Studies in both humans and animal models show that acute behavioral responses to ethanol have predictive value regarding risk for long term ethanol drinking behavior. In rodent models, locomotor activation and anxiolytic-like activity are two widely documented acute behavioral responses to ethanol. Stress, anxiety and effects of ethanol or ethanol-withdrawal on anxiety have been proposed as important factors in the genesis of alcoholism and recidivism. Recent results in our laboratory have identified significant quantitative trait loci (QTLs) for acute ethanol anxiolytic-like activity using the light-dark box transition model of anxiety across 33 BXD recombinant inbred mouse strains. Simultaneously, we have generated microarray datasets from the same saline or acute ethanol-treated BXD lines, for prefrontal cortex and nucleus accumbens. Recent studies suggest that combining QTL analysis of gene expression and behavioral can improve identification of candidate genes for behavioral QTLs. Such "expression genetics" has the power to identify networks of highly correlated gene expression patterns. Correlating genetic expression networks with behavioral QTLs could provide evidence for the functional relevance of such expression networks and candidate mechanisms underlying complex traits. This developmental project will furthermore use the power of the overall experimental design of the VCU-ARC to prioritize gene expression networks linked to acute ethanol behavioral responses in mice. We will: 1) Complete microarray studies for ventral tegmental area across 33 BXD Rl lines +/- ethanol (1.8 g/kg x 4 hours);2) Identify gene expression networks correlated with behavioral measures of acute ethanol effects on locomotor activity and anxiety-like behavior;and 3) Through potential cross-species comparison (Projects 2, 3 and Pilot 1) and bioinformatics prioritization (Core 2) of PCR-verified expression changes, we will select a limited number of candidates for direct verification studies in mice. The latter will use behavioral testing of existing null mutation mouse lines or animals treated with viral-vector gene delivery. We expect this to provide a novel validation of gene networks correlated with the acute behavioral responses to ethanol. Furthermore, our mouse gene targeting and behavioral assays will provide resources for studies in Projects 2,3 and Pilot 1 of this Center. Together we expect a novel synergy of these cross-species studies on gene networks responding to acute ethanol.
Studying the mechanisms underlying acute behavioral responses to ethanol could result in novel new therapies for alcoholism. This project will identify novel genetic targets of acute ethanol action and prioritize these results with studies in other species together with other projects of this Center.
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