CELLULAR AND MOLECULAR STUDIES OF ETHANOL AND MEMORY

乙醇和记忆的细胞和分子研究

• 批准号: 2045937
• 负责人: MICHAEL D BROWNING
• 金额: $ 11.2万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-09-30 至 1996-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2045937
• 关键词: NMDA receptors; calmodulin dependent protein kinase; dissociative hysteria; dosage; electrophysiology; ethanol; guinea pigs; laboratory rat; long term potentiation; memory; neural plasticity; neurochemistry; neurotransmitters; phosphorylation; synapsins; synaptic vesicles

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.

急性摄入乙醇的健忘作用是有充分证据的。 在人类和动物研究中。然而，分子和细胞 这种遗忘效应背后的机制尚不清楚。致信地址 在这个问题上，P.I.建议检查乙醇对 长时程增强(LTP)是突触可塑性的一种形式，广泛 被认为是记忆的细胞底物。具体关注点 拟议的研究的一部分将是检查乙醇对 LTP的电生理和生化相关性。乙醇有 先前已被证明抑制大鼠CA1区LTP的诱导 海马片。之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， 关于酒精影响的大脑区域特异性，人们知之甚少 在LTP上。因此，P.I.将执行剂量反应和大脑 乙醇对LTP影响的区域分析。潜力 乙醇对LTP影响的分子靶点不同 酒精浓度敏感度。此外，其中至少有一项 NMDA受体乙醇的靶点是诱导LTP所必需的 一些大脑区域，但不是在其他区域。因此，剂量反应和大脑 区域分析应该有助于确定对分子的限制 乙醇抑制LTP的作用靶点。一直没有 乙醇对LTP作用后维持作用的研究 是被引诱的。因此，P.I.还建议检查剂量依赖关系 乙醇对维持LTP的影响。鉴于这一点不同 分子似乎参与维持和诱导，如 研究还可能提供有关分子靶标的新信息。 乙醇对LTP的影响。除了这些电生理学 分析，P.I.还建议检查乙醇对 蛋白质磷酸化。这些分析的重点将放在 突触素，突触小泡相关蛋白，是底物 钙/钙调蛋白依赖的蛋白激酶。突触素的磷酸化 显然被证明在调节递质释放方面发挥了作用， 据报道，乙醇可调节多种药物的释放。 不同的神经系统。此外，突触素的磷酸化是 与LTP诱导和LTP相关至少部分归因于 增加发射器释放。因此私家侦探建议检查 乙醇对化学法产生的突触素磷酸化的影响 和LTP的电诱导剂。