Ethanol Alteration of the Neurogenic Niche

Alcohol use disorders remain one of the nation's major public health problems with over 17 million Americans, or greater than 8.5% of the population, meeting the diagnostic criteria for alcohol abuse or dependence. Alcoholics demonstrate cognitive impairments that are related to a loss of brain mass or neurodegeneration in regions such as the hippocampus, an effect that may recover with abstinence. Many assumed that the mechanism of this recovery was due to glial regeneration, however recent discoveries from our laboratory show that alcohol-induced regulation of neural stem cells (NSCs) in the hippocampus parallels the changes in brain mass and cognition during active alcoholism (decrease/deficit) versus abstinence (increase/recovery). The regulation of NSCs relies on the milieu of the local cellular environment, or neurogenic niche. Microglial, one of three types of glia, contribute to this niche. Though microglial events were historically synonymous with cytotoxicity, a new role in neurogenesis is emerging. Some activated microglia secrete growth factors and antiinflammatory cytokines, an effect that is consistent with recent data that certain phenotypes of microglia promote NSC proliferation and adult neurogenesis. Thus, when we observed a microglial response that preceded a neurogenesis response in our model of an alcohol use disorder, we suspected a causal link between microglial events and promotion of neurogenesis in recovery. Therefore, this proposal will test the hypothesis that binge alcohol exposure produces a graded microglial response that drives the recruitment of quiescent NSCs into proliferation as a mechanism of recovery in abstinence. Three specific aims address this hypothesis by asking: (1) whether binge alcohol exposure recruits additional NSCs, (2) whether microglia show a graded, nonphagocytic phenotype predictive of a proneurogenic microenvironment and (3) whether we can modulate this phenotype to alter cellular and behavioral recovery in a model of an alcohol use disorder. Multiple approaches are proposed to investigate these aims: immunohistochemistry to assess microglia morphology, the expression of phagocyte markers in microglia, and the recruitment and proliferative dynamics of NSCs, followed by in situ hybridization, receptor autoradiography and Enzyme-Linked ImmunoSorbant Assays to determine microglia phenotype and cytokine expression. Finally, neuroanatomical and behavioral assays will confirm the role of microglia phenotype in cellular and behavioral recovery following binge alcohol exposure. Our overall goal for this project is to elucidate endogenous mechanisms involved in promoting NSC proliferation and neurogenesis so that future studies can target this pathway pharmacologically or behaviorally as a novel therapeutic strategy in the treatment of alcoholic brain damage.