CELLULAR AND MOLECULAR STUDIES OF ETHANOL AND MEMORY

急性摄入乙醇的遗忘作用是有据可查的 在人类和动物研究中。 然而，分子和细胞 这种遗忘效应的机制尚不清楚。 解决 这个问题私家侦探建议研究乙醇对 长时程增强（LTP）是一种突触可塑性的形式， 被认为是记忆的细胞基质。 所述特定聚焦 其中一项拟议的研究将是检查乙醇对 LTP的电生理和生化相关性。 乙醇具有 先前显示抑制大鼠CA 1区LTP的诱导 海马切片 以前的研究提供了相互矛盾的证据 关于阻断LTP所需的乙醇浓度。 此外，委员会认为， 关于乙醇作用的大脑区域特异性知之甚少 在LTP上 因此，PI。将进行剂量反应和大脑 乙醇对LTP影响的区域分析。 的潜在 乙醇对LTP影响的分子靶点不同， 酒精浓度敏感性。 此外，其中至少有一个 乙醇的目标，NMDA受体，是诱导LTP所必需的， 一些大脑区域，而不是在其他区域。 因此，剂量反应和大脑 区域分析应有助于确定对分子生物学的限制， 参与乙醇抑制LTP的靶点。 没有发生 研究了乙醇对LTP维持的影响， 被诱导。 因此，PI。还建议检查剂量依赖性 乙醇对维持LTP的影响。 鉴于不同 分子似乎参与维持和诱导， 这些研究还可能提供关于肿瘤的分子靶点的新信息。 乙醇对LTP的影响 除了这些电生理 分析，P.I.还建议研究乙醇对 蛋白质磷酸化 这些分析的重点将是 突触蛋白，突触囊泡相关蛋白，其是 Ca 2 +/钙调蛋白依赖性蛋白激酶。 突触蛋白磷酸化 已经清楚地表明在调节递质释放中起作用， 据报道，乙醇可以调节许多 不同的神经系统。 此外，突触蛋白磷酸化是 与LTP诱导相关，LTP至少部分是由于 增加发射器释放。 所以私家侦探。拟审查 乙醇对化学物质产生的突触蛋白磷酸化的影响 和LTP的电诱导物。

The amnestic effects of acute ingestion of ethanol are well documented in both human and animal studies. However, the molecular and cellular mechanisms which underlie this amnestic effect are unknown. To address this question, the P.I. proposes to examine the effects of ethanol on long-term potentiation (LTP) a form of synaptic plasticity that is widely thought to serve as a cellular substrate of memory. The specific focus of the proposed studies will be to examine the effects of ethanol on electrophysiological and biochemical correlates of LTP. Ethanol has previously been shown to inhibit induction of LTP in area CA1 of the rat hippocampal slice. Previous work has provided contradictory evidence concerning the concentration of ethanol required to block LTP. Moreover, little is known about the brain regional specificity of ethanol's effects on LTP. Therefore, the P.I. will perform dose-response and brain regional analyses of the effect of ethanol on LTP. The potential molecular targets underlying ethanol's effects on LTP differ in their alcohol concentration sensitivities. Moreover, at least one of these targets of ethanol, the NMDA-receptor, are required for induction LTP in some brain regions but not in others. Thus the dose response and brain regional analyses should help to identify constraints on the molecular targets involved in ethanol inhibition of LTP. There have been no studies of the effects of ethanol on the maintenance of LTP after it has been induced. Thus the P.I. also proposes to examine the dose dependency of ethanol's effects on the maintenance of LTP. Given that different molecules appear to participate in maintenance and induction, such studies may also provide new information about the molecular targets of ethanol's effects on LTP. In addition to these electrophysiological analyses, the P.I. also proposes to examine the effects of ethanol on protein phosphorylation. The focus of these analyses will be on the synapsins, synaptic vesicle-associated proteins that are substrates for Ca2+/calmodulin-dependent protein kinase. Synapsin phosphorylation has clearly been shown to play a role in regulation of transmitter release, and ethanol has been reported to modulate release in a number of different neuronal systems. Moreover, synapsin phosphorylation is correlated with LTP induction and LTP is due, at least in part, to increased transmitter release. Therefore the P.I. proposes to examine the effects of ethanol on synapsin phosphorylation produced by chemical and electrical inducers of LTP.