ETHANOL EFFECT ON THE BASAL FOREBRAIN CORTEX SYSTEM

长期酗酒会导致多种行为改变， 不可逆转的记忆丧失最近在大鼠中的数据表明，乙醇诱导的 行为缺陷可以通过移植胎儿， 富含胆碱的组织这些数据意味着从基底的投影 前脑到大脑皮层是乙醇的特定靶点。这 投射系统是少数表达神经生长因子（NGF）的系统之一。 神经生长因子和乙酰胆碱都是维持神经元 可塑性我们假设酒精导致的记忆丧失 神经元可塑性的丧失。该提案描述了一些研究， 探索乙醇暴露对胆碱能神经的结构影响 系统和基底前脑神经元的营养支持。 将进行六项实验。(1)乙醇对数量的影响 基底前脑和躯体感觉神经元 皮质（接受来自神秘触须的输入的部分）将被 使用严格的形态测定分析确定。神经元的数量 表达胆碱乙酰转移酶（ChAT）[促进 乙酰胆碱酯酶（AChE）[乙酰胆碱的合成]， 催化乙酰胆碱的降解]和γ-氨基丁酸 酸（GABA）将被确定。以ChAT、AChE和GABA为标记物， 对于胆碱能和非胆碱能神经元，我们将能够 以确定乙醇作用的特异性。(2)的 乙醇的特异性将通过研究以下因素的影响来进一步检查： 改变暴露于乙醇的持续时间。是胆碱能或 GABA能神经元首先受到影响？神经系统会补偿 随着时间的推移，这些缺陷？如果是，如何做到？(3)乙醇对神经生长因子和 将用化学方法检查NGF受体。我们亦会研究 乙醇对神经生长因子和神经生长因子mRNA转录的影响 受体使用原位杂交。(4)在随后的研究中，我们将 研究NGF受体在ChAT免疫反应神经元中的共定位 在基底前脑(5)我们将检验乙醇- 胆碱能系统中的诱导变化导致以下方面的损失或损害： 神经可塑性这些研究将检查乙醇对 丘脑皮质投射对周围损伤的反应 触须(6)两种方法来补救酒精毒性的影响将是 考察在一项研究中，胎儿基底前脑组织将被移植到 在另一种情况下，将给予神经生长因子。遵循这些 操作，我们将使用上述的生物测定（用于 乙醇毒性的特异性，NGF系统的作用，以及 神经系统对损伤的反应），以评估 操纵 总的来说，拟议的计划概述了一个统一的电池， 这些实验不仅确定了乙醇毒性的机制， 产生的，但也探讨了2种方式，其中乙醇- 可以克服诱发的缺陷。

Chronic alcohol abuse leads to multiple behavioral changes and to irreversible memory loss. Recent data in rats show that ethanol-induced behavioral deficits can be ameliorated by transplantation of fetal, choline-rich tissue. These data imply that the projection from the basal forebrain to cerebral cortex is a specific target of ethanol. This projection system is one of the few to express nerve growth factor (NGF). Both NGF and acetylcholine are essential for maintaining neuronal plasticity. We hypothesize that the ethanol-induced memory loss results from losses in neuronal plasticity. This proposal describes studies which explore the structural consequences of ethanol exposure on the cholinergic system and the trophic support of basal forebrain neurons. Six experiments will be executed. (1) The effect of ethanol on the number of neurons in the basal forebrain and in the barrels of somatosensory cortex (segments which receive input from the mystacial vibrissae) will be determined using rigorous morphometric analyses. The number of neurons expressing choline acetyltrans-ferase (ChAT)[the enzyme which facilitates the synthesis of acetylcholine], acetyl-cholinesterase (AChE) [the enzyme which catalyzes the degradation of acetylcholine], and gamma-aminobutyric acid (GABA) will be determined. By using ChAT, AChE and GABA as markers for cholinergic and non-cholinergic neurons, respectively, we will be able to determine the specificity of the effects of ethanol. (2) The specificity of ethanol will further be examined by studying the effects of varying the duration of the exposure to ethanol. Are cholinergic or GABAergic neurons affected first? Does the nervous system compensate for these defects over time? If so, how? (3) The effects of ethanol on NGF and NGF receptors will be examined immunohistochemically. We will also examine the effects of ethanol on the transcription of mRNA for NGF and NGF receptors using in situ hybridization. (4) In a subsequent study, we will study the co-localization of NGF receptors in ChAT-immunoreactive neurons in the basal forebrain. (5) We will test the hypothesis that ethanol- induced changes in the cholinergic system lead to losses or impairments in neuronal plasticity. These studies will examine the effect of ethanol on the response of thalamocortical projections to peripheral damage to the vibrissae. (6) Two ways to remedy the effects of ethanol toxicity will be examined. In one study, fetal basal forebrain tissue will be transplanted into cortex, and in another, NGF will be administered. Following these manipulations, we will use the bioassays described above (tests for the specificity of the ethanol toxicity, the role of the NGF system, and the response of the nervous system to injury) to assess the success of the manipulation. Taken together, the proposed program outlines a unified battery of experiments which not only determine a mechanism of ethanol toxicity produced by chronic exposure, but also explore 2 ways in which ethanol- induced defects can be overcome.