This proposal will prepare the candidate for an independent career in neuroscience research and includes both a training and research plan. The training plan combines formal mentorship, didactics, seminars and meetings designed to provide: 1) expertise in the breeding, maintenance and behavioral characterization of mice that have been subjected to X-irradiation, pharmacologic manipulation and genetic modification; 2) a fund of knowledge in relevant neurobiological issues that will enhance the candidate's ability to think creatively about animal models of psychiatric illness; 3) exposure to issues in the responsible conduct of science; and 4) experience in effective laboratory management and mentoring. In pursuit of these goals the candidate will benefit from the extensive educational and research resources available at the Columbia Center for Neurobiology and Behavior and at the New York State Psychiatric Institute. The research plan involves a comprehensive evaluation of the requirement for newborn hippocampal dentate granule neurons in a variety of behavioral paradigms in mice. Previous studies have shown that disrupting hippocampal neurogenesis in the dentate gyrus results in animals' inability to respond to behavioral paradigms sensitive to chronic antidepressants and in deficits in spatial learning tasks. Separate lines of investigation reveal a functional dissociation across the dorsal-ventral axis of the hippocampus, with the ventral hippocampus modulating behavior in anxiety paradigms, and the dorsal hippocampus modulating performance on spatial learning tasks. The research plan proposed here aims to specifically test the hypothesis that neurogenesis in the ventral dentate gyrus, but not the dorsal dentate gyrus, is required for the behavioral response to antidepressants. A secondary hypothesis is that other paradigms sensitive to disruption of neurogenesis will also show differential dependence on dorsal or ventral areas. Completing these plans will further define the functional role of newborn neurons in the hippocampus, including a role in the response to antidepressants. By demonstrating regional specificity, these results will also provide clues to other components of the neural circuitry involved in the response to antidepressants. This could lead to novel targets for the pharmacotherapy of depression and anxiety. At completion of this project, the candidate will have the knowledge and experience to independently develop and characterize mouse models of psychiatric disease. ? ? ?
