This Week in The Journal Cellular/Molecular The N-Terminal Portion of A 
The Journal of Neuroscience, October 22, 2014 • 34(43):i • i This Week in The Journal Cellular/Molecular The N-Terminal Portion of A Enhances LTP F James L.M. Lawrence, Mei Tong, Naghum Alfulaij, Tessi Sherrin, Mark Contarino, et al. (see pages 14210–14218) Amyloid precursor protein (APP) is cleaved by three secretases, resulting in several peptide products. Sequential cleavage by - then ␥-secretases generates -amyloid (A) peptides of various lengths. A activates nicotinic acetylcholine receptors (nAChRs) and at low concentrations it promotes long-term potentiation (LTP). But the aggregationprone 42-amino-acid A species, A1– 42, accumulates in Alzheimer’s disease (AD), and high A concentrations inhibit LTP. Normally, generation of A1– 42 is restrained by ␣-secretase, which cleaves APP in the middle of the A sequence. Recent studies suggest that ␣-secretase can also cleave a -secretase cleavage product of APP, yielding A1–15. Lawrence et al. show that A1–15 activates nAChRs at lower concentrations than A1– 42 and that low concentrations of A1–15 also enhance LTP in mouse hippocampal slices. Unlike A1– 42, however, A1–15 did not inhibit LTP at high concentrations; in fact, A1–15 reversed impairment of LTP induced by high levels of A1– 42. Thus, stimulating ␣-secretase might have multiple benefits in AD. Systems/Circuits REM Transition Does Not Require Cholinergic Input to SubC F Kevin P. Grace, Lindsay E. Vanstone, and Richard L. Horner (see pages 14198 –14209) Despite much investigation, the neural processes that initiate REM sleep remain uncertain. REM sleep requires activation of the subcoeruleus (SubC) region of the pons, and this activation has long been thought to depend on cholinergic input from pedunculopontine and laterodorsal tegemental nuclei (PPT and LDT, respectively). Indeed, cholinergic PPT and LDT neurons that innervate SubC are active during REM sleep, and administration of cholinergic agonists to SubC sometimes induces REM sleep. Nevertheless, inactivation of PPT and LDT does not reduce REM sleep and cholinergic agonists often induce prolonged wakefulness. Furthermore, Grace et al. report that microperfusion of muscarinic antagonists to rat SubC affected neither the frequency nor the total amount of REM sleep. The antagonist slightly reduced the duration of REM bouts, likely by prolonging the transition between non-REM and REM sleep, and it attenuated the increase in theta-frequency power that characterizes REM sleep. The authors propose that cholinergic input to SubC reinforces the non-REM-to-REM transition and contributes to the generation of theta oscillations. F Behavioral/Cognitive Dopamine Enhances Cue-Evoked Excitation in Nucleus Accumbens Presentationofareward-predictingcue(attimeindicatedbyvertical line)increasedspikingofaneuroninNAc(redrasterplot).Infusionofa D1DR antagonist reduced cue-induced spiking (blue raster plot). The presenceofabehavioralresponse(indicatedbyhorizontallinestothe left of rasters) depended on the size of the neuronal response. See thearticlebyduHoffmannandNicolafordetails. Neurobiology of Disease Benefits of HDAC Inhibitors Extend beyond HDAC Inhibition F (see pages 14349 –14364) Sama F. Sleiman, David E. Olson, Megan W. Bourassa, Saravanan S. Karuppagounder, Yan-Ling Zhang, et al. (see pages 14328–14337) When reward-associated cues appear, dopamine is released in the nucleus accumbens (NAc), promoting approach toward anticipated rewards. Local interference with dopaminergic signaling selectively increases the latency to initiate approach behavior. Because both D1- and D2-type dopamine receptors (DRs) are expressed in NAc, and because some NAc neurons are excited while others are inhibited by reward-predicting cues, the cellular mechanism by which dopamine promotes approach is unresolved. To tackle this problem, du Hoffmann and Nicola used a probe that allowed localized delivery of DR antagonists to recorded NAc neurons. Presentation of reward-associated cues increased firing in ⬃45% of recorded neurons. BilateralinfusionofeitherD1orD2/D3antagonist reduced cue-evoked excitation, and greaterreductionswereassociatedwithgreater latency to initiate approach behavior. Furthermore, neuronal and behavioral responses to cuesrecoveredinparallelasthedrugsworeoff. In contrast, neither antagonist reduced inhibitory effects of reward-predicting cues. Thus, dopamine appears to stimulate approach by enhancing excitation of D1- and D2/3expressing NAc neurons. Epigenetic modifications such as histone acetylation and deacetylation underlie the longterm changes in transcriptional programs that occur during development, memory consolidation, and neurodegenerative diseases. Epigenetic modifiers are potential therapeutic targets; in fact, broad-spectrum histone deacetylase (HDAC) inhibitors are neuroprotective in animal models of multiple sclerosis and stroke. But identifying and targeting specific HDAC isoforms will be necessary to avoid substantial side effects of such therapies. Although progress has been made in this endeavor, Sleiman et al. raise a note of caution in interpreting studies in which the roles of specific HDACs is investigated solely through pharmacological means. They found that the neuroprotective effects of an isoform-selective HDAC8 inhibitor, PCI-34051, did not result from HDAC inhibition. PCI-34051 protected HDAC8-deficient mouse neurons from oxidative stress, and a methylated derivative of PCI-34051 that lacked HDAC-inhibitory action protected wild-type neurons. The neuroprotective effects of these molecules apparently depended on the presence of a metal-chelating hydroxamic acid moiety that is present in many HDAC inhibitors. Johann du Hoffmann and Saleem M. Nicola The Journal of Neuroscience October 22, 2014 • Volume 34 Number 43 • www.jneurosci.org i This Week in The Journal Journal Club 14165 Jnk1 Activity is Indispensable for Appropriate Cortical Interneuron Migration in the Developing Cerebral Cortex J. Jacob Riches and Kathryn Reynolds 14167 Decoding the Role of the Angular Gyrus in the Subjective Experience of Recollection Alexandra Trelle Brief Communications Cover legend: A Voronoi decomposition of sleep state-space derived from an electroencephalographic (EEG) recording made in a naturally sleeping rat. A sleep state-space is a two-dimensional scatter plot bounded by EEG variables that correlate with sleep– wake state, in which the position of a single point represents the EEG state of the forebrain during a single recording epoch. A Voronoi decomposition partitions the state space into individual cells, each enclosing a single point; cell area is inversely proportional to local point density (coded by color). Two clusters are visible. The top left cluster represents rapid eye movement (REM) sleep while the bottom right cluster consists of non-REM sleep data points. This technique is used in the analysis of non-REM-toREM sleep transition dynamics, which revealed that cholinergic inputs to the pontine REM sleep generator reinforce, but do not initiate, the generation of REM sleep (contrary to a long standing hypothesis in sleep neurobiology). For more details, see the article by Grace et al. (14198 –14209). 14318 Oscillatory Neuronal Activity Reflects Lexical-Semantic Feature Integration within and across Sensory Modalities in Distributed Cortical Networks Markus J. van Ackeren, Till R. Schneider, Kathrin Mu¨sch, and Shirley-Ann Rueschemeyer 14324 Magnetoencephalography of Epilepsy with a Microfabricated Atomic Magnetrode Orang Alem, Alex M. Benison, Daniel S. Barth, John Kitching, and Svenja Knappe Articles CELLULAR/MOLECULAR 䊉 14181 Perimenstrual-Like Hormonal Regulation of Extrasynaptic ␦-Containing GABAA Receptors Mediating Tonic Inhibition and Neurosteroid Sensitivity Chase Matthew Carver, Xin Wu, Omkaram Gangisetty, and Doodipala Samba Reddy 14210 Regulation of Presynaptic Ca2ⴙ, Synaptic Plasticity and Contextual Fear Conditioning by a N-terminal -Amyloid Fragment James L.M. Lawrence, Mei Tong, Naghum Alfulaij, Tessi Sherrin, Mark Contarino, Michael M. White, Frederick P. Bellinger, Cedomir Todorovic, and Robert A. Nichols 14243 Effects of HIV-1 Tat on Enteric Neuropathogenesis Joy Ngwainmbi, Dipanjana D. De, Tricia H. Smith, Nazira El-Hage, Sylvia Fitting, Minho Kang, William L. Dewey, Kurt F. Hauser, and Hamid I. Akbarali 14375 PGC-1␣ Provides a Transcriptional Framework for Synchronous Neurotransmitter Release from Parvalbumin-Positive Interneurons Elizabeth K. Lucas, Sarah E. Dougherty, Laura J. McMeekin, Courtney S. Reid, Lynn E. Dobrunz, Andrew B. West, John J. Hablitz, and Rita M. Cowell 14463 Mechanisms Underlying Desynchronization of Cholinergic-Evoked Thalamic Network Activity Juan Diego Pita-Almenar, Dinghui Yu, Hui-Chen Lu, and Michael Beierlein DEVELOPMENT/PLASTICITY/REPAIR 14288 Detecting Pairwise Correlations in Spike Trains: An Objective Comparison of Methods and Application to the Study of Retinal Waves Catherine S. Cutts and Stephen J. Eglen 14403 Repressing Notch Signaling and Expressing TNF␣ Are Sufficient to Mimic Retinal Regeneration by Inducing Mu¨ller Glial Proliferation to Generate Committed Progenitor Cells Clay Conner, Kristin M. Ackerman, Manuela Lahne, Joshua S. Hobgood, and David R. Hyde 14420 Does Trans-Spinal Direct Current Stimulation Alter Phrenic Motoneurons and Respiratory Neuromechanical Outputs in Humans? A Double-Blind, Sham-Controlled, Randomized, Crossover Study Marie-Ce´cile Nie´rat, Thomas Similowski, and Jean-Charles Lamy 14430 Adult Neurogenesis Restores Dopaminergic Neuronal Loss in the Olfactory Bulb Franc¸oise Lazarini, Marie-Madeleine Gabellec, Carine Moigneu, Fabrice de Chaumont, Jean-Christophe Olivo-Marin, and Pierre-Marie Lledo SYSTEMS/CIRCUITS 䊉 14170 Gravity Influences the Visual Representation of Object Tilt in Parietal Cortex Ari Rosenberg and Dora E. Angelaki 14198 Endogenous Cholinergic Input to the Pontine REM Sleep Generator Is Not Required for REM Sleep to Occur Kevin P. Grace, Lindsay E. Vanstone, and Richard L. Horner 14272 Short-Term Depression, Temporal Summation, and Onset Inhibition Shape Interval Tuning in Midbrain Neurons Christa A. Baker and Bruce A. Carlson 14365 Amygdala Inputs to the Prefrontal Cortex Elicit Heterosynaptic Suppression of Hippocampal Inputs Hugo A. Tejeda and Patricio O’Donnell 14388 A Contrast and Surface Code Explains Complex Responses to Black and White Stimuli in V1 Guy Zurawel, Inbal Ayzenshtat, Shay Zweig, Robert Shapley, and Hamutal Slovin 14475 Thalamomuscular Coherence in Essential Tremor: Hen or Egg in the Emergence of Tremor? David J. Pedrosa, Eva-Lotte Quatuor, Christiane Reck, K. Amande M. Pauls, Carlo A. Huber, Veerle Visser-Vandewalle, and Lars Timmermann BEHAVIORAL/COGNITIVE 䊉 14233 Medial Temporal Lobe Coding of Item and Spatial Information during Relational Binding in Working Memory Laura A. Libby, Deborah E. Hannula, and Charan Ranganath 14338 The Importance of Premotor Cortex for Supporting Speech Production after Left Capsular-Putaminal Damage Mohamed L. Seghier, Juliana Bagdasaryan, Dorit E. Jung, and Cathy J. Price 14349 Dopamine Invigorates Reward Seeking by Promoting Cue-Evoked Excitation in the Nucleus Accumbens Johann du Hoffmann and Saleem M. Nicola 14443 In the Blink of an Eye: Relating Positive-Feedback Sensitivity to Striatal Dopamine D2-Like Receptors through Blink Rate Stephanie M. Groman, Alex S. James, Emanuele Seu, Steven Tran, Taylor A. Clark, Sandra N. Harpster, Maverick Crawford, Joanna Lee Burtner, Karen Feiler, Robert H. Roth, John D. Elsworth, Edythe D. London, and James David Jentsch 14455 DCDC2 Polymorphism Is Associated with Left Temporoparietal Gray and White Matter Structures during Development Fahimeh Darki, Myriam Peyrard-Janvid, Hans Matsson, Juha Kere, and Torkel Klingberg NEUROBIOLOGY OF DISEASE 䊉 14219 Urokinase-Type Plasminogen Activator Promotes Dendritic Spine Recovery and Improves Neurological Outcome Following Ischemic Stroke Fang Wu, Marcela Catano, Ramiro Echeverry, Enrique Torre, Woldeab B. Haile, Jie An, Changhua Chen, Lihong Cheng, Andrew Nicholson, Frank C. Tong, Jaekeun Park, and Manuel Yepes 14252 Sex and Disease-Related Alterations of Anterior Insula Functional Connectivity in Chronic Abdominal Pain Jui-Yang Hong, Lisa A. Kilpatrick, Jennifer S. Labus, Arpana Gupta, David Katibian, Cody Ashe-McNalley, Jean Stains, Nuwanthi Heendeniya, Suzanne R. Smith, Kirsten Tillisch, Bruce Naliboff, and Emeran A. Mayer 14260 Cognitive Deterioration and Functional Compensation in ALS Measured with fMRI Using an Inhibitory Task Kelsey Witiuk, Juan Fernandez-Ruiz, Ryan McKee, Nadia Alahyane, Brian C. Coe, Michel Melanson, and Douglas P. Munoz 14304 Loss of Mitochondrial Fission Depletes Axonal Mitochondria in Midbrain Dopamine Neurons Amandine Berthet, Elyssa B. Margolis, Jue Zhang, Ivy Hsieh, Jiasheng Zhang, Thomas S. Hnasko, Jawad Ahmad, Robert H. Edwards, Hiromi Sesaki, Eric J. Huang, and Ken Nakamura 14328 Hydroxamic Acid-Based Histone Deacetylase (HDAC) Inhibitors Can Mediate Neuroprotection Independent of HDAC Inhibition Sama F. Sleiman, David E. Olson, Megan W. Bourassa, Saravanan S. Karuppagounder, Yan-Ling Zhang, Jennifer Gale, Florence F. Wagner, Manuela Basso, Giovanni Coppola, John T. Pinto, Edward B. Holson, and Rajiv R. Ratan 14484 Inhibiting ACAT1/SOAT1 in Microglia Stimulates Autophagy-Mediated Lysosomal Proteolysis and Increases A1– 42 Clearance Yohei Shibuya, Catherine C.Y. Chang, Li-Hao Huang, Elena Y. Bryleva, and Ta-Yuan Chang 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, jn@sfn.org. BRIEF COMMUNICATIONS Oscillatory Neuronal Activity Reflects Lexical-Semantic Feature Integration within and across Sensory Modalities in Distributed Cortical Networks Markus J. van Ackeren,1 X Till R. Schneider,2 Kathrin Mu¨sch,2* and Shirley-Ann Rueschemeyer1* Department of Psychology, University of York, York YO10 5DD, United Kingdom, and 2Department of Neurophysiology and Pathophysiology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany 1 Research from the previous decade suggests that word meaning is partially stored in distributed modality-specific cortical networks. However, little is known about the mechanisms by which semantic content from multiple modalities is integrated into a coherent multisensory representation. Therefore we aimed to characterize differences between integration of lexical-semantic information from a single modality compared with two sensory modalities. We used magnetoencephalography in humans to investigate changes in oscillatory neuronal activity while participants verified two features for a given target word (e.g., “bus”). Feature pairs consisted of either two features from the same modality (visual: “red,” “big”) or different modalities (auditory and visual: “red,” “loud”). The results suggest that integrating modality-specific features of the target word is associated with enhanced high-frequency power (80 –120 Hz), while integrating features from different modalities is associated with a sustained increase in low-frequency power (2– 8 Hz). Source reconstruction revealed a peak in the anterior temporal lobe for low-frequency and high-frequency effects. These results suggest that integrating lexical-semantic knowledge at different cortical scales is reflected in frequency-specific oscillatory neuronal activity in unisensory and multisensory association networks. The Journal of Neuroscience, October 22, 2014 • 34(43):14318 –14323 Magnetoencephalography of Epilepsy with a Microfabricated Atomic Magnetrode X Orang Alem,2 Alex M. Benison,1 Daniel S. Barth,1 John Kitching,2 and Svenja Knappe1,2 Department of Psychology and Neuroscience, University of Colorado, Boulder, Colorado 80309, and 2Time and Frequency Division, National Institute of Standards and Technology, Boulder, Colorado 80305 1 Magnetoencephalography has long held the promise of providing a noninvasive tool for localizing epileptic seizures in humans because of its high spatial resolution compared with the scalp EEG. Yet, this promise has been elusive, not because of a lack of sensitivity or spatial resolution but because the large size and immobility of present cryogenic (superconducting) technology prevent long-term telemetry required to capture these very infrequent epileptiform events. To circumvent this limitation, we used Micro-Electro-Mechanical Systems technology to construct a noncryogenic (room temperature) microfabricated atomic magnetometer (“magnetrode”) based on laser spectroscopy of rubidium vapor and similar in size and flexibility to scalp EEG electrodes. We tested the magnetrode by measuring the magnetic signature of epileptiform discharges in a rat model of epilepsy. We were able to measure neuronal currents of single epileptic discharges and more subtle spontaneous brain activity with a high signal-to-noise ratio approaching that of present superconducting sensors. These measurements are a promising step toward the goal of high-resolution noninvasive telemetry of epileptic events in humans with seizure disorders. The Journal of Neuroscience, October 22, 2014 • 34(43):14324 –14327 Articles CELLULAR/MOLECULAR Perimenstrual-Like Hormonal Regulation of Extrasynaptic ␦-Containing GABAA Receptors Mediating Tonic Inhibition and Neurosteroid Sensitivity Chase Matthew Carver, Xin Wu, Omkaram Gangisetty, and Doodipala Samba Reddy Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M University Health Science Center, Bryan, Texas 77807 Neurosteroids are endogenous regulators of neuronal excitability and seizure susceptibility. Neurosteroids, such as allopregnanolone (AP; 3␣-hydroxy-5␣-pregnan-20-one), exhibit enhanced anticonvulsant activity in perimenstrual catamenial epilepsy, a neuroendocrine condition in which seizures are clustered around the menstrual period associated with neurosteroid withdrawal (NSW). However, the molecular mechanisms underlying such enhanced neurosteroid sensitivity remain unclear. Neurosteroids are allosteric modulators of both synaptic (␣␥2-containing) and extrasynaptic (␣␦-containing) GABAA receptors, but they display greater sensitivity toward ␦-subunit receptors in dentate gyrus granule cells (DGGCs). Here we report a novel plasticity of extrasynaptic ␦-containing GABAA receptors in the dentate gyrus in a mouse perimenstrual-like model of NSW. In molecular and immunofluorescence studies, a significant increase occurred in ␦ subunits, but not ␣1 , ␣2 , 2 , and ␥2 subunits, in the dentate gyrus of NSW mice. Electrophysiological studies confirmed enhanced sensitivity to AP potentiation of GABA-gated currents in DGGCs, but not in CA1 pyramidal cells, in NSW animals. AP produced a greater potentiation of tonic currents in DGGCs of NSW animals, and such enhanced AP sensitivity was not evident in ␦-subunit knock-out mice subjected to a similar withdrawal paradigm. In behavioral studies, mice undergoing NSW exhibited enhanced seizure susceptibility to hippocampus kindling. AP has enhanced anticonvulsant effects in fully kindled wild-type mice, but not ␦-subunit knock-out mice, undergoing NSW-induced seizures, confirming ␦-linked neurosteroid sensitivity. These results indicate that perimenstrual NSW is associated with striking upregulation of extrasynaptic, ␦-containing GABAA receptors that mediate tonic inhibition and neurosteroid sensitivity in the dentate gyrus. These findings may represent a molecular rationale for neurosteroid therapy of catamenial epilepsy. The Journal of Neuroscience, October 22, 2014 • 34(43):14181–14197 Regulation of Presynaptic Ca2⫹, Synaptic Plasticity and Contextual Fear Conditioning by a Nterminal -Amyloid Fragment James L.M. Lawrence,1* Mei Tong,1,2* Naghum Alfulaij,1 Tessi Sherrin,1 Mark Contarino,3 Michael M. White,3 Frederick P. Bellinger,1 Cedomir Todorovic,1 and Robert A. Nichols1 Department of Cell and Molecular Biology, University of Hawai’i at Manoa, Honolulu, Hawaii 96813, and Departments of 2Pharmacology and Physiology and 3Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102 1 Soluble -amyloid has been shown to regulate presynaptic Ca 2⫹ and synaptic plasticity. In particular, picomolar -amyloid was found to have an agonist-like action on presynaptic nicotinic receptors and to augment long-term potentiation (LTP) in a manner dependent upon nicotinic receptors. Here, we report that a functional N-terminal domain exists within -amyloid for its agonist-like activity. This sequence corresponds to a N-terminal fragment generated by the combined action of ␣- and -secretases, and resident carboxypeptidase. The N-terminal -amyloid fragment is present in the brains and CSF of healthy adults as well as in Alzheimer’s patients. Unlike full-length -amyloid, the N-terminal -amyloid fragment is monomeric and nontoxic. In Ca 2⫹ imaging studies using a model reconstituted rodent neuroblastoma cell line and isolated mouse nerve terminals, the N-terminal -amyloid fragment proved to be highly potent and more effective than full-length -amyloid in its agonist-like action on nicotinic receptors. In addition, the N-terminal -amyloid fragment augmented theta burst-induced post-tetanic potentiation and LTP in mouse hippocampal slices. The N-terminal fragment also rescued LTP inhibited by elevated levels of full-length -amyloid. Contextual fear conditioning was also strongly augmented following bilateral injection of N-terminal -amyloid fragment into the dorsal hippocampi of intact mice. The fragment-induced augmentation of fear conditioning was attenuated by coadministration of nicotinic antagonist. The activity of the N-terminal -amyloid fragment appears to reside largely in a sequence surrounding a putative metal binding site, YEVHHQ. These findings suggest that the N-terminal -amyloid fragment may serve as a potent and effective endogenous neuromodulator. The Journal of Neuroscience, October 22, 2014 • 34(43):14210 –14218 Effects of HIV-1 Tat on Enteric Neuropathogenesis Joy Ngwainmbi, Dipanjana D. De, Tricia H. Smith, Nazira El-Hage, X Sylvia Fitting, X Minho Kang, William L. Dewey, X Kurt F. Hauser, and Hamid I. Akbarali Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia 23298 The gastrointestinal (GI) tract presents a major site of immune modulation by HIV, resulting in significant morbidity. Most GI processes affected during HIV infection are regulated by the enteric nervous system. HIV has been identified in GI histologic specimens in up to 40% of patients, and the presence of viral proteins, including the trans-activator of transcription (Tat), has been reported in the gut indicating that HIV itself may be an indirect gut pathogen. Little is known of how Tat affects the enteric nervous system. Here we investigated the effects of the Tat protein on enteric neuronal excitability, proinflammatory cytokine release, and its overall effect on GI motility. Direct application of Tat (100 nM) increased the number of action potentials and reduced the threshold for action potential initiation in isolated myenteric neurons. This effect persisted in neurons pretreated with Tat for 3 d (19 of 20) and in neurons isolated from Tat ⫹ (Tat-expressing) transgenic mice. Tat increased sodium channel isoforms Nav1.7 and Nav1.8 levels. This increase was accompanied by an increase in sodium current density and a leftward shift in the sodium channel activation voltage. RANTES, IL-6, and IL-1, but not TNF-␣, were enhanced by Tat. Intestinal transit and cecal water content were also significantly higher in Tat ⫹ transgenic mice than Tat ⫺ littermates (controls). Together, these findings show that Tat has a direct and persistent effect on enteric neuronal excitability, and together with its effect on proinflammatory cytokines, regulates gut motility, thereby contributing to GI dysmotilities reported in HIV patients. The Journal of Neuroscience, October 22, 2014 • 34(43):14243–14251 PGC-1␣ Provides a Transcriptional Framework for Synchronous Neurotransmitter Release from Parvalbumin-Positive Interneurons Elizabeth K. Lucas,1 Sarah E. Dougherty,1 Laura J. McMeekin,1 Courtney S. Reid,1 Lynn E. Dobrunz,2 Andrew B. West,3 John J. Hablitz,2 and X Rita M. Cowell1 Departments of 1Psychiatry and Behavioral Neurobiology, 2Neurobiology, and 3Neurology, University of Alabama at Birmingham, Birmingham, Alabama 35294 Accumulating evidence strongly implicates the transcriptional coactivator peroxisome proliferator-activated receptor ␥ coactivator 1␣ (PGC-1␣) in the pathophysiology of multiple neurological disorders, but the downstream gene targets of PGC-1␣ in the brain have remained enigmatic. Previous data demonstrate that PGC-1␣ is primarily concentrated in inhibitory neurons and that PGC-1␣ is required for the expression of the interneuron-specific Ca 2⫹-binding protein parvalbumin (PV) throughout the cortex. To identify other possible transcriptional targets of PGC-1␣ in neural tissue, we conducted a microarray on neuroblastoma cells overexpressing PGC-1␣, mined results for genes with physiological relevance to interneurons, and measured cortical gene and protein expression of these genes in mice with underexpression and overexpression of PGC-1␣. We observed bidirectional regulation of novel PGC-1␣-dependent transcripts spanning synaptic [synaptotagmin 2 (Syt2) and complexin 1 (Cplx1)], structural [neurofilament heavy chain (Nefh)], and metabolic [neutral cholesterol ester hydrolase 1 (Nceh1), adenylate kinase 1 (Ak1), inositol polyphosphate 5-phosphatase J (Inpp5j), ATP synthase mitochondrial F1 complex O subunit (Atp5o), phytanol-CoA-2hydroxylase (Phyh), and ATP synthase mitrochondrial F1 complex ␣ subunit 1 (Atp5a1)] functions. The neuron-specific genes Syt2, Cplx1, and Nefh were developmentally upregulated in an expression pattern consistent with that of PGC-1␣ and were expressed in cortical interneurons. Conditional deletion of PGC-1␣ in PV-positive neurons significantly decreased cortical transcript expression of these genes, promoted asynchronous GABA release, and impaired long-term memory. Collectively, these data demonstrate that PGC-1␣ is required for normal PV-positive interneuron function and that loss of PGC-1␣ in this interneuron subpopulation could contribute to cortical dysfunction in disease states. The Journal of Neuroscience, October 22, 2014 • 34(43):14375–14387 Mechanisms Underlying Desynchronization of Cholinergic-Evoked Thalamic Network Activity Juan Diego Pita-Almenar,1 Dinghui Yu,2,3 Hui-Chen Lu,2,3,4 and Michael Beierlein1 Department of Neurobiology and Anatomy, University of Texas Medical School, Houston, Texas 77030, 2The Cain Foundation Laboratories, Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, 3Department of Pediatrics, and 4Program in Developmental Biology, Department of Neuroscience, Baylor College of Medicine, Houston, Texas 77030 1 Synchronous neuronal activity in the thalamocortical system is critical for a number of behaviorally relevant computations, but hypersynchrony can limit information coding and lead to epileptiform responses. In the somatosensory thalamus, afferent inputs are transformed by networks of reciprocally connected thalamocortical neurons in the ventrobasal nucleus (VB) and GABAergic neurons in the thalamic reticular nucleus (TRN). These networks can generate oscillatory activity, and studies in vivo and in vitro have suggested that thalamic oscillations are often accompanied by synchronous neuronal activity, in part mediated by widespread divergence and convergence of both reticulothalamic and thalamoreticular pathways, as well as by electrical synapses interconnecting TRN neurons. However, the functional organization of thalamic circuits and its role in shaping input-evoked activity patterns remain poorly understood. Here we show that optogenetic activation of cholinergic synaptic afferents evokes near-synchronous firing in mouse TRN neurons that is rapidly desynchronized in thalamic networks. We identify several mechanisms responsible for desynchronization: (1) shared inhibitory inputs in local VB neurons leading to asynchronous and imprecise rebound bursting; (2) TRN-mediated lateral inhibition that further desynchronizes firing in the VB; and (3) powerful yet sparse thalamoreticular connectivity that mediates re-excitation of the TRN but preserves asynchronous firing. Our findings reveal how distinct local circuit features interact to desynchronize thalamic network activity. The Journal of Neuroscience, October 22, 2014 • 34(43):14463–14474 DEVELOPMENT/PLASTICITY/REPAIR Detecting Pairwise Correlations in Spike Trains: An Objective Comparison of Methods and Application to the Study of Retinal Waves Catherine S. Cutts and X Stephen J. Eglen Cambridge Computational Biology Institute Department of Applied Mathematics and Theoretical Physics, University of Cambridge, Cambridge CB3 0WA, United Kingdom Correlations in neuronal spike times are thought to be key to processing in many neural systems. Many measures have been proposed to summarize these correlations and of these the correlation index is widely used and is the standard in studies of spontaneous retinal activity. We show that this measure has two undesirable properties: it is unbounded above and confounded by firing rate. We list properties needed for a measure to fairly quantify and compare correlations and we propose a novel measure of correlation—the spike time tiling coefficient. This coefficient, the correlation index, and 33 other measures of correlation of spike times are blindly tested for the required properties on synthetic and experimental data. Based on this, we propose a measure (the spike time tiling coefficient) to replace the correlation index. To demonstrate the benefits of this measure, we reanalyze data from seven key studies, which previously used the correlation index to investigate the nature of spontaneous activity. We reanalyze data from 2(KO) and 2(TG) mutants, mutants lacking connexin isoforms, and also the age-dependent changes in wild-type and 2(KO) correlations. Reanalysis of the data using the proposed measure can significantly change the conclusions. It leads to better quantification of correlations and therefore better inference from the data. We hope that the proposed measure will have wide applications, and will help clarify the role of activity in retinotopic map formation. The Journal of Neuroscience, October 22, 2014 • 34(43):14288 –14303 Repressing Notch Signaling and Expressing TNF␣ Are Sufficient to Mimic Retinal Regeneration by Inducing Mu¨ller Glial Proliferation to Generate Committed Progenitor Cells Clay Conner, Kristin M. Ackerman, Manuela Lahne, Joshua S. Hobgood, and David R. Hyde Department of Biological Sciences and the Center for Zebrafish Research, Galvin Life Sciences Building, University of Notre Dame, Notre Dame, Indiana 46556 Retinal damage in teleosts, unlike mammals, induces robust Mu¨ller glia-mediated regeneration of lost neurons. We examined whether Notch signaling regulates Mu¨ller glia proliferation in the adult zebrafish retina and demonstrated that Notch signaling maintains Mu¨ller glia in a quiescent state in the undamaged retina. Repressing Notch signaling, through injection of the ␥-secretase inhibitor RO4929097, stimulates a subset of Mu¨ller glia to reenter the cell cycle without retinal damage. This RO4929097induced Mu¨ller glia proliferation is mediated by repressing Notch signaling because inducible expression of the Notch Intracellular Domain (NICD) can reverse the effect. This RO4929097-induced proliferation requires Ascl1a expression and Jak1-mediated Stat3 phosphorylation/activation, analogous to the light-damaged retina. Moreover, coinjecting RO4929097 and TNF␣, a previously identified damage signal, induced the majority of Mu¨ller glia to reenter the cell cycle and produced proliferating neuronal progenitor cells that committed to a neuronal lineage in the undamaged retina. This demonstrates that repressing Notch signaling and activating TNF␣ signaling are sufficient to induce Mu¨ller glia proliferation that generates neuronal progenitor cells that differentiate into retinal neurons, mimicking the responses observed in the regenerating retina. The Journal of Neuroscience, October 22, 2014 • 34(43):14403–14419 Does Trans-Spinal Direct Current Stimulation Alter Phrenic Motoneurons and Respiratory Neuromechanical Outputs in Humans? A Double-Blind, Sham-Controlled, Randomized, Crossover Study Marie-Ce´cile Nie´rat,1,2 Thomas Similowski,1,2,3 and Jean-Charles Lamy4 Sorbonne Universite´s, Universite´ Pierre et Marie Curie (UPMC) Univ. Paris 06, UMR_S 1158, Neurophysiologie Respiratoire Expe´rimentale et Clinique, F-75005 Paris, France, 2Institut National de la Sante´ et de la Recherche Me´dicale (Inserm), UMR S 1158, Neurophysiologie Respiratoire Expe´rimentale et Clinique, F-75005 Paris, France, 3Assistance Publique–Hôpitaux de Paris, Groupe Hospitalier Pitie´-Salpeˆtrie`re Charles Foix, Service de Pneumologie et Re´animation Me´dicale (de´partement R3S), F-75013 Paris, France, and 4Inserm U 1127, CNRS UMR 7225, Sorbonne Universite´s, UPMC Univ. Paris 06, UMR S 1127, Institut du Cerveau et de la Moelle ´epinie`re, Centre de Neuro-imagerie de Recherche, F-75013 Paris, France 1 Although compelling evidence has demonstrated considerable neuroplasticity in the respiratory control system, few studies have explored the possibility of altering descending projections to phrenic motoneurons (PMNs) using noninvasive stimulation protocols. The present study was designed to investigate the immediate and long-lasting effects of a single session of transcutaneous spinal direct current stimulation (tsDCS), a promising technique for modulating spinal cord functions, on descending ventilatory commands in healthy humans. Using a double-blind, controlled, randomized, crossover approach, we examined the effects of anodal, cathodal, and sham tsDCS delivered to the C3–C5 level on (1) diaphragm motor-evoked potentials (DiMEPs) elicited by transcranial magnetic stimulation and (2) spontaneous ventilation, as measured by respiratory inductance plethysmography. Both anodal and cathodal tsDCS induced a progressive increase in DiMEP amplitude during stimulation that persisted for at least 15 min after current offset. Interestingly, cathodal, but not anodal, tsDCS induced a persistent increase in tidal volume. In addition, (1) short-interval intracortical inhibition, (2) nonlinear complexity of the tidal volume signal (related to medullary ventilatory command), (3) autonomic function, and (4) compound muscle action potentials evoked by cervical magnetic stimulation were unaffected by tsDCS. This suggests that tsDCS-induced aftereffects did not occur at brainstem or cortical levels and were likely not attributable to direct polarization of cranial nerves or ventral roots. Instead, we argue that tsDCS could induce sustained changes in PMN output. Increased tidal volume after cathodal tsDCS opens up the perspective of harnessing respiratory neuroplasticity as a therapeutic tool for the management of several respiratory disorders. The Journal of Neuroscience, October 22, 2014 • 34(43):14420 –14429 Adult Neurogenesis Restores Dopaminergic Neuronal Loss in the Olfactory Bulb Franc¸oise Lazarini,1,2 Marie-Madeleine Gabellec,1,2 Carine Moigneu,1,2 Fabrice de Chaumont,3,4 Jean-Christophe Olivo-Marin,3,4 and Pierre-Marie Lledo1,2 1Institut Pasteur, Laboratory for Perception and Memory, F-75015 Paris, France, 2Centre National de la Recherche Scientifique, Unite ´ Mixte de Recherche 3571, F-75015 Paris, France, 3Institut Pasteur, Unite´ d’Analyse d’Images Quantitative, F-75015 Paris, France, and 4Centre National de la Recherche Scientifique, Unite´ de Recherche Associe´e 2582, F-75015 Paris, France Subventricular zone (SVZ) neurogenesis continuously provides new GABA- and dopamine (DA)-containing interneurons for the olfactory bulb (OB) in most adult mammals. DAergic interneurons are located in the glomerular layer (GL) where they participate in the processing of sensory inputs. To examine whether adult neurogenesis might contribute to regeneration after circuit injury in mice, we induce DAergic neuronal loss by injecting 6-hydroxydopamine (6-OHDA) in the dorsal GL or in the right substantia nigra pars compacta. We found that a 6-OHDA treatment of the OB produces olfactory deficits and local inflammation and partially decreases the number of neurons expressing the enzyme tyrosine hydroxylase (TH) near the injected site. Blockade of inflammation by minocycline treatment immediately after the 6-OHDA administration rescued neither TH ⫹ interneuron number nor the olfactory deficits, suggesting that the olfactory impairments are most likely linked to TH ⫹ cell death and not to microglial activation. TH ⫹ interneuron number was restored 1 month later. This rescue resulted at least in part from enhanced recruitment of immature neurons targeting the lesioned GL area. Seven days after 6-OHDA lesion in the OB, we found that the integration of lentivirus-labeled adult-born neurons was biased: newly formed neurons were preferentially incorporated into glomerular circuits of the lesioned area. Behavioral rehabilitation occurs 2 months after lesion. This study establishes a new model into which loss of DAergic cells could be compensated by recruiting newly formed neurons. We propose that adult neurogenesis not only replenishes the population of DAergic bulbar neurons but that it also restores olfactory sensory processing. The Journal of Neuroscience, October 22, 2014 • 34(43):14430 –14442 SYSTEMS/CIRCUITS Gravity Influences the Visual Representation of Object Tilt in Parietal Cortex X Ari Rosenberg and Dora E. Angelaki Department of Neuroscience, Baylor College of Medicine, Houston, Texas 77030 Sensory systems encode the environment in egocentric (e.g., eye, head, or body) reference frames, creating inherently unstable representations that shift and rotate as we move. However, it is widely speculated that the brain transforms these signals into an allocentric, gravity-centered representation of the world that is stable and independent of the observer’s spatial pose. Where and how this representation may be achieved is currently unknown. Here we demonstrate that a subpopulation of neurons in the macaque caudal intraparietal area (CIP) visually encodes object tilt in nonegocentric coordinates defined relative to the gravitational vector. Neuronal responses to the tilt of a visually presented planar surface were measured with the monkey in different spatial orientations (upright and rolled left/right ear down) and then compared. This revealed a continuum of representations in which planar tilt was encoded in a gravity-centered reference frame in approximately one-tenth of the comparisons, intermediate reference frames ranging between gravity-centered and egocentric in approximately two-tenths of the comparisons, and in an egocentric reference frame in less than half of the comparisons. Altogether, almost half of the comparisons revealed a shift in the preferred tilt and/or a gain change consistent with encoding object orientation in nonegocentric coordinates. Through neural network modeling, we further show that a purely gravity-centered representation of object tilt can be achieved directly from the population activity of CIP-like units. These results suggest that area CIP may play a key role in creating a stable, allocentric representation of the environment defined relative to an “earth-vertical” direction. The Journal of Neuroscience, October 22, 2014 • 34(43):14170 –14180 Endogenous Cholinergic Input to the Pontine REM Sleep Generator Is Not Required for REM Sleep to Occur X Kevin P. Grace,1 Lindsay E. Vanstone,2 and Richard L. Horner1,2 Departments of 1Medicine and 2Physiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada Initial theories of rapid eye movement (REM) sleep generation posited that induction of the state required activation of the pontine subceruleus (SubC) by cholinergic inputs. Although the capacity of cholinergic neurotransmission to contribute to REM sleep generation has been established, the role of cholinergic inputs in the generation of REM sleep is ultimately undetermined as the critical test of this hypothesis (local blockade of SubC acetylcholine receptors) has not been rigorously performed. We used bilateral microdialysis in freely behaving rats (n ⫽ 32), instrumented for electroencephalographic and electromyographic recording, to locally manipulate neurotransmission in the SubC with select drugs. As predicted, combined microperfusion of D-AP5 (glutamate receptor antagonist) and muscimol (GABAA receptor agonist) in the SubC virtually eliminated REM sleep. However, REM sleep was not reduced by scopolamine microperfusion in this same region, at a concentration capable of blocking the effects of cholinergic receptor stimulation. This result suggests that transmission of REM sleep drive to the SubC is acetylcholine-independent. Although SubC cholinergic inputs are not majorly involved in REM sleep generation, they may perform a minor function in the reinforcement of transitions into REM sleep, as evidenced by increases in non-REM-to-REM sleep transition duration and failure rate during cholinergic receptor blockade. Cholinergic receptor antagonism also attenuated the normal increase in hippocampal oscillations that characterize REM sleep. Using computational modeling, we show that our in vivo results are consistent with a mutually excitatory interaction between the SubC and cholinergic neurons where, importantly, cholinergic neuron activation is gated by SubC activity. The Journal of Neuroscience, October 22, 2014 • 34(43):14198 –14209 Short-Term Depression, Temporal Summation, and Onset Inhibition Shape Interval Tuning in Midbrain Neurons Christa A. Baker and Bruce A. Carlson Department of Biology, Washington University in St. Louis, St. Louis, Missouri 63130-4899 A variety of synaptic mechanisms can contribute to single-neuron selectivity for temporal intervals in sensory stimuli. However, it remains unknown how these mechanisms interact to establish single-neuron sensitivity to temporal patterns of sensory stimulation in vivo. Here we address this question in a circuit that allows us to control the precise temporal patterns of synaptic input to interval-tuned neurons in behaviorally relevant ways. We obtained in vivo intracellular recordings under multiple levels of current clamp from midbrain neurons in the mormyrid weakly electric fish Brienomyrus brachyistius during stimulation with electrosensory pulse trains. To reveal the excitatory and inhibitory inputs onto interval-tuned neurons, we then estimated the synaptic conductances underlying responses. We found short-term depression in excitatory and inhibitory pathways onto all interval-tuned neurons. Short-interval selectivity was associated with excitation that depressed less than inhibition at short intervals, as well as temporally summating excitation. Long-interval selectivity was associated with long-lasting onset inhibition. We investigated tuning after separately nullifying the contributions of temporal summation and depression, and found the greatest diversity of interval selectivity among neurons when both mechanisms were at play. Furthermore, eliminating the effects of depression decreased sensitivity to directional changes in interval. These findings demonstrate that variation in depression and summation of excitation and inhibition helps to establish tuning to behaviorally relevant intervals in communication signals, and that depression contributes to neural coding of interval sequences. This work reveals for the first time how the interplay between short-term plasticity and temporal summation mediates the decoding of temporal sequences in awake, behaving animals. The Journal of Neuroscience, October 22, 2014 • 34(43):14272–14287 Amygdala Inputs to the Prefrontal Cortex Elicit Heterosynaptic Suppression of Hippocampal Inputs Hugo A. Tejeda1,2 and Patricio O’Donnell1,3 Department of Anatomy and Neurobiology, 2Program in Neuroscience/National Institutes of Health Graduate Partnership Program, and 3Department of Psychiatry, University of Maryland School of Medicine, Baltimore, Maryland 21201 1 Whereas cooperative communication between the hippocampus (HP) and prefrontal cortex (PFC) is critical for cognitive functions, an antagonistic relationship may exist between the basolateral amygdala (BLA) and PFC during emotional processing. As PFC neurons integrate information from converging excitatory BLA and HP inputs, we explored whether the ability of BLA inputs to evoke feedforward inhibition in the PFC affects converging HP synaptic inputs using in vivo intracellular recordings in anesthetized rats. BLA train stimulation decreased HP synaptic responses in the PFC in vivo. This effect was dependent on the timing of HP-evoked responses and the strength of BLA activation. BLA train stimulation also produced heterosynaptic suppression of responses from the amygdalo-piriform cortex, an associative temporal cortical structure. Heterosynaptic suppression was unidirectional as HP trains failed to modify BLA synaptic responses. These findings provide a mechanism by which BLA activation could decrease PFC neural activity and transiently attenuate the HP influence on PFC function. The Journal of Neuroscience, October 22, 2014 • 34(43):14365–14374 A Contrast and Surface Code Explains Complex Responses to Black and White Stimuli in V1 Guy Zurawel,1 Inbal Ayzenshtat,1 Shay Zweig,1 Robert Shapley,2 and Hamutal Slovin1 The Gonda Multidisciplinary Brain Research Center, Bar-Ilan University, 52900 Ramat Gan, Israel and 2Center for Neural Science, New York University, New York, New York 10003 1 We investigated the cortical mechanisms underlying the visual perception of luminance-defined surfaces and the preference for black over white stimuli in the macaque primary visual cortex, V1. We measured V1 population responses with voltage-sensitive dye imaging in fixating monkeys that were presented with white or black squares of equal contrast around a mid-gray. Regions corresponding to the squares’ edges exhibited higher activity than those corresponding to the center. Responses to black were higher than to white, surprisingly to a much greater extent in the representation of the square’s center. Additionally, the square-evoked activation patterns exhibited spatial modulations along the edges and corners. A model comprised of neural mechanisms that compute local contrast, local luminance temporal modulations in the black and white directions, and cortical center-surround interactions, could explain the observed population activity patterns in detail. The model captured the weaker contribution of V1 neurons that respond to positive (white) and negative (black) luminance surfaces, and the stronger contribution of V1 neurons that respond to edge contrast. Also, the model demonstrated how the response preference for black could be explained in terms of stronger surface-related activation to negative luminance modulation. The spatial modulations along the edges were accounted for by surround suppression. Overall the results reveal the relative strength of edge contrast and surface signals in the V1 response to visual objects. The Journal of Neuroscience, October 22, 2014 • 34(43):14388 –14402 Thalamomuscular Coherence in Essential Tremor: Hen or Egg in the Emergence of Tremor? X David J. Pedrosa,1 X Eva-Lotte Quatuor,1 Christiane Reck,1 K. Amande M. Pauls,1 Carlo A. Huber,1 Veerle Visser-Vandewalle,2 and Lars Timmermann1 1 Department of Neurology and 2Department of Stereotactic and Functional Neurosurgery, University Hospital Cologne, 50924 Cologne, Germany Thalamomuscular coherence in essential tremor (ET) has consistently been detected in numerous neurophysiological studies. Thereby, spatial properties of coherence indicate a differentiated, somatotopic organization; so far, however, little attention has been paid to temporal aspects of this interdependency. Further insight into the relationship between tremor onset and the onset of coherence could pave the way to more efficient deep brain stimulation (DBS) algorithms for tremor. We studied 10 severely affected ET patients (six females, four males) during surgery for DBS-electrode implantation and simultaneously recorded local field potentials (LFPs) and surface electromyographic signals (EMGs) from the extensor and flexor muscles of the contralateral forearm during its elevation. The temporal relationship between the onset of significant wavelet cross spectrum (WCS) and tremor onset was determined. Moreover, we examined the influence of electrode location within one recording depth on this latency and the coincidence of coherence and tremor for depths with strong overall coherence (“tremor clusters”) and those without. Data analysis revealed tremor onset occurring 220 ⫾ 460 ms before the start of significant LFP-EMG coherence. Furthermore, we could detect an anterolateral gradient of WCS onset within one recording depth. Finally, the coincidence of tremor and coherence was significantly higher in tremor clusters. We conclude that tremor onset precedes the beginning of coherence. Besides, within one recording depth there is a spread of the tremor signal. This reflects the importance of somatosensory feedback for ET and questions the suitability of thalamomuscular coherence as a biomarker for “closed-loop” DBS systems to prevent tremor emergence. The Journal of Neuroscience, October 22, 2014 • 34(43):14475–14483 BEHAVIORAL/COGNITIVE Medial Temporal Lobe Coding of Item and Spatial Information during Relational Binding in Working Memory X Laura A. Libby,1 Deborah E. Hannula,3 and Charan Ranganath1,2 Department of Psychology and 2Center for Neuroscience, University of California, Davis, Davis, California 95618, and 3Department of Psychology, University of Wisconsin, Milwaukee, Milwaukee, Wisconsin 53211 1 Several models have proposed that different medial temporal lobe (MTL) regions represent different kinds of information in the service of long-term memory. For instance, it has been proposed that perirhinal cortex (PRC), parahippocampal cortex (PHC), and hippocampus differentially support long-term memory for item information, spatial context, and item– context relations present during an event, respectively. Recent evidence has indicated that, in addition to long-term memory, MTL subregions may similarly contribute to processes that support the retention of complex spatial arrangements of objects across short delays. Here, we used functional magnetic resonance imaging and multivoxel pattern similarity analysis to investigate the extent to which human MTL regions independently code for object and spatial information, as well as the conjunction of this information, during working memory encoding and active maintenance. Voxel activity patterns in PRC, temporopolar cortex, and amygdala carried information about individual objects, whereas activity patterns in the PHC and posterior hippocampus carried information about the configuration of spatial locations that was to be remembered. Additionally, the integrity of multivoxel patterns in the right anterior hippocampus across encoding and delay periods was predictive of accurate short-term memory for object–location relationships. These results are consistent with parallel processing of item and spatial context information by PRC and PHC, respectively, and the binding of item and context by the hippocampus. The Journal of Neuroscience, October 22, 2014 • 34(43):14233–14242 The Importance of Premotor Cortex for Supporting Speech Production after Left CapsularPutaminal Damage X Mohamed L. Seghier, Juliana Bagdasaryan, Dorit E. Jung, and Cathy J. Price Wellcome Trust Centre for Neuroimaging, Institute of Neurology, University College London, London, United Kingdom The left putamen is known to be important for speech production, but some patients with left putamen damage can produce speech remarkably well. We investigated the neural mechanisms that support this recovery by using a combination of techniques to identify the neural regions and pathways that compensate for loss of the left putamen during speech production. First, we used fMRI to identify the brain regions that were activated during reading aloud and picture naming in a patient with left putamen damage. This revealed that the patient had abnormally high activity in the left premotor cortex. Second, we used dynamic causal modeling of the patient’s fMRI data to understand how this premotor activity influenced other speech production regions and whether the same neural pathway was used by our 24 neurologically normal control subjects. Third, we validated the compensatory relationship between putamen and premotor cortex by showing, in the control subjects, that lower connectivity through the putamen increased connectivity through premotor cortex. Finally, in a lesion-deficit analysis, we demonstrate the explanatory power of our fMRI results in new patients who had damage to the left putamen, left premotor cortex, or both. Those with damage to both had worse reading and naming scores. The results of our four-pronged approach therefore have clinical implications for predicting which patients are more or less likely to recover their speech after left putaminal damage. The Journal of Neuroscience, October 22, 2014 • 34(43):14338 –14348 Dopamine Invigorates Reward Seeking by Promoting Cue-Evoked Excitation in the Nucleus Accumbens Johann du Hoffmann1 and Saleem M. Nicola1,2 Dominick P. Purpura Department of Neuroscience and 2Department of Psychiatry and Behavioral Science, Albert Einstein College of Medicine, New York, New York 10461 1 Approach to reward is a fundamental adaptive behavior, disruption of which is a core symptom of addiction and depression. Nucleus accumbens (NAc) dopamine is required for reward-predictive cues to activate vigorous reward seeking, but the underlying neural mechanism is unknown. Reward-predictive cues elicit both dopamine release in the NAc and excitations and inhibitions in NAc neurons. However, a direct link has not been established between dopamine receptor activation, NAc cue-evoked neuronal activity, and reward-seeking behavior. Here, we use a novel microelectrode array that enables simultaneous recording of neuronal firing and local dopamine receptor antagonist injection. We demonstrate that, in the NAc of rats performing a discriminative stimulus task for sucrose reward, blockade of either D1 or D2 receptors selectively attenuates excitation, but not inhibition, evoked by reward-predictive cues. Furthermore, we establish that this dopamine-dependent signal is necessary for reward-seeking behavior. These results demonstrate a neural mechanism by which NAc dopamine invigorates environmentally cued reward-seeking behavior. The Journal of Neuroscience, October 22, 2014 • 34(43):14349 –14364 In the Blink of an Eye: Relating Positive-Feedback Sensitivity to Striatal Dopamine D2-Like Receptors through Blink Rate Stephanie M. Groman,1,5,6 Alex S. James,1 Emanuele Seu,1 Steven Tran,1 Taylor A. Clark,1 Sandra N. Harpster,1 Maverick Crawford,1 Joanna Lee Burtner,1 Karen Feiler,1 Robert H. Roth,5,6 John D. Elsworth,5,6 Edythe D. London,2,3,4 and X James David Jentsch1,2,4 Departments of 1Psychology, 2Psychiatry and Biobehavioral Sciences, and 3Molecular and Medical Pharmacology and 4Brain Research Institute, University of California, Los Angeles, Los Angeles, California 90095, and Departments of 5Psychiatry and 6Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06510 For ⬎30 years, positron emission tomography (PET) has proven to be a powerful approach for measuring aspects of dopaminergic transmission in the living human brain; this technique has revealed important relationships between dopamine D2-like receptors and dimensions of normal behavior, such as human impulsivity, and psychopathology, particularly behavioral addictions. Nevertheless, PET is an indirect estimate that lacks cellular and functional resolution and, in some cases, is not entirely pharmacologically specific. To identify the relationships between PET estimates of D2-like receptor availability and direct in vitro measures of receptor number, affinity, and function, we conducted neuroimaging and behavioral and molecular pharmacological assessments in a group of adult male vervet monkeys. Data gathered from these studies indicate that variation in D2-like receptor PET measurements is related to reversal-learning performance and sensitivity to positive feedback and is associated with in vitro estimates of the density of functional dopamine D2-like receptors. Furthermore, we report that a simple behavioral measure, eyeblink rate, reveals novel and crucial links between neuroimaging assessments and in vitro measures of dopamine D2 receptors. The Journal of Neuroscience, October 22, 2014 • 34(43):14443–14454 DCDC2 Polymorphism Is Associated with Left Temporoparietal Gray and White Matter Structures during Development Fahimeh Darki,1 Myriam Peyrard-Janvid,2 Hans Matsson,2 Juha Kere,2,3,4 and Torkel Klingberg1 Department of Neuroscience, Karolinska Institutet, 171 77 Solna, Sweden, 2Department of Biosciences and Nutrition, Karolinska Institutet, 141 83 Huddinge, Sweden, 3Science for Life Laboratory, Karolinska Institutet, 171 77 Solna, Sweden, and 4Research Programs Unit, Haartman Institute, University of Helsinki, and Folkha¨lsan Institute of Genetics, 00014 Helsinki, Finland 1 Three genes, DYX1C1, DCDC2, and KIAA0319, have been previously associated with dyslexia, neuronal migration, and ciliary function. Three polymorphisms within these genes, rs3743204 (DYX1C1), rs793842 (DCDC2), and rs6935076 (KIAA0319) have also been linked to normal variability of left temporoparietal white matter volume connecting the middle temporal cortex to the angular and supramarginal gyri. Here, we assessed whether these polymorphisms are also related to the cortical thickness of the associated regions during childhood development using a longitudinal dataset of 76 randomly selected children and young adults who were scanned up to three times each, 2 years apart. rs793842 in DCDC2 was significantly associated with the thickness of left angular and supramarginal gyri as well as the left lateral occipital cortex. The cortex was significantly thicker for T-allele carriers, who also had lower white matter volume and lower reading comprehension scores. There was a negative correlation between white matter volume and cortical thickness, but only white matter volume predicted reading comprehension 2 years after scanning. These results show how normal variability in reading comprehension is related to gene, white matter volume, and cortical thickness in the inferior parietal lobe. Possibly, the variability of gray and white matter structures could both be related to the role of DCDC2 in ciliary function, which affects both neuronal migration and axonal outgrowth. The Journal of Neuroscience, October 22, 2014 • 34(43):14455–14462 NEUROBIOLOGY OF DISEASE Urokinase-Type Plasminogen Activator Promotes Dendritic Spine Recovery and Improves Neurological Outcome Following Ischemic Stroke Fang Wu,1* Marcela Catano,1* Ramiro Echeverry,1* Enrique Torre,1 Woldeab B. Haile,1 Jie An,1,2 Changhua Chen,1 Lihong Cheng,1 Andrew Nicholson,3 Frank C. Tong,4 Jaekeun Park,5 and X Manuel Yepes1,6 Department of Neurology and Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, Georgia 30322, 2Department of Pharmacology, Shandong University School of Medicine, 250100 Jinan, China, 3Department of Radiology and Imaging Sciences and 4Departments of Radiology and Neurosurgery, Emory University School of Medicine, Atlanta, Georgia 30322, 5Wallace H. Coulter Department of Biomedical Engineering, Emory University, Atlanta, Georgia 30322, and 6Department of Neurology, Veterans Affairs Medical Center, Atlanta, Georgia 30349 1 Spines are dendritic protrusions that receive most of the excitatory input in the brain. Early after the onset of cerebral ischemia dendritic spines in the peri-infarct cortex are replaced by areas of focal swelling, and their re-emergence from these varicosities is associated with neurological recovery after acute ischemic stroke (AIS). Urokinasetype plasminogen activator (uPA) is a serine proteinase that plays a central role in tissue remodeling via binding to the urokinase plasminogen activator receptor (uPAR). We report that cerebral cortical neurons release uPA during the recovery phase from ischemic stroke in vivo or hypoxia in vitro. Although uPA does not have an effect on ischemia- or hypoxia-induced neuronal death, genetic deficiency of uPA (uPA ⫺/⫺) or uPAR (uPAR ⫺/⫺) abrogates functional recovery after AIS. Treatment with recombinant uPA after ischemic stroke induces neurological recovery in wild-type and uPA ⫺/⫺ but not in uPAR ⫺/⫺ mice. Diffusion tensor imaging studies indicate that uPA ⫺/⫺ mice have increased water diffusivity and decreased anisotropy associated with impaired dendritic spine recovery and decreased length of distal neurites in the peri-infarct cortex. We found that the excitotoxic injury induces the clustering of uPAR in dendritic varicosities, and that the binding of uPA to uPAR promotes the reorganization of the actin cytoskeleton and re-emergence of dendritic filopodia from uPAR-enriched varicosities. This effect is independent of uPA’s proteolytic properties and instead is mediated by Rac-regulated profilin expression and cofilin phosphorylation. Our data indicate that binding of uPA to uPAR promotes dendritic spine recovery and improves functional outcome following AIS. The Journal of Neuroscience, October 22, 2014 • 34(43):14219 –14232 Sex and Disease-Related Alterations of Anterior Insula Functional Connectivity in Chronic Abdominal Pain Jui-Yang Hong,1,5,8 Lisa A. Kilpatrick,1,2,3,5 Jennifer S. Labus,1,2,3,4,5 Arpana Gupta,1,3,5 XDavid Katibian,1 X Cody Ashe-McNalley,1,2,3,5 Jean Stains,1,3,5 Nuwanthi Heendeniya,1,3,5 Suzanne R. Smith,1,3,5 Kirsten Tillisch,1,2,3,5 Bruce Naliboff,1,2,3,4,5 and X Emeran A. Mayer1,2,3,4,5,6,7 Gail and Gerald Oppenheimer Family Center for Neurobiology of Stress, 2Pain and Interoception Imaging Network, 3Department of Medicine, 4Brain Research Institute, 5Division of Digestive Diseases, 6Department of Psychiatry, 7Ahmanson Lovelace Brain Mapping Center, David Geffen School of Medicine, and 8Department of Bioengineering, University of California, Los Angeles, Los Angeles, California 90095 1 Resting-state functional magnetic resonance imaging has been used to investigate intrinsic brain connectivity in healthy subjects and patients with chronic pain. Sexrelated differences in the frequency power distribution within the human insula (INS), a brain region involved in the integration of interoceptive, affective, and cognitive influences, have been reported. Here we aimed to test sex and disease-related alterations in the intrinsic functional connectivity of the dorsal anterior INS. The anterior INS is engaged during goal-directed tasks and modulates the default mode and executive control networks. By comparing functional connectivity of the dorsal anterior INS in age-matched female and male healthy subjects and patients with irritable bowel syndrome (IBS), a common chronic abdominal pain condition, we show evidence for sex and disease-related alterations in the functional connectivity of this region: (1) male patients compared with female patients had increased positive connectivity of the dorsal anterior INS bilaterally with the medial prefrontal cortex (PFC) and dorsal posterior INS; (2) female patients compared with male patients had greater negative connectivity of the left dorsal anterior INS with the left precuneus; (3) disease-related differences in the connectivity between the bilateral dorsal anterior INS and the dorsal medial PFC were observed in female subjects; and (4) clinical characteristics were significantly correlated to the insular connectivity with the dorsal medial PFC in male IBS subjects and with the precuneus in female IBS subjects. These findings are consistent with the INS playing an important role in modulating the intrinsic functional connectivity of major networks in the resting brain and show that this role is influenced by sex and diagnosis. The Journal of Neuroscience, October 22, 2014 • 34(43):14252–14259 Cognitive Deterioration and Functional Compensation in ALS Measured with fMRI Using an Inhibitory Task Kelsey Witiuk,1* X Juan Fernandez-Ruiz,2* Ryan McKee,3 Nadia Alahyane,1 Brian C. Coe,1 Michel Melanson,3 and Douglas P. Munoz1,3,4,5 1Centre for Neuroscience Studies, Queen’s University, Kingston, Ontario K7L 3N6, Canada, 2Departamento de Fisiología, Facultad de Medicina, Universidad Nacional Auto´noma de Me´xico, Distrito Federal 04510, Me´xico, 3Department of Medicine, Division of Neurology, Queen’s University, Kingston, Ontario K7L 3N6, Canada, 4Department of Biomedical and Molecular Sciences, Queen’s University, Kingston, Ontario K7L 3N6, Canada, and 5Department of Psychology, Queen’s University, Kingston, Ontario K7L 3N6, Canada Amyotrophic lateral sclerosis (ALS) is characterized by degeneration of upper and lower motor neurons, resulting in progressive weakness and muscle atrophy. Recent studies suggest that nondemented ALS patients can show selective cognitive impairments, predominantly executive dysfunction, but little is known about the neural basis of these impairments. Oculomotor studies in ALS have described deficits in antisaccade execution, which requires the implementation of a task set that includes inhibition of automatic responses followed by generation of a voluntary action. It has been suggested that the dorsolateral prefrontal cortex (DLPFC) contributes in this process. Thus, we investigated whether deterioration of executive functions in ALS patients, such as the ability to implement flexible behavior during the antisaccade task, is related to DLPFC dysfunction. While undergoing an fMRI scan, 12 ALS patients and 12 age-matched controls performed an antisaccade task with concurrent eye tracking. We hypothesized that DLPFC deficits would appear during the antisaccade preparation stage, when the task set is being established. ALS patients made more antisaccade direction errors and showed significant reductions in DLPFC activation. In contrast, regions, such as supplementary eye fields and frontal eye fields, showed increased activation that was anticorrelated with the number of errors. The ALS group also showed reduced saccadic latencies that correlated with increased activation across the oculomotor saccade system. These findings suggest that ALS results in deficits in the inhibition of automatic responses that are related to impaired DLPFC activation. However, they also suggest that ALS patients undergo functional changes that partially compensate the neurological impairment. The Journal of Neuroscience, October 22, 2014 • 34(43):14260 –14271 Loss of Mitochondrial Fission Depletes Axonal Mitochondria in Midbrain Dopamine Neurons Amandine Berthet,1 Elyssa B. Margolis,2 Jue Zhang,1 Ivy Hsieh,6 X Jiasheng Zhang,6 Thomas S. Hnasko,4 Jawad Ahmad,1 Robert H. Edwards,2,3 Hiromi Sesaki,5 Eric J. Huang,3,6 and Ken Nakamura1,2,3 Gladstone Institute of Neurological Disease, San Francisco, California 94158, 2Department of Neurology and 3Graduate Programs in Neuroscience and Biomedical Sciences, University of California, San Francisco, San Francisco, California 94158, 4Department of Neurosciences, Translational Neurosciences Institute, University of California, San Diego, La Jolla, California 92093, 5Department of Cell Biology, School of Medicine, Johns Hopkins University, Baltimore, Maryland 21287, and 6Department of Pathology, University of California, San Francisco, San Francisco, California 94158 1 Disruptions in mitochondrial dynamics may contribute to the selective degeneration of dopamine (DA) neurons in Parkinson’s disease (PD). However, little is known about the normal functions of mitochondrial dynamics in these neurons, especially in axons where degeneration begins, and this makes it difficult to understand the disease process. To study one aspect of mitochondrial dynamics—mitochondrial fission—in mouse DA neurons, we deleted the central fission protein dynamin-related protein 1 (Drp1). Drp1 loss rapidly eliminates the DA terminals in the caudate–putamen and causes cell bodies in the midbrain to degenerate and lose ␣-synuclein. Without Drp1, mitochondrial mass dramatically decreases, especially in axons, where the mitochondrial movement becomes uncoordinated. However, in the ventral tegmental area (VTA), a subset of midbrain DA neurons characterized by small hyperpolarization-activated cation currents (Ih) is spared, despite near complete loss of their axonal mitochondria. Drp1 is thus critical for targeting mitochondria to the nerve terminal, and a disruption in mitochondrial fission can contribute to the preferential death of nigrostriatal DA neurons. The Journal of Neuroscience, October 22, 2014 • 34(43):14304 –14317 Hydroxamic Acid-Based Histone Deacetylase (HDAC) Inhibitors Can Mediate Neuroprotection Independent of HDAC Inhibition Sama F. Sleiman,1,3 David E. Olson,2 Megan W. Bourassa,3,4 Saravanan S. Karuppagounder,3,4 Yan-Ling Zhang,2 Jennifer Gale,2 Florence F. Wagner,2 Manuela Basso,5 Giovanni Coppola,6 John T. Pinto,7 Edward B. Holson,2 and X Rajiv R. Ratan1,2 Burke Medical Research Institute, White Plains, New York 10605, 2Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, New York 10021, 3Department of Natural Sciences, Lebanese American University, Byblos, Lebanon, 4Stanley Center for Psychiatric Research, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts 02142, 5Centre for Integrative Biology, University of Trento, Trento, Italy, 6Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California 90095, and 7Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, New York 10595 1 Histone deacetylase (HDAC) inhibition improves function and extends survival in rodent models of a host of neurological conditions, including stroke, and neurodegenerative diseases. Our understanding, however, of the contribution of individual HDAC isoforms to neuronal death is limited. In this study, we used selective chemical probes to assess the individual roles of the Class I HDAC isoforms in protecting Mus musculus primary cortical neurons from oxidative death. We demonstrated that the selective HDAC8 inhibitor PCI-34051 is a potent neuroprotective agent; and by taking advantage of both pharmacological and genetic tools, we established that HDAC8 is not critically involved in PCI-34051’s mechanism of action. We used BRD3811, an inactive ortholog of PCI-34051, and showed that, despite its inability to inhibit HDAC8, it exhibits robust neuroprotective properties. Furthermore, molecular deletion of HDAC8 proved insufficient to protect neurons from oxidative death, whereas both PCI-34051 and BRD3811 were able to protect neurons derived from HDAC8 knock-out mice. Finally, we designed and synthesized two new, orthogonal negative control compounds, BRD9715 and BRD8461, which lack the hydroxamic acid motif and showed that they stably penetrate cell membranes but are not neuroprotective. These results indicate that the protective effects of these hydroxamic acid-containing small molecules are likely unrelated to direct epigenetic regulation via HDAC inhibition, but rather due to their ability to bind metals. Our results suggest that hydroxamic acid-based HDAC inhibitors may mediate neuroprotection via HDAC-independent mechanisms and affirm the need for careful structure–activity relationship studies when using pharmacological approaches. The Journal of Neuroscience, October 22, 2014 • 34(43):14328 –14337 Inhibiting ACAT1/SOAT1 in Microglia Stimulates Autophagy-Mediated Lysosomal Proteolysis and Increases A1– 42 Clearance Yohei Shibuya, Catherine C.Y. Chang, Li-Hao Huang, Elena Y. Bryleva, and Ta-Yuan Chang Department of Biochemistry, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire 03755 Acyl-CoA:cholesterol acyltransferase 1 (ACAT1) is a resident endoplasmic reticulum enzyme that prevents the buildup of cholesterol in membranes by converting it to cholesterol esters. Blocking ACAT1 pharmacologically or by Acat1 gene knock-out (KO) decreases amyloidopathy in mouse models for Alzheimer’s disease. However, the beneficial actions of ACAT1 blockage to treat Alzheimer’s disease remained not well understood. Microglia play essential roles in the proteolytic clearance of amyloid  (A) peptides. Here we show that Acat1 gene KO in mouse increases phagocytic uptake of oligomeric A1– 42 and stimulates lysosomal A1– 42 degradation in cultured microglia and in vivo. Additional results show that Acat1 gene KO or a specific ACAT1 inhibitor K604 stimulates autophagosome formation and transcription factor EB-mediated lysosomal proteolysis. Surprisingly, the effect of ACAT1 blockage does not alter mTOR signaling or endoplasmic reticulum stress response but can be modulated by agents that disrupt cholesterol biosynthesis. To our knowledge, our current study provides the first example that a small molecule (K604) can promote autophagy in an mTOR-independent manner to activate the coordinated lysosomal expression and regulation network. Autophagy is needed to degrade misfolded proteins/peptides. Our results implicate that blocking ACAT1 may provide a new way to benefit multiple neurodegenerative diseases. The Journal of Neuroscience, October 22, 2014 • 34(43):14484 –14501
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