This Week in the Journal

The Journal of Neuroscience, November 9, 2005 • 25(45):i • i This Week in The Journal

F Cellular/Molecular axons along distinct paths? This week, Liu and Halloran address that question in Snapin-Less Mice and Chromaffin Rohon-Beard (RB) sensory neurons in ze- Cell Exocytosis brafish embryos. Using live imaging, the authors report that central axons chugged Jin-Hua Tian, Zheng-Xing Wu, Michael along straight paths at a steady 20 ␮m/h. Unzicker, Li Lu, Qian Cai, Cuiling Li, Peripheral axons emerged from the cen- Claudia Schirra, Ulf Matti, David tral axon and exited the spinal cord, scat- Stevens, Chuxia Deng, Jens Rettig, and tering and branching often to form an epi- Zu-Hang Sheng dermal network covering the trunk. The authors injected antisense morpholinos to (see pages 10546–10555) knock down, or cDNAs to misexpress, The calcium-dependent exocytosis of syn- putative guidance molecules. Sema- Want to test your sense of body ownership? Try the somatic aptic vesicles requires assembly of the sol- phorin3D, normally expressed in the spi- rubber hand illusion. See the article by Ehrsson et al. for uble N-ethyl maleimide sensitive factor nal cord roof plate, repelled peripheral but details. adaptor protein receptor (SNARE) com- not central axons, suggesting it may guide plex, consisting of the vesicular mem- peripheral axons out of the spinal cord. brane-associated protein synaptobrevin, The RB-expressed Ig superfamily mole- degree that correlated with the strength of the plasma membrane-associated protein cule transient axonal glycoprotein-1, the illusion. however, was required for forward growth syntaxin, and synaptosomal-associated ࡗ Neurobiology of Disease protein 25 kDa (SNAP-25). Before re- of central axons but had no effect on peripheral axons. lease, the calcium-sensing protein synap- A2A, mGlu5, and Parkinsonism totagmin also must bind SNAP-25. f Behavioral/Systems/Cognitive Anil Kachroo, Lianna R. Orlando, David Snapin, first identified as a SNAP-25- K. Grandy, Jiang-Fan Chen, Anne B. binding protein, enhances the association The Rubber-Hand Illusion Revisited Young, and Michael A. Schwarzschild of synaptotagmin with SNAP-25. This H. Henrik Ehrsson, Nicholas P. Holmes, week, Tian et al. examine the role of (see pages 10414–10419) snapin in the release of dense-core vesicles and Richard E. Passingham in chromaffin cells using snapin-deficient (see pages 10564–10572) Antagonists for the metabotropic gluta- mice. Heterozygous animals appeared mate receptor mGlu5 and the adenosine normal, but homozygotes did not survive In this week’s Journal, Ehrsson et al. tested receptor A2A have shown anti-parkin- past birth. Although the loss of snapin did the feeling of body ownership using the sonian effects in preclinical studies. These not affect formation of the SNARE com- somewhat creepy sensation associated receptors also assemble in heteromeric plex, it did reduce the association between with the rubber-hand illusion. In the au- complexes in the striatum, suggesting SNAP-25 and synaptotagmin. In chro- thors’ version of the illusion, blindfolded they might work in concert. This week, maffin cells lacking snapin, the fast exocy- participants were guided to touch a rub- Kachroo et al. treated mice with reserpine, totic burst of release was reduced by ber hand with their left index finger. Si- which depletes striatal dopamine, and ex- nearly one-half and was rescued by over- multaneously, the experimenter touched amined interactions between mGlu5 and expression of snapin. Snapin appears to subjects on their right hand, creating, af- A2A receptors. In normal and dopamine- stabilize the readily releasable pool of ter some seconds, the feeling in most sub- depleted mice, the mGlu5 antagonist primed vesicles. jects that they were touching their own 2-methyl-6-(phenylethynyl)-pyridine hand. The rubber hand, experimenter, (MPEP) induced locomotor activity that Œ Development/Plasticity/Repair and subjects all wore gloves to minimize was augmented by the A2A antagonist tactile differences. Temporal synchrony of KW-6002. The MPEP action was absent in Two Axon Branches, Two Targets, the sensory signals was key to the illusion. mice lacking mGlu5 receptors and, inter- Two Guidance Molecules As opposed to previous uses of the illu- estingly, also in mice lacking A2A recep- sion, these experiments did not include a tors, D2 dopamine receptors, or both. The Yan Liu and Mary C. Halloran visual component, showing that tactile behavior was similarly missing from mice (see pages 10556–10563) and proprioceptive sensations are suffi- in which A2A receptors were conditionally cient to fool the subject into ownership of knocked out in postnatal forebrain, thus

Axons and dendrites often respond differ- the hand. Functional magnetic resonance excluding a developmental effect. The D1 entially to guidance factors in developing imaging revealed that the ventral premo- dopamine receptor agonist SKF 38393, their characteristic patterns and orienta- tor and intraparietal cortices and cerebel- however, increased motor behavior in all tions, but what about cells that send two lum were activated during the illusion to a genotypes. The Journal of Neuroscience November 9, 2005 • Volume 25 Number 45 www.jneurosci.org

i This Week in The Journal Journal Club 10337 Not Every Graft Has What It Takes to Attract a Mossy Fiber Yevgenia Kozorovitskiy

10339 The Tuning Properties of Antennal Lobe Projection Neurons Jason Aungst and Marc Spehr Toolbox 10341 Brain Microarray: Finding Needles in Molecular Haystacks Nicole M. Lewandowski and Scott A. Small Cover picture: A computer-rendered right- hemisphere looking at a slant rivalry stimulus. The Symposia and Mini-Symposia image is rendered such that when viewed with anaglyphic filters (i.e., a red filter in front of the left 10347 Neural Circuitry Underlying Rule Use in Humans and Nonhuman Primates eye and a green filter in front of the right eye), Silvia A. Bunge, Jonathan D. Wallis, Amanda Parker, Marcel Brass, stereoscopic depth is perceived. See article by Eveline A. Crone, Eiji Hoshi, and Katsuyuki Sakai Brouwer et al. for details (pages 10403–10413). This 10351 Lateralization of the VertebrateBrain: Taking the Side of Model Systems cover image may also be viewed in 3-D at Marnie E. Halpern, Onur Gu¨ntu¨rku¨n, William D. Hopkins, and Lesley J. Rogers www.jneurosci.org/content/vol25/issue45 with anaglyphic glasses. For a set of anaglyphic glasses, 10358 Flashy Science: Controlling Neural Function with Light print subscribers may send a self-addressed, stamped Scott M. Thompson, Joseph P. Y. Kao, Richard H. Kramer, Kira E. Poskanzer, envelope to the Journal Central Office. Anaglyphic R. Angus Silver, David Digregorio, and Samuel S.-H. Wang glasses available while supplies last. 10366 New Neurons in the Adult Mammalian Brain: Synaptogenesis and Functional Integration Hongjun Song, Gerd Kempermann, Linda Overstreet Wadiche, Chunmei Zhao, Alejandro F. Schinder, and Josef Bischofberger

10369 Time and the Brain: How Subjective Time Relates to Neural Time David M. Eagleman, Peter U. Tse, Dean Buonomano, Peter Janssen, Anna Christina Nobre, and Alex O. Holcombe

10372 The Role of RNA and RNA Processing in Neurodegeneration Jean-Marc Gallo, Peng Jin, Charles A. Thornton, Hong Lin, Janice Robertson, Ian D’Souza, and William W. Schlaepfer

10376 Wnt Signaling in Neural Circuit Development Lee G. Fradkin, Gian Garriga, Patricia C. Salinas, John B. Thomas, Xiang Yu, and Yimin Zou

10379 Epigenetic Mechanisms and Gene Networks in the Nervous System Christine M. Colvis, Jonathan D. Pollock, Richard H. Goodman, Soren Impey, John Dunn, Gail Mandel, Frances A. Champagne, Mark Mayford, Edward Korzus, Arvind Kumar, William Renthal, David E. H. Theobald, and Eric J. Nestler 10390 Neurobiological Mechanisms of the Placebo Effect Fabrizio Benedetti, Helen S. Mayberg, Tor D. Wager, Christian S. Stohler, and Jon-Kar Zubieta Articles CELLULAR/MOLECULAR ⑀ 10462 Kinetics and Spontaneous Open Probability Conferred by the Subunit of the GABAA Receptor David A. Wagner, Marcel P. Goldschen-Ohm, Tim G. Hales, and Mathew V. Jones

10469 Gephyrin Regulates the Cell Surface Dynamics of Synaptic GABAA Receptors Tija C. Jacob, Yury D. Bogdanov, Christopher Magnus, Richard S. Saliba, Josef T. Kittler, Philip G. Haydon, and Stephen J. Moss

10479 Src-Family Kinases Stabilize the Neuromuscular Synapse In Vivo via Protein Interactions, Phosphorylation, and Cytoskeletal Linkage of Acetylcholine Receptors Gayathri Sadasivam, Raffaella Willmann, Shuo Lin, Susanne Erb-Vo¨gtli, Xian Chu Kong, Markus A. Ru¨egg, and Christian Fuhrer

10520 Metabotropic Glutamate Receptor 8-Expressing Nerve Terminals Target Subsets of GABAergic Neurons in the Hippocampus Francesco Ferraguti, Thomas Klausberger, Philip Cobden, Agnes Baude, J. David B. Roberts, Peter Szucs, Ayae Kinoshita, Ryuichi Shigemoto, Peter Somogyi, and Yannis Dalezios

10537 Dopamine Modulation of State-Dependent Endocannabinoid Release and Long-Term Depression in the Striatum Anatol C. Kreitzer and Robert C. Malenka

᭹ 10546 The Role of Snapin in Neurosecretion: Snapin Knock-Out Mice Exhibit Impaired Calcium-Dependent Exocytosis of Large Dense-Core Vesiclesin Chromaffin Cells Jin-Hua Tian, Zheng-Xing Wu, Michael Unzicker, Li Lu, Qian Cai, Cuiling Li, Claudia Schirra, Ulf Matti, David Stevens, Chuxia Deng, Jens Rettig, and Zu-Hang Sheng

DEVELOPMENT/PLASTICITY/REPAIR

10437 Migration from a Mitogenic Niche Promotes Cell-Cycle Exit Yoojin Choi, Paul R. Borghesani, Jennifer A. Chan, and Rosalind A. Segal

Œ 10556 Central and Peripheral Axon Branches from One Neuron Are Guided Differentially by Semaphorin3D and Transient Axonal Glycoprotein-1 Yan Liu and Mary C. Halloran

BEHAVIORAL/SYSTEMS/COGNITIVE

10403 Activation in Visual Cortex Correlates with the Awareness of Stereoscopic Depth Gijs Joost Brouwer, Raymond van Ee, and Jens Schwarzbach

10420 Neural Activity in Macaque Parietal Cortex Reflects Temporal Integration of Visual Motion Signals during Perceptual Decision Making Alexander C. Huk and Michael N. Shadlen

10446 Localization and Identification of Concurrent Sounds in the Owl’s Auditory Space Map Clifford H. Keller and Terry T. Takahashi

10494 Event-Related Brain Potential Correlates of Human Auditory Sensory Memory-Trace Formation Corinna Haenschel, David J. Vernon, Prabuddh Dwivedi, John H. Gruzelier, and Torsten Baldeweg 10510 Peptide YY3–36 Inhibits Both Anorexigenic Proopiomelanocortin and Orexigenic Neuropeptide Y Neurons: Implications for Hypothalamic Regulation of Energy Homeostasis Claudio Acuna-Goycolea and Anthony N. van den Pol f 10564 Touching a Rubber Hand: Feeling of Body Ownership Is Associated with Activity in Multisensory Brain Areas H. Henrik Ehrsson, Nicholas P. Holmes, and Richard E. Passingham

NEUROBIOLOGY OF DISEASE ࡗ 10414 Interactions between Metabotropic Glutamate 5 and Adenosine A2A Receptors in Normal and Parkinsonian Mice Anil Kachroo, Lianna R. Orlando, David K. Grandy, Jiang-Fan Chen, Anne B. Young, and Michael A. Schwarzschild

10502 Silencing Primary Dystonia: Lentiviral-Mediated RNA Interference Therapy for DYT1 Dystonia Pedro Gonzalez-Alegre, Nicole Bode, Beverly L. Davidson, and Henry L. Paulson

10573 Errata: In the article “Differential Maturation of GABA Action and Anion Reversal Potential in Spinal Lamina I Neurons: Impact of Chloride Extrusion Capacity,” by Matilde Cordero- Erausquin, Jeffrey A. M. Coull, Dominic Boudreau, Matthias Rolland, and Yves De Koninck, which appeared on pages 9613–9623 of the October 19, 2005 issue, the most recent versions of Figures 6 and 7 were not used because of a printer’s error. The correct versions of both figures, as well as each corresponding legend, are printed in this issue. 10575 In the article “A Highly Specific Inhibitor of Matrix Metalloproteinase-9 Rescues Laminin from Proteolysis and Neurons from Apoptosis in Transient Focal Cerebral Ischema” by Zezong Gu, Jiankun Cui, Stephen Brown, Rafael Fridman, Shahriar Mobashery, Alex Y. Strongin, and Stuart A. Lipton, which appeared on pages 6401–6408 of the July 6, 2005 issue, the blots in Figure 2C contained a misprint. The labes for “Control” and “Ischemia” were inadvertently switched. This error was not reflected in the figure legend or the statistical analysis in Figure 2D, and thus the conclusions of the study were not affected. To mitigate this error, the authors have provided a corrected version of Figure 2 in this issue.

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Not Every Graft Has What It Takes to Attract a Mossy Fiber

Yevgenia Kozorovitskiy Department of Psychology and Program in Neuroscience, Princeton University, Princeton, New Jersey 08544 The Journal of Neuroscience, November 9, 2005 • 25(45):10337–10338

The Tuning Properties of Antennal Lobe Projection Neurons

Jason Aungst and Marc Spehr Department of Anatomy and Neurobiology, Program in Neuroscience, University of Maryland School of Medicine, Baltimore, Maryland 21201 The Journal of Neuroscience, November 9, 2005 • 25(45):10339–10340

TOOLBOX

Brain Microarray: Finding Needles in Molecular Haystacks

Nicole M. Lewandowski and Scott A. Small The Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Department of Neurology, and Center for Neurobiology and Behavior, Columbia University College of Physicians and Surgeons, New York, New York 10032 The Journal of Neuroscience, November 9, 2005 • 25(45):10341–10346

MINI-SYMPOSIUM

Neural Circuitry Underlying Rule Use in Humans and Nonhuman Primates

Silvia A. Bunge,1 Jonathan D. Wallis,2 Amanda Parker,3 Marcel Brass,4 Eveline A. Crone,1,5 Eiji Hoshi,6 and Katsuyuki Sakai7 1Department of Psychology and Center for Mind and Brain, University of California at Davis, Davis, California 95616, 2Helen Wills Neuroscience Institute and Department of Psychology, University of California at Berkeley, Berkeley, California 94720, 3Psychology, Brain, and Behaviour, University of Newcastle, Newcastle upon Tyne NE1 7RU, United Kingdom, 4Department of Neurology, Max Planck Institute for Human Cognitive and Brain Sciences, D-04103 Leipzig, Germany, 5Department of Psychology, Leiden University, 2300 RA Leiden, The Netherlands, 6Brain Science Research Center, Tamagawa University Research Institute, Machida, Tokyo 194-8610, Japan, and 7Graduate School of Medicine, University of Tokyo, Hongo Bunkyo-ku, Tokyo 113-8654, Japan The Journal of Neuroscience, November 9, 2005 • 25(45):10347–10350

SYMPOSIUM

Lateralization of the VertebrateBrain: Taking the Side of Model Systems

Marnie E. Halpern,1* Onur Gu¨ntu¨rku¨n,2* William D. Hopkins,3,4 and Lesley J. Rogers5 1Carnegie Institution of Washington, Department of Embryology, Baltimore, Maryland 21218, 2Department of Biopsychology, Institute for Cognitive Neuroscience, Faculty of Psychology, Ruhr-Universita¨t Bochum, 44780 Bochum, Germany, 3Berry College, Mount Berry, Georgia 30149, 4Division of Psychobiology, Yerkes National Primate Research Center, Emory University, Atlanta, Georgia 30322, and 5Centre for Neuroscience and Animal Behaviour, University of New England, School of Biological, Biomedical, and Molecular Sciences, Armidale, New South Wales 2351, Australia The Journal of Neuroscience, November 9, 2005 • 25(45):10351–10357 MINI-SYMPOSIUM

Flashy Science: Controlling Neural Function with Light

Scott M. Thompson,1 Joseph P. Y. Kao,1,2 Richard H. Kramer,3 Kira E. Poskanzer,4 R. Angus Silver,5 David Digregorio,5 and Samuel S.-H. Wang6 1Department of Physiology, University of Maryland School of Medicine, Baltimore, Maryland, 21201, 2Medical Biotechnology Center, University of Maryland Biotechnology Institute, Baltimore, Maryland 21201, 3Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, California 94720, 4Department of Biochemistry, University of California, San Francisco, San Francisco, California 94143, 5Department of Physiology, University College, London WC1E 6BT, United Kingdom, and 6Department of Molecular Biology and Program in Neuroscience, Princeton University, Princeton, New Jersey 08544 The Journal of Neuroscience, November 9, 2005 • 25(45):10358–10365

New Neurons in the Adult Mammalian Brain: Synaptogenesis and Functional Integration

Hongjun Song,1 Gerd Kempermann,2 Linda Overstreet Wadiche,3 Chunmei Zhao,4 Alejandro F. Schinder,5 and Josef Bischofberger6 1Institute for Cell Engineering, Departments of Neurology and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, 2Max Delbru¨ck Center for Molecular Medicine Berlin-Buch, 13125 Berlin, Germany, 3Vollum Institute, Oregon Health and Sciences University, Portland, Oregon 97239, 4Laboratory of Genetics, The Salk Institute, La Jolla, California 92037, 5Laboratory of Neuronal Plasticity, Leloir Institute, 1405 Buenos Aires, Argentina, and 6Physiology Department, University of Freiburg, D-79104 Freiburg, Germany The Journal of Neuroscience, November 9, 2005 • 25(45):10366–10368

Time and the Brain: How Subjective Time Relates to Neural Time

David M. Eagleman,1 Peter U. Tse,2 Dean Buonomano,3 Peter Janssen,4 Anna Christina Nobre,5 and Alex O. Holcombe6 1Neurobiology and Anatomy, University of Texas–Houston, Houston, Texas 77030, 2Physiological and Brain Sciences, Dartmouth College, Hanover, New Hampshire 03755, 3Department of Neurobiology, University of California, Los Angeles Brain Research Institute, Los Angeles, California 90095, 4Laboratorium voor Neuro-en Psychofysiologie, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium, 5Department of Experimental Psychology, University of Oxford, Oxford OX1 2JD, United Kingdom, and 6School of Psychology, Cardiff University, CF10 3XQ Wales, United Kingdom

Most of the actions our brains perform on a daily basis, such as perceiving, speaking, and driving a car, require timing on the scale of tens to hundreds of milliseconds. New discoveries in psychophysics, electrophysiology, imaging, and computational modeling are contributing to an emerging picture of how the brain processes, learns, and perceives time. The Journal of Neuroscience, November 9, 2005 • 25(45):10369–10371

The Role of RNA and RNA Processing in Neurodegeneration

Jean-Marc Gallo,1 Peng Jin,2 Charles A. Thornton,3 Hong Lin,4 Janice Robertson,5 Ian D’Souza,6 and William W. Schlaepfer4 1Medical Research Council Centre for Neurodegeneration Research and Department of Neurology, Institute of Psychiatry, King’s College London, London SE5 8AF, United Kingdom, 2Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia 30322, 3Department of Neurology, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642, 4Division of Neuropathology, University of Pennsylvania Medical School, Philadelphia, Pennsylvania 19104-6100, 5University of Toronto, Centre for Research in Neurodegenerative Diseases, Toronto, Ontario, Canada M5S 3H2, and 6University of Washington and Veterans Affairs Medical Center, Seattle, Washington 98108 The Journal of Neuroscience, November 9, 2005 • 25(45):10372–10375 Wnt Signaling in Neural Circuit Development

Lee G. Fradkin,1 Gian Garriga,2 Patricia C. Salinas,3 John B. Thomas,4 Xiang Yu,5 and Yimin Zou6 1Department of Molecular and Cell Biology, Leiden University Medical Center, 2333 AL, Leiden, The Netherlands, 2Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, California 94720, 3Department of Anatomy and Developmental Biology, University College London, London WC1E 6BT, United Kingdom, 4Salk Institute, San Diego, California 92186, 5Institute of Neuroscience, Chinese Academy of Sciences, Shanghai 200031, China, and 6Department of Neurobiology, Pharmacology, and Physiology, The University of Chicago, Chicago, Illinois 60637 The Journal of Neuroscience, November 9, 2005 • 25(45):10376–10378

SYMPOSIUM

Epigenetic Mechanisms and Gene Networks in the Nervous System

Christine M. Colvis,1 Jonathan D. Pollock,1 Richard H. Goodman,2 Soren Impey,2 John Dunn,3 Gail Mandel,4 Frances A. Champagne,5 Mark Mayford,6 Edward Korzus,6 Arvind Kumar,7 William Renthal,7 David E. H. Theobald,7 and Eric J. Nestler7 1Genetics and Molecular Neurobiology Research Branch, Division of Basic Neurosciences and Behavioral Research, National Institute on Drug Abuse, Bethesda, Maryland 20892, 2Oregon Health and Science University, Vollum Institute, Portland, Oregon 97201-3098, 3Biology Department, Brookhaven National Laboratory, Upton, New York 11973-5000, 4Howard Hughes Medical Institute, Department of Neurobiology and Behavior, State University of New York, Stony Brook, New York 11794-5230, 5Subdepartment of Animal Behaviour, University of Cambridge, Madingley, Cambridge CB3 8AA, United Kingdom, 6Institute for Childhood and Neglected Disease, Department of Cell Biology, The Scripps Research Institute, La Jolla, California 92037-1000, and 7Department of Psychiatry and Center for Basic Neuroscience, The University of Texas Southwestern Medical Center, Dallas, Texas 75390-9070 The Journal of Neuroscience, November 9, 2005 • 25(45):10379–10389

Neurobiological Mechanisms of the Placebo Effect

Fabrizio Benedetti,1 Helen S. Mayberg,2 Tor D. Wager,3 Christian S. Stohler,4 and Jon-Kar Zubieta5 1Department of Neuroscience, University of Turin Medical School, 10125 Turin, Italy, 2Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, Georgia 30322, 3Department of Psychology, Columbia University, New York, New York 10027, 4School of Dentistry, University of Maryland, Baltimore, Maryland 21201, and 5Department of Psychiatry and Molecular and Behavioral Neuroscience Institute, The University of Michigan, Ann Arbor, Michigan 48109 The Journal of Neuroscience, November 9, 2005 • 25(45):10390–10402

Articles

CELLULAR/MOLECULAR

⑀ Kinetics and Spontaneous Open Probability Conferred by the Subunit of the GABAA Receptor

David A. Wagner,1 Marcel P. Goldschen-Ohm,2 Tim G. Hales,3 and Mathew V. Jones2 1Department of Biological Sciences, Marquette University, Milwaukee, Wisconsin 53201, 2Department of Physiology, University of Wisconsin, Madison, Wisconsin 53706, and 3Departments of Pharmacology and Physiology, and Anesthesiology and Critical Care Medicine, The George Washington University, Washington, DC 20037

␣ ␤ GABAA receptors mediate synaptic and extrasynaptic inhibition. Native receptors consist of and subunits, which are required for function, and another “modulatory” subunit, for example, ␥, ␦,or⑀. Of these, the ⑀ subunit has the most restricted distribution, confers resistance to neurosteroid and anesthetic modulation, and causes spontaneous channel opening. Little is known, however, about how ⑀ affects receptor kinetics, which in turn shape responses to both ambient and synaptic GABA exposure. Here, we expressed human ␣2␤1, ␣2␤1␥2, or ␣2␤1⑀ subunit combinations in human embryonic kidney 293 cells and used rapid solution exchange to study receptor kinetics in outside-out patches. The ⑀ subunit greatly slowed deactivation and recovery after brief GABA pulses. During long, saturating GABA pulses, the rate of desensitization was slower for ␣2␤1⑀ and ␣2␤1␥2 than for ␣2␤1. However, in ␣2␤1⑀, the final extent of desensitization was large compared with that of ␣2␤1␥2. Responses in ␣2␤1⑀, but not the others, were often followed by an “overshoot” above the baseline, suggesting that a fraction of channels are spontaneously open and are transiently silenced by receptor activation and subsequent desensitization. The baseline current and associated noise were reduced by picrotoxin, revealing that ⑀-containing channels are open ϳ4% of the time in the absence of GABA. These results suggest that, if ⑀-containing receptors are expressed at synapses, the synaptic currents would be long-lasting but may rundown quickly under high-frequency activation. In addition, silencing of spontaneous openings by desensitization raises the possibility that tonic inhibition mediated by ⑀-containing receptors may be regulated by phasic inhibition. The Journal of Neuroscience, November 9, 2005 • 25(45):10462–10468

Gephyrin Regulates the Cell Surface Dynamics of Synaptic GABAA Receptors

Tija C. Jacob,1* Yury D. Bogdanov,2* Christopher Magnus,2 Richard S. Saliba,2 Josef T. Kittler,1 Philip G. Haydon,1 and Stephen J. Moss1,2 1Department of Pharmacology, University College London, London WC1E 6BT, United Kingdom, and 2Department of Neuroscience, University of Pennsylvania, Philadelphia, Pennsylvania 19104

The efficacy of fast synaptic inhibition is critically dependent on the accumulation of GABAA receptors at inhibitory synapses, a process that remains poorly understood.

Here, we examined the dynamics of cell surface GABAA receptors using receptor subunits modified with N-terminal extracellular ecliptic pHluorin reporters. In hippocam- pal neurons, GABAA receptors incorporating pHluorin-tagged subunits were found to be clustered at synaptic sites and also expressed as diffuse extrasynaptic staining. By combining FRAP (fluorescence recovery after photobleaching) measurements with live imaging of FM4-64-labeled active presynaptic terminals, it was evident that clustered synaptic receptors exhibit significantly lower rates of mobility at the cell surface compared with their extrasynaptic counterparts. To examine the basis of this confinement, we used RNAi to inhibit the expression of gephyrin, a protein shown to regulate the accumulation of GABAA receptors at synaptic sites. However, whether gephyrin acts to control the actual formation of receptor clusters, their stability, or is simply a global regulator of receptor cell surface number remains unknown. Inhibiting gephyrinexpressiondidnotmodifythetotalnumberofGABAA receptorsexpressedontheneuronalcellsurfacebutsignificantlydecreasedthenumberofreceptorclusters. Live imaging revealed that clusters that formed in the absence of gephyrin were significantly more mobile compared with those in control neurons. Together, our results demonstrate that synaptic GABAA receptors have lower levels of lateral mobility compared with their extrasynaptic counterparts, and suggest a specific role for gephyrin in reducing the diffusion of GABAA receptors, facilitating their accumulation at inhibitory synapses. The Journal of Neuroscience, November 9, 2005 • 25(45):10469–10478

Src-Family Kinases Stabilize the Neuromuscular Synapse In Vivo via Protein Interactions, Phosphorylation, and Cytoskeletal Linkage of Acetylcholine Receptors

Gayathri Sadasivam,1 Raffaella Willmann,1 Shuo Lin,2 Susanne Erb-Vo¨gtli,1 Xian Chu Kong,2 Markus A. Ru¨egg,2 and Christian Fuhrer1 1Department of Neurochemistry, Brain Research Institute, University of Zu¨rich, CH-8057 Zu¨rich, Switzerland, and 2Biozentrum, University of Basel, CH- 4056 Basel, Switzerland

Postnatal stabilization and maturation of the postsynaptic membrane are important for development and function of the neuromuscular junction (NMJ), but the underlying mechanisms remain poorly characterized. We examined the role of Src-family kinases (SFKs) in vivo. Electroporation of kinase-inactive Src constructs into soleus muscles of adult mice caused NMJ disassembly: acetylcholine receptor (AChR)-rich areas became fragmented; the topology of nerve terminal, AChRs, and synaptic nuclei was disturbed; and occasionally nerves started to sprout. Electroporation of kinase-overactive Src produced similar but milder effects. We studied the mechanism of SFK action using cultured srcϪ/Ϫ;fynϪ/Ϫ myotubes, focusing on clustering of postsynaptic proteins, their interaction with AChRs, and AChR phosphorylation. Rapsyn and the utrophin-glycoprotein complex were recruited normally into AChR-containing clusters by agrin in srcϪ/Ϫ;fynϪ/Ϫ myotubes. But after agrin withdrawal, clusters of these proteinsdisappearedrapidlyinparallelwithAChRs,revealingthatSFKsareofgeneralimportanceinpostsynapticstability.Atthesametime,AChRinteractionwithrapsyn and dystrobrevin and AChR phosphorylation decreased after agrin withdrawal from mutant myotubes. Unexpectedly, levels of rapsyn protein were increased in srcϪ/Ϫ; fynϪ/Ϫ myotubes, whereas rapsyn–cytoskeleton interactions were unaffected. The overall cytoskeletal link of AChRs was weak but still strengthened by agrin in mutant cells, consistent with the normal formation but decreased stability of AChR clusters. These data show that correctly balanced activity of SFKs is critical in maintaining adult NMJs in vivo. SFKs hold the postsynaptic apparatus together through stabilization of AChR–rapsyn interaction and AChR phosphorylation. In addition, SFKs control rapsyn levels and AChR-cytoskeletal linkage. The Journal of Neuroscience, November 9, 2005 • 25(45):10479–10493 Metabotropic Glutamate Receptor 8-Expressing Nerve Terminals Target Subsets of GABAergic Neurons in the Hippocampus

Francesco Ferraguti,1,2 Thomas Klausberger,1,3 Philip Cobden,1 Agnes Baude,1,4 J. David B. Roberts,1 Peter Szucs,5 Ayae Kinoshita,6 Ryuichi Shigemoto,7 Peter Somogyi,1 and Yannis Dalezios1,8 1Medical Research Council Anatomical Neuropharmacology Unit, Department of Pharmacology, Oxford University, Oxford OX1 3TH, United Kingdom, 2Department of Pharmacology, Innsbruck Medical University, A-6020 Innsbruck, Austria, 3Centre for Brain Research, Medical University Vienna, A-1090 Vienna, Austria, 4Laboratoire de NeuroPhysiologie Cellulaire, Centre National de la Recherche Scientifique, Unite´ Mixte de Recherche 6150, 13402 Cedex 20 Marseille, France, 5Department of Anatomy, Histology, and Embryology, Faculty of Medicine, Medical and Health Centre, University of Debrecen, H-4012 Debrecen, Hungary, 6Horizontal Medical Research Organization, Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan, 7Division of Cerebral Structure, National Institute for Physiological Sciences, Okazaki 444-8787, Japan, and 8Department of Basic Sciences, Faculty of Medicine, University of Crete, GR-71003 Heraklion, Greece

Presynaptic metabotropic glutamate receptors (mGluRs) show a highly selective expression and subcellular location in nerve terminals modulating neurotransmitter release. We have demonstrated that alternatively spliced variants of mGluR8, mGluR8a and mGluR8b, have an overlapping distribution in the hippocampus, and besides perforant path terminals, they are expressed in the presynaptic active zone of boutons making synapses selectively with several types of GABAergic interneurons, primarily in the stratum oriens. Boutons labeled for mGluR8 formed either type I or type II synapses, and the latter were GABAergic. Some mGluR8-positive boutons also expressed mGluR7 or vasoactive intestinal polypeptide. Interneurons strongly immunopositive for the muscarinic M2 or the mGlu1 receptors were the primary targets of mGluR8- containingterminalsinthestratumoriens,butonlyneurochemicallydistinctsubsetswereinnervatedbymGluR8-enrichedterminals.ThemajorityofM2-positiveneurons were mGluR8 innervated, but a minority, which expresses somatostatin, was not. Rare neurons coexpressing calretinin and M2 were consistently targeted by mGluR8- positive boutons. In vivo recording and labeling of an mGluR8-decorated and strongly M2-positive interneuron revealed a trilaminar cell with complex spike bursts during theta oscillations and strong discharge during sharp wave/ripple events. The trilaminar cell had a large projection from the CA1 area to the subiculum and a preferential innervation of interneurons in the CA1 area in addition to pyramidal cell somata and dendrites. The postsynaptic interneuron type-specific expression of the high-efficacy presynaptic mGluR8 in both putative glutamatergic and in identified GABAergic terminals predicts a role in adjusting the activity of interneurons depending on the level of network activity. The Journal of Neuroscience, November 9, 2005 • 25(45):10520–10536

Dopamine Modulation of State-Dependent Endocannabinoid Release and Long-Term Depression in the Striatum

Anatol C. Kreitzer and Robert C. Malenka Department of Psychiatry and Behavioral Sciences, Nancy Pritzker Laboratory, Stanford University Medical School, Palo Alto, California 94305

Endocannabinoids are important mediators of short- and long-term synaptic plasticity, but the mechanisms of endocannabinoid release have not been studied extensively outside the hippocampus and cerebellum. Here, we examined the mechanisms of endocannabinoid-mediated long-term depression (eCB-LTD) in the dorsal striatum, a brain region critical for motor control and reinforcement learning. Unlike other cell types, strong depolarization of medium spiny neurons was not sufficient to yield detectable endocannabinoid release. However, when paired with postsynaptic depolarization sufficient to activate L-type calcium channels, activation of postsynaptic metabotropic glutamate receptors (mGluRs), either by high-frequency tetanic stimulation or an agonist, induced eCB-LTD. Pairing bursts of afferent stimulation with brief subthreshold membrane depolarizations that mimicked down-state to up-state transitions also induced eCB-LTD, which not only required activationof mGluRs and L-type calcium channels but also was bidirectionally modulated by dopamine D2 receptors. Consistent with network models, these results demonstrate that dopamine regulates the induction of a Hebbian form of long-term synaptic plasticity in the striatum. However, this gating of plasticity by dopamine is accomplished via an unexpected mechanism involving the regulation of mGluR-dependent endocannabinoid release. The Journal of Neuroscience, November 9, 2005 • 25(45):10537–10545

The Role of Snapin in Neurosecretion: Snapin Knock-Out Mice Exhibit Impaired Calcium- Dependent Exocytosis of Large Dense-Core Vesiclesin Chromaffin Cells

Jin-Hua Tian,1* Zheng-Xing Wu,2* Michael Unzicker,2 Li Lu,1 Qian Cai,1 Cuiling Li,3 Claudia Schirra,2 Ulf Matti,2 David Stevens,2 Chuxia Deng,3 Jens Rettig,2 and Zu-Hang Sheng1 1Synaptic Function Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892-3701, 2Physiologisches Institut, Universitaet des Saarlandes, 66424 Homburg/Saar, Germany, and 3Mammalian Genetics Section, Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892

Identification of the molecules that regulate the priming of synaptic vesicles for fusion and the structural coupling of the calcium sensor with the soluble N-ethyl maleimide sensitive factor adaptor protein receptor (SNARE)-based fusion machinery is critical for understanding the mechanisms underlying calcium-dependent neurosecretion. Snapin binds to synaptosomal-associated protein 25 kDa (SNAP-25) and enhances the association of the SNARE complex with synaptotagmin. In the present study, we abolished snapin expression in mice and functionally evaluated the role of Snapin in neuroexocytosis. We found that the association of synaptotagmin-1 with SNAP-25 in brain homogenates of snapin mutant mice is impaired. Consequently, the absence of Snapin in embryonic chromaffin cells leads to a significant reduction of calcium- dependent exocytosis resulting from a decreased number of vesicles in releasable pools. Overexpression of Snapin fully rescued this inhibitory effect in the mutant cells. Furthermore, Snapin is relatively enriched in the purified large dense-core vesicles of chromaffin cells and associated with synaptotagmin-1. Thus, our biochemical and electrophysiological studies using snapin knock-out mice demonstrate that Snapin plays a critical role in modulating neurosecretion by stabilizing the release-ready vesicles. The Journal of Neuroscience, November 9, 2005 • 25(45):10546–10555

DEVELOPMENT/PLASTICITY/REPAIR

Migration from a Mitogenic Niche Promotes Cell-Cycle Exit

Yoojin Choi,1,2 Paul R. Borghesani,1,2 Jennifer A. Chan,1,3 and Rosalind A. Segal1,2 1Department of Pediatric Oncology, Dana-Farber Cancer Institute, 2Department of Neurobiology, Harvard Medical School, and 3Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts 02115

During development, neural precursors proliferate in one location and migrate to the residence of their mature function. The transition from a proliferative stage to a migratory stage is a critical juncture; errors in this process may result in tumor formation, mental retardation, or epilepsy. This transition could be the result of a simple sequential process in which precursors exit the cell cycle and then begin to migrate or a dynamically regulated process in which migration away from a mitogenic niche induces precursors to exit the cell cycle. Here, we show, using in vivo and in vitro approaches, that granule cell precursors proliferate when they are exposed to the microenvironment of the external granule cell layer (EGL) and exit the cell cycle as a result of migrating away from this environment. In vivo, granule cell precursors that remain in the EGL because of impaired migration continue to proliferate in the mitogenic niche of the EGL. In vitro, granule cell precursors that are introduced into an organotypic cerebellar slice proliferate preferentially in the EGL. We identify Sonic Hedgehog as a critical component of the EGL mitogenic niche. Together, these data indicate that migration away from a mitogenic niche promotes transition from a proliferative to a nonproliferative, migratory stage. The Journal of Neuroscience, November 9, 2005 • 25(45):10437–10445

Central and Peripheral Axon Branches from One Neuron Are Guided Differentially by Semaphorin3D and Transient Axonal Glycoprotein-1

Yan Liu and Mary C. Halloran Departments of Zoology and Anatomy, University of Wisconsin, Madison, Wisconsin 53706

For multiple axons from one neuron to extend in different directions to unique targets, the growth cones of each axon must have distinct responses to guidance cues. However, the mechanisms by which separate axon branches are guided along different pathways are mainly unknown. Zebrafish Rohon-Beard (R-B) sensory neurons extend central axon branches in the spinal cord and peripheral axons to the epidermis. To investigate the differential guidance mechanisms of the central versus peripheral R-B axon branches, we used live-growth cone imaging in vivo combined with manipulation of individual guidance molecules. We show that a semaphorin expressed at the dorsal spinal cord midline, Semaphorin3D (Sema3D), may act to repel the peripheral axons out of the spinal cord. Sema3D knock-down reduces the number of peripheral axons. Remarkably, Sema3D ectopic expression repels and induces branching of peripheral axons in vivo but has no effect on central axons from the same neurons. Conversely, central axons require a growth-promoting molecule, transient axonal glycoprotein-1 (TAG-1), to advance, whereas peripheral axons do not. After TAG-1 knock-down, central growth cones display extensive protrusive activity but make little forward advance. TAG-1 knock-down has no effect on the motility or advance of peripheral growth cones. These experiments show how Sema3D and TAG-1 regulate the motility and behavior of growth cones extending in their natural in vivo environment and demonstrate that two different axon branches from one neuron respond differently to guidance cues in vivo. The Journal of Neuroscience, November 9, 2005 • 25(45):10556–10563

BEHAVIORAL/SYSTEMS/COGNITIVE

Activation in Visual Cortex Correlates with the Awareness of Stereoscopic Depth

Gijs Joost Brouwer,1 Raymond van Ee,1 and Jens Schwarzbach2,3 1Helmholtz Institute, Utrecht University, 3584 CC Utrecht, The Netherlands, 2F. C. Donders Centre for Cognitive Neuroimaging, 6500 HB Nijmegen, The Netherlands, and 3Maastricht University, 6200 MD Maastricht, The Netherlands

Using event-related functional magnetic resonance imaging, we studied the activation correlating with the awareness of stereoscopic depth using a bistable slanted surface (slant rivalry). Bistability resulted from incongruence between two slant-defining cues: binocular disparity and monocular perspective. The stimulus was perceived as alternating between the perspective-dominated percept (monocular depth) and the disparity-dominated percept (stereopsis), while sensory input remained constant, enabling us to study changes in awareness of depth associated with either cue. Transient activation relating to perceptual alternations was found bilaterally in the caudal part of the intraparietal sulcus, in the right-hemispheric anterior intraparietal sulcus, within visual area V4d-topo, and inferior to area MTϩ. Transient activation correlating specifically with alternations toward the disparity-dominated percept was found in a number of visual areas, including dorsal visual areas V3A, V7, and V4d-topo and visual areas MTϩ and lateral occipital complex. No activation was found for alternations toward the perspective-dominated percept. Our results show that of all visual areas responsive to disparity-defined depth, V4d-topo shows the most robust signal changes correlating with the instigation of stereoscopic depth awareness (stereopsis). The Journal of Neuroscience, November 9, 2005 • 25(45):10403–10413 Neural Activity in Macaque Parietal Cortex Reflects Temporal Integration of Visual Motion Signals during Perceptual Decision Making

Alexander C. Huk1 and Michael N. Shadlen2 1Section of Neurobiology, Center for Perceptual Systems, and Department of Psychology, University of Texas at Austin, Austin, Texas 78712, and 2Howard Hughes Medical Institute, Department of Physiology and Biophysics and National Primate Research Center, University of Washington, Seattle, Washington 98195

Decision-making often requires the accumulation and maintenance of evidence over time. Although the neural signals underlying sensory processing have been studied extensively, little is known about how the brain accrues and holds these sensory signals to guide later actions. Previous work has suggested that neural activity in the lateral intraparietal area (LIP) of the monkey brain reflects the formation of perceptual decisions in a random dot direction-discrimination task in which monkeys communicate their decisions with eye-movement responses. We tested the hypothesis that decision-related neural activity in LIP represents the time integral of the momentary motion “evidence.” By briefly perturbing the strength of the visual motion stimulus during the formation of perceptual decisions, we tested whether this LIP activity reflected a persistent, integrated “memory” of these brief sensory events. We found that the responses of LIP neurons reflected substantial temporal integration. Brief pulses had persistent effects on both the monkeys’ choices and the responses of neurons in LIP, lasting up to 800 ms after appearance. These results demonstrate that LIP is involved in neural time integration underlying the accumulation of evidence in this task. Additional analyses suggest that decision-related LIP responses, as well as behavioral choices and reaction times, can be explained by near-perfect time integration that stops when a criterion amount of evidence has been accumulated. Temporal integration may be a fundamental computation underlying higher cognitive functions that are dissociated from immediate sensory inputs or motor outputs. The Journal of Neuroscience, November 9, 2005 • 25(45):10420–10436

Localization and Identification of Concurrent Sounds in the Owl’s Auditory Space Map

Clifford H. Keller and Terry T. Takahashi Institute of Neuroscience, University of Oregon, Eugene, Oregon 97403

In nature, sounds from multiple sources sum at the eardrums, generating complex cues for sound localization and identification. In this clutter, the auditory system must determine “what is where.” We examined this process in the auditory space map of the barn owl’s (Tyto alba) inferior colliculus using two spatially separated sources simultaneously emitting uncorrelated noise bursts, which were uniquely identified by different frequencies of sinusoidal amplitude modulation. Spatial response profiles ofisolatedneuronswereconstructedbytestingthesource-paircenteredatvariouslocationsinvirtualauditoryspace.Theneuronsrespondedwheneverasourcewasplaced within the receptive field, generating two clearly segregated foci of activity at appropriate loci. The spike trains were locked strongly to the amplitude modulation of the sourcewithinthereceptivefield,whereastheothersourcehadminimalinfluence.Twosourcesamplitudemodulatedatthesameratewereresolvedsuccessfully,suggesting that source separation is based on differences of fine structure. The spike rate and synchrony were stronger for whichever source had the stronger average binaural level. A computational model showed that neuronal activity was primarily proportional to the degree of matching between the momentary binaural cues and the preferred values of the neuron. The model showed that individual neurons respond to and synchronize with sources in their receptive field if there are frequencies having an average binaural-level advantage over a second source. Frequencies with interaural phase differences that are shared by both sources may also evoke activity, which may be synchronized with the amplitude modulations from either source. The Journal of Neuroscience, November 9, 2005 • 25(45):10446–10461

Event-Related Brain Potential Correlates of Human Auditory Sensory Memory-Trace Formation

Corinna Haenschel,1,2 David J. Vernon,3 Prabuddh Dwivedi,4 John H. Gruzelier,4 and Torsten Baldeweg5 1Laboratory for Neurophysiology and Neuroimaging, Department of Psychiatry, Johann Wolfgang Goethe University, 60590 Frankfurt, Germany, 2Max Planck Institute for Brain Research, 60528 Frankfurt, Germany, 3Department of Applied Social Sciences, Canterbury Christ Church University College, Canterbury CT1 1QU, United Kingdom, 4Division of Neuroscience and Mental Health, Faculty of Medicine, Imperial College, London W6 8RP, United Kingdom, and 5Institute of Child Health, University College London and Great Ormond Street Hospital for Children, London WC1N 1EH, United Kingdom

The event-related potential (ERP) component mismatch negativity (MMN) is a neural marker of human echoic memory. MMN is elicited by deviant sounds embedded in a stream of frequent standards, reflecting the deviation from an inferred memory trace of the standard stimulus. The strength of this memory trace is thought to be proportional to the number of repetitions of the standard tone, visible as the progressive enhancement of MMN with number of repetitions (MMN memory-trace effect). However, no direct ERP correlates of the formation of echoic memory traces are currently known. This study set out to investigate changes in ERPs to different numbers of repetitions of standards, delivered in a roving-stimulus paradigm in which the frequency of the standard stimulus changed randomly between stimulus trains. Normal healthy volunteers (n ϭ 40) were engaged in two experimental conditions: during passive listening and while actively discriminating changes in tone frequency. As predicted, MMN increased with increasing number of standards. However, this MMN memory-trace effect was caused mainly by enhancement with stimulus repetition of a slow positive wave from 50 to 250 ms poststimulus in the standard ERP, which is termed here “repetition positivity” (RP). This RP was recorded from frontocentral electrodes when participants were passively listening to or actively discriminating changes in tone frequency. RP may represent a human ERP correlate of rapid and stimulus-specific adaptation, a candidate neuronal mechanism underlying sensory memory formation in the auditory cortex. The Journal of Neuroscience, November 9, 2005 • 25(45):10494–10501 Peptide YY3–36 Inhibits Both Anorexigenic Proopiomelanocortin and Orexigenic Neuropeptide Y Neurons: Implications for Hypothalamic Regulation of Energy Homeostasis

Claudio Acuna-Goycolea and Anthony N. van den Pol Department of Neurosurgery, Yale University School of Medicine, New Haven, Connecticut 06520

Peptide YY3–36 (PYY3–36) is released by endocrine cells of the gut and may serve as an important long-distance neuropeptide signal relating energy balance information to the brain to depress food intake. The postulated mechanism is the activation of anorexigenic proopiomelanocortin (POMC) neurons of the hypothalamic arcuate nucleus.

In striking contrast, using voltage and current-clamp recording, we found that PYY3–36 consistently, dose dependently, and reversibly inhibited POMC cells by reducing action potentials, hyperpolarizing the membrane potential, decreasing input resistance and inward calcium currents, increasing G-protein-gated inwardly rectifying K ϩ channel currents, and presynaptically inhibiting release of excitatory glutamate. Importantly, we found PYY3–36 had similar inhibitory effects on identified orexigenic neuropeptide Y (NPY) neurons. In both cell types, these effects were blocked by BIIE0246, a Y2 receptor antagonist. Together, these data argue that anorexigenic actions of

PYY3–36 are mediated more likely by inhibition of NPY neurons. Dual PYY3–36 inhibition of both NPY and POMC cells may temporarily reduce the contribution of arcuate cells to feeding circuits, enhancing the role of other CNS loci. The Journal of Neuroscience, November 9, 2005 • 25(45):10510–10519

Touching a Rubber Hand: Feeling of Body Ownership Is Associated with Activity in Multisensory Brain Areas

H. Henrik Ehrsson,1 Nicholas P. Holmes,2 and Richard E. Passingham1,2 1Wellcome Department of Cognitive Neurology, Institute of Neurology, London WC1N 3BG, United Kingdom, and 2Department of Experimental Psychology, University of Oxford, Oxford OX1 3UD, United Kingdom

In the “rubber-hand illusion,” the sight of brushing of a rubber hand at the same time as brushing of the person’s own hidden hand is sufficient to produce a feeling of ownership of the fake hand. We shown previously that this illusion is associated with activity in the multisensory areas, most notably the ventral premotor cortex (Ehrsson et al., 2004). However, it remains to be demonstrated that this illusion does not simply reflect the dominant role of vision and that the premotor activity does not reflect a visual representation of an object near the hand. To address these issues, we introduce a somatic rubber-hand illusion. The experimenter moved the blindfolded participant’s left index finger so that it touched the fake hand, and simultaneously, he touched the participant’s real right hand, synchronizing the touches as perfectly as possible. After ϳ9.7 s, this stimulation elicited an illusion that one was touching one’s own hand. We scanned brain activity during this illusion and two control conditions, using functional magnetic resonance imaging. Activity in the ventral premotor cortices, intraparietal cortices, and the cerebellum was associated with the illusion of touching one’s own hand. Furthermore, the rated strength of the illusion correlated with the degree of premotor and cerebellar activity. This finding suggests that the activity in these areas reflects the detection of congruent multisensory signals from one’s own body, rather than of visual representations. We propose that this could be the mechanism for the feeling of body ownership. The Journal of Neuroscience, November 9, 2005 • 25(45):10564–10573

NEUROBIOLOGY OF DISEASE

Interactions between Metabotropic Glutamate 5 and Adenosine A2A Receptors in Normal and Parkinsonian Mice

Anil Kachroo,1 Lianna R. Orlando,1 David K. Grandy,2 Jiang-Fan Chen,1 Anne B. Young,1 and Michael A. Schwarzschild1 1MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts 02129, and 2Department of Physiology and Pharmacology, Oregon Health Sciences University, Portland, Oregon 97201

Evidence for heteromeric receptor complexes comprising adenosine A2A and metabotropic glutamate 5 (mGlu5) receptors in striatum has raised the possibility of synergistic interactions between striatal A2A and mGlu5 receptors. We investigated the role of striatal A2A receptors in the locomotor stimulant and antiparkinsonian properties of mGlu5 antagonists using complementary pharmacologic and genetic approaches. Locomotion acutely stimulated by the mGlu5 antagonist [2-methyl-6-

(phenylethynyl)-pyridine(MPEP)]wasabsentinmGlu5knock-out(KO)miceandwaspotentiatedbyanA2A antagonistKW-6002[(E)-1,3-diethyl-8-(3,4-dimethoxystyryl)- 7-methylxanthine], both in normal and in dopamine-depleted (reserpinized) mice. Conversely, the MPEP-induced motor response was markedly attenuated in single and double A2A and D2 receptor KO mice. In contrast, motor stimulation by a D1 dopamine agonist was not attenuated in the KO mice. The A2A receptor dependence of

MPEP-induced motor stimulation was investigated further using a postnatal forebrain-specific conditional (Cre/loxP system) KO of the A2A receptor. MPEP loses the ability to stimulate locomotion in conditional KO mice, suggesting that this mGlu5 antagonist effect requires the postdevelopmental action of striatal A2A receptors. The potentiation of mGlu5 antagonist-induced motor stimulation by an A2A antagonist and its dependence on both D2 and forebrain A2A receptors highlight the functional interdependence of these receptors. These data also strengthen a rationale for pursuing a combinational drug strategy for enhancing the antiparkinsonian effects of A2A and mGlu5 antagonists. The Journal of Neuroscience, November 9, 2005 • 25(45):10414–10419 Silencing Primary Dystonia: Lentiviral-Mediated RNA Interference Therapy for DYT1 Dystonia

Pedro Gonzalez-Alegre,1 Nicole Bode,1 Beverly L. Davidson,1,2 and Henry L. Paulson1 Departments of 1Neurology and 2Medicine, Carver College of Medicine at the University of Iowa, Iowa City, Iowa 52242

DYT1 is the most common inherited dystonia. Currently, there are no preventive or curative therapies for this dominantly inherited disease. DYT1 dystonia is caused by a common three-nucleotide deletion in the TOR1A gene that eliminates a glutamic acid residue from the protein torsinA. Recent studies suggest that torsinA carrying the disease-linked mutation, torsinA(⌬E) acts through a dominant-negative effect by recruiting wild-type torsinA [torsinA(wt)] into oligomeric structures in the nuclear envelope. Therefore, suppressing torsinA(⌬E) expression through RNA interference (RNAi) could restore the normal function of torsinA(wt), representing a potentially effective therapy regardless of the biological role of torsinA. Here, we have generated short hairpin RNAs (shRNAs) that mediate allele-specific suppression of torsinA(⌬E) and rescue cells from its dominant-negative effect, restoring the normal distribution of torsinA(wt). In addition, delivery of this shRNA by a recombinant feline immuno- deficiencyviruseffectivelysilencedtorsinA(⌬E)inaneuralmodelofthedisease.Wefurtherestablishthefeasibilityofthisviral-mediatedRNAiapproachbydemonstrating significant suppression of endogenous torsinA in mammalian neurons. Finally, this silencing of torsinA is achieved without triggering an interferon response. These results support the potential use of viral-mediated RNAi as a therapy for DYT1 dystonia and establish the basis for preclinical testing in animal models of the disease. The Journal of Neuroscience, November 9, 2005 • 25(45):10502–10509 Postdoctoral Research Awards Senior Research Awards

! " #" ' Opportunities for research in US government $ "! " "! laboratories in the fields of: ' # # " ! Neurology Neurobiology Neurochemistry Neurophysiology Neuropsychology Neuropharmacology Neurotoxicology Neuroendocrinology and related disciplines

Among participating laboratories are: National Institutes of Health )551-,5 US Army Research Laboratory "0- -56 :2 574- . 4 ' 74 , )45 US Naval Research Laboratory US Air Force Research Laboratory "0- 74) . -745+1-+- 15 ) 9--; 27*1+)61 4-), *; 4- US Army Night Vision Laboratory 60) 62 -745+1-+- 4-5-)4+0-45 74 2)+--6 ), FAA/Civil Aerospace Medical Institute US Environmental Protection Agency +.-4-+- ),8-46151/ 4)6-5 )4- 60- *-56 )47, ), 74 9--; Edgewood Chemical & Biological Center 27*1+)61 5+0-,7- ), 1- 24-5-+- -)5 /4-)6 )7,1-+- US Army Medical Research & Materiel Command -:2574- %0; 6 /18- )551 -,5 ) 64; National Institute for Occupational Safety & Health Naval Medical Research Ctr/Naval Health Research Ctr 6 999-745+14/15+),8-46151/506 National Institutes of Health/National Institute of .4 ,-6)15 57*1661/ ) ), Standards and Technology, Joint Program

Competitive awards for independent research Duration of 12 months renewable for up to 3 years Annual stipend ranging from $38,000 to $65,000 for recent Ph.D. recipients; higher for additional experience Relocation, professional travel, health insurance Annual application deadlines Feb 1, May 1, Aug 1 and Nov 1

Detailed program information, including instructions on how to apply, can be obtained from the NRC Web site at: www.national-academies.org/rap Questions should be directed to

202-334-2760 (tel) or [email protected]

Visit NRC booth # 3502 in the exhibit hall.

Qualified applicants will be reviewed without regard to race, religion, color, age, sex or national origin.

Dystonia Medical Research Foundation www.dystonia-foundation.org

2006 Funding Opportunities Research Grants & Contracts–Grants & contracts are available in support of hypothesis-driven research relative to the causes, mechanisms, prevention and treatment of the various forms of dystonia, the third most common neurologic movement disorder. Amount: $75,000/year up to 2 years; $100,000/year for 3 years (Fahn Award) for outstanding tenure- track junior faculty. Contracts are negotiable in duration and amount. Deadline: 1/10/06

Fellowships–This program is designed to assist post-doctoral fellows establish careers in research relevant to the field of dystonia. Amount: $50,000 per year for two years. Deadline: 1/10/06

Residency Elective Program–This program provides an opportunity for PGY 2 or 3 residents in neurology to gain experience in the evaluation and treatment of patients with dystonia as “visiting trainees” with dystonia experts at their respective institutions. Amount: up to $4,000 Deadline: on-going

Research materials, including brain tissue and reagents, are available to qualified investigators. For more information and applications, please contact DMRF at 312.755.0198 or visit www.dystonia-foundation.org

Please visit us at SFN Booth #1113 1/1+) 15+8-4; 1 %,5 -

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The Linda and Jack Gill Center for Biomoleuclar Science Endowed Chairs in Molecular Neuroscience Indiana University seeks applications and nominations for three endowed professorships. These positions are part of the ongoing expansion of the Program in Neuroscience supported by a generous endowment, the construction of a new building to house the appointees, and the infusion of greater than $400 million since the year 2000 from state and private funds for life sciences research. The area of focus for the positions is the genetic and molecular basis of synaptic plasticity broadly defined to include changes in synaptic activity as a result of experience, development or injury. The goal of these appointments is to attract internationally recognized scientists to enhance research and bring forth important discoveries in neuroscience. Recently described by Newsweek as the “hottest big state school" in the United States, Indiana University is a vibrant and beautiful campus set amongst the hills of southern Indiana in Bloomington, a safe, culturally rich environment. Nominations should include a letter describing the qualifications of the candidate along with contact information. Applications should include a statement of research interests, a curriculum vitae, and names of three references. The positions will remain open until filled, but for full consideration, please submit materials by January 15, 2006. Nominations and applications should be addressed to:

J. Michael Walker http://www.indiana.edu/~gillctr/ Indiana University 1101 E. 10th St. Bloomington, IN 47405 USA [email protected] Indiana University is an Equal Opportunity/Affirmative Action Employer. Nominations of and applications from women and minorities are strongly encouraged. MIDDLEBURY COLLEGE Tenure-track position in Biopsychology/Behavioral Neuroscience

The Department of Psychology invites applications for a tenure- track position in Biopsychology/Behavioral Neuroscience beginning September 2006. We are interested in a neuroscientist whose research focuses on nonhuman species. The successful candidate must be able to teach Biopsychology or Behavioral Neuroscience, Learning, Introduction to Psychology, and upper and mid-level courses in areas of biopsychology or neuroscience. Appointments will be made at the rank of Assistant Professor (Ph.D.) or Instructor (ABD). The psychology department at Middlebury College is committed to exceptional teaching and to the involvement of undergraduates in an active research program. The department is housed in a state-of-the-art science center and currently has eleven fully equipped faculty research labs. Candidates should provide evidence of commitment to excellent teaching and of their desire to develop and sustain a program of research, including research that actively involves undergraduates at a liberal arts institution. Please send a letter of application with a statement of teaching and research interests, copies of teaching evaluations, curriculum vitae, graduate transcript, a sample of scholarly work, and three current letters of recommendation, at least two of which must speak to teaching ability, to:

Professor Carlos Vélez, Chair; Department of Psychology; Middlebury College; Middlebury, VT 05753.

Review of applications will begin November 1, 2005 and continue until the position is filled. Middlebury College is an Equal Opportunity Employer committed to recruiting a diverse faculty to complement the increasing diversity of our student body.

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726 14+ - % Q !716- %)501/6 "- -20- Q 999 5. 4/ RESEARCH GRANT AWARDS

Five-Year named Chairs for Senior and Junior !! # " !" "! Faculty, maximum of $1,100,000 over a five-year period. I One-Time Start-Up Cost Grant, maximum of $ "! $1,000,000. Individual Grants, maximum of $200,000 I per year, research grants for basic or clinical research on & '# "% !" % spinal cord injury and disease. Postdoctoral & Graduate Student Fellowship Awards. Applicants must be associated with a New Jersey Institution and may )6-, 56 $)7)*- !+1-6; collaborate with researchers out-of-state and country. "0- !+1-6; .4 -745+1- +- 9)5 4)6-, D56 $)7)*- !+1-6; .4 4.-551) )4--45L Application form and details at: 1 60- 11 .4$)61+5 !+1- +- ,8154; )4, 5748-; www.state.nj.us/health/spinalcord/

Application form and details from:

New Jersey Commission on Spinal Cord Research PO Box 360; Market and Warren Streets Trenton, New Jersey 08625-0360 Tel: 609-292-4055. E-mail: [email protected]

Closing Date for Grant Applications: December 8, 2005 1 /1+) 15+8-4; 1 %,5 -

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Assistant/Associate Professor Behavioral Neuropharmacology

The Department of Pharmacology, University of Tennessee (UT) Health Science Center (website: http://www.utmem.edu/pharmacology), invites applications for a tenure-track assistant/associate professor faculty position in the area of behavioral pharmacology or behavioral neuroscience. We seek a faculty member who will be a major contributor to the UT Center of Excellence in the Neurobiology of Brain Diseases. The faculty member will direct an independent program in an aspect of psychopharmacology or drug abuse research. Ideal candidates will be those who employ an integrative, mechanistic approach, utilizing neurochemical, molecular or electrophysiological techniques to complement their behavioral research. Candidates who will administer a core animal behavior laboratory will receive additional consideration. Candidates should be enthusiastic about engaging in collaborative research within a highly interactive, well-funded community of neuroscientists. The selected candidate will participate in the teaching of graduate and professional students. Applicants should have a doctorate in pharmacology, neuroscience, experimental psychology or a related discipline, and relevant postdoctoral experience. Applications will be reviewed beginning December 1, 2005, but will continue to be accepted until the position is filled. Curriculum vitae, statement of research interests and three reference letters should be sent to:

Jeffery D. Steketee, Ph.D., Behavioral Neuropharmacology Search Committee Department of Pharmacology, University of Tennessee Health Science Center 874 Union Avenue, Memphis, TN 38163 E-mail: [email protected].

The University of Tennessee is an Equal Opportunity / Affirmative Action / Title VI / Title IX / Section 504 / Americans With Disabilities Act / Age Discrimination in Employment Act Employer. Postdoctoral Associate in Computational Genomics of Eukaryotic Cells & Neuroinformatics

McKnight Brain Institute and Whitney Laboratory of Marine Bioscience University of Florida Research Asst. B Regular position available at Farber Institute for Neurosciences, We are seeking a computational biologist / Thomas Jefferson Univ. Requires MS and 4 year lab work bioinformatician to join an interdisciplinary team to experience. Able to anesthetize rats, do brain surgery in develop an integrated suite of neuroinformatic stereotaxic apparatus, transcardial perfusion and tissue databases, tools, algorithms, languages, and standards extraction. Perform immunocytochemistry experiments focused on the biology of neurons, stem cells, and including immunofluorescence, immunoperoxidase and neuronal evolution. Our work in computational and immunogold labelings for electron microscopy. Expertise in comparative neuroinformatics is directed at annotating EM, animal protocol compliance and lab operation mgt required. and characterizing the gene networks, signaling Send Resume to: Dr. Elisabeth Van Bockstaele, Farber Institute, pathways and neuron specific genes required to 900 Walnut St, Ste. 417, Philadelphia, PA 19107 generate a computational model of a living neuron, one in which genomics, molecular, imaging, and physiological data will be part of one integrated platform: The Portrait of a Living Neuron.˚ To apply, send a curriculum vitae and letters of recommendation to:

Peter A. Anderson, Ph.D. Professor and Director Whitney Marine Laboratory of Marine Bioscience University of Florida 9505 Oceanshore Boulevard St. Augustine, FL 32080-9610˚

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