Substantial evidence has accumulated to indicate that chronic ethanol treatment (CET) results in a complex sequence of events in the hippocampus including cell loss, specific deafferentation, and morphological and physiological evidence of compensatory synaptic reorganization in surviving neurons. In addition, the time-course of development and recovery and the specific characteristics of altered synaptic innervation and function vary depending on the specific hippocampal subfield examined. The proposed research will focus on the use of the rat hippocampus as a model system to investigate the dynamic characteristics, selectivity and potential mechanisms of the effect of CET on neuronal structure, connectivity and function. The objectives of the proposed research are divided into three interdependent categories of inquiry: 1) Studies assessing the effect of CET on the morphology and function of specific afferent synaptic connections within the hippocampus. Parallel anatomical and physiological studies will assess the effects of CET on the morphology and function of several intrinsic hippocampal afferents. Quantitative analysis of autoradiographic and histochemical material will be used to evaluate the effect of CET on the spatial extent and density of afferent terminal fields. Physiological studies in the in vitro hippocampal slice will evaluate the effect of CET on synaptic potency, afferent distribution, transmitter release and long-term potentiation in specific afferent pathways. 2) Studies investigating potential mechanisms of the neuronal loss in hippocampus associated with CET. We will test the hypothesis that adrenal glucocorticoids and CET interact to produce selective loss of glucocorticoid-concentrating hippocampal neurons using both glucocorticoid receptor binding and autoradiographic techniques. We will also test the hypothesis that the loss of dentate gyrus granule cells during CET results from a suppressed generation of new cells rather than solely to cell death. 3) Studies investigating the time-course of development and recovery from CET-induced alterations in dendritic structure and synaptic function in the hippocampus. We will use quantitative Golgi analysis to determine the time-course of development of dendritic alterations in the hippocampus after CET. We will then examine the time-course of structural and functional recovery in these cells by examining dendritic structure and synaptic function after varying periods of abstinence following a fixed duration of CET.
