Depressive disorders are among the most common diseases with 8-16 percent of the population in the United States afflicted during their lifetime. The etiology of this illness is unknown, but stressful life events and genetic predisposition are clearly important risk factors. Family, twin and adoption studies of depressive disorders suggest a multigenic genetic transmission, making genetic studies in the heterogeneous human population quite difficult. Complex diseases have been approached genetically by using rodent models, opening up possibilities for genetic analysis of polygenic traits. No animal models, to date, have been used to study the genetic basis of depressive disorders. We believe that the inbred Wistar Kyoto (WKY) rat is an excellent model to pursue underlying genetic causes of depressive disorder, because some of their behavior and hormonal characteristics mimic symptoms of depression in humans and they are phenotypically very different from other inbred strains, including Fisher 344 (F344). The normotensive WKY rat exhibits depressive-like behavior in accepted behavioral paradigms that is normalized by chronic treatment with antidepressants. WKY rats also show stress-hyperreactivity both behaviorally and by hypersecreting stress hormones. Here, we propose to conduct a quantitative trait loci (QTL) study of depressive and stress hyperreactive behavior in the WKY rats as a first step to understanding possible genetic mechanisms in humans. We specifically aim first to construct a two-generation intercross between WKY and F344. We will analyze the behavioral and hormonal phenotypes of the parents and the F2 progeny of the WKY/F344 cross. These series of studies will characterize the relationship between depressive and stress-hyperreactive behavior in the WKY rat. Then we will map, with a QTL analysis, genetic markers whose inheritance correlate with the behavioral and hormonal phenotypes in the F2 generation. By demonstrating an association between an extreme expression of these phenotypes and marker alleles whose genetic map position is known, we will map putative loci to specific regions of individual chromosomes. Once the QTL are identified, they will need to be fine-mapped and confirmed. Loci will be introgressed, with marker-assisted selection, into separate congenic strains. This will both validate the locus phenotypically and permit its further genetic, physiological, and biochemical analysis in isolation from other segregating loci that may modify its expression. Finally, we will conduct a search for putative candidate genes in the chromosomal regions identified. Using comparative information from mouse and human genomes, we will investigate candidate genes that may be involved in the depressive and stress-hyperreactive behavior of the WKY rat. We hypothesize that the characterization of QTL and candidate genes in this animal model will facilitate the identification of depression-related genes in humans.
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