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, is the third largest risk factor for disease across the world, and 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. Recovery of hippocampal volume loss has been observed after protracted abstinence, 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 intoxication produces deficits in neurogenesis in the hippocampus, however, after 7 days of abstinence a reactive increase in adult neurogenesis is observed. 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 increase in reactive 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 this phase of reactive neurogenesis are functionally normal. Following training on the hippocampal-dependent Morris water maze task, functional incorporation will be assessed via activation of granule cells born during alcohol-induced reactive neurogenesis.
Aim 2 will examine the structural and behavioral effects of inhibiting alcohol-induced reactive neurogenesis to probe its significance in the recovery process. First we will determine the optimal dose of the antimitotic Temozolomide needed to attenuate alcohol-induced reactive neurogenesis in the dentate gyrus. Next, the alcohol-induced reduction in granule cells will be quantified to determine if reactive neurogenesis serves to promote the structural recovery of the dentate gyrus 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 AUDs. Furthermore, these studies will provide valuable insight into modulation of the NPC pool as a potential therapeutic target for the treatment of AUDs.

Public Health Relevance

In the United States roughly 8.5% of the US population suffers from alcoholism and unfortunately treatment options, although effective for some, are severely limited in scope. This project will determine if brain stem cells, already present in mammals of all ages, are responsible for helping the brain recover from alcoholism. These brain stem cells represent a novel target for the treatment of alcoholism, specifically for the treatment of brain damage associated with alcoholism.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Predoctoral Individual National Research Service Award (F31)
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Biomedical Research Review Subcommittee (AA)
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Regunathan, Soundar
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University of Kentucky
Schools of Pharmacy
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Nickell, Chelsea R Geil; Peng, Hui; Hayes, Dayna M et al. (2017) Type 2 Neural Progenitor Cell Activation Drives Reactive Neurogenesis after Binge-Like Alcohol Exposure in Adolescent Male Rats. Front Psychiatry 8:283
Peng, Hui; Geil Nickell, Chelsea R; Chen, Kevin Y et al. (2017) Increased expression of M1 and M2 phenotypic markers in isolated microglia after four-day binge alcohol exposure in male rats. Alcohol 62:29-40
Marshall, Simon Alex; Geil, Chelsea Rhea; Nixon, Kimberly (2016) Prior Binge Ethanol Exposure Potentiates the Microglial Response in a Model of Alcohol-Induced Neurodegeneration. Brain Sci 6: