Alcohol in Neocortex Development and Plasticity

描述(申请人提供)：胎儿酒精综合症(FAS)是人们学习和感觉障碍的主要原因。越来越多的证据表明，新皮质功能和可塑性的异常是这些缺陷的基础。在相当于人类妊娠的第三个三个月期间暴露在酒精中的动物，在长时间的无酒精期后接受检查，其特征是新皮质功能和可塑性中断。然而，产前酒精暴露扰乱新皮质发育和可塑性的机制仍然难以捉摸。在以Fas为特征的学习障碍的背景下，新皮质的神经可塑性尤其有趣，因为它与学习和记忆共享基本机制，包括激活N-甲基-D-天冬氨酸(NMDAR)受体和转录因子cAMP/钙依赖反应元件结合蛋白(CREB)，后者调节皮质可塑性所需基因的表达。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，而这些对皮质功能和可塑性都是至关重要的。这一提议的中心假设是，这些效应导致突触信号异常地传递到细胞核，扰乱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挽救Fas动物模型的皮质可塑性。拟议的研究将使用分子遗传学和药理学方法来加强突触信号向皮质神经元核的传递。第二个主要目标是防止大脑皮层出现发育问题。拟议的研究将在动物接触酒精期间和之后将皮质的可塑性和抑制恢复到正常水平。总而言之，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。这些研究的结果有朝一日可能有助于设计出预防或减轻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.