QTL ANALYSIS OF FEAR-RELATED BEHAVIOR IN RODENTS

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A genetic contribution to anxiety-related disorders is not in doubt, but the nature of that contribution is still poorly understood. We propose to conduct a quantitative trait loci (QTL) study of fear- related/emotional behavior in the mouse as a first step to understanding possible genetic mechanisms in humans. An extensive test battery will be used to characterize fear-related behaviors in the mice and to identify potential confounds with general activity, photophobia, and thigmotaxis. We will use both simple univariate QTL mapping techniques and more recent multivariate mapping techniques to locate QTLs in F2 mice. These methods have been remarkably successful in mapping QTLs in plants and more recently in animal studies. The studies outlined in this proposal will use an inbred strain of mice that was derived from lines that were selectively bred for what may be fear- related behaviors. The mouse stains (developed by DeFries) were selectively bred for differences in open-field activity; two high (H1 and H2) and two low (L1 and L2) strains were developed. The H-L strains also differ in open-field defecation (L more H). F2 hybrids will be developed from L1 - H1 crosses and L2-H2 crosses. The F2 mice will be evaluated for activity in home cage and several measures of fear- related and depressive behaviors. Approximately 800 F2 animals will be scored in each cross (1600 animals total) and DNA from these same animals will be screened for polymorphisms using 84 microsatellites. The strategy of testing the replicability of the QLT method using two crosses derived from the mouse should serve as a rigorous test of the QTL methodology and could also facilitate the identification of fear- related genes in humans.