Date of Award


Document Type


Degree Name

Master of Science (MS)


Cellular, Molecular and Biomedical Sciences

First Advisor

James M. Stafford


Alcohol consumption and abuse has been an ongoing public health concern across the globe for many years. Over the past decade, it has become a critical epidemic in the United States. Excessive alcohol use costs more than $249 billion annually and affects 17 million people, 8% of the adult population, and is the fifth leading risk factor for premature death and disability. Alcohol use disorder (AUD) is inherently complex with a myriad of genetic and environmental contributors. Ultimately, this complexity makes AUD difficult to treat. Recent literature suggests that changes in the genetic sequence only partially accounts for the molecular profile of AUD. An emerging theme is that the overall expression of several genes is markedly different in the alcoholic brain. This regulation of gene expression, sometimes termed epigenetic regulation, plays a key role in AUD. However, the exact factors responsible for these changes are not well understood. Recent literature suggests that autism susceptibility candidate 2 (AUTS2) may be a possible regulator of phenotypes related to AUD. AUTS2 is part of a larger complex known as Polycomb Repressive Complex 1 (PRC1). Together, they play a major role in epigenetic regulation in the body. However, in the brain, aberrations in AUTS2 may cause changes in the expression of certain genes that result in behaviors that are commonly associated with AUD. Normally, the PRC1 complex works to inhibit the expression of certain genes. However, when this complex is associated with AUTS2, genes tend to be activated instead. In humans, there is a single nucleotide polymorphism (SNP) in the AUTS2 gene associated with less alcohol consumption among the general population, and these same individuals have increased expression of AUTS2. Despite its association with addiction-related diseases, the direct role of AUTS2 and PRC1 in gene expression in the brain and ultimately, in AUD-phenotypes is not known. We show here that AUTS2 impacts AUD phenotypes in brain-region specific knockdown mouse models. Using CRE recombinase driver lines to delete AUTS2 from the whole brain, prefrontal cortex (PFC), and cerebellum, we have elucidated a role for AUTS2 within the brain in the context of AUD. In whole brain knockdown models, loss of AUTS2 does not affect performance in the rotarod or loss of righting reflex (LORR) tasks following ethanol injection. These same mice drink more during intermittent access to ethanol. In PFC knockdown mice, loss of AUTS2 does not affect performance in rotarod, LORR, or intermittent access. In cerebellar knockdown mice, loss of AUTS2 does not affect performance in rotarod or LORR, but surprisingly these mice may drink less during intermittent access than their wildtype (WT) littermates. These results reveal that AUTS2 differentially effects AUD characteristics such as ataxia and ethanol consumption depending on where it is expressed in the brain. By better understanding AUTS2 and what components drive excessive AUD characteristics, we can identify key drivers of AUD that may represent novel predictors or targetable therapeutic strategies for individuals with AUD.



Number of Pages

57 p.

Available for download on Thursday, January 23, 2025