Alcohol in Neocortex Development and Plasticity

描述（由申请人提供）：胎儿酒精谱系障碍（FASD）是一个总括术语，描述了母亲在怀孕期间饮酒的个体可能发生的一系列影响。这种情况被认为是西方世界智力迟钝的主要原因，在美国每年有多达40，000例。感觉皮层是FASD最受影响的区域之一，患有这种疾病的儿童表现出躯体感觉，听觉和视觉处理的改变。越来越多的证据表明，这些感觉问题可能与皮质地图的细化，组织和可塑性差有关。然而，这种影响的机制仍有待阐明。我们开发了一种独特的FASD雪貂模型，提供了一种新的方法来测试早期酒精暴露如何损害感觉皮层功能的机制假说。我们发现，孕晚期酒精暴露导致视觉皮层组织和神经元可塑性的持续破坏。近年来，星形胶质细胞对神经元功能的调控受到了广泛关注。研究表明，星形胶质细胞分泌的分子可以调节突触的形成、稳定和可塑性。这些星形胶质细胞释放的分子中有许多是由转录因子SRF（血清反应因子）介导的。在这里，我们假设，不适当的SRF功能的星形胶质细胞有助于FASD神经元可塑性的损害。作为一个必然的结果，在星形胶质细胞中SRF功能的改善可能会改善这种缺陷。为了验证这一假设，我们将使用多种技术，如病毒介导的基因转移，离体基因传递，内在信号的体内光学成像，体内细胞外电生理学，单型细胞培养，共聚焦激光显微镜和多种生化和分子测定。总的来说，这一建议将有助于我们了解早期酒精暴露如何影响星形胶质细胞神经元信号传导及其对皮质可塑性的影响。这些信息可能与设计FASD的治疗干预措施高度相关 公共卫生相关性：胎儿酒精谱系障碍（FASD）是智力迟钝的主要原因。在这里，我们测试的假设，星形胶质细胞功能的损害可以影响神经元的可塑性。作为推论，星形胶质细胞功能的改善可以导致神经元可塑性的增加。这些研究应有助于制定治疗干预措施，可能会减轻发病率在FASD。

DESCRIPTION (provided by applicant): Fetal Alcohol Spectrum Disorders (FASD) is an umbrella term describing a range of effects that can occur in an individual whose mother imbibed alcohol during pregnancy. This condition is considered the leading cause of mental retardation in the western world with as many as 40,000 cases per year in the United States. The sensory cortex is one of the most affected areas in FASD and children with this condition present altered somatosensory, auditory and visual processing. There is growing evidence indicating that these sensory problems may be related to poor cortical map refinement, organization and plasticity. However, the mechanisms that underlie such effects remain to be elucidated. We developed a unique ferret model of FASD that provides a novel approach to test mechanistic hypothesis of how early alcohol exposure can impair sensory cortex function. We showed that third trimester alcohol exposure lead to a persistent disruption in visual cortex organization and neuronal plasticity. In recent years, much attention has been devoted to the control of neuronal function by astrocytes. It has been shown that molecules secreted by astrocytes can regulate synaptic formation, stabilization and plasticity. Many of these astrocyte-released molecules are mediated by the transcription factor SRF (Serum Response Factor). Here we hypothesize that inappropriate SRF function in astrocytes contributes to the impairment of neuronal plasticity seen in FASD. As a corollary, improvement of SRF function in astrocytes may ameliorate this deficit. To test this hypothesis we will use multiple techniques such as viral-mediated gene transfer, ex vivo gene delivery, in vivo optical imaging of intrinsic signals, in vivo extracellular electrophysiology, monotypic cell cultures, confocal laser microscopy and multiple biochemical and molecular assays. Collectively, this proposal will help our understanding of how early alcohol exposure affects astrocyte to neuron signaling and its effects on cortical plasticity. This information may be highly relevant to devise therapeutic interventions for FASD PUBLIC HEALTH RELEVANCE: Fetal alcohol spectrum disorder (FASD) is a leading cause of mental retardation. Here we test the hypothesis that impairment of astrocytes function can impact plasticity in neurons. As corollary, improvement of astrocytes function can lead to an increase in neuronal plasticity. These studies should contribute to devise therapeutic interventions that may alleviate morbidity in FASD.