Date of Award

Spring 1-1-2013

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Integrative Physiology

First Advisor

Marissa A. Ehringer

Second Advisor

Monika R. Fleshner

Third Advisor

Matthew B. McQueen

Fourth Advisor

Robert L. Spencer

Fifth Advisor

Richard A. Radcliffe

Abstract

An estimated 5% of Americans currently have an alcohol use disorder (AUD), either abuse alcohol or are dependent, causing an incredible health and economic burden, as well as increased strain on family and friends. AUDs are approximately 50% heritable, and the purpose of these studies was to investigate aspects of genetic influence (initial sensitivity to alcohol) as well as environmental influence (exercise) on alcohol behaviors.

The Inbred Long Sleep (ILS) and Inbred Short Sleep (ISS) mouse strains are a model of genetic sensitivity to ethanol. We observed many genes differentially expressed between the two strains, including several in chromosomal regions previously shown to influence initial sensitivity to ethanol. Furthermore, utilizing Weighted Gene Co-expression Network Analysis (WGCNA) we identified several modules of co-expressed genes corresponding to strain differences. Several candidate genes were identified as well as functional categories and signaling pathways, which may play a role in the phenotypic differences between the two strains.

It has become apparent that different rewarding stimuli activate common reward pathways, with the potential to influence each other, i.e. hedonic substitution. We demonstrate that voluntary access to a running wheel substantially reduces the consumption and preference of ethanol in mice. Furthermore, we observed differential gene expression of several candidate genes involved in regulating the mesolimbic dopaminergic pathway, which we hypothesized to be the focal point of hedonic substitution. These data suggest an important role for this pathway, and especially for Bdnf and Slc18a2 in regulating hedonic substitution.

In order to identify additional candidate genes and pathways underlying hedonic substitution in the striatum, we quantitatively sequenced the striatal transcriptome of mice consuming ethanol, exercising, and doing both or neither, and identified differentially expressed genes and WGCNA co-expression modules. Interestingly, several genes and functional groups differentially expressed in response to exercise were previously identified in our study of ILS and ISS mice. This suggests that one way exercise might influence ethanol behavior is by sensitizing mice to the acute effects, thereby decreasing consumption.

In conclusion, baseline genetic differences contribute to differential sensitivity to ethanol. In addition, the environmental influence of exercise induces a transcriptional response, possibly altering the response to ethanol, and resulting in hedonic substitution.

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