Alcohol in Neocortex Development and Plasticity

胎儿酒精综合症（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，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妊娠晚期暴露于酒精的动物，以及在长时间无酒精期后进行检查的动物，其特征是新皮质功能和可塑性受到破坏。然而，产前酒精的作用机制

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 Nmethyl- 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 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.