Neurogenesis & the Therapeutic Action of Antidepressants

神经发生

• 批准号: 6770674
• 负责人: TARIQUE DHYAN PERERA
• 金额: $ 16.66万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-08 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6770674
• 关键词: BCL2 gene /protein; Macaca; apoptosis; behavior test; bromodeoxyuridine; cell proliferation; cerebrospinal fluid; dentate gyrus; fluoxetine; hippocampus; hypothalamic pituitary adrenal axis; major depression; neurogenesis; neuropharmacology; neuropsychology; pharmacokinetics; psychological models; psychopharmacology; psychosocial separation; stereotaxic techniques

DESCRIPTION (provided by applicant): This K08 application requests support for a MCSDA focusing on the role of neurogenesis in the therapeutic mechanisms of antidepressants. Recent evidence suggests that, beyond neurotransmitter effects, antidepressant treatments impact on signaling and transduction pathways, resulting in structural and functional changes in specific brain regions. All classes of antidepressants, as well as mood stabilizers and environmental enrichment, enhance neuronal proliferation in rodent hippocampus. In contrast, social stress and drugs of abuse appear to blunt proliferation. While the functional significance of neurogenesis is unknown, this pattern of enhancement and suppression and the delayed onset of action of most antidepressants have raised the possibility that neurogenesis is a key factor in the neurobiological cascade that ameliorates depressive states. However, the evidence linking neurogenesis and antidepressant action is largely circumstantial and comes mostly from work with rodents or tree shrews. Through the study of adult Old World monkeys, who have strong neurobiological and behavioral similarities to humans, the candidate will embark on a training and research program designed explicitly to bridge this gap in knowledge. The Training Plan broadens the candidate's knowledge in specific domains: (1) basic science with a focus on immunohistology and neuroanatomy; (2) animal behavior focused on nonhuman primate models of depression and anxiety; (3) molecular-cellular theories and research on antidepressant mechanisms; (4) experimental design, biostatistics, and ethics. Implementation of the training and research components will be mentored by Dr. Harold A. Sackeim, who is joined by an eminent group of scientists serving as the candidate's preceptors and science advisors. The Research Plan concentrates on determining whether enhanced neurogenesis is necessary for antidepressant effects and is framed around the question: Does blocking neurogenesis negate the antidepressant effects of potent interventions? Addressing this issue will require the development of new skills and the conduct of carefully designed experiments over three interim steps. These steps will validate a credible model of mood disturbance that is reliably reversed by antidepressants; demonstrate that fluoxetine stimulates neurogenesis in the adult monkey, as ECS did in the applicant's pilot studies; and validate a method that specifically blocks hippocampal neurogenesis without evidence of damage in adjacent or distal mature neurons. The candidate will then combine these tools to determine if blocking neurogenesis eliminates the "therapeutic action" of fluoxetine in non-human primates. The applicant's training and commitment to clinical psychiatry, his expanding neuroscience background, the scientific and educational resources at Columbia, and the invaluable access to the nonhuman primate colony at SUNY Downstate provides a unique foundation for this proposal.

描述（由申请人提供）：该K08申请要求支持MCSDA，重点是神经发生在抗抑郁药的治疗机制中的作用。最近的证据表明，除了神经递质效应之外，抗抑郁药对信号传导和转导途径的影响，从而导致特定大脑区域的结构和功能变化。所有类别的抗抑郁药以及情绪稳定剂和环境富集都可以增强啮齿动物海马的神经元增殖。相比之下，社会压力和虐待药物似乎钝化。虽然神经发生的功能意义尚不清楚，但这种增强和抑制的模式以及大多数抗抑郁药的作用延迟发作已经提高了神经发生是神经生物学级联的关键因素，从而改善了抑郁状态。但是，与神经发生和抗抑郁作用联系起来的证据在很大程度上是间接的，主要来自与啮齿动物或树sh的工作。通过对与人类具有很强神经生物学和行为相似之处的成年旧世界猴子的研究，候选人将明确设计旨在弥合知识差距的培训和研究计划。培训计划扩大了候选人在特定领域的知识：（1）基础科学，重点是免疫组织学和神经解剖学； （2）动物行为集中在抑郁和焦虑的非人类灵长类动物模型上； （3）关于抗抑郁机制的分子细胞理论和研究； （4）实验设计，生物统计学和伦理。 Harold A. Sackeim博士将指导培训和研究组件的实施，他由一群著名的科学家组成，担任候选人的主持人和科学顾问。研究计划集中于确定抗抑郁作用是否需要增强的神经发生，并且围绕以下问题构成：阻止神经发生是否抵消了有效干预措施的抗抑郁作用？解决此问题将需要开发新技能，并在三个临时步骤中进行精心设计的实验。这些步骤将验证一种可靠的情绪干扰模型，该模型可由抗抑郁药可靠地逆转。表明氟西汀像申请人的初步研究一样刺激成年猴子的神经发生。并验证一种特异性阻断海马神经发生的方法，而没有证据表明相邻或远端成熟神经元的损伤。然后，候选人将结合这些工具，以确定阻断神经发生是否消除了非人类灵长类动物中氟西汀的“治疗作用”。申请人对临床精神病学的培训和承诺，他不断扩大的神经科学背景，哥伦比亚的科学和教育资源以及对纽约州立大学（Suny Downy）的非人类灵长类动物群体的宝贵访问为该提案提供了独特的基础。