Mechanism of the antidepressant response in 5-HT1AR mice

描述(由申请者提供)：拟议的培训奖项旨在为申请者的独立研究生涯做准备，研究抑郁症的潜在神经生物学和抗抑郁药物反应。该培训计划提供了对显微解剖的脑区和单细胞的转录分析的深入培训，以研究抗抑郁反应的分子机制。哥伦比亚基因组中心(CGC)的合作者将提供转录分析和生物信息学方面的培训。单细胞转录分析方面的具体培训将在共同发起人杜拉克博士在哈佛大学的实验室进行。申请人还将在赞助商Hen博士的实验室接受免疫组织化学和转基因技术方面的培训。所有提供培训的人都是各自领域的专家，并同意参加培训计划。实习生将参加课程，为学习这些技术做准备。哥伦比亚大学的培训环境非常适合培训计划的目标，并促进神经生物学家、遗传学家和统计学家之间的互动，以解决复杂的生物学问题。申请人已经建立了对慢性抗抑郁药物治疗的行为反应的小鼠模型。该研究计划建议使用这些模型来检查抗抑郁剂反应的潜在机制。利用突触后但不在突触前诱导表达5-HT1A受体的小鼠，受训者将评估突触前和突触后5-HT1A受体在慢性氟西汀行为反应中的作用。这些受体在抗抑郁药物治疗的下游靶点上的作用也将被评估，包括脑源性神经营养因子(BDNF)mRNA(外显子1-5)的增加，以及神经发生。最后，利用转录分析，受训者将尝试识别与抗抑郁反应有关的全新基因。识别这些基因将极大地帮助申请者开始独立的研究生涯，研究抑郁症的潜在神经生物学和抗抑郁药物反应。因此，拟议的培训计划将为候选人成功领导一个实验室做好准备，该实验室使用分子生物学、行为学和生物信息学来阐明情绪调节的分子机制。

DESCRIPTION (provided by applicant): 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.