CHRONIC ETHANOL NEUROTOXICITY AND LONG-TERM POTENTIATION

长期酗酒会导致脑损伤和神经元功能障碍。 对实验动物的研究提供了令人信服的证据 乙醇在诱导这种神经元功能障碍中的特异性。 然而，我们仍然对潜在的机制知之甚少。 乙醇的神经毒性或形态或功能基础 与慢性酒精滥用有关的助记缺陷。一个主要目标 这一建议的目的是开始刻画其性质和机制 乙醇神经毒性导致的助记缺陷。 慢性乙醇治疗已被证明导致显著的损失 海马神经元，改变树突结构和存活功能 神经元和突触连接的丢失或重排。长期的 增强作用现在被认为是一种重要的生理机制 因此，海马体和其他大脑区域编码或索引 实验陈述和证据表明慢性乙醇 治疗可能会深刻改变脑内长时程增强的特性 海马体。这项提案的一个主要目标是描述 慢性乙醇处理扰乱长时程增强的方式 在海马区使用细胞外和细胞内生理学 录音技术。我们还建议开始描述自然界的特征 慢性乙醇治疗扰乱长期的 增强功能。已经知道了相当多的关于诱导 海马体的长时程增强。长效的诱导 增强作用需要激活N-甲基-D-天冬氨酸(NMDA)受体 导致钙瞬变局限于受限的复合体 突触后膜的位置。这种钙瞬变很可能 导致一种或多种钙敏感酶的特异性激活 系统。这种分子级联在某种程度上导致了 突触传递的强度可持续数小时至数天。一个 这项建议中要研究的主要假设是慢性 乙醇处理通过一种机制破坏长时程增强 包括该分子中涉及的一个或多个步骤的改变 卡斯卡德。我们的研究将集中在基本的慢性酒精作用上 谷氨酸-突触传递、细胞内钙调节过程 和蛋白激酶活性。我们将利用电生理学， 生化、放射自显影和免疫细胞化学技术以及 对基因表达的研究，以表征慢性粒细胞白血病的方式 乙醇处理破坏了长时程增强的诱导。在……里面 谷氨酸突触和谷氨酸的作用的推论证据的观点 多种疾病兴奋性毒性中的细胞内钙调节 我们的研究结果可能还会对全球产生更大的影响 关于乙醇产生神经元毒性和 功能障碍。

Chronic ethanol abuse results in brain damage and neuronal dysfunction. Studies in laboratory animals have provided convincing evidence of the specificity of ethanol in inducing this neuronal dysfunction. Nevertheless, we still know little regarding the mechanisms underlying ethanol neurotoxicity nor the morphological or functional basis of the mnemonic deficits associated with chronic ethanol abuse. A major objective of this proposal is to begin to characterize the nature and mechanisms underlying the mnemonic deficit resulting from ethanol neurotoxicity. Chronic ethanol treatment has been shown to result in significant loss of hippocampal neurons, altered dendritic structure and function of surviving neurons and loss or rearrangement of synaptic connections. Long-term potentiation is now considered to be a significant physiological mechanism whereby the hippocampus and other brain regions encode or index experimental representations and evidence indicates that chronic ethanol treatment may profoundly alter the properties of long-term potentiation in the hippocampus. A major objective of this proposal is to characterize the manner in which chronic ethanol treatment disrupts long-term potentiation in the hippocampus using extracellular and intracellular physiological recording techniques. We also propose to begin to characterize the nature of the mechanisms whereby chronic ethanol treatment disrupts long-term potentiation. A considerable amount is known regarding the induction of long-term potentiation in the hippocampus. The induction of long-term potentiation requires activation of an n-methyl-d-aspartate (NMDA) receptor complex which leads to a calcium transient localized to restricted locations in the postsynaptic membrane. This calcium transient likely leads to a specific activation of one or more calcium-sensitive enzyme systems. This molecular cascade in some way results in an increase in the strength of synaptic transmission which can last for hours to days. A major hypothesis to be investigated in this proposal is that chronic ethanol treatment disrupts long-term potentiation through a mechanism that includes alterations in one or more of the steps involved in this molecular cascade. Our studies will focus upon basic chronic ethanol actions upon glutamatesynaptic transmission, intracellular calcium regulatory processes and protein kinase activity. We will utilize electrophysiological, biochemical, autoradiographic and immunocytochemical techniques as well as studies of gene expression to characterize the manner in which chronic ethanol treatment disrupts the induction of long-term potentiation. In view of corollary evidence indicating a role for glutamate synapses and intracellular calcium regulation in excitotoxicity in a variety of disease states, the results of our studies may also have more global implications for the mechanisms whereby ethanol produces neuronal toxicity and dysfunction.