Behavior in Mouse Tryptophan Hydroxylase Mutants

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DESCRIPTION (provided by applicant): The candidate is a child and adolescent psychiatrist with experience in molecular biology and neuroscience. He holds a tenure track junior faculty appointment with 80 percent research time at the University of Michigan Medical Center. This career development award will serve to expand his skills to include the development of genetic animal models and their behavioral phenotyping. The skill base interdigitates with a commitment by the University of Michigan Mental Health Research Institute (MHRI) to apply novel molecular approaches to identify new candidate genes for major depression and undertake their anatomic, structural, and functional characterizations. It is expected that by the end of this grant, the candidate will have gained sufficient experience and generated several informative animal models for independent research and collaboration. The University of Michigan Medical Center is a thriving research community with ample resources for carrying out the proposed studies. A highly successful core facility is available for transgenic manipulation. Faculty in the MHRI bear expertise in the areas of genetic engineering, biochemistry, rodent anatomy, and animal behavior. The candidate is being supervised by a senior research scientist in the MHRI with consultative support from leaders in the field of mouse transgenics and behavior phenotyping. This project applies emerging molecular technology to expand understanding on the role of serotonin biosynthesis and neurotransmitter levels on nervous system development and behavior. The design employs neuron specific and tetracycline-inducible genetic elements to engineer transgenic mice permitting regulation of tryptophan hydroxylase (TPH) activity. TPH is the rate-limiting enzyme in serotonin biosynthesis, and is thereby critical to serotonin turnover. The recombinant animals will permit probing the effects of temporal and tissue-selective up- or down-regulation of brain serotonin on measures of anxiety, attention, learning, memory, aggression, appetite, drug preference, and other behaviors. The proposed research is central to the serotonin hypothesis of mood and anxiety disorders, and offers a model for studying the developmental effects of serotonin turnover on brain maturation. The candidate's long-term career plan is academic research integrating human clinical, genetic and animal model information for major mood disorders