Journal of Neuroscience

Specialized cortical subnetworks differentially connect frontal cortex to parahippocampal areas.

Publication Date: 2012 Feb 1 PMID: 22302828
Authors: Hirai, Y. - Morishima, M. - Karube, F. - Kawaguchi, Y.
Journal: J Neurosci

How information is manipulated and segregated within local circuits in the frontal cortex remains mysterious, in part because of inadequate knowledge regarding the connectivity of diverse pyramidal cell subtypes. The frontal cortex participates in the formation and retrieval of declarative memories through projections to the perirhinal cortex, and in procedural learning through projections to the striatum/pontine nuclei. In rat frontal cortex, we identified two pyramidal cell subtypes selectively projecting to distinct subregions of perirhinal cortex (PRC). PRC-projecting cells in upper layer 2/3 (L2/3) of the frontal cortex projected to perirhinal area 35, while neurons in L5 innervated perirhinal area 36. L2/3 PRC-projecting cells partially overlapped with those projecting to the basolateral amygdala. L5 PRC-projecting cells partially overlapped with crossed corticostriatal cells, but were distinct from neighboring corticothalamic (CTh)/corticopontine cells. L5 PRC-projecting and CTh cells were different in their electrophysiological properties and dendritic/axonal morphologies. Within the frontal cortex, L2/3 PRC-projecting cells innervated L5 PRC-projecting and CTh cells with similar probabilities, but received feedback excitation only from PRC-projecting cells. These data suggest that specific neuron subtypes in different cortical layers are reciprocally excited via interlaminar loops. Thus, two interacting output channels send information from the frontal cortex to different hierarchical stages of the parahippocampal network, areas 35 and 36, with additional collaterals selectively targeting the amygdala or basal ganglia, respectively. Combined with the hierarchical connectivity of PRC-projecting and CTh cells, these observations demonstrate an exquisite diversification of frontal projection neurons selectively connected according to their participation in distinct memory subsystems.

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Gene coexpression networks in human brain identify epigenetic modifications in alcohol dependence.

Publication Date: 2012 Feb 1 PMID: 22302827
Authors: Ponomarev, I. - Wang, S. - Zhang, L. - Harris, R. A. - Mayfield, R. D.
Journal: J Neurosci

Alcohol abuse causes widespread changes in gene expression in human brain, some of which contribute to alcohol dependence. Previous microarray studies identified individual genes as candidates for alcohol phenotypes, but efforts to generate an integrated view of molecular and cellular changes underlying alcohol addiction are lacking. Here, we applied a novel systems approach to transcriptome profiling in postmortem human brains and generated a systemic view of brain alterations associated with alcohol abuse. We identified critical cellular components and previously unrecognized epigenetic determinants of gene coexpression relationships and discovered novel markers of chromatin modifications in alcoholic brain. Higher expression levels of endogenous retroviruses and genes with high GC content in alcoholics were associated with DNA hypomethylation and increased histone H3K4 trimethylation, suggesting a critical role of epigenetic mechanisms in alcohol addiction. Analysis of cell-type-specific transcriptomes revealed remarkable consistency between molecular profiles and cellular abnormalities in alcoholic brain. Based on evidence from this study and others, we generated a systems hypothesis for the central role of chromatin modifications in alcohol dependence that integrates epigenetic regulation of gene expression with pathophysiological and neuroadaptive changes in alcoholic brain. Our results offer implications for epigenetic therapeutics in alcohol and drug addiction.

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mu- and delta-Opioid-Related Processes in the Accumbens Core and Shell Differentially Mediate the Influence of Reward-Guided and Stimulus-Guided Decisions on Choice.

Publication Date: 2012 Feb 1 PMID: 22302826
Authors: Laurent, V. - Leung, B. - Maidment, N. - Balleine, B. W.
Journal: J Neurosci

Two motivational processes affect choice between actions: (1) changes in the reward value of the goal or outcome of an action and (2) changes in the predicted value of an action based on outcome-related stimuli. Here, we evaluated the role of mu-opioid receptor (MOR) and delta-opioid receptor (DOR) in the nucleus accumbens in the way these motivational processes influence choice using outcome revaluation and pavlovian-instrumental transfer tests. We first examined the effect of genetic deletion of MOR and DOR in specific knock-out mice. We then assessed the effect of infusing the MOR antagonist d-Phe-Cys-Tyr-d-Trp-Arg-Thr-Pen-Thr-NH(2) (CTAP) or the DOR antagonist naltrindole into the core or shell subregions of the nucleus accumbens on these tests in rats. We found that, whereas MOR knock-outs showed normal transfer, they failed to show a selective outcome revaluation effect. Conversely, DOR knock-outs showed normal revaluation but were insensitive to the influence of outcome-related cues on choice. This double dissociation was also found regionally within the nucleus accumbens in rats. Infusion of naltrindole into the accumbens shell abolished transfer but had no effect on outcome revaluation and did not influence either effect when infused into the accumbens core. Conversely, infusion of CTAP into the accumbens core abolished sensitivity to outcome revaluation but had no effect on transfer and did not influence either effect when infused into the accumbens shell. These results suggest that reward-based and stimulus-based values exert distinct motivational influences on choice that can be doubly dissociated both neuroanatomically and neurochemically at the level of the nucleus accumbens.

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Independent Vesicle Pools Underlie Different Modes of Release during Neuronal Development.

Publication Date: 2012 Feb 1 PMID: 22302825
Authors: Andreae, L. C. - Ben Fredj, N. - Burrone, J.
Journal: J Neurosci

Mature presynaptic terminals release neurotransmitter both in response to activity and spontaneously. We found that axons of rat hippocampal neurons initially show very high levels of exclusively spontaneous release, which progressively switches over to the mature phenotype during synapse formation. These two modes of vesicle cycling derive from distinct pools throughout development and the initiation of activity-dependent release was independent of postsynaptic contacts, suggesting it is an autonomous presynaptic event.

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Electrical brain stimulation improves cognitive performance by modulating functional connectivity and task-specific activation.

Publication Date: 2012 Feb 1 PMID: 22302824
Authors: Meinzer, M. - Antonenko, D. - Lindenberg, R. - Hetzer, S. - Ulm, L. - Avirame, K. - Flaisch, T. - Floel, A.
Journal: J Neurosci

Excitatory anodal transcranial direct current stimulation (atDCS) can improve human cognitive functions, but neural underpinnings of its mode of action remain elusive. In a cross-over placebo ("sham") controlled study we used functional magnetic resonance imaging (fMRI) to investigate neurofunctional correlates of improved language functions induced by atDCS over a core language area, the left inferior frontal gyrus (IFG). Intrascanner transcranial direct current stimulation-induced changes in overt semantic word generation assessed behavioral modulation; task-related and task-independent (resting-state) fMRI characterized language network changes. Improved word-retrieval during atDCS was paralleled by selectively reduced task-related activation in the left ventral IFG, an area specifically implicated in semantic retrieval processes. Under atDCS, resting-state fMRI revealed increased connectivity of the left IFG and additional major hubs overlapping with the language network. In conclusion, atDCS modulates endogenous low-frequency oscillations in a distributed set of functionally connected brain areas, possibly inducing more efficient processing in critical task-relevant areas and improved behavioral performance.

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Calpains Are Downstream Effectors of bax-Dependent Excitotoxic Apoptosis.

Publication Date: 2012 Feb 1 PMID: 22302823
Authors: D'Orsi, B. - Bonner, H. - Tuffy, L. P. - Dussmann, H. - Woods, I. - Courtney, M. J. - Ward, M. W. - Prehn, J. H.
Journal: J Neurosci

Excitotoxicity resulting from excessive Ca(2+) influx through glutamate receptors contributes to neuronal injury after stroke, trauma, and seizures. Increased cytosolic Ca(2+) levels activate a family of calcium-dependent proteases with papain-like activity, the calpains. Here we investigated the role of calpain activation during NMDA-induced excitotoxic injury in embryonic (E16-E18) murine cortical neurons that (1) underwent excitotoxic necrosis, characterized by immediate deregulation of Ca(2+) homeostasis, a persistent depolarization of mitochondrial membrane potential (Deltapsi(m)), and insensitivity to bax-gene deletion, (2) underwent excitotoxic apoptosis, characterized by recovery of NMDA-induced cytosolic Ca(2+) increases, sensitivity to bax gene deletion, and delayed Deltapsi(m) depolarization and Ca(2+) deregulation, or (3) that were tolerant to excitotoxic injury. Interestingly, treatment with the calpain inhibitor calpeptin, overexpression of the endogenous calpain inhibitor calpastatin, or gene silencing of calpain protected neurons against excitotoxic apoptosis but did not influence excitotoxic necrosis. Calpeptin failed to exert a protective effect in bax-deficient neurons but protected bid-deficient neurons similarly to wild-type cells. To identify when calpains became activated during excitotoxic apoptosis, we monitored calpain activation dynamics by time-lapse fluorescence microscopy using a calpain-sensitive Forster resonance energy transfer probe. We observed a delayed calpain activation that occurred downstream of mitochondrial engagement and directly preceded neuronal death. In contrast, we could not detect significant calpain activity during excitotoxic necrosis or in neurons that were tolerant to excitotoxic injury. Oxygen/glucose deprivation-induced injury in organotypic hippocampal slice cultures confirmed that calpains were specifically activated during bax-dependent apoptosis and in this setting function as downstream cell-death executioners.

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JNK1 Inhibits GluR1 Expression and GluR1-Mediated Calcium Influx through Phosphorylation and Stabilization of Hes-1.

Publication Date: 2012 Feb 1 PMID: 22302822
Authors: Lin, C. H. - Lee, E. H.
Journal: J Neurosci

The GluR1 subunit of the AMPA receptor plays an important role in excitatory synaptic transmission and synaptic plasticity in the brain, but the regulation mechanism for GluR1 expression is largely unknown. Hairy and enhancer of split 1 (Hes-1) is a mammalian transcription repressor that regulates neuronal differentiation and development, but the role of Hes-1 in differentiated neurons is also less known. Here, we examined the molecular mechanism in regulation of GluR1 expression in rat cultured cortical neurons. We found that Hes-1 suppressed GluR1 promoter activity and decreased GluR1 expression through direct binding to the N-box and through preventing Mash1/E47 from binding to the E-box of GluR1 promoter. We also found that Hes-1 could be regulated by c-Jun N-terminal kinase (JNK1). JNK1 directly phosphorylates Hes-1 at Ser-263. Furthermore, JNK1 phosphorylation of Hes-1 stabilized the Hes-1 protein and enhanced the suppressing effect of Hes-1 on GluR1 expression. These effects were demonstrated both in the soma and at the synapse. Moreover, this JNK1-mediated signaling pathway was found to inhibit AMPA-evoked calcium influx in cortical neurons and this regulation mechanism is Notch independent. Here, we provided the first evidence that Hes-1 plays an important role in synaptic function in differentiated neurons. We also identified a novel JNK1-Hes-1 signaling pathway that regulates GluR1 expression involved in synaptic function in rat cortical neurons.

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Arrest of Myelination and Reduced Axon Growth When Schwann Cells Lack mTOR.

Publication Date: 2012 Feb 1 PMID: 22302821
Authors: Sherman, D. L. - Krols, M. - Wu, L. M. - Grove, M. - Nave, K. A. - Gangloff, Y. G. - Brophy, P. J.
Journal: J Neurosci

In developing peripheral nerves, differentiating Schwann cells sort individual axons from bundles and ensheath them to generate multiple layers of myelin. In recent years, there has been an increased understanding of the extracellular and intracellular factors that initiate and stimulate Schwann cell myelination, together with a growing appreciation of some of the signaling pathways involved. However, our knowledge of how Schwann cell growth is regulated during myelination is still incomplete. The mammalian target of rapamycin (mTOR) is a core kinase in two major complexes, mTORC1 and mTORC2, that regulate cell growth and differentiation in a variety of mammalian cells. Here we show that elimination of mTOR from murine Schwann cells prevented neither radial sorting nor the initiation of myelination. However, normal postnatal growth of myelinating Schwann cells, both radially and longitudinally, was highly retarded. The myelin sheath in the mutant was much thinner than normal; nevertheless, sheath thickness relative to axon diameter (g-ratio) remained constant in both wild-type and mutant nerves from P14 to P90. Although axon diameters were normal in the mutant at the initiation of myelination, further growth as myelination proceeded was retarded, and this was associated with reduced phosphorylation of neurofilaments. Consistent with thinner axonal diameters and internodal lengths, conduction velocities in mutant quadriceps nerves were also reduced. These data establish a critical role for mTOR signaling in both the longitudinal and radial growth of the myelinating Schwann cell.

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Increased Excitability of Somatosensory Cortex in Aged Humans is Associated with Impaired Tactile Acuity.

Publication Date: 2012 Feb 1 PMID: 22302820
Authors: Lenz, M. - Tegenthoff, M. - Kohlhaas, K. - Stude, P. - Hoffken, O. - Gatica Tossi, M. A. - Kalisch, T. - Dinse, H. R.
Journal: J Neurosci

Aging affects all levels of neural processing, including changes of intracortical inhibition and cortical excitability. Paired-pulse stimulation, the application of two stimuli in close succession, is a useful tool to investigate cortical excitability in humans. The paired-pulse behavior is characterized by the second response being significantly suppressed at short stimulus onset asynchronies. While in rat somatosensory cortex, intracortical inhibition has been demonstrated to decline with increasing age, data from human motor cortex of elderly subjects are controversial and there are no data for the human somatosensory cortex (SI). Moreover, behavioral implications of age-related changes of cortical excitability remain elusive. We therefore assessed SI excitability by combining paired-pulse median nerve stimulation with recording somatosensory evoked potentials in 138 healthy subjects aged 17-86 years. We found that paired-pulse suppression was characterized by substantial interindividual variability, but declined significantly with age, confirming reduced intracortical inhibition in elderly subjects. To link the age-related increase of cortical excitability to perceptual changes, we measured tactile two-point discrimination in a subsample of 26 aged participants who showed either low or high paired-pulse suppression. We found that tactile performance was particularly impaired in subjects showing markedly enhanced cortical excitability. Our data demonstrate that paired-pulse suppression of human SI is significantly reduced in older adults, and that age-related enhancement of cortical excitability correlates with degradation of tactile perception. These findings indicate that cortical excitability constitutes an important mechanism that links age-related neurophysiological changes to behavioral alterations in humans.

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A TrkB Small Molecule Partial Agonist Rescues TrkB Phosphorylation Deficits and Improves Respiratory Function in a Mouse Model of Rett Syndrome.

Publication Date: 2012 Feb 1 PMID: 22302819
Authors: Schmid, D. A. - Yang, T. - Ogier, M. - Adams, I. - Mirakhur, Y. - Wang, Q. - Massa, S. M. - Longo, F. M. - Katz, D. M.
Journal: J Neurosci

Rett syndrome (RTT) results from loss-of-function mutations in the gene encoding the methyl-CpG-binding protein 2 (MeCP2) and is characterized by abnormal motor, respiratory and autonomic control, cognitive impairment, autistic-like behaviors and increased risk of seizures. RTT patients and Mecp2-null mice exhibit reduced expression of brain-derived neurotrophic factor (BDNF), which has been linked in mice to increased respiratory frequency, a hallmark of RTT. The present study was undertaken to test the hypotheses that BDNF deficits in Mecp2 mutants are associated with reduced activation of the BDNF receptor, TrkB, and that pharmacologic activation of TrkB would improve respiratory function. We characterized BDNF protein expression, TrkB activation and respiration in heterozygous female Mecp2 mutant mice (Het), a model that recapitulates the somatic mosaicism for mutant MECP2 found in typical RTT patients, and evaluated the ability of a small molecule TrkB agonist, LM22A-4, to ameliorate biochemical and functional abnormalities in these animals. We found that Het mice exhibit (1) reduced BDNF expression and TrkB activation in the medulla and pons and (2) breathing dysfunction, characterized by increased frequency due to periods of tachypnea, and increased apneas, as in RTT patients. Treatment of Het mice with LM22A-4 for 4 weeks rescued wild-type levels of TrkB phosphorylation in the medulla and pons and restored wild-type breathing frequency. These data provide new insight into the role of BDNF signaling deficits in the pathophysiology of RTT and highlight TrkB as a possible therapeutic target in this disease.

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Internalized timing of isochronous sounds is represented in neuromagnetic Beta oscillations.

Publication Date: 2012 Feb 1 PMID: 22302818
Authors: Fujioka, T. - Trainor, L. J. - Large, E. W. - Ross, B.
Journal: J Neurosci

Moving in synchrony with an auditory rhythm requires predictive action based on neurodynamic representation of temporal information. Although it is known that a regular auditory rhythm can facilitate rhythmic movement, the neural mechanisms underlying this phenomenon remain poorly understood. In this experiment using human magnetoencephalography, 12 young healthy adults listened passively to an isochronous auditory rhythm without producing rhythmic movement. We hypothesized that the dynamics of neuromagnetic beta-band oscillations ( approximately 20 Hz)-which are known to reflect changes in an active status of sensorimotor functions-would show modulations in both power and phase-coherence related to the rate of the auditory rhythm across both auditory and motor systems. Despite the absence of an intention to move, modulation of beta amplitude as well as changes in cortico-cortical coherence followed the tempo of sound stimulation in auditory cortices and motor-related areas including the sensorimotor cortex, inferior-frontal gyrus, supplementary motor area, and the cerebellum. The time course of beta decrease after stimulus onset was consistent regardless of the rate or regularity of the stimulus, but the time course of the following beta rebound depended on the stimulus rate only in the regular stimulus conditions such that the beta amplitude reached its maximum just before the occurrence of the next sound. Our results suggest that the time course of beta modulation provides a mechanism for maintaining predictive timing, that beta oscillations reflect functional coordination between auditory and motor systems, and that coherence in beta oscillations dynamically configure the sensorimotor networks for auditory-motor coupling.

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Neural correlates of humor detection and appreciation in children.

Publication Date: 2012 Feb 1 PMID: 22302817
Authors: Neely, M. N. - Walter, E. - Black, J. M. - Reiss, A. L.
Journal: J Neurosci

Humor is a vital component of human well-being. Neuroimaging studies conducted with adults indicate that humor activates specific brain regions, including the temporo-occipito-parietal junction (TOPJ), involved in incongruity resolution, and mesolimbic regions, involved in reward processing. However, no study to date has used neuroimaging to examine humor in typically developing children. Here, we illuminate the neural network involved in the detection and appreciation of humor in childhood. Fifteen typically developing children (ages, 6-12 years) were invited to watch and respond to video clips while neural activity was imaged with a 3T GE Discovery MR750 scanner. Before presentation during functional imaging, the clips were evaluated by age-matched controls and were representative of three categories: Funny, Positive (enjoyable but not funny), and Neutral (not intended to evoke any emotional response). We found TOPJ and mesolimbic activation in children's response to humor, suggesting these regions may form a humor-essential neural network already present in childhood. Furthermore, in a novel comparison of Funny to Positive stimuli, we found that bilateral TOPJ activation may be specific to humor processing and not part of a general constellation of neural activity in response to reward. Finally, we observed greater activation in the inferior frontal gyrus and nucleus accumbens in younger participants, indicating humor activation intensity changes during development. By providing a crucial link in studying the neurodevelopment of humor processing across the lifespan, our findings contribute valuable information about the evolution of how children understand their world.

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Generation of multiple classes of v0 neurons in zebrafish spinal cord: progenitor heterogeneity and temporal control of neuronal diversity.

Publication Date: 2012 Feb 1 PMID: 22302816
Authors: Satou, C. - Kimura, Y. - Higashijima, S.
Journal: J Neurosci

The developing spinal cord is subdivided into distinct progenitor domains, each of which gives rise to different types of neurons. However, the developmental mechanisms responsible for generating neuronal diversity within a domain are not well understood. Here, we have studied zebrafish V0 neurons, those that derive from the p0 progenitor domain, to address this question. We find that all V0 neurons have commissural axons, but they can be divided into excitatory and inhibitory classes. V0 excitatory neurons (V0-e) can be further categorized into three groups based on their axonal trajectories; V0-eA (ascending), V0-eB (bifurcating), and V0-eD (descending) neurons. By using time-lapse imaging of p0 progenitors and their progeny, we show that inhibitory and excitatory neurons are produced from different progenitors. We also demonstrate that V0-eA neurons are produced from distinct progenitors, while V0-eB and V0-eD neurons are produced from common progenitors. We then use birth-date analysis to reveal that V0-eA, V0-eB, and V0-eD neurons arise in this order. By perturbing Notch signaling and accelerating neuronal differentiation, we predictably alter the generation of early born V0-e neurons at the expense of later born ones. These results suggest that multiple types of V0 neurons are produced by two distinct mechanisms; from heterogeneous p0 progenitors and from the same p0 progenitor, but in a time-dependent manner.

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The Loop Diuretic Bumetanide Blocks Posttraumatic p75NTR Upregulation and Rescues Injured Neurons.

Publication Date: 2012 Feb 1 PMID: 22302815
Authors: Shulga, A. - Magalhaes, A. C. - Autio, H. - Plantman, S. - di Lieto, A. - Nykjaer, A. - Carlstedt, T. - Risling, M. - Arumae, U. - Castren, E. - Rivera, C.
Journal: J Neurosci

Injured neurons become dependent on trophic factors for survival. However, application of trophic factors to the site of injury is technically extremely challenging. Novel approaches are needed to circumvent this problem. Here, we unravel the mechanism of the emergence of dependency of injured neurons on brain-derived neurotrophic factor (BDNF) for survival. Based on this mechanism, we propose the use of the diuretic bumetanide to prevent the requirement for BDNF and consequent neuronal death in the injured areas. Responses to the neurotransmitter GABA change from hyperpolarizing in intact neurons to depolarizing in injured neurons. We show in vivo in rats and ex vivo in mouse organotypic slice cultures that posttraumatic GABA(A)-mediated depolarization is a cause for the well known phenomenon of pathological upregulation of pan-neurotrophin receptor p75(NTR). The increase in intracellular Ca(2+) triggered by GABA-mediated depolarization activates ROCK (Rho kinase), which in turn leads to the upregulation of p75(NTR). We further show that high levels of p75(NTR) and its interaction with sortilin and proNGF set the dependency on BDNF for survival. Thus, application of bumetanide prevents p75(NTR) upregulation and neuronal death in the injured areas with reduced levels of endogenous BDNF.

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Psychophysiological analyses demonstrate the importance of neural envelope coding for speech perception in noise.

Publication Date: 2012 Feb 1 PMID: 22302814
Authors: Swaminathan, J. - Heinz, M. G.
Journal: J Neurosci

Understanding speech in noisy environments is often taken for granted; however, this task is particularly challenging for people with cochlear hearing loss, even with hearing aids or cochlear implants. A significant limitation to improving auditory prostheses is our lack of understanding of the neural basis for robust speech perception in noise. Perceptual studies suggest the slowly varying component of the acoustic waveform (envelope, ENV) is sufficient for understanding speech in quiet, but the rapidly varying temporal fine structure (TFS) is important in noise. These perceptual findings have important implications for cochlear implants, which currently only provide ENV; however, neural correlates have been difficult to evaluate due to cochlear transformations between acoustic TFS and recovered neural ENV. Here, we demonstrate the relative contributions of neural ENV and TFS by quantitatively linking neural coding, predicted from a computational auditory nerve model, with perception of vocoded speech in noise measured from normal hearing human listeners. Regression models with ENV and TFS coding as independent variables predicted speech identification and phonetic feature reception at both positive and negative signal-to-noise ratios. We found that: (1) neural ENV coding was a primary contributor to speech perception, even in noise; and (2) neural TFS contributed in noise mainly in the presence of neural ENV, but rarely as the primary cue itself. These results suggest that neural TFS has less perceptual salience than previously thought due to cochlear signal processing transformations between TFS and ENV. Because these transformations differ between normal and impaired ears, these findings have important translational implications for auditory prostheses.

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Differentiated participation of thalamocortical subnetworks in slow/spindle waves and desynchronization.

Publication Date: 2012 Feb 1 PMID: 22302813
Authors: Ushimaru, M. - Ueta, Y. - Kawaguchi, Y.
Journal: J Neurosci

During sleep, the electroencephalogram exhibits synchronized slow waves that desynchronize when animals awaken [desynchronized states (DSs)]. During slow-wave states, the membrane potentials of cortical neurons oscillate between discrete depolarized states ("Up states") and periods of hyperpolarization ("Down states"). To determine the role of corticothalamic loops in generating Up/Down oscillations in rats, we recorded unit activities of layer 5 (L5) corticothalamic (CTh) cells in the frontal cortex, neurons in the thalamic reticular nucleus, and basal ganglia- and cerebellum-linked thalamic relay nuclei, while simultaneously monitoring the local cortical field potential to identify slow-wave/spindle oscillations and desynchronization. We found that (1) some basal ganglia-linked and reticular thalamic cells fire preferentially near the beginning of Up states; (2) thalamic cells fire more selectively at a given Up-state phase than do CTh cells; (3) CTh and thalamic cells exhibit different action potential timings within spindle cycles; and (4) neurons exhibit different firing characteristics when comparing their activity during Up states and DSs. These data demonstrate that cortico-thalamo-cortical subnetworks are temporally differentiated during slow and spindle oscillations, that the basal ganglia-linked thalamic nuclei are closely related with Up-state initiation, and that Up states and DSs are distinguished as different depolarization states of neurons within the network.

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Novel GalphaS-Protein Signaling Associated with Membrane-Tethered Amyloid Precursor Protein Intracellular Domain.

Publication Date: 2012 Feb 1 PMID: 22302812
Authors: Deyts, C. - Vetrivel, K. S. - Das, S. - Shepherd, Y. M. - Dupre, D. J. - Thinakaran, G. - Parent, A. T.
Journal: J Neurosci

Numerous physiological functions, including a role as a cell surface receptor, have been ascribed to Alzheimer's disease-associated amyloid precursor protein (APP). However, detailed analysis of intracellular signaling mediated by APP in neurons has been lacking. Here, we characterized intrinsic signaling associated with membrane-bound APP C-terminal fragments, which are generated following APP ectodomain release by alpha- or beta-secretase cleavage. We found that accumulation of APP C-terminal fragments or expression of membrane-tethered APP intracellular domain results in adenylate cyclase-dependent activation of PKA (protein kinase A) and inhibition of GSK3beta signaling cascades, and enhancement of axodendritic arborization in rat immortalized hippocampal neurons, mouse primary cortical neurons, and mouse neuroblastoma. We discovered an interaction between BBXXB motif of APP intracellular domain and the heterotrimeric G-protein subunit Galpha(S), and demonstrate that Galpha(S) coupling to adenylate cyclase mediates membrane-tethered APP intracellular domain-induced neurite outgrowth. Our study provides clear evidence that APP intracellular domain can have a nontranscriptional role in regulating neurite outgrowth through its membrane association. The novel functional coupling of membrane-bound APP C-terminal fragments with Galpha(S) signaling identified in this study could impact several brain functions such as synaptic plasticity and memory formation.

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Contrast-Enhanced Magnetic Resonance Microangiography Reveals Remodeling of the Cerebral Microvasculature in Transgenic ArcAbeta Mice.

Publication Date: 2012 Feb 1 PMID: 22302811
Authors: Klohs, J. - Baltes, C. - Princz-Kranz, F. - Ratering, D. - Nitsch, R. M. - Knuesel, I. - Rudin, M.
Journal: J Neurosci

Amyloid-beta (Abeta) deposition in the cerebral vasculature is accompanied by remodeling which has a profound influence on vascular integrity and function. In the current study we have quantitatively assessed the age-dependent changes of the cortical vasculature in the arcAbeta model of cerebral amyloidosis. To estimate the density of the cortical microvasculature in vivo, we used contrast-enhanced magnetic resonance microangiography (CE-muMRA). Three-dimensional gradient echo datasets with 60 mum isotropic resolution were acquired in 4- and 24-month-old arcAbeta mice and compared with wild-type (wt) control mice of the same age before and after administration of superparamagnetic iron oxide nanoparticles. After segmentation of the cortical vasculature from difference images, an automated algorithm was applied for assessing the number and size distribution of intracortical vessels. With CE-muMRA, cerebral arteries and veins with a diameter of less than the nominal pixel resolution (60 mum) can be visualized. A significant age-dependent reduction in the number of functional intracortical microvessels (radii of 20-80 mum) has been observed in 24-month-old arcAbeta mice compared with age-matched wt mice, whereas there was no difference between transgenic and wt mice of 4 months of age. Immunohistochemistry demonstrated strong fibrinogen and Abeta deposition in small- and medium-sized vessels, but not in large cerebral arteries, of 24-month-old arcAbeta mice. The reduced density of transcortical vessels may thus be attributed to impaired perfusion and vascular occlusion caused by deposition of Abeta and fibrin. The study demonstrated that remodeling of the cerebrovasculature can be monitored noninvasively with CE-muMRA in mice.

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Astrocytes Control the Development of the Migration-Promoting Vasculature Scaffold in the Postnatal Brain via VEGF Signaling.

Publication Date: 2012 Feb 1 PMID: 22302810
Authors: Bozoyan, L. - Khlghatyan, J. - Saghatelyan, A.
Journal: J Neurosci

New neurons are constantly being generated in the postnatal subventricular zone. They have to migrate long distances via the rostral migratory stream (RMS) to reach their final destination in the olfactory bulb (OB). In adults, these neuronal precursors migrate in chains, ensheathed by astrocytic processes, and travel toward the OB along blood vessels (BVs) that topographically outline the RMS. The molecular and cellular mechanisms leading to the development of the RMS and the formation of the migration-promoting vasculature scaffold in the adult mice remain unclear. We now reveal that astrocytes orchestrate the formation and structural reorganization of the vasculature scaffold in the RMS and, during early developmental stages, the RMS contains only a few BVs oriented randomly with respect to the migrating neuroblasts. The first parallel BVs appeared at the outer border of the RMS, where vascular endothelial growth factor (VEGF)-expressing astrocytes are located. Gain-of-function and loss-of-function experiments revealed that astrocyte-derived VEGF plays a crucial role in the formation and growth of new BVs. Real-time videoimaging also showed that the migration of neuronal precursors in the developing RMS differs substantially from neuronal displacement in the adult migratory stream partially because of not yet fully developed vasculature scaffold. The downregulation of VEGF in vivo, specifically in the astrocytes of the developing RMS, affected the development of the vasculature scaffold and led to alterations in neuroblast migration. Altogether, our results demonstrate that astrocytes orchestrate the formation and growth of parallel BVs, crucial migration-promoting scaffolds in the adult migratory stream, via VEGF signaling.

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Neuronal Responses in the Nucleus Accumbens Shell during Sexual Behavior in Male Rats.

Publication Date: 2012 Feb 1 PMID: 22302809
Authors: Matsumoto, J. - Urakawa, S. - Hori, E. - de Araujo, M. F. - Sakuma, Y. - Ono, T. - Nishijo, H.
Journal: J Neurosci

Previous behavioral studies have indicated that the nucleus accumbens (NAc) shell of a male rat is involved in its sexual behavior; however, no previous studies have investigated neuronal activities in the male rat NAc shell during sexual behavior. To investigate this issue, we recorded single unit activities in the NAc shell of male rats during sexual behavior. Of 123 NAc shell neurons studied, 53, 47, and 40 neurons exhibited significantly changed firing rates at various times during intromission, genital auto-grooming, and sniffing of females, respectively. The two types of NAc shell neurons [putative fast spiking interneurons (pFSIs) and medium spiny neurons (pMSNs)] responded differently during sexual behavior. First, more pFSIs than pMSNs exhibited inhibitory responses to thrusting with intromission and genital grooming, while pFSIs and pMSNs responded similarly to sniffing of females. Second, both pFSIs and pMSNs responded differently to thrusting with and without intromission. Furthermore, NAc shell neuronal activity was significantly different across the different phases of sexual behavior, and the number of NAc shell neurons with delta oscillation, which is related to behavioral inhibition, and high gamma oscillation, which is related to reward perception, increased after ejaculation. Together, our results suggest that the NAc shell is deeply involved in sexual behavior, and changes in NAc shell neuronal activity are related to performance of sexual behavior, encoding cues or contexts related to sexual behavior, reward-related processing, and the inhibition of sexual behavior after ejaculation.

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Noise overexposure alters long-term somatosensory-auditory processing in the dorsal cochlear nucleus--possible basis for tinnitus-related hyperactivity?

Publication Date: 2012 Feb 1 PMID: 22302808
Authors: Dehmel, S. - Pradhan, S. - Koehler, S. - Bledsoe, S. - Shore, S.
Journal: J Neurosci

The dorsal cochlear nucleus (DCN) is the first neural site of bimodal auditory-somatosensory integration. Previous studies have shown that stimulation of somatosensory pathways results in immediate suppression or enhancement of subsequent acoustically evoked discharges. In the unimpaired auditory system suppression predominates. However, damage to the auditory input pathway leads to enhancement of excitatory somatosensory inputs to the cochlear nucleus, changing their effects on DCN neurons (Shore et al., 2008; Zeng et al., 2009). Given the well described connection between the somatosensory system and tinnitus in patients we sought to determine whether plastic changes in long-lasting bimodal somatosensory-auditory processing accompany tinnitus. Here we demonstrate for the first time in vivo long-term effects of somatosensory inputs on acoustically evoked discharges of DCN neurons in guinea pigs. The effects of trigeminal nucleus stimulation are compared between normal-hearing animals and animals overexposed with narrow band noise and behaviorally tested for tinnitus. The noise exposure resulted in a temporary threshold shift in auditory brainstem responses but a persistent increase in spontaneous and sound-evoked DCN unit firing rates and increased steepness of rate-level functions. Rate increases were especially prominent in buildup units. The long-term somatosensory enhancement of sound-evoked responses was strengthened while suppressive effects diminished in noise-exposed animals, especially those that developed tinnitus. Damage to the auditory nerve is postulated to trigger compensatory long-term synaptic plasticity of somatosensory inputs that might be an important underlying mechanism for tinnitus generation.

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Dynamic Correlation between Whisking and Breathing Rhythms in Mice.

Publication Date: 2012 Feb 1 PMID: 22302807
Authors: Cao, Y. - Roy, S. - Sachdev, R. N. - Heck, D. H.
Journal: J Neurosci

Sniffing, a high-frequency, highly rhythmic inhalation and exhalation of air through the nose, plays an important role in rodent olfaction. Similarly, whisking, the active rhythmic movement of whiskers, plays an important role in rodent tactile sensation. Rodents whisk and sniff during exploratory behavior to sample odorants and surfaces. Whisking is thought to be coordinated with sniffing and normal respiratory behavior, but the precise temporal relationships between these movements are not known. Here, using direct measurements of whisking and respiratory movements, we examined the strength and temporal dynamics of the correlation between large-amplitude whisker movements and respiratory rhythm in mice. Whisking movements were detected using an optical sensor, and respiration was monitored with a thermistor placed close to the nostril. Our measurements revealed that breathing and whisking movements were significantly correlated only when the whisking rhythm was <5 Hz. Only a fraction ( approximately 13%) of all large-amplitude whisker movements occurred during episodes of high-frequency (>5 Hz) respiration typically associated with sniffing. Our results show that that the rhythms of respiratory and whisking movements are correlated only during low-frequency whisking and respiration. High-frequency whisking and sniffing behaviors are not correlated. We conclude that whisking and respiratory rhythms are generated by independent pattern-generating mechanisms.

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PTEN Regulation of Local and Long-Range Connections in Mouse Auditory Cortex.

Publication Date: 2012 Feb 1 PMID: 22302806
Authors: Xiong, Q. - Oviedo, H. V. - Trotman, L. C. - Zador, A. M.
Journal: J Neurosci

Autism spectrum disorders (ASDs) are highly heritable developmental disorders caused by a heterogeneous collection of genetic lesions. Here we use a mouse model to study the effect on cortical connectivity of disrupting the ASD candidate gene PTEN (phosphatase and tensin homolog deleted on chromosome 10). Through Cre-mediated recombination, we conditionally knocked out PTEN expression in a subset of auditory cortical neurons. Analysis of long-range connectivity using channelrhodopsin-2 revealed that the strength of synaptic inputs from both the contralateral auditory cortex and from the thalamus onto PTEN-cko neurons was enhanced compared with nearby neurons with normal PTEN expression. Laser-scanning photostimulation showed that local inputs onto PTEN-cko neurons in the auditory cortex were similarly enhanced. The hyperconnectivity caused by PTEN-cko could be blocked by rapamycin, a specific inhibitor of the PTEN downstream molecule mammalian target of rapamycin complex 1. Together, our results suggest that local and long-range hyperconnectivity may constitute a physiological basis for the effects of mutations in PTEN and possibly other ASD candidate genes.

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Bimodal optomotor response to plaids in blowflies: mechanisms of component selectivity and evidence for pattern selectivity.

Publication Date: 2012 Feb 1 PMID: 22302805
Authors: Saleem, A. B. - Longden, K. D. - Schwyn, D. A. - Krapp, H. G. - Schultz, S. R.
Journal: J Neurosci

Many animals estimate their self-motion and the movement of external objects by exploiting panoramic patterns of visual motion. To probe how visual systems process compound motion patterns, superimposed visual gratings moving in different directions, plaid stimuli, have been successfully used in vertebrates. Surprisingly, nothing is known about how visually guided insects process plaids. Here, we explored in the blowfly how the well characterized yaw optomotor reflex and the activity of identified visual interneurons depend on plaid stimuli. We show that contrary to previous expectations, the yaw optomotor reflex shows a bimodal directional tuning for certain plaid stimuli. To understand the neural correlates of this behavior, we recorded the responses of a visual interneuron supporting the reflex, the H1 cell, which was also bimodally tuned to the plaid direction. Using a computational model, we identified the essential neural processing steps required to capture the observed response properties. These processing steps have functional parallels with mechanisms found in the primate visual system, despite different biophysical implementations. By characterizing other visual neurons supporting visually guided behaviors, we found responses that ranged from being bimodally tuned to the stimulus direction (component-selective), to responses that appear to be tuned to the direction of the global pattern (pattern-selective). Our results extend the current understanding of neural mechanisms of motion processing in insects, and indicate that the fly employs a wider range of behavioral responses to multiple motion cues than previously reported.

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5-HT1A Receptor-Responsive Pedunculopontine Tegmental Neurons Suppress REM Sleep and Respiratory Motor Activity.

Publication Date: 2012 Feb 1 PMID: 22302804
Authors: Grace, K. P. - Liu, H. - Horner, R. L.
Journal: J Neurosci

Serotonin type 1A (5-HT(1A)) receptor-responsive neurons in the pedunculopontine tegmental nucleus (PPTn) become maximally active immediately before and during rapid eye movement (REM) sleep. A prevailing model of REM sleep generation indicates that activation of such neurons contributes significantly to the generation of REM sleep, and if correct then inactivation of such neurons ought to suppress REM sleep. We test this hypothesis using bilateral microperfusion of the 5-HT(1A) receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT, 10 mum) into the PPTn; this tool has been shown to selectively silence REM sleep-active PPTn neurons while the activity of wake/REM sleep-active PPTn neurons is unaffected. Contrary to the prevailing model, bilateral microperfusion of 8-OH-DPAT into the PPTn (n = 23 rats) significantly increased REM sleep both as a percentage of the total recording time and sleep time, compared with both within-animal vehicle controls and between-animal time-controls. This increased REM sleep resulted from an increased frequency of REM sleep bouts but not their duration, indicating an effect on mechanisms of REM sleep initiation but not maintenance. Furthermore, an increased proportion of the REM sleep bouts stemmed from periods of low REM sleep drive quantified electrographically. Targeted suppression of 5-HT(1A) receptor-responsive PPTn neurons also increased respiratory rate and respiratory-related genioglossus activity, and increased the frequency and amplitude of the sporadic genioglossus activations occurring during REM sleep. These data indicate that 5-HT(1A) receptor-responsive PPTn neurons normally function to restrain REM sleep by elevating the drive threshold for REM sleep induction, and restrain the expression of respiratory rate and motor activities.

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Organization of vomeronasal sensory coding revealed by fast volumetric calcium imaging.

Publication Date: 2012 Feb 1 PMID: 22302803
Authors: Turaga, D. - Holy, T. E.
Journal: J Neurosci

A long-standing goal in neuroscience is to perform exhaustive recording of each neuron in a functional local circuit. To achieve this goal, one promising approach is optical imaging of fluorescent calcium indicators, but typically the tens or hundreds of cells imaged simultaneously comprise only a tiny percentage of the neurons in an intact circuit. Here, we show that a recent innovation, objective-coupled planar illumination (OCPI) microscopy, permits simultaneous recording from three-dimensional volumes containing many thousand neurons. We used OCPI microscopy to record chemosensory responses in the mouse vomeronasal epithelium, for which expression of hundreds of receptor types implies high functional diversity. The implications of this diversity for sensory coding were examined using several classes of previously reported vomeronasal ligands, including sulfated steroids. A collection of just 12 sulfated steroids activated more than a quarter of the neurons in the apical vomeronasal epithelium; unexpectedly, responses were functionally organized into a modest number of classes with characteristic spatial distribution. Recording from a whole sensory system thus revealed new organizational principles.

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LRRK2 Inhibition Attenuates Microglial Inflammatory Responses.

Publication Date: 2012 Feb 1 PMID: 22302802
Authors: Moehle, M. S. - Webber, P. J. - Tse, T. - Sukar, N. - Standaert, D. G. - Desilva, T. M. - Cowell, R. M. - West, A. B.
Journal: J Neurosci

Missense mutations in leucine-rich repeat kinase 2 (LRRK2) cause late-onset Parkinson's disease (PD), and common genetic variation in LRRK2 modifies susceptibility to Crohn's disease and leprosy. High levels of LRRK2 expression in peripheral monocytes and macrophages suggest a role for LRRK2 in these cells, yet little is known about LRRK2 expression and function in immune cells of the brain. Here, we demonstrate a role for LRRK2 in mediating microglial proinflammatory responses and morphology. In a murine model of neuroinflammation, we observe robust induction of LRRK2 in microglia. Experiments with toll-like receptor 4 (TLR4)-stimulated rat primary microglia show that inflammation increases LRRK2 activity and expression, while inhibition of LRRK2 kinase activity or knockdown of protein attenuates TNFalpha secretion and nitric oxide synthase (iNOS) induction. LRRK2 inhibition blocks TLR4 stimulated microglial process outgrowth and impairs ADP stimulated microglial chemotaxis. However, actin inhibitors that phenocopy inhibition of process outgrowth and chemotaxis fail to modify TLR4 stimulation of TNFalpha secretion and inducible iNOS induction, suggesting that LRRK2 acts upstream of cytoskeleton control as a stress-responsive kinase. These data demonstrate LRRK2 in regulating responses in immune cells of the brain and further implicate microglial involvement in late-onset PD.

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Changing microcircuits in the subplate of the developing cortex.

Publication Date: 2012 Feb 1 PMID: 22302801
Authors: Viswanathan, S. - Bandyopadhyay, S. - Kao, J. P. - Kanold, P. O.
Journal: J Neurosci

Subplate neurons (SPNs) are a population of neurons in the mammalian cerebral cortex that exist predominantly in the prenatal and early postnatal period. Loss of SPNs prevents the functional maturation of the cerebral cortex. SPNs receive subcortical input from the thalamus and relay this information to the developing cortical plate and thereby can influence cortical activity in a feedforward manner. Little is known about potential feedback projections from the cortical plate to SPNs. Thus, we investigated the spatial distribution of intracortical synaptic inputs to SPNs in vitro in mouse auditory cortex by photostimulation. We find that SPNs fell into two broad classes based on their distinct spatial patterns of synaptic inputs. The first class of SPNs receives inputs from only deep cortical layers, while the second class of SPNs receives inputs from deep as well as superficial layers including layer 4. We find that superficial cortical inputs to SPNs emerge in the second postnatal week and that SPNs that receive superficial cortical input are located more superficially than those that do not. Our data thus suggest that distinct circuits are present in the subplate and that, while SPNs participate in an early feedforward circuit, they are also involved in a feedback circuit at older ages. Together, our results show that SPNs are tightly integrated into the developing thalamocortical and intracortical circuit. The feedback projections from the cortical plate might enable SPNs to amplify thalamic inputs to SPNs.

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Differential DNA methylation patterns define status epilepticus and epileptic tolerance.

Publication Date: 2012 Feb 1 PMID: 22302800
Authors: Miller-Delaney, S. F. - Das, S. - Sano, T. - Jimenez-Mateos, E. M. - Bryan, K. - Buckley, P. G. - Stallings, R. L. - Henshall, D. C.
Journal: J Neurosci

Prolonged seizures (status epilepticus) produce pathophysiological changes in the hippocampus that are associated with large-scale, wide-ranging changes in gene expression. Epileptic tolerance is an endogenous program of cell protection that can be activated in the brain by previous exposure to a non-harmful seizure episode before status epilepticus. A major transcriptional feature of tolerance is gene downregulation. Here, through methylation analysis of 34,143 discrete loci representing all annotated CpG islands and promoter regions in the mouse genome, we report the genome-wide DNA methylation changes in the hippocampus after status epilepticus and epileptic tolerance in adult mice. A total of 321 genes showed altered DNA methylation after status epilepticus alone or status epilepticus that followed seizure preconditioning, with >90% of the promoters of these genes undergoing hypomethylation. These profiles included genes not previously associated with epilepsy, such as the polycomb gene Phc2. Differential methylation events generally occurred throughout the genome without bias for a particular chromosomal region, with the exception of a small region of chromosome 4, which was significantly overrepresented with genes hypomethylated after status epilepticus. Surprisingly, only few genes displayed differential hypermethylation in epileptic tolerance. Nevertheless, gene ontology analysis emphasized the majority of differential methylation events between the groups occurred in genes associated with nuclear functions, such as DNA binding and transcriptional regulation. The present study reports select, genome-wide DNA methylation changes after status epilepticus and in epileptic tolerance, which may contribute to regulating the gene expression environment of the seizure-damaged hippocampus.

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Natural versus Synthetic Stimuli for Estimating Receptive Field Models: A Comparison of Predictive Robustness.

Publication Date: 2012 Feb 1 PMID: 22302799
Authors: Talebi, V. - Baker, C. L. Jr
Journal: J Neurosci

An ultimate goal of visual neuroscience is to understand the neural encoding of complex, everyday scenes. Yet most of our knowledge of neuronal receptive fields has come from studies using simple artificial stimuli (e.g., bars, gratings) that may fail to reveal the full nature of a neuron's actual response properties. Our goal was to compare the utility of artificial and natural stimuli for estimating receptive field (RF) models. Using extracellular recordings from simple type cells in cat A18, we acquired responses to three types of broadband stimulus ensembles: two widely used artificial patterns (white noise and short bars), and natural images. We used a primary dataset to estimate the spatiotemporal receptive field (STRF) with two hold-back datasets for regularization and validation. STRFs were estimated using an iterative regression algorithm with regularization and subsequently fit with a zero-memory nonlinearity. Each RF model (STRF and zero-memory nonlinearity) was then used in simulations to predict responses to the same stimulus type used to estimate it, as well as to other broadband stimuli and sinewave gratings. White noise stimuli often elicited poor responses leading to noisy RF estimates, while short bars and natural image stimuli were more successful in driving A18 neurons and producing clear RF estimates with strong predictive ability. Natural image-derived RF models were the most robust at predicting responses to other broadband stimulus ensembles that were not used in their estimation and also provided good predictions of tuning curves for sinewave gratings.

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Inflammatory Effects of Highly Pathogenic H5N1 Influenza Virus Infection in the CNS of Mice.

Publication Date: 2012 Feb 1 PMID: 22302798
Authors: Jang, H. - Boltz, D. - McClaren, J. - Pani, A. K. - Smeyne, M. - Korff, A. - Webster, R. - Smeyne, R. J.
Journal: J Neurosci

The A/VN/1203/04 strain of the H5N1 influenza virus is capable of infecting the CNS of mice and inducing a number of neurodegenerative pathologies. Here, we examined the effects of H5N1 on several pathological aspects affected in parkinsonism, including loss of the phenotype of dopaminergic neurons located in the substantia nigra pars compacta (SNpc), expression of monoamines and indolamines in brain, alterations in SNpc microglia number and morphology, and expression of cytokines, chemokines, and growth factors. We find that H5N1 induces a transient loss of the dopaminergic phenotype in SNpc and now report that this loss recovers by 90 d after infection. A similar pattern of loss and recovery was seen in monoamine levels of the basal ganglia. The inflammatory response in lung and different regions of the brain known to be targets of the H5N1 virus (brainstem, substantia nigra, striatum, and cortex) were examined at 3, 10, 21, 60, and 90 d after infection. In each of these brain regions, we found a significant increase in the number of activated microglia that lasted at least 90 d. We also quantified expression of IL-1alpha, IL-1beta, IL-2, IL-6, IL-9, IL-10, IL-12(p70), IL-13, TNF-alpha, IFN-gamma, granulocyte-macrophage colony-stimulating factor, granulocyte colony-stimulating factor, macrophage colony-stimulating factor, eotaxin, interferon-inducible protein 10, cytokine-induced neutrophil chemoattractant, monocyte chemotactic protein-1, macrophage inflammatory protein (MIP) 1alpha, MIP-1beta, and VEGF, and found that the pattern and levels of expression are dependent on both brain region and time after infection. We conclude that H5N1 infection in mice induces a long-lasting inflammatory response in brain and may play a contributing factor in the development of pathologies in neurodegenerative disorders.

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Mimicking Phosphorylation at Serine 87 Inhibits the Aggregation of Human alpha-Synuclein and Protects against Its Toxicity in a Rat Model of Parkinson's Disease.

Publication Date: 2012 Feb 1 PMID: 22302797
Authors: Oueslati, A. - Paleologou, K. E. - Schneider, B. L. - Aebischer, P. - Lashuel, H. A.
Journal: J Neurosci

Several lines of evidence suggest that phosphorylation of alpha-synuclein (alpha-syn) at S87 or S129 may play an important role in regulating its aggregation, fibrillogenesis, Lewy body formation, and neurotoxicity in vivo. However, whether phosphorylation at these residues enhances or protects against alpha-syn toxicity in vivo remains unknown. In this study, we investigated the cellular and behavioral effect of overexpression of wild-type (WT), S87A, and S87E alpha-syn to block or to mimic S87 phosphorylation, respectively, in the substantia nigra of Wistar rats using recombinant adeno-associated vectors. Our results revealed that WT and S87A overexpression induced alpha-syn aggregation, loss of dopaminergic neurons, and fiber pathology. These neuropathological effects correlated well with the induction of hemi-parkinsonian motor symptoms. Strikingly, overexpression of the phosphomimic mutant S87E did not show any toxic effect on dopaminergic neurons and resulted in significantly less alpha-syn aggregates, dystrophic fibers, and motor impairment. Together, our data demonstrate, for the first time, that mimicking phosphorylation at S87 inhibits alpha-syn aggregation and protects against alpha-syn-induced toxicity in vivo, suggesting that phosphorylation at this residue would play an important role in controlling alpha-syn neuropathology. In addition, our results provide strong evidence for a direct correlation between alpha-syn-induced neurotoxicity, fiber pathology, and motor impairment and the extent of alpha-syn aggregation in vivo, suggesting that lowering alpha-syn levels and/or blocking its aggregation are viable therapeutic strategies for the treatment of Parkinson's disease and related synucleinopathies.

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Neuronal glutamate transporters regulate glial excitatory transmission.

Publication Date: 2012 Feb 1 PMID: 22302796
Authors: Tsai, M. C. - Tanaka, K. - Overstreet-Wadiche, L. - Wadiche, J. I.
Journal: J Neurosci

In the CNS, excitatory amino acid transporters (EAATs) localized to neurons and glia terminate the actions of synaptically released glutamate. Whereas glial transporters are primarily responsible for maintaining low ambient levels of extracellular glutamate, neuronal transporters have additional roles in shaping excitatory synaptic transmission. Here we test the hypothesis that the expression level of the Purkinje cell (PC)-specific transporter, EAAT4, near parallel fiber (PF) release sites controls the extrasynaptic glutamate concentration transient following synaptic stimulation. Expression of EAAT4 follows a parasagittal banding pattern that allows us to compare regions of high and low EAAT4-expressing PCs. Using EAAT4 promoter-driven eGFP reporter mice together with pharmacology and genetic deletion, we show that the level of neuronal transporter expression influences extrasynaptic transmission from PFs to adjacent Bergmann glia (BG). Surprisingly, a twofold difference in functional EAAT4 levels is sufficient to alter signaling to BG, although EAAT4 may only be responsible for removing a fraction of released glutamate. These results demonstrate that physiological regulation of neuronal transporter expression can alter extrasynaptic neuroglial signaling.

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The Nucleosome Remodeling and Deacetylase Chromatin Remodeling (NuRD) Complex Is Required for Peripheral Nerve Myelination.

Publication Date: 2012 Feb 1 PMID: 22302795
Authors: Hung, H. - Kohnken, R. - Svaren, J.
Journal: J Neurosci

Several key transcription factors and coregulators important to peripheral nerve myelination have been identified, but the contributions of specific chromatin remodeling complexes to peripheral nerve myelination have not been analyzed. Chromodomain helicase DNA-binding protein 4 (Chd4) is the core catalytic subunit of the nucleosome remodeling and deacetylase (NuRD) chromatin remodeling complex. Previous studies have shown Chd4 interacts with Nab (NGFI-A/Egr-binding) corepressors, which are required for early growth response 2 (Egr2/Krox20), to direct peripheral nerve myelination by Schwann cells. In this study, we examined the developmental importance of the NuRD complex in peripheral nerve myelination through the generation of conditional Chd4 knock-out mice in Schwann cells (Chd4(loxP/loxP); P0-cre). Chd4 conditional null mice were found to have delayed myelination, radial sorting defects, hypomyelination, and the persistence of promyelinating Schwann cells. Loss of Chd4 leads to elevated expression of immature Schwann cell genes (Id2, c-Jun, and p75), and sustained expression of the promyelinating Schwann cell gene, Oct6/Scip, without affecting the levels of Egr2/Krox20. Furthermore, Schwann cell proliferation is upregulated in Chd4-null sciatic nerve. In vivo chromatin immunoprecipitation studies reveal recruitment of Chd4 and another NuRD component, Mta2, to genes that are positively and negatively regulated by Egr2 during myelination. Together, these results underscore the necessity of Chd4 function to guide proper terminal differentiation of Schwann cells and implicate the NuRD chromatin remodeling complex as a requisite factor in timely and stable peripheral nerve myelination.

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Using interocular suppression and EEG to study semantic processing.

Publication Date: 2012 Feb 1 PMID: 22302794
Authors: Heyman, T. - Moors, P.
Journal: J Neurosci

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The frequency of visually induced gamma-band oscillations depends on the size of early human visual cortex.

Publication Date: 2012 Jan 25 PMID: 22279235
Authors: Schwarzkopf, D. S. - Robertson, D. J. - Song, C. - Barnes, G. R. - Rees, G.
Journal: J Neurosci

The structural and functional architecture of the human brain is characterized by considerable variability, which has consequences for visual perception. However, the neurophysiological events mediating the relationship between interindividual differences in cortical surface area and visual perception have, until now, remained unknown. Here, we show that the retinotopically defined surface areas of central V1 and V2 are correlated with the peak frequency of visually induced oscillations in the gamma band, as measured with magnetoencephalography. Gamma-band oscillations are thought to play an important role in visual processing. We propose that individual differences in macroscopic gamma frequency may be attributed to interindividual variability in the microscopic architecture of visual cortex.

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Concentration-dependent requirement for local protein synthesis in motor neuron subtype-specific response to axon guidance cues.

Publication Date: 2012 Jan 25 PMID: 22279234
Authors: Nedelec, S. - Peljto, M. - Shi, P. - Amoroso, M. W. - Kam, L. C. - Wichterle, H.
Journal: J Neurosci

Formation of functional motor circuits relies on the ability of distinct spinal motor neuron subtypes to project their axons with high precision to appropriate muscle targets. While guidance cues contributing to motor axon pathfinding have been identified, the intracellular pathways underlying subtype-specific responses to these cues remain poorly understood. In particular, it remains controversial whether responses to axon guidance cues depend on axonal protein synthesis. Using a growth cone collapse assay, we demonstrate that mouse embryonic stem cell-derived spinal motor neurons (ES-MNs) respond to ephrin-A5, Sema3f, and Sema3a in a concentration-dependent manner. At low doses, ES-MNs exhibit segmental or subtype-specific responses, while this selectivity is lost at higher concentrations. Response to high doses of semaphorins and to all doses of ephrin-A5 is protein synthesis independent. In contrast, using microfluidic devices and stripe assays, we show that growth cone collapse and guidance at low concentrations of semaphorins rely on local protein synthesis in the axonal compartment. Similar bimodal response to low and high concentrations of guidance cues is observed in human ES-MNs, pointing to a general mechanism by which neurons increase their repertoire of responses to the limited set of guidance cues involved in neural circuit formation.

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Stress-Induced Activation of the Dynorphin/kappa-Opioid Receptor System in the Amygdala Potentiates Nicotine Conditioned Place Preference.

Publication Date: 2012 Jan 25 PMID: 22279233
Authors: Smith, J. S. - Schindler, A. G. - Martinelli, E. - Gustin, R. M. - Bruchas, M. R. - Chavkin, C.
Journal: J Neurosci

Many smokers describe the anxiolytic and stress-reducing effects of nicotine, the primary addictive component of tobacco, as a principal motivation for continued drug use. Recent evidence suggests that activation of the stress circuits, including the dynorphin/kappa-opioid receptor system, modulates the rewarding effects of addictive drugs. In the present study, we find that nicotine produced dose-dependent conditioned place preference (CPP) in mice. kappa-Receptor activation, either by repeated forced swim stress or U50,488 (5 or 10 mg/kg, i.p.) administration, significantly potentiated the magnitude of nicotine CPP. The increase in nicotine CPP was blocked by the kappa-receptor antagonist norbinaltorphimine (norBNI) either systemically (10 mg/kg, i.p.) or by local injection in the amygdala (2.5 mug) without affecting nicotine reward in the absence of stress. U50,488 (5 mg/kg, i.p.) produced anxiety-like behaviors in the elevated-plus maze and novel object exploration assays, and the anxiety-like behaviors were attenuated both by systemic nicotine (0.5 mg/kg, s.c.) and local injection of norBNI into the amygdala. Local norBNI injection in the ventral posterior thalamic nucleus (an adjacent brain region) did not block the potentiation of nicotine CPP or the anxiogenic-like effects of kappa-receptor activation. These results suggest that the rewarding effects of nicotine may include a reduction in the stress-induced anxiety responses caused by activation of the dynorphin/kappa-opioid system. Together, these data implicate the amygdala as a key region modulating the appetitive properties of nicotine, and suggest that kappa-opioid antagonists may be useful therapeutic tools to reduce stress-induced nicotine craving.

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Event-related nociceptive arousal enhances memory consolidation for neutral scenes.

Publication Date: 2012 Jan 25 PMID: 22279232
Authors: Schwarze, U. - Bingel, U. - Sommer, T.
Journal: J Neurosci

The superior memory for emotional events has been attributed to the beneficial effects of noradrenaline released into the amygdala attributable to arousal. Noradrenaline mediates the effects of different hormones and neurotransmitters, including adrenal stress hormones on consolidation (McGaugh, 2004; Roozendaal et al., 2009). The majority of human fMRI studies of the enhancement of emotional memories contrasted successful encoding of emotionally arousing and neutral stimuli (LaBar and Cabeza, 2006; Murty et al., 2010). Recently, it was highlighted that emotional stimuli elicit not only arousal but also intensify cognitive processes that contribute to the enhanced memory. In particular, the enhanced use of selective attention as well as the greater distinctiveness and semantic relatedness of emotional stimuli influence memory formation (Talmi et al., 2007a). The present study aimed to explore the effects of arousal on memory formation independent of these cognitive factors in an event-related manner. Arousal was induced by the application of a nociceptive stimulus briefly after the presentation of neutral scenes. The results show a purely arousal-driven memory enhancement for the neutral scenes that differs in critical aspects from the superior memory for emotional stimuli. In particular, the enhancement was only evident after consolidation and exclusively based on an increase in item familiarity but not recollection. Moreover, successful memory formation for stimuli followed by arousal was correlated with activity in the parahippocampal cortex but not the amygdala, as is the case for emotional stimuli.

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Retromer Binds the FANSHY Sorting Motif in SorLA to Regulate Amyloid Precursor Protein Sorting and Processing.

Publication Date: 2012 Jan 25 PMID: 22279231
Authors: Fjorback, A. W. - Seaman, M. - Gustafsen, C. - Mehmedbasic, A. - Gokool, S. - Wu, C. - Militz, D. - Schmidt, V. - Madsen, P. - Nyengaard, J. R. - Willnow, T. E. - Christensen, E. I. - Mobley, W. B. - Nykjaer, A. - Andersen, O. M.
Journal: J Neurosci

sorLA is a sorting receptor for amyloid precursor protein (APP) genetically linked to Alzheimer's disease (AD). Retromer, an adaptor complex in the endosome-to-Golgi retrieval pathway, has been implicated in APP transport because retromer deficiency leads to aberrant APP sorting and processing and levels of retromer proteins are altered in AD. Here we report that sorLA and retromer functionally interact in neurons to control trafficking and amyloidogenic processing of APP. We have identified a sequence (FANSHY) in the cytoplasmic domain of sorLA that is recognized by the VPS26 subunit of the retromer complex. Accordingly, we characterized the interaction between the retromer complex and sorLA and determined the role of retromer on sorLA-dependent sorting and processing of APP. Mutations in the VPS26 binding site resulted in receptor redistribution to the endosomal network, similar to the situation seen in cells with VPS26 knockdown. The sorLA mutant retained APP-binding activity but, as opposed to the wild-type receptor, misdirected APP into a distinct non-Golgi compartment, resulting in increased amyloid processing. In conclusion, our data provide a molecular link between reduced retromer expression and increased amyloidogenesis as seen in patients with sporadic AD.

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NP1 Regulates Neuronal Activity-Dependent Accumulation of BAX in Mitochondria and Mitochondrial Dynamics.

Publication Date: 2012 Jan 25 PMID: 22279230
Authors: Clayton, K. B. - Podlesniy, P. - Figueiro-Silva, J. - Lopez-Domenech, G. - Benitez, L. - Enguita, M. - Abad, M. A. - Soriano, E. - Trullas, R.
Journal: J Neurosci

In cultured cerebellar granule neurons, low neuronal activity triggers the intrinsic program of apoptosis, which requires protein synthesis-dependent BAX translocation to mitochondria, a process that may underlie neuronal damage in neurodegeneration. However, the mechanisms that link neuronal activity with the induction of the mitochondrial program of apoptosis remain unclear. Neuronal pentraxin 1 (NP1) is a pro-apoptotic protein induced by low neuronal activity that is increased in damaged neurites in Alzheimer's disease-affected brains. Here we report that NP1 facilitates the accumulation of BAX in mitochondria and regulates mitochondrial dynamics during apoptosis in rat and mouse cerebellar granule neurons in culture. Reduction of neuronal activity increases NP1 protein levels in mitochondria and contributes to mitochondrial fragmentation in a Bax-dependent manner. In addition, NP1 is involved in mitochondrial transport in healthy neurons. These results show that NP1 is targeted to mitochondria acting upstream of BAX and uncover a novel function for NP1 in the regulation of mitochondrial dynamics and trafficking during apoptotic neurodegeneration.

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Novelty detection in the human auditory brainstem.

Publication Date: 2012 Jan 25 PMID: 22279229
Authors: Slabu, L. - Grimm, S. - Escera, C.
Journal: J Neurosci

Auditory deviance detection has been associated with a human auditory-evoked potential (AEP), the mismatch negativity, generated in the auditory cortex 100-200 ms from sound change onset. Yet, single-unit recordings in animals suggest much earlier ( approximately 20-40 ms), and anatomically lower (i.e., thalamus and midbrain) deviance detection. In humans, recordings of the scalp middle-latency AEPs have confirmed early ( approximately 30-40 ms) deviance detection. However, involvement of the human auditory brainstem in deviance detection has not yet been demonstrated. Here we recorded the auditory brainstem frequency-following response (FFR) to consonant-vowel stimuli (/ba/, /wa/) in young adults, with stimuli arranged in oddball and reversed oddball blocks (deviant probability, p = 0.2), allowing for the comparison of FFRs to the same physical stimuli presented in different contextual roles. Whereas no effect was observed for the /wa/ syllable, we found for the /ba/ syllable a reduction in the brainstem FFR to deviant stimuli compared with standard ones and to similar stimuli arranged in a control block, with five equiprobable, rarely occurring sounds. These findings demonstrate that the human auditory brainstem is able to encode regularities in the recent auditory past to detect novel events, and confirm the multiple anatomical and temporal scales of human deviance detection.

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Wandering neuronal migration in the postnatal vertebrate forebrain.

Publication Date: 2012 Jan 25 PMID: 22279228
Authors: Scott, B. B. - Gardner, T. - Ji, N. - Fee, M. S. - Lois, C.
Journal: J Neurosci

Most non-mammalian vertebrate species add new neurons to existing brain circuits throughout life, a process thought to be essential for tissue maintenance, repair, and learning. How these new neurons migrate through the mature brain and which cues trigger their integration within a functioning circuit is not known. To address these questions, we used two-photon microscopy to image the addition of genetically labeled newly generated neurons into the brain of juvenile zebra finches. Time-lapse in vivo imaging revealed that the majority of migratory new neurons exhibited a multipolar morphology and moved in a nonlinear manner for hundreds of micrometers. Young neurons did not use radial glia or blood vessels as a migratory scaffold; instead, cells extended several motile processes in different directions and moved by somal translocation along an existing process. Neurons were observed migrating for approximately 2 weeks after labeling injection. New neurons were observed to integrate in close proximity to the soma of mature neurons, a behavior that may explain the emergence of clusters of neuronal cell bodies in the adult songbird brain. These results provide direct, in vivo evidence for a wandering form of neuronal migration involved in the addition of new neurons in the postnatal brain.

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Gustatory receptors required for avoiding the insecticide L-canavanine.

Publication Date: 2012 Jan 25 PMID: 22279227
Authors: Lee, Y. - Kang, M. J. - Shim, J. - Cheong, C. U. - Moon, S. J. - Montell, C.
Journal: J Neurosci

Insect survival depends on contact chemosensation to sense and avoid consuming plant-derived insecticides, such as l-canavanine. Members of a family of approximately 60 gustatory receptors (GRs) comprise the main peripheral receptors responsible for taste sensation in Drosophila. However, the roles of most Drosophila GRs are unknown. In addition to GRs, a G protein-coupled receptor, DmXR, has been reported to be required for detecting l-canavanine. Here, we showed that GRs are essential for responding to l-canavanine and that flies missing DmXR displayed normal l-canavanine avoidance and l-canavanine-evoked action potentials. Mutations disrupting either Gr8a or Gr66a resulted in an inability to detect l-canavanine. We found that l-canavanine stimulated action potentials in S-type sensilla, which were where Gr8a and Gr66a were both expressed, but not in Gr66a-expressing sensilla that did not express Gr8a. l-canavanine-induced action potentials were also abolished in the Gr8a and Gr66a mutant animals. Gr8a was narrowly required for responding to l-canavanine, in contrast to Gr66a, which was broadly required for responding to other noxious tastants. Our data suggest that GR8a and GR66a are subunits of an l-canavanine receptor and that GR8a contributes to the specificity for l-canavanine.

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Single neuron firing properties impact correlation-based population coding.

Publication Date: 2012 Jan 25 PMID: 22279226
Authors: Hong, S. - Ratte, S. - Prescott, S. A. - De Schutter, E.
Journal: J Neurosci

Correlated spiking has been widely observed, but its impact on neural coding remains controversial. Correlation arising from comodulation of rates across neurons has been shown to vary with the firing rates of individual neurons. This translates into rate and correlation being equivalently tuned to the stimulus; under those conditions, correlated spiking does not provide information beyond that already available from individual neuron firing rates. Such correlations are irrelevant and can reduce coding efficiency by introducing redundancy. Using simulations and experiments in rat hippocampal neurons, we show here that pairs of neurons receiving correlated input also exhibit correlations arising from precise spike-time synchronization. Contrary to rate comodulation, spike-time synchronization is unaffected by firing rate, thus enabling synchrony- and rate-based coding to operate independently. The type of output correlation depends on whether intrinsic neuron properties promote integration or coincidence detection: "ideal" integrators (with spike generation sensitive to stimulus mean) exhibit rate comodulation, whereas ideal coincidence detectors (with spike generation sensitive to stimulus variance) exhibit precise spike-time synchronization. Pyramidal neurons are sensitive to both stimulus mean and variance, and thus exhibit both types of output correlation proportioned according to which operating mode is dominant. Our results explain how different types of correlations arise based on how individual neurons generate spikes, and why spike-time synchronization and rate comodulation can encode different stimulus properties. Our results also highlight the importance of neuronal properties for population-level coding insofar as neural networks can employ different coding schemes depending on the dominant operating mode of their constituent neurons.

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The head of the table: marking the "front" of an object is tightly linked with selection.

Publication Date: 2012 Jan 25 PMID: 22279225
Authors: Xu, Y. - Franconeri, S. L.
Journal: J Neurosci

Objects in the world do not have a surface that can be objectively labeled the "front." We impose this designation on one surface of an object according to several cues, including which surface is associated with the most task-relevant information or the direction of motion of an object. However, when these cues are competing, weak, or absent, we can also flexibly assign one surface as the front. One possibility is that this assignment is guided by the location of the "spotlight" of selection, where the selected region becomes the front. Here we used an electrophysiological correlate to show a direct temporal link between object structure assignments and the spatial locus of selection. We found that when human participants viewed a shape whose front and back surfaces were ambiguous, seeing a given surface as front was associated with selectively attending to that location. In Experiment 1, this pattern occurred during directed rapid (every 1 s) switches in structural percepts. In Experiment 2, this pattern occurred during spontaneous reversals, from 900 ms before to 600 ms after the reported percept. These results suggest that the distribution of selective attention might guide the organization of object structure.

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The Amplitude and Timing of the BOLD Signal Reflects the Relationship between Local Field Potential Power at Different Frequencies.

Publication Date: 2012 Jan 25 PMID: 22279224
Authors: Magri, C. - Schridde, U. - Murayama, Y. - Panzeri, S. - Logothetis, N. K.
Journal: J Neurosci

There is growing evidence that several components of the mass neural activity contributing to the local field potential (LFP) can be partly separated by decomposing the LFP into nonoverlapping frequency bands. Although the blood oxygen level-dependent (BOLD) signal has been found to correlate preferentially with specific frequency bands of the LFP, it is still unclear whether the BOLD signal relates to the activity expressed by each LFP band independently of the others or if, instead, it also reflects specific relationships among different bands. We investigated these issues by recording, simultaneously and with high spatiotemporal resolution, BOLD signal and LFP during spontaneous activity in early visual cortices of anesthetized monkeys (Macaca mulatta). We used information theory to characterize the statistical dependency between BOLD and LFP. We found that the alpha (8-12 Hz), beta (18-30 Hz), and gamma (40-100 Hz) LFP bands were informative about the BOLD signal. In agreement with previous studies, gamma was the most informative band. Both increases and decreases in BOLD signal reliably followed increases and decreases in gamma power. However, both alpha and beta power signals carried information about BOLD that was largely complementary to that carried by gamma power. In particular, the relationship between alpha and gamma power was reflected in the amplitude of the BOLD signal, while the relationship between beta and gamma bands was reflected in the latency of BOLD with respect to significant changes in gamma power. These results lay the basis for identifying contributions of different neural pathways to cortical processing using fMRI.

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Time of day regulates subcellular trafficking, tripartite synaptic localization, and polyadenylation of the astrocytic fabp7 mRNA.

Publication Date: 2012 Jan 25 PMID: 22279223
Authors: Gerstner, J. R. - Vanderheyden, W. M. - Lavaute, T. - Westmark, C. J. - Rouhana, L. - Pack, A. I. - Wickens, M. - Landry, C. F.
Journal: J Neurosci

The astrocyte brain fatty acid binding protein (Fabp7) has previously been shown to have a coordinated diurnal regulation of mRNA and protein throughout mouse brain, and an age-dependent decline in protein expression within synaptoneurosomal fractions. Mechanisms that control time-of-day changes in expression and trafficking Fabp7 to the perisynaptic process are not known. In this study, we confirmed an enrichment of Fabp7 mRNA and protein in the astrocytic perisynaptic compartment, and observed a diurnal change in the intracellular distribution of Fabp7 mRNA in molecular layers of hippocampus. Northern blotting revealed a coordinated time-of-day-dependent oscillation for the Fabp7 mRNA poly(A) tail throughout murine brain. Cytoplasmic polyadenylation element-binding protein 1 (CPEB1) regulates subcellular trafficking and translation of synaptic plasticity-related mRNAs. Here we show that Fabp7 mRNA coimmunoprecipitated with CPEB1 from primary mouse astrocyte extracts, and its 3'UTR contains phylogenetically conserved cytoplasmic polyadenylation elements (CPEs) capable of regulating translation of reporter mRNAs during Xenopus oocyte maturation. Given that Fabp7 expression is confined to astrocytes and neural progenitors in adult mouse brain, the synchronized cycling pattern of Fabp7 mRNA is a novel discovery among known CPE-regulated transcripts. These results implicate circadian, sleep, and/or metabolic control of CPEB-mediated subcellular trafficking and localized translation of Fabp7 mRNA in the tripartite synapse of mammalian brain.

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Early exposure to alcohol leads to permanent impairment of dendritic excitability in neocortical pyramidal neurons.

Publication Date: 2012 Jan 25 PMID: 22279222
Authors: Granato, A. - Palmer, L. M. - De Giorgio, A. - Tavian, D. - Larkum, M. E.
Journal: J Neurosci

Exposure to alcohol in utero is a well known cause of mental retardation in humans. Using experimental models of fetal alcohol spectrum disorder, it has been demonstrated that cortical pyramidal neurons and their projections are profoundly and permanently impaired. Yet, how the functional features of these cells are modified and how such modifications impact cognitive processes is still unknown. To address this, we studied the intrinsic electrophysiological properties of pyramidal neurons in young adult rats (P30-P60) exposed to ethanol inhalation during the first week of postnatal life (P2-P6). Dual whole-cell recordings from the soma and distal apical dendrites were performed and, following the injection of depolarizing current into the dendrites, layer 5 neurons from ethanol-treated (Et) animals displayed a lower number and a shorter duration of dendritic spikes, attributable to a downregulation of calcium electrogenesis. As a consequence, the mean number of action potentials recorded at the soma after dendritic current injection was also lower in Et animals. No significant differences between Et and controls were observed in the firing pattern elicited in layer 5 neurons by steps of depolarizing somatic current, even though the firing rate was significantly lower in Et animals. The firing pattern and the firing rate of layer 2/3 neurons were not affected by alcohol exposure.

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Saccular-specific hair cell addition correlates with reproductive state-dependent changes in the auditory saccular sensitivity of a vocal fish.

Publication Date: 2012 Jan 25 PMID: 22279221
Authors: Coffin, A. B. - Mohr, R. A. - Sisneros, J. A.
Journal: J Neurosci

The plainfin midshipman fish, Porichthys notatus, is a seasonal breeding teleost fish for which vocal-acoustic communication is essential for its reproductive success. Female midshipman use the saccule as the primary end organ for hearing to detect and locate "singing" males that produce multiharmonic advertisement calls during the summer breeding season. Previous work has shown that female auditory sensitivity changes seasonally with reproductive state; summer reproductive females become better suited than winter nonreproductive females to detect and encode the dominant higher harmonic components in the male's advertisement call, which are potentially critical for mate selection and localization. Here, we test the hypothesis that these seasonal changes in female auditory sensitivity are concurrent with seasonal increases in saccular hair cell receptors. We show that there is increased hair cell density in reproductive females and that this increase is not dependent on body size since similar changes in hair cell density were not found in the other inner ear end organs. We also observed an increase in the number of small, potentially immature saccular hair bundles in reproductive females. The seasonal increase in saccular hair cell density and smaller hair bundles in reproductive females was paralleled by a dramatic increase in the magnitude of the evoked saccular potentials and a corresponding decrease in the auditory thresholds recorded from the saccule. This demonstration of correlated seasonal plasticity of hair cell addition and auditory sensitivity may in part facilitate the adaptive auditory plasticity of this species to enhance mate detection and localization during breeding.

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Phosphorylation of CRMP2 (Collapsin Response Mediator Protein 2) Is Involved in Proper Dendritic Field Organization.

Publication Date: 2012 Jan 25 PMID: 22279220
Authors: Yamashita, N. - Ohshima, T. - Nakamura, F. - Kolattukudy, P. - Honnorat, J. - Mikoshiba, K. - Goshima, Y.
Journal: J Neurosci

Collapsin response mediator proteins (CRMPs) are intracellular proteins that mediate signals for several extracellular molecules, such as Semaphorin3A and neurotrophins. The phosphorylation of CRMP1 and CRMP2 by Cdk5 at Ser522 is involved in axonal guidance and spine development. Here, we found that the Ser522-phosphorylated CRMP1 and/or CRMP2 are enriched in the dendrites of cultured cortical neurons and P7 cortical section. To determine the physiological role of CRMPs in dendritic development, we generated CRMP2 knock-in mutant mice (crmp2(ki/ki)) in which the Ser residue at 522 was replaced with Ala. Strikingly, the cortical basal dendrites of double mutant crmp2(ki/ki) and crmp1(-/-) mice exhibited severe abnormal dendritic patterning, which we defined as "curling phenotype." These findings demonstrate that the function of CRMP1 and CRMP2 synergistically control dendritic projection, and the phosphorylation of CRMP2 at Ser522 is essential for proper dendritic field organization in vivo.

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Higher Binding of the Dopamine D3 Receptor-Preferring Ligand [11C]-(+)-Propyl-Hexahydro-Naphtho-Oxazin in Methamphetamine Polydrug Users: A Positron Emission Tomography Study.

Publication Date: 2012 Jan 25 PMID: 22279219
Authors: Boileau, I. - Payer, D. - Houle, S. - Behzadi, A. - Rusjan, P. M. - Tong, J. - Wilkins, D. - Selby, P. - George, T. P. - Zack, M. - Furukawa, Y. - McCluskey, T. - Wilson, A. A. - Kish, S. J.
Journal: J Neurosci

Positron emission tomography (PET) findings suggesting lower D(2)-type dopamine receptors and dopamine concentration in brains of stimulant users have prompted speculation that increasing dopamine signaling might help in drug treatment. However, this strategy needs to consider the possibility, based on animal and postmortem human data, that dopaminergic activity at the related D(3) receptor might, in contrast, be elevated and thereby contribute to drug-taking behavior. We tested the hypothesis that D(3) receptor binding is above normal in methamphetamine (MA) polydrug users, using PET and the D(3)-preferring ligand [(11)C]-(+)-propyl-hexahydro-naphtho-oxazin ([(11)C]-(+)-PHNO). Sixteen control subjects and 16 polydrug users reporting MA as their primary drug of abuse underwent PET scanning after [(11)C]-(+)-PHNO. Compared with control subjects, drug users had higher [(11)C]-(+)-PHNO binding in the D(3)-rich midbrain substantia nigra (SN; +46%; p < 0.02) and in the globus pallidus (+9%; p = 0.06) and ventral pallidum (+11%; p = 0.1), whereas binding was slightly lower in the D(2)-rich dorsal striatum (approximately -4%, NS; -12% in heavy users, p = 0.01) and related to drug-use severity. The [(11)C]-(+)-PHNO binding ratio in D(3)-rich SN versus D(2)-rich dorsal striatum was 55% higher in MA users (p = 0.004), with heavy but not moderate users having ratios significantly different from controls. [(11)C]-(+)-PHNO binding in SN was related to self-reported "drug wanting." We conclude that the dopamine D(3) receptor, unlike the D(2) receptor, might be upregulated in brains of MA polydrug users, although lower dopamine levels in MA users could have contributed to the finding. Pharmacological studies are needed to establish whether normalization of D(3) receptor function could reduce vulnerability to relapse in stimulant abuse.

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The alpha1K276E Startle Disease Mutation Reveals Multiple Intermediate States in the Gating of Glycine Receptors.

Publication Date: 2012 Jan 25 PMID: 22279218
Authors: Lape, R. - Plested, A. J. - Moroni, M. - Colquhoun, D. - Sivilotti, L. G.
Journal: J Neurosci

Loss-of-function mutations in human glycine receptors cause hyperekplexia, a rare inherited disease associated with an exaggerated startle response. We have studied a human disease mutation in the M2-M3 loop of the glycine receptor alpha1 subunit (K276E) using direct fitting of mechanisms to single-channel recordings with the program HJCFIT. Whole-cell recordings from HEK293 cells showed the mutation reduced the receptor glycine sensitivity. In single-channel recordings, rat homomeric alpha1 K276E receptors were barely active, even at 200 mm glycine. Coexpression of the beta subunit partially rescued channel function. Heteromeric mutant channels opened in brief bursts at 300 mum glycine (a concentration that is near-maximal for wild type) and reached a maximum one-channel open probability of about 45% at 100 mm glycine (compared to 96% for wild type). Distributions of apparent open times contained more than one component in high glycine and, therefore, could not be described by mechanisms with only one fully liganded open state. Fits to the data were much better with mechanisms in which opening can also occur from more than one fully liganded intermediate (e.g., "primed" models). Brief pulses of glycine ( approximately 3 ms, 30 mm) applied to mutant channels in outside-out patches activated currents with a slower rise time (1.5 ms) than those of wild-type channels (0.2 ms) and a much faster decay. These features were predicted reasonably well by the mechanisms obtained from fitting single-channel data. Our results show that, by slowing and impairing channel gating, the K276E mutation facilitates the detection of closed reaction intermediates in the activation pathway of glycine channels.

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Modulation of Frontostriatal Interaction Aligns with Reduced Primary Reward Processing under Serotonergic Drugs.

Publication Date: 2012 Jan 25 PMID: 22279217
Authors: Abler, B. - Gron, G. - Hartmann, A. - Metzger, C. - Walter, M.
Journal: J Neurosci

Recently, functional interactions between anteroventral prefrontal cortex and nucleus accumbens (NAcc) have been shown to relate to behavior counteracting reward-desiring (Diekhof and Gruber, 2010). Downregulation of the reward system by serotonin has also been suggested as the mode of action accounting for unsatisfactory effects of serotonin reuptake inhibitors (SSRIs) such as insufficient alleviation or even increase of anhedonia, and loss of interest. However, understanding of the in vivo mechanisms of SSRI-related alteration of the human reward system is still incomplete. Using functional magnetic resonance imaging (fMRI) within a double-blind cross-over within-subjects study design and administering the SSRI paroxetine, the dopamine/norepinephrine reuptake inhibitor bupropione, and placebo for 7 d each, we investigated a group of 18 healthy male subjects. Under paroxetine, subjects showed significantly decreased activation of the bilateral NAcc during processing of primary rewards (erotic videos), but not under bupropion. Similar to the previous study, analysis of psychophysiological interactions revealed that this downregulation relied on negative interactions between left and right NAcc fMRI signals and the bilateral anteroventral prefrontal cortex that now were significantly enhanced under paroxetine and reduced under bupropion. Individual drug-dependent modulations of interacting brain regions were significantly associated with individual expressions of impulsivity as a personality trait. Our results corroborate and extend previous insights on interregional crosstalk from secondary to primary rewards and demonstrate parallels between active inhibitory control of and serotonergic effects on the dopaminergic reward system's activity.

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Cav2.1 in Cerebellar Purkinje Cells Regulates Competitive Excitatory Synaptic Wiring, Cell Survival, and Cerebellar Biochemical Compartmentalization.

Publication Date: 2012 Jan 25 PMID: 22279216
Authors: Miyazaki, T. - Yamasaki, M. - Hashimoto, K. - Yamazaki, M. - Abe, M. - Usui, H. - Kano, M. - Sakimura, K. - Watanabe, M.
Journal: J Neurosci

In the adult cerebellum, each Purkinje cell (PC) is innervated by a single climbing fiber (CF) in proximal dendrites and 10(5)-10(6) parallel fibers (PFs) in distal dendrites. This organized wiring is established postnatally through heterosynaptic competition between PFs and CFs and homosynaptic competition among multiple CFs. Using PC-specific Ca(v)2.1 knock-out mice (PC-Ca(v)2.1 KO mice), we have demonstrated recently that postsynaptic Ca(v)2.1 plays a key role in the homosynaptic competition by promoting functional strengthening and dendritic translocation of single "winner" CFs. Here, we report that Ca(v)2.1 in PCs, but not in granule cells, is also essential for the heterosynaptic competition. In PC-Ca(v)2.1 KO mice, the extent of CF territory was limited to the soma and basal dendrites, whereas PF territory was expanded reciprocally. Consequently, the proximal somatodendritic domain of PCs displayed hyperspiny transformation and fell into chaotic innervation by multiple CFs and numerous PFs. PC-Ca(v)2.1 KO mice also displayed patterned degeneration of PCs, which occurred preferentially in aldolase C/zebrin II-negative cerebellar compartments. Furthermore, the mutually complementary expression of phospholipase Cbeta3 (PLCbeta3) and PLCbeta4 was altered such that their normally sharp boundary was blurred in the PCs of PC-Ca(v)2.1 KO mice. This blurring was caused by an impaired posttranscriptional downregulation of PLCbeta3 in PLCbeta4-dominant PCs during the early postnatal period. A similar alteration was noted in the banded expression of the glutamate transporter EAAT4 in PC-Ca(v)2.1 KO mice. Therefore, Ca(v)2.1 in PCs is essential for competitive synaptic wiring, cell survival, and the establishment of precise boundaries and reciprocity of biochemical compartments in PCs.

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Kainate receptor-induced retrograde inhibition of glutamatergic transmission in vasopressin neurons.

Publication Date: 2012 Jan 25 PMID: 22279215
Authors: Bonfardin, V. D. - Theodosis, D. T. - Konnerth, A. - Oliet, S. H.
Journal: J Neurosci

Presynaptic kainate receptors (KARs) exert a modulatory action on transmitter release. We here report that applications of agonists of GluK1-containing KARs in the rat supraoptic nucleus has an opposite action on glutamatergic transmission according to the phenotype of the postsynaptic neuron. Whereas glutamate release was facilitated in oxytocin (OT) neurons, it was inhibited in vasopressin (VP) cells. Interestingly, an antagonist of GluK1-containing KARs caused an inhibition of glutamate release in both OT and VP neurons, revealing the existence of tonically activated presynaptic KARs that are positively coupled to transmitter release. We thus postulated that the inhibition of glutamate release observed with exogenous applications of GluK1 agonists on VP neurons could be indirect. In agreement with this hypothesis, we first showed that functional GluK1-containing KARs were present postsynaptically on VP neurons but not on OT cells. We next showed that the inhibitory effect induced by exogenous GluK1 receptor agonist was compromised when BAPTA was added in the recording pipette to buffer intracellular Ca(2+) and block the release of a putative retrograde messenger. Under these conditions, GluK1-containing KAR agonist facilitates glutamatergic transmission in VP neurons in a manner similar to that observed for OT neurons and that resulted from the activation of presynaptic GluK1 receptors. GluK1-mediated inhibition of glutamate release in VP neurons was also blocked by a kappa-opioid receptor antagonist. These findings suggest that activation of postsynaptic GluK1-containing KARs on VP neurons leads to the release of dynorphin, which in turn acts on presynaptic kappa-opioid receptors to inhibit glutamate release.

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Human motor plasticity induced by mirror visual feedback.

Publication Date: 2012 Jan 25 PMID: 22279214
Authors: Nojima, I. - Mima, T. - Koganemaru, S. - Thabit, M. N. - Fukuyama, H. - Kawamata, T.
Journal: J Neurosci

The clinical use of mirror visual feedback (MVF) was initially introduced to alleviate phantom pain, and has since been applied to the improvement of hemiparesis following stroke. However, it is not known whether MVF can restore motor function by producing plastic changes in the human primary motor cortex (M1). Here, we used transcranial magnetic stimulation to test whether M1 plasticity is a physiological substrate of MVF-induced motor behavioral improvement. MVF intervention in normal volunteers using a mirror box improved motor behavior and enhanced excitatory functions of the M1. Moreover, behavioral and physiological measures of MVF-induced changes were positively correlated with each other. Improved motor performance occurred after observation of a simple action, but not after repetitive motor training of the nontarget hand without MVF, suggesting the crucial importance of visual feedback. The beneficial effects of MVF were disrupted by continuous theta burst stimulation (cTBS) over the M1, but not the control site in the occipital cortex. However, MVF following cTBS could further improve the motor functions. Our findings indicate that M1 plasticity, especially in its excitatory connections, is an essential component of MVF-based therapies.

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Causal interactions in attention networks predict behavioral performance.

Publication Date: 2012 Jan 25 PMID: 22279213
Authors: Wen, X. - Yao, L. - Liu, Y. - Ding, M.
Journal: J Neurosci

Lesion and functional brain imaging studies have suggested that there are two anatomically nonoverlapping attention networks. The dorsal frontoparietal network controls goal-oriented top-down deployment of attention; the ventral frontoparietal network mediates stimulus-driven bottom-up attentional reorienting. The interaction between the two networks and its functional significance has been considered in the past but no direct test has been carried out. We addressed this problem by recording fMRI data from human subjects performing a trial-by-trial cued visual spatial attention task in which the subject had to respond to target stimuli in the attended hemifield and ignore all stimuli in the unattended hemifield. Correlating Granger causal influences between regions of interest with behavioral performance, we report two main results. First, stronger Granger causal influences from the dorsal attention network (DAN) to the ventral attention network (VAN), i.e., DAN-->VAN, are generally associated with enhanced performance, with right intraparietal sulcus (IPS), left IPS, and right frontal eye field being the main sources of behavior-enhancing influences. Second, stronger Granger causal influences from VAN to DAN, i.e., VAN-->DAN, are generally associated with degraded performance, with right temporal-parietal junction being the main sources of behavior-degrading influences. These results support the hypothesis that signals from DAN to VAN suppress and filter out unimportant distracter information, whereas signals from VAN to DAN break the attentional set maintained by the dorsal attention network to enable attentional reorienting.

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Transgenic Expression of Intraneuronal Abeta42 But Not Abeta40 Leads to Cellular Abeta Lesions, Degeneration, and Functional Impairment without Typical Alzheimer's Disease Pathology.

Publication Date: 2012 Jan 25 PMID: 22279212
Authors: Abramowski, D. - Rabe, S. - Upadhaya, A. R. - Reichwald, J. - Danner, S. - Staab, D. - Capetillo-Zarate, E. - Yamaguchi, H. - Saido, T. C. - Wiederhold, K. H. - Thal, D. R. - Staufenbiel, M.
Journal: J Neurosci

An early role of amyloid-beta peptide (Abeta) aggregation in Alzheimer's disease pathogenesis is well established. However, the contribution of intracellular or extracellular forms of Abeta to the neurodegenerative process is a subject of considerable debate. We here describe transgenic mice expressing Abeta(1-40) (APP47) and Abeta(1-42) (APP48) with a cleaved signal sequence to insert both peptides during synthesis into the endoplasmic reticulum. Although lower in transgene mRNA, APP48 mice reach a higher brain Abeta concentration. The reduced solubility and increased aggregation of Abeta(1-42) may impair its degradation. APP48 mice develop intracellular Abeta lesions in dendrites and lysosomes. The hippocampal neuron number is reduced already at young age. The brain weight decreases during aging in conjunction with severe white matter atrophy. The mice show a motor impairment. Only very few Abeta(1-40) lesions are found in APP47 mice. Neither APP47 nor APP48 nor the bigenic mice develop extracellular amyloid plaques. While intracellular membrane expression of Abeta(1-42) in APP48 mice does not lead to the AD-typical lesions, Abeta aggregates develop within cells accompanied by considerable neurodegeneration.

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Similar intracellular Ca2+ requirements for inactivation and facilitation of voltage-gated Ca2+ channels in a glutamatergic Mammalian nerve terminal.

Publication Date: 2012 Jan 25 PMID: 22279211
Authors: Lin, K. H. - Erazo-Fischer, E. - Taschenberger, H.
Journal: J Neurosci

Voltage-gated Ca(2+) channels (VGCCs) of the P/Q-type, which are expressed at a majority of mammalian nerve terminals, show two types of Ca(2+)-dependent feedback regulation-inactivation (CDI) and facilitation (CDF). Because of the nonlinear relationship between Ca(2+) influx and transmitter release, CDI and CDF are powerful regulators of synaptic strength. To what extent VGCCs inactivate or facilitate during spike trains depends on the dynamics of free Ca(2+) ([Ca(2+)](i)) and the Ca(2+) sensitivity of CDI and CDF, which has not been determined in nerve terminals. In this report, we took advantage of the large size of a rat auditory glutamatergic synapse-the calyx of Held-and combined voltage-clamp recordings of presynaptic Ca(2+) currents (I(Ca(V))) with UV-light flash-induced Ca(2+) uncaging and presynaptic Ca(2+) imaging to study the Ca(2+) requirements for CDI and CDF. We find that nearly half of the presynaptic VGCCs inactivate during 100 ms voltage steps and require several seconds to recover. This inactivation is caused neither by depletion of Ca(2+) ions from the synaptic cleft nor by metabotropic feedback inhibition, because it is resistant to blockade of metabotropic and ionotropic glutamate receptors. Facilitation of I(Ca(V)) induced by repetitive depolarizations or preconditioning voltage steps decays within tens of milliseconds. Since Ca(2+) buffers only weakly affect CDI and CDF, we conclude that the Ca(2+) sensors are closely associated with the channel. CDI and CDF can be induced by intracellular photo release of Ca(2+) resulting in [Ca(2+)](i) elevations in the low micromolar range, implying a surprisingly high affinity of the Ca(2+) sensors.

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Calcium Binding by Synaptotagmin's C2A Domain is an Essential Element of the Electrostatic Switch That Triggers Synchronous Synaptic Transmission.

Publication Date: 2012 Jan 25 PMID: 22279210
Authors: Striegel, A. R. - Biela, L. M. - Evans, C. S. - Wang, Z. - Delehoy, J. B. - Sutton, R. B. - Chapman, E. R. - Reist, N. E.
Journal: J Neurosci

Synaptotagmin is the major calcium sensor for fast synaptic transmission that requires the synchronous fusion of synaptic vesicles. Synaptotagmin contains two calcium-binding domains: C(2)A and C(2)B. Mutation of a positively charged residue (R233Q in rat) showed that Ca(2+)-dependent interactions between the C(2)A domain and membranes play a role in the electrostatic switch that initiates fusion. Surprisingly, aspartate-to-asparagine mutations in C(2)A that inhibit Ca(2+) binding support efficient synaptic transmission, suggesting that Ca(2+) binding by C(2)A is not required for triggering synchronous fusion. Based on a structural analysis, we generated a novel mutation of a single Ca(2+)-binding residue in C(2)A (D229E in Drosophila) that inhibited Ca(2+) binding but maintained the negative charge of the pocket. This C(2)A aspartate-to-glutamate mutation resulted in approximately 80% decrease in synchronous transmitter release and a decrease in the apparent Ca(2+) affinity of release. Previous aspartate-to-asparagine mutations in C(2)A partially mimicked Ca(2+) binding by decreasing the negative charge of the pocket. We now show that the major function of Ca(2+) binding to C(2)A is to neutralize the negative charge of the pocket, thereby unleashing the fusion-stimulating activity of synaptotagmin. Our results demonstrate that Ca(2+) binding by C(2)A is a critical component of the electrostatic switch that triggers synchronous fusion. Thus, Ca(2+) binding by C(2)B is necessary and sufficient to regulate the precise timing required for coupling vesicle fusion to Ca(2+) influx, but Ca(2+) binding by both C(2) domains is required to flip the electrostatic switch that triggers efficient synchronous synaptic transmission.

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Distinct roles for specific leptin receptor signals in the development of hypothalamic feeding circuits.

Publication Date: 2012 Jan 25 PMID: 22279209
Authors: Bouret, S. G. - Bates, S. H. - Chen, S. - Myers, M. G. Jr - Simerly, R. B.
Journal: J Neurosci

Circulating hormones influence multiple aspects of hypothalamic development and play a role in directing formation of neural circuits. Leptin is secreted by adipocytes and functions as a key developmental signal that promotes axon outgrowth from the arcuate nucleus (ARH) during a discrete developmental critical period. To determine the cellular mechanisms by which leptin impacts development of hypothalamic circuits, we examined roles for leptin receptor (LepRb) signals in neonatal mice. LepRb, ERK, and STAT3 signaling were required for leptin-stimulated neurite outgrowth from ARH explants in vitro. Neonatal mice with disrupted LepRb-->ERK signaling displayed impaired ARH projections but were able to compensate by adulthood. LepRb-->STAT3 signaling also plays a role in early circuit formation and controls the ultimate architecture of POMC, but not AgRP, projections. Thus, the developmental actions of leptin on feeding circuits are dependent on LepRb, and distinct signaling pathways are responsible for directing formation of NPY and POMC projections.

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Cytosolic calcium coordinates mitochondrial energy metabolism with presynaptic activity.

Publication Date: 2012 Jan 25 PMID: 22279208
Authors: Chouhan, A. K. - Ivannikov, M. V. - Lu, Z. - Sugimori, M. - Llinas, R. R. - Macleod, G. T.
Journal: J Neurosci

Most neurons fire in bursts, imposing episodic energy demands, but how these demands are coordinated with oxidative phosphorylation is still unknown. Here, using fluorescence imaging techniques on presynaptic termini of Drosophila motor neurons (MNs), we show that mitochondrial matrix pH (pH(m)), inner membrane potential (Deltapsi(m)), and NAD(P)H levels ([NAD(P)H](m)) increase within seconds of nerve stimulation. The elevations of pH(m), Deltapsi(m), and [NAD(P)H](m) indicate an increased capacity for ATP production. Elevations in pH(m) were blocked by manipulations that blocked mitochondrial Ca(2+) uptake, including replacement of extracellular Ca(2+) with Sr(2+) and application of either tetraphenylphosphonium chloride or KB-R7943, indicating that it is Ca(2+) that stimulates presynaptic mitochondrial energy metabolism. To place this phenomenon within the context of endogenous neuronal activity, the firing rates of a number of individually identified MNs were determined during fictive locomotion. Surprisingly, although endogenous firing rates are significantly different, there was little difference in presynaptic cytosolic Ca(2+) levels ([Ca(2+)](c)) between MNs when each fires at its endogenous rate. The average [Ca(2+)](c) level (329 +/- 11 nm) was slightly above the average Ca(2+) affinity of the mitochondria (281 +/- 13 nm). In summary, we show that when MNs fire at endogenous rates, [Ca(2+)](c) is driven into a range where mitochondria rapidly acquire Ca(2+). As we also show that Ca(2+) stimulates presynaptic mitochondrial energy metabolism, we conclude that [Ca(2+)](c) levels play an integral role in coordinating mitochondrial energy metabolism with presynaptic activity in Drosophila MNs.

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Encoding of coordinated reach and grasp trajectories in primary motor cortex.

Publication Date: 2012 Jan 25 PMID: 22279207
Authors: Saleh, M. - Takahashi, K. - Hatsopoulos, N. G.
Journal: J Neurosci

Though the joints of the arm and hand together comprise 27 degrees of freedom, an ethological movement like reaching and grasping coordinates many of these joints so as to operate in a reduced dimensional space. We used a generalized linear model to predict single neuron responses in primary motor cortex (MI) during a reach-to-grasp task based on 40 features that represent positions and velocities of the arm and hand in joint angle and Cartesian coordinates as well as the neurons' own spiking history. Two rhesus monkeys were trained to reach and grasp one of five objects, located at one of seven locations while we used an infrared camera motion-tracking system to track markers placed on their upper limb and recorded single-unit activity from a microelectrode array implanted in MI. The kinematic trajectories that described hand shaping and transport to the object depended on both the type of object and its location. Modeling the kinematics as temporally extensive trajectories consistently yielded significantly higher predictive power in most neurons. Furthermore, a model that included all feature trajectories yielded more predictive power than one that included any single feature trajectory in isolation, and neurons tended to encode feature velocities over positions. The predictive power of a majority of neurons reached a plateau for a model that included only the first five principal components of all the features' trajectories, suggesting that MI has evolved or adapted to encode the natural kinematic covariations associated with prehension described by a limited set of kinematic synergies.

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alpha4* Nicotinic Acetylcholine Receptors Modulate Experience-Based Cortical Depression in the Adult Mouse Somatosensory Cortex.

Publication Date: 2012 Jan 25 PMID: 22279206
Authors: Brown, C. E. - Sweetnam, D. - Beange, M. - Nahirney, P. C. - Nashmi, R.
Journal: J Neurosci

The molecular mechanisms that mediate experience-based changes in the function of the cerebral cortex, particularly in the adult animal, are poorly understood. Here we show using in vivo voltage-sensitive dye imaging, that whisker trimming leads to depression of whisker-evoked sensory responses in primary, secondary and associative somatosensory cortical regions. Given the importance of cholinergic neurotransmission in cognitive and sensory functions, we examined whether alpha4-containing (alpha4*) nicotinic acetylcholine receptors (nAChRs) mediate cortical depression. Using knock-in mice that express YFP-tagged alpha4 nAChRs subunits, we show that whisker trimming selectively increased the number alpha4*-YFP nAChRs in layer 4 of deprived barrel columns within 24 h, which persisted until whiskers regrew. Confocal and electron microscopy revealed that these receptors were preferentially increased on the cell bodies of GABAergic neurons. To directly link these receptors with functional cortical depression, we show that depression could be induced in normal mice by topical application or micro-injection of alpha4* nAChR agonist in the somatosensory cortex. Furthermore, cortical depression could be blocked after whisker trimming with chronic infusions of an alpha4* nAChR antagonist. Collectively, these results uncover a new role for alpha4* nAChRs in regulating rapid changes in the functional responsiveness of the adult somatosensory cortex.

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Defective Retinal Vascular Endothelial Cell Development As a Consequence of Impaired Integrin alphaVbeta8-Mediated Activation of Transforming Growth Factor-beta.

Publication Date: 2012 Jan 25 PMID: 22279205
Authors: Arnold, T. D. - Ferrero, G. M. - Qiu, H. - Phan, I. T. - Akhurst, R. J. - Huang, E. J. - Reichardt, L. F.
Journal: J Neurosci

Deletions of the genes encoding the integrin alphaVbeta8 (Itgav, Itgb8) have been shown to result in abnormal vascular development in the CNS, including prenatal and perinatal hemorrhage. Other work has indicated that a major function of this integrin in vivo is to promote TGFbeta activation. In this paper, we show that Itgb8 mRNA is strongly expressed in murine Muller glia and retinal ganglion cells, but not astrocytes. We further show that Itgb8 deletion in the entire retina severely perturbs development of the murine retinal vasculature, elevating vascular branch point density and vascular coverage in the superficial vascular plexus, while severely impairing formation of the deep vascular plexus. The stability of the mutant vasculature is also impaired as assessed by the presence of hemorrhage and vascular basal lamina sleeves lacking endothelial cells. Specific deletion of Itgb8 in Muller glia and neurons, but not deletion in astrocytes, recapitulates the phenotype observed following Itgb8 in the entire retina. Consistent with alphaVbeta8's role in TGFbeta1 activation, we show that retinal deletion of Tgfb1 results in very similar retinal vascular abnormalities. The vascular deficits appear to reflect impaired TGFbeta signaling in vascular endothelial cells because retinal deletion of Itgb8 reduces phospho-SMAD3 in endothelial cells and endothelial cell-specific deletion of the TGFbetaRII gene recapitulates the major deficits observed in the Itgb8 and TGFbeta1 mutants. Of special interest, the retinal vascular phenotypes observed in each mutant are remarkably similar to those of others following inhibition of neuropilin-1, a receptor previously implicated in TGFbeta activation and signaling.

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Increased Excitatory Synaptic Input to Granule Cells from Hilar and CA3 Regions in a Rat Model of Temporal Lobe Epilepsy.

Publication Date: 2012 Jan 25 PMID: 22279204
Authors: Zhang, W. - Huguenard, J. R. - Buckmaster, P. S.
Journal: J Neurosci

One potential mechanism of temporal lobe epilepsy is recurrent excitation of dentate granule cells through aberrant sprouting of their axons (mossy fibers), which is found in many patients and animal models. However, correlations between the extent of mossy fiber sprouting and seizure frequency are weak. Additional potential sources of granule cell recurrent excitation that would not have been detected by markers of mossy fiber sprouting in previous studies include surviving mossy cells and proximal CA3 pyramidal cells. To test those possibilities in hippocampal slices from epileptic pilocarpine-treated rats, laser-scanning glutamate uncaging was used to randomly and focally activate neurons in the granule cell layer, hilus, and proximal CA3 pyramidal cell layer while measuring evoked EPSCs in normotopic granule cells. Consistent with mossy fiber sprouting, a higher proportion of glutamate-uncaging spots in the granule cell layer evoked EPSCs in epileptic rats compared with controls. In addition, stimulation spots in the hilus and proximal CA3 pyramidal cell layer were more likely to evoke EPSCs in epileptic rats, despite significant neuron loss in those regions. Furthermore, synaptic strength of recurrent excitatory inputs to granule cells from CA3 pyramidal cells and other granule cells was increased in epileptic rats. These findings reveal substantial levels of excessive, recurrent, excitatory synaptic input to granule cells from neurons in the hilus and proximal CA3 field. The aberrant development of these additional positive-feedback circuits might contribute to epileptogenesis in temporal lobe epilepsy.

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Looming Signals Reveal Synergistic Principles of Multisensory Integration.

Publication Date: 2012 Jan 25 PMID: 22279203
Authors: Cappe, C. - Thelen, A. - Romei, V. - Thut, G. - Murray, M. M.
Journal: J Neurosci

Multisensory interactions are a fundamental feature of brain organization. Principles governing multisensory processing have been established by varying stimulus location, timing and efficacy independently. Determining whether and how such principles operate when stimuli vary dynamically in their perceived distance (as when looming/receding) provides an assay for synergy among the above principles and also means for linking multisensory interactions between rudimentary stimuli with higher-order signals used for communication and motor planning. Human participants indicated movement of looming or receding versus static stimuli that were visual, auditory, or multisensory combinations while 160-channel EEG was recorded. Multivariate EEG analyses and distributed source estimations were performed. Nonlinear interactions between looming signals were observed at early poststimulus latencies ( approximately 75 ms) in analyses of voltage waveforms, global field power, and source estimations. These looming-specific interactions positively correlated with reaction time facilitation, providing direct links between neural and performance metrics of multisensory integration. Statistical analyses of source estimations identified looming-specific interactions within the right claustrum/insula extending inferiorly into the amygdala and also within the bilateral cuneus extending into the inferior and lateral occipital cortices. Multisensory effects common to all conditions, regardless of perceived distance and congruity, followed ( approximately 115 ms) and manifested as faster transition between temporally stable brain networks (vs summed responses to unisensory conditions). We demonstrate the early-latency, synergistic interplay between existing principles of multisensory interactions. Such findings change the manner in which to model multisensory interactions at neural and behavioral/perceptual levels. We also provide neurophysiologic backing for the notion that looming signals receive preferential treatment during perception.

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Renshaw Cells and Ia Inhibitory Interneurons Are Generated at Different Times from p1 Progenitors and Differentiate Shortly after Exiting the Cell Cycle.

Publication Date: 2012 Jan 25 PMID: 22279202
Authors: Benito-Gonzalez, A. - Alvarez, F. J.
Journal: J Neurosci

Spinal interneurons modulating motor output are highly diverse but surprisingly arise from just a few embryonic subgroups. The principles governing their development, diversification, and integration into spinal circuits are unknown. This study focuses on the differentiation of adult Renshaw cells (RCs) and Ia inhibitory interneurons (IaINs), two subclasses that respectively mediate recurrent and reciprocal inhibition of motoneurons from embryonic V1 interneurons (V1-INs). V1-INs originate from p1 progenitors and, after they become postmitotic, specifically express the transcription factor engrailed-1, a property that permits genetic labeling of V1 lineages from embryo to adult. RCs and IaINs are V1 derived, but differ in morphology, location, calcium-binding protein expression, synaptic connectivity, and function. These differences are already present in neonates, and in this study we show that their differentiation starts in the early embryo. Using 5'-bromodeoxyuridine birth dating we established that mouse V1-INs can be divided into early (E9.5-E10.5) and late (E11.5-E12.5) groups generated from the p1 domain (where E is embryonic day). The early group upregulates calbindin expression soon after becoming postmitotic and includes RCs, which express the transcription factor MafB during early differentiation and maintain calbindin expression throughout life. The late group includes IaINs, are calbindin-negative, and express FoxP2 at the start of differentiation. Moreover, developing RCs follow a characteristic circumferential migratory route that places them in unique relationship with motor axons with whom they later synaptically interact. We conclude that the fate of these V1-IN subclasses is determined before synaptogenesis and circuit formation by a process that includes differences in neurogenesis time, transcription factor expression, and migratory pathways.

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Interleukin-17A Increases Neurite Outgrowth from Adult Postganglionic Sympathetic Neurons.

Publication Date: 2012 Jan 25 PMID: 22279201
Authors: Chisholm, S. P. - Cervi, A. L. - Nagpal, S. - Lomax, A. E.
Journal: J Neurosci

Inflammation can profoundly alter the structure and function of the nervous system. Interleukin (IL)-17 has been implicated in the pathogenesis of several inflammatory diseases associated with nervous system plasticity. However, the effects of IL-17 on the nervous system remain unexplored. Cell and explant culture techniques, immunohistochemistry, electrophysiology, and Ca(2+) imaging were used to examine the impact of IL-17 on adult mouse sympathetic neurons. Receptors for IL-17 were present on postganglionic neurons from superior mesenteric ganglia (SMG). Supernatant from activated splenic T lymphocytes, which was abundant in IL-17, dramatically enhanced axonal length of SMG neurons. Importantly, IL-17-neutralizing antiserum abrogated the neurotrophic effect of splenocyte supernatant, and incubation of SMG neurons in IL-17 (1 ng/ml) significantly potentiated neurite outgrowth. The neurotrophic effect of IL-17 was accompanied by inhibition of voltage-dependent Ca(2+) influx and was recapitulated by incubation of neurons in a blocker of N-type Ca(2+) channels (omega-conotoxin GVIA; 30 nm). IL-17-induced neurite outgrowth in vitro appeared to be independent of glia, as treatment with a glial toxin (AraC; 5 mum) did not affect the outgrowth response to IL-17. Moreover, application of the cytokine to distal axons devoid of glial processes enhanced neurite extension. An inhibitor of the NF-kappaB pathway (SC-514; 20 mum) blocked the effects of IL-17. These data represent the first evidence that IL-17 can act on sympathetic somata and distal neurites to enhance neurite outgrowth, and identify a novel potential role for IL-17 in the neuroanatomical plasticity that accompanies inflammation.

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Examining the expectation deficit in normal aging.

Publication Date: 2012 Jan 25 PMID: 22279200
Authors: Pincham, H. L. - Killikelly, C. - Vuillier, L. - Power, A. J.
Journal: J Neurosci

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Reduced Activity of AMP-Activated Protein Kinase Protects against Genetic Models of Motor Neuron Disease.

Publication Date: 2012 Jan 18 PMID: 22262909
Authors: Lim, M. A. - Selak, M. A. - Xiang, Z. - Krainc, D. - Neve, R. L. - Kraemer, B. C. - Watts, J. L. - Kalb, R. G.
Journal: J Neurosci

A growing body of research indicates that amyotrophic lateral sclerosis (ALS) patients and mouse models of ALS exhibit metabolic dysfunction. A subpopulation of ALS patients possesses higher levels of resting energy expenditure and lower fat-free mass compared to healthy controls. Similarly, two mutant copper zinc superoxide dismutase 1 (mSOD1) mouse models of familial ALS possess a hypermetabolic phenotype. The pathophysiological relevance of the bioenergetic defects observed in ALS remains largely elusive. AMP-activated protein kinase (AMPK) is a key sensor of cellular energy status and thus might be activated in various models of ALS. Here, we report that AMPK activity is increased in spinal cord cultures expressing mSOD1, as well as in spinal cord lysates from mSOD1 mice. Reducing AMPK activity either pharmacologically or genetically prevents mSOD1-induced motor neuron death in vitro. To investigate the role of AMPK in vivo, we used Caenorhabditis elegans models of motor neuron disease. C. elegans engineered to express human mSOD1 (G85R) in neurons develops locomotor dysfunction and severe fecundity defects when compared to transgenic worms expressing human wild-type SOD1. Genetic reduction of aak-2, the ortholog of the AMPK alpha2 catalytic subunit in nematodes, improved locomotor behavior and fecundity in G85R animals. Similar observations were made with nematodes engineered to express mutant tat-activating regulatory (TAR) DNA-binding protein of 43 kDa molecular weight. Altogether, these data suggest that bioenergetic abnormalities are likely to be pathophysiologically relevant to motor neuron disease.

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Attentional capture? Synchronized feedback signals from the isthmi boost retinal signals to higher visual areas.

Publication Date: 2012 Jan 18 PMID: 22262908
Authors: Marin, G. J. - Duran, E. - Morales, C. - Gonzalez-Cabrera, C. - Sentis, E. - Mpodozis, J. - Letelier, J. C.
Journal: J Neurosci

When a salient object in the visual field captures attention, the neural representation of that object is enhanced at the expense of competing stimuli. How neural activity evoked by a salient stimulus evolves to take precedence over the neural activity evoked by other stimuli is a matter of intensive investigation. Here, we describe in pigeons (Columba livia) how retinal inputs to the optic tectum (TeO, superior colliculus in mammals), triggered by moving stimuli, are selectively relayed on to the rotundus (Rt, caudal pulvinar) in the thalamus, and to its pallial target, the entopallium (E, extrastriate cortex). We show that two satellite nuclei of the TeO, the nucleus isthmi parvocelullaris (Ipc) and isthmi semilunaris (SLu), send synchronized feedback signals across tectal layers. Preventing the feedback from Ipc but not from SLu to a tectal location suppresses visual responses to moving stimuli from the corresponding region of visual space in all Rt subdivisions. In addition, the bursting feedback from the Ipc imprints a bursting rhythm on the visual signals, such that the visual responses of the Rt and the E acquire a bursting modulation significantly synchronized to the feedback from Ipc. As the Ipc feedback signals are selected by competitive interactions, the visual responses within the receptive fields in the Rt tend to synchronize with the tectal location receiving the "winning" feedback from Ipc. We propose that this selective transmission of afferent activity combined with the cross-regional synchronization of the areas involved represents a bottom-up mechanism by which salient stimuli capture attention.

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Injury-Dependent Muller Glia and Ganglion Cell Reprogramming during Tissue Regeneration Requires Apobec2a and Apobec2b.

Publication Date: 2012 Jan 18 PMID: 22262907
Authors: Powell, C. - Elsaeidi, F. - Goldman, D.
Journal: J Neurosci

Unlike mammals, adult zebrafish are able to regenerate multiple tissues including those of the CNS. In the zebrafish retina, injury stimulates Muller glia dedifferentiation into a multipotent retinal progenitor that is capable of regenerating all lost cell types. This dedifferentiation is driven by the reactivation of gene expression programs that share many characteristics with those that operate during early development. Although the mechanisms underlying the reactivation of these programs remain unknown, it is likely that changes in DNA methylation play a significant role. To begin investigating whether DNA demethylation may contribute to retina regeneration, we characterized the expression of genes associated with DNA demethylation in the uninjured and injured retina. We found that two cytidine deaminases (apobec2a and apobec2b) were expressed basally in the uninjured retina and that they were induced in proliferating, dedifferentiated Muller glia. The maximal induction of apobec2b required Ascl1a, but was independent of Lin28, and therefore defines an independent signaling pathway stemming from Ascl1a. Strikingly, when Apobec2a or Apobec2b was knocked down by antisense morpholino oligonucleotides, the proliferative response of Muller glia following injury was significantly reduced and injury-dependent induction of ascl1a and its target genes were inhibited, suggesting the presence of a regulatory feedback loop between Apobec proteins and ascl1a. Finally, Ascl1a, Apobec2a and Apobec2b were found to be essential for optic nerve regeneration. These data identify an essential role for Apobec proteins during retina and optic nerve regeneration and suggest DNA demethylation may underlie the reprogramming of cells to mount a regenerative response.

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Predicting Aversive Events and Terminating Fear in the Mouse Anterior Cingulate Cortex during Trace Fear Conditioning.

Publication Date: 2012 Jan 18 PMID: 22262906
Authors: Steenland, H. W. - Li, X. Y. - Zhuo, M.
Journal: J Neurosci

A variety of studies have implicated the anterior cingulate cortex (ACC) in fear, including permanent storage of fear memory. Recent pharmacological and genetic studies indicate that early synaptic plasticity in the ACC may also contribute to certain forms of fear memory at early time points. However, no study has directly examined the possible changes in neuronal activity of ACC neurons in freely behaving mice during early learning. In the present study, we examined the neural responses of the ACC during trace fear conditioning. We found that ACC putative pyramidal and nonpyramidal neurons were involved in the termination of fear behavior ("un-freezing"), and the spike activity of these neurons was reduced during freezing. Some of the neurons were also found to acquire un-freezing locked activity and change their tuning. The results implicate the ACC neurons in fear learning and controlling the abolition of fear behavior. We also show that the ACC is important for making cue-related fear memory associations in the trace fear paradigm as measured with tone-evoked potentials and single-unit activity. Collectively, our findings indicate that the ACC is involved in predicting future aversive events and terminating fear during trace fear.

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Amygdala central nucleus interacts with dorsolateral striatum to regulate the acquisition of habits.

Publication Date: 2012 Jan 18 PMID: 22262905
Authors: Lingawi, N. W. - Balleine, B. W.
Journal: J Neurosci

The role of the amygdala central nucleus (CeN) in habit learning was assessed in two experiments. First, we examined the effects of bilateral lesions of the anterior CeN on an overtraining-induced lever press habit evaluated using an outcome devaluation protocol. Overtraining generated habitual performance and rendered sham lesioned rats insensitive to outcome devaluation, an effect that was also found in rats given control lesions of the posterior CeN. In contrast, rats with lesions of the anterior CeN did not show normal habit acquisition and their performance remained goal-directed and sensitive to outcome devaluation. Nevertheless, lesions of either the posterior or the anterior CeN abolished the general excitatory influence of a Pavlovian conditioned stimulus on instrumental performance. Second, we assessed the functional interaction between the CeN and dorsolateral striatum (DLS), a region previously implicated in the acquisition of habits, using asymmetrical lesions to disconnect these structures. Rats were given a unilateral lesion of anterior CeN and a unilateral lesion of the DLS, made either ipsilateral (control) or contralateral (disconnection) to the CeN lesion, and given overtraining followed by outcome devaluation. Although the ipsilateral lesioned rats were insensitive to devaluation, the contralateral CeN-DLS lesion impaired habit acquisition, rendering performance sensitive to the devaluation treatment. These results are the first to implicate the CeN and its connection with a circuit involving DLS in habit learning. They imply that, in instrumental conditioning, regions of amygdala parse the instrumental outcome into the reward and reinforcement signals mediating goal-directed and habitual actions, respectively.

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Maximal variability of phase synchrony in cortical networks with neuronal avalanches.

Publication Date: 2012 Jan 18 PMID: 22262904
Authors: Yang, H. - Shew, W. L. - Roy, R. - Plenz, D.
Journal: J Neurosci

Ongoing interactions among cortical neurons often manifest as network-level synchrony. Understanding the spatiotemporal dynamics of such spontaneous synchrony is important because it may (1) influence network response to input, (2) shape activity-dependent microcircuit structure, and (3) reveal fundamental network properties, such as an imbalance of excitation (E) and inhibition (I). Here we delineate the spatiotemporal character of spontaneous synchrony in rat cortex slice cultures and a computational model over a range of different E-I conditions including disfacilitated (antagonized AMPA, NMDA receptors), unperturbed, and disinhibited (antagonized GABA(A) receptors). Local field potential was recorded with multielectrode arrays during spontaneous burst activity. Synchrony among neuronal groups was quantified based on phase-locking among recording sites. As network excitability was increased from low to high, we discovered three phenomena at an intermediate excitability level: (1) onset of synchrony, (2) maximized variability of synchrony, and (3) neuronal avalanches. Our computational model predicted that these three features occur when the network operates near a unique balanced E-I condition called "criticality." These results were invariant to changes in the measurement spatial extent, spatial resolution, and frequency bands. Our findings indicate that moderate average synchrony, which is required to avoid pathology, occurs over a limited range of E-I conditions and emerges together with maximally variable synchrony. If variable synchrony is detrimental to cortical function, this is a cost paid for moderate average synchrony. However, if variable synchrony is beneficial, then by operating near criticality the cortex may doubly benefit from moderate mean and maximized variability of synchrony.

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Optimal encoding of interval timing in expert percussionists.

Publication Date: 2012 Jan 18 PMID: 22262903
Authors: Cicchini, G. M. - Arrighi, R. - Cecchetti, L. - Giusti, M. - Burr, D. C.
Journal: J Neurosci

We measured temporal reproduction in human subjects with various levels of musical expertise: expert drummers, string musicians, and non-musicians. While duration reproduction of the non-percussionists showed a characteristic central tendency or regression to the mean, drummers responded veridically. Furthermore, when the stimuli were auditory tones rather than flashes, all subjects responded veridically. The behavior of all three groups in both modalities is well explained by a Bayesian model that seeks to minimize reproduction errors by incorporating a central tendency prior, a probability density function centered at the mean duration of the sample. We measured separately temporal precision thresholds with a bisection task; thresholds were twice as low in drummers as in the other two groups. These estimates of temporal precision, together with an adaptable Bayesian prior, predict well the reproduction results and the central tendency strategy under all conditions and for all subject groups. These results highlight the efficiency and flexibility of sensorimotor mechanisms estimating temporal duration.

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Cortactin-binding protein 2 modulates the mobility of cortactin and regulates dendritic spine formation and maintenance.

Publication Date: 2012 Jan 18 PMID: 22262902
Authors: Chen, Y. K. - Hsueh, Y. P.
Journal: J Neurosci

Dendritic spines, the actin-rich protrusions emerging from dendrites, are the locations of excitatory synapses in mammalian brains. Many molecules that regulate actin dynamics also influence the morphology and/or density of dendritic spines. Since dendritic spines are neuron-specific subcellular structures, neuron-specific proteins or signals are expected to control spinogenesis. In this report, we characterize the distribution and function of neuron-predominant cortactin-binding protein 2 (CTTNBP2) in rodents. An analysis of an Expressed Sequence Tag database revealed three splice variants of mouse CTTNBP2: short, long, and intron. Immunoblotting indicated that the short form is the dominant CTTNBP2 variant in the brain. CTTNBP2 proteins were highly concentrated at dendritic spines in cultured rat hippocampal neurons as well as in the mouse brain. Knockdown of CTTNBP2 in neurons reduced the density and size of dendritic spines. Consistent with these morphological changes, the frequencies of miniature EPSCs in CTTNBP2 knockdown neurons were lower than those in control neurons. Cortactin acts downstream of CTTNBP2 in spinogenesis, as the defects caused by CTTNBP2 knockdown were rescued by overexpression of cortactin but not expression of a CTTNBP2 mutant protein lacking the cortactin interaction. Finally, immunofluorescence staining demonstrated that, unlike cortactin, CTTNBP2 stably resided at dendritic spines even after glutamate stimulation. Fluorescence recovery after photobleaching further suggested that CTTNBP2 modulates the mobility of cortactin in neurons. CTTNBP2 may thus help to immobilize cortactin in dendritic spines and control the density of dendritic spines.

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Processing of Emotional Reactivity and Emotional Memory over Sleep.

Publication Date: 2012 Jan 18 PMID: 22262901
Authors: Baran, B. - Pace-Schott, E. F. - Ericson, C. - Spencer, R. M.
Journal: J Neurosci

Sleep enhances memories, particularly emotional memories. As such, it has been suggested that sleep deprivation may reduce posttraumatic stress disorder. This presumes that emotional memory consolidation is paralleled by a reduction in emotional reactivity, an association that has not yet been examined. In the present experiment, we used an incidental memory task in humans and obtained valence and arousal ratings during two sessions separated either by 12 h of daytime wake or 12 h including overnight sleep. Recognition accuracy was greater following sleep relative to wake for both negative and neutral pictures. While emotional reactivity to negative pictures was greatly reduced over wake, the negative emotional response was relatively preserved over sleep. Moreover, protection of emotional reactivity was associated with greater time in REM sleep. Recognition accuracy, however, was not associated with REM. Thus, we provide the first evidence that sleep enhances emotional memory while preserving emotional reactivity.

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Cdk5/p25-Induced Cytosolic PLA2-Mediated Lysophosphatidylcholine Production Regulates Neuroinflammation and Triggers Neurodegeneration.

Publication Date: 2012 Jan 18 PMID: 22262900
Authors: Sundaram, J. R. - Chan, E. S. - Poore, C. P. - Pareek, T. K. - Cheong, W. F. - Shui, G. - Tang, N. - Low, C. M. - Wenk, M. R. - Kesavapany, S.
Journal: J Neurosci

The deregulation of cyclin-dependent kinase 5 (Cdk5) by p25 has been shown to contribute to the pathogenesis in a number of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD) and Alzheimer's disease (AD). In particular, p25/Cdk5 has been shown to produce hyperphosphorylated tau, neurofibrillary tangles as well as aberrant amyloid precursor protein processing found in AD. Neuroinflammation has been observed alongside the pathogenic process in these neurodegenerative diseases, however the precise mechanism behind the induction of neuroinflammation and the significance in the AD pathogenesis has not been fully elucidated. In this report, we uncover a novel pathway for p25-induced neuroinflammation where p25 expression induces an early trigger of neuroinflammation in vivo in mice. Lipidomic mass spectrometry, in vitro coculture and conditioned media transfer experiments show that the soluble lipid mediator lysophosphatidylcholine (LPC) is released by p25 overexpressing neurons to initiate astrogliosis, neuroinflammation and subsequent neurodegeneration. Reverse transcriptase PCR and gene silencing experiments show that cytosolic phospholipase 2 (cPLA2) is the key enzyme mediating the p25-induced LPC production and cPLA2 upregulation is critical in triggering the p25-mediated inflammatory and neurodegenerative process. Together, our findings delineate a potential therapeutic target for the reduction of neuroinflammation in neurodegenerative diseases including AD.

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Scaling of Movement Is Related to Pallidal gamma Oscillations in Patients with Dystonia.

Publication Date: 2012 Jan 18 PMID: 22262899
Authors: Brucke, C. - Huebl, J. - Schonecker, T. - Neumann, W. J. - Yarrow, K. - Kupsch, A. - Blahak, C. - Lutjens, G. - Brown, P. - Krauss, J. K. - Schneider, G. H. - Kuhn, A. A.
Journal: J Neurosci

Neuronal synchronization in the gamma (gamma) band is considered important for information processing through functional integration of neuronal assemblies across different brain areas. Movement-related gamma synchronization occurs in the human basal ganglia where it is centered at approximately 70 Hz and more pronounced contralateral to the moved hand. However, its functional significance in motor performance is not yet well understood. Here, we assessed whether event-related gamma synchronization (ERS) recorded from the globus pallidus internus in patients undergoing deep brain stimulation for medically intractable primary focal and segmental dystonia might code specific motor parameters. Pallidal local field potentials were recorded in 22 patients during performance of a choice-reaction-time task. Movement amplitude of the forearm pronation-supination movements was parametrically modulated with an angular degree of 30 degrees , 60 degrees , and 90 degrees . Only patients with limbs not affected by dystonia were tested. A broad contralateral gamma band (35-105 Hz) ERS occurred at movement onset with a maximum reached at peak velocity of the movement. The pallidal oscillatory gamma activity correlated with movement parameters: the larger and faster the movement, the stronger was the synchronization in the gamma band. In contrast, the event-related decrease in beta band activity was similar for all movements. Gamma band activity did not change with movement direction and did not occur during passive movements. The stepwise increase of gamma activity with movement size and velocity suggests a role of neuronal synchronization in this frequency range in basal ganglia control of the scaling of ongoing movements.

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Combinatorial expression of brn3 transcription factors in somatosensory neurons: genetic and morphologic analysis.

Publication Date: 2012 Jan 18 PMID: 22262898
Authors: Badea, T. C. - Williams, J. - Smallwood, P. - Shi, M. - Motajo, O. - Nathans, J.
Journal: J Neurosci

The three members of the Brn3 family of POU-domain transcription factors (Brn3a/Pou4f1, Brn3b/Pou4f2, and Brn3c/Pou4f3) are expressed in overlapping subsets of visual, auditory/vestibular, and somatosensory neurons. Using unmarked Brn3-null alleles and Brn3 conditional alleles in which gene loss is coupled to expression of an alkaline phosphatase reporter, together with sparse Cre-mediated recombination, we describe the following: (1) the overlapping patterns of Brn3 gene expression in somatosensory neurons; (2) the manner in which these patterns correlate with molecular markers, peripheral afferent arbor morphologies, and dorsal horn projections; and (3) the consequences for these neurons of deleting individual Brn3 genes in the mouse. We observe broad expression of Brn3a among DRG neurons, but subtype-restricted expression of Brn3b and Brn3c. We also observe a nearly complete loss of hair follicle-associated sensory endings among Brn3a(-/-) neurons. Together with earlier analyses of Brn3 gene expression patterns in the retina and inner ear, these experiments suggest a deep functional similarity among primary somatosensory neurons, spiral and vestibular ganglion neurons, and retinal ganglion cells. This work also demonstrates the utility of sparse genetically directed labeling for visualizing individual somatosensory afferent arbors and for defining cell-autonomous mutant phenotypes.

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The Rett Syndrome Protein MeCP2 Regulates Synaptic Scaling.

Publication Date: 2012 Jan 18 PMID: 22262897
Authors: Qiu, Z. - Sylwestrak, E. L. - Lieberman, D. N. - Zhang, Y. - Liu, X. Y. - Ghosh, A.
Journal: J Neurosci

Synaptic scaling is a form of homeostatic synaptic plasticity characterized by cell-wide changes in synaptic strength in response to changes in overall levels of neuronal activity. Here we report that bicuculline-induced increase in neuronal activity leads to a decrease in mEPSC amplitude and a decrease in expression of the AMPA receptor subunit GluR2 in rat hippocampal cultures. Bicuculline treatment also leads to an increase in the levels of the transcriptional repressor MeCP2, which binds to the GluR2 promoter along with the corepressors HDAC1 and mSin3A. Downregulation of MeCP2 by shRNA expression or genetic deletion blocks the bicuculline-induced decrease in GluR2 expression and mEPSC amplitude. These observations indicate that MeCP2 mediates activity-dependent synaptic scaling, and suggest that the pathophysiology of Rett syndrome, which is caused by mutations in MeCP2, may involve defects in activity-dependent regulation of synaptic currents.

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Short-Term Plasticity of Unitary Inhibitory-to-Inhibitory Synapses Depends on the Presynaptic Interneuron Subtype.

Publication Date: 2012 Jan 18 PMID: 22262896
Authors: Ma, Y. - Hu, H. - Agmon, A.
Journal: J Neurosci

Excitatory-to-inhibitory cortical synapses exhibit either short-term facilitation or depression, depending on the subtype identity of the postsynaptic interneuron, while the short-term plasticity (STP) of inhibitory-to-excitatory synapses depends on the presynaptic interneuron. However, the rules governing STP of inhibitory-to-inhibitory synapses have not yet been determined. We recorded 109 unitary connections made by the two major inhibitory interneuron subtypes in layer 4 of mouse somatosensory cortex, fast-spiking (FS) and somatostatin-containing (SOM) interneurons, on each other and on excitatory, regular-spiking (RS) neurons. In all pairs, we measured dynamic changes in the postsynaptic response to a 20 Hz train of presynaptic action potentials. In half of our dataset, we also measured kinetic properties of the unitary IPSC: latency, rise time, and decay time constant. We found a pronounced dependency of STP on the presynaptic, but not the postsynaptic, identity: FS interneurons made strongly depressing connections on FS, SOM, and RS targets, while in synapses made by SOM interneurons on FS and RS targets, weak early depression was followed by weak late facilitation. IPSC latency and rise time were also strongly dependent on the presynaptic interneuron subtype, being 1.5-2x slower in output synapses of SOM compared with FS interneurons. In contrast, the IPSC decay time constant depended only on the postsynaptic class, with 1.5x slower decay on excitatory compared with inhibitory targets. The properties of the inhibitory outputs of FS and SOM interneurons reciprocate the properties of their excitatory inputs and imply a dynamic spatiotemporal division of labor between these two major inhibitory subsystems.

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Becoming consistent: developmental reductions in intraindividual variability in reaction time are related to white matter integrity.

Publication Date: 2012 Jan 18 PMID: 22262895
Authors: Tamnes, C. K. - Fjell, A. M. - Westlye, L. T. - Ostby, Y. - Walhovd, K. B.
Journal: J Neurosci

Cognitive development is known to involve improvements in accuracy, capacity, and processing speed. Less is known about the role of performance consistency, and there has been virtually no empirical examination of the neural underpinnings of within-person variability in development. In a sample of 92 healthy children and adolescents aged 8-19 years, we aimed to characterize age-related changes in trial-to-trial intraindividual variability (IIV) of reaction time (RT) and to test whether IIV is related to white matter (WM) integrity as indexed by diffusion tensor imaging. IIV was quantified as the SD of correct RTs in a speeded arrow flanker task, and Tract-Based Spatial Statistics was used to test relationships with diffusion characteristics. Large age-related reductions in IIV in both simple congruent trials and more complex incongruent trials were found. Independently of sex, age, and median RT (mRT), lower IIV was associated with higher fractional anisotropy and lower overall diffusivity. Effects were seen for IIV in one or both trial types in the corticospinal tract, the left superior longitudinal fasciculus, the uncinate fasciculus, the forceps minor, and in the genu and splenium of the corpus callosum. There were no significant associations between mRT and any of the diffusion indices. The findings support the proposition that developmental reductions in IIV reflect maturation of WM connectivity and highlight the importance of considering within-person variability in theories of cognitive development and its neurobiological foundation.

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Human ROBO1 Regulates Interaural Interaction in Auditory Pathways.

Publication Date: 2012 Jan 18 PMID: 22262894
Authors: Lamminmaki, S. - Massinen, S. - Nopola-Hemmi, J. - Kere, J. - Hari, R.
Journal: J Neurosci

In rodents, the Robo1 gene regulates midline crossing of major nerve tracts, a fundamental property of the mammalian CNS. However, the neurodevelopmental function of the human ROBO1 gene remains unknown, apart from a suggested role in dyslexia. We therefore studied axonal crossing with a functional approach, based on magnetoencephalography, in 10 dyslexic individuals who all share the same rare, weakly expressing haplotype of the ROBO1 gene. Auditory-cortex responses were recorded separately to left- and right-ear sounds that were amplitude modulated at different frequencies. We found impaired interaural interaction that depended on the ROBO1 in a dose-dependent manner. Our results indicate that normal crossing of the auditory pathways requires an adequate ROBO1 expression level.

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Cervicolumbar coordination in Mammalian quadrupedal locomotion: role of spinal thoracic circuitry and limb sensory inputs.

Publication Date: 2012 Jan 18 PMID: 22262893
Authors: Juvin, L. - Le Gal, J. P. - Simmers, J. - Morin, D.
Journal: J Neurosci

Effective quadrupedal locomotion requires a close coordination between the spatially distant central pattern generators (CPGs) controlling forelimb and hindlimb movements. Using isolated preparations of the neonatal rat spinal cord, we explore the role of intervening thoracic circuitry in cervicolumbar CPG coordination and the contribution to this remote coupling of limb somatosensory inputs. In preparations activated with bath-applied N-methyl-d,l-aspartate, serotonin, and dopamine, the coordination between locomotor-related bursts recorded in cervical and lumbar ventral roots was substantially weakened, although not abolished, when the thoracic segments were selectively withheld from neurochemical stimulation or were exposed to a low Ca(2+) solution to block synaptic transmission. Moreover, cervicolumbar CPG coordination was reduced after a thoracic midsagittal section, suggesting that cross-cord projections participate in the anteroposterior coupling. In quiescent preparations, either cyclic or tonic electrical stimulation of low-threshold afferent pathways in C8 or L2 dorsal roots (DRs) could elicit coordinated ventral root bursting at both cervical and lumbar levels via an activation of the underlying CPG networks. When lumbar rhythmogenesis was prevented by local synaptic transmission blockade, L2 DR stimulation could still drive left-right alternating cervical bursting in preparations otherwise exposed to normal bathing medium. In contrast, when the cervical generators were selectively blocked, C8 DR stimulation was unable to activate the lumbar CPGs. Thus, in the newborn rat, anteroposterior limb coordination relies on active burst generation within midcord thoracic circuitry that additionally conveys ascending and weaker descending coupling influences of distant limb proprioceptive inputs to the cervical and lumbar generators, respectively.

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Sialic Acid on the neuronal glycocalyx prevents complement c1 binding and complement receptor-3-mediated removal by microglia.

Publication Date: 2012 Jan 18 PMID: 22262892
Authors: Linnartz, B. - Kopatz, J. - Tenner, A. J. - Neumann, H.
Journal: J Neurosci

Microglial cells are professional phagocytes of the CNS responsible for clearance of unwanted structures. Neuronal processes are marked by complement C1 before they are removed in development or during disease processes. Target molecules involved in C1 binding and mechanisms of clearance are still unclear. Here we show that the terminal sugar residue sialic acid of the mouse neuronal glycocalyx determines complement C1 binding and microglial-mediated clearance function. Several early components of the classical complement cascade including C1q, C1r, C1s, and C3 were produced by cultured mouse microglia. The opsonin C1q was binding to neurites after enzymatic removal of sialic acid residues from the neuronal glycocalyx. Desialylated neurites, but not neurites with intact sialic acid caps, were cleared and taken up by cocultured microglial cells. The removal of the desialylated neurites was mediated via the complement receptor-3 (CR3; CD11b/CD18). Data demonstrate that mouse microglial cells via CR3 recognize and remove neuronal structures with an altered neuronal glycocalyx lacking terminal sialic acid.

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Kisspeptin-GPR54 Signaling in Mouse NO-Synthesizing Neurons Participates in the Hypothalamic Control of Ovulation.

Publication Date: 2012 Jan 18 PMID: 22262891
Authors: Hanchate, N. K. - Parkash, J. - Bellefontaine, N. - Mazur, D. - Colledge, W. H. - d'Anglemont de Tassigny, X. - Prevot, V.
Journal: J Neurosci

Reproduction is controlled in the brain by a neural network that drives the secretion of gonadotropin-releasing hormone (GnRH). Various permissive homeostatic signals must be integrated to achieve ovulation in mammals. However, the neural events controlling the timely activation of GnRH neurons are not completely understood. Here we show that kisspeptin, a potent activator of GnRH neuronal activity, directly communicates with neurons that synthesize the gaseous transmitter nitric oxide (NO) in the preoptic region to coordinate the progression of the ovarian cycle. Using a transgenic Gpr54-null IRES-LacZ knock-in mouse model, we demonstrate that neurons containing neuronal NO synthase (nNOS), which are morphologically associated with kisspeptin fibers, express the kisspeptin receptor GPR54 in the preoptic region, but not in the tuberal region of the hypothalamus. The activation of kisspeptin signaling in preoptic neurons promotes the activation of nNOS through its phosphorylation on serine 1412 via the AKT pathway and mimics the positive feedback effects of estrogens. Finally, we show that while NO release restrains the reproductive axis at stages of the ovarian cycle during which estrogens exert their inhibitory feedback, it is required for the kisspeptin-dependent preovulatory activation of GnRH neurons. Thus, interactions between kisspeptin and nNOS neurons may play a central role in regulating the hypothalamic-pituitary-gonadal axis in vivo.

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Microcircuits mediating feedforward and feedback synaptic inhibition in the piriform cortex.

Publication Date: 2012 Jan 18 PMID: 22262890
Authors: Suzuki, N. - Bekkers, J. M.
Journal: J Neurosci

Local inhibition by GABA-releasing neurons is important for the operation of sensory cortices, but the details of these inhibitory circuits remain unclear. We addressed this question in the olfactory system by making targeted recordings from identified classes of inhibitory and glutamatergic neurons in the piriform cortex (PC) of mice. First, we looked for feedforward synaptic inhibition provided by interneurons located in the outermost layer of the PC, layer Ia, which is the unique recipient of afferent fibers from the olfactory bulb. We found two types of feedforward inhibition: a fast-rising, spatially restricted kind that was generated by horizontal cells, and a slow-rising, more diffuse kind generated by neurogliaform cells. Both cell types targeted the distal apical dendrites of layer II principal neurons. Next, we studied feedback synaptic inhibition in isolation by making a tissue cut across layer I to selectively remove feedforward inhibitory connections. We identified a powerful type of feedback inhibition of layer II neurons, mostly generated by soma-targeting fast-spiking multipolar cells in layer III, which in turn were driven by feedforward excitation from layer II semilunar cells. Dynamic clamp simulation of feedback inhibition revealed differential effects of this inhibition on the two main types of layer II principal neurons. Thus, our results articulate the connectivity and functions of two important classes of inhibitory microcircuits in the PC. Feedforward and feedback inhibition generated by these circuits is likely to be required for the operation of this sensory paleocortex during the processing of olfactory information.

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Neural activity and neurotransmission regulate the maturation of the innervation field of cortical GABAergic interneurons in an age-dependent manner.

Publication Date: 2012 Jan 18 PMID: 22262889
Authors: Baho, E. - Di Cristo, G.
Journal: J Neurosci

Neural activity guides the patterning of neuron synaptic territory in the developing nervous system. Evidence supporting this hypothesis comes from numerous studies on projection neurons in neuromuscular and visual systems. It is unknown whether the innervation field of GABAergic interneurons, which forms local dense innervations, follows similar rules. Cortical basket cells innervate hundreds of pyramidal cell somata and proximal dendrites. Thanks to this connectivity pattern, they can tightly control neural excitability and synchronization. Here we show that reducing excitation, and thus neurotransmitter release, in mouse cortical single basket cells in slice cultures decreases the number of innervated cells without changing the pattern of perisomatic innervation, both at the peak and after the proliferation phase of perisomatic synapse formation. Conversely, suppressing neurotransmitter release in single basket cells can have completely opposite effects depending on the developmental stage. Our results reveal a remarkably specific and age-dependent role of neural activity and neurotransmission levels in the establishment of the synaptic territory of cortical GABAergic cells.

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Epilepsy Gene LGI1 Regulates Postnatal Developmental Remodeling of Retinogeniculate Synapses.

Publication Date: 2012 Jan 18 PMID: 22262888
Authors: Zhou, Y. D. - Zhang, D. - Ozkaynak, E. - Wang, X. - Kasper, E. M. - Leguern, E. - Baulac, S. - Anderson, M. P.
Journal: J Neurosci

Retinogeniculate connections undergo postnatal refinement in the developing visual system. Here we report that non-ion channel epilepsy gene LGI1 (leucine-rich glioma-inactivated), mutated in human autosomal dominant lateral temporal lobe epilepsy (ADLTE), regulates postnatal pruning of retinal axons in visual relay thalamus. By introducing an ADLTE-associated truncated mutant LGI1 (836delC) or excess full-length LGI1 into transgenic mice, we found that mutant LGI1 blocks, whereas excess LGI1 accelerates, retinogeniculate axon pruning. The normal postnatal single fiber strengthening was arrested by mutant LGI1 and, contrastingly, was enhanced by excess wild-type LGI1. The maximum response of the retinogeniculate synapses, conversely, remained the same in mature LGI1 transgenic mice, indicating that mutant LGI1 blocks, whereas excess wild-type LGI1 promotes, weak axon fiber elimination. Heterozygous deletion of the LGI1 gene, as found in ADLTE patients, inhibited postnatal retinogeniculate synapse elimination, an effect similar to the ADLTE truncated mutant LGI1. The results identify sensory axon remodeling defects in a sensory aura-associated human epilepsy disorder.

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Gating of Sensory Input at Spinal and Cortical Levels during Preparation and Execution of Voluntary Movement.

Publication Date: 2012 Jan 18 PMID: 22262887
Authors: Seki, K. - Fetz, E. E.
Journal: J Neurosci

All bodily movements stimulate peripheral receptors that activate neurons in the brain and spinal cord through afferent feedback. How these reafferent signals are processed within the CNS during movement is a key question in motor control. We investigated cutaneous sensory-evoked potentials in the spinal cord, primary somatosensory and motor cortex, and premotor cortex in monkeys performing an instructed delay task. Afferent inputs from cutaneous receptors were suppressed at several levels in a task-dependent manner. We found two types of suppression. First, suppression during active limb movement was observed in the spinal cord and all three cortical areas. This suppression was induced by both bottom-up and top-down gating mechanisms. Second, during preparation for upcoming movement, evoked responses were suppressed exclusively in the motor cortical areas and the magnitude of suppression was correlated with the reaction time of the subsequent movement. This suppression could be induced by a top-down gating mechanism to facilitate the preparation and execution of upcoming movement.

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Command and compensation in a neuromodulatory decision network.

Publication Date: 2012 Jan 18 PMID: 22262886
Authors: Luan, H. - Diao, F. - Peabody, N. C. - White, B. H.
Journal: J Neurosci

The neural circuits that mediate behavioral choices must not only weigh internal demands and environmental circumstances, but also select and implement specific actions, including associated visceral or neuroendocrine functions. Coordinating these multiple processes suggests considerable complexity. As a consequence, even circuits that support simple behavioral decisions remain poorly understood. Here we show that the environmentally sensitive wing expansion decision of adult fruit flies is coordinated by a single pair of neuromodulatory neurons with command-like function. Targeted suppression of these neurons using the Split Gal4 system abrogates the fly's ability to expand its wings in the face of environmental challenges, while stimulating them forces expansion by coordinately activating both motor and neuroendocrine outputs. The arbitration and implementation of the wing expansion decision by this neuronal pair may illustrate a general strategy by which neuromodulatory neurons orchestrate behavior. Interestingly, the decision network exhibits a plasticity that is unmasked under conducive environmental conditions in flies lacking the function of the command-like neuromodulatory neurons. Such flies can often expand their wings using a motor program distinct from that of wild-type animals and controls. This compensatory program may be the vestige of an ancestral, environmentally insensitive program used for wing expansion that existed before the evolution of the environmentally adaptive program currently used by Drosophila and other cyclorrhaphan flies.

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TRPV1 Channels Regulate Cortical Excitability in Humans.

Publication Date: 2012 Jan 18 PMID: 22262885
Authors: Mori, F. - Ribolsi, M. - Kusayanagi, H. - Monteleone, F. - Mantovani, V. - Buttari, F. - Marasco, E. - Bernardi, G. - Maccarrone, M. - Centonze, D.
Journal: J Neurosci

Studies in rodents show that transient receptor potential vanilloid 1 (TRPV1) channels regulate glutamate release at central and peripheral synapses. In humans, a number of nonsynonymous single-nucleotide polymorphisms (SNPs) have been described in the TRPV1 gene, and some of them significantly alter the functionality of the channel. To address the possible role of TRPV1 channels in the regulation of synaptic transmission in humans, we studied how TRPV1 genetic polymorphisms affect cortical excitability measured with transcranial magnetic stimulation (TMS). Two SNPs of the TRPV1 gene were selected and genotyped (rs222747 and rs222749) in a sample of 77 healthy subjects. In previous cell expression studies, the "G" allele of rs222747 was found to enhance the activity of the channel, whereas rs222749 had no functional effect. Allelic variants in the rs222749 region were not associated with altered cortical response to single, paired, and repetitive TMS. In contrast, subjects homozygous for the G allele in rs222747 exhibited larger short-interval intracortical facilitation (a measure of glutamate transmission) explored through paired-pulse TMS of the primary motor cortex. Recruitment curves, short-interval intracortical inhibition, intracortical facilitation, and long-interval intracortical inhibition were unchanged. LTP- and LTD-like plasticity explored through intermittent or continuous theta-burst stimulation was also similar in the "G" and "non-G" subjects. To our knowledge, our results provide the first evidence that TRPV1 channels regulate cortical excitability to paired-pulse stimulation in humans.

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GDNF Is Predominantly Expressed in the PV+ Neostriatal Interneuronal Ensemble in Normal Mouse and after Injury of the Nigrostriatal Pathway.

Publication Date: 2012 Jan 18 PMID: 22262884
Authors: Hidalgo-Figueroa, M. - Bonilla, S. - Gutierrez, F. - Pascual, A. - Lopez-Barneo, J.
Journal: J Neurosci

Glial cell line-derived neurotrophic factor (GDNF) is absolutely required for survival of dopaminergic (DA) nigrostriatal neurons and protect them from toxic insults. Hence, it is a promising, albeit experimental, therapy for Parkinson's disease (PD). However, the source of striatal GDNF is not well known. GDNF seems to be normally synthesized in neurons, but numerous reports suggest GDNF production in glial cells, particularly in the injured brain. We have studied in detail striatal GDNF production in normal mouse and after damage of DA neurons with MPTP. Striatal GDNF mRNA was present in neonates but markedly increased during the first 2-3 postnatal weeks. Cellular identification of GDNF by unequivocal histochemical methods demonstrated that in normal or injured adult animals GDNF is expressed by striatal neurons and is not synthesized in significant amounts by astrocytes or microglial cells. GDNF mRNA expression was not higher in reactive astrocytes than in normal ones. Approximately 95% of identified neostriatal GDNF-expressing cells in normal and injured animals are parvalbumin-positive (PV+) interneurons, which only represent approximately 0.7% of all striatal neurons. The remaining 5% of GDNF+ cells are cholinergic and somatostatin+ interneurons. Surprisingly, medium spiny projection neurons (MSNs), the vast majority of striatal neurons that receive a strong DA innervation, do not express GDNF. PV+ interneurons constitute an oscillatory functional ensemble of electrically connected cells that control MSNs' firing. Production of GDNF in the PV+ neurons might be advantageous to supply synchronous activity-dependent release of GDNF in broad areas of the striatum. Stimulation of the GDNF-producing striatal PV+ ensemble in PD patients could have therapeutic effects.

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Cellular mechanisms underlying spatiotemporal features of cholinergic retinal waves.

Publication Date: 2012 Jan 18 PMID: 22262883
Authors: Ford, K. J. - Felix, A. L. - Feller, M. B.
Journal: J Neurosci

Before vision, a transient network of recurrently connected cholinergic interneurons, called starburst amacrine cells (SACs), generates spontaneous retinal waves. Despite an absence of robust inhibition, cholinergic retinal waves initiate infrequently and propagate within finite boundaries. Here, we combine a variety of electrophysiological and imaging techniques and computational modeling to elucidate the mechanisms underlying these spatial and temporal properties of waves in developing mouse retina. Waves initiate via rare spontaneous depolarizations of SACs. Waves propagate through recurrent cholinergic connections between SACs and volume release of ACh as demonstrated using paired recordings and a cell-based ACh optical sensor. Perforated-patch recordings and two-photon calcium imaging reveal that individual SACs have slow afterhyperpolarizations that induce SACs to have variable depolarizations during sequential waves. Using a computational model in which the properties of SACs are based on these physiological measurements, we reproduce the slow frequency, speed, and finite size of recorded waves. This study represents a detailed description of the circuit that mediates cholinergic retinal waves and indicates that variability of the interneurons that generate this network activity may be critical for the robustness of waves across different species and stages of development.

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Methylphenidate-Elicited Dopamine Increases in Ventral Striatum Are Associated with Long-Term Symptom Improvement in Adults with Attention Deficit Hyperactivity Disorder.

Publication Date: 2012 Jan 18 PMID: 22262882
Authors: Volkow, N. D. - Wang, G. J. - Tomasi, D. - Kollins, S. H. - Wigal, T. L. - Newcorn, J. H. - Telang, F. W. - Fowler, J. S. - Logan, J. - Wong, C. T. - Swanson, J. M.
Journal: J Neurosci

Stimulant medications, such as methylphenidate, which are effective treatments for attention deficit hyperactivity disorder (ADHD), enhance brain dopamine signaling. However, the relationship between regional brain dopamine enhancement and treatment response has not been evaluated. Here, we assessed whether the dopamine increases elicited by methylphenidate are associated with long-term clinical response. We used a prospective design to study 20 treatment-naive adults with ADHD who were evaluated before treatment initiation and after 12 months of clinical treatment with a titrated regimen of oral methylphenidate. Methylphenidate-induced dopamine changes were evaluated with positron emission tomography and [(11)C]raclopride (D(2)/D(3) receptor radioligand sensitive to competition with endogenous dopamine). Clinical responses were assessed using the Conners' Adult ADHD Rating Scale and revealed a significant reduction in symptoms of inattention and hyperactivity with long-term methylphenidate treatment. A challenge dose of 0.5 mg/kg intravenous methylphenidate significantly increased dopamine in striatum (assessed as decreases in D(2)/D(3) receptor availability). In the ventral striatum, these dopamine increases were associated with the reductions in ratings of symptoms of inattention with clinical treatment. Statistical parametric mapping additionally showed dopamine increases in prefrontal and temporal cortices with intravenous methylphenidate that were also associated with decreases in symptoms of inattention. Our findings indicate that dopamine enhancement in ventral striatum (the brain region involved with reward and motivation) was associated with therapeutic response to methylphenidate, further corroborating the relevance of the dopamine reward/motivation circuitry in ADHD. It also provides preliminary evidence that methylphenidate-elicited dopamine increases in prefrontal and temporal cortices may also contribute to the clinical response.

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Disparity-specific spatial interactions: evidence from EEG source imaging.

Publication Date: 2012 Jan 18 PMID: 22262881
Authors: Cottereau, B. R. - McKee, S. P. - Ales, J. M. - Norcia, A. M.
Journal: J Neurosci

Using cortical source estimation techniques based on high-density EEG and fMRI measurements in humans, we measured how a disparity-defined surround influenced the responses to the changing disparity of a central disk within five visual ROIs: V1, V4, lateral occipital complex (LOC), hMT+, and V3A. The responses in the V1 ROI were not consistently affected either by changes in the characteristics of the surround (correlated or uncorrelated) or by its disparity value, consistent with V1 being responsive only to absolute, not relative, disparity. Correlation in the surround increased the responses in the V4, LOC, and hMT+ ROIs over those measured with the uncorrelated surround. Thus, these extrastriate areas contain neurons that are sensitive to disparity differences. However, their evoked responses did not vary systematically with the surround disparity. Responses in the V3A ROI, in contrast, were increased by correlation in the surround and varied with its disparity. We modeled these V3A responses as attributable to a gain modulation of the absolute disparity response, where the gain amplitude is proportional to the center-surround disparity difference. An additional experiment identified a nonlinear center-surround interaction in V3A that facilitates the responses when center and surround are misaligned but suppresses it when they share the same disparity plane.

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Genetic Variants of FOXP2 and KIAA0319/TTRAP/THEM2 Locus Are Associated with Altered Brain Activation in Distinct Language-Related Regions.

Publication Date: 2012 Jan 18 PMID: 22262880
Authors: Pinel, P. - Fauchereau, F. - Moreno, A. - Barbot, A. - Lathrop, M. - Zelenika, D. - Le Bihan, D. - Poline, J. B. - Bourgeron, T. - Dehaene, S.
Journal: J Neurosci

Recent advances have been made in the genetics of two human communication skills: speaking and reading. Mutations of the FOXP2 gene cause a severe form of language impairment and orofacial dyspraxia, while single-nucleotide polymorphisms (SNPs) located within a KIAA0319/TTRAP/THEM2 gene cluster and affecting the KIAA0319 gene expression are associated with reading disability. Neuroimaging studies of clinical populations point to partially distinct cerebral bases for language and reading impairments. However, alteration of FOXP2 and KIAA0319/TTRAP/THEM2 polymorphisms on typically developed language networks has never been explored. Here, we genotyped and scanned 94 healthy subjects using fMRI during a reading task. We studied the correlation of genetic polymorphisms with interindividual variability in brain activation and functional asymmetry in frontal and temporal cortices. In FOXP2, SNPs rs6980093 and rs7799109 were associated with variations of activation in the left frontal cortex. In the KIAA0319/TTRAP/THEM2 locus, rs17243157 was associated with asymmetry in functional activation of the superior temporal sulcus (STS). Interestingly, healthy subjects bearing the KIAA0319/TTRAP/THEM2 variants previously identified as enhancing the risk of dyslexia showed a reduced left-hemispheric asymmetry of the STS. Our results confirm that both FOXP2 and KIAA0319/TTRAP/THEM2 genes play an important role in human language development, but probably through different cerebral pathways. The observed cortical effects mirror previous fMRI results in developmental language and reading disorders, and suggest that a continuum may exist between these pathologies and normal interindividual variability.

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Dissociating the Role of Prefrontal and Premotor Cortices in Controlling Inhibitory Mechanisms during Motor Preparation.

Publication Date: 2012 Jan 18 PMID: 22262879
Authors: Duque, J. - Labruna, L. - Verset, S. - Olivier, E. - Ivry, R. B.
Journal: J Neurosci

Top-down control processes are critical to select goal-directed actions in flexible environments. In humans, these processes include two inhibitory mechanisms that operate during response selection: one is involved in solving a competition between different response options, the other ensures that a selected response is initiated in a timely manner. Here, we evaluated the role of dorsal premotor cortex (PMd) and lateral prefrontal cortex (LPF) of healthy subjects in these two forms of inhibition by using an innovative transcranial magnetic stimulation (TMS) protocol combining repetitive TMS (rTMS) over PMd or LPF and a single pulse TMS (sTMS) over primary motor cortex (M1). sTMS over M1 allowed us to assess inhibitory changes in corticospinal excitability, while rTMS was used to produce transient disruption of PMd or LPF. We found that rTMS over LPF reduces inhibition associated with competition resolution, whereas rTMS over PMd decreases inhibition associated with response impulse control. These results emphasize the dissociable contributions of these two frontal regions to inhibitory control during motor preparation. The association of LPF with competition resolution is consistent with the role of this area in relatively abstract aspects of control related to goal maintenance, ensuring that the appropriate response is selected in a variable context. In contrast, the association of PMd with impulse control is consistent with the role of this area in more specific processes related to motor preparation and initiation.

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Recurrent neural processing and somatosensory awareness.

Publication Date: 2012 Jan 18 PMID: 22262878
Authors: Auksztulewicz, R. - Spitzer, B. - Blankenburg, F.
Journal: J Neurosci

The neural mechanisms of stimulus detection, despite extensive research, remain elusive. The recurrent processing hypothesis, a prominent theoretical account of perceptual awareness, states that, although stimuli might in principle evoke feedforward activity propagating through the visual cortex, stimuli that become consciously detected are further processed in feedforward-feedback loops established between cortical areas. To test this theory in the tactile modality, we applied dynamic causal modeling to electroencephalography (EEG) data acquired from humans in a somatosensory detection task. In the analysis of stimulation-induced event-related potentials (ERPs), we focused on model-based evidence for feedforward, feedback, and recurrent processing between primary and secondary somatosensory cortices. Bayesian model comparison revealed that, although early EEG components were well explained by both the feedforward and the recurrent models, the recurrent model outperformed the other models when later EEG segments were analyzed. Within the recurrent model, stimulus detection was characterized by a relatively early strength increase of the feedforward connection from primary to secondary somatosensory cortex (>80 ms). At longer latencies (>140 ms), also the feedback connection showed a detection-related strength increase. The modeling results on relative evidence between recurrent and feedforward model comparison support the hypothesis that the ERP responses from sensory areas arising after aware stimulus detection can be explained by increased recurrent processing within the somatosensory network in the later stages of stimulus processing.

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Neural representations of courtship song in the Drosophila brain.

Publication Date: 2012 Jan 18 PMID: 22262877
Authors: Tootoonian, S. - Coen, P. - Kawai, R. - Murthy, M.
Journal: J Neurosci

Acoustic communication in drosophilid flies is based on the production and perception of courtship songs, which facilitate mating. Despite decades of research on courtship songs and behavior in Drosophila, central auditory responses have remained uncharacterized. In this study, we report on intracellular recordings from central neurons that innervate the Drosophila antennal mechanosensory and motor center (AMMC), the first relay for auditory information in the fly brain. These neurons produce graded-potential (nonspiking) responses to sound; we compare recordings from AMMC neurons to extracellular recordings of the receptor neuron population [Johnston's organ neurons (JONs)]. We discover that, while steady-state response profiles for tonal and broadband stimuli are significantly transformed between the JON population in the antenna and AMMC neurons in the brain, transient responses to pulses present in natural stimuli (courtship song) are not. For pulse stimuli in particular, AMMC neurons simply low-pass filter the receptor population response, thus preserving low-frequency temporal features (such as the spacing of song pulses) for analysis by postsynaptic neurons. We also compare responses in two closely related Drosophila species, Drosophila melanogaster and Drosophila simulans, and find that pulse song responses are largely similar, despite differences in the spectral content of their songs. Our recordings inform how downstream circuits may read out behaviorally relevant information from central neurons in the AMMC.

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Learning acts on distinct processes for visual form perception in the human brain.

Publication Date: 2012 Jan 18 PMID: 22262876
Authors: Mayhew, S. D. - Li, S. - Kourtzi, Z.
Journal: J Neurosci

Learning is known to facilitate our ability to detect targets in clutter and optimize brain processes for successful visual recognition. Previous brain-imaging studies have focused on identifying spatial patterns (i.e., brain areas) that change with learning, implicating occipitotemporal and frontoparietal areas. However, little is known about the interactions within this network that mediate learning-dependent improvement in complex perceptual tasks (i.e., discrimination of visual forms in clutter). Here we take advantage of the complementary high spatial and temporal resolution of simultaneous EEG-fMRI to identify the learning-dependent changes in spatiotemporal brain patterns that mediate enhanced behavioral sensitivity in the discrimination of global forms after training. We measured the observers' choices when discriminating between concentric and radial patterns presented in noise before and after training. Similarly, we measured the choices of a pattern classifier when predicting each stimulus from EEG-fMRI signals. By comparing the performance of human observers and classifiers, we demonstrated that learning alters sensitivity to visual forms and EEG-fMRI activation patterns related to distinct visual recognition processes. In particular, behavioral improvement after training was associated with changes in (1) early processes involved in the integration of global forms in higher occipitotemporal and parietal areas, and (2) later processes related to categorical judgments in frontal circuits. Thus, our findings provide evidence that learning acts on distinct visual recognition processes and shapes feedforward interactions across brain areas to support performance in complex perceptual tasks.

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The zebra finch paradox: song is little changed, but number of neurons doubles.

Publication Date: 2012 Jan 18 PMID: 22262875
Authors: Walton, C. - Pariser, E. - Nottebohm, F.
Journal: J Neurosci

New neurons are added to the high vocal center (HVC) of adult males in seasonally breeding songbirds such as the canary (Serinus canaria) that learns new songs in adulthood, and the song sparrow (Melospiza melodia) that does not. In both cases, the new neurons numerically replace others that have died, resulting in a seasonal fluctuation in HVC volume and neuron number. Peaks in neuronal replacement in both species occur in the fall when breeding is over and song is variable. New neurons are added, too, to the HVC of zebra finches (Taeniopygia guttata) that do not learn new songs in adulthood and whose song remains stereotyped throughout the year. Here, we show that, in contrast to the observations in seasonal songbirds, neurons added to the zebra finch HVC are not part of a replacement process. Rather, they lead to a doubling in the number of neurons that project from HVC to the robust nucleus of the arcopallium (RA). As this happens, HVC volume remains constant and the packing density of its neurons increases. The HVC-RA neurons are part of a descending pathway that carries the pattern of learned song; some HVC-RA neurons are also responsive to song playback. The addition of HVC-RA neurons happens in zebra finches housed singly, but becomes more acute if the birds are housed communally. We speculate that new neurons added to the adult HVC may help with the production or perception of learned song, or both.

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Visuomotor Representations within the Human Primary Motor Cortex: The Elusive Markers of Visuomotor Associative Learning.

Publication Date: 2012 Jan 18 PMID: 22262874
Authors: Taschereau-Dumouchel, V. - Hetu, S.
Journal: J Neurosci

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Axonal transport of neurofilaments: a single population of intermittently moving polymers.

Publication Date: 2012 Jan 11 PMID: 22238110
Authors: Li, Y. - Jung, P. - Brown, A.
Journal: J Neurosci

Studies on mouse optic nerve have led to the controversial proposal that only a small proportion of neurofilaments are transported in axons and that the majority are deposited into a persistently stationary and extensively cross-linked cytoskeletal network that remains fixed in place for months without movement. We have used computational modeling to address this issue, taking advantage of the wealth of published kinetic and morphometric data available for neurofilaments in the mouse visual system. We show that the transport kinetics and distribution of neurofilaments in mouse optic nerve can all be explained fully by a "stop-and-go" model of neurofilament transport, in which axons contain a single population of neurofilaments that all move stochastically in a rapid, intermittent, and bidirectional manner. Importantly, we find that the transport kinetics are not consistent with deposition of neurofilaments into a persistently stationary phase, and that deposition models cannot account for the observed distribution of neurofilaments along mouse optic nerve axons. Finally, we show that the apparent existence of a stationary neurofilament network in mouse optic nerve is most likely an experimental artifact due to contamination of the neurofilament transport kinetics with cytosolic proteins that move at faster rates. Thus, there is no evidence for the deposition of axonally transported neurofilaments into a persistently stationary neurofilament network in optic nerve axons. We conclude that all of the neurofilaments move and that they do so with a single broad and continuous distribution of average rates that is dictated by their intermittent and stochastic motile behavior.

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Disrupted-in-Schizophrenia 1 (DISC1) Is Necessary for the Correct Migration of Cortical Interneurons.

Publication Date: 2012 Jan 11 PMID: 22238109
Authors: Steinecke, A. - Gampe, C. - Valkova, C. - Kaether, C. - Bolz, J.
Journal: J Neurosci

Disrupted-in-Schizophrenia 1 (DISC1) is a prominent susceptibility gene for major psychiatric disorders. Previous work indicated that DISC1 plays an important role during neuronal proliferation and differentiation in the cerebral cortex and that it affects the positioning of radial migrating pyramidal neurons. Here we show that in mice, DISC1 is necessary for the migration of the cortical interneurons generated in the medial ganglionic eminence (MGE). RT-PCR, in situ hybridizations, and immunocytochemical data revealed expression of DISC1 transcripts and protein in MGE-derived cells. To study the possible functional role of DISC1 during tangential migration, we performed in utero and ex utero electroporation to suppress DISC1 in the MGE in vivo and in vitro. Results indicate that after DISC1 knockdown, the proportion of tangentially migrating MGE neurons that reached their cortical target was strongly reduced. In addition, there were profound alterations in the morphology of DISC1-deficient neurons, which exhibited longer and less branched leading processes than control cells. These findings provide a possible link between clinical studies reporting alterations of cortical interneurons in schizophrenic patients and the current notion of schizophrenia as a neurodevelopmental disorder.

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Prefrontal cortex mediates extinction of responding by two distinct neural mechanisms in accumbens shell.

Publication Date: 2012 Jan 11 PMID: 22238108
Authors: Ghazizadeh, A. - Ambroggi, F. - Odean, N. - Fields, H. L.
Journal: J Neurosci

Suppression of ill-timed or competing actions optimizes goal-directed behaviors. Diminished inhibitory control over such actions is a central feature of such disorders as impulsivity, obesity, and drug addiction. The ventromedial prefrontal cortex (vmPFC) is involved in suppression of unreinforced actions. Using reversible inactivation in rats, we demonstrate that vmPFC activity is also required for inhibition of unreinforced actions extinguished during learning of a cued appetitive task and that behavioral disinhibition following vmPFC inactivation depends on dopamine signaling in nucleus accumbens shell (NAcS). Combining electrophysiological recording in NAcS with vmPFC inactivation in rats reveals two neural mechanisms by which vmPFC inhibits unreinforced actions. The first is by suppressing phasic excitations that promote behavioral cue responding. The second is by increasing the basal firing of NAcS neurons that tonically inhibit reward seeking. These results identify the vmPFC and the NAcS as critical elements of the circuits relevant to suppression of inappropriate actions.

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Neuronal Gap Junction Coupling Is Regulated by Glutamate and Plays Critical Role in Cell Death during Neuronal Injury.

Publication Date: 2012 Jan 11 PMID: 22238107
Authors: Wang, Y. - Song, J. H. - Denisova, J. V. - Park, W. M. - Fontes, J. D. - Belousov, A. B.
Journal: J Neurosci

In the mammalian CNS, excessive release of glutamate and overactivation of glutamate receptors are responsible for the secondary (delayed) neuronal death following neuronal injury, including ischemia, traumatic brain injury (TBI), and epilepsy. The coupling of neurons by gap junctions (electrical synapses) increases during neuronal injury. We report here that the ischemic increase in neuronal gap junction coupling is regulated by glutamate via group II metabotropic glutamate receptors (mGluRs). Specifically, using electrotonic coupling, Western blots, and siRNA in the mouse somatosensory cortex in vivo and in vitro, we demonstrate that activation of group II mGluRs increases background levels of neuronal gap junction coupling and expression of connexin 36 (Cx36) (neuronal gap junction protein), and inactivation of group II mGluRs prevents the ischemia-mediated increases in the coupling and Cx36 expression. We also show that the regulation is via cAMP/PKA (cAMP-dependent protein kinase)-dependent signaling and posttranscriptional control of Cx36 expression and that other glutamate receptors are not involved in these regulatory mechanisms. Furthermore, using the analysis of neuronal death, we show that inactivation of group II mGluRs or genetic elimination of Cx36 both dramatically reduce ischemia-mediated neuronal death in vitro and in vivo. Similar results are obtained using in vitro models of TBI and epilepsy. Our results indicate that neuronal gap junction coupling is a critical component of glutamate-dependent neuronal death. They also suggest that causal link among group II mGluR function, neuronal gap junction coupling, and neuronal death has a universal character and operates in different types of neuronal injuries.

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Matrix Metalloproteinase-7 Regulates Cleavage of Pro-Nerve Growth Factor and Is Neuroprotective following Kainic Acid-Induced Seizures.

Publication Date: 2012 Jan 11 PMID: 22238106
Authors: Le, A. P. - Friedman, W. J.
Journal: J Neurosci

The neurotrophin nerve growth factor (NGF) regulates neuronal growth, differentiation, and survival during development. However, the precursor of NGF, proNGF, is a potent apoptotic ligand for the p75 neurotrophin receptor (p75(NTR))-sortilin complex. The mechanisms that regulate cleavage of proNGF, therefore, are critical determinants of whether this factor promotes neuronal survival or death. In this study, we demonstrate that, following kainic acid-induced seizures, the proNGF processing enzyme matrix metalloproteinase 7 (MMP-7) and its inhibitor TIMP-1 (tissue inhibitor of matrix metalloproteinase 1) are regulated in a manner that prevents proneurotrophin cleavage and leads to increased proNGF in the extracellular milieu. Furthermore, we demonstrate both in vitro and in vivo that exogenous MMP-7 enhances proNGF cleavage and provides neuroprotection following kainic acid treatment. These data demonstrate that increased extracellular proNGF levels following seizures are stabilized by altered MMP-7 enzymatic activity, leading to increased neuronal death via activation of p75(NTR).

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Subplate neurons promote spindle bursts and thalamocortical patterning in the neonatal rat somatosensory cortex.

Publication Date: 2012 Jan 11 PMID: 22238105
Authors: Tolner, E. A. - Sheikh, A. - Yukin, A. Y. - Kaila, K. - Kanold, P. O.
Journal: J Neurosci

Patterned neuronal activity such as spindle bursts in the neonatal cortex is likely to promote the maturation of cortical synapses and neuronal circuits. Previous work on cats has shown that removal of subplate neurons, a transient neuronal population in the immature cortex, prevents the functional maturation of thalamocortical and intracortical connectivity. Here we studied the effect of subplate removal in the neonatal rat primary somatosensory cortex (S1). Using intracortical EEG we show that after selective removal of subplate neurons in the limb region of S1, endogenous and sensory evoked spindle burst activity is largely abolished. Consistent with the reduced in vivo activity in the S1 limb region, we find by in vitro recordings that thalamocortical inputs to layer 4 neurons are weak. In addition, we find that removal of subplate neurons in the S1 barrel region prevents the development of the characteristic histological barrel-like appearance. Thus, subplate neurons are crucially involved in the generation of particular types of early network activity in the neonatal cortex, which are an important feature of cortical development. The altered EEG pattern following subplate damage could be applicable in the neurological assessment of human neonates.

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L-DOPA Impairs Proteasome Activity in Parkinsonism through D1 Dopamine Receptor.

Publication Date: 2012 Jan 11 PMID: 22238104
Authors: Berthet, A. - Bezard, E. - Porras, G. - Fasano, S. - Barroso-Chinea, P. - Dehay, B. - Martinez, A. - Thiolat, M. L. - Nosten-Bertrand, M. - Giros, B. - Baufreton, J. - Li, Q. - Bloch, B. - Martin-Negrier, M. L.
Journal: J Neurosci

Aberrant membrane localization of dopamine D(1) receptor (D1R) is associated with l-DOPA-induced dyskinesia (LID), a major complication of l-DOPA treatment in Parkinson's disease (PD). Since the proteasome plays a central role in modulating neuronal response through regulation of neurotransmitter receptor intraneuronal fate, we hypothesized that the ubiquitine-proteasome proteolytic pathway could be impaired in LID. Those LIDs are actually associated with a striatum-specific decrease in proteasome catalytic activity and accumulation of polyubiquitinated proteins in experimental rodent and monkey parkinsonism. We then demonstrated that such decreased proteasome catalytic activity (1) results from D1R activation and (2) feed-back the D1R abnormal trafficking, i.e., its exaggerated cell surface abundance. We further showed that the genetic invalidation of the E3 ubiquitin-protein ligase parkin PD gene leads to exaggerated abnormal involuntary movements compared with wild-type mice. We thus established in an unprecedented series of experimental models that impairment of the ubiquitine-proteasome system at specific nodes (E3 ligase parkin, polyubiquitination, proteasome catalytic activity) leads to the same phenomenon, i.e., aberrant behavioral response to dopamine replacement therapy in PD, highlighting the intimate interplay between dopamine receptor and proteasome activity in a nondegenerative context.

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Fetal Testosterone Influences Sexually Dimorphic Gray Matter in the Human Brain.

Publication Date: 2012 Jan 11 PMID: 22238103
Authors: Lombardo, M. V. - Ashwin, E. - Auyeung, B. - Chakrabarti, B. - Taylor, K. - Hackett, G. - Bullmore, E. T. - Baron-Cohen, S.
Journal: J Neurosci

In nonhuman species, testosterone is known to have permanent organizing effects early in life that predict later expression of sex differences in brain and behavior. However, in humans, it is still unknown whether such mechanisms have organizing effects on neural sexual dimorphism. In human males, we show that variation in fetal testosterone (FT) predicts later local gray matter volume of specific brain regions in a direction that is congruent with sexual dimorphism observed in a large independent sample of age-matched males and females from the NIH Pediatric MRI Data Repository. Right temporoparietal junction/posterior superior temporal sulcus (RTPJ/pSTS), planum temporale/parietal operculum (PT/PO), and posterior lateral orbitofrontal cortex (plOFC) had local gray matter volume that was both sexually dimorphic and predicted in a congruent direction by FT. That is, gray matter volume in RTPJ/pSTS was greater for males compared to females and was positively predicted by FT. Conversely, gray matter volume in PT/PO and plOFC was greater in females compared to males and was negatively predicted by FT. Subregions of both amygdala and hypothalamus were also sexually dimorphic in the direction of Male > Female, but were not predicted by FT. However, FT positively predicted gray matter volume of a non-sexually dimorphic subregion of the amygdala. These results bridge a long-standing gap between human and nonhuman species by showing that FT acts as an organizing mechanism for the development of regional sexual dimorphism in the human brain.

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Subsynaptic AMPA receptor distribution is acutely regulated by actin-driven reorganization of the postsynaptic density.

Publication Date: 2012 Jan 11 PMID: 22238102
Authors: Kerr, J. M. - Blanpied, T. A.
Journal: J Neurosci

AMPA receptors (AMPARs) mediate synaptic transmission and plasticity during learning, development, and disease. Mechanisms determining subsynaptic receptor position are poorly understood but are key determinants of quantal size. We used a series of live-cell, high-resolution imaging approaches to measure protein organization within single postsynaptic densities in rat hippocampal neurons. By photobleaching receptors in synapse subdomains, we found that most AMPARs do not freely diffuse within the synapse, indicating they are embedded in a matrix that determines their subsynaptic position. However, time lapse analysis revealed that synaptic AMPARs are continuously repositioned in concert with plasticity of this scaffold matrix rather than simply by free diffusion. Using a fluorescence correlation analysis, we found that across the lateral extent of single PSDs, component proteins were differentially distributed, and this distribution was continually adjusted by actin treadmilling. The C-terminal PDZ ligand of GluA1 did not regulate its mobility or distribution in the synapse. However, glutamate receptor activation promoted subsynaptic mobility. Strikingly, subsynaptic immobility of both AMPARs and scaffold molecules remained essentially intact even after loss of actin filaments. We conclude that receptors are actively repositioned at the synapse by treadmilling of the actin cytoskeleton, an influence which is transmitted only indirectly to receptors via the pliable and surprisingly dynamic internal structure of the PSD.

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Intermittent visual feedback can boost motor learning of rhythmic movements: evidence for error feedback beyond cycles.

Publication Date: 2012 Jan 11 PMID: 22238101
Authors: Ikegami, T. - Hirashima, M. - Osu, R. - Nozaki, D.
Journal: J Neurosci

Movement error is a driving force behind motor learning. For motor learning with discrete movements, such as point-to-point reaching, it is believed that the brain uses error information of the immediately preceding movement only. However, in the case of continuous and repetitive movements (i.e., rhythmic movements), there is a ceaseless inflow of performance information. Thus, an accurate temporal association of the motor commands with the resultant movement errors is not necessarily guaranteed. We investigated how the brain overcomes this challenging situation. Human participants adapted rhythmic movements between two targets to visuomotor rotations, the amplitudes of which changed randomly from cycle to cycle (the duration of one cycle was approximately 400 ms). A system identification technique revealed that the motor adaptation was affected not just by the preceding movement error, but also by a history of errors from the previous cycles. Error information obtained from more than one previous cycle tended to increase, rather than decrease, movement error. This result led to a counterintuitive prediction: providing visual error feedback for only a fraction of cycles should enhance visuomotor adaptation. As predicted, we observed that motor adaptation to a constant visual rotation (30 degrees ) was significantly enhanced by providing visual feedback once every fourth or fifth cycle rather than for every cycle. These results suggest that the brain requires a specific processing time to modify the motor command, based on the error information, and so is unable to deal appropriately with the overwhelming flow of error information generated during rhythmic movements.

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Vision Modulates Corticospinal Suppression in a Functionally Specific Manner during Movement of the Opposite Limb.

Publication Date: 2012 Jan 11 PMID: 22238100
Authors: Carson, R. G. - Ruddy, K. L.
Journal: J Neurosci

The effect of vision on the excitability of corticospinal projections to the flexor carpi radialis (FCR) and extensor carpi radialis (ECR) muscles of right human forearm was investigated before and during discrete movement of the opposite limb. An external force opposed the initial phase of the movement (wrist flexion) and assisted the reverse phase, so that recruitment of the wrist extensors was minimized. Three conditions were used as follows: viewing the inactive right limb (Vision), viewing the mirror image of the moving left limb (Mirror), and with vision of the right limb occluded (No Vision). Transcranial magnetic stimulation was delivered to the left motor cortex: before, at the onset of, or during the left limb movement to obtain motor evoked potentials (MEPs) in the muscles of the right forearm. At and following movement onset, MEPs obtained in the right FCR were smaller in the Vision condition than in the Mirror and No Vision conditions. A distinct pattern of variation was obtained for the ECR. In all conditions, MEPs in this muscle were elevated upon or following movement of the opposite limb. An additional analysis of ipsilateral silent periods indicated that interhemispheric inhibition plays a role in mediating these effects. Activity-dependent changes in corticospinal output to a resting limb during discrete actions of the opposite limb are thus directly contingent upon where one looks. Furthermore, the extent to which vision exerts an influence upon projections to specific muscles varies in accordance with the functional contribution of their homologs to the intended action.

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Disruption of NMDA Receptors in Oligodendroglial Lineage Cells Does Not Alter Their Susceptibility to Experimental Autoimmune Encephalomyelitis or Their Normal Development.

Publication Date: 2012 Jan 11 PMID: 22238099
Authors: Guo, F. - Maeda, Y. - Ko, E. M. - Delgado, M. - Horiuchi, M. - Soulika, A. - Miers, L. - Burns, T. - Itoh, T. - Shen, H. - Lee, E. - Sohn, J. - Pleasure, D.
Journal: J Neurosci

Pharmacological studies have suggested that oligodendroglial NMDA glutamate receptors (NMDARs) mediate white matter injury in a variety of CNS diseases, including multiple sclerosis (MS). We tested this hypothesis in experimental autoimmune encephalomyelitis (EAE), a model of human MS, by timed conditional disruption of oligodendroglial NR1, an essential subunit of functional NMDARs, using an inducible proteolipid protein (Plp) promoter-driven Cre-loxP recombination system. We found that selective ablation of oligodendroglial NR1 did not alter the clinical severity of EAE elicited in C57BL/6 mice by immunization with myelin oligodendrocyte glycoprotein peptide 35-55 (MOG-peptide), nor were there significant differences between the oligodendroglial NR1 KO and non-KO mice in numbers of axons lost in spinal cord dorsal funiculi or severity of spinal cord demyelination. Similarly, constitutive deletion of NR3A, a modulatory subunit of oligodendroglial NMDARs, did not alter the course of MOG-peptide EAE. Furthermore, conditional and constitutive ablation of NR1 in neonatal oligodendrocyte progenitor cells did not interrupt their normal maturation and differentiation. Collectively, our data suggest that oligodendroglial lineage NMDARs are neither required for timely postnatal development of the oligodendroglial lineage, nor significant participants in the pathophysiology of MOG-peptide EAE.

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Why do axons differ in caliber?

Publication Date: 2012 Jan 11 PMID: 22238098
Authors: Perge, J. A. - Niven, J. E. - Mugnaini, E. - Balasubramanian, V. - Sterling, P.
Journal: J Neurosci

CNS axons differ in diameter (d) by nearly 100-fold ( approximately 0.1-10 mum); therefore, they differ in cross-sectional area (d(2)) and volume by nearly 10,000-fold. If, as found for optic nerve, mitochondrial volume fraction is constant with axon diameter, energy capacity would rise with axon volume, also as d(2). We asked, given constraints on space and energy, what functional requirements set an axon's diameter? Surveying 16 fiber groups spanning nearly the full range of diameters in five species (guinea pig, rat, monkey, locust, octopus), we found the following: (1) thin axons are most numerous; (2) mean firing frequencies, estimated for nine of the identified axon classes, are low for thin fibers and high for thick ones, ranging from approximately 1 to >100 Hz; (3) a tract's distribution of fiber diameters, whether narrow or broad, and whether symmetric or skewed, reflects heterogeneity of information rates conveyed by its individual fibers; and (4) mitochondrial volume/axon length rises >/=d(2). To explain the pressure toward thin diameters, we note an established law of diminishing returns: an axon, to double its information rate, must more than double its firing rate. Since diameter is apparently linear with firing rate, doubling information rate would more than quadruple an axon's volume and energy use. Thicker axons may be needed to encode features that cannot be efficiently decoded if their information is spread over several low-rate channels. Thus, information rate may be the main variable that sets axon caliber, with axons constrained to deliver information at the lowest acceptable rate.

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Tune It Down to Live It Up? Rapid, Nongenomic Effects of Cortisol on the Human Brain.

Publication Date: 2012 Jan 11 PMID: 22238097
Authors: Strelzyk, F. - Hermes, M. - Naumann, E. - Oitzl, M. - Walter, C. - Busch, H. P. - Richter, S. - Schachinger, H.
Journal: J Neurosci

The stress hormone cortisol acts on the brain, supporting adaptation and time-adjusted coping processes. Whereas previous research has focused on slow emerging, genomic effects of cortisol, we addressed the rapid, nongenomic cortisol effects on in vivo neuronal activity in humans. Three independent placebo-controlled studies in healthy men were conducted. We observed changes in CNS activity within 15 min after intravenous administration of a physiological dose of 4 mg of cortisol (hydrocortisone). Two of the studies demonstrated a rapid bilateral thalamic perfusion decrement using continuous arterial spin labeling. The third study revealed rapid, cortisol-induced changes in global signal strength and map dissimilarity of the electroencephalogram. Our data demonstrate that a physiological concentration of cortisol profoundly affects the functioning and perfusion of the human brain in vivo via a rapid, nongenomic mechanism. The changes in neuronal functioning suggest that cortisol acts on the thalamic relay of background as well as on task-specific sensory information, allowing focus and facilitation of adaptation to challenges.

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A Conditioning Lesion Protects Axons from Degeneration via the Wallenda/DLK MAP Kinase Signaling Cascade.

Publication Date: 2012 Jan 11 PMID: 22238096
Authors: Xiong, X. - Collins, C. A.
Journal: J Neurosci

Axons are vulnerable components of neuronal circuitry, and neurons are equipped with mechanisms for responding to axonal injury. A highly studied example of this is the conditioning lesion, in which neurons that have been previously injured have an increased ability to initiate new axonal growth (Hoffman, 2010). Here we investigate the effect of a conditioning lesion on axonal degeneration, which occurs in the distal stump after injury, and also occurs in neuropathies and neurodegenerative disorders (Coleman, 2005). We found that Drosophila motoneuron axons that had been previously injured had an increased resiliency to degeneration. This requires the function of a conserved axonal kinase, Wallenda (Wnd)/DLK, and a downstream transcription factor. Because axonal injury leads to acute activation of Wnd (Xiong et al., 2010), and overexpression studies indicate that increased Wnd function is sufficient to promote protection from degeneration, we propose that Wnd regulates an adaptive response to injury that allows neurons to cope with axonal stress.

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RNA binding proteins accumulate at the postsynaptic density with synaptic activity.

Publication Date: 2012 Jan 11 PMID: 22238095
Authors: Zhang, G. - Neubert, T. A. - Jordan, B. A.
Journal: J Neurosci

Neuronal activity elicits changes in synaptic composition that play an important role in experience-dependent plasticity (Choquet and Triller, 2003; Lisman and Raghavachari, 2006; Bourne and Harris, 2008; Holtmaat and Svoboda, 2009). We used a modified version of stable isotope labeling by amino acids in cell culture to identify activity-dependent modifications in the composition of postsynaptic densities (PSDs) isolated from rat primary neuronal cultures. We found that synaptic activity altered approximately 2% of the PSD proteome, which included an increase in diverse RNA binding proteins (RNABPs). Indeed, 12 of the 37 identified proteins whose levels changed with synaptic activity were RNABPs and included the heterogeneous nuclear ribonucleoproteins (hnRNPs) G, A2/B1, M, and D. Knockdown of hnRNPs M and G using shRNAs resulted in altered numbers of dendritic spines, suggesting a crucial role for these proteins in spine density. Synaptic activity also resulted in a concomitant increase in dendritic and synaptic poly(A) mRNA. However, this increase was not affected by knockdown of hnRNPs M or G. Our results suggest that hnRNP proteins regulate dendritic spine density and may play a role in synaptodendritic mRNA metabolism.

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Kinases SPAK and OSR1 Are Upregulated by Estradiol and Activate NKCC1 in the Developing Hypothalamus.

Publication Date: 2012 Jan 11 PMID: 22238094
Authors: Nugent, B. M. - Valenzuela, C. V. - Simons, T. J. - McCarthy, M. M.
Journal: J Neurosci

In immature neurons the amino acid neurotransmitter, GABA provides the dominant mode for neuronal excitation by inducing membrane depolarization due to Cl(-) efflux through GABA(A) receptors (GABA(A)Rs). The driving force for Cl(-) is outward because the Na(+)-K(+)-2Cl(-) cotransporter (NKCC1) elevates the Cl(-) concentration in these cells. GABA-induced membrane depolarization and the resulting activation of voltage-gated Ca(2+) channels is fundamental to normal brain development, yet the mechanisms that regulate depolarizing GABA are not well understood. The neurosteroid estradiol potently augments depolarizing GABA action in the immature hypothalamus by enhancing the activity of the NKCC1 cotransporter. Understanding how estradiol controls NKCC1 activity will be essential for a complete understanding of brain development. We now report that estradiol treatment of newborn rat pups significantly increases protein levels of two kinases upstream of the NKCC1 cotransporter, SPAK (STE20/SPS1-related proline alanine rich kinase) and OSR1 (oxidative stress response kinase). The estradiol-induced increase is transcription dependent, and its time course parallels that of estradiol-enhanced phosphorylation of NKCC1. Antisense oligonucleotide-mediated knockdown of SPAK, and to a lesser degree of OSR1, precludes estradiol-mediated enhancement of NKCC1 phosphorylation. Functionally, knockdown of SPAK or OSR1 in embryonic hypothalamic cultures diminishes estradiol-enhanced Ca(2+) influx induced by GABA(A)R activation. Our data suggest that SPAK and OSR1 may be critical factors in the regulation of depolarizing GABA-mediated processes in the developing brain. It will be important to examine these kinases with respect to sex differences and developmental brain anomalies in future studies.

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Prohibitin reduces mitochondrial free radical production and protects brain cells from different injury modalities.

Publication Date: 2012 Jan 11 PMID: 22238093
Authors: Zhou, P. - Qian, L. - D'Aurelio, M. - Cho, S. - Wang, G. - Manfredi, G. - Pickel, V. - Iadecola, C.
Journal: J Neurosci

Prohibitin is an essential mitochondrial protein that has been implicated in a wide variety of functions in many cell types, but its role in neurons remains unclear. In a proteomic screen of rat brains in which ischemic tolerance was induced by electrical stimulation of the cerebellar fastigial nucleus, we found that prohibitin is upregulated in mitochondria. This observation prompted us to investigate the role of prohibitin in neuronal death and survival. We found that prohibitin is upregulated also in the ischemic tolerance induced by transient ischemia in vivo, or oxygen-glucose deprivation in neuronal cultures. Cell fractionation and electron-microscopic immunolabeling studies demonstrated that prohibitin is localized to neuronal mitochondria. Upregulation of prohibitin in neuronal cultures or hippocampal slices was markedly neuroprotective, whereas prohibitin gene silencing increased neuronal vulnerability, an effect associated with loss of mitochondrial membrane potential and increased mitochondrial production of reactive oxygen species. Prohibitin upregulation was associated with reduced production of reactive oxygen species in mitochondria exposed to the complex I inhibitor rotenone. In addition, prohibitin protected complex I activity from the inhibitory effects of rotenone. These observations, collectively, establish prohibitin as an endogenous neuroprotective protein involved in ischemic tolerance. Prohibitin exerts beneficial effects on neurons by reducing mitochondrial free radical production. The data with complex I activity suggest that prohibitin may stabilize the function of complex I. The protective effect of prohibitin has potential translational relevance in diseases of the nervous system associated with mitochondrial dysfunction and oxidative stress.

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GABA Is Excitatory in Adult Vasopressinergic Neuroendocrine Cells.

Publication Date: 2012 Jan 11 PMID: 22238092
Authors: Haam, J. - Popescu, I. R. - Morton, L. A. - Halmos, K. C. - Teruyama, R. - Ueta, Y. - Tasker, J. G.
Journal: J Neurosci

Neuronal excitability in the adult brain is controlled by a balance between synaptic excitation and inhibition mediated by glutamate and GABA, respectively. While generally inhibitory in the adult brain, GABA(A) receptor activation is excitatory under certain conditions in which the GABA reversal potential is shifted positive due to intracellular Cl(-) accumulation, such as during early postnatal development and brain injury. However, the conditions under which GABA is excitatory are generally either transitory or pathological. Here, we reveal GABAergic synaptic inputs to be uniformly excitatory in vasopressin (VP)-secreting magnocellular neurons in the adult hypothalamus under normal conditions. The GABA reversal potential (E(GABA)) was positive to resting potential and spike threshold in VP neurons, but not in oxytocin (OT)-secreting neurons. The VP neurons lacked expression of the K(+)-Cl(-) cotransporter 2 (KCC2), the predominant Cl(-) exporter in the adult brain. The E(GABA) was unaffected by inhibition of KCC2 in VP neurons, but was shifted positive in OT neurons, which express KCC2. Alternatively, inhibition of the Na(+)-K(+)-Cl(-) cotransporter 1 (NKCC1), a Cl(-) importer expressed in most cell types mainly during postnatal development, caused a negative shift in E(GABA) in VP neurons, but had no effect on GABA currents in OT neurons. GABA(A) receptor blockade caused a decrease in the firing rate of VP neurons, but an increase in firing in OT neurons. Our findings demonstrate that GABA is excitatory in adult VP neurons, suggesting that the classical excitation/inhibition paradigm of synaptic glutamate and GABA control of neuronal excitability does not apply to VP neurons.

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Improved Outcome after Peripheral Nerve Injury in Mice with Increased Levels of Endogenous Omega-3 Polyunsaturated Fatty Acids.

Publication Date: 2012 Jan 11 PMID: 22238091
Authors: Gladman, S. J. - Huang, W. - Lim, S. N. - Dyall, S. C. - Boddy, S. - Kang, J. X. - Knight, M. M. - Priestley, J. V. - Michael-Titus, A. T.
Journal: J Neurosci

Functional recovery after a peripheral nerve injury (PNI) is often poor. There is a need for therapies that protect neurons against injury and enhance regeneration. Omega-3 polyunsaturated fatty acids (PUFAs) have been shown to have therapeutic potential in a variety of neurological disorders, including acute traumatic injury. The objective of this study was to assess the neuroprotective and pro-regenerative potential of omega-3 PUFAs in PNI. We investigated this in mice that express the fat-1 gene encoding for omega-3 fatty acid desaturase, which leads to an increase in endogenous omega-3 PUFAs and a concomitant decrease in omega-6 PUFAs. Dorsal root ganglion (DRG) neurons from wild-type or fat-1 mice were subjected to a mechanical strain or hypoxic injury, and cell death was assessed using ethidium homodimer-1 labeling. The fat-1 background appears to confer robust neuroprotection against both injuries. We then examined the early functional and morphological changes in wild-type and fat-1 mice after a sciatic nerve crush. An accelerated functional recovery 7 d after injury was seen in fat-1 mice when assessed using von Frey filaments and the sciatic nerve functional index. These observations were also mapped to changes in injury-related markers. The injury-induced expression of ATF-3 was decreased in the DRG of fat-1 mice, whereas the axons detected 6 mm distal to the crush were increased. Fat-1 animals also had some protection against muscle atrophy after injury. In conclusion, both in vitro and in vivo experiments support the idea that a higher endogenous omega-3 PUFA could lead to beneficial effects after a PNI.

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Neural prediction errors reveal a risk-sensitive reinforcement-learning process in the human brain.

Publication Date: 2012 Jan 11 PMID: 22238090
Authors: Niv, Y. - Edlund, J. A. - Dayan, P. - O'Doherty, J. P.
Journal: J Neurosci

Humans and animals are exquisitely, though idiosyncratically, sensitive to risk or variance in the outcomes of their actions. Economic, psychological, and neural aspects of this are well studied when information about risk is provided explicitly. However, we must normally learn about outcomes from experience, through trial and error. Traditional models of such reinforcement learning focus on learning about the mean reward value of cues and ignore higher order moments such as variance. We used fMRI to test whether the neural correlates of human reinforcement learning are sensitive to experienced risk. Our analysis focused on anatomically delineated regions of a priori interest in the nucleus accumbens, where blood oxygenation level-dependent (BOLD) signals have been suggested as correlating with quantities derived from reinforcement learning. We first provide unbiased evidence that the raw BOLD signal in these regions corresponds closely to a reward prediction error. We then derive from this signal the learned values of cues that predict rewards of equal mean but different variance and show that these values are indeed modulated by experienced risk. Moreover, a close neurometric-psychometric coupling exists between the fluctuations of the experience-based evaluations of risky options that we measured neurally and the fluctuations in behavioral risk aversion. This suggests that risk sensitivity is integral to human learning, illuminating economic models of choice, neuroscientific models of affective learning, and the workings of the underlying neural mechanisms.

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Action reprogramming in Parkinson's disease: response to prediction error is modulated by levels of dopamine.

Publication Date: 2012 Jan 11 PMID: 22238089
Authors: Galea, J. M. - Bestmann, S. - Beigi, M. - Jahanshahi, M. - Rothwell, J. C.
Journal: J Neurosci

Humans are able to use knowledge of previous events to estimate the probability of future actions. Consequently, an unexpected event will elicit a prediction error as the prepared action has to be replaced by an unprepared option in a process known as "action reprogramming" (AR). Here we show that people with Parkinson's disease (PD) have a dopamine-sensitive deficit in AR that is proportional to the size of the prediction error. Participants performed a probabilistic reaction time (RT) task in the context of either a predictable or unpredictable environment. For an overall predictable sequence, PD patients, on and off dopamine medication, and healthy controls showed similar improvements in RT. However, in the context of a generally predictable sequence, PD patients off medication were impaired in reacting to unexpected events that elicit large prediction errors and require AR. Critically, this deficit in AR was modulated by the prediction error associated with the upcoming event. The prolongation of RT was not observed during an overall unpredictable sequence, in which relatively unexpected events evoke little prediction error and the requirement for AR should be minimal, given the context. The data are compatible with recent theoretical accounts suggesting that levels of dopamine encode the reliability, i.e., precision, of sensory information. In this scheme, PD patients off medication have low dopamine levels and may therefore be less confident about incoming sensory information and more reliant on top-down predictions. Consequently, when these internal predictions are incorrect, PD patients take longer to respond appropriately to unexpected sensory information.

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Preservation of Cone Photoreceptors after a Rapid yet Transient Degeneration and Remodeling in Cone-Only Nrl-/- Mouse Retina.

Publication Date: 2012 Jan 11 PMID: 22238088
Authors: Roger, J. E. - Ranganath, K. - Zhao, L. - Cojocaru, R. I. - Brooks, M. - Gotoh, N. - Veleri, S. - Hiriyanna, A. - Rachel, R. A. - Campos, M. M. - Fariss, R. N. - Wong, W. T. - Swaroop, A.
Journal: J Neurosci

Cone photoreceptors are the primary initiator of visual transduction in the human retina. Dysfunction or death of rod photoreceptors precedes cone loss in many retinal and macular degenerative diseases, suggesting a rod-dependent trophic support for cone survival. Rod differentiation and homeostasis are dependent on the basic motif leucine zipper transcription factor neural retina leucine zipper (NRL). The loss of Nrl (Nrl(-/-)) in mice results in a retina with predominantly S-opsin-containing cones that exhibit molecular and functional characteristics of wild-type cones. Here, we report that Nrl(-/-) retina undergoes a rapid but transient period of degeneration in early adulthood, with cone apoptosis, retinal detachment, alterations in retinal vessel structure, and activation and translocation of retinal microglia. However, cone degeneration stabilizes by 4 months of age, resulting in a thinner but intact outer nuclear layer with residual cones expressing S- and M-opsins and a preserved photopic electroretinogram. At this stage, microglia translocate back to the inner retina and reacquire a quiescent morphology. Gene profiling analysis during the period of transient degeneration reveals misregulation of genes related to stress response and inflammation, implying their involvement in cone death. The Nrl(-/-) mouse illustrates the long-term viability of cones in the absence of rods and retinal pigment epithelium defects in a rodless retina. We propose that Nrl(-/-) retina may serve as a model for elucidating mechanisms of cone homeostasis and degeneration that would be relevant to understanding diseases of the cone-dominant human macula.

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Alteration of Synaptic Network Dynamics by the Intellectual Disability Protein PAK3.

Publication Date: 2012 Jan 11 PMID: 22238087
Authors: Dubos, A. - Combeau, G. - Bernardinelli, Y. - Barnier, J. V. - Hartley, O. - Gaertner, H. - Boda, B. - Muller, D.
Journal: J Neurosci

Several gene mutations linked to intellectual disability in humans code for synaptic molecules implicated in small GTPase signaling. This is the case of the Rac/Cdc42 effector p21-activated kinase 3 (PAK3). The mechanisms responsible for the intellectual defects and the consequences of the mutation on the development and wiring of brain networks remain unknown. Here we show that expression of PAK3 mutants, suppression of PAK3, or inhibition of PAK3 function in rat hippocampal slice cultures interfere with activity-mediated spine dynamics. Inhibition of PAK3 resulted in two main alterations: (1) an increased growth of new, unstable spines, occurring in clusters, and mediated by activity; and (2) an impairment of plasticity-mediated spine stabilization interfering with the formation of persistent spines. Additionally, we find that PAK3 is specifically recruited by activity from dendrites into spines, providing a new mechanism through which PAK3 could participate in the control of both spine stabilization and local spine growth. Together, these data identify a novel function of PAK3 in regulating activity-mediated rearrangement of synaptic connectivity associated with learning and suggest that defects in spine formation and refinement during development could account for intellectual disability.

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Neural correlation is stimulus modulated by feedforward inhibitory circuitry.

Publication Date: 2012 Jan 11 PMID: 22238086
Authors: Middleton, J. W. - Omar, C. - Doiron, B. - Simons, D. J.
Journal: J Neurosci

Correlated variability of neural spiking activity has important consequences for signal processing. How incoming sensory signals shape correlations of population responses remains unclear. Cross-correlations between spiking of different neurons may be particularly consequential in sparsely firing neural populations such as those found in layer 2/3 of sensory cortex. In rat whisker barrel cortex, we found that pairs of excitatory layer 2/3 neurons exhibit similarly low levels of spike count correlation during both spontaneous and sensory-evoked states. The spontaneous activity of excitatory-inhibitory neuron pairs is positively correlated, while sensory stimuli actively decorrelate joint responses. Computational modeling shows how threshold nonlinearities and local inhibition form the basis of a general decorrelating mechanism. We show that inhibitory population activity maintains low correlations in excitatory populations, especially during periods of sensory-evoked coactivation. The role of feedforward inhibition has been previously described in the context of trial-averaged phenomena. Our findings reveal a novel role for inhibition to shape correlations of neural variability and thereby prevent excessive correlations in the face of feedforward sensory-evoked activation.

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Catenin-dependent cadherin function drives divisional segregation of spinal motor neurons.

Publication Date: 2012 Jan 11 PMID: 22238085
Authors: Bello, S. M. - Millo, H. - Rajebhosale, M. - Price, S. R.
Journal: J Neurosci

Motor neurons that control limb movements are organized as a neuronal nucleus in the developing ventral horn of the spinal cord called the lateral motor column. Neuronal migration segregates motor neurons into distinct lateral and medial divisions within the lateral motor column that project axons to dorsal or ventral limb targets, respectively. This migratory phase is followed by an aggregation phase whereby motor neurons within a division that project to the same muscle cluster together. These later phases of motor neuron organization depend on limb-regulated differential cadherin expression within motor neurons. Initially, all motor neurons display the same cadherin expression profile, which coincides with the migratory phase of motor neuron segregation. Here, we show that this early, pan-motor neuron cadherin function drives the divisional segregation of spinal motor neurons in the chicken embryo by controlling motor neuron migration. We manipulated pan-motor neuron cadherin function through dissociation of cadherin binding to their intracellular partners. We found that of the major intracellular transducers of cadherin signaling, gamma-catenin and alpha-catenin predominate in the lateral motor column. In vivo manipulations that uncouple cadherin-catenin binding disrupt divisional segregation via deficits in motor neuron migration. Additionally, reduction of the expression of cadherin-7, a cadherin predominantly expressed in motor neurons only during their migration, also perturbs divisional segregation. Our results show that gamma-catenin-dependent cadherin function is required for spinal motor neuron migration and divisional segregation and suggest a prolonged role for cadherin expression in all phases of motor neuron organization.

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Predicting conceptual processing capacity from spontaneous neuronal activity of the left middle temporal gyrus.

Publication Date: 2012 Jan 11 PMID: 22238084
Authors: Wei, T. - Liang, X. - He, Y. - Zang, Y. - Han, Z. - Caramazza, A. - Bi, Y.
Journal: J Neurosci

Conceptual processing is a crucial brain function for humans. Past research using neuropsychological and task-based functional brain-imaging paradigms indicates that widely distributed brain regions are related to conceptual processing. Here, we explore the potential contribution of intrinsic or spontaneous brain activity to conceptual processing by examining whether resting-state functional magnetic resonance imaging (rs-fMRI) signals can account for individual differences in the conceptual processing efficiencies of healthy individuals. We acquired rs-fMRI and behavioral data on object conceptual processing tasks. We found that the regional amplitude of spontaneous low-frequency fluctuations in the blood oxygen level-dependent signal in the left (posterior) middle temporal gyrus (LMTG) was highly correlated with participants' semantic processing efficiency. Furthermore, the strength of the functional connectivity between the LMTG and a series of brain regions-the left inferior frontal gyrus, bilateral anterior temporal lobe, bilateral medial temporal lobe, posterior cingulate gyrus, and ventromedial and dorsomedial prefrontal cortices-also significantly predicted conceptual behavior. The regional amplitude of low-frequency fluctuations and functionally relevant connectivity strengths of LMTG together accounted for 74% of individual variance in object conceptual performance. This semantic network, with the LMTG as its core component, largely overlaps with the regions reported in previous conceptual/semantic task-based fMRI studies. We conclude that the intrinsic or spontaneous activity of the human brain reflects the processing efficiency of the semantic system.

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Perceptual learning reduces crowding in amblyopia and in the normal periphery.

Publication Date: 2012 Jan 11 PMID: 22238083
Authors: Hussain, Z. - Webb, B. S. - Astle, A. T. - McGraw, P. V.
Journal: J Neurosci

Amblyopia is a developmental visual disorder of cortical origin, characterized by crowding and poor acuity in central vision of the affected eye. Crowding refers to the adverse effects of surrounding items on object identification, common only in normal peripheral but not central vision. We trained a group of adult human amblyopes on a crowded letter identification task to assess whether the crowding problem can be ameliorated. Letter size was fixed well above the acuity limit, and letter spacing was varied to obtain spacing thresholds for central target identification. Normally sighted observers practiced the same task in their lower peripheral visual field. Independent measures of acuity were taken in flanked and unflanked conditions before and after training to measure crowding ratios at three fixed letter separations. Practice improved the letter spacing thresholds of both groups on the training task, and crowding ratios were reduced after posttest. The reductions in crowding in amblyopes were associated with improvements in standard measures of visual acuity. Thus, perceptual learning reduced the deleterious effects of crowding in amblyopia and in the normal periphery. The results support the effectiveness of plasticity-based approaches for improving vision in adult amblyopes and suggest experience-dependent effects on the cortical substrates of crowding.

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Adaptation of binaural processing in the adult brainstem induced by ambient noise.

Publication Date: 2012 Jan 11 PMID: 22238082
Authors: Siveke, I. - Leibold, C. - Schiller, E. - Grothe, B.
Journal: J Neurosci

Interaural differences in stimulus intensity and timing are major cues for sound localization. In mammals, these cues are first processed in the lateral and medial superior olive by interaction of excitatory and inhibitory synaptic inputs from ipsi- and contralateral cochlear nucleus neurons. To preserve sound localization acuity following changes in the acoustic environment, the processing of these binaural cues needs neuronal adaptation. Recent studies have shown that binaural sensitivity adapts to stimulation history within milliseconds, but the actual extent of binaural adaptation is unknown. In the current study, we investigated long-term effects on binaural sensitivity using extracellular in vivo recordings from single neurons in the dorsal nucleus of the lateral lemniscus that inherit their binaural properties directly from the lateral and medial superior olives. In contrast to most previous studies, we used a noninvasive approach to influence this processing. Adult gerbils were exposed for 2 weeks to moderate noise with no stable binaural cue. We found monaural response properties to be unaffected by this measure. However, neuronal sensitivity to binaural cues was reversibly altered for a few days. Computational models of sensitivity to interaural time and level differences suggest that upregulation of inhibition in the superior olivary complex can explain the electrophysiological data.

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Saccadic interception of a moving visual target after a spatiotemporal perturbation.

Publication Date: 2012 Jan 11 PMID: 22238081
Authors: Fleuriet, J. - Goffart, L.
Journal: J Neurosci

Animals can make saccadic eye movements to intercept a moving object at the right place and time. Such interceptive saccades indicate that, despite variable sensorimotor delays, the brain is able to estimate the current spatiotemporal (hic et nunc) coordinates of a target at saccade end. The present work further tests the robustness of this estimate in the monkey when a change in eye position and a delay are experimentally added before the onset of the saccade and in the absence of visual feedback. These perturbations are induced by brief microstimulation in the deep superior colliculus (dSC). When the microstimulation moves the eyes in the direction opposite to the target motion, a correction saccade brings gaze back on the target path or very near. When it moves the eye in the same direction, the performance is more variable and depends on the stimulated sites. Saccades fall ahead of the target with an error that increases when the stimulation is applied more caudally in the dSC. The numerous cases of compensation indicate that the brain is able to maintain an accurate and robust estimate of the location of the moving target. The inaccuracies observed when stimulating the dSC that encodes the visual field traversed by the target indicate that dSC microstimulation can interfere with signals encoding the target motion path. The results are discussed within the framework of the dual-drive and the remapping hypotheses.

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Prenatal immune activation interacts with genetic nurr1 deficiency in the development of attentional impairments.

Publication Date: 2012 Jan 11 PMID: 22238080
Authors: Vuillermot, S. - Joodmardi, E. - Perlmann, T. - Ove Ogren, S. - Feldon, J. - Meyer, U.
Journal: J Neurosci

Prenatal exposure to infection has been linked to increased risk of neurodevelopmental brain disorders, and recent evidence implicates altered dopaminergic development in this association. However, since the relative risk size of prenatal infection appears relatively small with respect to long-term neuropsychiatric outcomes, it is likely that this prenatal insult interacts with other factors in shaping the risk of postnatal brain dysfunctions. In the present study, we show that the neuropathological consequences of prenatal viral-like immune activation are exacerbated in offspring with genetic predisposition to dopaminergic abnormalities induced by mutations in Nurr1, a transcription factor highly essential for normal dopaminergic development. We combined a mouse model of heterozygous genetic deletion of Nurr1 with a model of prenatal immune challenge by the viral mimetic poly(I:C) (polyriboinosinic polyribocytidilic acid). In our gene-environment interaction model, we demonstrate that the combination of the genetic and environmental factors not only exerts additive effects on locomotor hyperactivity and sensorimotor gating deficits, but further produces synergistic effects in the development of impaired attentional shifting and sustained attention. We further demonstrate that the combination of the two factors is necessary to trigger maldevelopment of prefrontal cortical and ventral striatal dopamine systems. Our findings provide evidence for specific gene-environment interactions in the emergence of enduring attentional impairments and neuronal abnormalities pertinent to dopamine-associated brain disorders such as schizophrenia and attention deficit/hyperactivity disorder, and further emphasize a critical role of abnormal dopaminergic development in these etiopathological processes.

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Cross-Frequency Phase-Phase Coupling between Theta and Gamma Oscillations in the Hippocampus.

Publication Date: 2012 Jan 11 PMID: 22238079
Authors: Belluscio, M. A. - Mizuseki, K. - Schmidt, R. - Kempter, R. - Buzsaki, G.
Journal: J Neurosci

Neuronal oscillations allow for temporal segmentation of neuronal spikes. Interdependent oscillators can integrate multiple layers of information. We examined phase-phase coupling of theta and gamma oscillators in the CA1 region of rat hippocampus during maze exploration and rapid eye movement sleep. Hippocampal theta waves were asymmetric, and estimation of the spatial position of the animal was improved by identifying the waveform-based phase of spiking, compared to traditional methods used for phase estimation. Using the waveform-based theta phase, three distinct gamma bands were identified: slow gamma(S) (gamma(S); 30-50 Hz), midfrequency gamma(M) (gamma(M); 50-90 Hz), and fast gamma(F) (gamma(F); 90-150 Hz or epsilon band). The amplitude of each sub-band was modulated by the theta phase. In addition, we found reliable phase-phase coupling between theta and both gamma(S) and gamma(M) but not gamma(F) oscillators. We suggest that cross-frequency phase coupling can support multiple time-scale control of neuronal spikes within and across structures.

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Central Adaptation to Odorants Depends on PI3K Levels in Local Interneurons of the Antennal Lobe.

Publication Date: 2012 Jan 11 PMID: 22238078
Authors: Acebes, A. - Devaud, J. M. - Arnes, M. - Ferrus, A.
Journal: J Neurosci

We have previously shown that driving PI3K levels up or down leads to increases or reductions in the number of synapses, respectively. Using these tools to assay their behavioral effects in Drosophila melanogaster, we showed that a loss of synapses in two sets of local interneurons, GH298 and krasavietz, leads to olfaction changes toward attraction or repulsion, while the simultaneous manipulation of both sets of neurons restored normal olfactory indexes. We show here that olfactory central adaptation also requires the equilibrated changes in both sets of local interneurons. The same genetic manipulations directed to projection (GH146) or mushroom body (201Y, MB247) neurons did not affect adaptation. Also, we show that the equilibrium is a requirement for the glomerulus-specific size changes which are a morphological signature of central adaptation. Since the two sets of local neurons are mostly, although not exclusively, inhibitory (GH298) and excitatory (krasavietz), we interpret that the normal phenomena of sensory perception, measured as an olfactory index, and central adaptation rely on an inhibition/excitation ratio.

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Genetic Analysis of DSCAM's Role as a Netrin-1 Receptor in Vertebrates.

Publication Date: 2012 Jan 11 PMID: 22238077
Authors: Palmesino, E. - Haddick, P. C. - Tessier-Lavigne, M. - Kania, A.
Journal: J Neurosci

Down syndrome cell adhesion molecule (DSCAM) has mainly been characterized for its function as an adhesion molecule in axon growth and in self-recognition between dendrites of the same neuron. Recently, it has been shown that DSCAM can bind to Netrin-1 and that downregulation of DSCAM expression by siRNAs in chick and rodent spinal cords leads to impaired growth and turning response of commissural axons to Netrin-1. To investigate the effect of complete genetic ablation of DSCAM on Netrin-1-induced axon guidance, we analyzed spinal commissural neurons in DSCAM-null mice and found that they extend axons that reach and cross the floor plate and express apparently normal levels of the Netrin receptors DCC (deleted in colorectal carcinoma) and Neogenin. In vitro, commissural neurons in dorsal spinal cord explants of DSCAM-null embryos show normal outgrowth in response to Netrin-1. We therefore conclude that DSCAM is not required for Netrin-induced commissural axon outgrowth and guidance in mice.

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Inner hair cells are not required for survival of spiral ganglion neurons in the adult cochlea.

Publication Date: 2012 Jan 11 PMID: 22238076
Authors: Zilberstein, Y. - Liberman, M. C. - Corfas, G.
Journal: J Neurosci

Studies of sensorineural hearing loss have long suggested that survival of spiral ganglion neurons (SGNs) depends on trophic support provided by their peripheral targets, the inner hair cells (IHCs): following ototoxic drugs or acoustic overexposure, IHC death is rapid whereas SGN degeneration is always delayed. However, recent noise-trauma studies show that SGNs can die even when hair cells survive, and transgenic mouse models show that supporting cell dysfunction can cause SGN degeneration in the absence of IHC pathology. To reexamine this issue, we studied a model of IHC loss that does not involve noise or ototoxic drugs. Mice lacking the gene for the high-affinity thiamine transporter (Slc19a2) have normal cochlear structure and function when fed a regular (thiamine-rich) diet. However, dietary thiamine restriction causes widespread, rapid (within 10 d) loss of IHCs. Using this model, we show that SGNs can survive for months after IHC loss, indicating that (1) IHCs are not necessary for neuronal survival, (2) neuronal loss in the other hearing loss models is likely due to effects of the trauma on the sensory neurons or other inner ear cells, and (3) that other cells, most likely supporting cells of the organ of Corti, are the main source of SGN survival factors. These results overturn a long-standing dogma in the study of sensorineural hearing loss and highlight the importance of cochlear supporting cells in neuronal survival in the adult inner ear.

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The role of Beta-frequency neural oscillations in motor control.

Publication Date: 2012 Jan 11 PMID: 22238075
Authors: Davis, N. J. - Tomlinson, S. P. - Morgan, H. M.
Journal: J Neurosci

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