Mechanism of Increased Anxiety in 5-HT1AR Knockout Mice

DESCRIPTION (provided by applicant): This award is designed to establish the candidate as a competitive researcher with expertise in both the behavioral as well as molecular analysis of anxiety-like behavior in mice. Following a three year period of postdoctoral research training in the analysis of anxiety-like behavior in mice, the candidate is seeking further training in the construction and molecular analysis of transgenic and knockout mice. Educational Plan: Specifically, the award will facilitate the acquisition of (1) knockout and transgenic technology for the tissue-specific and conditional expression of genes in mice, (2) gene expression profiling, or "genomics," techniques, (3) histochemical methods needed to identify and quantitate molecular and morphological changes in mice, (4) general knowledge in developmental neurobiology and anatomy via coursework, and (5) experience in effective laboratory mentoring and the responsible conduct of research. The first, second, and fifth areas of training will be provided by Dr. Rene Hen, while the third will be overseen by Dr. Bruce McEwen, both well known leaders in their fields. Research Plan: Anxiety disorders affect more than 12 percent of the population during their lifetime. Knockout mice lacking the serotonin 1A receptor (5-HT1AR knockout) show increased anxiety-like behavior and represent a valuable genetic model of anxiety disorders. We present preliminary evidence showing that, contrary to the commonly held notion in the field, the 5-HT1AR is not required in the adult for normal anxiety-like behavior, and that, instead, it is likely to play a critical role during development. The first part of the proposed research will use tissue-specific and conditional transgenic animals to define the critical tissue and time period for 5-HTIA receptor function. The second part proposes to isolate and characterize critical genes involved in the anxiety-like behavior modulation by this receptor. Part of this approach will rely on an unbiased search for genes downstream of the 5-HT 1AR using gene expression profiling techniques. The identification of critical molecules in this circuit will be important for two reasons. First, they will offer new targets for developing more effective and specific anxiolytic drugs, and second, mutations in these genes may be important factors in the inheritance of vulnerability to anxiety.