The proposed research will extend our ongoing project investigating alcohol-related processes in mice using an adaptation of the recombinant inbred (RI) strain method. RI analysis, which has previously been used to identify and map major-gene effects, has been adapted for analysis of quantitative traits and quantitative trait loci (QTL). The integrative and cumulative nature of this approach holds great promise for advancing our understanding of alcohol-related processes. Our current grant characterizes the most widely-used RI mouse series, BXD RI, on an extensive battery of alcohol-related traits and applies RI QTL analysis to these data. Multivariate RI QTL analysis has also been developed to analyze QTL sources of genetic correlations among these alcohol-related processes, as well as to BXD data reported by other investigators. The proposed research has three goals. The first goal is to confirm, extend, and generalize our RI QTL results using a series of increasingly informative procedures: F1 crosses among the RI strains will be used to attempt replication of our RI results with increased power, and to investigate dominance; F2 crosses will provide a further replication test of the RI and F1 results and extend them to genetically-segregating individuals; heterogeneous stock (HS) will test the generalization of BXD RI results to outbred mice more representative than the F2 of the mouse genome. The HS research will also set the stage for the use of QTL markers in chromosomal regions syntenic to the human genome as candidate genes in QTL analyses of human alcohol use and abuse. The second goal is to extend our ongoing characterization of alcohol-related behaviors to neuropharmacological mechanisms which have been shown either to modulate or respond to ethanol actions. Specifically, the BXD series will be characterized in relation to ethanol effects on neurotensin, corticotropin-releasing hormone and tyrosine hydroxylase. The third goal is to initiate the first selection studies based upon genotype rather than phenotype in the generation of single and multiple QTL animal models of alcohol-related processes in otherwise genetically segregating (HS) animals.
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