Utilizing Human Induced Pluripotent Stem Cells in the Study of Alcohol Use Disorder

Alcohol use disorder is a complex, heterogeneous disorder that affects ≈14% of the U.S. population. Much of what is known about the molecular effects of alcohol on the brain has been derived from studies utilizing rodent or human post-mortem tissue model systems. The advent of induced pluripotent stem cell (iPSC) technologies allows for the examination of phenotypically- and genetically-characterized human neural cells in vitro. Much of the work presented in this dissertation explores the utility of iPSCs in the study of alcohol use disorder. We start by exploring whether human iPSC-derived neural cells can recapitulate the findings in animal models examining the molecular effects of acute and chronic alcohol exposure on ligand gated ion channel function and gene expression (chapter 2). Next, we utilize iPSCs in the study of a common single nucleotide polymorphism in the GABRA2 gene that has been linked to the development of AUD (chapter 3). Finally, we use in a large human sample to identify a novel gene x environment interaction for a polymorphism in the FKBP5 gene that moderates heavy alcohol consumption in the setting of early life trauma, and explore the molecular implications of the polymorphism in human iPSC-derived neural cultures (chapters 4 and 5). This work suggests that iPSC neural differentiation is a promising tool in the study of complex psychiatric disorders such as drug addiction