881 resultados para Neuronal Plasticity


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Behavioral and neurophysiological studies suggest that skill learning can be mediated by discrete, experience-driven changes within specific neural representations subserving the performance of the trained task. We have shown that a few minutes of daily practice on a sequential finger opposition task induced large, incremental performance gains over a few weeks of training. These gains did not generalize to the contralateral hand nor to a matched sequence of identical component movements, suggesting that a lateralized representation of the learned sequence of movements evolved through practice. This interpretation was supported by functional MRI data showing that a more extensive representation of the trained sequence emerged in primary motor cortex after 3 weeks of training. The imaging data, however, also indicated important changes occurring in primary motor cortex during the initial scanning sessions, which we proposed may reflect the setting up of a task-specific motor processing routine. Here we provide behavioral and functional MRI data on experience-dependent changes induced by a limited amount of repetitions within the first imaging session. We show that this limited training experience can be sufficient to trigger performance gains that require time to become evident. We propose that skilled motor performance is acquired in several stages: “fast” learning, an initial, within-session improvement phase, followed by a period of consolidation of several hours duration, and then “slow” learning, consisting of delayed, incremental gains in performance emerging after continued practice. This time course may reflect basic mechanisms of neuronal plasticity in the adult brain that subserve the acquisition and retention of many different skills.

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Whereas adult sex differences in brain morphology and behavior result from developmental exposure to steroid hormones, the mechanism by which steroids differentiate the brain is unknown. Studies to date have described subtle sex differences in levels of proteins and neurotransmitters during brain development, but these have lacked explanatory power for the profound sex differences induced by steroids. We report here a major divergence in the response to injection of the γ-aminobutyric acid type A (GABAA) agonist, muscimol, in newborn male and female rats. In females, muscimol treatment primarily decreased the phosphorylation of cAMP response element binding protein (CREB) within the hypothalamus and the CA1 region of the hippocampus. In contrast, muscimol increased the phosphorylation of CREB in males within these same brain regions. Within the arcuate nucleus, muscimol treatment increased the phosphorylation of CREB in both females and males. Thus, the response to GABA can be excitatory or inhibitory on signal-transduction pathways that alter CREB phosphorylation depending on the sex and the region in developing brain. This divergence in response to GABA allows for a previously unknown form of steroid-mediated neuronal plasticity and may be an initial step in establishing sexually dimorphic signal-transduction pathways in developing brain.

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L-Glutamate is the most common excitatory neurotransmitter in the brain and plays a crucial role in neuronal plasticity as well as in neurotoxicity. While a large body of literature describes the induction of immediate-early genes, including c-fos, fosB, c-jun, junB, zif/268, and krox genes by glutamate and agonists in neurons, very little is known about preexisting transcription factors controlling the induction of such genes. This prompted us to investigate whether stimulation of glutamate receptors can activate NF-kappa B, which is present in neurons in either inducible or constitutive form. Here we report that brief treatments with kainate or high potassium strongly activated NF-kappa B in granule cells from rat cerebellum. This was detected at the single cell level by immunostaining with a monoclonal antibody that selectively reacts with the transcriptionally active, nuclear form of NF-kappa B p65. The activation of NF-kappa B could be blocked with the antioxidant pyrrolidine dithiocarbamate, suggesting the involvement of reactive oxygen intermediates. The data may explain the kainate-induced cell surface expression of major histocompatibility complex class I molecules, which are encoded by genes known to be controlled by NF-kappa B. Moreover, NF-kappa B activity was found to change dramatically in neurons during development of the cerebellum between days 5 and 7 after birth.

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Brain-derived neurotrophic factor (BDNF), a member of the nerve growth factor (NGF) gene family, has been shown to influence the survival and differentiation of specific classes of neurons in vitro and in vivo. The possibility that neurotrophins are also involved in processes of neuronal plasticity has only recently begun to receive attention. To determine whether BDNF has a function in processes such as long-term potentiation (LTP), we produced a strain of mice with a deletion in the coding sequence of the BDNF gene. We then used hippocampal slices from these mice to investigate whether LTP was affected by this mutation. Homo- and heterozygous mutant mice showed significantly reduced LTP in the CA1 region of the hippocampus. The magnitude of the potentiation, as well as the percentage of cases in which LTP could be induced successfully, was clearly affected. According to the criteria tested, important pharmacological, anatomical, and morphological parameters in the hippocampus of these animals appear to be normal. These results suggest that BDNF might have a functional role in the expression of LTP in the hippocampus.

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Introdução: Crianças com transtorno fonológico (TF) apresentam dificuldade na percepção de fala, em processar estímulos acústicos quando apresentados de forma rápida e em sequência. A percepção dos sons complexos da fala, dependem da integridade no processo de codificação analisado pelo Sistema Nervoso Auditivo. Por meio do Potencial Evocado Auditivo de Tronco Encefálico com estímulo complexo (PEATEc) é possível investigar a representação neural dos sons em níveis corticais e obter informações diretas sobre como a estrutura do som da sílaba falada é codificada no sistema auditivo. Porém, acredita-se que esse potencial sofre interferências tanto de processos bottom-up quanto top-down, o que não se sabe é quanto e como cada um desses processos modifica as respostas do PEATEc. Uma das formas de investigar a real influência dos aspectos top-down e bottom-up nos resultados do PEATEc é estimulando separadamente esses dois processos por meio do treinamento auditivo e da terapia fonoaudiológica. Objetivo: Verificar o impacto da estimulação sensorial (processamento bottom-up) e cognitiva (processamento top-down), separadamente, nos diferentes domínios da resposta eletrofisiológica do PEATEc. Método: Participaram deste estudo 11 crianças diagnosticadas com TF, com idades entre 7 e 10:11, submetidas a avaliação comportamental e eletrofisiológica e então dividas nos grupos Bottom-up (B-U) (N=6) e Top-down T-D (N=5). A estimulação bottom-up foi voltada ao treinamento das habilidades sensoriais, através de softwares de computador. A estimulação top-down foi realizada por meio de tarefas para estimular as habilidades cognitiva por meio do Programa de Estimulação Fonoaudiológica (PEF). Ambas as estimulações foram aplicadas uma vez por semana, num período de aproximadamente 45 minutos por 12 semanas. Resultados: O grupo B-U apresentou melhoras em relação aos domínios onset e harmônicos e no valor da pontuação do escore após ser submetido à estimulação bottom-up. Por sua vez, após serem submetidos à estimulação top-down, o grupo T-D apresentou melhoras em relação aos domínios onset, espectro-temporal, fronteiras do envelope e harmônicos e para os valores da pontuação do escore. Conclusão: Diante dos resultados obtidos neste estudo, foi possível observar que a estimulação sensorial (processamento bottom-up) e a estimulação cognitiva (processamento top-down) mostraram impactar de forma diferente a resposta eletrofisiológica do PEATEc

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Introdução: A esclerose mesial temporal (EMT) é a principal causa de epilepsia resistente ao tratamento medicamentoso. Pacientes com EMT apresentam dificuldades no processamento semântico e fonológico de linguagem e maior incidência de reorganização cerebral da linguagem (bilateral ou à direita) em relação à população geral. A ressonância magnética funcional (RMf) permite avaliar a reorganização cerebral das redes de linguagem, comparando padrões de ativação cerebral entre diversas regiões cerebrais. Objetivo: Investigar o desempenho linguístico de pacientes com EMT unilateral esquerda e direita e a ocorrência de reorganização das redes de linguagem com RMf para avaliar se a reorganização foi benéfica para a linguagem nestes pacientes. Métodos: Utilizamos provas clínicas de linguagem e paradigmas de nomeação visual e responsiva para RMf, desenvolvidos para este estudo. Foram avaliados 24 pacientes com EMTe, 22 pacientes com EMTd e 24 controles saudáveis, submetidos a provas de linguagem (fluência semântica e fonológica, nomeação de objetos, verbos, nomes próprios e responsiva, e compreensão de palavras) e a três paradigmas de linguagem por RMf [nomeação por confrontação visual (NCV), nomeação responsiva à leitura (NRL) e geração de palavras (GP)]. Seis regiões cerebrais de interesse (ROI) foram selecionadas (giro frontal inferior, giro frontal médio, giro frontal superior, giro temporal inferior, giro temporal médio e giro temporal superior). Índices de Lateralidade (ILs) foram calculados com dois métodos: bootstrap, do programa LI-Toolbox, independe de limiar, e PSC, que indica a intensidade da ativação cerebral de cada voxel. Cada grupo de pacientes (EMTe e EMTd) foi dividido em dois subgrupos, de acordo com o desempenho em relação aos controles na avaliação clinica de linguagem. O <= -1,5 foi utilizado como nota de corte para dividir os grupos em pacientes com bom e com mau desempenho de linguagem. Em seguida, comparou-se o desempenho linguístico dos subgrupos ao índices IL-boot. Resultados: Pacientes com EMT esquerda e direita mostraram pior desempenho que controles nas provas clínicas de nomeação de verbos, nomeação de nomes próprios, nomeação responsiva e fluência verbal. Os mapas de ativação cerebral por RMf mostraram efeito BOLD em regiões frontais e temporoparietais de linguagem. Os mapas de comparação de ativação cerebral entre os grupos revelaram que pacientes com EMT esquerda e direita apresentam maior ativação em regiões homólogas do hemisfério direito em relação aos controles. Os ILs corroboraram estes resultados, mostrando valores médios menores para os pacientes em relação aos controles e, portanto, maior simetria na representação da linguagem. A comparação entre o IL-boot e o desempenho nas provas clínicas de linguagem indicou que, no paradigma de nomeação responsiva à leitura, a reorganização funcional no giro temporal médio, e possivelmente, nos giros temporal inferior e superior associou-se a desempenho preservado em provas de nomeação. Conclusão: Pacientes com EMT direita e esquerda apresentam comprometimento de nomeação e fluência verbal e reorganização da rede cerebral de linguagem. A reorganização funcional de linguagem em regiões temporais, especialmente o giro temporal médio associou-se a desempenho preservado em provas de nomeação em pacientes com EMT esquerda no paradigma de RMf de nomeação responsiva à leitura

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Dendritic spines of pyramidal cells are the main postsynaptic targets of cortical excitatory synapses and as such, they are fundamental both in neuronal plasticity and for the integration of excitatory inputs to pyramidal neurons. There is significant variation in the number and density of dendritic spines among pyramidal cells located in different cortical areas and species, especially in primates. This variation is believed to contribute to functional differences reported among cortical areas. In this study, we analyzed the density of dendritic spines in the motor, somatosensory and visuo-temporal regions of the mouse cerebral cortex. Over 17,000 individual spines on the basal dendrites of layer III pyramidal neurons were drawn and their morphologies compared among these cortical regions. In contrast to previous observations in primates, there was no significant difference in the density of spines along the dendrites of neurons in the mouse. However, systematic differences in spine dimensions (spine head size and spine neck length) were detected, whereby the largest spines were found in the motor region, followed by those in the somatosensory region and those in visuo-temporal region. (c) 2005 IBRO. Published by Elsevier Ltd. All rights reserved.

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The discovery of genetic factors that contribute to schizophrenia susceptibility is a key challenge in understanding the etiology of this disease. Here, we report the identification of a novel schizophrenia candidate gene on chromosome 1q32, plexin A2 (PLXNA2), in a genome-wide association study using 320 patients with schizophrenia of European descent and 325 matched controls. Over 25 000 single-nucleotide polymorphisms (SNPs) located within approximately 14 000 genes were tested. Out of 62 markers found to be associated with disease status, the most consistent finding was observed for a candidate locus on chromosome 1q32. The marker SNP rs752016 showed suggestive association with schizophrenia (odds ratio (OR) = 1.49, P = 0.006). This result was confirmed in an independent case control sample of European Americans (combined OR = 1.38, P = 0.035) and similar genetic effects were observed in smaller subsets of Latin Americans (OR = 1.26) and Asian Americans (OR = 1.37). Supporting evidence was also obtained from two family-based collections, one of which reached statistical significance (OR = 2.2, P = 0.02). High-density SNP mapping showed that the region of association spans approximately 60 kb of the PLXNA2 gene. Eight out of 14 SNPs genotyped showed statistically significant differences between cases and controls. These results are in accordance with previous genetic findings that identified chromosome 1q32 as a candidate region for schizophrenia. PLXNA2 is a member of the transmembrane semaphorin receptor family that is involved in axonal guidance during development and may modulate neuronal plasticity and regeneration. The PLXNA2 ligand semaphorin 3A has been shown to be upregulated in the cerebellum of individuals with schizophrenia. These observations, together with the genetic results, make PLXNA2 a likely candidate for the 1q32 schizophrenia susceptibility locus.

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Attention-deficit hyperactivity disorder (ADHD) is the most prevalent and impairing neurodevelopmental disorder, with worldwide estimates of 5.29%. ADHD is clinically characterized by hyperactivity-impulsivity and inattention, with neuropsychological deficits in executive functions, attention, working memory and inhibition. These cognitive processes rely on prefrontal cortex function; cognitive training programs enhance performance of ADHD participants supporting the idea of neuronal plasticity. Here we propose the development of an on-line puzzle game based assessment and training tool in which participants must deduce the ‘winning symbol’ out of N distracters. To increase ecological validity of assessments strategically triggered Twitter/Facebook notifications will challenge the ability to ignore distracters. In the UK, significant cost for the disorder on health, social and education services, stand at £23m a year. Thus the potential impact of neuropsychological assessment and training to improve our understanding of the pathophysiology of ADHD, and hence our treatment interventions and patient outcomes, cannot be overstated.

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Reactive oxygen species (ROS) and nitric oxide (NO) are important participants in signal transduction that could provide the cellular basis for activity-dependent regulation of neuronal excitability. In young rat cortical brain slices and undifferentiated PC12 cells, paired application of depolarization/agonist stimulation and oxidation induces long-lasting potentiation of subsequent Ca2+ signaling that is reversed by hypoxia. This potentiation critically depends on NO production and involves cellular ROS utilization. The ability to develop the Ca2+ signal potentiation is regulated by the developmental stage of nerve tissue, decreasing markedly in adult rat cortical neurons and differentiated PC12 cells.

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Astrocytes release gliotransmitters, notably glutamate, that can affect neuronal and synaptic activity. In particular, astrocytic glutamate release results in the generation of NMDA receptor (NMDA-R)-mediated slow inward currents (SICs) in neurons. However, factors underlying the emergence of SICs and their physiological roles are essentially unknown. Here we show that, in acute slices of rat somatosensory thalamus, stimulation of lemniscal or cortical afferents results in a sustained increase of SICs in thalamocortical (TC) neurons that outlasts the duration of the stimulus by 1 h. This long-term enhancement of astrocytic glutamate release is induced by group I metabotropic glutamate receptors and is dependent on astrocytic intracellular calcium. Neuronal SICs are mediated by extrasynaptic NR2B subunit-containing NMDA-Rs and are capable of eliciting bursts. These are distinct from T-type Ca2+ channel-dependent bursts of action potentials and are synchronized in neighboring TC neurons. These findings describe a previously unrecognized form of excitatory, nonsynaptic plasticity in the CNS that feeds forward to generate local neuronal firing long after stimulus termination.

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Astrocytes are increasingly implicated in a range of functions in the brain, many of which were previously ascribed to neurons. Much of the prevailing interest centers on the role of astrocytes in the modulation of synaptic transmission and their involvement in the induction of forms of plasticity such as long-term potentiation and long-term depression. However, there is also an increasing realization that astrocytes themselves can undergo plasticity. This plasticity may be manifest as changes in protein expression which may modify calcium activity within the cells, changes in morphology that affect the environment of the synapse and the extracellular space, or changes in gap junction astrocyte coupling that modify the transfer of ions and metabolites through astrocyte networks. Plasticity in the way that astrocytes release gliotransmitters can also have direct effects on synaptic activity and neuronal excitability. Astrocyte plasticity can potentially have profound effects on neuronal network activity and be recruited in pathological conditions. An emerging principle of astrocyte plasticity is that it is often induced by neuronal activity, reinforcing our emerging understanding of the working brain as a constant interaction between neurons and glial cells. © The Author(s) 2013.

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Addictive drugs can activate systems involved in normal reward-related learning, creating long-lasting memories of the drug's reinforcing effects and the environmental cues surrounding the experience. These memories significantly contribute to the maintenance of compulsive drug use as well as cue-induced relapse which can occur even after long periods of abstinence. Synaptic plasticity is thought to be a prominent molecular mechanism underlying drug-induced learning and memories. Ethanol and nicotine are both widely abused drugs that share a common molecular target in the brain, the neuronal nicotinic acetylcholine receptors (nAChRs). The nAChRs are ligand-gated ion channels that are vastly distributed throughout the brain and play a key role in synaptic neurotransmission. In this review, we will delineate the role of nAChRs in the development of ethanol and nicotine addiction. We will characterize both ethanol and nicotine's effects on nAChR-mediated synaptic transmission and plasticity in several key brain areas that are important for addiction. Finally, we will discuss some of the behavioral outcomes of drug-induced synaptic plasticity in animal models. An understanding of the molecular and cellular changes that occur following administration of ethanol and nicotine will lead to better therapeutic strategies.

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The lateral amygdala (LA) receives information from auditory and visual sensory modalities, and uses this information to encode lasting memories that predict threat. One unresolved question about the amygdala is how multiple memories, derived from different sensory modalities, are organized at the level of neuronal ensembles. We previously showed that fear conditioning using an auditory conditioned stimulus (CS) was spatially allocated to a stable topography of neurons within the dorsolateral amygdala (LAd) (Bergstrom et al, 2011). Here, we asked how fear conditioning using a visual CS is topographically organized within the amygdala. To induce a lasting fear memory trace we paired either an auditory (2 khz, 55 dB, 20 s) or visual (1 Hz, 0.5 s on/0.5 s off, 35 lux, 20 s) CS with a mild foot shock unconditioned stimulus (0.6 mA, 0.5 s). To detect learning-induced plasticity in amygdala neurons, we used immunohistochemistry with an antibody for phosphorylated mitogen-activated protein kinase (pMAPK). Using a principal components analysis-based approach to extract and visualize spatial patterns, we uncovered two unique spatial patterns of activated neurons in the LA that were associated with auditory and visual fear conditioning. The first spatial pattern was specific to auditory cued fear conditioning and consisted of activated neurons topographically organized throughout the LAd and ventrolateral nuclei (LAvl) of the LA. The second spatial pattern overlapped for auditory and visual fear conditioning and was comprised of activated neurons located mainly within the LAvl. Overall, the density of pMAPK labeled cells throughout the LA was greatest in the auditory CS group, even though freezing in response to the visual and auditory CS was equivalent. There were no differences detected in the number of pMAPK activated neurons within the basal amygdala nuclei. Together, these results provide the first basic knowledge about the organizational structure of two different fear engrams within the amygdala and suggest they are dissociable at the level of neuronal ensembles within the LA

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During Pavlovian auditory fear conditioning a previously neutral auditory stimulus (CS) gains emotional significance through pairing with a noxious unconditioned stimulus (US). These associations are believed to be formed by way of plasticity at auditory input synapses on principal neurons in the lateral nucleus of the amygdala (LA). In order to begin to understand how fear memories are stored and processed by synaptic changes in the LA, we have quantified both the entire neural number and the sub-cellular structure of LA principal neurons.We first used stereological cell counting methods on Gimsa or GABA immunostained rat brain. We identified 60,322+/-1408 neurons in the LA unilaterally (n=7). Of these 16,917+/-471 were GABA positive. The intercalated nuclei were excluded from the counts and thus GABA cells are believed to represent GABAergic interneurons. The sub-nuclei of the LA were also independently counted. We then quantified the morphometric properties of in vitro electrophysiologically identified principal neurons of the LA, corrected for shrinkage in xyz planes. The total dendritic length was 9.97+/-2.57mm, with 21+/-4 nodes (n=6). Dendritic spine density was 0.19+/-0.03 spines/um (n=6). Intra-LA axon collaterals had a bouton density of 0.1+/-0.02 boutons/um (n=5). These data begin to reveal the finite cellular and sub-cellular processing capacity of the lateral amygdala, and should facilitate efforts to understand mechanisms of plasticity in LA.