The objective of this R21 exploratory/developmental grant application is to genetically dissect anxiety in mice. Anxiety disorders comprise the majority of mental illnesses and affect more than 19 million Americans in a given year. Researchers are still trying to understand the etiology of these disorders. Although researchers have established that anxiety disorders are affected by genetic factors, the exact mechanisms remain elusive. Animal models of anxiety and the elevated plus-maze, in particular, have effectively been used to model anxiety and to test the efficacy of anxiolytic agents. Recently, the elevated zero-maze was developed as an alternative to the plus maze, and is perhaps a more sensitive test. However, in either of these tests, the exposures are usually short-term. Subsequently, little is known about the stability of anxiety-related phenotypes in animal models. Therefore, a repeated trials design may prove to be a more appropriate model of the persistent anxiety- provoking events in humans. We would like to further characterize anxiety-related behaviors over repeated zero maze trials and determine if behaviors, over repeated trials, are controlled by the same or different genetic mechanisms. Thus, the specific aims of the proposed research are to:(1) A. Determine the effects of anxiolytics on zero-maze performance. We will use different classes of anxiolytics to confirm use of the zero-maze for screening anxiety in mice. B. Characterize variations in anxiety-related behaviors in mice over repeated zero-maze trials. We will use C57BL/6 and DBA/2J mice to characterize anxiety-related behaviors over daily and weekly repeated trials. C. Characterize anxiety-related behaviors in mice over repeated zero-maze trials. We will use an early advanced intercross generation, G4, to characterize these behaviors. The parental strains are C57BL/6J and DBA/2J. (2) Identify chromosomal regions containing genes that influence anxiety-related phenotypes over repeated trials. We will genotype animals using a full genome scan to identify quantitative trait loci (QTL) influencing behaviors measured over the three zero-maze trials. The rationale for the proposed research is that understanding the genetic mechanisms involved in anxiety will aid in the treatment and prevention of anxiety-related disorders. Furthermore, understanding genetic factors that influence anxiety-related phenotypes, over repeated trials, may help in the identification of new targets for the development of therapeutic agents for the treatment of anxiety-related disorders. The results of this R21 application will create a body of data regarding the genetic mechanisms of anxiety upon which future research can be built.
