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.