The proposed training award is designed to prepare the applicant for an independent research career studying the underlying neurobiology of depression and the antidepressant response. The training plan provides in-depth training in the transcriptional analysis of both micro-dissected brain regions and single-cells to investigate the molecular mechanisms underlying the antidepressant response. Trainning in transcriptional analysis and bioinformatics will be provided by collaborators at the Columbia Genome Center (CGC). Specific training in single-cell transcriptional analysis will occur in the laboratory of the co-sponsor, Dr. Dulac, at Harvard University. The applicant will also receive training in immunohistochemistry and transgenic technology in the laboratory of the sponsor, Dr. Hen. All individuals providing training are experts in their fields and have agreed to participate in the training program. The trainee will attend courses to prepare her to learn these techniques. The training environment at Columbia University is ideally suited to the goals of the training program, and fosters interactions among neurobiologists, geneticists, and statisticians to solve complex biological problems. The applicant has already generated mouse models of the behavioral response to chronic antidepressant treatment. The research plan proposes to use these models to examine the mechanisms underlying the antidepressant response. Using mice which inducibly express serotonin 1A (5-HT1A) receptors postsynaptically, but not presynaptically, the trainee will assess the role of pre vs. postsynaptic 5-HT1A receptors in the behavioral response to chronic fluoxetine. The role of these receptors on downstream targets of antidepressant treatment, including increases in brain-derived neurotrophic factor (BDNF) mRNA (exons 1-5), and neurogenesis, will also be assessed. Finally, using transcriptional analysis, the trainee will attempt to identify completely novel genes involved in the antidepressant response. Identifying such genes will greatly aid the applicant in beginning an independent research career studying the underlying neurobiology of depression and the antidepressant response. Thus, the proposed training program will prepare the candidate to successfully head a laboratory using molecular biology, behavior, and bioinformatics to elucidate the molecular mechanisms underlying mood regulation.
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