Although hereditary links to abusive and dependent alcohol use have been hypothesized since before the Modern Genetic Era, attempts to identify therapeutic targets have had limited success. This fact reflects the complex genetic architecture underlying alcohol use disorders. Due to the advent of genome-wide expression platforms such as microarrays and RNA-seq technologies, systems genetics has emerged as a new route of study in alcohol research. Systems genetics uses network analysis, and modeling techniques to draw links between the gene expression response to alcohol exposure, and alcohol related behaviors. Animal models seek to reflect behavioral patterns seen in humans such as excessive drinking and repeated binge/withdrawal cycles. This project will use Weight Gene Co-expression Network Analysis (WGCNA), a scale-free based model that builds expression networks based on distance measures of correlated expression, to investigate gene expression patterns in the brain underlying excessive drinking. This will be done with two animal models of chronic alcohol exposure. Expression quantitative trait loci mapping, and functional bioinformatics will serve as complimentary analyses to WGCNA in order to best identify a candidate gene that influences alcohol drinking. This objective will be accomplished though the following specific aims: 1) Identify expression networks associated with chronic intermittent ethanol exposure, and increased drinking using the BXD recombinant inbred mouse panel;2) Perform an in-depth genomic analysis across multiple brain regions of C57BL/6J mice after chronic intermittent ethanol exposure by vapor chamber;3) Refine ethanol responsive gene networks identified in the mouse by comparing them to ethanol responsive gene networks in the pre- frontal cortex of rhesus macaques (Macaca mulatta) under the schedule induced polydipsia paradigm;4) Target a candidate gene identified from ethanol responsive networks with adeno-associated viral vectors to determine the effect of altered gene expression on ethanol related behaviors.
Alcohol use disorders include physical or mental dependence on alcohol, and the overuse of alcohol in spite of negative physical or social consequences. Treatment options for alcohol use disorders rely mostly on behavior modification techniques that have high relapse rates. Expanding our understanding of the molecular mechanisms underlying excessive alcohol use through continued study of genome-wide alcohol response may provide new therapeutic targets for the treatment of alcohol use disorders.
|Smith, Maren L; Lopez, Marcelo F; Archer, Kellie J et al. (2016) Time-Course Analysis of Brain Regional Expression Network Responses to Chronic Intermittent Ethanol and Withdrawal: Implications for Mechanisms Underlying Excessive Ethanol Consumption. PLoS One 11:e0146257|