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

The Winter Conference on Brain Research (WCBR) was founded in 1968 to promote free exchange of information and ideas within neuroscience. It was the intent of the founders that both formal and informal interactions would occur between clinical and laboratory-based neuroscientists. During the past thirty years neuroscience has grown and expanded to include many new fields and methodologies. This diversity is also reflected by WCBR participants and in our program. A primary goal of the WCBR is to enable participants to learn about the current status of areas of neuroscience other than their own. Another objective is to provide a vehicle for scientists with common interests to discuss current issues in an informal setting. On the other hand, WCBR is not designed for presentations limited to communicating the latest data to a small group of specialists; this is best done at national society meetings. The program includes panels (reviews for an audience not necessarily familiar with the area presented), workshops (informal discussions of current issues and data), and a number of posters. The annual conference lecture will be presented at the Sunday breakfast on January 23. Our guest speaker will be Dr. William H. Calvin, University of Washington. The title of his talk will be The Mind’s Big Bang Only 50,000 Years Ago! On Tuesday, January 25, a town meeting will be held for the Breckenridge community, at which Dr. Ski Chilton, Wake Forest University School of Medicine, will give a talk entitled Inflammation Nation: Have our “Healthiest” Foods led to an Epidemic of Inflammatory Diseases? Also, participants in the WCBR School Outreach Program will present sessions at local schools throughout the week to pique students’ interest in science. Finally, the banquet, including a special program, music, and dancing, will be held on Friday evening, January 28. Conference Chair Elizabeth Abercrombie

January 23–28, 2005 • Breckenridge, Colorado 1 2 38th Annual Winter Conference on Brain Research Contents

General Information ...... 10 Special Events ...... 11 Preamble to the Program ...... 12 Sunday, January 23 ...... 13 Monday, January 24 ...... 14 Tuesday, January 25 ...... 16 Wednesday, January 26 ...... 17 Thursday, January 27 ...... 19 Friday, January 28 ...... 20 Poster Session 1 ...... 22 Poster Session 2 ...... 24 Poster Abstracts ...... 26 Sessions Abstracts ...... 64 Participants ...... 135

January 23–28, 2005 • Breckenridge, Colorado 3 Conference Chair Board of Directors Elizabeth Abercrombie Constance Atwell David Goldman Program Committee Barbara Lipska Jakie McGinty Monte Westerfield, Chair Hugh McIntyre Wendy Macklin, Program Marsha Melnick Chair-Elect Patricio O’Donnell Valina L. Dawson Ralph Siegel Paula Dore-Duffy Thomas Swanson Janet Finlay Robert Foehring Fellowship Program Curt Freed Karen Gale Marjorie A. Ariano, Chair Gerald F. Gebhart Constance Atwell Karen Greif Patricio O’Donnell Thomas Hyde James Surmeier Paul Huang Donald Stein Michael Iuvone Ray Bartus Paul Katz Phil Skolnick Halina Offner Ed Hall George Richerson Ralph M. Siegel Exhibits Celia Sladek Mark A. Smith Steve Levison William Spain School Outreach Treasurer Karen Greif, Chair Suzanne Haber Kristin Anstrom Anne Boullerne Facilities Committee Paula Dore-Duffy Kyle Frantz Kimberly Topp, Chair Karen Greif Kristen Keefe, Facilities Chair-Elect James McElligott Veronique Andre Hugh McIntyre Paul Ardayfio Vladimir Parpura Roberta Calzavara Ruth Perez David Daberkow Suzanne Roffler-Tarlov Emily Jocoy Roy Schwarz Cordelia Stearns Brad Stokes Tom Swanson Kimberly Topp Frank Welsh

4 38th Annual Winter Conference on Brain Research Town Meeting Fellowship Mentors Kristen Anstrom William Catterall Fulton Crews 2005 Fellowship Awardees Paula Dore-Duﬀy Peter Fox Rosa Cossart Tim Greenamyre Kelly Dinley Theresa Hastings Timothy Duong John Isaac Sarah French Mike Iuvone Jon Handley Mike Levine Samer Hatar Ron Lukas Laura Hurley Robert Lundy Lisa Jackson Ken Mackie Hank Jedema Patricio O’Donnell Edward Lien Jan-Marino Ramirez Giovanni Marsicano Ralph Siegel Astrid Prinz Gretchen Snyder Indira Raman David Standaert Gerald Rameau Anthony West Susanna Rosi Kuei-Yuan Tseng Nicole Ward

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

January 23–28, 2005 • Breckenridge, Colorado 5 Exhibitors MED Associates Inc. Karl Zurn Association Book Exhibit PO Box 319 Mark Trocchi St. Albans, VT 05478 8728-A Cooper Road Phone: 802-527-2343 Alexandria, VA 22309 Fax: 802-527-5095 Phone: 703-619-5030 [email protected] Fax: 703-619-5035 [email protected] Microbrightfield Geoff Greene Chemicon International 185 Allen Brook Ln, Ste 201 Carol Birmingham Williston, VT 05495 28835 Single Oak Drive Phone: 802-288-9290 Temecula, CA 92590 Fax: 802-288-9002 Phone: 909-676-8080x223 ggreene@microbrightfield.com Fax: 909-676-9209 [email protected] Division of Neuroscience and Behavioral Research ESA Minda Lynch Brent Morrison National Institute on Drug Abuse 22 Alpha Road 6001 Executive Blvd., Rm. 4282, Chelmsford, MA 01824 MSC 9555 Phone: 978-250-7081 Bethesda, MD 20892 Fax: 978-250-7087 Phone: 301-435-1322 [email protected] Fax: 301-594-6043 [email protected] Fine Science Tools Jeff Wiley Division of Neuroscience and 373-G Vintage Park Drive Basic Behavioral Science Foster City, CA 94404 Beth-Anne Sieber Phone: 650-349-1636 Fax: 650-349-3729 National Institute of Mental jwiley@finescience.com Health 6001 Executive Blvd, Room 7186 S. Karger AG Bethesda, MD 20892-9641 Corina Maetzler Phone: 301-443-5288 Allschwilerstrasse 10 Fax: 301-402-4740 Postfach [email protected] 4009 Basel, SWITZERLAND Phone: 41-61-306-1264 Fax: [email protected]

6 38th Annual Winter Conference on Brain Research NeuroStructural Research Labs San Diego Instruments Ron Mervis Bob Lischer 10500 University Center Dr, Ste 180 Phone: 858-530-2600 Tampa, FL 33612 Fax: 858-530-2646 Phone: 813-972-5535 [email protected] Fax: 813-972-5754 [email protected] or Springer [email protected] Kathleen Lyons 233 Spring Street, 7th Fl Nikon Inc. New York, NY 10013 Gerald Benham Phone: 212-460-1615 PO Box 2464 Fax: 212-463-0742 Evergreen, CO 80437 [email protected] Phone: 303-674-1569 Fax: 303-674-1569/ny631-547-8596 [email protected]

Olympus America Kathleeen Karmel 8874 Cheyenne Way Park City, UT 84098 Phone: 801-209-8472 Fax: 435-615-8350 [email protected]

January 23–28, 2005 • Breckenridge, Colorado 7 8 38th Annual Winter Conference on Brain Research January 23–28, 2005 • Breckenridge, Colorado 9 General Information

Headquarters is the Beaver Run Resort and Conference Center. All scien- tiﬁc activities will be held there. WCBR Information Desk and Message Center are in the Beaver Run Resort & Conference Center. The desk hours are as follows: Morning Afternoon Evening Saturday 1/22 9:00–11:00 AM 3:30–5:30 PM 6:30–10:00 PM Sunday 1/23 7:00–8:00 AM 3:30–6:30 PM Monday 1/24– 7:00–8:00 AM 3:30–4:30 PM Friday 1/28

The telephone number for messages is 970-453-4239. The Beaver Run Resort and Conference Center fax number is 970-453-2454. The person sending or receiving faxes is responsible for all charges. Registration packets containing a conference badge, registration receipt, tickets for breakfasts, mid-week lunch and banquet, and program book should be picked up at the WCBR Information Desk. Attendance at this conference is strictly limited to PREREGISTERED participants. On-site registration is not available. Posters will be available for viewing in two different sessions during the week in Peaks 1–5: Poster Session 1, Sunday–Tuesday and Poster Session 2, Wednesday–Friday. Poster presenters will be by their posters for discussion from 3:30–4:30 PM according to the schedule listed on pages 22–25. Presenters may put up their posters after 1:00 PM on the day their session starts. Presenters should take down their posters by 10:00 PM on the final day of their session. Please see Poster Sessions section in program for titles and names of presenters. Exhibits and Lounge are in the Peaks 1–5. Coffee is available there from 9:30–10:30 AM Monday through Friday. Refreshments are provided 3:30– 4:30 PM, Sunday through Friday. Exhibits close after 10:30 AM on Friday. Friday’s afternoon break will be in the ballroom lobby. Breakfast is served to all registrants on Sunday 7:30–8:30 AM, in Peaks 1–5, and on Monday through Friday, 6:30–7:30 AM, in Peaks 1–5. (Social guests ONLY may have breakfast until 10:00 AM.) The tickets in your registration packet are required for admission. On Saturday morning (January 29) before departure, a continental breakfast is available in Peaks 1–4.

10 38th Annual Winter Conference on Brain Research Ski Lift Tickets will be available from the WCBR Information Desk. Daily tickets can be purchased or prepaid tickets can be picked up during desk hours.

Special Events

Saturday, January 22 Welcome Wine and Cheese Party • 7:00–10:00 PM, Peaks 1–4

Sunday, January 23 Conference Breakfast and Opening Address • 7:30 AM, Peaks 1–5 (Your required ticket is in your registration packet.) The plenary keynote speaker will Dr. William H. Calvin, University of Washington Meeting of Panel and Workshop Organizers • 9:30–10:30 AM, Peaks 1–5, immediately after breakfast. The meeting will be brief but important. Organizers and WCBR staﬀ please attend. Travel Fellows Meeting • 3:30–4:20 PM, Peak 6–8

Monday, January 24 First Meeting of the Board of Directors • 6:30–8:30 AM, Spencer’s

Tuesday, January 25 Town Meeting • 7:00 PM, Summit High School, Frisco, CO

Wednesday, January 26 Travel Fellows & Mentors Breakfast • 6:30–7:30 AM, Peak 1–5 Smitty Stevens Memorial (NASTAR) Ski Race • 10:00–11:30 AM, Peak 9 NASTAR registration cards to be completed no later than Monday, January 24, 8:00 AM at WCBR Information Desk. Mountain Lunch • Noon–2:00 PM, 3rd Floor Vista Haus at Peak 9 Required lunch ticket is in your registration packet. Non-skiers requir- ing transportation should sign up at the WCBR Information Desk. Business Meeting • 6:30 PM, Peak 17 Election of Conference Chair-elect and three members of the Board of Directors.

January 23–28, 2005 • Breckenridge, Colorado 11 Friday, January 28 Second Meeting of the Board of Directors • 6:30–7:30 AM, Spencer’s Banquet and Dance • 7:30 PM, Peaks 1–5 Required ticket is in your registration packet. Cash bar opens at 6:30 PM in the Ballroom Lobby.

Preamble to the Program

The 2005 WCBR Program consists of panels, workshops, and posters. Please consult the program booklet and posted announcements for details regarding the scientiﬁc presentations as well as information regarding the School Outreach program and the Town Meeting. Session Organizers’ names are in bold. Fellows’ names are in italics.

12 38th Annual Winter Conference on Brain Research Sunday, January 23 7:30 AM Panel PM • Peak 9–10 Plenary Breakfast • Peaks 1–5 Multiple Problems with Multi-Site The Mind’s Big Bang Only 50,000 Brain Imaging Studies—Partial Years Ago Solutions Dr. William H. Calvin, University of William Bunney, Anders Dale, Washington Steven Potkin, Arthur Toga, Bruce Rosen 3:30–4:30 PM 8:30–10:00 PM Exhibits and Posters • Peaks 1–5 Panel • Peak 11–12 4:30–6:30 PM The Effect of Chronic Stress on Panel • Peak 11–12 Central Noradrenergic Function. Corticalization of Pain Hank Jedema, Stephen Gold, George Wilcox, Luc Jasmin, LeeAnn Miner, Gregory Ordway Vania Apkarian, Richard Gracely, Workshop • Peak 14 Robert C. Coghill Addiction across the Life Span: Panel • Peak 14 From the Womb to the Tomb, Your Cortex on Drugs: Plasticities Almost beyond the Nucleus Accumbens John Mendelson, John Bruno, Peter Kalivas, Gabriele Fischer, Reese Jones, Terry Robinson, Karen Bolla Elmer Yu, Brian Yamamoto, Conan Kornetsky Panel • Peak 15 Panel • Peak 15 Estrogen Replacement: A Double- Edged Sword? Air Pollutants, Intercellular Messengers, or Both? Inorganic Gretchen Snyder, Lisa Jackson, Signaling Molecules in Cerebral Jill Becker, Catherine Woolley Circulation Panel • Peak 17 Charles Leffler, Dale Pelli- Astrocytes and Disease grino, Robert Bryan, Rui Wang, Michael Brenner, Mahendra Rao, David Busija Harold Sontheimer, Sue Griffin, Panel • Peak 17 Christoph Proschel Neuromodulation in Sensory Panel • Peak 6–8 Systems DA/NE Interaction Governing Robert Lundy, Thomas Cleland, Frontostriatal Functions Laura Hurley, Yuan Peng Antonieta Lavin, Carlos Pala- dini, Susan Sesack, Janet Finlay, David Jentsch

January 23–28, 2005 • Breckenridge, Colorado 13 Sunday, January 23, continued

Panel • Peak 6–8 Panel PM • Peak 9–10 Mitochondrial Targets of Oxida- High on Neurosteroids— tive Stress in Neurodegeneration For Better or Worse ? Gary Fiskum, Nina Solenski, A. Leslie Morrow, Deborah Finn, Steve Scheﬀ, Ella Bossy-Wetzel Sindy Mellon, Henry Kranzler

Monday, January 24 7:30–9:30 AM Panel • Peak 6–8 Panel • Peak 11–12 Mechanisms of Stress-Induced New Approaches to Pain Plasticity Research: Target Genes, Popu- Anthony Grace, Bita Moghad- lation Genetics, Regulatory dam, Rita Valentino, Pier Vincenzo Pathways, and Neuro-Immune Piazza Interactions Panel • Peak 9–10 John Kusiak, Z. David Luo, The Inextricable Relationship Luda Diatchenko, Andrew Russo, between Norepinephrine and Wendy Campana Serotonin Panel • Peak 14 Gregory Ordway, Rick Lin, Why is Parkinson’s Disease Pierre Blier, Irwin Lucki, Progressive? Alan Frazer Michael J. Zigmond, Jau-Shyong 3:30–4:30 PM Hong, J. Timothy Grennamyre, Teresa G. Hastings, Luigi Zecca Exhibits and Posters • Peaks 1–5 Minicourse • Peak 15 4:30–6:30 PM Translational Neuroimaging: Panel • Peak 11–12 Physiology and Pharmacology New Research Perspectives on D1 Peter Fox ,Timothy Duong, Receptors Seong-Hwan Yee, Duﬀ Davis, Larry Siever, E. Christopher Muly, Bruce Jenkins, Graham Williams, Stacey Castner Panel • Peak 17 Panel • Peak 14 Human Embryonic Stem Cells and Matrix Metalloproteinases, Integ- Dopaminergic Neurons rins, Rafts and Neurotransmitters: William J. Freed, Curt R. Freed, What Do They Have to Do with Lorenz Studer, Mahendra S. Rao Oligodendrocyte Migration and Maturation? Wendy Macklin, Wia Baron, Babette Fuss, Wee Yong

14 38th Annual Winter Conference on Brain Research Panel • Peak 15 Workshop • Peak 14 Beyond Microarrays: The Involve- Function Follows Form: From ment of Neuronal Plasticity in Molecule to Mind Pain Processing and Neuroprotec- Vladimir Parpura, tion Sabina Hrabetova, Glenn Hatton, John Quinn, Andrew Russo, Daniel Silverman Ross Kinloch, Sandip Biswal Panel • Peak 15 Panel • Peak 17 Vascular Adaptation in the Brain Multiple Sclerosis: New Insights Paula Dore-Duffy, Jeffrey Dunn, into Axonal-Oligodendroglial Greg del Zoppo, Nicole Ward Signaling, Markers of Disease Panel • Peak 17 Progression, and Novel Approaches for Therapy Beyond the “Amines” in Amphetamines George De Vries, Sara Becker- Catania, Anne Boullerne, Bryan Yamamoto, Kristen Ashley Karen Chandross, Douglas Horner, Jacqueline McGinty, Feinstein Gary Gudelsky Panel • Peak 6–8 Panel • Peak 6–8 Neuroscience Funding AMPA Receptor Trafficking and Opportunities and Basic Research Synaptic Plasticity: Role and Priorities at NIH Importance of Subunit Specific Mechanisms Kim Pham, Michael Weinrich, Steven Snyder, Laura Mamounas, John Isaac, Jon Hanley, Ernie Lyons, Minda Lynch, Kath- Roberto Malinow, Roger Nicoll leen Anderson, Beth-Anne Sieber Panel • Peak 9–10 Panel • Peak 9–10 Models of Injury Induced Neuroinflammation: When, Where Reorganization in the and How Does It Contribute to Somatosensory Neuraxis Degeneration? Richard Lane, Charles Fulton Crews, Jau-Shyong Hong, Pluto, Robert Waters, Susanna Rosi, Stephen C. Bondy Douglas Rasmusson

8:30–10:00 PM Panel • Peak 11–12 Run to Save Your Brain: How Exer- cise Enhances Cognitive Function Fernando Gomez-Pinilla, Monika Fleshner, Arthur Kramer, Amelia Russo-Neustadt

January 23–28, 2005 • Breckenridge, Colorado 15 Tuesday, January 25 7:30–9:30 AM Panel • Peak 9–10 Panel • Peak 11–12 Nominations for Astro- and What Evolution Can Teach Us Micro-glia as Best Supporting and about Nervous System Function Leading Actors in “The Neurode- generation Story” Paul Katz, Larry Young, Heather Eisthen, Kenneth Catania Richard Smeyne, Jeff Johnson, Greg Cole, Jim Morgan Panel • Peak 14 Translational Research in PD: 3:30–4:30 PM Can We Really Go from Lab Bench Exhibits and Posters • Peaks 1–5 to Bedside? Margie Ariano, David Standaert, 4:30–6:30 PM Tim Greenamyre, Jeff Bronstein, Panel • Peak 11–12 Karl Kieburtz Opioids, Neuroplasticity, and Panel • Peak 15 Addiction: What’s Hot? Plasticity of Auditory Neurons Jacqueline McGinty, Leonard K. Kaczmarek, Christopher Evans, Katrina MacLeod, Ian Forsythe, Gary Aston-Jones, Karina Cramer Peter Kalivas, James Frost Panel • Peak 17 Panel • Peak 14 Dissecting and Visualising the Decisions, Decisions: Orbitofron- Molecular Basis of Neural Devel- tal Cortex as an Arbiter of Reward opment and Regeneration Choices Malcolm Maden, Esther Bell, Ronald See, Suzanne Haber, David Chambers, Jonathan Clarke Carl Olson, Karen Bolla Panel • Peak 6–8 Panel • Peak 15 Why Stressed Adolescent Males I Had a Dream Last Night—Useful Should Not Become London Cab Molecular Biology for in vivo Drivers: The Differential Effects of System Neurophysiology—What Glucocorticoids and Stress over a Lovely Dream It Was Development, Sex, and Brain Ralph Siegel, Ehud Isacoff, Region Edward Callaway, Edward Lein Brenda Anderson, Cheryl Conrad, Panel • Peak 17 Cheryl McCormick, Cara Wellman Diet and Exercise: What Happens to My Brain? Fulton Crews, Carl Cotman, William T. Greenough, Jim Joseph, Donald K. Ingram

16 38th Annual Winter Conference on Brain Research Panel • Peak 6–8 Workshop • Peak 15 “No Sugar, No Enlightenment”: Molecules that Make Patterns in Metabolic Signaling in the CNS the Developing Somatosensory Dianne Lattemann, Barry Levin, System Kevin Niswender, Nicole Sanders, Mark Jacquin, Maria Donoghue, Ewan McNay Robert Rhoades, Thomas Woolsey Workshop • Peak 9–10 Workshop • Peak 17 From Z(inc) to A(poptosis), a Zinc- Amyloid-beta Interactions with along for Death by Heavy Metal Nicotinic Receptors: Roles in Michael Bennett, Elizabeth Jonas, Alzheimer’s Disease? Elias Aizenman, Karen Gale Ronald Lukas, Daniel Lee, Robert Nichols, Kelly Dinley 7:00 PM Panel • Peak 6–8 Town Meeting The Cortex Midbrain and Basal 8:30–10:00 PM Ganglia—Neural Collaborators in Selecting and Guiding Overt Panel • Peak 11–12 Movement What’s Up With Ecstasy? Barry Stein, John McHaﬃe, Una McCann, George Ricaurte, Peter Redgrave, Terrence Stanford John Mendelson, Leslie Jacobsen Panel • Peak 9–10 Workshop • Peak 14 Signaling: What You May Not The Genomic Basis of Circadian Know Could Help You! Rhythms: DNA Microarray Ken Kramer, Philip Stork, Analyses Maarten Reith, Joeseph Yeretsian Gianluca Tosini, John Hogenesch, Giles Duﬃeld, Vincent Cassone

Wednesday, January 26 7:30–9:30 AM Panel • Peak 14 Panel • Peak 11–12 Moving Beyond GAT1: Emerging GABA, GABA, Hey! Translational Role for Other GABA Transporters Neuroscience Insights into GABA in the Control of Neuronal Func- tion? John Krystal, Kari Buck, David Goldman, Marc Schuckit H. Steve White, Charles Ribak, Arne Schousboe, Misty Smith- Yockman, George Richerson

January 23–28, 2005 • Breckenridge, Colorado 17 Wednesday, January 26, continued

Panel • Peak 15 Panel • Peak 14 A Double Hit on a Double Edge Cells, Genes or Machines: What’s Sword? NO or Spermine in Best for Treating Parkinson’s Huntington’s Disease Disease Carol Colton, James Burke, Don Gash, Jean Saint-Cyr, Wallace Deckel, Carol Colton, Chris Bankiewicz, Clive Svendsen, Stefano Vicini Michael Zigmond Panel • Peak 17 Panel • Peak 15 Nicotine, Cigarettes and Dopa- Manipulation of the mine: Is the Smoke Beginning to Endocannabinoid System as a Clear? Novel Therapeutic Tool Paul Clarke, Derek van der Kooy, Ken Mackie, Andrea Stephanie Cragg, Athina Markou Giufrida, Giovanni Marsicano, Panel • Peak 6–8 George Kunos Novel Perspectives on the Mecha- Panel • Peak 17 nisms of Feedback Inhibition by Sodium Channels and Cellular Glucocorticoids in the Hypotha- Plasticity: A New Job for an Old lamic Adrenal Axis Channel Greti Aguilera, Stafford Lightman, William Catterall, James Surmeier, Jeffrey Tasker, Mary Dallman Indira Raman, Todd Scheuer Panel • Peak 9–10 Panel • Peak 6–8 Anything But V1: Imaging Some- Discovery Neuroscience thing Really Different Stephen Koslow, David Van Daniel Tso, Heather Read, Essen, Arthur Toga, Ralph Siegel, Arthur Toga Dietrich Stephan, Mary Hatten Panel • Peak 9–10 3:30–4:30 PM CRF Actions on State-Dependent Exhibits and Posters • Peaks 1–5 Neural Signal Processing: Stress 4:30–6:30 PM and Beyond Panel • Peak 11–12 David Devilbiss, Mark Opp, Rita Valentino, Lisa Conti Emerging Insights into Molecu- lar Substrates of Alternate Brain 6:30–7:30 PM States: Of Clocks and Sleep and Business Meeting and Elections • Genes Peak 17 Martha Gillette, Fred Turek, Joseph Takahashi, Chiara Cirelli, Paul Shaw

18 38th Annual Winter Conference on Brain Research Thursday, January 27 7:30–9:30 AM Panel • Peak 9–10 Panel • Peak 11–12 Gaining Insight into Synaptic Phosphorylation and Synaptic Function by Listening to Regulation Specialized Synapses Katherine Roche, David Bredt, Karl Kandler, Alapakkam Johannes Hell, Josef Kittler Sampath, Joshua Singer, Thomas Parsons Panel • Peak 14 The Differentiation and Functional 3:30–4:30 PM Potential of Embryonic Stem Cells Exhibits and Posters • Peaks 1–5 Oswald Steward, Hans Keirstead, Ron McKay, Evan Snyder, 4:30–6:30 PM John McDonald Panel • Peak 11–12 Panel • Peak 15 Neuroprotection and Immuno- Regional Distinctions of Striatal regulation in EAE and MS Dopamine Function in Human Richard Jones, Gregory Konat, and Non-Human Primates in Rela- Halina Offner, Arthur Vandenbark tion to Motivation and Reward Workshop • Peak 14 Charles Bradberry, Suzanne Human Embryonic Stem Cells: Haber, Stephanie Cragg, Will They Ever Cure Anything? Charles Bradberry, Marc Laruelle Jeanne Loring, John McDonald, Panel • Peak 17 Tom Schultz, Evan Snyder Homeostatic Plasticity: The Good Panel • Peak 15 and Bad News for Neuronal Refractory Periods Revisited: Network Function Calcium-Dependent AHPs from Jan-Marino Ramirez, Astrid Prinz, Genes to Function Ronald Harris-Warrick, Florin Robert Foehring, Rodrigo Amzica Andrade, Pankaj Sah, Panel • Peak 6–8 William Spain Vasopressinergic Mechanisms in Panel • Peak 17 Cognition and Affective Behavior Combinatorial Strategies to Treat J. David Jentsch, Donald Pfaff, CNS Injury Larry Young, David Feifel Scott Whittemore, Wolfram Tetzlaff, John Houle, Phillip Popovich

January 23–28, 2005 • Breckenridge, Colorado 19 Thursday, January 27, continued

Panel • Peak 6–8 Panel • Peak 15 Retinal Circuitry pH and Brain pHunction Stephen Massey, Ron Gregg, Kevin Staley, Stephen Traynelis, Maureen McCall, Nicholas Brecha Mitch Chesler, George Richerson Panel • Peak 9–10 Panel • Peak 17 Ultra Fast/Small Analysis Homocysteine and Deranged Modalities Yield Novel Insights Iron Metabolism in Alzheimer’s into Brain Function—Partnerships Disease in Analytical Chemistry and Barney Dwyer, Mark Smith, Neurobiology Steven Aust Anne Andrews, Robert Kennedy, Panel • Peak 6–8 Andrew Ewing, Mark Wightman Gene Expression Analysis 8:30–10:00 PM in Human Neuropsychiatric Disorders Panel • Peak 11–12 Carlo Colantuoni, Elin Lehrmann, Mesolimbic Plasticity and Behav- Christine Konradi, Marquis Vawter ioral Sensitization to Psychostimu- lants Panel • Peak 9–10 Antonello Bonci, Patricio The Grip on Dopamine and NMDA O’Donnell, Marina E. Wolf, Receptors Terry E. Robinson Ralph Nixon, David Sibley, Panel • Peak 14 Fang Liu, Henry Sershen New Insights into the Regulation of Neuronal Nitric Oxide Synthase and Nitrergic Signaling Pathways Anthony West, Sarah French, Gerald Rameau, Margie Ariano

Friday, January 28 7:30–9:30 AM Panel Friday • Peak 14 Panel • Peak 11–12 Comparative Studies of Nerve Modulation of Active States in Regeneration Neocortex Ronald Meyer, Herbert Geller, Patricio O’Donnell, Rosa Cossart, James Fawcett, Ken Muller Maria Victoria Sanchez Vives, Igor Timofeev, Kuei-Yuan Tseng

20 38th Annual Winter Conference on Brain Research Panel • Peak 15 Panel • Peak 14 Smart, Skinny, and Pain Free: Glial Immunity and Neurotoxicity Therapeutic Endpoints of Hista- Tsuneya Ikezu, Howard Gendel- mine H3 Receptor Modulation man, G. Jean Harry, Dennis Kolson Michael Ahlijanian, Panel • Peak 15 Phil Iredale, Gerard Fox, Ion Channel Localization, Func- Karin Rimvall, Keri Cannon tion, and Targeting in Axons Panel • Peak 17 Matthew Rasband, Stephen Novel Ways of Seeing the Light: Lambert, Edward Cooper, James Photosensitive Ganglion Cells, S. Trimmer Melanopsin, and Cryptochromes Panel • Peak 17 in Circadian Entrainment and Non-Image Forming Vision From the Primary Afferent to the Brain: Mechanisms Underlying Michael Iuvone, David Berson, Sex Differences in Pain and Anal- Samer Hattar, Russel van Gelder gesia Panel • Peak 6–8 Anne Murphy, Michael Gold, Regulated mRNA Trafficking and Alvin Beitz, Jon-Kar Zubieta Local Protein Synthesis in Synap- Panel • Peak 6–8 tic Remodeling and Plasticity Non-Homeostatic Central Mecha- R. Suzanne Zukin, Hollis Cline, nisms Involved in Feeding Regula- Tim Tully, Gary Bassell tion and Dietary Obesity Panel • Peak 9–10 Emmanuel Pothos, Novel Immunotherapies Against Sarah Leibowitz, Bartley Hoebel, ß-amyloid, Brain Tumors, and Amy MacDonald Ischemic Damage Panel • Peak 9–10 Sylvain Dore, Maciej Lesniak, Novel Quantitative Trait Genes Eduardo Zamora, Remi Quirion (QTGs) for Sedative-Hypnotic 4:30–6:30 PM Drug Dependence, Withdrawal, and Sensitivity Panel • Peak 11–12 Kari Buck, Thomas Johnson, CaM-Kinase Signaling from Robert Hitzemann, Synapse to the Nucleus Robert Williams Tom Soderling, Johannes Hell, Andres Barria, Anthony Means 7:30 PM Banquet and Dance • Peaks 1–5

January 23–28, 2005 • Breckenridge, Colorado 21 Poster Session 1

Sunday–Tuesday • Peak 5 Posters will be available for viewing from 3:30 PM Sunday through 4:30 PM Tuesday. Presenters will be with posters on Monday from 3:30 through 4:30 PM.

1. Electrophysiological Properties 7. D2 Modulation of Nucleus of Genetically-Defined Striatal Accumbens Medium Spiny Neurons Neurons and Fast Spiking GABA Véronique M. André Interneurons in Adult Rats 2. Inhibition of Phasic Neural M.C. Benoit-Marand Activity in the Ventral Tegmental 8. Orexin A Modulates Area Impairs Appetitive NMDACurrents in Rat Ventral Pavlovian Approach Learning. Tegmental Area Neurons Luigi Anzivino S.L. Borgland 3. Homocysteine- and Ferritin- 9. The Brain Architecture Dependent Membrane Management System Phospholipid Peroxidation Mihail Bota Steven D. Aust 10. Cerebral Metabolic Defects 4. Decreased Prepulse Inhibition Presage Pathologic Changes in and Increased Striatal D2 Mouse Models of Huntington’s Receptors in Brattleboro Rats: A Disease. Genetic Model of Schizophrenia S.E. Browne D. Feifel 11. Variation in RGS4 and 5. Environmental Modulation Information Processing of Amphetamine-Induced during Working Memory in Locomotor Activity and Fos Schizophrenic Patients, Their Expression Unaffected Siblings, and Healthy Aldo Badiani Subjects 6. Cholinesterase Inhibitor Joshua W. Buckholtz Treatment Slows Decline in 12. Excitatory and Inhibitory Multiple Cognitive Domains in Responses of Basolateral Alzheimer’s Disease: A One-Year, Amygdala Cells to Entorhinal Prospective, Cohort Study Stimulation: Modulation by the Pearl Behl Norepinephrine System Deanne M. Buffalari 13. N-terminus of Synapsin II Inhibits Transmitter Release at Mouse Motor Terminals M. Bykhovskaia

22 38th Annual Winter Conference on Brain Research 14. 3D Reconstruction of the 20. Adenosine Links PCO2 to Striatum and Its Functional Neuronal Excitability via pH: Regions in the Macaque Monkey The Roles of Ecto-ATPases, R. Calzavara Adenosine Kinase, and the Nucleoside Transporter 15. Effects of Early Methylphenidate Exposure on Morphine-Induced Chris Dulla CPP And Dopamine D2 Binding 21. Multifocal Transplants Induce Sites Extensive Migration and C.A Crawford Myelination Throughout the Neuraxis of the Myelin Deficient 16. Tau Exon 10 Splicing Mutation Rat Recapitulates FTDP-17 in Transgenic Mice Ian D. Duncan Hana N. Dawson 22. Influence of Medial Septal Galanin and Muscarinic Agents 17. Basolateral Amygdala on Spatial Learning in the Rat Stimulation Evokes Complex Synaptic Response in Prefrontal Elin Elvander Cortex Pyramidal Cells that 23. Role of Á4â2 Nicotinic Project to the Ventral Tegmental Acetylcholine Receptors and Area in vivo Lobeline in the Protection J. E. Dilgen against Methamphetamine Toxicity 18. COMT Genotype and Neural Mechanisms of Anxiety D.J. Eyerman Emily Drabant 19. Evolution of the Pineal Gland: A Tale of Conflict and Resolution David C. Klein

January 23–28, 2005 • Breckenridge, Colorado 23 Poster Session 2

Wednesday–Friday • Peak 5 Posters will be available for viewing from 3:30 PM Wednesday through 10:00 AM Friday. Presenters will be with posters on Thursday from 3:30 through 4:30 PM.

24. On the Assay for Homocysteine 32. Modulation of NMDA-Induced Involving Paraquat Currents in Medium-Sized Steven D. Aust Striatal Neurons 25. Long-Term Attenuation of Emily L. Jocoy Amygdala-Kindled Seizures in 33. Contributions of the Proton- Rats by Botulinum Toxin Type A Gated Ion Channels Asic3 and M. Gasior Trpv1 to Visceral Mechano- and Chemo-Sensation 26. Gdf11 is Required for Development of Carter Jones Neuroendocrine Cells in the 34. Different Expression Profiles Pancreas in Rats Displaying a High vs. A. Apelqvist Low Behavioral Response to Methamphetamine 27. Long-Term Light Deprivation: A Cause of Depression John Kelsoe Monica M. Gonzalez 35. A Novel Mechanism for N- myc Destabilization in Neural 28. Type II Lissencephaly in Mice Precursors Deficient for the APP-Binding Proteins FE65 and FE65L1 Anna Kenney Suzanne Guénette 36. Real-Time Two-Photon Microscopy of Volume Changes 29. Control of Neurogenesis in in Pyramidal Neurons and the Adult Hippocampus by Dendrites Deep within Cortical Corticoids and Serotonin Slices J. Herbert S.A. Kirov 30. The Serotonin Releaser 37. Hippocampal Formation Fenfluramine Alters Auditory Modulates Sensory Cortical Responses in the Inferior Inputs into the Basolateral Colliculus Amygdala of the Rat L.M. Hurley W.J. Lipski 31. Organization of the Projections 38. Role of DJ-1 in Mitochondrial from the Ventral Tegmental Area Apoptosis Pathways to the Ventral Striatum in the Rat David W. Miller Satoshi Ikemoto

24 38th Annual Winter Conference on Brain Research 39. Limbic Activation in Affective 45. Glycogen Synthase Kinase 3 Priming: An MEG Study Activity Regulates Neuronal K.E. Munoz Pentraxin 1 Expression and Cell Death Induced by Potassium 40. Dopamine Receptor Interactions Deprivation in Cerebellar with Arrestins in Neostriatal Granule Cells Neurons R. Trullas Kim A. Neve 46. Agonal Factors, Aging, and Drug 41. Effects of Moderate and Severe Abuse Affect Mitochondrial Calorie Restriction on Avian Gene Expression in Postmortem Species Brain: Implications for Mary Ann Ottinger Neuropsychiatric Disorders 42. Cortical Interneuron Changes Marquis Vawter in Conditional BDNF Knockout 47. Ethanol Inhibits Persistent Mice Activity of Prefrontal Cortical Ronald Paletzki Neurons in Slice Co-Cultures 43. Total Number of Hippocampal J.J. Woodward Synapses in People with Mild 48. Influence of Infrared Cognitive Impairment Illumination on the Learning S.W. Scheff and Activity Behavior of Rats 44. Administration of D1-like or D2 J. Brooks Zurn Dopamine Receptor Agonists 49. A Role for HLH Transcription into the Nucleus Accumbens Factor Inhibitor of DNA Binding Shell Reinstates Cocaine- (Id) Genes in the Mammalian Seeking Behavior Circadian Clockwork. H.D. Schmidt Giles E. Duffield

January 23–28, 2005 • Breckenridge, Colorado 25 Poster Abstracts

0Poster Session 1 • Sunday–Tuesday • Peak 50 Posters will be available for viewing from 3:30 PM Sunday through 4:30 PM Tuesday. Presenters will be with posters on Monday from 3:30 through 4:30 PM.

1. Electrophysiological Properties of Genetically- Defined Striatal Neurons Véronique M. André*, Carlos Cepeda, Amaal J. Starling, Mary Kay Lobo, X. William Yang, Michael S. Levine Mental Retardation Research Center and Neuropsychiatric Institute, UCLA, Los Angeles CA 90095 There has been considerable effort to differentiate the function of subpopulations of striatal medium-sized spiny neurons (MSSNs) that contain the different subtypes of dopamine (DA) receptors. Recently, mice that express enhanced green fluorescent protein (EGFP) reporter genes coupled to specific DA and acetylcholine receptor subtypes in MSSNs have been generated. We compared some of the electrophysiological properties of EGFP-positive MSSNs expressing DA D1 or muscarinic M4 (direct pathway) and DA D2 receptor subtypes (indirect pathway). EGFP-positive cells were visualized in slices or after acute enzymatic dissociation. Whole-cell patch clamp recordings in dissociated MSSNs revealed a larger capacitance in D1/M4- compared to D2-positive cells while other basic membrane properties were similar. In dissociated MSSNs, inward currents evoked by N-methyl-D-aspartate (NMDA) were similar in both populations. NMDA currents were enhanced by a D1 receptor agonist. The percent increase was greater in D1/M4- than in D2-positive MSSNs. In contrast, a D2 receptor agonist reduced the amplitude of NMDA currents in all cells. Whole-cell patch clamp recordings in slices revealed that spontaneous synaptic activity was similar in D1/M4- and D2-positive cells, but large-amplitude inward currents were observed in D2-positive cells. After blockade of GABAA receptors, only D2-positive cells displayed large, long-lasting spontaneous membrane depolarizations. These data demonstrate differences in electrophysiological properties of subpopulations of MSSNs defined by selective expression of D1/M4 and D2 receptors and could explain the selective vulnerability of subgroups of MSSNs in specific neurodegenerative diseases.

Supported by NIH Grant NS33538 and GENSAT.

26 38th Annual Winter Conference on Brain Research 2. Inhibition of Phasic Neural Activity in the Ventral Tegmental Area Impairs Appetitive Pavlovian Approach Learning Luigi Anzivino*, J. David Jentsch University of California, Los Angeles The burst-firing (phasic) activity of DA cells is stimulus-specific and dynamic; it changes according to the predicted occurrence of stimuli, and to learning. AP-5 (a competitive NMDA antagonist) has been shown to inhibit the burst-firing activity without affecting overall firing rate: therefore, it provides a means to selectively eliminate the phasic activity of dopamine cells. Here, we examined the effects AP-5 infusions into VTA on an appetitive Pavlovian learning procedure, and compared these effects with those produced by systemic administration of the dopamine D1/D5 antagonist, SCH23390. In experiment 1 rats were infused with AP-5 (1 or 10 nmol) vs. vehicle prior to each of three training sessions in which a tone was paired with delivery of food pellets. The rate of acquisition was monitored during training, and the final conditioning ratio was measured in a drug-free extinction session on day 4. In experiment 2, we assessed learning after systemic administration of the D1/D5 receptor antagonist SCH 23390 (0.01 mg/kg, 15 min prior to training) vs. vehicle. In experiment 3, highly trained rats received one AP-5 infusion prior to testing in extinction. Both systemic DA antagonism and inhibition of DA phasic activity during acquisition resulted in a slower learning curve. AP-5 infusion prior to testing resulted in lower conditioning ratio, suggesting a role for burst- firing activity in the processing of a CS that predicts an appetitive reward.

3. Homocysteine- and Ferritin-Dependent Membrane Phospholipid Peroxidation Bradley G. Bishop, T. Zane Davis, Steven D. Aust* Utah State University Ferritin (or iron), homocysteine and cysteine are risk factors for Alzheimer and other diseases where oxidative stress is involved. These risk factors may be related or even confounding because aminothiols like homocysteine and cysteine are reductants of iron. Homocysteine and cysteine reduced iron in ferritin, promoting the release of iron from safe storage in ferritin. Glutathione (GSH) cannot reduce iron and did not release iron from ferritin. GSH is consumed during oxidative stress, for the metabolism H2O2 and lipid hydroperoxidases by GSH peroxidase, and is therefore correlated with cognitive scores. Homocysteine promoted the peroxidation of rat

January 23–28, 2005 • Breckenridge, Colorado 27 liver microsomal phospholipids, assayed as malondialdehyde production. Ferritin copuriﬁes with rat liver microsomes and can serve as a source of iron for lipid peroxidation. Microsomes also contain signiﬁcant catalase activity. Thus, homocysteine-dependent microsomal lipid peroxidation, an indicator of oxidative stress, cannot be the result of the hydroxyl radical produced by Fenton reaction. We propose that lipid peroxidation is promoted directly by iron, and requires both ferrous and ferric iron. The result of many studies on the toxicity of iron and other factors such as Amyloid â peptide to cells in culture may be explained by understanding how lipid peroxidation is initiated. An investigation into the mechanism of oxidative stress as relevant to the pathology of Alzheimer and other diseases may lead to novel therapeutic strategies.

4. Decreased Prepulse Inhibition and Increased Striatal D2 Receptors in Brattleboro Rats: A Genetic Model of Schizophrenia D. Feifel*, P.D. Shilling, B. Kinkead, T. Murray, G. Melendez, C.B.Nemeroff The Brattleboro (BB) rat is a strain of Long Evans rat that does not secrete the neuropeptide vasopressin due to a single gene mutation. We have reported that the BB rat exhibits prepulse inhibition (PPI) deficits that are analogous to schizophrenia patients and these PPI deficits are reversed by established antipsychotics. These findings suggest that the BB rat is a useful genetic model with strong face and predictive validity for information processing abnormalities exhibited by schizophrenia patients. In this study we sought to explore the construct validity of this model by determining if BB rats, like schizophrenia patients, have increased striatal D2 receptor levels. Brains of BB (n=8) and WT (n=7) rats were removed after they were tested in startle chambers. PPI was lower in BB compared to LE rats. D2 binding density was elevated in BB rats compared to LE rats in the nucleus accumbens shell and the dorsomedial caudate but not in other relevant brain areas. Furthermore, PPI levels in individual BB rats was inversely correlated with their D2 binding levels (P<0.05) in these areas. There were no significant between strain differences in D1 receptor levels in any of the regions measured. These data further support the BB rat as a useful genetic animal model, which displays construct as well as face, and predictive validity for schizophrenia.

28 38th Annual Winter Conference on Brain Research 5. Environmental Modulation of Amphetamine-Induced Locomotor Activity and Fos Expression Aldo Badiani *1, Davide Conversi 2, Giovanna Paolone 1, Daniele Caprioli 1, Simona Cabib 2 1 Department of Human Physiology and Pharmacology and 2 Department of Psychology, University “La Sapienza”, Rome, Italy Previous research has shown that amphetamine produces greater hyper- activity in the rat when administered in association with environmental novelty (novelty group) than when administered in the home cage (home group). The novelty group also exhibits higher levels of amphetamine- induced Fos mRNA in the caudate-putamen and in the medial prefrontal cortex (mPFC) relative to the home group. However, it is not known whether these differences in Fos mRNA are coupled with actual differences in the synthesis of the protein. In the present study we investigated the effect of novelty on amphetamine-induced Fos expression. Amphetamine was administered at the dose of 1 or 2 mg/kg, i.p. to animals tested under either home or novelty conditions and locomotor activity was quantified. Fifty minutes after the treatment the brains of the animals were excised and processed following a standard immunohistochemistry protocol to quantify Fos expression. Amphetamine produced greater locomotor activity in the novelty group (1.9±0.5 crossings/min) relative to the home group (0.4±0.1 crossings/min). Amphetamine also induced higher Fos levels in the novelty vs. the home group in the caudate-putamen (90±32 vs. 27±3 Fos-positive cells) and mPFC (193±16 vs. 120±11 Fos-positive cells) The present results confirm and expand earlier reports on the role of environmental context in modulating the neurobehavioral effects of amphetamine.

January 23–28, 2005 • Breckenridge, Colorado 29 6. Cholinesterase Inhibitor Treatment Slows Decline in Multiple Cognitive Domains in Alzheimer’S Disease: A 1-Year, Prospective, Cohort Study Pearl Behl*1-5, Sandra Black1-6, David Streiner3-5,7,8, Krista Lanctot2,3,5,7 1Cognitive Neurology Unit & Imaging Research, 2Sunnybrook and Women’s, 3Institute of Medical Science, 4Program in Neuroscience, 5University of Toronto, 6Department of Medicine/Division of Neurology, 7Department of Psychiatry, 8Rotman Research Institute, Baycrest Centre, Toronto, ON, Canada To assess overall and selective cognitive treatment effects of cholinesterase inhibitors (CHIs) in Alzheimer‚s disease (AD) over one year in a cohort matched to untreated controls in the same longitudinal observation study. Participants (Untreated=60, Treated=60) meeting NINCDS-ADRDA crite- ria for mild (MMSE 20-30) or moderate (MMSE 10-19) AD were recruited from the Cognitive Neurology clinic at Sunnybrook and Women‚s. All patients underwent standardized neuropsychological testing, including the Dementia Rating Scale (DRS) at baseline and 12 to 17 months later. Groups were matched on education and baseline MMSE.A repeated measures ANOVA was performed on the DRS total scores with treated patients showing less decline overall over the course of one year (F=6.297, p=0.013). Similar analyses on the 5 subscores of the DRS (Bonferroni correction) revealed a significant interaction (F=1.888, p=0.042) with post-hoc comparisons showing less decline in treated patients in all domains (attention, initiation, construction and conceptualization) except memory with medium effect sizes (0.4-0.6). More specifically, treated patients showed less decline in the ability to attend to and execute verbal and visual commands of varied complexity, in the ability to copy graphomotor designs, and in the ability to identify similarities and differences among objects. These indices relate to working memory, verbal fluency, abstract thinking, concept formation, problem solving, and copying visual designs with attention to detail. This reflects executive function, in addition to visuoconstructive and language components. This suggests that executive functions mediated by the frontal regions may be particularly responsive to cholinesterase inhibitor treatment in patients with AD over one year.

7. D2 Modulation of Nucleus Accumbens Medium Spiny Neurons and Fast Spiking GABA Interneurons in Adult Rats M.C. Benoit-Marand*, P. O’Donnell Center for Neuropharmacol. & Neurosci, Albany Medical College, Albany, NY The dopaminergic projection to the nucleus accumbens (Nacc) is known to decrease the synaptic response of medium spiny neurons (MSN) to

30 38th Annual Winter Conference on Brain Research glutamatergic inputs from the prefrontal cortex. We used whole cell patch-clamp recordings in the Nacc core of adult (50-65 days old) rat brain slices to study the effect of D2 receptors on Nacc MSN and fast spiking interneurons (FS). Bath application of the D2 agonist quinpirole (5 µM) increased the number of spikes in response to intracellular current injection, indicating an increased excitability. The synaptic response, measured as the amplitude of EPSP evoked by cortical stimulation, was increased by quinpirole. Bath application of the GABA antagonist picrotoxin (50 µM) prevented the quinpirole effects on EPSP but not on excitability, revealing a quinpirole-induced decrease in EPSP amplitude. Moreover, quinpirole decreased FS excitability. It appears that the effect of D2 receptor on MSN was partially due to a GABA component involving FS. These results may help us understand how dopamine participates to the integration of cortical inputs through the Nacc network. Support Contributed By: MH60131 and Fondation Simone et Cino Del Duca

8. Orexin A Modulates NMDACurrents in Rat Ventral Tegmental Area Neurons Stephanie Borgland*, A. Bonci EGCRC at University of California, San Francisco, Emeryville, CA 94608 Orexin/hypocretin neuropeptides are implicated in energy homeostasis, feeding and sleep regulation. Orexin-containing neurons project from the lateral hypothalamus to many brain regions including the ventral tegmental area (VTA) where they activate both orexin type 1 (OXR1) and type 2 (OXR2) receptors. Intra-cerebroventricular injections of orexin A results in dopamine-dependent hyperlocomotor activity. Furthermore, orexin applied to VTA neurons increases firing rate and, in some cases, causes burst firing. VTA dopamine neurons are under regulatory control from excitatory glutamatergic projections and modulation of these synapses is involved in both long term and short term changes in dopaminergic activity. The goal of the present study was to determine the effect of orexin on glutamatergic synapses in the VTA. We observed that orexin A concentration-dependently increases NMDA currents, but not AMPA currents. This effect was mediated through OXR1 receptors via a PLC/PKC dependent mechanism. These data suggest that orexin A can modulate dopaminergic neurotransmission by acting on excitatory synapses and may play a role in dopamine-mediated motivational behaviors.

January 23–28, 2005 • Breckenridge, Colorado 31 9. The Brain Architecture Management System Mihail Bota*, Larry Swanson University of Southern California The Brain Architecture Knowledge Management System (BAMS; http:// brancusi.usc.edu/bkms) is an online neuroinformatics environment designed to assist the neuroscience community in organizing and processing neurobiological information. BAMS contains five interrelated modules: Brain Parts, Cell Types, Relations, Connections, and Molecules. BAMS is designed to be used both as a reposi- tory for structural neuroscience information collated from the literature, and as a set of expert systems for analyzing this information. BAMS has a public component that can be searched by the neuroscience community, and a private part where registered users can store and process experimental data. The public part of BAMS allows users to search for information in different ways, organize data in complex reports of data and includes different inference engines for relating information across different levels of organization of the mammalian central nervous system. BAMS contains an inference engine for constructing possible functional networks of brain regions from the inserted connectivity data, by evaluating up to three intermediary stations between starting and ending regions defined by users. The public part of BAMS also includes inference engines for recon- structing connectivity patterns and fiber tracts from tract tracing data inserted in the system and for relating different cell types and molecules. BAMS now contains more than 7000 brain part names from 11 human, monkey, cat, mouse and rat nomenclatures, more than 15,000 reports of neuroanatomical connections dealing with the rat visual and limbic systems, and more than 2000 reports of different molecules identified in different rat brain regions.

10. Cerebral Metabolic Defects Presage Pathologic Changes in Mouse Models of Huntington’s Disease A.A. Starkov, S.W. Fuller, J-P. DiMauro, H.N. Burr, and S.E. Browne*. Department of Neurology and Neuroscience, Weill Medical College, New York, NY Huntington’s disease (HD) is a devastating neurodegenerative disease characterized by the progressive development of a movement disorder, behavioral changes, cognitive impairments, and premature death. The disease is caused by a mutant expansion of a CAG repeat region in the gene encoding huntingtin (htt). Symptoms arise from selective neuronal damage within the CNS, largely targeting the neostriatum and cerebral

32 38th Annual Winter Conference on Brain Research cortex. The mechanism of htt toxicity is unknown. Findings in symptomatic HD patients suggest the involvement of bioenergetic defects in disease etiology, but their speciﬁc role is unclear. We used Hdh knock-in mice to determine if htt‚s toxicity trigger involves metabolic defects. [14C]-2-Deox- yglucose in vivo autoradiography in conscious mice revealed widespread increases in cerebral glucose utilization rates in HdhQ92, but not HdhQ50, mice prior to the appearance of HD markers (4 months of age). In older HdhQ111 mice (18 months) glucose use was reduced in the striatum. To determine if the early hypermetabolism is in response to impaired oxidative metabolism, we examined mitochondrial function in 4 month-old HdhQ111 mice. Results show that mutant htt induces early changes in mitochondrial function, notably impairments in calcium handling, prior to neuronal dysfunction and death. We propose that in HdhQ111 mice, early compensatory increases in glucose uptake are ultimately insuﬃcient to protect cells from htt toxicity, and neuronal damage eventually ensues.

11. Variation in RGS4 and Information Processing during Working Memory in Schizophrenic Patients, Their Unaffected Siblings and Healthy Subjects Joshua W. Buckholtz*, Michael F. Egan, Richard E. Straub, Rishi Balkissoon, Terry E. Goldberg, Venkata S. Mattay, Daniel R. Weinberger, Joseph H. Callicott The Regulator of G-Protein Signaling (RGS) family of proteins negatively modulates post-synaptic receptor activation in G-protein coupled receptors. A member of this family, RGS4, mediates signal transduction in the human brain and has been associated with schizophrenia in several studies (Chowdari et al. 2002, Williams et al. 2004, Morris et al. 2004). The N-back working memory (WM) task during fMRI has proven useful in identifying alterations in information processing presumably related to allelic variation in genes associated with schizophrenia (COMT, BDNF, DTNBP1, GRM3, DISC1, G72). We examined four RGS4 SNPs, shown in prior reports to affect risk for schizophrenia, with this paradigm. We studied 95 normal subjects, 26 schizophrenic patients and 44 unaffected siblings, matched for age, gender, years of education and WAIS IQ at 3 Tesla using a block design alternating between 0-back and 2-back WM conditions. We grouped subjects by diagnosis and genotype for each SNP and performed standard group analyses using SPM99. Subjects carrying the high risk G allele at each of the four SNPs exhibited significantly increased activation in the caudate, putamen and thalamus. This effect was seen in all subject groups, regardless of diagnosis. These results demonstrate a clear effect of RGS4 genotype on WM related activation in the basal ganglia. Thus, RGS4 high risk alleles may exert their deleterious effects on risk for schizophrenia at

January 23–28, 2005 • Breckenridge, Colorado 33 least in part by impacting information processing in subcortical structures including the striatum.

12. Excitatory and Inhibitory Responses of Basolateral Amygdala Cells to Entorhinal Stimulation: Modulation by the Norepinephrine System Deanne M. Buffalari*, Anthony A. Grace The basolateral amygdala (BLA) and the entorhinal cortex (EC) play a role in the accurate performance of many behavioral tasks, including passive and active avoidance. Information regarding cues or context may reach the BLA via afferents from the EC, with BLA providing affective information about the stimuli. This information may then be propagated to downstream sites to affect behavioral responses. However, recent evidence indicates that EC lesions facilitate some tasks that rely on an intact BLA, such as conditioned odor aversion. Therefore, it has become less clear what impact EC activation has on BLA activity, in particular in situations involving learning about affective stimuli. We used in vivo extracellular recording from BLA neurons in anesthetized rats, and applied single-pulse and train stimulation to the EC. We also modeled exposure to aversive stimuli by increasing noradrenergic tone via systemic administration of the noradrenergic autoreceptor antagonist yohimbine. EC stimulation causes both excitatory and inhibitory responses in the BLA. Train stimulation to EC increases the probability of evoking a response in the BLA. In addition, in the presence of increased NA tone, EC afferent input is facilitated in a subset of BLA neurons (n=9), but attenuated in others (n=7). This provides evidence that, while EC activation does excite some BLA cells, there is evidence of an inhibitory influence which may support the EC lesion-induced facilitation of certain behaviors.

13. N-terminus of Synapsin II Inhibits Transmitter Release at Mouse Motor Terminals M. Bykhovskaia*, D. Samigullin, F. Simsek-Duran, G. Lonart Synapsins control the size of the readily realizable pool of vesicles in presynaptic terminals. We have recently found that transmitter release is increased in synapsin II knockout (Syn II KO) mouse motor terminals during repetitive stimulation of the phrenic nerve at the reduced Ca2+ concentration. To discriminate between the eﬀect of synapsin II and possible compensatory mechanisms, we injected glutathione S-transferase (GST) tagged recombinant synapsin II protein containing the ABC domains of synapsin

34 38th Annual Winter Conference on Brain Research II (GST-SynII[1-421]). GST-SynII[1-421] was expressed in E. coli, purified on glutathione beads, eluted by reduced glutathione, and extensively dia- lyzed to remove glutathione and other impurities. Control recordings from visualized (2-Di-4-Asp) endplates innervating diaphragm muscle fibers were performed with macropatch electrodes during the nerve stimulation at the frequency of 15 Hz at the reduced Ca2+ concentration (0.5 mM). Under these conditions, quantal release at Syn II KO synapses significantly exceeds quantal release at wild type (WT) synapses. After control recordings, GST-SynII[1-421] (1mg/ml in 200 mM KCl with fast green added) was pressure injected with sharp microelectrodes in the fine nerve brunches at the distance of 50-100 ∞†m from the endplate. Recordings from the same endplate were repeated within five minutes after injection. We found that after GST-SynII[1-421] injection, quantal release was reduced by 17% in WT terminals and by 52% in Syn II KO terminals. Mock injection did not result in any reduction of quantal release. Our results suggest that ABC domains of synapsin II are responsible for the ability of synapsin II to inhibit transmitter release.

14. 3D Reconstruction of the Striatum and Its Functional Regions in the Macaque Monkey R. Calzavara1*, P. Mailly2, S.N. Haber1 1Dept. of Pharmacology and Physiology, University of Rochester School of Medicine, Rochester, NY, 14642, 2Centre National de la Reserche Scientifique, Universite Pierre et Marie Curie, 75005 Paris, France Corticostriatal projections are segregated in specific neural circuits involved in cognitive, motor and emotional functions. The dorsolateral prefrontal cortex (DLPC) is involved in higher cognitive functions, orbital and cingulate cortex are primarily associated with motivational drive and reward. Agranular frontal cortex is involved in planning, preparation and execution of motor tasks. Based on the pattern of cortical afferents, the general organization of functional areas in the striatum are as follows: caudate-associative; putamen-premotor and motor and ventral-motivation and emotion. The main scope of this experiment was to define the topography and the extent of cortico-striatal projections from specific functional areas in the macaque monkey. We used small injections of anterograde neural tracers in DLPC, in orbital cortex, in medial cortex , in premotor cortex , and in primary motor cortex . The results confirmed the topographical organization of the cortical output to the striatum but, they also demonstrate an interface between the terminal fields. In particular, we found that the DPLPC terminal field overlap ventrally with the cingulate and the orbital terminal fields, and laterally with the anterior premotor cortex terminal field. This overlap is also showed in a 3D view of the stria-

January 23–28, 2005 • Breckenridge, Colorado 35 tum. These results suggest that the complex interdigitation of terminals in the striatum may facilitate transition from motivation and planning of goal- directed behaviors to their execution. Animal procedures were conducted in accordance with the Guide for the Care and Use of Laboratory Animals as adopted by NIH.

15. Effects of Early Methylphenidate Exposure on Morphine-Induced CPP And Dopamine D2 Binding Sites *C.A Crawford, S.W. Villafranca, J. L. Sibole, M.C. Cyr, S.A. McDougall, Department of Psychology, California State University, San Bernardino, CA 92407 Methylphenidate (MPH) is commonly used to treat ADHD. While the efficacy of MPH is not in question, there is increasing evidence that early treatment with these drugs may have long-term effects on brain reward pathways. The goal of the present study was to determine whether early exposure to MPH would alter morphine-induced conditioned place preference (CPP) in adult rats. We also assessed whether early MPH exposure would impact dopamine D2 binding sites. A total of 111 rats were treated with MPH (0, 2, and 5 mg/kg) once a day from PD 10 to PD 20. Rats were left undisturbed until PD 60, when morphine-induced CPP was assessed. After completing the CPP procedure, brains were removed for determination of striatal D2 binding. Rats conditioned with 5 mg/kg morphine showed CPP. Early exposure to 5 mg/kg MPH increased the magnitude of the morphine-induced place preference. Exposure to MPH did not alter the number of D2 binding sites, however there were significant positive cor- relations between the number of D2 binding sites and the strength of the place preference for saline and MPH (5 mg/kg) exposed rats. The present results suggest that early MPH exposure impacts reward processes in adulthood, with alterations in D2 binding site density being implicated.

16. Tau Exon 10 Splicing Mutation Recapitulates FTDP-17 in Transgenic Mice Hana N. Dawson*, Viviana Cantillana, Michael P. Vitek Tauopathies are a group of neurodegenerative diseases that share a cardinal pathological feature: intracellular aggregates composed of highly phosphorylated tau protein ﬁlaments. Tauopathy is consistently found in Alzheimer‚s disease, Frontotemporal Dementia and Parkinsonism linked to chromosome 17 (FTDP-17), and several other neurodegenerative diseases. The discovery of mutations in the tau gene, resulting in tauopathy in FTDP-

36 38th Annual Winter Conference on Brain Research 17, demonstrated that abnormal tau expression is sufficient to induce nerve cell degeneration. Missense or deletion mutations in the tau gene associated with FTDP-17 fall under two categories; 1) exonic mutations that alter the function of tau protein and 2) both intronic and exonic mutations that alter the splicing of exon 10. In order to study the splicing of exon 10, we have engineered a unique human tau minigene construct which contains intronic sequences that allow differential expression of exon 10. This construct carries the FTDP- 17 exon 10 N279K splicing mutation which in effected patients increases the inclusion of exon 10. Using this minigene under the regulation of the tau promoter we were able to recapitulate, for the first time, tauopathy in transgenic mice as a result of a splicing mutation. The mice show; 1) increased exon 10 inclusion, 2) tau pathology in neurons and glia, 3) cognitive deficits 4) motor deficits and 5) an increased rate of mortality. Further- more, we have discovered that the human tau promoter is crucial in the regulation of tau exon 10 splicing and may be required for the pathology in these transgenic mice.

17. Basolateral Amygdala Stimulation Evokes Complex Synaptic Response in Prefrontal Cortex Pyramidal Cells That Project to the Ventral Tegmental Area in vivo J.E. Dilgen* and P. O’Donnell Center for Neuropharmacology & Neuroscience, Albany Medical College, Albany, NY 12208 Amygdala inputs to the medial prefrontal cortex (mPFC) may be important for the selection of behavioral responses that are appropriate for the animal¡œs emotional valence. Although the basolateral amygdala (BLA) provides important projections to the mPFC, their inﬂuence upon PFC physiology remain poorly understood. Here, we evaluated responses of deep-layer pyramidal neurons in the mPFC to BLA stimulation using in vivo intracellular recordings. Electrical stimulation of the BLA (0.5 ms, 0.4 to 1.0 mA) evoked excitatory post-synaptic potentials (EPSPs) with multiple components, suggesting a combination of mono- and poly-synaptic responses. These EPSPs had an amplitude of 4 to 27 mV, a latency of 11 ≥b 2 ms (n=13; mean ≥b SE), with a duration of 38 ≥b 3 ms and were followed by a long lasting inhibition (300 ≥b 36 ms). Spike ﬁring was not observed during the BLA evoked EPSPs. These data indicate the complex nature of emotional control of PFC function. A subset of mPFC pyramidal neurons (n=4) that were responsive to BLA stimulation, were also antidromically activated by electrical stimulation of the ventral tegmental area (0.5ms, 1.0mA). These

January 23–28, 2005 • Breckenridge, Colorado 37 results indicate that it is possible that emotional input to mPFC neurons can in turn modulate mesolimbic/mesocortical projections.

Supported by MH57683, and NARSAD independent investigator award (P.O¡œD.).

18. COMT Genotype and Neural Mechanisms of Anxiety E. M. Drabant*, A. R. Hariri, K. E. Munoz, B. S. Kolachana, M. F. Egan, D. R. Weinberger A functional polymorphism in the gene coding for catechol-O-methyltransferase (COMT) results in a high activity valine allele and a low activity methionine allele, which influence synaptic DA availability. Although DA modulates limbic systems important for affective behavior, previous in vivo research of COMT effects has focused primarily on cortically mediated cognitive consequences of COMT driven variation in DA availability. The present study sought to examine the effect of the COMT val108/158met polymorphism on the response of limbic circuitry in a large cohort of healthy subjects. 101 Caucasian subjects were divided into genotype groups (met/met=24, val/met=57, val/val=20) matched for age, sex, IQ and 5-HTTLPR genotype. Subjects completed a simple perceptual task involving matching of affective facial expressions during fMRI. Group differences in task-specific BOLD responses were calculated using second-level random effects models. We found task-specific bilateral hippocampal and amygdala engagement across all 101 subjects. While there was no main effect of COMT genotype on amygdala reactivity, there was a significant main effect of genotype on hippocampal activation, with met/met homo- zygotes exhibiting greater reactivity than val/val and val/met subjects. Functional connectivity analyses revealed relatively greater coupling of right hippocampus and left PFC as well as right hippocampus and amygdala in met/met subjects. Our results indicate that heritable variation in DA neurotransmission associated with the COMT polymorphism impacts the reactivity and functional coupling of limbic and cortical circuitry during the perceptual processing of emotional stimuli. Such heightened functional reactivity in met/met individuals may contribute to the increased anxiety previously reported in these subjects.

38 38th Annual Winter Conference on Brain Research 19. Evolution of the Pineal Gland: A Tale of Conflict and Resolution David C. Klein* Section on Neuroendocrinology, NICHD, NIH, Bethesda, MD A theory outlining the evolution of the pineal gland is presented which proposes that the pineal gland and the photoreceptors of the retina evolved from a common ancestral cell. The initial step towards separation of the two was the acquisition of the enzymes which convert serotonin to melatonin. Acquisition of these enzymes was probably by lateral gene transfer. These acquisitions were advantageous to the ancestral photoreceptor because they enhanced detoxification. Specifically, they removed arylalkylamines including serotonin, through acetylation and O-methylation. The former reaction—acetylation by arylalkylamine N-acetyltransfer- ase—was important because acetylation of primary amines blocks their interaction with retinaldehyde. This is critical to improving vision because it prevents depletion of retinaldehyde, which is of critical importance in light detection. O-Methylation by hydroxyindole-O-methyltransferase was important because it enhanced the elimination of serotonin and N-acetyl- serotonin. In this theory a rhythm in arylalkylamine N-acetylation is seen to have evolved to prevent depletion of retinaldehyde at night through reactions with arylalkylamines; this would enhance visual sensitivity. The increase in melatonin production at night became recognized as ‘information’ by the ancestral chordate, through the evolution of melatonin rec- etpors, thereby providing a ‘time-of-day’ signal. The evolution of melatonin as a signal required a reliable high local level of serotonin. However, this trend was in conflict with the continued evolution of vision in the same cell. This conflict was resolved by the partitioning of the two chemistries involved in phototransduction—melatonin production became concentrated in the pinealocyte and was reduced in the cells which evolved into retinal photoreceptor cells. This partitioning removed the potential threat of retinaldehyde depletion through reactions with high levels of serotonin. This theory has potential impact on human retinal biology, because it points to the possibility that the reaction between aryalkylamines and retinaldehyde may play a role in the development of macular degeneration, because the reaction products are likely to be toxic and cause cell death in the retina.

January 23–28, 2005 • Breckenridge, Colorado 39 20. Adenosine Links PCO2 to Neuronal Excitability via pH: The roles of ecto-ATPases, Adenosine Kinase, and the Nucleoside Transporter Chris Dulla*, Tim Pearson, Bruno Frenguelli, Susan Masino, Kevin Staley Brain carbon dioxide (CO2) levels change in many physiologic and pathologic conditions. Hypocapnia is used lower seizure threshold and can induce absence seizures. Hypercapnia has profound effects on respiration, memory, and consciousness. Here we investigate how CO2 alters neuronal excitability using a model of interictal activity in adult rat hippocampal slices. We focus on pH-related changes in synaptic activity and extracellular adenosine levels simultaneously using both electrophysiological recordings and an enzymatic adenosine sensor. Hypercapnic acidosis (20% CO2) caused a significant decrease in fEPSP amplitude in area CA1 and attenuated epileptiform activity in area CA3 via the adenosine A1 receptor. After correcting for a pH-dependent alteration in adenosine sensor sensitivity, extracellular adenosine rose by 0.6 0.1 M. Milder acidosis (10% CO2) also increased extracellular adenosine in a pH-dependent manner. Hypocapnia (2% CO2) had opposite effects on all parameters measured, increasing fEPSP amplitude, decreasing in extracellular adenosine, and increasing in the frequency of epileptiform activity in area CA3. The increase in CA1 excitability due to hypocapnic alkalosis was attenuated significantly by blockade of adenosine A1 receptors and purinergic P2 receptors, and this effect was mimicked by inhibition of ecto-ATPases. Based on our studies, we conclude that alterations in brain CO2 levels cause changes in pH, which alters extracellular adenosine concentration.

Support Contributed By: Epilepsy Foundation of America, American Epilepsy Soc., NIH

21. Multifocal Transplants Induce Extensive Migration and Myelination Throughout the Neuraxis of the Myelin Deﬁcient Rat Abdelmadjid Belkadi, Ian D. Duncan* Department of Medical Sciences, University of Wisconsin–Madison, 2015 Linden Drive, Madison, WI 53706 Repair of myelin disorders by cell transplantation may call for cells to be able to migrate to several areas of demyelination such as in multiple sclerosis, or colonize the entire CNS as in the inherited disorders of myelin such as Pelizaeus Merzbacher disease (PMD). This study addresses the issues of increasing myelination at focal sites and enhancing cell migration to repair multiple areas of myelin loss or absence. We developed a multifo-

40 38th Annual Winter Conference on Brain Research cal transplant procedure using oligodendrocyte progenitor cells (OPCs) derived from the Long Evans rat striatal oligospheres that were transduced to express â-gal. The OPCs were transplanted into the lateral ventricles, cisterna magna, and cervical and thoracic spinal cord of the myelin deﬁ- cient rat, a model of PMD, at P2 (brain) and P7 (spinal cord). Two weeks after transplantation, X-gal staining showed in those rats that received injections into the cord alone either a large focal patch or multiple areas of cell migration along the cord. Importantly, those animals that received cells into the brain and cord showed more extensive cell dispersal with the entire cervical and thoracic cord containing transplanted cells. These cells made myelin at these sites as seen by proteolipid protein immunolabeling and in 1-micron sections. These data suggest that multiple transplants of OPCs may result in signiﬁcantly widespread repair of the CNS.

Supported by a grant from the Myelin Project.

22. Inﬂuence of Medial Septal Galanin and Muscarinic Agents on Spatial Learning in the Rat Elin Elvander*, Pär A. Schött, Jan Kehr, Johan Sandin, Sven Ove Ögren Dept. of Neurosci., Karolinska Institutet, SE-171 77 Stockholm, Sweden The septohippocampal pathway, projecting from the medial septal/diago- nal band of Broca (MS/dBB) to the hippocampus, has been implicated in a number of functions including learning and memory. The two major transmitters in this pathway are acetylcholine (ACh) and GABA, the former being co-localized with the neuropeptide galanin (GAL). Several studies imply that GAL exerts an inhibitory action on these cholinergic neurons, which in turn has been associated with impairments in spatial learning and memory. To test this hypothesis, rats were microinjected with GAL (0.3-3 nmol/rat) into the MS/dBB and tested in the Morris water maze. Surpris- ingly, infusion of GAL did not impair cognitive performance but instead facilitated spatial acquisition (1 and 3 nmol/rat). Intraseptal injections of the muscarinic antagonist scopolamine (SCO)(10-15 µg/rat) failed to alter learning performance while co-injections of GAL and SCO resulted in a marked impairment of spatial acquisition. Subsequently, in vivo microdialysis was used to evaluate the eﬀect of intraseptal GAL on basal ACh release in the ventral hippocampus. Both GAL (1 or 3 nmol/rat) and SCO (10 µg/rat) alone increased basal ACh release. Combined injections of GAL and SCO resulted in a further enhancement of ACh release. These results indicate, contrary to earlier suggestions, that GAL can enhance activity in septohippocampal cholinergic neurons and that septal GAL may have a facilitatory

January 23–28, 2005 • Breckenridge, Colorado 41 role in spatial learning. However, GAL appears to impair spatial acquisition when there exist a concomitant reduction in muscarinic tone within the MS/dBB. These results suggests that for optimal hippocampal function a limited range of cholinergic muscarinic transmission is required, which could be of importance for future therapeutic approaches.

23. Role of α4β2 Nicotinic Acetylcholine Receptors and Lobeline in the Protection Against Methamphetamine Toxicity David Eyerman*, Bryan Yamamoto Previous studies have shown that methamphetamine (METH) decreases vesicular monoamine transporter 2 (VMAT-2) activity 1 and 24 hrs after METH in the stratum. We have shown that the nicotinic receptor ligand, lobeline, when administered 5 hrs after the last injections of METH, blocks the METH-induced decreases in striatal VMAT-2 24 hrs after METH and depletions of striatal dopamine 7-days after METH. To further examine the role of nicotinic receptors in mediating the protective eﬀect of lobeline, the α4β2 nicotinic acetylcholine receptor selective antagonist, DHBE was administered alone or in combination with lobeline. VMAT-2 immunoreactivity and tissue content of dopamine were examined. DHBE did not block the protective eﬀects of lobeline against METH-induced depletions of striatal dopamine content 7 days after METH administration. However, DHBE alone administered after METH attenuated the decreases in striatal dopamine tissue content when measured 7 days after the METH administration regimen. Preliminary data indicate that the decreases in VMAT-2 immunoreactivity at 24 hrs (n=10) and 7 days (n=5) after repeated METH was also attenuated by DHBE (n=3/group). These results suggest that antagonism of the α4β2 nicotinic receptor may protect against METH-induced long-term decreases in dopamine content and damage to striatal VMAT-2. Supported by DA07606.

42 38th Annual Winter Conference on Brain Research 0Poster Session 2 • Wednesday–Friday • Peak 50 Posters will be available for viewing from 3:30 PM Wednesday through 10:00 AM Friday. Presenters will be with posters on Thursday from 3:30 through 4:30 PM.

24. On the Assay for Homocysteine Involving Paraquat Landon J. Karren, Steven D. Aust* Utah State University There is currently considerable interest in homocysteine as an indicator of oxidative stress. It is considered a risk factor for Alzheimer and other cognitive diseases and cardiovascular diseases. There is therefore interest in developing an assay specific for homocysteine, especially in the presence of other sulfhydryl amino acids and glutathione. Wang, et al (J. Am. Chem. Soc. 126: 3400-3401, 2004) recently proposed an assay dependent upon the specific reduction of paraquat (methyl viologen, MV) to its blue cation radical by homocysteine. A comparison of the redox potentials for MV and sulfhydryls, -0.45 volts and +0.92 volts, respectively, would suggest that homocysteine is thermodynamically unlikely to reduce parquat. We propose that the results reported by Wang et al are due to contaminating iron. Electron transfer reactions involving reductants such as homocysteine can be significantly affected by transition metals. Indeed, when care was taken to avoid transition metals, no reduction of MV by homocysteine was observed. Rapid reduction of MV by homocysteine was observed when a catalytic amount of iron was included. When the same reaction was performed in the presence of Desferal, an iron chelator, no reaction was observed. Similarly, no reaction was observed when GSH was included, but we have previously shown that the ã-glutamyl group of GSH prevents its reduction of iron. We conclude that assays for homocysteine, based upon its ability to reduce paraquat, are inappropriate.

25. Long-Term Attenuation of Amygdala-Kindled Seizures in Rats by Botulinum Toxin Type A Maciej Gasior*, R. Tang, N. White, M.A. Rogawski Epilepsy Research Section, NINDS/NIH, Bethesda, MD Temporal lobe epilepsy (TLE) is the most drug-resistant form of epilepsy for which resective surgery can often be the last therapeutic option. Delivery of therapeutic agents into the epileptic focus may be a novel approach to the treatment of TLE. Botulinum toxin type A (BTX-A) is one of the most potent agents capable of producing long-term inhibition of the release

January 23–28, 2005 • Breckenridge, Colorado 43 of various neurotransmitters including those that are involved in seizure activity. The present study evaluated the effects of BTX-A on seizures in the rat amygdala-kindling model of TLE. Rats were kindled by stimulation of the basolateral amygdala until a crite- rion of five consecutive stage 5 seizures was met. Then, the fully-kindled rats received infusions of BTX-A or carbamazepine for comparison into the stimulation site. Infusions of BTX-A (1-10 ng/infusion) produced a dose- and time-dependent attenuation of kindled seizures as reflected by significant increases in the afterdischarge threshold with accompanying decreases in the afterdischarge duration, seizure stage and seizure duration. The protective effects of BTX-A reached a maximum at 21 days post infusion and gradually dissipated within the next 40 days. In contrast, attenuation of seizures produced by carbamazepine (0.1 mg/infusion) lasted only for a few hours post infusion. In summary, the present study revealed anticonvulsant properties of BTX- A. The long-lasting attenuation of seizures produced by BTX-A warrants its further evaluation as a candidate for the treatment of TLE.

26. Gdf11 Is Required for Development of Neuroendocrine Cells in the Pancreas A. Apelqvist*3, E. Harmon1, N. Smart, X. Gu1, D. Osborne1, S. Kim1,2 1Departments of Developmental Biology and 2Medicine (Oncology Division), Stanford University, Stanford CA 94305-5329, USA, 3 MRC Centre for Developmental Neurobiology, King’s College London, Guy’s Campus, London SE1 1UL, UK Despite their difference in origin, neurons and pancreatic neuroendocrine cells share a number of similarities. For example, the mechanism by which neurons are generated (Notch mediated lateral inhibition) is also deployed for neuroendocrine cell specification in the pancreas. Furthermore, mature cell types in both systems express many of the same transcriptional regulators (Isl-1, NeuroD, Nkx etc.). This study highlights yet another similarity between neuronal and neuroendocrine cell differentiation. Mice deficient for growth/differentation factor 11 (Gdf11) have increased numbers of Neurogenin1 (Ngn1) expressing neuronal progenitors and olfactory neurons. Gdf11-/- mice harbour increased numbers of Ngn3+ neuroendocrine progenitors in the pan-

44 38th Annual Winter Conference on Brain Research creas, which reveals that Gdf11 negatively regulates their production also. Despite this marked expansion of neuroendocrine progenitors, Gdf11-/- mice have reduced numbers of mature neuroendocrine cells indicating that it is also required for cell maturation. This illustrates an apparent difference in pancreatic development where Gdf11 influences both progenitor specification and terminal differentiation. Our data further suggests that Gdf11 coregulates neuroendocrine differentiation in parallel to the Notch pathway, which has been previously shown to regulate Ngn3+ expression.

27. Long-Term Light Deprivation: A Cause of Depression Monica M. Gonzalez*, Gary Aston-Jones Dept. Psychiatry, Lab. Neuromodulation & Behavior, University of Pennsylvania, Philadelphia, PA Multiple studies have associated impairment of norepinephrine (NE) from the locus coeruleus (LC) and serotonin (5-HT) from dorsal raphe (DRN) nuclei with mood disorders like depression. The factors that cause this aminergic dysfunction are unknown. Previously we showed that compared to animals kept under 12:12 light-dark conditions (LD), rats kept in complete darkness (DD) during 6 weeks exhibited decreased amplitude of the circadian sleep-waking rhythms and cortical NE and 5-HT levels. These results raise the possibility that light deprivation could cause depression as result of NE-LC/5-HT-DRN deficit. To test this hypothesis we evaluated the behavioral depressive profile of animals kept in DD using a forced swim test (FST). Adult Sprague Dawley male rats were kept for six weeks on a LD (n=19) or DD (n=19) schedule. Subsequently, under their current lighting conditions and wearing a flotation aid they were individually submitted to a FST for 15 min, and 24 h later re-tested for 5 min. Increase in immo- bility (IMMOB) during the swim test is considered helplessness, thought to model depression. Light deprived animals showed more IMMOB than LD subjects during the 15 min test (+ 635%, P< 0.05) and 5 min re-test (+ 484%, P< 0,01). These results suggest that long-term light deprivation is an environmental factor that causes depression perhaps in part by impairment of the NE-LC and 5-HT-DRN systems. Light stimulation may be required for maintenance of proper functioning of NE-LC and 5-HT-DRN systems and their related behavioral and mental functions (i.e. mood).

Supported by PHS grant NS24698 and the NARSAD Young Investigator Award 2004

January 23–28, 2005 • Breckenridge, Colorado 45 28. Phenotype Resembling Type II lissencephaly in Mice Deficient for the APP-Binding Proteins FE65 and FE65L1 Suzanne Guénette*1, Yang Chang1, Thomas Hiesberger2, James A. Richardson3, Joachim Herz2 1Genet. & Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Charlestown, MA; 2 Depts. of Molecular Genetics, 3 Pathology & Molecular Biology, UT Southwestern, Dallas, TX The FE65 adaptor proteins, FE65, FE65L1 and FE65L2, bind the amyloid precursor proteins and increase beta-amyloid peptide secretion when overexpressed in cultured cells. Yet, little is known about the function of the FE65 proteins in vivo. We generated mice with targeted deletions of FE65 and FE65L1 to address this question. Single null mice were viable, fertile and had no overt neuropathology. In contrast, FE65-/-FE65L1-/- adult mice exhibited cortical dysplasia characterized by marginal zone heterotopias, aberrant cortical projections, mispositioned fimbria and loss of infrapyramidal mossy fibers. Marginal zone neuronal heterotopias, resembling those found in cobblestone lissencephalies and those of mice lacking all three APP family members, were observed throughout cortical plate development in the FE65-/-FE65L1-/- mice. Similar heterotopias consisting predominantly of reelin-positive neurons were also found in the ventral pallium of E12.5 FE65-/-FE65L1-/- mice indicating that overmigra- tion was not restricted to neurons migrating along radial glia. Disruption of pial laminin at sites of heterotopia formation combined with poor laminin organization in FE65-/-FE65L1-/- primary meningeal fibroblasts suggested that defects in the pial basement membrane might be responsible for heterotopia formation. Collectively, these data suggest that the FE65/APP protein interactions contribute to basement membrane assembly.

Supported by the NIH AG15903.

29. Control of Neurogenesis in the Adult Hippocampus by Corticoids and Serotonin Joe Herbert*, G-J Huang, E Y H Wong Department of Anatomy and Cambridge Centre for Brain Repair, University of Cambridge, UK Neurogenesis in the dentate gyrus of the adult consists of three phases: proliferation of progenitor cells, their survival and diﬀerentiation, and the formation of new connections with CA3. Glucocorticoids markedly suppress proliferation, an action dependent on both mineralo- (MR) and

46 38th Annual Winter Conference on Brain Research gluco- (GR) corticoid receptors. Depleting serotonin reduces sensitivity to corticosterone (the dentate gyrus has a profuse serotoninergic innerva- tion). Serotonin reduction (icv 5,7 DHT) by itself has no effect, but renders the proliferating cells sensitive to 5HT1A agonists. Fluoxetine, an SSRI, increases proliferation, but this is dependent on the presence of an intact adrenal gland since clamping corticosterone levels prevents it. The survival of new cells in the dentate is also under corticoid control. Even under basal conditions, about 30-40% of newly-formed cells do not survive to 28 days, but this is accentuated by corticosterone given during the period after cell division. Timed injections of corticosterone after pre-labelling proliferating cells with BrdU show that there is a sensitive period of about 14 days following cell division: after this, corticosterone no longer decreases survival. Double-staining labelled cells with markers such as double-cortin (DBX) and Neu-N show that post-mitotic corticosterone also decreases differentiation of newly-formed cells into mature neurons. These studies show a close interaction between serotonin and corticoids on the control of proliferating cells in the adult hippocampus, and a separable action of glucocorticoids on survival and differentiation of new neurons. Since neurogenesis has been linked to the onset and treatment of major depression, these findings have both neurobiological and clinical interest.

30. The Serotonin Releaser Fenfluramine Alters Auditory Responses in the Inferior Colliculus Laura Hurley*, I.C. Hall As in other sensory systems, the neuromodulator serotonin influences neural processing in the auditory system. Previous experiments estab- lishing the effects of serotonin on auditory midbrain neurons have used iontophoresed serotonin, bypassing the endogenous network of serotonergic fibers. Here we explore the contribution of endogenous sources of serotonin in the inferior colliculus (IC) of the Mexican free-tailed bat by iontophoretically applying fenfluramine, a releaser of serotonin. Fenflura- mine had effects that were broadly similar to those previously reported for iontophoresed serotonin. Fenfluramine changed the spike counts of 28 out of a sample of 50 IC neurons, usually decreasing (25 neurons) but occasion- ally increasing (3 neurons) spike counts in response to tone bursts or linear FM sweeps. For 20 neurons to which both fenfluramine and serotonin were applied, 12 showed similar responses to both, 5 responded more to serotonin, and 3 responded more to fenfluramine. One difference in the effects of fenfluramine and serotonin was in the timecourse of the response. Seven neurons showed a peak and subsequent decline in the effects of fenfluramine, something not seen with serotonin iontophoresis. This sug-

January 23–28, 2005 • Breckenridge, Colorado 47 gests that fenfluramine depletes serotonin in some cases, a hypothesis supported by the fact that, after responding to initial application of fenfluramine, several neurons became unresponsive to subsequent applications. These results are consistent with the hypothesis that locally iontophoresed fenfluramine releases serotonin within the IC, facilitating a comparison of the dynamics of endogenous and exogenous sources of serotonin.

31. Organization of the Projections from the Ventral Tegmental Area to the Ventral Striatum in the Rat Satoshi Ikemoto * Behavioral studies suggest that the ventral tegmental area (VTA) is functionally heterogeneous. Administration of drugs including cholinergic receptor agonists, GABAA receptor agonists, opiates, nicotine or ethanol into the posterior VTA is reinforcing, while administration of the same drugs into the anterior VTA is not. We examined whether neurons in the posterior VTA project to different regions of the ventral striatum than those in the anterior VTA. The retrograde tracer Fluorogold (FG) was inontophoretically deposited into various regions in the ventral striatum. Ten to fourteen days later, the animals were euthanized, and the tissues were processed for an anti-FG immunohistochemical procedure. When FG was deposited in the medial olfactory tubercle or the medial accumbens shell, FG-filled cell bodies were largely found in the paranigral nucleus and caudal linear nucleus, which are localized in the posterior VTA. When FG was deposited in the accumbens core or the lateral olfactory tubercle, FG-filled cell bodies were largely found in the anterior VTA and dorsolateral portion of the posterior VTA, which appear to correspond to the parabra- chial pigmented nucleus. Therefore, the medial ventral striatum largely receives projections from different zones in the VTA than the lateral ventral striatum. Since the medial shell and medial tubercle are more responsible for the reinforcing effects of cocaine, amphetamine, and other dopaminergic drugs, the dopamine neurons projecting from the paranigral nucleus and the caudal linear nucleus may play an important role in triggering reinforcing effects of dopaminergic drugs; in addition, these neurons may mediate the reinforcing effects of opiates, nicotine, and ethanol via their somato-dendritic regions.

48 38th Annual Winter Conference on Brain Research 32. Modulation of NMDA-Induced Currents in Medium-Sized Striatal Neurons Emily L. Jocoy*, Michael S. Levine University of California at Los Angeles NMDA receptors in medium-sized neurons (MSNs) of the striatum consist primarily of three receptor subunits: NR1, NR2A and NR2B. While NR1 is necessary for a functional receptor, NR2A and NR2B subunits confer different properties to the receptor. We tested the hypothesis that pharmacological blockade of specific subunits of the NMDA receptor will modulate receptor responses differentially. Acutely dissociated neurons were voltage-clamped at ˆ70 mV in the presence of TTX and in the absence of Mg2+. Dose-dependent application of ifenprodil, a preferential NR2B subunit antagonist, attenuated the steady-state component of the NMDA current more than the peak. Furthermore, ifenprodil blocked NMDA currents in a regional specific manner. Currents from dorsal medial MSNs were blocked more than those from dorsal lateral MSNs. In contrast, dose- dependent application of NVP-AAM077 (generously supplied by Novartis), a preferential NR2A subunit antagonist blocked NMDA currents in a different manner. We also examined modulation of NMDA currents by dopamine receptors. We tested the hypothesis that D2-NMDA interactions become predictable in acutely isolated neurons. Quinpirole (10 µM), a D2 receptor agonist, attenuated both the peak and steady-state components of the NMDA current. Quinpirole attenuated the steady-state more than the peak. Together these results indicate that NMDA currents of striatal MSNs consist of differential components mediated by NR2A and NR2B and can be decreased by postsynaptic activation of D2 receptors.

Supported by NS33538.

33. Contributions of the Proton-Gated Ion Channels Asic3 and Trpv1 to Visceral Mechano- and Chemo- Sensation Carter Jones*, G. F. Gebhart University of Iowa Enhanced perception of mechanical stimuli underlies the visceral hyperalgesia characteristic of functional gastrointestinal diseases, like irritable bowel syndrome. Yet, molecules mediating visceral mechanosensation and sensitization remain largely unknown. We tested the hypothesis that genetic deletion of the acid-sensing ion channel 3 (ASIC3) or the transient receptor potential vanilloid 1 (TRPV1) channel in knockout mice

January 23–28, 2005 • Breckenridge, Colorado 49 would disrupt visceral mechanosensation at the levels of whole animal behavior and sensory neuron excitability. Consistent with this hypothesis, visceromotor responses to colorectal distension of both ASIC3 and TRPV1 knockout mice were lower than control C57BL6 mice, with areas under the stimulus-response function of only 66 and 40%, respectively, of controls. The diminished behavioral responses of both knockout strains were mirrored by reduced mechanosensitivity of colon afferent fibers in the pelvic nerve assessed by in vitro electrophysiology. Although four types of mechanosensitive afferents (mucosal, muscular, muscular/mucosal, serosal) were present in similar proportions among control and knockout mice, muscular/mucosal afferents from ASIC3 and TRPV1 knockout mice were less responsive to circular stretch (1-5g) than similar afferents from control mice, with responses to 5g stretch of only 33 and 50%, respectively, of control afferents. In addition, whereas muscular/mucosal afferents of control mice were sensitized by exposure to an acidic inflammatory soup (pH 6.0), this effect was not observed in afferents from ASIC3 or TRPV1 knockouts. These results support a role for both ASIC3 and TRPV1 in mechanical nociception from the viscera and suggest that these ion channels confer mechanical and chemical sensitivity to colon primary afferent neurons.

34. Different Expression Profiles in Rats Displaying a High vs. Low Behavioral Response to Methamphetamine John Kelsoe*, Paul Shilling, Ronald Kuczenski, David Segal University of California at San Diego Acute amphetamine administration mimics many of the symptoms of mania, while chronic administration can produce psychosis. A differential sensitivity to amphetamine similarly may underlie the genetic susceptibility to stimulant abuse and psychosis. We have attempted to identify genes and pathways involved in sensitivity to amphetamine by conducting microarray expression profiling analysis of brain regions in animals with high or low behavioral response to amphetamine. 50 Sprague-Dawley rats were treated with methamphetamine (4mg/kg). The 10 with the shortest and longest time to stereotopy were selected as high and low responders respectively. RNA was extracted from prefrontal cortex (PFC) and caudate (CAU) of these animals and 10 others treated with saline. Expression profiling was conducted using the Affymetrix 230 oligonucleotide arrays. Expression data was normalized using the RMA algorithm and significant changes between low vs saline and high vs. saline detected using SAM. Genes were predominantly upregulated in the PFC of low responders, and down-regulated in high responders. In the CAU, genes were predominantly

50 38th Annual Winter Conference on Brain Research upregulated in both high and low responders, but the fold change was greater in the low responders. There was substantial overlap of changed genes in the four comparisons made. Immediate early genes were prominent among the changed genes. D box binding protein (DBP) was among the most robustly changed in 3 of the four comparisons.

35. A Novel Mechanism for N-myc Destabilization in Neural Precursors Anna Kenney,* David Rowitch, Sarah Sjostrom, Qing Zhao Dana-Farber Cancer Institute The Sonic hedgehog (Shh) signaling pathway is a critical determinant of brain development and tumorigenesis. Shh promotes neural precursor proliferation in the developing cerebellum. De-regulated hedgehog pathway activity is etiologic in medulloblastoma, a childhood cerebellar tumor. We found that the proto-oncogene transcription factor N-myc is a direct target of the hedgehog pathway in cerebellar granule neuron precursors (CGNPs). N-myc is expressed in the developing cerebellum, and its expression is up-regulated in mouse and human medulloblastomas. The hedgehog pathway is also mitogenic for adult neural stem cells, a proposed cell-of-origin for glioma, where N-myc expression is also found. Identification of modulators of N-myc activity may give insight into novel ways to treat adult and childhood brain cancer. N-myc phosphorylation by GSK-3b and its subsequent destabilization is necessary for CGNP cell cycle exit. We now ask whether N-myc is stabi- lized by endogenous phosphatase activity. Protein phosphatases 1 and 2A are highly expressed in the brain and play important roles in cell cycle control. We show that inhibiting PP1 and PP2A accelerates N-myc turnover. This affect is independent of GSK-3b-mediated N-myc destabilization, as phosphatase inhibition increased turnover of non-phosphorylatable N- myc mutants. Phosphatase inhibition causes a mobility shift, suggesting the existence of a new post-translational modification regulating N-myc turnover. Using microarray analysis, we identified two endogenous phosphatase inhibitors as late-induced downstream Shh targets in CGNPs. These mRNAs are expressed in CGNPs in vivo. Thus phosphatase inhibition in vitro and in vivo promote N-myc turnover, through a novel, non-GSK-3b-mediated pathway. The identification of phosphatase inhibitors as Shh targets also exemplifies negative feedback of Shh-regulated proliferation.

January 23–28, 2005 • Breckenridge, Colorado 51 36. Real-Time Two-Photon Microscopy of Volume Changes in Pyramidal Neurons and Dendrites Deep within Cortical Slices Sergei Kirov1*, C. Molnar2, R.D. Andrew2 1Dept. Neurosurgery, Medical College of Georgia, USA; 2Dept. Anatomy and Cell Biology, Queen’s University, Canada Maintenance of osmotic homeostasis and volume in the brain is critical for normal neuronal function. In the intact brain, neurons can volume regulate if plasma osmolality changes slowly over many hours. However rapid osmotic shifts occur in several clinical situations, resulting in acute brain swelling or shrinkage that may be lethal. Cultured or dissociated nerve cell bodies quickly volume respond and then adjust their volume in the face of acute (but unphysiological) osmotic stress. An important open question is whether cortical neurons and their dendrites volume respond and then volume regulate during physiologically relevant osmotic change. To directly examine this question, single pyramidal cell bodies and dendrites of GFP-expressing neurons were imaged with 2-photon microscopy in living cortical slices from adult mice of the B6.Cg-TgN(thy1-GFP)MJrc strain. The evoked CA1 field potential was recorded to ensure slice viability during osmotic challenge and to indirectly measure extracellular resistance, which is inversely proportional to osmolality. Cell bodies and dendrites displayed no detectable volume change (n=15 experiments, resolution 0.38 mm in x,y axes) during 15 min of osmotic stress ranging from ˆ40 to +40 mOsm, even as the slice was clearly swelling or shrinking. The same neurons were then imaged during oxygen/glucose deprivation. This evoked the anoxic depolarization with obvious swelling of pyramidal cell bodies, dendritic beading and spine loss, confirming prior neuronal health and responsiveness. Our findings reveal a surprising structural resiliency of cortical neurons to acute osmotic stress, more likely the result of a rigid cytoskel- eton than volume regulation.

Supported by NIH KO1MH02000 and HSFO T-5437.

37. Hippocampal Formation Modulates Sensory Cortical Inputs into the Basolateral Amygdala of the Rat W.J. Lipski*, A.A. Grace University of Pittsburgh The ventral hippocampal formation (vHPC) is reciprocally connected with the lateral and basolateral nucleus of the amygdala (BLA), a region criti-

52 38th Annual Winter Conference on Brain Research cally important for establishment of emotional memories. Although it is thought that the hippocampus is necessary for generating certain types of amygdala-dependent associations, little is known about the way that inputs from the vHPC influence the excitability of single neurons in the BLA. It is known that perirhinal and association sensory cortices can drive BLA output and are believed to play a crucial role in fear conditioning. Using standard electrophysiological procedures, extracellular single unit recordings were obtained from neurons in the BLA of chloral hydrate-anesthetized rats. Neurons were probed for excitatory responses to electrical stimulation of auditory association cortex (Te3). Stimulation of the vHPC strongly diminished the response of 30/38 BLA neurons to subsequent Te3 stimulation, attenuating the efficacy of these cortical inputs with inter- stimulus intervals between 0-60 ms following vHPC stimulation. In addition, pairing Te3 stimulation with an aversive stimulus (footshock) changed the firing probability to Te3 stimulation in 18/33 BLA neurons for 2-7 min following pairing. Preliminary results show that vHPC modulates this plasticity in the Te3-BLA pathway. This study shows that the vHPC can directly influence sensory cortical inputs to the BLA, and therefore may play an important role in the assignment of emotional relevance to specific stimuli based on context.

38. Role of DJ-1 in Mitochondrial Apoptosis Pathways David W. Miller*, Rili Ahmad, Ibardo A. Zambrano, Jeﬀ Blackinton, Rosa M. Canet-Aviles, Chris McLendon, Mark R. Cookson Laboratory of Neurogenetics, National Institute on Aging, NIH, Bethesda, MD Early-onset Parkinson‚s disease can be caused by point mutations in the DJ-1 gene that result in instability and reduction of the steady-state levels of DJ-1 protein. We have recently shown that DJ-1 is neuroprotective under oxidizing conditions by formation of a cysteine-sulﬁnic acid at residue C106 and that the oxidized protein relocalizes to the outer membrane of the mitochondria (OMM) (Canet-Aviles et al., 2004). M17 neuroblastoma cells were transfected with constructs for V5-tagged DJ-1 (wild-type, C53A, and C106A). Clonal cell lines were then generated and maintained under zeocin (50ug/ml) selection. Here we demonstrate that MPP+ (250uM) induction of cytochrome c release from mitochondria is enhanced in cells that overexpress the C106A form of DJ-1 relative to wild-type. We propose that C106A acts as a dominant negative mutant by dimerizing with endogenous DJ-1 and therefore sequestering it from its protective function. Several apoptotic molecules act in the OMM to regulate cytochrome c release and the consequent activation of downstream caspases. Co-immu- noprecipitation assays have revealed a potential interaction between DJ-1

January 23–28, 2005 • Breckenridge, Colorado 53 and Bax, oligomerization of which can lead to cytochrome c release. We are currently using in vitro cross-linking methods to examine the eﬀects of DJ-1 on Bax multimerization. Such an interaction upstream of cytochrome c release may be critical for DJ-1‚s role in neuroprotection.

39. Limbic Activation in Affective Priming: An MEG Study Karen Munoz*, M. Garolera, T.E. Goldberg, B. Elvevåg, F.W. Carver, B.J. Zoltick, D.R. Weinberger, R. Coppola NIH/NIMH Functional magnetic resonance imaging (fMRI) has been effectively used to map brain activation with acute spatial accuracy; however, temporal capa- bilities are quite limited. Magnetoencephalography (MEG) is a non-invasive procedure able to detect the weak magnetic fields produced by brain activity. Specifically, MEG is able to provide excellent temporal resolution within 1ms. Previous fMRI studies have involved emotional priming, but few of these studies have been replicated in MEG. Temporal details, therefore, remain unclear. In the current task, we used semantic priming (250ms SOA) as a method to assess automatic processing of affective valence with MEG. Eight normal controls (4 males, 4 females) were presented with a word-word paradigm involving emotional decision-making. The relationship between the prime and target stimuli was systematically manipulated, and both affectively congruent and incongruent words were presented. We focused our analysis on 60 affectively congruent prime-target word pairs (30 negative-negative, 30 positive-positive). Using Synthetic Aperture Magnetometry (SAM), an adaptive beamformer technique, we analyzed the task activation differences between these two groups. These data show a differential activation of the left amygdala in the theta (5-8Hz) frequency band in the negative-negative condition when compared to the positive- positive condition. Additionally, time-frequency analyses may help clarify the functional interactions between the limbic system and the prefrontal cortex.

40. Dopamine Receptor Interactions with Arrestins in Neostriatal Neurons Tara A. Macey, Kim A. Neve* VA Medical Center Dopamine (DA) receptor interactions with arrestins and arrestin-dependent internalization have been characterized using heterologously expressed receptors and arrestins. The purpose of this work was to inves-

54 38th Annual Winter Conference on Brain Research tigate DA receptor interaction with endogenous arrestins in neostriatal neurons. Two-hr agonist treatment selectively increased the colocalization of the endogenous D2 receptor with arrestin2. Agonist stimulation caused translocation of arrestin2, but not arrestin3, to the membrane, and selectively enhanced the coprecipitation of the D2 receptor and arrestin2. All three measures of receptor:arrestin interaction (colocalization, translocation, and coprecipitation) demonstrated selective agonist-induced interaction between the D2 receptor and arrestin2. Although there seemed to be a temporal mismatch between two measures of receptor:arrestin interaction and receptor internalization, siRNA-induced depletion of arrestins in NS20Y cells prevented internalization of the D2 receptor. In contrast, agonist treatment rapidly increased the colocalization of the D1 receptor and arrestin3 immunoreactivity, without altering the colocalization of the D1 receptor and arrestin2. Further, agonist treatment caused translocation of arrestin3, but not arrestin2, to the membrane, and increased the coprecipitation of the D1 receptor and arrestin3, but not arrestin2. Agonist treatment of neurons induced D1 receptor internalization (35-45%) that was maximal within 2-5 min, a time course similar to that of the increase in colocalization of the D1 receptor with arrestin3. These data indicate that the DA D1 receptor is preferentially regulated by arrestin3 in neostriatal neurons, whereas the DA D2 receptor interacts with arrestin2. (MH45372, DA07262, and VA Merit Review)

41. Effects of Moderate and Severe Calorie Restriction on Avian Species Mary Ann Ottinger*, Mohammed Mobarak, Mahmoud Abdelnabi University of Maryland Previous studies showed 15% lifelong CR provided maximum benefits for health and reproduction in heavy strains of chickens. Subsequent studies were conducted in Japanese quail, a short lived bird. Male Japanese quail were pair fed 0% (ad libitum), 20%, or 40% CR of ad lib bird diet during sexual maturation (3-7 weeks of age). Results showed that both CR groups matured slowly; 40% CR males had reduced testes weight, plasma androgen and LH, with increased corticosterone. CR males showed LH release in with GnRH challenge (20 ∞†g/kg), suggesting hypothalamic inhibition. Therefore, males (n=10males/treatment) castrated at 2 weeks of age were raised on CR (0%, 20%, or 40%) until maturity. Again, 40% CR resulted in lower circulating LH. Both CR groups showed LH release with LHRH challenge. This provided evidence that the pituitary gland maintained releasable LH, even in the 40% CR males. These results infer that 20% CR exerted relatively mild effects, whereas 40% CR provided significant stress, resulting in central inhibition of the HPG axis. To test this hypothesis, we measured

January 23–28, 2005 • Breckenridge, Colorado 55 hypothalamic catecholamine content and turnover from adults raised on 20% or 40% CR. Results showed reduced DA in 20% CR males, and reduced DA and NE in 40% CR males; DA and NE turnover was signiﬁcantly lower in the 40% CR males. These data support our hypothesis that catecholamines are key neural substrates of CR.

42. Cortical Interneuron Changes in Conditional BDNF Knockout Mice Ronald Paletzki* NIH/NIMH To determine the effects of BDNF on adult cortical neurons, we used a conditional BDNF knockout mouse that restricts gene deletion to adult forebrain neurons. Microarray analysis revealed that some cortical inter- neuronal markers were altered in the BDNF knockout mice. In situ hybridization confirmed that somatostatin and neuropeptide Y (NPY) were reduced whereas NOS was increased. The mRNA expression of other inter- neuronal markers, GAD67, parvalbumin, calretinin and calbindin, where unaltered. The time course of changes in BDNF and somatostatin expression showed normal levels up to 21 days after birth and reduced levels by day 60. Infusion of a viral vector expressing BDNF into the cortex of knockout mice reversed the reduction in somatostatin and NPY. NPY and NOS are both expressed by a subgroup of somatostatin positive neurons indicating that BDNF in the adult cortex reversibly affects the somatostatin group of interneurons with no detected effects on the other primary subgroups of cortical interneurons. Additionally, the cortex of BDNF knockout mice expressed lower levels of IEGs suggesting a general decrease in neuronal activity in the cortex. Infusion of a BDNF expressing virus into the cortex increased the expression of IEGs in the area in which BDNF expression was reversed, and in the comparable location in the contralateral hemisphere where BDNF expression was not reversed. These data suggest that BDNF in the adult cortex can reversibly affect the activity of cortical neurons and circuits either directly or via changes in interneuron function.

43. Total Number of Hippocampal Synapses in People with Mild Cognitive Impairment Stephen Scheﬀ*, D.A. Price, F.A. Schmitt, E.J. Cochran, D.A. Bennett, E.J. Mufson Synaptic decline in Alzheimer‚s disease (AD) is associated with many diﬀer- ent brain regions including the hippocampus. Little is known about such changes in individuals with mild cognitive impairment (MCI) although these individuals may convert to AD. The dentate gyrus Outer Molecular

56 38th Annual Winter Conference on Brain Research Layer (OML) and the CA1 Stratum Radiatum (SR) region of the hippocampus were assessed. The OML receives a direct projection from the ipsilateral entorhinal cortex, an area known to be affected in AD. The SR receives a direct projection from the CA3 region and is known to play an important role in learning and memory. All individuals underwent detailed clinical evaluation within 12 months of death and were categorized as AD (n=10), MCI (n=9) or no cognitive impairment (NCI) (n=10). Unbiased stereological techniques coupled with electron microscopy were used to estimate the total number of synapses in both SR and OML. The AD group had significantly less synapses than both MCI and NCI. Although the mean number of synapses was lower in the MCI group compared to NCI (84%) there was considerable variance in the MCI group with approximately half of the subjects in the AD range. The SR field in both AD and MCI appeared to be more severely affected than the OML. Cognitive variables such as mini-mental status and delayed recall correlated with the total number of synapses in both hippocampal regions. These results suggest that individuals with MCI are a highly diverse group with some individuals clearly showing synaptic loss equivalent to AD subjects while others equivalent to age-matched NCI subjects.

44. Administration of D1-Like or D2 Dopamine Receptor Agonists into the Nucleus Accumbens Shell Reinstates Cocaine-seeking Behavior Heath Schmidt*1, R.C. Pierce1,2 Departments of Pharmacology1 and Psychiatry2, Boston University School of Medicine, Boston, MA 02118 Although increases in dopamine transmission in the nucleus accumbens are clearly involved in cocaine reinforcement, the role of accumbal dopamine in the reinstatement of cocaine seeking has not been fully described. The goal of these experiments is to further evaluate the relative contributions of D1-like and D2-like dopamine receptors in the nucleus accumbens core and shell in the reinstatement of cocaine-seeking behavior. Initially, rats were trained to press a lever for cocaine (0.254 mg/60 ?l, i.v.) using a fixed-ratio five (FR5) schedule of reinforcement. Responding then was extinguished by substituting saline for cocaine. Following extinction, subtype specific dopamine receptor agonists were microinjected into the nucleus accumbens core and shell in order to assess their ability to induce cocaine seeking. Administration of the D1-like dopamine receptor agonist, SKF-81297 (1.0 µg/0.5 µl), into the nucleus accumbens shell, but not core, reinstated drug-seeking behavior. Furthermore, microinjection of quinpirole (3.0 µg/0.5 µl), a D2-preferring dopamine receptor agonist, into the nucleus accumbens shell and not core reinstated drug-seeking behavior. In

January 23–28, 2005 • Breckenridge, Colorado 57 contrast, administration of the D3- and D4-preferring dopamine receptor agonists, PD 128,907 (1.0 and 3.0 µg/0.5 µl) and PD 168,077 (3.0 µg/0.5 µl) respectively, did not promote reinstatement when administered into either the core or the shell. Taken together, these results indicate that activation of D1-like receptors and D2 dopamine receptors in the nucleus accumbens promotes cocaine seeking in a region-speciﬁc fashion. These ﬁndings indicate a critical role for dopamine in the nucleus accumbens shell, and not in the core, in cocaine-priming induced reinstatement of drug seeking behavior.

45. Glycogen Synthase Kinase 3 Activity Regulates Neuronal Pentraxin 1 Expression and Cell Death Induced by Potassium Deprivation in Cerebellar Granule Cells Ramon Trullas*, M. Enguita, E. De Gregorio-Rocasolano, A. Abad Neurobiology Unit, IIBB, CSIC, IDIBAPS, 08036 Barcelona, Spain Expression of Neuronal Pentraxin 1 (NP1) is part of the apoptotic cell death program activated in mature cerebellar granule neurons when potassium concentrations drop below depolarizing levels. NP1 is a glycopro- tein homologous to the pentraxins of the acute phase immune response and it is involved in both synaptogenesis and synaptic remodeling. We have studied whether the signaling pathways known to control neuronal cell death and survival inﬂuence NP1 expression. Both activation of the phosphatidylinositol 3-kinase/Akt (PI-3-K/AKT) pathway by Insulin-like growth factor I and pharmacological blockage of the stress activated c-jun N-terminal kinase (JNK) oﬀer transitory neuroprotection from the cell death evoked by non-depolarizing concentrations of potassium. However, neither of these neuroprotective treatments prevent the overexpression of NP1 upon potassium depletion, indicating that non-depolarizing conditions activate additional cell death signaling pathways. Inhibiting the phosphorylation of the p38 mitogen activated protein kinase without modifying JNK, neither diminishes cell death nor inhibits NP1 overexpression in non-depolarizing conditions. In contrast, impairing the activity of Glycogen Synthase Kinase 3 (GSK3) completely blocks NP1 overexpression induced by potassium depletion and provides transient protection against cell death. Moreover, simultaneous pharmacological blockage of both JNK and GSK3 activities provides long-term protection against the cell death evoked by potassium depletion. These results show that both the JNK and GSK3 signaling pathways are the main routes by which potassium deprivation activates apoptotic cell death, and that NP1 overexpression is regulated by GSK3 activity independently of the PI-3-K/AKT or JNK pathways.

58 38th Annual Winter Conference on Brain Research Supported by BFI2001-1035 from Ministerio Educación y Ciencia, FIS-PI02055 and G03/167 from Ministerio de Sanidad y Consumo, and Fundació La Caixa.

46. Agonal Factors, Aging, and Drug Abuse Affect Mitochondrial Gene Expression in Postmortem Brain Implications for Neuropsychiatric Disorders Marquis Vawter* University of California at Irvine Reports of mitochondrial related gene expression in bipolar disorder and schizophrenia have increased interest as to whether the observed mitochondrial gene expression differences are relevant to agonal and diagnostic group differences. The broad effects of pH and agonal factors on microarray analysis of gene expression were also reported in pathways related to stress and oxidative phosphorylation. We analyzed gene expression from bipolar disorder type I (BPD), recurrent major depression (MDD), and control groups for mitochondrial related gene expression by microarray, Q-PCR, and in situ hybridization. Comparison of microarray results between control subjects stratified by either pH or agonal factors resulted in gene expression differences related to mitochondrial pathways such as oxidative phosphorylation. The direction of gene expression differences is such that lower pH in controls resulted in an apparent down-regulation of gene expression in a large number of genes related to mitochondrial function in cortical and cerebellar cortices. After eliminating low pH cases with agonal factors from all three groups, the BPD and MDD groups were compared to control subjects. The ‘mitochondrial effect’ is reduced in amplitude in affective disorder group comparisons to controls in cases without agonal factors. Alterations in mitochondrial-encoded transcript levels by Q-PCR were found in mood disorders compared to controls. Taken together, the data suggest dysregulation at the mitochondrial level in affective disorders independent of agonal factors and pH and offers evidence in support of the mitochondrial dysregulation hypothesis of bipolar disorder and extension to major depression.

47. Ethanol Inhibits Persistent Activity of Prefrontal Cortical Neurons in Slice Co-Cultures J. J. Woodward*, Y. Tu, J.K. Seamans, L.J. Chandler Medical University of South Carolina, Department of Physiology and Neuroscience and Center for Drug and Alcohol Programs, Charleston, SC 29425 In vivo, neurons in the medial prefrontal cortex (mPFC) display patterns of persistent activity characterized by ﬂuctuations between a hyperpolarized

January 23–28, 2005 • Breckenridge, Colorado 59 membrane potential (down-state) and a sustained depolarized state (up- state) during which action potential firing is observed. Persistent activity is modulated by afferent inputs from dopaminergic neurons residing in the ventral tegmental area (VTA). Importantly, persistent activity is normally absent in acutely prepared brain slices but can be reconstituted in slice co-cultures containing VTA, mPFC and hippocampus. The present study used whole-cell patch-clamp recording from deep layer mPFC neurons in brain slice co-cultures to examine the effect of acute ethanol on mPFC neuron bistability. Ethanol decreased the frequency, duration and spike- activity of spontaneously generated up-states as well as those elicited by electrical stimulation of VTA neurons. The threshold concentration of ethanol that produced inhibition was approximately 17 mM and concentrations of 50 mM ethanol typically eliminated bistability in most neurons studied. Similar to ethanol, a low concentration of the NMDA antagonist, APV (5 µM) also reduced the duration and spike activity of up-states. After washout of the ethanol containing solution, the duration and firing activity of PFC neurons was dramatically increased for up to 30 minutes. These results indicate that acute ethanol inhibits both spontaneous and VTA- evoked membrane bistability in the PFC and produces a rebound excita- tion after washout. Ethanol-induced alterations in this circuit may be one mechanism underlying the development of alcohol addiction and alcohol- related behaviors.

Supported by grants AA00238 and AA09986 to J.J.W. and AA10761 to J.J.W. and L.J.C.

48. Influence of Infrared Illumination on the Learning and Activity Behavior of Rats J. Brooks Zurn1, Steven I. Dworkin2, Yuichi Motai1 University of Vermont1 and University of North Carolina Wilmington2 Behavioral analysis of rodents is an important measure for determining the effects of experimental conditions such as brain lesions, genetic manipulations, and drugs. Near-infrared illumination (750nm to 1100nm) could be less intrusive when using video monitoring than visible light and also allow monitoring when rodents are more active during their dark cycle. However, little research has been done on the influence of such illumination on rodent behavior. Although it is generally believed that rodents cannot see in the infrared range (light with wavelengths > 750 nm), there is evidence that even 940 nm light can cause visual evoked potentials in the visual cortex. Therefore, it is important to assess the potential disruptive effects of illumination within this range.

60 38th Annual Winter Conference on Brain Research Open-field activity and a hole board learning task were utilized to evaluate potential effects of overhead illumination conditions of 880 nm, 940 nm, visible white light or no illumination. For the learning task, two holes were baited with food and crumbs were scattered under the board to reduce the use of scent for locating the food. The effects of the infrared illumination on the rodent’s ability to learn the location of the bait after repeated trials will be shown, as will the influence of the illumination on open-field activity.

49. A Role for HLH Transcription Factor Inhibitor of DNA Binding (Id) Genes in the Mammalian Circadian Clockwork Giles E. Duffield1,2*, Nathan P. Watson3, Stuart N. Peirson2, Jennifer J. Loros1, Mark A. Israel1,3, Jay C. Dunlap1 1Department of Genetics, Dartmouth Medical School, Hanover, New Hampshire 03755, 2Department of Visual Neuroscience, Imperial College, Charing Cross Hospital, St. Dunstan’s Road, London W6 8RF, U.K., 3Norris Cotton Cancer Center & Department of Pediatrics, 1 Medical Center Drive, Rubin Building, Lebanon, New Hampshire 03756 Id2 (Inhibitor of DNA binding 2) is a helix loop helix (HLH) transcriptional repressor implicated in development, cell cycle, and apoptosis, and was identified in a cDNA microarray screen for rhythmically expressed genes in rat-1 fibroblasts (Duffield et al., 2002, Current Biology 12: 551-557). Subse- quent gene expression analysis by real-time quantitative RT-PCR reveals a conserved rhythmic pattern across multiple tissues including mouse 3T3 cells and murine peripheral tissues (e.g. heart) in addition to the suprachiasmatic nucleus (SCN) in vivo. The peak phase of the Id2 rhythm in all tissues appears to be phase locked to the rhythms of the canonical clock genes. This rhythm lags the phase of the bmal1 rhythm by 4-8 hrs. Id2 is one of a family of four structurally related genes (Id1-4). Examination of the expression profiles of Id1, Id3 and Id4, also revealed rhythmic patterns within the SCN and heart. In vitro transient transfection studies using an mPer1 promoter linked to a luciferase gene was used to examine the potential of ID1-4 to interact with the basic HLH clock proteins BMAL1 and CLOCK, and to potentially inhibit their heterodimerization and binding to the mPer1 promoter. Co-transfection with either ID1, ID2 or ID3 produced marked inhibition of CLOCK:BMAL1 transactivation of the mPer1 promoter, suggesting a potential role for members of the Id gene family in regulating central components of the circadian clock. Research supported by the Wellcome Trust (058332/C/99/Z to G.E.D.), the Royal Society (University Research Fellowship to G.E.D), the Betz Foundation, and NIMH (MH44651 to J.C.D. and J.J.L.).

January 23–28, 2005 • Breckenridge, Colorado 61 62 38th Annual Winter Conference on Brain Research January 23–28, 2005 • Breckenridge, Colorado 63 Sessions Abstracts

0Panel • Sunday 4:30–6:30 PM • Peak 11–120

Corticalization of Pain George Wilcox, Luc Jasmin, Vania Apkarian, Richard Gracely, Robert C. Coghill Most would agree that immediate, conscious perception of any sensation is a cortical phenomenon. Several cortical areas have been shown in animal and human studies to be specifically activated by noxious stimuli. These observations suggested that the representation of pain involves many cortical regions and activation of different sites is responsible for the division of discriminative and affective components of sensation. Further, cortical regions other than the primary somatosensory cortex are probably key to the cortical control of pain as will be explored below. Jasmin will describe recent studies in his laboratory in which it was examined how GABA in a small cortical area called the rostral agranular insular cortex (RAIC) works to change nociceptive behavior. They found that GABA inhibits at least two efferent RAIC excitatory projections. The first predominantly terminates on brainstem GABAergic neurons that suppress the activity of the pain inhibitory noradrenergic bulbospinal projections such that increasing GABA in the RAIC results in a noradrenaline mediated spinal analgesia. A second projection is from the RAIC to the amygdala, and GABA mediated inhibition of this projection prevents the appearance of hyperalgesia but does not produce analgesia. Apkarian will report multi-modal brain imaging studies in humans exposed to acute pain or suffering from chronic pain. Results from normal subjects for acute thermal stimuli will be contrasted with brain activity for chronic back pain, chronic post-herpetic neuropathy pain, and psoriatic arthritis. Also, cognitive, biochemical and morphologic evidence will be presented showing that chronic pain is associated with cortical abnormalities. The data will be integrated with animal studies of cortical interventions to present an overall model of cortical events involved in the transition from acute to chronic pain. Gracely will present brain fMRI studies in patients with chronic low back pain (CLBP) and patients with widespread pain (fibromyalgia). Pain testing revealed hyperalgesia in both group compared to normal controls. When equal amounts of pressure were applied to the 3 groups, fMRI detected 5 common regions of neuronal activation in pain-related cortical areas in the CLBP and fibromyalgia groups (in the contralateral primary and secondary [S2] somatosensory cortices, inferior parietal lobule, cerebellum,

64 38th Annual Winter Conference on Brain Research and ipsilateral S2). This same stimulus resulted in activation of only the contralateral S2 somatosensory cortex in controls. When subjects in the 3 groups received stimuli that evoked subjectively equal pain, fMRI revealed common neuronal activation in all 3 groups. These results indicate that at equal levels of pressure, patients with chronic low back pain or fibromyalgia experienced significantly more pain and showed more extensive, common patterns of neuronal activation in pain-related cortical areas. These findings are consistent with the occurrence of augmented central pain processing in patients with idiopathic chronic low back pain.

0Panel • Sunday 4:30–6:30 PM • Peak 140

Your Cortex on Drugs: Plasticities Beyond the Nucleus Accumbens John Bruno, Peter Kalivas, Terry Robinson, Karen Bolla Traditional perspectives on drug abuse have focused on the role of the nucleus accumbens and mesolimbic DA systems in reward mechanisms. Recent analyses have revealed persistent changes in cortically-mediated events in addicts and in animal models of of addiction. Enduring cortical plasticities, following repeated drug exposure, are consistent with the complex cognitive processes believed to underlie cycles of craving and relapse, including: monopolization of attentional processes, heightened impulsivity and diminished response inhibition, attribution of incentive salience, and the conditioning of drug-related stimuli. This Panel Discussion will present research findings from both clinical and pre-clinical studies and will integrate neuroimaging, neuroanatomical, neurochemical and behavioral data related to cortical plasticity and drug abuse. Karen Bolla will discuss impaired decision-making and alterations in orbitofrontal cortex and dorsolateral prefrontal cortex in cocaine and marijuana users. Peter Kalivas will discuss findings that a G protein regulatory protein, AG3, is upregulated following cocaine self-administration and that normalizing AG3 eliminates drug-seeking behavior. Terry Robin- son will discuss evidence that repeated exposure to psychostimulants is associated with structural plasticity in medial and orbital prefrontal cortex and that these effects of drugs interact with the ability of other life experiences to alter synaptic organization. John Bruno will discuss findings that repeated administration of amphetamine and nicotine sensitize the release of ACh in frontal cortex and link these changes in cholinergic transmission to changes in attentional processes that may contribute to craving and relapse.

January 23–28, 2005 • Breckenridge, Colorado 65 0Panel • Sunday 4:30–6:30 PM • Peak 150

Estrogen Replacement: A Double-Edged Sword? Gretchen Snyder, Lisa Jackson, Jill Becker, Catherine Woolley The potential benefits and health risks associated with estrogen replacement therapy are extremely controversial, particularly with regard to cardiovascular disease and cancer. Amidst this debate, data on the impact of estrogen on the brain is no less ambiguous. Emerging evidence from animal studies points to both beneficial and non-beneficial effects of estrogen on cognitive, emotional, and motor behavior. For example, estrogen can improve or impair memory performance depending upon many factors including the task being studied and circulating estrogen levels, and the duration of estrogen exposure. Estrogen also promotes undesirable behaviors such as addiction to drugs of abuse. A major hurdle in understanding these disparate actions of estrogen is that precise cellular targets relevant to these effects are largely unknown. This panel explores some of the diverse behavioral effects of estrogen in animals and seeks to identify cellular substrates useful in understanding the behavior. Lisa Jackson will discuss the ability of estrogen to promote behavioral sensitization to cocaine. Jill Becker will present evidence for neurochemical effects of estrogen on GABA release that may underlie the enhanced propensity for female rats to self-administer cocaine. Gretchen Snyder will discuss estrogen‚s ability to promote DA-stimulated protein phosphorylation and its possible role in mitigating working memory deficits in PCP-treated rats. Catherine Woolley will discuss estrogen effects on hippocampal circuitry and the implication of these actions for beneficial effects of the hormone on working memory. Together these presentations will highlight effects of estrogen on behavior, both beneficial and deleterious, and possible cellular targets for these actions.

0Panel • Sunday 4:30–6:30 PM • Peak 170

Astrocytes and Disease Michael Brenner, Mahendra Rao, Harold Sontheimer, Sue Griﬃn, Christoph Proschel Astrocytes perform critical functions in development and maintenance of the human brain and rapidly respond to injury. Despite this, relatively little attention has been paid to the role of these cells in pathogenesis. The purpose of this panel is to redress this deﬁcit. Participants will show that

66 38th Annual Winter Conference on Brain Research the role of astrocytes in disease extends to gliomas and to other disorders more traditionally attributed to neurons and oligodendrocytes. We start at the beginning: Mahendra Rao will discuss astrocyte progenitors, methods for their isolation, and their behavior after transplantation. This information will be related to findings that reactive astrocytes are significant contribu- tors to multiple sclerosis. Harry Sontheimer will discuss how astrocyte- derived tumors support their growth and dissemination by co-opting the function of glutamate transporters designed to be neuroprotective. Growing tumors release glutamate as an excitotoxic agent to clear space for growth, whereas single invading cells release glutamate as a signal to promote their motility. Sue Griffin will discuss the role of astrocyte activation and astrocyte-microglia interactions in propagating and amplifying neurodegenerative cascades, emphasizing the contribution of S100beta overexpression in the genesis and progression of disease. Vanishing White Matter disease is a genetic disorder of myelin formation caused by mutations in translation initiation factor 2B. Chris Proschel will present evidence from patient-derived CNS cultures to suggest that astrocytes, rather than oligodendrocytes, are the primary target of this lesion. Similarly, Mike Brenner will show that nearly all cases of Alexander disease, another leu- kodystrophy, are due to mutations in the astrocyte specific intermediate filament GFAP.

0Panel • Sunday 4:30–6:30 PM • Peak 6–80

DA/NE Interaction Governing Frontostriatal Functions Antonieta Lavin, Carlos Paladini, Susan Sesack, Janet Finlay, David Jentsch The ventral tegmental area (VTA) provides the main dopaminergic input to the prefrontal cortex (PFC); however, the PFC and VTA are also modulated by a noradrenergic input arising from the locus coeruleus (LC). Thus, the interactions between these catecholamines are crucial for the regulation and eﬃciency of cognitive, attentional and executive functions. The main focus of this panel is to discuss the interactions occurring between DA/ NE in the VTA-PFC circuit and the relevance of these interactions for the optimum functioning of the circuit. In this context, Dr. David Jentsch will focus on mutual pre- and post-synaptic interactions between NE and DA terminals in PFC that govern spatial working memory and visual attention performance Dr. Janet Finlay will discuss the potential for harnessing DA/ NE interactions in the PFC as a mean of alleviating hypoactivity of meso- prefrontal DA neurons and the associated cognitive deﬁcits.

January 23–28, 2005 • Breckenridge, Colorado 67 On the other side of the circuit Dr. Susan Sesack will present evidence from her laboratory showing that brainstem NE neurons innervate DA cells in the VTA and that DA and NE axons send convergent projections to a number of forebrain regions, including the PFC. Dr. Carlos Paladini will discuss how receptors that couple to phosphoinositide hydrolysis, which includes alpha-adrenergic receptors, are known to either activate or inhibit the activity of dopamine cells depending on the pattern of receptor activation. This panel will attempt to synthesize anatomical, physiological, neurochemical and behavioral data into a coherent model for DA/NE interactions and to provide insights for mental disorders that involve abnormal catecholamine function.

0Panel • Sunday 4:30–6:30 PM • Peak 9–10 0

Multiple Problems with Multi-Site Brain Imaging Studies—Partial Solutions William Bunney, Anders Dale, Steven Potkin, Arthur Toga, Bruce Rosen This panel will review the multiple problems in combining structural and functional imaging data across sites. The potential of multi-site imaging studies is considerable in providing access to unique populations, in defining the generalizablity of the findings, and in collecting large cohorts rapidly. Combining data is limited by intersite variability which is related to different vendors, head coils, magnetic strengths, and imaging environments. New data obtained on 5 subjects scanned multiple times at 10 geo- graphically dispersed sites will be presented by Dale showing that intersite variability is greater than between subject variability, precluding meaning- ful combination of multisite imaging data. New methods for standardization of functional data acquisition including measures of vascular dynamic range and responses to standardized sensory motor tasks will be described by Rosen. The strengths and limitations of various statistical approaches for quantifying variability and new algorithms to adjust for these intersite differences will be discussed by Toga. The implications of methods such as scaling, smoothing, STAPLE, and hierarchical models will be contrasted. The application of these calibration algorithms to multisite fMRI working memory and auditory processing tasks will be presented by Potkin. Potkin will describe the FBIRN collaboration as an example of a unified effort of researchers across 10 universities to produce novel approaches to human subject data sharing, experimental design, fMRI data standardization, and clinical and imaging database design. Issues related to multi-site integration of fMRI images will be demonstrated for data obtained on sensorimotor tasks. The panel will summarize the power of these new approaches.

68 38th Annual Winter Conference on Brain Research 0Panel • Sunday 8:30–10:00 PM • Peak 11–120

The Effect of Chronic Stress on Central Noradrenergic Function Hank Jedema, Stephen Gold, LeeAnn Miner, Gregory Ordway Abnormalities in central norepinephrine (NE) systems in humans have been reported in several affective disorders. Given that symptoms of these disorders are often precipitated/exacerbated by exposure to stress and that noradrenergic neurons are highly responsive to stressful stimuli, many investigators examine the effects of acute stress on neurons of the major noradrenergic nucleus, the locus coeruleus (LC). It is likely, however, that the alterations in LC function in mood and anxiety disorders represent multiple compensatory adaptations elicited by prolonged stress exposure. Therefore, changes occurring in the LC system in response to chronic stress are crucial to our understanding of affective disorders. The amount of NE available to elicit postsynaptic responses is controlled by many factors, including activity of LC neurons, their capacity to release NE, as well as (auto)-receptor and NE transporter (NET) function. This panel will examine effects of chronic stress exposure on factors influencing noradrenergic function and relate these to evidence of LC dysfunction in humans with depressive disorders. Hank Jedema will present electrophysiological and neurochemical data on chronic stress-induced alterations in LC function. As has been shown for the cAMP system, chronic stress leads to marked alterations in metabotropic receptor signaling cascades in the LC. Stephen Gold will present data on changes to regulators of G proteins signaling (RGS) expression following chronic stress exposure and antidepres- sive treatment with electroconvulsive shock. LeeAnn Miner will present the first ultrastructural data on chronic stress-induced increases in the expression of the NE synthetic enzyme tyrosine hydroxylase (TH) and alterations of the association of NET with the plasma membrane in NE terminals typically lacking appreciable TH levels. Gregory Ordway will present findings of alterations in gene expression, and related protein and neurotransmitter levels in the human postmortem LC from depressed subjects and suicide victims.

January 23–28, 2005 • Breckenridge, Colorado 69 0Workshop • Sunday 8:30–10:00 PM • Peak 140

Addiction across the Life Span: From the Womb to the Tomb, Almost John Mendelson, Gabriele Fischer, Reese Jones, Elmer Yu, Brian Yamamoto, Conan Kornetsky Most addictive disorders start in late adolescence or young adulthood. Unfortunately, little is known about developmental factors affecting addiction. This workshop will bring together experts who study addiction or treat patients from neonates to the elderly. We plan to explore com- monalities and issues in measurement, diagnosis and treatment in drug dependence across the lifespan. Presenters will be limited to 2 hypothesis and 2 data slides so that adequate time for discussion of key issues will be available. Dr. Fischer will present data on treatment and outcomes in opiate dependent pregnant women and the effects of opiate stabilization treatment on later human development. Dr. Mendelson will discuss possible age related changes in MDMA effects. Differences in vasopressin secretion, androgen levels, adenosine-dopamine interactions will be explored as possible sources of age related differences in vulnerability to addiction. Dr. Yamamoto will discuss the role of increases in extracellular glutamate in the striatum and hippocampus with age and the role of D2 receptors. Dr. Kornetsky will highlight changes in the reward system in the aged rat and its relevance for the rewarding and analgesic effects of opiates. Dr. Elmer Yu will discuss the effects of alpha-2 sympathomimetic agonists in older versus younger methadone patients. Dr. Reese Jones will consider the differential consequences of nicotine and marijuana exposure during adolescence.

0Panel • Sunday 8:30–10:00 PM • Peak 150

Air Pollutants, Intercellular Messengers, or Both? Inorganic Signaling Molecules in Cerebral Circulation Charles Leﬄer, Dale Pelligrino, Robert Bryan, Rui Wang, David Busija Regulation of cerebral circulation is complex, incompletely understood, but critically important to any resemblance of cognitive function. In addition to the long appreciated organic intercellular communication molecules that utilize membrane receptors coupled to second messengers to transduce signaling, a novel collection of inorganic signaling molecules that are not well corralled by lipid membranes and operate independently of classical G-protein coupled receptors is becoming appreciated; and

70 38th Annual Winter Conference on Brain Research the group is expanding. Vascular, glial, and neuronal cells employ tightly controlled mechanisms to synthesize these molecules that alter functions of adjacent cells by directly activating guanylyl cyclase (NO), large conductance Ca activated potassium channels (KCa) (CO), ATP sensitive potassium channels (KATP) (H2S), etc. Dale Pelligrino will discuss the most extensively studied of these molecules, the endothelium derived relaxing factor, NO. He will examine the newest aspects of endothelial, neuronal, and glial derived NO in regulation of cerebrovascular tone. I will report our current understanding of mechanisms by which endogenous CO, generated from cellular heme via the enzyme heme oxygenase, manipulates KCa channel activity, vascular tone, and thus cerebrovascular circulation. Bob Bryan will present new information on the possible identity(s) of endothelial derived hyperpolarizing factor (EDHF) and exciting recent results of novel interactions among EDHF, NO, and CO in cerebral microcirculation. Rui Wang will discuss the latest about swamp gas (hydrogen sulfide), enzymatically produced in brain from L-cysteine, hyperpolarizing vascular smooth muscle, altering cellular redox state, interacting with other gasotransmitters, and modifying vascular tone and likely brain function. The collection of reactive oxygen species known for cataclysmic cellular injury with uncontrolled production are produced by a myriad of physiological cellular processes that are tightly regulated and contribute to cerebrovascular function by interactions with all the other gasotransmitters and directly modifying cellular effectors. Dave Busija will expound on modification and modulation of cerebrovascular circulation by these reactive oxygen species.

0Panel • Sunday 8:30–10:00 PM • Peak 170

Neuromodulation in Sensory Systems Robert Lundy, Thomas Cleland, Laura Hurley, Yuan Peng Animals respond to a wide variety of sensory stimuli on a daily basis. The central nervous system processes sensory information in such a way that an identical stimulus may elicit distinct reactions under diﬀerent environmental and behavioral conditions. This multifarious responsiveness implies that modulatory systems in the brain are essential components of the neural circuitry underlying adaptive behavioral output. Lower-order sensory nuclei are reciprocally connected with the forebrain and neuromodulatory cell groups. This anatomical arrangement is a common feature of sensory systems and provides a substrate for reversibly reconﬁguring the function of a sensory circuit without changing the Œhard-wiring‚. Through facilitatory and inhibitory mechanisms, centrifugal projections can selectively shape the response characteristics of sensory neurons at each stage of the system. Such altered neural representations

January 23–28, 2005 • Breckenridge, Colorado 71 of sensory stimuli reflect the neural plasticity associated with processes like learning and motivation. This panel will present evidence that sensory information derived from different systems does not just ascend the neuraxis unhindered, but is cen- trally filtered. Gustatory System: Robert Lundy will discuss how descending forebrain projections influence taste processing in the pontine parabra- chial nucleus. Olfactory System: Thomas Cleland will discuss how local and centrifugal projections shape odor representations in the olfactory bulb. Auditory System: Laura Hurley will describe how the neuromodulator serotonin selectively shapes responses in the auditory midbrain. Somatosen- sory System: Yuan Peng will discuss how descending projections modulate both spinal dorsal horn neurons and peripheral sensory nerve activity (dorsal root reflex).

0Panel • Sunday 8:30–10:00 PM • Peak 6–80

Mitochondrial Targets of Oxidative Stress in Neurodegeneration Gary Fiskum, Steve Scheff, Nina Solenski, Ella Bossy-Wetzel Mitochondrial dysfunction and oxidative stress contribute to necrotic and apoptotic neural cell death in acute CNS injury and in neurodegenerative diseases. Identification of the mitochondrial molecular targets of reactive oxygen and nitrogen species is essential for understanding the pathogenesis and treatment of these disorders. These targets include mitochondrial DNA, RNA, proteins and lipids, all of which are critical for normal mitochondrial energy-transduction activities including oxidative phosphorylation. Oxidative modification impairs normal metabolic functions and impairs mitochondrial mobility within cells. In addition to these inhibitory effects, oxidative stress also activates certain mitochondrial activities, e.g., the permeability transition pore, and can trigger the translocation of pro-apoptotic proteins, e.g., Bax and p53, from the cytosol to the mitochondrion. This panel will cover topics ranging from the direct effects of reactive oxygen and nitrogen species on mitochondrial metabolism and membrane permeability to the influence of oxidative stress on mitochondrial structure and mobility. Gary Fiskum will describe how the use of high inspired oxygen following cardiac arrest and resuscitation exacerbates mitochondrial protein nitration, inactivates pyruvate dehydrogenase, and impairs oxidative cerebral energy metabolism. Steve Scheff will describe the remarkable differences in the vulnerability of spinal cord and brain

72 38th Annual Winter Conference on Brain Research mitochondria to oxidative injury in situ and the relationship to differences in sensitivity to the mitochondrial permeability transition. Nina Solenski will discuss the acute effects of nitric oxide and its metabolites on mitochondrial energetics and intraneuronal trafficking. Along this same theme, Ella Bossy-Wetzel will explain how mitochondrial fission and fusion play important physiological roles but also contribute to apoptosis and neurodegeneration.

0Panel • Sunday 8:30–10:00 PM • Peak 9–100

High on Neurosteroids—For Better or Worse? A. Leslie Morrow, Deborah Finn, Sindy Mellon, Henry Kranzler GABAergic neurosteroids contribute to the physiological actions of ethanol in rodents and humans. Neurosteroids are synthesized in adrenals, gonads and brain from cholesterol or circulating steroid precursors that readily cross into the brain. The 5a-reductase enzymes (5AR) catalyze the metabolism of progesterone and deoxycorticosterone to the potent GABAergic neurosteroids allopregnanolone (ALLO) and 3a,5a-THDOC (THDOC). Using different avenues to examine the interactive effects of neuroactive steroids and ethanol on behavior, this panel will focus on recent evidence in both animal and human models suggesting that neuroactive steroids contribute to ethanol sensitivity, ethanol withdrawal sensitivity and genetic vulnerability for alcohol dependence. Dr. Morrow will describe the role of endogenous GABAergic neuroactive steroids in various actions of ethanol and ethanol self-administration. Dr. Finn will present data showing an amino acid change within the coding region of Srd5a1 (which encodes the enzyme 5AR-1) produces a marked difference in the functional activity of 5AR-1 associated with ethanol withdrawal severity. Dr. Mellon will present clinical data showing that pregnenolone, a GABA-A receptor negative modulator with no significant behavioral effects, attenuates the sedative and intoxicating effects of ethanol in humans. Dr. Kranzler will present data showing that alleles of GABRA2 (the gene encoding the GABA alpha-2 subunit) are associated with alcohol dependence and moderate subjective responses to ethanol in healthy individuals. Pre-treatment with finasteride also dampened subjective responses to ethanol, but only in subjects who lacked the risk-associated GABRA2 allele. Together, these studies suggest that neurosteroid responses to ethanol moderate drug sensitivity and vulnerability to alcohol dependence.

January 23–28, 2005 • Breckenridge, Colorado 73 0Panel • Monday 7:30–9:30 AM • Peak 11–120

New Approaches to Pain Research: Target Genes, Population Genetics, Regulatory Pathways, and Neuro-Immune Interactions John Kusiak, Z. David Luo. Luda Diatchenko, Andrew Russo, Wendy Campana Chronic pain can be thought of as a complex disease, since it involves many changes in the central and peripheral nervous systems and includes alterations in sensory and affective components of pain. This pain is not well treated with current therapies, in part, because of an incomplete understanding of the basic mechanisms of nociception and pain perception. Also, traditional research approaches have focused on single molecules or sets of molecules that are altered after noxious stimuli with little regard for the occurrence of other coincident or subsequent molecular events. The emergence of more global approaches to study disease will allow us to expand the focus of research and improve our understanding of the molecular mechanisms of chronic pain. In this Panel, new approaches in pain research will be discussed. After a brief introduction by John Kusiak, David Luo will open the Panel by discussing his genomic approaches in rodents to identify target genes that contribute to neuropathic hypersensitive pain states. Luda Diatchenko will describe her multidisciplinary approach of examining the correlation of human genetic haplotypes in several genes with sensitivity to pain and propose a molecular mechanism by which these haplotypes influence activity of key enzymes and proteins in pain pathways. Andrew Russo will then present work from his laboratory on the plasticity of PKC/PKA regulated pain pathways in inflammatory pain. Wendy Campana will conclude with a discussion of the important contributions of glial/neuronal cell interactions in hypersensitive pain states and why certain cytokines may be novel analgesic agents.

0Panel • Monday 7:30–9:30 AM • Peak 140

Why is Parkinson’s Disease Progressive? Michael J. Zigmond, Jau-Shyong Hong, Teresa G. Hastings, Luigi Zecca, J. Timothy Greenamyre Parkinson’s disease (PD) is thought by many to be triggered by environmental toxins However, current theories fail to explain why the disease is progressive. Indeed, the loss of dopamine (DA) neurons in the substantia nigra—which may be responsible for many of the motor dysfunctions associated with PD—begins 5–10 years before frank neurological symp-

74 38th Annual Winter Conference on Brain Research toms and then continues throughout the patient’s lifetime. Moreover, additional neuronal loss gradually develops, including loss of neurons in the ventral tegmental area, raphé nucleus, and locus coeruleus. This panel will discuss four theories regarding the progressive nature of disorder. Michael Zigmond will introduce the neurological and pathological characteristics of PD. Jau-Shyong Hong will discuss the hypothesis that an initial loss of DA neurons initiates a toxic inflammatory response that then provokes further degeneration. Teresa Hastings will discuss the possibility that ROS formed from DA are increased because of compensatory increases in DA turnover and mitochondrial dysfunction, and that this promotes further cell loss. Luigi Zecca will focus on the toxic effects of neuromelanin which, when released by dying neurons, can activate microglia and cause release of potentially toxic molecules, including NO, TNFα, and IL-6. Tim Greena- myre will provide evidence that the partial loss of DA neurons results in an increase in the activity of the subthalamic nucleus, which in turn increases glutamate release with excitotoxic effects. In each case, panelists will comment on the implications of their hypotheses for the development of treatments that might slow or halt disease progression.

0Minicourse • Monday 7:30–9:30 AM • Peak 150

Translationtional Neuroimaging: Physiology and Pharmacology Peter Fox, Timothy Duong, Seong-Hwan Yee, Duff Davis, Bruce Jenkins Non-invasive, physiological imaging has been a work-horse of human neuroscience research for more than two decades. Positron emission tomography (PET) and functional MRI (fMRI) have been extensively used to study brain physiology and pharmacology under a wide variety of conditions and in many patient populations. Until very recently, non-invasive physiological imaging techniques could not be applied effectively in small animals, due to limitations of spatial resolution and signal-to-noise ratio. Over the past five years, steady progress has been made in physiological imaging of rodents using both PET and fMRI. With parallel advances in instrumenta- tion, in modeling, and in experimental design the outcome is that small animals (rats and mice) can now be imaged using the same methods that are routinely applied in human imaging research. Thus, brain imaging has become a truly translational method, reaching from mouse to man. The purpose of this mini-course is to inform our colleagues about the state-of- the-art in rodent imaging and to give examples of physiological neuroimaging applications in rodent models of human disorders. Timothy Duong will address physiological fMRI (CBF, CMRO2 and CBV), with examples in stroke and drug abuse. Seong-Hwan Yee will address physiological PET

January 23–28, 2005 • Breckenridge, Colorado 75 (CBF, CMRO2 and CBV), with examples in stroke and aging. Duﬀ Davis will address pharmacological PET, with an emphasis on assessing brain eﬀects of psychotherapeutic agents. Bruce Jenkins will address pharmacological fMRI, with an emphasis on drug abuse and neurodegenerative disorders.

0Panel • Monday 7:30–9:30 AM • Peak 170

Human Embryonic Stem Cells and Dopaminergic Neurons William J. Freed, Curt R. Freed, Lorenz Studer, Mahendra S. Rao The recent availability of human embryonic stem (ES) cells has sparked interest in the possibility that these cells can be differentiated in vitro, so that unlimited numbers of specific types of human CNS cells may be made available. Such cells may be useful for a variety of applications, including direct use in therapy. Differentiation of human ES cells into dopaminergic neurons is of particular interest, in part because of the many possible research applications, but especially because of the potential for transplantation into the brain in Parkinson‚s disease. This panel will consider the properties of human ES cells, differences between human and mouse ES cells, and the potential for use both as research tools and in therapy. Speak- ers from three laboratories which have recently reported on the differentiation of human ES cells into dopaminergic neurons will describe similarities and differences in their techniques and results. The speakers will describe effects of various cell substrates and growth factors, gene expression patterns, initial studies on the transplantation into the brains of rats and monkeys, and in vitro experiments on neurotoxicity and stimulated dopamine release. Speakers will consider the potential advantages and possible applications of these cells, but will also consider the obstacles and techni- cal difficulties which are related to the use of these cells in human therapy.

0Panel • Monday 7:30–9:30 AM • Peak 6–80

Mechanisms of Stress-Induced Plasticity Anthony Grace, Bita Moghaddam, Rita Valentino, Pier Vincenzo Piazza Maladaptive responses to stress are a major contributing factor to the development and treatment outcome of major psychiatric disorders. Understanding the underlying mechanisms of stress-induced plasticity is, therefore, fundamental to our understanding of how stress inﬂuences the disease process. Despite the critical nature of this topic and the surge of recent mechanistic ﬁndings, surprisingly little information has been presented in previous Biological Psychiatry meetings. The aim of this sym-

76 38th Annual Winter Conference on Brain Research posium will be to present an integrative view of some of the most recent findings on how those regions of the brain that are implicated in major psychiatric disorders respond and adapt to stress. Speakers and topics include: (1) Pier V Piazza (INSERM, Bordeaux) will discuss the genetic basis of individual differences in stress-related behavioral adaptation in mice.(2) Anthony Grace (University of Pittsburgh) will discuss the mechanisms that govern the plasticity and adaptation of amygdala neurons to acute and repeated stress, (3) Bita Moghaddam (University of Pittsburgh) will discuss the rapid plastic response of prefrontal cortex neurons to stress, and the impact of different environmental manipulations on this plasticity. (4) Rita Valentino (Children’s Hospital of Philadelphia) will compare stress- and opiate-induced plasticity of monoamine neurons. Although all the speakers will present basic data, the topics and are some of the most clinically relevant new data on stress-induced plasticity and, therefore, will be of interest to clinical researchers.

0Panel • Monday 7:30–9:30 AM • Peak 9–100

The Inextricable Relationship between Norepinephrine and Serotonin Gregory Ordway, Rick Lin, Pierre Blier, Irwin Lucki, Alan Frazer The putative roles of norepinephrine and serotonin in the pathophysiology and treatment of psychiatric disorders has received enormous attention over the past 50 years. Prior to the “invention” of selective serotonin uptake inhibitors (SSRIs), norepinephrine held a prominent role in the presumed pathophysiology of affective disorders, particularly depressive disorders. In the 1980‚s, the rapid rise in popularity of SSRIs for the treatment of depression led to an awakening of the importance of serotonin in brain function. That SSRIs are selective in terms of their effects on the serotonergic system relative to the noradrenergic system is a bias that has been perpetuated against considerable argument. Anatomical, physiological, and pharmacological evidence demonstrates that norepinephrine and serotonin systems are inextricably connected such that translation of pharmacological selectivity to physiological selectivity is difficult, if even possible. This panel will examine the intimate relationship between norepinephrine and serotonin systems in the brain. Rick Lin will discuss anatomical relationships between central noradrenergic and serotonergic nuclei, including recent findings of locus coeruleus projections to specific subnuclei of the dorsal raphe. Pierre Blier will discuss functional interactions between the locus coeruleus and

January 23–28, 2005 • Breckenridge, Colorado 77 dorsal raphe nuclei, including recent data demonstrating mixed noradrenergic/serotonergic actions of pharmacologically selective drugs. Irwin Lucki will address interactions between these transmitters at the level of functional output, i.e. behavior, including recent data demonstrating a permis- sive role of norepinephrine on SSRI-induced behavioral and neurochemical eﬀects. Finally, Alan Frazer will critically evaluate how laboratory demon- strations of norepinephrine-serotonin interactions translate to signiﬁcance in the realm of human behavior and therapeutics.

0Panel • Monday 4:30–6:30 PM • Peak 11–120

New Research Perspectives on D1 Receptors Larry Siever, E. Christopher Muly, Graham Williams, Stacey Castner D1 receptors play a critical role in cognitive functions mediated by prefrontal cortex and new data from neuroanatomical, molecular biological, imaging, cognitive, and clinical studies in primates and humans shed light on how this receptor generates signals and modulates prefrontal circuitry and cognitive function. Chris Muly has studied D1‚s effects on signal transduction proteins including isoforms of protein phosphataseˆ1 and their scaffolding proteins, spinophilin and neurabin. While the D1 receptor is present in both pyramidal cell spines and interneuron dendrites, the signal transduction milieu available to D1 differs in these two cell types. Local- ization of the PP1 isoforms in dendritic spines is modulated by chronic haloperidol and cocaine treatment. Graham Williams will focus on cellular correlates of D1 modulation of prefrontal circuitry in cognition and particularly its inhibitory effects in cortex. His latest findings suggest that D1 regulation of functional connectivity has a direct impact on the strength of pyramidal cell memory fields. Stacey Castner will focus on behavioral /cognitive correlates of D1 modulation of prefrontal function with an emphasis on sensitization of this receptor for treating cognitive deficits in hypodopa- minergic states. New FDG-PET data antagonist treatment will be presented. Larry Siever will discuss new measures of D1 binding in the schizophrenia spectrum suggesting increased D1 receptor number and new analyses of the effects of pergolide, a mixed D1/D2 agonist in these patients suggesting improvement in baseline working memory impairment and verbal learning following pergolide.

78 38th Annual Winter Conference on Brain Research 0Panel • Monday 4:30–6:30 PM • Peak 140

Matrix Metalloproteinases, Integrins, Rafts and Neurotransmitters: What Do They Have to Do with Oligodendrocyte Migration and Maturation? Wendy Macklin, Wia Baron, Babette Fuss, Wee Yong Oligodendrocyte progenitor cells arise in restricted germinal areas of the CNS, and migrate significant distances in the developing brain. When they reach their target destination, they differentiate and elaborate myelin sheaths around axons. How this migration and subsequent differentiation are regulated has been the subject of extensive investigation. These studies may be relevant for developing remyelination strategies in adult pathologies, such as multiple sclerosis. The current session focuses on the interaction of oligodendrocyte proteins, the extracellular matrix (ECM) and the environment in regulating myelination. Oligodendrocyte progenitor cells express a limited set of integrins, and their interactions with the ECM are controlled by integrin signaling. Dr. Macklin will discuss the potential of neurotransmitters to modulate oligodendrocyte migration, through an av integrin/myelin proteolipid protein complex. Dr. Baron will discuss the importance of ECM, sulfatide and membrane microdomains in regulating integrin-growth factor interactions, which are important regulators of oligodendrocyte development and function. Dr. Fuss will discuss the role of phosphodiesterase Iá, (PD-Iá/ATX) as a matricellular protein, which antago- nizes the adhesion between oligodendroglial cells and ECM molecules. This protein is released, presumably through a metalloproteolytic mechanism, and modulates focal adhesion kinase-dependent integrin signaling. Dr. Yong will discuss the role of matrix metalloproteinases (MMPs) in oligodendrocytes during development in this same environment. MMP-9 is essential for oligodendrocyte process extension, and may act by reducing adhesion to the ECM. The data discussed in this session should provide important insight into the regulatory mechanisms of oligodendrocyte interactions with the ECM.

0Panel • Monday 4:30–6:30 PM • Peak 150

Beyond Microarrays: The Involvement of Neuronal Plasticity in Pain Processing and Neuroprotection John Quinn, Andrew Russo, Ross Kinloch, Sandip Biswal Dynamic changes in gene expression occur as a result of nerve injury or dysfunction. The challenge is to determine better pharmaceutical intervention from a greater understanding of the basic mechanisms that regulate

January 23–28, 2005 • Breckenridge, Colorado 79 this expression. Russo will outline how CGRP triggers release of cytokines and inflammatory agents during neurogenic inflammation. Delivery of viral vectors to the trigeminal ganglion for modulating, measuring and regulating neuronal gene activity will be discussed including use of a CCD camera to directly detect gene expression. Quinn will discuss the temporal regulation and interplay of the transcription factor REST/NRSF (Neuron restrictive silencer factor) with NO and Activity Dependent Neuroprotec- tive Protein (ADNP) in response to injury in the DRG and hippocampus. Kinloch will demonstrate how plasticity of expression of the calcium channel alpha2delta-1 subunit may contribute to the development and maintenance of neuropathic pain. He will present evidence supporting alpha2delta-1 subunit auxiliary subunit as the pharmacological site of action of Pregabalin in preclinical models of neuropathic pain. This will be complemented with studies addressing alpha2delta-1 expression in the same models. Biswal is following in vivo nociceptive processing using molecular imaging techniques including PET/CT, SPECT/CT, and optical (bioluminescence/fluorescence) to monitor gene expression in transgenic mice or from virus vectors with appropriate promoter constructs. Alter- natively optical/radioactive labelling of ligands of interest (e.g. Sub P and opiates) can be used and image their biodistribution in animal models of pain/inflammation.

0Panel • Monday 4:30–6:30 PM • Peak 170

Multiple Sclerosis: New Insights into Axonal- Oligodendroglial Signaling, Markers of Disease Progression, and Novel Approaches for Therapy George De Vries, Sara Becker-Catania, Anne Boullerne, Karen Chandross, Douglas Feinstein Multiple sclerosis (MS) is complex autoimmune disease with progressive demyelination characterized by reoccurring episodes of demyelination, inflammation, and remylination. Axonal damage and subsequent neurodegeneration contribute to the progressive nature of the disease. This panel will present diverse approaches to better understand factors affecting oligodendrocyte biology, the use of biomarkers predictive of the disease course, and potential strategies for endogenous repair and immunomodu- latory MS therapy. Sara Becker-Catania will present data showing soluble factors released from the axonal plasma membrane signal to oligodendrocyte progenitors (OPC) affecting proliferation, differentiation, and survival. Morphologic and immunocytochemical characterization as well as changes in MAP kinase expression support the role of growth factors in modulating OPC activity and maturation. Anne Boullerne will describe evidence

80 38th Annual Winter Conference on Brain Research that increased levels of circulating anti-SNO (S-nitrosocysteine) antibodies precede the onset of experimental autoimmune encephalomyelitis (EAE). Elevated anti-SNO levels in sera from MS patients may serve as a predictive biological marker for both the onset and severity of clinical episodes of the disease. Karen Chandross will present target and validation approaches to identifying pathways that direct progenitor cell expansion, migration and diﬀerentiation, and will discuss how small molecules can be used to target resident progenitor cells of the diseased adult brain for regeneration-based therapy currently being tested in animal models of human MS. Finally, Doug Feinstein will present data showing that oral administration of peroxisomal proliferator-activated receptor (PPAR) agonists ameliorate the clinical progression in EAE as well as suppress proliferation of MS-derived T lymphocytes and will discuss their potential use as therapeutic agents.

0Panel • Monday 4:30–6:30 PM • Peak 6–80

Neuroscience Funding Opportunities and Basic Research Priorities at NIH Kim Pham, Michael Weinrich, Steven Snyder, Laura Mamounas, Ernie Lyons, Minda Lynch, Kathleen Anderson, Beth-Anne Sieber This workshop will provide information for researchers at all stages of their careers about the different funding opportunities and current research priorities in basic neuroscience at NIH. Program and review officers from several institutes within NIH will discuss funding objectives, specific initia- tives, and trans-NIH activities including the NIH Roadmap. Ample time will be allotted for questions from the audience.

0Panel • Monday 4:30–6:30 PM • Peak 9–100

Neuroinflammation: When, Where and How does it contribute to Degeneration? Fulton Crews, Jau-Shyong Hong, Susanna Rosi, Stephen C. Bondy Increasing evidence suggests that neuroinflammation contributes to a variety of brain diseases. Neurodegeneration is associated with neuroinflammation, however, inflammation is often considered the result of degeneration as apposed to the cause. This panel will present studies suggesting that neuroinflammation my be a key causal process in neurodegeneration. J.S. Hong (NIEHS) will present studies on „Inflammation- mediated Degeneration of Dopaminergic Neurons: Models, Mechanisms, and Therapeutic Interventions for Parkinson‚s Disease‰ that include

January 23–28, 2005 • Breckenridge, Colorado 81 new rodent Parkinson‚s disease (PD) models that mimic the delayed and progressive disease development in PD patients. Studies elucidating the mechanisms regulating the activation microglia, their role in mediating neuroinflammation and neurodegeneration and the development of innovative anti-inflammatory therapy for PD will be presented. S. Rosi (UA) will present studies on a neuroinflammatory model of Alzheimer‚s Disease. Endotoxin infusion into brain results in cognitive deficits, selective neurodegeneration and alterations in hippocampal NMDA receptors and immediate early gene expression that likely contribute to cognitive dysfunction. Steve Bondy (UCI) will present a talk entitled “Elevated CNS Inflammation after Exposure to Environmental Factors” Neuropathological and biochemical studies relating to colliodal metals, and brain inflammation will be presented. F.T. Crews (UNC) will present studies relating systemic cytokines to brain inflammatory responses, cytokine induced changes in glutamate neurotoxicity and neurodegeneration as well as disruption of neurogenesis. Together these studies will promote the provocative concept that neuroinflammation is a major contributor to neurodegenerative disease, particularly those associated with aging.

0Panel • Monday 8:30–10:00 PM • Peak 11–120

Run to Save Your Brain: How Exercise Enhances Cognitive Function Fernando Gomez-Pinilla, Monika Fleshner, Arthur Kramer, Amelia Russo- Neustadt Exercise has long been perceived as a good predictor of improved neural faculty. Yet it is only recently that the effects of exercise on specific brain functions and mechanisms have started to be elucidated. We are now in a realistic situation to implement therapeutic strategies aimed at harnessing the benefits of exercise on reducing the consequences of neurodegenerative diseases and functional loss following CNS injury. Arthur Kramer will review the results of cross-sectional and longitudinal studies in humans showing the capacity of exercise to improve specific cognitive abilities. Evidence exists that hippocampal degeneration is an important part of the pathophysiology of chronic depression, and that severe and prolonged stress may be a direct cause of this pathology. Amelia Russo-Neustadt will discuss how exercise practice can synergize with pharmacological interventions to decrease clinical depression. Monika Fleshner will describe the results of studies that demonstrate a protective effect of chronic voluntary exercise on stress-induced emotional dysregulation (learned helplessness). These findings suggest that exercise produces a stress-resistant brain. Select neurotrophins such as BDNF and its interaction with neurotrans-

82 38th Annual Winter Conference on Brain Research mitter systems are emerging as crucial underlying factors for the eﬀects of exercise on the brain. Fernando Gomez-Pinilla will discuss some of the molecular mechanisms by which exercise can promote cognitive enhancement, involving the action of select neurotrophins on synaptic plasticity. Discussion will focus on the crucial role of an active lifestyle to increase neural plasticity and to promote a healthy brain.

0Workshop • Monday 8:30–10:00 PM • Peak 140

Function Follows Form: From Molecule to Mind Vladimir Parpura, Sabina Hrabetova, Glenn Hatton, Daniel Silverman The view that function follows form dates back to the Romans. Galen tried to deduce brain function from the physical properties of the cerebrum and the cerebellum by poking them with his finger; softer cerebrum was assigned to be the recipient of sensation, while the harder cerebellum he thought commanded the muscles. Although nearly 20 centuries later his reasoning may appear dubious, he was not too far from the truth. In the proposed workshop all speakers will explore relationships between brain‚s form and function using contemporary tools. Our journey will start from molecular level, where Dr. Parpura will discuss the insights into the process of vesicular docking by studying single molecular interactions between proteins of the SNARE complex using Atomic Force Microscopy and nanomechanics. Next, Dr. Hrabetova will discuss changes in the extracellular space as a conduit for molecular signals (volume transmission) using diffusion analysis. Dr. Hatton will discuss reversible plastic cellular changes in astrocyte morphology and juxtapositions with neighboring neurons in response to physiological stimuli in the magnocellular hypo- thalamo-neurohypophysial system of the rat. Dr. Silverman will discuss monitoring microstructural and functional changes with positron emission tomography in patients suffering from cognitive impairment. Together, these speakers will provide a view of the form-function relationship within mammalian brain ranging from molecule to mind.

0Panel • Monday 8:30–10:00 PM • Peak 150

Beyond the “Amines” in Amphetamines Bryan Yamamoto, Kristen Ashley Horner, Jacqueline McGinty, Gary Gudelsky Research on the substituted amphetamines has focused traditionally on the monoamines to the relative exclusion of other possible mediators of the acute and long-term consequences of these abused drugs. However,

January 23–28, 2005 • Breckenridge, Colorado 83 emerging new data indicate that there is more to the amphetamine psychostimulants than just monoamines. This panel will address the neglected but increasingly important and novel roles of the opiates, growth factors, nitric oxide, glutamate, and tyrosine in mediating the acute and long-term effects of the substituted amphetamines. Ashley Horner will address the hypothesis that mu opioid receptors in the striatum contribute to psycho- stimulant-induced increases in dynorphin expression in the striatal patch compartment and may underlie the expression of stereotypical behavior seen with some psychostimulants. Jakie McGinty will discuss the toxic effects of methamphetamine in GDNF+/- and BDNF+/- mice. Her data indicate that a combination of methamphetamine and reduced neurotrophic factor expression results in a more profound insult to dopaminergic neurons than either insult alone. Gary Gudelsky will discuss his recent findings implicating nitric oxide and reactive nitrogen species in the neurotoxic effects of MDMA. Finally, Bryan Yamamoto will present a new model and supporting data that highlight how increases in tyrosine could mediate the neurotoxic effects of MDMA to 5HT neurons while addressing the caveat of how dopamine-derived oxidative stress can occur in non-dopaminergic brain areas. The breadth and scope of coverage will attract an audience from a variety of disciplines and will prompt lively discussion.

0Panel • Monday 8:30–10:00 PM • Peak 6–80

AMPA Receptor Trafficking and Synaptic Plasticity: Role and Importance of Subunit Specific Mechanisms John Isaac, Jon Hanley, Roberto Malinow, Roger Nicoll There is currently intense interest in the mechanisms by which AMPA receptors are trafficked around neurons. It is hypothesised that this rep- resents a major class of mechanism for the expression long-term potentiation (LTP) and long-term depression (LTD). A considerable number of AMPA receptor interacting proteins have been identified that are involved in trafficking mechanisms associated with LTP and LTD. A common theme is that these proteins bind specific subunits that AMPA receptor subunit- specific rules exist for the trafficking of receptors during synaptic plasticity. However, proteins that interact in a non-specific fashion with all subunits have also been identified and shown to play a major role in plasticity expression mechanisms. The challenge now, and the focus of this session, is to understand the relative importance of these two types of competing mechanisms and to elucidate the spatiotemporal interactions between these processes. Robert Malinow will present evidence that subunit specific rules govern the insertion of AMPA receptor subunits during LTP

84 38th Annual Winter Conference on Brain Research in hippocampus and barrel cortex. Jon Hanley will present biochemical evidence that certain AMPA receptor interactoring proteins act as calcium sensors during synaptic plasticity providing a potential molecular mechanism transducing calcium influx into the expression of synaptic plasticity. John Isaac will present recent findings on the role of the PICK1-GluR2/3 interaction in regulating synaptic strength during LTP and LTD. Roger Nicoll will summarise his recent work on the role of TARPs in regulating AMPA receptors in a mechanism not specific to particular subunits.

0Panel • Monday 8:30–10:00 PM • Peak 9–100

Models of Injury Induced Reorganization in the Somatosensory Neuraxis Richard Lane, Charles Pluto, Robert Waters, Douglas Rasmusson Recovery from peripheral nerve injury as well as various pathological sequelae such as phantom sensations and hyperalgesia have been linked to reorganization of the somatosensory system. Numerous studies have demonstrated a variety of changes in the somatosensory system in response to peripheral nerve injury. The relative contribution of subcortical versus cortical mechanisms in defining cortical reorganization and the cellular mechanisms underlying acute versus chronic reorganization are controversial issues in this field. This panel will focus on recent studies that examine the effects of forelimb amputation in the rat and digit amputation in the raccoon. Analysis of the data from these studies has engendered the development of neuronal circuitry models to explain specific types of reorganization. Ric Lane will present an overview of this topic and introduce the speakers. Charlie Pluto will discuss a model of cortical circuitry involving GABAergic suppression of receptive field information from adjacent body representations in primary somatosensory cortex (S-1) of neonatally amputated rats. Bob Waters will discuss a model system to explain delayed- large-scale reorganization in the forepaw barrel subfield (FBS) in S-1 cortex that involves GABAergic modulation of subcortical circuitry in the thalamus and cuneate nucleus. Doug Rasmusson will present evidence for both cortical and subcortical reorganization in the raccoon. These presentations will emphasize the key role that GABAergic modulation of receptive field information plays in the multi-level response of the sensory neuraxis to peripheral injury.

January 23–28, 2005 • Breckenridge, Colorado 85 0Panel • Tuesday 7:30–9:30 AM • Peak 11–120

What Evolution Can Teach Us about Nervous System Function Paul Katz, Larry Young, Heather Eisthen, Kenneth Catania Neural circuits and brain pathways did not evolve explicitly for their current functions. Understanding the evolutionary history of a brain region and comparing its behavioral role in different species can provide information about fundamental organization principles. There are three situations that will be examined in this session: Divergent, Convergent, and Parallel evolution. In divergent evolution, differences emerge in the functioning of homologous brain areas that lead to differences in the behavior of closely related species. Larry Young will speak about how differences between rodent species in the promotor regions of genes encoding vasopressin and oxytocin receptors leads to differential expression of these receptors in homologous brain areas, resulting in differences in affiliative behaviors. In convergent evolution, non-homologous structures take on similar functions in diverse species. Heather Eisthen will discuss an example of convergent evolution in the organization of olfactory systems across very diverse phyla and Ken Catania will talk about convergence in the functional organization of the somatosensory system of the star-nosed mole and the visual systems of other mammals. In parallel evolution, homologous structures come to have similar functions in separate lineages. Paul Katz will explain the evidence that homologous identified neurons in sea slugs have independently evolved to have the same function. These talks will all highlight how understanding the evolutionary history can help explain the current functioning of neural pathways.

0Panel • Tuesday 7:30–9:30 AM • Peak 140

Translational Research in PD: Can We Really Go from Lab Bench to Bedside? Margie Ariano, David Standaert, Tim Greenamyre, Jeff Bronstein, Karl Kieburtz Levodopa is the most potent therapy available for Parkinson’s disease (PD), but long term use in patients is limited by the development of “motor complications” such as on/off and dyskinesias. This has driven an aggres- sive search for alternative therapies. This panel will examine translational research in PD and how basic laboratory findings can be formulated into effective treatments for patients or NOT. David Standaert will provide information on the role of striatal NMDA receptor trafficking mechanisms that are altered in experimental PD and how treatments targeted to the NMDA

86 38th Annual Winter Conference on Brain Research receptor may be forthcoming in PD therapy. Tim Greenamyre will present the rotenone model of PD and how it may be used to screen potential neuroprotective strategies for their eﬃcacy in reducing cellular changes in PD models, leading to alternative treatment of patients. Jeﬀ Bronstein will discuss the association of PD predisposition in humans after pesticide exposure through the mechanism of proteasome inhibition, and if this can be implemented as a novel therapy. Karl Kieburtz has designed many of the multi-centered clinical trials for basal ganglia disorders and will consider how animal and human experimental designs can be improved to result in more successful translation of therapeutic interventions from animals to patients.

0Panel • Tuesday 7:30–9:30 AM • Peak 150

Plasticity of Auditory Neurons Leonard K. Kaczmarek, Katrina M. MacLeo, Ian D. Forsythe, Karina Cramer Neurons within auditory brainstem nuclei detect differences in the level or timing of interaural stimuli. Processing of sensory information by neurons in these nuclei is usually considered to be fixed. Recent work has shown, however, that the intrinsic electrical properties of such neurons and their ability to release neurotransmitter can be modified very rapidly by sound stimuli and by synaptic inputs. This panel will discuss how changes in protein phosphorylation, synaptic plasticity, and signaling through the Eph family proteins produces both rapid short-term, and long-lasting changes in response properties and connectivity of auditory neurons. Katrina MacLeod will describe how short term synaptic plasticity in avian neurons allows these neurons to encode information about the absolute sound levels during ongoing activity. Len Kaczmarek will present data on the ability of auditory stimuli to produce rapid changes in the phosphorylation state of the Kv3.1 potassium channel, thereby adjusting neuronal excitability for optimal accuracy of timing at different ambient sound intensities. One attractive feature of these nuclei in mammals, and their counterparts in birds, is that auditory inputs are organized tonotopically with neurons at the medial end of the nuclei receiving input corresponding to the highest frequency sounds. Ian Forsythe will discuss how the processing of auditory inputs differs along the tonotopic axis, and how these differences in processing can be explained by differences in potassium channels and non-selective cation channels. Finally Karina Cramer will present data on the role of Eph proteins in the establishment and maintenance of these tonotopic gradients.

January 23–28, 2005 • Breckenridge, Colorado 87 0Panel • Tuesday 7:30–9:30 AM • Peak 170

Dissecting and Visualising the Molecular Basis of Neural Development and Regeneration Malcolm Maden, Esther Bell, David Chambers, Jonathan Clarke Modern molecular analyses are beginning to discover novel genes involved in the complex processes of neural development and regeneration. These analyses have progressed from simply cloning Drosophila homologues, as was common several years ago, to using microarray analysis to identify the full panoply of gene expression. We are beginning, therefore, to assemble complex gene pathways that are involved in neural induction, in later aspects of development and in neural regeneration. But how are we to identify the important players and how do we analyse their function? This workshop will discuss three approaches to this problem. One is to choose specific neural inducers and look at their gene targets. A second approach is to compare the genes identified from arrays of neural induction with those from neural development with those from neural regeneration. It is a widely held view that regeneration recapitulates development and this concept can now be tested. The third approach is to use modern imaging techniques to examine the dynamic behaviour of candidate neuronal genes both during development and regeneration to ensure that their behaviour is consistent with array data. Ester Bell has investigated the molecular basis of neural induction in Xenopus laevis using a microarray screen to identify the downstream targets of Smad7. This has resulted in the identification of novel players involved in neural induction and anterior patterning. David Chambers has used a microarray screen of individual developing rhombomeres from the hindbrain and the midbrain of the developing mouse embryo. He will discuss the identity and location of positionally unique genes as well as whether there is any overlap with neural induction genes. Malcolm Maden has used microarrays to identify gene targets of the retinoic acid receptor b which, when transfected into the adult rodent spinal cord induces neural regeneration. Are there any gene targets in common with these regeneration experiments and the development studies? Jon Clarke will discuss the use of the isl1-GFP transgenic zebrafish line to study questions of neural development and regeneration and how this experimental system could be used to analyse candidate genes identified in microarray screens.

88 38th Annual Winter Conference on Brain Research 0Panel • Tuesday 7:30–9:30 AM • Peak 6–80

Why Stressed Adolescent Males Should Not Become London Cab Drivers: The Differential Effects of Glucocorticoids and Stress over Development, Sex and Brain Region Brenda Anderson, Cheryl Conrad, Cheryl McCormick, Cara Wellman Stress and glucocorticoids, steroids released during stress, are known to affect behavior and hippocampal neuronal morphology. Recent evidence from rodents suggest that behavioral and structural effects of stress and glucocorticoid exposure may be moderated by a variety of factors, including age, sex, and brain region, and that the relationship between morphological change and behavioral alterations may be more complex than previously suggested. The panel will introduce the audience to these new findings. McCormick will describe the effects of stress in adolescence on adult drug-related behavior and stress responses in male and female rats. Conrad will discuss the effects of chronic stress in adult male rats, demonstrating the traditional parallel between hippocampal morphology and function. Then, she will present recent findings showing that stress-induced hippocampal CA3 dendritic retraction is disconnected from memory impairment when the task is highly aversive or when females are used. Anderson will describe the effects of chronically elevated corticosterone on spatial memory, symptoms associated with depression and CA3 synapse numbers. Wellman will describe how dendritic morphology in medial prefrontal cortex is exquisitely sensitive to chronic stress, and how the dendrites are dramatically remodeled after as little as one week of daily 10-minute restraint stress. Glucocorticoids are chronically elevated in a number of neuropsychological disorders, making the relationship between these steroids and neuronal structure and behavior of concern.

0Panel • Tuesday 7:30–9:30 AM • Peak 9–100

Nominations for Astro- and Micro-Glia as Best Supporting and Leading Actors in “The Neurodegeneration Story” Richard Smeyne, Jeﬀ Johnson, Greg Cole, Jim Morgan Glial cells play more than a supporting role in the physiology and structure of the normal nervous system. Moreover, accumulating evidence indicates that these cells can also play a leading role in both adaptive and maladaptive responses in the brain, and thereby contribute to neurode-

January 23–28, 2005 • Breckenridge, Colorado 89 generation. This Panel will discuss current research aimed at illuminating the critical role played by glia in the pathophysiology of Parkinson‚s (PD) and Alzheimer‚s (AD) diseases and Amyotrophic Lateral Sclerosis (ALS). Richard Smeyne will discuss the role that astrocytic architectonics plays in determining toxin susceptibility in an animal model of PD. He will also discuss in vitro studies showing that manipulation of glial cell number alters a neuron‚s ability to survive an MPTP-induced oxidative insult. Jeﬀ Johnson will describe data showing that Nrf2-dependent activation of the antioxidant response element (ARE) and subsequent increased expression of the ARE-driven gene cluster in astrocytes protects neurons from oxidative stress-induced apoptosis. The potential utility of this astrocyte-derived pathway in slowing neurodegenerative diseases such as ALS and PD will be discussed. Greg Cole will cover the active roles of glia as both protectors and eﬀectors in neurodegeneration and lesions associated with AD. Inte- grating in vitro, animal model and pathology data, he will discuss whether overacting glia should be more inhibited or simply need better direction. Using microarray analyses in normal and mutant mice in response to environmental neurotoxins, Jim Morgan will present a transcriptome-based approach to elucidate both common and unique mechanisms in glia that contribute to the parkinsonian condition.

0Panel • Tuesday 4:30–6:30 PM • Peak 11–120

Opioids, Neuroplasticity, and Addiction: What’s Hot? Jacqueline McGinty, Christopher Evans, Gary Aston-Jones, Peter Kalivas, James Frost The analysis of opioid receptors and the use of a variety of selective alkaloid and peptide ligands have yielded many insights into drug reward and addiction. We will present hot, new data from analyses of opioid receptor complexes and studies of opioid circuitry and neuroplasticity in animal and human addictive processes. After a brief introduction by Jakie McGinty, Chris Evans will present evidence from convergent areas of receptor research, including signaling, oligomerization and trafficking, that encourages visualizing opioid receptors, not as isolated units in the membrane, but as dynamic heterogeneous complexes that could offer novel pharmacological targets. Gary Aston-Jones will present novel data on drug seeking during protracted morphine withdrawal and altered activity of neurons in amygdala, hypothalamus and cortex. His results indicate that prior morphine dependence has prolonged effects on the motivation for drug and natural rewards, which in turn may compromise the ability of former addicts to overcome their addictions. Peter Kalivas will present new data indicating that selective blockade of mu opioid receptors in the

90 38th Annual Winter Conference on Brain Research ventral pallidum, but not in the nucleus accumbens, decreases cocaine- primed reinstatement and reverses cocaine-induced decreases in extracellular GABA levels in ventral pallidum without aﬀecting locomotor activity or responding for food. Jim Frost will discuss PET studies that demonstrate a strong functional relationship between alcohol and cocaine craving, regional brain mu-opioid receptor binding, and relapse. At the end, we will discuss the implications of these data for opioid receptor plasticity processes underlying drug craving and addiction and the potential for brain molecular imaging to reveal those processes in drug development studies and clinical trials.

0Panel • Tuesday 4:30–6:30 PM • Peak 140

Decisions, Decisions: Orbitofrontal Cortex as an Arbiter of Reward Choices Ronald See, Suzanne Haber, Carl Olson, Karen Bolla The orbitofrontal cortex (OFC) has been characterized as a critical component of the functional neuroanatomy of emotion and decision making based on reward values. Using novel animal models and advanced brain imaging, OFC function is being explored with greater precision and across a wider range of emotive processing paradigms. Determination of the neurobiology and behavioral relationships of the OFC will advance our understanding of basic cognitive processing, as well as maladaptive conditions, including addiction, memory dysfunction, and psychosis. This panel brings together a unique assemblage of data from different experimental approaches focused on the OFC and its role in various appetitive behaviors in rats, primates, and humans. Suzanne Haber will begin with an overview of OFC neuroanatomy and the functional relationship of the OFC with the basal ganglia and thalamus. Ronald See will present evidence showing the critical role of OFC subregions in reinstatement of cocaine-seeking behavior in a rat model of relapse. Using electrophysiological techniques, Carl Olson will show that the activity in the OFC in the macaque brain repre- sents the value of an expected reward. Karen Bolla will present findings showing changes in cerebral blood flow in the OFC in abstinent cocaine and marijuana abusers during decision-making. The panel and ensuing discussion will appeal to WCBR attendees interested in cognition, cortical physiology, motivation, learning, and addiction.

January 23–28, 2005 • Breckenridge, Colorado 91 0Panel • Tuesday 4:30–6:30 PM • Peak 150

I Had a Dream Last Night—Useful Molecular Biology for in vivo System Neurophysiology— What a Lovely Dream It Was Ralph Siegel, Ehud Isacoff, Edward Callaway, Edward Lein Molecular biology has held out a promise of breaking open some of the deeper conundrums of system physiology for years. Instead of massive ablation lesions or gross pharmacological manipulation, we were promised pinpoint accuracy in selecting target neurons to remove from circuits, fine manipulation of single neuron genetics would allow us to visualize cellular biochemistry as development and plasticity altered the operation of circuits. But what happened were bewildering papers in cell culture or in vitro systems that seemed to overwhelm our favorite journals-- indeed a crucial and well received first step, but a long ways from the dream. A favorable cross-disciplinary alignment of viral delivery systems, arrays of promoters, ligand binding systems, and new fluorescence sensors have conspired to perhaps breakthrough to the other side: molecular biology really applied to in vivo physiology. Ed Lein uses cell type specific targeting of gene expression, an essential component of studies using molecular and genetic methods, to probe and manipulate the organization and function of the CNS. Methods based on laser capture and gene chip analysis successfully identify genes expressed in specific subregions of the hippocampus and in specific layers of the cerebral cortex, and are verified by in situ hybridization. Ehud Isacoff, a biophysicist by trade, has developed a range of rationally designed fluorescence sensors that can be used to assess membrane potential, calcium at the post-synaptic density, and the formation of new synapses. Trafficking proteins are used to guide the newly synthesized fluorescence proteins to targets. Edward Callaway, formally known as a neuroanatomist, has designed novel genetic methods to selectively and reversibly inactivate specific cell types. To understand the role of numerous cell types with spatially intermingled dendrites and axons in the LGN, the drosophila allatostatin receptor (AlstR) was expressed in mammalian neurons. When activated by its ligand, allatostatin, G protein mediated opening of potassium channels occurs eliminating both spontaneous and visual stimulus-evoked activity in LGN of ferrets and monkeys.

92 38th Annual Winter Conference on Brain Research Ralph Siegel, once an electrophysiologist, will describe the incorporation of one of Isacoﬀ‚s ﬂuorescence voltage sensors into neurons in rat and monkey cortex, permitting the two-photon imaging of the activity of individual neurons in vivo.

0Panel • Tuesday 4:30–6:30 PM • Peak 170

Diet and Exercise: What happens to My Brain? Fulton Crews, Carl Cotman, William T. Greenough, Jim Joseph, Donald K. Ingram F. T. Crews (UNC) will introduce the session with a short review of human and non-human studies on exercise, alcohol and diet effects on cognition, mood and neuroplasticity related to functional and structural changes in adult brain. The panel speakers will follow with detailed cutting edge animal studies. Carl Cotman (UCI) will present studies on the effects of exercise on brain gene expression including: the promoter CREB, the gene BDNF, and how changes in gene expression relate to measures of learning ability and how age related changes in brain are altered by exercise. Bill Greenough (UI) will present a talk entitled “Plasticity cuts both ways: Posi- tive and pathological environment effects on the brain.” Studies on brain neuroplasticity, synaptogenesis, and angiogenesis responses to enriched environments, alcohol and exercise will be presented. Jim Joseph (Tufts) will discuss the effects of dietary anti-oxidants found in fruits and veg- etables on adult neurogenesis, as well as age related declines in learning and motor ability. Don Ingram (NIA/NIH) will review studies on dietary restriction and dietary restriction mimetics, on brain gene expression, morphology and behavior. Together these studies will provide insight into the beneficial effects of exercise and certain diets on trophic factor expression and signaling that appear mediate many of the beneficial effects of these positive behaviors.

0Panel • Tuesday 4:30–6:30 PM • Peak 6–80

No Sugar, No Enlightenment: Metabolic Signaling in the CNS Dianne Lattemann, Barry Levin, Kevin Niswender, Nicole Sanders, Ewan McNay The ability of glucose and other metabolites to modulate electrical activity of speciﬁc neuronal populations in the CNS has been known for several decades, and more recently the convergence of metabolic signals with

January 23–28, 2005 • Breckenridge, Colorado 93 other inputs such as insulin and leptin has been identified. With increasing incidence of diabetes and obesity, the relevance of this interactive CNS signaling is now becoming appreciated: Metabolic signaling plays important roles throughout the CNS, and is neither limited to the hypothalamus, traditionally considered the main CNS target for such signaling, nor to direct electrophysiological effects. In this panel we will provide an update of cellular and behavioral evidence for the roles of glucose (and other metabolic signals), insulin, and leptin, signaling in the CNS. Dianne Lattemann will provide a brief introduction and overview. Barry Levin will discuss hypothalamic glucose-sensing neurons and their role in food intake and as potential integrators of metabolic sensing. Kevin Niswender will build upon this with discussion of the integration of insulin and leptin signaling with several types of metabolic signals and intracellular signaling pathways. Nicole Sanders will discuss brainstem glucose-sensing neurons and hindbrain/forebrain interaction in the context of insulin-induced hypogly- cemia, and their crucial role in the emergency response to drops of blood glucose. Finally, Ewan McNay will review clinical and animal data on the effects of acute and chronic changes of glucose on cognition. The panel will emphasize how these signals may be modified by, or may contribute to, the pathology of obesity- and diabetes-related CNS dysfunctions.

0Workshop • Tuesday 4:30–6:30 PM • Peak 9–100

From Z(inc) to A(poptosis), a Zinc-along for Death by Heavy Metal Michael Bennett, Elizabeth A. Jonas, Elias Aizenman, Karen Gale Mechanisms of delayed cell death following neuronal insult are a subject of active inquiry. Zn2+ is required for mitochondrial release of cytochrome c induced by hypoxia (Jonas). Patch clamp recording from in situ mitochondria (squid giant synapse) and from mitochondria isolated from ischemic brain shortly after ischemia reveals large single channel openings, presumably in the inner membrane, that are inhibited by Zn2+ chelation. Inhibition of p38 MAP kinase protects cultured neurons against oxidative- and nitrosative-induced apoptosis (Aizenman). Cytoplasmic chelatable Zn2+, apparently released from intracellular stores by these insults, leads to an increase in K+ currents that is blocked by p38 inhibition and necessary for caspase-9 and -3 activation. The K+ current increase likely results from membrane insertion of Kv2.1 channels.

94 38th Annual Winter Conference on Brain Research Zn2+ mediates delayed CA1 neurodegeneration following global ischemia, since the Zn2+ chelater, CaNa2EDTA, is neuroprotective (Bennett). When administered i.c.v. just before global ischemia but not 3-6 h later, expression of caspase-3 and other apoptotic markers is blocked. Cytoplasmic chelatable Zn2+ is not detectable immediately after ischemia, but rises at ~ 72h, and CaNa2EDTA again becomes neuroprotective. Prolonged kainate induced seizures decrease presynaptic (chelatable) Zn2+, presumably secreted into the synaptic cleft, and increase chelatable Zn2+ in dying neuron somata (Gale). Seizure-exposed neurons are protected from cell death by preconditioning with noninjurious electroshock seizures. Does the Zn2+ still appear in protected neurons, i.e., does preconditioning prevent the rise in Zn2+ or protect against it? Workshop questions: Where does the chelatable Zn2+ come from? What does it do?

0Panel • Tuesday 8:30–10:00 PM • Peak 11–120

What’s Up with Ecstasy? Una McCann, George Ricaurte, John Mendelson, Leslie Jacobsen 3,4-Methylenedioxymethamphetamine (MDMA, “Ecstasy”) is a recreational drug of abuse that is a potent brain serotonin neurotoxin in animals. The relevance of preclinical neurotoxicity studies to humans is not yet clear, in part because studies in animals have typically involved drug administration regimens different than those used by humans. Nevertheless, several neuroimaging studies have found a reduction in serotonin transporters in the brains of MDMA users. Further, more than a dozen studies have documented that abstinent MDMA users have cognitive deficits, although the relationship between MDMA-induced serotonin neurotoxicity and cognitive dysfunction in MDMA users remains to be determined. This panel will focus on recent pharmacokinetic and neuroimaging studies that help bridge the gap between preclinical and clinical research on MDMA neurotoxicity. Dr. Ricaurte will present data from studies in non-human primates and humans that address potential pharmacokinetic differences between the two species, and that suggest some recreational MDMA users may engender neurotoxic plasma concentrations of MDMA. Dr. Mendelson will present data on the physiological, pharmacological and pharmacokinetic effects of MDMA in humans when administered in a controlled laboratory setting. Dr. Jacobsen will conclude the panel by reviewing neuroimaging evidence for MDMA-induced loss of serotonin transporters and presenting recent data from fMRI studies in adolescent MDMA users that provides evidence for alterations in brain function of abstinent MDMA users perform- ing a mnemonic task.

January 23–28, 2005 • Breckenridge, Colorado 95 0Workshop • Tuesday 8:30–10:00 PM • Peak 140

The Genomic Basis of Circadian Rhythms: DNA Microarray Analyses Gianluca Tosini, John Hogenesch, Giles Duffield, Vincent Cassone Several aspects of physiology and behavior are organized into daily 24 hr rhythms, driven by an endogenous circadian clock. The molecular mechanism responsible for the circadian oscillation is modeled around cell-auton- omous, autoregulatory transcriptional/post-translational feedback loops, in which protein products of clock genes Period and Cryptochrome periodi- cally oppose transcription driven by CLOCK:BMAL complexes. Advances in the last few years have demonstrated that the capability to generate circadian oscillations is not restricted to the master circadian pacemaker located in the Suprachiasmatic nuclei (SCN) of the hypothalamus but is widespread within the mammalian body. Until recently our knowledge about what proportion of the cellular transcriptome is regulated by circadian clock was very limited. Recent investigation using DNA microarray analysis have addressed these questions in a global fashion and identified rhythmically expressed genes in numerous tissues of rodents (SCN, pineal gland, liver, heart, kidney and retina). These clock controlled genes represent 1% of probed genes, with functional groups covering a large spectrum of cellular pathways. There is considerable tissue specificity, with only approximately 10% rhythmic genes common to at least one other tissue, principally consisting of known clock genes. The remaining common genes may constitute genes operating close to the clock mechanism or novel core clock components. The workshop will focuses on the similarity found between tissues and organisms, and on the connections between the molecular core oscillator and aspects of circadian physiology. Finally, the workshop will also address the limitations of the microarray technology and analyses, and suggests directions for future studies.

0Workshop • Tuesday 8:30–10:00 PM • Peak 150

Molecules That Make Patterns in the Developing Somatosensory System Mark Jacquin, Maria Donoghue, Robert Rhoades, Thomas Woolsey We are struck by the paucity of molecules currently known to have a speciﬁc function in mammalian CNS pattern formation. Semaphorins have been shown to control sensory aﬀerent growth into the spinal cord, but whether they perform this function in vivo is unclear. Thus, there is a clear need for molecular resolution of mechanisms dictating somatosensory

96 38th Annual Winter Conference on Brain Research development, especially in the whisker-barrel model system, which is a heavily published model system in mammalian neurobiology. A limited number of molecules have been shown to directly contribute to barrel-like pattern formation. This list includes NGF, serotonin, GAP43, NMDA NR1, FGF8, adenylyl cyclase type I, and ephrin-A5. In all of these studies, detailed background information on the whisker-barrel system has served to put structure, function, development, behavior, and interpreta- tions in a standard context. Most recently, members of this workshop have applied new, exciting and powerful genetic based approaches to the study of the whisker-barrel system. There are now exceptional opportunities to understand mechanisms underlying the formation of the mammalian nervous system. Mark Jacquin will introduce transcription factors that are necessary for specifying the central targets of the trigeminal ganglion, and that this specification is reflected in thalamic and cortical pattern formation. Maria Donoghue will discuss Eph receptor tyrosine kinases and their associated ligands, the Ephrins, which are known to be important in thalamocortical axon growth and cortical parcellation. Robert Rhoades will discuss mechanisms by which activation of a serotonin receptor induces excess growth in thalamocortical axons; one such mechanism may involve the Eph receptors. Thomas Woolsey will lead the general discussion and offer a synthesis on the progress made over the past 35 years in revealing mechanisms of whisker-barrel pattern formation.

0Workshop • Tuesday 8:30–10:00 PM • Peak 170

Amyloid-Beta Interactions with Nicotinic Receptors: Roles in Alzheimer’s disease? Ronald Lukas, Daniel Lee, Robert Nichols, Kelly Dineley The cholinergic hypothesis of Alzheimer’s disease remains viable given the clear loss of cholinergic neurons and nicotinic acetylcholine receptors in the disorder and has been a focal point for early disease therapies. However, the amyloid-beta deposition hypothesis dominates current thought about disease etiology and treatment. Is there a way to reconcile and link these hypotheses? Participants in this workshop first will briefly present their own findings relative to interactions between amyloid-beta and nicotinic receptors. Then, all of the speakers and the audience will discuss these observations as well as other pieces of evidence regarding cholinergic modulation of amyloid precursor protein processing and novel means of signal transduction through amyloid-beta. Excitement about nicotinic receptor-amyloid

January 23–28, 2005 • Breckenridge, Colorado 97 beta interactions was stimulated by initial findings of Daniel Lee, Hoau-Yan Wang, and colleagues, and Dr. Lee will discuss their evidence for interactions based on ligand binding nand signal transduction studies. Bob Nichols will present results from his studies and relate them to possible function of presynaptic nicotinic receptors. Kelly Dineley will describe her findings relating to amyloid-beta interactions with nicotinic receptors andreceptor subunit peptides. Ron Lukas will present data obtained in collaboration with Jie Wu defining nicotinic receptor subtype selectivity of amylopid-beta functional effects. Because a consensus does not exist about some fundamental experimental observations, vigorous debate about experimental conditions and causes for discrepant findings is expected.

0Panel • Tuesday 8:30–10:00 PM • Peak 6–80

The Cortex Midbrain and Basal Ganglia – Neural Collaborators in Selecting and Guiding Overt Movement Barry Stein, John McHaffie, Peter Redgrave, Terrence Stanford Efforts to trace the neural control of movement are often targeted toward individual structures, ignoring the essentials of the circuit within which they function. This is particularly evident in many studies of the contributions of cortex, midbrain and basal ganglia in shifts of gaze. Speakers in the present session will show how evaluating these various structures independently gives little insight into how they interact to select and coordi- nate sensorimotor behavior. Barry Stein will present a brief overview of the issues that will be dealt with as well as the presumptive biological roles of this circuit in dealing with environmental events, and its conservation across multiple species adapted to dealing with very different ecological pressures. He will deal specifically with higher-order control over superior colliculus-mediated orientation behavior. Peter Redgrave will provide anatomical and immunohistochemical evidence to show that the superior colliculus actually projects directly to dopaminergic neurons in the substantia nigra. This connection is the likely explanation for the exquisite sensitivity of substantia nigra neurons to unexpected, yet biologically salient, stimuli. Of particular interest in this regard is a simmering controversy about the functional role of dopamine release – is it as some believe the brain’s general mechanism of mediating reward, or it a means of simply signalling the novelty of an event, independent of its reward value?

98 38th Annual Winter Conference on Brain Research Terrence Stanford will then extend these discussions to show how functional loops among motor thalamus, motor cortex, basal ganglia and superior colliculus underlie the context-dependent control of shifts of gaze. John McHaﬃe will then use these discussions as a platform to construct a model of cortex-basal ganglia-superior colliculus interactions that mediate interhemispheric control of shifts of gaze. He will show how this functional model, when disrupted by cortical lesions, predicts the profound contralateral hemineglect that is produced by lesions of visual cortex. He will also show how how a second, strategically placed lesion within this circuit, can reverse this hemineglect. It is the intent of these presentations to show how coordinated sequential activity along these loops can be initiated by sensory activity and how understanding of loop architecture and functional interdependence can explain behavior in ways that are unapproachable by studying the component structures independently. In doing so, they will also help explain the relationships between laboratory studies of these loops and such traumatic induced anomalies as parietal neglect.

0Panel • Tuesday 8:30–10:00 PM • Peak 9–100

Signaling: What You May Not Know Could Help You! Ken Kramer, Philip Stork, Maarten Reith, Joeseph Yeretsian The cell has evolved multiple mechanisms to respond to extracellular stimuli. One pathway that lies at the nexus between extracellular signals and nuclear events s the MAP kinase cascade. Within neurons, the MAP kinase ERK is activated in response to neurotrophic and hormonal stimuli. The complexity of hormonal activation of MAP kinase is seen at multiple levels. The MAP kinase cascade is triggered by the activation of small G proteins, Ras and Rap1, both which are highly expressed within the CNS. Each small G protein can be activated by additional G protein-coupled pathways involving the heterotrimeric G protein families. Heterotrimeric G proteins utilize multiple mechanisms to activate small G proteins. In particular, activation of Ras and Rap1 by small intracellular second messengers calcium and cAMP provide a direct link from heterotrimeric to small G proteins. We will discuss recent advances in the study of G protein coupling to ERKs, focusing on neuronal mechanism of coupling hormones to Ras and Rap1.

January 23–28, 2005 • Breckenridge, Colorado 99 0Panel • Wednesday 7:30–9:30 AM • Peak 11–120

GABA, GABA, Hey! Translational Neuroscience Insights into GABA John Krystal, Kari Buck, David Goldman, Marc Schuckit GABA receptors are important targets for alcohol in the brain. Increasingly genes that code for GABA receptors have been implicated in the risk for developing alcohol dependence. The presentations in this session will provide new insights into the role of GABA systems in the phenotypes associated with alcohol dependence. Kari Buck, Ph.D. (OHSU) will present new results from a series of recent QTL studies that implicate GABA-related genes in phenotypes associated with alcohol dependence in inbred rodent strains. David Goldman, M.D. (NIAAA-IRP) will present evidence that polymorphisms in two clusters of GABA receptor genes, one on chromosome 4 (particularly alpha-2 subunit) and one on chromosome 5 (particularly alpha-6 subunit), may play a role in the development and expression of alcohol dependence. Marc Schuckit, M.D. (UCSD) will present the results from a series of studies that build on his observation that individuals at increased familial risk for developing alcoholism show reduced sensitivity to ethanol. He will then describe a polymorphism in the alpha-6 subunit that may contribute to this risk phenotype. John Krystal, M.D. (Yale) will present the ﬁndings from a new study that concurrently measured cortical GABA-A receptor density ([123I]iomazenil binding) and cortical GABA levels (1H-MRS) during the recovery from alcohol dependence. He will show data that describe the adaptations in GABA systems and present new evidence that these adaptations are not observed in alcohol dependent smokers.

0Panel • Wednesday 7:30–9:30 AM • Peak 140

Moving Beyond GAT1: Emerging Role for Other GABA Transporters in the Control of Neuronal Function? H. Steve White, Charles Ribak, Arne Schousboe, Misty Smith-Yockman, George Richerson The concentration of GABA in the synaptic and extrasynaptic cleft is controlled by a family of GABA transporters, four of which have been cloned and characterized. These are named GABA transporters 1-4 (GAT1-4) and

100 38th Annual Winter Conference on Brain Research GAT2 is identical to the betaine-GABA transporter 1 (BGT-1). GAT1 is the most abundant of the four on GABAergic neurons. In addition, GAT1 has been considered to be the most important. However, recent developments in the pharmacological characterization of these transporters using novel GABA analogs of restricted conformation have suggested a functional role for non-GAT1 transporters. For example, it appears that both GAT2 and GAT4 may have important roles in seizure control. This activity could well be related to their ability to regulate extrasynaptic GABA levels and to their unique anatomical localization. The overall purpose of the proposed panel is to provide the audience with an overview of the factors that contribute to the expression, regulation, and function of GABA transporters. The four speakers will provide the audience with an up to date overview of the molecular biology, physiology, pharmacology and function of GABA transporters in normal and diseased brain. Dr. Ribak will discuss the anatomical localization of GABA transporters and factors that regulate their expression. Dr. Schousboe will discuss the molecular pharmacology of a new generation of non-GAT1 transport inhibitors. Dr. Smith-Yockman will discuss the physiology and in vivo pharmacology of non-GAT1 GABA transporters. Dr. Richerson will discuss the role of GABA transporters in controlling synaptic and extrasynaptic inhibitory neurotransmission.

0Panel • Wednesday 7:30–9:30 AM • Peak 150

A Double Hit on a Double Edge Sword? NO or Spermine in Huntington’s Disease Carol Colton, James Burke, Wallace Deckel, Stefano Vicini Disruption of function is inevitable in striatal neurons expressing pathological-length polyglutamine proteins. Functional changes preceding cell death are associated with aggregate formation and are reversible, disap- pearing when aggregate formation is stopped. The recognized importance of specific glutamatergic processes in Huntington‚s disease (HD) focuses attention on glutamate receptors as a site for functional modulation. But how can a pathologic-length polyglutamine protein alter glutamate receptor function? This panel will suggest novel mechanisms that can lead to specific changes in NMDA channels in HD. Jim Burke will lead off by describing how polyglutamine aggregates come and go in test tubes and in cells. Oligomerization of polyQ proteins is enhanced by polyamines and reduced by peptides that disrupt the expanded polyQ stretch. What happens to function? Wally Deckel will show that regulation of nitric oxide and neuronal nitric oxide synthase (nNOS) is significantly effected. Abnormalities in protein expression of nNOS and its regulators, CAMKII

January 23–28, 2005 • Breckenridge, Colorado 101 and CAMKIV, correlate with symptom onset, behavioral decline and altered cerebral blood flow in R6/1 and R6/2 HD transgenic mice. But NO is not the only NMDA channel modulator affected. NO is linked to spermine through their common precursor, arginine. Carol Colton will describe the fierce competition for arginine by the NO and polyamine synthetic pathways. In the presence of pathologic-length polyQ proteins, polyamine synthesis wins and spermine homeostasis is disrupted. Stefano Vicini will forecast how these changes will impact NMDA channel function by discussing the important role polyamines play in regulating glutamate-mediated synaptic transmission.

0Panel • Wednesday 7:30–9:30 AM • Peak 170

Nicotine, Cigarettes and Dopamine: Is the Smoke Beginning to Clear? Paul Clarke, Derek van der Kooy, Stephanie Cragg, Athina Markou Understanding how nicotine reinforces tobacco smoking could have major therapeutic implications. Dopamine is thought to play an important role in nicotine dependence, but quite what this role may be is far from settled. The aim of this session is to highlight major points of agreement and disagreement in this debate. Paul Clarke will briefly overview the pharmacology of CNS nAChRs, showing why nicotine is a tricky drug to study, and will then critically examine the widely held notion that people smoke cigarettes largely to trigger mesolimbic dopamine release. He will also stress the importance of compartments within the nucleus accumbens in mediating nicotine’s actions. Derek van der Kooy will present animal studies supporting the novel and controversial notion that dopamine mediates aversive rather than rewarding effects of nicotine. Stephanie Cragg will describe electrochemical experiments suggesting that nicotine selectively increases dopamine release during phasic but not tonic dopaminergic cell activity; this action occurs via nAChR desensitization, thought to be prominent in smokers. She will discuss how nicotine’s ability to filter dopaminergic cell firing may provide a mechanism by which the drug could facilitate reward-related signals without being particularly rewarding itself. Lastly, Athina Markou will discuss the adaptations that develop in the function of dopamine D1 receptors with the development of nicotine dependence, and how such adaptations may lead to the affective aspects of nicotine withdrawal and the perpetuation of the tobacco smoking habit. With this in mind, she will outline novel therapeutic strategies for smoking cessation.

102 38th Annual Winter Conference on Brain Research 0Panel • Wednesday 7:30–9:30 AM • Peak 6–80

Novel Perspectives on the Mechanisms of Feedback Inhibition by Glucocorticoids in the Hypothalamic Adrenal Axis Greti Aguilera, Stafford Lightman, Jeffrey Tasker, Mary Dallman The secretion of glucocorticoids, key regulators of metabolic, immunological, and developmental processes, is tightly controlled by pituitary ACTH, the secretion of which is under the stimulatory effect of hypothalamic cor- ticotrophin releasing hormone (CRH) and vasopressin (VP), and glucocorticoid feedback inhibition. This panel will discuss novel regulatory effects of glucocorticoids on hypothalamic pituitary adrenal (HPA) axis activity, challenging the traditional view that glucocorticoids act by direct genomic inhibition of CRH expression. Greti Aguilera will start by describing different mechanisms by which glucocorticoids can affect HPA axis activity, and will present data indicating that glucocorticoids can exert rapid inhibition of CRH transcription, an effect which depends on the prevailing levels of glucocorticoids. Stafford Lightman will follow by demonstrating that injection of corticosteroids such as prednisolone results in rapid inhibition of HPA activity (faster than could be explained at genomic level), probably at central levels since pituitary CRH responsiveness is preserved. He will also show evidence that long term administration of glucocorticoid antagonists has major effects on circadian variations of HPA activity, particularly during active night time. Jeff Tasker will present electrophysiological and mass spectrometry data in hypothalamic slices indicating that the rapid effects of glucocorticoids on hypothalamic neuroendocrine cells are mediated by interaction of glucocorticoids with a G-protein coupled plasma membrane receptor coupled to cAMP signaling. Glucocorticoids elicit a dose-dependent release of endocannabinoids in the paraventricular and supraoptic nuclei, which in turn suppress glutamate secretion through interaction with presynaptic CB1 receptors, thereby suppressing the excitatory drive to hypothalamic neuroendocrine cells. Finally, Mary Dallman will provide experimental evidence supporting the provocative hypothesis that chronic stress initiates changes in the brain that result in glucocorticoids acting both to increase high density caloric intake and to facilitate HPA responses to novel stress. Glucocorticoids themselves increase caloric intake and result in selective increase in intra-abdominal fat, which in turn would activate a novel indirect feedback route on CRF expression in the paraventricular hypothalamus. Discussion of these topics will provide new insight on the mechanisms of feedback regulation of the HPA axis, as well as opening novel perspectives for the development of diagnostic and therapeutic tools for neuroendocrine disorders.

January 23–28, 2005 • Breckenridge, Colorado 103 0Panel • Wednesday 7:30–9:30 AM • Peak 9–100

Anything but V1: Imaging Something Really Different Daniel Tso, Heather Read, Ralph Siegel, Arthur Toga The striking success of intrinsic signal optical imaging in primary visual cortex, beginning some twenty years ago, has inspired investigators to employ this methodology in other parts of the brain and to other types of study of brain function. The original imaging techniques developed for anesthetized V1, however, have not always been appropriate and, in many instances, substantial modifications to the original imaging protocols have been required to address the special circumstances posed by each novel system. In this panel, we will highlight new and unexpected research findings that have arisen from innovative adaptations of the optical imaging paradigm to the study of brain function. Heather Read has employed the improved spatiotemporal resolution of a new rapid imaging technique to the study of plasticity and abnormal development of cochleotopic representations in auditory cortex in response to either altered growth factor expression in the brainstem, or early disruption of somatosensory cortex. The results show that cortical and brainstem developmental manipulations result in very distinct patterns of cochleotopic re-organization. The somatosensory cortex also has met with success as a platform for optical imaging studies, and as will be described by Arthur Toga, served to reveal mechanisms of cortical development and plasticity. In addition, these studies have provided insights into the nature of the intrinsic optical signals themselves, and to the coupling of hemodynamics to neuronal activity. By imaging primate inferior parietal cortex, a region crucial for visuo-spatial perception, Ralph Siegel has observed that the representations for different classes of information have markedly different temporal stability. The mapping of eye position information was found to be very stable, while the representation of retinally-derived information shifts between days, and the patterns of attentional influences changes rapidly. Finally, sensory epithelium itself has recently been studied with these imaging techniques. Since the retina itself is light sensitive, the optical imaging of retinal function dictates a series of adaptations to the basic imaging method that will be discussed by Daniel Tso. This new, non-invasive method has revealed several distinct optical signals from the retina, in response to spatially patterned visual stimuli, including a signal similar to that seen in neocortex, and signals that are likely to be unique to the retina.

104 38th Annual Winter Conference on Brain Research 0Panel • Wednesday 4:30–6:30 PM • Peak 11–12 0

Emerging Insights into Molecular Substrates of Alternate Brain States: Of Clocks and Sleep and Genes Martha Gillette, Fred Turek, Joseph Takahashi, Chiara Cirelli, Paul Shaw Patterns of gene expression and function are emerging that alter behavior or are modulated by brain state over the 24-h cycle. Significant progress is being made in elucidating molecular substrates of 1) alternating day-night states in the circadian clock and 2) sleep and wakefulness in mammalian cortex and cerebellum as well as fly brain. This panel will assess present understanding and implications of these findings from a functional and cross-species perspective. M. Gillette will provide an overview and moderate the session. F. Turek will examine the potential roles of circadian clock genes in regulating sleep/wake state. J. Takahashi will discuss alterations in gene families expressed in the circadian clock between night and day. C. Cirelli will provide functional genomic evidence that sleep and wakefulness may favor different cellular processes. These may help the brain to face differing energy demand, synaptic excitatory transmission, transcriptional activity, and need for neural plasticity related to acquisition of new information. P. Shaw will present new data regarding sleep homeostasis and the cellular stress that may derive from one or more of these processes. Participants are engaging speakers and evaluation of each presentation in the context of the others will be encouraged.

0Panel • Wednesday 4:30–6:30 PM • Peak 140

Cells, Genes or Machines: What’s Best for Treating Parkinson’s Disease Don Gash, Jean Saint-Cyr, Krys Bankiewicz, Clive Svendsen, Michael Zigmond With the relentless progression of Parkinson‚s disease (PD), the quality of life diminishes and patients become increasingly disabled. Current medical therapies can be very effective in the early stages of PD, but their efficacy often decreases over time. Some new treatments, such as bilateral deep brain stimulation of the subthalamic nucleus, are improving the outlook for advanced PD patients. Others therapies in preclinical testing or in clinical trials are emerging that promise more effective late stage management and interventions that may slow disease processes. This session will evaluate and compare new therapeutic approaches, where they are in development, their potential advantages and possible limitations. Michael Zigmond will moderate the session. Jean Saint-Cyr will review Deep Brain

January 23–28, 2005 • Breckenridge, Colorado 105 Stimulation, its proposed mechanism of action and its future. Don Gash will cover the site-speciﬁc delivery of trophic factors, focusing on the con- stant infusion of GDNF into the putamen. Sometimes hailed as the treatment of the future, the current state of the art and future perspectives of stem cell research will be presented by Clive Svendsen. Krys Bankiewicz will discuss gene therapy approaches, possibly the ultimate treatment, since the counteraction of those factors could theoretically prevent the disease from being manifest. The goal of this workshop is to assess the state-of-the art of research in the treatment and potential prevention of PD. The scien- tiﬁc questions that need to be addressed are the biological mechanisms underlying the development of treatments and the anticipated roadblocks to progress.

0Panel • Wednesday 4:30–6:30 PM • Peak 150

Manipulation of the Endocannabinoid System as a Novel Therapeutic Tool Ken Mackie, Andrea Giufrida, Giovanni Marsicano, George Kunos The endocannabinoid system consists of endogenous cannabinoids (endocannabinoids), cannabinoid receptors, and the enzymes responsible for the synthesis and degradation of endocannabinoids. The last few years has seen a remarkable increase in our understanding of the basic biology of the endocannabinoid system and the role it may play in both health and disease. How might manipulations of the endocannabinoid system be therapeutically beneficial? Early clinical studies suggest CB1 receptor antagonists may be effective appetite suppressants and block specific types of craving. Preclinical studies suggest an even wider group of potential therapeutic targets including anxiety-related behaviors, chronic pain, and movement disorders. The goal of this session will be to discuss key physiological and behavioral effects of endocannabinoids and how these might be manipulated for therapeutic benefit. The session will start with Ken Mackie (University of Washington) giving a brief overview of the components of the endocannabinoid system. Andrea Giuffrida (UTHSC San Antonio) will next discuss the role of endocannabinoids in movement disorders and the interplay between dopamine and endocannabinoids. Next, Giovanni Marsicano (Max Planck Institute, Munich) will speak on how CB1 activation in specific forebrain neurons can be neuroprotective in animal models of excitotoxicity. Finally, George Kunos (NIAAA) will present

106 38th Annual Winter Conference on Brain Research data from animal and human studies suggesting CB1 receptor antagonists can block craving and may be eﬃcacious in treating tobacco and alcohol dependence. The pathological conditions highlighted in these talks represent just a few of a growing list of diseases where a rational basis for therapeutic targeting of the endocannabinoid system has been recently identiﬁed.

0Panel • Wednesday 4:30–6:30 PM • Peak 17 0

Sodium Channels and Cellular Plasticity: A New Job for an Old Channel William Catterall, James Surmeier, Indira Raman, Todd Scheuer In addition to their traditional role in axonal conduction, voltage-gated sodium channels have recently emerged as important players in integration of synaptic signals, determination of pattern and frequency of firing, and regulation of input-output relationships of central neurons. Slow inactivation of sodium channels, generation of resurgent and persistent sodium currents, and regulation of sodium currents by neurotransmitters acting through second messenger pathways all contribute crucially to these processes. This Panel will provide an overview of this rich field of modulation of neuronal activity and present results of current experiments probing the cellular and molecular basis for these novel aspects of sodium channel function. After a brief introduction, Surmeier will present recent results on the role of sodium currents in pacemaking of basal ganglia neurons and their modulation by G protein coupled receptors. Raman will follow with an introduction to resurgent sodium current and its role in repetitive firing in neurons. She will provide new evidence for intracellular peptide blockers of sodium channels that generate resurgent sodium current. Catterall will present recent work on regulation of sodium channels by dopamine and acetylcholine acting through PKA and PKC directly anchored to the channel by AKAP-15 and RACK-II. These results implicate macromolecular signaling complexes in regulation of sodium channels by modulation of their intrinsic slow inactivation process. Scheuer will describe persistent sodium currents and present recent evidence for their regulation by intracellular signaling pathways, including direct binding of G protein beta/gamma subunits. The Panel will conclude with a general discussion by the participants.

January 23–28, 2005 • Breckenridge, Colorado 107 0Panel • Wednesday 4:30–6:30 PM • Peak 6–80

Discovery Neuroscience Stephen Koslow, David Van Essen, Arthur Toga, Dietrich Stephan, Mary Hatten The field of Neuroscience is rapidly moving from only hypothesis driven research to discovery science. This mirrors what has happened in the file of genomics and should rapidly change this research field, leading perhaps to the faster discovery of important neuronal processes. There are many contributing factors to this development, including the support of database production and sharing of data through NIH and NSF granting programs, as well as similar activities internationally and the ability to have high throughput technology. This approach is welcomed and supported by many. The aim of this session is to discuss some of the national, international and professional society efforts in this area, and to present current efforts to produce and make data available through GENSAT, and the Microarray Consortium. Critical to all of this work is the precise localization of this data in the CNS. Van Essen will make a presentation on the recent efforts and goals of the Society for Neuroscience. Hatten and Stephan will provide and update and the progress to date of the GENSAT project and Microarray Consortium. Toga will discuss the issues and progress being made to provide an accurate neuroanatomical backbone for all of this data. While some of the efforts in the community are arising from single labs or fields, the GENSAT and Microarray Consortium are federally sponsored project that are currently providing data to the whole field. The participants will discuss these and other efforts and the problems and potential solutions.

0Panel • Wednesday 4:30–6:30 PM • Peak 9–100

CRF Actions on State-Dependent Neural Signal Processing: Stress and Beyond David Devilbiss, Mark Opp, Rita Valentino, Lisa Conti A large body of evidence indicates a critical role for corticotropin-releasing factor (CRF) in behavioral and physiological processes in stress. The neural circuitry through which CRF modulates behavior remains largely unclear. In this regard, it is of interest that CRF containing ﬁbers and receptors are found widely throughout the CNS including the ascending brainstem monoaminergic modulatory systems. CRF exerts excitatory actions on locus coeruleus-noradrenergic (LC-NA) and dorsal raphe-serotonergic (DR- 5HT) neurotransmission. LC-NA and DR-5HT systems have been implicated in the modulation of behavioral state and a variety of state-dependent pro-

108 38th Annual Winter Conference on Brain Research cesses, including cortical information processing. Combined, these observations indicate potential actions of CRF on state and state-dependent information processing via actions on ascending monoaminergic systems. Such actions may play important roles in cognition and affect outside that of stress. This panel will review recent observations that indicate robust modulatory actions of CRF on monoaminergic neurotransmission, behavioral state and state-dependent sensory processing. Mark Opp will describe related behavioral studies regarding actions of CRF on sleep/waking and stress. Rita Valentino will present the effects of CRF on LC-NA and DR-5HT neurotransmission. David Devilbiss will discuss the electrophysiological effects of CRF on thalamic and cortical sensory information processing. Lisa Conti will describe behavioral effects of CRF on sensory tasks of prepulse inhibition in the acoustic startle response. As a group, the functional implications of these extra-hypothalamic actions of CRF under normal and pathological conditions will be discussed.

0Panel • Thursday 7:30–9:30 AM • Peak 11–12 0

Phosphorylation and Synaptic Regulation Katherine Roche, David Bredt, Johannes Hell, Joseph Kittler Protein phosphorylation is a major regulatory mechanism in neurons controlling both pre- and postsynaptic signaling. Many synaptic proteins such as neurotransmitter receptors and ion channels are substrates for phosphorylation, and a balance of kinase and phosphatase activity critically regulates neural communication. Presentations in this panel will address recent studies on the role of phosphorylation in receptor trafficking, synaptic clustering, and neuronal signaling. Katherine Roche will discuss phosphorylation of metabotropic glutamate receptors by PKC. The specific residues phosphorylated on mGluR5 will be discussed along with the effect of phosphorylation on mGluR-mediated intracellular Ca2+ oscillations. David Bredt will discuss the phosphorylation of the AMPA receptor-associated protein stargazin. Synaptic NMDA receptor activity can induce stargazin phosphorylation via PKC and CaMKII and can also cause stargazin de-phosphorylation by activation of PP1 downstream of PP2B. At hippocampal synapses, long-term potentiation and long-term depression require stargazin phosphorylation and dephosphorylation, respectively. Johannes Hell will discuss how PKA and the phosphatase PP2A interact with the L-type Ca channel Cav1.2. This channel is clustered at postsynaptic sites, and assembles a macromolecular signaling complex that includes the beta2 adrenergic receptor, Gs, adenylyl cyclase, PKA and PP2A for highly localized signaling. Josef Kittler will discuss the accumulation and stabilization of GABAA receptors at synaptic sites. The relative dynamics of

January 23–28, 2005 • Breckenridge, Colorado 109 synaptic and extrasynaptic GABAA receptors will be evaluated, describing the distinct phospho-dependent protein- protein interactions that regulate cell surface stability and endocytic sorting.

0Panel • Thursday 7:30–9:30 AM • Peak 140

The Differentiation and Functional Potential of Embryonic Stem Cells Oswald Steward, Hans Keirstead, Ron McKay, Evan Snyder, John McDonald This session will focus on the cellular and molecular control of stem cell differentiation, and potential clinical applications for human stem cells. Ron McKay will begin the session by presenting his finding concerning the contact dependent and soluble signals that control the proliferation and differentiation of stem cells, and the clinical potential of stem cells. Evan Snyder will then discuss the cross-talk between stem cells and the degenerating or injured host, and how this fundamental biology may be harnessed for therapeutic benefit. John McDonald will present his work elucidating the mechanisms of white matter injury and remyelination following spinal cord injury, as well as his findings concerning the transplantation of embryonic stem cells into the injured spinal cord. Hans Keirstead will then discuss his development of a method to generate high purity oligodendrocyte progenitor populations from human embryonic stem cells, and consequences of their transplantation into sites of either acute or chronic spinal cord injuries. These core talks will be followed by two 5-10 minute presentations. Nicole Berchtold will present an emerging story concerning the novel use of exercise to enhance the migration and differentiation of transplanted human embryonic stem cell derivatives in the brains of adult rats. Finally, Michelle Goldman, a Regulatory Affairs Officer, will present a brief summary of the unique challenges that face the translation of stem cell treatments from animals to humans.

0Panel • Thursday 7:30–9:30 AM • Peak 15 0

Regional Distinctions of Striatal Dopamine Function in Human and Non-Human Primates in Relation to Motivation and Reward Charles Bradberry, Suzanne Haber, Stephanie Cragg, Marc Laruelle This symposium will cover regional distinctions in the dopaminergic inner- vation of the primate striatum, and how those distinctions might relate to dopaminergic modulation of motivation and reward. Areas of convergence

110 38th Annual Winter Conference on Brain Research and divergence across a broad range of anatomical and functional inves- tigations will be explored. Suzanne Haber will present a neuroanatomical backdrop for the other presentations. She will present data on the regional comparison of dopamine transporter and tyrosine hydroxylase immu- nopositive fiber distribution in the normal and partial dopamine lesioned rhesus macaque, and discuss those regional differences in relation to functionally distinct corticostriatal networks. Stephanie Cragg will present studies using fast-scan cyclic voltammetry at carbon-fiber microelectrodes that have explored the release probability of dopamine and its plasticity in different domains of the striatum of the marmoset. Charles Bradberry will present data from microdialysis studies in cocaine self-administering rhesus monkeys showing clear regional distinctions in basal and cocaine- evoked increases in extracellular dopamine. Marc Laruelle will present human PET imaging studies employing new higher resolution technology enabling measurement of DA function in striatal subregions. Data on DA function in substance abuse, alcoholism, major depression and schizophrenia will be presented.

0Panel • Thursday 7:30–9:30 AM • Peak 170

Homeostatic Plasticity: The Good and Bad News for Neuronal Network Function Jan-Marino Ramirez, Astrid Prinz, Ronald Harris-Warrick, Florin Amzica In neuronal networks synaptic and intrinsic membrane properties are continuously modulated. In order to avoid catastrophic upregulation of synaptic properties or an imbalance in ion channels, homeostatic mechanisms are essential to maintain these mechanisms at a given set-point, a regulatory process generally referred to as homeostatic plasticity. Astrid Prinz will use computational approaches to discuss how activity-dependent homeostatic mechanisms control the expression of ionic conductances and synaptic properties in order to maintain stable neuronal activity. Ron Harris-Warrick will discuss the interaction of inward and outward currents in regulating discharge properties in rhythm generating networks. He will show how genetic manipulations of single ionic conductances lead to compensatory mechanisms that maintain a given discharge pattern of a neuron. Using slice preparations from mice and from the seizure focus of pediatric patients with intractable epilepsy Jan-Marino Ramirez will discuss the necessity of persistent activity in order to continuously allow homeostatic mechanisms to balance synaptic and intrinsic membrane properties in cortical networks. In the absence of neuronal activity the same homeostatic mechanisms, however, will lead to hyperexcitability and epileptic seizures. Recordings from alert and sleeping cats reveal similar plastic

January 23–28, 2005 • Breckenridge, Colorado 111 changes in the activity of cortical neurons indicating that activity deprivation may trigger homeostatic mechanisms leading to hyperexcitability and epileptogenesis as will be discussed by Florin Amzica.

0Panel • Thursday 7:30–9:30 AM • Peak 6–80

Vasopressinergic Mechanisms in Cognition and Affective Behavior J. David Jentsch, Donald Pfaff, Larry Young, David Feifel Molecular, cellular and behavioral neuroscience studies are revealing a fundamental role for neurophysin hormones in the regulation of cognition and emotionality. Vasopressin is synthesized and released by neurons found within the hypothalamus and extended amygdala, indicating that it may contribute to affective and cognitive behaviors. In this symposium, we will discuss research indicating that vasopressin exerts complex control of cognition, information processing, social behavior and emotionality. Donald Pfaff will discuss electrophysiological and behavioral studies of paraventricular nucleus functions in oxytocin knockout mice with a view to highlighting dual roles for vasopressin, influencing both autonomic and EEG arousal. Larry Young will describe work that focuses on the mechanisms by which vasopressin regulates social cognition and anxiety; he has shown that V1a receptors in the lateral septum are necessary and sufficient for social recognition while having little impact on anxiety. David Feifel will review studies showing that genetic vasopressin deficiency causes deficits in prepulse inhibition (PPI) of the startle response, suggesting that vasopressin mutant rats represent a genetic model for the information processing abnormalities associated with schizophrenia. Finally, David Jentsch will survey recent work indicating that vasopressin systems in the extended amygdala regulate neocortical cognitive functions through indirect control over monoaminergic neurons. Our goal will be to expand the scope of current conceptual hypotheses of vasopressin function and to discuss ways in which studying the neurobiology of vasopressin function will contribute to a better understanding of motivation, emotion and cognition, as well as the relevance of these hypotheses for psychiatric disorders.

112 38th Annual Winter Conference on Brain Research 0Panel • Thursday 7:30–9:30 AM • Peak 9–100

Gaining Insight into Synaptic Function by Listening to Specialized Synapses Karl Kandler, Alapakkam Sampath, Joshua Singer, Thomas Parsons At all chemical synapses, Ca2+ triggers exocytosis and neurotransmitter released from synaptic vesicles diffuses across the synaptic cleft and binds to postsynaptic receptors. Each type of synapse, however, exhibits special properties that make it well-suited to transmit information within its resident neural circuit. Circuit-specific specializations are particularly evident in developing and mature sensory circuits, in which synapses are designed to parse and transfer particular features of the sensory input. This panel will present studies of four sensory synapses in the visual and auditory systems that demonstrate how generic synaptic parameters can be modified to suit the requirements of individual circuits. Alapakkam Sampath and Joshua Singer will discuss physiological specializations at ribbon synapses in the rod pathway of the mammalian retina. Alapakkam Sampath will present results that provide new insights into signal transfer between rods and rod bipolar cells: a threshold non-linearity resulting from the saturation of the second-messenger pathway gating a postsynaptic conductance allows the reliable transfer of signals arising from the absorption of single photons by rods. Joshua Singer will present evidence that transmission from rod bipolar cell terminals involves coordinated exocytosis from multiple release sites in the same presynaptic active zone; this coordinated multivesicular release, which ensures that evoked events are larger than the spontaneous synaptic noise, may preserve the non-linearity generated at the rod-rod bipolar cell synapse. Thomas Parsons and Karl Kandler will provide examples of synaptic specializations in the auditory system. Thomas Parsons will discuss presynaptic mechanisms, such as large releasable vesicle pools, that allow cochlear hair cells to sustain extremely high rates of exocytosis for the long periods necessary to encode sounds of varying frequencies. Karl Kandler will present recent evidence that individual inhibitory synapses in a developing sound localization circuit release not only GABA and glycine but also the excitatory transmitter glutamate. This may constitute a mechanism by which this inhibitory circuit becomes organized tonotopically. Because the physiological functions of sensory circuits are relatively well-characterized, they can serve as accessible models by which the importance of individual synaptic specializations to circuit function can be

January 23–28, 2005 • Breckenridge, Colorado 113 understood. Results discussed in this panel session can serve as a starting point from which the contributions of synaptic physiology to network behavior in more complex circuits can be approached.

0Panel • Thursday 4:30–6:30 PM • Peak 11–120

Neuroprotection and Immunoregulation in EAE and MS Richard Jones, Gregory Konat, Halina Offner, Arthur Vandenbark Clinical, pathological and immunological characteristics of experimental autoimmune encephalomyelitis (EAE) are similar to the human disease multiple sclerosis (MS) and suggest that common etiological and pathogenic mechanisms cause paralysis in EAE and MS. Emerging evidence reveals compelling details of competing cellular and molecular mechanisms capable of retarding or promoting disease progression. Thus, clinical disease in EAE and MS results from a net balance between disease retarding and disease promoting processes. Autoimmune reactivity directed by T lymphocytes against myelin antigens initiates inflammation and activates inflammatory cells within the CNS to elaborate cytotoxic and myelin destroying agents. Inflammation and demyelination are associated with loss of neuronal function and neurodegeneration. Regulatory immune pathways modulate the severity and time course of inflammation and neuroprotective pathways retard neuronal loss and/or promote regeneration in response to inflammatory or other insults. Thus, concurrent and overlapping inflammatory, immunoregulatory, neurodegenerative and neuroprotective processes interact at the cellular and molecular levels to control status and functionality within the CNS. The panel will discuss a range of possibilities for disease etiology and pathogenesis suggested by this view, including enhanced susceptibility to inflammation and inflammatory damage; enhanced inflammatory activity; imbalance between neurodegenerative versus regenerative, protective pathways; and defects in immunoregulation. Pre-pathogenic regulation of susceptibility to CNS inflammation will be discussed by Richard Jones. Gregory Konat will reveal the crucial roles played by CNS toll-like receptors and the innate immune response in the CNS. Halina Offner will discuss the effects of estrogen on neuroprotection and immunoregulation in EAE. Arthur Vandenbark will provide insights into soluble mediators of neuroprotection by T cell-receptor-reactive T cells in EAE and MS.

114 38th Annual Winter Conference on Brain Research 0Panel • Thursday 4:30–6:30 PM • Peak 140

Human Embryonic Stem Cells: Will They Ever Cure Anything? Jeanne Loring, John McDonald, Tom Schultz, Evan Snyder Everyone‚s talking about human embryonic stem cells. The clerks in the grocery store, the mailman, the hairdresser, all know about them. Scien- tists disagree on virtually everything: how hES cells originate, how they’re defined, and what medical uses they may have. This workshop will inform the attendees of real state of the scientific research (which is largely unpublished), the politics and legal issues, and the basis for hope in the clinic. The four speakers are all deeply involved in hES research, and are from three different types of institutions: research institute, biotechnology company, and clinical practice. The organizer and first speaker, Jeanne Loring, produced 9 of the first group of “presidential” human ES cell lines. She will introduce the controversy, offering history, hype and reality, the politics and the patents. The second speaker is Evan Snyder, who will discuss the successes and failures of transplanted neural stem cells. Third, John McDonald will talk about the potential of using stem cells for treating human spinal cord injury. The last speaker, Tom Schultz is from one of the very few biotechnology companies developing human ES cell applications; he’ll talk about the future of the science and the industry. Each speaker has been asked to focus on the balance of hope and hype in his or her area of experience, and to indulge in some philosophizing about what concerns him or her most about the current stem cell field. Since this stem cells are a very public issue, it is certain that some piece of news will come out just before the meeting, just in time to add it to our discussions.

0Panel • Thursday 4:30–6:30 PM • Peak 150

Refractory Periods Revisited: Calcium-Dependent AHPs from Genes to Function Robert Foehring, Rodrigo Andrade, Pankaj Sah, William Spain Excitability in neurons is subject to feedback regulation. One important form of feedback involves calcium entry during action potentials, eleva- tion of intracellular calcium concentration, and subsequent activation of potassium channels. Pyramidal cells exhibit multiple calcium-dependent afterhyperpolarizations (AHPs) which vary in their kinetics and pharmacology. These include the apamin-sensitive medium AHP (mAHP) and the slow AHP (sAHP), which is sensitive to several signaling pathways. SK-type

January 23–28, 2005 • Breckenridge, Colorado 115 potassium channels are expressed throughout the CNS in varying distribu- tions. These channels likely mediate the mAHP. However, their functional role in most central neurons remains enigmatic. The channel that underlies the sAHP is not known. This panel will address the channels underlying these AHPs in pyramidal neurons, the relationships between the AHPs and intracellular calcium, and the functional roles of these channels. Dr. Pankaj Sah will discuss current ideas about the possible functional roles of the AHP currents in central neurons and review the data that indicates that known SK channels may not underlie this current. Dr. Rodrigo Andrade will discuss recent ﬁndings from his lab, where genetic manipulations were used to conclusively show that sK type channels underlie the faster, apamin-sensitive mAHP but not the sAHP. To provide further insight into properties of the channels and to relate spiking behavior to AHPs, Dr. Robert Foehring will discuss the relationships between action potentials, changes in intracellular calcium, and activation of AHPs. Finally, Dr. William Spain will discuss new approaches to determining the functional roles of the conductances underlying the mAHP and sAHP.

0Panel • Thursday 4:30–6:30 PM • Peak 170

Combinatorial Strategies to Treat CNS Injury Scott Whittemore, Wolfram Tetzlaff, John Houle, Phillip Popovich Extensive research over the past two decades has clearly shown that the CNS has the capacity for regeneration and repair after traumatic injury or neurodegenerative disease. However, the extent to which regeneration occurs is limited and interventive approaches to facilitate the limited endogenous repair are necessary. Moreover, it is becoming increasingly evident that multiple interventive strategies will be necessary to maximize functional recovery after CNS injury. This panel will focus on a number of distinct approaches to enhance repair in the injured CNS. We will focus on spinal cord injury, but the concepts discussed are applicable to all aspects of CNS injury. Phillip Popovich will explain why inflammatory cascades are a necessary but detrimental component of acute post-traumatic spinal cord injury. He will focus on the role of macrophages and T-lymphocytes in post-injury neurodegeneration and repair in models of rat and mouse spinal trauma. John Houle will discuss strategies to promote neuroprotection and neuroregeneration in acute and chronic spinal cord injury situations. Studies utilizing a combination of neurotrophic factor treatment, neurotransplantation, matrix degrading enzymes and physical therapy/ training will be highlighted, with emphasis on defining the “windows of opportunity” after a spinal cord injury when specific treatment paradigms might be most appropriate. Wolfram Tetzlaff will discuss differences in gene expression in axotomized PNS versus CNS neurons and strategies

116 38th Annual Winter Conference on Brain Research to treat the neuronal cell bodies of CNS neurons to promote their regenerative capacity after acute and chronic spinal cord injury. Scott Whitte- more will discuss the multiple approaches needed to facilitate functional recovery after stem cell grafting into the contused spinal cord - partial lineage restriction prior to graft, genetic modiﬁcation to express speciﬁc neurotrophic factors, and inhibition of intracellular signaling cascades in the engrafted cells.

0Panel • Thursday 4:30–6:30 PM • Peak 6–80

Retinal Circuitry Stephen Massey, Ron Gregg, Maureen McCall, Nicholas Brecha The mammalian retina is a ready made brain slice containing six major cell types, which may be further divided into many distinct subtypes for a total of about 60–80 different neurons. Cells of a given type form non-random mosaics across the retina. They share essential morphological features and use the same neurotransmitter(s). Furthermore, they ramify at a characteristic depth in the retina and they make stereotyped synaptic connections with surprising consistency. A number of different retinal pathways serve well-defined roles in the processing of visual information. Neuronal communication in the retina occurs via electrical synapses, also known as gap junctions, as well as by conventional synaptic transmission. Steve Massey will present high resolution images which show that photoreceptor coupling is served by Cx36 gap junctions on the matrix of cone telodendria in the primate retina. Ron Gregg will discuss mutations that affect cone to ON bipolar cell synaptic transmission and cause Con- genital Stationary Night Blindness in mice and humans. Maureen McCall will present data from wild type and knock-out mice on the role of GABAC receptors. In null mice, GABAC-mediated currents are absent from all bipolar cell terminals. Negative feedback at GABAC receptors also appears to restrict the activation of NMDA receptors on post-synaptic ganglion cells. Nick Brecha will discuss the role of neuropeptides in the retina. Emerging findings a “mismatch” between the distribution of peptide-containing processes that are often sparse and peptide receptor-expressing processes that are abundant. This expression pattern suggests that neuropeptides have a broad functional role in the retina, and perhaps they act globally to modulate different retinal networks.

January 23–28, 2005 • Breckenridge, Colorado 117 0Panel • Thursday 4:30–6:30 PM • Peak 9–10 0

Ultra Fast/Small Analysis Modalities Yield Novel Insights into Brain Function—Partnerships in Analytical Chemistry and Neurobiology Anne Andrews, Robert Kennedy, Andrew Ewing, Mark Wightman One of the true frontiers for Chemistry remains in improving our understanding of chemical signaling processes in the brain. Ralph N. Adams pioneered this area using electrochemical techniques in the 1970‚s. Today, it is at its forefront as analytical methodologies have advanced via micron- scale sampling devices such as carbon fiber microelectrodes and silica capillaries, millisecond measurements of neurotransmitters in the extracellular milieu, rapid multiplexed separations and the ability to interrogate individual neurons using microfluidics and microsampling techniques ˆ all with the selectivity and sensitivity necessary to probe chemically diverse brain microenvironments. Is this science or science fiction? Furthermore, can ultrafast measurements with probes of diminishing proportions really reveal novel aspects of neurotransmission with relevance to complex behavior? These questions will be addressed by this panel focused on the scientific crossroads between Analytical Chemistry and Neurobiol- ogy. Anne Andrews will discuss causes for discrepancies between uptake rates determined by chronoamperometry versus traditional radiochemical methods with an emphasis on elucidating modest but biologically relevant changes in serotonin uptake. Robert Kennedy will present evidence that determining extracellular amino acid neurotransmitter levels in the second regime reveals dynamic changes of functional relevance. Andrew Ewing will convey efforts to investigate and control connections between individual neurons and Mark Wightman will address the necessity of employing millisecond measurements of dopamine release to probe the intricacies of behaviors surrounding substance abuse. Overall, this panel aimed at the cutting edge of neurochemistry will acquaint participants with the state of the art, its ability to glean new insight into relationships between neurotransmission and behavior and a glimpse of future challenges.

0Panel • Thursday 8:30–10:00 PM • Peak 11–12 0

Mesolimbic Plasticity and Behavioral Sensitization to Psychostimulants Antonello Bonci, Patricio O’Donnell, Marina E. Wolf, Terry E. Robinson One of the main goals of my lab is to understand the correlation between cocaine-induced plasticity at VTA excitatory synapses and dopamine

118 38th Annual Winter Conference on Brain Research release. Therefore, I will present data generated by using simultaneous electrophysiological and electrochemical techniques to examine the effect of single and repeated cocaine exposure on DA neuron cell firing in the VTA and synaptic dopamine release in the nucleus accumbens. Marina Wolf and colleagues are testing the hypothesis that psychostimulants influence LTP by modulating AMPA receptor trafficking. In primary cultures, they found that activation of the D1 receptor-PKA pathway leads to AMPA receptor externalization and promotes LTP. Using methods developed to study AMPA receptor surface expression following in vivo drug treatment, they are investigating changes in AMPA receptor trafficking associated with behavioral sensitization. Patricio O’Donnell will present data from in vivo intracellular recordings from nucleus accumbens neurons in animals that received repeated methamphetamine. Animals that developed behavioral sensitization exhibited more prolonged up-states and changes in cell excitability, compared to animals that received the treatment but did not develop sensitization, suggesting that changes in the mesoaccum- bens system are important in the expression of sensitization. Finally, Terry Robinson will review evidence that behavioral sensitization is associated with structural plasticity in brain circuits that mediate drug reward and cognitive function, and that these effects of drugs interact with the ability of other life experiences to alter synaptic organization.

0Panel • Thursday 8:30–10:00 PM • Peak 140

New Insights into the Regulation of Neuronal Nitric Oxide Synthase and Nitrergic Signaling Pathways Anthony West, Sarah French, Gerald Rameau, Margie Ariano Nitric oxide (NO) producing interneurons play a critical role in modulating neural processing in many diverse brain regions. Under physiological conditions, NO is produced in the brain primarily by the neuronal isoform of NO synthase (nNOS) in response to excitatory stimuli which induce increases in intracellular Ca2+ levels. The most well characterized pathway for nNOS activation involves glutamatergic activation of postsynaptic NMDA receptors. NO formed following NMDA receptor activation can diﬀuse freely across cell membranes and activate or inhibit postsynaptic eﬀector proteins. Recent studies indicate that this process is likely to be highly regulated by multiple neuromodulators and intracellular signaling cascades. This panel will detail recent advances in our understanding of the regulation of nNOS activity and the signaling mechanisms involved in nitrergic neurotransmission in the hippocampus and striatal complex (caudate-putamen and nucleus accumbens). Sarah French will present insights from her neuroanatomical studies examining the source of excit-

January 23–28, 2005 • Breckenridge, Colorado 119 atory and modulatory inputs contacting the dendritic arbors of nNOS positive interneurons in the nucleus accumbens. Gerald Rameau will discuss the bi-phasic regulation of nNOS phosphorylation by the NMDA receptor in primary cultured hippocampal neurons. Margie Ariano will report on the impact of partial DA depletion on nNOS activity and cGMP signaling pathways in striatum. Tony West will discuss the role of dopaminergic inputs in modulating striatal nNOS activity and the impact of NO signaling pathways on striatal neuron activity. We anticipate that together, these reports will extend our knowledge of the regulation of nNOS activity and nitrergic signaling under both physiological and pathological conditions.

0Panel • Thursday 8:30–10:00 PM • Peak 150 pH and Brain pHunction Kevin Staley, Stephen Traynelis, Mitch Chesler, George Richerson The impact of pH on brain function will be approached from the network cellular, and channel perspectives. At the whole-brain level, hyperventila- tion has long been used diagnostically to reduce seizure threshold. Kevin Staley will describe how CO2 levels are linked via pH to adenosine release and hippocampal excitability. George Richerson will describe an alternative mechanism by which CO2 alters cortical arousal through activation of CO2- sensitive serotonergic neurons. Steve Traynelis will describe direct eﬀects of pH on neuronal function, focusing on the mechanisms by which protons alter NMDA receptor-activated ionic currents. Mitch Chesler will address the supply side of these pH feedback loops, discussing activity-dependent pH transients, and in particular the role of membrane-associated neuronal and glial carbonic anhydrases in activity-dependent alteration of pH.

0Panel • Thursday 8:30–10:00 PM • Peak 170

Homocysteine and Deranged Iron Metabolism in Alzheimer’s Disease Barney Dwyer, Mark Smith, Steven Aust Mark Smith’s introduction will review current information on neuropathological correlates of Alzheimer‚s disease progression and discuss evidence that early oxidative change is critical in disease pathogenesis. We (MAS, BED) recently proposed a hypothesis which reconciles the epidemiologi- cal observation of elevated plasma homocysteine in Alzheimer‚s disease with clinico-pathological features of the disease. Brieﬂy, we proposed that

120 38th Annual Winter Conference on Brain Research homocysteine participates in an iron dysregulation/oxidative stress cycle (ferric cycle) that involves ferritin. A novel prediction from this hypotheti- cal model is the possibility that a critical heme deﬁciency develops in AD neurons. The ferric cycle and its potential consequences will be discussed by Barney Dwyer. Continuing the discussion of abnormal iron metabolism in AD brain, Steve Aust will review the mechanism of ferritin iron storage and release and recent data from his laboratory, which suggests the importance of cysteine residues in ferritin which may be important during iron sequestration. Implications of ferric cycle activity for AD pathophysiology and therapy will be discussed after the formal presentations.

0Panel • Thursday 8:30–10:00 PM • Peak 6–80

Gene Expression Analysis in Human Neuropsychiatric Disorders Carlo Colantuoni, Elin Lehrmann, Christine Konradi, Marquis Vawter Gene expression analysis technologies are currently being used to investigate a wide range of experimental and disease states. This session will focus on the application of these techniques in studies investigating neuropsychiatric disorders in postmortem human brain tissue. As an introduction, several potential problems in postmortem human brain expression analyis will be discussed briefly. Following the introduction, Elin Lehrmann will discuss gene expression changes observed in microarray studies of the orbital fronal cortex in drug abuse cases. Christine Konradi will talk about altered gene expression levels of proteins involved in energy metabolism in prefrontal cortex and hippocampus, in bipolar disorder. Particular emphasis will be placed on mitochondrial respiration and creatine kinase. Close to this same topic, Marquis Vawter will discuss mitochondrial related gene expression in affective disorders in postmortem brain. The impact of diagnosis as well as factors such as agonal state and pH on the expression of genes related to mitochondrial function will be covered. Potential common findings between these two bipolar datasets will be explored. The focus of Carlo Colantuoni’s talk will be on expression changes in the normal human brain that are associated with genetic polymorphisms that confer risk for schizophrenia. This discussion will focus on polymorphisms in the COMT gene, and will include individual genes as well functionally related groups of genes that are differentially expressed across genotype.

January 23–28, 2005 • Breckenridge, Colorado 121 0Panel • Thursday 8:30–10:00 PM • Peak 9–100

The Grip on Dopamine and NMDA Receptors Ralph Nixon, David Sibley, Fang Liu, Henry Sershen DA and NMDA receptors are implicated in psychiatric conditions ranging from addictive disorders to schizophrenia. Evidence is emerging that some of their functions may be linked through shared interactions with the cyto- skeleton and surprisingly, with neurofilaments, the most abundant “structural” element in neurons. Neurofilaments (NFs) are highly concentrated in large myelinated axons where they are determinants of axonal caliber, but it is also known that the composition of NFs and subunit phosphorylation state in other parts of the neuron may be a „signature‰ of neuronal populations with distinct functional attributes. New roles for NFs, including the regulation of cell surface receptor expression are coming to light, which may now begin to explain why the NF regulation by phosphorylation is so complex. In particular, NF-M has been suggested to interact with D1 DA receptors to regulate cell surface expression and desensitization to DA agonists (D. Sibley). NMDAR-associated intracellular proteins may also play a role in regulating NMDAR activity and glutamate neurotransmission. The glutamate system is anatomically and functionally linked to the DA system. Are known selective interactions between gluNR1 subunits and NF-L part of this functional link? (F. Liu). Since stimulant drugs also involve DA receptors as one of their primary site(s) of action, changes in NFs may be involved in their mechanism(s) of action. Consistent with findings of drug-induced changes in NFs, gene-targeted mice lacking the NF-M subunit exhibit extreme behavioral responses to stimulant drugs, which are mediated by the D1 receptor and are influenced by gender, consistent with recent clinical data on addiction (H. Sershen).

0Panel • Friday 7:30–9:30 AM • Peak 11–120

Modulation of Active states in Neocortex Patricio O’Donnell, Rosa Cossart, Maria Victoria Sanchez Vives, Igor Timofeev, Kuei-Yuan Tseng Neocortical pyramidal neurons exhibit spontaneous plateau depolarizations (up states) in vivo. This is an emergent property of cortical networks in various states of vigilance. The source of up states remains controversial, with various degrees of synaptic vs. intrinsic involvement being postulated. The panel will discuss intrinsic and synaptic factors mediating active neo-

122 38th Annual Winter Conference on Brain Research cortical states using data obtained in vivo in anesthetized and behaving cats, as well as in vitro in slices and cellular cultures using electrophysiological and imaging approaches. Rosa Cossart will present data of spontaneous cortical activity using two-photon calcium imaging of large neuronal populations combined with targeted recordings of individual neurons to investigate intracellular correlates of network events. Mavi Sanchez-Vives will present data regarding generation of up and down states across different areas of the neocortex and she will discuss the cellular and network mechanisms that underlie the diﬀerent patterns based both on the data and on a cortical model.. Kuei-Yuan Tseng will show that co-activation of dopamine and NMDA receptors is involved in depolarizing plateaus in both acute prefrontal cortical slices and organotypic cortico-striatal co-cultures. Igor Timofeev will discuss the role of intrinsic and synaptic factors in active states of cortical neurons using simultaneous multisite intracellular recordings in anesthetized and behaving cats in vivo. The presentations will provide a broad specter of opinions on the source of cortical active states. These oscillations may have an important role in the sleep-wake cycle, epilepsy, sensory processing as well as cognitive functions such as the process of memory formation.

0Panel • Friday 7:30–9:30 AM • Peak 140

Comparative Studies of Nerve Regeneration Ronald Meyer, Herbert Geller, James Fawcett, Ken Muller When axons are severed in the adult mammalian CNS, they typically show an abortive regenerative response but fail to grow beyond the injury site leading to permanent disability. In contrast, nerves in the PNS of adult mammals regenerate for long distances and establish connections though with mistakes. In lower vertebrates and invertebrates, many CNS axons readily regenerate and can reform accurate synaptic connections. A comparative analysis of nerve regeneration may provide insights into what is required for successful nerve regeneration and suggest strategies for promoting CNS regeneration in mammals. The session will begin with a review by Herb Geller on regenerative failure in the mammalian CNS with emphasis on inhibitory molecules and will summarize current eﬀorts at promoting regeneration. James Fawcett will discuss recent work comparing CNS and PNS nerve regeneration which suggests that local protein synthesis and growth cone reformation may explain the diﬀerence between CNS and PNS axons. Optic nerve regenera-

January 23–28, 2005 • Breckenridge, Colorado 123 tion in goldﬁsh will be discussed by Ron Meyer who will show that regeneration involves massive restructuring of axons, rearrangement of synaptic connections by competition and abnormal activity patterns in the target. Ken Muller will discuss leech CNS regeneration and will provide evidence that microglia migration may be critical for regeneration and will show that restoration of function entails more than the formation of the correct synapses.

0Panel • Friday 7:30–9:30 AM • Peak 150

Smart, Skinny and Pain Free: Therapeutic Endpoints of Histamine H3 Receptor Modulation Michael Ahlijanian, Phil Iredale, Gerard Fox, Karin Rimvall, Keri Cannon Originating in the hypothalamus, histaminergic neurons project to key brain regions including forebrain, hippocampus, amygdala and hypothalamus. The four histamine receptors, H1-H4, are GPCRs. The H3 receptor is expressed primarily in brain and is localized to nerve terminals. H3 receptors function as autoreceptors at histaminergic terminals but are also expressed heterologously and regulate neurotransmitter release at cholinergic, dopaminergic, serotonergic and noradrenergic synapses. Given the projection targets of histaminergic neurons and the regulation by H3 receptors of the release of several neurotransmitters, it is hypothesized that H3 receptors play a significant role in key CNS functions. Recently, the development of selective pharmacological tools and genetically modified mice have enabled a clearer picture of the role of H3 receptors. Phil Iredale will provide an overview of the physiology, pharmacology and function of the H3 receptor system. Gerry Fox will present a perspective of how different behavioral domains that are relevant to disorders such as attention deficit, Alzheimer’s disease and schizophrenia are influenced by H3 ligands. Karin Rimvall will provide an overview of histaminergic involvement in the regulation of energy homeostasis, relate this to other “energy-relevant” CNS systems such as POMC/NPY and describe food- intake/body-weight data with H3 antagonists in various animal models. Keri Cannon will discuss the antinociceptive profile that distinguishes H3 agonists as a unique and selective class of analgesics acting at the level of the spinal cord.

124 38th Annual Winter Conference on Brain Research 0Panel • Friday 7:30–9:30 AM • Peak 170

Novel Ways of Seeing the Light: Photosensitive Ganglion Cells, Melanopsin, and Cryptochromes in Circadian Entrainment and Non-Image Forming Vision Michael Iuvone, David Berson, Samer Hattar, Russel van Gelder Traditional, image-forming vision requires rod and cone photoreceptors, degeneration of which results in “blindness.” However, animals without rods and cones retain certain visual functions, such as light entrainment of circadian rhythms and the pupillary light reﬂex. This panel focuses on the cellular sources of this residual visual function. The ganglion cells in the mammalian retina that form the retino-hypothalamic tract are intrinsically light sensitive. These ganglion-cell photoreceptors express the novel phot- opigment melanopsin, encode ambient light intensity, and drive circadian and pupillary responses to daylight. David Berson will describe the physiology of these cells and their projections to the suprachiasmatic nucleus and other areas, including limbic regions involved in arousal and motivation and a brainstem gaze-control center. He will describe the synaptic regulation of these cells and evidence that the phototransduction machinery in these cells diﬀers substantially from that in rods, cones, or invertebrate photoreceptors. Samer Hattar will discuss the individual contribution of rods, cones and melanopsin to light signaling for a variety of non-image forming visual functions. Russ van Gelder will describe the photoresponses of two non-visual, ocular photoreceptors: intrinsically photosensitive murine retinal ganglion cells and the isolated embryonic chicken iris. Analysis of the relative contributions of melanopsin and cryptochromes in these photoreceptors will be presented. Mike Iuvone will present an analysis of chick retina, where melanopsin and cryptochrome 1 are expressed in multiple cell types, in addition to ganglion cells, under the control of local circadian clocks.

0Panel • Friday 7:30–9:30 AM • Peak 6–80

Regulated mRNA Traﬃcking and Local Protein Synthesis in Synaptic Remodeling and Plasticity R. Suzanne Zukin, Hollis Cline, Tim Tully, Gary Bassell The localization of polyribosomes to subsynaptic sites in dendrites provides an important mechanism to inﬂuence synaptic architecture and plasticity. Recent studies have begun to elucidate mechanisms of mRNA localization and translational regulation at synapses. This session will high-

January 23–28, 2005 • Breckenridge, Colorado 125 light the broad spectrum of research on this topic including physiological, cellular and molecular approaches to this question. Bassell will speak on a role for Fragile X Mental Retardation Protein (FMRP) in dendritic mRNA trafficking, synaptic protein synthesis and morphological plasticity. He will present data showing that mGluR activation stimulates the trafficking of FMRP and associated mRNAs into dendrites of hippocampal neurons. Zukin will discuss evidence for the localization and bidirectional regulation of AMPA receptor mRNA trafficking in dendrites. Whereas NMDA receptor activation promotes retrieval of AMPAR mRNA from dendrites, mGluR activation promotes mRNA targeting to synapses. Tully will discuss molecular mechanisms of long-term memory formation. Long-lasting synaptic plasticity in many species depends on CREB-mediated gene transcription and subsequent structural and functional modification of synapses. He will summarize evidence that the pumilio/staufen pathway is critical to memory formation. Cline will discuss the control of dendritic arbor structural plasticity by local protein synthesis. She will present new findings that CFP-tagged CPEB is concentrated in granules at the base of new dendritic branches and that CPEB-mediated protein synthesis controls structural plasticity of optic tectal cell dendritic arbors in living Xenopus tadpoles. These studies underscore the importance of regulated mRNA localization and translation as a means to influence the protein composition at postsynaptic sites and achieve changes in synaptic architecture and strength.

0Panel • Friday 7:30–9:30 AM • Peak 9–100

Novel Immunotherapies Against B-Amyloid, Brain Tumors, and Ischemic Damage Sylvain Dore, Maciej Lesniak, Eduardo Zamora, Remi Quirion The immune reactivity of the brain is becoming a unique target for several therapeutic interventions against either acute or chronic neurodegenerative disorders. Diﬀerent interventional aspects will be presented by a neuropathologist, a neurosurgeon, and neuroscientists. Lesniak is looking at new therapies against brain tumors that would speciﬁcally target tumor cells and spare normal cells. Malignant brain tumors rank second in the pediatric population and fourth in the middle-aged population as the cause of death due to cancer. Conventional therapy consists primarily of surgical debulking followed by radiation therapy. Unfortunately, the median survival after surgical intervention alone is six months, with only 7.5% of patients surviving for two years. One treatment modality, immu- notherapy, has shown promise in the spectrum of agents utilized against malignant brain tumors. Recent data will be presented in regard to current and future immunotherapeutic approaches to the treatment of these brain

126 38th Annual Winter Conference on Brain Research tumors, including the application of hematopoietic stem cells, dendritic cell, cytokines, and peptide vaccines. Zamora will present evidence that the papillomavirus-like particle A_ vaccine induces specific antibody response and prevents behavioral impairment in the APP/PS1 transgenic AD mouse model. Neuropathologic analysis shows a higher number of activated microglial cells surrounding plaques of mice immunized, as compared to controls, suggesting the activation of these neuroinflammatory cells as one of the mechanisms for amyloid removal and cognitive improvement in these mice. Quirion will focus on the use of genomics and proteomics approaches to identify new leads and intracellular pathways potentially involved in the etiology of aged-related dementia and cognitive impairments. Doré will offer a potential explanation as to why COX-2 inhibitors have failed in AD clinical trials. Anti-inflammatory drugs have been suggested to decrease the incidence of AD and potentially reduce infarct damage, while the mechanism of action is still poorly understood. PGE2 has been traditionally called the “proinflammatory” prostaglandin. Evidence suggests that depending on which G protein-coupled receptors, PGE2 can either promote neurotoxicity or neuroprotection. Revising the immune role of the brain and targeting a unique path can help in the design of new therapies against brain damage. (Supported by NINDS, NIA and CIHR.)

0Panel • Friday 4:30–6:30 PM • Peak 11–120

CaM-Kinase Signaling from Synapse to the Nucleus Tom Soderling, Johannes Hell, Andres Barria, Anthony Means Calcium signaling is essential for neuronal development and plasticity. Many of these calcium responses are mediated by the family of Ca2+/ calmodulin-dependent protein kinases (CaMK) that are highly expressed in neurons. This panel presentation will give the audience an overview of CaMK signaling in neurons with an emphasis on recent developments of physiological importance. Most attention in the CaMK field has been focused on the multifunctional CaMKII that is localized in postsynaptic densities (PSD) with multiple substrates (e.g., the GluR1 subunit of the AMPA-type glutamate receptor). Studies in the past five years have demonstrated an activity-dependent translocation of CaMKII to the PSD where it interacts with multiple proteins such as the NMDA-R. Dr. Johannes Hell will describe recent work from his laboratory on multiple interactions of CaMKII and CaM with different NMDA-R subunits. Dr. Andres Barria will present data showing that the developmental switch in NMDA-R subunit composition, that controls receptor current, is due to altered binding of active CaMKII.

January 23–28, 2005 • Breckenridge, Colorado 127 In addition to CaMKII, members of the CaMK cascade are also critical for neuronal development and plasticity. The CaMK cascade consists of CaMKI, CaMKIV and their upstream activator CaMKK. CaMKI is cytosolic whereas CaMKIV is largely nuclear and regulates gene transcription. Dr. Tom Soderling will describe regulatory functions of CaMKKÆCaMKI in axonal outgrowth and LTP in hippocampus. Dr. Anthony Means will present experiments from knockout mice illustrating a role for CaMKKÆCaMKIV in regulation of neurotropin expression and cerebellar granule cell migration during development.

0Panel • Friday 4:30–6:30 PM • Peak 140

Glial Immunity and Neurotoxicity Tsuneya Ikezu, Howard Gendelman, G. Jean Harry, Dennis Kolson Accumulating evidence suggests that immune/inflammatory responses play a major contributory role to the injury process in multiple neuronal injury models; including trimethyltin (TMT), HIV-1 associated dementia (HAD), Parkinson‚s disease (PD), and Alzheimer‚s disease (AD). The mechanism of neurotoxicity has both diversity and commonality. Differ- ent disease-related molecules are responsible for the direct neurotoxicity, such as TMT, a hippocampal toxicant, viral proteins for HAD, beta-amyloid peptide for AD, and a-synuclein and parkin for PD. Each molecule induces distinct signaling for neuronal cell death in vitro. However, these molecules are also responsible for indirect neurotoxicity via mononuclear phagocyte (MP) activation, which commonly involves reactive oxygen species (ROS, such as nitric oxide and superoxide), excitotoxins (such as glutamate, quinolinic acid, and D-serine), and host cell factors (such as TNF-a, SDF-1a, C1q, and cyclins). These studies address many emerging issues for mononuclear phagocyte (MP)-mediated neurotoxicity: What is the common pathway for inducing MP-mediated neurotoxicity by different disease-related molecule stimulation? Is the common pathway related to neuroprotective function of MP? Can we target a common pathway for the treatment of a broad range of neurodegenerative disorders? How important is MP-mediated neurotoxicity as compared to the direct neurotoxicity of disease-related molecules? Is there synergy between direct and MP-mediated neurotoxicity? We will discuss these controversial issues with leading investigators studying neurotoxicity in TMT, HAD, PD, and AD models. This is an exciting area of research and has a significant potential for application to other neurodegenerative disorders, such as Huntington’s disease, amyotrophic lateral sclerosis, and Lewy body diseases.

128 38th Annual Winter Conference on Brain Research 0Panel • Friday 4:30–6:30 PM • Peak 150

Vascular Adaptation in the Brain Paula Dore-Duffy, Jeffrey Dunn, Greg del Zoppo, Nicole Ward The heterogeneous distribution of the CNS microvasculature is likely to result from the coupling of blood flow (delivery) with metabolic demand. Neuronal activation or altered substrate or oxygen availability may result in profound changes in blood flow. Long term changes in neuronal activity or oxygen availability are accompanied by profound adaptive vascular remodeling. In fact, these findings have led to a new appreciation of vascular plasticity in the adult mammalian brain and an intense interest in uncovering the cellular and molecular mechanisms responsible for new vessel formation or angiogenesis. Regulation of angiogenesis involves complex interaction of vascular cells (endothelial cells and pericytes) and parenchymal cells such a glia and neurons. On a molecular level this interaction involves a number of signaling molecules such as membrane metalloproteinases (MMPs) angiogenic growth factors. Failure of adaptive remodeling through various pathological influences can lead to loss of brain function. This workshop will focus on regulation of CNS angiogenesis and its inter- relationship to neural plasticity. Following an introduction of the basic tenants of CNS angiogenesis, Jeff Dunn will use MRI, NIR and EPR data as a framework to discuss the link between physiological parameters such as oxygen availability and cerebral blood flow, and vascular remodeling as indicated by capillary morphometrics and changes in blood volume. Cell-cell interactions and vascular plasticity will be discussed by Paula Dore-Duffy. Greg del Zoppo will discuss the importance and role of MMPs in cerebral angiogenesis and ischemia. Nicole Ward will present evidence of co-dependence between molecular signals and growth factors linking neurons and blood vessels in forebrain.

0Panel • Friday 4:30–6:30 PM • Peak 170

From the Primary Afferent to the Brain: Mechanisms Underlying Sex Differences in Pain and Analgesia Anne Murphy, Michael Gold, Alvin Beitz, Jon-Kar Zubieta There is increasing evidence that men and women differ both in their responsiveness to painful stimuli and in the ability of analgesics, particularly opioids, to suppress it. For example, in both human and animal

January 23–28, 2005 • Breckenridge, Colorado 129 studies, the effective dose of morphine for females is generally 4-8x higher than males. The basis for this difference remains unknown, however, in the last several years, a number of potential mechanisms have been identified. This symposium will feature three basic scientists and one research clini- cian whose research programs focus on mechanisms that may contribute to sex differences in pain and analgesia. A unique feature of this symposia is that the speakers will address potential sexually-dimorphic mechanisms throughout the neuraxis: Dr. Michael Gold will talk about steroid modulation of primary afferent excitability; Dr. Alvin Beitz will speak on spinal cord mechanisms contributing to sex-based differences in sensory perception, and estrogen modulation of dorsal horn nociceptive responses; Dr. Anne Murphy (Chairperson) will speak on the role of the endogenous pain circuits, in particular the periaqueductal gray (PAG), as a potential neural substrate for sex-based differences in opioid analgesia; and Dr. Jon-Kar Zubieta will present his human brain imaging data showing sexually dimorphic features and responses of the endogenous opioid system to pain, as well as their regulation by gonadal steroids. Together, this symposium will provide a broad, yet in depth view of potential CNS and PNS mechanisms underlying sex based differences in pain and analgesia.

0Panel • Friday 4:30–6:30 PM • Peak 6–80

Non-Homeostatic Central Mechanisms Involved in Feeding Regulation and Dietary Obesity Emmanuel Pothos, Sarah Leibowitz, Bartley Hoebel, Amy MacDonald Research on body weight regulation has traditionally focused on homeostatic mechanisms of energy balance. However, the explosive prevalence of dietary obesity in 54% of US adult population strongly suggests that non-homeostatic central mechanisms may induce a strong preference for high-energy diets and increase weight gain. This panel will focus on central circuits and signals in rodents that may induce excessive caloric intake disproportionate to energy needs and override any compensatory homeostatic response. Sarah Leibowitz will consider whether an increased availability of nutrients can initiate a positive feedback “vicious cycle” between dietary and circulating fats and hypothalamic peptides and may contribute to overconsump- tion of high-fat diets. Bart Hoebel will discuss whether repeated intermittent sugar intake can lead to behavioral and neurochemical signs of addiction, with changes in delta Fosb, opiate receptor and D3 binding and dopamine and acetylcholine release in the accumbens.

130 38th Annual Winter Conference on Brain Research Amy MacDonald will describe an opioid network of feeding-related sites in the midbrain. Evidence for this network arises from dual-site opioid microinjection feeding studies in the ventral tegmental area and nucleus accumbens. Emmanuel Pothos will discuss the signiﬁcant depression of basal synaptic central dopamine levels induced by dietary obesity and the upregulation of neuronal vesicular monoamine transporters in neonatal obesity-resistant rats. Together, the presentations will show how inborn, learned and dietary factors can interact to program brain functions that contribute to obesity.

0Panel • Friday 4:30–6:30 PM • Peak 9–100

Novel Quantitative Trait Genes (QTGs) for Sedative- Hypnotic Drug Dependence, Withdrawal, and Sensitivity Kari Buck, Thomas Johnson, Robert Hitzemann, Robert Williams Sedative-hypnotic drugs are widely abused for their euphoric and sedative effects. A host of biological (genetic) and environmental factors interact throughout the addictive process to influence drug use/abuse. There is a great deal of common genetic influence on response to and withdrawal from sedative-hypnotics including benzodiazepines, inhalants, alcohol, and barbiturates. Physiological dependence and associated withdrawal episodes can constitute a motivational force that perpetuates sedative- hypnotic use/abuse and contributes to relapse. The identification of genes that influence sedative-hypnotic sensitivity and dependence/withdrawal has been very limited. The use of preclinical (animal) models that closely approximate the clinical situation is essential for advancing elucidation of the genes, pathways and neural circuits involved, and to evaluate their roles in motivation to use/abuse drugs and relapse. Kari Buck will discuss identification of Mpdz as a QTG with pleiotropic effects on sedative-hypnotic withdrawal using fine-mapping, sequence, expression, and transgenic analyses. Signal transduction pathways and neural circuits affected by Mpdz, which encodes the multiple PDZ domain protein, will be discussed. Thomas Johnson will discuss genes of interest for sensitivity to alcohol sedation-hypnosis tested using phenotypic, gene-expression, neurochemical, knock-out, and siRNA analyses. Robert Hitzemann will discuss the integration of quantitative trait locus and gene expresssion analyses as a strategy for high-throughput detection of QTGs associated with ethanol preference and ethanol-induced locomotor activation. The value of short-term selective breeding to facilitate integration

January 23–28, 2005 • Breckenridge, Colorado 131 will be discussed. Robert Williams will discuss that large families of genes involved in synapse function and vesicle traﬃcking are modulated by a few master QTGs including Mpdz.

0Panel • Friday 4:30–6:30 PM • Peak 150

Ion Channel Localization, Function, and Targeting in Axons Matthew Rasband, Stephen Lambert, Edward Cooper, James S. Trimmer Dr. Lambert will talk about the targeting of voltage-gated sodium channels in the myelinated axon. He will describe a universal motif in Na+ channels that promotes binding to cytoskeletal adaptor proteins, and the role this interaction plays in trafficking and retention at specialized areas of the axonal membrane. He will discuss mechanisms by which Schwann cells direct clustering of voltage-gated ion channels. Dr. Cooper will describe studies showing that KCNQ channels are targeted to nodes of Ranvier and axon initial segments. He will discuss the subunit composition of these channels and the molecular signals mediating their selective concentration at these axonal subdomains. He will review morphological and electrophysiological studies using normal and transgenic animals that allow analysis of the functions played by axonal KCNQ channels at the cellular, network, and behavioral level, during development and in adult animals. Dr. Trimmer will describe studies on the regulation of surface expression, subunit composition and localization of axonal Kv1 potassium channels. He will describe molecular, electrophysiological and biochemical studies that defined an endoplasmic reticulum retention signal near the pore of certain Kv1 subunits. He will also discuss the surprising relationship of this trafficking signal to the binding site of certain neurotoxins, and implications for regulation of channel expression by endogenous mammalian pro- totoxins. Dr. Rasband will discuss both cellular and molecular mechanisms responsible for ion channel clustering and localization at nodes of Ranvier and axon initial segments. He will focus on the role of neuronal cytoskeletal scaffolding proteins in this process.

132 38th Annual Winter Conference on Brain Research January 23–28, 2005 • Breckenridge, Colorado 133 134 38th Annual Winter Conference on Brain Research Participants Elizabeth Abercrombie Margie Ariano, 86, 119 Rutgers University Rosalind Franklin University of Medicine & [email protected] Science [email protected] Mary Abood California Pacific Medical Center Gary Aston-Jones, 90 [email protected] University of Pennsylvania [email protected] Frederick Adewale Smith Technologies Limited Steven Aust, 27, 43, 120 [email protected] Utah State University [email protected] Greti Aguilera, 103 National Institute of Child Health and Aldo Badiani, 29 Human Development University of Rome “La Sapienza” [email protected] [email protected] Michael Ahlijanian, 124 Wia Baron, 79 Pfizer, Inc. University of Groningen [email protected]fizer.com [email protected] Elias Aizenman, 94 Andres Barria, 127 University of Pittsburgh School of Medicine Cold Spring Harbor Laboratory [email protected] [email protected] Florin Amzica, 111 Anthony Basile Laval University DOV Pharmaceuticals fl[email protected] [email protected] Brenda Anderson, 89 Gary Bassell, 125 Psychology Albert Einstein College of Medicine [email protected] [email protected] Kathleen Anderson, 81 Jill Becker, 66 National Institute of Mental Health University of Michigan [email protected] [email protected] Rodrigo Andrade, 115 Sara Becker-Catania, 80 Wayne State University Hines VA Hospital [email protected] [email protected] Veronique Andre, 26 Alvin Beitz, 129 University of California Los Angeles University of Minnesota [email protected] [email protected] Anne Andrews, 118 Esther Bell. 88 Pennsylvania State University Rockefeller University [email protected] [email protected] Luigi Anzivino, 27 Michael VL Bennett, 94 UCLA Albert Einstein College of Medicine [email protected] [email protected] Paul Ardayfio Nicole Berchtold Harvard Medical School/Mclean Hospital University of California Irvine paul_ardayfi[email protected] [email protected]

January 23–28, 2005 • Breckenridge, Colorado 135 Richard Beresford Anne Boullerne, 80 Univesrity of Rochester School of Medicine University of Chicago [email protected] [email protected] Craig Berridge Charles Bradberry, 110 University of Wisconsin University of Pittsburgh [email protected] [email protected] David Berson, 125 Nicholas Brecha, 117 Brown University University of California Los Angeles School [email protected] of Medicine Llewellyn Bigelow David Bredt, 109 NIMH UCSF [email protected] [email protected] Carol Birmingham Michael Brenner, 66 Chemicon International University of Alabama Birmingham [email protected] [email protected] Pierre Blier, 77 Jeff Bronstein, 86 University of Ottawa, Institute of Mental University of California Los Angeles Health R [email protected] [email protected] John Bruno, 65 Jim Bloedel The Ohio State University Iowa State University [email protected] [email protected] Robert Bryan, 70 Martha Bohn Baylor College of Medicine Northwestern University, Feinberg School [email protected] of Medicine [email protected] Kari Buck, 100, 131 Oregon Health & Science University Karen Bolla, 65, 91 [email protected] Johns Hopkins University School of Medicine Joshua Buckholtz, 33 [email protected] National Institute of Mental Health [email protected] Stephen Bondy, 81 University of California Irvine Deanne Buffalari, 34 [email protected] University of Pittsburgh buff[email protected] Stephanie Borgland, 31 Ernest Gallo Clinic and Research Center at William Bunney, 68 UCSF Universtiy of California Irvine [email protected] [email protected] Blaise Bossy James Burke, 101 The Burnham Institute Duke University Medical Center [email protected] [email protected] Ella Bossy-Wetzel, 72 David Busija, 70 The Burnham Institute Wake Forest University Health Sciences [email protected] [email protected]

136 38th Annual Winter Conference on Brain Research William H. Calvin Chiara Cirelli, 105 University of Washington University of Wisconsin, Madison [email protected] [email protected] [email protected] Jon Clarke, 88 Roberta Calzavara, 35 University College London Univ Rochester MC [email protected] [email protected] Paul Clarke, 102 Wendy Campana, 74 McGill University University of California San Diego [email protected] [email protected] Thomas Cleland, 71 Keri Cannon, 124 Cornell University Albany Medical College [email protected] [email protected] Holly Cline, 125 Melissa Carpenter Cold Spring Harbor Lab Robarts Research Institute [email protected] [email protected] Robert Coghill Vincent Cassone, 96 Wake Forest University School of Medicine Texas A&M University [email protected] Stacy Castner, 78 Carlo Colantuoni, 121 Yale University School of Medicine National Institutes of Health [email protected] [email protected] Kenneth Catania, 85 Carol Colton, 101 Vanderbilt University Duke Univ Medical Center [email protected] Cheryl Conrad, 89 William Catterall, 107 Arizona State University University of Washington [email protected] [email protected] Lisa Conti, 108 Jane Cavanaugh University of Connecticut Health Center University of Pittsburgh [email protected] [email protected] Tim Cook David Chambers, 88 Biopac Systems King’s College London [email protected] [email protected] Jone Cooner Judson Chandler [email protected] MUSC [email protected] Rosa Cossart, 122 INSERM/ Universite de Marseilles Karen Chandross, 80 [email protected] Aventis Pharmaceuticals [email protected] Carl Cotman, 93 University of California Irvine Mitchell Chesler, 120 [email protected] New York University School of Medicine [email protected] Stephanie Cragg, 102, 110 University of Oxford Ski Chilton [email protected] Wake Forest University School of Medicine

January 23–28, 2005 • Breckenridge, Colorado 137 Karina Cramer, 87 Paula Dore-Duffy, 129 University of California Irvine Wayne State University School of Medicine [email protected] pdduff[email protected] Fulton Crews, 81, 93 Emily Drabant, 38 University of North Carolina at Chapel Hill NIH/NIMH [email protected] [email protected] Mary Dallman, 103 Giles Duffield, 61, 96 University of California San Francisco Dartmouth Medical School [email protected] giles.duffi[email protected] Duff Davis, 75 Jeff F. Dunn, 129 Pfizer Inc. University of Calgary duff.davis@pfizer.com [email protected] Hana Dawson, 37 Timothy Duong, 75 Duke University Emory University [email protected] [email protected] Jean De Vellis Barney Dwyer, 120 University of California, Los Angeles VA Medical Center [email protected] [email protected] George De Vries, 80 Burr Eichelman Hines Va Hospital University of Wisconsin [email protected] [email protected] Albert Wallace Deckel, 101 Heather Eisthen, 85 University of Connecticut Health Center Michigan State University [email protected] [email protected] Gregory J del Zoppra, 129 Lisa Ellerby The Scripps Research Institute Buck Institute for Age Research [email protected] [email protected] David Devilbiss, 108 Helene Emsellem University of Wisconsin The Center for Sleep& Wake Disorders [email protected] [email protected] Luda Diatchenko, 74 Mary Anne Enoch University of North Carolina Chapel Hill National Institutes of Health [email protected] [email protected] Kelly Dineley, 97 Chris Evans, 90 University of Texas Medical Branch UCLA [email protected] [email protected] Maria Donoghue, 96 Andrew Ewing, 118 Yale University School of Medicine Penn State University [email protected] [email protected] Sylvain Dore, 126 David Eyerman, 42 Johns Hopkins University Boston University School of Medicine [email protected] [email protected]

138 38th Annual Winter Conference on Brain Research James Fawcett, 123 William Freed, 76 Cambridge University DHHS/NIH/NIDA/Intramural Research [email protected] Program [email protected] David Feifel, 28, 112 University of California, San Diego Sarah French, 119 [email protected] University of Oxford [email protected] Douglas Feinstein, 80 University of Illinois Lloyd Fricker [email protected] Albert Einstein College of Medicine [email protected] Janet Finlay, 67 Western Washington University James Frost, 90 janet.fi[email protected] Johns Hopkins University [email protected] Deborah Finn, 73 Oregon Health & Science University Denson Fujikawa fi[email protected] VA GLAHS/UCLA [email protected] Gabriele Fischer, 70 Medical University Vienna Babette Fuss, 79 gabriele.fi[email protected] Virginia Commonwealth University [email protected] Gary Fiskum, 72 University of Maryland School of Medicine Don Gash, 105 gfi[email protected] University of Kentucky [email protected] Bob Foehring, 115 University of Tennessee Maciej Gasior, 43 [email protected] NINDS/NIH [email protected] Ian Forsythe, 87 University of Leicester Maria J Gasior [email protected] DHHS/NIH/NIDA/IRP [email protected] Gerard Fox, 124 Abbott Laboratories Jerry Gebhart [email protected] University of Iowa [email protected] Peter Fox, 75 University of Texas Health Sciences Center Herbert Geller, 123 San Antonio NIH [email protected] [email protected] Donald Franz Mark Geyer University of Utah University California San Diego [email protected] Alan Frazer, 77 University of Texas Health Science Center Martha Gillette, 105 [email protected] Univesrity of Illinois [email protected] Curt Freed, 76 University of Colorado Health Sciences Asa Gilthorpe (Apelqvist), 44 Center MRC Centre [email protected] [email protected]

January 23–28, 2005 • Breckenridge, Colorado 139 Andrea Giuffrida, 106 Suzanne Guenette, 46 University of Texas Health Science Center Massachusettes General Hospital giuff[email protected] [email protected] Michael Gold, 129 Suzanne Haber, 91, 110 University of Maryland, Baltimore University of Rochester [email protected] [email protected] Stephen Gold, 69 Edward Hall University of Texas University of Kentucky [email protected] [email protected] Michelle Goldman Jonathan Hanley, 84 University of Califonia at Irvine University of Bristol [email protected] [email protected] Monica Gonzalez, 45 Sami Harik University of Pennsylvania University of Arkansas College of Medicine [email protected] [email protected] Anthony Grace, 76 Ronald Harris-Warrick, 111 University of Pittsburgh Cornell University [email protected] [email protected] Richard Gracely, 64 Jean Harry, 128 University of Michigan National Institute of Environmental Health [email protected] Sciences [email protected] Tim Greenamyre, 74, 86 Emory University Teresa Hastings, 74 [email protected] University of Pittsburgh [email protected] Geoff Greene MicroBrightField, icn. Samer Hattar, 125 shannon@microbrightfield.com Johns Hopkins University [email protected] William T Greenough, 93 University of Illinois Urbana-Champaign Mary Hatten, 108 [email protected] Rockefeller University [email protected] Ron Gregg, 117 University of Louisville Glenn Hatton, 83 [email protected] University of California [email protected] Karen Greif Bryn Mawr College Johannes W Hell, 109, 127 [email protected] University of Iowa [email protected] Sue Griffin, 66 University of Arkansas Medical Sciences Fritz Henn griffi[email protected] University of Heidelberg [email protected] Gary Gudelsky, 83 University of Cincinnati Joe Herbert, 46 [email protected] University of Cambridge [email protected]

140 38th Annual Winter Conference on Brain Research Sandra Hewett Donald Ingram, 93 University of Connecticut Health Center National Institute on Aging [email protected] [email protected] Robert Hitzemann, 131 Philip Iredale, 124 Oregon Health & Science University Pﬁzer [email protected] [email protected]ﬁzer.com Bart Hoebel, 130 John Isaac, 84 Princeton University NIH [email protected] [email protected] John Hogenesch, 96 Michael Iuvone, 125 The Scripps Research Institute Emory University School of Medicine [email protected] [email protected] Jau-Shyong Hong, 74, 81 Lisa Jackson, 66 National Institute of Environmental Health University of Michigan Sciences/National Institutes of Health [email protected] [email protected] Leslie Jacobsen, 95 Kristen Ashley Horner, 83 Yale University School of Medicine University of Utah [email protected] [email protected] Mark Jacquin, 96 Michael Howren Washington University School of Medicine Carl Zeiss Micro Imaging [email protected] [email protected] Luc Jasmin, 64 Sabina Hrabetova, 83 University of California, San Francisco New York University School of Medicine [email protected] [email protected] Hank Jedema, 69 Kun Huang University of Pittsburgh University of British Columbia [email protected] [email protected] Bruce Jenkins, 75 Paul Huang Massachusetts General Hospital Massachusetts General Hospital [email protected] [email protected] J. David Jentsch, 67, 112 Robert Huber University of California Los Angeles Bowling Green State [email protected] [email protected] Sheilah Jewart Laura Hurley, 47, 71 American Society for Neurochemistry Indiana University [email protected] [email protected] Emily Jocoy, 49 Thomas Hyde UCLA National Institute of Mental Health, IRP, NIH [email protected] [email protected] Alan Kim Johnson Satoshi Ikemoto, 48 University of Iowa NIDA/NIH [email protected] [email protected]

January 23–28, 2005 • Breckenridge, Colorado 141 Delinda Johnson Hans Keirstead, 110 University of Wisconsin University of California at Irvine [email protected] [email protected] Jeff Johnson, 89 Edward Keller University of Wisconsin Smith-Kettlewell Institute [email protected] [email protected] Thomas Johnson, 131 Ann Kelley University of Colorado University of Wisconsin [email protected] [email protected] Rolf Joho John Kelsoe, 50 UT Southwestern University of California, San Diego [email protected] [email protected] Elizabeth Jonas, 94 John Kemp Yale University School of Medicine Evotec Neurosciences [email protected] [email protected] Carter Jones, 49 Robert Kennedy, 118 University of Iowa University of Michigan [email protected] [email protected] Richard Jones, 114 Anna Kenney, 51 VA Medical Center/Oregon Health & Science Dana-Farber Cancer Institute University [email protected] [email protected] Andrew Kertesz James Joseph, 93 University of Western Ontario USDA HNRCA at Tufts University [email protected] [email protected] Karl Kieburtz, 86 Leonard Kaczmarek, 87 University of Rochester Medical Center Yale University School of Medicine [email protected] [email protected] Ross Kinloch, 79 Peter Kalivas, 65, 90 Pfizer Global Research and Development Medical University of South Carolina ross.kinloch@pfizer.com [email protected] Sergei Kirov, 52 Karl Kandler, 113 Medical College of Georgia University of Pittsburgh [email protected] [email protected] Josef Kittler, 109 Kathleen Karmel University College London Olympus America, Inc [email protected] @olympus.com David Klein, 39 Harvey Karten NIH University of California, San Diego [email protected] [email protected] and mdbeaupre@ucsd. edu Joel Kleinman National Institute of Mental Health Paul Katz, 85 [email protected] Georgia State University [email protected]

142 38th Annual Winter Conference on Brain Research Gregory Konat, 114 Gabrielle Leblanc West Virginia University School of Medicine NINDS [email protected] [email protected] Christine Konradi, 121 Daniel Lee, 97 McLean Hospital-Harvard Medical School Biogen Idec Inc., [email protected] [email protected] George Koob Charles Leffler, 70 The Scripps Research Institute University of Tennessee [email protected] cleffl[email protected] Conan Kornetsky, 70 Elin Lehrman, 121 Boston University School of Medicine NIH/NIDA Intramural Research Program [email protected] [email protected] Stephen H. Koslow, 108 Sarah Leibowitz, 130 National Institute of Mental Health/National The Rockefeller University Institutes of Health [email protected] [email protected] Ed Lein, 92 Henry Kranzler, 73 Allen Institute for Brain Science University of Connecticut Health Center [email protected] [email protected] Maciej Lesniak, 126 John Krystal, 100 University of Chicago Yale University School of Medicine [email protected] [email protected] Barry Levin, 93 George Kunos, 106 VA Medical Center NIH/NIAAA/DICBR [email protected] [email protected] Joel Levine John Kusiak, 74 SUNY at Stony Brook Division of Basic and Translational Sciences [email protected] [email protected] Michael Levine Joseph C. LaManna Universtiy of California Los Angeles Case Western Reserve University [email protected] Steve Levison UMDNJ-NJMS Richard Lane, 85 [email protected] Medical College of Ohio [email protected] Irwin Levitan University of Pennsylvania Marc Laruelle, 110 [email protected] NYSPI/Columbia University [email protected] Anita Lewin RTI International Dianne Lattemann, 93 [email protected] VA Puget Sound Health Care System [email protected] Stafford Lightman, 103 University of Bristol Antonieta Lavin, 67 staff[email protected] Medical University of South Carolina [email protected] Rick C. S. Lin, 77 University of Mississippi Medical Center [email protected]

January 23–28, 2005 • Breckenridge, Colorado 143 Iris Lindberg Wendy Macklin, 79 Louisiana State University Cleveland Clinic Foundation [email protected] [email protected] Barbara Lipska Katrina MacLeod, 87 NIMH University of Maryland [email protected] [email protected] Witold Lipski, 52 Malcolm Maden, 88 University of Pittsburgh King’s College London [email protected] [email protected] C. Robert Lischer Timothy Maher San Diego Instruments, Inc. Massachusetts College of Pharmacy [email protected] [email protected] Fang Liu, 122 Nigel Maidment Center for Addiction and Mental Health University of California Los Angeles [email protected] [email protected] Jeanne Loring, 115 Roberto Malinow, 84 The Burnham Institute Cold Spring Harbor Laboratory [email protected] [email protected] Irwin Lucki, 77 Laura Mamounas, 81 University of Pennsylvania NINDS/NIH [email protected] [email protected] Ronald Lukas, 97 Athina Markou, 102 Barrow Neurological Institute The Scripps Research Institute [email protected] [email protected] Robert Lundy, 71 Neville Marks Penn State College of Medicine New York University rﬂ[email protected] [email protected] David Luo, 74 Giovanni Marsicano, 106 University of California Irvine Max Planck Institute of Psychiatry [email protected] [email protected] Minda Lynch, 81 Hugh Marston National Institute on Drug Abuse Organon Laboratories [email protected] [email protected] Ernie Lyons, 81 Steve Massey, 117 NINDS/NIH University of Texas Medical School at [email protected] Houston [email protected] Amy MacDonald, 130 University of Minnesota Maureen McCall, 117 [email protected] University of Louisville [email protected] Ken Mackie, 106 University of Washington Una McCann, 95 [email protected] The Johns Hopkins School of Medicine [email protected]

144 38th Annual Winter Conference on Brain Research Cheryl McCormick, 89 David W Miller, 53 Brock University National Institute of Health [email protected] [email protected] John McDonald, 110, 115 LeeAnn Miner, 69 Washington University University of Pittsburgh [email protected] [email protected] James G. McElligott Bita Moghaddam, 76 Temple University University of Pittsburgh [email protected] [email protected] Krista McFarland James Morgan, 89 Medical University of South Carolina St. Jude Children’s Research Hospital [email protected] [email protected] Jacqueline McGinty, 83, 90 A. Leslie Morrow, 73 Medical University of South Carolina UNC School of Medicine [email protected] [email protected] John McHaﬃe, 98 Thomas Morrow Wake Forest University School of Medicine VA Hospital / University of Michitan mchaﬃ[email protected] [email protected] Hugh B McIntyre Ken Muller, 123 Harbor-UCLA Medical Center University of Miami School of Medicine [email protected] Ewan McNay, 93 Yale University School of Medicine Chris Muly, 78 [email protected] Emory University [email protected] Dana McTigue Ohio State University Karen Munoz, 54 [email protected] NIH/NIMH [email protected] Anthony R. Means, 127 Duke University Medical Center Anne Murphy, 129 [email protected] Georgia State University [email protected] Synthia Mellon, 73 University of California San Francisco N. Eric Naftchi [email protected] New York University Medical Center Marsha Melnick Kim Neve, 54 UCSF/SFSU VA Medical Center [email protected] [email protected] Simon Melov Robert Nichols, 97 Buck Institute for Age Research Drexel University College of Medicine [email protected] [email protected] John Mendelson, 70, 95 Roger Nicoll, 84 UCSF and CPMCRI University of California San Francisco [email protected] [email protected] Ronald Meyer, 70, 123 Akiko Nishiyama University of California Irvine University of Connecticut [email protected] [email protected]

January 23–28, 2005 • Breckenridge, Colorado 145 Kevin Niswender, 93 Yuan Bo Peng, 71 Vanderbilt University University of Texas at Arlington [email protected] [email protected] Ralph Nixon, 122 Ruth Perez NYU School of Medicine/Nathan Kline University of Pittsburgh Institute [email protected] [email protected] Regino Perez-Polo Charles O’Brien UTMB University of Pennsylvania [email protected] [email protected] Paul Phillips Patricio O’Donnell, 118, 122 University of Washington Albany Medical College [email protected] [email protected] Pier Vincenzo Piazza, 76 Halina Oﬀner, 114 INSERM Oregon Health & Science University [email protected] oﬀ[email protected] Chris Pierce Carl Olson, 91 Boston University School of Medicine Carnegie Mellon University [email protected] [email protected] Charles Pluto, 85 Mark Opp, 108 Medical College of Ohio University of Michigan [email protected] [email protected] Phillip Popovich, 116 Gregory Ordway, 69, 77 The Ohio State University University of Mississippi Medical Center [email protected] [email protected] Linda Porter Mary Ann Ottinger, 55 National Institutes of Health University of Maryland [email protected] [email protected] Emmanuel Pothos, 130 Carlos Paladini, 67 Tufts University School of Medicine Oregon Health & Science University [email protected] [email protected] Steven Potkin, 68 Ronald Paletzki, 56 University of California Irvine NIMH [email protected] [email protected] Astrid Prinz, 111 Vladimir Parpura, 83 Brandeis University University of California Riverside [email protected] [email protected] Chris Proschel, 66 Thomas Parsons, 113 University of Rochester Medical Center University of Pennsylvania [email protected] [email protected] John Quinn, 79 Dale Pelligrino, 70 University of Liverpool University of Illinois at Chicago [email protected] [email protected]

146 38th Annual Winter Conference on Brain Research Remi Quirion, 126 George Richerson, 100, 120 Douglas Hospital McGill Univ Yale University [email protected] [email protected] Indira Raman, 107 Karin Rimvall, 124 Northwestern University Novo Nordisk A/S [email protected] [email protected] Gerald Rameau, 119 Terry Robinson, 65, 118 NYU School of Medicine University of Michigan [email protected] [email protected] Jan Ramirez, 111 Katherine Roche, 109 University of Chicago NINDS/NIH [email protected] [email protected] Bruce Ransom Suzanne Roffler-Tarlov University of Washington Tufts University School of Medicine [email protected] [email protected] Mahendra Rao, 66, 76 Bruce Rosen, 68 National Institute on Aging Athinoula A Martinos Center for Biomedical [email protected] Imaging [email protected] Matthew Rasband, 132 University of Connecticut Health Center Susanna Rosi, 81 [email protected] University of Arizona [email protected] Douglas Rasmusson, 85 Dalhousie University Christopher Ross [email protected] Johns Hopkins University [email protected] Heather Read, 104 University of Connecticut Elliott Ross [email protected] Oklahoma University Health Sciences Center Peter Redgrave, 98 [email protected] University of Sheffield P.Redgrave@sheffield.ac.uk Andrew Russo, 74, 79 University of Iowa Robert Rhoades, 96 [email protected] Medical College of Ohio [email protected] Amelia Russo-Neustadt, 82 California State University Charles Ribak, 100 [email protected] University of California Irvine [email protected] Pankaj Sah, 115 University of Queensland George Ricaurte, 95 [email protected] The Johns Hopkins School of Medicine [email protected] Jean Saint-Cyr, 105 University of Toronto Steve Richardson [email protected] University of Saskatchewan [email protected] Alapakkam Sampath, 113 University of Southern California Keck School of Medicine [email protected]

January 23–28, 2005 • Breckenridge, Colorado 147 Maria V. Sanchez-Vives – 122 David Sibley, 122 Universidad Miguel Hernández-CSIC NINDS/NIH [email protected] [email protected] Nicole Sanders, 93 Beth-Anne Sieber, 81 Univeristy of Washington National Institute of Mental Health [email protected] [email protected] Stephen Scheff, 56, 72 Larry Siever, 78 University of Kentucky Mount Sinai School of Medicine sscheff@email.uky.edu [email protected] Todd Scheuer, 107 Dan H Silverman, 83 University of Washington University of California, Los Angeles [email protected] [email protected] Heath D. Schmidt, 57 Joshua Singer, 113 Boston University School of Medicine National Institutes of Health [email protected] [email protected] Arne Schousboe, 100 Phil Skolnick The Danish University Pharm. Sci. DOV Pharmaceutical, Inc. [email protected] [email protected] Andrew Schwartz Celia Sladek University of Pittsburgh University of Colorado Health Sciences [email protected] Center [email protected] Roy Schwarz Pfizer Global Research & Development Richard Smeyne, 89 roy.schwarz@pfizer.com Saint Jude Children’s Research Hospital [email protected] Erik Schwetizer UCLA Misty Smith-Yockman, 100 [email protected] University of Utah [email protected] Ronald See, 91 Medical University of South Carolina D Stephen Snyder, 81 [email protected] National Institute on Aging NIH [email protected] Henry Sershen, 122 Nathan Kline Institute Evan Snyder, 110, 115 [email protected] The Burnham Institute [email protected] Susan Sesack, 67 University of Pittsburgh Gretchen Snyder, 66 [email protected] Intra-Cellular Therapies, Inc www.intracellulartherapies.com Paul Shaw, 105 Washington University School of Medicine Thomas Soderling, 127 [email protected] Oregon Health Sciences University [email protected] Kent Shellenberger NeuroClin2 Nina J. Solenski, 72 [email protected] University of Virginia [email protected]

148 38th Annual Winter Conference on Brain Research Harald Sontheimer, 66 Kimberly Topp The University of Alabama at Birmingham University of California San Francisco [email protected] [email protected] William Spain, 115 Gianluca Tosini, 96 University of Washington/Seattle VA Morehouse School of Medicine [email protected] [email protected] David Standaert, 86 Stephen Traynelis, 120 Massachusetts General Hospital Emory University [email protected] [email protected] Terrence Stanford, 98 James Trimmer, 132 Wake Forest University School of Medicine University of California, Davis [email protected] [email protected] Cordelia Stearns Mark A. Trocchi Bryn Mawr College Association Book Exhibits [email protected] [email protected] Barry Stein, 98 Ramon Trullas, 58 Wake Forest University School of Medicine IIBB/CSIC [email protected] [email protected] Donald Stein Kuei-Yuan Tseng, 122 Emory University School of Medicine Albany Medical College [email protected] [email protected] Dietrich Stephan, 108 Daniel Tso, 104 The Translational Genomic Research SUNY Health Science Center Institute [email protected] [email protected] Tim Tully, 125 D. James Surmeier, 107 Cold Spring Harbor Laboratory Northwestern University [email protected] [email protected] Fred W. Turek, 105 Clive Svendsen, 105 Northwestern University University of Wisconsin-Madison [email protected] [email protected] Rita Valentino, 76, 108 Tom Swanson The Children’s Hospital of Philadelphia Midwest Neuroscience Inc. [email protected] [email protected] David Van Essen, 108 Jeﬀrey Tasker, 103 Washington University Tulane University [email protected] [email protected] Russell van Gelder, 125 Igor Timofeev, 122 Washington University Medical School Laval University [email protected] [email protected] Arthur Vandenbark, 114 Arthur Toga, 68, 104, 108 Portland VA Medical Center University of California Los Angeles School [email protected] of Medicine [email protected]

January 23–28, 2005 • Breckenridge, Colorado 149 Marquis Vawter, 59, 121 Monte Westerﬁeld University of California Irvine University of Oregon [email protected] [email protected] Stefano Vicini, 101 William Wetsel Georgetown University Duke University [email protected] [email protected] Mike Vitek H. Steve White, 100 Duke University Medical Center University of Utah [email protected] [email protected] Rui Wang, 70 Scott Whittemore, 116 University of Saskatchewan University of Louisville [email protected] [email protected] John Waraska Mark Wightman, 118 ESA, Inc. University of North Carolina at Chapel Hill [email protected] [email protected] Nicole Ward, 129 George Wilcox, 64 Case Western Reserve University University of Minnesota [email protected] [email protected] Claude Wasterlain Graham Williams, 78 UCLA Yale University School of Medicine [email protected] [email protected] Barry Waterhouse Robert W. Williams, 131 Drexel University University of Tennessee Health Science [email protected] Center [email protected] Robert Waters, 85 University of Tennessee Health Science Roy Wise Center NIDA/NIH [email protected] [email protected] Friedbert Weiss Marina Wolf, 118 The Scripps Research Institute Chicago Medical School [email protected] [email protected] Cara Wellman, 89 Terri Wood Indiana University Penn State College of Medicine [email protected] [email protected] Frank Welsh Donald Woodward University of Pennsylvania Wake Forest Health Sciences [email protected] [email protected] Joan Welton John Woodward, 59 Olympus America, Inc Medical University of South Carolina [email protected] [email protected] Anthony West, 119 Catherine Woolley, 66 RFUMS/The Chicago Medical School Northwestern University westa@ﬁnchcms.edu [email protected]

150 38th Annual Winter Conference on Brain Research Doug Wright Eduardo Zamora, 126 University of Kansas Medical Center Johns Hopkins [email protected] [email protected] Bryan Yamamoto, 70, 83 Luigi Zecca, 74 Boston University School of Medicine Italian National Council of Research [email protected] [email protected] F. Eugene Yates Michael Zigmond, 74, 105 UCLA University of Pittsburgh [email protected] [email protected] Seonghwan Yee, 75 Jon-Kar Zubieta, 129 University of Texas Health Science Center University of Michigan [email protected] [email protected] V. Wee Yong, 79 Suzanne Zukin, 125 University of Calgary Albert Einstein College of Medicine [email protected] [email protected] Larry Young, 86, 112 J. Brooks Zurn, 60 Emory University University of Vermont [email protected] [email protected] Elmer Yu, 70 Karl Zurn University of Pennsylvainia/Philadelphia Med Associates, Inc VAMC [email protected] [email protected]

January 23–28, 2005 • Breckenridge, Colorado 151 Notes

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152 38th Annual Winter Conference on Brain Research Notes

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January 23–28, 2005 • Breckenridge, Colorado 153 Notes

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January 23–28, 2005 • Breckenridge, Colorado 155 Notes

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January 23–28, 2005 • Breckenridge, Colorado 157 Notes

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January 23–28, 2005 • Breckenridge, Colorado 159 160 38th Annual Winter Conference on Brain Research