Hippocampal Neurogenesis: Mechanisms of Antidepressant Action

描述（由申请人提供）：该提案将为候选人在神经科学研究中的独立职业生涯做好准备，并包括培训和研究计划。该培训计划结合了正式的指导，教学，研讨会和会议，旨在提供：1）在繁殖，维护和行为表征的小鼠已经受到X射线照射，药理学操作和遗传修饰的专业知识; 2）在相关的神经生物学问题的知识基金，这将提高候选人的能力，创造性地思考精神疾病的动物模型; 3）接触负责任的科学行为问题; 4）有效的实验室管理和指导经验。在追求这些目标的过程中，候选人将受益于哥伦比亚神经生物学和行为中心以及纽约州立精神病学研究所提供的广泛的教育和研究资源。该研究计划包括对小鼠各种行为模式中新生海马齿状颗粒神经元的需求进行全面评估。先前的研究表明，破坏齿状回中的海马神经发生导致动物无法对对慢性抗抑郁药敏感的行为范式做出反应，并导致空间学习任务的缺陷。单独的调查显示，在海马体的背腹轴的功能分离，与腹侧海马调制行为的焦虑范式，和背侧海马调制性能的空间学习任务。这里提出的研究计划旨在专门测试这一假设，即腹侧齿状回而不是背侧齿状回的神经发生是对抗抑郁药的行为反应所必需的。一个次要的假设是，其他范式敏感的神经发生中断也将显示差异依赖于背侧或腹侧地区。完成这些计划将进一步确定海马体中新生神经元的功能作用，包括对抗抑郁药的反应中的作用。通过证明区域特异性，这些结果也将为参与抗抑郁药反应的神经回路的其他组成部分提供线索。这可能会导致抑郁症和焦虑症的药物治疗的新目标。在这个项目完成后，候选人将有知识和经验，独立开发和表征精神疾病的小鼠模型。

DESCRIPTION (provided by applicant): 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.