO-2, a constitutive enzyme is present inhigh concentration in the brain and selectively expressed in neurons. We haveshown that stimulation of HO activity, resulting in production of BR, known tobe an endogenous free radical scavenger, protects primary hippocampal neuronsagainst H2O2-induced oxidative stress injury. The rate of apoptosis induced byserum deprivation along with low potassium concentrations is significantly in-creased in the HO-2 knockout granular cells as compared with the wildtype.Moreover, a cell line overexpressing HO-2 is resistant to death-induced by serumstarvation. Using an in vivo stroke model, we examined the extent of damagefollowing middle cerebral artery occlusion (MCAO)(1h) followed by 23h-reperfusion. We observed a significant increase in the infarct core in HO-2 knock-out compared to wildtype mice (mean ± sd: 76 ± 27 vs 44 ± 14 mm3). Using theyeast two hybrid technique to detect protein-protein interaction, we observed aspecific interaction of HO with amyloid precursor proteins (APPs). We con-firmed this interaction with co-IP experiments and are now evaluating its impor-tance in Alzheimer Disease. These findings suggest that modulating HO activitycan modify the rate of neurodegeneration. Supported by USPHS DA-00266 toSHS, HL 48517 and NS 20020 to RCK and RJT and Medical Research Councilof Canada to SD.

HIPPOCAMPAL NAA AND COGNITIVE DYSFUNCTION INPATIENTS WITH SCHIZOPHRENIA AND WELL SIBLINGS:DISTINCT PHENOTYPES?

Michael Egan

Genetic studies of schizophrenia have been confounded by phenotypic uncer-tainty and low relative risk of susceptibility loci. An alternate strategy is to lookat associated biological phenotypes. Patients with schizophrenia have reducedhippocampal n-acetyl aspartate (NAA), a neurochemical whose reduction sug-gests reduced neuronal integrity. Estimations of relative risk suggest reduced hip-pocampal NAA may be a useful trait for genetic studies. It is unclear, however,whether NAA is related to cognitive dysfunction typically associated with schizo-phrenia. While a strong correlation would suggest reduced NAA is associatedwith cognitive impairment, it would also indicate that NAA may not give muchadditional information beyond such measures. Given the expense of gatheringNAA data, to justify its use as a phenotype in genetic studies, reduced hippocam-pal NAA should give additional information beyond that more easily derivedfrom cognitive testing. To examine the correlation of NAA with cognitive vari-ables, we assessed 110 patients with schizophrenia, 160 siblings, and 40 controls.Subjects received brain scans using MR spectroscopy and extensive neuropsy-chological testing. A highly significant group effect was found for cognitive mea-sures (p<10-7). Siblings (n=156) had worse performance than controls (n=36)only for the Weschler memory scale (p=.02). For the combined group of patients(n=76) and siblings (n=101), no significant correlations were found between hip-

81

pocampal NAA and any cognitive measure. These data suggest that NAA andcognition are not correlated and may assess distinct phenotypes. Despite ascer-tainment costs, NAA may give important phenotypic information that cannot bederived from cognitive measures alone.

DEVELOPMENT OF NOVEL DIPEPTIDES WITH NEUROPROTECTIVEAND COGNITIVE ENHANCING PROPERTIES

Alan Faden

As part of a program to develop novel neuroprotective agents for treatment ofCNS injury, we have developed a series of cyclized dipeptides. Compound 35b isa diketopiperazine that shows strong protective effects following fluid-percus-sion induced traumatic brain injury (FPI) in rats or following controlled corticalimpact (CCI) in mice. When administered iv 30 min after trauma, 35b treatedanimals showed significantly better motor recovery than vehicle treated controlsafter FPI or CCI, and significantly improved cognitive function. Administeredbeginning one month after injury, 35b significantly improved spatial learning/memory in chronically injured mice. Other related dipeptides also showneuroprotective actions. Administration of 35b also provided neuroprotectionfollowing traumatic neuronal injury in rat mixed cortical-neuronal cultures orafter exposure to glutamate. Together these findings demonstrate that our noveldiketopiperazine provides neuroprotection across multiple in vivo and in vitromodels of injury, as well as having clear cognitive enhancing actions followingchronic injury. Funded in part by DAMD 17-93-v-3018

DIFFERENTIAL TARGETING OF GABA-A RECEPTOR SUBTYPESREVEALED BY SINGLE-CHANNEL PROPERTIES OF SYNAPTIC ANDEXTRASYNAPTIC RECEPTORS

Mark Farrant

Cerebellar granule cells display, at various stages of development, more than tendifferent GABAA subunit types. This subunit diversity is expected to result insignificant receptor heterogeneity, yet the functional consequences of such het-erogeneity remain poorly understood. We have used single-channel properties tocharacterize GABAA receptor types in the synaptic and extra-synaptic mem-brane of granule cells. In the presence of high concentrations of GABA, whichinduce receptor desensitization, extrasynaptic receptors in outside-out patchesfrom the soma enter long-lived closed states interrupted by infrequent clusters ofopenings. Each cluster of openings, which is assumed to result from the repeatedactivation of a single channel, displays one of three main conductance states(28, 17 or 12 pS), the relative frequency of which differs between patches. Suchbehavior indicates the presence of at least three different receptor types. Thisheterogeneity is not replicated by individual recombinant receptors (alpha1 beta2gamma2S or alpha1 beta3 gamma2S), which give rise to clusters of a single type

82

only. By contrast, the conductance of synaptic receptors, determined by fluctua-tion analysis of the synaptic current or direct resolution of channel events, isremarkably uniform, and similar to the highest conductance value seen inextrasynaptic patches. These results suggest that granule cells express multipleGABAA receptor types, but only those with a high-conductance, most likely con-taining a gamma subunit, are incorporated into the postsynaptic membrane.

SOMATOSTATIN REGULATION OF C6 GLIOMA CELL GROWTH

Susan Feldman

Somatostatin (SS) has been shown to regulate growth in a number of celllines,mainly through the SSTR2 receptor. Although C6 cells overexpress the re-ceptor, exogenous SS has no effect on growth. We were interested in the possibil-ity that forcing C6 cells to constitutively synthesize SS might alter their growthcharacteristics. The coding portion of the gene for pre-pro-SS was inserted intothe viral vector P-Babe-Puro in both sense and antisense orientations. C6 cellswere transfected with these constructs and selected for in puromycin-containingmedium. Cells transfected with SS in the sense (C6SS), but not antisense (C6AS)grew at about one-tenth the rate of controls. Only the C6SS cells synthesized SS,as determined by RT-PCR and immunocytochemistry. Interestingly, in the C6SScells the gene for the SSTR2 receptor was extremely down-regulated. C6SS cells,but not C6AS cells, also showed altered morphology and colony formation. Ex-periments are now underway to determine if constitutive synthesis of SS resultsreduces growth of glioma cells in vitro directly, by affecting the cells passagethrough the cell cycle, or indirecly, by affecting the synthesis of a receptor orother signal transducing protein.

EXPRESSION OF C-FOS IN RAT FOREBRAIN AFTER LATERAL VEN-TRICLE INJECTIONS OF THE TACHYKININ AGONIST SENKTIDE

Francis Flynn

Injections of NK3 receptor agonists selectively inhibit salt intake. The brain sys-tems that are activated by lateral ventricular injections of senktide, a NK3 ago-nist, were identified using neurohistological techniques. Rats (n=8) were treatedwith either senktide or isotonic saline and the brains were then processed for c-fosimmunoreactivity. The pattern of activation showed that senktide activates anumber of forebrain sites, including the median preoptic n., supraoptic n., arcu-ate n., and most strongly, the paraventricular n. Next, experiments sought todetermine if PVN neurons that are activated by senktide project to medullarynuclei, which directly or indirectly regulate autonomic preganglionic neurons.Flurogold was injected bilaterally into the dorsal vagal complex and 7 days later,rats were administered intraventricular injections of senktide (200 ng) or iso-tonic saline and the brains were processed for c-fos immunoreactivity. Senktideinduced the strongest c-fos expression in the rostral and medial PVN (greater

83

than 200 cells/level) and little in the caudal parts (less than 20 cells). Overall,c-fos expression was more concentrated in the magnocellular than parvocellularPVN. In the parvocellular PVN, the greatest number of retrogradely labeled cellswere found in the medial and posterior parts. Cells expressing c-fos were closelyintermixed with cells projecting to the dorsal vagal complex but none of the cellsshowed double labeling. The pattern of c-fos expression suggests a close relation-ship to the magnocellular neurosectretory system (Supported by DK50586 toF.W.F.)

EFFECTS OF PARAVENTRICULAR NUCLEUS (PVN) INJECTION OFMELANOCORTIN 4 RECEPTOR (MC4-R) LIGAND

Silvia Giraudo

The MC4-R has been implicated in the control of food intake and body weight.Melanocyte-stimulating hormone (α-MSH) derived from the arcuate nucleus pro-opioimelanocortin neurons is the primary source of ligand for MC4-R. The cur-rent study confirmed the interaction of PVN MC4 receptors with neuropeptideY (NPY) and leptin levels by injecting α-MSH into the PVN. Sprague Dawleyrats (n=24) received either 3 injections of saline or 600 pmol α-MSH over 24 hinto the PVN. Two hours following last injection, rats were sacrificed. Adminis-tration of α-MSH caused a significant decrease in feeding (F2,26 =7.845,P=.002), serum leptin levels (F2,26 =2.152, P= .04) and NPY mRNA gene expres-sion in the arcuate nucleus (F2,26 =2.215, P= .04). Our findings provide directevidence that MC4-R signaling is important is mediating food intake and thatmelanocortin neurons in the PVN exert a tonic inhibition of NPY gene expres-sion and leptin levels.

UNABLE TO LINK GLUTAMATE EXCITOTOXICITY TO ALCOHOLINDUCED NEURODEGENERATION.

Carol Hamelink

Short-term high-level alcohol consumption in the rat selectively inducesneurodegeneration in the dentate gyrus (DG), piriform and entorhinal cortices(EC), as well as the olfactory glomerulus. Several studies have been performedexamining the mechanism of this alcohol induced neurotoxicity. Unilateral ol-factory bulbectomies were performed on one group of rats to determine if theolfactory pathways to the piriform and EC are necessary for damage in theseareas. We have previously shown that NMDA antagonists MK-801 andmemantine, as well as the L-type calcium channel blocker nimodipine, were un-able to provide neuro-protection in these regions when given with the alcohol.Acamprosate, an anti-craving drug, furosemide, a kidney loop diuretic, and L644-711, a non-diuretic derivative of loop diuretics were tested for possibleneuroprotective effects. In addition to diuresis, furosemide affects astrocyte swell-ing thus affecting synaptic glutamate clearance. L644-711 similarly affects astro-

84

cytes without the systemic diuresis. Rats were given 10% w/v ethanol diet viagastric cannula 3 times per day for 4 days. Blood alcohol levels were 300-350mg/dl 2 hours after feeding. Olfactory bulbectomies did not influence degenera-tion in the piriform and EC, indicating that these cells are likely to be directlysensitive to ethanol. Furosemide (10 mg/kg/day) decreased the amount of cel-lular degeneration in both the DG and EC. Neither L644-711 (20 mg/kg/day)nor acamprosate (450 mg/kg/day) were able to decrease the amount of damagecaused by alcohol in these regions. These results do not implicate the glutamateneurotransmitter system in our observed alcohol induced neurodegeneration.

REGIONAL AND SERIAL VARIATION IN SOLUBLE FACTORSFOLLOWING NEONATAL BORNA DISEASE VIRUS INFECTION OFLEWIS RATS

Mady Hornig

Neonatal infection of rats with Borna disease virus (BDV) is associated withpersistent central nervous system (CNS) infection, disruption of hippocampaland cerebellar morphology, and subtle behavioral and cognitive abnormalitiesreminiscent of autism in the absence of an aggressive cellular inflammatory re-sponse. To identify mechanisms of developmental CNS damage, we examinedregional expression of genes for neuronotrophic factors (cytokines and classicalneurotrophic factors), and apoptosis-related products at 2, 4, 6, 12, and 24 weeksfollowing neonatal BDV infection of Lewis rats in conjunction with serial analy-ses of locomotion, coordination, and stereotypic behavior. Ribonuclease protec-tion assays were performed using RNA extracted from hypothalamus, cerebel-lum, olfactory cortex, prefrontal cortex, striatum, nucleus accumbens, hippoc-ampus, and amygdala. Locomotor activity was quantitated using photocell-acti-vated activity chambers. Behavioral disturbances included hyperactivity and mildstereotypies at all timepoints following infection, and abnormal responses to novelenvironments (ranging from excessive inhibition to excessive exploratory behav-ior) that shifted across timepoints. Distinct profiles in expression of mRNAs forcytokines, neurotrophic factors and apoptosis-related products were observed ininfected animals that varied by brain region and time. Differences were maximalat 4 weeks and declined gradually thereafter. Neurotrophic factor profiles wereconsistent with temporal disturbances in the development of specific brain cir-cuits. These results demonstrate the utility and relevance of the neonatal rat modelof BDV infection as a tool for the study of human neurodevelopmental disordersin which viral and immune factors may be implicated.

85

ACTIVATION OF CNS CIRCUITS PRODUCING A NEUROGENICCYSTITIS: EVIDENCE FOR CENTRALLY INDUCED PERIPHERALINFLAMMATION

Luc Jasmin

We present a model of neurogenic cystitis induced by viral infection of specificneuronal circuits of the rat CNS. Retrograde infection by pseudorabies virus(PRV) of neuronal populations neighboring those that innervate the bladder con-sistently led to a localized immune response in the CNS and bladder inflamma-tion. Infection of bladder circuits themselves or of circuits distant from theserarely produced cystitis. Absence of virus in bladder and urine ruled out an in-fectious cystitis. Total denervation of the bladder, selective C-fiber deafferenta-tion, or bladder sympathectomy prevented cystitis without affecting the CNSdisease, indicating a neurogenic component to the inflammation. The integrityof central bladder related circuits is necessary for the appearance of bladder in-flammation, as only CNS lesions affecting bladder circuits, i.e., bilateral dorso-lateral or ventrolateral funiculectomy, as well as bilateral lesions of Barrington snucleus/locus coeruleus area (Bar/LC), prevented bladder inflammation. Theclose proximity in the CNS of non-infected visceral circuits to infected somaticneurons would thus permit a bystander effect, leading to activation of the sen-sory and autonomic circuits innervating the bladder and resulting in a neuro-genic inflammation localized to the bladder. The present study indicates thatCNS dysfunction can bring about a peripheral inflammation.

ENHANCED CRH-EVOKED INCREASE IN ELECTROPHYSIOLOGI-CAL ACTIVITY OF NORADRENERGIC NEURONS OF THE LOCUSCOERULEUS IN CHRONICALLY COLD EXPOSED RATS

Hank Jedema

Chronic exposure to cold (4°C for 14 days) has been demonstrated to alter bothneurochemical and electrophysiological activity of noradrenergic neurons of thelocus coeruleus (LC). Recent studies also demonstrated an enhanced release ofnorepinephrine (NE) in the prefrontal cortex following intraventricular (ICV)administration of corticotropin releasing hormone (CRH) in cold exposed rats.To investigate whether this could be a result of an enhanced responsivity of LCneurons to CRH, single unit extracellular recordings were made in halothane-anesthetized rats. Following chronic exposure cold (4°C for 14 days) there was atrend towards an increase in the mean basal firing rate (FR) of LC neurons. Inresponse to administration of a moderate dose of CRH (1.0 µg, ICV), a morepronounced increase in FR was observed in cold exposed rats compared to na v econtrols. Furthermore, CRH administration seemed to recruit previously quies-cent neurons in cold exposed rats. These data extend previous findings of anenhanced basal FR in chloral hydrate anesthetized rats following cold exposureand indicate that the increased release of NE in response to CRH is likely medi-

86

ated by an increase in spike firing of LC neurons. Thus, these data, together withprevious findings from this laboratory, indicate that the responsivity of LC neu-rons to multiple excitatory inputs is enhanced following chronic exposure to thisphysiological stressor. The increased responsivity of LC neurons may, in part,underlie complex behavioral adaptations that occur in response to chronic expo-sure to stress.

NUTRITIONAL MODULATION OF AGE RELATED DECLINES INBEHAVIORAL AND NEURONAL FUNCTION

James Joseph

Numerous experiments have suggested that the consumption of fruits and veg-etables reduce both the incidence and mortality rates of cancer in several humancohort and case-control studies for all common cancer sites. Similarly, in animalexperiments, diets containing fruits and vegetables which are common in humandiets have been found to have antitumorigenic effects. One common property ofthese diets high in fruits and vegetables appears to be their antioxidant effects.Given these considerations and given the findings that oxidative stress (OS) ap-pears to be one of the primary factors involved in neuronal aging and age-relatedneurodegenerative diseases, it became of interest to determine if diets high fruitand vegetable intake would be effective in reducing the age-related deficits inneuronal function. To this end we have recently shown that F344 rats main-tained from 8-15 months on diets containing strawberry or spinach extracts whichwere put into an AIN-93 defined diet and pelletized, did not exhibit any of thechanges in neuronal signal transduction (e.g., calcium clearance from hippoc-ampal synaptosomes; striatal cerebellar Purkinje cell firing, oxotremorine en-hanced K+-evoked dopamine release) and cognitive behavior normally seen byrats at this age (Joseph et al., J. Neurosci. 18, 8047-8055, 1998). Subsequent datahas suggested that these dietary supplements, as well as a blueberry extract, wereable to reverse these deficits when 20 month old F344 rats were maintained onthese diets for 6-wks. These results suggest that fruit and vegetable supplementa-tion may have the same positive benefit with respect to CNS aging as has beenseen with respect to carcinogenesis and cardiovascular disease. We are currentlyexamining the flavonid components of these compounds to determine their mosteffectve combinations and mechanisms of action.

EFFECT OF MU-OPIOID RECEPTOR STIMULATION IN THE NUCLEUSOF THE SOLITARY TRACT ON C-FOS IN THE RAT

Catherine Kotz

DAMGO, a mu opioid receptor agonist, stimulates feeding when injected intothe nucleus of the solitary tract (NTS), whereas naltrexone, an opioid receptorantagonist, decreases feeding when injected into the NTS. Naltrexone in the NTSalso inhibits feeding induced by neuropeptide Y (NPY) injected into the hypo-

87

thalamic paraventricular nucleus (PVN) and results in elevated NPY gene ex-pression in the hypothalamic arcuate nucleus (Arc). Together, these data suggestcommunication between Arc-PVN NPY feeding signals and NTS opioid path-ways. To determine potential brain sites involved in NTS DAMGO-induced feed-ing, we measured c-fos immunoreactivity (c-fos-ir) following DAMGO adminis-tration into the medial NTS. Twenty male Sprague Dawley rats received eithersaline or 2 nmol DAMGO into the mNTS (in a 0.5 µl volume over a 30 secondinfusion period). Food was not allowed. One hour following injection, rats wereanesthetized; transcardially perfused and brains processed for c-fos-ir. DAMGOinduced a significant increase in c-fos-ir in the PVN, (F1,12=9.485, P=.0095),whereas c-fos-ir was unchanged in the parabrachial nucleus, the central nucleusof the amygdala, and several regions of the NTS. These data suggest that feedinginduced by opioid receptor stimulation in the NTS involves neural signaling path-ways in the PVN. With previous evidence implicating the NTS in feeding stimu-lated by NPY in the PVN, the accumulated data indicates a bidirectional path-way connecting the PVN and NTS within the network regulating appetite andbody weight.

IMPLICATIONS OF NITRIC OXIDE IN THE SELECTIVE VULNER-ABILITY OF DOPAMINERGIC CELLS: PEROXYNITRITE- ANDNITRITE- INDUCED DOPAMINE OXIDATION

Matthew LaVoie

Dopamine (DA) has the ability to oxidize and form oxygen free radicals and DAquinones that have been implicated in models of neuronal damage, includingDA- and methamphetamine-induced toxicity. DA quinones can covalently bindto the sulfhydryl groups found in cysteine, modifying protein structure and func-tion. Nitric oxide, via the formation of peroxynitrite (ONOO), has also beenimplicated in models of neurodegeneration, including selective damage to DAcells. In this study, we found that ONOO was able to oxidize DA in vitro andpromote the binding of DA quinones to protein. Buffered reaction mixtures (1ml; pH 7.2) contained 50 mM 3H-DA, 3 mg of the cysteine-rich protein, alcoholdehydrogenase, and varying concentrations of ONOO were incubated for 10min at 37°C. The amount of radioactivity covalently bound to acid-precipitatedprotein was determined by liquid scintillation counting. Concentrations of ONOOas low as 1 mM caused a significant increase (+28%) in the binding of 3H-DA toprotein as compared to control (p<0.01). Higher concentrations of ONOO (500mM) resulted in a 2200% increase in 3H-DA bound to protein (p<0.01). HPLCanalyses of the protein following hydrolysis confirmed that the 3H-DA had co-valently bound to cysteinyl residues, isolated as 5-cysteinyl-DA conjugates. Inaddition, we observed that a more stable product of ONOO decomposition alsowas able to initiate the oxidation of DA. Both nitrate (NO3

—) and nitrite(NO2

—) are thought to be products of ONOO decomposition, and therefore wereexamined for their ability to oxidize DA. NaNO3 demonstrated no ability tooxidize DA, however, NaNO2 showed a very robust effect on DA oxidation.

88

NO2 was as effective as ONOO at concentrations up to 100 mM. These datasuggest that the generation of nitric oxide may present a unique oxidative stressto DA cells, as both ONOO and its degradation products may cause the oxida-tion of DA and the covalent modification of protein. Supported in part by USPHSgrants DA09601 (TGH) and DA05811 (MJL).

CARBON MONOXIDE AND CEREBRAL MICROVASCULAR TONE INNEWBORN PIGS

Charles Leffler

A growing body of evidence indicates that the neurotrophins play a critical rolein plasticity in the adult mammalian nervous system. Repeated treatment withamphetamine-like compounds in rats results in a variety of changes in the cen-tral nervous system that drive in an enduring augmentation in the hyperactivebehavioral response to psychostimulants; this phenomenon is known as behav-ioral sensitization. Recent evidence indicates that the neurotrophins play an im-portant role in the induction of behavioral sensitization to cocaine. The presentexperiments evaluated the role of two of the neurotrophins, NT-3 and BDNF, incocaine behavioral sensitization in rats. The first series of experiments assessedthe ability of NT-3 and BDNF to cross-sensitize with cocaine. NT-3, BDNF orsaline was microinjected bilaterally into the ventral tegmental area (VTA) oncedaily for three consecutive days. Following a two week withdrawal period, all ofthe rats were challenged with an injection of 15 mg/kg cocaine. The results indi-cated that pre-exposure to either NT-3 or BDNF resulted in a sensitized behav-ioral response to a subsequent injection of cocaine. A second series of experi-ments used RT-PCR to assess the effects of acute or repeated injections of co-caine or saline on mRNA for NT-3 and BDNF in the VTA. These experimentsrevealed that an acute injection of cocaine (30 mg/kg) resulted in a robust in-crease in NT-3 mRNA in the VTA; an acute cocaine injection resulted in a mod-est increase in BDNF mRNA in the VTA. Following a sensitizing regimen ofcocaine injections (30 mg/kg once daily for 7 days), an acute challenge injectionof cocaine (30 mg/kg) did not influence the mRNA for NT-3 or BDNF in theVTA. Taken together, these results suggest that changes in NT-3 and BDNFsynthesis in the VTA may contribute to the initiation of behavioral sensitizationto cocaine.

ALTERATIONS IN BRAIN RECEPTOR FUNCTION AS A RESULT OFGP120/BM5D

Anita Lewin

The tragedy of HIV-1 is frequently compounded by the associated cognitive/motor dysfunction termed AIDS Dementia Complex (ADC). The HIV-1 enve-lope glycoprotein gp120 has been implicated in producing brain injury respon-sible for ADC. In particular, gp120 neurotoxicity involves activation of NMDAreceptors since the effects of this glycoprotein are abrogated by NMDA receptor

89

antagonists in retinal ganglion cells (Lipton, 1992) and in rat midbrain dopam-ine cultures (Bennett et al., 1995). In addition, rgp120 was found to selectivelyand non-competitively inhibit ligand binding at NMDA receptors in rat fore-brain (Sweetnam et al., 1993). It has also been suggested that, since 3-day expo-sure of midbrain dopamine cultures to gp120 reduces dopamine transport, dopam-inergic neuronal damage may contribute to the manifestations of ADC (Bennettet al., 1995). We have found that, following a 5-day icv regimen of gp120,radioligand binding to NMDA receptors prepared from rat cortex is unaffectedwhile binding at the dopamine transporter (DAT) is decreased. Evaluation ofbinding in the brains of LP-BM5 (murine AIDS) mice showed binding at NMDAand DAT receptors to be reduced as the load of BM5d, the specific agent respon-sible for induction of MAIDS, increased. Chronic morphine self-administrationreversed these effects. The results have important ramifications in terms of CNSeffects associated with ADC and murine models of ADC. Investigations of theconnection between the CNS and AIDS require a suitable animal model. Theresults presented serve to further validate the MAIDS model, particularly as ap-plied to CNS effects. Moreover, the results, which include the effects of absti-nence and preceipitated withdrawal, indicate significant interaction between vi-rus and CNS-active drugs.

A NEW MUTANT: EVIDENCE FOR A NOVEL GENE ESSENTIAL TONEOCORTICAL DEVELOPMENT AND NEURONAL EXCITABILITY

Joe LoTurco

Mutations that disrupt specific aspects of neural development define essentialdevelopmental processes and can be used to ultimately identify the genes under-lying these processes. We will describe a new, spontaneous, autosomal recessivemutation in rats, Flathead (fh), that results in both a dramatic reduction in thesize of cerebral and cerebellar cortices, and in spontaneous seizures that occurthrough a proscribed period in early post-natal development (P7-P19). The seg-regation pattern of a set of polymorphic microsatelite markers in 51 affected F2offspring from a single F2 intercross indicate that fh is approximately 2cMteleomeric to nos1 on rat chromosome 12. There are no known mutations inhomologous regions of either mouse or human genomes that result in a similarphenotype. The unique phenotype of fh/fh animals and the location of the fhmutation suggests the presence of a novel gene on chromosome 12 that is essen-tial to normal brain development and neuronal excitability in early postnataldevelopment.

A NEW PURKINJE CELL DEGENERATION MUTANT EXHIBITS DET-RIMENTAL EFFECTS ON OLIGODENDROCYTE DIFFERENTIATION

Wendy Macklin

The weebler (wb) mouse is a spontaneous mutation observed in an FVB line.The wb gene is unknown, but it is inherited as an autosomal recessive mutation.

90

The wb phenotype manifests as severe ataxia, first appearing around day 12 andworsens with age. The lifespan of affected mice is 6-7 months and both sexes arefertile. Histological examination of the brains revealed the only striking abnor-mality to be the loss of cerebellar Purkinje cells (PC). Developmental studiesrevealed that PC loss started around day 14 and by 30 day, only approximately25% of the PC remained. Calbindin, a calcium binding protein enriched in PC,was absent from some areas of the PC layer at day 14, with a major loss ofcalbindin immunoreactivity and RNA occurring between 21 and 30 days. Themyelin protein, proteolipid protein (PLP) showed an unusual pattern of stainingin wb cerebellum starting at day 14, in the early period of myelination. At day14, the wb cerebellum appeared to have less PLP staining in general, and by day30, significant PLP immunoreactivity was seen accumulating in oligodendro-cyte (OL) cell bodies. In normal cerebellum, by 30 days of age, very few OL cellbodies stain for PLP, because the PLP protein moves out of the cell body into themyelin sheath. PLP only accumulates in OL cell bodies in pathological condi-tions. In addition, in wb mice, very few oligodendrocytes were detected in theinner granule cell layer, compared to wild type mice, suggesting that some aspectof the interaction between the wb PC and OL alters the ability of OL to migrateinto the granule cell layer and/or differentiate. Our preliminary data indicatethat the wb mutant is a useful tool for understanding genes that control PC devel-opment as well as the neuronal factors that influence oligodendrocyte develop-ment and migration.

STRIATAL COINCIDENCE DETECTION MODEL OF INTERVALTIMING

Matthew Matell

A model of temporal perception in the seconds to minutes range has been devel-oped in which a specific time of reinforcement can be encoded by selectivelyweighting the medium frequency (5-15 Hz) oscillating cortical inputs to the stria-tum which are firing at a criterion time. This model has been developed underthe behavioral, anatomical, and pharmacological constraints as specified by pre-vious work in the interval timing field (Gibbon, Malapani, Dale, & Gallistel,1997) and is physiologically realistic in terms of neural processing mechanisms.By encoding time in a manner similar to the determination of a least commonmultiple, long durations (e.g., 30 s) may be accurately represented by very short(<200 ms) neuronal mechanisms (Miall, 1989). Upon onset of a meaningfulstimulus, dopaminergic neurons briefly burst fire (Schultz, Dayan, & Montague,1997), thereby hyperpolarizing the striatal membrane. Additionally, cortical/tha-lamic oscillatory neurons are transiently synchronized. This hyperpolarizationof the striatal spiny neurons, coupled with the synchronization of cortical oscil-lations, functions to r eset the temporal integration processes. Following thetransient synchronization, the cortical neurons return to oscillating at their in-trinsic period, allowing repeatable patterns of activity to develop in time. Striatalspiny neurons are connected to 10,000 to 30,000 separate cortical and thalamic

91

inputs and have previously been hypothesized to be capable of detecting andresponding to particular patterns of input. Selection of meaningful cortical in-puts in the striatum is carried out by long-term potentiation/depression, viadopaminergic activity from the midbrain following reinforcement (Wickens, Begg,& Arbuthnott, 1996). By weighting only those inputs that are firing at the crite-rion time, striatal neurons may function as coincidence detectors of temporallyencoded patterns of cortical activity. Following the crossing of a detection/simi-larity threshold, set by dopaminergic and interneuronal activity in the striatum,an ensemble of spiny neurons fire, thereby engendering a response that the en-coded time has been reached. This striatal activity passes through the striatal-thalamic-cortical loop, impinging on the current cortical oscillations, allowing adynamic alteration to ongoing temporal discriminations. By implementing vari-ability in the cortical oscillatory period both within and between trials, computersimulations produce data that are qualitatively similar to data obtained in ratsperforming a psychophysical timing procedure. Such data is characterized by anincrease in activity up to the time of previous reinforcement, a symmetrical de-crease in activity following the criterion time on non-reinforced trials, as well asshowing Weber s Law, or a constant coefficient of variation, over multiple dura-tions (Church, Miller, Meck, & Gibbon, 1991).

THE CONANTOKIN FAMILY OF PEPTIDES ISOLATED FROMPREDATORY MARINE SNAILS: UNIQUE NMDA RECEPTORSUBUNIT SELECTIVITY

Tyler McCabe

Conantokins are a family of small peptides (17-26 amino acids) from the venomof Conus marine snails that interact with NMDA receptors. Conantokins pos-sess potent anticonvulsant and neuroprotectant activity with low behavioral tox-icity in animals. Since the antagonist activity of these peptides at NMDA recep-tors has not been fully characterized, we examined and compared electrophysi-ological recordings from native and recombinant NMDA receptors to assess sub-unit selectivity. Previously, Conantokin-R (Con-R) isolated from Conus radiatuswas shown to be a selective antagonist for NMDA receptors containing the NR2Aand NR2B subunit. A series of related conantokins have been isolated from otherConus species and include Con-G, Con-T, Con-L, Con-S, and Con-O (from Co-nus geographus, tulipa, lynceus, sulcatus, and ochroleucus, respectively). In wholecell recordings from cultured mouse cortical neurons, the conantokins, apart fromCon-O, were potent antagonists of NMDA-evoked responses with potencies simi-lar to that of Con R (IC50 ~ 300 nM). As previously seen with Con-R, Con-T, -L, and -S also blocked NMDA-evoked current responses in two electrode volt-age clamp recordings from Xenopus oocytes expressing NR2A and NR2B sub-units. In addition, Con-S was also active at receptors containing the NR2D sub-unit. On the other hand, Con-G was active only at receptors containing the NR2Bsubunit. These studies demonstrate that conantokins are potent antagonists ofthe NMDA receptor with unique NR2 subunit selectivity that differs between

92

various snail species. Moreover, these observations may also help to elucidatethe remarkable therapeutic potential of conantokin compounds devoid of be-havioral side effects traditionally associated with other NMDA antagonists.NMDA receptor cDNAs were used with kind permission from S. Heinemann.Contributors: S. Donevan1, H. Armstrong2, S. White2, C. Walker3, B. Olivera3,L-M. Zhou4, and J. Nielsen4. Depts. of 1Neurology, 2Pharmacology & Toxicol-ogy, and 3Biology, University of Utah, Salt Lake City UT 84112; 4CognetixInc., Salt Lake City, UT 84108.

PATTERN OF EXPRESSION OF SYNAPTIC VESICLE PROTEINS INTHE DEVELOPING RAT PINEAL GLAND

Sujatha Narayan

The sequence of appearance of synaptic vesicle proteins at the nerve terminalduring synaptogenesis may provide insight into their roles at the synapse In thesuperior cervical ganglion (SCG), levels of vesicle proteins decline with postna-tal development suggesting that the newly synthesized proteins are redistributedto terminals in target tissues. The pineal gland is a neuroendocrine organ, inner-vated exclusively by the SCG. Innervation commences on embryonic day 16 andis not complete until the end of the first post-natal week. Serial sections of thepineal from Sprague-Dawley rats aged p0, 4, 7, 10, 14, 21 and adult are acetonefixed and incubated with monoclonal antibodies directed against vesicle pro-teins and processed for immunohistochemistry. Simultaneously, adjacent sec-tions are processed for catecholamine histofluorescence to track the pattern ofinnervation by sympathetic fibers. Synaptotagmin immunoreactivity is first de-tected in nerve terminals at p4. It peaks in the second postnatal week. Syntaxin,on the other hand, is detected in pinealocytes at birth after which levels decline.Histofluorescence is confined to the capsule of the pineal at p0. On p4, fluores-cence is observed in the apical part of the gland. By p7, norepinephrinehistofluorescence can be detected through most of the body of the gland and isat adult levels by p21. The patterns of expression of synaptic vesicle proteinssuggests that their distribution is subject to changes during growth and develop-ment of the SCG and its target organ, the pineal gland. This may have importantimplications for the establishment of functional synaptic transmission in devel-oping systems. Further, an investigation of vesicle protein expression in the pi-neal may provide insights given its neuroendocrine functions.

THE ROLE OF GAP JUNCTIONS IN THE PATHOPHYSIOLOGY OFSTROKE

Christian Naus

The existence of glial-neuronal interactions at various levels has been well estab-lished. These interactions have been implicated in both normal information pro-cessing as well as neuronal protection in the brain. One pathway of cellular in-

93

teractions involves gap junctional intercellular communication (GJIC). In astro-cytes, gap junctions are composed of the channel protein, connexin43 (Cx43),and provide a substrate for formation of a functional syncytium. This has beenimplicated in the spatial buffering capacity of astrocytes, particularly dealingwith extracellular K+ arising from neuronal activity. One approach to study thefunction of Cx43 in brain involves targeted gene knockout through homologousrecombination. Astrocytes cultured from homozygous null mice (Cx43—/—) ex-hibit some differences compared to wild type astrocytes (Cx43+/+), includingimpaired gap junctional coupling and attenuation of intercellular Ca++ signal-ling. Furthermore, heterozygote mice also exhibit a significant reduction in Cx43expression and GJIC. Although homozygous null mice die at birth, heterozy-gotes survive and have reduced Cx43 expression. To assess the effect of reducedGJIC on neuroprotection, we examined wildtype and heterozygote mice withrespect to the response to middle cerebral artery occlusion (MCAO). We antici-pated that lack of GJIC in astrocytes would interfere with their spatial bufferingcapacity, thus rendering neurons more susceptible to ischemic damage. Malemice (8 wildtype and 8 heterozygotes) were anaesthetised, the temporalis muscleretracted, a small burr hole made to expose the overlying dura mater, which wasretracted to expose the MCA for coagulation. Four days after surgery, mice werere-anaesthetised and perfused transcardially with 10 % formalin. The brains weresectioned and stained for Thionine. Analysis of infarct size was done on thesections using a Leitz Diaplan microscope and images digitized for computeranalysis (Mocha; Jandel Scientific). We observed a significant increase in theinfarct size in Cx43 heterozygous null versus wildtype mice: the infarct for het-erozygotes was 14.4 + 1.4 mm3, and for wildtypes was 7.7 + 0.82 mm3 (p <0.002). These results suggest that augmentation of GJIC in astrocytes may im-prove neuroprotection following ischemic injury. Supported by the Medical Re-search Council of Canada (CCGN) and Ontario Heart & Stroke Foundation(DC).

SEROTONERGIC MODULATION OF THE PERSISTENT POTASSIUMCURRENT IN STRIATAL NEURONS

Eric Nisenbaum

Previous studies have shown that serotonin (5-HT) receptor stimulation enhancesthe frequency of spike discharge in striatal neurons. This enhanced excitability isdue in part to a decrease in subthreshold potassium (K) currents. A likely targetof 5-HT modulation is the persistent K current (IKrp) which is available at sub-threshold membrane potentials. The hypothesis that 5-HT can depress IKrp wastested in acutely isolated striatal neurons. As described previously, 5-HT (200µM) reversibly reduced the total K current evoked by long (1 s) depolarizingvoltage steps. A similar depressive effect was produced by the 5-HT2A/2C ago-nist, DOI (10 µM). The large decrease in total K current at the end of a 1 sdepolarization suggested that IKrp was a target of 5-HT modulation. Indeed,DOI depressed IKrp in a concentration-dependent manner (EC50=8.9 µM).

94

Although a similar effect was produced by the 5-HT1A agonist, 8-OH-DPAT,much higher concentrations were required (EC50~100 µM). Possible involve-ment of a G-protein-dependent signaling pathway was suggested by an attenua-tion of the effect of DOI following by intracellular dialysis of GDP-§-S. Consis-tent with a decrease in IKrp, DOI reversibly increased the frequency of spikedischarge in curent-clamp experiments. The present data suggest that IKrp canbe modulated by 5-HT2A/2C receptor stimulation and that this modulatory ef-fect involves a G-protein-dependent signaling pathway. Given the role IKrp playsin limiting the depolarizing episodes of striatal neurons in vivo, the effect of 5-HT would be expected to reduce its ability to dampen the depolarizing responses,leading to an increased probability of spike discharge.

COMPARISON OF AMPHETAMINE-INDUCED DOPAMINE EFFLUX INTHE PRELIMBIC AND CINGULATE CORTICES OF THE RAT

Betsy Pehek

Much research has sought to understand dopamine (DA) regulation in the me-dial prefrontal cortex (mPFC) because of its putative involvement in disorderssuch as drug abuse and schizophrenia. One new development has been the char-acterization of the DA transporter (DAT) protein in different mPFC subregions.Recently, Sesack and colleagues (1998) have reported a relatively sparser distri-bution of DAT sites in the prelimbic, relative to the cingulate, mPFC. The presentstudy aimed to examine if these differences correlated with an in vivo functionalmeasure reflecting DAT activity. This was accomplished by examining whetherthese two subregions differed in their responses to administration of the DAreleaser/uptake blocker d-amphetamine (AMPH). In vivo microdialysis was uti-lized to recover extracellular fluid, which was subsequently analyzed for DAcontent by HPLC coupled with electrochemical detection. AMPH (10 and 100M) was dissolved in the perfusion medium and administered into the brain re-gion of interest through reverse dialysis for one hour. Three areas, the anteriorcingulate mPFC, the prelimbic/infralimbic mPFC, and the anterodorsolateralcaudate-putamen (CP) were examined. Local AMPH administration increasedDA efflux in all areas. However, the percentage increase was greatest in the CPand significantly greater in the prelimbic, relative to the cingulate, cortex. Fol-lowing the 100 (µM concentration, the peak effect was 285% relative to baselinein the cingulate cortex, whereas it was 762% in the prelimbic area. In contrast,the peak effect was 3052% in the caudate-putamen. These results suggest thatDA innervation density may be the crucial determinant of the relative magni-tude of responsivity to AMPH administration, rather than the number of DATsites/neuron. Furthermore, they add to recent studies demonstrating a neuro-chemical heterogeneity of the rat mPFC.

95

GLUTAMATE STIMULATES NA+/K+ ATPASE IN ASTROCYTES VIAACTIVATION OF A SUBUNIT HIGHLY SENSITIVE TO OUABAIN

Luc Pellerin

Several lines of evidence indicate that astrocytes may play a pivotal role in cou-pling neuronal activity with energy metabolism (Magistretti & Pellerin,CerebralCortex 6:50-61, 1996). We have observed that excitatory amino acids (EAAs)like glutamate increase 2-deoxyglucose (2-DG) uptake and phosphorylation bymouse cortical astrocytes in culture. The stimulatory effect of EAAs is mediatedby a Na+-dependent glutamate transporter. Since the effect on 2DG uptake canbe prevented by ouabain, an inhibitor of the Na+/K+ ATPase, we have engagedin a more direct demonstration of the involvement of the pump. Using 86Rbuptake as an index of the activity of the Na+/K+ ATPase, we have found that L-glutamate increases Rb uptake into astrocytes in a concentration-dependentmanner with a Km of 67 µM. Both D- and L-aspartate, but not D-glutamateexert a similar effect, indicating a transporter-mediated effect. Under basal con-ditions, ouabain inhibited the Na+/K+ ATPase activity with an IC50 = 113 µM.This low affinity site likely corresponds to the a1 subunit of the Na+/K+ AT-Pase. When astrocytes were exposed to glutamate, stimulation of the Na+/K+

ATPase was almost entirely prevented by low concentrations of ouabain (IC50 =20 nM). This observation strongly suggests that activation of an additionalNa+/K+ ATPase subunit (a2) is responsible for the effect of glutamate. SinceEAAs also increase lactate release by astrocytes, these observations also stronglysupport the view that EAAs stimulate glycolysis in astrocytes via activation ofthe Na+/K+ ATPase. When viewed within their physiological context, thesedata suggest that upon cortical activation, EAAs released by activated neuronsprovide a direct signal for astrocytes to take up glucose and metabolize it tolactate, which can be used by neurons as an energy source. (Supported by FNRSgrant 31-40565.94 to PJM)

STRONG INWARD POTASSIUM RECTIFICATION IN ADULTASTROCYTES IN CNS INJURY

Pablo Perillan

Potassium ions released into the extracellular space by CNS injury are taken upby way of inward rectifier (Kir) channels into astrocytes. This mechanism, alongwith heterogeneous channel density on glial cell membranes, is the foundationsfor non-neuronal K spatial buffering in the CNS. We evaluated Kir currents inastrocytes from adult rat brain that had been harvested from a cortical lesion andmaintained in primary culture for 0-21 days. Macroscopic currents were studiedusing a nystatin-perforated patch technique. Properties typical of inward recti-fier were observed, including shift with increasing extracellular K and block bybarium. Two categories of cells with Kir currents were observed: (1) one withstrong inward rectification, defined as whole cell current in which the chord

96

conductance decreased by more than an order of magnitude from the conduct-ing state to the non-conducting state; and (2) another with weak inward rectifica-tion. Strongly inwardly rectifying K currents were seen in most reactive astro-cytes, but in a subgroup, usually cells with multiple filamentous processes, wholecell currents were usually weakly rectifying. Single channel studies of cell-at-tached patches (pipette [K]=145 mM) revealed four single channel conductancescorrelating with whole cell current rectification. Events observed at -130 mV to -30 mV indicated openings with mean slope conductances of 14.2 (n=9), 24.5(n=9), 43.2 (n=2) and 79.3 pS (n=3), showing rectification at positive potentials.We conclude that astrocytes in adult brain injury express multiple Kir channels,and exhibit strongly rectifying inward currents that may be important for han-dling increased extracellular [K] associated with CNS injury.

THE ROLE OF THE NEUROTROPHINS IN THE INITIATION OF BEHAV-IORAL SENSITIZATION TO COCAINE

R. Christopher Pierce

A growing body of evidence indicates that the neurotrophins play a critical rolein plasticity in the adult mammalian nervous system. Repeated treatment withamphetamine-like compounds in rats results in a variety of changes in the cen-tral nervous system that drive in an enduring augmentation in the hyperactivebehavioral response to psychostimulants; this phenomenon is known as behav-ioral sensitization. Recent evidence indicates that the neurotrophins play an im-portant role in the induction of behavioral sensitization to cocaine. The presentexperiments evaluated the role of two of the neurotrophins, NT-3 and BDNF, incocaine behavioral sensitization in rats. The first series of experiments assessedthe ability of NT-3 and BDNF to cross-sensitize with cocaine. NT-3, BDNF orsaline was microinjected bilaterally into the ventral tegmental area (VTA) oncedaily for three consecutive days. Following a two week withdrawal period, all ofthe rats were challenged with an injection of 15 mg/kg cocaine. The results indi-cated that pre-exposure to either NT-3 or BDNF resulted in a sensitized behav-ioral response to a subsequent injection of cocaine. A second series of experi-ments used RT-PCR to assess the effects of acute or repeated injections of co-caine or saline on mRNA for NT-3 and BDNF in the VTA. These experimentsrevealed that an acute injection of cocaine (30 mg/kg) resulted in a robust in-crease in NT-3 mRNA in the VTA; an acute cocaine injection resulted in a mod-est increase in BDNF mRNA in the VTA. Following a sensitizing regimen ofcocaine injections (30 mg/kg once daily for 7 days), an acute challenge injectionof cocaine (30 mg/kg) did not influence the mRNA for NT-3 or BDNF in theVTA. Taken together, these results suggest that changes in NT-3 and BDNFsynthesis in the VTA may contribute to the initiation of behavioral sensitizationto cocaine.

97

DOPAMINE ACTIVATES CREB PHOSPHORYLATION AND GENE EX-PRESSION IN AN NMDA RECEPTOR DEPENDENT MECHANISM

Anjali Rajadhyaksha

Dopaminergic neurotransmission is a major mechanism of striatal plasticity. D1dopamine receptors are required for the dopamine-dependent activation of geneexpression. Dopamine phosphorylates the cAMP response element binding pro-tein (CREB) at Ser133 which activates gene expression. CREB has been impli-cated in mechanisms of neuronal plasticity. There is strong evidence that dopam-ine regulates gene expression by an N-methyl-D-aspartate (NMDA) receptor-dependent mechanism. We have examined the cellular processes involved inCREB phosphorylation and gene expression in response to activation of thecAMP pathway by forskolin and dopamine. In primary rat striatal cultures,forskolin and dopamine induce CREB phosphorylation and c-fos gene expres-sion. CREB phosphorylation and c-fos gene expression are inhibited by the NMDAantagonists MK-801 and APV, and require extracellular calcium. Activation ofthe D1 receptor phosphorylates the NR1 subunit of the NMDA receptor at Ser897.We hypothesize that in the striatum, the dopaminergic signal transduction path-way recruits the NMDA pathway via a mechanism that involves phosphoryla-tion of the NMDA receptor. The regulation of the phosphorylation state of theNR1 subunit by dopamine receptor activation and the effect of phosphorylationon receptor function and gene expression will be presented.

NEONATAL PERSISTENT PAIN ALTERS SPINAL NEURAL CIRCUITRY

M. A. Ruda

Nociceptive neural circuits develop during both embryonic and postnatal times.Under normal conditions, painful stimuli are absent or limited during this criti-cal developmental period. Pain thus represents a unique sensory stimulus, wherethe neuronal connections develop without sensory stimulation. To study the ef-fect of early postnatal pain on the development of pain pathways, neonatal ratpups received an unilateral injection of an irritant, complete Freund s adjuvant,into their left hindpaw. The animals were allowed to recover and when 8-10 weeksof age, the distribution of their primary afferent pain fibers was examined usinga WGA/HRP conjugate as a marker. The labeled axons were visualized usingTMB histochemistry. After WGA/HRP was injected bilaterally into the sciaticnerve of the adult rat one sees uniform label in the motor neurons on both sidesof the spinal cord. However on the left side which experienced the neonatal pain,there are labeled primary afferents in areas of the spinal cord where they are notfound on the unstimulated right side of the spinal cord. These altered neuronalciruits are particularily prominent at the more caudal levels of sciatic nerve terri-tories. These data demonstrate a dramatic alteration in pain pathways in responseto neonatal pain that persists into adulthood. This plasticity in nociceptive neu-ral circuits may result in altered responses to painful stimuli throughout the life-

98

time of the animal and draws attention to the need for careful pain managementin the newborn.

EFFECTS OF ANTICHOLINESTERASE THERAPY ON REGIONAL CE-REBRAL ACTIVITY OF PATIENTS WITH ALZHEIMER S DISEASE

Daniel H. Silverman

BACKGROUND: Decreased density of cholinergic projections has been con-sistently identified in the brains of patients with Alzheimer s Disease (AD), alongwith other histopathologic changes. Two therapies, specifically directed at im-proving cognition in patients with AD, have won approval for this indication bythe U.S. FDA, and both are cholinesterase inhibitors. These drugs, tacrine anddonepezil, increase the concentration of acetylcholine in the vicinity of cholin-ergic receptors, with the aim of correspondingly increasing the level of appropri-ate neuronal activity along cholinergic-dependent pathways. That activity canbe noninvasively assessed in the living human brain by measuring the regionaldistribution of the radiolabeled glucose analogue [F-18]fluorodeoxyglucose, us-ing positron emission tomography (PET). METHODS: Sixteen PET scans wereobtained in eight right-handed patients, all of whom were diagnosed with ADfollowing an extensive battery of clinical and neuropsychologic evaluative toolsadministered under the direction of the UCLA Aging Program and/orAlzheimer s Disease Center. On the day of each PET session, each patient alsotook a Mini- Mental State Exam (MMSE). Baseline PET scans were obtained ofthe brains of all patients quietly resting in a dimly lit room, 40 min following i.v.administration of 10 milliCuries of a tracer mass of [F-18]deoxyglucose. Allpatients then initiated a therapeutic course of what is widely currently consid-ered the clinical drug regimen of first choice done pezil, orally administered ata dosage of 10 mg per day. Twelve weeks after initiation of pharmacotherapy,PET scans were repeated in all patients under conditions identical to those em-ployed during acquisition of baseline scans. PET images were examined by re-gion of interest (ROI) analysis, and by statistical parametric mapping utilizingSPM96 software (distributed courtesy of the Wellcome Cognitive Laboratoryand MRC Cyclotron Unit faculties, U.K.) These analyses were performed in con-junction with a priori hypotheses predicting therapy-associated increases in ac-tivities of the bilateral dorsolateral prefrontal, posterior parietal, and mesial tem-poral regions; statistical analyses included appropriate Bonferroni-type correc-tions for multiple comparisons, both for predicted (relatively mild correction)and unpredicted (relatively severe correction) regions. RESULTS: Regions foundto undergo significant change in activity after pharmacotherapy, following ap-propriate statistical adjustments as outlined above, included increases in the dor-solateral prefrontal cortex (Brodmann s area 10 bilaterally, plus more extensiveinvolvement of the prefrontal cortex on the left extending to Brodmann s areas 8and 46), and an increase in Broca s region (left Brodmann s area 45); in addition,there was a strong trend towards decreased activity in the posterior cingulategyrus. Analysis of covariance of MMSE scores with regional activity levels, per-

99

formed for more than 100,000 cubic voxels of 2 mm linear dimension utilizingSPM96 software, demonstrated significant positive correlation only in the leftdorsolateral prefrontal cortex, after appropriate statistical adjustment. CONCLU-SION: Anticholinesterase therapy for AD, employing a common clinical drugregimen, resulted in significant increases in activity levels of Broca s area, as wellas of the bilateral prefrontal cortex. The latter included an area strongly corre-lated with cognitive performance, as assessed by patients MMSEscores.Supported by the Department of Energy, the NIA/UCLA Alzheimer sDisease Center, and NIMH Grant #MH5243-01.

HIGH GRADE HUMAN GLIOMA CELLS EXPRESS Ca2+-ACTIVATEDK+ CHANNELS

Harald Sontheimer

The majority of primary neoplasms occurring in the central nervous system aregliomas. These tumors are highly invasive and uniformly fatal. Ion channels maycontribute to this invasive behavior by influencing the movement of salt andwater between intracellular and extracellular compartments. We undertook apatch clamp study to characterize the electrophysiological properties of severalhuman glioma cell lines. With an intracellular free calcium of 20 nM a voltage-dependent current was observed, that activated at potentials >+50 mV. Tetra-ethylammonium ion (TEA)(1 mM), iberiotoxin (100 nM), and charybdotoxin(100 nM) produced >80% reduction in currents. Intracellular Ca2+ buffered to100 µM and extracellular phloretin, an opener of BK(Ca2+) channels, shifted theactivation potential to —50 mV and +20 mV, respectively. In addition, a pronouncednegative slope in the I-V curve was observed at voltages >+40 mV, suggestive ofa voltage-dependent block. Both phloretin- and 100 µM Ca2+-induced currentswere blocked by 1 mM TEA. The open-probability of channels in inside-outpatches was dramatically increased by applying 100 µM Ca2+ to the cytosolicface. The unitary conductance of channels in inside-out patches with symmetri-cal KCl was 200 pS and the single channel currents reversed near 0 mV. Takentogether these data suggest high-grade human glioma cells express a Ca2+-de-pendent K+ current. The presence of these currents in high grade gliomas sug-gests a functional role for them in shaping glioma responses to signals whichincrease [Ca2+]i.

MOLECULAR MECHANISM FOR ALCOHOL SUPPRESSION OF IN-NATE CNS IMMUNITY

Peter Syapin

Transcriptional induction of the NOS2 gene product iNOS, the high output ni-tric oxide (NO) synthase isoform, is a major part of the nonspecific innate im-mune response of mammals. Although the CNS has traditionally been consid-ered an immunologically privileged site, iNOS expression by glia is well docu-mented following in vivo infections of the CNS and readily occurs in CNS glial

100

cell cultures exposed to inflammatory cytokines or LPS. Thus, it is hypothesizedthat NO is a critical component of the innate immunity in controlling infectionsin the CNS. CNS immune suppression by alcohol is not well studied. Therefore,we examined alcohol effects on iNOS activity induced in glial cell cultures. GlialiNOS activity (nitrite production) was decreased by alcohol exposure due to sup-pression of iNOS mRNA and protein, implying that alcohol may inhibit tran-scriptional activity of the NOS2 gene. This was tested with C6 glial cells express-ing a luciferase gene under control of rat NOS2 promoter/enhancer elements(kindly provided by W. Eberhardt and J. Pfeilschifter). L3/2T cells have a full 1.7kb promoter/enhancer region and express LPS-inducible, interferon-g -enhancedluciferase. L3/1T cells have only the first 0.5 kb and express LPS-inducible lu-ciferase unaffected by interferon-g. Interferon-g/LPS- induced L3/2T cells ex-posed to ethanol had reduced nitrite production and equipotent ethanol-inducedreductions in luciferase activity. L3/1T cells re- acted nearly identically, indicat-ing that ethanol inhibition of NOS2 gene transcriptional activation in glial cellsdoes not require the interferon-g enhancer region, among other upstream sites,but is mediated by cis-acting elements within the first 0.5 kb of the NOS2 pro-moter. Work to delineate the cis-acting element(s) involved is ongoing.

DOPAMINE-MEDIATED ADENYLATE CYCLASE ACTIVITY IN RATSTRIATUM: SELECTIVE BLOCKADE BY ANTISERA DIRECTEDAGAINST VARIOUS G-PROTEIN SIGNALLING COMPONENTS

Elizabeth Thomas

Dopamine neurotransmission in the striatum plays a key role in motor and cog-nitive function. Using specific antibodies, we have investigated the couplingmechanisms of G-proteins to dopamine receptor signalling in rat striatum. Inthe presence of haloperidol (1 mM), dopamine elicited an approximate two-foldstimulation of adenylate cyclase activity over basal in rat striatal homogenates.Preincubation of striatal membranes with antiserum directed against the Gα01f-subunit, which is predominantly expressed in striatum, nucleus accumbens, andolfactory tubercle, resulted in a concentration-dependent inhibition of the ade-nylate cyclase activity induced by dopamine. Preincubation of the membraneswith anti-Gα01f -antibody had no inhibitory effect on forskolin-mediated adeny-late cyclase stimulation, but caused a slight decrease in isoproterenol-inducedincreases. Specific antisera directed against the Gg7-subunit and RGS9, two ad-ditional proteins with highly enriched expression in the striatum, were also in-vestigated in functional assays of adenylate cyclase. These results demonstratethat the dopamine D1 receptor is coupled to adenylate cyclase via Gα01f in thestriatum and suggest that dopaminergic neurotransmission is controlled by aunique system of G protein signalling components that have enriched expres-sion in the striatum.

101

NITRIC OXIDE GENERATORS MODULATE THE RESPONSIVENESSOF STRIATAL NEURONS TO ELECTRICAL STIMULATION OF THEPREFRONTAL CORTEX

Anthony West

Recent studies demonstrate that striatal nitric oxide (NO) production facilitatesthe electrotonic coupling of striatal neurons and enhances dopamine andglutamate efflux. To investigate the potential modulatory role of NO in the regu-lation of neuron activity in the dorsolateral striatum by corticostriatal afferents,single unit extracellular recordings were made concurrently with reversemicrodialysis in chloral hydrate-anesthetized rats. The firing activity of striatalcells was assessed under basal conditions and following electrical stimulation ofthe prefrontal cortex (PFC) during separate intrastriatal infusions of artificialCSF and NO generators. In order to examine potential differences in the respon-siveness of functionally distinct subpopulations of striatal neurons to PFC stimu-lation, neurons were designated as Type 1 or Type 2 based on their extracellularaction potential wave form. Stimulation of the PFC (250µA 0.6Hz 2 min) didnot affect the mean firing rate (FR) of Type 1 striatal cells (n=5) but decreasedthe FR of Type 2 cells from 0.08 (control) to 0.05 spikes/sec (n=5) during thestimulation period. Local infusion of exogenous NO increased the FR of a sub-population of striatal neurons from 0.7 to 1.0 spikes/sec (n=4) and attenuatedthe inhibitory effect of PFC stimulation on striatal cell FR and firing pattern(n=3). These studies indicate that striatal NO signaling may modulate informa-tion processing in the basal ganglia by activating striatal output neurons andregulating their response to corticostriatal inputs.

THE CLINICAL AND SPECT STUDIES OF PHOTIC STIMULATIONTHERAPY IN PATIENTS WITH HOMONYMOUS HEMIANOPIA

Rui-Man Xie

Since it was found that the recovery from complete homonymous hemianopia(CHH) is low, partial and only in early stage after damage in which 125 caseswith CHH were followed-up with a mean follow time of 2.4 years. So compari-son of SPECT rCBF and clinical function of 12 cases with CHH were takenbefore and after a course of oriented dynamic color photic stimulation (ODCPS)therapy. In which 80x80 cm screen with stroboscope light (arrangement alongmultimeridional direction, red-yellow-green alternation) was used, one coursecounted 30 times ( 1h for each time) and one side CHH stimulated by same sidehalf screen photic. It was suggested that ODCPS therapy in patients with CHHwas an effective method for increasing visual field and improving visual func-tion. Cerebral metabolic patterns of increasing rCBF reflected the mechanismof ODCPS effecting the patients with CHH. The activating neurons of retinal-midbrain-occipital visual pathway may play an important role in mediating theincrease of visual field and restoration of visual function. Together with other

102

clinical studies of aphasia and cognition function rehabilitation in our researchgroup, it may be concluded that once those deactivated brain regions could beprimed to action, defective neural function might get better and rCBF wouldincrease in proportion. However, different means to activate different kinds ofpatients should be found.

AN OPEN LABEL PILOT SAFETY STUDY OF LOFEXIDINE FOR THETREATMENT OF OPIATE WITHDRAWAL

Elmer Yu

Hyperactivity of brain noradrenergic systems plays an important role in opiatewithdrawal. Open studies have indicated that lofexidine, an alpha-2 adrenergicagonist, may be effective for alleviating methadone withdrawal signs and symp-toms with little hypotension (Gold et al., 1981). Two double-blind studies sug-gested that lofexidine produces less hypotension than clonidine (Kahn et al.,1996; Lin et al., 1997) while another (Bearn et al., 1996) indicated that lofexidinewas clinically comparable to methadone for the alleviation of opiate withdrawalfollowing methadone stabilization. The present 20-day, open, inpatient studyconducted at two sites is designed to assess the safety/tolerability of lofexidineand obtain preliminary efficacy data. Three plateau doses of lofexidine (1.6, 2.4,and 4.0 mg/day) are being examined. Subjects are first stabilized on morphinegiven subcutaneously (100 mg/day) on days 1-8. On day 9, morphine is discon-tinued and lofexidine is administered through day 18. No medication is adminis-tered on days 19 or 20. This is the first study to use peak lofexidine doses on thefirst or second day of administration, and to systematically examine lofexidinedoses higher than 2.4 mg/day. No serious adverse events have been observed.However, transient dose-dependent systolic orthostatic hypotension (< 85 mmHg)has been noted. Safety and efficacy data will be reported. Support: BritanniaPharmaceutical Ltd and an interagency agreement between MDD, NIDA, NIHand the Philadelphia and Brentwood/LA VAMCs.

103

Developmental Neuroscience(camera-ready)

104

MED Associates(camera ready)

110

Elizabeth AbercrombieRutgers UniversityCMBN197 University AvenueNewark NJ [email protected]

Patrick AebischerDivision of Surgical ResearchCHUV—PAVILLON 4Lausanne [email protected]

Margot AlbusDistrict Hospital HaarDepartment of Teaching & ResearchVocuestr 7ZHaar 85529GERMANY

Brenda AndersonSUNY at Stony BrookDept. of PsychologyStony Brook NY [email protected]

Rodrigo AndradeWayne State UniversityPsychiatry & Behavioral NeurosciencesDetroit MI [email protected]

Bruce AppelVanderbilt UniversityMolecular BiologyP.O. Box 1820, Station BNashville TN [email protected]

Margie ArianoChicago Medical SchoolNeuroscience3333 Green Bay RoadNorth Chicago IL [email protected]

ParticipantsGary Aston-JonesUniversity of PennsylvaniaPsychiatryVA Medical Center (151)Room A-520University and Woodland Aves.Philadelphia PA [email protected]

Constance AtwellNINDSDEAFederal Bldg 10167550 Wisconsin AveBethesda MD [email protected]

Etienne AudinatCNRSLaboratoire de Biologie, ESPCI10 reu VauquelinParis FR [email protected]

Peter W. BaasUniversity of Wisconsin Medical SchoolDepartment of Anatomy1300 University AvenueMadison WI [email protected]

Susan BachusCBDB, NIMH, NIHNeuropathologyBldg 9, Rm 1N 124Bethesda MD [email protected]

Aldo BadianiThe University of MichiganDepartment of Psychology525 E University StAnn Arbor MI [email protected]

(Names in bold denote first-time attendees.)

111

Michael BardoUniversity of KentuckyPsychologyKastle HallLexington KY [email protected]

Steve W. Barger, Ph.D.McCellan VAMC/UAMSDepartment of Geriatrics4300 W 7th St Research Service 151/LRLittle Rock AR [email protected]

Raymond BartusAlkermes, Inc.Preclinical R&D64 Sidney StCambridge MA [email protected]

George Bartzokis, M.D.University of Arkansas for Medical

ScienceDepartment of Psychiatry2200 Fort Roots DrNorth Little Rock AR 72114USA

Allan BasbaumUniversity California San FranciscoAnatomy513 Parnassus Ave.Box 0542San Francisco CA [email protected]

Anthony BasileNational Institutes of HealthLab BioOrganic Chemistry, NIDDKBuilding 8, Room 121, MSC 0826NIDDK, NIH9000 Rockville PikeBethesda MD [email protected]

Gillian BatesKings College LondonDepartment of Medical & Molecular

Genetics8th Fl Guys Tower Guys HospitalLONDON SE19RtUNITED [email protected]

Steven L. BealerUniversity of TennesseeDepartment of Physiology894 Union AveMemphis TN [email protected]

Michael V.L. BennettAlbert Einstein College of MedicineDepartment of Neuroscience1300 Morris Park Ave.Bronx NY [email protected]

Paul BennettMerck Research Labs, Merck & Co.Department of Pharmacology / 875WP26-265770 Sumnneytown PikeWest Point PA [email protected]

Darwin K. BergUniversity of California, San DiegoDepartment of Biology9500 Gilman DrLaJolla CA [email protected]

Hagai BergmanThe Hebrew University Hadassah Medical

SchoolDepartment of PhysiologyPO Box 12272Jerusalem [email protected]

112

Craig BerridgeUniversity of WisconsinPsychology1202 W. Johnson St.Madison WI [email protected]

Alessandro BertolinoNIHClinical Brain Disorders Branch9000 Rockville PikeBldg 10, Room 3C101Bethesda MD [email protected]

Heinnch BetzMax-Planck Institute for Brain ResearchDepartment of NeurochemistryDeutschorden Strasse 47Frankfurt [email protected]

Charles BillingtonUniversity of MinnesotaMedicineMinneapolis VA Medical Center1 Veteran s DriveMinneapolis MN [email protected]

Marc D. BinderUniversity of Washington Sch.MedicineDepartment of Physiology & BiophysicsPO Box 357290Seattle WA [email protected]

Jan G. BjaalieUniversity of OsloDepartment of AnatomyInst of Basic Medical SciencesPO Box 1105 BlindenOslo [email protected]

James R. BloedelBarrow Neurological InstituteDepartment of Neurobiology350 W Thomas RdPhoenix AZ [email protected]

Danny BodekerPharmacia&UpjohnMedical Science Liaisoncns14637 Cardinal Creek CtHouston TX [email protected]

Martha C. Bohn, Ph.D.Northwestern University Medical School/

Childrens MemorialDepartment of Neurobiology/Pediatrics2300 Children s Plaza no. 209Chicago IL [email protected]

John BojaNEOUCOMDepartment of Pharmacology4209 State Route 44P.O. Box 95Rootstown OH [email protected]

J.P. BolamMRC Anatomicial Neuropharmacology

UnitDepartment of PharmacologyMansfield RdOxford OX1 [email protected]

Stephen BondyUniversity of California, IrvineDepartment of Community &

Environmental MedicineIrvine CA [email protected]

113

Alexander BorstMax-Planck InstituteFriedrich-Miescher LaboratorySpemannstr. 37-39Tuebingen [email protected]

Blastislav BrachaBarrow Neurological InstituteDepartment of Neurobiology350 W Thomas RdPhoenix AZ [email protected]

Alan BreierEli Lilly & CoLilly Research LaboratoriesLilly Corporate Center Drop Code 0538Indianapolis IN [email protected]

Timothy J. BrennanUniversity of IowaDepartment of Anesthesia200 Hawkins Dr UIHC 6JCPIowa City IA [email protected]

Gregory J. BrewerSouthern Illinois University School of

MedicineDepartment of Medical Microbiology and

ImmunologyP.O. Box 19230Springfield IL [email protected]

Gerald L. Brown MDUniversity of VirginiaDepartment of Psychiatric MedicineHSC School of MedicinePO Box 623Charlottesville VA [email protected]

John BrunoThe Ohio State UniversityDepartment of Psychology31 Townshend Hall1885 Neil AveColumbus OH 43210—[email protected]

Roberto BruzzoneInstitut PasteurUnite de Neurovirologie et Regeneration du25 rue du Dr. RoueParis Cedex 15 [email protected]

Christian BuchelFunctional Imaging LaboratoryWellcome Department of Cogn

Neurology12 Queen SquareLondon WC1N 3BGUNITED [email protected]

William E. Bunney, Jr. MDUniversity of California, IrvineDepartment of Psychiatry & Human

BehaviorCollege of MedicineD438 Medical Sciences Bldg 1Irvine CA [email protected]

Robert BurkeLab. of Neural Control, NINDSNational Institutes of HealthBldg. 49, Rm. 3A50National Institutes of HealthMSC 4455Bethesda MD [email protected]

114

Amy ButlerSalk InstituteDepartment of SNLSNL-C10010 N Torrey PinesLa Jolla CA [email protected]

William A. CarlezonYale University School of MedicineDepartment of Psychiatry34 Park StNew Haven CT [email protected]

Susan M. Carlton, Ph.D.The Marine Biomedical InstituteDepartment of Anatomy & Neurosience301 University BoulevardGalveston TX [email protected]

Marilyn CarrollUniversity of MinnesotaDepartment of Psychiatry and

NeuroscienceBox 392 UMHCMinneapolis MN [email protected]

Vivien CasagrandeVanderbilt Medical SchoolCell BiologyDepartment of Cell BiologyVanderbilt Medical SchoolC2310 MCNNashville TN [email protected]

Manuel Castro-AlamancosMontreal Neurological InstituteDepartment of Neurology &

Neurosurgery3801 University St WB 210Montreal QC H3A [email protected]

Jang-Ho ChaMassachusetts General HospitalDepartment of NeurologyNeurology Research WRN 408, Fruit StBoston MA [email protected]

Leo ChalupaUniversity of California, DavisDepartment of Neurobiology, Physiology

& Behavior196 Briggs HallOne Shields AveDavis CA [email protected]

John ChapinAllegheny University of the Health

SciencesDepartment of Neurobiology & AnatomyEPPI 3200 Henry AvePhiladelphia PA [email protected]

Andrew CharlesUCLA School of MedicineDepartment of Neurology710 W Wood PlazaLos Angeles CA [email protected]

Nirupa ChaudmariUniversity of Miami School of MedicineDepartment of Physiology & BiophysicsPO Box 016430 (R430)Miami FL [email protected]

Marie-Francoise ChesseletUniversity of California, Los AngelesDepartment of Neurology710 Westwood PlazaLos Angeles CA [email protected]

115

Dennis ChoiWashington University School of

MedicineDepartment of Neurology660 S. Euclid Ave Box 8111St. Louis MO [email protected]

Michael ChoppHenry Ford Health Science CenterDepartment of Neurology ResearchNeurology, E&R 30562799 W Grand BlvdDetroit MI [email protected]

James C.-Y. Chou, MDNathan Kline InstituteDepartment of Clinical ResearchOrangeburg NY [email protected]

Beverley ClarkUniversity College LondonDepartment of PharmacologyGower StreetLondon WC1E [email protected]

Paul ClarkeMcGill UniversityPharmacologyMcIntyre Building3655 Drummond Street Room 1325Montreal CANADA H3G [email protected]

John D. ClementsAustralian National UniversityDivision of Neuroscience JCSMRCanberra ACT [email protected]

Stuart CobbUniversity of EdinburghNeuroscienceNeuroscience DepartmentUniversity of Edinburgh1 George SquareEdinburgh, U.K. EH8 [email protected]

Jeffrey ConnEmory UniversityDepartment of Pharmacology1510 Clifton RdAtlanta GA [email protected]

James M. ConnerUniversity of California San DiegoDepartment of Neurosciences955 Gilman DrLa Jolla CA [email protected]

James ConnorPenn State UniversityDepartment of Neuroscience & AnatomyM.C. H109M.S. Hershey Medical CenterHershey PA [email protected]

Martha Constantine-PatonYale UniversityDepartment of Cellular Molecular &

Developmental BiologyPO Box 208103New Haven CT 06520—[email protected]

Diego ContrerasUniversity of Pennsylvanya School of

MedicineDepartment of Neuroscience215 Stemmler HallPhiladelphia PA [email protected]

116

Ellis CooperMcGill UniversityDepartment of PhysiologyMcIntyre Medical Science Bldg3655 Drummond StMontreal Que H3G [email protected]

Michael CostiganMGH & Harvard Medical SchoolDepartment of AnesthesiaNPRG, 149 13th St #4309Charlestown MA [email protected]

Ann Marie CraigUniversity of IllinoisDepartment of Cell & Structural Biology601 S Goodwin Ave CLSL B107Urbana IL [email protected]

Steven CramerUniversity of WashingtonDepartment of Neurology1959 NE Pacific St.Box 356465Seattle WA [email protected]

Fulton CrewsThe University of North Carolina at

Chapel HillCenter for Alcohol StudiesDirector, Center for Alcohol StudiesCB# 7178, 1021 Thurston-Bowles Bldg.University of North Carolina at Chapel HillChapel Hill NC [email protected]

Nathan CroneJohn Hopkins University School of

MedicineDepartment of Neurology600 N Wolff St Meyer 2-147Balitmore MD 21287USAncroen.jhmi.edu

Kathryn A. CunninghamUniversity of Texas Medical BranckDepartment of Pharmacology &

ToxicologyGalveston TX [email protected]

Cynthia M. CzajkowskiUniversity of Wisconsin-MadisonDepartment of Physiology1300 University Ave Rm 197 MSCMadison WI [email protected]

Mauro C. Dal CantoNorthwestern University Medical SchoolDepartment of Pathology303 E Chicago AveChicago IL [email protected]

Nicholas DaleUniversity of St AndrewsSchool of Biomedical SciencesBute Medical BldgSt Andrews Fife KY16 9TSUNITED [email protected]

Ted M. DawsonJohn Hopkins University School of

MedicineDepartment of Neurology600 N Wolfe St Carnegie 2-214Baltimore MD [email protected]

117

Jean de Vellis, Ph.D.UCLAMental Retardation Research Center760 Westwood Plaza68-177 NPILos Angeles CA [email protected]

Guy DebonnelMcGill UniversityPsychiatry1033 Pine Avenue WestMontreal PQ H3A [email protected]

Isabelle DeCosterdMassachusetts General HospitalMeural Plasticity Research Group149 13th St Rm 4309Charlestown MA [email protected]

Jill DelfsUniversity of PennsylvaniaDepartment of PsychiatryVA Medical Center (151)University and Woodland AvenuesPhiladelphia PA [email protected]

Victor DenenbergUniversity of CTDepartment Behavioral SciencesU154Storrs Ct [email protected]

Rolf DermietzelRuhr University BochumDepartment of Neuroanatomy &

Molecular Brain ResearchUniversity St 150Bochum [email protected]

Alain DestexheLaval UniversityDepartment of PhysiologyFaculte de MedecineCite UniversitaireQuebec QC [email protected]

Dennis W. DicksonMayo Clinic JacksonvilleDepartment of Pathology

(Neuropathology)4500 San Pablo RdBirdsall Bldg 317Jacksonville FL [email protected]

Sylvain DoreJohns Hopkins University / School of

MedicineDepartment of Neuroscience (WBSB 807)725 North Wolfe StreetBaltimore MD [email protected]

Kelly L. Drew Ph.D.University of Alaska FairbanksInstitute of Arctic BiologyPO Box 757000Fairbanks AK [email protected]

Michael Duff DavisParke-Davis CoDepartment of Neuroscience2800 Plymouth RdAnn Arbor MI [email protected]

Tom DunwiddieUniversity of Colorado Health Sciences

CenterDepartment of PharmacologyDept. Pharmacology C2364200 E. 9th Ave.Denver CO [email protected]

118

Linda P. DwoskinUniversity of KentuckyDepartment of Pharmaceutical SciencesCollege of PharmacyLexington KY [email protected]

Christopher J. EarleyJohns Hopkins Medical InstitutionDepartment of Neurology4940 Eastern AveBaltimore MD [email protected]

Ford EbnerVanderbilt UniversityInstitute for Developmental NeuroscienceP.O. Box 152-GPC18th Avenue South105 Hobbs BuildingNashville TN [email protected]

Michael EganN.I.M.H.CBDB4301 Stanford StChevy Chase MD [email protected]

Burr EichelmanCNR Health IncDepartment of Behavioral Health4020 Highway MMiddleton WI [email protected]

Abdel El ManiraKarolinska InstitutetDepartment of NeuroscienceStockholm [email protected]

Helene Emsellem, M.D.The Center for Sleep & Wake Disorders5454 Wisconsin Ave Suite 1725Chevy Chase MD [email protected]

Robert EskayNIAAA/DICBRNIHBldg 10—3C21810 Center Dr MSC 1256Bethesda MD 20892-1256USA

Alan I. FadenGeorgetown University Medical CenterInstitute for Cognitive & Computational

Sciences3970 Reservior Rd Research Bldg EP-04Washington DC [email protected]

Carolyn FairbanksUniversity of MinnesotaDepartment of Pharmacology3-249 Millard Hall435 Delaware St SEMinneapolis MN [email protected]

Mark FarrantUniversity College LondonPharmacologyGower StreetLondon UK WC1E [email protected]

J. FawcettCambridge UniversityDepartment of PhysiologyDowning StCambridge [email protected]

119

Howard FeitHenry Ford HospitalNeurologyDept. of NeurologyHenry Ford Hospital2799 West Grand Blvd.Detroit MI [email protected]

Jack L. FeldmanUniversity of California Los AngelesDepartment of NeurobiologyBox 951763 UCLALos Angeles CA [email protected]

Susan C. Feldman, Ph.D.New Jersey Medical SchoolDepartment of Anatomy, Cell Biology &

Injury Science185 S. Orange AveNeward NY [email protected]

Giora Z. FeuersteinSmithKline Beecham PharmaceuticalsDepartment of Cardiovascular

Pharmacology709 Swedeland RdKing of Prussia PA 19406-0939USAGIORA Z

[email protected]

H. Christian Fibiger, Ph.D.Eli Lilly & CoNeuroscience Discovery Research &

Clinical InvestigationLilly Coporate CenterIndianaplis IN 46285USA

Dianne Figlewicz Lattemann, Ph.D.University of WashingtonDepartment of PsychologyBox 351525Seattle WA [email protected]

Thomas FingerUniversity of Colorado Medical Sch.Department of Cellular & Structural

BiologyDept. CSBUCHSC B-1114200 E Ninth Ave.Denver CO [email protected]

George FinkMRC Brain Metabolism UnitUniversity Department of Pharmacology1 George SquareEdinburgh EH8 [email protected]

Seth FinklesteinMassachusetts General HospitalNeurologyWarren 408Massachusetts General HospitalBoston MA [email protected]

Janet M. FinlayUniversity of PittsburghDepartment of Neuroscience446 Crawford HallPittsburgh PA [email protected]

Francis W. FlynnUniversity of WyomingDepartment of PsychologyBox 3415 University StationLaramie WY [email protected]

Peter T. FoxThe University of Texas Health Science

Center at San AntonioResearch Imaging Center7703 Floyd Curl DrSan Antonio TX [email protected]

120

Donald N. Franz, Ph.D.University of UtahDepartment of Pharmacology410 Chipeta Way Rm 215Salt Lake City UT [email protected]

Alan Frazer, Ph.D.The University of Texas Health Science

Center at San AntonioPharmacology7703 Floyd Curl DrSan Antonio TX [email protected]

Curt R. Freed, M.D.University of Colorado Health Sciences

CenterDepartment of Medicine &

Pharmacology4200 E Ninth Ave Rm 5512Denver CO [email protected]

William Freed, Ph.D.National Institutes of HealthNational Institute on Drug Abuse5500 Nathan Shock DrBaltimore MD [email protected]

Robert J. FrenchUniversity of CalgaryDepartment of Physiology & Bioshysics3330 Hospital Dr N.W.Calgary AB T2N [email protected]

Kai FrerichsBrigham & Women s Hospital/Harvard

Medical SchoolDepartment of Neurosurgery300 Longwood Ave Bader 3Boston MA [email protected]

Denson FujikawaVA Southern California System of ClinicsNeurologyExperimental Neurology Laboratory

(151B4)16111 Plummer StreetSepulveda CA [email protected]

Shinji FushikiKyoto Prefectural University of MedicineDepartment of Dynamic PathologyKawaramachi Hirokoji, Kamigyo-kuKyoto [email protected]

Fred H. GageThe Salk Institute for Biological StudiesLaboratory of Genetics10010 N Torrey Pines RdLa Jolla CA [email protected]

Charles GallistelUCLADepartment of Psychology1282A Franz HallBox 951563Los Angeles CA [email protected]

Gianluca Gallo, Ph.D.University of MinnesotaDepartment of Cell Biology &

Neuroanatomy4-144 Jackson Hall321 Church St SEMinneapolis MN [email protected]

Eliot GardnerAlbert Einstein College Of MedicinePsychiatry And NeuroscienceForchheimer Building 111Albert Einstein College Of Medicine1300 Morris Park AvenueBronx Ny [email protected]

121

Don M. GashUniversity of Kentucky Medical CenterDepartment of Anatomy & Neurobiology800 Rose St MN224 Medical CenterLexington KY [email protected]

Gerald F. Gebhart, Ph.D.University of Iowa College of MedicineDepartment of Pharmacology2-471 BSBIowa City IA [email protected]

Herbert GellerRobert Wood Johnson Medical SchoolDepartment of Pharmacology675 Hoes LanePiscataway NJ [email protected]

Greg A. Gerhardt, Ph.D.Univ of Colorado Health Sciences CenterDepartment of Psychiatry4200 E. 9th Ave Campus Box C268-71Denver CO [email protected]

Mark GeyerUniversity of California, San DiegoDepart ment of Psychiatry9500 Gilman DriveLaJolla CA [email protected]

John Gibbon Ph.D.NYSPI & Columbia UniversityDepartment of Biopsychology722 W 168st Unit #50New York NY [email protected]

Richard GillisGeorgetown University School of

MedicineDepartment of Pharmacology3900 Reservoir Rd NWWashington DC 20007USA

Edward GinigerFred Hutchinson Cancer Research CenterDivision of Basic Science1100 Fairview Ave NMailstop B2-152Seattle WA [email protected]

David GintyJohns Hopkins UniversityDepartment of NeurosciencePCTB Rm 1000 725 N Wolfe StBaltimore MD [email protected]

Silvia Q GiravdoVA Medical CenterResearch Service (151)One Veterans DrMinneapolis MN [email protected]

Simon GiszterAllegheny Universtity, MCP/HahnemannDepartment of Neurobiology and

AnatomyEPPI Bldg 3200 Henry AvEPhiladelphia PA [email protected]

Ben GivensOhio State UniversityDepartment of Psychology1885 Neil AveColumbus OH [email protected]

122

Alan GoldinUniversity of California, IrvineDepartment of Microbiology & Molecular

Genetics240 Med Sci I, Bldg BIrvine CA [email protected]

James GoldmanColumbia UniversityPathologyP&S 15-420Columbia University College of P&S630 W 168th St.New York NY [email protected]

David Goldman, M.D.NIAAA/National Institutes of HealthLab of Neurogenetics12420 Parkhaven DrPark 5 Bldg Rm 451Rockville MD [email protected]

Gerald GottliebBoston UniversityNeuroMuscular Research Center44 Cummington StBoston MA [email protected]

Anthony A. GraceUniversity of PittsburghDepartment of Neurosciece458 Crawford HallPittsburgh PA [email protected]

Gregory A. GrantWashington UniversityDepartment of Molecular Biology &

PharmacologyCampus Box 8103 660 S Euclid AveSt Louis MO [email protected]

J. Timothy GreenamyreEmory UniversityDepartment of Neurology1639 Pierce DriveWMB 6000Atlanta GA [email protected]

Robert GreeneHMS & VAMCPsychiatryNeuroscience Lab151C940 Belmont St.Brockton MA [email protected]

Bill GreenoughUniversity of Illinois at Urbana-

ChampaignBeckman Institute405 N. MathewsUrbana IL [email protected]

Charles P. GreerYale University School of MedicineDepartment of Neurosurgery333 Cedar StNew Haven CT 06520—[email protected]

Karen GreifBryn Mawr CollegeDepartment of Biology101 N. Merion AveBryn Mawr PA [email protected]

Sue T. Griffin, Ph.D.McClellan VAMC/UAMSDepartment of Geriatrics4300 W 7th St Research Service 151/LRLittle Rock AR [email protected]

123

Sten GrillnerKarolinska InstitutetDepartment of NeuroscienceStockholm [email protected]

Suzanne HaberUniversity of RochesterDepartment of Neurobiology & Anatomy601 Elmwood AveRochester NY [email protected]

Edward HallParke-Davis Pharmaceutical ResearchDepartment of Neuroscience

Therapeutics2800 Plymouth RoadAnn Arbor MI [email protected]

John HallenbeckNINDS/NIHStroke BranchBldg 36 Rm 4A0336 Convent Dr MSC 4128Bethesda MD [email protected]

Carol HamelinkNIHNIAAA/DICBRBldg 10 3C218-10 Center Dr MCS 1256Bethesda MD 20892-1256USA

Sami I. HarikUniversity of Arkansas for Medical

SciencesDepartment of Neurology4301 W Markham Slot 500Little Rock AR [email protected]

Eric HarrisAstra Arcus USACell BiologyP.O.box 20890Rocehster NY [email protected]

Ronald Harris-WarrickCornell UniversityDepartment of Neurobiology & BehaviorSeeley G. Mdd HallIthaca NY [email protected]

Neil HarrisonUniversity of ChicagoDepartment of Anesthesia & Critical Care915 E 57th StChicago IL [email protected]

John Hart, Jr.The Johns Hopkins HospitalDepartment of Neurology600 N Wolfe St Meyer 222Baltimore MD [email protected]

Teresa HastingsUniversity of PittsburgDepartment of Neurology & Neuro

SciencesS-505 Biomedical Sciences TowerPittsburg PA [email protected]

Michael HäusserUniversity College LondonDepartment of PhysiologyGower StLondon WC1E 6BTUNITED [email protected]

124

Edward HawrotBrown UniversityDepartment of Mol. Pharmacology,

Physiology & Biotechnology75 Waterman StProvidence RI [email protected]

Phil HaydonIowa State UniversityDepartment of Zoology and GeneticsRoom 339 Science IIAmes IA [email protected]

Fritz HennCentral Institute of Mental HealthBiochemistry LaboratoryPO Box 122120Mannheim [email protected]

Karl HerrupCase Western Reserve UniversityAlsheimer Research LabCWRV Medical School (E504)10900 Euclid AveCleveland OH [email protected]

Shaul HestrinUniversity of Tennessee, MemphisDepartment of Anatomy and

NeurobiologyUT Medical School855 Monroe AveMemphis TN [email protected]

Joseph R. Hibbeln, M.D.National Institute on Alcohol Abuse and

AlcoholismLaboratory of Membrane Biochemistry

and BiophysicsPark 5 Room 15812420 Parklawn DriveRockville MD [email protected]

James D HigleyNIAAABldg 112 Rm 103 Elmer School RdPollesvile MD [email protected]

Jay HirshUniversity of VirginiaDepartment of BiologyGilmer HallCharlottesville VA [email protected]

Bart HoebelPrinceton UniversityDepartment of PsychologyGreen HallPrinceton NJ [email protected]

Beth HoffmanNIMHCellular & Molecular RecognitionBldg 36 Rm 3A-1736 Convent Dr MSC 4090Bethesda MD [email protected]

Gloria HoffmanUniversity of Maryland BaltimoreDepartment of Anatomy & Neurobiology655 W Baltimore StBaltimore MD [email protected]

125

Gregg HomanicsUniversity of PittsburghDepartment of AnesthesiologyW1356 Biomedical Science TowerPittsburgh PA [email protected]

Mady HornigUC IrvineNeurology3109 Gillespie NeuroscienceIrvine CA [email protected]

H. Robert HorvitzMassachusetts Institute of Technology

Howard Hughes Medical InstituteDepartment of BiologyBldg 68 Rm 425 77 Massachusetts AveCambridge MA [email protected]

Jorn HounsgaardUniversity of CopenhagenDepartment of Medical PhysiologyBlegdamsve3 3Copenhagen [email protected]

Jeffrey HouseOxford University Press198 Madison AveNew York NY 10016USA

Karen HsiaoUniversity of MinnesotaDepartment of NeurologyBox 295 UMHC420 Delaware Street SEMinneapolis MN [email protected]

Paul HuangMassachusetts General HospitalCardiology Division & Cadivascular

Research Center149 East 13th St Rm 4213Charlestown MA [email protected]

Xin-Yun HuangCornell University Medical CollegePhysiology1300 York AveNew York NY [email protected]

Antal HudetzMedical College of WisconsinDepartment of Anesthesiology8701 Watertown Plank RdMilwaukee WI [email protected]

Rita HuffPharmacia & UpjohnNeurobiology7251-209-4Pharmacia & Upjohn301 Henrietta StKalamazoo MI [email protected]

Thomas HughesYale Medical SchoolDepartment of Ophthalmology330 Cedar StNew Haven CT [email protected]

Stephen P. HuntMedawar Building University College

LondonDepartment of Anatomy &

Developmental BiologyGower StLondon WC1B6BTUNITED KINGDOM

126

Thomas HydeNational Institute of Mental HealthClinical Brain Disorders BranchSuite 2334701 Willard AvenueChevy Chase MD [email protected]

Steve HymanNIMH31 Center Dr Rm 4A52Bethesda MD 20892-2475USA

DiAnna L. HyndsUniversity of KentuckyDepartment of Anatomy and

NeurobiologyMN 232/234 UKMC, 800 Rose StLexington KY [email protected]

Costantino IadecolaUniversity of MinnesotaDepartment of Neurology420 Delaware St SE Box 295Minneapolis MN [email protected]

Michael IuvoneEmory UniversityDepartment of Pharmacology1510 Clifton RdAtlanta GA [email protected]

Russell JacobsCaltechDepartment of Biology139-74 Beckman InstitutePasadena CA [email protected]

Mark JacquinWashington University School of

MedicineDepartment of NeurologyBox 8111St. Louis [email protected]

Patricia Janak, Ph.D.National Institute on Drug AbuseCellular Neurophysiology SectionCellular Neurobiology Branch5500 nathan Shock DrBaltimore MD [email protected]

George JaskiwCleveland VAMCMental Health ServicesMental Health Services 116A(B)Cleveland VAMC10000 Brecksville Rd.Brecskville OH [email protected]

Luc JasminGeorgetown University, Washington DCDepartment of Neurosurgery1567 Masonic AveSan Francisco CA [email protected]

Daniel JavittNathan Kline Institute for Psychiatric

ResearchDepartment of Neurophysiology140 Old Orangeburg RdOrangeburg NY [email protected]

Diane JaworskiUniversity of Vermont College of

MedicineDepartment of Anatomy & NeurobiologyGiven C 454Burlington VT [email protected]

127

T.M. JayUniversite Paris-Sud; Bat 446Department of Neurobiologie De

L apprentissage et de la me moireCNRS URA 1431Orsay [email protected]

Hank P. JedemaUniversity of PittsburghDepartment of Neuroscience446 Crawford HallPittsburgh PA [email protected]

Wendell E. JeffreyUCLADepartment of Psychology3334 Scadlock LaneSherman Oaks CA [email protected]

Alan Kim JohnsonUniversity of IowaDepartment of Psychology11 Seashore Hall EIowa City IA [email protected]

Peter JonasAlbert-Ludwigns UniversitatPhysiological InstituteHermann-Herder—Str 7Freiburg 79104GERMANYjonaspatruf.uni-freibugh.de

Reese JonesUniversity of California San FranciscoDepartment of Psychiatry280 Madrona Ave.Belvedere CA [email protected]

Theresa A. JonesUniversity of WashingtonDepartment of PsychologyGuthrie Hall Box 351525Seattle WA [email protected]

Jim Joseph711 Washington StDepartment of NeuroscienceBoston MA [email protected]

Sharon L. Juliano Ph.D.Uniformed Services University of the

Health SciencesDepartment of Anatomy & Cell Biology4301 Jones Bridge RdBethesda MD [email protected]

Jon H. Kaas, Ph.D.Vanderbilt UniversityDepartment of Psychology301 Wilson Hall111 21st Ave SNashville TN [email protected]

Leonard K. KaczmarekYale University School of MedicineDepartment of Pharmacology333 Cedar StNew Haven CT [email protected]

Katherine KahlUniversity of Wisconsin-MadisonDepartment of Anatomy1300 University AveMadison WI [email protected]

128

Robin KanarekTufts UniversityDepartment of PsychologyResearch Building490 Boston AvenueMedford MA [email protected]

Harvey J. KartenUniversity of California, San DiegoDepartment of Neurosciences 06089500 Gilman DrLa Jolla CA [email protected]

Paul KatzGeorgia State UniversityDepartment of BiologyPO Box 4010Atlanta GA [email protected]

Kristen KeefeUniversity of UtahDepartment of Pharmacology and

Toxicology30 South 2000 East, Room 201112 Skaggs HallSalt Lake City UT [email protected]

Edward KellerSmith-Kettlewell Eye Research Institute2232 Webster StreetSan Francisco CA [email protected]

Ann KelleyUniversity of WisconsinDepartment of Psychiatry6001 Research Park BlvdMadison WI [email protected]

David KennedyMassachusetts General HospitalDepartment of NeurologyCMA, MGH-EastRoom 6014149 13th StreetCharlestown MA [email protected]

Henry KennedyINSERMUnite 371, Cerveau et Vision18 avenue Doyen LepineBron, FRANCE [email protected]

James L. KennedyUniversity of TorontoDepartment of PsychiatryClaslce Institute250 College StToronto ON M5T [email protected]

John KesslerAlbert Einstein College of MedicineDepartment of Neurology and

Neuroscience1300 Morris Park AvenueBronx NY [email protected]

Harold K. Kimelberg, Ph.d.Albany Medical CollegeDivision of NeurosurgeryA-60Albany NY [email protected]

Sue C. KinnamonColorado State UniversityDepartment of Anatomy & NeurobiologyFort Collins CO [email protected]

129

Jeffrey KleimUniversity of LethbridgeDepartment of Psychology &

Neuroscience4401 University DrLethbridge AB T1K [email protected]

Rudiger KleinEuropean Molecular Biology LaboratoryDevelopmental BiologyMeyerhofstr.1Heidelberg [email protected]

Joel E. KleinmanNIMHCBDB9000 Rockville Pike Bldg 10 Rm45 237ABethesda MD [email protected]

Anna KlintsovaUniversity of IllinoisBeckman Institute405 N.Mathews AvenueUrbana IL [email protected]

Christine KonradiMassachusetts General Hospital-Harvard

Med. SchoolDepartment of PsychiatryMGH East, CNY2510Building 149, 13th streetCharlestown MA [email protected]

Raphael KopanWashington UniversityDepartment of Dermatology, Molecular

Biology & Pharmacology660 S Euclid Ave Box 8123St Louis MO [email protected]

Jeffrey KordowerRush Presbyterian Medical CenterDepartment of Neurological Sciences2242 W. Harrison StChicago IL [email protected]

Conan KornetskyBoston University School of MedicineDepartment of Psychiatry715 Albany St. L602Boston MA [email protected]

Stephen H. Koslow, Ph.D.National Institute on Mental HealthOffice on Neuroinformation5600 Fishers Lane Rm 10C-24Rockville MD [email protected]

Barry KosofskyMGH-EastDepartment of NeurologyMGH-East Rm 2508149 13th StCharlestown MA [email protected]

Cathy KotzVA Medical CenterResearch 151One Veterans DrMinneapolis MN [email protected]

Mary Jeanne KreekRockefeller UniversityLab of the Biology of Addictive Diseases1230 York Ave Box 171New York NY [email protected]

130

Arnold KriegsteinColumbia College of Physicians &

SurgeonsDepartment of Neurology630 W 168th StNew York NY [email protected]

John H. KrystalYale UniversityDepartment of PsychiatryG7E-Rm 85-MVA Connecticut Healthcare System950 Campbell AveWest Haven CT [email protected]

Ronald KuczenskiUC San DiegoPsychiatryDepartment of Psychiatry (0603)UCSD School of MedicineLa Jolla CA [email protected]

Pinky Kushner1362 6th AveSan Francisco CA [email protected]

Joseph C. LaMannaCase Western Reserve UniversityDepartment of NeurologySchool of Medicine10900 Euclid Ave (BRB 525)Cleveland OH [email protected]

Anthony LamantiaUniversity of North Carolina School of

MedicineDepartment of Cell & Molecular

PhysiologyCB#7545Chapel Hill NC [email protected]

Bruce LambCase Western Reserve UniversityDepartment of GeneticsBiomedical Research Building, Room 62210900 Euclid AvenueCleveland OH [email protected]

Richard D. LaneMedical College of OhioDepartment of Anatomy & Neurobiology3035 Arlington AveToledo OH [email protected]

Jean M. LauderUniversity of North Carolina School of

MedicineDepartmentof Cell Biology & AnatamyCB #7090Chapel Hill NC [email protected]

Matthew J. LaVoieUniversity of PittsburghDepartment of Neuroscience446 Crawford HallPittsburgh PA [email protected]

Charles LefflerUniversity of Tennessee, MemphisDepartment of Physiology894 Union AveMemphis TN [email protected]

Paul LetourneauUniversity of MinnesotaDepartment of Cell Biology &

Neuroanatomy4-144 Jackson Hall312 Church St SEMinneapolis MN [email protected]

131

Mark M. LevandoskiBrown UniversityDepartment of Molecular Pharmacology,

Physiology & BiotechnologyBox G-B4, Brown UniversityProvidence RI [email protected]

Barry LevinVA Medical CenterDepartment of Neurology (127C)385 Tremont AveE Orange NJ [email protected]

Allen S. LevineVA Medical CenterDepartment of Research1 Veterans DrMinneapolis MN [email protected]

Michael LevineUCLAMental Retardation Research CenterMRRC760 Westwood Plaza NPI 58-258UCLALos Angeles CA [email protected]

Steve LevisonPenn State College of MedicineDepartment of Neuroscience & AnatomyPO Box 850Hershey PA [email protected]

Irwin LevitanBrandeis UniversityVolen Center for Complex SystemsMS 013415 South StWaltham MA [email protected]

Anita LewinResearch Triangle InstituteDepartment of Organic & Medicinal

ChemistryPO Box 12194RTP NC [email protected]

Kelvin O. Lim, MDNathan Kling InstituteDepartment of Medical Physics140 Old Orange RdOrangeburg NY [email protected]

Iris LindbergLSUMCDepartment of Biochemistry & Molecular

Biology1901 Perdido StNew Orleans LA [email protected]

Jon LindstromMedical School of the University of

PennsylvaniaDepartment of Neuroscience217 Stemmler HallPhiladelphia PA [email protected]

Joseph LipinskiClinical Neuroscience Research

Foundation, Inc.Director of Research34 Walden StreetP.O. Box 236Concord MA [email protected]

Barbara LipskaNIHNIMH/CBDBNIMH, CBDB, Bldg. 9, Rm 1N124BBethesda MD [email protected]

132

Edythe D. London Ph.D.NIDA Brain Imaging CenterBrain Imaging CenterNIDA Intramural Research Program5500 Nathan Shock DrBaltimore MD [email protected]

Jeanne LoringARC Genomics Research701 Santa Cruz LaneFoster City CA [email protected]

Joe LoTurcoUniversity of ConnecticutPhysiology and NeurobiologyUniversity of ConnecicutU-156Physiology and NeurobiologyStorrs CT [email protected]

David M. LovingerVanderbilt UniversityDepartment of Molecular Physiology &

Biophysics702 Light HallNashville TN [email protected]

Ronald J. LukasBarrow Neurological InstituteDivision of Neurobiology350 W Thomas RdPhoenix AZ [email protected]

Carl R. Lupica Ph.D.University of Colorado Health Sciences

CntrDepartment of Pharmacology (C236)4200 E 9th AveDenver CO [email protected]

William LymanWayne State University School of

MedicinePediatricsChildren s Research Center of Michigan3901 BeaubienDetroit MI [email protected]

Eduardo MacagnoColumbia UniversityDepartment of Biological Sciences1011 FairchildNew York NY [email protected]

Maria MaccecchiniBearsden Bio IncDepartment of Research and

Development34 Mound Pleasant DriveAston PA [email protected]

Bruce MacIverStanford UniversityDepartment of AnesthesiaSUMC S 288School of MedicineStanford CA [email protected]

Ken MackieUniversity of WashingtonDepartment of AnesthesiologyBox 356540HSB BB14281959 NE Pacific St.Seattle WA [email protected]

Scott MacklerUniversity of PA/Phila VAMCDepartment of MedicineMedical Research Service (151C)University & Woodland AvesPhila VAMCPhila PA [email protected]

133

Wendy MacklinCleveland Clinic FoundationNeurosciencesDepartment of Neurosciences/NC309500 Euclid AvenueCleveland OH [email protected]

Daniel MadisonStanford University School of MedicineDepartment of Molecular and Cellular

PhysiologyBeckman Center Rm 111bStanford CA [email protected]

Pierre J. MagistrettiUniversity of LausanneInstitute of Physiology7 rue du BugnonLausanne VD [email protected]

Greg MaguireUCSDDepartment of OphthalmologyOphthalmology-0946UCSDLa Jolla CA [email protected]

Zachary MainenCold Spring Harbor Lab1 Bungtown RdCold Spring Harbor NY [email protected]

Dan MajorUniversity of California, San DiegoDepartment of Neurosciences9500 Gilman Dr.La Jolla CA [email protected]

Robert MalenkaUniversity of California, San FranciscoPsychiatry401 Parnassus Ave.LPPI, Box 0984University of CaliforniaSan Francisco CA [email protected]

Robert MansbachPfizer, Inc.Department of NeurosciencePfizer Central ResearchEastern Point Rd.Groton CT [email protected]

Patrick W. MantyhUniversity of MinnesotaNeuro Systems Center18-208 Moos Health Sciences Tower515 Delware St SEMinneapolis MN [email protected]

Athina MarkouThe Scripps Research InstituteDepartment of Neuropharmacology10550 N Torrey Pines RdLa Jolla CA [email protected]

Jasna MarkovacAcademic Press525 B StreetSuite 1900San Diego CA [email protected]

Neville MarksNathan Kline InstituteDepartment Neuro Chemistry140 Old Orangeburg RdOrangeburg NY [email protected]

134

Daniel R. MarshakOsiris Therapeutics Inc2001 Aliceanna StBaltimore MD [email protected]

Robert MarvitUniversity of HawaiiPublic Health1314 South King StreetSuite 759Honolulu HI [email protected]

Richard H. MaslandHoward Hughes Medical InstituteMassachusetts General HospitalWellman 42950 Blossom StBoston MA [email protected]

Matthew MatellDuke UniversityDept. of Psychology: ExperimentalDurham NC [email protected]

Michael MatiseSkirball Institute/NYU Medical CenterDepartment of Develomental GeneticsNYU/Skirball Institute4th floor540 First AvenueNew York NY [email protected]

John MazziottaUCLABrain Mapping CenterBrain Mapping CenterUCLA School of Medicine604 Charles E Young Dr, SouthLos Angeles CA [email protected]

Tyler McCabeCognetix, Inc.421 Wakara WaySuite 201Salt Lake City UT [email protected]

Anthony McCallOregon Health Sciences UniversityDepartment of Medicine and NeurologyP3MED CA Med Ctr 3710 US Vet Hosp

RdPortland OR [email protected]

Annette McClellanUniversity of UtahHMBG/Pharmacology & ToxicologyHuman Molecular Biology & Genetics15 N 2030 E, Room 2490Salt Lake City UT [email protected]

William McClureUniv. of Southern CaliforniaBiological Sciences, NeurologyDept of Biological SciencesUniv. of Southern CaliforniaUniversity ParkLos Angeles CA [email protected]

Lisa McConlogueAthena NeurosciencesDepartment of Molecular Biology800 Gateway BlvdSouth San Francisco CA [email protected]

David McCormickYale University School of MedicineDepartment of NeurobiologySection of NeurobiologyEastern Point Rd.333 Cedar StreetNew Haven CT [email protected]

135

James G. McElligottTemple University School of MedicineDepartment of Pharmacology3420 North Broad StreetPhiladelphia PA [email protected]

Jacqueline McGintyEast Carolina UniversityDepartment of Anatomy and Cell BiologySchool of Medicine600 Moye Blvd.Greenville NC [email protected]

Hugh McIntyreHarbor-UCLA Medical CenterDepartment of NeurologyEastern Point Rd.1000 West Carson StreetTorrance Ca [email protected]

Robert McKeonEmory UniversityDepartment of Cell BiologyRobert McKeon, Ph.D.1648 Pierce DriveAtlanta GA 30322USA

F. Arthur McMorrisWistar Institute3601 Spruce StPhiladelphia PA [email protected]

Warren H. MeckDuke UniversityDepartment of Psychology-Experimental9 Flowers DrDurham NC [email protected]

David MendelowitzUniversity of TennesseeDepartment of Physiology894 Union AveMemphis TN [email protected]

Kalpana MerchantPharmacia & Upjohn, Inc.NeurobiologyPharmacia & Upjohn, Inc.Mail Stop: 7251-209-5301 Henrietta StreetKalamazoo MI [email protected]

Diane MerryUniversity of Pennsylvania School of

MedicineDepartment of Neurology250 Clinical Research Building415 Curie Blvd.Philadelphia PA [email protected]

Ronald MeyerUniversity of California IrvineDepartment of Developmental and Cell

BiologyDevelopmental Biology CenterBio Sci 2, ZOT 2275University of California IrvineIrvine CA [email protected]

Neil MillarUniversity College LondonDepartment of PharmacologyGower StLondon WC1E 6BTUNITED [email protected]

Gordon MitchellUniversity of WisconsinDepartment of Comparative Biosciences2015 Linden Dr WestMadison WI 53706USA

136

Bita MoghaddamYale University School of MedicineDepartment of PsychiatryVAMC Research 116A/2950 Campbell AveWest Haven CT [email protected]

Hannah MonyerZMBHDepartment of Molecular NeurosciencesYahnstr-29Heidelberg [email protected]

Eric MoodyJohns Hopkins UniversityDepartment of Anesthesiology/Critical

Care MedicineTower 711Johns Hopkins Hospital600 N. Wolfe St.Baltimore MD [email protected]

Richard MorrisettUniversity of Texas at AustinDepartment Pharmacology & ToxicologyCollege of PharmacyAustin TX [email protected]

Stephen MossMRC LMCBUniversity CollegeGower StLondon WC1EGBTUNITED [email protected]

Karen A. MoxonAllegheny University of the Health


David MuirUniversity of FloridaDepartment of Pediatric NeurologyPediatric Neurology, Box 100296University of Florida College of MedicineGainesville FL [email protected]

Marion Murrayallegheny university of the health sciencesneurobiology3200 Henry Ave.Philadelphia Pa [email protected]

N. Eric NaftchiNY University Medical CenterRehabilation Center389 Forest AveTurneck NJ [email protected]

Angus NairnRockefeller UniversityLab. Molec. & Cell. Neuroscience1230 York AvenueNew York NY [email protected]

Yasuko Nakajima, MD, Ph.D.University of Illinois at ChicagoDepartment of Anatomy & Cell BiologyCollege of Medicine808 S Wood StChicago IL [email protected]

T. Celeste NapierLoyola University chicago Stritch School

of MedicineDepartment of Pharmacology2160 S 1st AveMaywood IL [email protected]

137

Sujatha NarayanBryn Mawr CollegeBiologyDept of BiologyBryn Mawr College101 North Merion AvenueBryn Mawr PA [email protected]

Christain NausThe University of Western OntarioDepartment of Anatomy & Cell BiologyMedical Sciences BldgLondon Ontario N6A [email protected]

Maiken NedergaardNYMCDepartment of Cell Biology & AnatomyBSB 204Valhalla NY [email protected]

Simona NeumannMassachusetts General HospitalMeural Plasticity Research Group149 13th St Rm 4309Charlestown MA [email protected]

Miguel A. NicolelisDuke UniversityDepartment of Neurobiology101 Research DrDurham NC [email protected]

David A. Nielson, Ph.D.NIHNIAAAPark V Rm 45112420 Parklawn DrRockville MD [email protected]

Eric NisenbaumEli Lilly and CompanyDepartment of NeuroscienceLilly Research LaboratoriesLCC, Drop Code 0510Indianapolis IN [email protected]

Laura NisenbaumEli Lilly and CompanyDepartment of NeuroscienceLilly Research LaboratoriesLilly Corporate CenterDrop Code 0510Indianapolis IN [email protected]

Richard NowakowskiRobert Wood Johnson Medical SchoolNeuroscience and Cell Biology675 Hoes LanePiscataway NJ 08854

Jeffrey S. NyeNorthwestern UniversityDepartment of Mole Pharmacology &

Pediatrics303 E Chicago AveChicago IL [email protected]

Judith K. NyquistNational Research Council/National

Academy of SciencesDepartment of Associateship Programs2101 Constitution Ave NW (TJ2114Washington DC [email protected]

Charles O BrienUniversity of Pennsylvania/VAMCDepartment of Psychiatry3900 Chestnut StPhiladelphia PA [email protected]

138

Patricio O DonnellAlbany Medical CollegeDepartment of Pharmacology &

Neuroscience47 New Scotland AveAlbany NY 12208USApatricio.o donnellWccgateway.amc.edu

Karen O MalleyWashington University School of

MedicineDepartment of Anatomy and

NeurobiologyBox 8108660 So. EuclidSt. Louis MO [email protected]

Richard W. OlsenUCLA School of MedicineDepartment of Molecular & Medical

Pharmacology10833 LeConte AveLos Angeles CA [email protected]

David OsgoodMini-Mitter Co IncPO Box 3386Sunriver OR [email protected]

Judy OsgoodMini-Mitter Co IncPO Box 3386Sunriver OR [email protected]

Gene C. PalmerAstra Arcus USARes. PlanningPO Box 20890Rochester NY [email protected]

Loren ParsonsThe Scripps Research InstituteDepartment of Neuro-PharmacologyMail Drop CVN-7La Jolla CA [email protected]

Tomas PausMontreal Neurological InstituteDepartment of Neurology &

Neurosurgery3801 University StMontreal QC H3A [email protected]

Sandra PearlUniversity of PittsburghDepartment of Neurology3500 Terrace St S-BST S26Pittsburgh PA [email protected]

Betsy PehekCass Western Reserve UniversityDepartment of PsychiatryVA Medical CenterMail Code 116 A(B)10000 BrecksvilleRdBrecksville OH [email protected]

Luc PellerinUniversity of LausanneInstitute of Physiology7 rue du BugnonLausanne VD [email protected]

Dale PelligrinoUniversity of Illinois at ChicagoNeuroanesthesia ResearchMolecular Biology Research Building (M/

C 513)900 South Ashland AvenueChicago IL [email protected]

139

John PenneyMassachusetts General HospitalNeurology ServiceJohn B Penney, Jr., M.D.Neurology Service/Warren 408Boston MA [email protected]

Laura PeoplesRutgers, The State University of New

JerseyDepartment of Psychology152 Prelinghuysen RdPiscataway [email protected]

Pablo Perillan685 W. Baltimore St MSTF Bldg Rm 618Neurological SurgeryBaltimore MD [email protected]

David PerkelUniversity of PennsylvaniaNeuroscience215 Stemmler Hall3600 Hamilton WalkPhiladelphia PA [email protected]

Stephen J. PeroutkaSpectra Biomedical IncNeuropharmacology1025 Tournament DrBurlington CA 94010—[email protected]

Agu PertNIMH/NIHBiological Psychiatry BranchBldg 10 Rm 3N-212Bethesda MD [email protected]

Steve PfeifferNORAN Instruments Inc.Confocal Microscopes7800 SW Bayberry DriveBeaverton OR [email protected]

Anthony G. PhillipsUniversity of British ColumbiaDepartment of Psychology2136 W MallVancouver B.C. V6T [email protected]

Marina PicciottoYale UniversityDepartment of Psychiatry34 Park St 3rd Floor ResearchNew Haven CT [email protected]

R. Christopher PierceBoston University Shool of MedicineDepartment of Pharmacology715 Albany St R612Boston MA [email protected]

David J. PinskyColumbia UniversityDepartment of Medicine630 W 168th StNew York NY [email protected]

Dietmar PlenzNational Institute of Mental HealthLaboratory of Systems NeuroscienceDept. Anatomy & NeurobiologyUniv. Tennessee, School of Medicine855 Monroe AvenueMemphis TN [email protected]

140

Frank PorrecaUniversity of ArizonaDepartment of Pharmacology1501 N Campbell AveTucson AZ [email protected]

Steven G. Potkin, MDUniversity of California, IrvineBrain Imaging CenterIrvine Hall Rm 166Irwin CA [email protected]

Huntington PotterUniversity of South FloridaBiochemistry and Molecular BiologyDept. Biochemistry and Molecular

BiologyUniversity of South Florida MDC712901 Bruce B. Downs Blvd.Tampa FL [email protected]

Darwin J ProckopAllegheny University of the Health

SciencesCenter for Gene Therapy245 N 15 St 10118 NCB Mail Stop 421Philadelphia PA [email protected]

Remi QuirionMcGill UniversityDouglas Hospital res Ctr6875 Blvd LasalleVerdun Qc H4H [email protected]

Anjali RajadhyakshaMassachusetts General Hospital Harvard

Medical SchoolDepartment of Molecular &

Developmental NeuroscienceBldg 149 13th St. CNY2 Rm 2510Charlestown MA [email protected]

Pasko RakicYale University School of MedicineNeurobiology333 Cedar StNew Haven CT [email protected]

Sammanda RamamoorthyVanderbilt UniversityDepartment of PharmacologyBldg # MRB-2 Rm #412Nashville TN [email protected]

Jan Marino RamirezUniversity of ChicagoDepartment of Anatomy1027 East 57th StChicago IL [email protected]

Burce R. RansomUniversity of WashingtonDepartment of NeurologyBox 356465Seattle WA [email protected]

Christopher B. RansomUniversity of Alabama at BirminghamDepartment of Neurobiology1719 6th Ave SouthBirmingham AL [email protected]

Lawrence P. Reagan, Ph.D.The Rockefeller UniversityLaboratory of Neuroendocrinology1230 York Ave Box 165New York NY [email protected]

141

Eric Reiman MDGood Samaritan Regional Medical CenterDepartment of Behavioral Health925 E McDonald Rd 4th FlPhoenix AZ [email protected]

Maarten E.A. ReithUniversityIllinois, College of MedicineBiomed. Ther. Sci.Box 1649Peoria IL [email protected]

William RenehanHenry Ford Health SystemDepartment of Gastroenterology2799 W Grand BlvdDetroit MI 48202USAwreneha1@hfhs

Alex ReyesNew York UniversityCenter for Neural ScienceCenter for Neural Science4 Washington PlRm 809New York NY [email protected]

Robert W. RhoadesMedical College of OhioDepartment of Anatomy & Neurobiology3035 Arlington AveToledo OH [email protected]

Margaret RiceNYU School of MedicineDepartment of Physiology and

Neuroscience550 First AvenueNew York NY [email protected]

J. Steven RichardsonUniversity of SaskatchewanPharmacology107 Wiggins RoadSaskatoon SK S7N [email protected]

George RichersonYale UniversityDepartment of Neurology333 Cedar St LCI—704New Haven CT [email protected]

Brenda RitchieYale UniversityPediatrics47 Deepwood DriveHamden CT 06520 [email protected]

J.Murdoch RitchieYale UniversityPharmacologyDepartment of PharmacologyYale Univ. Medical School333 Cedar StreetNew Haven CT 06520 [email protected]

Christopher A. RossJohns Hopkins UniversityDepartment of Psychiatry &

NeuroscienceRoss 618 720 Rutland AveBaltimore MD [email protected]

Elliott RossUniv. Okla. Health Sci. CenterNeurologyVA Medical Center (11AZ)921 N.E., 13th StreetOklahoma City OK [email protected]

142

Peter RubenUtah State UniversityDepartment of Biology5305 University DrLogan UT [email protected]

John RubensteinUniversity of California, San FranciscoDepartment of Psychiatry401 Parnassus AveSan Francisco Ca [email protected]

Eliana ScemesAlbert Einstein College of MedicineDepartment of NeuroscienceKennedy Center, room 7121410 Pelham Parkay SouthBronx NY [email protected]

Stephen ScheffUniversity of KentuckyCenter on AgingUniversity of KentuckyCenter on Aging233 Sanders-Brown BldgLexington KY [email protected]

Todd ScheuerUnversity of WashingtonDepartment of PharmacologyBox 357280 DepSeatle WA [email protected]

Arne SchousboeRoyal Danish School of PharmacyDepartment of Pharmacology2 Universitet SparkenCopenhagen [email protected]

Steven SchreiberUniversity of Southern CaliforniaDepartment of NeurologySchool of Medicine1333 San Palo St MCH142Los Angeles CA [email protected]

Bernard G. SchreursNIHDepartment of Behavioral Neuroscience

UnitBldg. 36, Rm B2059000 Rockville PikeBethesda MD [email protected]

Wolfram SchultzUniversity of FrihomyInstitute of PhysiologyRue dur Orusee 5Finbourg [email protected]

Gunter Schumann, M.D.University of FreibergDepartment of PsychiatryHauptstrasse 5Freiburg 75104Germany

Joe SchwabPharmacia & Upjohn871 Century WayDanville CA [email protected]

Robert SchwarczUniversity of MarylandMaryland Psychiatric Research CenterPO Box 21247Baltimore MD [email protected]

143

Andrew SchwartzThe Neurosciences Institute10640 John Jay Hopkins DriveSan Diego CA [email protected]

Roy SchwarzParke-Davis Pharm. ResearchNeuroscience Therapeutics2800 Plymouth RoadAnn Arbor MI [email protected]

Peter H. SeeburgMax-Planck Institute Medical ResearchDepartment of Molecular NeuroscienceJahnstr 29Heidelberg [email protected]

Henry SershenNathan S. Kline InstituteNeurochemistryNathan S. Kline Institute140 Old Orangeburg Rd.Orangeburg NY [email protected]

Susan SesackUniversity of PittsburghDepartment of Neuroscience446 Crawford HallPittsburgh PA [email protected]

M. Kent ShellenbergerElan PharamacicalDepartment of Clinical Affairs800 Gateway BlvdSan Francisco CA 94080USA

Gordon ShepherdYale Medical SchoolDepartment of Neurobiology333 Cedar StNew Haven CT [email protected]

Judith Shivak16 Blackwell LaneStony Brook NY 11790—[email protected]

Allan SiegelNew Jersey Medical SchoolDepartment of Neuroscience185 S Orange AveNewark New Jersey [email protected]

Steven A. SiegelbaumColumbia UniversityCenter for Neurobiology & Behavior722 W 168 St Rm 620New York NY [email protected]

Robin Angus SilverUniversity College LondonDepartment of PhysiologyGower StLondon WC1E 6BTUNITED [email protected]

Daniel SilvermanUCLA Medical CenterDepartment of Molecular & Medical

PharmacologyNuclear Medicine Clinic CHS AR-144Los Angeles CA [email protected]

Eric J. SimonNYU Medical SchoolPsychiatryRoom THN 609NYU Medical School550 First AvenueNew York NY [email protected]

144

Ian A. SimpsonNIHDepartment of Diabetics BranchBldg 10 Rm 5N 10210 Center DrBethesda MD [email protected]

Phil SkolnickEli Lilly & CoNeuroscience DiscoveryDC 0510 Lilly Corp CenterIndianapolis IN [email protected]

Celia SladekChicago Medical SchoolDepartment of Physiology3333 Green Bay RdNorth Chicago IL [email protected]

John SladekChicago Medical SchoolNeuroscience3333 Green Bay RdNorth Chicago IL [email protected]

Steven SmallUniversity of MarylandDepartment of Neurology22 South Greene StreetBaltimore MD [email protected]

Adam SmithUniversity of OxfordDepartment of PhysiologyParks RdOxford OX1 3PTUNITED KINGDOMadam [email protected]

Jeffrey SmithNINDS, NIHLaboratory of Neural ControlLab of Neural ControlBldg. 49, Rm. 3A5049 Convent Dr. MSC 4455NINDS, NIHBethesda Md [email protected]

Marion E. SmithVA Health Care SystemDepartment of Neurology3801 Miranda AvePalo Alto CA [email protected]

Mark A. SmithCase Western Reserve UniversityInstitute of Pathology2085 Adelbert RoadCleveland OH [email protected]

Sheryl SmithAllegheny Univeresity of the Health


Stephen SmithStanford University Medical CenterDepartment of Molecular & Cell

PhysiologyBeckman Center B-141Stanford, CA 94305-5426 [email protected]

Yoland SmithYerkes Primate Center Emory UniversityDiv of Neuroscience954 Gate Wood Rd NEAtlanta GA [email protected]

145

Harald Sontheimer, Ph.D.University of Alabama at BirminghamDepartment of Neurobiology1719 6th Ave SouthBirmingham AL [email protected]

Linda S. SorkinUniversity of California San DiegoDepartment of Anesthesiology9500 Gilman DrLa Jolla CA [email protected]

William SpainUniversity of WashingtonDepartment of NeurologyMail Stop S-127 NEUROPugent S VA Health System1660 S Columbian WaySeatle Washington [email protected]

Shel SparberUniv of MinnPharmacology435 Delaware St SEMpls MN 55455until Jan 4th [email protected]

David SprayAlbert Einstein College of MedicineDepartment of NeuroscienceDepartment of NeuroscienceKennedy Center Rm 712Albert Einstein College of Medicine1410 Pelham Parkway SouthBronx NY [email protected]

David G. StandaertMassachusetts General HospitalDepartment of NeurologyWarren 408 Fruit StBoston MA [email protected]

Barry SteinWakeforest University School of

MedicineDepartment of Neurobiology & AnatomyMed Cntr BlvdWinston-Salem NC [email protected]

Donald SteinEmory UniversityGraduate School of Arts and Sciences202 Administration BuildingAtlanta GA [email protected]

Hermann StellerHoward Hughes Medical Institute/MITDepartment of Biology68-430 77 Massachusetts AveCambridge MA [email protected]

Fiona StevensOxford University Press465 California St Suite 1030San Francisco CA [email protected]

Oswald StewardUniversity of VirginiaDeparment of NeuroscienceBox 5148 MR4Charlottesville VA [email protected]

Alex StraikerUniversity of California, San DiegoDepartment of Neurosciences9500 Gilman Dr.La Jolla CA [email protected]

146

Marina StrakhovaEli Lilly & CoNeuroscience Discovery ResearchBldg 48 r.A1110 Drop code 0510Indianapolis IN [email protected]

Kevin StrangeVanderbilt University Medical CenterDepartment of Anesthesiology504 Oxford House1313 21st Ave SNashville TN [email protected]

Wolfgang J. StreitUniversity of FLoridaDepartment of Neuroscience1600 SW Archer RDGainesville FL [email protected]

Jane SullivanSalk InstituteMolecular & Neurobiology10010 N Torrey Pines RdLa Jolla CA [email protected]

David SulzerColumbia UniversityDepartment of Neurology88 305 650 W 168th StNew York NY [email protected]

Rodney SwainUniversity of Wisconsin-MilwaukeeDepartment of PsychologyGarland Hall2441 E. Hartford Ave.Milwaukee WI [email protected]

Tom SwansonBowling Green State UniversityDepartment of PsychologyB6SUBowling Green OH [email protected]

Peter SyapinTexas Tech University Health Sciences

CenterPharmacology3601 4th StreetLubbock TX [email protected]

Stan ThayerUniversity of MinnesotaDepartment of Pharmacology3-249 Millard Hall435 Delaware St SEMinneapolis MN [email protected]

Evelyn ThomanUniversity of ConnecticutBioBehavior Science3107 Horsebarn Hill RdStorres CT 06269USA860 [email protected]

Elizabeth A. ThomasThe Scripps Research InstituteMolecular Biology10550 N Torrey Pines RdLa Jolla CA [email protected]

Steven ThomasUniversity of PennsylvaniaDepartment of Pharmacology3620 Hamilton WalkPhiladelphia PA [email protected]

147

Scott ThompsonUniversity of MarylandPhysiology655 W. Baltimore St.Baltimore MD [email protected]

Staurt ThompsonProfessorHopkins Marine StationStanford UniversityOcean View Blvd.Pacific Grove, CA [email protected]

Arthur TogaUCLA School of MedicineDepartment of Neurology710 Westwood Plz Rm 4238Los Angeles CA [email protected]

R. Alberto TravagliCWRU-Henry Ford Health Sciences

CenterGastroenterology ResearchHenry Ford Health Sciences Center2799 West Grand BlvdDetroit MI [email protected]

Mark TrocchiAssociation Book Exhibit639 South Washington StreetAlexandria VA 22314

Ramon TrullasIIBB/CSICNeurobiologyJordi Girona 18Barcelona, Spain [email protected]

Rachel TyndaleUniveresity of TorontoDepartment of Pharmacology1 King s College CircleToronto Ont. M5S [email protected]

George R. Uhl, M.D., Ph.D.NIH, NIDA, IRPDepartment Molecular Neurobiology

Branch5500 Nathan Shock DrBaltimore MD [email protected]

Jaap Van PeltNetherlands Institute for Brain ResearchDepartment of Neurons & NetworksMeibergdreef 33Amsterdam [email protected]

Hubert Van TolCentre for Addiction & Mental Health;

Clarke Div.Department of Psychiatry; Univ. of

TorontoLab. Mol. Neurobiology250 College streetToronto Ont M5T [email protected]

David L. Van VactorHarvard Medical SchoolDepartment of Cell Biology & Program in

Neuroscience240 Lonewood AveBoston MA [email protected]

Susan VannucciPenn State UniversityDepartment of Pediatrics/Neuroscience

& AnatomyCollege of MedicineHershey Med CtrP.O. Box 850Hershey PA [email protected]

148

Michael R VaskoIndiana University School of MedicineDepartment of Pharmacology635 Barnhill DrIndianapolis IN [email protected]

Paul F.M.J. VerachureInstitute of Neuroinformatik derGloriastrasse 32Zurich [email protected]

Stefano ViciniGeorgetown University Medical SchoolDepartment Physiology and BiophysicsRoom 225 Basic Science Building3900 Reservoir Road NWWashington DC [email protected]

Inez VincentUniversity of WashingtonDepartment of Pathology1959 NE Pacific, K065Box 357470Seattle WA [email protected]

Jan VolavkaNathan Kline Institute140 Old Orangeburg RdOrangeburg NY [email protected]

Steve WagnerSIBIA Neurosciences, Inc.Department of Protein Biochemistry505 Coast Blvd South Ste 300LaJolla CA [email protected]

Claude WasterlainUCLADepartment of NeurologyVA Medical Center (127)16111 Plummer StreetSepulveda CA [email protected]

Ellie WateletUniversity of California, San DiegoDepartment of Neurosciences, 06089500 Gilman DrLa Jolla CA [email protected]

Forrest F. Weight, MDNIH/NIAAALab Molecular & Cellular NeurobiologyPark Bldg Rm 158 MSC8115Bethesad MD [email protected]

Daniel R. WeinbergerNIMH NIHClinical Brain Disorders BranchBldg 10 M4S-2359000 Rockville PikeBethesda MD [email protected]

Jeff WeinerWake Forest University School of

MedicineDepartment of Physiology &

PharmacologyMedical Center BlvdWinston-Salem NC [email protected]

Frank WelshUniversity of PennsylvaniaNeurosurgery371 Stemmler Hall36th and Hamilton WalkPhiladelphia PA [email protected]

149

Bernice M. WenzelUCLADepartment of Physiology3334 Scadlock LaneSherman Oaks CA [email protected]

Jurgen WessNIH-NIDDKLab of Bioorganic ChemistryBldg 8A Rm B1A-05Bethesda MD [email protected]

Anthony R. WestUniversity of PittsburghDepartment of Neuroscience446 Crawford HallPittsburgh PA [email protected]

Monte WesterfieldUniversity of OregonInstitute of NeuroscienceEugene OR [email protected]

Karin N. Westlund Ph. D.University of Texas Medical BranchDepartment of Anatomy &

Neurosciences & The MarineBiomedical Institute

301 University BoulevardGalveston TX [email protected]

Francis WhiteChicago Medical SchoolCellular and Molecular Pharmacology3333 Green Bay RdNorth Chicago IL [email protected]

Clayton WileyUniversity of PittsburghDepartment of Pathology200 Lothrop Street, A-506Pittsburgh PA [email protected]

William WisdenMedical Research CouncilLaboratory of Molecular BiologyNeurotransmitter ReceptorsMRC CentreMills RoadCambridge CB2 2QHUNITED [email protected]

Phyllis M. WiseUniversity of KentuckyDepartment of PhysiologyMS 509 Chandler Medical Center800 Rose StreetLexington KY [email protected]

Roy A. WiseNational Institute on Drug AbuseBehavioral Neuroscience Branch5500 Nathan Shock Dr.Baltimore MD [email protected]

Terri WoodPSU/College of MedicineNeuroscience & AnatomyP.O. Box 850500 University DriveHershey PA [email protected]

Stephen WoodsUniversity of CincinnatiDepartment of PsychiatryP.O.Box 670559Cincinnati OH [email protected]

150

Donald Woodward, Ph.D.Wake Forest University Medical SchoolDepartment of Physiology &

PharmacologyMedical Ctr BlvdWinston Salem NC 27157-1083USA

Clifford WoolfMassachusetts General HospitalDepartment of AnesthesiaNeural Plasticity Research Group149 13th Street Room 4310Charlestown MA [email protected]

Douglas WrightUniversity of Kansas Medical CenterAnatomy and Cell Biology3901 Rainbow BlvdKansas City KS [email protected]

Jinhu XiongThe University of Texas Health Science

Center at San antonioResearch Imaging Center7703 Floyd Curl DrSan Antonio TX [email protected]

Takeshu YagiNational Institute for Physiological

SciencesLab of Neurobiology & Behavioral

GeneticsMyodajiOkazaki [email protected]

Bryan YamamotoCase Western Reserve UniversityDepartment of Psychiatry11100 Euclid AveCleveland OH [email protected]

F. Eugene YatesU.C.L.A.Department of Medicine1950 Sawtelle Ste 330Los Angeles CA [email protected]

Byron YoburnCollege of Pharmacy, St. John s

UniversityPharmaceutical Sciences8000 Utopia ParkwayQueens NY [email protected]

Laurence R. YoungMasachusetts Institute of TechnologyDepartment of GeronauticsBldg 37-219Mass AveCambridge MA [email protected]

Elmer Yu, M.D.Univ of Penn/Philadelphia VAMCDepartment of Psychiatry30 Boulder Brook DriveWilmington DE [email protected]

151

Junying YuanHarvard Medical SchoolDepartment of Cell Biology240 Longwood AveBoston MA [email protected]

Michael J. ZigmondUniversity of PittsburghDepartment of NeurologyS526 BST, 3500 Terrace StreetPittsburgh PA [email protected]

Suzanne ZukinAlbert Einstein College of MedicineDepartment of Neuroscience1300 Morris Park AvenueRoom 603 KennedyBronx NY [email protected]

152

Index

AAebischer˚Patrick 67Anderson˚Brenda 74Andrade˚Rodrigo 48Appel˚Bruce 35Audinat˚Etienne 56

BBaas˚Peter 48Bachus˚Susan 76Badiani˚Aldo 38Baker˚Robert 34Bardo˚Michael 72Barger˚Steve 68Bartzokis˚George 31Basbaum˚Allan 54Bates˚Gillian 37Bealer˚Steve 52Bennett˚Michael 39, 41Bennett˚Paul 53Berg˚Darwin 62Bergman˚Hagai 43Bertolino˚Alessandro 72Betz˚Heinrich 69Binder˚Marc 59Bjaalie˚Jan 36Bloedel˚James 34Bohn˚Martha 53Bolam˚J. Paul 43Bondy˚Steve 31Borst˚Alexander 64Breier˚Alan 36Brennan˚Timothy 33Brewer˚Gregory 50Brown˚Gerald 47Bruno˚John 40Bruzzone˚Roberto 39Bueciel˚Christian 57Bunney˚William 39Burke˚Robert 59, 66

CCallicott˚Joseph 76Carlezon˚William 66

Carlton˚Susan 33Carroll˚Marilyn 29Casagrande˚Vivien 32Castro-Alamancos˚Manuel

75Cha˚Jang-Ho John 37Chalupa˚Leo 32Chapin˚John 65Charles˚Andy 71Chaudhari˚Nirupa 47Chesselet˚Marie-Francoise

42, 46Choi˚Dennis 41Chopp˚Michael 32, 62Clark˚Beverley 77Clements˚John 63Cobb˚Stuart 78Conn˚P. Jeffrey 70Conner˚James 31, 67Constantine-Paton˚Martha

73Contreras˚Diego 75Cooper˚Ellis 57Costigan˚Michael 78Craig˚Ann Marie 73Cramer˚Steven 62Crews˚Fulton 31, 41Crone˚Nathan 49Cunningham˚Kathryn 61Czajkowski˚Cynthia 65

DDale˚Nicholas 28Davies˚Peter 50Dawson˚Ted 30De Souza˚Errol 46de Vellis˚Jean 30Delfs˚Jill 79Dermietzel˚Rolf 31Destexhe˚Alain 75Dickson˚Dennis 68Dore˚Sylvain 79Drew˚Kelly 54Dunwiddie˚Tom 55Dwoskin˚Linda 72

EEarley˚Christopher 31Ebner˚Ford 65Egan˚Michael 80El Manira˚Abdel 28

FFaden˚Alan 81Farrant˚Mark 81Fawcett˚James 73Feinstein˚DouglasFeldman˚Jack 45Feldman˚Susan 82Feuerstein˚Giora 62Fibiger˚Christian 28Finger˚Thomas 47Finklestein˚Seth 62Finlay˚Janet 40Flynn˚Francis 82Fox˚Peter 57Frazer˚Alan 60Freed˚William 58French˚Robert 53Frerichs˚Kai 54Fujikawa˚Denson 32

GGage˚Fred 30Gallistel˚Charles 38Gallo˚Gianluca 48Gash˚Don 67Gebhart˚Gerald 33Geller˚Herb 58, 73Gerhardt˚Greg 60, 67Geyer˚Mark 36Gibbon˚John 38Gillis˚Richard 44Giniger˚Edward 35Ginty˚David 60Giraudo˚Silvia 83Giszter˚Simon 66Givens˚Bennett 69Goldin˚Alan 53Goldman˚David 39Grace˚Anthony 66Grant˚Gregory 57Greenamyre˚Tim 46Greer˚Charles 47Griffin˚Sue 68Grillner˚Sten 28, 36

HHaber˚Suzanne 43Hall˚Edward 59Hallenbeck˚John 54Hamelink˚Carol 83

153

Harris-Warrick˚Ronald28, 66

Harrison˚Neil 65Hart, Jr.˚John 49Hausser˚Michael 63Hawrot˚Edward 57Haydon˚Philip 40, 71Henn˚Fritz 63Herrup˚Karl 58Hestrin˚Shaul 56Hibbeln˚Joseph 47Higley˚J. 47Hirsh˚Jay 51Hoffman˚Beth 61Hoffman˚Gloria 52Homanics˚Gregg 65Hornig˚Mady 84Horvitz˚H. Robert 44Hounsgaard˚Jorn 28Hsiao˚Karen 43Huang˚Paul 30Hughes˚Thomas 47Hunt˚Stephen 54Hyman˚Steven 42Hynds˚DiAnna 38

IIadecola˚Constantino 30

JJanak˚Patricia 69Jasmin˚Luc 85Javitt˚Daniel 28Jaworski˚Diane 38Jay˚Therese 72Jedema˚Hank 85Johnson˚Alan 52Jonas˚Peter 56Jones˚Theresa 74Joseph˚James 86Juliano˚Sharon 50

KKaas˚Jon 65Kaczmarek˚Leonard 49Kalil˚Katherine 48Kanarek˚Robin 29Karten˚Harvey 64Kater˚Stanley 71Katz˚Paul 66

Keefe˚Kristen 40Kelley˚Ann 29Kennedy˚David 57Kennedy˚Henry 32Kennedy˚James 39Kessler˚John 30Kimelberg˚Harold 31Kinnamon˚Sue 47Kleim˚Jeffrey 74Klein˚R dig er 63Klintsova˚Anna 74Konradi˚Christine 60Koob˚George 41Kopan˚Raphael 35Koslow˚Stephen 36Kotz˚Catherine 86Kreek˚Mary 41Kriegstein˚Arnold 50, 73Krystal˚John 36

LLaBonne˚Carole 56LaMantia˚Anthony 53Lamb˚Bruce 43Lattemann˚Dianne 52Lauder˚Jean 53LaVoie˚Matthew 87Leffler˚Charles 88Letourneau˚Paul 48Levandoski˚Mark 57Levin˚Barry 52Levine˚Allen 29Levine˚Michael 46Levison˚Steven 73Lewin˚Anita 88Lim˚Kelvin 28Lindstrom˚Jon 62Lipska˚Barbara 72London˚Edythe 72Loring˚Jeanne 43LoTurco˚Joe 89Lovinger˚David 70Lukas˚Ronald 62Lupica˚Carl 55

MMacagno˚Eduardo 48Mackie˚Ken 35Mackler˚Scott 61Macklin˚Wendy 89

Madison˚Daniel 55Magistretti˚Pierre 52Maguire˚Greg 35Mainen˚Zachary 63Mansbach˚Robert 72Mantyh˚Patrick 54Marshak˚Daniel 53Masland˚Richard 64Matell˚Matthew 90Matise˚Michael 56McCabe˚Tyler 91McCall˚Anthony 46McCall Bob 42McConlogue˚Lisa 43McCormick˚David 75McElligott˚James 34McGinty˚Jacqueline 60McKeon˚Robert 38McMorris˚Arthur 30Meck˚Warren 38Mendelowitz˚David 44Merry˚Diane 46Meyer˚Ron 73Millar˚Neil 62Mitchell˚Gordon 45Moghaddam˚Bita 36Monyer˚Hannah 50Moody˚Eric 69Morris˚ArthurMorrisett˚Richard 69Muir˚David 38

NNagy˚Zsuzsanna 50Nakajima˚Yasuko 49Napier˚T. Celeste 43Narayan˚Sujatha 92Naus˚Christian 39, 92Nedergaard˚Maiken 39,

40, 71Nicolelis˚Miguel 65Nielson˚David 47Nisenbaum˚Eric 93Nowakowski˚Richard 58Nye˚Jeffrey 35

OO Brien˚Charles 41O Donnell˚Patricio 72O Malley˚Karen 51Olsen˚Richard 65

154

PParsons˚Loren 61Paus˚Thomas 57Pearl˚Sandra 51Pehek˚Betsy 94Pellerin˚Luc 95Pelligrino˚Dale 59Penney˚John 37Peoples˚Laura 66Perillan˚Pablo 95Pert˚Agu 41, 68Phillips˚Anthony 68Picciotto˚Marina 57Pierce˚R. Christopher 96Pinsky˚David 30Piomelli˚Daniele 35Plenz˚Dietmar 51Porreca˚Frank 33Potkin˚Steven 39Prockop˚Darwin 53

RRajadhyaksha˚Anjali 97Rakic˚Pasko 44Ramamoorthy˚Sammanda

60Ramirez˚Jan 45Ransom˚Bruce 52Reagan˚Lawrence 46Reeh˚Peter 33Reiman˚Eric 39Renehan˚William 44Reyes˚Alex 59Rice˚Margaret 54Richerson˚George 45Ross˚Christopher 37, 46Ruben˚Peter 53Rubenstein˚John 56Ruda˚M. A. 97

SScemes˚Eliah 71Scemes˚Eliana 31Scheuer˚Todd 53Schousboe˚Arne 40Schreiber˚Steven 32Schreurs˚Bernard 34Schultz˚Wolfram 68Schumann˚Gunter 63

Sesack˚Susan 72Shepherd˚Gordon 42Siegelbaum˚Steven 49Silver˚Angus 63Silverman˚Daniel H. 98Simon˚Roger 41Simpson˚Ian 52Skolnick˚Phil 69Sladek˚Celia 52Small˚Steven 49Smith˚Adam 50Smith˚Jeffrey 66Smith˚Mark 50Smith˚Sheryl 65Smith˚Stephen 40Smith˚Yoland 70Sontheimer˚Harald 99Sorkin˚Linda 33Spain˚William 59Spray˚David 39Standaert˚David 70Stein˚Barry 32Stein˚Donald 59Steller˚Hermann 44Strakhova˚Marina 69Strange˚Kevin 31Strausfeld˚Nick 64Streit˚Wolfgang 68Sulzer˚David 60Swain ˚Rodney 74Syapin˚Peter 99

TThayer˚Stanley 35Thomas˚Elizabeth 100Thomas˚Steven 51Thompson˚Scott 56Thompson˚Stuart 40Travagli˚Renato 44Tsien˚Richard 60Tyndale˚Rachel 72

Vvan Pelt˚Jaap 36van Vactor˚David 63Vasko˚Michael 33Verschure˚Paul 36Vicini˚Stefano 73Vincent˚Inez 50

WWagner˚Steven 43Wasterlain˚Claude 32Weight˚Forrest 69Weinberger˚Daniel 28Weiner˚Jeff 55Wess˚Jurgen 69West˚Anthony 101Westerfield˚Monte 56Westlund˚Karin 33White˚Francis 66Wise˚Phyllis 59Wise˚Roy 66Woods˚Stephen 46Woodward˚Donald 68Woolf˚Clifford 54

XXie˚Rui-Man 101Xiong˚Jin-Hu 57

YYagi˚Takeshi 63Yamamoto˚Bryan 40Yu˚Elmer 102Yuan˚Junying 44

ZZigmond˚Michael 42Zukin˚Suzanne 41

welcome to the thirty-second annual winter conference on...

Documents