Blast exposure can cause auditory deficits that have a lasting, significant impact on patients. Although the effects of blast on auditory functions localized to the ear have been well documented, the impact of blast on central auditory processing is largely undefined. Understanding the structural and functional alterations in the central nervous system (CNS) associated with blast injuries is crucial for unraveling blast-induced pathophysiological pathways and advancing development of therapeutic interventions. In this study, we used electrophysiology in combination with optogenetics assay, proteomic analysis, and morphological evaluation to investigate the impairment of synaptic connectivity in the auditory cortex (AC) of mice following blast exposure. Our results show that the long-range functional connectivity between the medial geniculate nucleus (MGN) and AC was impaired in the acute phase of blast injury. We also identified impaired synaptic transmission and dendritic spine alterations within 7 days of blast exposure, which recovered at 28 days post-blast. Additionally, proteomic analysis identified a few differentially expressed proteins in the cortex that are involved in synaptic signaling and plasticity. These findings collectively suggest that blast-induced alterations in the sound signaling network in the auditory cortex may underlie hearing deficits in the acute and sub-acute phases after exposure to shockwaves. This study may shed light on the perturbations underlying blast-induced auditory dysfunction and provide insights into the potential therapeutic windows for improving auditory outcomes in blast-exposed individuals.

This study aims to solve the problem of the cell temperature rise and performance decline caused by dusty particulate matter covering the surface of the cell through the allocation of airflow velocities at the inlets of the battery cooling box under the goal of low energy consumption. We take the maximum temperature of the battery pack at a specified airflow velocity and dust-free environment as the expected temperature in a dusty environment. The maximum temperature of the battery pack in a dusty environment is solved at different inlet airflow velocities, which are the boundary conditions of the analysis model constructed in the simulation software. The arrays representing the different airflow velocity combinations of inlets are generated randomly through the optimal Latin hypercube algorithm (OLHA), where the lower and upper limits of velocities corresponding to the temperatures above the desired temperature are set in the optimization software. We establish an approximate QRSM between the velocity combination and the maximum temperature using the fitting module of the optimization software. The QRSM is optimized based on the ASAM, and the optimal result is in good agreement with the analysis result obtained by the simulation software. After optimization, the flow rate of the middle inlet is changed from 5.5 m/s to 5 m/s, and the total airflow velocity is decreased by 3%. The protocol here presents an optimization method simultaneously considering energy consumption and thermal performance of the battery management system that has been established, and it can be widely used to improve the life cycle of the battery pack with minimum operating cost.

This study aims to solve the problem of the cell temperature rise and performance decline caused by dusty particulate matter covering the surface of the cell through the allocation of airflow velocities at the inlets of the battery cooling box under the goal of low energy consumption. We take the maximum temperature of the battery pack at a specified airflow velocity and dust-free environment as the expected temperature in a dusty environment. The maximum temperature of the battery pack in a dusty environment is solved at different inlet airflow velocities, which are the boundary conditions of the analysis model constructed in the simulation software. The arrays representing the different airflow velocity combinations of inlets are generated randomly through the optimal Latin hypercube algorithm (OLHA), where the lower and upper limits of velocities corresponding to the temperatures above the desired temperature are set in the optimization software. We establish an approximate QRSM between the velocity combination and the maximum temperature using the fitting module of the optimization software. The QRSM is optimized based on the ASAM, and the optimal result is in good agreement with the analysis result obtained by the simulation software. After optimization, the flow rate of the middle inlet is changed from 5.5 m/s to 5 m/s, and the total airflow velocity is decreased by 3%. The protocol here presents an optimization method simultaneously considering energy consumption and thermal performance of the battery management system that has been established, and it can be widely used to improve the life cycle of the battery pack with minimum operating cost.

Increased expression of the 3.1 isoform of the KCNH2 potassium channel has been associated with cognitive dysfunction and with schizophrenia, yet little is known about the underlying pathophysiological mechanisms. Here, by using in vivo wireless local field potential recordings during working memory processing, in vitro brain slice whole-cell patching recordings and in vivo stereotaxic hippocampal injection of AAV-encoded expression, we identified specific and delayed disruption of hippocampal-mPFC synaptic transmission and functional connectivity associated with reductions of SERPING1, CFH , and CD74 in the KCNH2-3.1 overexpression transgenic mice. The differentially expressed genes in mice are enriched in neurons and microglia, and reduced expression of these genes dysregulates the complement cascade, which has been previously linked to synaptic plasticity. We find that knockdown of these genes in primary neuronal–microglial cocultures from KCNH2-3.1 mice impairs synapse formation, and replenishing reduced CFH gene expression rescues KCNH2-3.1-induced impaired synaptogenesis. Translating to humans, we find analogous dysfunctional interactions between hippocampus and prefrontal cortex in coupling of the fMRI blood oxygen level-dependent (BOLD) signal during working memory in healthy subjects carrying alleles associated with increased KCNH2-3.1 expression in brain. Our data uncover a previously unrecognized role of the truncated KCNH2-3.1 potassium channel in mediating complement activation, which may explain its association with altered hippocampal–prefrontal connectivity and synaptic function. These results provide a potential molecular link between increased KCNH2-3.1 expression, synapse alterations, and hippocampal–prefrontal circuit abnormalities implicated in schizophrenia.

Signaling of brain-derived neurotrophic factor (BDNF) via tropomyosin receptor kinase B (TrkB) plays a critical role in the maturation of cortical inhibition and controls expression of inhibitory interneuron markers, including the neuropeptide cortistatin (CST). CST is expressed exclusively in a subset of cortical and hippocampal GABAergic interneurons, where it has anticonvulsant effects and controls sleep slow-wave activity (SWA). We hypothesized that CST-expressing interneurons play a critical role in regulating excitatory/inhibitory balance, and that BDNF, signaling through TrkB receptors on CST-expressing interneurons, is required for this function. Ablation of CST-expressing cells caused generalized seizures and premature death during early postnatal development, demonstrating a critical role for these cells in providing inhibition. Mice in which TrkB was selectively deleted from CST-expressing interneurons were hyperactive, slept less and developed spontaneous seizures. Frequencies of spontaneous excitatory post-synaptic currents (sEPSCs) on CST-expressing interneurons were attenuated in these mice. These data suggest that BDNF, signaling through TrkB receptors on CST-expressing cells, promotes excitatory drive onto these cells. Loss of excitatory drive onto CST-expressing cells that lack TrkB receptors may contribute to observed hyperexcitability and epileptogenesis.

The small ubiquitin-like modifier protein (SUMO) regulates various cellular events inside the nucleus. The identification of SUMO substrates outside the nucleus is progressing but little is yet known about the neuronal role of protein SUMOylation. Here we report that in neurons multiple SUMOylation targets are present at synapses and we show that the kainate receptor subunit GluR6 exhibits low levels of SUMOylation under resting conditions and is rapidly SUMOylated in response to a kainate treatment. Reducing GluR6 SUMOylation using the SUMOspecific isopeptidase prevents kainate-evoked endocytosis of the kainate receptor. Furthermore, a mutated non-SUMOylatable form of GluR6 is not endocytosed in response to kainate. Consistent with this, recordings in hippocampal slices demonstrate that kainate receptor mediated EPSCs are diminished by SUMOylation and augmented by deSUMOylation. These data reveal a previously unsuspected role for SUMO in the regulation of synaptic function.

OBJECTIVE:CD4+CD25+ regulatory T cells (Tregs) have been found to have a decreased effector function in patients with multiple sclerosis (MS). In this study, we co-cultured naïve CD4+ T cells of MS patients with myelin basic protein (MBP)85-99 peptide as specific antigen and allogenic B cells as antigen-presenting cells, in an attempt to generate adequate antigen-specific CD4+CD25+ Tregs with normal or improved immune function.PATIENTS AND METHODS:Naïve CD4+ T cells were isolated from peripheral blood mononuclear cells (PBMCs) from patients with MS (n=5) and healthy controls (HC, n=5). Furthermore, these purified naive CD4+ T cells were co-cultured with the CD40-activated B cells and MBP85-99 peptide to induce MBP-reactive CD4+CD25highCD127low Tregs. After harvesting these Tregs via a flow sorter, real-time PCR and mixed lymphocyte reaction (MLR) assay were performed to characterize cellular immune function. Supernatant interleukin (IL)-10 and transforming growth factor (TGF)-β1 protein levels were detected by an enzyme-linked immunosorbent assay (ELISA).RESULTS:With this method, the frequency of CD4+CD25highCD127low Tregs in CD4+ T cells was 3.5%-6%. In both MS and HC groups, there were relatively lower proliferation indices (PI) of MLR assay but higher supernatant IL-10 and TGF-β1 levels in the presence of MBP than those in the presence of other control antigens, where no significant differences were found.CONCLUSIONS:Via the ex vivo culture, adequate MBP-reactive CD4+CD25+ Tregsderived from autologous naïve CD4+ T cells of MS patients, were obtained and returned to normal without immune defects, and even upregulated their immunosuppressive function mostly through the elevated release of IL-10 and TGF-β1.

The goal of this paper is to research the vibration suppression of a vehicle magnetic flywheel battery system. It is found that the flywheel rotor is always instability near a certain rotation speed controlled on the basis of the rigid model. Accordingly, regarding the rotor as a flexible rotor is investigated based on the FEM model. The original controller used for the rigid model is also applied to the flexible model for analyzing the root locus. The result reveals the poles associated with the first bending backward mode move to the half right complex plane. Finally, a simple cross-feedback control is proposed instead of complex controller design based on the flexible model. The effectiveness is verified through the experiment.

Overexpression in humans of KCNH2-3.1, which encodes a primate-specific and brain-selective isoform of the human ether-a-go-go-related potassium channel, is associated with impaired cognition, inefficient neural processing and schizophrenia. Here, we describe a new mouse model that incorporates the KCNH2-3.1 molecular phenotype. KCNH2-3.1 transgenic mice are viable and display normal sensorimotor behaviors. However, they show alterations in neuronal structure and microcircuit function in the hippocampus and prefrontal cortex, areas affected in schizophrenia. Specifically, in slice preparations from the CA1 region of the hippocampus, KCNH2-3.1 transgenic mice have fewer mature dendrites and impaired theta burst stimulation long-term potentiation. Abnormal neuronal firing patterns characteristic of the fast deactivation kinetics of the KCNH2-3.1 isoform were also observed in prefrontal cortex. Transgenic mice showed significant deficits in a hippocampal-dependent object location task and a prefrontal cortex-dependent T-maze working memory task. Interestingly, the hippocampal-dependent alterations were not present in juvenile transgenic mice, suggesting a developmental trajectory to the phenotype. Suppressing KCNH2-3.1 expression in adult mice rescues both the behavioral and physiological phenotypes. These data provide insight into the mechanism of association of KCNH2-3.1 with variation in human cognition and neuronal physiology and may explain its role in schizophrenia.

The activity-regulated gene Arc/Arg3.1 encodes a postsynaptic protein crucially involved in glutamatergic synaptic plasticity. Genetic mutations in Arc pathway and altered Arc expression in human frontal cortex have been associated with schizophrenia. Although Arc expression has been reported to vary with age, what mechanisms regulate Arc mRNA levels in frontal cortex during postnatal development remains unclear. Using quantitative mRNA analysis of mouse frontal cortical tissues, we mapped the developmental profiles of Arc expression and found that its mRNA levels are sharply amplified near the end of the second postnatal week, when mouse pups open their eyes for the first time after birth. Surprisingly, electrical stimulation of the frontal cortex before eye-opening is not sufficient to drive the amplification of Arc mRNA. Instead, this amplification needs both electrical stimulation and dopamine D1-type receptor (D1R) activation. Furthermore, visual stimuli-driven amplification of Arc mRNA is also dependent on D1R activation and dopamine neurons located in the ventral midbrain. These results indicate that dopamine is required to drive activity-dependent amplification of Arc mRNA in the developing postnatal frontal cortex and suggest that joint electrical and dopaminergic activation is essential to establish the normal expression pattern of a schizophrenia-associated gene during frontal cortical development.

International Journal of Developmental NeuroscienceVolume 47, Issue Part_A p. 95-95 Article ISDN2014_0312: Phasic dopamine neuron activity elicits unique mesofrontal plasticity in adolescence Surjeet Mastwal, Surjeet Mastwal Unit on Neural Circuits and Adaptive Behaviors, Genes Cognition and Psychosis Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, 20892 USASearch for more papers by this authorYizhou Ye, Yizhou Ye Unit on Neural Circuits and Adaptive Behaviors, Genes Cognition and Psychosis Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, 20892 USASearch for more papers by this authorMing Ren, Ming Ren Unit on Neural Circuits and Adaptive Behaviors, Genes Cognition and Psychosis Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, 20892 USASearch for more papers by this authorDennisse Jimenez, Dennisse Jimenez Lieber Institute for Brain Development, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205 USASearch for more papers by this authorKeri Martinowich, Keri Martinowich Lieber Institute for Brain Development, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205 USA Departments of Psychiatry & Behavioral Sciences and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, 21205 USASearch for more papers by this authorCharles R. Gerfen, Charles R. Gerfen Laboratory of Systems Neuroscience, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, 20892 USASearch for more papers by this authorKuan Hong Wang, Corresponding Author Kuan Hong Wang [email protected] Unit on Neural Circuits and Adaptive Behaviors, Genes Cognition and Psychosis Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, 20892 USAE-mail address: [email protected] (K.H. Wang).Search for more papers by this author Surjeet Mastwal, Surjeet Mastwal Unit on Neural Circuits and Adaptive Behaviors, Genes Cognition and Psychosis Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, 20892 USASearch for more papers by this authorYizhou Ye, Yizhou Ye Unit on Neural Circuits and Adaptive Behaviors, Genes Cognition and Psychosis Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, 20892 USASearch for more papers by this authorMing Ren, Ming Ren Unit on Neural Circuits and Adaptive Behaviors, Genes Cognition and Psychosis Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, 20892 USASearch for more papers by this authorDennisse Jimenez, Dennisse Jimenez Lieber Institute for Brain Development, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205 USASearch for more papers by this authorKeri Martinowich, Keri Martinowich Lieber Institute for Brain Development, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205 USA Departments of Psychiatry & Behavioral Sciences and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, 21205 USASearch for more papers by this authorCharles R. Gerfen, Charles R. Gerfen Laboratory of Systems Neuroscience, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, 20892 USASearch for more papers by this authorKuan Hong Wang, Corresponding Author Kuan Hong Wang [email protected] Unit on Neural Circuits and Adaptive Behaviors, Genes Cognition and Psychosis Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, 20892 USAE-mail address: [email protected] (K.H. Wang).Search for more papers by this author First published: 05 November 2015 https://doi.org/10.1016/j.ijdevneu.2015.04.259Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume47, IssuePart_AISDN 2014 AbstractsDecember 2015Pages 95-95 RelatedInformation

BACKGROUND: Genetic variations in dystrobrevin binding protein 1 (DTNBP1 or dysbindin-1) have been implicated as risk factors in the pathogenesis of schizophrenia. The encoded protein dysbindin-1 functions in the regulation of synaptic activity and synapse development. Intriguingly, a loss of function mutation in Dtnbp1 in mice disrupted both glutamatergic and gamma-aminobutyric acidergic transmission in the cerebral cortex; pyramidal neurons displayed enhanced excitability due to reductions in inhibitory synaptic inputs. However, the mechanism by which reduced dysbindin-1 activity causes inhibitory synaptic deficits remains unknown.METHODS: We investigated the role of dysbindin-1 in the exocytosis of brain-derived neurotrophic factor (BDNF) from cortical excitatory neurons, organotypic brain slices, and acute slices from dysbindin-1 mutant mice and determined how this change in BDNF exocytosis transsynaptically affected the number of inhibitory synapses formed on excitatory neurons via whole-cell recordings, immunohistochemistry, and live-cell imaging using total internal reflection fluorescence microscopy.RESULTS: A decrease in dysbindin-1 reduces the exocytosis of BDNF from cortical excitatory neurons, and this reduction in BDNF exocytosis transsynaptically resulted in reduced inhibitory synapse numbers formed on excitatory neurons. Furthermore, application of exogenous BDNF rescued the inhibitory synaptic deficits caused by the reduced dysbindin-1 level in both cultured cortical neurons and slice cultures.CONCLUSIONS: Taken together, our results demonstrate that these two genes linked to risk for schizophrenia (BDNF and dysbindin-1) function together to regulate interneuron development and cortical network activity. This evidence supports the investigation of the association between dysbindin-1 and BDNF in humans with schizophrenia.

The mesofrontal dopaminergic circuit, which connects the midbrain motivation center to the cortical executive center, is engaged in control of motivated behaviors. In addition, deficiencies in this circuit are associated with adolescent-onset psychiatric disorders in humans. Developmental studies suggest that the mesofrontal circuit exhibits a protracted maturation through adolescence. However, whether the structure and function of this circuit are modifiable by activity in dopaminergic neurons during adolescence remains unknown. Using optogenetic stimulation and in vivo two-photon imaging in adolescent mice, we found that phasic, but not tonic, dopamine neuron activity induces the formation of mesofrontal axonal boutons. In contrast, in adult mice, the effect of phasic activity diminishes. Furthermore, our results showed that dopaminergic and glutamatergic transmission regulate this axonal plasticity in adolescence and inhibition of dopamine D2-type receptors restores this plasticity in adulthood. Finally, we found that phasic activation of dopamine neurons also induces greater changes in mesofrontal circuit activity and psychomotor response in adolescent mice than in adult mice. Together, our findings demonstrate that the structure and function of the mesofrontal circuit are modifiable by phasic activity in dopaminergic neurons during adolescence and suggest that the greater plasticity in adolescence may facilitate activity-dependent strengthening of dopaminergic input and improvement in behavioral control.

Motor behaviors recruit task-specific neuronal ensembles in motor cortices, which are consolidated over subsequent learning. However, little is known about the molecules that can identify the participating neurons and predict the outcomes of the consolidation process. Using a mouse rotarod-learning task, we showed that lesion or inactivation of the secondary motor (M2) cortex disrupts learning of skilled movements. We tracked the endogenous promoter activity of the neuronal activity-regulated gene Arc in individual M2 neurons during rotarod learning by in vivo two-photon imaging of a knockin reporter. We found that task training initially recruits Arc-promoter-activated neurons and then consolidates them into a specific ensemble exhibiting persistent reactivation of Arc-promoter. The intensity of a neuron's initial Arc-promoter activation predicts its reactivation probability and neurons with weak initial Arc-promoter activation are dismissed from the ensemble during subsequent training. Our findings demonstrate a task-specific Arc-dependent cellular consolidation process in M2 cortex during motor learning.

Composite materials are increasingly used in wind blade because of their superior mechanical properties such as high strength-to-weight and stiffness-to-weight ratio. This paper presents vibration and damping analysis of fiberreinforced composite wind turbine blade with viscoelastic damping treatment. The finite element method based on full layerwise displacement theory was employed to analyze the damping, natural frequency, and modal loss factor of composite shell structure. The lamination angle was considered in mathematical modeling. The curved geometry, transverse shear, and normal strains were exactly considered in present layerwise shell model, which can depict the zig-zag in-plane and out-of-plane displacements. The frequency response functions of curved composite shell structure and wind blade were calculated. The results show that the damping ratio of viscoelastic layer is found to be very sensitive to determination of magnitude of composite structures. The frequency response functions with variety of thickness of damping layer were investigated. Moreover, the natural frequency, modal loss factor, and mode shapes of composite fiber reinforced wind blade with viscoelastic damping control were calculated.

Amyotrophic lateral sclerosis (ALS) is an idiopathic and lethal neurodegenerative disease that currently has no effective treatment. A recent study found that the Notch signaling pathway was up-regulated in a TAR DNA-binding protein-43 (TDP-43) Drosophila model of ALS. Notch signaling acts as a master regulator in the central nervous system. However, the mechanisms by which Notch participates in the pathogenesis of ALS have not been completely elucidated. Recent studies have shown that the mood stabilizers lithium and valproic acid (VPA) are able to regulate Notch signaling. Our study sought to confirm the relationship between the Notch pathway and ALS and whether the Notch pathway contributes to the neuroprotective effects of lithium and VPA in ALS. We found that the Notch pathway was activated in in vitro and in vivo models of ALS, and suppression of Notch activation with a Notch signaling inhibitor, N-[N-(3,5-difluorophenacetyl-L-alanyl)]-S-phenylglycine t-butyl ester (DAPT) and Notch1 siRNA significantly reduced neuronal apoptotic signaling, as evidenced by the up-regulation of Bcl-2 as well as the down-regulation of Bax and cytochrome c. We also found that lithium and VPA suppressed the Notch activation associated with the superoxide dismutase-1 (SOD1) mutation, and the combination of lithium and VPA produced a more robust effect than either agent alone. Our findings indicate that the Notch pathway plays a critical role in ALS, and the neuroprotective effects of lithium and VPA against mutant SOD1-mediated neuronal damage are at least partially dependent on their suppression of Notch activation.

The brain encodes information about past experience in specific populations of neurons that communicate with one another by firing action potentials. Studies of experience-dependent neural plasticity have largely focused on individual synaptic changes in response to neuronal input. Indicative of the neuronal output transmitted to downstream neurons, persistent firing patterns are affected by prior experience in selective neuronal populations. However, little is known about the molecular and cellular mechanisms by which experience-related persistent firing patterns are regulated in specific neuronal populations. Using frontal cortical slices prepared from transgenic mice carrying a fluorescent reporter of Arc gene expression, this study investigates how behavioral experience and the activity-regulated Arc gene affect patterns of neuronal firing. We found that motor training increases Arc expression in subsets of excitatory neurons. Those neurons exhibit persistent firing in contrast to Arc-negative neurons from the same mice or neurons from the untrained mice. Furthermore, in mice carrying genetic deletion of Arc, the frontal cortical circuitry is still in place to initiate experience-dependent gene expression, but the level of persistent firing thereafter is diminished. Finally, our results showed that the emergence of persistent activity is associated with Arc-dependent changes in the function of NMDA-type glutamate receptors, rather than changes in AMPA-type receptors or membrane excitability. Our findings therefore reveal an Arc-dependent molecular pathway by which gene-experience interaction regulates the emergence of persistent firing patterns in specific neuronal populations.