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领域的独立职业生涯做好准备，包括培训和研究计划。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x射线照射、药物操作和基因改造小鼠的繁殖、维持和行为特征方面的专业知识；2)在相关神经生物学问题方面的知识基础，将增强候选人创造性思考精神疾病动物模型的能力；3)了解负责任的科学行为中的问题；4)有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精神病学研究所广泛的教育和研究资源。本研究计划综合评估小鼠在不同行为模式下对新生海马齿状颗粒神经元的需求。先前的研究表明，破坏齿状回的海马神经发生会导致动物对慢性抗抑郁药敏感的行为范式无法做出反应，并导致空间学习任务的缺陷。不同的研究揭示了海马背-腹侧轴的功能分离，其中腹侧海马调节焦虑范式中的行为，背侧海马调节空间学习任务的表现。本文提出的研究计划旨在专门验证一种假设，即抗抑郁药物的行为反应需要腹侧齿状回而不是背侧齿状回的神经发生。第二种假设是，其他对神经发生破坏敏感的范例也会表现出对背侧或腹侧区域的不同依赖。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。通过展示区域特异性，这些结果也将为抗抑郁药反应中涉及的神经回路的其他组成部分提供线索。这可能会为抑郁和焦虑的药物治疗带来新的靶点。在完成本项目后，候选人将具备独立开发和表征精神疾病小鼠模型的知识和经验。

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.