Alcohol in Neocortex Development and Plasticity

描述（申请人提供）：胎儿酒精综合征（FAS）是人类学习和感觉缺陷的主要原因。越来越多的证据表明，这些缺陷的基础是新皮质功能和可塑性的异常。在相当于人类妊娠的第三个三个月期间暴露于酒精的动物，在长时间无酒精期后进行检查，其特征在于新皮质功能和可塑性的破坏。然而，产前酒精暴露破坏新皮层发育和可塑性的机制仍然难以捉摸。新皮质中的神经可塑性在表征FAS的学习缺陷的背景下特别有趣，因为它与学习和记忆共享基本机制，包括需要激活N-甲基-D-天冬氨酸（NMDAR）受体和转录因子cAMP/钙依赖性反应元件结合蛋白（CREB），其调节皮质可塑性所需的基因的表达。慢性酒精暴露对NMDA受体功能、CREB激活和皮质内抑制有重要影响，所有这些都对皮质功能和可塑性至关重要。这一提议的中心假设是，这些效应导致突触信号向细胞核的异常传递，破坏调节可塑性基因表达的转录因子的激活。这项建议的主要目标是拯救FAS动物模型中的皮质可塑性。拟议的研究将使用分子遗传学和药理学方法来增强突触信号到皮层神经元核的传递。第二个主要目标是防止新皮层的发育问题。拟定研究将在动物暴露于酒精期间和之后将皮质可塑性和抑制恢复至正常水平。总的来说，这些研究应该提供一个新的令人兴奋的机会来阐明早期酒精暴露如何损害皮质功能和可塑性。这些研究的结果可能有一天有助于设计预防或减轻FAS发病率的治疗干预措施。

DESCRIPTION (provided by applicant): Fetal alcohol syndrome (FAS) is a major cause of learning and sensory deficits in people. There is growing evidence that abnormalities of neocortical function and plasticity underlie these deficits. Animals exposed to alcohol during the third trimester equivalent of human gestation and examined following a prolonged alcohol- free period were characterized by disruption of neocortical function and plasticity. However, the mechanisms by which prenatal alcohol exposure disrupts neocortical development and plasticity remain elusive. Neural plasticity in the neocortex is especially interesting in the context of the learning deficits that characterize FAS since it shares basic mechanisms with learning and memory, including a requirement for activation of the N- methyl-D-aspartate (NMDAR) receptor and the transcription factor cAMP/calcium-dependent response element binding protein (CREB), which regulates expression of genes required for cortical plasticity. Chronic alcohol exposure has important effects on NMDA receptor function, CREB activation and intracortical inhibition, all of which are crucial for cortical function and plasticity. The central hypothesis of this proposal is that these effects result in abnormal transmission of synaptic signals to the nucleus, disrupting activation of transcription factors that regulate expression of plasticity genes. The primary goal of this proposal is to rescue cortical plasticity in an animal model of FAS. The proposed studies will use molecular-genetic and pharmacological approaches to enhance transmission of synaptic signals to the nucleus of cortical neurons. The second major goal is to prevent developmental problems in the neocortex. The proposed studies will restore cortical plasticity and inhibition to normal level during and after the period when the animal is exposed to alcohol. Collectively, these studies should provide a new and exciting opportunity to elucidate how early alcohol exposure impairs cortical function and plasticity. The results of these studies may one day contribute to devise therapeutic interventions that will prevent or alleviate morbidity in FAS.