GENETIC ANALYSIS OF ANXIETY RELATED BEHAVIORS

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Anxiety is prevalent, disabling, and costly. The identification of genes that predispose individuals to anxiety should greatly improve our ability to prevent, diagnose, and treat various psychiatric disorders. The goal of my proposed work during the NRSA Fellowship is to use quantitative trait locus analysis to identify loci (and, if possible, the genes within the loci) that affect-related behaviors in particular inbred mouse strains. Two inbred mouse strains that differ greatly in anxiety-related behaviors (as measured in the elevated plus-maze [EPM] and dark-light box [DLB] assays) will be identified. First- generation hybrid (F1) animals (produced by crossbreeding the two strains) will be backcrossed to one of the parental strains to produce a population of 250 to 400 second-generation (N2) animals. Each N2 generation animal will undergo the EPM and DLB assays of anxiety. Those N2 animals that show extreme (high or low) levels of anxiety-related behaviors will undergo genotyping using microsatellite markers. Quantitative trait loci (QTLs) will be localized by finding correlations between levels of behavior and the presence of particular microsatellite markers. The expressed sequence tag database will then be searched for genes in the region of the QTLs that might be candidates for anxiety-related traits. If there are no candidate genes located within the QTLs that prove to be associated with the anxiety-related behaviors, advanced intercross lines will be produced for fine genetic mapping of the QTLs. My hope is that this work will ultimately lead to the identification of homologous human genes that predispose people to severe anxiety.