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许多靶点产生广泛的影响。在这一提议中，需要检验的中心假设是，长期饮酒会导致对特定行为任务，即空间学习的获得减少，并且这种减少与涉及Brocha斜角带内侧隔/核(MS/NDB)神经元的功能重组有关，反映在隔海马区(S-H)系统胆碱能和GABA能信号的有效性降低。其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明确认知表现的空间学习障碍。一个必然的目标是确定长期戒酒是否可以扭转空间学习障碍，如果是的话，确定这种行为逆转的功能、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系统被认为具有助记功能。其次，MS/NDB胆碱能神经元和GABA能神经元及其通过S-H通路在海马的投射，以及它们在海马区的靶神经元，构成了S-H通路的主要组成部分。第三，长期使用乙醇治疗啮齿动物会耗尽胆碱能S-H纤维，并扰乱隔区和海马区的胆碱能功能。第四，长期使用乙醇治疗会导致学习和记忆能力下降，这在人类和啮齿动物身上得到了各种行为范式的检验，特别是空间学习。第五，MS/NDB内的胆碱能活动维持一种毒扁豆碱张力，反映了S-H通路的活动，可作为评估慢性酒精摄入导致的S-H系统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生物学相结合的方法，研究慢性酒精摄入对MS/NDB胆碱能和GABA能神经元的影响。总体而言，这项工作将有助于更好地了解慢性酒精中毒的细胞和亚细胞底物，因为它与学习和认知能力受损有关，以及戒酒后其逆转。

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.