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Showing papers in "The Journal of Neuroscience in 2010"


Journal ArticleDOI
TL;DR: It is concluded that people with schizophrenia tend to have a less strongly integrated, more diverse profile of brain functional connectivity, associated with a less hub-dominated configuration of complex brain functional networks.
Abstract: Schizophrenia has often been conceived as a disorder of connectivity between components of large-scale brain networks. We tested this hypothesis by measuring aspects of both functional connectivity and functional network topology derived from resting-state fMRI time series acquired at 72 cerebral regions over 17 min from 15 healthy volunteers (14 male, 1 female) and 12 people diagnosed with schizophrenia (10 male, 2 female). We investigated between-group differences in strength and diversity of functional connectivity in the 0.06-0.125 Hz frequency interval, and some topological properties of undirected graphs constructed from thresholded interregional correlation matrices. In people with schizophrenia, strength of functional connectivity was significantly decreased, whereas diversity of functional connections was increased. Topologically, functional brain networks had reduced clustering and small-worldness, reduced probability of high-degree hubs, and increased robustness in the schizophrenic group. Reduced degree and clustering were locally significant in medial parietal, premotor and cingulate, and right orbitofrontal cortical nodes of functional networks in schizophrenia. Functional connectivity and topological metrics were correlated with each other and with behavioral performance on a verbal fluency task. We conclude that people with schizophrenia tend to have a less strongly integrated, more diverse profile of brain functional connectivity, associated with a less hub-dominated configuration of complex brain functional networks. Alongside these behaviorally disadvantageous differences, however, brain networks in the schizophrenic group also showed a greater robustness to random attack, pointing to a possible benefit of the schizophrenia connectome, if less extremely expressed.

1,264 citations


Journal ArticleDOI
TL;DR: The results show for the first time that cell-produced α- Synuclein is secreted via an exosomal, calcium-dependent mechanism and suggest that α-synuclein secretion serves to amplify and propagate Parkinson's disease-related pathology.
Abstract: α-Synuclein is central in Parkinson's disease pathogenesis. Although initially α-synuclein was considered a purely intracellular protein, recent data suggest that it can be detected in the plasma and CSF of humans and in the culture media of neuronal cells. To address a role of secreted α-synuclein in neuronal homeostasis, we have generated wild-type α-synuclein and β-galactosidase inducible SH-SY5Y cells. Soluble oligomeric and monomeric species of α-synuclein are readily detected in the conditioned media (CM) of these cells at concentrations similar to those observed in human CSF. We have found that, in this model, α-synuclein is secreted by externalized vesicles in a calcium-dependent manner. Electron microscopy and liquid chromatography–mass spectrometry proteomic analysis demonstrate that these vesicles have the characteristic hallmarks of exosomes, secreted intraluminar vesicles of multivesicular bodies. Application of CM containing secreted α-synuclein causes cell death of recipient neuronal cells, which can be reversed after α-synuclein immunodepletion from the CM. High- and low-molecular-weight α-synuclein species, isolated from this CM, significantly decrease cell viability. Importantly, treatment of the CM with oligomer-interfering compounds before application rescues the recipient neuronal cells from the observed toxicity. Our results show for the first time that cell-produced α-synuclein is secreted via an exosomal, calcium-dependent mechanism and suggest that α-synuclein secretion serves to amplify and propagate Parkinson's disease-related pathology.

947 citations


Journal ArticleDOI
TL;DR: These studies establish the cellular mechanisms through which antibodies of patients with anti-NMDAR encephalitis cause a specific, titer-dependent, and reversible loss of NMDARs.
Abstract: We recently described a severe, potentially lethal, but treatment-responsive encephalitis that associates with autoantibodies to the NMDA receptor (NMDAR) and results in behavioral symptoms similar to those obtained with models of genetic or pharmacologic attenuation of NMDAR function. Here, we demonstrate that patients' NMDAR antibodies cause a selective and reversible decrease in NMDAR surface density and synaptic localization that correlates with patients' antibody titers. The mechanism of this decrease is selective antibody-mediated capping and internalization of surface NMDARs, as Fab fragments prepared from patients' antibodies did not decrease surface receptor density, but subsequent cross-linking with anti-Fab antibodies recapitulated the decrease caused by intact patient NMDAR antibodies. Moreover, whole-cell patch-clamp recordings of miniature EPSCs in cultured rat hippocampal neurons showed that patients' antibodies specifically decreased synaptic NMDAR-mediated currents, without affecting AMPA receptor-mediated currents. In contrast to these profound effects on NMDARs, patients' antibodies did not alter the localization or expression of other glutamate receptors or synaptic proteins, number of synapses, dendritic spines, dendritic complexity, or cell survival. In addition, NMDAR density was dramatically reduced in the hippocampus of female Lewis rats infused with patients' antibodies, similar to the decrease observed in the hippocampus of autopsied patients. These studies establish the cellular mechanisms through which antibodies of patients with anti-NMDAR encephalitis cause a specific, titer-dependent, and reversible loss of NMDARs. The loss of this subtype of glutamate receptors eliminates NMDAR-mediated synaptic function, resulting in the learning, memory, and other behavioral deficits observed in patients with anti-NMDAR encephalitis.

933 citations


Journal ArticleDOI
TL;DR: It is found in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of PD that AP accumulation and dopaminergic cell death are preceded by a marked decrease in the amount of lysosomes within dopamine neurons, indicating that restoration of lYSosomal levels and function may represent a novel neuroprotective strategy in PD.
Abstract: Mounting evidence suggests a role for autophagy dysregulation in Parkinson's disease (PD). The bulk degradation of cytoplasmic proteins (including α-synuclein) and organelles (such as mitochondria) is mediated by macroautophagy, which involves the sequestration of cytosolic components into autophagosomes (AP) and its delivery to lysosomes. Accumulation of AP occurs in postmortem brain samples from PD patients, which has been widely attributed to an induction of autophagy. However, the cause and pathogenic significance of these changes remain unknown. Here we found in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of PD that AP accumulation and dopaminergic cell death are preceded by a marked decrease in the amount of lysosomes within dopaminergic neurons. Lysosomal depletion was secondary to the abnormal permeabilization of lysosomal membranes induced by increased mitochondrial-derived reactive oxygen species. Lysosomal permeabilization resulted in a defective clearance and subsequent accumulation of undegraded AP and contributed directly to neurodegeneration by the ectopic release of lysosomal proteases into the cytosol. Lysosomal breakdown and AP accumulation also occurred in PD brain samples, where Lewy bodies were strongly immunoreactive for AP markers. Induction of lysosomal biogenesis by genetic or pharmacological activation of lysosomal transcription factor EB restored lysosomal levels, increased AP clearance and attenuated 1-methyl-4-phenylpyridinium-induced cell death. Similarly, the autophagy-enhancer compound rapamycin attenuated PD-related dopaminergic neurodegeneration, both in vitro and in vivo, by restoring lysosomal levels. Our results indicate that AP accumulation in PD results from defective lysosomal-mediated AP clearance secondary to lysosomal depletion. Restoration of lysosomal levels and function may thus represent a novel neuroprotective strategy in PD.

681 citations


Journal ArticleDOI
TL;DR: Findings provide the first demonstration that OT can facilitate amygdala-dependent, socially reinforced learning and emotional empathy in men, as well as two patients with selective bilateral damage to the amygdala.
Abstract: Oxytocin (OT) is becoming increasingly established as a prosocial neuropeptide in humans with therapeutic potential in treatment of social, cognitive, and mood disorders. However, the potential of OT as a general facilitator of human learning and empathy is unclear. The current double-blind experiments on healthy adult male volunteers investigated first whether treatment with intranasal OT enhanced learning performance on a feedback-guided item-category association task where either social (smiling and angry faces) or nonsocial (green and red lights) reinforcers were used, and second whether it increased either cognitive or emotional empathy measured by the Multifaceted Empathy Test. Further experiments investigated whether OT-sensitive behavioral components required a normal functional amygdala. Results in control groups showed that learning performance was improved when social rather than nonsocial reinforcement was used. Intranasal OT potentiated this social reinforcement advantage and greatly increased emotional, but not cognitive, empathy in response to both positive and negative valence stimuli. Interestingly, after OT treatment, emotional empathy responses in men were raised to levels similar to those found in untreated women. Two patients with selective bilateral damage to the amygdala (monozygotic twins with congenital Urbach-Wiethe disease) were impaired on both OT-sensitive aspects of these learning and empathy tasks, but performed normally on nonsocially reinforced learning and cognitive empathy. Overall these findings provide the first demonstration that OT can facilitate amygdala-dependent, socially reinforced learning and emotional empathy in men.

672 citations


Journal ArticleDOI
TL;DR: An absolute requirement of Notch signaling for the maintenance of neural stem cells and a proper control of neurogenesis in both embryonic and adult brains is indicated.
Abstract: Activation of Notch signaling induces the expression of transcriptional repressor genes such as Hes1, leading to repression of proneural gene expression and maintenance of neural stem/progenitor cells. However, a requirement for Notch signaling in the telencephalon was not clear, because in Hes1;Hes3;Hes5 triple-mutant mice, neural stem/progenitor cells are depleted in most regions of the developing CNS, but not in the telencephalon. Here, we investigated a role for Notch signaling in the telencephalon by generating tamoxifen-inducible conditional knock-out mice that lack Rbpj, an intracellular signal mediator of all Notch receptors. When Rbpj was deleted in the embryonic brain, almost all telencephalic neural stem/progenitor cells prematurely differentiated into neurons and were depleted. When Rbpj was deleted in the adult brain, all neural stem cells differentiated into transit-amplifying cells and neurons. As a result, neurogenesis increased transiently, but 3 months later all neural stem cells were depleted and neurogenesis was totally lost. These results indicated an absolute requirement of Notch signaling for the maintenance of neural stem cells and a proper control of neurogenesis in both embryonic and adult brains.

642 citations


Journal ArticleDOI
TL;DR: It is demonstrated that schizophrenia involves an aberrant topology of the structural infrastructure of the brain network, which suggests that schizophrenia patients have a less strongly globally integrated structural brain network with a reduced central role for key frontal hubs.
Abstract: Brain regions are not independent. They are interconnected by white matter tracts, together forming one integrative complex network. The topology of this network is crucial for efficient information integration between brain regions. Here, we demonstrate that schizophrenia involves an aberrant topology of the structural infrastructure of the brain network. Using graph theoretical analysis, complex structural brain networks of 40 schizophrenia patients and 40 human healthy controls were examined. Diffusion tensor imaging was used to reconstruct the white matter connections of the brain network, with the strength of the connections defined as the level of myelination of the tracts as measured through means of magnetization transfer ratio magnetic resonance imaging. Patients displayed a preserved overall small-world network organization, but focusing on specific brain regions and their capacity to communicate with other regions of the brain revealed significantly longer node-specific path lengths (higher L) of frontal and temporal regions, especially of bilateral inferior/superior frontal cortex and temporal pole regions. These findings suggest that schizophrenia impacts global network connectivity of frontal and temporal brain regions. Furthermore, frontal hubs of patients showed a significant reduction of betweenness centrality, suggesting a less central hub role of these regions in the overall network structure. Together, our findings suggest that schizophrenia patients have a less strongly globally integrated structural brain network with a reduced central role for key frontal hubs, resulting in a limited structural capacity to integrate information across brain regions.

625 citations


Journal ArticleDOI
TL;DR: Age-related changes in homotopic RSFC are systematically investigated in 214 healthy individuals ranging in age from 7 to 85 years to motivate studies of the physiological mechanisms underlying functional homotopy in neurodegenerative and psychiatric disorders.
Abstract: Functional homotopy, the high degree of synchrony in spontaneous activity between geometrically corresponding interhemispheric (i.e., homotopic) regions, is a fundamental characteristic of the intrinsic functional architecture of the brain. However, despite its prominence, the lifespan development of the homotopic resting-state functional connectivity (RSFC) of the human brain is rarely directly examined in functional magnetic resonance imaging studies. Here, we systematically investigated age-related changes in homotopic RSFC in 214 healthy individuals ranging in age from 7 to 85 years. We observed marked age-related changes in homotopic RSFC with regionally specific developmental trajectories of varying levels of complexity. Sensorimotor regions tended to show increasing homotopic RSFC, whereas higher-order processing regions showed decreasing connectivity (i.e., increasing segregation) with age. More complex maturational curves were also detected, with regions such as the insula and lingual gyrus exhibiting quadratic trajectories and the superior frontal gyrus and putamen exhibiting cubic trajectories. Sex-related differences in the developmental trajectory of functional homotopy were detected within dorsolateral prefrontal cortex (Brodmann areas 9 and 46) and amygdala. Evidence of robust developmental effects in homotopic RSFC across the lifespan should serve to motivate studies of the physiological mechanisms underlying functional homotopy in neurodegenerative and psychiatric disorders.

617 citations


Journal ArticleDOI
TL;DR: The A β-induced effects on microtubule and mitochondria depletion, Tau missorting, and loss of spines are prevented by taxol, indicating that Aβ-induced microtubules destabilization and corresponding traffic defects are key factors in incipient degeneration.
Abstract: Aggregation of amyloid-β (Aβ) and Tau protein are hallmarks of Alzheimer's disease (AD), and according to the Aβ-cascade hypothesis, Aβ is considered toxic for neurons and Tau a downstream target of Aβ. We have investigated differentiated primary hippocampal neurons for early localized changes following exposure to Aβ oligomers. Initial events become evident by missorting of endogenous Tau into the somatodendritic compartment, in contrast to axonal sorting in normal neurons. In missorted dendritic regions there is a depletion of spines and local increase in Ca2+, and breakdown of microtubules. Tau in these regions shows elevated phosphorylation at certain sites diagnostic of AD-Tau (e.g., epitope of antibody 12E8, whose phosphorylation causes detachment of Tau from microtubules, and AT8 epitope), and local elevation of certain kinase activities (e.g., MARK/par-1, BRSK/SADK, p70S6K, cdk5, but not GSK3β, JNK, MAPK). These local effects occur without global changes in Tau, tubulin, or kinase levels. Somatodendritic missorting occurs not only with Tau, but also with other axonal proteins such as neurofilaments, and correlates with pronounced depletion of microtubules and mitochondria. The Aβ-induced effects on microtubule and mitochondria depletion, Tau missorting, and loss of spines are prevented by taxol, indicating that Aβ-induced microtubule destabilization and corresponding traffic defects are key factors in incipient degeneration. By contrast, the rise in Ca2+ levels, kinase activities, and Tau phosphorylation cannot be prevented by taxol. Incipient and local changes similar to those of Aβ oligomers can be evoked by cell stressors (e.g., H2O2, glutamate, serum deprivation), suggesting some common mechanism of signaling.

616 citations


Journal ArticleDOI
TL;DR: Cellular indicators of functional activity, including the immediate early genes (IEGs) zif268 (egr1), c-fos, and arc, in the prefrontal cortex of clinically depressed humans obtained postmortem and mice after chronic social defeat stress indicate that the activity of the mPFC is a key determinant of depression-like behavior, as well as antidepressant responses.
Abstract: Brain stimulation and imaging studies in humans have highlighted a key role for the prefrontal cortex in clinical depression; however, it remains unknown whether excitation or inhibition of prefrontal cortical neuronal activity is associated with antidepressant responses. Here, we examined cellular indicators of functional activity, including the immediate early genes (IEGs) zif268 (egr1), c-fos, and arc, in the prefrontal cortex of clinically depressed humans obtained postmortem. We also examined these genes in the ventral portion of the medial prefrontal cortex (mPFC) of mice after chronic social defeat stress, a mouse model of depression. In addition, we used viral vectors to overexpress channel rhodopsin 2 (a light-activated cation channel) in mouse mPFC to optogenetically drive "burst" patterns of cortical firing in vivo and examine the behavioral consequences. Prefrontal cortical tissue derived from clinically depressed humans displayed significant reductions in IEG expression, consistent with a deficit in neuronal activity within this brain region. Mice subjected to chronic social defeat stress exhibited similar reductions in levels of IEG expression in mPFC. Interestingly, some of these changes were not observed in defeated mice that escape the deleterious consequences of the stress, i.e., resilient animals. In those mice that expressed a strong depressive-like phenotype, i.e., susceptible animals, optogenetic stimulation of mPFC exerted potent antidepressant-like effects, without affecting general locomotor activity, anxiety-like behaviors, or social memory. These results indicate that the activity of the mPFC is a key determinant of depression-like behavior, as well as antidepressant responses.

596 citations


Journal ArticleDOI
TL;DR: The test in the human brain whether the oscillation in the alpha band is causally shaping perception through directly stimulating visual areas via short trains of rhythmic TMS shows that the posterior alpha rhythm is actively involved in shaping forthcoming perception and, hence, constitutes a substrate rather than a mere correlate of visual input regulation.
Abstract: The posterior alpha rhythm (8-14 Hz), originating in occipito-parietal areas through thalamocortical generation, displays characteristics of visual activity in anticipation of visual events. Posterior alpha power is influenced by visual spatial attention via top-down control from higher order attention areas such as the frontal eye field. It covaries with visual cortex excitability, as tested through transcranial magnetic stimulation (TMS), and predicts the perceptual fate of a forthcoming visual stimulus. Yet, it is still unknown whether the nature of the relationship between this prestimulus alpha oscillation and upcoming perception is causal or only correlative. Here, we tested in the human brain whether the oscillation in the alpha band is causally shaping perception through directly stimulating visual areas via short trains of rhythmic TMS. We compared stimulation at alpha frequency (10 Hz) with two control frequencies in the theta (5 Hz) and beta bands (20 Hz), and assessed immediate perceptual outcomes. Target visibility was significantly modulated by alpha stimulation, relative to both control conditions. Alpha stimulation selectively impaired visual detection in the visual field opposite to the stimulated hemisphere, while enhancing detection ipsilaterally. These frequency-specific effects were observed both for stimulation over occipital and parietal areas of the left and right hemispheres and were short lived: they were observed by the end of the TMS train but were absent 3 s later. This shows that the posterior alpha rhythm is actively involved in shaping forthcoming perception and, hence, constitutes a substrate rather than a mere correlate of visual input regulation.

Journal ArticleDOI
TL;DR: Fast modulation of serotonergic and cholinergic transmission may influence cortical activity through an enhancement of GABAergic synaptic transmission from 5-HT3AR-expressing neurons during sensory process depending on different behavioral states.
Abstract: A highly diverse population of neocortical GABAergic inhibitory interneurons has been implicated in multiple functions in information processing within cortical circuits. The diversity of cortical interneurons is determined during development and primarily depends on their embryonic origins either from the medial (MGE) or the caudal (CGE) ganglionic eminences. Although MGE-derived parvalbumin (PV)- or somatostatin (SST)-expressing interneurons are well characterized, less is known about the other types of cortical GABAergic interneurons, especially those of CGE lineage, because of the lack of specific neuronal markers for these interneuron subtypes. Using a bacterial artificial chromosome transgenic mouse line, we show that, in the somatosensory cortex of the mouse, the serotonin 5-hydroxytryptamine 3A (5-HT(3A)) receptor, the only ionotropic serotonergic receptor, is expressed in most, if not all, neocortical GABAergic interneurons that do not express PV or SST. Genetic fate mapping and neurochemical profile demonstrate that 5-HT(3A)R-expressing neurons include the entire spectrum of CGE-derived interneurons. We report that, in addition to serotonergic responsiveness via 5-HT(3A)Rs, acetylcholine also depolarizes 5-HT(3A)R-expressing neurons via nicotinic receptors. 5-HT(3A)R-expressing neurons in thalamocortical (TC) recipient areas receive weak but direct monosynaptic inputs from the thalamus. TC input depolarizes a subset of TC-recipient 5-HT(3A)R neurons as strongly as fast-spiking cells, in part because of their high input resistance. Hence, fast modulation of serotonergic and cholinergic transmission may influence cortical activity through an enhancement of GABAergic synaptic transmission from 5-HT(3A)R-expressing neurons during sensory process depending on different behavioral states.

Journal ArticleDOI
TL;DR: Evidence is presented that Mfn2 is directly involved in and required for axonal mitochondrial transport, distinct from its role in mitochondrial fusion, and important insight is offered into the cell type specificity and molecular mechanisms of axonal degeneration in CMT2A and dominant optic atrophy.
Abstract: Mitofusins (Mfn1 and Mfn2) are outer mitochondrial membrane proteins involved in regulating mitochondrial dynamics. Mutations in Mfn2 cause Charcot-Marie-Tooth disease (CMT) type 2A, an inherited disease characterized by degeneration of long peripheral axons, but the nature of this tissue selectivity remains unknown. Here, we present evidence that Mfn2 is directly involved in and required for axonal mitochondrial transport, distinct from its role in mitochondrial fusion. Live imaging of neurons cultured from Mfn2 knock-out mice or neurons expressing Mfn2 disease mutants shows that axonal mitochondria spend more time paused and undergo slower anterograde and retrograde movements, indicating an alteration in attachment to microtubule-based transport systems. Furthermore, Mfn2 disruption altered mitochondrial movement selectively, leaving transport of other organelles intact. Importantly, both Mfn1 and Mfn2 interact with mammalian Miro (Miro1/Miro2) and Milton (OIP106/GRIF1) proteins, members of the molecular complex that links mitochondria to kinesin motors. Knockdown of Miro2 in cultured neurons produced transport deficits identical to loss of Mfn2, indicating that both proteins must be present at the outer membrane to mediate axonal mitochondrial transport. In contrast, disruption of mitochondrial fusion via knockdown of the inner mitochondrial membrane protein Opa1 had no effect on mitochondrial motility, indicating that loss of fusion does not inherently alter mitochondrial transport. These experiments identify a role for mitofusins in directly regulating mitochondrial transport and offer important insight into the cell type specificity and molecular mechanisms of axonal degeneration in CMT2A and dominant optic atrophy.

Journal ArticleDOI
TL;DR: Elevated mTOR signaling may provide a functional link between overactivation of group I mGluRs and aberrant synaptic plasticity in the fragile X mouse, mechanisms relevant to impaired cognition in fragile X syndrome.
Abstract: Fragile X syndrome, the most common form of inherited mental retardation and leading genetic cause of autism, is caused by transcriptional silencing of the Fmr1 gene. The fragile X mental retardation protein (FMRP), the gene product of Fmr1, is an RNA binding protein that negatively regulates translation in neurons. The Fmr1 knock-out mouse, a model of fragile X syndrome, exhibits cognitive deficits and exaggerated metabotropic glutamate receptor (mGluR)-dependent long-term depression at CA1 synapses. However, the molecular mechanisms that link loss of function of FMRP to aberrant synaptic plasticity remain unclear. The mammalian target of rapamycin (mTOR) signaling cascade controls initiation of cap-dependent translation and is under control of mGluRs. Here we show that mTOR phosphorylation and activity are elevated in hippocampus of juvenile Fmr1 knock-out mice by four functional readouts: (1) association of mTOR with regulatory associated protein of mTOR; (2) mTOR kinase activity; (3) phosphorylation of mTOR downstream targets S6 kinase and 4E-binding protein; and (4) formation of eukaryotic initiation factor complex 4F, a critical first step in cap-dependent translation. Consistent with this, mGluR long-term depression at CA1 synapses of FMRP-deficient mice is exaggerated and rapamycin insensitive. We further show that the p110 subunit of the upstream kinase phosphatidylinositol 3-kinase (PI3K) and its upstream activator PI3K enhancer PIKE, predicted targets of FMRP, are upregulated in knock-out mice. Elevated mTOR signaling may provide a functional link between overactivation of group I mGluRs and aberrant synaptic plasticity in the fragile X mouse, mechanisms relevant to impaired cognition in fragile X syndrome.

Journal ArticleDOI
TL;DR: Using the amblyopic visual system as a model, genetic, pharmacological, and environmental removal of brakes to enable recovery of vision in adult rodents are discussed and it is considered how these mechanisms may provide a biological foundation for the remarkable increase in plasticity after action video game play by amblyopy subjects.
Abstract: Adult brain plasticity, although possible, remains more restricted in scope than during development. Here, we address conditions under which circuit rewiring may be facilitated in the mature brain. At a cellular and molecular level, adult plasticity is actively limited. Some of these "brakes" are structural, such as perineuronal nets or myelin, which inhibit neurite outgrowth. Others are functional, acting directly upon excitatory-inhibitory balance within local circuits. Plasticity in adulthood can be induced either by lifting these brakes through invasive interventions or by exploiting endogenous permissive factors, such as neuromodulators. Using the amblyopic visual system as a model, we discuss genetic, pharmacological, and environmental removal of brakes to enable recovery of vision in adult rodents. Although these mechanisms remain largely uncharted in the human, we consider how they may provide a biological foundation for the remarkable increase in plasticity after action video game play by amblyopic subjects.

Journal ArticleDOI
TL;DR: The finding that trimethylation of histone H3 at lysine 4 (H3K4), an active mark for transcription, is upregulated in hippocampus 1 h following contextual fear conditioning, demonstrates that histone methylation is actively regulated in the hippocampus and facilitates long-term memory formation.
Abstract: It has been established that regulation of chromatin structure through post-translational modification of histone proteins, primarily histone H3 phosphorylation and acetylation, is an important early step in the induction of synaptic plasticity and formation of long-term memory. In this study, we investigated the contribution of another histone modification, histone methylation, to memory formation in the adult hippocampus. We found that trimethylation of histone H3 at lysine 4 (H3K4), an active mark for transcription, is upregulated in hippocampus 1 h following contextual fear conditioning. In addition, we found that dimethylation of histone H3 at lysine 9 (H3K9), a molecular mark associated with transcriptional silencing, is increased 1 h after fear conditioning and decreased 24 h after context exposure alone and contextual fear conditioning. Trimethylated H3K4 levels returned to baseline levels at 24 h. We also found that mice deficient in the H3K4-specific histone methyltransferase, Mll, displayed deficits in contextual fear conditioning relative to wild-type animals. This suggests that histone methylation is required for proper long-term consolidation of contextual fear memories. Interestingly, inhibition of histone deacetylases (HDACs) with sodium butyrate (NaB) resulted in increased H3K4 trimethylation and decreased H3K9 dimethylation in hippocampus following contextual fear conditioning. Correspondingly, we found that fear learning triggered increases in H3K4 trimethylation at specific gene promoter regions (Zif268 and bdnf) with altered DNA methylation and MeCP2 DNA binding. Zif268 DNA methylation levels returned to baseline at 24 h. Together, these data demonstrate that histone methylation is actively regulated in the hippocampus and facilitates long-term memory formation.

Journal ArticleDOI
TL;DR: Evidence is considered that deafferentation of tonotopically organized central auditory structures leads to increased neuron spontaneous firing rates and neural synchrony in the hearing loss region, which covers the frequency spectrum of tinnitus sounds.
Abstract: Tinnitus is a phantom sound (ringing of the ears) that affects quality of life for millions around the world and is associated in most cases with hearing impairment. This symposium will consider evidence that deafferentation of tonotopically organized central auditory structures leads to increased neuron spontaneous firing rates and neural synchrony in the hearing loss region. This region covers the frequency spectrum of tinnitus sounds, which are optimally suppressed following exposure to band-limited noise covering the same frequencies. Cross-modal compensations in subcortical structures may contribute to tinnitus and its modulation by jaw-clenching and eye movements. Yet many older individuals with impaired hearing do not have tinnitus, possibly because age-related changes in inhibitory circuits are better preserved. A brain network involving limbic and other nonauditory regions is active in tinnitus and may be driven when spectrotemporal information conveyed by the damaged ear does not match that predicted by central auditory processing.

Journal ArticleDOI
TL;DR: Investigating the possible coexpression of kisspeptin, neurokinin B (NKB), and dynorphin A (Dyn) in neurons of the ARC of the goat and evaluating their potential roles in generating GnRH pulses found that all three neuropeptides are coexpressed in the same population of neurons.
Abstract: Gonadotropin-releasing hormone (GnRH) neurons in the basal forebrain are the final common pathway through which the brain regulates reproduction. GnRH secretion occurs in a pulsatile manner, and indirect evidence suggests the kisspeptin neurons in the arcuate nucleus (ARC) serve as the central pacemaker that drives pulsatile GnRH secretion. The purpose of this study was to investigate the possible coexpression of kisspeptin, neurokinin B (NKB), and dynorphin A (Dyn) in neurons of the ARC of the goat and evaluate their potential roles in generating GnRH pulses. Using double and triple labeling, we confirmed that all three neuropeptides are coexpressed in the same population of neurons. Using electrophysiological techniques to record multiple-unit activity (MUA) in the medial basal hypothalamus, we found that bursts of MUA occurred at regular intervals in ovariectomized animals and that these repetitive bursts (volleys) were invariably associated with discrete pulses of luteinizing hormone (LH) (and by inference GnRH). Moreover, the frequency of MUA volleys was reduced by gonadal steroids, suggesting that the volleys reflect the rhythmic discharge of steroid-sensitive neurons that regulate GnRH secretion. Finally, we observed that central administration of Dyn-inhibit MUA volleys and pulsatile LH secretion, whereas NKB induced MUA volleys. These observations are consistent with the hypothesis that kisspeptin neurons in the ARC drive pulsatile GnRH and LH secretion, and suggest that NKB and Dyn expressed in those neurons are involved in the process of generating the rhythmic discharge of kisspeptin.

Journal ArticleDOI
TL;DR: The results demonstrate that reward has an impact on vision that is independent of its role in the strategic establishment of endogenous attention and suggests that reward plays an important and undervalued role in attentional control.
Abstract: Reward-related mesolimbic dopamine steers animal behavior, creating automatic approach toward reward-associated objects and avoidance of objects unlikely to be beneficial. Theories of dopamine suggest that this reflects underlying biases in perception and attention, with reward enhancing the representation of reward-associated stimuli such that attention is more likely to be deployed to the location of these objects. Using measures of behavior and brain electricity in male and female humans, we demonstrate this to be the case. Sensory and perceptual processing of reward-associated visual features is facilitated such that attention is deployed to objects characterized by these features in subsequent experimental trials. This is the case even when participants know that a strategic decision to attend to reward-associated features will be counterproductive and result in suboptimal performance. Other results show that the magnitude of visual bias created by reward is predicted by the response to reward feedback in anterior cingulate cortex, an area with strong connections to dopaminergic structures in the midbrain. These results demonstrate that reward has an impact on vision that is independent of its role in the strategic establishment of endogenous attention. We suggest that reward acts to change visual salience and thus plays an important and undervalued role in attentional control.

Journal ArticleDOI
TL;DR: By combining an inducible genetic fate mapping strategy with electrophysiological analysis, this work systematically characterized the populations of cortical GABAergic interneurons that originate from the caudal ganglionic eminence (CGE), and determined the spatial and temporal origins of the vast majority of cortical interneuron subtypes.
Abstract: By combining an inducible genetic fate mapping strategy with electrophysiological analysis, we have systematically characterized the populations of cortical GABAergic interneurons that originate from the caudal ganglionic eminence (CGE). Interestingly, in comparison to medial ganglionic eminence (MGE)-derived cortical interneuron populations, the initiation (E12.5) and peak production (E16.5) of interneurons from this embryonic structure occurs three days later in development. Moreover, unlike either pyramidal cells or MGE-derived cortical interneurons, CGE-derived interneurons do not integrate into the cortex in an inside-out manner but preferentially (75%) occupy superficial cortical layers independent of birthdate. In contrast to previous estimates, CGE-derived interneurons are both considerably greater in number (around 30% of all cortical interneurons) and diversity (comprised by at least nine distinct subtypes). Furthermore, we have found that a large proportion of CGE-derived interneurons, including the neurogliaform subtype, express the glycoprotein Reelin. In fact, most CGE-derived cortical interneurons express either Reelin or vasoactive intestinal polypeptide (VIP). Thus, in conjunction with previous studies, we have now determined the spatial and temporal origins of the vast majority of cortical interneuron subtypes.

Journal ArticleDOI
TL;DR: It is demonstrated for the first time that the Alzheimer's brain was associated with disrupted topological organization in the large-scale WM structural networks, thus providing the structural evidence for abnormalities of systematic integrity in this disease.
Abstract: Recent research on Alzheimer's disease (AD) has shown that the decline of cognitive and memory functions is accompanied by a disrupted neuronal connectivity characterized by white matter (WM) degeneration. However, changes in the topological organization of WM structural network in AD remain largely unknown. Here, we used diffusion tensor image tractography to construct the human brain WM networks of 25 AD patients and 30 age- and sex-matched healthy controls, followed by a graph theoretical analysis. We found that both AD patients and controls had a small-world topology in WM network, suggesting an optimal balance between structurally segregated and integrative organization. More important, the AD patients exhibited increased shortest path length and decreased global efficiency in WM network compared with controls, implying abnormal topological organization. Furthermore, we showed that the WM network contained highly connected hub regions that were predominately located in the precuneus, cingulate cortex, and dorsolateral prefrontal cortex, which was consistent with the previous diffusion-MRI studies. Specifically, AD patients were found to have reduced nodal efficiency predominantly located in the frontal regions. Finally, we showed that the alterations of various network properties were significantly correlated with the behavior performances. Together, the present study demonstrated for the first time that the Alzheimer's brain was associated with disrupted topological organization in the large-scale WM structural networks, thus providing the structural evidence for abnormalities of systematic integrity in this disease. This work could also have implications for understanding how the abnormalities of structural connectivity in AD underlie behavioral deficits in the patients.

Journal ArticleDOI
TL;DR: Results showed training-induced plasticity in regions that are thought to be critical in working memory, including regions adjacent to the intraparietal sulcus and the anterior part of the body of the corpus callosum after training.
Abstract: Working memory is the limited capacity storage system involved in the maintenance and manipulation of information over short periods of time. Individual capacity of working memory is associated with the integrity of white matter in the frontoparietal regions. It is unknown to what extent the integrity of white matter underlying the working memory system is plastic. Using voxel-based analysis (VBA) of fractional anisotropy (FA) measures of fiber tracts, we investigated the effect of working memory training on structural connectivity in an interventional study. The amount of working memory training correlated with increased FA in the white matter regions adjacent to the intraparietal sulcus and the anterior part of the body of the corpus callosum after training. These results showed training-induced plasticity in regions that are thought to be critical in working memory. As changes in myelination lead to FA changes in diffusion tensor imaging, a possible mechanism for the observed FA change is increased myelination after training. Observed structural changes may underlie previously reported improvement of working memory capacity, improvement of other cognitive functions, and altered functional activity following working memory training.

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TL;DR: The results provide definitive physiological evidence for VGLUT2-mediated glutamate release by mature dopamine neurons projecting to the NAc shell, but not to the dorsal striatum, and the unique ability of NAc-projecting dopamine neurons to synchronously activate both dopamine and glutamate receptors may have crucial implications for the ability to respond to motivationally significant stimuli.
Abstract: Coincident signaling by dopamine and glutamate is thought to be crucial for a variety of motivated behaviors. Previous work has suggested that some midbrain dopamine neurons are themselves capable of glutamate corelease, but this phenomenon remains poorly understood. Here, we expressed the light-activated cation channel Channelrhodopsin-2 (ChR2) in genetically defined midbrain dopamine neurons to stimulate exocytosis specifically from dopaminergic terminals in both the nucleus accumbens (NAc) shell and dorsal striatum of brain slices from adult mice. Optical activation resulted in robust glutamate-mediated EPSCs in all medium spiny neurons examined in the NAc shell. In contrast, optically evoked glutamatergic currents were nearly undetectable in the dorsal striatum. Further, we used a conditional knock-out mouse lacking vesicular glutamate transporter 2 (VGLUT2) specifically in dopamine neurons to determine whether VGLUT2 is required for the exocytotic release of glutamate from dopamine neurons. Our data show that conditional knock-out completely abolished all optically evoked glutamate release. These results provide definitive physiological evidence for VGLUT2-mediated glutamate release by mature dopamine neurons projecting to the NAc shell, but not to the dorsal striatum. Thus, the unique ability of NAc-projecting dopamine neurons to synchronously activate both dopamine and glutamate receptors may have crucial implications for the ability to respond to motivationally significant stimuli.

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TL;DR: Transgenic mice expressing full-length human TDP-43 (hTDP- 43) driven by the mouse prion promoter are generated to provide a tool to analyze the role of wild-type hT DP-43 in the brain and spinal cord and for studying TDP -43-associated neurotoxicity.
Abstract: Transactivation response DNA-binding protein 43 (TDP-43) is a principal component of ubiquitinated inclusions in frontotemporal lobar degeneration with ubiquitin-positive inclusions and in amyotrophic lateral sclerosis (ALS). Mutations in TARDBP, the gene encoding TDP-43, are associated with sporadic and familial ALS, yet multiple neurodegenerative diseases exhibit TDP-43 pathology without known TARDBP mutations. While TDP-43 has been ascribed a number of roles in normal biology, including mRNA splicing and transcription regulation, elucidating disease mechanisms associated with this protein is hindered by the lack of models to dissect such functions. We have generated transgenic (TDP-43PrP) mice expressing full-length human TDP-43 (hTDP-43) driven by the mouse prion promoter to provide a tool to analyze the role of wild-type hTDP-43 in the brain and spinal cord. Expression of hTDP-43 caused a dose-dependent downregulation of mouse TDP-43 RNA and protein. Moderate overexpression of hTDP-43 resulted in TDP-43 truncation, increased cytoplasmic and nuclear ubiquitin levels, and intranuclear and cytoplasmic aggregates that were immunopositive for phosphorylated TDP-43. Of note, abnormal juxtanuclear aggregates of mitochondria were observed, accompanied by enhanced levels of Fis1 and phosphorylated DLP1, key components of the mitochondrial fission machinery. Conversely, a marked reduction in mitofusin 1 expression, which plays an essential role in mitochondrial fusion, was observed in TDP-43PrP mice. Finally, TDP-43PrP mice showed reactive gliosis, axonal and myelin degeneration, gait abnormalities, and early lethality. This TDP-43 transgenic line provides a valuable tool for identifying potential roles of wild-type TDP-43 within the CNS and for studying TDP-43-associated neurotoxicity.

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TL;DR: It is found that overgrowth clearly begins before 2 years of age, and future longitudinal studies would benefit from inclusion of even younger populations as well as further characterization of genetic and other biomarkers to determine the underlying neuropathological processes causing the onset of autistic symptoms.
Abstract: Cross-sectional MRI studies have long hypothesized that the brain in children with autism undergoes an abnormal growth trajectory that includes a period of early overgrowth; however this has never been confirmed by a longitudinal study. We carried out the first longitudinal study of brain growth in toddlers at the time symptoms of autism are becoming clinically apparent utilizing structural MRI scans at multiple time points beginning at 1.5 years up to 5 years of age. We collected 193 scans on 41 toddlers who received a confirmed diagnosis of Autistic Disorder at ~48 months of age and 44 typically developing controls. By 2.5 years of age, both cerebral gray and white matter was significantly enlarged in toddlers with Autistic Disorder, with the most severe enlargement occurring in frontal, temporal and cingulate cortices. In the longitudinal analyses, which we accounted for age and gender effect, we found that all regions (cerebral gray, cerebral white, frontal gray, temporal gray, cingulate gray, and parietal gray) except occipital gray developed at an abnormal growth rate in toddlers with Autistic Disorder that was mainly characterized by a quadratic age effect. Females with Autistic Disorder displayed a more pronounced abnormal growth profile in more brain regions than males with the disorder. Given that overgrowth clearly begins before 2 years of age, future longitudinal studies would benefit from inclusion of even younger populations as well as further characterization of genetic and other biomarkers in order to determine the underlying neuropathological processes causing the onset of autistic symptoms.

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TL;DR: Serum BDNF is identified as a significant factor related to hippocampal shrinkage and memory decline in late adulthood and is associated with smaller hippocampi and poorer memory.
Abstract: Hippocampal volume shrinks in late adulthood, but the neuromolecular factors that trigger hippocampal decay in aging humans remains a matter of speculation. In rodents, brain-derived neurotrophic factor (BDNF) promotes the growth and proliferation of cells in the hippocampus and is important in long-term potentiation and memory formation. In humans, circulating levels of BDNF decline with advancing age, and a genetic polymorphism for BDNF has been related to gray matter volume loss in old age. In this study, we tested whether age-related reductions in serum levels of BDNF would be related to shrinkage of the hippocampus and memory deficits in older adults. Hippocampal volume was acquired by automated segmentation of magnetic resonance images in 142 older adults without dementia. The caudate nucleus was also segmented and examined in relation to levels of serum BDNF. Spatial memory was tested using a paradigm in which memory load was parametrically increased. We found that increasing age was associated with smaller hippocampal volumes, reduced levels of serum BDNF, and poorer memory performance. Lower levels of BDNF were associated with smaller hippocampi and poorer memory, even when controlling for the variation related to age. In an exploratory mediation analysis, hippocampal volume mediated the age-related decline in spatial memory and BDNF mediated the age-related decline in hippocampal volume. Caudate nucleus volume was unrelated to BDNF levels or spatial memory performance. Our results identify serum BDNF as a significant factor related to hippocampal shrinkage and memory decline in late adulthood.

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TL;DR: The data support the notion that Aβ, tau, and α-synuclein interact in vivo to promote the aggregation and accumulation of each other and accelerate cognitive dysfunction.
Abstract: Alzheimer's disease (AD), the most prevalent age-related neurodegenerative disorder, is characterized pathologically by the accumulation of β-amyloid (Aβ) plaques and tau-laden neurofibrillary tangles. Interestingly, up to 50% of AD cases exhibit a third prevalent neuropathology: the aggregation of α-synuclein into Lewy bodies. Importantly, the presence of Lewy body pathology in AD is associated with a more aggressive disease course and accelerated cognitive dysfunction. Thus, Aβ, tau, and α-synuclein may interact synergistically to promote the accumulation of each other. In this study, we used a genetic approach to generate a model that exhibits the combined pathologies of AD and dementia with Lewy bodies (DLB). To achieve this goal, we introduced a mutant human α-synuclein transgene into 3xTg-AD mice. As occurs in human disease, transgenic mice that develop both DLB and AD pathologies (DLB-AD mice) exhibit accelerated cognitive decline associated with a dramatic enhancement of Aβ, tau, and α-synuclein pathologies. Our findings also provide additional evidence that the accumulation of α-synuclein alone can significantly disrupt cognition. Together, our data support the notion that Aβ, tau, and α-synuclein interact in vivo to promote the aggregation and accumulation of each other and accelerate cognitive dysfunction.

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TL;DR: The results demonstrate, for the first time, that whereas chronic ethanol intake upregulates the immunoreactive levels of CD11b and glial fibrillary acidic protein (astrocyte marker), and also increases caspase-3 activity and inducible nitric oxide synthase, COX-2, and cytokine levels in the cerebral cortex of female wild-type mice, TLR4 deficiency protects against ethanol-induced glial activation, induction of inflammatory mediators,
Abstract: Toll-like receptors play an important role in the innate immune response, although emerging evidence indicates their role in brain injury and neurodegeneration. Alcohol abuse induces brain damage and can sometimes lead to neurodegeneration. We recently found that ethanol can promote TLR4 signaling in glial cells by triggering the induction of inflammatory mediators and causing cell death, suggesting that the TLR4 response could be an important mechanism of ethanol-induced neuroinflammation. This study aims to establish the potential role of TLR4 in both ethanol-induced glial activation and brain damage. Here we report that TLR4 is critical for ethanol-induced inflammatory signaling in glial cells since the knockdown of TLR4, by using both small interfering RNA or cells from TLR4-deficient mice, abolished the activation of microtubule-associated protein kinase and nuclear factor-κB pathways and the production of inflammatory mediators by astrocytes. Our results demonstrate, for the first time, that whereas chronic ethanol intake upregulates the immunoreactive levels of CD11b (microglial marker) and glial fibrillary acidic protein (astrocyte marker), and also increases caspase-3 activity and inducible nitric oxide synthase, COX-2, and cytokine levels [interleukin (IL)-1β, tumor necrosis factor-α, IL-6] in the cerebral cortex of female wild-type mice, TLR4 deficiency protects against ethanol-induced glial activation, induction of inflammatory mediators, and apoptosis. Our findings support the critical role of the TLR4 response in the neuroinflammation, brain injury, and possibly in the neurodegeneration induced by chronic ethanol intake.

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TL;DR: It is found in human subjects that activity in a network comprising dorsal anterior cingulate cortex, anterior insula, anterior prefrontal cortex and thalamus is positively correlated with global field power (GFP) of upper alpha band (10–12 Hz) oscillations, the most consistent electrical index of tonic alertness.
Abstract: Trial-by-trial variability in perceptual performance on identical stimuli has been related to spontaneous fluctuations in ongoing activity of intrinsic functional connectivity networks (ICNs). In a paradigm requiring sustained vigilance for instance, we previously observed that higher prestimulus activity in a cingulo-insular-thalamic network facilitated subsequent perception. Here, we test our proposed interpretation that this network underpins maintenance of tonic alertness. We used simultaneous acquisition of functional magnetic resonance imaging (fMRI) and electroencephalography (EEG) in the absence of any paradigm to test an ensuing hypothesis, namely that spontaneous fluctuations in this ICN's activity (as measured by fMRI) should show a positive correlation with the electrical signatures of tonic alertness (as recorded by concurrent EEG). We found in human subjects (19 male, 7 female) that activity in a network comprising dorsal anterior cingulate cortex, anterior insula, anterior prefrontal cortex and thalamus is positively correlated with global field power (GFP) of upper alpha band (10-12 Hz) oscillations, the most consistent electrical index of tonic alertness. Conversely, and in line with earlier findings, alpha band power was negatively correlated with activity in another ICN, the so-called dorsal attention network which is most prominently involved in selective spatial attention. We propose that the cingulo-insular-thalamic network serves maintaining tonic alertness through generalized expression of cortical alpha oscillations. Attention is mediated by activity in other systems, e.g., the dorsal attention network for space, selectively disrupts alertness-related suppression and hence manifests as local attenuation of alpha activity.

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TL;DR: The data and mechanistic framework provide a functional role for endogenous electric fields, specifically illustrating that modulation of gamma oscillations during theta-modulated gamma activity can result from field effects alone.
Abstract: Clinical effects of transcranial electrical stimulation with weak currents are remarkable considering the low amplitude of the electric fields acting on the brain. Elucidating the processes by which small currents affect ongoing brain activity is of paramount importance for the rational design of noninvasive electrotherapeutic strategies and to determine the relevance of endogenous fields. We propose that in active neuronal networks, weak electrical fields induce small but coherent changes in the firing rate and timing of neuronal populations that can be magnified by dynamic network activity. Specifically, we show that carbachol-induced gamma oscillations (25–35 Hz) in rat hippocampal slices have an inherent rate-limiting dynamic and timing precision that govern susceptibility to low-frequency weak electric fields (<50 Hz; <10 V/m). This leads to a range of nonlinear responses, including the following: (1) asymmetric power modulation by DC fields resulting from balanced excitation and inhibition; (2) symmetric power modulation by lower frequency AC fields with a net-zero change in firing rate; and (3) half-harmonic oscillations for higher frequency AC fields resulting from increased spike timing precision. These underlying mechanisms were elucidated by slice experiments and a parsimonious computational network model of single-compartment spiking neurons responding to electric field stimulation with small incremental polarization. Intracellular recordings confirmed model predictions on neuronal timing and rate changes, as well as spike phase-entrainment resonance at 0.2 V/m. Finally, our data and mechanistic framework provide a functional role for endogenous electric fields, specifically illustrating that modulation of gamma oscillations during theta-modulated gamma activity can result from field effects alone.