Date of Award

2017

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Neuroscience

Abstract

Binge drinking during adolescence is a common occurrence which is associated with increased risk of developing alcohol dependence and other mental health disorders. Hypothalamo-pituitary-adrenal (HPA) axis dysfunction is one characteristic commonly observed in many affective disorders, including anxiety and depression. Our laboratory has previously demonstrated that adolescent binge-pattern alcohol exposure results in long-term dysfunction of the HPA axis in a Wistar rat model, characterized by deficient glucocorticoid feedback inhibition. The current study aimed to characterize the behavioral phenotype of these rats in response to psychological stress during adulthood, and furthermore sought to understand the molecular mechanisms by which adolescent binge alcohol exposure may induce changes in HPA axis function and behavior.

To address the behavioral consequences of adolescent binge alcohol exposure, Wistar rats were exposed to our laboratory's established adolescent binge alcohol paradigm, then subject to further acute or chronic psychological stress during young adulthood. The anxiety behaviors of these rats were measured using the elevated plus maze, then tissues were collected to assess HPA axis effector levels. To address the mechanisms by which alcohol may alter HPA axis signaling, glucocorticoid receptor (GR) co-immunoprecipitation experiments were performed using brain tissue samples from adolescent binge alcohol exposed Wistar rats. Additionally, a proximity-

dependent biotinylation (BioID) screen was established to identify novel GR protein:protein interactions in a neuroblastoma-derived cell line.

The data demonstrated that adolescent binge alcohol exposure in combination with either acute or chronic adulthood stress resulted in increased anxiety-like behaviors, accompanied by HPA axis dysfunction. Adolescent binge alcohol exposure selectively altered HPA-related GR target gene expression, but not other target genes; furthermore, adolescent binge alcohol exposure did not alter GR interactions with its chaperone hsp90. Together, these data suggest alcohol specifically alters GR-mediated HPA axis regulation, but not global GR signaling. The BioID screen preliminarily identified 59 putative GR-interacting proteins, the majority of which were novel potential protein:protein interactions. Further work is needed to assess whether alcohol may affect these novel interactions. Collectively, the work presented here contributes important information regarding the effects of adolescent binge alcohol exposure at both behavioral and molecular levels.

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