Molecular pathways in alcohol consumption and dependence : emphasis on gut-brain and neuroimmune signaling




Grantham, Emily Kathleen

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Alcohol use disorder (AUD) is a chronic, relapsing brain disease with few effective treatment options. Chronic alcohol abuse leads to cellular and molecular changes throughout the brain and body. These molecular adaptations, such as gene expression changes, drive the pathophysiology of AUD. Therefore, it is critical to profile and understand gene expression changes underlying the various components of AUD, such as voluntary alcohol consumption, alcohol dependence, and stress-induced alcohol consumption. Microarray and transcriptome studies have revealed neuroimmune signaling as a consistent and significant molecular pathway involved in the regulation of alcohol consumption and dependence, though the mechanisms for how this pathway modulates behavior are unclear. In addition, given the limited availability of FDA-approved therapies for AUD, novel approaches to targeting the brain are necessary. One promising approach for therapeutic development involves targeting anti-inflammatory signaling via the gut-brain axis. In the first part of this dissertation, I describe transcriptome changes caused by chronic alcohol exposure and stress in critical stress- and addiction-related brain regions, the nucleus of the solitary tract (NTS) and bed nucleus of the stria terminalis (BNST). Results from these experiments identify neuroimmune signaling, specifically type I interferon signaling, as an important dependence-related signaling pathway across the brain. Next, I show that pharmacologically manipulating type I interferon signaling affects addiction-related behaviors depending on the timing of drug administration. Finally, I take advantage of the neural connection between gut and brain to develop a novel drug delivery system that targets neuroimmune signaling and has the potential to reduce alcohol consumption. Altogether, this work provides new information about molecular drivers of alcohol dependence and consumption and lays a foundation for novel therapeutic development in the future.



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