Year of Publication

2016

Degree Name

Doctor of Philosophy (PhD)

Document Type

Doctoral Dissertation

College

Pharmacy

Department

Pharmaceutical Sciences

First Advisor

Dr. Kimberly Nixon

Abstract

Alcoholism, or alcohol use disorders (AUDs), represent a major public health concern both locally and globally. 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 prolonged abstinence, but the mechanisms underlying this process are not well understood. Adult neurogenesis is thought to contribute to this recovery since after alcohol exposure a reactive increase in adult neurogenesis is observed. This reactive neurogenesis (the process by which brain insult results in a compensatory increase in neurogenesis) may represent a beneficial endogenous mechanism of brain recovery. However, the role of alcohol-induced reactive neurogenesis in hippocampal recovery is not known. We hypothesize that this reactive neurogenesis promotes the functional recovery of the hippocampus following a 4-day binge model of an AUD. To that end, the experimental studies herein were developed to decrease reactive proliferation to study its impact on hippocampal function (learning and memory). The first set of experiments attempted to decrease reactive proliferation by administering alcohol during the period of increased proliferation. Although these experiments were unsuccessful, they triggered an informative investigation into the timing of alcohol-induced reactive neurogenesis. The second set of experiments established an in-depth time course and revealed that increased proliferation occurred 5-7 days after binge alcohol exposure. With the new time course of proliferation in mind, the third set of experiments used an anti-proliferative drug that successfully decreased alcohol-induced reactive proliferation/neurogenesis but revealed no differences between groups in a hippocampal-dependent task. The fourth set of experiments revealed that granule cells born during reactive neurogenesis were capable of activation. In conclusion, the finding that reactive neurogenesis resulted in neurons capable of activation indicated that reactive neurogenesis may be involved in promoting the recovery of hippocampal function. These studies furthered our understanding of the role of alcohol-induced reactive neurogenesis in recovery from AUDs. Furthermore, these studies provided valuable insight into modulation of the NPC pool as a potential therapeutic target for the treatment of AUDs.

Digital Object Identifier (DOI)

https://doi.org/10.13023/ETD.2016.415