Alcohol use disorders remain as one of the nation's major public health problems with over 17 million Americans meeting the diagnostic criteria for alcohol abuse or dependence. Chronic alcoholics demonstrate cognitive impairments that are related to a loss of brain mass or neurodegeneration, effects 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) parallels the changes in brain mass and cognition during active alcoholism (decrease) versus abstinence (increase) in the hippocampus. The regulation of NSCs relies on the milieu of the local environment, or neurogenic niche. Microglial, one of three types of glia, contribute to this niche. Though microglial events historically were synonymous with cytotoxicity, a new role in neurogenesis is emerging. Some activated microglia secrete growth factors and anti-inflammatory cytokines, an effect that is consistent with recent data that certain types of microglia promote NSC proliferation and adult neurogenesis. Thus, when we observed a microglial response that precedes the neurogenic response in our model of chronic alcoholism, we suspected a causal link between microglial events and the promotion of neurogenesis. 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 and neurogenesis 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 can we modulate this phenotype to alter neurogenesis in a model of chronic alcoholism. Multiple approaches will be used, namely immunohistochemistry to assess the recruitment and proliferative dynamics of NSCs, the morphology of microglia, as well as in situ hybridization, receptor autoradiography and Enzyme-Linked ImmunoSorbant Assays to determine microglia phenotype and cytokine expression. And finally, neuroanatomical and behavioral work will confirm the role of microglia phenotype in neurodegneration and regeneration following binge alcohol exposure. Relevance to public health: This proposal will uncover a mechanism of brain regrowth in abstinence from alcohol by investigating the role of activated microglia on neural stem cells and the neurogenic environment. The results will lead to a novel approach in our long term goal of treating brain damage associated with chronic alcoholism: Identifying agents or behaviors that promote protective actions of microglia in recruiting NSCs to repair sites of damage with the hope of reversing or preventing cognitive deficits associated with alcoholic neurodegeneration.
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