GENETIC APPROACH TO STUDY ACETYLCHOLINE FUNCTIONS

研究乙酰胆碱功能的遗传学方法

• 批准号: 2645448
• 负责人: EUGENE P BRANDON
• 金额: $ 2.62万
• 依托单位: SALK INSTITUTE FOR BIOLOGICAL STUDIES
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-01 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/2645448
• 关键词: acetylcholine; animal genetic material tag; behavioral /social science research tag; choline acetyltransferase; disease /disorder model; enzyme activity; genetically modified animals; laboratory mouse; learning; model design /development; neural transmission; neurons; prosencephalon

A great deal of research has been devoted to understanding the functions of forebrain acetylcholine (ACh) in mammalian cognitive processes. However, conclusions from many of the studies have been tempered by caveats related to the inherent limitations of pharmacological and lesion approaches. Thus, specific functions of ACh remain equivocal. In order to look directly at the role of ACh in learning, we will develop a conditional genetic approach which will allow us to eliminate ACh from discrete regions of the brain with spatial and temporal precision. Specifically, mice carrying a loxP modification of the gene encoding choline acetyltransferase (ChAT) will be generated by standard gene targeting techniques. Adult homozygous mice will be administered a viral vector encoding Cre recombinase. Infected neurons will functionally inactivate their ChAT genes, and thus will no longer be able to synthesize ACh. Once the parameters of the methodology are worked out, we will determine if loss of basal forebrain ACh alters either basic behavioral or cognitive functions. If successful, this system will have general applicability for re-examination of many putative functions of ACh in mammals.

大量研究致力于理解这些功能 在哺乳动物认知过程中的前脑乙酰胆碱（ACH）。 但是，许多研究的结论已被调整 警告与药理和 病变方法。 因此，ACH的特定功能保持模棱两可。 为了直接查看ACH在学习中的作用，我们将 开发有条件的遗传方法，这将使我们能够消除 来自空间和时间的大脑离散区域的ACH 精确。具体而言，携带基因LOXP修饰的小鼠 编码胆碱乙酰转移酶（CHAT）将由标准生成 基因靶向技术。 成年纯合小鼠将被施用 编码CRE重组酶的病毒载体。感染的神经元会 在功能上使他们的聊天基因失活，因此将不再是 能够合成ACH。 一旦该方法的参数是 解决了，我们将确定基础前脑ACH的损失是否改变 基本的行为或认知功能。 如果成功，这 系统将普遍适用于重新检查许多 ACH在哺乳动物中的推定功能。