ETHANOL EFFECT ON THE BASAL FOREBRAIN CORTEX SYSTEM

乙醇对基底前脑皮层系统的影响

• 批准号: 2413245
• 负责人: MICHAEL W MILLER
• 金额: $ 18.44万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-05-01 至 2000-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2413245
• 关键词: acetylcholinesterase; cerebral cortex; choline acetyltransferase; cytotoxicity; ethanol; gamma aminobutyrate; genetic transcription; immunocytochemistry; in situ hybridization; laboratory rat; memory; messenger RNA; neural plasticity; neuroanatomy; neurochemistry; neurotrophic factors; prosencephalon; western blottings

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.

长期酗酒会导致多种行为改变并 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 行为缺陷可以通过胎儿移植来改善 富含胆碱的组织。这些数据意味着从基础数据的投影 前脑到大脑皮层是乙醇的特定目标。这 投影系统是少数表达神经生长因子（NGF）的系统之一。 NGF 和乙酰胆碱对于维持神经元功能至关重要 可塑性。我们假设乙醇引起的记忆丧失导致 来自神经元可塑性的损失。该提案描述了以下研究 探索乙醇暴露对胆碱能的结构影响 系统和基底前脑神经元的营养支持。 将进行六个实验。 (1)乙醇对数的影响 基底前脑和体感桶中的神经元 皮质（接收来自神秘触须输入的部分）将是 使用严格的形态测量分析确定。神经元数量 表达胆碱乙酰转移酶（ChAT）[该酶促进 乙酰胆碱的合成]，乙酰胆碱酯酶（AChE）[该酶 催化乙酰胆碱]和γ-氨基丁酸的降解 酸（GABA）将被测定。使用 ChAT、AChE 和 GABA 作为标记 分别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其影响来进一步检验 改变接触乙醇的持续时间。是否具有胆碱能或 GABA能神经元首先受到影响？神经系统是否代偿 随着时间的推移这些缺陷？如果是这样，怎么办？ (3)乙醇对NGF的影响 NGF 受体将通过免疫组织化学方法进行检查。我们还将检查 乙醇对NGF和NGF mRNA转录的影响 使用原位杂交的受体。 （4）在后续的研究中，我们将 研究 ChAT 免疫反应性神经元中 NGF 受体的共定位 在基底前脑中。 (5) 我们将检验以下假设：乙醇- 胆碱能系统的诱发变化导致胆碱能系统的损失或损害 神经元的可塑性。这些研究将检验乙醇对 丘脑皮质投射对周围损伤的反应 触须。 (6) 补救乙醇毒性影响的方法有两种： 检查了。在一项研究中，胎儿​​基底前脑组织将被移植 在另一种情况下，将施用 NGF。遵循这些 操作，我们将使用上述生物测定（测试 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）来评估治疗的成功 操纵。 总而言之，拟议的计划概述了一个统一的电池组 实验不仅确定了乙醇毒性的机制 长期接触产生的，但也探索了乙醇的两种方式 诱发的缺陷是可以克服的。