Neural stem cells persist in the adult hippocampal subgranular zone (SGZ) and generate dentate gyrus (DG) granule cell neurons (GCNs) ? a process known as adult hippocampal neurogenesis. Alcohol use disorders, commonly called alcoholism is a chronic, relapsing disorder, characterized by withdrawal syndromes of negative emotional symptoms that putatively promote relapse via pathological neuroadaptations in the hippocampus. Of notable interest is the discovery of ethanol (TSRI-ARC model of excessive drinking during chronic ethanol induced dependence (CEID))-induced inhibition of neurogenesis in the DG, and withdrawal from ethanol (CEID and binge alcohol)-induced ?aberrant? neurogenesis in the DG of the hippocampus. These studies suggest that the inhibitory effect of CEID on the regenerative capacity of the adult hippocampus can be considered as a precursor for alcohol-induced neurodegeneration, and that alcohol withdrawal-induced aberrant neurogenesis in the DG may be due to central nervous system hyperexcitability that is associated with alcohol withdrawal symptomatology resulting from termination of CEID. However, cellular mechanisms regulating alcohol withdrawal-induced aberrant neurogenesis in the DG have not been identified. Particularly interesting is the accumulating evidence from Component 02 (Zorrila) and others using the TSRI-ARC CEID model that altered corticotropin-releasing factor (CRF) signaling in the basolateral complex of the amygdala (BLA) and concurrent hyperglutamatergic activity (perhaps manifested as ?kindling-like? activity) in the BLA are evident in withdrawn dependent rats. Therefore we hypothesize that specific neuroadaptations in the CRF system in the BLA following ethanol withdrawal could produce a hyperglutamatergic state in the hippocampus that may regulate aberrant neurogenesis in the DG, and the resulting pathological plasticity could be facilitating the recruitment of new GCNs into emotional memory circuits and therefore contributing to the pathology underlying alcohol dependence via our specific hypotheses that inhibiting this process will alleviate dependence by preventing aberrant DG neurogenesis and withdrawal-associated behaviors. Integration within TSRI-ARC: Our component will use retroviral vectors produced by viral vector core (Contet) and will draw dependence models from animal models core (Koob &George). The proposed studies will require close communication and collaboration with other center components, most notably, Components 01(Roberto) and 03 (Zorrilla).

Public Health Relevance

Millions of Americans meet the diagnostic criteria for alcoholism, cutting across all socio-economic lines, increasing morbidity, mortality and economic costs. Psychopathology of the hippocampus has been implicated in alcohol abuse and alcoholism. In this proposal, we will begin to identify the cellular mechanisms underlying dependence-induced neuroadaptations in hippocampal plasticity and determine a putative role for aberrant hippocampal neurogenesis in negative affect symptoms associated with alcohol use disorders.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Comprehensive Center (P60)
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Scripps Research Institute
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