This Week in The Journal - The Journal of Neuroscience
The Journal of Neuroscience, February 18, 2015 • 35(7):i • i This Week in The Journal FoxP2 Overexpression Impedes Song Learning Jonathan B. Heston and Stephanie A. White (see pages 2885–2894) Speech is a complex motor skill in which muscles controlling the tongue, lips, and larynx must be coordinated to make rapid transitions between phonemes. The ability to string syllables together in the proper sequence is impaired in people who have mutations in FoxP2, a transcription factor expressed in projection neurons of cortex, thalamus, cerebellum, and basal ganglia. Because zebra finches, like humans, produce complex vocalizations composed of stereotyped sequences of syllables that juveniles learn by imitating adults, these birds are a useful model system for exploring how FoxP2 expression influences complex motor behavior. FoxP2 is expressed in Area X, a songdedicated nucleus of zebra finch basal ganglia, and it is upregulated during the juvenile song-learning period. However, FoxP2 levels are acutely downregulated after juveniles practice singing by themselves. FoxP2 expression also decreases when adult birds sing by themselves, but interestingly, not when the birds sing to females. Notably, songs are more variable during undirected singing than during female-directed singing, suggesting FoxP2 expression is associated with song stability. Indeed, when FoxP2 is knocked down in Area X in juvenile finches, the birds fail to accurately reproduce a tutor’s song and they sing more variable songs as adults. To further investigate the role of FoxP2 in song learning and variability, Heston and White overexpressed the protein in Area X. Like FoxP2 knockdown, overexpression prevented juvenile birds from accurately reproducing their tutor’s song. FoxP2-overexpressing birds skipped more syllables than controls, and the syllables that were present were poorer imitations. FoxP2 overexpression did not produce the predicted decrease in song variability, however. In fact, the songs of juvenile FoxP2-overexpressing birds were more variable than controls’. Unlike in FoxP2deficient finches, however, songs became more stereotyped over time in FoxP2overexpressing birds, and their adult songs, although different than the tutor’s, were no more variable than those of controls. These results clearly indicate that dynamic regulation of FoxP2 levels is required for songbirds to accurately reproduce a tutor song. But they also suggest that the relationship between FoxP2 levels and song variability is not as simple as previously hypothesized. Moreover, how FoxP2 promotes motor sequencing remains a mystery. A mutation that reduces expression of an ER chloride channel causes loss of granule cells in the rostral cerebellum of 11month-old mice. See the article by Jia et al. for details. Loss of ER Chloride Channel Causes Neurodegeneration Yichang Jia, Thomas J. Jucius, Susan A. Cook, and Susan L. Ackerman (see pages 3001–3009) Many neurodegenerative diseases involve accumulation of misfolded proteins. How this accumulation causes neurons to die is largely unknown, but prolonged activation of the unfolded protein response (UPR) in the endoplasmic reticulum (ER) may be a common contributor. All transmembrane and secreted proteins are processed in the ER, where chaperone proteins help ensure proper folding. Abnormally folded proteins are targeted for degradation, and if they begin to accumulate, the UPR is activated. The UPR involves increased synthesis of proteins involved in protein folding and degradation along with decreased synthesis of most other proteins. If the UPR fails to relieve ER stress, apoptosis is triggered. Any factor that interferes with protein processing in the ER can activate the UPR. This includes mutations that prevent transmembrane proteins from folding properly, mutations in resident ER proteins, exogenous toxins, and other cellular stressors. These factors can combine to cause prolonged activation of the UPR, leading to cell death. This week, Jia et al. report that mutations in Clcc1, a gene that encodes a largely ignored ER chloride channel, contribute to UPR induction and neurodegeneration in mice. Jia et al. examined inbred mice in which a spontaneous mutation produced ataxia along with progressive degeneration of cerebellar granule cells and peripheral motor axons. This phenotype was linked to the insertion of a transposable element into the Clcc1 gene, which reduced CLCC1 protein levels in cerebellum and spinal cord. Importantly, signs of elevated UPR activity were present in cerebellar granule cells of Clcc1-deficient mice before significant neurodegeneration had occurred, suggesting that UPR activation contributed to degeneration. Interestingly, Clcc1 expression was reduced in several brain areas, including the hippocampus and cerebral cortex, but neither ER stress nor degeneration were detected in these areas, indicating a cell-type specific effect. Reintroducing wild-type Clcc1 via a bacterial artificial chromosome rescued granule cell loss and motor nerve degeneration. These results exemplify a common theme in neurodegenerative diseases: a widely expressed protein of unknown function is linked to degeneration of a specific neuronal type. Given that prolonged activation of the UPR often precedes degeneration, relieving ER stress might be an expedient strategy to treat many diseases. This Week in The Journal is written by X Teresa Esch, Ph.D. The Journal of Neuroscience February 18, 2015 • Volume 35 Number 7 • www.jneurosci.org i This Week in The Journal Journal Club 2839 KIS: Synaptic Plasticity’s Missing Molecular Link? Jon Brudvig and Jacob Cain 2842 Probing Perceptual Performance after Microsaccades Xiaoguang Tian and Chih-Yang Chen Brief Communications Cover legend: This pseudocolored confocal image shows a vGluT1-expressing muscle-spindle sensory ending in the gluteus maximus muscle of a 10-dayold wild-type mouse. Superimposed on the image are extracellular electrophysiological recordings of a soleus muscle nerve in a wild-type mouse (upper trace) and a mouse homozygous mutant for the PDZdomain protein Whirlin. The recordings, made during four episodes of soleus muscle stretch, demonstrate that stretch-induced activity in Whirlin mutant proprioceptive afferents is much reduced compared to those in wild-type. Cover image produced by Ira Schieren and Joriene de Nooij. For more information, see the article by de Nooij et al. (pages 3073–3084). 3010 Controlling Your Impulses: Electrical Stimulation of the Human Supplementary Motor Complex Prevents Impulsive Errors Laure Spieser, Wery van den Wildenberg, Thierry Hasbroucq, K. Richard Ridderinkhof, and Borís Burle 3016 Stimulation-Evoked Ca2ⴙ Signals in Astrocytic Processes at Hippocampal CA3–CA1 Synapses of Adult Mice Are Modulated by Glutamate and ATP Wannan Tang, Karolina Szokol, Vidar Jensen, Rune Enger, Chintan A. Trivedi, Øivind Hvalby, P. Johannes Helm, Loren L. Looger, Rolf Sprengel, and Erlend A. Nagelhus 3201 Depression of Excitatory Synapses onto Parvalbumin Interneurons in the Medial Prefrontal Cortex in Susceptibility to Stress Zinaida Perova, Kristen Delevich, and Bo Li Articles CELLULAR/MOLECULAR 2860 Interleukin 1 Type 1 Receptor Restore: A Genetic Mouse Model for Studying Interleukin 1 Receptor-Mediated Effects in Specific Cell Types Xiaoyu Liu, Tetsuji Yamashita, Qun Chen, Natalya Belevych, Daniel B. Mckim, Andrew J. Tarr, Vincenzo Coppola, Nikitaa Nath, Daniel P. Nemeth, Zunera W. Syed, John F. Sheridan, Jonathan P. Godbout, Jian Zuo, and Ning Quan 2927 Identification of 12/15-Lipoxygenase as a Regulator of Axon Degeneration through High-Content Screening York Rudhard, Arundhati Sengupta Ghosh, Beatrix Lippert, Alexander Bo¨cker, Mehdi Pedaran, Joachim Kra¨mer, Hai Ngu, Oded Foreman, Yichin Liu, and Joseph W. Lewcock 3034 Dynamics of Elongation Factor 2 Kinase Regulation in Cortical Neurons in Response to Synaptic Activity Justin W. Kenney, Oksana Sorokina, Maja Genheden, Anatoly Sorokin, J. Douglas Armstrong, and Christopher G. Proud 3073 The PDZ-Domain Protein Whirlin Facilitates Mechanosensory Signaling in Mammalian Proprioceptors Joriene C. de Nooij, Christian M. Simon, Anna Simon, Staceyann Doobar, Karen P. Steel, Robert W. Banks, George Z. Mentis, Guy S. Bewick, and Thomas M. Jessell 3100 SIRT1-FOXO3a Regulate Cocaine Actions in the Nucleus Accumbens Deveroux Ferguson, Ningyi Shao, Elizabeth Heller, Jian Feng, Rachael Neve, Hee-Dae Kim, Tanessa Call, Samantha Magazu, Li Shen, and Eric J. Nestler 3155 Regulation of Postsynaptic Function by the Dementia-Related ESCRT-III Subunit CHMP2B Romain Chassefeyre, Jose´ Martínez-Herna´ndez, Federica Bertaso, Nathalie Bouquier, Be´atrice Blot, Marine Laporte, Sandrine Fraboulet, Yohann Coute´, Anny Devoy, Adrian M. Isaacs, Karin Pernet-Gallay, Re´my Sadoul, Laurent Fagni, and Yves Goldberg 3190 The 16p11.2 Deletion Mouse Model of Autism Exhibits Altered Cortical Progenitor Proliferation and Brain Cytoarchitecture Linked to the ERK MAPK Pathway Joanna Pucilowska, Joseph Vithayathil, Emmanuel J. Tavares, Caitlin Kelly, J. Colleen Karlo, and Gary E. Landreth 3230 Positively Charged Amino Acids at the SNAP-25 C Terminus Determine Fusion Rates, Fusion Pore Properties, and Energetics of Tight SNARE Complex Zippering Qinghua Fang, Ying Zhao, Adam Drew Herbst, Brian N. Kim, and Manfred Lindau 3263 Spiral Ganglion Degeneration and Hearing Loss as a Consequence of Satellite Cell Death in Saposin B-Deficient Mice Omar Akil, Ying Sun, Sarath Vijayakumar, Wujuan Zhang, Tiffany Ku, Chi-Kyou Lee, Sherri Jones, Gregory A. Grabowski, and Lawrence R. Lustig DEVELOPMENT/PLASTICITY/REPAIR 2942 DBZ Regulates Cortical Cell Positioning and Neurite Development by Sustaining the Anterograde Transport of Lis1 and DISC1 through Control of Ndel1 Dual-Phosphorylation Masayuki Okamoto, Tokuichi Iguchi, Tsuyoshi Hattori, Shinsuke Matsuzaki, Yoshihisa Koyama, Manabu Taniguchi, Munekazu Komada, Min-Jue Xie, Hideshi Yagi, Shoko Shimizu, Yoshiyuki Konishi, Minoru Omi, Tomohiko Yoshimi, Taro Tachibana, Shigeharu Fujieda, Taiichi Katayama, Akira Ito, Shinji Hirotsune, Masaya Tohyama, and Makoto Sato 3139 Overexpression of Sox11 Promotes Corticospinal Tract Regeneration after Spinal Injury While Interfering with Functional Recovery Zimei Wang, Ashley Reynolds, Adam Kirry, Christopher Nienhaus, and Murray G. Blackmore 3218 Valproate-Induced Neurodevelopmental Deficits in Xenopus laevis Tadpoles Eric J. James, Jenny Gu, Carolina M. Ramirez-Vizcarrondo, Mashfiq Hasan, Torrey L.S. Truszkowski, Yuqi Tan, Phouangmaly M. Oupravanh, Arseny S. Khakhalin, and Carlos D. Aizenman SYSTEMS/CIRCUITS 2845 New Whole-Body Sensory-Motor Gradients Revealed Using Phase-Locked Analysis and Verified Using Multivoxel Pattern Analysis and Functional Connectivity Noa Zeharia, Uri Hertz, Tamar Flash, and Amir Amedi 2895 Stimulus Statistics Shape Oscillations in Nonlinear Recurrent Neural Networks Je´re´mie Lefebvre, Axel Hutt, Jean-Franc¸ois Knebel, Kevin Whittingstall, and Micah M. Murray 2959 Reciprocal Interareal Connections to Corticospinal Neurons in Mouse M1 and S2 Benjamin A. Suter and Gordon M.G. Shepherd 2975 Mapping of Functionally Characterized Cell Classes onto Canonical Circuit Operations in Primate Prefrontal Cortex Salva Ardid, Martin Vinck, Daniel Kaping, Susanna Marquez, Stefan Everling, and Thilo Womelsdorf 2992 Cell Assemblies of the Basal Forebrain David Tingley, Andrew S. Alexander, Laleh K. Quinn, Andrea A. Chiba, and Douglas A. Nitz 3048 Synchronous Inhibitory Potentials Precede Seizure-Like Events in Acute Models of Focal Limbic Seizures Laura Uva, Gian Luca Breschi, Vadym Gnatkovsky, Stefano Taverna, and Marco de Curtis 3056 7 Tesla fMRI Reveals Systematic Functional Organization for Binocular Disparity in Dorsal Visual Cortex Nuno R. Goncalves, Hiroshi Ban, Rosa M. Sa´nchez-Panchuelo, Susan T. Francis, Denis Schluppeck, and Andrew E. Welchman 3112 Cell-Specific Activity-Dependent Fractionation of Layer 2/3¡5B Excitatory Signaling in Mouse Auditory Cortex Ankur Joshi, Jason W. Middleton, Charles T. Anderson, Katharine Borges, Benjamin A. Suter, Gordon M. G. Shepherd, and Thanos Tzounopoulos 3124 Neural Heterogeneities Determine Response Characteristics to Second-, but Not First-Order Stimulus Features Michael G. Metzen and Maurice J. Chacron 3174 Differential Dynamics of Spatial Attention, Position, and Color Coding within the Parietofrontal Network Elaine Astrand, Guilhem Ibos, Jean-Rene´ Duhamel, and Suliann Ben Hamed BEHAVIORAL/COGNITIVE 䊉 2885 Behavior-Linked FoxP2 Regulation Enables Zebra Finch Vocal Learning Jonathan B. Heston and Stephanie A. White 2904 Vicarious Reinforcement Learning Signals When Instructing Others Matthew A.J. Apps, Elise Lesage, and Narender Ramnani 2914 Neural Activity in the Medial Temporal Lobe Reveals the Fidelity of Mental Time Travel James E. Kragel, Neal W Morton, and Sean M. Polyn 3085 Anticipatory Anxiety Disrupts Neural Valuation during Risky Choice Jan B. Engelmann, Friederike Meyer, Ernst Fehr, and Christian C. Ruff 3146 Economic Choices Reveal Probability Distortion in Macaque Monkeys William R. Stauffer, Armin Lak, Peter Bossaerts, and Wolfram Schultz 3207 Influence of Motivation on Control Hierarchy in the Human Frontal Cortex Jo¨rg Bahlmann, Esther Aarts, and Mark D’Esposito 3256 Alpha Phase Determines Successful Lexical Decision in Noise Antje Strauß, Molly J. Henry, Mathias Scharinger, and Jonas Obleser 3276 Converging Evidence for the Neuroanatomic Basis of Combinatorial Semantics in the Angular Gyrus Amy R. Price, Michael F. Bonner, Jonathan E. Peelle, and Murray Grossman 3285 Cerebellar Direct Current Stimulation Enhances On-Line Motor Skill Acquisition through an Effect on Accuracy Gabriela Cantarero, Danny Spampinato, Janine Reis, Loni Ajagbe, Tziporah Thompson, Kopal Kulkarni, and Pablo Celnik NEUROBIOLOGY OF DISEASE 䊉 2871 Stabilization of Nontoxic A-Oligomers: Insights into the Mechanism of Action of Hydroxyquinolines in Alzheimer’s Disease Timothy M. Ryan, Blaine R. Roberts, Gawain McColl, Dominic J. Hare, Philip A. Doble, Qiao-Xin Li, Monica Lind, Anne M. Roberts, Haydyn D. T. Mertens, Nigel Kirby, Chi L. L. Pham, Mark G. Hinds, Paul A. Adlard, Kevin J. Barnham, Cyril C. Curtain, and Colin L. Masters 3001 Loss of Clcc1 Results in ER Stress, Misfolded Protein Accumulation, and Neurodegeneration Yichang Jia, Thomas J. Jucius, Susan A. Cook, and Susan L. Ackerman 3022 Microglial Activation Enhances Associative Taste Memory through Purinergic Modulation of Glutamatergic Neurotransmission Jean-Christophe Delpech, Nicolas Saucisse, Shauna L. Parkes, Chloe Lacabanne, Agnes Aubert, Fabrice Casenave, Etienne Coutureau, Nathalie Sans, Sophie Laye´, Guillaume Ferreira, and Agnes Nadjar 3240 Brain Amyloid- Burden Is Associated with Disruption of Intrinsic Functional Connectivity within the Medial Temporal Lobe in Cognitively Normal Elderly Zhuang Song, Philip S. Insel, Shannon Buckley, Seghel Yohannes, Adam Mezher, Alix Simonson, Sarah Wilkins, Duygu Tosun, Susanne Mueller, Joel H. Kramer, Bruce L. Miller, and Michael W. Weiner 3248 Alcohol Decreases Baseline Brain Glucose Metabolism More in Heavy Drinkers Than Controls But Has No Effect on Stimulation-Induced Metabolic Increases Nora D. Volkow, Gene-Jack Wang, Ehsan Shokri Kojori, Joanna S. Fowler, Helene Benveniste, and Dardo Tomasi Persons interested in becoming members of the Society for Neuroscience should contact the Membership Department, Society for Neuroscience, 1121 14th St., NW, Suite 1010, Washington, DC 20005, phone 202-962-4000. Instructions for Authors are available at http://www.jneurosci.org/misc/itoa.shtml. Authors should refer to these Instructions online for recent changes that are made periodically. Brief Communications Instructions for Authors are available via Internet (http://www.jneurosci.org/misc/ifa_bc.shtml). Submissions should be submitted online using the following url: http://jneurosci.msubmit.net. Please contact the Central Office, via phone, fax, or e-mail with any questions. Our contact information is as follows: phone, 202-962-4000; fax, 202-962-4945; e-mail, [email protected]. BRIEF COMMUNICATIONS Controlling Your Impulses: Electrical Stimulation of the Human Supplementary Motor Complex Prevents Impulsive Errors Laure Spieser,1 Wery van den Wildenberg,2,3 Thierry Hasbroucq,1 K. Richard Ridderinkhof,2,3 and Borís Burle1 Aix-Marseille Universite´, Centre National de la Recherche Scientifique, LNC Unite´ Mixte de Recherche 7291, 13331 Marseille Cedex 3, France, 2Amsterdam Center for the study of Adaptive Control in Brain and Behavior (Acacia), University of Amsterdam, 1018 XA Amsterdam, the Netherlands, and 3Amsterdam Brain & Cognition, University of Amsterdam, 1018 WB Amsterdam, the Netherlands 1 To err is human. However, an inappropriate urge does not always result in error. Impulsive errors thus entail both a motor system capture by an urge to act and a failed inhibition of that impulse. Here we show that neuromodulatory electrical stimulation of the supplementary motor complex in healthy humans leaves action urges unchanged but prevents them from turning into overt errors. Subjects performed a choice reaction-time task known to trigger impulsive responses, leading to fast errors that can be revealed by analyzing accuracy as a function of poststimulus time. Yet, such fast errors are only the tip of the iceberg: electromyography (EMG) revealed fast subthreshold muscle activation in the incorrect response hand in an even larger proportion of overtly correct trials, revealing covert response impulses not discernible in overt behavior. Analyzing both overt and covert response tendencies enables to gauge the ability to prevent these incorrect impulses from turning into overt action errors. Hyperpolarizing the supplementary motor complex using transcranial direct current stimulation (tDCS) preserves action impulses but prevents their behavioral expression. This new combination of detailed behavioral, EMG, and tDCS techniques clarifies the neurophysiology of impulse control, and may point to avenues for improving impulse control deficits in various neurologic and psychiatric disorders. The Journal of Neuroscience, February 18, 2015 • 35(7):3010 –3015 Stimulation-Evoked Ca2⫹ Signals in Astrocytic Processes at Hippocampal CA3–CA1 Synapses of Adult Mice Are Modulated by Glutamate and ATP Wannan Tang,1,3,4 Karolina Szokol,1,3,6 Vidar Jensen,1,3 Rune Enger,1,3,6 Chintan A. Trivedi,5 Øivind Hvalby,2 P. Johannes Helm,3 Loren L. Looger,7 Rolf Sprengel,4 and Erlend A. Nagelhus1,3,6,8 Centre for Molecular Medicine Norway, The Nordic EMBL Partnership, 2Department of Physiology, and 3Letten Centre and GliaLab, Department of Physiology, Institute of Basic Medical Sciences, University of Oslo, 0317 Oslo, Norway, 4Department of Molecular Neurobiology and 5Neural Circuits and Behaviour Research Group, Department of Biomedical Optics, Max Planck Institute for Medical Research, D-69120 Heidelberg, Germany, and 6Oslo University Hospital, Department of Neurology, 0027 Oslo, Norway, 7Howard Hughes Medical Institute, Janelia Farm Research Campus, Ashburn, Virginia 20147, and 8Center for Translational Neuromedicine, Department of Neurosurgery, University of Rochester Medical Center, Rochester, New York 14618 1 To date, it has been difficult to reveal physiological Ca 2⫹ events occurring within the fine astrocytic processes of mature animals. The objective of the study was to explore whether neuronal activity evokes astrocytic Ca 2⫹ signals at glutamatergic synapses of adult mice. We stimulated the Schaffer collateral/commissural fibers in acute hippocampal slices from adult mice transduced with the genetically encoded Ca 2⫹ indicator GCaMP5E driven by the glial fibrillary acidic protein promoter. Two-photon imaging revealed global stimulation-evoked astrocytic Ca 2⫹ signals with distinct latencies, rise rates, and amplitudes in fine processes and somata. Specifically, the Ca 2⫹ signals in the processes were faster and of higher amplitude than those in the somata. A combination of P2 purinergic and group I/II metabotropic glutamate receptor (mGluR) antagonists reduced the amplitude of the Ca 2⫹ transients by 30 – 40% in both astrocytic compartments. Blockage of the mGluRs alone only modestly reduced the magnitude of the stimulation-evoked Ca 2⫹ signals in processes and failed to affect the somatic Ca 2⫹ response. Local application of group I or I/II mGluR agonists or adenosine triphosphate (ATP) elicited global astrocytic Ca 2⫹ signals that mimicked the stimulation-evoked astrocytic Ca 2⫹ responses. We conclude that stimulationevoked Ca 2⫹ signals in astrocytic processes at CA3–CA1 synapses of adult mice (1) differ from those in astrocytic somata and (2) are modulated by glutamate and ATP. The Journal of Neuroscience, February 18, 2015 • 35(7):3016 –3021 Depression of Excitatory Synapses onto Parvalbumin Interneurons in the Medial Prefrontal Cortex in Susceptibility to Stress Zinaida Perova, Kristen Delevich, and Bo Li Watson School of Biological Sciences, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724 In response to extreme stress, individuals either show resilience or succumb to despair. The prefrontal cortex (PFC) is required for coping with stress, and PFC dysfunction has been implicated in stress-related mental disorders, including depression. Nevertheless, the mechanisms by which the PFC participates in stress responses remain unclear. Here, we investigate the role of parvalbumin (PV) interneurons in the medial PFC (mPFC) in shaping behavioral responses to stress induced by the learned helplessness procedure, in which animals are subjected to an unpredictable and inescapable stressor. PV interneurons in the mPFC were probed and manipulated in knock-in mice expressing the Cre recombinase under the endogenous parvalbumin promoter. Notably, we found that excitatory synaptic transmission onto these neurons was decreased in mice showing helplessness, a behavioral state that is thought to resemble features of human depression. Furthermore, selective suppression of PV interneurons in the mPFC using hM4Di, a DREADD (designer receptor exclusively activated by designer drug), promoted helplessness, indicating that activation of these neurons during stress promotes the establishment of resilient behavior. Our results reveal a cellular mechanism of mPFC dysfunction that may contribute to the emergence of maladaptive behavioral responses in the face of adverse life events. The Journal of Neuroscience, February 18, 2015 • 35(7):3201–3206 Articles CELLULAR/MOLECULAR Interleukin 1 Type 1 Receptor Restore: A Genetic Mouse Model for Studying Interleukin 1 Receptor-Mediated Effects in Specific Cell Types Xiaoyu Liu,1,2 Tetsuji Yamashita,3 Qun Chen,1,2 Natalya Belevych,1,2 Daniel B. Mckim,2,4 Andrew J. Tarr,1,2 Vincenzo Coppola,5 Nikitaa Nath,2 Daniel P. Nemeth,2 Zunera W. Syed,2 John F. Sheridan,1,2 Jonathan P. Godbout,2,4 Jian Zuo,3 and Ning Quan1,2 Division of Biosciences, The Ohio State University, Columbus, Ohio 43210, 2Institute for Behavioral Medicine Research, The Ohio State University Wexner Medical Center, Columbus, Ohio 43210, 3Department of Developmental Neurobiology, St. Jude Children’s Research Hospital, Memphis, Tennessee 38105, 4Department of Neuroscience, The Ohio State University, Columbus, Ohio 43210, and 5Department of MVIMG, Wexner Medical Center Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210 1 Interleukin-1 (IL-1) mediates diverse neurophysiological and neuropathological effects in the CNS through type I IL-1 receptor (IL-1R1). However, identification of IL-1R1-expressing cell types and cell-type-specific functions of IL-1R1 remains challenging. In this study, we created a novel genetic mouse model in which IL-1R1 gene expression is disrupted by an intronic insertion of a loxP flanked disruptive sequence that can be deleted by Cre recombinase, resulting in restored IL-1R1 gene expression under its endogenous promoters. A second mutation was introduced at stop codon of the IL-1R1 gene to allow tracking of the restored IL-1R1 protein by a 3HA tag and IL-1R1 mRNA by tdTomato fluorescence. These animals were designated as IL-1R1 r/r and exhibited an IL-1R1 knock-out phenotype. We used IL-1R1 globally restored mice (IL-1R1 GR/GR) as an IL-1R1 reporter and observed concordant labeling of IL-1R1 mRNA and protein in brain endothelial cells. Two cell-type-specific IL-1R1 restore lines were generated: Tie2Cre-IL-1R1 r/r and LysMCre-IL-1R1 r/r. Brain endothelial COX-2 expression, CNS leukocyte infiltration, and global microglia activation induced by intracerebroventricular injection of IL-1 were not observed in IL-1R1 r/r or LysMCre-IL-1R1 r/r mice, but were restored in Tie2Cre-IL-1R1 r/r mice. These results reveal IL-1R1 expression in endothelial cells alone is sufficient to mediate these central IL-1-induced responses. In addition, ex vivo IL-1 stimulation increased IL-1 expression in bone marrow cells in wild-type, Tie2Cre-IL-1R1 r/r, and LysMCre-IL-1R1 r/r, but not IL-1R1 r/r mice. These results demonstrate this IL-1R1 restore model is a valuable tool for studying cell-type-specific functions of IL-1R1. The Journal of Neuroscience, February 18, 2015 • 35(7):2860 –2870 Identification of 12/15-Lipoxygenase as a Regulator of Axon Degeneration through HighContent Screening York Rudhard,1* Arundhati Sengupta Ghosh,2* Beatrix Lippert,1 Alexander Bo¨cker,1 Mehdi Pedaran,1 Joachim Kra¨mer,1 Hai Ngu,3 Oded Foreman,3 Yichin Liu,4 and Joseph W. Lewcock2 1In Vitro Pharmacology, Evotec AG, Manfred Eigen Campus, 22419 Hamburg, Germany, 2Departments of Neuroscience, 3Pathology, and 4Biochemical and Cellular Pharmacology, Genentech, South San Francisco, California 94080 Axon degeneration is a programed process that takes place during development, in response to neuronal injury, and as a component of neurodegenerative disease pathology, yet the molecular mechanisms that drive this process remain poorly defined. In this study, we have developed a semi-automated, 384-well format axon degeneration assay in rat dorsal root ganglion (DRG) neurons using a trophic factor withdrawal paradigm. Using this setup, we have screened a library of known drugs and bioactives to identify several previously unappreciated regulators of axon degeneration, including lipoxygenases. Multiple structurally distinct lipoxygenase inhibitors as well as mouse DRG neurons lacking expression of 12/15-lipoxygenase display protection of axons in this context. Retinal ganglion cell axons from 12/15-lipoxygenase-null mice were similarly protected from degeneration following nerve crush injury. Through additional mechanistic studies, we demonstrate that lipoxygenases act cell autonomously within neurons to regulate degeneration, and are required for mitochondrial permeabilization and caspase activation in the axon. These findings suggest that these enzymes may represent an attractive target for treatment of neuropathies and provide a potential mechanism for the neuroprotection observed in various settings following lipoxygenase inhibitor treatment. The Journal of Neuroscience, February 18, 2015 • 35(7):2927–2941 Dynamics of Elongation Factor 2 Kinase Regulation in Cortical Neurons in Response to Synaptic Activity Justin W. Kenney,1 Oksana Sorokina,2 Maja Genheden,1 Anatoly Sorokin,3 J. Douglas Armstrong,2 and Christopher G. Proud1 University of Southampton, Centre for Biological Sciences, Southampton, SO17 1BJ, United Kingdom, 2University of Edinburgh, School of Informatics, Edinburgh, EH8 9AB, United Kingdom, and 3Institute of Cell Biophysics, Pushchino, 142290, Russia 1 The rapid regulation of cell signaling in response to calcium in neurons is essential for real-time processing of large amounts of information in the brain. A vital regulatory component, and one of the most energy-intensive biochemical processes in cells, is the elongation phase of mRNA translation, which is controlled by the Ca 2⫹/CaM- dependent elongation factor 2 kinase (eEF2K). However, little is known about the dynamics of eEF2K regulation in neurons despite its established role in learning and synaptic plasticity. To explore eEF2K dynamics in depth, we stimulated synaptic activity in mouse primary cortical neurons. We find that synaptic activity results in a rapid, but transient, increase in eEF2K activity that is regulated by a combination of AMPA and NMDA-type glutamate receptors and the mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) and mammalian target of rapamycin complex 1 (mTORC1) pathways. We then used computational modeling to test the hypothesis that considering Ca 2⫹-coordinated MEK/ERK, mTORC1, and eEF2k activation is sufficient to describe the observed eEF2K dynamics. Although such a model could partially fit the empirical findings, it also suggested that a crucial positive regulator of eEF2K was also necessary. Through additional modeling and empirical evidence, we demonstrate that AMP kinase (AMPK) is also an important regulator of synaptic activity-driven eEF2K dynamics in neurons. Our combined modeling and experimental findings provide the first evidence that it is necessary to consider the combined interactions of Ca 2⫹ with MEK/ERK, mTORC1, and AMPK to adequately explain eEF2K regulation in neurons. The Journal of Neuroscience, February 18, 2015 • 35(7):3034 –3047 The PDZ-Domain Protein Whirlin Facilitates Mechanosensory Signaling in Mammalian Proprioceptors Joriene C. de Nooij,1 Christian M. Simon,2,4 Anna Simon,7 Staceyann Doobar,1 Karen P. Steel,8 Robert W. Banks,9 George Z. Mentis,2,3,4 Guy S. Bewick,7 and Thomas M. Jessell1,5,6 Departments of 1Neuroscience, and Biochemistry and Molecular Biophysics, 2Pathology and Cell Biology, 3Neurology, 4Motor Neuron Center for Biology and Disease, 5Kavli Institute for Brain Science, 6Howard Hughes Medical Institute, Columbia University, New York, New York 10032, 7School of Medical Sciences, University of Aberdeen, Aberdeen AB25 2ZD, United Kingdom, 8Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, United Kingdom, and 9School of Biological and Biomedical Sciences, University of Durham, Durham DH1 3LE, United Kingdom Mechanoreception is an essential feature of many sensory modalities. Nevertheless, the mechanisms that govern the conversion of a mechanical force to distinct patterns of action potentials remain poorly understood. Proprioceptive mechanoreceptors reside in skeletal muscle and inform the nervous system of the position of body and limbs in space. We show here that Whirlin/Deafness autosomal recessive 31 (DFNB31), a PDZ-scaffold protein involved in vestibular and auditory hair cell transduction, is also expressed by proprioceptive sensory neurons (pSNs) in dorsal root ganglia in mice. Whirlin localizes to the peripheral sensory endings of pSNs and facilitates pSN afferent firing in response to muscle stretch. The requirement of Whirlin in both proprioceptors and hair cells suggests that accessory mechanosensory signaling molecules define common features of mechanoreceptive processing across sensory systems. The Journal of Neuroscience, February 18, 2015 • 35(7):3073–3084 SIRT1-FOXO3a Regulate Cocaine Actions in the Nucleus Accumbens Deveroux Ferguson,1,2 Ningyi Shao,1 Elizabeth Heller,1 Jian Feng,1 Rachael Neve,3 Hee-Dae Kim,2 Tanessa Call,2 Samantha Magazu,2 Li Shen,1 and Eric J. Nestler1 Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, 2Department of Basic Medical Sciences, University of Arizona College of Medicine-Phoenix, Phoenix, Arizona 85004, and 3Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139 1 Previous studies have shown that chronic cocaine administration induces SIRT1, a Class III histone deacetylase, in the nucleus accumbens (NAc), a key brain reward region, and that such induction influences the gene regulation and place conditioning effects of cocaine. To determine the mechanisms by which SIRT1 mediates cocaine-induced plasticity in NAc, we used chromatin immunoprecipitation followed by massively parallel sequencing (ChIP-seq), 1 d after 7 daily cocaine (20 mg/kg) or saline injections, to map SIRT1 binding genome-wide in mouse NAc. Our unbiased results revealed two modes of SIRT1 action. First, despite its induction in NAc, chronic cocaine causes depletion of SIRT1 from most affected gene promoters in concert with enrichment of H4K16ac (itself a deacetylation target of SIRT1), which is associated with increased expression of these genes. Second, we deduced the forkhead transcription factor (FOXO) family to be a downstream mechanism through which SIRT1 regulates cocaine action. We proceeded to demonstrate that SIRT1 induction causes the deacetylation and activation of FOXO3a in NAc, which leads to the induction of several known FOXO3a gene targets in other systems. Finally, we directly establish a role for FOXO3a in promoting cocaine-elicited behavioral responses by use of viral-mediated gene transfer: we show that overexpressing FOXO3a in NAc enhances cocaine place conditioning. The discovery of these two actions of SIRT1 in NAc in the context of behavioral adaptations to cocaine represents an important step forward in advancing our understanding of the molecular adaptations underlying cocaine action. The Journal of Neuroscience, February 18, 2015 • 35(7):3100 –3111 Regulation of Postsynaptic Function by the Dementia-Related ESCRT-III Subunit CHMP2B Romain Chassefeyre,1,2* Jose´ Martínez-Herna´ndez,1,2* Federica Bertaso,3,4,5 Nathalie Bouquier,3,4,5 Be´atrice Blot,1,2 Marine Laporte,1,2 Sandrine Fraboulet,1,2 Yohann Coute´,6,7 Anny Devoy,8 Adrian M. Isaacs,8 Karin Pernet-Gallay,1,2 Re´my Sadoul,1,2 Laurent Fagni,3,4,5 and Yves Goldberg1,2,9 Institut National de la Sante´ et de la Recherche Me´dicale (INSERM), Unite´ 836, F-38042 Grenoble, France, 2Universite´ Grenoble Alpes, Grenoble Institut des Neurosciences (GIN), F-38042 Grenoble, France, 3CNRS, UMR-5203, Institut de Ge´nomique Fonctionnelle, F-34094 Montpellier, France, 4Universite´s de Montpellier 1 & 2, UMR-5203, F-34094 Montpellier, France, 5INSERM, Unite´ 661, F-34094 Montpellier, France, 6INSERM, Unite´ 1038, F-38054 Grenoble, France, 7Commissariat a` l’Energie Atomique (CEA), Institut de Recherches en Technologies et Sciences pour le Vivant (iRTSV), Laboratoire de Biologie a` Grande Echelle, F-38054 Grenoble, France, 8Department of Neurodegenerative Disease, University College London Institute of Neurology, London WC1N 3BG, United Kingdom, and 9CEA, iRTSV, Groupe Physiopathologie du Cytosquelette (GPC), F-38054 Grenoble, France 1 The charged multivesicular body proteins (Chmp1–7) are an evolutionarily conserved family of cytosolic proteins that transiently assembles into helical polymers that change the curvature of cellular membrane domains. Mutations in human CHMP2B cause frontotemporal dementia, suggesting that this protein may normally control some neuron-specific process. Here, we examined the function, localization, and interactions of neuronal Chmp2b. The protein was highly expressed in mouse brain and could be readily detected in neuronal dendrites and spines. Depletion of endogenous Chmp2b reduced dendritic branching of cultured hippocampal neurons, decreased excitatory synapse density in vitro and in vivo, and abolished activity-induced spine enlargement and synaptic potentiation. To understand the synaptic effects of Chmp2b, we determined its ultrastructural distribution by quantitative immuno-electron microscopy and its biochemical interactions by coimmunoprecipitation and mass spectrometry. In the hippocampus in situ, a subset of neuronal Chmp2b was shown to concentrate beneath the perisynaptic membrane of dendritic spines. In synaptoneurosome lysates, Chmp2b was stably bound to a large complex containing other members of the Chmp family, as well as postsynaptic scaffolds. The supramolecular Chmp assembly detected here corresponds to a stable form of the endosomal sorting complex required for transport-III (ESCRT-III), a ubiquitous cytoplasmic protein complex known to play a central role in remodeling of lipid membranes. We conclude that Chmp2b-containing ESCRT-III complexes are also present at dendritic spines, where they regulate synaptic plasticity. We propose that synaptic ESCRT-III filaments may function as a novel element of the submembrane cytoskeleton of spines. The Journal of Neuroscience, February 18, 2015 • 35(7):3155–3173 The 16p11.2 Deletion Mouse Model of Autism Exhibits Altered Cortical Progenitor Proliferation and Brain Cytoarchitecture Linked to the ERK MAPK Pathway Joanna Pucilowska, Joseph Vithayathil, Emmanuel J. Tavares, Caitlin Kelly, J. Colleen Karlo, and Gary E. Landreth Department of Neurosciences, Case Western Reserve University, Cleveland, Ohio 44106-4928 Autism spectrum disorders are complex, highly heritable neurodevelopmental disorders affecting ⬃1 in 100 children. Copy number variations of human chromosomal region 16p11.2 are genetically linked to 1% of autism-related disorders. This interval contains the MAPK3 gene, which encodes the MAP kinase, ERK1. Mutations in upstream elements regulating the ERK pathway are genetically linked to autism and other disorders of cognition including the neuro-cardio-facial cutaneous syndromes and copy number variations. We report that a murine model of human 16p11.2 deletion exhibits a reduction in brain size and perturbations in cortical cytoarchitecture. We observed enhanced progenitor proliferation and premature cell cycle exit, which are a consequence of altered levels of downstream ERK effectors cyclin D1 and p27 Kip1 during mid-neurogenesis. The increased progenitor proliferation and cell cycle withdrawal resulted in premature depletion of progenitor pools, altering the number and frequency of neurons ultimately populating cortical lamina. Specifically, we found a reduced number of upper layer pyramidal neurons and an increase in layer VI corticothalamic projection neurons, reflecting the altered cortical progenitor proliferation dynamics in these mice. Importantly, we observed a paradoxical increase in ERK signaling in mid-neurogenesis in the 16p11.2del mice, which is coincident with the development of aberrant cortical cytoarchitecture. The 16p11.2del mice exhibit anxiety-like behaviors and impaired memory. Our findings provide evidence of ERK dysregulation, developmental abnormalities in neurogenesis, and behavioral impairment associated with the 16p11.2 chromosomal deletion. The Journal of Neuroscience, February 18, 2015 • 35(7):3190 –3200 Positively Charged Amino Acids at the SNAP-25 C Terminus Determine Fusion Rates, Fusion Pore Properties, and Energetics of Tight SNARE Complex Zippering Qinghua Fang,1,2 Ying Zhao,1,2 Adam Drew Herbst,1 Brian N. Kim,1 and Manfred Lindau1,2 School of Applied and Engineering Physics, Cornell University, Ithaca, New York 14853, and 2Laboratory for Nanoscale Cell Biology, Max-Planck-Institute for Biophysical Chemistry, D-37077 Go¨ttingen, Germany 1 SNAP-25 is a Q-SNARE protein mediating exocytosis of neurosecretory vesicles including chromaffin granules. Previous results with a SNAP-25 construct lacking the nine C terminal residues (SNAP-25⌬9) showed changed fusion pore properties (Fang et al., 2008), suggesting a model for fusion pore mechanics that couple C terminal zipping of the SNARE complex to the opening of the fusion pore. The deleted fragment contains the positively charged residues R198 and K201, adjacent to layers 7 and 8 of the SNARE complex. To determine how fusion pore conductance and dynamics depend on these residues, single exocytotic events in bovine chromaffin cells expressing R198Q, R198E, K201Q, or K201E mutants were investigated by carbon fiber amperometry and cell-attached patch capacitance measurements. Coarse grain molecular dynamics simulations revealed spontaneous transitions between a loose and tightly zippered state at the SNARE complex C terminus. The SNAP-25 K201Q mutant showed no changes compared with SNAP-25 wild-type. However, K201E, R198Q, and R198E displayed reduced release frequencies, slower release kinetics, and prolonged fusion pore duration that were correlated with reduced probability to engage in the tightly zippered state. The results show that the positively charged amino acids at the SNAP-25 C terminus promote tight SNARE complex zippering and are required for high release frequency and rapid release in individual fusion events. The Journal of Neuroscience, February 18, 2015 • 35(7):3230 –3239 Spiral Ganglion Degeneration and Hearing Loss as a Consequence of Satellite Cell Death in Saposin B-Deficient Mice Omar Akil,1 Ying Sun,2,4 Sarath Vijayakumar,5 Wujuan Zhang,3 Tiffany Ku,1 Chi-Kyou Lee,1 Sherri Jones,5 Gregory A. Grabowski,2,4,6 and Lawrence R. Lustig7 1Department of Otolaryngology, Head & Neck Surgery, University of California San Francisco, San Francisco, California 94143-0449, 2Division of Human Genetics, 3Division of Pathology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio 45229-3039, 4Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio 45229-3039, 5Department of Special Education & Communication Disorders, School of Veterinary and Biomedical Sciences, University of Nebraska–Lincoln, Lincoln, Nebraska 68583-0738, 6Synageva BioPharma Corporation, Lexington, Massachusetts 02421, and 7Department of Otolaryngology–Head & Neck Surgery, Columbia University Medical Center, New York, New York 10032 Saposin B (Sap B) is an essential activator protein for arylsulfatase A in the hydrolysis of sulfatide, a lipid component of myelin. To study Sap B’s role in hearing and balance, a Sap B-deficient (B ⫺/⫺) mouse was evaluated. At both light and electron microscopy (EM) levels, inclusion body accumulation was seen in satellite cells surrounding spiral ganglion (SG) neurons from postnatal month 1 onward, progressing into large vacuoles preceding satellite cell degeneration, and followed by SG degeneration. EM also revealed reduced or absent myelin sheaths in SG neurons from postnatal month 8 onwards. Hearing loss was initially seen at postnatal month 6 and progressed thereafter for frequency-specific stimuli, whereas click responses became abnormal from postnatal month 13 onward. The progressive hearing loss correlated with the accumulation of inclusion bodies in the satellite cells and their subsequent degeneration. Outer hair cell numbers and efferent function measures (distortion product otoacoustic emissions and contralateral suppression) were normal in the B ⫺/⫺ mice throughout this period. Alcian blue staining of SGs demonstrated that these inclusion bodies corresponded to sulfatide accumulation. In contrast, changes in the vestibular system were much milder, but caused severe physiologic deficits. These results demonstrate that loss of Sap B function leads to progressive sulfatide accumulation in satellite cells surrounding the SG neurons, leading to satellite cell degeneration and subsequent SG degeneration with a resultant loss of hearing. Relative sparing of the efferent auditory and vestibular neurons suggests that alternate glycosphingolipid metabolic pathways predominate in these other systems. The Journal of Neuroscience, February 18, 2015 • 35(7):3263–3275 DEVELOPMENT/PLASTICITY/REPAIR DBZ Regulates Cortical Cell Positioning and Neurite Development by Sustaining the Anterograde Transport of Lis1 and DISC1 through Control of Ndel1 Dual-Phosphorylation Masayuki Okamoto,1,2* Tokuichi Iguchi,1,3,4,6* Tsuyoshi Hattori,6,7* Shinsuke Matsuzaki,6,9 Yoshihisa Koyama,6 Manabu Taniguchi,6 Munekazu Komada,1,4 Min-Jue Xie,1,3,4 Hideshi Yagi,1 Shoko Shimizu,6 Yoshiyuki Konishi,4,5 Minoru Omi,1,4 Tomohiko Yoshimi,8 Taro Tachibana,8 Shigeharu Fujieda,2 Taiichi Katayama,9 Akira Ito,7 Shinji Hirotsune,10 Masaya Tohyama,6,9 and Makoto Sato1,3,4,6,9 Divisions of 1Cell Biology and Neuroscience, Department of Morphological and Physiological Sciences, 2Otorhinolaryngology Head and Neck Surgery, Department of Sensory and Locomotor Medicine, Faculty of Medical Sciences, and 3Research Center for Child Mental Development, University of Fukui, Fukui, 910-1193, Japan, 4Research and Education Program for Life Science, and 5Department of Human and Artificial Intelligent Systems, Faculty of Engineering, University of Fukui, Fukui, 910-8507, Japan, 6Departments of Anatomy and Neuroscience, and 7Molecular Neuropsychiatry, Graduate School of Medicine, Osaka University, Osaka, 565-0871, Japan, 8Department of Bioengineering, Graduate School of Engineering, Osaka City University, Osaka, 558-0022, Japan, 9United Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu University School of Medicine, Chiba University and University of Fukui, Osaka, 565-0871, Japan, and 10Department of Genetic Disease Research, Osaka City University, Graduate School of Medicine, Osaka, 545-8585, Japan Cell positioning and neuronal network formation are crucial for proper brain function. Disrupted-in-Schizophrenia 1 (DISC1) is anterogradely transported to the neurite tips, together with Lis1, and functions in neurite extension via suppression of GSK3 activity. Then, transported Lis1 is retrogradely transported and functions in cell migration. Here, we show that DISC1-binding zinc finger protein (DBZ), together with DISC1, regulates mouse cortical cell positioning and neurite development in vivo. DBZ hindered Ndel1 phosphorylation at threonine 219 and serine 251. DBZ depletion or expression of a double-phosphorylated mimetic form of Ndel1 impaired the transport of Lis1 and DISC1 to the neurite tips and hampered microtubule elongation. Moreover, application of DISC1 or a GSK3 inhibitor rescued the impairments caused by DBZ insufficiency or double-phosphorylated Ndel1 expression. We concluded that DBZ controls cell positioning and neurite development by interfering with Ndel1 from disproportionate phosphorylation, which is critical for appropriate anterograde transport of the DISC1-complex. The Journal of Neuroscience, February 18, 2015 • 35(7):2942–2958 Overexpression of Sox11 Promotes Corticospinal Tract Regeneration after Spinal Injury While Interfering with Functional Recovery Zimei Wang, Ashley Reynolds, Adam Kirry, Christopher Nienhaus, and Murray G. Blackmore Department of Biomedical Sciences, Marquette University, Milwaukee, Wisconsin 53201 Embryonic neurons, peripheral neurons, and CNS neurons in zebrafish respond to axon injury by initiating pro-regenerative transcriptional programs that enable axons to extend, locate appropriate targets, and ultimately contribute to behavioral recovery. In contrast, many long-distance projection neurons in the adult mammalian CNS, notably corticospinal tract (CST) neurons, display a much lower regenerative capacity. To promote CNS repair, a long-standing goal has been to activate pro-regenerative mechanisms that are normally missing from injured CNS neurons. Sox11 is a transcription factor whose expression is common to a many types of regenerating neurons, but it is unknown whether suboptimal Sox11 expression contributes to low regenerative capacity in the adult mammalian CNS. Here we show in adult mice that dorsal root ganglion neurons (DRGs) and CST neurons fail to upregulate Sox11 after spinal axon injury. Furthermore, forced viral expression of Sox11 reduces axonal dieback of DRG axons, and promotes CST sprouting and regenerative axon growth in both acute and chronic injury paradigms. In tests of forelimb dexterity, however, Sox11 overexpression in the cortex caused a modest but consistent behavioral impairment. These data identify Sox11 as a key transcription factor that can confer an elevated innate regenerative capacity to CNS neurons. The results also demonstrate an unexpected dissociation between axon growth and behavioral outcome, highlighting the need for additional strategies to optimize the functional output of stimulated neurons. The Journal of Neuroscience, February 18, 2015 • 35(7):3139 –3145 Valproate-Induced Neurodevelopmental Deficits in Xenopus laevis Tadpoles Eric J. James,1 Jenny Gu,1 Carolina M. Ramirez-Vizcarrondo,1 Mashfiq Hasan,1 Torrey L.S. Truszkowski,1 Yuqi Tan,1 Phouangmaly M. Oupravanh,1 Arseny S. Khakhalin,1,2 and Carlos D. Aizenman1 Department of Neuroscience, Brown University, Providence, Rhode Island 02912, and 2Bard College, Biology Program, Annandale-on-Hudson, New York 12504 1 Autism spectrum disorder (ASD) is increasingly thought to result from low-level deficits in synaptic development and neural circuit formation that cascade into more complex cognitive symptoms. However, the link between synaptic dysfunction and behavior is not well understood. By comparing the effects of abnormal circuit formation and behavioral outcomes across different species, it should be possible to pinpoint the conserved fundamental processes that result in disease. Here we use a novel model for neurodevelopmental disorders in which we expose Xenopus laevis tadpoles to valproic acid (VPA) during a critical time point in brain development at which neurogenesis and neural circuit formation required for sensory processing are occurring. VPA is a commonly prescribed antiepileptic drug with known teratogenic effects. In utero exposure to VPA in humans or rodents results in a higher incidence of ASD or ASD-like behavior later in life. We find that tadpoles exposed to VPA have abnormal sensorimotor and schooling behavior that is accompanied by hyperconnected neural networks in the optic tectum, increased excitatory and inhibitory synaptic drive, elevated levels of spontaneous synaptic activity, and decreased neuronal intrinsic excitability. Consistent with these findings, VPA-treated tadpoles also have increased seizure susceptibility and decreased acoustic startle habituation. These findings indicate that the effects of VPA are remarkably conserved across vertebrate species and that changes in neural circuitry resulting from abnormal developmental pruning can cascade into higher-level behavioral deficits. The Journal of Neuroscience, February 18, 2015 • 35(7):3218 –3229 SYSTEMS/CIRCUITS New Whole-Body Sensory-Motor Gradients Revealed Using Phase-Locked Analysis and Verified Using Multivoxel Pattern Analysis and Functional Connectivity Noa Zeharia,1,2,3 Uri Hertz,1,4 Tamar Flash,5 and Amir Amedi1,2,3 The Edmond and Lily Safra Center for Brain Sciences (ELSC) and Medical Neurobiology Department of IMRIC and The Hebrew University of Jerusalem Medical School and 2Hebrew University of Jerusalem, Jerusalem 91220, Israel, 3Sorborne Universite´s, UPMC Univ Paris 06, Institute de la Vision, UMR_S968, Paris, F-75012, France, 4University College London, 17 Queen Square, London WCIN 3AR, United Kingdom, and 5Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot 76 100, Israel 1 Topographic organization is one of the main principles of organization in the human brain. Specifically, whole-brain topographic mapping using spectral analysis is responsible for one of the greatest advances in vision research. Thus, it is intriguing that although topography is a key feature also in the motor system, whole-body somatosensory-motor mapping using spectral analysis has not been conducted in humans outside M1/SMA. Here, using this method, we were able to map a homunculus in the globus pallidus, a key target area for deep brain stimulation, which has not been mapped noninvasively or in healthy subjects. The analysis clarifies contradictory and partial results regarding somatotopy in the caudal-cingulate zone and rostral-cingulate zone in the medial wall and in the putamen. Most of the results were confirmed at the single-subject level and were found to be compatible with results from animal studies. Using multivoxel pattern analysis, we could predict movements of individual body parts in these homunculi, thus confirming that they contain somatotopic information. Using functional connectivity, we demonstrate interhemispheric functional somatotopic connectivity of these homunculi, such that the somatotopy in one hemisphere could have been found given the connectivity pattern of the corresponding regions of interest in the other hemisphere. When inspecting the somatotopic and nonsomatotopic connectivity patterns, a similarity index indicated that the pattern of connected and nonconnected regions of interest across different homunculi is similar for different body parts and hemispheres. The results show that topographical gradients are even more widespread than previously assumed in the somatosensory-motor system. Spectral analysis can thus potentially serve as a gold standard for defining somatosensorymotor system areas for basic research and clinical applications. The Journal of Neuroscience, February 18, 2015 • 35(7):2845–2859 Stimulus Statistics Shape Oscillations in Nonlinear Recurrent Neural Networks Je´re´mie Lefebvre,1 Axel Hutt,2 Jean-Franc¸ois Knebel,1,3 Kevin Whittingstall,4,5 and Micah M. Murray1,3 Laboratory for Investigative Neurophysiology (The LINE), Department of Radiology and Department of Clinical Neurosciences, University Hospital Center and University of Lausanne, 1011 Lausanne, Switzerland, 2INRIA CR Nancy–Grand Est, Team NEUROSYS, Villers-les-Nancy, 54600, France, 3EEG Brain Mapping Core, Centre for Biomedical Imaging (CIBM), 1011 Lausanne, Switzerland, and 4Department of Nuclear Medicine and Radiobiology, and 5Department of Diagnostic Radiology, Faculty of Medicine and Health Science, Universite ´ de Sherbrooke, Sherbrooke, Que´bec, Canada, J1K 2R1 1 Rhythmic activity plays a central role in neural computations and brain functions ranging from homeostasis to attention, as well as in neurological and neuropsychiatric disorders. Despite this pervasiveness, little is known about the mechanisms whereby the frequency and power of oscillatory activity are modulated, and how they reflect the inputs received by neurons. Numerous studies have reported input-dependent fluctuations in peak frequency and power (as well as couplings across these features). However, it remains unresolved what mediates these spectral shifts among neural populations. Extending previous findings regarding stochastic nonlinear systems and experimental observations, we provide analytical insights regarding oscillatory responses of neural populations to stimulation from either endogenous or exogenous origins. Using a deceptively simple yet sparse and randomly connected network of neurons, we show how spiking inputs can reliably modulate the peak frequency and power expressed by synchronous neural populations without any changes in circuitry. Our results reveal that a generic, non-nonlinear and input-induced mechanism can robustly mediate these spectral fluctuations, and thus provide a framework in which inputs to the neurons bidirectionally regulate both the frequency and power expressed by synchronous populations. Theoretical and computational analysis of the ensuing spectral fluctuations was found to reflect the underlying dynamics of the input stimuli driving the neurons. Our results provide insights regarding a generic mechanism supporting spectral transitions observed across cortical networks and spanning multiple frequency bands. The Journal of Neuroscience, February 18, 2015 • 35(7):2895–2903 Reciprocal Interareal Connections to Corticospinal Neurons in Mouse M1 and S2 Benjamin A. Suter and Gordon M.G. Shepherd Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611 Primary motor (M1) and secondary somatosensory (S2) cortices, although anatomically and functionally distinct, share an intriguing cellular component: corticospinal neurons (CSP) in layer 5B. Here, we investigated the long-range circuits of CSPs in mouse forelimb-M1 and S2. We found that interareal projections (S2 ¡ M1 and M1 ¡ S2) monosynaptically excited pyramidal neurons across multiple layers, including CSPs. Area-specific differences were observed in the relative strengths of inputs to subsets of CSPs and other cell types, but the general patterns were similar. Furthermore, subcellular mapping of the dendritic distributions of these corticocortical excitatory synapses onto CSPs in both areas also showed similar patterns. Because layer 5B is particularly thick in M1, but not S2, we studied M1-CSPs at different cortical depths, quantifying their dendritic morphology and mapping inputs from additional cortical (M2, contralateral M1, and local layer 2/3) and thalamic (VL nucleus) sources. These results indicated that CSPs exhibit area-specific modifications on an otherwise conserved synaptic organization, and that different afferents innervate M1-CSP dendritic domains in a source-specific manner. In the cervical spinal cord, CSP axons from S2 and M1 partly converged on middle layers, but S2-CSP axons extended further dorsally, and M1-CSP axons ventrally. Thus, our findings identify many shared features in the circuits of M1 and S2 and show that these areas communicate via mutual projections that give each area monosynaptic access to the other area’s CSPs. These interareally yoked CSP circuits may enable M1 and S2 to operate in a coordinated yet differentiated manner in the service of sensorimotor integration. The Journal of Neuroscience, February 18, 2015 • 35(7):2959 –2974 Mapping of Functionally Characterized Cell Classes onto Canonical Circuit Operations in Primate Prefrontal Cortex Salva Ardid,1,2 Martin Vinck,3 Daniel Kaping,1 Susanna Marquez,1 Stefan Everling,4 and Thilo Womelsdorf1,4 Department of Biology, Centre for Vision Research, York University, Toronto, Ontario M6J 1P3, Canada, 2Center for Computational Neuroscience and Neural Technology (CompNet), Department of Mathematics and Statistics, Boston University, Boston, Massachusetts 02215, 3Department of Neurobiology, Yale University School of Medicine, New Haven, Connecticut 06510, and 4Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario N6A 5K8, Canada 1 Microcircuits are composed of multiple cell classes that likely serve unique circuit operations. But how cell classes map onto circuit functions is largely unknown, particularly for primate prefrontal cortex during actual goal-directed behavior. One difficulty in this quest is to reliably distinguish cell classes in extracellular recordings of action potentials. Here we surmount this issue and report that spike shape and neural firing variability provide reliable markers to segregate seven functional classes of prefrontal cells in macaques engaged in an attention task. We delineate an unbiased clustering protocol that identifies four broad spiking (BS) putative pyramidal cell classes and three narrow spiking (NS) putative inhibitory cell classes dissociated by how sparse, bursty, or regular they fire. We speculate that these functional classes map onto canonical circuit functions. First, two BS classes show sparse, bursty firing, and phase synchronize their spiking to 3–7 Hz (theta) and 12–20 Hz (beta) frequency bands of the local field potential (LFP). These properties make cells flexibly responsive to network activation at varying frequencies. Second, one NS and two BS cell classes show regular firing and higher rate with only marginal synchronization preference. These properties are akin to setting tonically the excitation and inhibition balance. Finally, two NS classes fired irregularly and synchronized to either theta or beta LFP fluctuations, tuning them potentially to frequency-specific subnetworks. These results suggest that a limited set of functional cell classes emerges in macaque prefrontal cortex (PFC) during attentional engagement to not only represent information, but to subserve basic circuit operations. The Journal of Neuroscience, February 18, 2015 • 35(7):2975–2991 Cell Assemblies of the Basal Forebrain David Tingley,1,2 Andrew S. Alexander,1 Laleh K. Quinn,1 Andrea A. Chiba,1 and Douglas A. Nitz1 University of California, San Diego Department of Cognitive Science, San Diego, California 92093-0515, and 2NYU Neuroscience Institute, School of Medicine, New York University, New York, New York 10016 1 The basal forebrain comprises several heterogeneous neuronal subgroupings having modular projection patterns to discrete sets of cortical subregions. Each cortical region forms recurrent projections, via prefrontal cortex, that reach the specific basal forebrain subgroups from which they receive afferents. This architecture enables the basal forebrain to selectively modulate cortical responsiveness according to current processing demands. Theoretically, optimal functioning of this distributed network would be enhanced by temporal coordination among coactive basal forebrain neurons, or the emergence of “cell assemblies.” The present work demonstrates assembly formation in rat basal forebrain neuronal populations during a selective attention task. Neuron pairs exhibited coactivation patterns organized within beta-frequency time windows (55 ms), regardless of their membership within distinct bursting versus nonbursting basal forebrain subpopulations. Thus, the results reveal a specific temporal framework for integration of information within basal forebrain networks and for the modulation of cortical responsiveness. The Journal of Neuroscience, February 18, 2015 • 35(7):2992–3000 Synchronous Inhibitory Potentials Precede Seizure-Like Events in Acute Models of Focal Limbic Seizures Laura Uva,1* Gian Luca Breschi,2* Vadym Gnatkovsky,1 Stefano Taverna,2 and Marco de Curtis1 Unit of Epileptology and Experimental Neurophysiology, Fondazione Istituto Neurologico Carlo Besta, 20133 Milano, Italy, and 2Department of Neuroscience and Brain Technologies, Italian Institute of Technology, 16163 Genova, Italy 1 Interictal spikes in models of focal seizures and epilepsies are sustained by the synchronous activation of glutamatergic and GABAergic networks. The nature of population spikes associated with seizure initiation (pre-ictal spikes; PSs) is still undetermined. We analyzed the networks involved in the generation of both interictal and PSs in acute models of limbic cortex ictogenesis induced by pharmacological manipulations. Simultaneous extracellular and intracellular recordings from both principal cells and interneurons were performed in the medial entorhinal cortex of the in vitro isolated guinea pig brain during focal interictal and ictal discharges induced in the limbic network by intracortical and brief arterial infusions of either bicuculline methiodide (BMI) or 4-aminopyridine (4AP). Local application of BMI in the entorhinal cortex did not induce seizure-like events (SLEs), but did generate periodic interictal spikes sensitive to the glutamatergic non-NMDA receptor antagonist DNQX. Unlike local applications, arterial perfusion of either BMI or 4AP induced focal limbic SLEs. PSs just ahead of SLE were associated with hyperpolarizing potentials coupled with a complete blockade of firing in principal cells and burst discharges in putative interneurons. Interictal population spikes recorded from principal neurons between two SLEs correlated with a depolarizing potential. We demonstrate in two models of acute limbic SLE that PS events are different from interictal spikes and are sustained by synchronous activation of inhibitory networks. Our findings support a prominent role of synchronous network inhibition in the initiation of a focal seizure. The Journal of Neuroscience, February 18, 2015 • 35(7):3048 –3055 7 Tesla fMRI Reveals Systematic Functional Organization for Binocular Disparity in Dorsal Visual Cortex Nuno R. Goncalves,1 Hiroshi Ban,2,3 Rosa M. Sa´nchez-Panchuelo,4 Susan T. Francis,4 Denis Schluppeck,5 and Andrew E. Welchman1 Department of Psychology, University of Cambridge, Cambridge, CB2 3EB, United Kingdom, 2Center for Information and Neural Networks, National Institute of Information and Communications Technology, Suita City, Osaka, 565-0871, Japan, 3Graduate School of Frontier Biosciences, Osaka University, Suita City, Osaka 565-0871, Japan, and 4Sir Peter Mansfield Magnetic Resonance Centre, School of Physics and Astronomy, and 5Visual Neuroscience Group, School of Psychology, University of Nottingham, Nottingham NG7 2RD, United Kingdom 1 The binocular disparity between the views of the world registered by the left and right eyes provides a powerful signal about the depth structure of the environment. Despite increasing knowledge of the cortical areas that process disparity from animal models, comparatively little is known about the local architecture of stereoscopic processing in the human brain. Here, we take advantage of the high spatial specificity and image contrast offered by 7 tesla fMRI to test for systematic organization of disparity representations in the human brain. Participants viewed random dot stereogram stimuli depicting different depth positions while we recorded fMRI responses from dorsomedial visual cortex. We repeated measurements across three separate imaging sessions. Using a series of computational modeling approaches, we report three main advances in understanding disparity organization in the human brain. First, we show that disparity preferences are clustered and that this organization persists across imaging sessions, particularly in area V3A. Second, we observe differences between the local distribution of voxel responses in early and dorsomedial visual areas, suggesting different cortical organization. Third, using modeling of voxel responses, we show that higher dorsal areas (V3A, V3B/KO) have properties that are characteristic of human depth judgments: a simple model that uses tuning parameters estimated from fMRI data captures known variations in human psychophysical performance. Together, these findings indicate that human dorsal visual cortex contains selective cortical structures for disparity that may support the neural computations that underlie depth perception. The Journal of Neuroscience, February 18, 2015 • 35(7):3056 –3072 Cell-Specific Activity-Dependent Fractionation of Layer 2/3¡5B Excitatory Signaling in Mouse Auditory Cortex Ankur Joshi,1,2* Jason W. Middleton,1,2* Charles T. Anderson,1,2 Katharine Borges,3 Benjamin A. Suter,3 Gordon M. G. Shepherd,3,4 and Thanos Tzounopoulos1,2,4 Departments of Otolaryngology and 2Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, 3Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, and 4Whitman Center, Marine Biological Laboratory, Woods Hole, Massachusetts 02543 1 Auditory cortex (AC) layer 5B (L5B) contains both corticocollicular neurons, a type of pyramidal-tract neuron projecting to the inferior colliculus, and corticocallosal neurons, a type of intratelencephalic neuron projecting to contralateral AC. Although it is known that these neuronal types have distinct roles in auditory processing and different response properties to sound, the synaptic and intrinsic mechanisms shaping their input– output functions remain less understood. Here, we recorded in brain slices of mouse AC from retrogradely labeled corticocollicular and neighboring corticocallosal neurons in L5B. Corticocollicular neurons had, on average, lower input resistance, greater hyperpolarization-activated current (Ih ), depolarized resting membrane potential, faster action potentials, initial spike doublets, and less spikefrequency adaptation. In paired recordings between single L2/3 and labeled L5B neurons, the probabilities of connection, amplitude, latency, rise time, and decay time constant of the unitary EPSC were not different for L2/3¡corticocollicular and L2/3¡corticocallosal connections. However, short trains of unitary EPSCs showed no synaptic depression in L2/3¡corticocollicular connections, but substantial depression in L2/3¡corticocallosal connections. Synaptic potentials in L2/3¡corticocollicular connections decayed faster and showed less temporal summation, consistent with increased Ih in corticocollicular neurons, whereas synaptic potentials in L2/ 3¡corticocallosal connections showed more temporal summation. Extracellular L2/3 stimulation at two different rates resulted in spiking in L5B neurons; for corticocallosal neurons the spike rate was frequency dependent, but for corticocollicular neurons it was not. Together, these findings identify cell-specific intrinsic and synaptic mechanisms that divide intracortical synaptic excitation from L2/3 to L5B into two functionally distinct pathways with different input– output functions. The Journal of Neuroscience, February 18, 2015 • 35(7):3112–3123 Neural Heterogeneities Determine Response Characteristics to Second-, but Not First-Order Stimulus Features Michael G. Metzen1 and Maurice J. Chacron1,2 1 Department of Physiology and 2Department of Physics, McGill University, Montre´al, Que´bec H3G 1Y6, Canada Neural heterogeneities are seen ubiquitously, but how they determine neural response properties remains unclear. Here we show that heterogeneities can either strongly, or not at all, influence neural responses to a given stimulus feature. Specifically, we recorded from peripheral electroreceptor neurons, which display strong heterogeneities in their resting discharge activity, in response to naturalistic stimuli consisting of a fast time-varying waveform (i.e., first-order) whose amplitude (i.e., second-order or envelope) varied slowly in the weakly electric fish Apteronotus leptorhynchus. Although electroreceptors displayed relatively homogeneous responses to first-order stimulus features, further analysis revealed two subpopulations with similar sensitivities that were excited or inhibited by increases in the envelope, respectively, for stimuli whose frequency content spanned the natural range. We further found that a linear–nonlinear cascade model incorporating the known linear response characteristics to first-order features and a static nonlinearity accurately reproduced experimentally observed responses to both first- and second-order features for all stimuli tested. Importantly, this model correctly predicted that the response magnitude is independent of either the stimulus waveform’s or the envelope’s frequency content. Further analysis of our model led to the surprising prediction that the mean discharge activity can be used to determine whether a given neuron is excited or inhibited by increases in the envelope. This prediction was validated by our experimental data. Thus, our results provide key insight as to how neural heterogeneities can determine response characteristics to some, but not other, behaviorally relevant stimulus features. The Journal of Neuroscience, February 18, 2015 • 35(7):3124 –3138 Differential Dynamics of Spatial Attention, Position, and Color Coding within the Parietofrontal Network Elaine Astrand, Guilhem Ibos, Jean-Rene´ Duhamel, and Suliann Ben Hamed Centre de Neuroscience Cognitive, CNRS UMR 5229, Universite´ Claude Bernard Lyon I, 69675 Bron cedex, France Despite an ever growing knowledge on how parietal and prefrontal neurons encode low-level spatial and color information or higher-level information, such as spatial attention, an understanding of how these cortical regions process neuronal information at the population level is still missing. A simple assumption would be that the function and temporal response profiles of these neuronal populations match that of its constituting individual cells. However, several recent studies suggest that this is not necessarily the case and that the single-cell approach overlooks dynamic changes in how information is distributed over the neuronal population. Here, we use a time-resolved population pattern analysis to explore how spatial position, spatial attention and color information are differentially encoded and maintained in the macaque monkey prefrontal (frontal eye fields) and parietal cortex (lateral intraparietal area). Overall, our work brings about three novel observations. First, we show that parietal and prefrontal populations operate in two distinct population regimens for the encoding of sensory and cognitive information: a stationary mode and a dynamic mode. Second, we show that the temporal dynamics of a heterogeneous neuronal population brings about complementary information to that of its functional subpopulations. Thus, both need to be investigated in parallel. Last, we show that identifying the neuronal configuration in which a neuronal population encodes given information can serve to reveal this same information in a different context. All together, this work challenges common views on neural coding in the parietofrontal network. The Journal of Neuroscience, February 18, 2015 • 35(7):3174 –3189 BEHAVIORAL/COGNITIVE Behavior-Linked FoxP2 Regulation Enables Zebra Finch Vocal Learning Jonathan B. Heston1,2 and Stephanie A. White1,2 Interdepartmental Program in Neuroscience, and 2Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, California 90095 1 Mutations in the FOXP2 transcription factor cause an inherited speech and language disorder, but how FoxP2 contributes to learning of these vocal communication signals remains unclear. FoxP2 is enriched in corticostriatal circuits of both human and songbird brains. Experimental knockdown of this enrichment in song control neurons of the zebra finch basal ganglia impairs tutor song imitation, indicating that adequate FoxP2 levels are necessary for normal vocal learning. In unmanipulated birds, vocal practice acutely downregulates FoxP2, leading to increased vocal variability and dynamic regulation of FoxP2 target genes. To determine whether this behavioral regulation is important for song learning, here, we used viral-driven overexpression of FoxP2 to counteract its downregulation. This manipulation disrupted the acute effects of song practice on vocal variability and caused inaccurate song imitation. Together, these findings indicate that dynamic behavior-linked regulation of FoxP2, rather than absolute levels, is critical for vocal learning. The Journal of Neuroscience, February 18, 2015 • 35(7):2885–2894 Vicarious Reinforcement Learning Signals When Instructing Others Matthew A.J. Apps,1,2,3 Elise Lesage,3,4 and Narender Ramnani3 Nuffield Department of Clinical Neuroscience, University of Oxford, Oxford OX1 9DU, United Kingdom, 2Department of Experimental Psychology, University of Oxford, Oxford OX1 2JD, United Kingdom, 3Department of Psychology, Royal Holloway, University of London, Surrey TW20 0EX, United Kingdom, and 4Neuroimaging Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland 21224 1 Reinforcement learning (RL) theory posits that learning is driven by discrepancies between the predicted and actual outcomes of actions (prediction errors [PEs]). In social environments, learning is often guided by similar RL mechanisms. For example, teachers monitor the actions of students and provide feedback to them. This feedback evokes PEs in students that guide their learning. We report the first study that investigates the neural mechanisms that underpin RL signals in the brain of a teacher. Neurons in the anterior cingulate cortex (ACC) signal PEs when learning from the outcomes of one’s own actions but also signal information when outcomes are received by others. Does a teacher’s ACC signal PEs when monitoring a student’s learning? Using fMRI, we studied brain activity in human subjects (teachers) as they taught a confederate (student) action– outcome associations by providing positive or negative feedback. We examined activity time-locked to the students’ responses, when teachers infer student predictions and know actual outcomes. We fitted a RL-based computational model to the behavior of the student to characterize their learning, and examined whether a teacher’s ACC signals when a student’s predictions are wrong. In line with our hypothesis, activity in the teacher’s ACC covaried with the PE values in the model. Additionally, activity in the teacher’s insula and ventromedial prefrontal cortex covaried with the predicted value according to the student. Our findings highlight that the ACC signals PEs vicariously for others’ erroneous predictions, when monitoring and instructing their learning. These results suggest that RL mechanisms, processed vicariously, may underpin and facilitate teaching behaviors. The Journal of Neuroscience, February 18, 2015 • 35(7):2904 –2913 Neural Activity in the Medial Temporal Lobe Reveals the Fidelity of Mental Time Travel James E. Kragel,1,2 Neal W Morton,1 and Sean M. Polyn1 1 Department of Psychology and 2Neuroscience Graduate Program, Vanderbilt University, Nashville, Tennessee 37240 Neural circuitry in the medial temporal lobe (MTL) is critically involved in mental time travel, which involves the vivid retrieval of the details of past experience. Neuroscientific theories propose that the MTL supports memory of the past by retrieving previously encoded episodic information, as well as by reactivating a temporal code specifying the position of a particular event within an episode. However, the neural computations supporting these abilities are underspecified. To test hypotheses regarding the computational mechanisms supported by different MTL subregions during mental time travel, we developed a computational model that linked a blood oxygenation level-dependent signal to cognitive operations, allowing us to predict human performance in a memory search task. Activity in the posterior MTL, including parahippocampal cortex, reflected how strongly one reactivates the temporal context of a retrieved memory, allowing the model to predict whether the next memory will correspond to a nearby moment in the study episode. A signal in the anterior MTL, including perirhinal cortex, indicated the successful retrieval of list items, without providing information regarding temporal organization. A hippocampal signal reflected both processes, consistent with theories that this region binds item and context information together to form episodic memories. These findings provide evidence for modern theories that describe complementary roles of the hippocampus and surrounding parahippocampal and perirhinal cortices during the retrieval of episodic memories, shaping how humans revisit the past. The Journal of Neuroscience, February 18, 2015 • 35(7):2914 –2926 Anticipatory Anxiety Disrupts Neural Valuation during Risky Choice Jan B. Engelmann,1,2* Friederike Meyer,1* Ernst Fehr,1† and Christian C. Ruff1† 1 2 Laboratory for Social and Neural Systems Research (SNS-Lab), Department of Economics, University of Zurich, CH-8006 Zurich, Switzerland, and Donders Institute for Brain, Cognition and Behaviour, Centre for Cognitive Neuroimaging, Radboud University, 6525 HP, Nijmegen, The Netherlands Incidental negative emotions unrelated to the current task, such as background anxiety, can strongly influence decisions. This is most evident in psychiatric disorders associated with generalized emotional disturbances. However, the neural mechanisms by which incidental emotions may affect choices remain poorly understood. Here we study the effects of incidental anxiety on human risky decision making, focusing on both behavioral preferences and their underlying neural processes. Although observable choices remained stable across affective contexts with high and low incidental anxiety, we found a clear change in neural valuation signals: during high incidental anxiety, activity in ventromedial prefrontal cortex and ventral striatum showed a marked reduction in (1) neural coding of the expected subjective value (ESV) of risky options, (2) prediction of observed choices, (3) functional coupling with other areas of the valuation system, and (4) baseline activity. At the same time, activity in the anterior insula showed an increase in coding the negative ESV of risky lotteries, and this neural activity predicted whether the risky lotteries would be rejected. This pattern of results suggests that incidental anxiety can shift the focus of neural valuation from possible positive consequences to anticipated negative consequences of choice options. Moreover, our findings show that these changes in neural value coding can occur in the absence of changes in overt behavior. This suggest a possible pathway by which background anxiety may lead to the development of chronic reward desensitization and a maladaptive focus on negative cognitions, as prevalent in affective and anxiety disorders. The Journal of Neuroscience, February 18, 2015 • 35(7):3085–3099 Economic Choices Reveal Probability Distortion in Macaque Monkeys William R. Stauffer,1 Armin Lak,1 Peter Bossaerts,2,3 and Wolfram Schultz1 Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3DY, United Kingdom, 2Utah Laboratory for Experimental Economics and Finance, University of Utah, Salt Lake City, Utah 84112, and 3Faculty of Business and Economics, University of Melbourne, Parkville, Victoria 3010, Australia 1 Economic choices are largely determined by two principal elements, reward value (utility) and probability. Although nonlinear utility functions have been acknowledged for centuries, nonlinear probability weighting (probability distortion) was only recently recognized as a ubiquitous aspect of real-world choice behavior. Even when outcome probabilities are known and acknowledged, human decision makers often overweight low probability outcomes and underweight high probability outcomes. Whereas recent studies measured utility functions and their corresponding neural correlates in monkeys, it is not known whether monkeys distort probability in a manner similar to humans. Therefore, we investigated economic choices in macaque monkeys for evidence of probability distortion. We trained two monkeys to predict reward from probabilistic gambles with constant outcome values (0.5 ml or nothing). The probability of winning was conveyed using explicit visual cues (sector stimuli). Choices between the gambles revealed that the monkeys used the explicit probability information to make meaningful decisions. Using these cues, we measured probability distortion from choices between the gambles and safe rewards. Parametric modeling of the choices revealed classic probability weighting functions with inverted-S shape. Therefore, the animals overweighted low probability rewards and underweighted high probability rewards. Empirical investigation of the behavior verified that the choices were best explained by a combination of nonlinear value and nonlinear probability distortion. Together, these results suggest that probability distortion may reflect evolutionarily preserved neuronal processing. The Journal of Neuroscience, February 18, 2015 • 35(7):3146 –3154 Influence of Motivation on Control Hierarchy in the Human Frontal Cortex Jo¨rg Bahlmann,1,2 Esther Aarts,2,3 and Mark D’Esposito2 Department of Neurology, University of Lu¨beck, D-23538 Lu¨beck, Germany, 2Helen Wills Neuroscience Institute, University of California, Berkeley, California 94720, and 3Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen, 6500 GL Nijmegen, The Netherlands 1 The frontal cortex mediates cognitive control and motivation to shape human behavior. It is generally observed that medial frontal areas are involved in motivational aspects of behavior, whereas lateral frontal regions are involved in cognitive control. Recent models of cognitive control suggest a rostro-caudal gradient in lateral frontal regions, such that progressively more rostral (anterior) regions process more complex aspects of cognitive control. How motivation influences such a control hierarchy is still under debate. Although some researchers argue that both systems work in parallel, others argue in favor of an interaction between motivation and cognitive control. In the latter case it is yet unclear how motivation would affect the different levels of the control hierarchy. This was investigated in the present functional MRI study applying different levels of cognitive control under different motivational states (low vs high reward anticipation). Three levels of cognitive control were tested by varying rule complexity: stimulus-response mapping (low-level), flexible task updating (mid-level), and sustained cue-task associations (high-level). We found an interaction between levels of cognitive control and motivation in medial and lateral frontal subregions. Specifically, flexible updating (mid-level of control) showed the strongest beneficial effect of reward and only this level exhibited functional coupling between dopamine-rich midbrain regions and the lateral frontal cortex. These findings suggest that motivation differentially affects the levels of a control hierarchy, influencing recruitment of frontal cortical control regions depending on specific task demands. The Journal of Neuroscience, February 18, 2015 • 35(7):3207–3217 Alpha Phase Determines Successful Lexical Decision in Noise Antje Strauß,1 Molly J. Henry,1 Mathias Scharinger,1 and Jonas Obleser1,2 1 2 Max Planck Research Group “Auditory Cognition,” Max Planck Institute for Human Cognitive and Brain Sciences, 04103 Leipzig, Germany, and Department of Psychology, University of Lu¨beck, 23562 Lu¨beck, Germany Psychophysical target detection has been shown to be modulated by slow oscillatory brain phase. However, thus far, only low-level sensory stimuli have been used as targets. The current human electroencephalography (EEG) study examined the influence of neural oscillatory phase on a lexical-decision task performed for stimuli embedded in noise. Neural phase angles were compared for correct versus incorrect lexical decisions using a phase bifurcation index (BI), which quantifies differences in mean phase angles and phase concentrations between correct and incorrect trials. Neural phase angles in the alpha frequency range (8 –12 Hz) over right anterior sensors were approximately antiphase in a prestimulus time window, and thus successfully distinguished between correct and incorrect lexical decisions. Moreover, alpha-band oscillations were again approximately antiphase across participants for correct versus incorrect trials during a later peristimulus time window (⬃500 ms) at left-central electrodes. Strikingly, lexical decision accuracy was not predicted by either event-related potentials (ERPs) or oscillatory power measures. We suggest that correct lexical decisions depend both on successful sensory processing, which is made possible by the alignment of stimulus onset with an optimal alpha phase, as well as integration and weighting of decisional information, which is coupled to alpha phase immediately following the critical manipulation that differentiated words from pseudowords. The current study constitutes a first step toward characterizing the role of dynamic oscillatory brain states for higher cognitive functions, such as spoken word recognition. The Journal of Neuroscience, February 18, 2015 • 35(7):3256 –3262 Converging Evidence for the Neuroanatomic Basis of Combinatorial Semantics in the Angular Gyrus Amy R. Price,1,2 Michael F. Bonner,1 Jonathan E. Peelle,3 and Murray Grossman1 1 3 Penn FTD Center and Department of Neurology and 2Neuroscience Graduate Group, University of Pennsylvania, Philadelphia, Pennsylvania 19104 and Department of Otolaryngology, Washington University in St. Louis, St. Louis, Missouri 63130 Human thought and language rely on the brain’s ability to combine conceptual information. This fundamental process supports the construction of complex concepts from basic constituents. For example, both “jacket” and “plaid” can be represented as individual concepts, but they can also be integrated to form the more complex representation “plaid jacket.” Although this process is central to the expression and comprehension of language, little is known about its neural basis. Here we present evidence for a neuroanatomic model of conceptual combination from three experiments. We predicted that the highly integrative region of heteromodal association cortex in the angular gyrus would be critical for conceptual combination, given its anatomic connectivity and its strong association with semantic memory in functional neuroimaging studies. Consistent with this hypothesis, we found that the process of combining concepts to form meaningful representations specifically modulates neural activity in the angular gyrus of healthy adults, independent of the modality of the semantic content integrated. We also found that individual differences in the structure of the angular gyrus in healthy adults are related to variability in behavioral performance on the conceptual combination task. Finally, in a group of patients with neurodegenerative disease, we found that the degree of atrophy in the angular gyrus is specifically related to impaired performance on combinatorial processing. These converging anatomic findings are consistent with a critical role for the angular gyrus in conceptual combination. The Journal of Neuroscience, February 18, 2015 • 35(7):3276 –3284 Cerebellar Direct Current Stimulation Enhances On-Line Motor Skill Acquisition through an Effect on Accuracy Gabriela Cantarero,1 Danny Spampinato,1 Janine Reis,2 Loni Ajagbe,1 Tziporah Thompson,1 Kopal Kulkarni,1 and Pablo Celnik1,3 Department of Physical Medicine and Rehabilitation, Johns Hopkins Medical Institution, Baltimore, Maryland 21205, 2Department of Neurology, AlbertLudwigs-University Freiburg, 79106 Freiburg, Germany, and 3Department of Neurology, Johns Hopkins Medical Institution, Baltimore, Maryland 21205 1 The cerebellum is involved in the update of motor commands during error-dependent learning. Transcranial direct current stimulation (tDCS), a form of noninvasive brain stimulation, has been shown to increase cerebellar excitability and improve learning in motor adaptation tasks. Although cerebellar involvement has been clearly demonstrated in adaptation paradigms, a type of task that heavily relies on error-dependent motor learning mechanisms, its role during motor skill learning, a behavior that likely involves error-dependent as well as reinforcement and strategic mechanisms, is not completely understood. Here, in humans, we delivered cerebellar tDCS to modulate its activity during novel motor skill training over the course of 3 d and assessed gains during training (on-line effects), between days (off-line effects), and overall improvement. We found that excitatory anodal tDCS applied over the cerebellum increased skill learning relative to sham and cathodal tDCS specifically by increasing on-line rather than off-line learning. Moreover, the larger skill improvement in the anodal group was predominantly mediated by reductions in error rate rather than changes in movement time. These results have important implications for using cerebellar tDCS as an intervention to speed up motor skill acquisition and to improve motor skill accuracy, as well as to further our understanding of cerebellar function. The Journal of Neuroscience, February 18, 2015 • 35(7):3285–3290 NEUROBIOLOGY OF DISEASE Stabilization of Nontoxic A-Oligomers: Insights into the Mechanism of Action of Hydroxyquinolines in Alzheimer’s Disease Timothy M. Ryan,1* Blaine R. Roberts,1* Gawain McColl,1* Dominic J. Hare,1,2 Philip A. Doble,2 Qiao-Xin Li,1 Monica Lind,1 Anne M. Roberts,1 Haydyn D. T. Mertens,3 Nigel Kirby,3 Chi L. L. Pham,4 Mark G. Hinds,5,6 Paul A. Adlard,1 Kevin J. Barnham,1,4,5 Cyril C. Curtain,1 and Colin L. Masters1 Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville 3052, Victoria, Australia, 2Elemental Bio-imaging Facility, University of Technology Sydney, Broadway 2007, New South Wales, Australia, 3Australian Synchrotron, Clayton 3168, Victoria, Australia, 4Department of Pharmacology, University of Melbourne, Parkville 3052, Victoria, Australia, 5Bio21 Molecular Science and Technology Institute, University of Melbourne, Parkville 3052, Victoria, Australia, and 6School of Chemistry, University of Melbourne, Parkville 3052, Victoria, Australia 1 The extracellular accumulation of amyloid  (A) peptides is characteristic of Alzheimer’s disease (AD). However, formation of diffusible, oligomeric forms of A, both on and off pathways to amyloid fibrils, is thought to include neurotoxic species responsible for synaptic loss and neurodegeneration, rather than polymeric amyloid aggregates. The 8-hydroxyquinolines (8-HQ) clioquinol (CQ) and PBT2 were developed for their ability to inhibit metal-mediated generation of reactive oxygen species from A:Cu complexes and have both undergone preclinical and Phase II clinical development for the treatment of AD. Their respective modes of action are not fully understood and may include both inhibition of A fibrillar polymerization and direct depolymerization of existing A fibrils. In the present study, we find that CQ and PBT2 can interact directly with A and affect its propensity to aggregate. Using a combination of biophysical techniques, we demonstrate that, in the presence of these 8-HQs and in the absence of metal ions, A associates with two 8-HQ molecules and forms a dimer. Furthermore, 8-HQ bind A with an affinity of 1–10 M and suppress the formation of large (⬎30 kDa) oligomers. The stabilized low molecular weight species are nontoxic. Treatment with 8-HQs also reduces the levels of in vivo soluble oligomers in a Caenorhabditis elegans model of A toxicity. We propose that 8-HQs possess an additional mechanism of action that neutralizes neurotoxic A oligomer formation through stabilization of small (dimeric) nontoxic A conformers. The Journal of Neuroscience, February 18, 2015 • 35(7):2871–2884 Loss of Clcc1 Results in ER Stress, Misfolded Protein Accumulation, and Neurodegeneration Yichang Jia,1,2 Thomas J. Jucius,1,2 Susan A. Cook,2 and Susan L. Ackerman1,2 1 Howard Hughes Medical Institute and 2The Jackson Laboratory, Bar Harbor, Maine 04609 Folding of transmembrane and secretory proteins occurs in the lumen of the endoplasmic reticulum (ER) before transportation to the cell surface and is monitored by the unfolded protein response (UPR) signaling pathway. The accumulation of unfolded proteins in the ER activates the UPR that restores ER homeostasis by regulating gene expression that leads to an increase in the protein-folding capacity of the ER and a decrease in the ER protein-folding load. However, prolonged UPR activity has been associated with cell death in multiple pathological conditions, including neurodegeneration. Here, we report a spontaneous recessive mouse mutation that causes progressive cerebellar granule cell death and peripheral motor axon degeneration. By positional cloning, we identify the mutation in this strain as a retrotransposon insertion in the Clcc1 gene, which encodes a putative chloride channel localized to the ER. Furthermore, we demonstrate that the C3H/HeSnJ inbred strain has late onset cerebellar degeneration due to this mutation. Interestingly, acute knockdown of Clcc1 expression in cultured cells increases sensitivity to ER stress. In agreement, GRP78, the major HSP70 family chaperone in the ER, is upregulated in Clcc1-deficient granule cells in vivo, and ubiquitinated proteins accumulate in these neurons before their degeneration. These data suggest that disruption of chloride homeostasis in the ER disrupts the protein-folding capacity of the ER, leading to eventual neuron death. The Journal of Neuroscience, February 18, 2015 • 35(7):3001–3009 Microglial Activation Enhances Associative Taste Memory through Purinergic Modulation of Glutamatergic Neurotransmission Jean-Christophe Delpech,1,2 Nicolas Saucisse,1,2 Shauna L. Parkes,1,2,3,4 Chloe Lacabanne,1,2 Agnes Aubert,1,2 Fabrice Casenave,1,2 Etienne Coutureau,3,4 Nathalie Sans,5,6 Sophie Laye´,1,2 Guillaume Ferreira,1,2* and Agnes Nadjar1,2* INRA, Nutrition et Neurobiologie inte´gre´e, Unite´ Mixte de Recherche 1286, Bordeaux, France, 2University of Bordeaux, Nutrition et Neurobiologie inte´gre´e, Unite´ Mixte de Recherche 1286, Bordeaux, France, 3Centre National de la Recherche Scientifique, Institut de Neurosciences Cognitives et Inte´gratives d’Aquitaine, Unite´ Mixte de Recherche 5287, 33076 Bordeaux, France, 4Universite´ de Bordeaux, Institut de Neurosciences Cognitives et Inte´gratives d’Aquitaine, 33076 Bordeaux, France, 5Institut National de la Sante´ et de la Recherche Me´dicale, U862 NeuroCentre Magendie, Planar Polarity and Plasticity Group, Bordeaux, France, and 6University of Bordeaux, U862 NeuroCentre Magendie, Bordeaux, France 1 The cerebral innate immune system is able to modulate brain functioning and cognitive processes. During activation of the cerebral innate immune system, inflammatory factors produced by microglia, such as cytokines and adenosine triphosphate (ATP), have been directly linked to modulation of glutamatergic system on one hand and learning and memory functions on the other hand. However, the cellular mechanisms by which microglial activation modulates cognitive processes are still unclear. Here, we used taste memory tasks, highly dependent on glutamatergic transmission in the insular cortex, to investigate the behavioral and cellular impacts of an inflammation restricted to this cortical area in rats. We first show that intrainsular infusion of the endotoxin lipopolysaccharide induces a local inflammation and increases glutamatergic AMPA, but not NMDA, receptor expression at the synaptic level. This cortical inflammation also enhances associative, but not incidental, taste memory through increase of glutamatergic AMPA receptor trafficking. Moreover, we demonstrate that ATP, but not proinflammatory cytokines, is responsible for inflammation-induced enhance- ment of both associative taste memory and AMPA receptor expression in insular cortex. In conclusion, we propose that inflammation restricted to the insular cortex enhances associative taste memory through a purinergic-dependent increase of glutamatergic AMPA receptor expression at the synapse. The Journal of Neuroscience, February 18, 2015 • 35(7):3022–3033 Brain Amyloid- Burden Is Associated with Disruption of Intrinsic Functional Connectivity within the Medial Temporal Lobe in Cognitively Normal Elderly Zhuang Song,1,2,3 Philip S. Insel,3 Shannon Buckley,3 Seghel Yohannes,3,4 Adam Mezher,3 Alix Simonson,3 Sarah Wilkins,4 Duygu Tosun,3 Susanne Mueller,3 Joel H. Kramer,4 Bruce L. Miller,4 and Michael W. Weiner2,3,4,5 Center for Vital Longevity, University of Texas at Dallas, Dallas, Texas 75235, 2Northern California Institute of Research and Education, Department of Veterans Affairs Medical Center, San Francisco, California 94121, and 3Center for Imaging of Neurodegenerative Diseases, Department of Radiology and Biomedical Imaging, 4Department of Neurology, and 5Department of Psychiatry, University of California, San Francisco, San Francisco, California 94143 1 The medial temporal lobe is implicated as a key brain region involved in the pathogenesis of Alzheimer’s disease (AD) and consequent memory loss. Tau tangle aggregation in this region may develop concurrently with cortical A deposition in preclinical AD, but the pathological relationship between tau and A remains unclear. We used task-free fMRI with a focus on the medical temporal lobe, together with A PET imaging, in cognitively normal elderly human participants. We found that cortical A load was related to disrupted intrinsic functional connectivity of the perirhinal cortex, which is typically the first brain region affected by tauopathies in AD. There was no concurrent association of cortical A load with cognitive performance or brain atrophy. These findings suggest that dysfunction in the medial temporal lobe may represent a very early sign of preclinical AD and may predict future memory loss. The Journal of Neuroscience, February 18, 2015 • 35(7):3240 –3247 Alcohol Decreases Baseline Brain Glucose Metabolism More in Heavy Drinkers Than Controls But Has No Effect on Stimulation-Induced Metabolic Increases Nora D. Volkow,1 Gene-Jack Wang,1 Ehsan Shokri Kojori,1 Joanna S. Fowler,2 Helene Benveniste,3 and Dardo Tomasi1 National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland 20892, 2Biosciences Department, Brookhaven National Laboratory, Upton, New York 11973-5000, and 3Department of Anesthesiology, Stony Brook Medicine, Stony Brook, New York 11794 1 During alcohol intoxication, the human brain increases metabolism of acetate and decreases metabolism of glucose as energy substrate. Here we hypothesized that chronic heavy drinking facilitates this energy substrate shift both for baseline and stimulation conditions. To test this hypothesis, we compared the effects of alcohol intoxication (0.75 g/kg alcohol vs placebo) on brain glucose metabolism during video stimulation (VS) versus when given with no stimulation (NS), in 25 heavy drinkers (HDs) and 23 healthy controls, each of whom underwent four PET-18FDG scans. We showed that resting whole-brain glucose metabolism (placebo-NS) was lower in HD than controls (13%, p ⫽ 0.04); that alcohol (compared with placebo) decreased metabolism more in HD (20 ⫾ 13%) than controls (9 ⫾ 11%, p ⫽ 0.005) and in proportion to daily alcohol consumption (r ⫽ 0.36, p ⫽ 0.01) but found that alcohol did not reduce the metabolic increases in visual cortex from VS in either group. Instead, VS reduced alcoholinduced decreases in whole-brain glucose metabolism (10 ⫾ 12%) compared with NS in both groups (15 ⫾ 13%, p ⫽ 0.04), consistent with stimulation-related glucose metabolism enhancement. These findings corroborate our hypothesis that heavy alcohol consumption facilitates use of alternative energy substrates (i.e., acetate) for resting activity during intoxication, which might persist through early sobriety, but indicate that glucose is still favored as energy substrate during brain stimulation. Our findings are consistent with reduced reliance on glucose as the main energy substrate for resting brain metabolism during intoxication (presumably shifting to acetate or other ketones) and a priming of this shift in HDs, which might make them vulnerable to energy deficits during withdrawal. The Journal of Neuroscience, February 18, 2015 • 35(7):3248 –3255
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