Alcohol in Neocortex Development and Plasticity

酒精在新皮质发育和可塑性中的作用

• 批准号: 8583074
• 负责人: Alexandre Esteves Medina
• 金额: $ 35.13万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-06-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8583074
• 关键词: Alcohol; Neocortex; Development; Plasticity

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.

描述（由申请人提供）：胎儿酒精谱系障碍（FASD）是一个伞术，描述了一系列可能发生的影响，该效果可能发生在其母亲在怀孕期间吸收酒精的个人。在美国，这种情况被认为是西方世界智力低下的主要原因，在美国每年多达40,000例。感觉皮层是FASD中受影响最大的地区之一，患有这种状况的儿童的体感，听觉和视觉处理改变了。越来越多的证据表明，这些感觉问题可能与不良的皮质图，组织和可塑性有关。但是，这种效果依据的机制仍有待阐明。我们开发了一种独特的FASD雪貂模型，该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理假设。我们表明，三个月的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控制很多。已经表明，由星形胶质细胞分泌的分子可以调节突触形成，稳定和可塑性。这些星形胶质细胞释放的分子中的许多是由转录因子SRF（血清反应因子）介导的。在这里，我们假设星形胶质细胞中不适当的SRF功能有助于FASD中看到的神经元可塑性受损。作为推论，星形胶质细胞中SRF功能的改善可能会改善这种赤字。为了检验这一假设，我们将使用多种技术，例如病毒介导的基因转移，体内基因递送，内部信号的体内光学成像，体内细胞外电生理学，单型细胞培养，共焦激光显微镜和多种生物学和生物学和分子分析。总的来说，该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对神经元信号的影响及其对皮质可塑性的影响。此信息可能与设计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）是智力低下的主要原因。在这里，我们测试了星形胶​​质细胞功能受损的假设会影响神经元的可塑性。作为推论，星形胶质细胞功能的改善会导致神经元可塑性的增加。这些研究应有助于设计可能减轻FASD发病率的治疗干预措施。