Alcohol in Neocortex Development and Plasticity

描述（由申请人提供）：胎儿酒精谱系障碍（FASD）是一个概括性术语，描述了母亲在怀孕期间摄入酒精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4万例。感觉皮层是FASD中受影响最严重的区域之一，患有这种疾病的儿童表现出体感、听觉和视觉处理的改变。越来越多的证据表明，这些感官问题可能与皮层地图的细化、组织和可塑性差有关。然而，这种影响背后的机制仍有待阐明。我们开发了一种独特的雪貂FASD模型，为测试早期酒精暴露如何损害感觉皮质功能的机制假设提供了一种新的方法。我们发现妊娠晚期酒精暴露会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。许多星形胶质细胞释放的分子是由转录因子SRF（血清反应因子）介导的。在这里，我们假设星形胶质细胞中不适当的SRF功能有助于FASD中所见的神经元可塑性损伤。因此，星形胶质细胞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、体外基因传递、体内固有信号的光学成像、体内细胞外电生理、单型细胞培养、共聚焦激光显微镜和多种生化和分子分析。总的来说，这一建议将有助于我们理解早期酒精暴露如何影响星形胶质细胞对神经元的信号传导及其对皮质可塑性的影响。这一信息可能与FASD的治疗干预措施高度相关

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.