SYSTEM GENETIC ANALYSIS OF MECHANISMS UNDERLYING EXCESSIVE ALCOHOL CONSUMPTION

Increased alcohol consumption over time is one of the characteristic symptoms of Alcohol Use Disorder (AUD). The molecular mechanisms underlying this escalation in intake is still the subject of study. However, the mesocortical and mesolimbic dopamine pathways, and the extended amygdala, because of their involvement in reward and reinforcement are believed to play key roles in these behavioral changes. Multiple gene expression studies have shown that alcohol affects the expression of thousands of genes in the brain. The studies discussed in this document use the systems biology technique of co-expression network analysis to attempt to find patterns within genome-wide expression data from two animal models of chronic, high-dose ethanol exposure. These analyses have identified time-dependent and brain-regions specific patterns of expression in C57Bl/6J mice after multiple exposures to intoxicating doses of ethanol and withdrawal. Specifically, they have identified the PFC and HPC as showing long-term ethanol regulation, and identified Let-7 family miRNAs as potential gene expression regulators of chronic ethanol response. Network analysis also indicates neurotransmitter release and neuroimmune response are very correlated to ethanol intake in chronically exposed mice. Examining gene expression response to chronic ethanol exposure across a variable genetic background revealed that, although gene expression response may show conserved patterns, underlying differences in gene expression influence by genetic background may be what truly underlies voluntary ethanol consumption. Finally, combined network analysis of gene expression in the prefrontal cortex (PFC) of mice and macaques following prolonged ethanol exposure demonstrated that neurotransmission, myelination, transcription, cellular respiration, and, possibly, neurovasculature are affected by chronic ethanol across species. Taken together, these studies generate several new hypothesis and areas of future research into the continued study of druggable targets for AUD