This project involves the genetic dissection of a mouse model of fearful behavior. Human studies of the inheritance for psychiatric disorders and genes that modulate or influence behavior have been hindered by complicated, multi-gene inheritance, phenocopies, diagnostic uncertainties in classification, and the limitations of breeding in humans. An alternative approach is to study a mouse model of complex behavior(s) involving multiple genes. The goal of this study is to localize, define, and characterize genes that modulate or influence """"""""responses to novelty""""""""behavior in mice. Specifically, we will study the genetics of mice in twowell-defined mouse behavioral assays, open field behavior and light-dark transition. Both tests place animals in novel circumstances (bright light and an environment other than their home cage) and measure their exploratory activity. The strategy is to study the segregation of genes and their correlation with behavior in a large breeding experiment, inter-crossing two parental strains A/J mice (low for exploration) with C57BL/6 mice (high for exploration) and examining the F2 generation (i.e., the grandchildren). We have completed the initial whole genome search (114 markers, namely a spacing of roughly 13 centimorgans), genotyping a panel of 96 individual mice, consisting of the 5% extremes (high & low) on the Open Field traits of """"""""total distance ambulated """""""" and the number of """"""""rearings"""""""". To date, by """"""""model-free"""""""" statistical analysis, we have identified two quantitative trait loci (QTL) for open field total ambulation and three QTL for vertical movements. Two of these QTLs influence both total distance ambulated and the number of vertical movements. The largest """"""""major effect"""""""" loci contributes only 6-8.8% of the entire population's phenotypic variance. By examining mouse lines selectively bred for a difference in open field total ambulation, further support for both QTL was obtained. We anticipate that these multiple QTL, representing """"""""major effect"""""""" loci with gene(s) influencing a complex behavior, will ultimately provide reasonable """"""""candidate loci"""""""" for human psychiatric conditions.
