Ethanol Consumption and Muscarinic Tone in Medial Septum

描述（由申请人提供）：乙醇对中枢神经系统的众多靶点产生广泛的影响。在本研究中，需要验证的中心假设是，慢性乙醇消耗导致特定行为任务（即空间学习）习得能力下降，并且这种下降与布氏斜带（MS/nDB）内侧隔/核神经元的功能重组有关，这反映在沿海马隔（S-H）系统的胆碱能和gaba能信号传导效率下降。目的是阐明慢性酒精摄入后S-H系统的功能、结构和分子变化，并评估这些变化是否可以解释作为一种定义的认知表现的空间学习缺陷。一个必然的目标是确定长期戒酒是否可以逆转空间学习缺陷，如果是的话，确定这种行为逆转的功能、结构和分子基础。

DESCRIPTION (provided by applicant): Ethanol exerts wide-ranging effects on a multitude of targets in the central nervous system. In this proposal, the central hypothesis to be tested is that chronic ethanol consumption results in a decrement in the acquisition of a specific behavioral task, namely, spatial learning, and that this decrement is correlated with functional reorganization involving neurons in the medial septum/nucleus of the diagonal Band of Brocha (MS/nDB), as reflected in decreased efficacy of cholinergic and GABAergic signaling along the septohippocampal (S-H) system. The goal is to elucidate the functional, structural, and molecular changes in the S-H system following chronic ethanol consumption, and to assess whether such changes may account for the resultant deficits in spatial learning as a defined cognitive manifestation. A corollary goal is to determine whether abstinence from chronic ethanol consumption can reverse the spatial learning deficit and, if so identify the functional, structural and molecular substrates for such a behavioral reversal. We focus on the in the MS/nDB for the following reasons. First, the S-H system has been implicated in mnemonic functions. Second, the MS/nDB cholinergic and GABAergic neurons, their hippocampal projections via the S-H pathway, and their target neurons within the hippocampus, comprise the major components of the S-H pathway. Third, chronic treatment of rodents with ethanol depletes cholinergic S-H fibers and disrupts cholinergic function in the septum and hippocampus. Fourth, chronic treatment with ethanol results in a decline of learning and memory, as tested in humans and rodents by a variety of behavioral paradigms, notably, spatial learning. Fifth, cholinergic activity within the MS/nDB sustains a muscarinic tone which reflects activity along the S-H pathway and which can be used as a physiological index for assessing functional plasticity within the S-H system as a consequence of chronic ethanol consumption. Employing a combination of behavioral, electrophysiological, immunohistochemical and molecular assays, three specific aims are proposed to investigate the consequence of chronic ethanol consumption on (1) spatial learning, (2) muscarinic tone and (3) the disposition of cholinergic and GABAergic neurons in the MS/nDB. Overall, this work will contribute to a better understanding of the cellular and subcellular substrates underlying the etiology of chronic alcoholism as it relates to compromised learning and cognitive capacities, as well as of its reversal following abstinence from ethanol consumption.