NRSA: Chelsea Geil: Probing the Functional Relevance of Reactive Neurogenesis in Hippocampal Integrity in Alcohol Use Disorders

Alcoholism, or alcohol use disorders (AUDs), represent a major public health concern both locally and globally. Alcohol is responsible for 2.5 million deaths per year and is the third largest risk factor for disease across the world. Indeed, over 8% of Americans meet the diagnostic criteria for an AUD. Critically, excessive alcohol consumption results in neurodegeneration in brain regions such as the hippocampus which is known for its role in learning and memory. During protracted abstinence, recovery of hippocampal volume loss has been observed, but the mechanism underlying this process is not well understood. Adult neurogenesis, the process by which neural progenitor cells (NPC) proliferate, differentiate, migrate, and integrate into the granule cell layer of the hippocampal dentate gyrus, is thought to contribute to this recovery. Alcohol produces deficits in neurogenesis in the hippocampus during intoxication, however, after 7 days of abstinence a reactive increase is observed in adult neurogenesis. Reactive neurogenesis is the process by which CNS injury yields an increase in neurogenesis and is a potentially beneficial endogenous mechanism of brain recovery. At this time, the role of alcohol-induced reactive neurogenesis in hippocampal recovery is not known. Therefore, since alcohol reduces neurogenesis and adult neurogenesis produces mature granule cells, we hypothesize that the alcohol-induced reactive increase in neurogenesis promotes the functional and structural recovery of the dentate gyrus following alcohol exposure. Aim 1 will utilize confocal microscopy and fluorescent triple-label immunohistochemistry (IHC) techniques to determine if granule cells born during reactive neurogenesis are functionally normal. Following training on the hippocampal-dependent Morris water maze task, activation of granule cells born during alcohol-induced reactive neurogenesis will be assessed. Aim 2 examines the structural and behavioral effects of inhibiting alcohol-induced reactive neurogenesis. First we will determine the optimal dose of the antimitotic Temozolomide needed to attenuate alcohol-induced reactive neurogenesis in the dentate gyrus. Next, the granule cells will be quantified to determine the ability of reactive neurogenesis to promote structural recovery following alcohol exposure. Finally, the functional implications of inhibiting reactive neurogenesis will be examined by investigating changes in Morris water maze performance. The proposed studies are critical in evaluating the role of alcohol-induced reactive neurogenesis in recovery from an AUD. Furthermore, these studies may provide valuable insight into modulation of the NPC pool as a potential therapeutic target for the treatments of AUDs.