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Welcome to the Thirty-Fourth AnnualWinter Conference on Brain ResearchThe Winter Conference on Brain Research (WCBR) was founded in1968 to promote free exchange of information and ideas withinneuroscience. It was the intent of the founders that both formal andinformal interactions would occur between clinical and laboratorybased neuroscientists. During the past thirty years neuroscience hasgrown and expanded to include many new fields and methodologies.This diversity is also reflected by WCBR participants and in ourprogram. A primary goal of the WCBR is to enable participants tolearn about the current status of areas of neuroscience other than theirown. Another objective is to provide a vehicle for scientists withcommon interests to discuss current issues in an informal setting. Onthe other hand, WCBR is not designed for presentations limited tocommunicating the latest data to a small group of specialists; this isbest done at national society meetings.

The program includes panels (reviews for an audience not necessarilyfamiliar with the area presented), workshops (informal discussions ofcurrent issues and data), and a number of posters. The annual confer-ence lecture will be presented at breakfast on Sunday, January 21. Ourguest speaker will be Dr. Gerald Fischbach, Director of the NationalInstitute for Neurological Disorders and Stroke at the NationalInstitutes of Health. On Tuesday, January 23, a town meeting will beheld for the Steamboat Springs community. Here Dr. Charles O Brien,and WCBR participants will discuss the neurobiological basis ofmental illness. Also, participants in the WCBR outreach program willpresent sessions at local schools throughout the week to pique stu-dents interest in science. Finally, the banquet, including music anddancing, will be held on Friday evening.

Generous donations from sponsors have permitted us to continue theWCBR Fellowship Award Program. These awards are given to youngneuroscientists who are on the program and who are newcomers toWCBR. Congratulations and a warm welcome to this year s fellows:Bill Carlezon, David Chambers, Gersham Dent, Cecilia Flores,

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Timothy Gomez, Ryder Gwinn, Andrew Jenkins, Gregory Kinney,Oliver Manzoni, Haley Melikian, Claudio Mello, David W. Miller,Derek Molliver, Cheryl L. Stucky, and Kevin Wickman.

Please plan to attend the business meeting at 6:30 p.m. on Wednesday,January 24. We will elect a Facilities Chair-Elect and three membersof the Board of Directors. A sign-up sheet will be available on themessage board to indicate your interest in running for a Board ofDirectors position. Other important matters will be discussed includingproposed changes in the by-laws and the selection of future conferencesites.

Don’t forget to visit the exhibit area.

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Conference ChairAllan BasbaumMichael S. Levine, Chair-Elect

Program CommitteePaul C. Letourneau, ChairElizabeth Abercrombie,

Chair-ElectAllan BasbaumJill B. BeckerMarc D. BinderMarie-Francoise ChesseletThomas V. DunwiddieNeil L. HarrisonKarl HerrupKatherine KalilPaul S. Katz

Christine KonradiMichael S. LevineJoseph F. Lipinski, Jr.Wendy B. MacklinDavid J. PerkelBruce R. RansomSuzanne K. Roffler-TarlovOswald StewardJames SurmeierThomas H. Swanson

TreasurerElizabeth Abercrombie

Facilities CommitteeKaren Greif, ChairMonte Westerfield, Chair-ElectMurray BlackmoreHsin ChuBill CobbScott Gehler

Stanislav (Stas) KholmanskikhSimona NeumannKarla Petersen-ZeitzJames Zackheim

Board of DirectorsMarjorie ArianoMartha BohnWilliam E. BunneyKaren GaleBart HoebelThomas M. Hyde

Kristen KeefeJoel E. KleinmanBruce RansomJames SurmeierClaude WesterlainDonald Woodward

Fellowship ProgramJames Surmeier, ChairRay Bartus

Ed HallPhil Skolnik

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ExhibitsMichael Levine Wendy B. Macklin

School OutreachKim Topp, CoordinatorVictor DenenbergPaula Dore-DuffyHelene EmsellemJanet FinlayKyle FrantzKaren GreifA. Chistina GrobinSamil HarikLuc Jasmin

Joseph LaMannaHugh McIntyreMarsha MelnickGene PalmerBruce RansomChris RansomSuzanne Roffler-TarlovBrad StokesTom SwansonFrank Welsh

Town MeetingJanet Finlay Laura Peoples

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

2001 Fellowship AwardeesBill CarlezonDavid ChambersGersham DentCecilia FloresTimothy GomezRyder GwinnAndrew JenkinsGregory Kinney

Oliver ManzoniHaley MelikianClaudio MelloDavid W. MillerDerek MolliverCheryl L. StuckyKevin Wickman

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Winter Conference on Brain ResearchFellowship SponsorsBenefactors: $1000+AventisDystonia FoundationEli Lilly and Co.Fine Science ToolsJanssen PharmaceuticalsPfizer, Inc.WCBR Board of Directors

Patron: $500-$999Alkermes, Inc.Dov PharmaceuticalsDupont ParmaceuticalsPharmacia UpJohnSchering Plough Research InstituteWyeth-Ayerst Pharmaceuticals

ExhibitorsAcademic Press525 B Street, Suite 1900San Diego, CA 92101-4495Contact: Sue Boyer / Tari PaschallTel (619) 699-6820Email: sboyer@acad.com

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

Carl ZeissOne Zeiss DriveThornwood, NY 10594Contact: Troy TholenTel (801) 484-8872 Voice mail (800) 543-1033 x7981Email: ttholen@zeiss.com

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Durect Corporation10240 Bubb RoadCupertino, CA 95014Contact: Stacey Matsuoka / Clarisa PeerTel (408) 367-4038 Fax (408) 865-1406Email: stacey.matsuoka@durect.com

Elsevier Science London84 Theobalds RoadLondon WC1X 8RR, ENGLANDContact: Emily MilesTel 44-020-761-4378 Fax 44-020-761-4401Email: emily.miles@current-trends.com

Elsevier Science LondonThe Online Community of NeuroscientistsMiddlesex House34-42 Cleveland StreetLondon W1P 6LE, ENGLANDContact: Samar SyedTel 44-207- 611-4362 Fax 44-207-611-4201Email: samar.syed@biomednet.com

ESA Inc.22 Alpha RoadChelmsford, MA 01824-4171Contact: Brent Morrison / Michael Baker / Damian FreezeTel (978) 250-7081 Fax (978) 250-7087Email: brentm@esainc.com

Fine Science Tools373-G Vintage Park DriveFoster City, CA 94404Contact: Daron Brown / Jeff WileyTel (800) 521-2109 Fax (800) 523-2109Email: dbrown@finescience.com / jwiley@finescience.com

Instrutech Corporation20 Vanderventer Ave., Ste 101EPort Washington, NY 11050-3752Contact: Milan KeslerTel (516) 883-1300 Fax (516) 883-1558Email: milan@instrutech.com

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S. Karger AGAllschwilerstrasse 10Postfach4009 Basel, SWITZERLANDContact: Angela GasserTel 41-61-306-1264Email: a.gasser@karger.ch

Leica Microsystems Inc.Harbor Tech Center724 Anthony TrailNorthbrook, IL 60062Contact: Wayne A. Buttermore / Andy LeeEmail: wayne.buttermore@leica-microsystems.com

MED Associates Inc.PO Box 319St. Albans, VT 05478Contact: Karl ZurnTel (802) 527-2343 Fax (802) 527-5095Email: karl@med-associates.com

Mini-Mitter Co., Inc.PO Box 3386Sunriver, OR 97707Contact: David or Judy OsgoodTel (541) 593-8639 Fax (541) 593-5604Email: judyo@minimitter.com

The MIT PressNE25-40935 Cambridge CenterCambridge, MA 02142Contact: John CostelloTel (617) 258-5764 Fax (617) 253-1709Email: jcostell@mit.edu

Molecular and Cellular Neurosciences Research BranchDivision of Neuroscience and Basic Behavioral ScienceNational Institute of Mental Health6001 Executive Blvd., Room 7168Bethesda, MD 20892-9641Contact: Beth-Anne SieberTel (301) 443-5288 Fax (301) 402-4740Email: sieberb@helix.nih.gov

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Natural Research Council/National Academy of Science2101 Constitution Ave NW (TJ2114)Washington, DC 20418Contact: Jane Dell AmoreTel (202)334-2768 Fax (202) 334-2759Email: jdellamo@nas.edu

Nikon Inc.PO Box 2464Evergreen, CO 80437Contact: Gerald BenhamColorado Office Ph.&Fax (303) 674-1569NY Tel: (516)547-8596 Fax (516) 547-4033Email: jbenhamnnikon@msn.com

Olympus AmericaTwo Corporate Center DriveMelville, NY 11747Contact: Angela GoodacreTel (800) 645-8100 Fax (972) 625-6439Email: goodaa@olympus.comContact: Kathleen KarmelTel (800) 645-8100 Box 6462 Fax (972) 625-6439Email: hudgek@olympus.com

Oxford University Press198 Madison AvenueNew York, NY 10016Contact: Lanvi Tran / Fiona StevensTel (212) 726-6079 Fax (212) 726-6441Email: lvt@oup-usa.org

Pacer Scientific5649 Valley Oak DriveLos Angeles, CA 90068Contact: Richard and Kathy BellamyTel (323) 462-0636 Fax (323) 462-1430Email: kathy@pacersci.com

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General InformationHeadquarters is the Sheraton Steamboat Resort and ConferenceCenter. All scientific activities will be held there.

WCBR Information Desk and Message Center are in Sunset A just tothe right off the Main Lobby when entering from the front entrance.The desk hours are as follows:

Morning Afternoon Evening

Saturday 1/20 9:00—11:00 AM 3:30—5:30 PM 7:30—10:00 PM

Sunday 1/21 7:00—8:00 AM 3:30—6:30 PM

Monday 1/22—Friday 1/26

7:00—8:00 AM 3:30—4:30 PM.

The telephone number for messages is 970-879-2220, ext. 1112. TheSheraton Steamboat Resort and Conference Center fax number is 970-870-9278. The person sending or receiving faxes is responsible for allcharges.

Each registration packet contains: a conference badge; registrationreceipt; tickets for breakfasts, mid-week lunch, and banquet; programbook. The packets should be picked up at the WCBR InformationDesk. PLEASE NOTE that your housing reservation must be shownbefore these 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 PRE-REGISTERED participants. On-site registration is not available.

Posters will be available for viewing throughout the week in theSunshine Peak. Poster presenters will be by their posters for discussionfrom 3:30—4:30 PM on the first day of each of the three poster ses-sions: Poster Session 1 Sunda y/Monday; Poster Session 2 T ues-day/Wednesday; and Poster Session 3 T hursday/Friday. Presentersmay put up their posters after 9:30 AM on the day their session starts.

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Presenters should take down their posters by 10 PM on the second dayof their session. Please see Poster Sessions section in program for titlesand names of presenters.

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

Breakfast is served to all registrants on Sunday 7:30—8:20 AM, in theGrand Ballroom, and on Monday through Friday, 6:30—7:30 AM, inboth Buddy s Run and Sevens Restaurant. (Social guests may breakfastuntil 10:00 AM in Sevens). The tickets in your registration packet arerequired for admission to all meals. On Saturday morning (January 26)before departure continental breakfast is available in the foyer of theSheraton Steamboat Resort and Conference Center.

Ski Lift Tickets will be available from the WCBR Information Desk inSunset A. Daily tickets can be purchased or prepaid tickets can bepicked up during desk hours.

Don’t forget to visit the exhibit area.

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Special EventsSaturday, January 20:Welcome Wine and Cheese Party ¥ 7:30—10:30 PM, Grand Ballroom.

Sunday, January 21:Conference Breakfast and Opening Address ¥ 7:30 AM, Grand Ballroom

(Your required ticket is in your registration packet). Our plenary keynotespeaker will be Gerald Fischbach, Director of the National Institute forNeurobiological Disorders and Stroke at NIH. The title of his plenarylecture is Neur oscience at the New Millenium.

Meeting of Panel and Workshop Organizers ¥ 9:30—10:30 AM, GrandBallroom. The meeting will be brief but important. Organizers and WCBRstaff please attend.

Monday, January 22:First Meeting of Board of Directors ¥ 6:30—8:30 AM, Ante Board Room.

Tuesday, January 23:Town Meeting ¥ 8:30—10:30 PM

Wednesday, January 24:Smitty Stevens Memorial (NASTAR) Ski Race ¥ 1:30—3:00 PM. NASTAR

registration cards to be completed no later than Monday, January 22, 8:00AM at WCBR Information Desk.

Mountain Lunch ¥ 11:00—1:00, Bear River Bar and Grill at base of gondola.(Required lunch ticket is in your registration packet). Non-skiers, requiringtransportation, should sign up at the WCBR Information Desk.

Business Meeting ¥ 6:30 PM, Mt. Werner, Election of Facilities Chair-Electand three Members of the Board of Directors.

Friday, January 26:Second Meeting Board of Directors ¥ 6:30 AM, Ante Board Room.

Banquet and Dance ¥ 8:00 PM, Grand Ballroom. (Required ticket is in yourregistration packet). Cash bar opens at 7:00 PM in the foyer of theSheraton Steamboat Resort and Conference Center.

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Preamble to the ProgramThe 2001 WCBR Program consists of panels,workshops, and posters. Please consult the Pro-gram Booklet and posted announcements fordetails regarding the scientific presentations, aswell as information regarding the school outreachprogram and the town meeting.

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7:30 AMBREAKFAST ADDRESS

Guest Speaker: Gerald Fischbach

Grand Ballroom

3:30–4:30 PMPOSTER SESSION 1 ¥ Presenters

available for discussion

Sunshine

4:30–6:30 PMPANEL ¥ Neurotrophic Factor-

Induced Dopaminergic Plasticityin Animal Models of Parkinson sDisease and Drug Addiction

R.C. Pierce, K.B Seroogy, C.A.Altar, J.R. Taylor, C. Flores

Mt. Werner

PANEL ¥ Cytoskeletal Restructuringin the Formation of Dendritesand Synapses

R.H. Lenox, S. Halpain, D.Benson, A. Matus

Storm Peak

PANEL ¥ The Orbitofrontal Cortexand the Addictions:Neuroimaging Studies

B. Adinoff , L. Porrino, R.Anton, E. London

Twilight

PANEL ¥ Rhythms and Patterns inNeural Firing

C.C. Chow, A. Bose, D. Terman,J. Rubin

Rainbow

Sunday, January 21PANEL ¥ The Biological Clock: Of

Molecular Gears, Timing Beltsand Post-transcriptional Modifi-cations

R. Baler, D. Virshup, P. Lowrey,A. Keesler

Skyline

PANEL ¥ Evolution of Neurohypo-physeal Peptide Systems: WhySex Matters

T.R. Insel, M.S. Grober, F.L.Moore, L.J. Young, G.J. De Vries

Sunset

8:30–10:00 PMWORKSHOP ¥ Role of Noradrener-

gic NTS Neurons in Drug Abuse:The Forgotten System

G. Aston-Jones, T. De Vries, Y.Shaham, G. Koob, C. O Brien

Mt. Werner

PANEL ¥ Dopaminergic Projectionsand Neural Ensembles inPrefrontal Cortical-VentralStriatal Loops

P. O’Donnell, A.A. Grace, L.L.Peoples, W. Schultz

Storm Peak

PANEL ¥ Glial Involvement inNeurodegeneration: The Revengeof Unintended Consequences

S. Griffin, S. Barger, L. VanEldik, J. Schwartz

Twilight

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PANEL ¥ Positive Modulation ofAMPA Receptors: Mechanismsand Therapeutics

E. Nisenbaum, D. Bleakman, K.Partin, U. Staubli

Rainbow

PANEL ¥ New Teeth on an Old Saw:Evaluating Cholinergic Mecha-nisms in Brain Aging

D. Ingram, N. Greig, R. Perez-Polo, J. Joseph

Skyline

PANEL ¥ Success Comes fromHaving the Right Connections:Integrating the CNS and PNS

D. Chambers, E. Bell, J. Begbie

Sunset

Monday, January 227:30–9:30 AMPANEL ¥ Integrated Regulation of

Synaptic Transmission by Ca++

Channels, K+ Channels, andMitochondrial Ca++ Uptake

W. A. Catterall, I. Forsythe, L.Kaczmarek, T. Scheuer, D.Lipscombe

Mt. Werner

PANEL ¥ Group I MetabotropicGlutamate Receptors: Role inPain, Epilepsy, MovementDisorders, and Brain Injury.

R. Schwarz, J. Conn, A. Faden,A. Kingston, C. Woolf

Storm Peak

PANEL ¥ Exactly How Is DopamineInvolved in MethamphetamineNeurotoxicity?

T. Hastings, D. Sulzer, R.Gainetdinov, G. Ricaurte,

Twilight

PANEL ¥ The HPA Axis: A Para-digm for Both Short and LongTerm Plasticity in CNS Respon-siveness

G. Aguilera, J. Herman, S.L.Lightman, J. A. Cidlowski

Rainbow

PANEL ¥ Immune Regulation, CNSPathogenesis and TherapeuticInterventions in MultipleSclerosis

R. Jones, G. Konat, P. Dore-Duffy, H. Offner, A. Vandenbark

Skyline

PANEL ¥ The Raphe and Breathing:What Is the Connection?

G. Richerson, E. Nattie, L.Kubin, A. Berger, J. Ramirez

Sunset

Sunday, January 21, continued

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3:30–4:30 PMPOSTER SESSION 1 ¥ Posters

available for viewing only

Sunshine

4:30–6:30 PMPANEL ¥ New Vistas on Prefrontal

Cortex: From Neuroanatomy toComputational Modeling

M. Banich, J. Giedd, A. Belger,R. O Reilly

Mt. Werner

PANEL ¥ Torsin, Parkin, Alpha-Synuclein and Tau: FourHorsemen of the Basal Ganglia

D. Standaert, M. Schlossmacher,D. Miller, M. Hutton

Storm Peak

PANEL ¥ Multimodal Multidimen-sional Digital DevelopmentalAtlas of the Mouse Brain

R.E. Jacobs, G. Burns, D.Laidlaw, R. Moats, A. Toga

Twilight

PANEL ¥ Death and the Lyso-some Ne w Insights intoNeuronal Ceroid Lipofuscinoses

H. Geller, S. Hofmann, P. Lobel,D. Pearce, B. Davidson

Rainbow

PANEL ¥ See No Evil, Hear No Evil,Smell No Evil The Origins ofHead Placodes

M. Westerfield, H. Chu, R.Karlstrom, R. Grainger,

Skyline

PANEL ¥ The Bane of Cancer Pain:A Role for Peptides and Protons?

G. Wilcox, A. Beitz, G. Davar, P.Reeh

Sunset

8:30–10:00 PMWORKSHOP ¥ Gene Profiling in the

Nervous System Using NucleicAcid Microarrays

J. McGinty, G. Dent, B. Meurers,K. Merchant, G. Uhl

Mt. Werner

WORKSHOP ¥ GlutamatergicMechanisms in the Pathophysiol-ogy of Drug Abuse

J. Weiner, F. Valenzuela, J.Kauer, O. Manzoni , A. Bonci

Storm Peak

PANEL ¥ Genetic Variation inHuman Catecholamine Systems:Impact on Neurobiology andSusceptibility to PsychiatricDisorders

D.R. Weinberger, M.F. Egan, D.Goldman, J. Cubells

Twilight

WORKSHOP ¥ 5-HT2A Receptorsand Forebrain Function: Fromthe Cell to the Clinic

L. Parsons, G. Marek, B. Pehek,K. Cunningham, J.H. Krystal

Rainbow

PANEL ¥ Free Radicals inAlzheimer s Disease. Where DoThey Come from?

S. Richardson, A. Butterfield, M.Smith, M. Vitek

Skyline

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WORKSHOP ¥ A Decade of Hits(and Misses): HeterologousExpression of Nicotinic Acetyl-choline Receptors in MammalianCells

R.J. Lukas, N.S. Millar, J.M.Lindstrom, K.J. Kellar

Sunset

Tuesday, January 237:30–9:30 AMPANEL ¥ Dimerization of G Protein-

coupled Receptors FunctionalImplications

L. Devi, M. Bouvier, S. George,K. Mackie, Y. Patel

Mt. Werner

PANEL ¥ Apoptotic Mechanisms:Are They also Used to RegulateSynaptic Stability?

E.A.Jonas, J.M. Hardwick, M.P.Charlton, J. Zimmerberg

Storm Peak

PANEL ¥ Cell and Gene Therapy forBasal Ganglia Disorders

O. Isacson, J. Kordower, C.Svendsen, K.S. Kim

Twilight

PANEL ¥ The Price of Ecstasy : TheFunctional Consequences ofMDMA Neurotoxicity

G. A. Gudelsky, B. Yamamoto,G. Ricaurte, A. Fleckenstein, S.White

Rainbow

PANEL ¥ Epitope Spreading: ANovel Concept with GreatRelevance to Multiple Sclerosis

M.C. Dal Canto, P. Lehmann, V.Tuohy, S. Miller

Skyline

PANEL ¥ Fragile X Mental Retarda-tion Syndrome: Clinical Diagno-sis and Symptoms, Genetic andMolecular Mechanisms andNeural Correlates

W. Greenough, D. Nelson, R.Hagerman, E. Berry-Kravis

Sunset

3:30–4:30 PMPOSTER SESSION 2 ¥ Presenters

available for discussion

Sunshine

4:30–6:30 PMPANEL ¥ Origin and Fate of New

Neurons in the Adult Brain

H. Scharfman, A. Alvarez-Buylla, T. Palmer, J. Parent

Mt. Werner

Monday, January 22, continued

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PANEL ¥ New Horizons in theMechanisms Mediating theEffects of Estrogen in the Brain:The Evidence for MembraneReceptors

J.B. Becker, C.S. Watson, D.M.Dorsa, M.J. Kelly

Storm Peak

PANEL ¥ Dopamine and SerotoninTransporters: Siblings Do NotAlways Behave the Same

A. Frazer, A. Galli, G. Gerhardt,and M. Sonders

Twilight

PANEL ¥ Proteases in theNeurodegeneration of AlzheimerDisease (AD): Chickens or Eggs?

R. Nixon, L-H. Tsai, K. Wang,C. Cotman

Rainbow

PANEL ¥ The Fruit Fly, DrosophilaMelanogaster: A Model Systemfor the Study of ComplexBehaviors.

J. Hirsh, R.L. Davis, J.C.Hendricks, U. Heberlein

Skyline

PANEL ¥ NGF and GDNF: The Yinand Yang of UnmyelinatedNociceptors

D. Wright, D. Molliver,C. Stucky, K. Albers

Sunset

8:30–10:00 PMWORKSHOP ¥ Mechanisms of

Neuronal Migration and SynapseStabilization in NeocorticalDevelopment

S. Juliano, K. Nakajima, K.Herrup, A. Kriegstein

Mt. Werner

WORKSHOP ¥ Electrophysiology ofIncentive Motivation: Can WeMeasur e the Affective States ofGoal-directed Behavior?

K. Anstrom, T. Robinson,G. Schoenbaum, W. Schultz

Storm Peak

WORKSHOP ¥ Is Peer ReviewPeerless?

C. Atwell, M. Martin, N.Steneck

Twilight

PANEL ¥ Pediatric Epilepsy: Fromthe Clinic to Basic Mechansims

G.W. Mathern, M. Levine, S.N.Roper, J. Veliskova

Rainbow

WORKSHOP ¥ Beyond Lozengesand Dandruff: Zn2+ Toxicity inthe CNS

I. Reynolds, E. Aizenman,D. Choi, J. Weiss

Skyline

PANEL ¥ Vasopressin/Vasotocin:Key Regulators of SocialBehavior Across Species?

E. Albers, S. Boyd, D. Maney,J. Winslow

Sunset

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7:30–9:30 AMPANEL ¥ The Map Kinase Signaling

Pathway and Synaptic Plasticity:Activators, Regulators andEffectors

P. Chapman, D. Kuhl, J.Naranjo, J. Yin

Mt. Werner

PANEL ¥ Mechanisms of CNSRegeneration and Repair

W.J. Streit, W. Tetzlaff, T. Hagg,S.R. Whittemore

Storm Peak

PANEL ¥ Mechanisms of Addiction:The Brain Opioid System Ain tJust for Opiates Anymore

T.S. Shippenberg, J.J. Frost, C.J.Evans, J.F. McGinty, C.T. Napier

Twilight

PANEL ¥ Perinatal Cell Death inPathological Environments:Which Cells Are Most Suscep-tible and How/When Do TheyRespond?

W. Macklin, M. Miller, S.Levinson, S. Vannucci

Rainbow

PANEL ¥ Peptide Nucleic Acid —New Life for Antisense (andAntigene)?

P. Clarke, B. Tyler-McMahon, U.Langel, L. Boffa

Skyline

PANEL ¥ Stimulation, Lesioning andTransplantation: Application forthe Treatment of Parkinson sDisease and Dystonia

J. Vitek, A. Lozano, J. Kordower,R. Bakay

Sunset

3:30–4:30 PMPOSTER SESSION 2 ¥ Posters

available for viewing only

Sunshine

4:30–6:30 PMPANEL ¥ Cholinergic Modulation of

Cortical Function: Channels toCircuits

R.C. Foehring, R. Metherate,F.F. Ebner, R. Andrade

Mt. Werner

PANEL ¥ Axon Guidance: FromExtracellular Cues to GrowthCone Behaviors

K. Kalil, T. O Connor, P.Letourneau, T. Gomez

Storm Peak

PANEL ¥ Recording from a WholeBunch of Neurons all at Once:Problems, Payoffs and Promise

J.Walters, B.Waterhouse,P. Janak, D. Kipke, D. Woodward

Twilight

Wednesday, January 24

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PANEL ¥ GABA Receptors asAnesthetic Targets: What We veLearned from Gene and IonChannel Structure/FunctionStudies

A. Jenkins, G. Houmanics, S.J.Mihic, D.S. Weiss, C.M.Czajkowski

Rainbow

PANEL ¥ The Response to CO2 andO2: From Ion Channels toNeural Networks.

J.M. Ramirez, M.M. Tamkun,N.R. Prabhakar, G.B. Richerson

Skyline

PANEL ¥ Role of Rhythmic NeuralActivity in CardiovascularBehavior: From MolecularDetails to Black Diamonds

J. P. Horn, P.G. Guyenet, M.P.Gilbey, D. Weinreich

Sunset

6:30 PMBUSINESS MEETING

Mt. Werner

Thursday, January 257:30–9:30 AMPANEL ¥ Kainate Receptors and

Synaptic Plasticity

G.L.Collingridge, R.A.Nicoll,J.T.R. Isaac, D. Lodge

Mt. Werner

PANEL ¥ Microarrays in Neuropsy-chiatric Research: A Delusion,Illusion, or Reality?

T.M. Hyde, C. Colantuoni, R.Coppola, W.J. Freed

Storm Peak

PANEL ¥ Regulation of MonoamineTransporter Characteristics andTrafficking

A. Janowsky, M. Reith, H.Melikian, A. Eshleman, N.Zahniser

Twilight

PANEL ¥ Neuroimmunophilins: CanSmall Molecules StimulateTherapeutic Neurorestoration?

E. Hall, P. Letourneau, E.Villafranca, B. Gold, D. Cole

Rainbow

PANEL ¥ The Brain is a CookieMonster: Contribution of FoodComposition and HedonicCircuitry to the Regulation ofFood Intake.

D. Lattemann, B. Levin, C.Billington, A.Kelley

Skyline

PANEL ¥ Mitotic RegulatorsProspero-us in PostmitoticNeurons from Become toSuccumb?

I. Vincent, H. Vaessin, R. Slack ,P. Baas

Sunset

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3:30–4:30 PMPOSTER SESSION 3 ¥ Presenters

available for discussion

Sunshine

4:30–6:30 PMPANEL ¥ Can Neuronal Glutamate

Release Be Measured In Vivo?Microdialysis vs Biosensors

N.Maidment, M. Boutelle, R.Kennedy, A. Michael, B. Dunn

Mt. Werner

PANEL ¥ Signal Transduction inNeuronal and NeuroendocrineCells: What the Mutant MiceSaid to Me

M.R. Picciotto, I. Lindberg, P.Allen, K. Wickman

Storm Peak

PANEL ¥ Regulation of Voltage-Dependent Sodium Channels byProtein Kinases and Phos-phatases

T. Scheuer, A.R. Goldin, A.R.Cantrell, P.C. Ruben

Twilight

PANEL ¥ Oligodendrocyte Precur-sors in Development, Health andDisease

J.W. Fawcett, W. D. Richardson,S. Goldman, J.M. Levine

Rainbow

PANEL ¥ New Insights aboutAbnormal DevelopmentalProcesses and Their Relevance toEpilepsy

R.S. Sloviter, F.E. Jensen, K.S.Lee, D.H. Lowenstein

Skyline

PANEL ¥ Vestibular Adaptation

L. Young, J. McElligott, M.Shelhamer, H. Hecht

Sunset

8:30–10:00 PMWORKSHOP ¥ Is Enhanced

Dopaminergic Neurotransmis-sion the Primary Mediator ofHedonic Reward? A Comparisonof Human and Animal Labora-tory Studies.

C. Bradberry, H. de Wit, G.Koob, T. Robinson

Mt. Werner

WORKSHOP ¥ Within-VTADifferences in Drug Action: AHouse Divided?

W. Carlezon, S. Ikemoto, R.A.Wise, D. van der Kooy

Storm Peak

WORKSHOP ¥ Excito-toxicity vsExcito-trophicity : Do SeizuresSwitch the Set-point for Survival?

K. Gale, R. Simon, R. Gwinn, D.McIntyre

Twilight

WORKSHOP ¥ What Really Is theFood for Thought: Glucose orLactate ?

I.A. Simpson, G. Dienel, E.Novotny, M. McKenna,L.Pellerin

Rainbow

Thursday, January 25, continued

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PANEL ¥ Neurotrophin-3: A Tool toQuery, and a Mechanism forSensory System Developmentand Plasticity

R. Lane, M. Jacquin, R.Rhoades, D. Wright

Skyline

WORKSHOP ¥ MultifunctionalNeurons and Networks forHearing and Vocal Control

J.S. Kanwal, C.V. Mello, M.S.Fee, G.D. Pollak, Z.M. Fuzessery

Sunset

Friday, January 267:30–9:30 AMPANEL ¥ Location, Location,

Location—Scaffolding Proteins inthe CNS

D. Ron, C. Garner, H-J. Chung,R. Olsen

Mt. Werner

PANEL ¥ The Glutamate-GlutamineCycle: Potential Targets forModulating GlutaminergicFunction

J.D. Erickson, A. Schousboe,M.P. Kavanaugh, R.H. Edwards

Storm Peak

PANEL ¥ The Role of PregnaneNeurosteroids in Brain Functionand Drug Action

L. Morrow, R. Rupprecht, C.Grobin, S. Mellon

Twilight

PANEL ¥ Neurotrophins andDepression

P. Skolnick, C.A. Altar, L.A.Mamounas, A. Russo-Neustadt

Rainbow

PANEL ¥ Epileptogenesis: To Fit orNot to Fit.

C. Wasterlain, E. Dudek, K.Staley, T. Sutula

Skyline

PANEL ¥ Prospects forRemyelination Therapies

T. Wood, J. Goldman, R.Armstrong, I. Duncan, R.Franklin

Sunset

3:30–4:30 PMPOSTER SESSION 3 ¥ Posters

available for viewing only

Sunshine

4:30–6:30 PMPANEL ¥ Ups and Downs in

Synaptic Transmission: Factorsthat Affect Short-Term SynapticEfficacy

R. E. Burke, L. Kaczmarek, B.Walmsley, F. Weight

Mt. Werner

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Don’t forget to visit the exhibit area.

PANEL ¥ New Mechanisms For AnOld Question: How DoesPrefrontal Cortex Affect Subcor-tical Dopamine Function?

B. Moghaddam, S. Sesack, J.A.Kauer, J. Krystal

Storm Peak

PANEL ¥ Microarray Profiling:Complex Diseases and DrugDevelopment

S. Potkin, W. Bunney, R.Thompson, N. Patil, M. Oliver

Twilight

PANEL ¥ GABA TransporterLocalization, Development andFunction

W. Spain, F. Conti, M. Quick,G. Kinney, M. Jones

Rainbow

PANEL ¥ Orphan G Protein-coupledReceptors as Novel Drug Targets

P. Iredale, O. Civelli, M.Yanagisawa, M. Fidock, S.Wilson

Skyline

PANEL ¥ The 5HT2b Receptor: ACandidate for Serotonin Medi-ated Morphogenesis Inside andOutside the Brain

S.W. Schwarzacher,J.M. Lauder, E. Fiorica-Howells,J.L. Maroteaux

Sunset

8:00 PMBANQUET AND DANCE

Grand Ballroom

Friday, January 26, continued

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Poster Sessions Schedule and AbstractsPoster Session 1 • Sunday/MondaySunshine

Posters will be available for viewing from 3:30 PM Sunday to 4:30 PMMonday. Presenters will be with the posters on Sunday from 3:30 to 4:30 PM.

Trafficking of Zip Code Binding Protein and Binding to the ß-actinZip Code Mediate the Regulation of ß-actin mRNA Localization toNeuronal Processes

H.L.Zhang,T.Eom, Y.Oleynikov, S.M. Shenoy, R.H. Singer and G.J. Bassell*.Department of Neuroscience, Albert Einstein College of Medicine,Bronx, NY.

The active transport of § -actin mRNA to neuronal processes may be a regulatedmechanism to promote the enrichment of § -actin pr otein within growth conesand filopodia. Our previous results have demonstrated a microtubule-dependent§ -actin mRNA localization mechanism which is regulated by the neurotrophin,NT-3. We have now identified cis-acting elements and trans-acting factors whichare involved in this localization mechanism. Two zip code sequences, within the3 UTR, which were previously identified for their role in fibroblasts, localized aheterologous reporter to neuronal processes. Antisense oligonucleotides to thesezip codes, applied to the culture medium, were shown to inhibit the NT-3 stimu-lation of § -actin mRNA localization. Gel shift assays indicated that antisenseoligonucleotides inhibited zip code function by preventing the formation of anRNA-protein complex. Zip Code Binding Protein, ZBP, was shown to bind the §-actin zip code in neuronal extracts using supershift, immunodepletion and UV-crosslinking experiments. RT-PCR, sequence analysis and Western Blot revealedthe expression of ZBP in developing chick forebrain. Using high-resolution fluo-rescence in situ hybridization and immunofluorescence, ZBP was observed ingranules which co-localized with § -actin mRNA in growth cones. ZBP granuleswere observed to colocalize along microtubules. Zip Code Binding Protein, fusedto EGFP, was transfected into cultured neurons for analysis in live cells. ZBP-EGFP was observed in the form of particles which exhibited rapid anterogradeand retrograde movements. These results suggest a novel mechanism for the regu-lated delivery of cytoskeletal precursors to growth cones, which involves the for-mation of an RNA-protein complex and its active transport to the growth cone,the site of local § -actin synthesis .

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The Shaping of Presynaptic Calcium Transient by Mitochondria

Brian Billups and Ian Forsyth, Department of Cell Physiology and Pharmacology,University of Leicester, Leicester LE1 9HN. UK

Calcium entry into the presynaptic terminal triggers neurotransmitter release.This calcium must be swiftly removed to prevent neurotoxic accumulation andallow continuous high frequency synaptic transmission. Various mechanisms arethought to be responsible for terminating the calcium signal, including mobileand fixed calcium buffering proteins, pumps into intracellular organelles (ERand mitochondria) and pumps and ion exchangers on the plasma membrane.Residual calcium remaining in the terminal following stimulation is an impor-tant intracellular signal, contributing to long and short-term changes in synapticefficacy. The location, affinity and kinetics of the various calcium clearancemechanisms are important in determining how the synaptic terminal will re-spond to rapid trains of action potentials. We investigated the role of mitochon-dria in calcium clearance at the rat Calyx of Held. This glutamatergic presynapticterminal in the auditory brainstem is the output from the globular bushy cells inthe anterio-ventral cochlear nucleus (AVCN) onto the contralateral medial nucleusof the trapezoid body (MNTB). It is specialized for accurate high-frequency trans-mission and plays a role in sound source localization. Its large size is suitable forwhole-terminal patch-clamp recording and measurements of intracellular cal-cium concentration using fluorescent dyes. Conventional intracellular calciumdyes (Fura-FF and Fluo-3) were used to measure the calcium concentration inthe cytoplasm of the presynaptic terminal. Rhod-2 was used to concurrentlymeasure the free calcium concentration in the mitochondria. Short trains of 2msstep depolarizations applied to the terminal by the voltage-clamp pipette resultin a calcium entry via a P-type calcium channel. A brief rise in intracellularcytoplasmic calcium concentration is observed, which decays with a time con-stant of less than 100ms at 37oC. A rise in mitochondrial free calcium is alsoobserved that decays over several seconds. Inhibitors of mitochondrial functionaffect these calcium concentration changes. Rotenone inhibits mitochondrial elec-tron transport (at complex I), causing rundown of the mitochondrial membranepotential and thus inhibiting the membrane potential driven uptake of calciuminto the mitochondria. The rise of mitochondrial free calcium concentration uponstimulation is almost completely blocked by the application of rotenone. At thesame time, the cytoplasmic calcium transient is lengthened. The effect of roten-one on the cytoplasmic calcium transient is unlikely to be due to depletion ofATP since ATP is continually applied through the patch pipette and oligomycinwhich blocks mitochondrial ATP synthesis has no effect on the calcium tran-sient. TPP, a drug which blocks the mitochondrial calcium uniporter withoutinhibiting ATP synthesis, has similar effects to rotenone, lengthening the cyto-plasmic calcium transient and blocking the rise in mitochondrial calcium. Theseresults suggest a role for mitochondrial calcium uptake in shaping the cytoplas-mic calcium transient in presynaptic terminals.

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Regulation of the Effects of Chronic Cocaine by CDK5

James A. Bibb1, Jingshan Chen2, Per Svenningsson1, Gretchen L. Snyder1, Zhen Yan3,Richard L. Huganir4, Angus C. Nairn1, Jane R. Taylor2, Eric J. Nestler5, PaulGreengard1

1Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, 1230York Avenue, New York, NY, U.S.A. 10021, 2Department of Psychiatry, YaleUniversity School of Medicine, New Haven, CT, U.S.A. 06520, 3Department ofPhysiology and Biophysics, School of Medicine and Biomedical Sciences, StateUniversity of New York at Buffalo, Buffalo, NY 14214, 4Department of Neuroscience,Howard Hughes Medical Institute, Johns Hopkins University School of Medicine,Baltimore, MD, USA 21205, 5Department of Psychiatry, University of TexasSouthwestern Medical Center, Dallas, TX, U.S.A. 75235

Cocaine addiction is accompanied by long-term molecular and cellular changesin the brain. Chronic cocaine exposure causes accumulation of the transcriptionfactor _FosB in dopaminoceptive neurons of the striatum. DNA array analysisof inducible transgenic mice was used to identify Cyclin-dependent kinase 5(CDK5) as a downstream target gene of _FosB. Moreover, _FosB over expres-sion or chronic cocaine administration raised CDK5 mRNA and protein levels.Intra-striatal injection of CDK5 inhibitors potentiated behavioral effects of re-peated cocaine administration. Chronic cocaine increased CDK5-dependent phos-phorylation of DARPP-32 (Dopamine and cyclic AMP-RegulatedPhospho-Protein, Mr 32 kDa), a critical modulator of D1-dopamine/PKA sig-naling in striatal neurons. These results suggest that _FosB-mediated changes inCDK5 levels, and resulting alterations in D1/PKA/DARPP-32 signaling, con-tribute to adaptive changes in the brain related to cocaine abuse.

Heme Oxygenase-2 Prevents Neuronal Apoptosis in Brain Culturesand Following Transient Cerebral Ischemia

Sylvain Dor , Johns Hopkins University/SOM, Dept Anesthesiology/Critical CareMedicine, Baltimore, MD

Heme oxygenase (HO) cleaves the heme ring to form biliverdin, which is rapidlyreduced to bilirubin, carbon monoxide, and iron. HO2 is constitutive and mosthighly concentrated in neural tissues. We demonstrated an association of amy-loid precursor proteins (APP) with HO which inhibits catalytic activity and aug-ments neurotoxicity in familiar Alzheimer s disease mutants. Bilirubin appearsto be a physiologic neuroprotectant. Activation of HO2 by phorbol esters, aug-ments production of bilirubin which protects brain cultures from oxidative stress.Bilirubin itself in low concentrations is neuroprotective, while HO2 deletion(HO2-/-) leads to increased neurotoxicity in brain cultures and increased neuraldamage following in vivo transient cerebral ischemia (1h-middle cerebral arteryocclusion followed by 23h-reperfusion). Mechanisms whereby HO2 providesneuroprotection have not been clarified including whether protection is prima-rily associated with apoptotic or necrotic cell death. Moreover, the generality of

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neurotoxic stimuli influenced by HO2 has been unclear. We now demonstrateincreased neuronal death in cerebellar granule cultures of HO2-/- mice with aselective augmentation of apoptotic death. We also demonstrate that cell linesoverexpressing HO2 are resistant to induced apoptotosis. In intact mice, we showan increased incidence of apoptotic morphology in the penumbra area surround-ing the infarct core in HO2-/- mice undergoing transient focal ischemia. In thepresent study, we have provided new evidence supporting earlier indications fora protective role for neuronal HO2. (Supported by the American Heart and StrokeAssociation).

The Neurotoxicity of Nitroxyl Anion: Peroxynitrite-initiatedSecondary Excitotoxicity

Sandra J. Hewett* and Tracy F. Uliasz. Dept. of Neuroscience, The University ofConnecticut Health Center, Farmington, CT 06030

Experimental evidence suggests that reactive nitrogen oxide species can contrib-ute significantly to cerebral ischemic injury. Recently, several in vitro studies havesuggested that nitroxyl anion (NO-), the one electron reduction product of nitricoxide (NO), can be formed by NO Synthase either directly or indirectly. Weinvestigated the neurotoxic potential of NO- using Angeli s salt (AS) as a sponta-neous NO- generating compound. When murine mixed cortical cell cultures wereexposed to increasing concentrations of AS (1-5 mM; 1 hr), there was a decreasein neuron survival that progressed markedly over the next 20-24 hr. Co-adminis-tration of AS (5 mM) with tempol (1 mM), a one electron oxidant that convertsNO- to NO, completely prevented the toxic effects of AS. As NO- can react withO2 to form peroxynitrite (OONO-), we next set out to determine if OONO- wasformed and responsible for the toxicity of AS. Dot Blot analysis of supernatantsremoved from cultures that had been exposed to AS (1-5 mM; 1 hr) revealed aconcentration-dependent increase in 3-nitrotyrosine-immunoreactivity, a foot-print of OONO-. Further, AS-induced neuronal damage was prevented in a con-centration-dependent manner by the concomitant addition of FeTPPS (25-100mM), an OONO- decomposition catalyst. Finally, addition of the glutamate re-ceptor antagonists, MK-801 (10 mM) and CNQX (30 mM), to the cultures pre-vented the delayed toxicity which occurred over the next 20-24 hr. Taken in toto,our data suggest that NO- neurotoxicity is initiated by OONO- and progressesvia secondary excitotoxicity. Supported in part by NINDS grant NS 36812 (SJH).

Rac1A Mediates the Production of Reactive Oxygen Species inMotor Neurons in Response to Proinflammatory Cytokines

M. V. Wright and T. B. Kuhn, Institute of Arctic Biology, University of AlaskaFairbanks

Reactive oxygen species (ROS) have emerged as mediators in the pathogenesisof numerous neurological disorders and recently, also in normal cellular signal-ing. Increasing evidence implicates the neuronal plasma membrane as an impor-tant source of ROS production, yet the underlying biochemical mechanismsremain poorly characterized. Many NAD(P)H-dependent plasma membrane oxi-

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doreductases (PMORs), some ligand-regulated, exist in various cell types includingchick central nervous system (CNS) neurons. Subjecting plasma membranes de-rived from chick motor neuron to non-denaturing gel electrophoresis followedby NBT reductase staining, we have obtained evidence for a rac1A-sensitiveNADH-dependent PMOR, which may help maintain the antioxidant capacityof the plasma membrane. Second, chick motor neurons contain an NADPH-dependent PMOR, which exhibits strong similarity to the well-documentedNADPH oxidase of neutrophils. Other reports suggest that this NADPH-depen-dent PMOR be regulated by rac1A analogous to the rac2-dependent regulationof the neutrophil NADPH-oxidase. Adenoviral-mediated expression of consti-tutively active (V12) rac1A in primary motor neurons significantly stimulatedROS production (1.67+0.06, p<0.01) compared to a normalized control (lacZ).Similarly, 100 ng/ml tumor necrosis factor _ (TNF__) or interleukin _ (Il-1__),key mediators of CNS inflammation associated with acute and chronic CNStrauma, increased ROS levels (1.25+0.05 and 1.3+0.06, respectively, p<0.01),which was negated upon expression of dominant negative (N17) rac1A. Anti-oxidants and the flavoprotein inhibitor diphenylene iodonium but not rotenoneall abolished ROS production mediated by V12rac1A, TNF_, or Il-1_ suggestingthe neuronal plasma membrane as the ROS source rather than mitochondria.Interestingly, actin filament reorganization accompanies both V12rac1A expres-sion and increases in intraneuronal ROS. Our data suggests that a rac1A-medi-ated generation of ROS in motor neurons constitutes a redox-signaling pathwaypossibly involved in redox homeostasis and cytoskeletal reorganization. Yet ab-errant function or overstimulation could result in oxidative damage to motorneurons as suggested by a significant increase in motor neuron cell death uponpersistent exposure to TNF_, or Il-1_. [Supported in part by NINDS/NIMH/NCRR and the Christopher Reeve Paralysis Foundation]

TAT-Facilitated Cell Entry of Peptide Nucleic Acid: A NovelAntisense Approach

Joseph A. Ludwig, M.D., Dept of Internal Medicine, Mayo Clinic Jacksonville

Peptide Nucleic Acids (PNAs) are DNA analogs that have potential to impedegene specific RNA polymerase II and ribosome elongation, thereby inhibitingtranscription and translation, respectively. Inhibition of at this DNA/RNA levelsubsequently reduces protein expression of targeted genes while leaving expres-sion of other genes unaffected. This is important because effective antisensetherapy may allow for suppression of pathogenic gene expression. In vivo effi-cacy of this antisense approach with unmodified PNAs has already been dem-onstrated in neurons. However, unmodified PNA treatment has several obstacles— PNAs are rapidly cleared in vivo and PNAs enter neurons poorly in vitro. It isproposed that these two obstacles can be overcome by covalently linking a car-rier peptide (TAT) to the utilized PNA. TAT is an eleven amino-acid carrierprotein that exists in nature as a subcomponent of the larger transactivating re-sponse element produced by the human immunodeficiency virus (HIV). Severalpublished reports demonstrate that TAT can facilitate transduction of large mol-ecules, previously impermeable, through the cell membrane of diverse cell types.

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We demonstrate the first report that TAT-PNA hybrids have the ability to enterrat neurons in vitro and in vivo. Administration of the TAT-PNA hybrid to neu-ronal cells in vitro and in vivo occurred through supplementation to standardcell culture media and a one-time intraperitoneal injection, respectively. TAT-mediated PNA cell entry offers one approach to increase PNA cell entry. Thistechnique for enhanced PNA uptake may improve antisense inhibition of patho-genic neuronal genes.

Dream Regulates Immediate Early Gene Expression in Neurons

Britt Mellstr m, Dpto. Biolog a Molecular y Celular Centro Nacional de Biotecnolog a.CSIC Madrid Spain

Induction of immediate early genes underlies short-term to long-term adapta-tion processes within the CNS in response to extracellular stimuli and is largelyinfluenced by variations in the level of cAMP and Ca2+ ions. We have recentlycharacterized the DREAM protein, the first known transcriptional repressor thatis regulated by changes in the concentration of the second messengers cAMPand Ca2+ (Carri n et al. Mol. Cell. Biol. 18:6921-6929, 1998; Nature 398:80-84,1999). Under basal conditions DREAM binds to the sequence-specific regula-tory element DRE and represses transcription of target genes including immedi-ate early genes c-fos, c-jun and ICERCREM. Upon neuronal stimulation,EF-hands present in the DREAM protein sense the rise in nuclear calcium in-ducing a conformational change of DREAM that results in unbinding from theDRE sequence and de-repression of the target gene. Moreover, de-repressionafter cAMP is cell-specific and depends on a direct protein-protein interactionbetween DREAM and aCREM (Ledo et al. Mol. Cell. Biol.Dec, 2000). To fur-ther understand the functional significance of DREAM as a transcriptional re-pressor of the immediate early response, we have prepared transgenic miceoverexpressing dominant negative mutants of DREAM in neurons by the use ofthe neuron-specific CaMKIIa promoter. Work funded by CAM and DGICYT,Spain.

The Ultrastructural Basis for Synaptic Transmission at LargeCalyceal Terminals in the Anteroventral Cochlear Nucleus

Madeleine J. Nicol, The Synaptic Structure and Function Group, The John CurtinSchool of Medical Research, The Australian National University, Australia

Auditory nerve fibers enter the mammalian brainstem and make large synaptic

contacts with bushy cells in the anteroventral cochlear nucleus. Over the pastseveral years, our laboratory has made an intensive electrophysiological investi-gation of the endbulb-bushy cell connection in rat brainstem slices. One of ourrecent studies (Oleskevich, S., Clements,J. and Walmsley, B., Journal of Physiol-ogy, 524(2), 513-523, 2000) has used variance-mean analysis to show that themean quantal release probability is high (approx. p = 0.6) at endbulb releasesites, and that there are many active release sites (in the order of several hun-dred). This study also showed that there are considerable differences between

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connections in the mean release probability and release during paired stimuli. Inthe present study we have performed serial section electron microscopy of endulbsof Held to provide insight into our electrophysiological observations. Serial sec-tion reconstructions of endbulbs revealed a large number (several hundred) ofseparate synaptic specializations within a single endbulb. A wide range of shapesand sizes was observed in the presynaptic active zones, and in the number ofmorphologically docked vesicles at these active zones. Large active zones usu-ally exhibited multiple distinct clusters of vesicles, suggesting that a single pr-esynaptic active zone may contain more than one functional release site.Differences between active zones in the number of docked vesicles, and in thenumber of vesicles immediately adjacent (<300 nm) to these active zones, mayprovide a structural basis for the observed variability in release probability andthe paired-pulse response at endbulb-bushy cell connections.

NMDA Receptor Phosphorylation Is Critical for Dopamine D1Receptor-Mediated CREB Phosphorylation and Gene Expression

A. Rajadhyaksha and C. Konradi. Laboratory of Neuroplasticity, McLean Hospitaland Harvard Medical School, Belmont, MA 02178

Dopaminergic neurotransmission is a major mechanism of striatal plasticity.Dopamine D1 receptors phosphorylate the cAMP response element binding pro-tein (CREB) at Ser133. CREB is involved in many biological processes, includ-ing synaptic plasticity, learning, and memory formation. In primary striatalcultures, we have examined the intracellular pathway that leads from D1 recep-tor activation at the membrane to Ser133 CREB phosphorylation and CRE-me-diated gene expression in the nucleus. We find that D1 receptors recruit theNMDA second messenger pathway through an intracellular mechanism. Pro-tein kinase A (PKA) activated by D1 receptors phosphorylates the NMDAR1(NR1) subunit of the NMDA receptor at Ser897 as seen with phosphorylationspecific antibodies. We will present work that examines the importance of NR1phosphorylation in the D1 pathway. Two approaches will be presented, trans-fecting phosphorylation site-specific mutants into primary striatal cultures usingthe calcium phosphate method and the use of the herpes simplex virus-1 (HSV-1) as a vector for gene delivery. HSV-1 infection allows stable expression of re-combinant proteins and provides a powerful technique to examine signaltransduction pathways in the brain.

Novel System A Transporters Mediating Na+:Glutamine/AlanineCotransport in Glutamatergic Neurons

Helene Varoqui, Bryan Mackenzie, Dongdong Yao, Matthias Hediger and Jeffrey D.Erickson, Neuroscience Center, LSUHSC, New Orleans, LA and the Membrane BiologyProgram and Renal Division, Brigham & Women s Hospital, Harvard Medical School,Boston, MA

cDNA clones encoding plasma membrane glutamine- and alanine-preferringtransporters (SAT1 and SAT2) have been isolated from glutamatergic neurons in

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culture and represent two novel members of the system A family of neutral aminoacid transporters. SAT1 mRNA and protein expression are abundant in the brain,compared to peripheral organs, and display a widespread distribution with en-richment on neurons that use glutamate as their neurotransmitter. SAT2 displaysa more widespread distribution and is expressed in most tissues, but in the brainit is also enriched on glutamatergic neurons. Both SAT1 and SAT2 are signifi-cantly upregulated during differentiation and depolarization of cerebellar gran-ule cells. Both isoforms are absent from astrocytes in primary culture. Thefunctional properties of SAT1 and SAT2, examined using transfected fibroblastsand in cRNA-injected voltage-clamped Xenopus oocytes, show that small ali-phatic neutral amino acids are preferred substrates, transport is voltage and Na+-dependent (1:1 stoichiometry), pH-sensitive and inhibited by alpha-(methylamino)isobutyric acid (MeAIB), a specific inhibitor of system A. Kineticanalyses of alanine, glutamine and MeAIB uptake by SAT1 and SAT2 are satu-rable, with Michaelis constants (Km) of 200-500µM. In addition to their ubiqui-tous roles as substrates for oxidative metabolism and major vehicles of nitrogentransport, SAT1 and SAT2 may provide glutamine and alanine to glutamatergicneurons to function as precursors for neurotransmitter synthesis.

Agonist Induced Trafficking of EGFP-Tagged Dopamine Receptors

Kim A.Neve, Tara A. Macey, and John N. Mason, Portland VA Medical Center

Desensitization of the dopamine D1receptor is thought to be due to phosphory-lation of the receptor by cyclic AMP-dependent protein kinase (PKA) and Gprotein-coupled receptor kinases (GRKs). We constructed an enhanced greenfluorescent protein (EGFP) tagged D1 receptor in which EGFP was fused to theC terminus of the D1 receptor, and we stably expressed the D1-EGFP fusionprotein in NS20Y neuroblastoma cells, a cell line that normally expresses a lowabundance of D1 receptors. The D1-EGFP receptor was indistinguishable fromthe wildtype D1 receptor in terms of affinity for several lagonists and antago-nists, stimulation of cyclic AMP accumulation, and agonist-induced desensiti-zation of cyclic AMP accumulation. D1-EGFP was phosphorylated when cellswere treated with dopamine, a reaction catalyzed by PKA, since it was preventedby the PKA inhibitor H-89. Fluorescence was primarily localized to the cellmembrane in NS20Y cells stably expressing the D1-EGFP receptor. Treatmentwith dopamine caused in increase in the ratio of intracellular-to-membrane fluo-rescence, due to the internalization of D1-EGFP in endocytotic vesicles, thatwas evident within 4 minutes and continued to increase for at least 20 minutes.Receptor internalization was prevented by inhibition of PKA. Mutant receptorswere constructed in which two potential sites of phosphorylation by PKA, Thr-268 and Ser-380, were converted to alanine. Mutation of Thr-268, but not Ser-380, prevented dopamine-induced phosphorylation and internalization of thereceptor. We conclude that phosphorylation of the D1 receptor on Thr-268 byPKA is a necessary step in dopamine-induced internalization of the D1 recep-tor. An EGFP-tagged D2 receptor has also been constructed, and the subcellularlocalization and agonist-induced internalization of this receptor will be described.(Supported by MH45372, MH12435, and VA Merit Review)

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AMPA Receptor Trafficking in Nucleus Accumbens Neurons

M.E. Wolf, S.Z. Chao, D.A. Peterson

While dopamine (DA) receptors mediate acute effects of amphetamine and co-caine, neuroadaptations produced by chronic drug administration requireglutamate transmission and are associated with changes in glutamate receptorfunction. We have therefore hypothesized that addiction is a maladaptive formof neuroplasticity that may involve cellular mechanisms similar to those impli-cated in LTP and LTD. Very recently, it has been shown that AMPA receptortrafficking is a regulated process that plays an important role in LTP and LTD.We are interested in the possibility that chronic DA receptor over-stimulation(e.g., during repeated cocaine or amphetamine treatment) might influence AMPAreceptor trafficking and thereby produce changes in synaptic strength in addic-tion-related neuronal circuits. Nucleus accumbens neurons play a critical role inaddiction and receive convergent DA and glutamate inputs. We have thereforedeveloped postnatal rat nucleus accumbens cultures as a model system to studyinteractions between DA and glutamate receptors. The present study examinedthe effect of D1 and glutamate receptor stimulation on surface expression of theAMPA receptor subunit GluR1 using fluorescence and confocal microscopy.Surface GluR1 was labeled by incubating live cultures with antibody recogniz-ing the extracellular portion of GluR1. Cultures were then fixed and incubatedwith fluorescent secondary antibody. Surface GluR1 labeling on neuronal pro-cesses was enhanced by D1 receptor stimulation and decreased by glutamatereceptor stimulation. These results suggest that AMPA receptors on nucleusaccumbens neurons may be subject to dynamic regulation in response to changesin the activity of DA and glutamate inputs. This may be important for triggeringmore enduring adaptations related to addiction. Support: DA09621, DA00453,DA13006, NARSAD (MEW); DA06024 (SZC); Alzheimer s Association (DAP).

Molecular Mechanisms and Modulation of Glial Activation: LigandModulation of Biological Responses Mediated by Gene-RegulatingProtein Kinases

D.M. Watterson, A.R. Sawkar, L. Guo, S. Mirzoeva, A. Velentza, T.J. Lukas, T.Koppal, M. Hibert, J.-J. Bourguignon, , J. Haiech and L.J. Van Eldik.Drug DiscoveryProgram and Northwestern University Medical School, Chicago, IL, and IFRG.Laustriat, Facult de Pharmacie, ILLKIRCH, France

Neuroinflammation in the CNS is a process that results primarily from an ab-normally high level or chronic activation of glial cells (astrocytes and microglia).Activation of glial cells leads to induction of pro-inflammatory cytokines likeinterleukin-1_ (IL-1_) and tumor necrosis factor-_ (TNF_), and oxidative stress-related enzymes like inducible nitric oxide synthase (iNOS) which generates ni-tric oxide (NO) and NO-derived neurotoxic species like peroxynitrite. Whiletransient glial activation is beneficial for brain repairing processes, a chronic re-active state or an abnormally high proportion of activated glia may lead to neu-rotoxicity through propagation of inflammation and oxidative stress. Increasingbasic science and clinical evidence suggests that neuroinflammation is a con-

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tributor to pathology in neurodegenerative disorders, and that suppressing in-flammatory responses may be beneficial in terms of slowing progression of dis-ease. Therefore, elucidation of key signal transduction pathways and geneexpression changes in activated glia is important to provide insight into mecha-nisms for down-regulation of these detrimental responses. In this regard, ourprevious investigations (Brain Res 1999, 844:126) found that certain anti-inflam-matory drugs and cell permeable kinase inhibitors could block iNOS inductionin a microglial cell line, possibly through the inhibition of calmodulin proteinkinase (CaMK) activity, and gene-regulating serine/threonine protein kinaseshave been demonstrated to be viable drug discovery targets in the regulation ofsome non-CNS inflammatory disorders (Drug Discovery Today 1999, 4:472).Therefore, we have initiated the discovery of new classes of cell-permeable ligandsthat are potential small molecule inhibitors of gene regulating CaMKs in orderto explore the feasibility of this approach toward selective modulation ofneuroinflammatory responses. We report here progress on exploring the role ofCaMKs in mediating iNOS and IL-1_ induction in activated astrocytes and mi-croglia stimulated with cytokines, lipopolysaccharide, or beta-amyloid peptide,and the development of new classes of cell-permeable protein kinase inhibitorscapable of downregulating iNOS and IL-1_ induction in response to glial acti-vating stimuli. Our results suggest roles for CaMKs in glial activation pathwaysthat are independent of, and potentially complementary to, NF_B- mediatedmechanisms. Current investigations using small molecule mimetics of peptideinhibitors (J.Med.Chem. 1999, 42:910; FASEB J. 2000, 14:306) and chemicalscaffolds from smar t chemical libraries, designed with pharmacological andtoxicological considerations, indicate that these new classes of compounds mightbe useful starting points for development of ligands capable of selectively modu-lating glial inflammatory responses and their neurotoxic consequences.

Neuronal/Glial Nitrogen Shuttling during Glutamate Synthesis inRetina Depends upon BCAT Enzymes

Charles P Taylor, Kathryn F LaNoue, Neuroscience and Anatomy, Pennsylvania StateUniv. College Med., Erich Lieth, SolOrganics, Susan M Hutson, Dept. Biochemistry,Wake Forest Univ.

The glutamate/glutamine shuttle between neurons and glial cells has been stud-ied for about 30 years and is widely accepted as the major pathway for the recy-cling of glutamate in neuronal tissues. However, the de-novo iformation ofglutamate in neuronal tissues is less clearly understood. The acutely isolated ratretina is a good system to study glutamate metabolism in vitro, because it is ananatomically normal neuronal/glial tissue with little acute injury. In isolatedretinas, measurement of new synthesis of 14C-glutamate and 14C-glutaminefrom H14CO3- showed that amino acid synthesis increased 70% when mediumpyruvate was increased from 0.2 to 5 mM. With addition of gabapentin (a weakbut specific inhibitor of branched-chain aminotransferase-C [BCATc]), new syn-

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thesis of 14C-glutamate and 14C-glutamine from H14CO3- was reduced by 31%.Furthermore, the oxidation of glutamate was increased by gabapentin treatment.These and additional results suggest that metabolism of pyruvate and subse-quent transamination of alpha-ketoglutarate to glutamate in glial cells (byBCATm) is rate limiting for de novo glutamine synthesis. They also suggest thatselective inhibition of BCATc causes an increased rate of glutamate degrada-tion. Furthermore, branched-chain amino acids are an obligatory nitrogen sourcefor de novo glutamate formation. A scheme relating the exchange of branched-chain amino acids for branched-chain ketoacids (mediated by BCAT isoenzymes,and existing in parallel to the glutamine/glutamate cycle) is described.

Modeling Huntington’s Disease in a Dish: Expression of ExpandedPolyglutamine Huntington Rapidly Kills Neuronal (PC12) but NotAstrocytic Cells in Culture

Erik S. Schweitzer, Brain Research Institute, UCLA

We have generated stable PC12 cell lines that express exon 1 of huntingtin (Htt)containing either wild type (Q25) or expanded polyglutamine (Q103) tract, fusedto enhanced green fluorescent protein (EGFP). We have placed these constructsin a plasmid containing the Bombyx mori ecdysone-responsive element, suchthat expression of the huntingtin protein is dependent on the presence of anecdysone analog, tebufenozide. We have also generated parallel Htt-expressingcells from a conditionally-immortalized astrocytic cell line, BAS8.1. In the ab-sence of tebufenozide, the engineered PC12 cells grow normally and respondnormally to NGF by exiting the cell cycle and differentiating morphologically.They express low-to-undetectable levels of the Htt transgene.

When tebufenozide is added to the culture medium of cells engineered to ex-press HttQ25, there is a rapid accumulation of Htt that reaches steady-state within24 hrs. Subsequent removal of the tebufenozide results in a return to baselinelevels of Htt within 48 hrs. This removal of HttQ25 after removal of tebufenozideis completely blocked by proteasome inhibitors, indicating that proteasomes aresolely responsible for the turnover of Htt. Direct fluorescence microscopy indi-cates that the HttQ25 is diffusely distributed throughout the cytoplasm, and isrelatively excluded from the nucleus. Adding tebufenozide to cells carrying theHttQ103 construct leads initially to a diffuse cytoplasmic distribution of HttQ103,similar to HttQ25. However, this diffuse distribution rapidly is replaced by thepresence of an intensely fluorescent perinuclear aggregate of HttQ103, reminis-cent of the intraneuronal aggregates seen in the brains of patients withHuntington s disease.

Within a day or two, virtually all PC12 cells expressing HttQ103 die. We do notsee this same toxic effect with either PC12 cells expressing HttQ25 or BAS8.1cells expressing HttQ103. We have therefore replicated the selective neurotoxic-ity that is one of the hallmarks of Huntington s Disease in patients.

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Volume-Actvated Cl– Currents Contribute to the Invasive Migrationof Human Glioma Cells

C.B. RANSOM1, J.T. O NEAL2*, AND H. SONTHEIMER1,2 1Dept. ofNeurobiology, Univ. of Alabama School of Medicine; 2Transmolecular Inc.,Birmingham, AL 35294

The vast majority of primary neoplasms in human CNS derive from glial cells.These tumors have a poor prognosis due to their invasive migration that renderssurgical treatment untenable. Ion channels may contribute to this behavior byinfluencing salt and water movements between intracellular and extracellularcompartments during shape and volume changes associated with migrationthrough brain tissue. We used patch-clamp techniques and a transwell migrationassay to examine the contribution of volume-activated Cl- channels to the inva-sive migration of human glioma cells from established lines (STTG-1, D54MG).Whole-cell currents evoked by cell swelling with hypotonic solutions were Cl-

selective and were sensitive to the Cl- channel blocker NPPB. The IC50 for cur-rent inhibition by NPPB was »20 mM and near complete block (>90%) was ob-tained at 100 mM. In addition, the resting conductance of glioma cells wasdominated by basal activation of these volume-activated Cl- currents, even innon-dialyzed cells (amphotericin perforated-patches). Migration of glioma cellsin our transwell migration assay (8 mm pores) was extracellular matrix-depen-dent and was sensitive to NPPB. Inhibition of cell migration had a similar con-centration-dependence as NPPB inhibition of volume-activated Cl- currents.These results suggest that volume-activated Cl- currents are activated during, andcontribute to, shape changes associated with glioma cell migration through nar-row spaces, such as would be encountered in the tortuous extracellular space ofbrain. This work was supported by RO1 NS36692.

Poster Session 2 • Tuesday/Wednesday SunshinePosters will be available for viewing from 3:30 PM Tuesday to 4:30 PM Wednes-day. Presenters will be with the posters on Tuesday from 3:30 to 4:30 PM

Alpha 2C-Adrenoceptors Modulate Striatal NeurotransmitterRelease and May Be Promiscuously Activated by Dopamine

G.A. Ordway and W. Zhang, Dept of Psychiatry and Human Behavior, University ofMississippi

The striatum has a high density of alpha 2C-adrenoceptors (alpha 2C-AR) rela-tive to other brain regions. However, the physiological significance of the striatalalpha 2C-AR is unknown. In our studies, a combination of molecular and phar-macological methods have been used to characterize the role of the alpha 2C-AR in striatal functions. To evaluate receptor function, mice with a targetedinactivation of the alpha 2C-AR gene (Adra2c-/-; KO mice) and genetically-related control mice expressing the wild-type 2C-AR (Adra2c+/+; WT mice)

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were used. In addition, normal rat kidney (NRK) cells transfected with mousealpha 2A-AR or ?2C-AR cDNA (NRK- alpha 2A or NRK- alpha 2C cells) wereused to evaluate receptor affinities and functions. The alpha 2-AR antagonist,RX821002, enhanced forskolin-stimulated cyclic AMP accumulation in striatalslices from WT mice. In contrast, RX821002 did not produce this effect in stri-atal slices from KO mice or from monoamine-depleted WT mice. RX821002increased electrically-stimulated [3H]acetylcholine release and reduced[3H]GABA release in striatal slices from WT mice, but these effects were absentin striatal slices from KO mice or from monoamine-depleted WT mice. RX821002had no effect on [3H]dopamine release in striatal slices from WT mice. Giventhe paucity of noradrenergic innervation of the striatum, we considered thatdopamine might act as an agonist at the striatal alpha 2C-AR. Dopamine inhib-ited forskolin-stimulated cyclic AMP accumulation in intact NRK- alpha 2Aand NRK- alpha 2C cells, effects that were antagonized by RX821002. The affin-ity of dopamine for the mouse alpha 2C-AR in NRK- alpha 2C cells, determinedin homogenate binding assays, was higher than the affinity of norepinephrinefor the mouse alpha 2A-AR in NRK- alpha 2A cells. Together, these findingsdemonstrate that activation of the alpha 2C-AR regulates neurotransmitter re-lease in the mouse striatum, possibly by inhibiting adenylyl cyclase. Further-more, dopamine may be an endogenous activator of the striatal alpha2C-adrenoceptor.

Dopamine Modulates Long-Term Depression in the MesolimbicSystem

Mark J. Thomas§, Robert C. Malenka§ and Antonello Bonci*, § Nancy PritzkerLaboratory, Department of Psychiatry and Behavioral Sciences, Stanford UniversitySchool of Medicine, Palo Alto, California 94134, USA, * Ernest Gallo Clinic andResearch Center, Department of Neurology, University, of California, San Francisco,California 94110, USA

Long-lasting adaptations in the mesolimbic dopamine (DA) system in responseto drugs of abuse appear to be crucial in mediating many of the behavioral changesthat underlie drug addiction. Long-term changes in synaptic plasticity at excita-tory synapses in the two major components of this system, the nucleus accumbens(NAc) and ventral tegmental area (VTA), may be particularly important for thedevelopment of drug-related behaviors such as behavioral sensitization, as wellas for normal response-reinforcement learning. Using whole-cell patch-clamprecording techniques from in vitro slice preparations, we have examined the ex-istence and basic mechanisms of long-term depression (LTD) at excitatory syn-apses on both GABAergic medium spiny neurons in the NAc and dopaminergicneurons in the VTA of C57 mice. Our results indicate that both sets of synapsesexpress LTD, but that their basic triggering mechanisms differ. Furthermore, DAblocks the induction of LTD in the VTA via activation of D2-like receptors buthas minimal effects on LTD in the NAc. The existence of LTD in mesolimbicstructures and its modulation by DA represent mechanisms that may contributeto the modifications of neural circuitry that mediate reward-related learning aswell as the development of addiction.

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Postinhibitory Rebound Firing in Vestibular Nucleus Neurons AltersFiring Dynamics

Chris Sekirnjak and Sascha du Lac, The Salk Institute for Biological Studies, 10010 NTorrey Pines Rd, La Jolla, CA 92037

Vestibular nucleus neurons encode information about head movements in modu-lations of firing rate. The transformation of incoming spike trains to output fir-ing is governed by both the nature of the input signals and intrinsic cellularproperties. Here we attempt to link a cellular phenomenon, postinhibitory re-bound firing (PRF), to the in vivo firing behavior of medial vestibular nucleus(MVN) neurons and show how this intrinsic membrane property can accountfor aspects of signal processing dynamics that have previously been thought toarise purely from network connectivity. A subset of MVN neurons in mousebrainstem slices respond to brief periods of membrane hyperpolarization with astrong transient increase in firing rate (up to 70 spikes/s), lasting several seconds.PRF could be evoked either with inhibitory synaptic stimulation or with intrac-ellular current injection and depended strongly on hyperpolarization amplitudeand duration. From studying MVN cells at physiological firing rates we con-clude that many cells routinely experience PRF under normal conditions in theliving animal. Contributions from three currents underlying PRF were identi-fied: the cesium-sensitive H-current, a calcium current blocked by cadmium, anda TTX-sensitive Na-current. We compared the neuronal response to simulatedhead movements (sinusoidal intracellular current injection) in different MVNcell types and found that neurons with pronounced PRF displayed an averagephase lead of about 10 degrees compared to low-PRF cells. A similar phase dif-ference between functionally distinct MVN neurons has been reported in vivo.This phase advance could aid in overcoming phase lags introduced by the oculo-motor plant and sharpen the time-varying motor output of the vestibulo-ocularsystem. The phase of the premotor signal would hence be regulated by bothintrinsic and network factors.

A 5-HT6 Receptor Antagonist Facilitates an Amphetamine-InducedIncrease in Frontal Cortical Dopamine

K. J. Frantz, D. G. Stouffer, I. Polis, L. H. Parsons. Department ofNeuropharmacology, The Scripps Research Institute, 10550 N. Torrey Pines Rd. LaJolla, CA 92037

Serotonin6 receptors are localized in high density in limbic and motor brainregions, and are occupied readily by several atypical antipsychotic agents. Thesecharacteristics suggest that 5-HT6 receptors may be involved in reward-relatedbehaviors and motor activity. In previous experiments from our laboratory, anovel 5-HT6 receptor antagonist (SB 258510A) potentiated the locomotor ef-fects of amphetamine. It also altered lever-pressing maintained by amphetamineon both fixed- and progressive-ratio schedules of reinforcement, in a manner

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suggestive of an enhancement of the reinforcing efficacy of amphetamine. In thepresent study, dual-probe microdialysis was employed to investigate possiblemesocorticolimbic mechanisms that could mediate these effects in male Wistarrats. A 3 mm probe in the frontal cortex revealed that 5-HT6 receptor blockadefacilitated an increase in dopamine induced by peripherally-administered am-phetamine. A 2 mm probe in the nucleus accumbens showed a much less robustfacilitation of the amphetamine-induced increase in dopamine. This study pointsto the frontal cortex as an important locus where 5-HT6 receptor activation mayserve to limit the stimulant and reinforcing effects of amphetamine. Recent lit-erature indicates that glutamate and acetylcholine neurotransmission may alsobe involved in this regulatory role of 5-HT6 receptors. Supported by NIDA:DA11004 (LHP) and DA05950-02 (KJF).

A Novel nNOS Knockout Mouse Lacking the Heme-BindingDomain Exhibits Preserved Brain Morphology, Infertility andSevere Pyloric Stenosis

Robert Gyurko, Sonal Jhaveri* and Paul L. Huang, Cardiovascular Research Center,Massachusetts General Hospital, Boston, MA and *Department of Brain and CognitiveSciences, MIT, Cambridge, MA

The first nNOS knockout mice (KN1) lacking exon 2 show residual nNOS activ-ity in the brain due to the presence of beta and gamma splice variants. Here wereport the deletion of the heme-binding domain (exon 6) of the nNOS gene us-ing Cre-Lox recombination system in embryonic stem cells (KN2). RT-PCR onbrain RNA reveals residual nNOS transcripts in both KN1 and KN2 mice. How-ever, the absence of the heme-binding domain should result in complete inacti-vation of the nNOS protein even in the presence of alternatively spliced mRNAs.Heterozygote KN2 offsprings are viable, fertile, and undistinguishable from wildtype littermates. Homozygote KN2 mutants are viable, but infertile. Mountingbehavior is absent when either male or female KN2 s are paired with wild-typemice of the opposite sex. Histological examination reveals the absence of corpusluteum in the ovaries, and the presence of immature sperm cells in the epididy-mis. In the central nervous system, the gonadotrophs of the pituitary are intact,as evidenced by LH immunostaining. The macroscopic and microscopic struc-ture of the brain, spinal cord, pituitary and dorsal root ganglia appear to be pre-served. The barrel-field cortex is intact at 15 days ofage, as evidenced by cytochrome c oxidase staining. Inthe enteric nervous system, KN2 appears to have a moreprofound defect in pyloric relaxation than KN1, resultingin enlarged stomachs in all KN2 s, as well as individualcases of acute complete functional pyloric blockade, re-sulting in rapid dehydration and death. In the absence of pyloric blockade, how-ever, KN2 are not starved, as evidenced by the absence of ketones in the serum,and the presence of abdominal fat. These data indicate that normal neural devel-opment is possible in the complete absence of nNOS, but the hypothalamic-pituitary-gonadal axis in both sexes requires nNOS for normal reproductivefunction.

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Proteasome Involvement in Agonist-induced Down Regulation ofMu and Delta Opioid Receptors

Richard D. Howells, Kirti Chaturvedi, Persis Bandari, Norihiro Chinen, Departmentof Biochemistry and Molecular Biology, University of Medicine and Dentistry of NewJersey-New Jersey Medical School, Newark, NJ 07103

This study investigated the mechanism of agonist-induced opioid receptor downregulation. Incubation of HEK 293 cells expressing FLAG-tagged delta and mureceptors with agonists caused a time-dependent decrease in opioid receptor lev-els assayed by immunoblotting. Pulse-chase experiments using [35S]methioninemetabolic labeling indicated that the turnover rate of delta receptors was acceler-ated 5-fold by agonist treatment. Inactivation of functional Gi and Go proteinsby pertussis toxin attenuated down regulation of the mu receptor, while downregulation of the delta receptor was unaffected. Pretreatment of cells with in-hibitors of lysosomal proteases, calpain, and caspases had little effect on mu anddelta receptor down-regulation. In marked contrast, pretreatment with proteasomeinhibitors attenuated agonist-induced mu and delta receptor down regulation. Inaddition, incubation of cells with proteasome inhibitors in the absence of ago-nists increased basal mu and delta receptor levels. Immunoprecipitation of muand delta opioid receptors followed by immunoblotting with ubiquitin antibod-ies suggested that preincubation with proteasome inhibitors promoted accumu-lation of polyubiquitinated receptors. These data provide evidence that theubiquitin/proteasome pathway plays a role in agonist-induced down regulationand basal turnover of opioid receptors. Supported by NIDA grant 09113.

Light Induced Potentiation of NMDA Receptors Enhanced byProtein Kinase Inhibition

Daniel Leszkiewicz, BethAnn McLaughlin, Karl Kandler and Elias Aizenman, Dept ofNeurobiology, University of Pittsburgh

We have previously reported that certain ligand-gated ion channels in rat corticaland retinal neurons can be modulated by light. Both NMDA and GABA recep-tor-mediated currents are rapidly potentiated in response to brief focal light pulses,while non-NMDA receptors are unresponsive to light stimuli (Leszkiewicz et al.J. Physiol 524:365, 2000; Soc Neurosci Abstr 2000). In order to elucidate themolecular mechanism behind the light induced potentiation, we have utilizedvarious phosphatase and protein kinase inhibitors. NMDA-mediated whole-cellresponses in cortical neurons were measured both before and after a brief focallight pulse (0.5—1 s) directed at the cell body and proximal dendrites via an opti-cal fiber (50 (m). Light-induced potentiation of NMDA-induced currents wassignificantly greater in the presence of 40 (M K252c, a PKA/PKC inhibitor (111.5% ( 19.3 enhancement, n=9), when compared to control (23.8 % ( 3.6, n=9). Incontrast, vanadate (1 mM), a phosphatase inhibitor, had no effect on the light-induced potentiation of NMDA-mediated responses (19.5 % ( 4.0, n=12). These

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results suggest that the light sensitive moiety may be closely related to proteinphosphorylation sites on the NMDA receptor. Future research will characterizethe modulation site using more specific protein kinase inhibitors, investigatingthe enhancement of GABA-mediated responses, and site-directed mutagenesisof recombinant receptors. Studying the modulation of NMDA receptors by lightwill further our understanding of the structure and function of the ion-channeland closely related structures.

Do Hebbian Pairing Protocols Alter the Release-dependence of Short-term Synaptic Depression?

Murat Okatan and Michael Cohen, Department of Cognitive and Neural Systems andCenter for Adaptive Systems, Boston University, 677 Beacon St., Boston, MA 02215

Short-term synaptic depression (STD) refers to a decrease in excitatory postsyn-aptic potential amplitude during repetitive stimulation. The exact biophysicalmechanisms that underlie STD in cortical synapses are not known. RecentlyMatveev & Wang (J. Neurosci., 20, 4, p1575, 2000) suggested that release prob-ability in cortical synapses is too low to deplete the releasable pool to the extentthat would explain the experimentally observed levels of STD (Markram &Tsodyks, 1996, Nature,382, p807). Using a stochastic synapse model, Matveev& Wang proposed that inactivation of release machinery (IRM) may be the ma-jor source of STD in synapses that couple cortical pyramidal neurons. In theirimplementation IRM was release-independent. Evidence suggests, however, thatSTD is release-dependent in these synapses (Thomson & Bannister, 1999, J.Phsyiol, 519.1, 57). To further investigate the mechanisms underlying STD, wedeveloped an expanded stochastic synapse model that includes postsynaptic re-ceptor desensitization (Jonas et al., 1994, Neuron, 12,p1281), the number ofsynaptic contacts per axon, and implements IRM in release-dependent (a) andindependent (b) scenarios. Using the model we fitted the pre- and post-Hebbian-pairing STD data of Markram & Tsodyks. The model predicted that IRM, andnot depletion or desensitization, might be the main cause of STD. Moreover, itsuggested that Hebbian pairing protocols alter the release-dependence of IRM:Pre-pairing STD data were fitted in scenarios (a) and (b) with comparable qual-ity, while the fit to post-pairing data was much better in scenario (b) than (a). Wenote that the experiments of Thomson and Bannister were conducted on neu-rons that were not subjected to a Hebbian pairing protocol. Thus, our results fillthe gap between their results and those of Matveev and Wang by predicting thatHebbian pairing protocols may convert STD from being release-dependent innormal conditions to being release-independent after Hebbian pairing protocols,possibly by altering the sensitivity of the protein synaptotagmin that acts as thecalcium sensor of the release machinery. These results raise the question ofwhether synaptic changes that are induced by artificial Hebbian pairing proto-cols are good approximations to naturally occurring synaptic plasticity. Supportedby: Defense Advanced Research Projects Agency and the Office of Naval Re-search (ONR N00014-95-1-0409) and the Office of Naval Research (ONRN00014-95-1-0657).

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Acute Sensitization to Cocaine after Single Injection of OrphaninFQ/Nociceptin into the Ventral Tegmental Area

Shridhar Narayanan, Kabirullah Lutfy and Nigel Maidment. Department ofPsychiatry and Biobehavioral Sciences, UCLA School of Medicine, Los Angeles, CA90024.

Orphanin FQ (OFQ), an endogenous neuropeptide with structural homology todynorphin, has been shown to modulate dopaminergic mechanisms in themesolimbic system. Administration of OFQ into the ventral tegmental area (VTA)produces hypolocomotion and also blocks the acute and sensitized motor effectsof cocaine. However, repeated administration of orphanin FQ into the VTAresults in a sensitized locomotor response to cocaine. The aim of the presentstudy was to examine the potential for OFQ to produce a sensitized locomotorresponse to cocaine after a single intra-cerebral administration and to identifythe locus of such an action. The bilateral administration of OFQ (30 mg/side)into the VTA on day 1 to male Sprague-Dawley rats resulted in an enhancedlocomotor response to cocaine (10 mg/kg i.p) administered on day 2. This sensi-tization was short-lived and was not evident 7 days after the administration ofOFQ. OFQ (3, 10 and 30 mg/side) administered on day 2, 5 mins prior to theadministration of cocaine (10 mg/kg i.p) blocked the sensitized locomotor re-sponse, suggesting that there was no tolerance to the effect of OFQ. The admin-istration of OFQ into the substantia nigra or the nucleus accumbens did notproduce a sensitized response to a cocaine challenge. These results demonstratethe ability of a single administration of OFQ to produce short-term changes inthe mesolimbic dopaminergic system that is specific to the VTA.

Phosphorylation Regulates Cellulr Gain in Medial VestubularNucleus Neurons

A. Nelson, Neurosciences Program, University of California-San Diego, La Jolla CA

The vestibulo-ocular reflex (VOR) maintains visual acuity during head motionby transforming vestibular inputs into eye movement outputs. Sensory-motorlearning produces adaptive changes in VOR gain (the ratio of eye and head move-ment) when image motion occurs persistently during head movement. As a sitefor integration of primary vestibular information and visual feedback, the me-dial vestibular nucleus (MVN) plays a role in plasticity of the VOR. MVN neu-rons demonstrate an extremely linear relationship between their inputs (synapticor injected current) and output (firing rate). This cellular gain may be modulatedduring sensory-motor learning to generate behavioral gain changes. This studyinvestigated protein phosphorylation as a candidate mechanisms for cellular gaincontrol in the MVN. Whole-cell patch clamp recordings from MVN neurons inrat brainstem slices showed that cellular gain is increased in the presence ofATPgammaS, a non-hydrolyzable analog of ATP. ATPgammaS also reducedthe range of firing rates attainable by MVN neurons. It has previously been shownthat one of the primary determinants of MVN gain is the small-conductancecalcium-dependent potassium (SK) channel, which regulates the interspike in-

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terval in many cell types. Phosphorylation may be acting at the SK or otherchannels to modify firing properties. These findings suggest that phosphoryla-tion may play a role in adaptive modulation of the VOR.

Group Ii Metabotropic Glutamate Receptors Suppress Basal and5-HT2a/2c-Induced C-fos Expression and Excitatory Responses in thePrefrontal Cortex

Laura K. Nisenbaum, Eric S. Nisenbaum and Michael P. Johnson Eli Lilly andCompany, Indianapolis, IN 46285

A common feature of psychotomimetic drugs, including PCP and DOI (a 5-HT2a/2c agonist), is their ability to increase glutamate release in the prefrontalcortex (PFC). Group II metabotropic glutamate receptors (mGluR 2/3) are knownto reduce glutamate release. Previous electrophysiological studies have shownthat mGluR 2/3 agonists suppress DOI-induced glutamate release. We exam-ined the ability of the mGluR 2/3 agonist, LY 379268, to reduce basal and DOI-induced EPSPs and c-fos mRNA expression in the PFC. Consistent with previousstudies, application of DOI (3 mM) enhanced electrically-evoked EPSPs in PFCpyramidal neurons in a slice preparation. Subsequent application of LY379268(0.01 — 1.0 mM) suppressed the enhanced response in a concentration dependentmanner. This effect was blocked by the mGluR 2/3 antagonist LY341495 (1mM). Furthermore, application of LY379268 reduced EPSPs in the absence ofDOI. To examine the functional consequences of mGluR2/3 receptor activa-tion, we measured the effect of LY379268 on c-fos mRNA levels. Administrationof DOI (12 mg/kg, i.p.) produced a significant increase in c-fos mRNA expres-sion in the PFC. Pretreatment with LY379268 (15 mg/kg, i.p.) blocked the DOI-induced enhancement. Furthermore, administration of LY379268 alonesignificantly decreased c-fos mRNA expression relative to control. Together, thesedata demonstrate that group II metabotropic glutamate receptors reduce bothglutamate release as well as c-fos mRNA levels in the PFC. This study providessupport for the potential therapeutic efficacy of mGluR 2/3 agonists asantipsychotics.

Calcium Transients in Higher Order Dendrites of Striatal Neuronsduring Spontaneous “Up” States

J. N. D. Kerr*, and D. Plenz. Unit of Neural Network Physiol., LSN, NIMH, NIH,Bethesda, MD 20892

Most cortical regions project to the striatum, the major input structure of thebasal ganglia. The corticostriatal axons predominantly contact spiny dendritesof striatal projection neurons. Finding the rules that govern the plasticity at thesecorticostriatal synapses will be necessary in order to understand how the stria-tum evaluates cortical activity. Upon synchronized cortical inputs, striatal pro-jection neurons display a fast transition from rest (-90 mV; Down state) to astable, subthreshold membrane potential region (-60 mV, Up state) during whichspiking is tightly controlled. As intracellular calcium levels are important forsynaptic plasticity, we examined the relationship between Up states, dendritic

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calcium transients and somatic spiking in striatal projection neurons. Spontane-ous striatal activity was analyzed using calcium imaging combined with wholecell patch recording in cortex-striatum-substantia nigra organotypic cultures grownfor 5 6 w eeks. Single, spontaneous Up states were detected and changes in intra-cellular calcium levels were measured at time resolutions of 20 and 40 ms. Over-all, calcium transients followed the time course of the membrane potential duringDown and Up states. Monitoring up to 60 striatal neurons simultaneously re-vealed that large calcium transients in single neurons indicate an overall activa-tion of the striatal network. Furthermore, in single neurons, sharp calciumtransients at soma and higher order dendrites were correlated with spontaneousaction potentials. Finally, action potentials evoked by current injection at thesoma elicited sharp calcium transients throughout the neuron, whereas subthresh-old membrane depolarizations did not. We suggest that spatially heterogeneouscalcium levels indicate local corticostriatal processing in striatal dendrites that islinked to firing success at the soma through back propagated calcium signals.

Correlated Multisecond Oscillations in Globus Pallidus Spiking andEEG Theta Rhythm: Prominent Effects of Apomorphine afterNigrostriatal Lesion

David N Ruskin , Debra A Bergstrom, Lauren E Freeman, Patrick L Tierney, Judith RWalters, Experimental Theurapeutics Branch, NINDS, NIH

Multisecond oscillations in firing rate with periods of 2 to 60 s are present in~75% of globus pallidus neurons in awake rats, and are modulated by dopamineagonists [1]. To further explore the modulatory role of dopamine, and to assessthe relationship of these subcortical oscillations to cerebral cortical activity, theeffects of apomorphine on these globus pallidus spiking oscil- lations were ex-amined with extracellular single unit recording in the globus pallidus during si-multaneous EEG recording. Unilateral nigrostriatal dopamine neuron lesionswere made by 6-hydroxydopamine infusion under chloral hydrate anesthesia (400mg/kg, i.p.). Recording were performed several weeks after lesion. Because gen-eral anesthesia greatly attenuates dopamine responsiveness of basal ganglia neu-rons, recordings were performed in rats immobilized with gallamine and locallytreated at surgical sites with injected (carbocaine s.c.) and topical (lidocaine) an-esthetics. Multisecond oscillations in globus pal- lidus firing rate often coincidedwith bursts of 4-7 Hz EEG rhythm: correla- tions between firing rate oscillationsand theta rhythm bursts were found in ~40% of recordings in baseline in intactrats. In nigrostriatal-lesioned rats, a low dose of apomorphine (0.05 mg/kg, i.v.)significantly decreased the frequency (from 20 s to 10 s) and increased the strength(89%) of globus pal- lidus firing rate oscillations. Apomorphine also significantlyincreased the correlation of slow activity between globus pallidus spiking andEEG theta power (to 91%). These effects were reversed by haloperidol (0.2 mg/kg, i.v.). Although the multisecond pattern of theta rhythm power was altered,apomorphine did not change the dominant frequency or the total power withinthe theta band. In intact animals, this low dose of apomorphine did not signifi-cantly alter any of these measures. However, as previously reported, a largerdose (0.32 mg/kg i.v.) increased the frequency and strength of multisecond oscil-

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lations in the globus pallidus and other basal ganglia nuclei in intact animals [1].The data show that the activity in basal ganglia-thalamocortical networks can besyn- chronized on multisecond time scales. Also, dopamine receptors modulatethis synchronization of slow activity, in a manner demonstrating supersensitiv-ity after nigrostriatal lesion. 1. Ruskin et al, J. Neurophysiol. 81:2046; J.Pharmacol. Exp. Ther. 290:1493.

Metabotropic Receptors In Rat Cortical Astrocytes ExhibitPharmacology Consistent With mGluR5

J.J. Schmidt, L.M. Rowse, K. Spiegel, R.D. Schwarz, P.A. Boxer; Pfizer GlobalResearch & Development, Ann Arbor, MI.

Group I metabotropic receptors (mGluRs), comprised of the mGluR1 andmGluR5 subtypes, appear to be expressed in astrocytes as well as neurons. Wehave chosen to study the Group I mediated calcium responses in primary ratastrocytes using FLIPR. Astrocytes from basal forebrain, cerebellum, cortex,hippocampus and striatum were exposed to quisqualate and glutamate. Onlyastrocytes from cortex and striatum demonstrated responses that were consis-tent with Group I mGluR expression. The mGluR response in cortex was largerthan that in striatum. Basal forebrain, cerebellum and hippocampus were gener-ally unresponsive to mGluR1 agents. The rank order potency of known mGluRGroup I agonists on cortical astrocytes was: L-quisqualate> S-DHPG>glutamate>1S,3R-ACPD. Western blot analysis of cortical astrocytemembrane preparations showed cross-reactivity with antibodies to mGluR5 butnot mGluR1. New selective mGluR5 antagonists allow pharmacological differ-entiation between mGluR1 and mGluR5, which is not readily made on the basisof agonist profile or antibody reactivity alone. These antagonists, SIB-1757, SIB-1893 and MPEP, inhibited 300nM quisqualate responses with IC50s of 6.9µM,9µM and 31nM, but were inactive in CHO cells expressing mGluR1 receptor.The potency, selectivity and complete inhibition exhibited by these compoundsimplicate the mGluR5 subtype as the predominant Group 1 mGluR receptor inrat cortical astrocytes. The presence of the mGluR5 receptor on rat primary cor-tical astrocytes suggests that mGluR5 receptor might be present on astrocytomaor glioma cell lines as well. We examined rat C6 glioma cells and 5 human astro-cytoma/glioblastoma cell lines. No evidence for functional Group I receptor wasfound. The absence of functional receptor in these cell lines and certain rat brainregions suggests that mGluR5 expression is not a general feature of cells of glialorigin.

AMPA Receptor Phosphorylation during Cocaine Withdrawal

GL Snyder, S Galdi, JA Bibb, RL Huganir*, AC Nairn, and P Greengard, TheRockefeller Univ., New York, NY 10021;*HHMI, The Johns Hopkins Univ., BaltimoreMD 21205

Chronic cocaine exposure results in sensitization-enhanced neurochemical andbehavioral responses to subsequent acute drug challenges. AMPA-type glutamatereceptor antagonists block sensitization in rodents. The mechanism by whichAMPA receptors facilitate sensitization is unclear. However, it is possible that

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cocaine induces long-term changes in AMPA receptor activity mediated by re-ceptor phosphorylation via dopamine D1 receptors. Using phospho-specific an-tibodies, we show that cocaine treatment increases AMPA receptorphosphorylation in vivo. Acute cocaine (10 mg/kg) induced a rapid, reversible,and selective increase in phosphorylation of striatal GluR1 at Ser845, a site thatcontrols AMPA channel open time. Cocaine also increased phosphorylation ofDARPP-32 (dopamine and cAMP-regulated phosphoprotein, Mr32kD) at Thr34,a PKA site that converts DARPP-32 into a protein phosphatase 1 inhibitor anddecreased phosphorylation at Thr75, a cdk5 site that converts DARPP-32 into aPKA inhibitor. Drug-induced phosphorylation of GluR1 was lost in DARPP-32knockout mice, indicating that control of PP1 and/or PKA by DARPP-32 isrequired. Moreover, control of GluR1 phosphorylation by dopamine was alteredafter chronic cocaine. Mice were injected daily with cocaine for 7 days. Striatalslices prepared from these mice during cocaine withdrawal (1 or 7 d) were treatedin vitro to assess D1/PKA-mediated regulation of DARPP-32 and GluR1 phos-phorylation. D1-stimulated phosphorylation of DARPP-32 at Thr34 and GluR1at Ser845 was reduced, compared to controls, at 1 d, but not 7 d after withdrawal.In fact, the phosphorylation of GluR1 in response to D1 agonists or PKA activa-tors was 2-fold greater in slices 7 d after withdrawal in cocaine-treated comparedwith saline-treated mice. These data identify Ser845, a PKA-dependent site onthe GluR1 AMPA receptor, as a striatal target regulated by psychostimulants invivo. The results suggest that repeated cocaine use results in progressive and per-sistent changes in the coupling of AMPA receptors with PKA-signaling path-ways that may underlie certain aspects of sensitization. Supported by USPHSGrant DA-10044 (GLS, ACN, and PG).

Regulation of Cortex by Striatal Dopamine

H. Steiner, Dept. of Cell. and Mol. Pharmacology, Finch University of HealthSciences/Chicago Medical School, North Chicago, IL 60064

Dopamine agonists produce increased immediate-early gene (IEG) expressionthroughout wide parts of the cerebral cortex, suggesting a widespread influenceon cortical function. In our earlier studies, blocking dopamine action in the stria-tum by local drug infusion resulted in attenuated IEG expression in the cortex,indicating a role for striatal dopamine receptors in such cortical effects. Here, wefurther investigated the influence of striatal dopamine on cortical IEG expres-sion and examined the dopamine receptor subtypes involved. Thus, the effectsof dopamine depletion by 6-OHDA, or systemic dopamine agonist treatment incombination with intrastriatal infusion of a D1 receptor antagonist on basaland sensory stimulation-evoked IEG expression in the cortex were assessed. Ratsexamined 2 days after unilateral 6-OHDA lesion showed a bilateral decrease inbasal IEG mRNA levels across sensorimotor, insular and piriform, but not cin-gulate, cortex that was more pronounced on the lesioned side. Moreover, whis-ker stimulation-evoked IEG expression in the ipsilateral barrel cortex was largelyabolished. Such rats displayed pronounced akinesia. Three weeks after the le-sion, both basal and sensory-evoked IEG expression in the cortex were back tocontrol levels. This recovery of cortical IEG expression was accompanied by a

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recovery in some, but not all, motor behaviors, and may be the result ofneuroadaptive changes after the lesion. Injection of the D1/D2 dopamine recep-tor agonist apomorphine in normal rats produced increased IEG expression acrosssensorimotor, insular and piriform cortex, but not in the cingulate cortex, as wellas behavioral activation.

Whisker stimulation-evoked IEG expression in the barrel cortex was also en-hanced. Unilateral intrastriatal infusion of the D1 antagonist SCH-23390 blockedsuch cortical IEG expression bilaterally and inhibited most behavior, thus mim-icking acute lesion effects. These results suggest that striatal dopamine, by actingon D1 receptors, exerts a general bilateral, facilitatory effect on cortical functionwhich seems to be necessary for normal behavior. (Supported by USPHS GrantDA11261).

CB2 Receptor Localization in the Retinas of the Rat and theMonkey

Alex Straiker, U.C.S.D. San Diego,California

Recent work (Straiker et al., 1999) has indicated the presence of a CB1 cannab-inoid receptor-based signaling system in the retinas of a wide variety of verte-brates. The other known cannabinoid receptor, CB2, is generally thought to bepresent in the immune system but not in the CNS, although a recent paper (Luetal., 2000) reported the presence of CB2 mRNA in retinas of the rat and themouse. Using a subtype specific antibody to the CB2 cannabinoid receptor, Idetected CB2-like cannabinoid receptor labeling in the retinas of the rat and themonkey. Labeling in the rat was highly consistent with previous in situ hybrid-ization studies demonstrating the presence of CB2 mRNA in all three nuclearlayers of the rat retina. Double-labeling studies with calbindin and parvalbuminin rat retina demonstrated localization to specific cell types. This provides fur-ther evidence for CB2 receptor presence in the CNS and suggests that CB2 repre-sents part of a novel cannabinoid signaling system in the mammalian retina.

Characterization of Dopamine Neurotransmission in theMesolimbic and Mesostriatal Pathways of Mutant Mice Lacking5-HT2C Receptors

O Dell L.E., *Tecott L.H., and Parsons L.H. The Scripps Research Institute,Department of Neuropharmacology, 10550 North Torrey Pines Road, La Jolla, CA92037 *The University of California at San Francisco, Department of Psychiatry, 401Parnassus Ave, San Francisco, CA 94143

Previous research suggests that serotonin2C (5-HT2C) receptors play an inhibi-tory role in mediating dopamine (DA) neurotransmission. Moreover, evidencesuggests that 5-HT2C receptors exert a relatively greater influence on mesolimbicversus mesostriatal DA transmission. The present study compared phenotypicdifferences in DA neurotransmission in the terminal regions of these DA path-ways in wildtype and mutant mice lacking 5-HT2C receptors. Microdialysis probeswere implanted into the nucleus accumbens (NAcc) and ipsilateral dorsal stria-tum. The next day, DA levels were monitored in both regions 1) under tonic

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basal conditions using conventional dialysis sampling and the no-net-flux method2) during placement into a novel open field and 3) following peripheral adminis-tration of cocaine (15 mg/kg). There were no phenotypic differences in DA lev-els during basal or no-net-flux conditions. Placement into the open field did notalter DA levels in the NAcc of either genotype. However, this manipulation pro-duced an elevation of DA levels in the dorsal striatum of wildtype mice that wasattenuated in knockout mice. Cocaine produced a more robust elevation of DAlevels in the NAcc of knockout mice relative to wildtype controls. However, therewere no phenotypic differences in the dorsal striatum following cocaine admin-istration. The latter finding supports the hypothesis that 5-HT2C receptors playan inhibitory role in mediating DA neurotransmission, and that these sites exerta greater influence in the mesolimbic versus mesostriatal pathway.

Binding of an AMPA Receptor Potentiator ([3H]LY395153) toNative and Recombinant AMPA Receptors

H. Yu1, A-M. Lind n1,2,3, H. Zarrinmayeh1, W. J. Wheeler1 and P. Skolnick1,2

1Lilly Research Laboratories, Lilly Corporate Center, DC 0510, Indianapolis, IN46285; 2Department of Pharmacology & Toxicology, Indiana University School ofMedicine, Indianapolis, IN 46202; 3A.I. Virtanen Institute, University of Kuopio,70210 Kuopio, Finland

Compounds that modulate AMPA receptor-mediated currents may be benefi-cial in a variety of neuropsychatric disorders. LY395153 is a member of a newlydescribed class of arylpropylsulfonamide AMPA receptor potentiators. In elec-trophysiological assays, LY395153 is ≥ two orders of magnitude more potentthan the prototypic AMPA receptor potentiator cyclothiazide. [3H]LY395153binding was characterized in both native AMPA receptors from rat cerebral cor-tex and recombinant human GluR4flip receptors expressed in HEK293 cells.Glutamate and AMPA increased [3H]LY395153 binding to both native and re-combinant AMPA receptors in a concentration dependent and stereoselectivemanner. This effect of AMPA receptor agonists reflects an apparent increase inligand affinity; in the presence of saturating concentrations of glutamate,[3H]LY395153 binding is saturable, with a significantly higher affinity at humanGluR4flip (Kd = 55.6 ± 5.3 nM) than rat cortical receptors (Kd = 110 ± 15.1nM). NBQX competitively inhibited glutamate-induced increases in[3H]LY395153 binding in both native and recombinant receptors, whilstLY303070 (the active isomer of GYKI53655) noncompetitively inhibited thiseffect in native, but not recombinant receptors. The prototypic AMPA receptorpotentiator cyclothiazide competitively inhibited [3H]LY395153 binding with apotency (Ki ~7 mM) comparable to EC50 values reported in electrophysiologi-cal studies. In contrast, the structurally unrelated AMPA receptor potentiatorCX 516 did not inhibit [3H]LY395153 binding at concentrations of up to 600mM. Further, thiocyanate competitively inhibited [3H]LY395153 binding (Kb ~1.9 mM) at concentrations reported to facilitate AMPA receptor desensitization,but significantly lower than the concentrations (50-100 mM) routinely included

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in [3H]AMPA binding assays to enhance the apparent affinity of this ligand.[3H]LY395153 binding was unaffected by a variety of structurally (and mecha-nistically) diverse compounds at 10 mM, including atenolol, baclofen, buspirone,caffeine, chlordiazepoxide, imipramine neomycin, phenylpropanolamine androlipram. These data indicate [3H]LY395153 is a useful probe for labeling a uniquemodulatory site on both native and recombinant AMPA receptors.

Overactivation of AMPA and NMDA but Not Kainate ReceptorsInhibits Phosphatidylcholine Synthesis before Excitotoxic NeuronalDeath

Ramon Trullas, Neurobiology Unit, IIBB/CSIC, Barcelona Spain

Glutamate receptor overactivation induces excitotoxic neuronal death, but thecontribution of glutamate receptor subtypes to this excitotoxicity is unclear. Wehave previously shown that excitotoxicity by NMDA receptor overactivation isassociated with choline release and inhibition of phosphatidylcholine synthesis.We have now investigated whether the ability of non-NMDA ionotropic glutamatereceptor subtypes to induce excitotoxicity is related with the ability to inhibitphosphatidylcholine synthesis. AMPA induced a concentration-dependent in-crease in extracellular choline and inhibited phosphatidylcholine synthesis whenreceptor desensitization was prevented. Kainate released choline and inhibitedphosphatidylcholine synthesis by an action at AMPA receptors, because theseeffects of kainate were blocked by the AMPA receptor antagonist LY300164.Selective activation of kainate receptors failed to release choline, even whenkainate receptor desensitization was prevented. The inhibition of phosphatidyl-choline synthesis evoked by activation of non-desensitizing AMPA receptorswas followed by neuronal death. In contrast, specific kainate receptor activation,which did not inhibit phosphatidylcholine synthesis, did not produce neuronaldeath. Choline release and inhibition of phosphatidylcholine synthesis were in-duced by AMPA at non-densensitizing AMPA receptors well before excitotoxicity.These results show that AMPA, but not kainate, receptor overactivation inducesexcitotoxic cell death, and that this effect is associated with inhibition phosphati-dylcholine synthesis. Moreover, these results indicate that inhibition of phos-phatidylcholine synthesis is an early event of the excitotoxic process, downstreamof glutamate receptor mediated Ca2+ overload, that may represent a specifictarget for neuroprotection.

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Poster Session 3 • Thursday/Friday SunshinePosters will be available for viewing from 3:30 PM Thursday to 4:30 PMFriday. Presenters will be with the posters on Thursday from 3:30 to 4:30 PM

Exercise That Alters Hippocampal-related Behavior and MetabolicCapacity in Motor Structures Does Not Alter Metabolic Capacity inthe Hippocampus

Brenda J. Anderson, Daniel P. McCloskey, David S. Adamo, and Pamela S. Coburn-Litvak, Dept of Psychology, SUNY-Stony Brook

Exercise has numerous effects on the hippocampus. Hippocampal pyramidal celldischarge rates and theta rhythm correlate with speed of locomotion, and move-ment increases hippocampal glucose utilization. Exercise has been reported toincrease hippocampal growth factor mRNAs and cell proliferation. In the firstexperiment, we tested whether or not exercise improves hippocampal-dependentbehavior in a radial maze. Control rats and rats that voluntarily exercised for 3months took the same average time to traverse an arm of the maze, but the exer-cising rats required significantly fewer trials to reach criterion-level performance.If exercise causes an increase in the level of sustained neural activity in the hip-pocampus, either directly or through a form of plasticity, then the hippocampusshould exhibit an increase in the capacity to meet the additional metabolic de-mand. Alterations in behavior and sustained levels of neural activity are knownto alter cytochrome oxidase (COX) activity, which is coupled to the productionof ATP. Therefore, we tested whether or not exercise increases cytochrome oxi-dase (COX) reactivity after rats voluntarily exercised for 6 months with dailyrates equivalent to those seen in the first experiment. Exercising rats relative tocontrol rats had greater COX reactivity in limb representations of the motorcortex, and in limb, but not face, representations in the triatum. In contrast toour hypothesis, exercise did not affect COX reactivity in any region of the hip-pocampus. Voluntary exercise affected the rate of 8-arm radial maze acquisi-tion, and COX reactivity in motor structures, but did not increase the hippocampalcapacity for oxidative metabolism.

Genetics and Age Alter Binge Drinking Induced Neurodegeneration

F. T. Crews, Center for Alcohol Studies, University of North Carolina

Human alcoholics are known to suffer from a loss of brain mass and function.Multiple day binge drinking is common among alcoholics as well as college stu-dents. Two factors that contribute risk to becoming alcoholic are genetics andage of onset of drinking. To determine if genetics and age contributed to bingedrinking induced neurodegeneration we used a 4-day i.g. ethanol binge model inrats and identified neuronal damage using silver stain and other methods. Twoinbred strains of rats, alcohol-preferring (P) and nonalcohol-preferring (NP), wereused to study the relationship of a genetic predisposition for alcohol preferenceand neurodegeneration. Both P and NP rats had significant neurodegenerationin the olfactory bulbs, posterior perirhinal cortex, and posterior entorhinal cor-

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tex following a 4-day ethanol treatment. P rats had significantly moreneurodegeneration in the posterior perirhinal and posterior entorhinal corticesbeing 239% + 50% (p<0.02) and 219% + 46% (p<0.01) of NP, respectively. Im-munohistochemical studies showed COX2 and phospho-MAPK immunoreac-tivity consistent with glutamate signaling contributing to the differential damage.A component of the genetic factors that lead to risk of addiction could involveneurodegenerative responses. Heavy binge drinking in adolescents is becomingincreasingly common. To determine if binge-induced neurodegeneration differsbetween adolescent (PN35) and adult (PN80-90) rats, the effects of a 4-day bingetreatment were investigated. The olfactory bulbs were equally damaged in bothgroups. The anterior portions of the piriform and perirhinal cortices were dam-aged to a greater extent in adolescent rats. For example, adolescent rats showed586 + 162 mm2 of argyrophilic area vs. 145 + 39 mm2 in the anterior piriform.The increased sensitivity of adolescents to ethanol induced neurodegenerationcould contribute to the increased risk of adolescent drinkers becoming alcoholdependent. These findings indicate that both genetic and age differences contrib-ute to ethanol-induced neurodegeneration. (Supported by NIAAA).

Hibernation, a Model of Neuroprotection

K. Drew, F. Zhou, X. Zhu, M.A Smith, R. Castellani

Hibernation, as a natural model of tolerance to cer ebral ischemia , representsa state of pronounced fluctuation in cerebral blood flow where no brain damageoccurs. Numerous neuroprotective aspects may contribute in concert to suchtolerance. The purpose of this study was to determine if hibernating brain tissueis tolerant to penetrating brain injury modeled by insertion of microdialysis probes.Guide cannulae were surgically implanted in striatum of arctic ground squirrelsbefore any of the animals began to hibernate. Microdialysis probes were theninserted in some animals after they entered hibernation and in others while theyremained euthermic. Analysis of dialysate glutamate concentrations, collectedat quantitative and non-quantitative flow rates, showed no difference betweenhibernating and euthermic animals. The brain tissue from hibernating and euth-ermic animals was examined 3 days after implantation of microdialysis probes.Tissue response, indicated by examination of H&E stained tissue sections andimmunocytochemical identification of activated microglia, astrocytes and HO-1immunoreactivity, was dramatically attenuated around probe tracks in hibernat-ing animals compared to euthermic controls. No difference in tissue responsearound guide cannulae was observed between groups. Further study of the mecha-nisms underlying neuroprotective aspects of hibernation may lead to novel thera-peutic strategies for stroke and traumatic brain injury.

Time Dependent Cue-induced Reinstatement during the FirstMonth of Withdrawal from Cocaine

J. W. Grimm, B. Hope, R. Wise, Y. Shaham

Clinical research indicates that the probability of relapse to cocaine taking maybecome increasingly under the influence of conditioned stimuli over the courseof drug withdrawal. Here we report a characterization of such a phenomenon in

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a rat model wherein drug-paired cues provoke relapse to cocaine seeking duringthe first month of drug withdrawal. Rats were trained to press a lever for IVcocaine for 10 days (0.5 mg/kg/infusion, two 3-hr sessions/day). Each responseon the drug-associated lever resulted in a cocaine infusion, and a presentation ofa tone+light cue. The rats were then tested for reinstatement of cocaine seekingafter 1, 2, 4, 7, 15, or 29 days of withdrawal (n=8-11 per group). Rats were given60-min sessions (separated 5 min apart) during which lever presses were not re-inforced and the cue was absent (extinction). After a minimum of 6 sessions andafter reaching a criterion of less than 15 responses/60 min on the cocaine associ-ated lever (rats reached criterion in 6-8 sessions), the effect of the cue on rein-statement was assessed in a session wherein lever presses resulted in cue delivery.Cue presentation resulted in a large increase in responding on the cocaine-asso-ciated lever after 15 or 29 days (p<0.05), but only a weak increase 1, 2, 4, or 7days into withdrawal. Furthermore, at one day of withdrawal, the rate of non-reinforced lever pressing prior to the cue session was markedly lower than thatobserved after 7, 15, or 29 days of withdrawal from cocaine (p<0.05). This effectwas replicated in a separate group using a within-subject design (n=6) whereagain, both extinction and cue responding at the 15 and 29 day time points weresignificantly greater than at the 1 day time point (p<0.05). The present findingsprovide an animal model in which the neural adaptations associated with timedependent increases in cocaine craving in abstinent cocaine addicts can be stud-ied.

The Role of Amino Acid Neurotransmission in the Acquisition andExpression of Conditioned Defeat

K. L. Huhman and A. M. Jasnow, Dept of Pyschology, Georgia State University

Conditioned defeat is a long-lasting and profound behavioral response of maleSyrian hamsters following a brief defeat by a larger, more aggressive opponent.Following this initial defeat, hamsters fail to show normal territorial aggression,but instead display only submissive and defensive behaviors even though a smaller,non-aggressive opponent (NAO) is used for subsequent testing. It has been hy-pothesized that changes in the balance between glutamatergic and GABAergicneurotransmission in the amygdala are critical for regulating behavioral responsesto anxiety provoking and aversive stimuli. In Experiment 1, we tested the hy-pothesis that increases in GABAergic neurotransmission in the amygdala wouldblock the acquisition and expression of conditioned defeat. Adult male, Syrianhamsters were implanted with bilateral cannulae aimed at the central nucleus ofthe amygdala. After a one week recovery, hamsters were bilaterally injected withmuscimol (0.0, 4.4 or 8.8 nM in 300 nl saline) either before training (the initialdefeat by a more aggressive hamster) or before testing the following day with asmaller NAO. Muscimol dose-dependently and selectively reduced submissiveand defensive behavior exhibited during testing when the drug was given eitherbefore training or before testing. This effect was not due to a general sedationcaused by muscimol as other behaviors were not effected by the injections, andmuscimol given before training did not alter the behavior of the aggressive trainer.The data indicate that an increase in GABAergic transmission in the amygdala

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can block the acquisition and expression of conditioned defeat. In Experiment2,we tested the hypothesis that decreased glutamatergic neuro-transmission in theamygdala would block the acquisition of conditioned defeat. Hamsters wereimplanted with cannulae as in Experiment 1. Following recovery, the animalswere injected with the glutamate (NMDA) antagonist AP5 (0.0, 2.5, 5.0 and10.0 µg in 300 nl saline) before training. All doses of AP5 selectively reducedsubmissive/defensive behaviors exhibited during testing. The highest dose alsodecreased the amount of aggressive behavior shown by the trainer males towardthe experimental males. Together, these data indicate that changes in amino acidneurotransmission in the amygdala can alter response to anxiety provoking andaversive stimuli in hamsters.

Lesions of the Amygdala Impair Sexual Behavior and AttenuateLevels of Extracellular Dopamine in the MPOA

J. Dominguez, J.V. Riolo, Z. Xu, and E.M. Hull, Department of Psychology, SUNYBuffalo, Buffalo, NY, USA

The medial preoptic area (MPOA) plays an important role in the regulation ofmale rats sexual behavior. Dopamine (DA) agonists or antagonists microinjectedinto the MPOA have been shown to facilitate or impair sexual behavior, respec-tively. Observations using microdialysis have shown an increase of extracellularDA in the MPOA of copulating animals. A major source of input to the MPOAis the medial amygdala (MeA). Lesions of the amygdala impair sexual behaviorof male rats; microinjection of a dopamine agonist into the MPOA reverses thiseffect. The present experiment tested whether MeA lesions inhibit extracellulardopamine release in the MPOA of male rats, in addition to impairing copula-tion. Rats received either MeA lesions or sham lesions, and received guide can-nulae for microdialysis. Two weeks later microdialysis samples were collectedand behavioral measures were obtained. Samples were later assayed using HPLC-EC. MeA lesions attenuated the increase of extracellular DA in the MPOA dur-ing exposure to an estrous female and during subsequent copulation. In addition,MeA lesions impaired measures of copulation, compared to shams. These datasuggest that one means by which the MeA facilitates copulation in male rats isby increasing dopamine release in the MPOA in response to an estrous femaleand during copulation. Furthermore, these data confirm the close relationshipbetween extracellular dopamine in the MPOA and copulatory ability in malerats. Supported by: NIMH grant#MH40826 to EMH

Life Without the Adrenaline Rush? Pain and Other Behaviors inDopamine Beta-hydroxylase Knock-out Mice

Luc Jasmin, Department of Neurological Surgery, University of California, SanFrancisco 505 Parnassus Avenue, Box 0112 San Francisco, CA94143-0112

Based on the available literature, it is unclear if a chronic lack of noradrenaline(NA) could be responsible for a state of hyperalgesia and decreased response toopiates.&nbsp; To address these questions we have used mice in which the genefor dopamine beta-hydroxylase (DBH) has been deleted leading to complete lack

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of NA. When compared with DBH +/+ mice (n = 6), DBH -/- mice (n = 6)showed clear hyperalgesia to heat and cold.&nbsp; None of the animals in eithergroup displayed signs of allodynia to innocuous heat or cold (42 and 20oC re-spectively) after 20 min.&nbsp; Administering DOPS-Carbidopa (1 mg/g and0.125 mg/g respectively) to restore noradrenaline in the CNS reestablished nor-mal withdrawal latencies in DBH -/- mice (p<0.01) while having no effect in theDBH +/+ mice. The antinociceptive effect of increasing doses of morphine (0.5,2.5, 5, 10, 15, 20 and 25 mg/kg s.c.) was tested on the hot plate.&nbsp; Mor-phine had a decreased potency in the DBH -/- mice since 3 times the dose ofmorphine was needed to reach the ED50 (25 mg in the DBH -/- mice vs. 7 mg inthe DBH +/+ mice).&nbsp; The antinociceptive effect of morphine was reversedby the opiate antagonist natrexone 10 mg/kg s.c. in both groups of mice. Thefinding of hyperalgesia in the DBH -/- mice is consistent with a previous sugges-tion that noradrenaline exerts a tonic inhibition of spinal nociceptive transmis-sion, and that decreasing noradrenaline or administration of noradrenergicantagonists results in behavioral hyperalgesia.&nbsp; Increasing NA in normalanimals, however, does not alter the baseline nociceptive threshold.&nbsp; Also,these findings are consistent with previous reports that NA potentiates theantinociceptive effect of morphine.

Aging Induced Changes in Orexin a Neural Signaling

C. Kotz, M. Mullett, A. Levine, C. Billington, Veterans Affairs Medical Center,Minneapolis MN

Appetite and sleep disorders are common among the elderly, and may contributeto the high prevalence of anorexia in this population. Orexin A is a recentlycharacterized neuropeptide that influences feeding behavior and plays a role insleep disorders. Orexin A is predominant in the lateral hypothalamus (LH) andLH-injected orexin A dose-dependently stimulates feeding and activates neu-rons in several feeding-regulatory brain areas. In the current study, we tested theeffect of LH-injected orexin A on feeding behavior and cfos-immunoreactivity(cFos-ir) in several brain regions in young and old male Fisher F/344 rats. Wehypothesized that advancing age diminishes the feeding and cFos-ir response toorexin A. LH-cannulated rats at ages 3, 12 and 24 mo. were given graded dosesof orexin A (0, .5, 1 and 2 nmol in 0.5 µl) in a repeated measures, counterbal-anced design. Food intake was measured at 1, 2 and 4 h following injection. Forthe cFos experiment, LH-cannulated rats at age 3 mo. and 24 mo. were injectedwith either artificial cerebrospinal fluid (aCSF) or orexin A (1 nmol/0.5 µl). Onehour following injection, rats were perfused and brains processed for cFos im-munohistochemistry. The feeding response to orexin A was significantly dimin-ished and delayed in the 24-mo. rats, and the 24-mo. rats exhibited significantlyattenuated or absent cFos-ir response to orexin in all brain regions examined.These data indicate that delayed and diminished feeding responses observed inthe older animals may be the result of ineffective neural signaling. In summary,these results provide the first evidence of aging-induced decreases in functioningof orexin A neural signaling pathways, and may have implications for sleep andappetite disorders observed in the elderly.

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Nucleus Accumbens Unit Activity in Rats Performing RadiallySymmetric Tasks for Food Reward

C.H. McCandless*; W.E. Skaggs, Depts Neuroscience and CNBC, Univ Pittsburgh,Pittsburgh, PA, USA

The shell and core of the nucleus accumbens (NA) receive significant input fromthe hippocampal region (CA1 and subiculum). This input strongly affects NAactivity and responses to prefrontal inputs (O Donnell & Grace, J.Neurosci. 15:5,1995). Hippocampal cells exhibit spatially tuned activity, which suggests oppor-tunities for NA neurons to integrate positional with reward information. To in-vestigate this possibility, independently movable tetrodes were placed in NA coreand shell in rats running for food reward on a circular platform. Rats were re-quired to contact any point at the edge of the platform before returning to thecenter for reward. This apparatus presents certain advantages over the radial maze.A variety of activity patterns were recorded. Many cells appeared to respond tothe reward location, a pericentral radial zone, or in association with the edge ofthe platform. Most firing fields were radially symmetric. Apparently spatial ac-tivity was most often differential with respect to inbound vs. outbound trajecto-ries. A small subset of cells showed strong theta-frequency modulation, consistentwith significant input from hippocampus. To account for the observed patterns,we hypothesize that NA neurons integrate information about context and behav-ioral state to encode the behavioral proximity of reward. The data support pre-vious suggestions that the NA participates in navigation by transducing thehippocampal place code into goal-relevant context. Data from a second experi-ment will also be presented which allows comparisons a) between internally-and externally-guided trajectories, b) with results obtained on a radial maze, c)between spatial and temporal determinants of firing, as well as correlations be-tween NA firing patterns and hippocampal EEG during relevant behavioral epi-sodes. Supported by: NINDS NS07433-02 and NSF 9720350

Prenatal Stress of Rats Causes Changes in Laterality of AdultBehaviors, but Only When Tested in Anxiogenic Situations

S. E. Welcome, A. Garner, and W. O. McClure, Department of Biological Sciences andKeck School of Medicine, University of Southern California, Los Angeles 90089-2520

Prenatal stress causes both behavioral and neuroanatomical changes in the re-sulting adults. We have previously shown that a specific amount of stress appliedto rats at a specific time of gestation causes neuroanatomical changes that mimicthose seen in human schizophrenics. We now report that animals treated withprenatal stress also exhibit several behavioral changes, and that these behaviorsare increased to statistical significance when the animals are tested under condi-tions of mild anxiety. Pregnant dams were treated with mild immobilizationstress (90 sec) on days e11 — e14. Control animals were born to mothers thatwere not stressed. Litters were culled to 4 males and 4 females at post-partumday 3 (p3). Animals were tested from p13 until sacrifice at p105. A previousexperiment suggested that both locomotion and rearing in the open field were

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affected by the presence of other rats in the testing room. To confirm this obser-vation, we carried out 5 trials with all the other rats (40 animals) in the testingroom, and 8 trials in which only the cage of 2 animals being tested was present.The presence or absence of conspecifics changed the results of testing. In theabsence of other animals, rearing of the prenatally treated animals became later-alized: these animals preferentially used one paw or the other to support them-selves at the wall. Locomotion was also significantly increased by the absence ofconspecifics. Neither effect was seen with control animals. To clarify the stimu-lus involved, animals were tested three times with only one cage at a time in thetesting area while a tape of the noise of conspecifics was played. In all three trialsnoise of other animals completely inhibited both lateralization and increasedlocomotion of the treated animals. To test the hypothesis that anxiety was in-volved in these effects animals were tested for laterality in the presence of con-specifics using a step-down paradigm. Treated animals were not lateralized incontrol situations, but were lateralized after exposure to either shaking or re-peated intense auditory pulses. Control animals were never lateralized. Theseresults suggest that anxiety is involved in generating the observed laterality. Theincreased laterality seen in prenatally stressed animals is highly reminiscent ofthe increased sinistrality reported in schizophrenics. It is possible that these pre-natally stressed animals will provide an useful model system for schizophrenia.

Behavioral Resetting of Circadian Rhythms Is Modulated byCaffeine: Role of Adenosine A1 Receptors

R. E. Mistlberger, M. C. Antle, N. M Steen,Department of Psychology, Simon FraserUniversity, Burnaby BC V5A 1S6,Canada.

Circadian rhythms in Syrian hamsters can be phase shifted by 2-4 h by proce-dures that stimulate arousal during the subjective day (the usual rest period oftheir daily rest-activity cycle). Phase resetting is thought to be mediated by neu-ropeptide Y (NPY) and possibly serotonin (5HT) inputs to the suprachiasmaticnucleus (SCN), the site of the circadian clock. Circadian rhythms can also beshifted by light exposure during the hamster s subjective night (active period), aresponse that is mediated by retinohypothalamic glutamate release. During thesubjective day, light or glutamate can attenuate phase shifts induced by behav-ioral arousal, NPY or 5HT. Light-induced shifts early in the night are dependenton mobilization of intracellular Ca++ via ryanodine receptors within SCN cells.Caffeine is an agonist at this receptor, and mimics the phase shifting effects ofglutamate in vitro. Caffeine can also potentiate glutamate release by blockingpresynaptic adenosine A1 receptors, leading to the prediction that caffeine, astimulant, might attenuate phase shifts induced by behavioral arousal. We foundthat caffeine (7.5, 37.5, 75 mg/kg, i.p.) did dose-dependently inhibit the phaseshifting effects of either sleep-deprivation or wheel exercise in the mid-subjectiveday. However, the selective A1 receptor antagonist CPT (1.25, 6.25 mg/kg, i.p.)did not, suggesting that ryanodine receptors may mediate this action of caffeine.

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The A1 agonist nCHA (1.25, 2.0, 2.5 mg/kg, i.p.), in the mid-subjective dayinduced dose-dependent phase shifts similar to arousal, but this may be a sec-ondary effect of the prolonged (up to 48 h) hypoactivity evident atthese doses.Caffeine, a widely used psychostimulant, has chronobiotic actions, but these ap-pear to be restricted to high dose effects at receptor sites to be determined.

Patients with Complex Regional Pain Syndrome (ReflexSympathetic Dystrophy/Causalgia) after Unilateral Injury CanHave Bilateral Loss of Nociceptive Neurites in Skin

Anne Louise Oaklander, Harvard Medical School

Our understanding of chronic neuropathic pain is poor because of the paucityof objective findings. Nerve conduction studies reflect activity of large myeli-nated fibers, and electromyographic abnormalities are present only with motordamage. Patients with injury to unmyelinated and thinly myelinated fibers canhave pain as their sole symptom and no abnormalities on exam or laboratorytests. Patients may be viewed with suspicion and have difficulty obtaining treat-ment and/or compensation. Patients with Complex Regional Pain Syndrome(CRPS, formerly known as Reflex Sympathetic Dystrophy or Causalgia) are es-pecially perplexing since their pain is excess for their injury, and they can reportpain distant to (or even contralateral from) the injury site. Small punch skin biop-sies immunolabeled against PGP9.5 allow LM visualization of cutaneous sen-sory nerves and quantitation of epidermal nerve endings. These representexclusively nociceptors (pain-sensing neurons). In an ongoing IRB-approved study,we compared the density of epidermal neurites in punch skin biopsies takenfrom the site of CRPS pain (P) on the arms, legs, or torso, an adjacent ipsilateralnon-painful control site (I), the contralateral mirror-image homologue of thepainful site (M) and the control site (C). To date, 11 consenting adults (3 withbilateral pain) and no risk for other peripheral nerve diseases have participated inthis study with these results: 1. There was no statistical difference in density ofepidermal neurites when comparing the ipsilateral (I) and contralateral controlpunches (C). 2. The average density of epidermal neurites at the painful site (P)was almost 40% less than the density at the ipsilateral control site (I). 3. Theaverage density of epidermal innervation at the contralateral site mirror-imageto the painful site (M) was almost equally reduced when compared to densities atthe contralateral control site (C). These data suggest the following preliminaryconclusions: 1. Punch skin biopsies can provide objective evidence of focal neu-ral damage in CRPS. 2. CRPS may be associated with damage to cutaneousnociceptive neurites. 3. Humans with unilateral injuries producing CRPS mayhave bilateral nerve damage. 4. Loss of cutaneous neurites contralateral to aCRPS-inducing injury is restricted to the area mirror-image to the painful area.5. The contralateral site mirror-image to an injury should not be used as a con-trol site. Supported by the Beatrice and Roy Backus Foundation, the Paul BeesonPhysician Faculty Scholarship in Aging Research, and the Ruth and MauriceFreeman Fund for Pain Research.

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Topographic Map for Visual Space In Association Cortex ofBehaving Monkey

R.M. Siegel, R.E. Phinney, J.A. Turner, G. Jando Center for Molecular and BehavioralNeuroscience, Rutgers University

Classical studies of the primate inferior parietal lobule began with shrapnel inju-ries during World War I. Modern refinements using electrophysiological mea-surements revealed the cortical fields and the neuronal properties are crucial inconstructing representations of surrounding visual space. Unlike striate and otherextrastriate cortical regions, there has been almost no evidence from any mea-surements of single cells for a mapping of visual space across the inferior pari-etal lobule s subfields in the behaving monkey or human. Although attemptshave been made to determine if there are organized topographic map of retinalor eye position across the inferior parietal lobule, the day-to-day variability in-herent in electrode positioning in a chronic monkey study over a typical two yearcourse has no revealed a map. Such maps would be expected to serve as a basisfor subsequent regions to plan and guide motor behaviors has been demonstrated.Intrinsic optical imaging, which uses changes in neuronal metabolism at a sub-millimeter scale, was used to assess neuronal tuning at thousands of locationsacross the cortex. The visually evoked optical signal time course in behavingmonkey is comparable in size and amplitude to those in anesthetized monkeys,however it is superimposed on a second waveform arising from the execution ofthe task itself. We have found two maps in the association cortex. There is afunctional architecture that has a reproducible gain field representing eye posi-tion. This map is confirmed with single electrode recording. The second repre-sentation of retinal position was variable over the two months of imaging. Themutability of the retinal topography across days may indicate modulation as aresult of past experience, or present attentional and intentional states. Supportedby the Whitehall Found. Foundation, NIH/NEI EY09223, NIH/NCRR1S10RR12873 (RMS), NIH/NEI EY06738 (REP), NIH/NEI EY06738 (JAT),Hungarian Scientific Research Foundation OTKA/T023657 (GJ).

Investigation of Novel Neurotensin Analogs in Brain

L. Warrington, Birdsall Research, Mayo Clinic Jacksonville FL

Schizophrenia is a disease that affects about 1% of the world s population, andhas devastating effects on patients and their families. Many theories exist regard-ing the etiology of schizophrenia. The most likely candidate neuropeptide withevident alteration in schizophrenia is neurotensin (NT), found in CNS and GItissue primarily. It shows pharmacologic interactions with dopamine and in somebrain regions colocalization and corelease. NT shares certain properties withantipsychotic drugs (APDs), especially the newer atypical APDs. Both NT andAPDs cause increased dopamine turnover rate and blockade of apomorphineinduced climbing behavior as well as amphetamine and cocaine induced loco-motor activity and rearing in rats. NT displays some differences from APDs.Certain APDs antagonize the stereotypic behavioral effects of dopamine ago-nists such as sniffing and licking while NT does not. Typical APDs cause cata-

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lepsy in rats, NT does not. Overall, NT resembles atypical APD s. NumerousAPDs exist and fall into two categories, older typical APDs and newer atypicalAPDs. Typical APDs suffer from debilitating side effects such as dystonia andtardive dyskinesia. Atypical APDs have fewer side effects but the most successfulatypical, clozapine, can cause potentially fatal agranulocytosis. NT has been triedas an APD but was found to be quickly degraded by proteases in the peripheryand must be given ICV. To combat this problem various analogs of NT, such asNT69 and NT77, have been developed in our laboratory with a high degree ofstability in the periphery, and which can cross theblood brain barrier intact.Through the use of microdialysis in freely moving rats, we have found that NT69shows a similar neurochemical profile to clozapine in striatum and prefrontalcortex, while NT77 shows a more similar profile to haloperidol in those samebrain regions. It is the ultimate hope that we can develop a NT analog whichmaintains the beneficial effects of atypical APDs with fewer side effects.

Does Mild Cognitive Impairment Lead to Synapse Loss in theHippocampal Dentate Gyrus?

Stephen Scheff, Sanders-Brown Center on Aging, U. Kentucky, Lexington KY

It is well documented that significant synapse loss occurs in many regions of theneocortex and hippocampus in Alzheimer s disease (AD), however it is unknownwhether similar changes occur in patients with mild cognitive impairment with-out AD. The outer molecular layer of the hippocampal dentate gyrus receives adirect input from the ipsilateral entorhinal cortex, an area known to play an im-portant role in the progression of dementia. The present study was designed toassess the total number of synaptic contacts in this region of the hippocampalformation. Tissue was examined from individuals in the ongoing Religious Or-ders Study who underwent detailed clinical evaluation within 12 months of deathand categorized as no cognitive impairment (NCI), mild cognitive impairment(MCI), or AD. Systematic random sections throughout the entire extent of thehippocampal formation were obtained at autopsy and processed for standardtransmission electron microscopy. Unbiased stereological techniques employingthe physical disector method were used to estimate the total number of synapsesin the outer molecular layer of the hippocampal dentate gyrus. Results demon-strate a substantial loss of synapses in individuals with AD but no differencebetween individuals with MCI and normal aging controls. The cognitive declineobserved in the MCI group may be the result of a more global loss in connectiv-ity and not localized to a single structure such as the hippocampus.

Emotional and Cognitive Responses to Mild and Strong AversiveStimuli in Mice Lacking Dopamine D4 Receptors

Marcelo Rubinstein, Instituto de Investigaciones en Ingenieria Genetica y BiologiaMolecular, CONICET and University of Buenos Aires, ARGENTINA

The frontal cortex receives a major dopaminergic input from the ventral tegmen-tal area that plays an important role in the integration of diverse neuronal signalsthat ultimately determine behavioral responses to novel environmental stimuli.Emotional and cognitive dimensions participating in these responses are depen-

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dent on mesofrontal dopamine transmission through the stimulation of multiplereceptor subtypes. The dopamine D4 receptor (D4R) is expressed at highest lev-els in the frontal cortex and is the predominant D2-like receptor localized in thisbrain area. To investigate the functional significance of the D4Rs in DA-medi-ated responses, and in the absence of pharmacological compounds with provenselectivity and efficacy in vivo, we have analyzed a strain of mutant mice thatlack D4Rs (Drd4-/-) on a C57Bl/6J x 129sv/Ola F2 genetic background. Wefirst challenged wild type, heterozygote and Drd4-/- in two different approach/avoidance conflict paradigms. In the elevated plus maze the Drd4-/- mice dis-played increased levels of anxiety as demonstrated by a significantly reducednumber of entries and time spent in the unprotected open arms of the maze.This behavior was completely reversed by ethanol and the benzodiazepinemidazolam, two well-known anxiolytic agents that do not increase novelty seek-ing behavior. In addition, when compared to their wild-type littermates, Drd4-/- mice exhibited significantly longer latencies with respect to their exploration ofthe bright, aversive compartment in a light/dark preference exploration test. Be-cause heightened anxiety may lead to an increase in ethanol consumption andthe rewarding effects of ethanol depend on D2-like receptor stimulation we chal-lenged wild type and Drd4-/- mice in a two bottle choice preference test. Nodifferences were observed in total EtOH consumption or preference between thetwo genotypes. To investigate whether another emotional and cognitive responsesto stressful stimuli were affected in Drd4-/ mice we performed a fear condition-ing test using contextual and auditory cues paired with an aversive uncondi-tioned foot shock and a passive avoidance test with another cohort of mice. Inboth behavioral paradigms all parameters evaluated showed no differences be-tween wild type and Drd4-/- mice. Taken together these results suggest that theabsence of D4Rs lead to hypervigilance under mild stressors but normal fearfulresponses to more aversive stimuli.

Divergent GABAA Receptor Mediated Synaptic Transmission inGenetically Seizure-prone and -resistant Rats

M.O.Poulter1, B. Hutcheon2, K. Schwabe1 and D.C. McIntyre1 Neuroscience ResearchInst., Carleton University, Ottawa Canada

Recent evidence suggests that the abnormal expression of genes coding forGABAA receptors underlies the development of epilepsy. By analysing individualminiature inhibitory postsynaptic currents (mIPSCs) in the neurones of normal,seizure-prone and resistant rats we have found that mIPSCs decayed at differentrats and had different amplitudes. These mIPSCS kinetics were correlated, aswell, to cell morphology. In the seizure-prone rats, the mIPSC amplitudes weresmaller (» 30 pA) than in normal (» 45 pA and seizure prone (»60 pA). Thesedifferences were independent of morphology. However, in non-pyramidalneurones of the seizure prone rat mIPSCs were significantly slower (» 400 %)that in normal or seizure resistant rats. In seizure-resistant rats, on the otherhand, in comparison to normal rats the kinetics of mIPSC deactivation was fasterin both pyramidal and non-pyramidal neurones alike. Despite substantial differ-ences in peak amplitude, the total charge transfer of mIPSCs did not differ be-

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tween the strains. Thus the timing of the inhibition and not the total amount wasdifferent between the strains. These data suggest, therefore, that epilepsy is asso-ciated with a dysregulation of inhibitory timing, primarily on non-pyramidalneurones in the brain.

Synaptic Inhibition Generates Long Lasting Increases in Firing Rateof MVN Neurons

Claudia M. Krispel, Alexandra B. Nelson,Chris Sekirnjak, Sascha du Lac, The SalkInstitute, La Jolla Ca

Medial vestibular nucleus (MVN) neurons fire spontaneously and stably in theabsence of synaptic input. We investigated how the history of synaptic inputaffects spontaneous firing rate in MVN neurons recorded intra- and extracellu-larly in mouse brainstem slices. Following five minutes of high frequency stimu-lation of inhibitory synaptic inputs, the majority of recorded neurons demonstratea substantial increase in spontaneous firing rate. This potentiation of firing rateappears stable and lasts in excess of thirty minutes. Substitution of intracellularcurrent injections for synaptic inhibition also elicits a stable increase in firingrate. MVN neurons encode vestibular information with changes in firing rateand receive high frequency inhibitory synaptic inputs from several sources invivo. Firing rate potentiation may have important physiological implications forcompensation following lesions to the vestibular system or homeostatic regula-tion of spontaneous firing rates. While reported here for the first time in thevestibular system, we expect similar forms of firing rate plasticity to be present inother spontaneously active cell types of the CNS.

Carbon Monoxide Is an Endogenous Mediator of Neonatal CerebralCirculation

C.W. Leffler, H. Parfenova, J.S. Robinson, Z. Fan, M. Pourcyrous, R.A. Neff III, A.Nasjletti, R.A. Johnson, and A.L. Fedinec, Dept of Physiology, University of Tennessee

CO is a potentially important paracrine relaxing factor in the neonatal cerebralcirculation. Heme oxygenase-2 (HO-2) is highly expressed in the cerebral mi-crovasculature of piglets and CO production by cerebral microvessels is highcompared to that of other vessels. CO and heme-l-lysinate, applied topically,cause dilation of neonatal pig pial arterioles. The dilation to heme-l-lysinate, butnot to CO, is blocked by chromium mesoporphyrin. Metal porphyrin inhibitorsof HO attenuate vasodilations to topically applied glutamate, to bicucullin-in-duced seizures, and to hypoxia. The putatively CO dependent dilations toglutamate and glutaminergic seizures could involve endothelium becauseglutamate increases CO production by cerebromicrovascular endothelial cells,in vitro. CO induced dilation appears to involve KCa channels. In vivo, KCachannel inhibitors block cerebral vasodilations to CO and heme-l-lysinate. COor heme-l-lysinate hyperpolarises cerebral microvascular smooth muscle cells inprimary culture. The effect of heme-l-lysinate membrane potential, but not ofCO, is blocked by chromium mesoporphyrin. Cerebral vasodilatory responses toCO involve interactions with both the prostanoid and NO systems. Either in-

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domethacin or nitro-L-arginine (LNA) can block cerebral vasodilatory responsesto heme-l-lysinate or to CO. Following indomethacin, topically applied iloprostrestores dilation to CO and to heme-l-lysinate, but sodium nitroprusside doesnot. Following LNA, sodium nitroprusside restores vasodilation to CO, butiloprost does not. Both prostacyclin and NO act upstream of KCa channels be-cause neither iloprost nor NO can restore dilation to CO following KCa channelinhibition. CO appears to be important in regulation of neonatal cerebral micro-circulation and may contribute to coupling of cerebral blood flow to neuronalactivity. Furthermore, prostacyclin and NO appear to play permissive enablingroles in CO-induced cerebral vasodilation in piglets.

Pharmacological Manipulation of Locus Coeruleus Tonic OutputAlters Information Transfer Through Forebrain Sensory Circuits

D. M. Devilbiss and B. D. Waterhouse

Microdialysis studies have shown that extracellular levels of norepinephrine (NE)in the forebrain increase in direct proportion to increased tonic output from thenucleus locus coeruleus (LC). Tonic activity of NE-containing LC neurons isincreased by systemic administration of idazoxan (alpha-2a antagonist; IDZ)and decreased by clonidine (alpha-2a agonist; CLON). Reports from our labora-tory as well as others have revealed a variety of actions of synaptically oriontophoretically released NE on individual forebrain sensory neurons. The goalof the present study was to pharmacologically manipulate the tonic output ofthe LC by systemic administration of IDZ or CLON and measure changes in theresponse properties of simultaneously recorded sensory neurons in terminal fieldregions of the LC efferent system. Spike train activity was recorded from mul-tiple, single neurons in whisker-related areas of the thalamus and cerebral cortexof awake, quietly resting male rats. A bipolar electrode implanted beneath thewhisker pad was used to activate the sensory afferent path to thalamic and corti-cal neurons. Individual neuronal responses to somatosensory pathway activa-tion were monitored before, during, and after i.p. administration of saline, CLON(2 mg/kg), or IDZ (2 mg/kg). Thirty min. after CLON administration, stimulus-evoked activity of thalamic neurons was suppressed from control conditions,whereas responses of cortical neurons were either suppressed or enhanced. CLONadministration also increased trial-to-trial variability of response latency for in-dividual neurons and increased spontaneous activity. By contrast, IDZ (30 min.inter-drug interval) administration either facilitated or suppressed stimulus-evokeddischarge of individual neurons in both the thalamus and cortex. Additionally,IDZ reduced spontaneous discharge and reduced trial-to-trial variability in re-sponse latency. Our preliminary conclusion from these data is that pharmaco-logical manipulation of LC output produces corresponding changes in theresponsiveness of individual thalamic and cortical neurons to peripheral sensorystimulation. Such changes in neuronal response properties are not uniform acrossLC-innervated cell populations and, thus, most likely reflect differential actionsof synaptically released NE on a variety of postsynaptic receptor targets.

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Micro-Infusion of NMDA into the Amygdala Induces Cocaine-Seeking Behavior

Stanislav R. Vorel*, Eliot L. Gardner**, *Dept of Neuroscience, Albert EinsteinCollege of Medicine, Bronx, NY 10461 **Intramural Research Program, NIDA, NIH,Baltimore, MD

The reinstatement paradigm of cocaine-seeking behavior is an animal modelof relapse to cocaine abuse. We addressed the question which neuroanatomicalsite(s) underlie cocaine-seeking by applying electrical brain stimulation. We foundthat electrical stimulation of the ventral subiculum (VSUB) of the hippocampalformation and the basolateral nucleus of the amygdala (AMY) induces cocaine-seeking behavior in anatomically selective and frequency-dependent fashion. Wehypothesized that this effect of VSUB stimulation may depend upon the VSUBconnection with the AMY. We therefore implanted an electrode in the VSUB,bilateral cannulae in the AMY and an intravenous catheter in rats(n=5). Afterrecovery from surgery the rats were trained to self-administer cocaine (0.5mg/kg/inf) in operant chambers equipped with two levers. Active lever presses re-sulted in cocaine delivery, inactive lever presses had no programmed conse-quence. After the acquisition of stable cocaine self-administration for 10 daysthe rats underwent a period of extinction during which saline was substituted forcocaine. When the extinction criterion was met (three consecutive sessions withno more than ten lever presses), the rats received a priming electrical burst stimu-lation of the VSUB (400uA, 200 pulses, 20 trains of 10 pulses at 20Hz, 200msbetween trains) 15 minutes after micro-infusion of 0.5uL vehicle (VEH) orkynurenic acid (KYN)(10ug) bilaterally into the AMY. There was no statisticallyreliable difference in the number of reinstated lever presses after VEH or KYNtreatment. However, when the rats met the extinction criterion again, micro-infusion of 0.5uL NMDA (0.25ug) bilaterally into the AMY reliably inducedrobust and selective cocaine-seeking behavior. We conclude that (1) glutamatergicneurotransmission in the AMY is not necessary for the reinstatement observedafter VSUB electrical burst stimulation; (2)glutamatergic neurotransmission inthe AMY is sufficient to induce cocaine-seeking behavior. This conclusion ex-tends our previous finding that electrical stimulation of the AMY induces co-caine-seeking behavior.

Don’t forget to visit the exhibit area.

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Session Abstracts

Panel • Sunday • 4:30-6:30 PM • Mt. WernerNeurotrophic Factor-induced Dopaminergic Plasticity in AnimalModels of Parkinson’s Disease and Drug Addiction

Organizer: R.C. Pierce; Participants: K.B Seroogy, C.A. Altar, J.R. Taylor, C. Flores

Neurotrophic factors are proteins that promote the development, differentiation,maintenance and survival of neurons. Whereas an overwhelming body of evi-dence indicates that neurotrophic factors play a critical role in neuronal survivalduring development, only recently were neurotrophic factors implicated in plas-ticity in the adult mammalian brain. This panel will focus on the influence ofneurotrophic factors on mesotelencephalic dopaminergic systems. Kim Seroogywill outline the short- and long-term plasticity of brain-derived neurotrophic fac-tor (BDNF), neurotrophin-3, transforming growth factor-alpha, neuregulins andtheir receptors in the dopaminergic nigrostriatal system following a neurotoxicinsult. Tony Altar will review the numerous physiological effects of BDNF ondopaminergic neurons, including electrical, biochemical, behavioral and struc-tural changes. Jane Taylor will focus on the ability of BDNF and glial-derivedneurotrophic factor to enhance the locomotor activating and conditioned reward-ing effects of cocaine. Cecilia Flores will discuss the role of basic fibroblast growthfactor in amphetamine-induced behavioral sensitization. Collectively, these pre-sentations will outline the profound effects of several classes of neurotrophicfactors on dopaminergic systems in the brain, which may play a role in the pro-gression of Parkinson s disease as well as the development of drug addiction.

Panel • Sunday • 4:30-6:30 PM • Storm PeakCytoskeletal Restructuring in the Formation of Dendrites andSynapses

Organizer: R.H. Lenox; Participants: S. Halpain, D. Benson, A. Matus

Alterations in neural function in both the mature and developing nervous systemoften involve activity-dependent changes in neuronal morphology. Cytoskeletalproteins are integral to changes in actin-membrane plasticity and may constituteintriguing future targets for therapeutic interventions in neuropsychiatric diseases.While much as been learned in the past about axonal morphogenesis, the gen-eration of dendritic architecture is just beginning to be characterized. This ses-sion will focus on molecular aspects of the regulation of plasticity at the synapse.Robert Lenox will discuss the role of the actin and membrane-associatedMARCKS protein in neuroplastic events in the developing and adult brain andas a target for psychotropic drugs. Shelley Halpain will present evidence for anexpanded role of MAP2 in signal transduction at both the microtubule and actin

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cytoskeletons. Deanna Benson will discuss the different roles of actin in emerg-ing versus established synapses. Andrew Matus will present evidence that den-dritic spines exhibit rapid actin-based motility that is altered by glutamate receptorsand volatile anesthetics. Together these investigators will initiate debate and dis-cussion among audience members on the key molecular events affecting den-drite growth and synapse formation.

Panel • Sunday • 4:30-6:30 PM • TwilightThe Orbitofrontal Cortex and the Addictions: NeuroimagingStudies

Organizer: B. Adinoff; Participants: L. Porrino, R. Anton, E. London

Approaches to the treatment of substance abuse have focused upon pharmaco-logical antagonism of drug-induced reward and craving, and ameliorating with-drawal and dysphoric states. More recently, interest in cognitive deficits as wellas neuroimaging studies of ¥ substance abusers have highlighted deficits in theprefrontal lobe par ticularly the orbitofrontal cortex. This alternate model ofaddiction suggests that, in an addicted individual, there is an imbalance betweenthe urge to consume drugs and the resistance to that behavior similar to aspectsof obsessive compulsive disorders (OCD). This panel will discuss both primateand human neuroimaging studies exploring the orbitofrontal dysfunction in sub-stance use disorders and the relationship of these findings to impulse disordersand OCD. Linda Porrino will discuss the unique position of the orbitofrontalcortex as a site of long-term neuroadaptation following chronic stimulant self-administration. In the non-human primate, imaging data will be presented de-scribing the topography of the functional response in the orbital and medialprefrontal cortex during the initial, later, and withdrawal phases of cocaine self-administration. Ray Anton will present the Obsessive Compulsive Drinking Scale(OCDS) as a measure of craving and addiction severity in humans. Using fMRI,Anton has assessed brain activity during alcohol cue exposure, observing areasof activation similar to those implicated in OCD. Eydie London will discussselective deficits on the Gambling Task, which is affected by the integrity of theorbitofrontal cortex, in cocaine addicted subjects. These subjects also show im-paired activation of orbitofrontal cortex using PET. Bryon Adinoff will discussstudies in cocaine addicted subjects. Following intravenous administration ofthe limbic-stimulant procaine, these subjects demonstrate increased rCBF in theorbitofrontal cortex compared to controls, suggesting hyperresponsivity of theorbitofrontal cortex following stimulation.

Panel • Sunday • 4:30-6:30 PM • RainbowRhythms and Patterns in Neural Firing

Organizer: C.C. Chow; Participants: A. Bose, D. Terman, C.C. Chow, J. Rubin

The brain is known to exhibit synchronous oscillations and spatiotemporal acti-vation patterns with correlates to behavior and cognition. These states are pre-

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sumed to arise from the collective dynamics of interacting neurons. Several mod-eling approaches both theoretical and computational have been developed tounravel the neural mechanisms underlying these states. The approaches are gen-erally based on either networks of spiking neurons or averaged population ratemodels. Bose will begin by demonstrating how the output of small networks ofneurons can be understood by identifying controlling elements. He will showhow phase precession and the emergence of place fields of rat CA3 hippocampalpyramidal cells can be understood by determining how control of interneuronsin CA3 changes during different behaviors. Terman will then explore the mecha-nisms behind the generation of synchronous oscillations in the basal ganglia inParkinsonian patients. Insights from the model may help to resolve controversiessurrounding the role of the indirect pathway of the basal ganglia in the genera-tion of resting tremor. Chow will follow with a model of localized self-sustainedneuronal activity as seen in working memory. The state requires asynchronouslyfiring neurons and synchrony may actually be used as a turn off mechanism.Rubin will round out the discussion with a model of the spontaneous formationof activity patterns in V1 that generate images in the visual field consistent withsome of the common forms of geometric visual hallucinations. The model in-corporates biologically plausible architecture in which the connections betweeniso-orientation patches in V1 are locally isotropic but non-locally anisotropic. Inthe all the presentations, modeling yields new explanations about the functionalrelationships within the network responsible for the observed neural activity whichwere not evident from experiments alone. These efforts also suggest new sets ofexperiments to test proposed hypotheses.

Panel • Sunday • 4:30-6:30 PM • SkylineThe Biological Clock: Of Molecular Gears, Timing Belts andPost-Transcriptional Modifications

Organizer: R. Baler; Participants: D. Virshup, P. Lowrey, A. Keesler

A complex transcriptional loop lies at the core of the molecular mechanismsthat constitute a circadian master oscillator. Essentially, positive factors can turnon transcription of state variable genes whose products, once they reach a cer-tain threshold, can travel to the nucleus where they can modulate their own aswell as their regulator s transcription. Variations on this theme have now beenreported in a wide range of organisms, including cyanobacteria, arabidopsis,neurospora, drosophila and mice. Given the astonishing reproducibility of pe-riod length one should expect a carefully orchestrated series of regulatory eventscontributing to the production of precise, self sustained, cycles. Expectedly, re-search on the role of post-transcriptional regulatory events in molecularchronobiology is advancing rapidly. As a result, significant progress is being madeon the effect ¥ of specific phosphorylation, guided translocation and degradationevents in establishing the delay devices required for the emergence of a ~24-hrcycle cellular timekeeper.

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Panel • Sunday • 4:30-6:30 PM • SunsetEvolution of Neurohypophyseal Peptide Systems: Why Sex Matters

Organizer: T.R. Insel; Participants: M.S. Grober, F.L. Moore, L.J. Young, G.J. DeVries

More than any other neurotransmitters/modulators, neuropeptides show strik-ing sex differences in their distribution. Prime examples are the mammalian neu-rohypophyseal peptides arginine vasopressin (AVP) and oxytocin (OT), whichare among the most sexually dimorphic systems in the brain. Males of mostmammalian species have more AVP cells in the bed nucleus of the stria terminalisand the medial nucleus of the amygdala and denser AVP fiber projections to thelateral septum than females. Consistent with these neuroanatomic sex differ-ences, AVP has been implicated in a series of male species-specific behaviors,such as territorial displays and paternal behavior. Recently, several studies havebegun to explore the evolutionary origins of these gender differences. AVP andOT are the mammalian representatives of a family of nine amino acid peptidesfound throughout vertebrate evolution. Arginine vasotocin (AVT) is the ances-tral form of AVP; and isotocin (IT) in fish and mesotocin (MT) in tetrapods arethe ancestral forms of OT. Matthew Grober has used a sex changing fish, themarine goby, to demonstrate the relationship between AVT cell size and func-tional gender differences (Neuroreport 7:2945-2949, 1996). Frank Moore pio-neered research on sex differences in AVT systems, using the rough skinned newtto explore the relationship between the number and distribution of AVT cellsand the modulation of reproductive behavior (Gen and Comp Endo, 117: 281-298, 2000). Larry Young has used a comparative approach in mammals to de-fine the molecular mechanisms for the diversity of OT and AVP effects, showingthat natural variations in promoter structure may lead to different patterns ofneuropeptide receptor gene expression (Nature, 400: 761, 1999). Geert De Vrieswas the first to describe sex differences in AVP pathways. His research on bipa-rental behavior in rodents (PNAS 91: 400, 1994) suggests that neural sex differ-ences may not only induce sex differences in behavior, they may compensate forphysiological sex differences, and thereby avoid sex differences in behavior (Beh.Brain Res, 1998). Taken together these presentations will provide an evolution-ary perspective on the origin and function of sex differences in the brain. Thispanel, focused on neuroanatomical sex differences, was designed to complementa proposal from Elliott Albers on the evolution of AVT-AVP effects on socialbehavior.

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Workshop • Sunday • 8:30-10:00 PM • Mt. WernerRole of Noradrenergic NTS Neurons in Drug Abuse:The Forgotten System

Organizer: G. Aston-Jones; Participants: T. De Vries, Y. Shaham, G. Koob, C. O Brien

The A2 norephinephrine (NE) cell group located in the nucleus tractus solitarius(NTS) provides a major noradrenergic innervation of several forebrain areas,including the amygdala, bed nucleus of the stria terminalis (BNST), nucleusaccumbens and hypothalamus. Although NE is implicated in the abuse of sev-eral classes of drugs, and many of the targets of the A2 neurons are involved indrug abuse, this major NE system has received little attention until recently forits possible role in drug addiction. This workshop will discuss new results fromseveral laboratories indicating a prominent role for A2 NE cells in opiate andstimulant abuse. Taco De Vries will present data showing that accumbens NEfrom the NTS is not regulated by autoreceptors, but is regulated by D1 and D2receptors. Also, he will show that following repeated amphetamine administra-tion, accumbens, but not prefrontal cortex NE release (from the locus coeruleus,LC) becomes supersensitive to electrical stimulation. These results show impor-tant differences between the LC and A2 NE systems that may be relevant to drugabuse. Yavin Shaham will present recent data showing that low doses of alpha-2adrenoceptor agonists attenuate stress-induced reinstatement of opiate or stimu-lant self-administration. These effects are not due to actions in the LC system,but instead are mimicked to some degree by lesions of the A2 fiber bundle in theventral midbrain. George Koob will discuss corticotropin-releasing hormone(CRH)/NE interactions in the basal forebrain that contribute to negative emo-tional states associated with drug dependence. Prior observations and his lesionwork indicate that this NE is from the A2 cell group. Finally, Chuck O Brien willdiscuss clinical studies in heroin and cocaine addicts where medications influ-encing the NE system have been used for relapse prevention. The beta-blockerpropranolol has been used in controlled studies and the enhancer of NE trans-mission desipramine has been studied. The results of these trials will be relatedto the available data with laboratory animals.

Panel • Sunday • 8:30-10:00 PM • Storm PeakDopaminergic Projections and Neural Ensembles in PrefrontalCortical-Ventral Striatal Loops

Organizer: P. O Donnell; Participants: A.A. Grace, L.L. Peoples, W. Schultz

The prefrontal cortex and limbic striatal areas are involved a variety of func-tions, including attention, reward and cognition. These functions involve theactivation of neural ensembles in those circuits, and require appropriate levels ofdopamine receptor activation. How is information processing in these circuitsmodulated by dopamine? Are neural ensembles in the accumbens and prefrontalcortex driven or modulated by their dopamine inputs? Is there a correlation be-

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tween dopamine cell firing and accumbens or prefrontal cortical neuron firing?How do such actions of dopamine translate in behavior? These and related ques-tions will be addressed in this panel. Patricio O Donnell will talk about the roleof accumbens and PFC neuron membrane potential states in defining neuronalensembles, as well as on synchronous activity between dopamine cells andaccumbal or prefrontal neurons. Tony Grace will address cortico-subcortical in-teractions, specifically those involved in withdrawal from long-term DA agonistsand recovery from DA depletion; these experiments reveal that the system iscapable of undergoing modulation at a network level as a means of respondingto long-term perturbations, which put the system into a new steady-state con-figuration. Laura Peoples will present data on accumbens neurons recorded frombehaving animals, focusing on neuronal firing during instrumental behavior re-inforced by cocaine. Accumbens neurons exhibit changes in background firingand phasic changes correlated with specific events. Wolfram Schultz will talkabout the relative roles of primate orbitofrontal and striatal neurons in the adap-tation of reward expectation during learning. Overall, the panel will bring to-gether important issues focusing on the role of the simultaneous activity of DA,accumbens and cortical neurons on specific behaviors. In short, DA neuronsparticipate in reinforcement mechanisms by defining ensembles of active PFCand accumbens neurons. As a consequence, a particular behavioral context maybe associated with relative enhancement of excitability of neural ensemble ap-propriate to that context.

Panel • Sunday • 8:30-10:00 PM • TwilightGlial Involvement in Neurodegeneration: The Revenge ofUnintended Consequences

Organizer: S. Griffin; Participants: S. Griffin, S. Barger, L. Van Eldik, J. Schwartz

It is becoming increasingly clear that glial-neuronal interactions that evolved topromote functionality and survival of neurons in the short-term can ultimatelycontribute to neuronal dysfunction and death when they become chronic. Inmany cases, the primary insult impacts on the neurons, made vulnerable by theextremes of their metabolic and physical attributes. Glia respond in ways thataid immediate survival and regenerative attempts. However, repetitive activationor unchecked persistence of such responses may have consequences detrimentalto neuronal function and viability. The studies presented by this panel will ad-dress the mechanisms responsible for such neurodegenerative consequences. Usingthe molecular components of Alzheimer s disease as a framework, Sue Griffinwill introduce the theme with examples of stimuli that initiate the glial response.Joan Schwartz will follow with data from animal and in vitro models demon-strating the neuroprotective contributions of cytokines and glia-derived neu-rotrophic factors. Linda Van Eldik will discuss molecular events involved in theautoregulation of glial reactions, including autocrine feedback loops. Steve Bargerwill discuss neurodegenerative sequelae propagated of activated glial cells, in-cluding the ability of microglia to both release and respond to excitotoxins in

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ways that interact with cellular antioxidant defenses. Finally, Dr. Griffin willdraw from these data sets to illustrate the key testable hypotheses of the overallconcept of glial contribution to neurodegenerative cascades.

Panel • Sunday • 8:30-10:00 PM • RainbowPositive Modulation of AMPA Receptors: Mechanisms andTherapeutics

Organizer: E. Nisenbaum; Participants: D. Bleakman, K. Partin, U. Staubli

Glutamate ionotropic AMPA receptors are tetramers formed by the assembly ofone or more distinct subunits (GluR1-4 or GluRA-D), yielding homomeric orheteromeric receptor-channels, respectively. Additional complexity among AMPAreceptors is conferred by alternative splicing and RNA editing of each subunit.Although all AMPA receptors form cation selective channels, these differencesgive rise to a heterogeneous distribution of receptors in brain with diverse bio-physical and pharmacological properties. Recent data indicate that positive al-losteric modulators of AMPA receptors can dramatically enhance currentsconducted through these channels. Moreover, the modulation of AMPA recep-tors may be restricted to specific subtypes using compounds that act preferen-tially on particular subunits or splice variants. In addition, electrophysiologicalexperiments have shown that AMPA potentiators can augment glutamatergicsynaptic responses and facilitate the induction of NMDA-dependent, long-termpotentiation, suggesting that they may enhance memory formation. Consistentwith this hypothesis, an accumulating body of clinical and experimental evi-dence indicates that positive modulators of AMPA receptors may be therapeuti-cally effective in the treatment of cognitive deficits in a variety of disorders. Thegoal of this panel is to provide an overview of positive modulators of AMPAreceptors. K. Partin will review the AMPA receptor family and present her re-search investigating the molecular mechanisms of action of AMPA receptorpotentiators in recombinant cell lines. E. Nisenbaum will discuss the activity ofseveral classes of AMPA receptor potentiators at native receptors and their im-pact on synaptic transmission. U. Staubli will describe her studies demonstratingthat AMPA potentiators can promote synaptic plasticity and enhance memoryencoding. D. Bleakman will discuss the therapeutic implications of positive modu-lation of AMPA receptor function.

Panel • Sunday • 8:30-10:00 PM • SkylineNew Teeth on an Old Saw: Evaluating Cholinergic Mechanisms inBrain Aging

Organizer: D. Ingram; Participants: N. Greig, R. Perez-Polo, J. Joseph

Since the late 1970 s the cholinergic hypothesis (ACh) has provided a useful av-enue for research on brain aging by elucidating mechanisms involved in the age-related decline in cognitive function as well as the neurodegeneration observedin Alzheimer s disease (AD). The three compounds used clinically for treating

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AD (tacrine, donepezil and rivastigmine) are cholinesterase inhibitors produceddirectly from research supporting this hypothesis. Despite this therapeuticprogress, many investigators and clinicians recognize the limited effectiveness ofthese treatments for AD and thus question the further utility of the ACh hypoth-esis. To address this issue, our panel will discuss new twists and turns for thehypothesis that argue for it s enduring viability within a multifactorial interactivesystem. To this end, D. Ingram will discuss the interaction of the ACh systemwith the glutamatergic (Glu) system and the possibilities for polypharmaceuticalapproaches for cognitive enhancement. Specifically, combined indirect stimula-tion of the ACh and Glu system synergistically enhances learning in aged ratscompared to stimulation of either system separately. N. Grieg will describe anew class of acetyl-cholinesterase and butrylcholinesterase inhibitors that notonly provide cognitive enhancement in rodent models but also reduce produc-tion of the amyloid precursor protein and its putatively toxic peptide, b-amyloid,implicated in the pathogenesis of AD. Interestingly, the mechanism for this ac-tion may be through non-ACh actions. R. Perez-Polo will expand the hypothesisto include the involvement of oxidative stress (OS) that increases the vulnerabil-ity of ACh neurons to neurodegeneration in AD compared to other neuronaltypes. A major factor is the NF-kB transcription factor, which is highly sensitiveto OS, and can bind to sites on the promoters for both choline acetyltransferaseand Bcl-x. Alterations in NFkB binding in the aging brain can promote commit-ment to apoptosis but also reduce inflammation. Finally, J. Joseph will also dis-cuss the involvement of OS in brain aging and its actions through the cholinergicsystem. Using COS7 cells as a model system, he will describe how there may beregionally selective vulnerability to OS that is the result of differences in OSsensitivity among muscarinic ACh receptor subtypes.

Panel • Sunday • 8:30-10:00 PM • SunsetSuccess Comes from Having the Right Connections: Integrating theCNS and PNS

Organizer: D. Chambers; Participants: E. Bell and J. Begbie

A primary goal of developmental neurobiologists is to elucidate the mechanismsunderlying the initial specification of both the central and peripheral nervoussystems (CNS/PNS), how these early events are further elaborated upon and thetwo systems subsequently integrated. Recent work has begun to shed light onboth the developmental processes and molecular effectors responsible for manyaspects of establishing and connecting neuronal circuitry. The CNS arises fromthe neural plate, which folds upon its anteroposterior (AP) axis to form the neu-ral tube. The imposition of AP identity on the neural tube is crucial for the laterspatial ordering of differentiated neurons. David Chambers will present a briefreview of the current understanding of how the nervous system is patternedalong the AP axis. This will be followed by a presentation of the results of acDNA screen designed to identify novel players involved in the specification offore/mid and hindbrain territories. In particular, we will focus upon the identity

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and functional role of some of the novel genes implicated in the specification ofrhombomere 1 (r1) in the hindbrain, the developmental precursor of the adultcerebellum. Significant studies have demonstrated that genes implicated in re-gional patterning of the CNS not only establish pattern in the CNS by assigningneuronal identity, but also impart pattern to the periphery. Esther Bell will presentevidence indicating that individual Hox gene action (Hoxb1) is sufficient for thespecification of distinct motor neuron identity as well as establishing the appro-priate connectivity of motor axon projections between the hindbrain and its pe-ripheral targets. The molecular mechanisms involved in the formation of thePNS have until recently remained elusive. With the advent of new molecularmarkers and recombinant proteins significant advances have been made in theunderstanding of the induction of the cranial neurogenic placodes, source ofcranial sensory neurons. Jo Begbie will firstly describe the molecular nature ofthe induction of the epibranchial placodes. This will be followed by recent datathat has cast light upon the mechanisms involved in the delamination and guid-ance of neuroblasts to the ganglion, and their subsequent innervation of appro-priate hindbrain entry point. Together, this panel will draw together recentadvances in our knowledge of the molecular events driving the specification andintegration of the embryonic CNS and PNS.

Panel • Monday • 7:30-9:30 AM • Mt. WernerIntegrated Regulation of Synaptic Transmission by Ca++ Channels,K+ Channels, And Mitochondrial Ca++ Uptake

Organizer: W. A. Catterall; Participants: I. Forsythe, L. Kaczmarek, T. Scheuer, D.Lipscombe

Neurotransmitter release is critically dependent on the Ca++ transient inducedby action potential propagation into the presynaptic nerve terminal, having thirdpower dependence on Ca++ entry. The level of Ca++ achieved in presynapticterminals is influenced by the duration of the action potential, the extent of acti-vation of presynaptic Ca++ channels, and the activity of intracellular organellessuch as the endoplasmic reticulum and mitochondria that actively accumulateCa++. This panel will consider the integrated regulation of Ca++ levels and syn-aptic transmission by each of these processes. Catterall will serve as chair andwill give a brief introduction to the structure of Ca++ channels and their role insynaptic transmission. Forsythe will describe recent work on synaptic transmis-sion at the calyx of Held in the auditory system, a synapse in the medial nucleusof the trapezoid body containing a large presynaptic terminal that is amenable tovoltage clamp analysis. He will present recordings of presynaptic Ca++ currentsand correlate them with efficacy of synaptic transmission as a function of thepattern of stimulation and changes in intracellular Ca++ concentration. He willalso describe the effects of mitochondrial Ca++ uptake on calcium dynamicsand synaptic transmission in this specialized synapse. Kaczmarek will presentstudies of voltage-gated K+ channels in the calyx of Held. He will describe regu-

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lation of the high threshold Kv3.1 potassium channel and how phosphorylationof these channels by casein kinase 2 and protein kinase C may be necessary forthe precise timing of transmitter release at different stimulus frequencies, as re-quired for correct processing of sensory information in the auditory system.Scheuer will describe the regulation of cloned and expressed P/Q-type Ca++

channels, the Ca++ channel type present in the calyx of Held. He will show thatthese Ca++ channels are regulated by interactions with SNARE proteins, G pro-tein bg subunits, and Ca++. Ca++ entering through these channels interacts withcalmodulin and binds to a site in the C-terminal domain, causing facilitation andthen inactivation as a function of stimulus duration and frequency. This mecha-nism may contribute to paired-pulse and post-tetanic facilitation at synapses.Lipscombe will show that the function of presynaptic Ca++ channels is alsoregulated by alternative splicing of their mRNAs. Alternative splicing of N-typeCa++ channels at multiple sites alters the voltage dependence and kinetics oftheir gating, providing an additional mechanism of functional diversity that isessential for signaling in complex nervous systems of higher organisms.

Panel • Monday • 7:30-9:30 AM • Storm PeakGroup I Metabotropic Glutamate Receptors: Role in Pain, Epilepsy,Movement Disorders, and Brain Injury.

Organizer: R. Schwarz; Participants: J. Conn, A. Faden, A. Kingston, and. C. Woolf

The eight G-protein-coupled metabotropic glutamate receptors (mGluRs) aregrouped into three families based upon similarities in sequence homology andsignal transduction pathways. Group I receptors(mGluRs 1 and 5) are positivelycoupled to phospholipase C and their activation results in the mobilization ofintracellular Ca++ and the production of diacylglycerol. In contrast, Group II(mGluRs 2 and 3)and Group III (mGluRs 4,6,7,and 8) are negatively coupled toadenyl cyclase. Experimental results, which include the use of newly identifiedsubtype selective compounds, have shown that Group I receptors play a criticalrole in a variety of physiological processes, such as pain processing, memoryand learning, motor function, seizures, and neurodegeneration following braininjury. Following a brief introduction to mGluR nomenclature and receptor char-acterization by Roy Schwarz, Clifford Woolf will discuss the role of Group Ireceptors within spinal pathways involved in pain perception and their functionin various types of pain. Jeffrey Conn will focus on the localization of mGluRswithin basal ganglia pathways and present data on their activity in the control ofmotor function and potential therapeutic utility in movement disorders. AlanFaden will present results showing that Group I mGluRs are involved inexcitotoxic cell injury/death with differential effects being observed on the pro-cesses of necrosis and apoptosis. Ann Kingston will describe the pharmacologyof potent and selective Group I agonists/antagonists and demonstrate their ac-tivity in various in vitro and in vivo models.

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Panel • Monday • 7:30-9:30 AM • TwilightExactly How is Dopamine Involved in MethamphetamineNeurotoxicity?

Organizers: T. Hastings, D. Sulzer; Participants: R. Gainetdinov, G. Ricaurte, T.Hastings, D. Sulzer

Methamphetamine (METH), is both a widely abused psychostimulant and aneurotoxin that produces selective degeneration of dopamine neurites in cultureand in vivo. While glutamate and temperature modulate METH neurotoxicity,the initial step appears to be due to oxidative stress following oxidation of dopam-ine. Roles have been proposed for 1) formation of extracellular oxyradicals bydopamine released by METH or 2) cytosolic oxyradical stress following dopam-ine redistribution from synaptic vesicles. Raul Gainetdinov will discuss the rolesof the dopamine uptake transporter (DAT) and the central vesicular monoaminetransporter (VMAT2) in METH toxicity as determined from results with knock-out mice. George Ricaurte will also address roles for DAT and extracellularoxyradicals in rodent and primate models. Teresa Hastings will address the spe-cific neurotransmitter pools involved and the likely toxic downstream productsof dopamine oxidation such as quinones and cysteinyl-dopamine, as well as thepotential protein modifications that may lead to neurite loss. David Sulzer willdemonstrate how postnatal neuronal cultures can be used to demonstrate intrac-ellular oxidation of dopamine, the differentiation of synaptic vesicle, cytosolic,and extracellular pools, and for elucidation of the role of VMAT2 sequestrationof dopamine in axonal degeneration.

Panel • Monday • 7:30-9:30 AM • RainbowThe HPA Axis: A Paradigm for Both Short and Long TermPlasticity in CNS Responsiveness

Organizer: G. Aguilera; Participants: J. Herman, S.L. Lightman, G. Aguilera, J. A.Cidlowski

Glucocorticoids, the end hormone of the hypothalamic pituitary adrenal (HPA)axis, influence behavior, metabolism, growth, reproductive and immune func-tions, and precise regulation of their secretion is critical for homeostasis spe-cially under stress conditions. Regulation of the system involves the hypothalamicpeptides, corticotropin releasing hormone (CRH) and vasopressin (VP), and anentire range of genomic and secretory changes through complex interactionsamong receptors, signaling systems and transcription factors. This panel willexplore recent advances in the mechanisms underlying the plasticity of the HPAaxis responses during adaptation to different types of chronic stress. This in-cludes analysis of how utilization of different neural pathways and regulators,and the interaction of multiple cellular signaling systems can modulate the ex-pression of components of the HPA axis and alter the sensitivity to glucocorti-coid feedback. After a brief overview of neural pathways, neuropeptides and

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neurotransmitters activated by different stressors, James Herman will presentstudies showing biphasic changes in HPA axis activity after middle age in rats,which correlate with changes in GABA biosynthesis in stress-regulatory path-ways. Stafford Lightman will describe how specific subgroups of serotonergicneurons are activated during stress and can be sensitized by repeated stress. Theseneurons are especially responsive to CRH and seem to represent an importantpathway for the mediation of the HPA response to stress. Greti Aguilera willshow that regulation of pituitary receptors for CRH and VP play a critical roledetermining ACTH responses, and will demonstrate mechanisms by which theinteractive actions of CRH, VP and glucocorticoids regulate levels of these re-ceptors at transcriptional and posttranscriptional sites. Finally, John Cidlowskiwill discuss the molecular mechanisms by which the glucocorticoid receptor re-presses gene expression, and how signaling pathways induced by activation ofplasma membrane receptors could modulate feedback inhibition by glucocorti-coids during stress. Discussion of these topics will provide new insight on themultiple mechanisms determining plasticity of the HPA axis during stress andaging, as well as opening novel perspectives for the development of diagnosticand therapeutical tools for stress related disorders.

Panel • Monday • 7:30-9:30 AM • SkylineImmune Regulation, CNS Pathogenesis and TherapeuticInterventions in Multiple Sclerosis

Organizer: R. Jones; Participants: G. Konat, P. Dore-Duffy, H. Offner, A. Vandenbark

T lymphocyte-mediated immune responses directed against myelin antigens causeparalytic inflammation and demyelination in the CNS. Animal models have beenused to elucidate many of the molecular and cellular mechanisms of pathogen-esis and this understanding has in turn facilitated a rationale approach towarddevelopment and testing of experimental treatments. This panel will present ex-perimental results demonstrating mechanisms of tissue damage, cellular andimmune processes regulating the progression of disease, and potentially effectivetreatment strategies based on our understanding of these mechanisms. RichardJones will describe studies demonstrating a direct relationship between cell-me-diated immune responses to non-neural antigens and susceptibility to T cell-me-diated CNS inflammation. Gregory Konat will present his current findingsregarding molecular and cellular mechanisms of oxidative damage to the oligo-dendrocyte-myelin unit during CNS inflammation, and their implications forloss of function and potential treatments. Paula Dore-Duffy will discuss the roleof the microvascular pericyte as it pertains to blood brain barrier function, im-mune regulation and therapeutic responses. Arthur Vandenbark will describeTCR therapy in MS patients and mechanisms of immune regulation involvingTCR-specific T cells. Halina Offner will present experimental results demon-strating that estrogen potentiates the clinical benefit of the TCR vaccine in EAE,and the implications of these results for treating MS.

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Panel • Monday • 7:30-9:30 AM • SunsetThe Raphe and Breathing: What Is the Connection?

Organizer: G. Richerson; Participants: E. Nattie, L. Kubin, A. Berger, J. Ramirez

The raphe nuclei are the primary source of serotonin in the brain, and project toall major respiratory nuclei. The neurotransmitters of the raphe (serotonin, TRHand substance P) can each stimulate breathing. The specific role of the raphe inmodulating respiratory output is the subject of active research whose implica-tions extend beyond the issues specific for the respiratory system. This panel willdiscuss the roles that the raphe play in regulating respiratory output based onrecent data at both the system and cellular levels. Eugene Nattie will describe theeffect on ventilation of local changes in CO2 and pH within the raphe, and howthis is modified by the sleep/wake cycle. Leszek Kubin will review the role ofserotonin receptors in activation of upper airway motoneurons and the expres-sion profiles of different neurotransmitter receptor mRNAs in dissociated hypo-glossal motoneurons and other brainstem cells. Albert Berger will describemechanisms of serotonergic modulation of hypoglossal motoneuron excitabil-ity, and will also focus on recently uncovered mechanisms by which glycinergicsynaptic transmission is reduced by 5-HT and potentiated by ethanol. NinoRamirez will discuss the role of raphe transmitters, including serotonin and sub-stance P, on generation of rhythmic bursting in the PreBotzinger complex inbrain slices. He will describe recent data indicating that putative respiratory out-put generated in this region is dependent on ongoing release of serotonin fromcoexisting raphe neurons within the slice. Taken together, these data indicatethat raphe neurons modulate ventilation at multiple sites and through a varietyof mechanisms, and disruption of their activity may impair respiratoryrhythmogenesis and weaken respiratory output. Thus, the raphe nucleus may becritical for production of normal respiratory output. The mechanisms by whichthe raphe modulate the respiratory system may also occur in other motor andsensory systems.

Panel • Monday • 4:30-6:30 PM • Mt. WernerNew Vistas on Prefrontal Cortex: From Neuroanatomy toComputational Modeling

Organizer: M. Banich; Participants: J. Giedd, A. Belger, M. Banich, R. O Reilly

The goal of this panel is to provide an overview of new insights into the organi-zation and function of prefrontal cortex from its cellular organization to thenature of its computational processes. Traditionally prefrontal cortex has beenconsidered to be critical for working memory, from which its role in executivefunction and psychopathology has been conceptualized to arise. In this panel wewill provide evidence that the role of prefrontal cortex can be better thought ofas playing a larger role in the control of behavior, providing a mechanism forintegrating contextual information and selecting information that is critical for

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task performance. To examine this issue, we will discuss converging evidencefrom different levels of investigation: neuroanatomy, neurophysiology,neuroimaging, and computational neuroscience. First, Jay Giedd will describerecent findings from neuroimaging that suggest continuing morphological devel-opment in prefrontal regions in humans during adolescence. He will discuss theimplications of these findings for changes in behavior and cognition during thisdevelopmental time period. Next, Marie Banich will summarize the recent floodof functional neuroimaging studies focusing on working memory and executivefunction in humans that yield activation in prefrontal regions. She will provide aconceptualization of prefrontal function that integrates the role it plays in theseprocesses. Third, Randy O Reilly will present an overview of computationalmodels of prefrontal function. He will discuss the insights that can be providedby these models as to how the underlying biology of frontal cortex can give riseto the various functions to which it has been ascribed. Finally, Aysenil Belgerwill discuss evidence that modulation of NMDA receptor function in prefrontalcortex is critical for executive control processes. She will present evidence fromboth healthy individuals and individuals with schizophrenia.

Panel • Monday • 4:30-6:30 PM • Storm PeakTorsin, Parkin, Alpha-synuclein and Tau: Four Horsemen of theBasal Ganglia

Organizer: D. Standaert; Participants: D. Standaert, M. Schlossmacher, D. Miller, M.Hutton

Mutations in several proteins cause diseases of the basal ganglia, including dys-tonia, Parkinson s disease, and frontotemporal dementia with parkinsonism linkedto chromosome 17 (FTDP-17). This Panel will review the current state of knowl-edge of the function and pathogenetic mechanisms of these proteins. DavidStandaert will discuss torsinA, a 332 amino acid protein encoded by the DYT1gene. A 3 base pair deletion in DYT1 is responsible for autosomal dominantearly onset torsion dystonia. The function of torsinA is ¥ unknown, but it hashomology to the AAA family of ATPases, which serve as chaperones in pro-tein trafficking. The gene is highly expressed in dopaminergic neurons of thehuman substantia nigra pars compacta, suggesting that the mutation may pro-duce impairment of dopaminergic transmission. Michael Schlossmacher willdiscuss the protein parkin. Mutations affecting the 500 kb parkin gene have beenidentified as the cause of autosomal recessive parkinsonism in families of di-verse ethnic backgrounds. He will discuss recent efforts to elucidate the functionof parkin, including studies of the expression pattern of parkin in rodent andhuman brains, and transfection experiments. Two different point mutations inthe gene for the protein alpha-synuclein have been found to cause autosomaldominant Parkinson s disease. In addition, aggregates of alpha-synuclein are foundin non-genetic Parkinson s disease, diffuse Lewy body disease, and multiple sys-tem atrophy. David Miller will review the biology of alpha-synuclein, and theexpression of the gene in normal brain and neurodegeneration. Tau is a phos-

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phoprotein that binds to microtubules. Michael Hutton will discuss the identifi-cation of missense and splicing mutations in tau associated with FTDP-17, whichhas lead to a re-evaluation of the role of tau in neurodegenerative disease. Hewill also discuss the current understanding of the mechanisms by which themutations lead to disease and recent efforts to model neurofibrillary tangle for-mation in transgenic mice.

Panel • Monday • 4:30-6:30 PM • TwilightMultimodal Multidimensional Digital Developmental Atlas of theMouse Brain

Organizer: R.E. Jacobs; Participants: G. Burns, D. Laidlaw, R. Moats, A. Toga

Gene expression patterns, receptor domains, arrays of innervation in the devel-oping nervous system, cell lineage patterns, and a host of other types of biologi-cal processes in embryonic and adult animals occur in three spatial and onetemporal dimensions. The creation of a comprehensive framework to encom-pass diverse imaging and genetic information about the mouse holds tremen-dous promise for integrating genotype and phenotype throughout the animal sdevelopment. A digital atlas provides such a framework. Digital atlases providea means to put specific data within the context of normal specimen anatomy,analyze the information in three (or more) dimensions, and examine relation-ships between different types of information. In this panel we discuss initial ef-forts at collecting data through several methodologies (blockface imaging, classicalhistology, CT, & MRI), amalgamating the various data structures into a coher-ent whole, annotating the 3D images (i.e. delineating anatomical structures),incorporating non-anatomical data from other formats (e.g. gene expression data),viewing the information, and disseminating the information. Arthur Toga willdiscuss blockface imaging and data integration issues. Gully Burns will reviewthe organization and dissemination of complex neuroanatomical informationvia databases and the web. David Laidlaw will show ways of visualizing com-plex multidimensional information. Rex Moats will discuss uses and abuses ofmicroCT in the context of the mouse atlas and Russell Jacobs will do the samefor microMRI.

Panel • Monday • 4:30-6:30 PM • Rainbow“Death and the Lysosome”—New Insights into Neuronal CeroidLipofuscinoses

Organizer: H. Geller; Participants: S. Hofmann, P. Lobel, D.Pearce, B. Davidson

Neuronal ceroid lipofuscinoses (NCLs) are a group of neurodegenerative lyso-somal storage diseases that are invariably fatal during childhood, adolescence orearly adulthood. Within the past several years, the molecular basis for several ofthese diseases have been identified using positional cloning methods as well asenzymological and proteomic approaches. Several genes encode lysosomal en-zymes while others encode membrane proteins of unknown function. The pre-

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senters will provide an overview of the discovery of these genes, their functions,hypotheses about why loss of function leads to neurodegeneration and discusspotential treatment strategies. Sandy Hofmann will talk about the molecular patho-genesis of infantile NCL, which is caused by a deficiency in palmitoyl-proteinthioesterase (PPT). Peter Lobel will discuss late infantile NCL and congenitalovine NCL, which are caused by deficiencies in the lysosomal proteases CLN2p/tripeptidyl peptidase I and cathepsin D. Dave Pearce will discuss the molecularcharacterization of the of CLN3 gene deficient in juvenile NCL (Batten s Dis-ease). Finally, Bev Davidson will review novel gene and other therapeutic ap-proaches for restoring the function of these proteins in affected individuals.

Panel • Monday • 4:30-6:30 PM • SkylineSee No Evil, Hear No Evil, Smell No Evil—The Origins of HeadPlacodes

Organizer: M. Westerfield; Participants: H. Chu, R. Karlstrom, R. Grainger, M.Westerfield

The majority of cells in the nervous system derive from the neural plate. In thehead, however, specialized sets of cells, termed placodes, arise at the lateral edgeof the anterior neural plate and form the ear, nose, lens and anterior pituitary.The origins of these placodes and the inductive mechanisms that lead their speci-fication and morphogenesis are largely unknown. This panel will compare andcontrast the results of recent embryological and genetic experiments aimed atunderstanding how placodes arise. Rolf Karlstrom will present genetic analysisthat implicates the Hedgehog signaling pathway in specification of the anteriorpituitary and lens placodes. Monte Westerfield will describe lineage analysis thathas revealed the morphogenetic movements that lead to formation of the olfac-tory placode. Rob Grainger will describe embryological experiments that havedefined critical intermediate tissue interactions leading to lens determination andthe onset of lens differentiation. We will also discuss several transcription factorsthat have been implicated in the early stages of nose (Westerfield), lens (Grainger)and ear (Hsin Chu) determination.

Panel • Monday • 4:30-6:30 AM • SunsetThe Bane of Cancer Pain: A Role for Peptides and Protons?

Organizer: G. Wilcox; Participants: G. Wilcox, A. Beitz, G. Davar, P. Reeh

The difficulty in treating cancer pain, particularly in late stages of disease andafter metastasis to bone and other tissues, contributes significantly to patientmorbidity and may derive in large part from a paucity of knowledge about itsbasic mechanisms. Two tumor types in which pain is a significant problem, pros-tate and breast cancer, often metastasize to bone. In order to understand howthese bony metastases might contribute to pain, an animal model for metastaticcancer pain has recently been developed. Osteolytic fibrosarcoma cells (NCTCclone 2472 cells derived from a spontaneous connective tissue tumor found in

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C3H mice) implanted in the femur or around calcaneous or humerus bones ofC3H mice promote osteoclastic reduction of bone mass and release cytokinesincluding TNF-alpha, ET-1 and NGF. The reduction of bone mass and releaseof cytokines is accompanied by hyperalgesia and nociceptor sensitization. GeorgeWilcox will introduce the behavioral and electrophysiological characteristics ofthe model. Al Beitz will discuss the neurochemical characterization of the model,including tissue dialysis for TNF, ET-1 and NGF and immunocytochemistry.Gudarz Davar will present evidence that exogenously applied ET-1, a potentvasoconstrictor and mitogen that is oversecreted by metastatic prostate and breastcancer cells, can selectively drive nociceptor activity in a receptor-dependent fash-ion. Finally, Peter Reeh will discuss the possibility that tumor growth along nervesheaths and into nervous tissue may activate archaic transduction mechanismspresent all along unmyelinated nerve fibers. Finally, the panel will discuss thepossibility that reduced pH accompanying osteoclast activation in bone may in-voke acid-sensing mechanisms, mediated either by ASIC or VR-1, in C-fiberaxons, releasing CGRP and causing neur ogenic inflammation of the nerve.We expect a lively debate over the nociceptive vs. neuropathic nature of cancerpain.

Workshop • Monday • 8:30-10:00 PM • Mt. WernerGene Profiling in the Nervous System Using Nucleic AcidMicroarrays

Organizer: J. McGinty; Participants: G. Dent, K. Merchant, B. Meurers, G. Uhl

High density nucleic acid microarrays provide the ability to monitor gene ex-pression profiles in a given tissue for thousands of genes simultaneously. In con-trast to other hybridization techniques that examine one selected gene at a time,microarrays offer the advantage of examining changes without any pre-existingbias or selection process based on the current state of knowledge. Thus, ratherthan a single or a handful of genes, expression profiles of thousands of gene enmasse can be generated and compared between two experimental conditions.With several iterations of this process, a focus on a few critical genes involved ina specific physiological/ pathological process can be obtained. In this workshopwe will discuss the potential, the advantages, and the disadvantages of differenttypes of nucleic acid microarrays1,2 in their application to neuroscience research.Technical issues to be addressed will include the sensitivity and reliability ofcDNA vs. oligo arrays, radioactivity vs. fluorescence, and bioinformatics. Dr.Kalpana Merchant will discuss her studies of genomic events underlyingpsychostimulant sensitization in the prefrontal cortex and neostriatum, whichhave uncovered a potential role of the ubiquitin-proteasome pathway. Dr. GershamDent will describe an anatomical dissection of the mouse amygdaloid complexinto subregions followed by microarray analysis of subregion-specific gene ex-pression. Dr. George Uhl will discuss murine chip evaluations from single andmultiple gene knockout mice and acute or chronic responses to psychostimulantsand opiates. Dr. Bernd Meurers will discuss his research combining T7-based

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RNA amplification with microarray technology applied to identified neuronalcell types isolated with laser capture microdissection, particularly gene expres-sion patterns in basal ganglia nuclei after dopamine depletion.

Audience participation will be encouraged.

1. The Chipping Forecast. Nature Genetics suppl. 21:1-60, Jan 1999.

2. Serafini et al., Of neurons and gene chips, Current Opin. Neurobiol. 9:641-644, 1999.

Workshop • Monday • 8:30-10:00 PM • Storm PeakGlutamatergic Mechanisms in the Pathophysiology of Drug Abuse

Organizer: J. Weiner; Participants: F. Valenzuela, J. Kauer, O. Manzoni , A. Bonci

Converging lines of evidence suggest that glutamatergic mechanisms may play acentral role in mediating the reinforcing effects of a wide variety of addictivedrugs. For example, within the nucleus accumbens (NAc), ethanol, cocaine,amphetamine, and morphine have all been shown to depress glutamatergic exci-tation of the primary GABAergic output neurons of this brain region. Recentevidence also suggests that chronic exposure to a number of drugs of abuse canresult in long-lasting changes in glutamatergic synaptic transmission. The goalsof this workshop are to bring together researchers that study a variety of drugs ofabuse to stimulate a lively debate regarding a) the mechanisms through whichthis diverse array of addictive drugs impinge upon glutamatergic neurotransmis-sion and b) the relevance of glutamatergic mechanisms to the addictive proper-ties of these drugs. F. Valenzuela will start the workshop off by providing a briefreview of the various receptor classes that make up the glutamate receptor fam-ily and will then discuss the long-term effects of ethanol exposure on glutamatereceptor expression and function in cultured hippocampal neurons. J. Weinerwill discuss the role of kainate receptors in the NAc and hippocampus and presentevidence that ethanol can inhibit kainate receptor activity in these brain regions.J. Kauer will describe the effects of amphetamine on long-term depression ofglutamatergic synapses in the ventral tegmental area. O. Manzoni will presentanatomical evidence of the expression of CB-1 receptors on excitatory afferentsto medium spiny neurons in the NAc and the functional consequences of acuteand chronic activation of these receptors.

Panel • Monday • 8:30-10:00 PM • TwilightGenetic Variation in Human Catecholamine Systems: Impact onNeurobiology and Susceptibility to Psychiatric Disorders

Organizer: D.R. Weinberger; Participants: M.F. Egan, D. Goldman, J. Cubells

Although genetic variation accounts for a major portion of susceptibility to manyneuropsychiatric disorders, finding specific genes has been problematic becauseof genetic and clinical heterogeneity. The recent development of high through-

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put variant detection methods has led to the discovery of non-conservative and/or functional variants in a number of candidate genes, such as those involved incatecholamine neurotransmission. A major clinical challenge is to determinehow these variants affect human neurobiology and susceptibility to psychiatricdisorders. David Goldman will begin by describing variant detection methods,recently discovered polymorphisms in genes related to catecholamine neurotrans-mission and results of association studies in several psychiatric disorders. MichaelEgan will review methods for detecting genes associated with psychiatric disor-ders and how intermediate phenotypes can improve power. As an example, hewill present data suggesting that a functional variant in the COMT gene affectsprefrontal function and risk for schizophrenia. Joe Cubells will present evidencethat functional variation at the dopamine beta hydroxylase (DBH) locus affectsvulnerability to cocaine-induced paranoia. Finally, Daniel Weinberger will re-view recent neuroimaging data demonstrating the in vivo effects of the dopam-ine transporter and COMT on dopamine neurotransmission and prefrontalphysiology, respectively. He will close by summarizing the pitfalls involved ingoing from genetic polymorphism to understanding variation in human neurobi-ology to clinical applications that could improve the lives of patients.

Workshop • Monday • 8:30-10:00 PM • Rainbow5-HT2a Receptors and Forebrain Function: From the Cell to theClinic

Organizer: L. Parsons; Participants: G. Marek, B. Pehek, K. Cunningham, J.H.Krystal

A wide variety of serotonin (5-HT) receptors are involved in cognitive process-ing. Among these particular attention has been focused on 5-HT2A receptorsbased on evidence that these receptors mediate the psychotomimetic effects ofhallucinogenic drugs and are involved in both the pathogenesis and treatment ofneuropsychiatric disorders such as schizophrenia. 5-HT2A receptors have beenobserved on GABAergic cells in many brain regions, cortical pyramidal neu-rons, midbrain mesolimbic and mesocortical dopamine neurons, and cholinergicprojections of the pontine nuclei. Accordingly there are a wide variety of neuralmechanisms through which 5-HT2A receptors may participate in psychiatricdysfunction. The goal of this workshop is to create an interactive discussion ofthe role played by 5-HT2A receptors in the regulation of forebrain function, withparticular regard to thalamo-cortico-striatal circuits. A multidisciplinary frame-work will be presented to foster discussion. Gerard Marek will present and dis-cuss electrophysiological evidence that activation of 5-HT2A receptors locatedon thalamocortical terminals stimulates cortical glutamate release. Evidence thatgroup II mGluR activation in turn suppresses transmitter release induced by 5-HT or other presynaptic releasing agents will also be discussed. Betsy Pehek willdiscuss in vivo neurochemical studies on the role of 5-HT2A receptors in theregulation of the mesocorticolimbic dopamine pathway along with correspond-ing immunohistochemical data on the localization of relevant 5-HT2A recep-

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tors. Kathryn Cunningham will focus on the involvement of 5-HT2A receptorsin the regulation of the discriminative stimulus and locomotor stimulant effectsof cocaine but not the psychotropic amphetamine derivative MDMA. The pos-sible cellular mechanisms through which these effects are mediated will be dis-cussed with regard to immunohistochemical and immediate early gene data. JohnKrystal will provide a clinical perspective on the involvement of 5-HT2A recep-tors in the etiology and treatment of schizophrenia.

Panel • Monday • 8:30-10:00 PM • SkylineFree Radicals in Alzheimer’s Disease. Where Do They Come From?

Organizer: S. Richardson; Participants: A. Butterfield, M. Smith, M. Vitek

Free radicals, long suspected of causing the deterioration of the body s organs inthe aging process, have been demonstrated to play active roles in variousneurodegenerative conditions as well. Over the past 10 years or so, evidence ofexcessive free radical activity has been found not only in situations of acute braindamage such as cerebral ischemia and head trauma, but also in chronic progres-sive neurodegenerative conditions such as Alzheimer s disease. Among the manyquestions suggested by these observations are: What is the initial source of theexcessive free radicals? What keeps the level of oxidative stress elevated for de-cades in the chronic neurodegenerative diseases? and Are free radicals the causeor the consequence (or both) of neurodegeneration? Previous panels and work-shops at WCBR have not focused on these specific aspects of oxidative stress inneurodegeneration. This panel, and the ensuing discussion, will contribute toanswering these questions with respect to Alzheimer s disease. Allan Butterfieldwill discuss oxidative stress in Alzheimer s disease and the formation of freeradicals by _-amyloid. Mark Smith will describe other sources of free radicals inAlzheimer s disease and the effects of free radicals on biological processes. MikeVitek will present the effects of apolipoprotein-E isoforms in Alzheimer s dis-ease ¥ and their role in controlling oxidative stress by regulating nitric oxide pro-duction. Steve Richardson will outline the neurotoxicity of, and the formationof free radicals by, a 5 amino acid sequence that is found in _-amyloid, and inproteins from three viruses associated with neurodegeneration: HIV-1, Japaneseencephalitis virus and Newcastle disease virus. Each panelist will also addressthe issue of free radicals as the primary aggressor in, or merely the byproduct of,neurodegeneration in Alzheimer s disease.

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Workshop • Monday • 8:30-10:00 PM • SunsetA Decade of Hits (and Misses): HeterologousExpression of Nicotinic Acetylcholine Receptorsin Mammalian Cells.

Organizer: R.J. Lukas; Participants: N.S. Millar, J.M. Lindstrom, R.J. Lukas, K.J.Kellar

Nicotinic acetylcholine receptors (nAChR) play critical physiological rolesthroughout the brain and body. They also are targets for the tobacco alkaloid,nicotine, dependence on which promotes use of tobacco products. nAChR alsoare potential targets for a number of novel therapeutic agents for treatment ofmood, cognitive, or sensory disorders. nAChR exist as a diverse family of mol-ecules assembled as different combinations of genetically-distinct subunits. Het-erologous expression of nAChR in Xenopus oocytes has been very useful towardfundamental characterization of diverse nAChR subtypes. This session aims tosummarize successes and failures to date in stable, heterologous expression ofnAChR in mammalian cells. It will also elaborate theoretical and technical con-siderations generally relevant to stable, heterologous expression of any kind ofcomplex, transmembrane molecule and advantages or limitations of the tech-nique. Neil Millar will introduce the problem of selection of a cell host. JonLindstrom will discuss strategies that led to the first success in heterologous ex-pression of non-muscle nAChR in a mammalian cell. Ron Lukas will describealternative strategies that led to success in stable, heterologous expression ofnAChR as functional entities. Ken Kellar will outline approaches for character-ization of a variety of heterologously expressed nAChR subtypes. All partici-pants and the audience will discuss how vector and host cell choices mightinfluence success or failure in expression. Potential roles played by chaperones,cell type-specific(?) patterns of membrane protein folding, sorting and traffick-ing, and metabolic regulation (e.g., calcium buffering) in successful expressionwill be elaborated. Findings from studies of wild-type and mutant nAChR thathelp to elucidate basic principles of ligand-gated ion channel structure and func-tion also will be presented.

Panel • Tuesday • 7:30-9:30 AM • Mt. WernerDimerization of G Protein-coupled Receptors—FunctionalImplications

Organizer: L. Devi; Participants: M. Bouvier, S. George, K. Mackie, Y. Patel

The ubiquity and functional importance of G protein-coupled receptor (GPCR)dimerization (or oligomerization) has only recently become appreciated. Dimer-ization of GPCR s affect their signaling, impacting phenomena that are of inter-est to a broad range of neuroscientists. Dimerization with an identical receptor

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(homodimerization) is a widespread and important in ligand binding and activa-tion of several GPCR s. Dimerization with non-identical GPCR s(heterodimerization) is also common. Heterodimerization gives rise to receptorswith novel binding and signaling properties. Heterodimerization may explainsome of the discrepancies between the behavior of native receptors in brain mem-branes and cloned receptors in expression systems. The aim of this panel is todiscuss the mechanisms and implications of GPCR dimerization using mem-bers of several different GPCR families as examples. Lakshmi Devi will intro-duce the field and give a brief overview. Michel Bouvier will speak on assessingGPCR oligomerization in living cells. Ken Mackie will discuss the role of CB1cannabinoid receptor dimerization in cell lines and brain. Susan George willpresent work relating to the dimerization of dopamine and serotonin receptorsand its implication in structure, trafficking, and signaling. Yogesh Patel will de-scribe the consequences of heterodimerization between somatostatin and dopam-ine receptors.

Panel • Tuesday • 7:30-9:30 AM • Storm PeakApoptotic Mechanisms: Are They also Used to Regulate SynapticStability?

Organizer: E.A.Jonas; Participants: J.M. Hardwick, M.P. Charlton, J. Zimmerberg

The molecular mechanisms that commit a cell to survive or to die in response toexternal signals include the activation of Bcl-2 family proteins. These proteins,acting either alone or in combination with endogenous mitochondrial channelproteins, are believed to alter the permeability of mitochondrial membranes. Withsome Bcl-2 family proteins, this permeability change leads to the release of cal-cium and cytochrome c from the mitochondria and subsequent cell death. Incontrast, other members of the Bcl-2 family are able to prevent these events, andconfer resistance to subsequent apoptotic signals. Neurons, however, differ frommany other types of cells in that death may not be an all or none decision, butcan be localized to specific synaptic connections. In particular, in the absence oftrophic factors from the environment or from their postsynaptic targets, axonterminals may retract and effectively die, while other terminals from the sameneurons can become stabilized. The very high density of mitochondria in synap-tic terminals suggests that these organelles may play a role in the decision ofwhether a terminal dies or survives. Marie Hardwick will introduce Bcl-2 familyproteins and their molecular modes of action in neurons. Milton Charlton willdiscuss the factors that determine different patterns of synaptic calcium dynam-ics and their relevance to synaptic stability. Liz Jonas will present recent findingson the actions of Bcl-2 family proteins on mitochondrial membranes in intactpresynaptic terminals. Finally, Josh Zimmerberg will discuss potential mecha-nisms for the formation of the ion channels and the a poptotic pore by Bcl-2family proteins.

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Panel • Tuesday • 7:30-9:30 AM • TwilightCell and Gene Therapy for Basal Ganglia Disorders

Organizer : O. Isacson; Participants: J. Kordower, C. Svendsen, K.S. Kim

The selective degeneration of dopaminergic (DA) synapses and cell loss seen inthe basal ganglia system can produce Parkinson s disease and other types of basalganglia dysfunction, such as Huntington s disease. In attempts to restore neu-ronal function for these systems, gene therapy allows a targeted delivery ofneuroprotective transmitter related genes to provide enhanced or normalizedfunction. In the exceptional case, new synapses could be produced by regenera-tive simulation or by implantation of naive cells from embryonic or stem cellorigin. The aim of this panel is to present recent data on gene therapy usingneuroprotective agents such as GDNF or neuroimmunophilins and new oppor-tunities available through gene transcription control of neural transmitter genesin normalizing basal ganglia function. Recent findings on stem cell biology andthe capacity of transplanted embryonic cells to develop into phenotypic matureneurons will be discussed. First, Ole Isacson will describe the various neuronaland ES cell types used for repairing the dopaminergic systems in models ofParkinson s disease. Second, Dr. Jeff Kordower will present his primate work onthe DA system and GDNF lenti-virus gene therapy. Third, Clive Svendson speakson embryonic cell development, including humans, and transplantation para-digms with relevance to basal ganglia function. Fourth, Kwang-Soo Kim willspeak on transcriptional regulators for catecholaminergic function in the centralnervous system, specifically the (TH) and DBH promoters and how these can beaffected by Nurr 1, Phox 2A/2B, and PTX3. This panel will provide an overviewof novel new cell and gene therapy efforts at the very basic science level withinsight into the way basal ganglia plasticity can be modified.

Panel • Tuesday • 7:30-9:30 AM • RainbowThe Price of ‘Ecstasy’: The Functional Consequences of MDMANeurotoxicity

Organizer: G. A. Gudelsky; Participants: B. Yamamoto, G. Ricaurte, A. Fleckenstein,S. White

The single or repeated administration of large doses of the amphetamine analog3,4-methylenedioxymethamphetamine, MDMA or Ecstasy, produces a long-termdepletion of the brain concentration of 5-HT, as well as the number of 5-HTuptake sites. The issue of whether these persistent neurochemical effects ofMDMA reflect neurotoxicity remains controversial. Important to an assessmentof the potential for MDMA-induced neurotoxicity is an examination of the long-term functional consequences of the repeated administration of this drug. Theparticipants in this panel will discuss electrophysiological, biochemical, behav-ioral, and human cognitive and PET imaging studies that document abnormal

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pharmacological and physiological responses following the repeated administra-tion of MDMA. The effects of MDMA on amine transporters will be discussedby Drs. Fleckenstein and Ricaurte. Dr. Ricaurte also will discuss the extent towhich behavior and cognition are altered in human abusers of MDMA. Dr.Yamamoto will focus on the effects of the repeated administration of MDMAon the subsequent neurochemical responses to stress. Finally, the effects ofMDMA administration on postsynaptic neurotransmitter function will be ad-dressed by Dr. White. Through a discussion of these data from studies involvingdiverse methodological approaches in animals and humans the participants willencourage a discussion of the potential risk (i.e., consequences) for human abus-ers of MDMA.

Panel • Tuesday • 7:30-9:30 AM • SkylineEpitope Spreading: A Novel Concept with Great Relevance toMultiple Sclerosis

Organizer: M.C. Dal Canto; Participants: P. Lehmann, V. Tuohy, S. Miller

Epitope spreading is characterized by widening of the immune response toepitopes distinct from, and non-cross-reactive with, the initiating epitope. Thisphenomenon has great implications for a variety of immune-mediated humandiseases, including Multiple Sclerosis (MS). The goal of this panel is to presentboth human and animal studies on epitope spreading, to explore its mechanisms,and to suggest future therapeutic approaches. Paul Lehmann will explore whetheractivation of T cells against secondary epitopes takes place at the periphery or inthe target organ in an autoimmune model of MS. In addition, he will discuss therole of microbial products, such as pertussis toxin, as important second signallinks. Vincent Tuohy will report on human studies of MS and will illustrate theconcomitant occurrence of two events, i.e., the spontaneous regression of theprimary established autoimmune repertoire associated with disease onset, andthe emergence of secondary T cell repertoires that recognize new self-antigensas disease progresses. He will point at the importance of this innate plasticity ofself-recognition as an opportunity to develop customized immunotherapy in thefuture. Steve Miller will illustrate the phenomenon of epitope spreading in thebest recognized viral model of MS, induced by Theiler s murine encephalomy-elitis virus (TMEV). He will show how a first phase of demyelination, producedby by-stander type mechanisms, driven by CD4+ lymphocytes specific for viralepitopes, is followed by a chronic phase, in which new T cell specificities againsta number of myelin epitopes participate in the protracted destruction of myelin.Dal Canto will follow up on these studies by showing that these new T cell speci-ficities are functionally relevant as they are able to produce demyelination in anorganotypic culture system. These studies are relevant to MS in the context ofthe widely held hypothesis of combined viral-immune-pathogenesis in this hu-man disease.

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Panel • Tuesday • 7:30-9:30 AM • SunsetFragile X Mental Retardation Syndrome: ClinicalDiagnosis and Symptoms, Genetic and MolecularMechanisms and Neural Correlates

Organizer: W. Greenough; Participants: D. Nelson, R. Hagerman, E. Berry-Kravis

Fragile X syndrome (FXS) is the leading cause of inherited mental retardation,yet its details remain remarkably unknown among both clinical practitioners andbasic scientists. In large part this reflects the recency of widespread knowledgeof the karyotype and even more recent cloning of the gene and discovery of thenature of the genetic disorder. FXS involves an trinucleotide repeat in the regula-tory region of the FMR-1 gene which is expanded from a longer-than-normalrepeat number in the carrier (premutation) female to a still longer repeat in theaffected offspring. Similar triplet repeat expansions have recently been describedin the etiology of a number of genetic disorders. The past few years have seen adramatic explosion in our knowledge of the clinical characteristics, brain abnor-malities and molecular biology associated with FXS. There is reason to believethat FMRP, the protein encoded by FMR-1, which is synthesized near synapses,may play a fundamental role in synaptogenesis and patterning of connections indevelopment and possibly also in adulthood. FMRP is an RNA-binding proteinand it is thought that it may be involved in RNA transport and/or protein syn-thesis regulation. This panel brings together clinician-researchers and basic sci-entists familiar with human clinical symptoms, the molecular and cellular biologyof FMRP expression and synaptic protein synthesis, the neuropathology of thesyndrome, experimental gene therapy, and the characteristics of a model FMR-1 knockout mouse. The session is intended to inform a general audience.

Panel • Tuesday • 4:30-6:30 PM • Mt. WernerOrigin and Fate of New Neurons in the Adult Brain

Organizer: H. Scharfman; Participants: A. Alvarez-Buylla, T. Palmer, J. Parent, H.Scharfman

One of the most exciting areas of Neuroscience in recent years has been therapidly growing field of adult neurogenesis. It is now fully recognized that newneurons are born in the adult nervous system. In addition, research continues toelucidate the various ways multipotent stem cells arise, migrate, and can be ma-nipulated experimentally. This panel will discuss the fundamental aspects of theseprocesses and their potential applications to neurological disorders such as epi-lepsy and stroke. Each speaker will provide an overview of fundamental cellbiological principles related to their work, followed by new data. Arturo Alvarez-Buylla will discuss the identification of stem cells in the adult subventricularzone and subgranular layer of the hippocampus. New data will be presented onthe organization of these germinal layers and on the role of bone morphogenicproteins (BMPs), and the BMP inhibitor Noggin, in the formation of new neu-

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rons. Theo Palmer will focus on the fate of stem cells that are taken from variousparts of the nervous system, amplified in culture, and then returned to novel siteswithin the adult brain. These studies emphasize the plasticity of stem cells andtheir potential use to repair or modify diverse areas of the nervous system. JackParent will describe the effects of prolonged seizures or focal ischemia on neu-ronal precursor proliferation and migration in the adult rat forebrain subventricularzone-olfactory bulb system, and potential implications for brain repair strate-gies. Helen Scharfman will discuss physiological characteristics of granule cellsthat are born after pilocarpine-induced status epilepticus. Recordings of the newly-born cells in hippocampal slices show that they develop intrinsic properties thatare indistinguishable from normal adult granule cells, but synchronize abnor-mally with area CA3 hippocampus pyramidal cells. The unexpected findingsconcerning the origin, migration, and differentiation of young neurons that haveresulted from studies of neural stem cells and neurogenesis in the adult brain willprovide an atmosphere of controversy intended to stimulated debate. We willalso discuss the potential use of adult neural progenitors to treat various braindiseases.

Panel • Tuesday • 4:30-6:30 PM • Storm PeakNew Horizons in the Mechanisms Mediating the Effects of Estrogenin the Brain: The Evidence for Membrane Receptors

Organizer: J.B. Becker; Participants: C.S. Watson, D.M. Dorsa, M.J. Kelly, J.B. Becker

The steroid hormone estrogen has been shown to have rapid effects on neuronalactivity that cannot be explained by its actions to induce transcription by bindingintracellularly to ERa or Er_. This panel will provide an overview of the evi-dence that estrogen can act on neurons and pituitary cells at the level of theplasma membrane to induce rapid, transient, changes in cellular activity. CherylWatson will provide evidence that the membrane receptor for estradiol is actu-ally ERa that is associated with the extracellular membrane. One effect of estro-gen that is thought to be mediated by this mechanism is the rapid release ofprolactin from pituicytes. Dan Dorsa will discuss the mechanisms through whichestrogen modulates activity in growth factor and cAMP signaling pathways. Hewill also present evidence that the known n uclear estrogen receptors, alphaand beta, can act at the cell membrane to initiate these effects. These effects ofestrogen are thought to play a role in the neuroprotective effects of estrogen.Martin Kelly will discuss the effect of estrogen to modulate the activity of G-protein coupled receptors on hypothalamic neurons, and the potential role thisplays in regulation of the reproductive cycle. Jill Becker will conclude with adiscussion of the mechanisms through which estrogen affects neural activity inthe striatum, and the implications of these findings, in general, for our under-standing of how steroid hormones act in the brain. These rapid, non-traditionaleffects of estrogen may play a role in reproductive function and behavior. Theymay also be involved in the effects of estrogen on cognitive processes, and forgender differences in responses to drugs of abuse.

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Panel • Tuesday • 4:30-6:30 PM • TwilightDopamine and Serotonin Transporters: Siblings DoNot Always Behave the Same

Organizer: A. Frazer; Participants: A. Frazer, A. Galli, G. Gerhardt, M. Sonders

The serotonin transporter (SERT) and dopamine transporter (DAT) are key cel-lular targets for several classes of psychoactive drugs, including antidepressantsor psychostimulants. These transporters are members of the same gene family.Nevertheless, important differences exist in both their regulation and the confor-mational changes elicited by drug binding. This panel will illustrate such differ-ences. Aurelio Galli will present data, using multiple techniques, showing thatexposure of HEK-293 cells stably transfected with human DAT to a gonistssuch as amphetamine causes internalization of this transporter with a conse-quent decrease in transporter capacity. The effects of amphetamine are not mim-icked by a DAT antagonist (cocaine); rather, cocaine blocks the effects ofamphetamine. By contrast, Alan Frazer will show that chronic exposure of ratsto SERT antagonists (sertraline, paroxetine) cause a time-dependentdownregulation of SERT binding sites that is accompanied by decreased SERTfunction in vivo. Greg Gerhardt will show, using both chronoamperometry andmicrodialysis, that acute administration of either antagonists of the SERT orterminal autoreceptors for 5-HT have a much more modest effect on the clear-ance of serotonin (5-HT) than antagonists of either the DAT or terminalautoreceptors for dopamine (DA) do on the clearance of DA. Dr. Sonders hasbeen studying structure-activity relationships of substrates for the cloned DATand SERT proteins, employing both electrophysiological and biochemical tech-niques. He will report that even though these related transporters carry many ofthe same substrates (amphetamines, phenethylamines, tryptamines, MPP+), DATand SERT have evolved different recognition criteria for substituent features ofthe solute molecules. Additionally, each transporter appears to have multiplefunctional modes for translocating various substrates.. All the speakers will em-phasize how such differences between DAT and SERT could have marked ef-fects on the functional consequences of psychoactive drug administration.

Panel • Tuesday • 4:30-6:30 PM • RainbowProteases in the Neurodegeneration of Alzheimer Disease (AD):Chickens or Eggs?

Organizer: R. Nixon; Participants: R. Nixon, L-H. Tsai, K. Wang, C. Cotman

The demise of neurons in (AD) is a protracted process that takes months or evenyears after the first cytoskeletal pathology appears. While few disagree that pro-teases mediate this degenerative process, the question of which hydrolases, ifany, are the most attractive therapeutic targets is unanswered. Are neurons so

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dysfunctional by the time they clog with tau aggregates that blocking executionof the agonal event(s) is counterproductive? Are there pathogenic proteolyticevents, other than those generating A_ peptide, that gradually cripple neuronalfunction before setting off the proteolytic chain reaction that kills the cell? Likethe chicken and egg riddle, the issue of which protease is activated first in trigger-ing neurodegeneration is complicated. In different forms of cell death includingapoptosis, calpains, cathepsins or other proteases may become activated eitherupstream or downstream of caspase activation. Further complicating the analy-sis in AD is evidence that end stage proteolytic events may occur in one part ofthe neuron, such as the synapse, well before the rest of the cell is irreversiblycompromised. Calpains, cathepsins and caspases are all activated during the neu-ropathological progression of AD. The aim of this panel is to review data impli-cating these proteases in neurodegeneration and in the early development ofpathologic lesions in AD. Cause and effect in their activation will be consideredas a springboard for discussing the proteases as therapeutic targets. Ralph Nixonwill present the concept of AD as a disorder of activated proteases and focus onthe contribution of early and progressive activation of the lysosomal system toAD pathogenesis in humans and animal models. Li-Huei Tsai will present datalinking calpains to the neurotoxicity of A_ and other AD-related stresses viacdk5-induced alterations of the cytoskeleton. Kevin Wang will discuss the inter-play of calpains and caspases in different patterns of neurodegeneration and itsrelevance to AD pathogenesis. Carl Cotman will present evidence supportingthe involvement of apoptotic mechanisms in AD and the particular contributionof caspases to the degenerative process.

Panel • Tuesday • 4:30-6:30 PM • SkylineThe Fruit Fly, Drosophila Melanogaster: A Model System for theStudy of Complex Behaviors

Organizer: J. Hirsh; Participants: R.L. Davis, J.C. Hendricks, U. Heberlein, J. Hirsh

This panel will present recent advances using the fruit fly, Drosophilamelanogaster, as a model for studying complex behaviors. A common themelinking each of these systems is that responses are modulated by cAMP signal-ing, and in each case there is ample evidence showing that the phenomena understudy show similarity with behaviors seen in higher vertebrates. Ron Davis willdiscuss advances in the analysis of genes, signaling pathways and brain struc-tures involved in learning and memory. Joan Hendricks will talk about the mo-lecular genetics of rest, a sleep-like state in flies, and how it is regulated by cAMPsignaling via CREB proteins. Ulrike Heberlein will discuss the molecular genet-ics underlying responses to drugs of abuse, focussing primarily on alcohol. JayHirsh will discuss progress in dissecting the pathways regulating cocaine respon-siveness and sensitization to repeated cocaine exposures.

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Panel • Tuesday • 4:30-6:30 PM • SunsetNGF and GDNF: The Yin and Yang of UnmyelinatedN o c i c e p t o r s

Organizer: D. Wright; Participants: D. Molliver, C. Stucky, K. Albers

Small unmyelinated primary sensory neurons that convey nociceptive informa-tion are uniquely tied to nerve growth factor (NGF) for their embryonic survival.Recent studies have established that nociceptive neurons undergo dramaticchanges during early postnatal development. The goal of this panel is to providenew information about nociceptive subpopulations using anatomical, electro-physiological and molecular approaches. Derek Molliver will illustrate how no-ciceptive neurons differentiate postnatally into subpopulations that are distinctin their neurochemistry, anatomy, and neurotrophin-responsiveness. Dr. Molliverwill demonstrate that a peptidergic nociceptive population maintains its relianceon nerve growth factor, while a separate non-peptidergic population undergoes adynamic shift in their neurotrophic responsiveness from NGF to glial cell-linederived neurotrophic factor (GDNF). Recently, it has been suggested that bothpeptidergic and nonpeptidergic nociceptors play an important role in the estab-lishment of chronic pain states, but that peptidergic nociceptors are particularlyimportant in inflammatory conditions and the nonpeptidergic nociceptors maybe more important in neuropathic states. To address this issue, Dr. Cheryl Stuckywill provide new information about the functional role(s) of peptidergic andnonpeptidergic nociceptors using both in vitro and in vivo electrophysiologicalapproaches. Next, Drs. Kathryn Albers and Doug Wright will discuss the bio-logical actions of GDNF on non-peptidergic nociceptors. Using new transgenicmice that overexpress GDNF in the skin, Dr. Albers will discuss the effects ofelevated levels of target-derived GDNF on nociceptive subpopulations. Finally,using a murine model of diabetic neuropathy, Dr. Wright will present work onthe fate of nonpeptidergic nociceptors in diabetes and provide evidence thatGDNF has therapeutic potential in treating neuropathic nonpeptidergicnociceptors.

Workshop • Tuesday • 8:30-10:00 PM • Mt. WernerMechanisms of Neuronal Migration and Synapse Stabilization inNeocortical Development

Organizer: S. Juliano; Participants: K. Nakajima, K. Herrup, A. Kriegstein

Factors that underlie neuronal migration, the formation of neocortical layers,and subsequent intrinsic circuitry are important features of CNS development.Interruption of these processes leads to human disorders ranging from seizuresto lissencephaly. Clearly, a range of molecules provide cues that direct neuronsalong their path, prompt them to g o or stop , and guide the normal laminarformation of neocortex. This workshop focuses on a limited number of such

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instructive molecules, including those identified as a result of the reeler and Cdk5deficient mouse, and their roles in neocortical layer formation and stabilizationof laminar properties. The speakers will provide an overview of several mecha-nisms that contribute to successful or disrupted migration and stabilization ofneocortical layers. Kazunori Nakajima has identified several alternate splicingisoforms of reelin that may have unique roles in brain development. Theseisoforms are truncated to exclude a repeat region that contains the binding sitesfor receptors. These and several other forms of reelin will be discussed in relationto their function in cortical development, including participation in migrationand laminar formation. Sharon Juliano will present a model of disrupted braindevelopment in which Cajal Retzius (CR) cells containing reelin are disorderedand misplaced from layer 1 following interruption of mitosis due to toxicity earlyduring corticogenesis. She will discuss whether the reelin positive CR cells canresult in abnormal cortical migration patterns due aberrant signals from unusu-ally placed reelin containing cells in the cortical plate and intermediate zone.Karl Herrup will discuss the significance of a different protein, the Cdk5 protein,in neuronal migration into the cerebral cortex. He reports that layer 1 and layer 6neurons do not require Cdk5, nor do the GABAergic interneurons that migratefrom the ganglionic eminence. A different set of neurons that reside in layers 2-5,however, are incapable of populating cortical plate in the absence of this kinase,suggesting its importance in guiding a subset of neurons into the neocortex.Arnold Kriegstein has identified a widespread, transient, GABAergic networkin layer 1 during cortical development. Neurites of intrinsic GABAergic corticalneurons, including a subset of CR cells and neurogliaform cells potentially con-tribute to this plexus, but the primary source is a projection from the zona incertaof the ventral thalamus. Studies of the developing neocortex indicate a role formembrane depolarization as a necessary step in associative processes includingthe conversion of silent synapses to functional synapses. A widespread excita-tory GABAergic projection within layer 1 could provide the membrane depolar-ization necessary to induce long-term changes in synaptic efficacy andconsolidation of the formation of neocortical layers. This workshop provides anoverview of a specific constellation of molecules and neuronal elements, andwill permit discussion of their differential roles in layer formation and stabiliza-tion of circuits in the neocortex.

Workshop • Tuesday • 8:30-10:00 PM • Storm PeakElectrophysiology of Incentive Motivation: Can We “Measure” theAffective States of Goal-directed Behavior?

Organizer: K. Anstrom; Participants: T. Robinson, G. Schoenbaum, K. Anstrom, W.Schultz

Historically, the coordinated activity of the corticomesolimbic system, most no-tably the VTA dopamine neurons and their projections to the nucleus accumbens,prefrontal cortex and amygdala, is thought of as the neural substrate drivinggoal-directed behavior. Classic reinforcement theories have cited the release of

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dopamine in these projection areas as a common endpoint of both drug andnatural reinforcement. However, this same dopamine system is activated by thecues predicting reward rather than the reinforcer itself, leading to the proposalthat the corticomesolimbic system should be thought of as a lear ning systemrather than a r eward system. Incentive motivation is defined as the process bywhich stimuli that predict future rewards, such as food, sex or drugs, shape be-havioral strategies during goal-directed behavior. But can we measure the valueof a stimulus in discrete areas of the corticomesolimbic system? Electrophysiol-ogy in awake, behaving animals provides insight to the specific functions of in-terconnected areas of the corticomesolimbic system as stimuli acquire and areused to obtain reward in context-specific paradigms. Terry Robinson will elabo-rate upon the concept of incentive-motivation driving goal-directed behaviors.Geoff Schoenbaum will discuss the roles of interconnected regions of prefrontalcortex and amygdala in linking incentive value and action. Kristin Anstrom willdemonstrate context-specific, orbitofrontal coding of taste cues in an alcoholself-administration paradigm. Wolfram Schultz will close the session with a dis-cussion integrating the roles of striatal and prefrontal components of thecorticomesolimbic system in goal-directed behavior.

Workshop • Tuesday • 8:30-10:00 PM • TwilightIs Peer Review Peerless?

Organizer: C. Atwell; Participants: M. Martin, N. Steneck

Was your grant funded or your manuscript accepted for publication? If so, youprobably think that peer review in science rewards the truly deserving and hascompetent, unbiased reviewers. If not,..... This workshop will address both factsand perceptions related to the current state of peer review in neuroscience. Stafffrom NIH and NSF will lead a discussion of the relative merits of panel vs. mailreview and separation of review from program decisions. Initial results from thenewly formed working groups to advise NIH on the effectiveness of the neuro-science study sections will be presented and discussed. Nick Steneck, an histo-rian of science and ethicist, will lead a discussion of research on the integrityand fairness of peer review, especially in publications. Discussion will center onhow peer review can be improved to facilitate the advance of neuroscience.

Panel • Tuesday • 8:30-10:00 PM • RainbowPediatric Epilepsy: From the Clinic to Basic Mechansims

Organizer: G.W. Mathern; Participants: M. Levine, S.N. Roper, J. Veliskova

Pediatric epilepsy is a common neurological problem, and when refractory tomedical management and from a symptomatic cause may need to be treatedwith surgery. The clinical and surgical treatment of children with refractory epi-lepsy from discrete etiologies has evolved considerable in the last 15 years, as hasour understanding of age-specific basic mechanisms of seizure generation. Thispanel will focus on clinical and basic science mechanisms of epileptogenesis in

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the developing brain. Mathern will describe the different pediatric epilepsy syn-dromes and substrates that often require surgical treatment. Emphasis will beplaced on cortical dysplasia (CD) which is the most com-mon etiology in young children. Levine will describe re-cent findings using in vitro visualization and electrophysiology techniques inbrain slices from human pediatric neocortical tissue removed at surgery that showhypo- and hyperexcitable cellular and synaptic features. Roper will discuss ani-mal models of CD, their mechanisms of epileptogenesis, and how the animalmodels relate to humans. Veliskova will highlight the important of deep brainstructures, such as the substantia nigra pars reticulata in the control and synchro-nization of seizures, and how this region shows sex- and age-specific differencesin rats.

Workshop • Tuesday • 8:30-10:00 PM • SkylineBeyond Lozenges and Dandruff: Zn2+ Toxicity in the CNS

Organizer: I. Reynolds; Participants: E. Aizenman, D. Choi, J. Weiss

Zn2+-mediated cell death has been suggested to contribute to neuronal damageassociated with ischemia and epilepsy. Zn2+ is present in synaptic vesicles, canbe released from neurons upon depolarization, and translocates from presynap-tic sites into postsynaptic neurons to induce cell death. Additionally, a large frac-tion of neuronal Zn2+ that may contribute to neurodegeneration is reversiblycomplexed to proteins such as metallothionein and Zn2+ finger-containing tran-scription factors. However, the mechanisms by which neurons manage Zn2+,and the cellular targets of Zn2+ mediated cell death pathways are poorly under-stood. This workshop will discuss various aspects of Zn2+-mediated damage inthe CNS with a particular focus on the controversies surrounding the mecha-nisms of zinc homeostasis and the processes by which Zn2+ kills neurons. IanReynolds will discuss the problems associated with measuring free Zn2+ in neu-rons and introduce the concept of neuronal Zn2+ homeostasis. John Weiss willlead a discussion on the relationship between Zn2+ influx into mitochondria andgeneration of free radicals. Dennis Choi will give us his latest thoughts on theeffects of Zn2+ on cellular energy status. Elias Aizenman will challenge the au-dience with a model that links the release of intracellular zinc with an apoptoticcascade. Zinc lozenges will be distributed to all participants that pose questionsto the panelists, except for those who are using dandruff control shampoo, forwhom such lozenges may be dangerous.

Panel • Tuesday • 8:30-10:00 PM • SunsetVasopressin/Vasotocin: Key Regulators of Social Behavior AcrossSpecies?

Organizer: E. Albers; Participants: S. Boyd, D. Maney, J. Winslow

Vasopressin and vasotocin are members of a large family of structurally andfunctionally related neuropeptides. These two nonapeptides were initially identi-

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fied as neurohypophysial hormones that regulate hydromineral balance. How-ever, more recently, these neuropeptides have been found to be important regula-tors of a variety of different types of social behavior in species ranging from fishto primates. In fact, agonists and antagonists of vasopressin and its non-mam-malian analog vasotocin have been found to turn certain social behaviors on oroff by their actions in specific brain sites.

This panel will review the rapid progress being made in identifying the role ofthese peptides in the control of reproductive, communicative and agonistic be-haviors across vertebrate taxa. The session will begin with Sunny Boyd review-ing the interaction of androgens and vasotocin in the control of reproductivebehaviors in amphibians. Donna Maney will then discuss the anatomical andbehavioral evidence implicating vasotocin in avian communication. Elliott Alberswill review the role of vasopressin containing circuits in the control of severalforms of agonistic and communicative behavior in hamsters and how hormonesand social experience alter these behaviors by modulating vasopressin receptors.Finally, Jim Winslow will review efforts to describe the interaction of social ex-perience with brain nonapeptide systems for the normal development of socialbehavior in non-human primates.

Panel • Wednesday • 7:30-9:30 AM • Mt. WernerThe Map Kinase Signaling Pathway and Synaptic Plasticity:Activators, Regulators and Effectors

Organizer: P. Chapman; Participants: D. Kuhl, J. Naranjo, J. Yin

We have know for quite some time that synaptic plasticity in the CNS of adultmammals can be induced by transient changes to the intracellular calcium con-centration of neurons. It is also clear that the establishment of plasticity dependsupon the activation of protein kinases and phosphatases, many of which arecalcium sensitive. More recently, evidence has suggested that long-lasting synap-tic plasticity requires modification of gene expression, and that the link betweentransient changes in calcium and long-term plasticity will involve the recruit-ment and/or modulation of inducible transcription factors. MAP kinase is apotentially important link in this pathway, as it can be recruited and modulatedby both calcium-dependent and neurotrophin-dependent second messengers, andcan in turn activate important transcription factors including the CREB family.Jerry Yin will describe evidence linking protein kinase C to activation of CREBand subsequent memory formation in both flies and mice. Paul Chapman willdiscuss the consequences of deleting upstream activators of MAP kinase on syn-aptic function and plasticity in several brain regions. JosT Naranjo will presentdata demonstrating the multiplicity of ways in which gene expression can beregulated by DREAM, a calcium-sensitive repressor of gene transcription whichitself is subject to regulation by protein kinase A through CREM. Dietmar Kuhlwill discuss an important class of immediate early genes that are induced inhippocampal neurons by stimuli that activate plasticity related signaling path-ways and translated locally at activated synapses. As a group, we will discuss

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strategies for making sense of the ever-increasing number of molecules that havebeen implicated in synaptic plasticity, and how these might one day be related tolearning and memory.

Panel • Wednesday • 7:30-9:30 AM • Storm PeakMechanisms of CNS Regeneration and Repair

Organizer: W.J. Streit; Participants: W. Tetzlaff, T. Hagg, S.R. Whittemore

The limited ability of central neurons to regenerate after injury is due to a num-ber of factors including a lack of trophic support and an inability of injuredneurons to express appropriate pro-regenerative genes. The goal of this panel isto summarize neuronal and glial cell responses that occur after CNS injury anddiscuss potential strategies for repair. Wolf Tetzlaff will describe how rubrospi-nal and corticospinal neurons respond to axotomy in terms of gene expressionpatterns and neuronal atrophy, and how these processes are affected by exog-enous application of BDNF. Jake Streit will contrast glial cell responses in regen-erating and non-regenerating systems, and suggest mechanisms by which glialcells may provide trophic support to injured neurons. He will emphasize theimportance of neuronal-glial signaling and discuss potential signaling molecules.Theo Hagg will present strategies for the use of neurotrophic factors in attractingsevered fiber tracts across injury and scar sites, guide lengthy outgrowth, induceappropriate innervation of the original target and induce (or prevent when nec-essary) collateral sprouting of uninjured fibers. Scott Whittemore will discussthe use of pluripotent stem cells for CNS repair. Specifically, he will describehow stem cells genetically modified to initiate lineage-specific differentiation intoneurons, oligodendrocytes, or astrocytes are used to facilitate neuron replace-ment, remyelination of demyelinated axons, and engender axonal regeneration,respectively.

Panel • Wednesday • 7:30-9:30 AM • TwilightMechanisms of Addiction: The Brain Opioid System Ain’t Just forOpiates Anymore

Organizer: T.S. Shippenberg; Participants: J.J. Frost, C.J. Evans, J.F. McGinty, C.T.Napier

Opiate drugs exert their effects by binding to opioid receptors, but it is increas-ingly recognized that non-opiate drugs of abuse modulate the activity of endog-enous opioid systems (EOS). Furthermore, their activation can profoundly alterthe effects of psychostimulants and alcohol. Stimulants cause changes in opioidpeptide concentration, opioid peptide mRNA, and opioid receptor regulation.The administration of _-opioid antagonists or knock-out of this receptor reducesthe behavioral effects of stimulants. In contrast, k-receptor activation attenuates,whereas k-receptor deletion exacerbates the behavioral and neurochemical ac-tions of these agents. The effects of other abused drugs, such as THC and etha-

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nol, also depend on intact EOS. This panel will address the role of _-, d- and k-opioid systems in modulating the neurochemical and behavioral effects of non-opiate drugs of abuse and provide an anatomic and mechanistic basis for theirinteraction with EOS. McGinty will provide evidence that k-agonists and d-an-tagonists suppress the behavioral effects of amphetamine and decrease amphet-amine-evoked extracellular levels of dopamine and glutamate in the dorsal andventral striatum. Whereas k-receptors appear to directly affect glutamate releaseas revealed by their localization in axon terminals and inhibition of glutamateefflux in synaptosomes, the effects of d-receptor manipulation appear indirect.Napier will discuss how regulation of neurotransmission by the _- and k- EOSoccurs at the level of limbic outputs and that EOS influence neuronal activity inbasal ganglia, cortex and, other regions of the brain s motive circuit. The impli-cations of this regulation for understanding interactions of EOS with abuseddrugs will be discussed. Evans will address mechanisms by which these drugscould ultimately influence opioid system function, including the role of opioidreceptor internalization and intracellular trafficking. Frost will discuss advancesin PET imaging of opioid receptors in substance abuse, including studies of co-caine and alcohol dependence. Data demonstrating _-receptor up-regulation inbrain regions involved in reward and a correlation between up-regulation, crav-ing and relapse will be presented. Changes in _-receptor binding after acute co-caine administration, likely due to cocaine-induced opioid peptide release, willalso be discussed. Integrating cellular and neurophysiological data with PETstudies of human substance abuse will be a key theme of this panel.

Panel • Wednesday • 7:30-9:30 AM • RainbowPerinatal Cell Death in Pathological Environments: Which CellsAre Most Susceptible and How/When Do They Respond?

Organizer: W. Macklin; Participants: M. Miller, S. Levinson, S. Vannucci

Hypoxic/ischemic (H/I) insults to the fetal or neonatal brain have long-termconsequences, in terms of cell death, altered cell migration and/or differentia-tion. The timing and duration of the insult clearly impacts the specific cellularresponses. The susceptibility and responses of different cell types are importantfor the overall survival and function of the tissue. In this panel, responses ofneurons, astrocytes, oligodendrocytes, oligodendrocyte progenitor cells and stemcells to hypoxic/ischemic events will be discussed. Dr. Miller will discuss cellresponses in a perinatal model of repeated hypoxia, which produces animalswith hypoxic ventilatory depression. Studies on cell death in this model usingboth TUNEL analysis and caspase immunoreactivity will be discussed, focusingon cells in the ventilatory centers of the brainstem, the nucleus tractus solitariusand the parapyramidal area. Dr. Vannucci will discuss the astrocytic responses

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to a single perinatal H/I insult. There is a rapid loss of GFAP mRNA and likelyastrocyte cell death in severe perinatal insults, which is followed later by signifi-cant gliosis. This contrasts with the transient induction of GFAP mRNA follow-ing milder insults. The mechanisms for these differential responses of astrocyteswill be discussed. Dr Levison will discuss how perinatal H/I affects the stemcells in the subependymal zone (SZ). Cellularity counts in tissue sections revealthat 25% of the cells within the SZ are depleted within 48 h of recovery from amoderate H/I insult. Histochemistry and electron microscopy reveal that thesecells undergo necrotic, apoptotic or hybrid cell deaths, with the majority of celldeaths being hybrid deaths. The susceptibility of these cells to death signals andthe mechanisms responsible for their demise will be discussed. Dr. Macklin willdiscuss oligodendrocyte and oligodendrocyte progenitor responses to a fetal hy-poxic insult, along with altered cell migration. In this model, animals are ex-posed to 45 min hypoxia by occlusion of the uterine arteries at E18. Less dramaticcell death results from this insult, but significant changes in cell organizationoccur along with changes in the development of oligodendrocytes. The data dis-cussed in this panel will provide insight into the timing and mechanisms of cellu-lar responses to H/I, with a particular focus on mechanisms of cell death.

Panel • Wednesday • 7:30-9:30 AM • SkylinePeptide Nucleic Acid – New Life for Antisense (and Antigene) ?

Organizer: P. Clarke; Participants: B. Tyler-McMahon, U. Langel, L. Boffa, P. Clarke

For neuroscientists, the antisense approach has thus far failed to live up to expec-tations. There are currently two main problems associated with this approach.The first is low efficacy — an effective antisense sequence is hard to find, andprotein expression is usually only partially inhibited. The second problem is tox-icity—administration of oligonucleotides can result in brain damage; almost cer-tainly, toxic antisense effects are inadequately investigated and under-reported.Peptide nucleic acids (PNAs) are synthetic oligodeoxynucleotide analogues thatpossess several important advantages over tr aditional antisense molecules (i.e.phosphodiester, phosphorothioate). Several recent publications suggest that PNAantisense work well in rat brain. The goal of the panel is to discuss the merits ofPNA vs. other antisense treatments. Paul Clarke will describe the in vivo target-ing of delta opioid receptors by PNA, and recall past experience (mostly painful)with phosphodiester or phosphorothioate antisense. Beth Tyler-McMahon willreport depletion of G-protein coupled receptors following central or systemicadministration of PNAs. She will also show that PNA can exert an antigeneeffect in vivo. Ulo Langel will show that PNA antisense can be rendered moreeffective by conjugation to peptides that facilitate cellular uptake. He will alsodescribe in vivo antisense effects in the spinal cord. Lidia Boffa will report howantigene effects of PNA can be enhanced by conjugation with a nuclear localiza-tion signal. She will describe several cellular model systems where appropriatePNA-conjugates can exert specific antigene effects.

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Panel • Wednesday • 7:30-9:30 AM • SunsetStimulation, Lesioning and Transplantation: Application for theTreatment of Parkinson’s Disease and Dystonia

Organizer: J. Vitek; Participants: J. Vitek, A. Lozano, J. Kordower, R. Bakay

Surgical therapy for the treatment of Parkinson s disease and dystonia has un-dergone a marked resurgence in the 1990 s and continues into the new millen-nium. Improved understanding of the pathophysiological basis underlying thedevelopment of the motor signs of PD has led to the refinement of old andimplementation of new surgical approaches for the treatment of this disorder.With the advent of deep brain stimulation we now have a mechanism wherebypatients may undergo bilateral procedures without the same risk associated withbilateral ablative procedures. Restorative methods continue to evolve with therefinement of fetal tissue transplantation techniques and the development of newapproaches employing alternative tissues. The application of the same lesioningand DBS techniques used for patients with PD have now been employed for thetreatment of patients with primary and secondary dystonia leading in some casesto an almost complete restoration of function. The purpose of this panel is toprovide the audience with the most recent developments in the application ofthese techniques for the treatment of these disorders. Andres Lozano will dis-cuss the use of DBS and pallidotomy for the treatment of PD, the relative meritsof each technique as well as the potential pitfalls and problems that one mayencounter when performing these procedures. Jeff Kordower will discuss recentdevelopments in fetal tissue transplantation for PD; problems that currently per-sist and methods that have been developed to address them. Roy Bakay will presentrecent data on the use of alternative tissues such as porcine cells inneurotransplatation, the rationale behind their use and the problems associatedwith this technique. Jerrold Vitek will discuss the reapplication of pallidotomyand the development of DBS for the treatment of dystonia. Results from a seriesof patients undergoing unilateral and bilateral procedures will be presented.

Panel • Wednesday • 4:30-6:30 PM • Mt. WernerCholinergic Modulation of Cortical Function: Channels to Circuits

Organizer: R.C. Foehring; Participants: R. Metherate, F.F. Ebner, R. Andrade

Cholinergic afferents from the basal forebrain provide one of the majorextrathalamic inputs to the neocortex. Cholinergic fibers ramify in all six corti-cal layers and both muscarinic and nicotinic receptors are expressed in pyrami-dal and nonpyramidal cells in cortex. Based upon fiber projections and receptordistribution, this cholinergic projection has been implicated in regulation of cor-tical activity, sleep-wake states, cognition, learning and memory, and plasticity.Consistent with these proposed functions, loss of the basal forebrain cholinergicprojection to cortex occurs early in the progression of Alzheimer s disease. Thispanel will discuss recent advances from in vitro and in vivo preparations which

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address cellular and circuitry mechanisms involved in acteylcholine s actions. R.Andrade will present evidence that nonselective cation currents are importantcontributors to cholinergic responses mediated via muscarinic receptors in pre-frontal cortex. He will also outline evidence indicating that one of these nonse-lective cation currents is also regulated by intracellular calcium, and hence canbe impacted by concurrent synaptic activity and cell firing. R. Foehring will dis-cuss muscarinic modulation of voltage-gated calcium channels and calcium-de-pendent potassium channels in neocortical pyramidal cells. Special emphasiswill be placed on the consequences of these modulations for synaptic transmis-sion and repetitive firing. R. Metherate will present evidence for differential cho-linergic regulation of thalamocortical vs. intracortical pathways in an auditorythalamo-cortical slice preparation. He will also present data suggesting a criticalrole for nicotinic cholinergic regulation of glutamatergic transmission in cortexduring a specific postnatal period. F. Ebner will discuss cholinergic modificationof cortical responses and plasticity in vivo. Both single cell response modulationand results of behavioral studies will be reviewed. The goal of the panel is toprovide a forum for synthesis of ionic, cellular, and network data on modulatoryactions of acetylcholine in neocortex and to present the audience with a currentview of important cholinergic effects on cortical function.

Panel • Wednesday • 4:30-6:30 PM • Storm PeakAxon Guidance: From Extracellular Cues to Growth ConeBehaviors

Organizer: K. Kalil; Participants: T. O Connor, P. Letourneau, T. Gomez

In recent years molecular cues have been discovered that guide axons as theynavigate toward targets. Axonal growth cones respond to cues such assemaphorins, netrins and ephrins by attraction or repulsion. These extracellularguidance cues function through surface receptors to control intracellular signal-ing events which are ultimately transduced through remodeling of the cytoskel-eton into effects on growth cone motility. The panel will present an overview ofaxon guidance mechanisms and will discuss exciting new findings from a varietyof neural systems to explore some of these linkages between extracellular guid-ance cues and intracellular events driving growth cone behaviors. O Connor willdemonstrate how spatial gradients of a secreted semaphorin axon guidancemolecule can provide directional information to growth cones of grasshopperpioneer axons during pathfinding. Letourneau will discuss how growth conesintegrate simultaneous interactions with multiple guidance cues. He will describerecent work on DRG and retinal neurons to demonstrate that neurotrophins canreduce the collapsing effects of molecules such as nitric oxide, semaphorin 3Aand ephrins that induce growth cone collapse and will present evidence thatneurotrophins appear to protect actin filaments against depolymerization inducedby collapsing signals. Kalil will demonstrate dynamic changes in the actin andmicrotubule cytoskeleton that underlie cortical growth cone behaviors leading toaxon branching and will discuss how some of these changes are affected by ap-

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plication of growth factors, such as FGF-2. Gomez will show in frog spinal neu-rons how highly localized transient elevations of intracellular calcium that propa-gate down individual growth cone filopodia can serve as both frequency-codedsignals that are integrated within the growth cone and as autonomous regulatorsof filopodial motility.

Panel • Wednesday • 4:30-6:30 PM • TwilightRecording from a Whole Bunch of Neurons All at Once: Problems,Payoffs and Promise

Organizer: J.Walters; Participants: B.Waterhouse P. Janak D. Kipke D. Woodward

Multichannel recording techniques offer significant promise for obtaining insightinto mechanisms of information processing within the CNS. The ability to recordsimultaneously from many neurons in multiple brain circuits over extended peri-ods of time has challenged investigators to develop experimental strategies anddata analysis routines that maximize the information obtained from this approach.Through examples from their current research, panel participants will discussdifferent approaches, problems and payoffs associated with many neuron record-ing techniques. Strategies for conducting large scale population recordings inprimate brain motor areas and the use of ensemble spike train data to drive ro-botic devices will be discussed by Daryl Kipke. Challenges and rewards of study-ing the activity of neuronal populations in themesocorticolimbic system in relation to drug- and food-reinforced behavior will be described by Patricia Janak.Barry Waterhouse will report on early surprises and ex-pectations from studies of brainstem monoaminergic sys-tems that project globally and exert modulatory effectson ensembles of neurons at multiple levels of intactsensory pathways. Donald Woodward will conclude with hisvision of the future of this technology (i.e. analysisalgorithms, software and hardware developments) and howit will be used to address a new generation of questionsabout multineuron interactions and basic neural networkoperations in behaving animals. Discussion will be moder-ated by Judith Walters. Contributions from the attendeeswill be encouraged. Bring a slide of your current many-neuron/multiple site recording problem, payoff or prom-i s e !

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Panel • Wednesday • 4:30-6:30 PM • RainbowGABA Receptors as Anesthetic Targets: What We’ve Learned fromGene and Ion Channel Structure/Function Studies

Organizer: A. Jenkins; Participants: G. Houmanics, S.J. Mihic, D.S. Weiss, C.M.Czajkowski

Over the past decade, the GABAa receptor (GABAaR) has emerged as a promis-ing target for general anesthetic agents including ethers, benzodiazepines (BZD),barbiturates and alcohols. More recently, molecular biology has permittedGABAaR manipulation, revealing a wealth of information on expression, acti-vation and modulation. This panel aims to present different approaches to an-swering the questions Ho w do these drugs modulate receptor function ? andHo w does this impact on the CNS ? Homanics will discuss the la test experi-ments utilizing genetically engineered mice that harbor mutations in GABAaRgenes. Included will be alcohol and anesthetic responses in mice, which lackspecific receptor subunits in either a global or tissue specific pattern. Mihic willexamine the modulation of wild-type and mutated GABAa and Glycine recep-tors by general anesthetics, inhaled drugs of abuse and ethanol. Two amino ac-ids have been identified which regulate receptor-ligand sensitivity and allostericmodulation. These data suggest that inhaled drugs of abuse affect ligand-gatedion channels and that the molecular sites of action of all these compounds mayoverlap. Weiss will discuss the kinetics of receptor activation, modulation andion-channel gating. [3H] binding experiments with single oocytes and site-di-rected mutagenesis experiments at a conserved leucine residue have led to theformulation of a novel activation mechanism for the receptor. These data sug-gest new pathways via which allosteric modulators may alter ion-channel func-tion. Czajkowski will discuss the mapping of the BZD binding and allostericcoupling domains of the GABAaR. Using the substituted cysteine accessibilitymethod and by constructing chimeric subunits, two domains have been identi-fied which are necessary to impart full BZD sensitivity to chimeric receptors.These novel residues provide insight into the mechanisms underlying the allos-teric coupling of all ligand-gated ion channels. Jenkins will discuss evidence fora general anesthetic binding cavity. By comparing the effects of a number ofanesthetics with different molecular volumes on a series of mutant receptors, it isproposed that these drugs bind to a ~250 +3 cavity located within the transmem-brane domain of the receptor.

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Panel • Wednesday • 4:30-6:30 PM • SkylineThe Response to CO2 and O2: From Ion Channels to NeuralNetworks

Organizer: J.M. Ramirez; Participants: M.M. Tamkun, N.R. Prabhakar, J.M.Ramirez, G.B. Richerson

The nervous system has to adapt to changes in CO2 and O2 to prevent irrevers-ible damage to the brain. Exposed to high-altitude, participants at the WinterBrain Conference have to face a hypoxic challenge while maintaining mentaland physical power. In this panel WCBR participants have the chance to learnabout the new developments in understanding how an organism adapts to alter-ations in CO2 and O2. The aim of this panel is to relate changes at the molecularlevel of ion channels with the adaptive response at the organismic level. MichaelTamkun will demonstrate how oxygen alters electrophysiological properties ofvoltage-gated K (KV) channels, which could lead to a hypoxic pulmonary vaso-constriction at the organismic level. The experimental use of cloned Kv channelsenables the Tamkun laboratory to gain insights into the subtype-specific effect ofhypoxia: Numerous ion channels localize to lipid rafts in nerve and muscle andthese membrane domains act as signal transduction centers. How channel tar-geting to lipid rafts may be involved in CO2 and O2 sensing will be discussed.The role of calcium-dependent pathways in mediating the hypoxic response willbe high-lighted in the presentation by Nanduri Prabhakar. Using RT-PCR tech-niques and reporter gene assays the Prabhakar laboratory demonstrates that thehypoxic modulation of L-type calcium channels leads to a cascade of cellularevents involving CaMK activation and CREB phosphorylation. These changesresult in an adaptive response of the carotid body, the major mammalian oxygensensory organ. To address the role of the central nervous system in response tohypoxia, Jan-Marino Ramirez investigates the effect of O2 changes on the iso-lated respiratory network using brainstem slices. With the patch-clamp techniquethe Ramirez lab demonstrates that the hypoxic modulation of the N-type cal-cium channel leads to alterations in Kca and Ih conductances which result in anincreased frequency of respiratory pacemaker activity and a reconfiguration ofthe respiratory network. George Richerson will discuss the effect of CO2 onserotonergic medullary Raphe neurons. Intracellular acidosis inhibits a novelcalcium-activated cation current in these neurons with a reversal potential of -61mV. This leads to an increased firing rate, which could be expected to stimulatebreathing through release of serotonin, TRH and Substance P. The four differentmechanisms described in this panel for detecting changes in blood gases wouldact together to maintain homeostasis, particularly during a hypoxic challenge athigh-altitude.

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Panel • Wednesday • 4:30-6:30 PM • SunsetRole of Rhythmic Neural Activity in Cardiovascular Behavior:From Molecular Details to Black Diamonds

Organizer: J. P. Horn; Participants: P.G. Guyenet, M.P. Gilbey, J.P. Horn. D.Weinreich

The autonomic nervous system enables one to ski downhill at high altitude. Al-though the best-known cardiovascular behavior, the baroreceptor reflex, can beviewed as simple, cardio-pulmonary adaptation during exercise is much morecomplex. How then does the nervous system orchestrate the appropriate motorelements during warm-up, the windy ride up the lift, and the rush down bigbumps? Recent evidence suggests that rhythmic activity may play a central rolenot only for timing jumps through bumps, but also for coordinating and regulat-ing the control of peripheral autonomic targets. The panel will outline recentprogress at different levels, from central circuitry to peripheral synaptic mecha-nisms. Patrice Guyenet will give a brief overview of the brainstem circuitry thatintegrates and drives the sympathetic and parasympathetic outflow to the car-diovascular system. He will describe how a new extracellular recording methodcan be used to mark physiologically identified neurons, and discuss how theseneurons may participate in the pattern-generating network. Michael Gilbey willaddress how central pattern generators may coordinate activity in postgangli-onic sympathetic axons that control peripheral blood flow for thermoregulation.Activity recorded under different states of cardio-respiratory drive will be dis-cussed in terms of synchronization and motor binding. John Horn will discusshow synaptic integration in sympathetic ganglia contributes to cardiovascularfunction. He will outline a computational analysis, which indicates ganglia func-tion as use-dependent synaptic amplifiers whose gain can be adjusted by oscilla-tory activity. Danny Weinreich will discuss how changes in long-term potentiationin sympathetic ganglia correlate with blood pressure in normal and hypertensiveanimals.

Panel • Thursday • 7:30-9:30 AM • Mt. WernerKainate Receptors and Synaptic Plasticity

Organizer: G.L.Collingridge; Participants: R.A.Nicoll, G.L.Collingridge, J.T.R. Isaac,D. Lodge

Fast excitatory transmission in the CNS is mediated by the ionotropic glutamatereceptors that can be divided into three subtypes: AMPA, NMDA and kainate.Of these subtypes, the functions of kainate receptors have until recently remainedlargely unexplored. However due to the development of new ligands selective forkainate and AMPA receptors, a rapid advance in our knowledge of kainate re-ceptors has taken place. For example, kainate receptors have been shown to beactivated at synapses and to mediate an excitatory postsynaptic current in a num-ber of regions of the mammalian CNS. One exciting emerging field is the in-

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volvement of kainate receptors in the induction and expression of long-termsynaptic plasticity, a process thought to underlie development, learning andmemory, and some neurodegenerative diseases. The aim of this panel is to presentrecent data on the involvement of kainate receptors in synaptic plasticity. Thepotential role of these receptors in development and learning and memory, andthe potential of the kainate receptor as a drug target for the prevention and treat-ment of certain neurodegenerative diseases will be discussed. Roger Nicoll willpresent his recent work on the role of kainate receptors in mediating and regulat-ing excitatory and inhibitory synaptic transmission in the hippocampus (Frerkinget al., 1999 Proc. Natl. Acad. Sci. USA 96, 12917-12922.), and discuss the poten-tial for long-term modifications of this during synaptic plasticity. GrahamCollingridge will present recent work on the involvement of kainate receptors inthe induction of long-term potentiation (LTP) at the mossy fibre-CA3 synapse inthe hippocampus (Bortolotto et al., 1999 Nature 402, 297-301). John Isaac willdescribe the involvement of kainate receptors in the expression of LTP at devel-oping synapses in primary sensory cortex (Kidd and Isaac, 1999 Nature 400,569-573), and the implications of this for the development of receptive fields.David Lodge will describe advances in kainate receptor pharmacology (Clarkeet al., 1997 Nature 389, 599-603) and present recent data on the suppression ofepileptiform activity by kainate receptor antagonists. We anticipate that this highlytopical panel will generate lots of interest and provide a useful discussion con-cerning the roles of kainate receptors at CNS synapses.

Panel • Thursday • 7:30-9:30 AM • Storm PeakMicroarrays in Neuropsychiatric Research: ADelusion, Illusion, or Reality?

Organizer: T.M. Hyde; Participants: C. Colantuoni, R. Coppola, W.J. Freed

Microarray technology holds great potential for deciphering the molecular basisof complex neuropsychiatric disorders that have defied conventional neuropatho-logical approaches. However, the utility of these arrays has only recently beenvalidated in human post-mortem brain studies. This panel will discuss the appli-cation of a variety of microarray techniques to normal human brain tissue andsuch diverse disorders as schizophrenia and Rett Syndrome. Carlo Colantuoniwill review the applications of competing microarray techniques to post-mortembrain tissue from patients with Rett Syndrome, a heritable disorder in femalescharacterized by seizures, motor dysfunction, and cognitive impairment. He willalso review recent applications of the same techniques to brain tissue from schizo-phrenic subjects. Richard Coppola will discuss an alternative approach to theuse of microarrays in schizophrenia, especially the use of pooled samples frommultiple cases. He will also review the bio-informatics issues that complicate thehandling and interpretation of data derived from microarrays. Finally, WilliamFreed will discuss the development of a novel cDNA neur oarray to probe forgenes associated with CNS function, leading to the identification of a small num-

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ber of genes involved in synaptic function, transcription, cell recognition, andsignal transduction that are abnormally expressed in schizophrenia.

Panel • Thursday • 7:30-9:30 AM • TwilightRegulation of Monoamine Transporter Characteristics andTrafficking

Organizer: A. Janowsky; Participants: M. Reith, H. Melikian, A. Eshleman, N.Zahniser

Transporters are the major mechanism for inactivating biogenic amine neurotrans-mitters. Abused drugs such as cocaine and methamphetamine, and therapeuticagents such as antidepressants and drugs that are used to treat Parkinson s dis-ease bind to the transporters and block neurotransmitter uptake. Alteration oftransporter function has been associated with euphoria, craving, symptoms ofwithdrawal, and exacerbation of symptoms that accompany schizophrenia andother neuropsychiatric disorders. This panel will describe new information ondrug-transporter interactions, and molecular mechanisms involved in regulatingtransporter expression. Specifically, Maarten Reith will discuss conformationalchanges that occur during the interaction of substrates and non-substrate inhibi-tors with monoamine transporters, and how carrier oligomerization could regu-late transporter characteristics. He will also address the impact of posttranslationalmodification of monoamine transporters by glycosylation, utilizing experimen-tal evidence of dopamine transporter (DAT) mutants that lack glycosylation con-sensus sites. Haley Melikian will describe how the DAT undergoes a substantiallevel of constitutive trafficking under basal conditions, and how activation ofprotein kinase C (PKC) impacts particular elements of pre-existing constitutivetrafficking, resulting in DAT downregulation. Amy Eshleman will explain differ-ences in the effects of PKC activation on internalization and on transporter char-acteristics among heterologously expressed DAT, serotonin and norepinephrinetransporters. Nancy Zahniser will discuss the evidence that dopamine D2autoreceptors regulate DAT function in brain. Shewill also present experimentalevidence from expression systems that activation of D2 receptors increases DATactivity by altering their expression at the cell surface. Receptor signaling andtransporter trafficking mechanisms involved in this regulation will also be dis-cussed.

Panel • Thursday • 7:30-9:30 AM • RainbowNeuroimmunophilins—Can Small Molecules Stimulate TherapeuticNeurorestoration?

Organizer: E. Hall; Participants: P. Letourneau, E. Villafranca, B. Gold, D. Cole

Unlocking the mechanisms that regulate axonal plasticity and regeneration haslong been a goal of neurobiology. This is based upon the hope of finding phar-macological means by which recovery of function (neurorestoration) could bestimulated after acute neurological injury and in neurodegenerative diseases. Sig-nificant advances have been made in our understanding of the ability of axons to

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grow during development and after injury, and some of the ¥ molecular mecha-nisms involved. This has lead to the identification of small molecule pharmaco-logical targets by which axonal sprouting and regeneration might be enhanced.The aim of this panel is to review the neurobiology of axonal growth and one ofthe more promising of these pro-regenerative targets the neuroimmunophilins(neurophilins, NIMMs). The NIMMs are putative members of a family of en-zymes known as peptidyl-prolyl cis-trans isomerases (PPIases) believed to play arole in regulation of protein folding. The PPIases of interest are known as FKbinding proteins (FKBPs), named for their binding of the prototype neurotrophicNIMM compound FK-506. In particular, the panel will review theneurorestorative mechanisms and efficacy of prototype NIMM-directed com-pounds including FK-506, GPI1046 and V-10,367, as well as other, novel NIMMcompounds. Paul Letourneau will discuss the neurobiology of axonal sproutingand growth cone elongation and guidance as well as growth factor effects onaxonal growth. Ernie Villafranca will introduce NIMM phar-macology focusing on the present mechanistic understand-ing of axonal growth-promoting effects and their dependence on neurotrophicfactors. Bruce Gold will discuss the roles of different FKBPs in NIMM actionsand interactions with steroid hormone chaperone/heat shock proteins. Addi-tionally, he will present data on the ability of NIMM compounds to stimulateneurite extension in cell-based systems and to promote neurorestoration in mod-els of peripheral nerve and spinal cord injury. Finally, Doug Cole will presentwork on the neuropharmacology of V- 10,367 and other, novel NIMM com-pounds.

Panel • Thursday • 7:30-9:30 AM • SkylineThe Brain is a Cookie Monster: Contribution of Food Compositionand “Hedonic Circuitry” to the Regulation of Food Intake

Organizer: D. Lattemann; Participants: B. Levin, C. Billington, A.Kelley, D.Lattemann

Studies over recent years have focused upon the role of the medial hypothalamusin the short- and long-term regulation of caloric intake. However, other studiesare beginning to elucidate the CNS neuroanatomical and neurochemical basesfor the under-appreciated observation that a calorie is not a calorie the compo-sition and the rewarding/hedonic qualities of food contribute significantly to theendpoint of total food intake, and its regulation. In this panel, we will summa-rize recent studies that evaluate the CNS regions and pathways that are impor-tant for mediating these attributes of food. Barry Levin will show how chronicintake of a palatable diet can alter the CNS neurochemical patterns of rats thatare genetically prone or resistant to diet-induced obesity, a model of diet-inducedneural plasticity. Charles Billington will discuss the involvement of brain opioidpathways in both ingestion of palatable foods and caloric-need driven ingestion.Ann Kelley will discuss the involvement of the ventral striatum in food intake,with particular focus on striatal enkephalin gene expression and intake of highfat/sweet food. Dianne Lattemann will discuss the interaction between periph-

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eral adiposity signals and brain systems of reward/hedonics. A synthesis of howthese systems may be integrated with the hypothalamic systems that regulateenergy balance will be presented.

Panel • Thursday • 7:30-9:30 AM • SunsetMitotic Regulators ‘Prospero-us’ in Postmitotic Neurons fromBecome to Succumb?

Organizer: I. Vincent; Participants: H. Vaessin, R. Slack , P. Baas

The downregulation of cell cycle regulators and the consequent inability of neu-rons to divide following their terminal differentiation have constituted a dogmaof neuroscience that has fascinated neurobiologists for almost a century. Onlyrecently is it becoming apparent that postmitotic neurons rely on mitotic regula-tors and mechanisms for some critical events in their life history, which has leftsome of us neurobiologists in awe as to how postmitotic these cells really are.In this panel, two participants will present new insights of the classical view ofneuronal determination, and another two participants will highlight the role ofmitotic mechanisms in postmitotic neurons. Drosophila prospero encodes a criti-cal regulator of the irreversible transition from mitotically active to differentiatedneuron. Dr Harald Vaessin will expound the mechanism by which prospero or-chestrates the asymmetric mitosis leading to the birth of a daughter cell identicalto the mother, and another cell committed to neuronal differentiation. Terminalmitosis and differentiation are tightly coupled and failure to exit the cell cycleresults in impaired differentiation and neuronal cell death. Dr Ruth Slack willdescribe how pRb, a regulator of normal cell division, also acts as a developmen-tal switch to cause progenitor cells to exit the cell cycle and express a neuronalphenotype. Contrary to the dependence of neuronal differentiation on the purg-ing of mitotic machinery, Dr Peter Baas and colleagues have found that the mecha-nisms by which neurons generate axons and dendrites are modifications of thesame mechanisms organizing mitotic spindles in dividing cells. Dr Baas will elabo-rate on this intriguing mechanism. Other evidence has suggested that reactiva-tion of mitotic regulators in mature neurons serves as a trigger for theirdegeneration in a variety of human neurological diseases, including Alzheimer sdisease. A better characterized example is that of Ataxia-Telangiectasia causedby mutation of the Atm gene, whose protein product is a regulator of the cellcycle G2 and M checkpoints. Strangely, the nosologic feature of this disease isprogressive degeneration of postmitotic cerebellar neurons. Dr Carrolee Barlowwill describe recent findings from Atm deficient mice, an excellent model forunderstanding the role of ATM in normal neuronal function.

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Panel • Thursday • 4:30-6:30 PM • Mt. WernerCan Neuronal Glutamate Release Be Measured in Vivo?Microdialysis vs Biosensors

Organizer: N.Maidment; Participants: M. Boutelle, R. Kennedy, A. Michael, B. Dunn

Controversy surrounds the use of microdialysis for measuring glutamate releasein vivo. Unlike the case for monoamines, most reports indicate that the basalextracellular glutamate sampled with this technique is unperturbed by TTX orby removal of calcium from the perfusion medium. This has led many to con-clude that microdialysis has limited utility for sampling the neurotransmitter poolof glutamate. However, recent developments in rapid sampling techniques andin enzyme-based biosensor design suggest that neuronally released glutamatemay be accessible in vivo. We will address several issues. 1. Are there conditionsunder which neuronally released glutamate can be measured with microdialysis?2. If microdialysis is not sampling vesicularly released glutamate, from whatpool is it sampling and is this information valuable? 3. Does the small size ofglutamate biosensors enable them to sample closer to glutamate release sitesthereby providing a better index of vesicularly released glutamate? MartynBoutelle will discuss the origin of extracellular glutamate as sampled bymicrodialysis. He will also describe the combination of microdialysis with en-zyme-based sensors for on-line detection of microdialysis-derived glutamate—theenzyme bed electr ode and the dialtr ode . Robert Kennedy will describe theuse of capillary electrophoresis for rapid measurement of extracellular glutamate,either in conjunction with microdialysis or as a direct sampling technique. AdrianMichael has developed a 10 um carbon fiber-based amperometric enzyme bio-sensor for direct measurement of glutamate in vivo. His design incorporatesglutamate oxidase, horseradish peroxidase, an osmium-polymer complex togetherwith a nafion coat resulting in a sensor that is uniquely selective for glutamate,and that provides TTX-sensitive signals in vivo. Bruce Dunn is developing a novelin vivo fiber optic sensor for glutamate employing sol-gel technology. Glutamatedehydrogenase is encapsulated in sol-gel at the tip of a fiber optic tube and theresultant production of NADH from NAD upon glutamate diffusion into thesol-gel is measured by a change in luminescence.

Panel • Thursday • 4:30-6:30 PM • Storm PeakSignal Transduction in Neuronal and Neuroendocrine Cells: Whatthe Mutant Mice Said to Me

Organizer: M.R. Picciotto; Participants: I. Lindberg, P. Allen, K. Wickman, M.Picciotto

Signaling pathways are critical for transducing information from neurotransmit-ters outside the cell into changes in neuronal function. While molecular, bio-chemical and physiological techniques have been critical in identifying the playersin intracellular signaling pathways, it has been difficult to develop highly spe-

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cific, cell-permeable pharmacological agents to manipulate intracellular signal-ing molecules, and thus to elucidate their function at the cellular, systems andbehavioral level. This is particularly true for molecules that are members of largegene families. Gene targeting in mice presents new opportunities to study theroles of proteins involved in signal transduction in the intact animal. The aim ofthis panel is to present experimental data that explore four different systems inwhich knockout mouse models have been used to elucidate the role of individualmolecules in complex neurobiological processes. Marina Picciotto will introducethe topic of transgenic and knockout mouse models, and will use experimentson nicotinic receptor knockout mice as an example of how studies on signalingcan start at the membrane. Kevin Wickman will present work on knockout micelacking subunits of the G protein-gated family of potassium channels (GIRK)and will describe how these animals can be used to elucidate the roles of ionchannel with no specific agonists or antagonists. Proceeding deeper into the cell,Iris Lindberg will talk about convertase pathways in neuroendocrine cells andhow two convertase knockout mouse strains have shed light on the cell biologyof peptide hormone production, suggesting novel roles for the binding proteinsin neuroendocrine physiology. Patrick Allen will conclude the session with adescription of how knockout mice lacking proteins that associate with proteinphosphatase 1 contribute to regulation of the cytoskeleton, neurotransmissionand synaptic plasticity.

Panel • Thursday • 4:30-6:30 PM • TwilightRegulation of Voltage-dependent Sodium Channels by ProteinKinases and Phosphatases

Organizer: T. Scheuer; Participants: A.R. Goldin, A.R. Cantrell, P.C. Ruben

Voltage-dependent sodium channels are the primary source of depolarizing in-ward current for neuronal action potentials. As such, their activity is criticallyimportant for the spread of excitation in neuronal cell bodies and dendrites, aswell as for initiation and transmission of axonal action potentials. Dynamic regu-lation of sodium currents is expected to have important effects on these pro-cesses. Voltage-dependent sodium channels are targets for phosphorylation by avariety of protein kinases. However, the details of this phosphorylation and itseffects, as well as entirely new modes of regulation are still being discovered.This panel will examine several aspects of regulation of sodium channels byphosphorylation. Sodium channels are known to be phosphorylated by proteinkinase A (PKA) and protein kinase C (PKC) as well as by tyrosine kinase activa-tion. The best-characterized effect of PKA and PKC activation is to reduce thesodium current. However, increases in current by both PKA and PKC have beenreported. Goldin will discuss mechanisms by which PKA can both increase anddecrease sodium current through brain sodium channels. PKA, PKC and mem-brane potential interact in a cooperative manner to reduce sodium current. Cantrellwill present evidence for phosphorylation at specific serines being responsiblefor reduction in sodium current by PKA and other, overlapping serines being

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responsible for reduction in current by PKC when either kinase is activated alone.The cooperative effects of simultaneous activation of the kinases require addi-tional serines, some that are phosphorylated by PKA and others that are phos-phorylated by PKC. In addition to their rapid voltage-dependent activation andinactivation, sodium channels are subject to slow inactivation and the probabil-ity of slow inactivation depends on the particular sodium channel isoform. Thoseprobabilities can be further modified in disease states and by association withsodium channel beta subunits. Ruben will discuss effects of phosphorylation onsodium channel slow inactivation that may underlie long-term changes in excit-ability. In addition to serine/threonine protein kinases, sodium channels are alsosubject to regulation by tyrosine phosphorylation. Scheuer will present evidencefor reversal of tyrosine phosphorylation due to receptor tyrosine phosphatasebeta that is bound specifically to sodium channel alpha and beta1 subunits.

Panel • Thursday • 4:30-6:30 PM • RainbowOligodendrocyte Precursors in Development, Health and Disease

Organizer: J.W. Fawcett; Participants: W. D. Richardson, S. Goldman, J.M. Levine

Oligodendrocyte precursors are responsible for myelination during development,but they do not disappear when this job is done. The adult CNS contains largenumbers of cells with the antigenic profile of oligodendrocyte precursors. Thefunction of these cells in the normal CNS is not fully understood, but they play apart in the CNS injury response, and probably in remyelination. The first speakeris Bill Richardson, who will talk about the oligodendrocyte precursor in develop-ment. Oligodendrocyte precursors have to spread throughout the nervous sys-tem to provide oligodendrocytes to all the myelinated pathways, so it has been asurprise to discover that their precursors have localized origins in the ventricularzones of the neural tube. In the embryonic spinal cord, oligodendrocyte progeni-tors are generated from a specialized region of the ventral VZ—the same regionthat at earlier times generates motor neurons. This suggests that the same neu-roepithelial precursors might first generate motor neurons then switch to pro-duction of oligodendrocyte progenitors. He reviews the evidence for a sharedmotor neuron-oligodendrocyte lineage and describes recent attempts to identifymolecular components of the neuron-glial switch, together with more generalquestions—where do astrocytes fit into the picture, and what are the evolutionaryimplications of the close relationship between motor neurons and oligodendro-cytes? The second speaker is Joel Levine. He will talk about the adult oligoden-drocyte precursor. These cells are found in large numbers throughout the CNS.They contact nodes of Ranvier and also synapses, and may have roles in modu-lation of conduction and transmission at these sites. After injury large numbersof oligodendrocyte precursors are recruited to the lesion and activated, to beform major participant in the glial scar. Following demyelination these cells prob-ably provide the pool of cells for remyelination. Joel will review these variousbehaviours of the oligodendrocyte precursor and speculate about other possiblefunctions. Steve Goldman will be speaking about the identification and isolationof a mitotically competent population of oligodendrocytic progenitor cells from

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the adult human white matter. He will cover the promoter-specified, GFP-basedextraction of these cells, their distribution and abundance, growth factor controland lineage potential. In addition, he will discuss the xenograft and integrationof these cells into demyelinated adult brain, and will consider appropriate dis-ease models for their use. James Fawcett will talk about factors that might influ-ence the ability of the oligodendrocyte precursor and the Schwann cell toremyelinate after demyelination. The first step in remyelination is for the cells tomigrate through the reactive astrocyte environment of the damaged CNS to-wards a demyelinated axon. However, the cells migrate poorly on astrocytes,inhibited by excessive adhesion mediated by N-cadherin. Myelination must thenoccur, and here again N-Cadherin plays a part, by mediating the first adhesivecontacts between axon and myelin-forming cell.

Panel • Thursday • 4:30-6:30 PM • SkylineNew Insights about Abnormal DevelopmentalProcesses and Their Relevance to Epilepsy

Organizer: R.S. Sloviter; Participants: F.E. Jensen, K.S. Lee, D.H. Lowenstein, R.S.Sloviter

The process of epileptogenesis has both intrinsic developmental and extrinsicacquired causes. Recent imaging data indicate that developmental anomalies anddevelopmental processes play a much larger role than previously appreciated insubsequent epileptogenesis and other brain disorders, yet we do not understandhow an abnormally developed network causes seizures. Dan Lowenstein willdiscuss new insights into the molecular basis of the development of the hippoc-ampus, and highlight potential developmental abnormalities that produce epi-leptogenic changes in the hippocampal network. Kevin Lee will address cases ofhuman temporal lobe epilepsy that are associated with extratemporal develop-mental malformations of the neocortex. Although it is unknown exactly howthese neocortical malformations impact the structure and/or function of the hip-pocampus, evidence from an animal model of neocortical dysplasia (the tish rat)suggests that developmental alterations in hippocampal circuitry precede thedevelopment of epilepsy, and may predispose the brain to seizures. Frances Jensenwill address how the developmental regulation of neurotransmitter receptorsmodifies susceptibility to epileptogenesis in the immature brain, and how sei-zures during development can perturb receptor development to potentiate longterm seizure susceptibility. Finally, Bob Sloviter will describe a previously unrec-ognized hippocampal malformation in human temporal lobe surgical specimensthat may represent an unidentified developmental neurological defect long sus-pected of causing both febrile seizures in childhood and subsequent epilepsy.

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Panel • Thursday • 4:30-6:30 PM • SunsetVestibular Adaptation

Organizer. L. Young; Participants: J. McElligott, M. Shelhamer, H. Hecht, L. Young

The remarkable ability of the nervous system to interpret vestibular signals inunusual environments permits us to ski, to see look around with and withouteyeglasses, and to adapt to the weightlessness of space flight. The adaptive char-acteristics of vestibulo-motor systems are examined with emphasis on recogni-tion of the context of the environment and the predictability of the stimulus.Young will introduce the problem of Coriolis stimulation in artificial gravity—when a centrifuge is used to overcome the debilitating effects of space flight.(Without vestibular adaptation the transitions between a rotating and non-rotat-ing spacecraft, popularized in the movie 2001 A Space Odyssey would be im-practical. Hecht will show how repeated head movements while rotating, althoughinitially sickening, can lead to reductions of the vestibulo-ocular reflex (VOR),illusions of body tilt, and motion sickness itself. Shelhamer will deal with con-text-specific adaptation of the linear VOR and of saccadic eye movements. Con-text cues include head and eye orientation and gravity level. McElligott willintroduce the predictability of the stimulus as an important factor in adaptationof the VOR.

Workshop • Thursday • 8:30-10:00 PM • Mt. WernerIs Enhanced Dopaminergic Neurotransmission the PrimaryMediator of Hedonic Reward? A Comparison of Human andAnimal Laboratory Studies

Organizer: C. Bradberry; Participants: H. de Wit, G. Koob, T. Robinson, C. Bradberry

This workshop will critically examine a concept which has wide acceptance withinthe neuroscience community, and is often referred to in the lay press, namely,that enhanced dopaminergic neurotransmission in the limbic striatum mediatesthe hedonic consequences of commerce with rewards. The majority of the evi-dence in support of dopaminergic mediation of reward derives from animal stud-ies. However, in human laboratory studies, which permit a verbalization ofsubjective effects of hedonic drugs, there are some results which appear inconsis-tent with this concept. This workshop will draw on both animal and humanlaboratory results and contrast them when possible. Harriet de Wit will presentevidence from human laboratory studies examining whether dopamine antago-nists block the subjective effects of amphetamine, and will also briefly reviewother comparisons between human and animal laboratory results. George Koobwill discuss evidence from animal studies and how it fits with a dopaminergicmediation of drug reward. Terry Robinson will present evidence that dopamin-ergic manipulations (including denervation) in rats do not alter hedonic responsesto taste stimuli. Charles Bradberry will present data from primate microdialysisstudies of cocaine and cocaethylene self-administration which, in comparison

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with human laboratory studies, both support and contradict a dopaminergicmediation of cocaine reward.

Workshop • Thursday • 8:30-10:00 PM • Storm PeakWithin-VTA Differences in Drug Action: A HouseDiv ided?

Organizer: W. Carlezon; Participants: W. Carlezon, S. Ikemoto, R.A. Wise, D. van derKooy

The mesolimbic system, which originates in the ventral tegmental area (VTA)and projects to the nucleus accumbens (NAcc), is a neural substrate for the re-warding effects of many drugs of abuse. The NAcc has been divided into 2 mainsubregions, the nucleus accumbens core and the nucleus accumbens shell. Thesesubdivisions have important anatomical and neurochemical differences, and ap-pear to be differentially involved in the rewarding effects of psychostimulants,opiates, and food. However, analogous functional subdivisions within the VTAhave not been described. This workshop will address accumulating evidence thatthere are functional differences in drug action within the VTA. The panel willfocus on studies involving drug reward mechanisms. Bill Carlezon (HarvardMedical School) will describe studies in which he used microinjections of viralvectors to elevate in the VTA expression of GluR1, an AMPA receptor proteinthat is regulated in this region by repeated drug exposure. Increased expressionof GluR1 in the rostral portion of the VTA enhanced morphine reward, whereasincreased expression of this protein in the caudal VTA enhanced morphine aver-sion. Satoshi Ikemoto (NIDA-Behavioral Neuroscience Branch) will describeintracranial self-administration studies in which he observes similar rostral-cau-dal differences in drug action. Rats self-administer GABA-A antagonists (butnot agonists) into the rostral VTA, and GABA-A agonists (but not antagonists)into the caudal VTA. Roy Wise (NIDA-Intramural Research Program) will dis-cuss rostrocaudal differences in intracranial self-administration of endomorphin,a recently described endogenous opioid peptide. Derek van der Kooy (Universityof Toronto) will discuss two GABAergic reward phenomena involving the VTA,one that appears to be dopamine-dependent and one that appears to be dopam-ine-independent. Together, these observations suggest that there may beunderappreciated within-VTA differences in drug action that can affect, and per-haps be affected by, motivational processes.

Workshop • Thursday • 8:30-10:00 PM • Twilight‘Excito-toxicity’ vs ‘Excito-trophicity’: Do Seizures Switch theSet-Point for Survival?

Organizer: K Gale; Participants: R. Simon, R. Gwinn, D. McIntyre

Much attention has focused on neuronal cell death produced by prolonged con-tinuous seizures (status epilepticus). Less attention has been paid to the neu-rotrophic and neuroprotective action of repeated noninjurious brief seizures. This

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workshop will explore the provocative concepts that seizures are a natural mecha-nism for inducing plasticity and neuroprotection, and that controlled seizuresmay have untapped therapeutic potential. We will discuss histopathological andmolecular evidence that animals experiencing repeated seizures (evoked by elec-troconvulsive shock, kindling, or chemoconvulsants) are protected againstapoptotic neuronal death induced by status epilepticus (in limbic structures),middle cerebral artery occlusion (in cortical regions), adrenalectomy (in dentategranule cells), and spinal cord contusion. Potential mechanisms for thisneuroprotection will be considered, including induction of bFGF andupregulation of neuronal apoptosis inhibitory protein (NAIP). Several challeng-ing questions will be tackled with the help of the audience: Are trophic responsesand cell death responses two sides of a coin or are they on a continuum? Whatdetermines the set-point for apoptotic reactions and how is this influenced byseizures? Is the seizure-evoked neuroprotection analogous to, or distinct from,ischemic tolerance ? What is the role of caspases and the bcl-2 genes? How canwe find out if one key mediator or several tissue-specific factors is/are respon-sible for the enhanced survival after repeated seizures? Can subconvulsant stimu-lation work as well? Are there therapeutic implications? The participants willcompare and contrast models and measurements in an effort to address thesequestions and generate others as part of a dynamic dialogue.

Workshop • Thursday • 8:30-10:00 PM • RainbowWhat Really is the Food for Thought: Glucose or Lactate ?

Organizer: I.A. Simpson; Participants: G. Dienel, E. Novotny, M. McKenna, L.Pellerin

For many years glucose has been considered the obligate, if not sole, metabolicfuel for the brain. Studies with the non-metabolizable glucose analogue 2-deoxyglucose in experimental animals, and fluoro-deoxyglucose in humans (PET),provided a methodology for the measurement of regional glucose utilizationassociated with cerebral functions and the ability to diagnose pathological con-ditions such as Alzheimer s or Parkinson s Disease based on alterations in suchutilization. Implicit in these observations was the assumption that the changes inaccumulation of the labeled 2-DG occurred in neurons whose activity was un-der consideration. This assumption has been brought into question by the stud-ies of Magistretti and colleagues who have proposed that glucose is converted tolactate in glia, which it is subsequently exported to neurons for further oxidation.In the true spirit of a WCBR workshop, we propose an interactive forum includ-ing participants with diverse backgrounds and disparate view points. In the firsthour the participants (3 slides, 5 minutes) will provide evidence to support orrefute the neuronal use of glucose or lactate as primary energy substrate for theneuron. In the second hour, time will be provided for audience participation (1-2 slides, 2-3 minutes) and more extensive discussion. Participants will also in-clude A. Gjedde and R.Greutter.

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Panel • Thursday • 8:30-10:00 PM • SkylineNeurotrophin-3: A Tool to Query, and a Mechanism for, SensorySystem Development and Plasticity

Organizer: R. Lane; Participants: M. Jacquin, R. Rhoades, D. Wright

Neurotrophins are involved in neuronal survival, proliferation, differentiation,growth and arborization of neuronal processes, synaptic refinement and plastic-ity. One of these factors, neurotrophin-3 (NT-3), has been identified at manysites during the development of the nervous system. Because of these features,the ability to manipulate the concentration of neurotrophins and specifically NT-3 within the neuronal environment provides a valuable tool that can be utilizedto study the development of the nervous system. The aim of this panel is topresent data from recent experiments in which NT-3 concentrations are manipu-lated to explore specific aspects of somatosensory development. Mark Jacquinwill outline the use of NT-3 to study trigeminal primary afferent growth andarbor formation in both in vivo and in vitro settings. Bob Rhoades will discuss theuse of this neurotrophin to investigate the requirements for maintenance of thevibrissae-related pattern in the trigeminal brainstem complex of the rat. DougWright will discuss his use of transgenic mice that over express NT-3 in studyingdevelopment of proprioceptive fibers and end organ morphogenesis associatedwith the mesencephalic nucleus of the trigeminal nerve. Rick Lane will describeNT-3 treatment as a method to investigate the relationship between the reorgani-zation observed in the brain stem with that seen in the primary somatosensorycortex of rats in response to a peripheral nerve injury.

Workshop • Thursday • 8:30-10:00 PM • SunsetMultifunctional Neurons and Networks for Hearing and VocalControl

Organizer: J.S. Kanwal; Participants: C.V. Mello, M.S. Fee, G.D. Pollak, Z.M.Fuzessery

The functional organization of the nervous system has been classically exam-ined by neurophysiologists who study either a single sensory or a motor func-tion. Neuroanatomists also typically describe relatively stable components ofneural organization, e.g., evolutionarily conserved lemniscal pathways, etc. Theseapproaches have led to the view that parallel-hierarchical pathways in the centralnervous system are dedicated to processing subsets of sensory information andthat neurons become increasingly specialized to process specific parameters. Thissimplistic notion drives many neuroanatomical and physiological descriptionsof the nervous system to date. A few studies, however, suggest that both, neuronsand small networks of neurons can be involved in multifunctional roles. In fact,at various levels of sensory processing and especially within the cerebral cortex,different types of information may be multiplexed within the activity of singleneurons and the configuration of local networks may change with the emotional

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state of the animal, the sensory or motor signal and the recent history of neuralactivity.

The aim of this panel is to present recent studies that illustrate multifunctionalprocessing in auditory and vocal systems in vertebrates. Examples of this will beprovided by experts working on songbirds and mustached bats: model specieswhich have been extensively used for studies of the auditory system and in whichrecent research either directly or indirectly supports this idea. Thus, Claudio Melloworking on budgerigars and songbirds has reported an overlap of auditory andvocal functions within audiovocal brain regions using gene expression analysis.Michale Fee has used intracellular recordings to show that single neurons canparticipate in different aspects of song production by functioning within mul-tiple time domains. In the laboratory of George Pollak, research at the level ofthe brainstem in bats shows that overlapping circuits are used for localizing singleand multiple sounds. Zoltan Fuzessery and co-worker s recent research has shownthat single neurons in the auditory cortex of pallid bats can play a role in bothecholocation and passive sound localization. Finally, Jagmeet Kanwal s and oth-ers research has shown that single cortical neurons in mustached bats show adual specialization for two distinct functions of the auditory system, namely,echolocation and sound communication. Whereas at subcortical levels multi-functional processing may be restricted to multiple dimensions of different as-pects of a single sensory modality, at the level of the association and sensorycortex this processing can become multisensory. More importantly, multifunc-tional processing within single neurons at higher cortical levels may be quiteplastic. Thus, networks of neurons within the association areas may be frequentlyreconfigured so that single neurons process different types of stored and incom-ing neural signals.

Panel • Friday • 7:30-9:30 AM • Mt. WernerLocation, Location, Location–Scaffolding Proteins in the CNS

Organizer: D. Ron; Participants: C. Garner, H- J. Chung, R. Olsen, D. Ron

Neurons function in a tightly orchestrated manner. In recent years it has becomeclear that scaffolding/anchoring proteins play a critical role in the molecularmechanisms that regulate synaptic function. Scaffolding/anchoring proteins areinvolved in clustering of ion channels, in coupling of receptors and ion channelsto intracellular signaling pathways, in regulating the function of receptors andion channels via phosphorylation and dephosphorylation, as well as connectingmembrane proteins with the cytoskeleton. Scaffolding/anchoring proteins func-tion by compartmentalizing signaling proteins, receptors and ion channels orcytoskeletal proteins to distinct intracellular sites. Compartmentalization is usu-ally achieved via direct protein-protein interactions of well-defined protein bind-ing domains. Protein domains such as the PDZ domain enable scaffolding/anchoring proteins to assemble signaling proteins such as kinases and phos-phatases from the same or from different cascades allowing tight regulation ofcascades as well as crosstalk of signaling pathways. The speakers on the panel

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will present examples that elucidate the significant role played by scaffolding/anchoring proteins for both pre- and post synaptic events. Craig Garner (U. ofAlabama at Birmingham) will present his work on the assembly of the presynap-tic active zone and on two presynaptic scaffolding proteins Piccolo and Bassoonthat play an important role in synaptic vesicle trafficking at the active zone. HeeJung Chung (Johns Hopkins) will present her work on the regulation of AMPAreceptor internalization during synaptic plasticity by the anchoring proteinsGRIP1 and PICK1. Richard Olsen (UCLA) will discuss the role of GABAAreceptor interacting protein (GABARAP) in connecting the GABAA receptorsto the cytoskeleton, and in the establishment of receptor clustering. Finally, DoritRon (Gallo Center, UCSF) will present work from her lab on RACK1 and itsrole as an inhibitory scaffolding protein for the NMDA receptor.

Panel • Friday • 7:30-9:30 AM • Storm PeakThe Glutamate-Glutamine Cycle: Potential Targets for ModulatingGlutaminergic Function

Organizer: J.D. Erickson; Participants: A. Schousboe, M.P. Kavanaugh, R.H.Edwards, J.D. Erickson

Glutamine is the preferred precursor for the neurotransmitter pool of glutamate.Upon synaptic release, glutamate is rapidly removed from the synaptic cleft byglutamate transporters that are located primarily on surrounding astroglial cells.There, glutamate is partially converted to glutamine by glutamine synthetase, anastrocyte-specific enzyme. To replenish the neurotransmitter pool of glutamate,glutamine is transported from astrocytes to glutaminergic neurons, converted toglutamate by phosphate-activated glutaminase, and then sequestered in synapticvesicles by a vesicular transporter to make it available for regulated neurosecre-tion. This panel will revisit the glutamate-glutamine cycle and explore new tar-gets to modulate presynaptic glutaminergic function. First, Arne Schousboe willdescribe the evidence supporting the glutamate/glutamine cycle and the meta-bolic dependence of glutaminergic neurons upon glia to provide glutamine, aswell as alternative precursors alpha-ketoglutarate and alanine for neurotransmit-ter synthesis. Michael Kavanaugh will consider astrocytic and neuronal glutamatetransporters as potential targets for pharmacophore development and pharma-cologically review substrate and nonsubstrate inhibitors of the high-affinity, so-dium-dependent glutamate transporters. Robert Edwards will then present theidentification of system N as a glutamate gated Na+/H+ exchanger linkingglutamate efflux from astrocytes with neural activity through changes in intrac-ellular pH. Finally, Jeff Erickson will present novel system A glutamine/alaninetransporters that are expressed on neurons that may be the molecular gatewayfor these substrates into glutaminergic neurons for neurotransmitter synthesis.

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Panel • Friday • 7:30-9:30 AM • TwilightThe Role of Pregnane Neurosteroids in Brain Function and DrugAction

Organizer- L. Morrow; Participants: R. Rupprecht, C. Grobin, S. Mellon, L. Morrow

Endogenous pregnane steroids, including 3a-hydroxy-5a-pregnan-20 one (3a,5a-THP, allopregnanolone) are present in brain in concentrations sufficient to modu-late ion channel receptor function during a variety of physiological eventsincluding stress, pregnancy, the estrus cycle and development. Exogenously ad-ministered 3a,5a-THP produces behavioral effects linked to potentiation ofGABA-A receptor activity, including anxiolysis, sedation and anticonvulsant aswell as antidepressant and neuroleptic-like actions. Mounting evidence suggeststhat neurosteroids may play a role in the psychopathology of depression andpanic disorder. Furthermore, recent studies have shown that various psychoac-tive drugs, including fluoxetine, alcohol and olanzapine increase brain concen-trations of 3a,5a-THP. The goal of this panel is to present evidence thatendogenous pregnane steroids modulate brain function and mediate the effectsof various drugs. Rainer Rupprecht will present evidence that pregnane steroidsinteract with various ion channels and may play a significant role in depression,alcohol withdrawal and panic disorder. Chistina Grobin will present evidencethat neurosteroids levels fluctuate across the ontogenetic development of the CNSand regulate the expression of GABA-A receptors and cortical neuron develop-ment in rats. Synthia Mellon will present evidence that specific serotonin reuptakeinhibitors used for the treatment of depression and anxiety disorders directlyenhance the biosynthesis of 3a,5a-THP. Leslie Morrow will present evidencethat 3a,5a-THP contributes to ethanol action, tolerance and dependence andthat novel neurosteroids may have therapeutic potential in the treatment of alco-hol-related problems.

Panel • Friday • 7:30-9:30 AM • RainbowNeurotrophins and Depression

Organizer: P. Skolnick; Participants: C.A. Altar, L.A. Mamounas, A. Russo-Neustadt

Biogenic-amine based hypotheses of depression have dominated thinking in bio-logical psychiatry for more than four decades. However, during the past five years,converging lines of evidence have linked members of the NGF family of neu-rotrophic factors to both the pathophysiology of depression and the antidepres-sant actions of biogenic-amine based as well as electroconvulsive therapies. Theobjective of this panel is to overview neuroanatomical, neurochemical, and phar-macological studies that have linked alterations in neurotrophin expression tothe pathophysiology of depression and chronic antidepressant treatment. TonyAltar will overview the plasticity of neuronal systems affected by neurotrophinsand discuss the antidepressant-like actions of exogenously applied neurotrophins.L. Mamounas will describe her studies demonstrating the ability of neurotrophins

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to promote the growth and function of intact serotonergic nerve terminals aswell as the ability of these neurotrophins to facilitate the regrowth of serotoner-gic axons following chemical insult. A. Russo-Neustadt will review evidencethat neurotrophin transcription is diminished by factors (e.g. stress) that can pre-cipitate depression and increased by chronic antidepressant. These findings willbe discussed in the context of her work demonstrating that exercise can affectantidepressant-induced changes in BDNF transcription. P. Skolnick will describestrategies to develop novel, non-biogenic amine based antidepressants based onthe data and principles described by the other participants.

Panel • Friday • 7:30-9:30 AM • SkylineEpileptogenesis: To Fit or Not to Fit

Organizer: C. Wasterlain; Participants: E. Dudek, K. Staley, T. Sutula

The nineteenth century dictum that seizur es beget seizures has recently re-ceived strong experimental support. Seizure-induced epileptogenesis is now rec-ognized as a common and widespread phenomenon, with several reliableexperimental models in which status epilepticus induced chemically or electri-cally in healthy animals is followed after a silent period by the development ofspontaneous seizures. However, the mechanisms and even the natural history ofseizure-induced epileptogenesis are still largely unknown. Is the epilepsy thatdevelops a molecular, cellular or network property? Is it a reflection of increasedexcitation, decreased inhibition or both? Is seizure-induced epilepsy a progres-sive disease in which each seizure adds to the likelihood of successive attacks,and does seizure control alter that natural history? What is the role of seizure-induced brain damage and of misdirected regeneration in that process? Is there acritical duration beyond which status epilepticus is epileptogenic, and are allagents that terminate status equally antiepileptogenic? The participants of thissession are active investigators of epileptogenesis, and will review recent evi-dence that may suggest new answers to those questions. Wasterlain will describethe natural history of epilepsy following status epilepticus induced by perforantpath stimulation in the rat, its temporal evolution and the factors that can modifyit. Staley will examine the relationship of spike distribution to seizure develop-ment during the silent period . Sutula will discuss the role of NMDA receptor-dependent plasticity in the generation of granule cell spiking, and Dudek willpresent physiological evidence for the presence of a reverberating granule cellexcitatory circuit in the epileptogenic hippocampus. The significance of thesefindings will be discussed in relation to the prevalent theories of epileptogenesis.Audience participation is strongly encouraged, and a limited number of slides ¥can be shown from the audience (contact the organizer). BYOT (Bring your owntheory)!

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Panel • Friday • 7:30-9:30 AM • SunsetProspects for Remyelination Therapies

Organizer: T. Wood; Participants: J. Goldman, R. Armstrong, I. Duncan, R. Franklin

Remyelination in the adult nervous system is critical to functional recovery fromdemyelinating diseases such as Multiple Sclerosis. Spontaneous remyelinationof demyelinated axons occurs; however, this process is limited and ultimatelyfails after repeated demyelination events. Current research on promotingremyelinatio processes in the adult is focussed on investigations of endogenousmechanisms of spontaneous remyelination and on transplantation of myelinproducing cells to promote remyelination. Studies on the endogenous mecha-nisms of remyelination include investigations of the adult oligodendrocyte pro-genitor cells and on the induction of growth and trophic factors in and around ademyelinating lesion. Recent evidence indicates that cycling progenitor cells inthe adult mammalian CNS participate in endogenous remyelination. This en-dogenous remyelination is associated with the production of growth and trophicfactors during the remyelination process. Jim Goldman will discuss the charac-teristics of the oligodendrocyte progenitor cells, including antigenic and mor-phologic heterogeneity, growth factor receptors, and responses to pathologicalcircumstances. Regina Armstrong will talk about in vitro and in vivo studies ofthe PDGF and FGF pathways in the remyelination process in adult mice. Func-tional analysis of the role of PDGF and FGF2 in development and remyelinationwill be addressed by the use of pharmacologic and genetic manipulations ofthese pathways. Transplantation of myelin producing cells has emerged recentlyas a potential therapeutic approach to treat myelin disorders in humans. Whichdisorders could be treated and the cells that would be used, however, remains amatter of debate. Ian Duncan will discuss the major issues that need to be an-swered before therapeutic trials can be initiated. He will address key challengesthat remain including issues of migration and myelination by transplanted cellsand how focal lesions could potentially be repaired by either endogenous Schwanncells or primary oligodendrocytes. Robin Franklin will discuss an alternative fortransplant-mediated remyelination, the use of olfactory ensheathing cells. Stud-ies will be presented on both rodent and human olfactory ensheathing cells, theirphenotypes and remyelination potential in the context of a demyelinated envi-ronment.

Panel • Friday • 4:30-6:30 PM • Mt. WernerUps and Downs in Synaptic Transmission: Factors that AffectShort-Term Synaptic Efficacy

Organizer: R. E. Burke; Participants: L. Kaczmarek, B. Walmsley, F. Weight

The efficacy of chemical synapses during repetitive activation is highly depen-dent of the frequency and patterning of input pulse trains. A great deal of workhas been done on this topic over the last half-century not only because of itsimportance to CNS function but also because the behavior of different synapticjunctions during repetitive trains provides critical clues about the basic mecha-

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nisms that control transmitter release. The development of in vitro models thatprovide access to pre- and postsynaptic elements for optical as well as electricalrecordings. The resulting large body of data from a variety of synaptic systemshave refined, and in some cases upset, classical views of short-term synapticdepression and facilitation. This panel will review some of this information, withparticular emphasis on the multiple roles played by calcium in controlling pro-cesses of transmitter release and recovery during repetitive activation. LenKaczmarek and Bruce Walmsley will discuss relevant findings made at the re-markably accessible calyx of Held in the brain stem auditory pathway in slicepreparations. Forrest Weight will present studies on the short-term modulationof NMDA receptor-mediated responses by endogenous neuropeptides that areco-released with glutamate on repetitive presynaptic stimulation. Bob Burke willend the session with data on short-term depression of a synaptic system in themouse spinal cord that, although not amenable to direct recording, also appearto involve similar mechanisms.

Panel • Friday • 4:30-6:30 PM • Storm PeakNew Mechanisms for an Old Question: How does Prefrontal CortexAffect Subcortical Dopamine Function

Organizer: B. Moghaddam; Participants: S. Sesack, J.A. Kauer, J. Krystal

Descending glutamatergic projections of the prefrontal cortex (PFC) are neces-sary for appropriate response of dopamine neurons in the ventral tegmental area(VTA) to stimuli within motivational and cognitive domains. Furthermore, clini-cal and basic investigations suggest that aberrant glutamatergic neurotransmis-sion in the PFC, leading to secondary disruption in the midbrain dopaminesystem, may contribute to the pathophysiology and etiology of schizophrenia.The aim of this panel is to present the most recent studies on the circuitry, plas-ticity, and neurochemical mechanisms underlying PFC- mediated changes indopamine cell activity. These findings indicate that, contrary to previously hy-pothesized mechanisms, the PFC may exert a predominantly indirect and in-hibitory influence on subcortical dopamine function. Specifically, anatomicalstudies (Sesack) show that excitatory projections from the PFC synapse onlyonto dopamine cells that project back to the PFC and not those that project tothe ventral striatum. In vivo neurochemical studies (Moghaddam) document dif-ferential tonic glutamate regulation of mesoprefrontal versus mesoaccumbensdopamine neurons, the latter being under tonic inhibitory AMPA control. Datafrom in vitro intracellular recording (Kauer) show that afferent stimulation ofVTA dopamine neurons leads to long-term depression of glutamate synapsesvia influx of Ca2+ through voltage-gated channels. Finally, these basic findingswill be integrated with recent clinical investigations (Krystal) employing imag-ing and pharmacological manipulations of glutamate and dopamine systems tohelp elucidate circuitry and physiological mechanisms that may have relevanceto glutamate-dopamine interactions in healthy individuals versus those withschizophrenia.

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Panel • Friday • 4:30-6:30 PM • TwilightMicroarray Profiling: Complex Diseases and Drug Development

Organizer: S. Potkin; Participants: W. Bunney, R. Thompson, N. Patil, M. Oliver

This panel will review the recent developments in the area of expression arrayand gene chip technology, and their utilization to study complex diseases anddrug development. This field has exploded especially in the last twelve months.In the past we have been able to compare the activity of single genes. With thenew microarray technology we can analyze 15,000 genes simultaneously to con-trast gene expression in two different tissues or brain regions. Bunney will reviewthe emerging application of microarray technology for the investigation of thedifferential expression of specific genes in complex diseases. Three approachesto microarray profiling will then be presented. Thompson will discuss the ex-pression array technology that starts with complimentary cDNA clones obtainedfrom an expression sequence tagged (EST) database. New data utilizing this tech-nology will be presented comparing gene expression profiles obtained from de-fined brain regions in animals treated with different classes of antidepressants.These studies may contribute not only to our understanding of the mechanismsof action for existing antidepressants but also to the potential identification ofnovel antidepressant drug targets. Patil will contrast the advantages and disad-vantages of oligonucleotide arrays or gene chips. She will present an example ofnew data using Affymetrix GeneChip arrays to study neurogenesis, and to iden-tify a set of genes that are differentially expressed in cells isolated from the prolif-erating subventricular zone with the goal of identifying novel molecular markersdifferentially expressed in the neural precursors during various times of develop-ment. Oliver will present a new technology developed over the last year, the In-vader Assay. One of the critical issues in microarray profiling is the requirementof defining expression of different genes accurately, especially difficult with lowlevels of gene expression. The Invader Assay offers a new possibility to preciselyquantify the expression levels of different genes even at low levels. At this mo-ment in science the extremely powerful combination of microarray technologycombined with the recent progress in sequencing of the human genome provideshope for a new era in therapeutics, diagnostics and research.

Panel • Friday • 4:30-6:30 PM • RainbowGABA Transporter Localization, Development and Function

Organizer: W. Spain; Participants: F. Conti, M. Quick, G. Kinney, M. Jones

Recent work on GABA transporters provides insight into the role of uptakemechanisms in regulating synaptic transmission. This panel will provide an over-view and recent developments in the study of these transporters. Bill Spain willprovide a brief introduction of the subject. Fiorenzo Conti will discuss localiza-tion and development of GABA transporters in the CNS with a focus on GAT-1, GAT-2 and GAT-3 in the cerebral cortex. Work on lower vertebrates will berelated to localization of GAT-1 and GAT-3 in the human cerebral cortex. Also

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data will be presented on altered expression of GAT-3 in some pathophysiologi-cal conditions. Mike Quick will discuss factors that regulate GAT-1 expressionand function. He will review work on the redistribution of the transporter to/from the plasma membrane as well as new data demonstrating that intracellulardomains of the GABA transporter and protein-protein interactions govern sub-strate translocation, and identify a link between the machinery involved in trans-mitter release and re-uptake. Greg Kinney will discuss experiments usingwhole-cell recordings from astrocytes in rat neocortical brain slices to measuretransporter currents during evoked synaptic release of GABA. The experimentsprovide insight into the time course and spread of GABA following release. Theultimate role of GABA transporters is to regulate the extracellular concentrationof GABA. Matt Jones will present measurements of the concentration and timecourse of GABA released from single vesicles at synapses in hippocampal slices,the desensitization of synaptic GABA-A receptors resulting from transporterblockade, and Monte Carlo simulations illustrating the implications of these find-ings for GABAergic signaling.

Panel • Friday • 4:30-6:30 PM • SkylineOrphan G Protein-coupled Receptors as Novel Drug Targets

Organizer: P. Iredale; Participants: O. Civelli, M. Yanagisawa, M. Fidock, S. Wilson

G protein-coupled receptors (GPCRs) are a superfamily of plasma membraneproteins that are involved in a multitude of intracellular signaling pathways. His-torically, they have provided a rich source of targets for drug discovery whichhave subsequently resulted in numerous development candidates. To date ap-proximately 1000 GPCRs have been cloned of which about 1/5th are humansequences. Recently, following the advent of mass sequencing of expressed se-quence tags (ESTs) from cDNA libraries there has been a dramatic increase inthe numbers of identified and cloned GPCRs. However, many of these remainas or phan GPCRs of unknown function with no identified ligand or apparentrelationship to a disease indication. The aim of this panel is to review the currentstrategies for identifying cognate ligands for orphan GPCRs and to give examplesof recent successes. After a brief introduction into the area by Phil Iredale, OlivierCivelli will continue by outlining the history of orphan ligand searching. He willbegin by discussing the identification of orphanin FQ, focussing on the lessonslearned, and subsequently how these have been applied to more recent examples.Next, Masashi Yanagisawa will present on the identification of the hypotha-lamic neuropeptides, orexin-A and -B, and their associated receptors. He willaddress findings suggesting a role for this novel peptide system in both the regu-lation of feeding and sleep. Mark Fidock will follow up with a review of thecurrent methodologies that are being employed to search for ligands (includingsurrogates) at orphan GPCRs. Topics covered will include the use of custom-ized G proteins, receptor internalization assays and constitutively active recep-tors. Lastly, Shelagh Wilson will discuss the role that orphan GPCRs play froma Pharmaceutical companies perspective, citing particular examples that haveemerged as potential new drug targets. In summary, this panel will provide anoverview of the current paradigms that have been developed to identify noveland interesting GPCRs and discuss some of the successes and lessons that havebeen learned along the way.

Don’t forget to visit the exhibit area.

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Elizabeth AbercrombieRutgers Universityabercrombie@axon.rutgers.edu

James AdamsUniversity Southern Californiajadams@hsc.usc.edu

Bryon Adinoff, 63University of Texas Southwesternbryadinoff@aol.com

Greti Aguilera, 72National Institutes of Healthgreti@helix.nih.gov

Elias Aizenman, 38, 93University of Pittsburghredox@pitt.edu

Elliot AlbersGeorgia State Universitybiohea@panther.gsu.edu

Kathryn Albers, 90, 93University of Kentuckykmalbe00@pop.uky.edu

Patrick Allen, 108The Rockefeller Universityallenp@rockvax.rockefeller.edu

C. Anthony Altar, 62, 117Otsuka America Pharmaceutical Inctonya@mrl.oapi.com

Arturo Alvarez-Buylla, 86The Rockefeller Universityalvarez@rockvax.rockefeller. edu

Brenda Anderson, 48SUNY Stony Brookbanderso@psych1.psy.sunysb.edu

Rodrigo Andrade, 98Wayne State Universityrandrade@med.wayne.edu

Kristin Anstrom, 91Wake Forest Universitykanstrom@wfubmc.edu

Index/Participant ListRaymond Anton, 63Medical University of South Carolinaantonr@musc.edu

Margie ArianoChicago Medical Schoolarianom@finchcms.edu

Regina Armstrong, 119Uniformed Services Universityrarmsrong@usuhs.mil

Andreas ArvanitogiannisHarvard Medical Schoolandreas@mclean.harvard.edu

Gary Aston-Jones, 66University of Pennsylvaniagaj@mail.med.upenn.edu

Constance Atwell, 92National Institute of Neurological

Disorders & Strokeca23c@nih.gov

Peter Baas, 106University of Wisconsinpwbaas@facstaff.wisc.edu

Roy Bakay, 98Emory Universityrbakay@emory.edu

Ruben Baler, 64National Institutes of Healthabri@codon.nih.gov

Marie Banich, 74University of Illinois Urbanambanich@s.psych.uiuc.edu

Steve Barger, 67University of Arkansasbargerstevenw@exchange. uams.edu

Allan I. BasbaumUniversity of California San Franciscoaib@phy.ucsf.edu

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Anthony BasileNational Institutes of Healthasbasile@helix.nih.gov

Gary Bassell, 23Albert Einstein Collegebassell@aecom.yu.edu

Steven BealerUniversity of Utahsteve.bealer@deans.pharm.utah.edu

Jill Becker, 87University of Michiganjbbecker@umich.edu

Jo Begbie, 69King s College Londonjo.begbie@kcl.ac.uk

Margery BeinfeldTufts Universitymbeinfel@opal.tufts.edu

Alvin Beitz, 77University of Minnesotaalvin@biosci.cbs.umn.edu

Aysenil Belger, 74University of North Carolina Chapel-Hillaysenil.belger@css.unc.edu

Esther Bell, 69The Rockefeller Universitybelle@rockvax.rockefeller.edu

Gerald BenhamNikonjbenhamnikon@msn.com

Michael V.L. BennettAlbert Einstein College of Medicinembennett@aecom.yu.edu

Deanna Benson, 62Mount Sinai School of Medicinebenson@neuro.mssm.edu

Albert Berger, 74University of Washingtonberger@u.washington.edu

Craig BerridgeUniversity of Wisconsinberridge@facstaff.wisc.edu

Elizabeth Berry-Kravis, 86RUSH Presbyterian St. Luke s Medical

Centereberrykr@rush.edu

James Bibb, 25The Rockefeller Universitybibbj@rockvax.rockefeller.edu

Charles Billington, 106Minneapolis VA Medical Centerbilli005@tc.umn.edu

Brian Billups, 24University of Leicesterbjb10@le.ac.uk

Murray BlackmoreUniversity of Minnesotablac0192@tc.umn.edu

David Bleakman, 68Eli Lilly and Companybleakman_david@lilly.com

James R. BloedelIowa State Universityjbloede@chw.edu

Lidia C. Boffa, 97National Cancer Institute ISTboffa@hp380.ist.unige.it

Stephen BondyUniversity of California Irvinescbondy@uci.edu

Amitabha Bose, 63New Jersey Institute of Technologybose@m.njit.edu

Martyn Boutelle, 107King s College Londonmartyn.boutelle@kcl.ac.uk

Michel Bouvier, 82University of Montrealbouvier@bcm.umontreal.ca

Sunny Boyd, 93University of Notre Dameboyd.1@nd.edu

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Charles Bradberry, 111West Haven Veterans Administrationcharles.bradberry@yale.edu

Daron BrownFine Science Toolsdbrown@finesceince.com

William Bunney, 121University of California Irvinewebunney@uci.edu

Robert Burke, 119National Institute of Neurological

Disorders & Strokesreburke@helix.nih.gov

Gully Burns, 76University of Southern Californiagully@usc.edu

Allan Butterfield, 81University of Kentuckydabcns@pop.uky.edu

Angela Cantrell, 108University of Tennesseeacantrell@utmem.edu

Bill Carlezon, 112Harvard Medical Schoolcarlezon@mclean.harvard.edu

Susan CarltonUniversity of Texassmcarlto@utmb.edu

BJ CaseyCornell Universitybjc2002@mail.med.cornell.edu

William Catterall, 70University of Washingtonwcatt@u.washington.edu

David Chambers, 69King s College Londonstrq1531@kcl.ac.uk

John ChapinSUNY Health Science Center Brooklynjohn_chapin@netmail.hscbklyn.edu

Paul Chapman, 94Cardiff UniversitychapmanPF@cf.ac.uk

Dennis Choi, 93Washington Universitychoid@neuro.wustl.edu

Michael ChoppHenry Ford Hospitalchopp@neuro.hfh.edu

James ChouNathan Kline Institutechou@nki.rfmh.org

Carson Chow, 63University of Pittsburghccchow@pitt.edu

Hsin Chu, 77University of Oregonchu@uoneuro.uoregon.edu

Hee Jung Chung, 115John Hopkins Universityheechung@jhmi.edu

John A. Cidlowski, 72National Institute Environmental Health

Sciencecidlowski@niehs.nih.gov

Olivier Civelli, 122University of California Irvineocvivelli@uci.edu

Paul Clarke, 97McGill Universitypclarke@pharma.mcgill.ca

William CobbRutgers Universitycobb@axon.rutgers.edu

Vicki CoffinShering Plough Research Institutevicki.coffin@spcorp.com

Jonathan CohenPrinceton Universityjdc@princeton.edu

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Carlo Colantuoni, 104Johns Hopkinsccolantu@jhmi.edu

Douglas Cole, 105Vertex Pharmaceuticalsdouglas_cole@vpharm.com

Graham L. Collingridge, 103University of Bristolg.l.coolingridge@bristol.ac.uk

Carol ColtonDuke Universityglia01@aol.com

Paul Conn, 71Emory Universitypconn@emory.edu

Fiorenzo Conti, 121Universita di Anconaf.conti@popcsi.unian.it

Richard Coppola, 104National Institute of Mental Healthcoppola@helix.nih.gov

John CostelloThe MIT Press Exhibitsjcostell@mit.edu

Michael CostiganMassachusetts General Hospital Harvardcostigan@helix.mgh.harvard.edu

Carl W. Cotman, 88University of California Irvinecwcotman@uci.edu

Fulton Crews, 48University of North Carolina Chapel Hillftcrews@med.unc.edu

Joseph Cubells, 79Yale Universityjoseph.cubells@yale.edu

Kathryn A. Cunningham, 80University of Texascunningham@utmb.edu

Cynthia Czajkowski, 100University of Wisconsinczajkowski@physiology.wisc.edu

Mauro Dal Canto, 85Northwestern Universitym-dalcanto@northwestern.edu

Gudarz Davar, 77Brigham and Women s Hospitalgdavar@zeus.bwh.harvard.edu

Beverly Davidson, 76University of Iowachristine-mclennan@uiowa.edu

Duff DavisPfizer IncDuff.Davis@pfizer.com

Ron Davis, 89Baylor College of Medicinerdavis@bcm.tmc.edu

Geert De Vries, 65University of Massachusettsdevries@cns.umass.edu

Taco De Vries, 66Research Institute Neurosciences Vrije

Universitytj.de_vries.pharm@med.vu.nl

Harriet de Wit, 111University of Chicagohdew@midway.uchicago.edu

Elizabeth DebskiUniversity of Kentuckydebski@pop.uky.edu

Victor DenenbergUniversity of Washingtondberg@uconnvm.uconn.edu

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Gersham Dent, 78University of Pennsylvaniagersham@mail.med.upenn.edu

Lakshmi Devi, 82New York Universitylakshmi.devi@med.nyu.edu

Dennis DicksonMayo Clinicdickson.dennis@mayo.edu

Gerald Dienel, 113University of Arkansasdienelgeralda@exchange.uams.edu

Sylvain Dor , 25Johns Hopkins Universitysdore@jhmi.edu

Paula Dore-Duffy, 73Wayne State Universitypdduffy@med.wayne.edu

Daniel M. Dorsa, 87University of Washingtondorsa@u.washington.edu

F. Edward Dudek, 118Colorado State Universityedudek@cvmbs.colostate.edu

Ian Duncan, 119University of Wisconsin Madisonian_duncan@svm.vetmed.wisc.edu

Bruce Dunn, 107University of California Los Angelesbdunn@ucla.edu

Tom DunwiddieUniversity of ColoradoTom.Dunwiddie@UCHSC.edu

Ford F. Ebner, 98Vanderbilt Universityford.ebner@vanderbilt.edu

Robert Edwards, 116University of California San Franciscoedwards@itsa.ucsf.eduMichael Egan, 79National Institute of Mental Healtheganm@intra.nimh.nih.gov

Mikhailova ElenaMental Health Research Centershevelev2@mail.ru

Helene EmsellemThe Center for Sleep & Wake Disorderssleepdoc@erols.com

Jeffrey Erickson, 116Louisiana State Universityjerick@lsuhsc.edu

Amy Eshleman, 104Oregon Health Sciences Universityeshleman@ohsu.edu

Chris Evans, 95University of California Los Angelescevans@ucla.edu

Alan I. Faden, 71Georgetown Universityfadena@giccs.georgetown.edu

Carolyn FairbanksUniversity of Minnesotacarfair@med.umn.edu

James Fawcett, 109Cambridge Universityjf108@cam.ac.uk

Michale Fee, 114Bell Labsfee@lucent.com

Mork Fidock, 122Pfizer Global Research and Developmentmork_fidock@sandwich.pfizer.com

Howard FieldsUniversity of Californiahlf@itsa.ucsf.edu

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David FinkUniversity of Pittsburghdfink@med.pitt.edu

George FinkPharmos Corpgfink@pharmos.com

Elena Fiorica-Howells, 123Columbia Universitymdg4@columbia.edu

Gerald FischbachNational Institutes of Health

Cecilia Flores, 62Harvard Medical Schoolflores@mclean.harvard.edu

Francis FlynnUniversity of Wyomingflynn@uwyo.edu

Bob Foehring, 98University of Tennessee Memphisfoehring@nb.utmem.edu

Ian Forsythe, 24, 70University of LeicesterIDF@leicester.ac.uk

Peter FoxUniversity of Texasfox@uthscsa.edu

Robin Franklin, 119University of Cambridgerjf1000@cam.ac.uk

Kyle Frantz, 36The Scripps Research Institutekfrantz@scripps.edu

Nigel FraserUniversity of Pennsylvanianfraser@mail.med.upenn.edu

Alan Frazer, 88University of Texas San Antoniofrazer@uthscsa.edu

Curt FreedUniversity of Coloradocurt.freed@uchsc.edu

William J. Freed, 104National Institute on Drug Abusewfreed@intra.nida.nih.gov

J. James Frost, 95The Johns Hopkins Universityjfrost@receptor.rad.jhu.edu

Denson FujikawaUniversity of California Los Angelesdfujikaw@ucla.edu

Zoltan Fuzessery, 114University of Wyomingzmf@uwyo.edu

Raul Gainetdinov, 72Duke UniversityR.Gainetdinov@cellbio.duke.edu

Karen Gale, 113Georgetown Universitygalek@georgetown.edu

Aurelio Galli, 88University of Texas San Antoniogalli@uthscsa.edu

Craig Garner, 115University of Alabama Birminghamgarner@nrc.uab.edu

Don GashUniversity of Kentuckydongash@pop.uky.edu

Angela GasserS Karger AGa.gasser@karger.ch

Scott GehlerUniversity of Minnesotagehl0014@tc.umn.edu

Herbert Geller, 76Robert Wood Johnson Medical Schoolgeller@umdnj.edu

Susan R. George, 82University of Torontos.george@utoronto.ca

Greg Gerhardt, 88University of Kentuckygreggg@pop.uky.edu

141

M. P. Gilbey, 102Royal Free Campusmpg@rfhsm.ac.uk

Bruce Gold, 105Oregon Health Sciences Universitygold@ohsu.edu

Alan Goldin, 108University of California Irvineagoldin@uci.edu

David Goldman, 79National Institute on Alcohol Abuse and

Alcoholismdgneuro@box-d.nih.gov

James Goldman, 119Columbia Universityjeg5@columbia.edu

Steve Goldman, 109Cornell University Medical Collegesgoldm@mail.med.cornell.edu

Timothy Gomez, 99University of Wisconsintmgomez@facstff.wisc.edu

Angela GoodacreOlympus Americagoodaa@olympus.com

Anthony Grace, 66University of Pittsburghgrace@bns.itt.edu

Robert Grainger, 77University of Virginiarmg9p@virginia.edu

Bill Greenough, 86University of Illinois Urbanawgreenou@uiuc.edu

Karen GreifBryn Mawr Collegekgreif@brynmawr.edu

Nigel Greig, 68National Institute on AgingGreigN@vax.grc.nia.nih.gov

Sue Griffin, 67University of Arkansasfreepamelaa@exchange.uams. edu

Jeffrey Grimm, 49National Institute on Drug Abusejgrimm@intra.nida.nih.gov

Matthew Grober, 65Arizona State Universitymgrober@asu.edu

Chistina Grobin, 117University of North Carolina Chapel Hillgrobinac@med.unc.edu

Rolf GruetterUniversity of Minnesotagruetter@cmrr.umn.edu

Gary Gudelsky, 84University of Cincinnatigary.gudelsky@uc.edu

Patrice G. Guyenet, 102University of Virginiapgg@virginia.edu

Ryder Gwinn, 113Georgetown Universitygwinnr@georgetown.edu

Suzanne HaberUniversity of Rochestersuzanne_haber@urmc.rochester.edu

Randi Hagerman, 86University of Colorado Health Sciences

Centerhagerman.randi@tchden.org

Theo Hagg, 95Dalhousie Universitythagg@is.dal.ca

Edward D. Hall, 105Pfizer Global Research and Developmentedward.hall@pfizer.com

Shelley Halpain, 62The Scripps Research Instituteshelley@scripps.edu

J. Marie Hardwick, 83Johns Hopkinshardwick@jhu.edu

142

Sami HarikUniversity of Arkansashariksamii@exchange.uams.edu

Neil HarrisonCornell Universityneh2001@med.cornell.edu

Teresa Hastings, 72University of Pittsburghhastings@bns.pitt.edu

Edward HawrotBrown UniversityEdward_Hawrot@brown.edu

Ulrike Heberlein, 89University of California San Franciscoulrike@itsa.ucsf.edu

Heiko Hecht, 111Massachusetts Institute of Technologyhecht@mit.edu

Johannes HellUniversity of Wisconsinjwhell@facstaff.wisc.edu

Hugh HemmingsWeill Medical College of Cornell

Universityhchemmi@mail.med.cornell.edu

Joan Hendricks, 89University of Pennsylvaniajch@phl.vet.upenn.edu

Fritz HennUniversity of Heidelberghenn@as200.zi-mannheim.de

James Herman, 72University of Cincinnatijpherman@psychiatry.uc.edu

Karl Herrup, 90University Hospitals Case Western

Reservekxh26@po.cwru.edu

Sandra Hewett, 26University of Connecticut Health Centershewett@neuron.uchc.edu

Jay Hirsh, 89University of Virginiajh6u@virginia.edu

Bart HoebelPrinceton Universityhoebel@princeton.edu

Sandy Hofmann, 76University Texas Southwesternhofmann@simmons.swmed.edu

Gregg Homanics, 100University of Pittsburghhomanicsge@anes.upmc.edu

John P. Horn, 102University of Pittsburghjph@pitt.edu

Richard Howells, 38University of Medicine & Denistry of

New Jerseyhowells@umdnj.edu

Paul Huang, 37Massachusetts General Hospitalhuangp@helix.mgh.harvard.edu

Kim Huhman, 50Georgia State Universitykhuhman@gsu.edu

Elaine Hull, 51SUNY Buffaloemhull@acsu.buffalo.edu

Michael Hutton, 75Mayo Clinichutton.michael@mayo.edu

Thomas Hyde, 104National Institute of Mental Healthhydet@intra.nimh.nih.gov

Satoshi Ikemoto, 112National Institute on Drug Abusesikemoto@intra.nida.nih.gov

Donald Ingram, 68National Institute on Agingdoni@vax.grc.nia.nih.gov

143

Thomas Insel, 65Emory Universityinsel@rmy.emory.edu

Philip Iredale, 122Pfizer, Inc.phili_a_iredale@groton.pfizer.com

John Isaac, 103University of Bristolj.t.r.isaac@bristol.ac.uk

Ole Isacson, 84McLean Hospitalisacson@helix.mgh.harvard.edu

Michael IuvoneEmory Universitymiuvone@pharm.emory.edu

Russell Jacobs, 76California Institute of Technologyrjacobs@caltech.edu

Mark Jacquin, 114Washington Universityjacquinm@neuro.wustl.edu

Patricia Janak, 100Univeresity of California San Franciscopjanak@itsa.ucsf.edu

Aaron Janowsky, 104Portland VA Medical Centerjanowsky@ohsu.edu

Luc Jasmin, 51University California San Franciscoucpain@itsa.ucsf.edu

Andrew Jenkins, 100Weill Medical Collegeanj2005@med.cornell.edu

Frances Jensen, 110Children s Hospitaljensen@a1.tch.harvard.edu

Alan Kim JohnsonUniversity of Iowaalan-johnson@uiowa.edu

Elizabeth Jonas, 82Yale Universityjonas@biomed.med.yale.edu

Mathew Jones, 121University of Wisconsin Madisonjonesmat@physiology.wisc.edu

Reese Jones, 73University of California San Franciscoreese@itsa.ucsf.edu

Richard JonesPortland VA Medical Centerjonesric@ohsu.edu

James Joseph, 68Tufts Universityjjoseph@hnrc.tufts.edu

Sharon Juliano, 90Uniformed Services University HSsjuliano@usuhs.mil

Kevin Ka-Wang Wang, 88Pfizer Global R & Dkevin.wang@pfizer.com

Leonard K. Kaczmarek, 70, 119Yale Universityleonard.kaczmarek@yale.edu

Katherine Kalil, 99University of Wisconsin Madisonkakalil@facstaff.wisc.edu

Jagmeet Kanwal, 114Georgetown UniversityKanwalJ@giccs.georgetown.edu

Rolf Karlstrom, 77University of Massachusettskarlstrom@bio.umass.edu

Kathleen KarmelOlympus Americahdgek@olympus.com

Julie Kauer, 79, 120Brown UniversityJulie_Kauer@Brown.edu

144

Michael Kavanaugh, 116Oregon Health Sciences Universitykavanaug@ohsu.edu

Kristen KeefeUniversity of UtahK.Keefe@m.cc.utah.edu

George KeeslerAventis PharmaceuticalsGeorge.Keesler@avenits.com

Ken Kellar, 82Georgetown Universitykellark@georgetown.edu

Ann Kelley, 106University of Wisconsin Madisonaekelley@facstaff.wisc.edu

Martin Kelly, 87Oregon Health Sciences Universitykellym@ohsu.edu

John KempHoffmann-La Roche Ltdjohn.kemp@roche.com

Robert Kennedy, 107University of Floridartkenn@chem.ufl.edu

Jason Kerr, 41National Institute of Mental Healthjkerr@codon.nih.gov

Andrew KerteszUniversity of Western Ontariokeresz@lri.sjhc.london.on.ca

Stanislav KholmanskikhUniversity of Minnesotakholm001@umn.edu

Kwang-Soo Kim, 84McLean Hospital Harvard Medical

Schoolkskim@mclean.harvard.edu

Ann Kingston, 71Eli Lillykingston-c-@lilly.com

Gregory Kinney, 121University of Washingtongkinney@u.washington.edu

Daryl R. Kipke, 100Arizona State Universitykipke@asu.edu

Joel KleinmanNational Institute of Mental Healthkleinmaj@intra.nimh.nih.gov

Gregory W. Konat, 73West Virginia UniversityGkonat@wvu.edu

George F. Koob, 66, 111The Scripps Research Institutegkoob@scripps.edu

Jeffrey Kordower, 84, 98Rush Presbyterian Medical Centerjkordowe@rush.edu

Conan KornetskyBoston Universityckornets@bu.edu

Stephen KoslowNational Institute of Mental Healthkoz@helix.nih.gov

Catherine Kotz, 52Veterans Administration Medical Centerkotzx004@umn.edu

Arnold Kriegstein, 90Columbia University

Claudia Krispel, 59University of California San Diegockrispel@ucsd.edu

John Krystal, 80, 120Yale Universityjohn.krystal@yale.edu

Leszek Kubin, 74University of Pennsylvanialkubin@vet.upenn.edu

Dietmar F. Kuhl, 94Hamburg Universitydietmar.kuhl@zmnh.uni-hamburg.de

145

David Laidlaw, 76Brown Universitydhl@cs.brown.edu

Joseph LaMannaCase Western Reserve UniversityJCL4@po.cwru.edu

Richard D. Lane, 114Medical College of Ohiorlane@mco.edu

Ulo Langel, 97The Scripps Research Instituteulangel@scripps.edu

Dianne Lattemann, 106University of Washingtonlatte@u.washington.edu

Jean Lauder, 123University of North Carolinaunclau@med.unc.edu

Kevin Lee, 110University of Virginiaksl3h@virginia.edu

Charles Leffler, 59University of Tennesseecleffler@physio1.utmem.edu

Paul Lehmann, 85Case Western Reserve UniversityPVL2@PO.CWRU.EDU

Sarah LeibowitzThe Rockefeller Universityleibow@rockvax.rockefeller.edu

Robert H. Lenox, 62University of Pennsylvaniarlenox@mail.med.upenn.edu

Paul C. Letourneau, 99, 105University of Minnesotawcbr@mail.ahc.umn.edu

Barry Levin, 106VA Medical Centerlevin@umdnj.edu

Joel Levine, 109SUNY Stony BrookJoel.Levine@sunysb.edu

Michael Levine, 92University of California Los Angelesmlevine@mednet.ucla.edu

Steve Levison, 96Penn State College of Medicineslevison@psu.edu

Irwin LevitanUniversity of Pennsylvanialevitani@mail.med.upenn.edu

Anita LewinResearch Triangle Instituteahl@rti.org

Stafford Lightman, 72University of Bristolstafford.lightman@bristol.ac.uk

Iris Lindberg, 108Louisiana State Universityilindb@lsuhsc.edu

Jon Lindstrom, 82University of Pennsylvaniajslkk@mail.med.upenn.edu

Diane Lipscombe, 70Brown UniversityDiane_Lipscombe@Brown.Edu

Barbara LipskaNational Institute of Mental HealthlipskaB@intra.nimh.nih.gov

Donald LoDuke University Medical Centerlo@neuro.duke.edu

Peter Lobel, 76Robert Wood Johnson Medical Schoollobel@cabm.rutgers.edu

David Lodge, 103Lilly Research CentreLodge_David@Lilly.com

Edythe D. London, 63University of California Los Angeleselondon@tracer

Daniel Lowenstein, 110Harvard Medical Schooldaniel_lowenstein@hms.harvard.edu

146

Phillip Lowrey, 64Northwestern Universityp-lowrey@northwestern.edu

Joseph Ludwig, 27Mayo Clinic Jacksonvilleludwig.joseph@mayo.edu

Ronald J. Lukas, 82Barrow Neurological InstituteRLUKAS@CHW.edu

William LymanWayne State Universitywlyman@med.wayne.edu

Maria MaccecchiniAnnovis Incmlm@annovis.com

Bruce MacIverStanford Universitymaciver@stanford.edu

Ken Mackie, 82University of Washingtonkmackie@u.washington.edu

Wendy Macklin, 96Cleveland Clinic Foundationmackliw@ccf.org

Daniel MadisonStanford Universitymadison@stanford.edu

Nigel Maidment, 107University of California Los Angelesnmaidmen@ucla.edu

Robert Malenka, 35Stanford Universityrmalenka@stanford.edu

Laura Mamounas, 117Johns Hopkins Medical InstitutionsMamounas@welch.jhu.edu

Donna Maney, 93Johns Hopkins Universitymaney@jhu.edu

Robert MansbachPfizer, Inc.mansbachrs@groton.pfizer.com

Oliver Manzoni, 79CNRSmanzoni@ccipe.montp.inserm.fr

Gerard Marek, 80Yale School of Medicinegerard.marek@yale.edu

Neville MarksNathan Klinemarks@nki.rfmh.org

Luc Maroteaux, 123Strasbourg Universitylucm@igbmc.u-strasbg.fr

Michael Martin, 92National Institutes of HealthMARTINM@CSR.NIH.GOV

Susan MasinoUniversity of Coloradosusan.masino@uchsc.edu

Gary Mathern, 92University of California Los Angelesgmathern@ucla.edu

Andrew Matus, 62Friedrich Miescher Institutematus@fmi-ch

Bob McCallPharmacia Corporationrobert.b.mccall@am.pnu.com

Cyrus McCandless, 53University of Pittsburghcyrus@cnbe.cmu.edu

William McClure, 53University of Southern Californiawmcclure@usc.edu

James McElligott, 111Temple Universitymcellig@astro.temple.edu

Jacqueline F. McGinty, 78, 95Medical University South Carolinamcginty@musc.edu

Dan McIntyre, 58, 113Carleton Universitydmcintyr@ccs.carleton.ca

147

Hugh McIntyreUniversity of California Los Angeleshbmcintyre@pol.net

Mary C. McKenna, 113University of Marylandmmckenna@umaryland.edu

F. Arthur McMorrisThe Wistar InstituteMcMorris@wistar.upenn.edu

Haley Melikian, 104Harvard Medical Schoolhmelikian@hms.harvard.edu

Claudio Mello, 114Oregon Health Sciences Universitymello@rockvx.rockefeller.edu

Synthia Mellon, 117University of California San Franciscomellon@cgl.ucsf.edu

Britt Mellstr m, 28National Center Biotechnologybmellstr@cnb.uam.es

Marsha MelnickUniversity California San Franciscommelnick@sfsu.edu

John MendelsonUniversity of California San Franciscojemmd@itsa.ucsf.edu

Kalpana Merchant, 78Pharmarcia Corporationkalpana.m.merchant@am.pnu.com

Raju Metherate, 98University of California Irvinermethera@uci.edu

Adrian C. Michael, 107University of Pittsburghamichael@pitt.edu

John Mihic, 100University of Texas Austinmihic@mail.utexas.edu

Neil Millar, 82University College Londonn.millar@ucl.ac.uk

David W. Miller, 75Massachusetts General Hospitalmillerd@helix.mgh.harvard.edu

Martha Miller, 96Case Western Reserve Universitymjm8@po.cwru.edu

Stephen Miller, 85Northwestern Universitys-d-miller@northwestern.edu

Rex Moats, 76Childrens Hospital Los Angelesmoats @hsc.usc.edu

Bita Moghaddam, 120Yale Universitybita.moghaddam@yale.edu

Derek Molliver, 90Oregon Health Sciences Universitymolliver@ohsu.edu

Eric MoodyJohns Hopkinsemoody@jhmi.edu

Frank Moore, 65Oregon State Universitymooref@bcc.orst.edu

A. Leslie Morrow, 117University of North Carolina Chapel Hillmorrow@med.unc.edu

Yuko MunakataUniversity of Denvermunakata@du.edu

N. Eric NaftchiNew York Universityjoyceric@worldnet.att.net

Angus NairnThe Rockefeller Universitynairn@rockvax.rockefeller.edu

Kazunori Nakajima, 90Jikei Universitynakajima@brain.riken.go.jp,

kazunori@jikei.ac.jp

148

T. Celeste Napier, 95Loyola Universitycnapier@luc.edu

Jose Naranjo, 94National Center Biotechnologynaranjo@cnb.uam.es

Shridhar Narayanan, 40University of California Los Angelesshridhar@ucla.edu

Eugene Nattie, 74Dartmouth Medical SchoolEugene.Nattie@Dartmouth.edu

Alexandra Nelson, 40University of California San Diegoabnelson@ucsd.edu

David Nelson, 86Baylor College of Medicinenelson@bcm.tmc.edu

Kim Neve, 30Portland VA Medical Centernevek@ohsu.edu

Madeleine Nicol, 28Australian National UniversityMadeleine.Nicol@anu.edu.au

Roger Nicoll, 103University of California San Francisconicoll@phy.ucsf.edu

Eric Nisenbaum, 41, 68Eli Lilly & CompanyESN@lilly.com

Laura Nisenbaum, 41Eli Lilly & Companyl.nisenbaum@lilly.com

Koichi NishikawaWeill Medical College of Cornell

Universitykon2002@med.cornell.edu

Ralph A. Nixon, 88Nathan Kline Institutenixon@nki.rfmh.org

Edward Novotny, 113Yale Universityedward.novotny@yale.edu

Charles O Brien, 66University of Pennsylvaniaobrien@research.trc.upenn.edu

Tim O Connor, 99University of British Columbiajimo@unixg.ubc.ca

Laura O Dell, 45Scripps Research InstituteLODELL@SCRIPPS.EDU

Patricio O Donnell, 66Albany Medical Collegeodonnep@mail.amc.edu

Randall O Reilly, 74University Colorado Boulderoreilly@psych.colorado.edu

Anne Louise Oaklander, 55Harvard Medical Schoolaoaklander@partners.org

Halina Offner, 73Oregon Health Sciences Universityoffnerva@ohsu.edu

Murat Okatan, 39Boston Universityokatan@cns.bu.edu

Michael Olivier, 121Stanford Human Genome Centerolivier@shgc.stanford.edu

Richard W. Olsen, 115University of California Los Angelesrolsen@mednet.ucla.edu

Michelle PageUniversity of Pennsylvaniapage@pharm.med.upenn.edu

Gene PalmerAstraZeneca R&D Bostoneugene.palmer@astrazeneca.com

Theo Palmer, 86Stanford University Medical Centertpalmer@stanford.edu

149

Jack M. Parent, 86University of Michiganparent@umich.edu

Larry (Loren) Parsons, 80The Scripps Research Institutelparsons@scripps.edu

Kathy Partin, 68Colorado State University

Yogesh C. Patel, 82McGill Universityyogesh.patel@muh.mcgill.ca

Nila Patil, 121Affymetrix Incnila_patil@affymetrix.com

Laura PauplesUniversity of Pennsylvanialpeuples@psych.upenn.edu

David Pearce, 76University of Rochesterdavid_pearce@urmc.rochester.edu

Robert PearceUniversity of Wisconsinrapearce@facstaff.wisc.edu

Betsy Pehek, 80Cleveland VA Medical Centereap6@po.cwru.edu

Luc Pellerin, 113University of Lausanneluc.pellerin@iphysiol.unil.ch

Dale PelligrinoUniversity of Illinois Chicagodpell@uic.edu

Regino Perez-Polo, 68University of Texasregino.perez-polo@utmb.edu

Stephen PeroutkaiO PhamaceuticalsDrPeroutka@aol.com

Pier Vincenzo PiazzaUniversity of Bordeauxpiazza@bordeaux.inserm.fr

Marina Picciotto, 108Yale Universitymarina.picciotto@yale.edu

Chris PierceBoston Universityrcpierce@bu.edu

Dietmar PlenzNational Institute of Mental Healthdplenz@codon.nih.gov

George D. Pollak, 114University of Texas at Austingpollak@mail.utexas.edu

Linda Porrino, 63Wake Forest Universitylporrino@wfubmc.edu

Steven Potkin, 121University of California Irvinesgpotkin@uci.edu

Nanduri Prabhakar, 101Case Western Reserve Universitynrp@po.cwru.edu

Michael W. Quick, 121University of Alabama Birminghamquick@nrc.uab.edu

Remi QuirionMcGill Universityquirem@douglas.mcgill.ca

Anjali RajadhyakshaMcLean Hospital Harvard Medical

Schoolrajadhan@helix.mgh.harvard.edu

Jan Marino Ramirez, 74, 101The University of ChicagoJramire@midway.uchicago.edu

Bruce RansonUniversity of Washingtonbransom@u.washington.edu

Peter Reeh, 77University of Erlangenreeh@physiologie1.uni-erlangen.de

150

Peter H. ReinhartDuke University Medical Centerreinhart@neuro.dueke.du

Maarten E.A. Reith, 104University of Illinois PeoriaMaartenR@uic.edu

Ian J. Reynolds, 93University of Pittsburghiannmda@pitt.edu

Robert W. Rhoades, 114Medical College of Ohiorrhoades@mco.edu

George Ricaurte, 72, 84Johns Hopkins Universityricaurte@jhmi.edu

J. Steven Richardson, 81University of Saskatchewanrichardson@sask.usask.ca

William Richardson, 109University College Londonw.richardson@ucl.ac.uk

George Richerson, 74, 101Yale UniversityGeorge.Richerson@Yale.Edu

Terry Robinson, 91, 111University of Michiganter@unich.edu

Dorit Ron, 115Ernest Gallo Clinic and Research Centerdorit@irsa.ucsf.edu

Oline K. RonnekleivOregon Health Sciences Universityronnekle@ohsu.edu

Steven Roper, 92University of Floridaroper@neurosurgery.ufl.edu

Elliott RossUniversity of Oklahomaelliott-ross@ouhsc.edu

Peter Ruben, 108

Utah State Universitypruben@biology.usu.edu

Jonathan Rubin, 63University of Pittsburghrubin@math.pitt.edu

Rainer Rupprecht, 117Ludwig Maximilian UniversityRainer.Rupprecht@psy.med.uni-

muenchen.de

David Ruskin, 42National Institutes of Healthruskind@ninds.nih.gov

Amelia Russo-Neustadt, 117California State University Los Angelesarusson@calstatela.edu

Helen Scharfman, 86Helen Hayes Hospitalscharfmann@helenhayeshosp.org

Stephen Scheff, 57University of Kentuckysscheff@pop.uky.edu

Todd Scheuer, 70, 108University of Washingtonscheuer@u.washington.edu

Michael G. Schlossmacher, 75Brigham and Women s Hospitalschloss@cnd.bwh.harvard.edu

Joann Schmidt, 43PfizerJoann.Schmidt@pfizer.com

Geoffrey Schoenbaum, 91Johns Hopkins Universityschoenbg@jhu.edu

Arne Schousboe, 116Royal Danish School of Pharmacyas@dfh.dk

W. Schultz, 66, 91University of Frihourgwolfram.schultz@unifr.ch

Joe Schwab

151

Pharmaciajoe_schwab@yahoo.com

Joan P. Schwartz, 67National Institute of Neurological

Disorders and Strokejps@helix.nih.gov

Roy Schwarz, 71Pfizer Global Research & Developmentroy-schwarz@pfizer.com

Stephan Schwarzacher, 123University of Goettingensschwar@gwdg.de

Erik Schweitzer, 33University California Los Angelesschweitzer@mednet.ucla.edu

Chris Sekirnjak, 36Salk Institute for Biological Studieschris@salk.edu

David SelfUniversity of Texas Southwesterndavid.self@utsouthwestern.edu

Kim B. Seroogy, 62University of Kentuckykseroog@pop.uky.edu

Susan Sesack, 120University of Pittsburghsesack@bns.pitt.edu

Yavin Shaham, 66National Institute on Drug Abuseyshaham@intra.nida.nih.gov

Mark Shelhamer, 111Johns Hopkins Universitymjs@dizzy.med.jhu.edu

Kent ShellenbergerElan Pharmaceuticalskshellenberger@elanpharma.com

Toni Shippenberg, 95National Institutes of Healthtshippen@intra.nida.nih.gov

Beth-Anne SieberNational Institute of Mental Healthsieberb@helix.nih.gov

Ralph Siegel, 56Rutgers Universityaxon@cortex.rutgers.edu

Angela SieglingBayer AGangela.siegling.as@bayer-ag.de

Eric J. SimonNew York Universityeric.simon@nyu.edu

Roger Simon, 113R.S.Dow Neurobiology Laboratoriesrsimon@DowNeurobiology.org

Ian Simpson, 113Penn State Universityixs10@psu.edu

Phil Skolnick, 117Eli Lilly and Companyskilnick-phil@lily.com

Ruth Slack, 106University of Ottawarslack@uottawa

Robert Sloviter, 110University of Arizonasloviter@v.arizona.edu

Marion SmithStanford Universitymesmith@leland.stanford.edu

Mark A. SmithCase Western Reserve Universitymas21@po.cwru.edu

Sherry Smith, 49, 81SUNY Health Science Center Brooklynsheryl_smith@netmail.hscbklyn.edu

Gretchen Snyder, 43The Rockefeller Universitysnyderg@rockvax.rockefeller.edu

Mark Sonders, 88Oregon Health Sciences Universitysondersm@ohsu.edu

Linda SorkinUniversity of California San Diegolsorkin@ucsd.edu

152

William Spain, 121VA Puget Sound Health Care Systemsspain@u.washington.edu

Kevin Staley, 118University of Coloradokevin.staley@uchsc.edu

David G. Standaert, 75Massachusetts General Hospitalstandaert@helix.mgh.harvard.edu

Ursula Staubli, 68Cortex Pharmaceuticals IncUStaubli@cortexpharm.com

Donald SteinEmory Universitydstei04@emory.edu

Heinz Steiner, 44Finch University of Health Servicessteinerh@finchcms.edu

Nicholas Steneck, 92University of Michigannsteneck@umich.edu

Fiona StevensOxford University Pressfxs@oup-usa.org

Bradford StokesThe Ohio State Universitystokes.1@osu.edu

Alex Straiker, 45Salk Instituteastraiker@ucsd.edu

Wolfgang Streit, 95University of Floridastreit@ufbi.ufl.edu

Cheryl L. Stucky, 90Medical College of Wisconsincstucky@mcw.edu

David Sulzer, 72Columbia Universityds43@columbia.edu

James SurmeierNorthwestern Universityj-surmeier@northwestern.edu

C. N. Svendsen, 84University of Cambridgecns1000@hermes.cam.ec.uk

Thomas SwansonMidwest Neuroscience Incdomino@wcnet.org

Michael Tamkun, 101Colorado State Universitytamkunmm@lamar.colostate.edu

Charlie Taylor, 32Pfizer Global R & Dcharles.taylor@pfizer.com

Jane Taylor, 62Yale Universityjane.taylor@yale.edu

David Terman, 63Ohio State Universityterman@math.ohio-state.edu

Wolfram Tetzlaff, 95University of British Columbiatetzlaff@cord.ubc.ca

Evelyn ThomanUniversity of Washingtonthoman@uconnvm.uconn.edu

Robert Thompson, 121University of Michiganmutant@umich.edu

Arthur W. Toga, 76University of California Los Angelestoga@loni.ucla.edu

Kimberly ToppUniversity of California San Franciscokstopp@itsa.ucsf.edu

Mark A. TrocchiAssociation Book Exhibitswfo@bookexhibit.com

Ramon Trullas, 47IIBB/CSICrtonbi@iibb.csic.es

Li-Huei Tsai, 88Harvard Medical Schoolli-huei_tsai@hms.harvard.edu

153

Vincent K. Tuohy, 85Cleveland Clinic Foundationtuohyv@ccf.org

Beth Tyler-McMahon, 97Mayo Clinicmcmahon.beth@mayo.edu

George Uhl, 78National Institutes of Healthguhl@intra.nida.nih.gov

Harold Vaessin, 106National Science Foundationhvaessin@nsf.gov

Carlos Valenzuela, 79University of New Mexicofvalenzuela@salud.unm.edu

Derek van der Kooy, 112University of Torontoderek.van.der.kooy@utornoto.ca

Linda Van Eldik, 67Northwestern Universityvaneldik@northwestern.edu

Arthur A. Vandenbark, 73Portland VA Medical Centervandenbark.arthur_a@portland.va.gov

Susan Vannucci, 96Penn State Univeresitysjv1@psu.edu

Helene Varoqui, 29Louisiana State Univeristyhvaroq@lsuhsc.edu

Jana Veliskova, 92Albert Einstein College of Medicinevelisek@aecom.yu.edu

J. Ernest Villafranca, 105Agouron Pfizer La Jollaernie.villafranca@agouron.com

Inez Vincent, 106University of Washingtonivincent@u.washington.edu

David Virshup, 64University of Utahdavid.virshup@hci.utah.edu

Jerrold Vitek, 98Emory Universityjvitek@emory.edu

Michael Vitek, 81The Duke Universityvitek001@mc.duke.edu

Bruce Walmsley, 119Australian National UniversityBruce.Walmsley@anu.edu.au

Judith Walters, 100National Institutes of Healthjwalters@helix.nih.gov

Claude Wasterlain, 118University of California Los Angeleswasterla@ucla.edu

Barry Waterhouse, 60, 100Hahnemann Universityb.waterhouse@drexel

Cheryl S. Watson, 87University of Texascswatson@utmb.edu

D. Martin Watterson, 31Northwestern Universitym-watterson@northwestern.edu

Daniel R. Weinberger, 79National Institute of Mental Healthweinbard@intra.nimh.nih.gov

Jeff Weiner, 79Wake Forest Universityjweiner@wfubmc.edu

Daniel Weinreich, 102University of Marylanddweiwrei@umaryland.edu

David Weiss, 100University of Alabama Birminghamdweiss@nrc.uab.edu

John Weiss, 93University of California Irvinejweiss@uci.edu

David WellsYale UniversityDavid.Wells@Yale.edu

154

Frank WelshUniversity of Pennsylvaniafwelsh@mail.med.upenn.edu

Monte Westerfield, 77University of Oregonmonte@uoneuro.uoregon.edu

Susan White, 84Washington State Universityswhite@vetmed.wsu.edu

Scott Whittemore, 95University of Louisvilleswhittemore@louisville.edu

Kevin Wickman, 108University of Minnesotawickm002@tc.umn.edu

George Wilcox, 77University of Minnesotageorge@umn.edu

John WilliamsOregon Health Sciences Universitywilliamj@ohsu.edu

Shelagh Wilson, 122SmithKline BeechamShelagh _Wilson@SBPHRD.com

James Winslow, 93Emory Universityjwinslow@rmy.emory.edu

Roy Wise, 112National Institute on Drug Abuserwise@intra.nida.nih.gov

Marina Wolf, 31Chicago Medical Schoolmarina.wolf@finchcms.edu

Terri Wood, 119Pennsylvania State Universitytwood@psu.edu

Donald Woodward, 100Wake Forest Universitywoodward@newton.neuro.wfubmc.edu

Clifford Woolf, 71Massachusetts General Hospitalcwoolf@partners.org

Doug Wright, 90, 114Kansas Universitydwright@kumc.edu

Bryan Yamamoto, 84Case Western Reserve Universitybky2@po.cwru.edu

Massashi Yanagisawa, 122The University of TexasMYanagisawa@aol.com

F. Eugene YatesUniversity of California Los Angelesgyates@ix.netcom.com

Jerry Yin, 94Cold Spring Harbor Laboratoryyin@cshl.org

Larry Young, 65Emory Universitylyoun03@emory.edu

Laurence Young, 111Massachusetts Institute of Technologylry@mit.edu

Elmer YuUniversity of Pennsylvainiayu_e@research.trc.upenn.edu

Hong Yu, 46Eli Lilly & Companyyu_hong@lilly.com

James ZackheimRutgers Universityzackheim@axon.rutgers.edu

Nancy Zahniser, 104University of Coloradonancy.zahniser@uchsc.edu

Michael ZigmondUniversity of Pittsburghzigmond+@pitt.edu

Joshua Zimmerberg, 83National Institutes of Healthjoshz@helix.nih.gov