Journal of Neuroscience (J Neurosci)

Publications in this journal

• Article: Vision dominates at the pre-response level and audition dominates at the response level in cross-modal interaction: Behavioral and neural evidence

  Qi Chen, Xiaolin Zhou
  Journal of Neuroscience 07/2013;
• Article: Neural Context Reinstatement Predicts Memory Misattribution

  Samuel J. Gershman,, Anna C. Shapiro,, Almut Hupbach,, Kenneth A. Norman
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  ABSTRACT: What causes new information to be mistakenly attributed to an old experience? Some theories predict that reinstating the context of a prior experience allows new information to be bound to that context, leading to source memory confusion. To examine this prediction, we had human participants study two lists of items (visual objects) on separate days while undergoing functional magnetic resonance imaging. List 1 items were accompanied by a stream of scene images during the intertrial interval, but list 2 items were not. As in prior work by Hupbach et al. (2009), we observed an asymmetric pattern of misattributions on a subsequent source memory test: participants showed a strong tendency to misattribute list 2 items to list 1 but not vice versa. We hypothesized that these memory errors were due to participants reinstating the list 1 context during list 2. To test this hypothesis, we used a pattern classifier to measure scene-related neural activity during list 2 study. Because scenes were visually present during list 1 but not list 2, scene-related activity during list 2 study can be used as a time-varying neural indicator of how much participants were reinstating the list 1 context during list 2 study. In keeping with our hypothesis, we found that prestimulus scene activation during the study of list 2 items was significantly higher for items subsequently misattributed to list 1 than for items subsequently correctly attributed to list 2. We conclude by discussing how these findings relate to theories of memory reconsolidation.
  Journal of Neuroscience 05/2013; 33(20):8590-8595.
• Article: The Synchronous Activity of Lateral Habenular Neurons Is Essential for Regulating Hippocampal Theta Oscillation

  Hidenori Aizawa, Shin Yanagihara, Megumi Kobayashi, Kazue Niisato, Takashi Takekawa, Rie Harukuni, Thomas J. McHugh, Tomoki Fukai, Yoshikazu Isomura, Hitoshi Okamoto
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  ABSTRACT: Lateral habenula (LHb) has attracted growing interest as a regulator of serotonergic and dopaminergic neurons in the CNS. However, it remains unclear how the LHb modulates brain states in animals. To identify the neural substrates that are under the influence of LHb regulation, we examined the effects of rat LHb lesions on the hippocampal oscillatory activity associated with the transition of brain states. Our results showed that the LHb lesion shortened the theta activity duration both in anesthetized and sleeping rats. Furthermore, this inhibitory effect of LHb lesion on theta maintenance depended upon an intact serotonergic median raphe, suggesting that LHb activity plays an essential role in maintaining hippocampal theta oscillation via the serotonergic raphe. Multiunit recording of sleeping rats further revealed that firing of LHb neurons showed significant phase-locking activity at each theta oscillation cycle in the hippocampus. LHb neurons showing activity that was coordinated with that of the hippocampal theta were localized in the medial LHb division, which receives afferents from the diagonal band of Broca (DBB), a pacemaker region for the hippocampal theta oscillation. Thus, our findings indicate that the DBB may pace not only the hippocampus, but also the LHb, during rapid eye movement sleep. Since serotonin is known to negatively regulate theta oscillation in the hippocampus, phase-locking activity of the LHb neurons may act, under the influence of the DBB, to maintain the hippocampal theta oscillation by modulating the activity of serotonergic neurons.
  Journal of Neuroscience 05/2013; 33(20):8909-8921.
• Article: A novel activator of CBP/p300 acetyltransferases promotes neurogenesis and extends memory duration in adult mice

  Snehajyoti Chatterjee, Pushpak Mizar, Raphaelle Cassel, Romain Neidl, B. Ruthrotha Selvi, DV Mohankrishna, Bhusainahalli Vedamurthy, Anne Schneider, Olivier Bousiges, Chantal Mathis, Jean-Christophe Cassel, M Eswaramoorthy, Tapas Kundu, Anne-Laurence Boutillier
  Journal of Neuroscience 05/2013;
• Article: The Human Brain Processes Syntax in the Absence of Conscious Awareness

  Laura Batterink, Helen Neville
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  ABSTRACT: Syntax is the core computational component of language. A longstanding idea about syntactic processing is that it is generally not available to conscious access, operating autonomously and automatically. However, there is little direct neurocognitive evidence on this issue. By measuring event-related potentials while human observers performed a novel cross-modal distraction task, we demonstrated that syntactic violations that were not consciously detected nonetheless produced a characteristic early neural response pattern, and also significantly delayed reaction times to a concurrent task. This early neural response was distinct from later neural activity that was observed only to syntactic violations that were consciously detected. These findings provide direct evidence that the human brain reacts to violations of syntax even when these violations are not consciously detected, indicating that even highly complex computational processes such as syntactic processing can occur outside the narrow window of conscious awareness.
  Journal of Neuroscience 05/2013; 33(19):8528-8533.
• Article: Small-Molecule Screen in Adult Drosophila Identifies VMAT as a Regulator of Sleep.

  Aleksandra H Nall, Amita Sehgal
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  ABSTRACT: Sleep is an important physiological state, but its function and regulation remain elusive. In Drosophila melanogaster, a useful model organism for studying sleep, forward genetic screens have identified important sleep-modulating genes and pathways; however, the results of such screens may be limited by developmental abnormalities or lethality associated with mutation of certain genes. To circumvent these limitations, we used a small-molecule screen to identify sleep-modulating genes and pathways. We administered 1280 pharmacologically active small molecules to adult flies and monitored their sleep. We found that administration of reserpine, a small-molecule inhibitor of the vesicular monoamine transporter (VMAT) that repackages monoamines into presynaptic vesicles, resulted in an increase in sleep. Supporting the idea that VMAT is the sleep-relevant target of reserpine, we found that VMAT-null mutants have an increased sleep phenotype, as well as an increased arousal threshold and resistance to the effects of reserpine. However, although the VMAT mutants are consistently resistant to reserpine, other aspects of their sleep phenotype are dependent on genetic background. These findings indicate that small-molecule screens can be used effectively to identify sleep-modulating genes whose phenotypes may be suppressed in traditional genetic screens. Mutations affecting single monoamine pathways did not affect reserpine sensitivity, suggesting that effects of VMAT/reserpine on sleep are mediated by multiple monoamines. Overall, we identify VMAT as an important regulator of sleep in Drosophila and demonstrate that small-molecule screens provide an effective approach to identify genes and pathways that impact adult Drosophila behavior.
  Journal of Neuroscience 05/2013; 33(19):8534-40.
• Article: Inattention blindness to motion in middle temporal area.

  Ian T Harrison, Katherine F Weiner, Geoffrey M Ghose
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  ABSTRACT: Subjects naturally form and use expectations to solve familiar tasks, but the accuracy of these expectations and the neuronal mechanisms by which these expectations enhance behavior are unclear. We trained animals (Macaca mulatta) in a challenging perceptual task in which the likelihood of a very brief pulse of motion was consistently modulated over time and space. Pulse likelihood had dramatic effects on behavior: unexpected pulses were nearly invisible to the animals. To examine the neuronal basis of such inattention blindness, we recorded from single neurons in the middle temporal (MT) area, an area related to motion perception. Fluctuations in how reliably MT neurons both signaled stimulus events and predicted behavioral choices were highly correlated with changes in performance over the course of individual trials. A simple neuronal pooling model reveals that the dramatic behavioral effects of attention in this task can be completely explained by changes in the reliability of a small number of MT neurons.
  Journal of Neuroscience 05/2013; 33(19):8396-410.
• Article: The Munc13 Proteins Differentially Regulate Readily Releasable Pool Dynamics and Calcium-Dependent Recovery at a Central Synapse.

  Zuxin Chen, Benjamin Cooper, Stefan Kalla, Frederique Varoqueaux, Samuel M Young
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  ABSTRACT: The Munc13 gene family encodes molecules located at the synaptic active zone that regulate the reliability of synapses to encode information over a wide range of frequencies in response to action potentials. In the CNS, proteins of the Munc13 family are critical in regulating neurotransmitter release and synaptic plasticity. Although Munc13-1 is essential for synaptic transmission, it is paradoxical that Munc13-2 and Munc13-3 are functionally dispensable at some synapses, although their loss in other synapses leads to increases in frequency-dependent facilitation. We addressed this issue at the calyx of Held synapse, a giant glutamatergic synapse that we found to express all these Munc13 isoforms. We studied their roles in the regulation of synaptic transmission and their impact on the reliability of information transfer. Through detailed electrophysiological analyses of Munc13-2, Munc13-3, and Munc13-2-3 knock-out and wild-type mice, we report that the combined loss of Munc13-2 and Munc13-3 led to an increase in the rate of calcium-dependent recovery and a change in kinetics of release of the readily releasable pool. Furthermore, viral-mediated overexpression of a dominant-negative form of Munc13-1 at the calyx demonstrated that these effects are Munc13-1 dependent. Quantitative immunohistochemistry using Munc13-fluorescent protein knock-in mice revealed that Munc13-1 is the most highly expressed Munc13 isoform at the calyx and the only one highly colocalized with Bassoon at the active zone. Based on these data, we conclude that Munc13-2 and Munc13-3 isoforms limit the ability of Munc13-1 to regulate calcium-dependent replenishment of readily releasable pool and slow pool to fast pool conversion in central synapses.
  Journal of Neuroscience 05/2013; 33(19):8336-8351.
• Article: Double Dissociation between the Anterior Cingulate Cortex and Nucleus Accumbens Core in Encoding the Context versus the Content of Pavlovian Cocaine Cue Extinction.

  Mary M Torregrossa, Jessica Gordon, Jane R Taylor
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  ABSTRACT: One strategy proposed to treat addictive disorders is to extinguish the association between environmental stimuli (cues) and actions associated with drug use to reduce relapse. The context specificity of extinction learning, however, impairs the ability of addicts to generalize extinction training to the drug-taking context. We previously reported that the NMDA receptor partial agonist d-cycloserine administered after pavlovian extinction of cocaine cues in the nucleus accumbens core (NAc) reduced cue-induced renewal. Nevertheless, it was unclear whether this was due to disrupted contextual encoding of extinction or enhanced extinction consolidation. Thus, we examined the effect of the NMDA receptor antagonist d-AP5 on context encoding versus cue extinction learning. We also determined the role of the anterior cingulate cortex (ACC) in encoding the cue extinction memory or the context, due to its projections to NAc, and hypothesized the role in conflict monitoring and contextual modulation of decision making. Using rats, we observed that NMDA receptor antagonism in the NAc did not alter context encoding but did interfere with acquisition of the cue extinction memory, i.e., learning, conversely inactivation of the ACC reduced the contextual encoding of extinction but did not interfere with the acquisition or expression of extinction. The observed effects were not present in the absence of cue extinction training. Additionally, the contextual memory did not appear to be consolidated in the ACC as neither postsession inactivation nor protein synthesis inhibition impaired context-appropriate responding. These results have implications for overcoming the context specificity of extinction to treat psychiatric disorders including addiction.
  Journal of Neuroscience 05/2013; 33(19):8370-7.
• Article: The nNOS-p38MAPK Pathway Is Mediated by NOS1AP during Neuronal Death.

  Li-Li Li, Vanessa Ginet, Xiaonan Liu, Olga Vergun, Minna Tuittila, Marc Mathieu, Christophe Bonny, Julien Puyal, Anita C Truttmann, Michael J Courtney
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  ABSTRACT: Neuronal nitric oxide synthase (nNOS) and p38MAPK are strongly implicated in excitotoxicity, a mechanism common to many neurodegenerative conditions, but the intermediary mechanism is unclear. NOS1AP is encoded by a gene recently associated with sudden cardiac death, diabetes-associated complications, and schizophrenia (Arking et al., 2006; Becker et al., 2008; Brzustowicz, 2008; Lehtinen et al., 2008). Here we find it interacts with p38MAPK-activating kinase MKK3. Excitotoxic stimulus induces recruitment of NOS1AP to nNOS in rat cortical neuron culture. Excitotoxic activation of p38MAPK and subsequent neuronal death are reduced by competing with the nNOS:NOS1AP interaction and by knockdown with NOS1AP-targeting siRNAs. We designed a cell-permeable peptide that competes for the unique PDZ domain of nNOS that interacts with NOS1AP. This peptide inhibits NMDA-induced recruitment of NOS1AP to nNOS and in vivo in rat, doubles surviving tissue in a severe model of neonatal hypoxia-ischemia, a major cause of neonatal death and pediatric disability. The highly unusual sequence specificity of the nNOS:NOS1AP interaction and involvement in excitotoxic signaling may provide future opportunities for generation of neuroprotectants with high specificity.
  Journal of Neuroscience 05/2013; 33(19):8185-8201.
• Article: Genomic imprinting effects of the x chromosome on brain morphology.

  Jean-Francois Lepage, David S Hong, Paul K Mazaika, Mira Raman, Kristen Sheau, Matthew J Marzelli, Joachim Hallmayer, Allan L Reiss
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  ABSTRACT: There is increasing evidence that genomic imprinting, a process by which certain genes are expressed in a parent-of-origin-specific manner, can influence neurogenetic and psychiatric manifestations. While some data suggest possible imprinting effects of the X chromosome on physical and cognitive characteristics in humans, there is no compelling evidence that X-linked imprinting affects brain morphology. To address this issue, we investigated regional cortical volume, thickness, and surface area in 27 healthy controls and 40 prepubescent girls with Turner syndrome (TS), a condition caused by the absence of one X chromosome. Of the young girls with TS, 23 inherited their X chromosome from their mother (X(m)) and 17 from their father (X(p)). Our results confirm the existence of significant differences in brain morphology between girls with TS and controls, and reveal the presence of a putative imprinting effect among the TS groups: girls with X(p) demonstrated thicker cortex than those with X(m) in the temporal regions bilaterally, while X(m) individuals showed bilateral enlargement of gray matter volume in the superior frontal regions compared with X(p). These data suggest the existence of imprinting effects of the X chromosome that influence both cortical thickness and volume during early brain development, and help to explain variability in cognitive and behavioral manifestations of TS with regard to the parental origin of the X chromosome.
  Journal of Neuroscience 05/2013; 33(19):8567-74.
• Article: Limited Encoding of Effort by Dopamine Neurons in a Cost-Benefit Trade-off Task.

  Benjamin Pasquereau, Robert S Turner
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  ABSTRACT: Animals are thought to evaluate the desirability of action options using a unified scale that combines predicted benefits ("rewards"), costs, and the animal's internal motivational state. Midbrain dopamine neurons have long been associated with the reward part of this equation, but it is unclear whether these neurons also estimate the costs of taking an action. We studied the spiking activity of dopamine neurons in the substantia nigra pars compacta of monkeys (Macaca mulatta) during a reaching task in which the energetic costs incurred (friction loads) and the benefits gained (drops of food) were manipulated independently. Although the majority of dopamine neurons encoded the upcoming reward alone, a subset predicted net utility of a course of action by signaling the expected reward magnitude discounted by the invested cost in terms of physical effort. In addition, the tonic activity of some dopamine neurons was slowly reduced in conjunction with the accumulated trials, which is consistent with the hypothesized role for tonic dopamine in the invigoration or motivation of instrumental responding. The present results shed light on an often-hypothesized role for dopamine in the regulation of the balance in natural behaviors between the energy expended and the benefits gained, which could explain why dopamine disorders, such as Parkinson's disease, lead to a breakdown of that balance.
  Journal of Neuroscience 05/2013; 33(19):8288-300.
• Article: The Long-term Structural Plasticity of Cerebellar Parallel Fiber Axons and Its Modulation by Motor Learning.

  Jennifer Carrillo, Shao-Ying Cheng, Kwang Woo Ko, Theresa A Jones, Hiroshi Nishiyama
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  ABSTRACT: Presynaptic axonal varicosities, like postsynaptic spines, are dynamically added and eliminated even in mature neuronal circuitry. To study the role of this axonal structural plasticity in behavioral learning, we performed two-photon in vivo imaging of cerebellar parallel fibers (PFs) in adult mice. PFs make excitatory synapses on Purkinje cells (PCs) in the cerebellar cortex, and long-term potentiation and depression at PF-PC synapses are thought to play crucial roles in cerebellar-dependent learning. Time-lapse vital imaging of PFs revealed that, under a control condition (no behavioral training), ∼10% of PF varicosities appeared and disappeared over a period of 2 weeks without changing the total number of varicosities. The fraction of dynamic PF varicosities significantly diminished during training on an acrobatic motor skill learning task, largely because of reduced addition of new varicosities. Thus, this form of motor learning was associated with greater structural stability of PFs and a slight decrease in the total number of varicosities. Together with prior findings that the number of PF-PC synapses increases during similar training, our results suggest that acrobatic motor skill learning involves a reduction of some PF inputs and a strengthening of others, probably via the conversion of some preexisting PF varicosities into multisynaptic terminals.
  Journal of Neuroscience 05/2013; 33(19):8301-7.
• Article: The Novel Gene tank, a Tumor Suppressor Homolog, Regulates Ethanol Sensitivity in Drosophila.

  Anita V Devineni, Mark Eddison, Ulrike Heberlein
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  ABSTRACT: In both mammalian and insect models of ethanol intoxication, high doses of ethanol induce motor impairment and eventually sedation. Sensitivity to the sedative effects of ethanol is inversely correlated with risk for alcoholism. However, the genes regulating ethanol sensitivity are largely unknown. Based on a previous genetic screen in Drosophila for ethanol sedation mutants, we identified a novel gene, tank (CG15626), the homolog of the mammalian tumor suppressor EI24/PIG8, which has a strong role in regulating ethanol sedation sensitivity. Genetic and behavioral analyses revealed that tank acts in the adult nervous system to promote ethanol sensitivity. We localized the function of tank in regulating ethanol sensitivity to neurons within the pars intercerebralis that have not been implicated previously in ethanol responses. We show that acutely manipulating the activity of all tank-expressing neurons, or of pars intercerebralis neurons in particular, alters ethanol sensitivity in a sexually dimorphic manner, since neuronal activation enhanced ethanol sedation in males, but not females. Finally, we provide anatomical evidence that tank-expressing neurons form likely synaptic connections with neurons expressing the neural sex determination factor fruitless (fru), which have been implicated recently in the regulation of ethanol sensitivity. We suggest that a functional interaction with fru neurons, many of which are sexually dimorphic, may account for the sex-specific effect induced by activating tank neurons. Overall, we have characterized a novel gene and corresponding set of neurons that regulate ethanol sensitivity in Drosophila.
  Journal of Neuroscience 05/2013; 33(19):8134-43.
• Article: Initiation, labile, and stabilization phases of experience-dependent plasticity at neocortical synapses.

  Jing A Wen, Mark C Deblois, Alison L Barth
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  ABSTRACT: Alteration of sensory input can change the strength of neocortical synapses. Selective activation of a subset of whiskers is sufficient to potentiate layer 4-layer 2/3 excitatory synapses in the mouse somatosensory (barrel) cortex, a process that is NMDAR dependent. By analyzing the time course of sensory-induced synaptic change, we have identified three distinct phases for synaptic strengthening in vivo. After an early, NMDAR-dependent phase where selective whisker activation is rapidly translated into increased synaptic strength, we identify a second phase where this potentiation is profoundly reduced by an input-specific, NMDAR-dependent depression. This labile phase is transient, lasting only a few hours, and may require ongoing sensory input for synaptic weakening. Residual synaptic strength is maintained in a third phase, the stabilization phase, which requires mGluR5 signaling. Identification of these three phases will facilitate a molecular dissection of the pathways that regulate synaptic lability and stabilization, and suggest potential approaches to modulate learning.
  Journal of Neuroscience 05/2013; 33(19):8483-93.
• Article: β-Actin and Fascin-2 Cooperate to Maintain Stereocilia Length.

  Benjamin J Perrin, Dana M Strandjord, Praveena Narayanan, Davin M Henderson, Kenneth R Johnson, James M Ervasti
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  ABSTRACT: Stereocilia are actin-based protrusions on auditory sensory hair cells that are deflected by sound waves to initiate the conversion of mechanical energy to neuronal signals. Stereocilia maintenance is essential because auditory hair cells are not renewed in mammals. This process requires both β-actin and γ-actin as knock-out mice lacking either isoform develop distinct stereocilia pathology during aging. In addition, stereocilia integrity may hinge on immobilizing actin, which outside of a small region at stereocilia tips turns over with a very slow, months-long half-life. Here, we establish that β-actin and the actin crosslinking protein fascin-2 cooperate to maintain stereocilia length and auditory function. We observed that mice expressing mutant fascin-2 (p.R109H) or mice lacking β-actin share a common phenotype including progressive, high-frequency hearing loss together with shortening of a defined subset of stereocilia in the hair cell bundle. Fascin-2 binds β-actin and γ-actin filaments with similar affinity in vitro and fascin-2 does not depend on β-actin for localization in vivo. Nevertheless, double-mutant mice lacking β-actin and expressing fascin-2 p.R109H have a more severe phenotype suggesting that each protein has a different function in a common stereocilia maintenance pathway. Because the fascin-2 p.R109H mutant binds but fails to efficiently crosslink actin filaments, we propose that fascin-2 crosslinks function to slow actin depolymerization at stereocilia tips to maintain stereocilia length.
  Journal of Neuroscience 05/2013; 33(19):8114-21.