This Week in The Journal - The Journal of Neuroscience
The Journal of Neuroscience, March 4, 2015 • 35(9):i • i This Week in The Journal Acetylcholine Receptors Distinguish STN Neurons Cheng Xiao, Julie M. Miwa, Brandon J. Henderson, Ying Wang, Purnima Deshpande, et al. (see pages 3734–3746) Abnormal synchronous oscillations in the subthalamic nucleus (STN) are closely linked to motor symptoms in Parkinson’s disease. Disruption of these oscillations is associated with motor improvement during L-DOPA treatment and deep brain stimulation (DBS). As a component of the basal ganglia’s “indirect pathway,” the STN excites GABAergic neurons in the substantia nigra pars reticulata (SNr) and globus pallidus interna. Additionally, the STN has reciprocal connections with cholinergic neurons in the pedunculopontine tegmental nucleus (PPT) and with dopaminergic neurons in the SN pars compacta (SNc). These modulatory inputs influence synchronous oscillations in the STN: loss of dopamine induces the oscillations, whereas activation of cholinergic pathways via chronic nicotine use or PPT stimulation enhances the ability of L-DOPA and DBS to disrupt the oscillations. Xiao et al. discovered that exogenous acetylcholine (ACh) increases spike rates in two distinct populations of mouse STN neurons in slices. One population expressed nicotinic ACh receptors (nAChRs) containing ␣42 subunits, while the other population expressed ␣7-containing nAChRs. Compared to ␣7-expressing neurons, those expressing ␣42 were more sensitive to ACh, and their activity remained elevated for a longer period after ACh application. Furthermore, ␣42-expressing neurons received twice as many excitatory inputs and one-third as many inhibitory inputs as ␣7expressing neurons, so ␣42-expressing neurons tended to be excited by local electrical stimulation, while ␣7-expressing neurons were more often inhibited. Chronic nicotine exposure only affected ␣42-expressing neurons: by increasing expression of ␣42 receptors, it increased nicotine-induced currents and spontaneous firing rate in these neurons. Finally, although both populations activated neurons in SNr and SNc, ␣42-expressing neurons had a greater effect on SNr GABAergic neurons, while ␣7-expressing neurons had a greater effect on SNc dopaminergic neurons. Together, these and previous results suggest that DBS disrupts synchronous oscillations in the STN partly by increasing the activity of ␣42-expressing neurons relative to that of ␣7-expressing neurons. This effect is probably enhanced by nicotine and by activation of cholinergic inputs. By primarily exciting GABAergic neurons in SNr, increased activation of ␣42expressing neurons likely increases inhibition of downstream dopaminergic neurons in SNc. Genetically targeting ␣42-expressing neurons will help to elucidate their contribution to normal and abnormal circuit activity. 1-integrin expression (red) is low in EZCs (green) of uninjured mice (left). Expression increases within 2 d of SCI (right). DAPI (blue) labels nuclei. See North et al. for details. 1-Integrin Influences BMP Signaling in Astrocytes Hilary A. North, Liuliu Pan, Tammy L. McGuire, Sarah Brooker, and John A. Kessler (see pages 3725–3733) After spinal cord injury (SCI), some ependymal zone stem cells (EZCs) that surround the central canal of the spinal cord differentiate into astrocytes. Initially, these and previously generated astrocytes limit infiltration of inflammatory cells, assist in wound healing, and help restore homeostasis; but they later form a dense glial scar that hinders axon regeneration. Bone morphogenetic protein (BMP), which helps specify astrocytic fate in stem cells, contributes to both the positive and negative effects of “reactive” astrocytes, but interestingly, it does so through activation of distinct receptors (BMPRs). Specifically, BMPR1a is essential for limiting inflammation and promoting healing, whereas BMPR1b is thought to promote glial scar formation. North et al. present evidence that 1integrins regulate reactive astrocytes by limiting astrocyte generation and BMP signaling. After SCI, as EZCs proliferated and migrated to the injury site, 1integrin expression increased. Selectively knocking out 1-integrin in ependymal cells caused more EZCs to migrate away from the central canal, differentiate, and express markers of reactive astrocytes after SCI. 1-integrin knockout also greatly reduced functional recovery from SCI. Interestingly, although knocking out 1-integrin reduced expression of BMPR1a and BMPR1b, it increased activation of SMAD1/5/8 and p38, two downstream mediators of BMPR signaling. This effect may have resulted from a redistribution of BMPR1b into lipid rafts, which are thought to facilitate receptor-mediated activation of downstream signaling complexes. Indeed, the amount of BMPR1b present in lipid raft fractions increased after 1-integrin was knocked out, and disrupting lipid rafts reduced activation of SMAD1/5/8 and p38. Additional experiments indicated that 1-integrin interacts directly with BMPRs and that activation of BMPR increases expression of 1-integrin. Together, these data suggest a model in which BMP signaling, activated in EZCs after SCI, is limited by BMPR-induced upregulation of 1-integrin. Through direct interaction with BMPR1b, 1-integrin prevents BMPR1b accumulation in lipid rafts, thus limiting its ability to activate downstream signaling. In this way, as well as by reducing the generation of new astrocytes, 1-integrin may limit glial scar formation, thus facilitating axon regeneration and functional recovery after SCI. This Week in The Journal is written by X Teresa Esch, Ph.D. The Journal of Neuroscience March 4, 2015 • Volume 35 Number 9 • www.jneurosci.org i This Week in The Journal Brief Communications 4065 Functional Roles of Complexin in Neurotransmitter Release at Ribbon Synapses of Mouse Retinal Bipolar Neurons Thirumalini Vaithianathan, Diane Henry, Wendy Akmentin, and Gary Matthews Articles CELLULAR/MOLECULAR 䊉 Cover legend: Neighboring neurons in layer 2 of a single barrel of vibrissal somatosensory cortex have heterogeneous receptive fields. Receptive field color denotes the whisker that best drove responses for each neuron, and the size corresponds to sharpness of tuning. For more information, see the article by Clancy et al. (pages 3946 –3958). 3734 Nicotinic Receptor Subtype-Selective Circuit Patterns in the Subthalamic Nucleus Cheng Xiao, Julie M. Miwa, Brandon J. Henderson, Ying Wang, Purnima Deshpande, Sheri L. McKinney, and Henry A. Lester 3842 Cannabinoid CB1 Receptor Calibrates Excitatory Synaptic Balance in the Mouse Hippocampus Krisztina Monory, Martin Polack, Anita Remus, Beat Lutz, and Martin Korte 3893 Coronin-1 and Calcium Signaling Governs Sympathetic Final Target Innervation Dong Suo, Juyeon Park, Samuel Young, Takako Makita, and Christopher D. Deppmann 3959 Obesity Is Associated with Decreased -Opioid But Unaltered Dopamine D2 Receptor Availability in the Brain Henry K. Karlsson, Lauri Tuominen, Jetro J. Tuulari, Jussi Hirvonen, Riitta Parkkola, Semi Helin, Paulina Salminen, Pirjo Nuutila, and Lauri Nummenmaa 4025 Extracellular pH Regulates Excitability of Vomeronasal Sensory Neurons Annika Cichy, Tobias Ackels, Chryssanthi Tsitoura, Anat Kahan, Nina Gronloh, Melanie So¨chtig, Corinna H. Engelhardt, Yoram Ben-Shaul, Frank Mu¨ller, Jennifer Spehr, and Marc Spehr DEVELOPMENT/PLASTICITY/REPAIR 䊉 3725 1-Integrin Alters Ependymal Stem Cell BMP Receptor Localization and Attenuates Astrogliosis after Spinal Cord Injury Hilary A. North, Liuliu Pan, Tammy L. McGuire, Sarah Brooker, and John A. Kessler 3756 The Subventricular Zone Continues to Generate Corpus Callosum and Rostral Migratory Stream Astroglia in Normal Adult Mice Jiho Sohn, Lori Orosco, Fuzheng Guo, Seung-Hyuk Chung, Peter Bannerman, Emily Mills Ko, Kostas Zarbalis, Wenbin Deng, and David Pleasure SYSTEMS/CIRCUITS 3772 Spine Loss in Primary Somatosensory Cortex during Trace Eyeblink Conditioning Bettina Joachimsthaler, Dominik Brugger, Angelos Skodras, and Cornelius Schwarz 3825 Neural Population Coding of Multiple Stimuli A. Emin Orhan and Wei Ji Ma 3865 Converging Structural and Functional Connectivity of Orbitofrontal, Dorsolateral Prefrontal, and Posterior Parietal Cortex in the Human Striatum Kevin Jarbo and Timothy D. Verstynen 3879 Corticotropin-Releasing Hormone Drives Anandamide Hydrolysis in the Amygdala to Promote Anxiety J. Megan Gray, Haley A. Vecchiarelli, Maria Morena, Tiffany T.Y. Lee, Daniel J. Hermanson, Alexander B. Kim, Ryan J. McLaughlin, Kowther I. Hassan, Claudia Ku¨hne, Carsten T. Wotjak, Jan M. Deussing, Sachin Patel, and Matthew N. Hill 3903 Executive Control Signals in Orbitofrontal Cortex during Response Inhibition Daniel W. Bryden and Matthew R. Roesch 3946 Structure of a Single Whisker Representation in Layer 2 of Mouse Somatosensory Cortex Kelly B. Clancy, Philipp Schnepel, Antara T. Rao, and Daniel E. Feldman 3978 Movement-Related Discharge in the Macaque Globus Pallidus during High-Frequency Stimulation of the Subthalamic Nucleus Andrew J. Zimnik, Gerald J. Nora, Michel Desmurget, and Robert S. Turner 4005 Sensitivity of Locus Ceruleus Neurons to Reward Value for Goal-Directed Actions Sebastien Bouret and Barry J. Richmond 4040 Spatiotemporal Memory Is an Intrinsic Property of Networks of Dissociated Cortical Neurons Han Ju, Mark R. Dranias, Gokulakrishna Banumurthy, and Antonius M.J. VanDongen 4052 Role of the Indirect Pathway of the Basal Ganglia in Perceptual Decision Making Wei Wei, Jonathan E. Rubin, and Xiao-Jing Wang 4081 A Direct Descending Pathway Informing Locomotor Networks about Tactile Sensor Movement Jan M. Ache, S. Shuichi Haupt, and Volker Du¨rr BEHAVIORAL/COGNITIVE 3764 Characterizing the Associative Content of Brain Structures Involved in Habitual and Goal-Directed Actions in Humans: A Multivariate fMRI Study Daniel McNamee, Mimi Liljeholm, Ondrej Zika, and John P. O’Doherty 3815 Attending to Pitch Information Inhibits Processing of Pitch Information: The Curious Case of Amusia Benjamin Rich Zendel, Marie-E´laine Lagrois, Nicolas Robitaille, and Isabelle Peretz 3929 Cortical Activity Predicts Which Older Adults Recognize Speech in Noise and When Kenneth I. Vaden, Jr., Stefanie E. Kuchinsky, Jayne B. Ahlstrom, Judy R. Dubno, and Mark A. Eckert 3966 Impaired Attention and Synaptic Senescence of the Prefrontal Cortex Involves Redox Regulation of NMDA Receptors Michael Guidi, Ashok Kumar, and Thomas C. Foster 3990 Dual Mechanism for Bitter Avoidance in Drosophila Alice Sarah French, Marie-Jeanne Sellier, Ali Agha Moutaz, Alexandra Guigue, Marie-Ange Chabaud, Pablo D. Reeb, Aniruddha Mitra, Yves Grau, Laurent Soustelle, and Fre´de´ric Marion-Poll 4015 Reward-Dependent Modulation of Movement Variability Sarah E. Pekny, Jun Izawa, and Reza Shadmehr 4071 Losing the Music: Aging Affects the Perception and Subcortical Neural Representation of Musical Harmony Oliver Bones and Christopher J. Plack 4092 Juvenile Obesity Enhances Emotional Memory and Amygdala Plasticity through Glucocorticoids Chloe´ Boitard, Mouna Maroun, Fre´de´ric Tantot, Amandine Cavaroc, Julie Sauvant, Alain Marchand, Sophie Laye´, Lucile Capuron, Muriel Darnaudery, Nathalie Castanon, Etienne Coutureau, Rose-Marie Vouimba, and Guillaume Ferreira 4104 Dopamine D2-Receptor Blockade Enhances Decoding of Prefrontal Signals in Humans Thorsten Kahnt, Susanna C. Weber, Helene Haker, Trevor W. Robbins, and Philippe N. Tobler NEUROBIOLOGY OF DISEASE 3747 Dissociable Rate-Dependent Effects of Oral Methylphenidate on Impulsivity and D2/3 Receptor Availability in the Striatum Daniele Caprioli, Bianca Jupp, Young T. Hong, Stephen J. Sawiak, Valentina Ferrari, Laura Wharton, David J. Williamson, Carolyn McNabb, David Berry, Franklin I. Aigbirhio, Trevor W. Robbins, Tim D. Fryer, and Jeffrey W. Dalley 3782 Early-Onset Epileptic Encephalopathy Caused by Gain-of-Function Mutations in the Voltage Sensor of Kv7.2 and Kv7.3 Potassium Channel Subunits Francesco Miceli, Maria Virginia Soldovieri, Paolo Ambrosino, Michela De Maria, Michele Migliore, Rosanna Migliore, and Maurizio Taglialatela 3794 Astrocyte-Mediated Ischemic Tolerance Yuri Hirayama, Yuri Ikeda-Matsuo, Shoji Notomi, Hiroshi Enaida, Hiroyuki Kinouchi, and Schuichi Koizumi 3806 Axonal and Schwann Cell BACE1 Is Equally Required for Remyelination of Peripheral Nerves Xiangyou Hu, Jinxuan Hu, Lu Dai, Bruce Trapp, and Riqiang Yan 3851 Impaired Leptomeningeal Collateral Flow Contributes to the Poor Outcome following Experimental Stroke in the Type 2 Diabetic Mice Yosuke Akamatsu, Yasuo Nishijima, Chih Cheng Lee, Shih Yen Yang, Lei Shi, Lin An, Ruikang K. Wang, Teiji Tominaga, and Jialing Liu 3915 A Novel Mouse Model of Subcortical Infarcts with Dementia Yorito Hattori, Jun-ichiro Enmi, Akihiro Kitamura, Yumi Yamamoto, Satoshi Saito, Yukako Takahashi, Satoshi Iguchi, Masahiro Tsuji, Kenichi Yamahara, Kazuyuki Nagatsuka, Hidehiro Iida, and Masafumi Ihara 3938 Homer Protein–Metabotropic Glutamate Receptor Binding Regulates Endocannabinoid Signaling and Affects Hyperexcitability in a Mouse Model of Fragile X Syndrome Ai-Hui Tang and Bradley E. Alger 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 Functional Roles of Complexin in Neurotransmitter Release at Ribbon Synapses of Mouse Retinal Bipolar Neurons Thirumalini Vaithianathan,1 Diane Henry,1 Wendy Akmentin,1 and Gary Matthews1,2 1 Department of Neurobiology and Behavior and 2Department of Ophthalmology, Stony Brook University, Stony Brook, New York 11794-5230 Ribbon synapses of photoreceptor cells and bipolar neurons in the retina signal graded changes in light intensity via sustained release of neurotransmitter. One molecular specialization of retinal ribbon synapses is the expression of complexin protein subtypes Cplx3 and Cplx4, whereas conventional synapses express Cplx1 and Cplx2. Because complexins bind to the molecular machinery for synaptic vesicle fusion (the SNARE complex) and modulate transmitter release at conventional synapses, we examined the roles of ribbon-specific complexin in regulating release at ribbon synapses of ON bipolar neurons from mouse retina. To interfere acutely with the interaction of native complexins with the SNARE complex, a peptide consisting of the highly conserved SNARE-binding domain of Cplx3 was introduced via a whole-cell patch pipette placed directly on the synaptic terminal, and vesicle fusion was monitored using capacitance measurements and FM-dye destaining. The inhibitory peptide, but not control peptides, increased spontaneous synaptic vesicle fusion, partially depleted reserve synaptic vesicles, and reduced fusion triggered by opening voltage-gated calcium channels under voltage clamp, without affecting the number of synaptic vesicles associated with ribbons, as revealed by electron microscopy of recorded terminals. The results are consistent with a dual role for ribbon-specific complexin, acting as a brake on the SNARE complex to prevent spontaneous fusion in the absence of calcium influx, while at the same time facilitating release evoked by depolarization. The Journal of Neuroscience, March 4, 2015 • 35(9):4065– 4070 Articles CELLULAR/MOLECULAR Nicotinic Receptor Subtype-Selective Circuit Patterns in the Subthalamic Nucleus Cheng Xiao,1 Julie M. Miwa,1,2 Brandon J. Henderson,1 Ying Wang,1 Purnima Deshpande,1 Sheri L. McKinney,1 and Henry A. Lester1 Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California 91125, and 2Department of Biological Sciences, Lehigh University, Bethlehem, Pennsylvania 18015 1 The glutamatergic subthalamic nucleus (STN) exerts control over motor output through nuclei of the basal ganglia. High-frequency electrical stimuli in the STN effectively alleviate motor symptoms in movement disorders, and cholinergic stimulation boosts this effect. To gain knowledge about the mechanisms of cholinergic modulation in the STN, we studied cellular and circuit aspects of nicotinic acetylcholine receptors (nAChRs) in mouse STN. We discovered two largely divergent microcircuits in the STN; these are regulated in part by either ␣42 or ␣7 nAChRs. STN neurons containing ␣42 nAChRs (␣42 neurons) received more glutamatergic inputs, and preferentially innervated GABAergic neurons in the substantia nigra pars reticulata. In contrast, STN neurons containing ␣7 nAChRs (␣7 neurons) received more GABAergic inputs, and preferentially innervated dopaminergic neurons in the substantia nigra pars compacta. Interestingly, local electrical stimuli excited a majority (79%) of ␣42 neurons but exerted strong inhibition in 58% of ␣7 neurons, indicating an additional diversity of STN neurons: responses to electrical stimulation. Chronic exposure to nicotine selectively affects ␣42 nAChRs in STN: this treatment increased the number of ␣42 neurons, upregulated ␣4-containing nAChR number and sensitivity, and enhanced the basal firing rate of ␣42 neurons both ex vivo and in vivo. Thus, chronic nicotine enhances the function of the microcircuit involving ␣42 nAChRs. This indicates chronic exposure to nicotinic agonist as a potential pharmacological intervention to alter selectively the balance between these two microcircuits, and may provide a means to inhibit substantia nigra dopaminergic neurons. The Journal of Neuroscience, March 4, 2015 • 35(9):3734 –3746 Cannabinoid CB1 Receptor Calibrates Excitatory Synaptic Balance in the Mouse Hippocampus Krisztina Monory,1 Martin Polack,2 Anita Remus,2,3 Beat Lutz,1 and Martin Korte2,3 Institute of Physiological Chemistry, Medical Center of the Johannes Gutenberg University Mainz, 55128 Mainz, Germany, 2Zoological Institute, Division Cellular Neurobiology, 38106 Braunschweig, Germany, and 3AG NIND, HZI, D-38124 Braunschweig, Germany 1 The endocannabinoid system negatively regulates the release of various neurotransmitters in an activity-dependent manner, thereby influencing the excitability of neuronal circuits. In the hippocampus, cannabinoid type 1 (CB1) receptor is present on both GABAergic and glutamatergic axon terminals. CB1 receptor-deficient mice were previously shown to have increased hippocampal long-term potentiation (LTP). In this study, we have investigated the consequences of cell-type-specific deletion of the CB1 receptor on the induction of hippocampal LTP and on CA1 pyramidal cell morphology. Deletion of CB1 receptor in GABAergic neurons in GABA-CB1-KO mice leads to a significantly decreased hippocampal LTP compared with WT controls. Concomitantly, CA1 pyramidal neurons have a significantly reduced dendritic branching both on the apical and on the basal dendrites. Moreover, the average spine density on the apical dendrites of CA1 pyramidal neurons is significantly diminished. In contrast, in mice lacking CB1 receptor in glutamatergic cells (Glu-CB1-KO), hippocampal LTP is significantly enhanced and CA1 pyramidal neurons show an increased branching and an increased spine density in the apical dendritic region. Together, these results indicate that the CB1 receptor signaling system both on inhibitory and excitatory neurons controls functional and structural synaptic plasticity of pyramidal neurons in the hippocampal CA1 region to maintain an appropriate homeostatic state upon neuronal activation. Consequently, if the CB1 receptor is lost in either neuronal population, an allostatic shift will occur leading to a long-term dysregulation of neuronal functions. The Journal of Neuroscience, March 4, 2015 • 35(9):3842–3850 Coronin-1 and Calcium Signaling Governs Sympathetic Final Target Innervation Dong Suo,1 Juyeon Park,1 Samuel Young,1 Takako Makita,2 and Christopher D. Deppmann1,3,4 1Department of Biology, University of Virginia, Charlottesville, Virginia 22903, 2Developmental Neuroscience Program, The Saban Research Institute, Children’s Hospital Los Angeles, University of Southern California Keck School of Medicine, Los Angeles, California 90027, and 3Departments of Cell Biology and 4Biomedical Engineering, University of Virginia, Charlottesville, Virginia 22903 Development of a functional peripheral nervous system requires axons to rapidly innervate and arborize into final target organs and then slow but not halt their growth to establish stable connections while keeping pace with organ growth. Here we examine the role of the NGF-TrkA effector protein, Coronin-1, on postganglionic sympathetic neuron final target innervation. In the absence of Coronin-1 we find that NGF-TrkA-PI3K signaling drives robust axon growth and branching in part by suppressing GSK3. In contrast, the presence of Coronin-1 (wild-type neurons) suppresses but does not halt NGF-TrkA-dependent growth and branching. This relative suppression in axon growth behaviors is due to Coronin-1-dependent calcium release via PLC-␥1 signaling, which releases PI3K-dependent suppression of GSK3. Finally, we demonstrate that Coro1a⫺/⫺ mice display sympathetic axon overgrowth and overbranching phenotypes in the developing heart. Together with previous work demonstrating the Coronin-1 expression is NGF dependent, this work suggests that periods before and after NGF-TrkA-induced Coronin-1 expression (and likely other factors) defines two distinct axon growth states, which are critical for proper circuit formation in the sympathetic nervous system. The Journal of Neuroscience, March 4, 2015 • 35(9):3893–3902 Obesity Is Associated with Decreased -Opioid But Unaltered Dopamine D2 Receptor Availability in the Brain Henry K. Karlsson,1 Lauri Tuominen,1,2 Jetro J. Tuulari,1 Jussi Hirvonen,1,3 Riitta Parkkola,3 Semi Helin,1 Paulina Salminen,4 Pirjo Nuutila,1,5 and Lauri Nummenmaa1,6 1 6 Turku PET Centre, and Departments of 2Psychiatry, 3Radiology, 4Surgery, and 5Endocrinology, Turku University Hospital, FI-20520 Turku, Finland, and Department of Neuroscience and Biomedical Engineering, School of Science, Aalto University, FI-00076 Aalto, Finland Neurochemical pathways involved in pathological overeating and obesity are poorly understood. Although previous studies have shown increased -opioid receptor (MOR) and decreased dopamine D2 receptor (D2R) availability in addictive disorders, the role that these systems play in human obesity still remains unclear. We studied 13 morbidly obese women [mean body mass index (BMI), 42 kg/m 2] and 14 nonobese age-matched women, and measured brain MOR and D2R availability using PET with selective radioligands [11C]carfentanil and [11C]raclopride, respectively. We also used quantitative meta-analytic techniques to pool previous evidence on the effects of obesity on altered D2R availability. Morbidly obese subjects had significantly lower MOR availability than control subjects in brain regions relevant for reward processing, including ventral striatum, insula, and thalamus. Moreover, in these areas, BMI correlated negatively with MOR availability. Striatal MOR availability was also negatively associated with self-reported food addiction and restrained eating patterns. There were no significant differences in D2R availability between obese and nonobese subjects in any brain region. Meta-analysis confirmed that current evidence for altered D2R availability in obesity is only modest. Obesity appears to have unique neurobiological underpinnings in the reward circuit, whereby it is more similar to opioid addiction than to other addictive disorders. The opioid system modulates motivation and reward processing, and low -opioid availability may promote overeating to compensate decreased hedonic responses in this system. Behavioral and pharmacological strategies for recovering opioidergic function might thus be critical to curb the obesity epidemic. The Journal of Neuroscience, March 4, 2015 • 35(9):3959 –3965 Extracellular pH Regulates Excitability of Vomeronasal Sensory Neurons Annika Cichy,1 Tobias Ackels,1 Chryssanthi Tsitoura,1 Anat Kahan,2 Nina Gronloh,1 Melanie So¨chtig,3 Corinna H. Engelhardt,1 Yoram Ben-Shaul,2 Frank Mu¨ller,3 Jennifer Spehr,1 and Marc Spehr1 Department of Chemosensation, Institute for Biology II, RWTH Aachen University, D-52074 Aachen, Germany, 2School of Medicine, Department of Medical Neurobiology, The Hebrew University of Jerusalem, Jerusalem, 91120 Israel, and 3Cellular Biophysics, Institute of Complex Systems, Forschungszentrum Ju¨lich, D-52425 Ju¨lich, Germany 1 The mouse vomeronasal organ (VNO) plays a critical role in semiochemical detection and social communication. Vomeronasal stimuli are typically secreted in various body fluids. Following direct contact with urine deposits or other secretions, a peristaltic vascular pump mediates fluid entry into the recipient’s VNO. Therefore, while vomeronasal sensory neurons (VSNs) sample various stimulatory semiochemicals dissolved in the intraluminal mucus, they might also be affected by the general physicochemical properties of the “solvent.” Here, we report cycle stage-correlated variations in urinary pH among female mice. Estrus-specific pH decline is observed exclusively in urine samples from sexually experienced females. Moreover, patch-clamp recordings in acute VNO slices reveal that mouse VSNs reliably detect extracellular acidosis. Acid-evoked responses share the biophysical and pharmacological hallmarks of the hyperpolarization-activated current Ih. Mechanistically, VSN acid sensitivity depends on a pH-induced shift in the voltage-dependence of Ih activation that causes the opening of HCN channels at rest, thereby increasing VSN excitability. Together, our results identify extracellular acidification as a potent activator of vomeronasal Ih and suggest HCN channel-dependent vomeronasal gain control of social chemosignaling. Our data thus reveal a potential mechanistic basis for stimulus pH detection in rodent chemosensory communication. The Journal of Neuroscience, March 4, 2015 • 35(9):4025– 4039 DEVELOPMENT/PLASTICITY/REPAIR 1-Integrin Alters Ependymal Stem Cell BMP Receptor Localization and Attenuates Astrogliosis after Spinal Cord Injury Hilary A. North, Liuliu Pan, Tammy L. McGuire, Sarah Brooker, and John A. Kessler Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611 Astrogliosis after spinal cord injury (SCI) is a major impediment to functional recovery. More than half of new astrocytes generated after SCI are derived from ependymal zone stem cells (EZCs). We demonstrate that expression of 1-integrin increases in EZCs following SCI in mice. Conditional knock-out of 1-integrin increases GFAP expression and astrocytic differentiation by cultured EZCs without altering oligodendroglial or neuronal differentiation. Ablation of 1-integrin from EZCs in vivo reduced the number of EZC progeny that continued to express stem cell markers after SCI, increased the proportion of EZC progeny that differentiated into GFAP⫹ astrocytes, and diminished functional recovery. Loss of 1-integrin increased SMAD1/5/8 and p38 signaling, suggesting activation of BMP signaling. Coimmunoprecipitation studies demonstrated that 1-integrin directly interacts with the bone morphogenetic protein receptor subunits BMPR1a and BMPR1b. Ablation of 1-integrin reduced overall levels of BMP receptors but significantly increased partitioning of BMPR1b into lipid rafts with increased SMAD1/5/8 and p38 signaling. Thus 1-integrin expression by EZCs reduces movement of BMPR1b into lipid rafts, thereby limiting the known deleterious effects of BMPR1b signaling on glial scar formation after SCI. The Journal of Neuroscience, March 4, 2015 • 35(9):3725–3733 The Subventricular Zone Continues to Generate Corpus Callosum and Rostral Migratory Stream Astroglia in Normal Adult Mice Jiho Sohn,1 Lori Orosco,1 Fuzheng Guo,1 Seung-Hyuk Chung,2 Peter Bannerman,1 Emily Mills Ko,1 Kostas Zarbalis,1 Wenbin Deng,1 and David Pleasure1 Institute for Pediatric Regenerative Medicine, University of California, Davis, School of Medicine, Sacramento, California 95817, and 2Department of Oral Biology, University of Illinois at Chicago, Chicago, Illinois 60612 1 Astrocytes are the most abundant cells in the CNS, and have many essential functions, including maintenance of blood– brain barrier integrity, and CNS water, ion, and glutamate homeostasis. Mammalian astrogliogenesis has generally been considered to be completed soon after birth, and to be reactivated in later life only under pathological circumstances. Here, by using genetic fate-mapping, we demonstrate that new corpus callosum astrocytes are continuously generated from nestin ⫹ subventricular zone (SVZ) neural progenitor cells (NPCs) in normal adult mice. These nestin fate-mapped corpus callosum astrocytes are uniformly postmitotic, express glutamate receptors, and form aquaporin-4 ⫹ perivascular endfeet. The entry of new astrocytes from the SVZ into the corpus callosum appears to be balanced by astroglial apoptosis, because overall numbers of corpus callosum astrocytes remain constant during normal adulthood. Nestin fate-mapped astrocytes also flow anteriorly from the SVZ in association with the rostral migratory stream, but do not penetrate into the deeper layers of the olfactory bulb. Production of new astrocytes from nestin ⫹ NPCs is absent in the normal adult cortex, striatum, and spinal cord. Our study is the first to demonstrate ongoing SVZ astrogliogenesis in the normal adult mammalian forebrain. The Journal of Neuroscience, March 4, 2015 • 35(9):3756 –3763 SYSTEMS/CIRCUITS Spine Loss in Primary Somatosensory Cortex during Trace Eyeblink Conditioning Bettina Joachimsthaler,1,2,4 Dominik Brugger,1,2 Angelos Skodras,3,5 and Cornelius Schwarz1,2 Werner Reichardt Center for Integrative Neuroscience, Systems Neuroscience, 2Hertie Institute for Clinical Brain Research, Department of Cognitive Neurology, 3Hertie Institute for Clinical Brain Research, Department of Cellular Neurology, 4Graduate School of Neural and Behavioural Science, and 5German Center for Neurodegenerative Diseases, Eberhard Karls University, 72076 Tu ¨ bingen, Germany 1 Classical conditioning that involves mnemonic processing, that is, a “trace” period between conditioned and unconditioned stimulus, requires awareness of the association to be formed and is considered a simple model paradigm for declarative learning. Barrel cortex, the whisker representation of primary somatosensory cortex, is required for the learning of a tactile variant of trace eyeblink conditioning (TTEBC) and undergoes distinct map plasticity during learning. To investigate the cellular mechanism underpinning TTEBC and concurrent map plasticity, we used two-photon imaging of dendritic spines in barrel cortex of awake mice while being conditioned. Monitoring layer 5 neurons’ apical dendrites in layer 1, we show that one cellular expression of barrel cortex plasticity is a substantial spine count reduction of ⬃15% of the dendritic spines present before learning. The number of eliminated spines and their time of elimination are tightly related to the learning success. Moreover, spine plasticity is highly specific for the principal barrel column receiving the main signals from the stimulated vibrissa. Spines located in other columns, even those directly adjacent to the principal column, are unaffected. Because layer 1 spines integrate signals from associative thalamocortical circuits, their column-specific elimination suggests that this spine plasticity may be the result of an association of top-down signals relevant for declarative learning and spatially precise ascending tactile signals. The Journal of Neuroscience, March 4, 2015 • 35(9):3772–3781 Neural Population Coding of Multiple Stimuli A. Emin Orhan1 and Wei Ji Ma1,2 1 Center for Neural Science and 2Department of Psychology New York University, New York, New York 10003 In natural scenes, objects generally appear together with other objects. Yet, theoretical studies of neural population coding typically focus on the encoding of single objects in isolation. Experimental studies suggest that neural responses to multiple objects are well described by linear or nonlinear combinations of the responses to constituent objects, a phenomenon we call stimulus mixing. Here, we present a theoretical analysis of the consequences of common forms of stimulus mixing observed in cortical responses. We show that some of these mixing rules can severely compromise the brain’s ability to decode the individual objects. This cost is usually greater than the cost incurred by even large reductions in the gain or large increases in neural variability, explaining why the benefits of attention can be understood primarily in terms of a stimulus selection, or demixing, mechanism rather than purely as a gain increase or noise reduction mechanism. The cost of stimulus mixing becomes even higher when the number of encoded objects increases, suggesting a novel mechanism that might contribute to set size effects observed in myriad psychophysical tasks. We further show that a specific form of neural correlation and heterogeneity in stimulus mixing among the neurons can partially alleviate the harmful effects of stimulus mixing. Finally, we derive simple conditions that must be satisfied for unharmful mixing of stimuli. The Journal of Neuroscience, March 4, 2015 • 35(9):3825–3841 Converging Structural and Functional Connectivity of Orbitofrontal, Dorsolateral Prefrontal, and Posterior Parietal Cortex in the Human Striatum Kevin Jarbo and Timothy D. Verstynen Department of Psychology, Center for the Neural Basis of Cognition, Carnegie Mellon University, Pittsburgh, Pennsylvania 15213 Modification of spatial attention via reinforcement learning (Lee and Shomstein, 2013) requires the integration of reward, attention, and executive processes. Corticostriatal pathways are an ideal neural substrate for this integration because these projections exhibit a globally parallel (Alexander et al., 1986), but locally overlapping (Haber, 2003), topographical organization. Here we explore whether there are unique striatal regions that exhibit convergent anatomical connections from orbitofrontal cortex, dorsolateral prefrontal cortex, and posterior parietal cortex. Deterministic fiber tractography on diffusion spectrum imaging data from neurologically healthy adults (N ⫽ 60) was used to map frontostriatal and parietostriatal projections. In general, projections from cortex were organized according to both a medial–lateral and a rostral– caudal gradient along the striatal nuclei. Within rostral aspects of the striatum, we identified two bilateral convergence zones (one in the caudate nucleus and another in the putamen) that consisted of voxels with unique projections from orbitofrontal cortex, dorsolateral prefrontal cortex, and parietal regions. The distributed cortical connectivity of these striatal convergence zones was confirmed with follow-up functional connectivity analysis from resting state fMRI data, in which a high percentage of structurally connected voxels also showed significant functional connectivity. The specificity of this convergent architecture to these regions of the rostral striatum was validated against control analysis of connectivity within the motor putamen. These results delineate a neurologically plausible network of converging corticostriatal projections that may support the integration of reward, executive control, and spatial attention that occurs during spatial reinforcement learning. The Journal of Neuroscience, March 4, 2015 • 35(9):3865–3878 Corticotropin-Releasing Hormone Drives Anandamide Hydrolysis in the Amygdala to Promote Anxiety J. Megan Gray,1,2,3 Haley A. Vecchiarelli,1,2,4 Maria Morena,1,2,3 Tiffany T.Y. Lee,1,5 Daniel J. Hermanson,6 Alexander B. Kim,1,4 Ryan J. McLaughlin,8 Kowther I. Hassan,1 Claudia Ku¨hne,9 Carsten T. Wotjak,9 Jan M. Deussing,9 Sachin Patel,7 and Matthew N. Hill1,2,3 Hotchkiss Brain Institute, 2Mathison Centre for Mental Health Research and Education, 3Departments of Cell Biology & Anatomy and Psychiatry, and Department of Neuroscience, University of Calgary, Calgary, Alberta T2N 4N1, Canada, 5Department of Psychology, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada, 6Department of Chemistry and 7Department of Psychiatry & Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee 37240, 8Department of Integrative Physiology and Neuroscience, Washington State University, Pullman, Washington 99164, and 9Department of Stress Neurobiology & Neurogenetics, Max Planck Institute of Psychiatry, Munich 80804, Germany 1 4 Corticotropin-releasing hormone (CRH) is a central integrator in the brain of endocrine and behavioral stress responses, whereas activation of the endocannabinoid CB1 receptor suppresses these responses. Although these systems regulate overlapping functions, few studies have investigated whether these systems interact. Here we demonstrate a novel mechanism of CRH-induced anxiety that relies on modulation of endocannabinoids. Specifically, we found that CRH, through activation of the CRH receptor type 1 (CRHR1), evokes a rapid induction of the enzyme fatty acid amide hydrolase (FAAH), which causes a reduction in the endocannabinoid anandamide (AEA), within the amygdala. Similarly, the ability of acute stress to modulate amygdala FAAH and AEA in both rats and mice is also mediated through CRHR1 activation. This interaction occurs specifically in amygdala pyramidal neurons and represents a novel mechanism of endocannabinoid–CRH interactions in regulating amygdala output. Functionally, we found that CRH signaling in the amygdala promotes an anxious phenotype that is prevented by FAAH inhibition. Together, this work suggests that rapid reductions in amygdala AEA signaling following stress may prime the amygdala and facilitate the generation of downstream stress-linked behaviors. Given that endocannabinoid signaling is thought to exert “tonic” regulation on stress and anxiety responses, these data suggest that CRH signaling coordinates a disruption of tonic AEA activity to promote a state of anxiety, which in turn may represent an endogenous mechanism by which stress enhances anxiety. These data suggest that FAAH inhibitors may represent a novel class of anxiolytics that specifically target stress-induced anxiety. The Journal of Neuroscience, March 4, 2015 • 35(9):3879 –3892 Executive Control Signals in Orbitofrontal Cortex during Response Inhibition Daniel W. Bryden1,2 and Matthew R. Roesch1,2 1 Department of Psychology, and 2Program in Neuroscience and Cognitive Science, University of Maryland, College Park, Maryland 20742 Orbitofrontal cortex (OFC) lesions produce deficits in response inhibition and imaging studies suggest that activity in OFC is stronger on trials that require suppression of behavior, yet few studies have examined neural correlates at the single-unit level in a behavioral task that probes response inhibition without varying other factors, such as anticipated outcomes. Here we recorded from single neurons in lateral OFC in a task that required animals in the minority of trials to STOP or inhibit an ongoing movement and respond in the opposite direction. We found that population and single-unit firing was modulated primarily by response direction and movement speed, and that very few OFC neurons exhibited a response independent inhibition signal. Remarkably, the strength of the directional signal was not diminished on STOP trials and was actually stronger on STOP trials during conflict adaptation. Finally, directional signals were stronger during sessions in which rats had the most difficulty inhibiting behavior. These results suggest that “inhibition” deficits observed with OFC interference studies reflect deficits unrelated to signaling the need to inhibit behavior, but instead support a role for OFC in executive functions related to dissociating between two perceptually similar actions during response conflict. The Journal of Neuroscience, March 4, 2015 • 35(9):3903–3914 Structure of a Single Whisker Representation in Layer 2 of Mouse Somatosensory Cortex Kelly B. Clancy, Philipp Schnepel, Antara T. Rao, and Daniel E. Feldman Department of Molecular and Cellular Biology and Helen Wills Neuroscience Institute, Biophysics Program, University of California Berkeley, Berkeley, California 94720 Layer (L)2 is a major output of primary sensory cortex that exhibits very sparse spiking, but the structure of sensory representation in L2 is not well understood. We combined two-photon calcium imaging with deflection of many whiskers to map whisker receptive fields, characterize sparse coding, and quantitatively define the point representation in L2 of mouse somatosensory cortex. Neurons within a column-sized imaging field showed surprisingly heterogeneous, salt-and-pepper tuning to many different whiskers. Single whisker deflection elicited low-probability spikes in highly distributed, shifting neural ensembles spanning multiple cortical columns. Whiskerevoked response probability correlated strongly with spontaneous firing rate, but weakly with tuning properties, indicating a spectrum of inherent responsiveness across pyramidal cells. L2 neurons projecting to motor and secondary somatosensory cortex differed in whisker tuning and responsiveness, and carried different amounts of information about columnar whisker deflection. From these data, we derive a quantitative, fine-scale picture of the distributed point representation in L2. The Journal of Neuroscience, March 4, 2015 • 35(9):3946 –3958 Movement-Related Discharge in the Macaque Globus Pallidus during High-Frequency Stimulation of the Subthalamic Nucleus Andrew J. Zimnik,1 Gerald J. Nora,1 Michel Desmurget,2 and Robert S. Turner1 Department of Neurobiology, Center for the Neural Basis of Cognition, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, and 2Centre for Cognitive Neuroscience, UMR5229, CNRS, 67 Boulevard Pinel 69500 Bron, France 1 Deep brain stimulation (DBS) of the subthalamic nucleus (STN-DBS) has largely replaced ablative therapies for Parkinson’s disease. Because of the similar efficacies of the two treatments, it has been proposed that DBS acts by creating an “informational lesion,” whereby pathologic neuronal firing patterns are replaced by low-entropy, stimulus-entrained firing patterns. The informational lesion hypothesis, in its current form, states that DBS blocks the transmission of all information from the basal ganglia, including both pathologic firing patterns and normal, task-related modulations in activity. We tested this prediction in two healthy rhesus macaques by recording single-unit spiking activity from the globus pallidus (232 neurons) while the animals completed choice reaction time reaching movements with and without STN-DBS. Despite strong effects of DBS on the activity of most pallidal cells, reach-related modulations in firing rate were equally prevalent in the DBS-on and DBS-off states. This remained true even when the analysis was restricted to cells affected significantly by DBS. In addition, the overall form and timing of perimovement modulations in firing rate were preserved between DBS-on and DBS-off states in the majority of neurons (66%). Active movement and DBS had largely additive effects on the firing rate of most neurons, indicating an orthogonal relationship in which both inputs contribute independently to the overall firing rate of pallidal neurons. These findings suggest that STN-DBS does not act as an indiscriminate informational lesion but rather as a filter that permits task-related modulations in activity while, presumably, eliminating the pathological firing associated with parkinsonism. The Journal of Neuroscience, March 4, 2015 • 35(9):3978 –3989 Sensitivity of Locus Ceruleus Neurons to Reward Value for Goal-Directed Actions Sebastien Bouret1,2 and Barry J. Richmond1 Laboratory of Neuropsychology, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland 20892, and 2Motivation, Brain Behavior (MBB) team, Institut du Cerveau et de la Moelle ´epinie`re (ICM), Groupe Hospitalier Pitie´-Salpeˆtrie`re, 75013 Paris, France 1 The noradrenergic nucleus locus ceruleus (LC) is associated classically with arousal and attention. Recent data suggest that it might also play a role in motivation. To study how LC neuronal responses are related to motivational intensity, we recorded 121 single neurons from two monkeys while reward size (one, two, or four drops) and the manner of obtaining reward (passive vs active) were both manipulated. The monkeys received reward under three conditions: (1) releasing a bar when a visual target changed color; (2) passively holding a bar; or (3) touching and releasing a bar. In the first two conditions, a visual cue indicated the size of the upcoming reward, and, in the third, the reward was constant through each block of 25 trials. Performance levels and lipping intensity (an appetitive behavior) both showed that the monkeys’ motivation in the task was related to the predicted reward size. In conditions 1 and 2, LC neurons were activated phasically in relation to cue onset, and this activation strengthened with increasing expected reward size. In conditions 1 and 3, LC neurons were activated before the bar-release action, and the activation weakened with increasing expected reward size but only in task 1. These effects evolved as monkeys progressed through behavioral sessions, because increasing fatigue and satiety presumably progressively decreased the value of the upcoming reward. These data indicate that LC neurons integrate motivationally relevant information: both external cues and internal drives. The LC might provide the impetus to act when the predicted outcome value is low. The Journal of Neuroscience, March 4, 2015 • 35(9):4005– 4014 Spatiotemporal Memory Is an Intrinsic Property of Networks of Dissociated Cortical Neurons Han Ju, Mark R. Dranias, Gokulakrishna Banumurthy, and Antonius M.J. VanDongen Program in Neuroscience and Behavioral Disorders, Duke-NUS Graduate Medical School, Singapore 169857, Singapore The ability to process complex spatiotemporal information is a fundamental process underlying the behavior of all higher organisms. However, how the brain processes information in the temporal domain remains incompletely understood. We have explored the spatiotemporal information-processing capability of networks formed from dissociated rat E18 cortical neurons growing in culture. By combining optogenetics with microelectrode array recording, we show that these randomly organized cortical microcircuits are able to process complex spatiotemporal information, allowing the identification of a large number of temporal sequences and classification of musical styles. These experiments uncovered spatiotemporal memory processes lasting several seconds. Neural network simulations indicated that both short-term synaptic plasticity and recurrent connections are required for the emergence of this capability. Interestingly, NMDA receptor function is not a requisite for these short-term spatiotemporal memory processes. Indeed, blocking the NMDA receptor with the antagonist APV significantly improved the temporal processing ability of the networks, by reducing spontaneously occurring network bursts. These highly synchronized events have disastrous effects on spatiotemporal information processing, by transiently erasing short-term memory. These results show that the ability to process and integrate complex spatiotemporal information is an intrinsic property of generic cortical networks that does not require specifically designed circuits. The Journal of Neuroscience, March 4, 2015 • 35(9):4040 – 4051 Role of the Indirect Pathway of the Basal Ganglia in Perceptual Decision Making Wei Wei,1,2 Jonathan E. Rubin,3 and Xiao-Jing Wang1,2,4 Center for Neural Science, New York University, New York, New York 10003, 2Department of Neurobiology and Kavli Institute for Neuroscience, Yale University School of Medicine, New Haven, Connecticut 06520, 3Department of Mathematics and Center for the Neural Basis of Cognition, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, and 4NYU-ECNU Institute of Brain and Cognitive Science, NYU Shanghai, Shanghai, China 200122 1 The basal ganglia (BG) play an important role in motor control, reinforcement learning, and perceptual decision making. Modeling and experimental evidence suggest that, in a speed–accuracy tradeoff, the corticostriatal pathway can adaptively adjust a decision threshold (the amount of information needed to make a choice). In this study, we go beyond the focus of previous works on the direct and hyperdirect pathways to examine the contribution of the indirect pathway of the BG system to decision making in a biophysically based spiking network model. We find that the mechanism of adjusting the decision threshold by plasticity of the corticostriatal connections is effective, provided that the indirect pathway counterbalances the direct pathway in their projections to the output nucleus. Furthermore, in our model, changes within basal ganglia connections similar to those that arise in parkinsonism give rise to strong beta oscillations. Specifically, beta oscillations are produced by an abnormal enhancement of the interactions between the subthalamic nucleus (STN) and the external segment of globus pallidus (GPe) in the indirect pathway, with an oscillation frequency that depends on the excitatory cortical input to the STN and the inhibitory input to the GPe from the striatum. In a parkinsonian state characterized by pronounced beta oscillations, the mean reaction time and range of threshold variation (a measure of behavioral flexibility) are significantly reduced compared with the normal state. Our work thus reveals a specific circuit mechanism for impairments of perceptual decision making associated with Parkinson’s disease. The Journal of Neuroscience, March 4, 2015 • 35(9):4052– 4064 A Direct Descending Pathway Informing Locomotor Networks about Tactile Sensor Movement Jan M. Ache,1,2 S. Shuichi Haupt,1 and Volker Du¨rr1,2 Department of Biological Cybernetics, Faculty of Biology, Bielefeld University, 33615 Bielefeld, Germany, and 2Cognitive Interaction Technology Center of Excellence, Bielefeld University, 33615 Bielefeld, Germany 1 Much like visually impaired humans use a white-cane, nocturnal insects and mammals use antennae or whiskers for near-range orientation. Stick insects, for example, rely heavily on antennal tactile cues to find footholds and detect obstacles. Antennal contacts can even induce aimed reaching movements. Because tactile sensors are essentially one-dimensional, they must be moved to probe the surrounding space. Sensor movement is thus an essential cue for tactile sensing, which needs to be integrated by thoracic networks for generating appropriate adaptive leg movements. Based on single and double recordings, we describe a descending neural pathway comprising three identified ON- and OFF-type neurons that convey complementary, unambiguous, and short-latency information about antennal movement to thoracic networks in the stick insect. The neurons are sensitive to the velocity of antennal movements across the entire range covered by natural movements, regardless of movement direction and joint angle. Intriguingly, none of them originates from the brain. Instead, they descend from the gnathal ganglion and receive input from antennal mechanoreceptors in this lower region of the CNS. From there, they convey information about antennal movement to the thorax. One of the descending neurons, which is additionally sensitive to substrate vibration, feeds this information back to the brain via an ascending branch. We conclude that descending interneurons with complementary tuning characteristics, gains, input and output regions convey detailed information about antennal movement to thoracic networks. This pathway bypasses higher processing centers in the brain and thus constitutes a shortcut between tactile sensors on the head and the thorax. The Journal of Neuroscience, March 4, 2015 • 35(9):4081– 4091 BEHAVIORAL/COGNITIVE Characterizing the Associative Content of Brain Structures Involved in Habitual and GoalDirected Actions in Humans: A Multivariate fMRI Study Daniel McNamee,1,2* Mimi Liljeholm,1,2,3* Ondrej Zika,1,2 and John P. O’Doherty1,2 Computation and Neural Systems Program and 2Division of Humanities and Social Sciences, California Institute of Technology, Pasadena, California 91125 and 3Department of Cognitive Sciences, University of California, Irvine, Irvine, California 92697 1 While there is accumulating evidence for the existence of distinct neural systems supporting goal-directed and habitual action selection in the mammalian brain, much less is known about the nature of the information being processed in these different brain regions. Associative learning theory predicts that brain systems involved in habitual control, such as the dorsolateral striatum, should contain stimulus and response information only, but not outcome information, while regions involved in goal-directed action, such as ventromedial and dorsolateral prefrontal cortex and dorsomedial striatum, should be involved in processing information about outcomes as well as stimuli and responses. To test this prediction, human participants underwent fMRI while engaging in a binary choice task designed to enable the separate identification of these different representations with a multivariate classification analysis approach. Consistent with our predictions, the dorsolateral striatum contained information about responses but not outcomes at the time of an initial stimulus, while the regions implicated in goal-directed action selection contained information about both responses and outcomes. These findings suggest that differential contributions of these regions to habitual and goal-directed behavioral control may depend in part on basic differences in the type of information that these regions have access to at the time of decision making. The Journal of Neuroscience, March 4, 2015 • 35(9):3764 –3771 Attending to Pitch Information Inhibits Processing of Pitch Information: The Curious Case of Amusia Benjamin Rich Zendel,1,2,3 Marie-E´laine Lagrois,1,2,3 Nicolas Robitaille,1,2,3 and Isabelle Peretz1,2,3 International Laboratory for Brain, Music and Sound Research, Montre´al, Que´bec H3C 3J7, Canada, 2Centre for Research on Brain, Language and Music, Montre´al, Que´bec H3G 2A8, Canada, and 3De´partement de Psychologie, Universite´ de Montre´al, Que´bec H3C 3J7, Canada 1 In normal listeners, the tonal rules of music guide musical expectancy. In a minority of individuals, known as amusics, the processing of tonality is disordered, which results in severe musical deficits. It has been shown that the tonal rules of music are neurally encoded, but not consciously available in amusics. Previous neurophysiological studies have not explicitly controlled the level of attention in tasks where participants ignored the tonal structure of the stimuli. Here, we test whether access to tonal knowledge can be demonstrated in congenital amusia when attention is controlled. Electric brain responses were recorded while asking participants to detect an individually adjusted near-threshold click in a melody. In half the melodies, a note was inserted that violated the tonal rules of music. In a second task, participants were presented with the same melodies but were required to detect the tonal deviation. Both tasks required sustained attention, thus conscious access to the rules of tonality was manipulated. In the click-detection task, the pitch deviants evoked an early right anterior negativity (ERAN) in both groups. In the pitch-detection task, the pitch deviants evoked an ERAN and P600 in controls but not in amusics. These results indicate that pitch regularities are represented in the cortex of amusics, but are not consciously available. Moreover, performing a pitch-judgment task eliminated the ERAN in amusics, suggesting that attending to pitch information interferes with perception of pitch. We propose that an impaired top-down frontotemporal projection is responsible for this disorder. The Journal of Neuroscience, March 4, 2015 • 35(9):3815–3824 Cortical Activity Predicts Which Older Adults Recognize Speech in Noise and When Kenneth I. Vaden, Jr.,1 Stefanie E. Kuchinsky,2 Jayne B. Ahlstrom,1 Judy R. Dubno,1 and Mark A. Eckert1 Hearing Research Program, Department of Otolaryngology-Head and Neck Surgery, Medical University of South Carolina, Charleston, South Carolina 29425, and 2Center for Advanced Study of Language, University of Maryland, College Park, Maryland 20742 1 Speech recognition in noise can be challenging for older adults and elicits elevated activity throughout a cingulo-opercular network that is hypothesized to monitor and modify behaviors to optimize performance. A word recognition in noise experiment was used to test the hypothesis that cingulo-opercular engagement provides performance benefit for older adults. Healthy older adults (N ⫽ 31; 50 – 81 years of age; mean pure tone thresholds ⬍32 dB HL from 0.25 to 8 kHz, best ear; species: human) performed word recognition in multitalker babble at 2 signal-to-noise ratios (SNR ⫽ ⫹3 or ⫹10 dB) during a sparse sampling fMRI experiment. Elevated cingulo-opercular activity was associated with an increased likelihood of correct recognition on the following trial independently of SNR and performance on the preceding trial. The cingulo-opercular effect increased for participants with the best overall performance. These effects were lower for older adults compared with a younger, normal-hearing adult sample (N ⫽ 18). Visual cortex activity also predicted trial-level recognition for the older adults, which resulted from discrete decreases in activity before errors and occurred for the oldest adults with the poorest recognition. Participants demonstrating larger visual cortex effects also had reduced fractional anisotropy in an anterior portion of the left inferior frontal-occipital fasciculus, which projects between frontal and occipital regions where activity predicted word recognition. Together, the results indicate that older adults experience performance benefit from elevated cingulo-opercular activity, but not to the same extent as younger adults, and that declines in attentional control can limit word recognition. The Journal of Neuroscience, March 4, 2015 • 35(9):3929 –3937 Impaired Attention and Synaptic Senescence of the Prefrontal Cortex Involves Redox Regulation of NMDA Receptors Michael Guidi,* Ashok Kumar,* and Thomas C. Foster Department of Neuroscience, McKnight Brain Institute, University of Florida, Gainesville, Florida 32610 Young (3– 6 months) and middle-age (10 –14 months) rats were trained on the five-choice serial reaction time task. Attention and executive function deficits were apparent in middle-age animals observed as a decrease in choice accuracy, increase in omissions, and increased response latency. The behavioral differences were not due to alterations in sensorimotor function or a diminished motivational state. Electrophysiological characterization of synaptic transmission in slices from the mPFC indicated an age-related decrease in glutamatergic transmission. In particular, a robust decrease in N-methyl-D-aspartate receptor (NMDAR)-mediated synaptic responses in the mPFC was correlated with several measures of attention. The decrease in NMDAR function was due in part to an altered redox state as bath application of the reducing agent, dithiothreitol, increased the NMDAR component of the synaptic response to a greater extent in middle-age animals. Together with previous work indicating that redox state mediates senescent physiology in the hippocampus, the results indicate that redox changes contribute to senescent synaptic function in vulnerable brain regions involved in age-related cognitive decline. The Journal of Neuroscience, March 4, 2015 • 35(9):3966 –3977 Dual Mechanism for Bitter Avoidance in Drosophila Alice Sarah French,1,2,7* Marie-Jeanne Sellier,1,2* Ali Agha Moutaz,1,7 Alexandra Guigue,1,2 Marie-Ange Chabaud,1* Pablo D. Reeb,3 Aniruddha Mitra,7 Yves Grau,4,5,6 Laurent Soustelle,4,5,6 and Fre´de´ric Marion-Poll1,2,7 Institut National de la Recherche Agronomique, Unite´ Mixte de Recherche (UMR) Institut d’Ecologie et des Sciences de l’Environnement de Paris, F-78026 Versailles, France, 2AgroParisTech, De´partement Sciences de la Vie et Sante´, F-75231 Paris, France, 3Universidad Nacional del Comahue, Facultad de Ciencias Agrarias, Departamento de Estadistica, RA-8303 Cinco Saltos, Argentina, 4Centre National de la Recherche Scientifique (CNRS), UMR 5203, Institut de Ge´nomique Fonctionnelle, F-34094 Montpellier, France, 5Institut National de la Sante´ et de la Recherche Me´dicale, U661, F-34094 Montpellier, France, 6Universite´s de Montpellier 1 and 2, UMR 5203, F-34094 Montpellier, France, and 7CNRS, Unite´ mixte de Recherches UMR 9191, Evolution, Ge´nomes, Comportement, Ecologie F-91198 Gif-sur-Yvette, France 1 In flies and humans, bitter chemicals are known to inhibit sugar detection, but the adaptive role of this inhibition is often overlooked. At best, this inhibition is described as contributing to the rejection of potentially toxic food, but no studies have addressed the relative importance of the direct pathway that involves activating bitter-sensitive cells versus the indirect pathway represented by the inhibition of sugar detection. Using toxins to selectively ablate or inactivate populations of bitter-sensitive cells, we assessed the behavioral responses of flies to sucrose mixed with strychnine (which activates bitter-sensitive cells and inhibits sugar detection) or with L-canavanine (which only activates bitter-sensitive cells). As expected, flies with ablated bitter-sensitive cells failed to detect L-canavanine mixed with sucrose in three different feeding assays (proboscis extension responses, capillary feeding, and two-choice assays). However, such flies were still able to avoid strychnine mixed with sucrose. By means of electrophysiological recordings, we established that bitter molecules differ in their potency to inhibit sucrose detection and that sugar-sensing inhibition affects taste cells on the proboscis and the legs. The optogenetic response of sugar-sensitive cells was not reduced by strychnine, thus suggesting that this inhibition is linked directly to sugar transduction. We postulate that sugar-sensing inhibition represents a mechanism in insects to prevent ingesting harmful substances occurring within mixtures. The Journal of Neuroscience, March 4, 2015 • 35(9):3990 – 4004 Reward-Dependent Modulation of Movement Variability Sarah E. Pekny,1* Jun Izawa,1,2* and Reza Shadmehr1 1 2 Laboratory for Computational Motor Control, Department of Biomedical Engineering, Johns Hopkins School of Medicine, Baltimore, Maryland 21205, and Faculty of Engineering, Information and Systems, University of Tsukuba, Ibaraki 305-8573, Japan Movement variability is often considered an unwanted byproduct of a noisy nervous system. However, variability can signal a form of implicit exploration, indicating that the nervous system is intentionally varying the motor commands in search of actions that yield the greatest success. Here, we investigated the role of the human basal ganglia in controlling reward-dependent motor variability as measured by trial-to-trial changes in performance during a reaching task. We designed an experiment in which the only performance feedback was success or failure and quantified how reach variability was modulated as a function of the probability of reward. In healthy controls, reach variability increased as the probability of reward decreased. Control of variability depended on the history of past rewards, with the largest trial-to-trial changes occurring immediately after an unrewarded trial. In contrast, in participants with Parkinson’s disease, a known example of basal ganglia dysfunction, reward was a poor modulator of variability; that is, the patients showed an impaired ability to increase variability in response to decreases in the probability of reward. This was despite the fact that, after rewarded trials, reach variability in the patients was comparable to healthy controls. In summary, we found that movement variability is partially a form of exploration driven by the recent history of rewards. When the function of the human basal ganglia is compromised, the reward-dependent control of movement variability is impaired, particularly affecting the ability to increase variability after unsuccessful outcomes. The Journal of Neuroscience, March 4, 2015 • 35(9):4015– 4024 Losing the Music: Aging Affects the Perception and Subcortical Neural Representation of Musical Harmony Oliver Bones and Christopher J. Plack School of Psychological Sciences, University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom M13 9PL When two musical notes with simple frequency ratios are played simultaneously, the resulting musical chord is pleasing and evokes a sense of resolution or “consonance”. Complex frequency ratios, on the other hand, evoke feelings of tension or “dissonance”. Consonance and dissonance form the basis of harmony, a central component of Western music. In earlier work, we provided evidence that consonance perception is based on neural temporal coding in the brainstem (Bones et al., 2014). Here, we show that for listeners with clinically normal hearing, aging is associated with a decline in both the perceptual distinction and the distinctiveness of the neural representations of different categories of two-note chords. Compared with younger listeners, older listeners rated consonant chords as less pleasant and dissonant chords as more pleasant. Older listeners also had less distinct neural representations of consonant and dissonant chords as measured using a Neural Consonance Index derived from the electrophysiological “frequency-following response.” The results withstood a control for the effect of age on general affect, suggesting that different mechanisms are responsible for the perceived pleasantness of musical chords and affective voices and that, for listeners with clinically normal hearing, age-related differences in consonance perception are likely to be related to differences in neural temporal coding. The Journal of Neuroscience, March 4, 2015 • 35(9):4071– 4080 Juvenile Obesity Enhances Emotional Memory and Amygdala Plasticity through Glucocorticoids Chloe´ Boitard,1,2 Mouna Maroun,3 Fre´de´ric Tantot,1,2 Amandine Cavaroc,1,2 Julie Sauvant,1,2 Alain Marchand,4,5 Sophie Laye´,1,2 Lucile Capuron,1,2 Muriel Darnaudery,1,2 Nathalie Castanon,1,2 Etienne Coutureau,4,5 Rose-Marie Vouimba,4,5 and Guillaume Ferreira1,2 INRA, Nutrition and Integrative Neurobiology, UMR 1286, 33076 Bordeaux, France, 2Universite´ de Bordeaux, Nutrition and Integrative Neurobiology, UMR 1286, 33076 Bordeaux, France, 3Sagol Department of Neurobiology, Faculty of Natural Sciences, University of Haifa, Haifa 31905, Israel, 4CNRS, Institut de Neurosciences Cognitives et Inte´gratives d’Aquitaine, UMR 5287, 33076 Bordeaux, France, and 5Universite´ de Bordeaux, Institut de Neurosciences Cognitives et Inte´gratives d’Aquitaine, UMR 5287, 33076 Bordeaux, France 1 In addition to metabolic and cardiovascular disorders, obesity is associated with adverse cognitive and emotional outcomes. Its growing prevalence during adolescence is particularly alarming since recent evidence indicates that obesity can affect hippocampal function during this developmental period. Adolescence is a decisive period for maturation of the amygdala and the hypothalamic–pituitary–adrenal (HPA) stress axis, both required for lifelong cognitive and emotional processing. However, little data are available on the impact of obesity during adolescence on amygdala function. Herein, we therefore evaluate in rats whether juvenile high-fat diet (HFD)-induced obesity alters amygdala-dependent emotional memory and whether it depends on HPA axis deregulation. Exposure to HFD from weaning to adulthood, i.e., covering adolescence, enhances long-term emotional memories as assessed by odor–malaise and tone–shock associations. Juvenile HFD also enhances emotion-induced neuronal activation of the basolateral complex of the amygdala (BLA), which correlates with protracted plasma corticosterone release. HFD exposure restricted to adulthood does not modify all these parameters, indicating adolescence is a vulnerable period to the effects of HFD-induced obesity. Finally, exaggerated emotional memory and BLA synaptic plasticity after juvenile HFD are alleviated by a glucocorticoid receptor antagonist. Altogether, our results demonstrate that juvenile HFD alters HPA axis reactivity leading to an enhancement of amygdala-dependent synaptic and memory processes. Adolescence represents a period of increased susceptibility to the effects of diet-induced obesity on amygdala function. The Journal of Neuroscience, March 4, 2015 • 35(9):4092– 4103 Dopamine D2-Receptor Blockade Enhances Decoding of Prefrontal Signals in Humans Thorsten Kahnt,1,2 Susanna C. Weber,2 Helene Haker,3 Trevor W. Robbins,4 and Philippe N. Tobler2 Northwestern University Feinberg School of Medicine, Department of Neurology, Chicago, Illinois 60611, 2Laboratory for Social and Neural Systems Research, Department of Economics, University of Zurich, 8006 Zurich, Switzerland, 3Translational Neuromodeling Unit, Institute for Biomedical Engineering, University of Zurich and ETH Zurich, 8032 Zurich, Switzerland, and 4Department of Psychology, and Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge CB2 3EB, United Kingdom 1 The prefrontal cortex houses representations critical for ongoing and future behavior expressed in the form of patterns of neural activity. Dopamine has long been suggested to play a key role in the integrity of such representations, with D2-receptor activation rendering them flexible but weak. However, it is currently unknown whether and how D2-receptor activation affects prefrontal representations in humans. In the current study, we use dopamine receptor-specific pharmacology and multivoxel pattern-based functional magnetic resonance imaging to test the hypothesis that blocking D2-receptor activation enhances prefrontal representations. Human subjects performed a simple reward prediction task after double-blind and placebo controlled administration of the D2-receptor antagonist amisulpride. Using a whole-brain searchlight decoding approach we show that D2-receptor blockade enhances decoding of reward signals in the medial orbitofrontal cortex. Examination of activity patterns suggests that amisulpride increases the separation of activity patterns related to reward versus no reward. Moreover, consistent with the cortical distribution of D2 receptors, post hoc analyses showed enhanced decoding of motor signals in motor cortex, but not of visual signals in visual cortex. These results suggest that D2-receptor blockade enhances content-specific representations in frontal cortex, presumably by a dopamine-mediated increase in pattern separation. These findings are in line with a dual-state model of prefrontal dopamine, and provide new insights into the potential mechanism of action of dopaminergic drugs. The Journal of Neuroscience, March 4, 2015 • 35(9):4104 – 4111 NEUROBIOLOGY OF DISEASE Dissociable Rate-Dependent Effects of Oral Methylphenidate on Impulsivity and D2/3 Receptor Availability in the Striatum Daniele Caprioli,1 Bianca Jupp,2,3 Young T. Hong,4 Stephen J. Sawiak,2,4 Valentina Ferrari,4 Laura Wharton,2,3 David J. Williamson,4 Carolyn McNabb,5 David Berry,6 Franklin I. Aigbirhio,2,4 Trevor W. Robbins,2,3 Tim D. Fryer,2,4 and Jeffrey W. Dalley2,3,7 Behavioral Neuroscience Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Baltimore, Maryland 21224, 2Behavioural and Clinical Neuroscience Institute, and 3Department of Psychology, University of Cambridge, Cambridge CB2 3EB, United Kingdom, 4Wolfson Brain Imaging Centre, Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0QQ, United Kingdom, 5School of Pharmacy, University of Auckland, Auckland 1142, New Zealand, 6Epilepsy Society, Chalfont St Peter SL9 0RJ, United Kingdom, and 7Department of Psychiatry, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 2QQ, United Kingdom 1 We have previously shown that impulsivity in rats is linked to decreased dopamine D2/3 receptor availability in the ventral striatum. In the present study, we investigated, using longitudinal positron emission tomography (PET), the effects of orally administered methylphenidate (MPH), a first-line treatment for attention deficit hyperactivity disorder, on D2/3 receptor availability in the dorsal and ventral striatum and related these changes to impulsivity. Rats were screened for impulsive behavior on a five-choice serial reaction time task. After a baseline PET scan with the D2/3 ligand [18F]fallypride, rats received 6 mg/kg MPH, orally, twice each day for 28 d. Rats were then reassessed for impulsivity and underwent a second [18F]fallypride PET scan. Before MPH treatment, we found that D2/3 receptor availability was significantly decreased in the left but not the right ventral striatum of high-impulse (HI) rats compared with low-impulse (LI) rats. MPH treatment increased impulsivity in LI rats, and modulated impulsivity and D2/3 receptor availability in the dorsal and ventral striatum of HI rats through inverse relationships with baseline levels of impulsivity and D2/3 receptor availability, respectively. However, we found no relationship between the effects of MPH on impulsivity and D2/3 receptor availability in any of the striatal subregions investigated. These findings indicate that trait-like impulsivity is associated with decreased D2/3 receptor availability in the left ventral striatum, and that stimulant drugs modulate impulsivity and striatal D2/3 receptor availability through independent mechanisms. The Journal of Neuroscience, March 4, 2015 • 35(9):3747–3755 Early-Onset Epileptic Encephalopathy Caused by Gain-of-Function Mutations in the Voltage Sensor of Kv7.2 and Kv7.3 Potassium Channel Subunits Francesco Miceli,1* Maria Virginia Soldovieri,2* Paolo Ambrosino,2 Michela De Maria,2 Michele Migliore,3 Rosanna Migliore,3 and Maurizio Taglialatela1,2 Department of Neuroscience, University of Naples Federico II, 80131 Naples, Italy, 2Department of Medicine and Health Science, University of Molise, 86100 Campobasso, Italy, and 3Institute of Biophysics, National Research Council, 90146 Palermo, Italy 1 Mutations in Kv7.2 (KCNQ2) and Kv7.3 (KCNQ3) genes, encoding for voltage-gated K ⫹ channel subunits underlying the neuronal M-current, have been associated with a wide spectrum of early-onset epileptic disorders ranging from benign familial neonatal seizures to severe epileptic encephalopathies. The aim of the present work has been to investigate the molecular mechanisms of channel dysfunction caused by voltage-sensing domain mutations in Kv7.2 (R144Q, R201C, and R201H) or Kv7.3 (R230C) recently found in patients with epileptic encephalopathies and/or intellectual disability. Electrophysiological studies in mammalian cells transfected with human Kv7.2 and/or Kv7.3 cDNAs revealed that each of these four mutations stabilized the activated state of the channel, thereby producing gain-of-function effects, which are opposite to the loss-of-function effects produced by previously found mutations. Multistate structural modeling revealed that the R201 residue in Kv7.2, corresponding to R230 in Kv7.3, stabilized the resting and nearby voltage-sensing domain states by forming an intricate network of electrostatic interactions with neighboring negatively charged residues, a result also confirmed by disulfide trapping experiments. Using a realistic model of a feedforward inhibitory microcircuit in the hippocampal CA1 region, an increased excitability of pyramidal neurons was found upon incorporation of the experimentally defined parameters for mutant M-current, suggesting that changes in network interactions rather than in intrinsic cell properties may be responsible for the neuronal hyperexcitability by these gain-of-function mutations. Together, the present results suggest that gain-of-function mutations in Kv7.2/3 currents may cause human epilepsy with a severe clinical course, thus revealing a previously unexplored level of complexity in disease pathogenetic mechanisms. The Journal of Neuroscience, March 4, 2015 • 35(9):3782–3793 Astrocyte-Mediated Ischemic Tolerance Yuri Hirayama,1,2 Yuri Ikeda-Matsuo,3 Shoji Notomi,4 Hiroshi Enaida,5 Hiroyuki Kinouchi,6 and Schuichi Koizumi1,7 Department of Neuropharmacology, Interdisciplinary Graduate School of Medicine and 2Department of Liaison Academy, Faculty of Medicine, University of Yamanashi, Yamanashi 409-3898, Japan, 3Department of Pharmacology, School of Pharmaceutical Sciences, Kitasato University, Tokyo 108-8641, Japan, 4Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 812-8582, Japan, 5Department of Ophthalmology, Faculty of Medicine, Saga University, Saga, 849-0937, Japan, 6Department of Neurosurgery, Interdisciplinary Graduate School of Medicine, University of Yamanashi, Yamanashi 409-3898, Japan, and 7Japan Science and Technology Agency, Core Research for Evolutional Science and Technology, Tokyo 1020076, Japan 1 Preconditioning (PC) using a preceding sublethal ischemic insult is an attractive strategy for protecting neurons by inducing ischemic tolerance in the brain. Although the underlying molecular mechanisms have been extensively studied, almost all studies have focused on neurons. Here, using a middle cerebral artery occlusion model in mice, we show that astrocytes play an essential role in the induction of brain ischemic tolerance. PC caused activation of glial cells without producing any noticeable brain damage. The spatiotemporal pattern of astrocytic, but not microglial, activation correlated well with that of ischemic tolerance. Interestingly, such activation in astrocytes lasted at least 8 weeks. Importantly, inhibiting astrocytes with fluorocitrate abolished the induction of ischemic tolerance. To investigate the underlying mechanisms, we focused on the P2X7 receptor as a key molecule in astrocyte-mediated ischemic tolerance. P2X7 receptors were dramatically upregulated in activated astrocytes. PC-induced ischemic tolerance was abolished in P2X7 receptor knock-out mice. Moreover, our results suggest that hypoxia-inducible factor-1␣, a well known mediator of ischemic tolerance, is involved in P2X7 receptor-mediated ischemic tolerance. Unlike previous reports focusing on neuron-based mechanisms, our results show that astrocytes play indispensable roles in inducing ischemic tolerance, and that upregulation of P2X7 receptors in astrocytes is essential. The Journal of Neuroscience, March 4, 2015 • 35(9):3794 –3805 Axonal and Schwann Cell BACE1 Is Equally Required for Remyelination of Peripheral Nerves Xiangyou Hu,1,2 Jinxuan Hu,1 Lu Dai,1 Bruce Trapp,1 and Riqiang Yan1 Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, and 2Department of Anatomy, Anhui Medical University, Hefei 230032, Anhui, People’s Republic of China 1 Inhibition of -site APP cleaving enzyme 1 (BACE1) is being pursued as a therapeutic target for treating patients with Alzheimer’s disease because BACE1 is the sole -secretase for generating -amyloid peptide. Knowledge regarding the other cellular functions of BACE1 is therefore critical for the safe use of BACE1 inhibitors in human patients. BACE1 deficiency in mice causes hypomyelination during development and impairs remyelination in injured sciatic nerves. Since BACE1 is expected to be ubiquitously expressed, we asked whether axonal or Schwann cell BACE1 is required for optimal remyelination. By swapping sciatic nerve segments from BACE1-null mice with the corresponding wild-type nerve segments or vice versa, we tested how a deficiency of BACE1 in Schwann cells or axons affects remyelination. Our results show that BACE1 in axons and Schwann cells is similarly important for remyelination of regenerated axons. Nerve injury induces BACE1 transcription and protein levels are elevated in Schwann cells. Expression of type I neuregulin 1 (Nrg1), rather than type III Nrg1, was induced by Schwann cells, and the abolished Nrg1 cleavage in BACE1-null Schwann cells contributed to decreased remyelination of regenerated axons. Hence, this study is the first to demonstrate the equal importance of axonal and Schwann cell BACE1 for remyelination of injured nerves. The Journal of Neuroscience, March 4, 2015 • 35(9):3806 –3814 Impaired Leptomeningeal Collateral Flow Contributes to the Poor Outcome following Experimental Stroke in the Type 2 Diabetic Mice Yosuke Akamatsu,1,2,3 Yasuo Nishijima,1,2,3 Chih Cheng Lee,1,2 Shih Yen Yang,1,2 Lei Shi,4 Lin An,4 Ruikang K. Wang,4 Teiji Tominaga,3 and Jialing Liu1,2 Department of Neurological Surgery, University of California at San Francisco and 2San Francisco Veterans Affairs Medical Center, San Francisco, California 94121, 3Department of Neurosurgery, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan, and 4Departments of Bioengineering and Ophthalmology, University of Washington, Seattle, Washington 98195 1 Collateral status is an independent predictor of stroke outcome. However, the spatiotemporal manner in which collateral flow maintains cerebral perfusion during cerebral ischemia is poorly understood. Diabetes exacerbates ischemic brain damage, although the impact of diabetes on collateral dynamics remains to be established. Using Doppler optical coherent tomography, a robust recruitment of leptomeningeal collateral flow was detected immediately after middle cerebral artery (MCA) occlusion in C57BL/6 mice, and it continued to grow over the course of 1 week. In contrast, an impairment of collateral recruitment was evident in the Type 2 diabetic db/db mice, which coincided with a worse stroke outcome compared with their normoglycemic counterpart db/⫹, despite their equally well-collateralized leptomeningeal anastomoses. Similar to the wild-type mice, both db/⫹ and db/db mice underwent collateral growth 7 d after MCA stroke, although db/db mice still exhibited significantly reduced retrograde flow into the MCA territory chronically. Acutely induced hyperglycemia in the db/⫹ mice did not impair collateral flow after stroke, suggesting that the state of hyperglycemia alone was not sufficient to impact collateral flow. Human albumin was efficacious in improving collateral flow and outcome after stroke in the db/db mice, enabling perfusion to proximal MCA territory that was usually not reached by retrograde flow from anterior cerebral artery without treatment. Our results suggest that the impaired collateral status contributes to the exacerbated ischemic injury in mice with Type 2 diabetes, and modulation of collateral flow has beneficial effects on stroke outcome among these subjects. The Journal of Neuroscience, March 4, 2015 • 35(9):3851–3864 A Novel Mouse Model of Subcortical Infarcts with Dementia Yorito Hattori,1 Jun-ichiro Enmi,2 Akihiro Kitamura,3 Yumi Yamamoto,1 Satoshi Saito,1,3 Yukako Takahashi,3,4 Satoshi Iguchi,2 Masahiro Tsuji,1 Kenichi Yamahara,1 Kazuyuki Nagatsuka,4 Hidehiro Iida,2 and Masafumi Ihara1,4 Departments of Regenerative Medicine and 2Investigative Radiology, National Cerebral and Cardiovascular Center, Suita, Osaka 565-8565 Japan, Department of Neurology, Kyoto University Graduate School of Medicine, Kyoto 606-8507 Japan, and 4Department of Stroke and Cerebrovascular Diseases, National Cerebral and Cardiovascular Center, Osaka 565-8565 Japan 1 3 Subcortical white matter (WM) is a frequent target of ischemic injury and extensive WM lesions are important substrates of vascular cognitive impairment (VCI) in humans. However, ischemic stroke rodent models have been shown to mainly induce cerebral infarcts in the gray matter, while cerebral hypoperfusion models show only WM rarefaction without infarcts. The lack of animal models consistently replicating WM infarct damage may partially explain why many neuroprotective drugs for ischemic stroke or VCI have failed clinically, despite earlier success in preclinical experiments. Here, we report a novel animal model of WM infarct damage with cognitive impairment can be generated by surgical implantation of different devices to the right and left common carotid artery (CCA) in C57BL/6J mice. Implantation of an ameroid constrictor to the right CCA resulted in gradual occlusion of the vessel over 28 d, whereas placement of a microcoil to the left CCA induced ⬃50% arterial stenosis. Arterial spin labeling showed a gradual reduction of cerebral blood flow over 28 d post operation. Such reductions were more marked in the right, compared with the left, hemisphere and in subcortical, rather than the cortical, areas. Histopathological analysis showed multiple infarct damage in right subcortical regions, including the corpus callosum, internal capsule, hippocampal fimbria, and caudoputamen, in 81% of mice. Mice displaying such damage performed significantly poorer in locomotor and cognitive tests. The current mouse model replicates the phenotypes of human subcortical VCI, including multiple WM infarcts with motor and cognitive impairment. The Journal of Neuroscience, March 4, 2015 • 35(9):3915–3928 Homer Protein–Metabotropic Glutamate Receptor Binding Regulates Endocannabinoid Signaling and Affects Hyperexcitability in a Mouse Model of Fragile X Syndrome Ai-Hui Tang (唐爱辉)1,2 and Bradley E. Alger1,2 1 Department of Physiology and 2Program in Neuroscience, University of Maryland School of Medicine, Baltimore, Maryland 21201 The Fmr1 knock-out mouse model of fragile X syndrome (Fmr1⫺/y) has an epileptogenic phenotype that is triggered by group I metabotropic glutamate receptor (mGluR) activation. We found that a membrane-permeable peptide that disrupts mGluR5 interactions with long-form Homers enhanced mGluR-induced epileptiform burst firing in wild-type (WT) animals, replicating the early stages of hyperexcitability in Fmr1⫺/y. The peptide enhanced mGluR-evoked endocannabinoid (eCB)-mediated suppression of inhibitory synapses, decreased it at excitatory synapses in WTs, but had no effect on eCB actions in Fmr1⫺/y. At a low concentration, the mGluR agonist did not generate eCBs at excitatory synapses but nevertheless induced burst firing in both Fmr1⫺/y and peptide-treated WT slices. This burst firing was suppressed by a cannabinoid receptor antagonist. We suggest that integrity of Homer scaffolds is essential for normal mGluR– eCB functioning and that aberrant eCB signaling resulting from disturbances of this molecular structure contributes to the epileptic phenotype of Fmr1⫺/y. The Journal of Neuroscience, March 4, 2015 • 35(9):3938 –3945
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