Ethanol Alteration of the Neurogenic Niche

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Abstract. Alcohol use disorders (AUDs) remain one of the nation's major public health problems with nearly 14% of U.S. population meeting diagnostic criteria. 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. The mechanism of this recovery is not clear, however recent discoveries from our laboratory show that alcohol-induced regulation of hippocampal neural stem cells and adult neurogenesis parallel the changes in brain mass and cognition during alcohol intoxication (decrease/deficit) versus abstinence (increase/recovery). Across the last funding period, our lab has shown that prior alcohol dependence results in a striking increase in adult neurogenesis in abstinence, an effect due to the recruitment of neural stem and progenitor cells into active cycling that drives this reactive neurogenesis response. Although this response appears reparative initially, based on ethanol rats showing behavioral recovery on a hippocampal-dependent learning task, stem cell activation has long term consequences. Specifically, reactive neurogenesis via neural stem cell activation can deplete or exhaust the neural stem cell pool, ultimately resulting in decreased neurogenesis and impairments in hippocampal structure and function in the long-term. Furthermore, the mechanism of neural stem cell activation in models of AUDs is not known, but converging evidence from stem cell activation and alcohol neuroplasticity literatures coupled with our preliminary data support a role for mammalian target of rapamycin (mTOR) signaling. Thus, our overarching hypothesis is that reactive neurogenesis is initially beneficial, resulting from the recruitment of neural stem cells out of quiescence via an induction of mTOR signaling from alcohol dependence, but neural stem cell activation may come at the expense of neural stem cell depletion and an eventual detrimental impact on hippocampal structure and function. Using an interdisciplinary array of histological, biochemical, electrophysiological and behavioral approaches, we propose to examine the role of, consequences of, and mechanisms of reactive neurogenesis in a four-day binge model of an AUD through three specific aims: 1) Determine the role of reactive neurogenesis in structure, function, and recovery in abstinence after alcohol dependence, 2) Test the hypothesis that reactive neurogenesis after alcohol dependence activates neural stem cells out of quiescence to ultimately deplete / exhaust the neural stem cell pool, and 3) Define the role of mTOR signaling in neural stem cell activation and reactive neurogenesis after alcohol dependence. Our ultimate goal is to elucidate the role of adult neurogenesis in promoting structural and functional recovery in abstinence so that future studies can target this pathway pharmacologically or behaviorally as a novel therapeutic strategy in the treatment of alcoholic brain damage.