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中的多种靶点产生广泛影响。在该提议中，待检验的中心假设是，慢性乙醇消耗导致特定行为任务（即空间学习）的获得减少，并且该减少与涉及内侧隔/对角Brocha带核（MS/nDB）中的神经元的功能重组相关，这反映在沿着隔海马（S-H）系统的胆碱能和GABA能信号传导的效力降低。我们的目标是阐明慢性乙醇消耗后S-H系统的功能，结构和分子变化，并评估这些变化是否可能导致空间学习作为一种定义的认知表现的缺陷。一个必然的目标是，以确定是否从慢性酒精消费的禁欲可以扭转空间学习缺陷，如果是这样，确定这样的行为逆转的功能，结构和分子底物。 我们将重点放在MS/nDB中，原因如下。首先，S-H系统与记忆功能有关。第二，MS/nDB胆碱能和GABA能神经元、它们通过S-H通路的海马投射以及它们在海马内的靶神经元构成了S-H通路的主要组分。第三，用乙醇对啮齿动物进行慢性治疗会耗尽胆碱能S-H纤维，并破坏隔和海马中的胆碱能功能。第四，长期使用乙醇治疗导致学习和记忆能力下降，这在人类和啮齿动物中通过各种行为范式进行了测试，特别是空间学习。第五，MS/nDB内的胆碱能活性维持毒蕈碱张力，其反映沿着S-H途径的活性，并且其可用作评估作为慢性乙醇消耗的结果的S-H系统内的功能可塑性的生理指标。采用行为学、电生理学、免疫组织化学和分子检测相结合的方法，提出了三个具体的目的来研究慢性乙醇消耗对MS/nDB中（1）空间学习、（2）毒蕈碱张力和（3）胆碱能和GABA能神经元的分布的影响。总的来说，这项工作将有助于更好地了解慢性酒精中毒的病因学的细胞和亚细胞基质，因为它涉及到受损的学习和认知能力，以及它的逆转后，从酒精消费的禁欲。

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.