Brain Gene Networks Modulating Acute Ethanol Responses and Consumption in Mice.

Michael F. Miles

Our prior genomic studies on acute ethanol-responsive genes in mouse genetic models ("genetical genomics") identified ethanol-responsive gene expression networks during the current P20-supported version of the VCU ARC. Several genes thus identified have been shown to alter ethanol behaviors in mouse or invertebrate models or to show association with AUD in human association studies (see Overview). Here we propose that gene networks derived from expression genetic analysis in a model of progressive ethanol consumption will have greater predictive validity in terms of identify networks affecting AUD. We will perform a genetical genomic analysis of a model of intermittent oral ethanol intake and integrate derived networks with data from both human genetics and model organism components of this Center. Our central hypothesis: A combined behavioral and expression genetics analysis of a model for intermittent, progressive ethanol consumption will identify gene networks containing key modulators of AUD. Cross-species analysis with human and invertebrate models within VCU-ARC will focus attention on major conserved network components as possible novel targets for future mechanistic studies or development of therapeutics for AUD. Aim 1 of the project will perform exon microarray profiling across 50 BXD recombinant inbred mouse strains during intermittent or continuous 2-bottle choice ethanol consumption. Scale-free network analysis will identify candidate networks associated with behavioral phenotypes. Genetic analysis will identify behavioral and expression quantitative trait loci. Aim 2 will integrate this data with networks derived from acute ethanol exposure in BXD mice, primate ethanol consumption expression data (collaboration with INIA-Stress) and genetic data from Projects 2-5. Aim 3 will utilize Core 3 (rodent behavioral core) to use gene targeting approaches for validating candidate genes in a battery of rodent ethanol behavioral assays. Finally, Aim 4 will collaborate directly with Projects 2-5 to validate networks derived in this project for their role in acute ethanol behaviors and AUD.