GENETIC APPROACH TO STUDY ACETYLCHOLINE FUNCTIONS

大量的研究致力于了解 前脑乙酰胆碱（ACh）在哺乳动物认知过程中的作用。 然而，许多研究的结论都受到了 与药理学的固有局限性有关的警告， 病变接近。 因此，ACh的具体功能仍然不明确。 为了直接观察ACh在学习中的作用，我们将 发展一种有条件的遗传学方法， ACh从离散区域的大脑与空间和时间 精度具体而言，携带基因loxP修饰的小鼠 编码胆碱乙酰转移酶（ChAT）的蛋白质将通过标准的 基因打靶技术 成年纯合子小鼠将给予 编码Cre重组酶的病毒载体。受感染的神经元 在功能上破坏了他们的ChAT基因，因此将不再是 能够合成乙酰胆碱。 一旦确定了方法的参数， 我们将确定基底前脑ACh的丢失是否会改变 基本的行为或认知功能。 如果成功，这 系统将具有普遍适用性， ACh在哺乳动物中的功能

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.