Regulation of Neurogenesis by Stress and Antidepressants

压力和抗抑郁药对神经发生的调节

• 批准号: 7064241
• 负责人: IRWIN LUCKI
• 金额: $ 59.59万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-10 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7064241
• 关键词: antidepressants; behavior test; behavioral /social science research tag; brain morphology; cooperative study; drug discovery /isolation; genetic models; laboratory mouse; mood disorders; neural plasticity; neurogenesis; pharmacokinetics; stressor

DESCRIPTION (provided by applicant): The purpose of this proposal is to develop and establish a National Cooperative Drug Discovery Group for the Treatment of Mood Disorders (NCDDG-MD) between investigators in the Center for Neurobiology and Behavior at the University and in the Division of Neuropharmacology at Wyeth Research Laboratory. The goal of this program is to provide a critical advance in drug discovery for mood disorders by focusing and combining the expertise of investigators from each institution on a problem of mutual interest and importance to the field. The program foundation emerges from morphological and molecular evidence that prolonged exposure to stress and depression produces neuronal atrophy and that chronic administration of antidepressant drugs to animals produce changes in neuronal proliferation and molecular markers for neurotrophic factors in the hippocampus that has only been discovered recently. These morphological effects may be key physiological elements that produce or sustain behavioral recovery during remission after chronic administration of antidepressants to patients. The focus of the NCDDG research program will be to develop this key idea as a paradigm for drug discovery in mood disorders. This will be done by establishing that the functional consequences of changes in neuroplasticity produced by chronic antidepressant drug treatment are important for the reversing the detrimental effects of stress on neural remodeling and sustaining behavioral recovery. The experimental program will examine the relationship between the morphological and behavioral consequences of multiple types of antidepressant drug treatments given to rats and mice exposed to stressors that have been demonstrated to be relevant for measuring antidepressant drug responses. Secondly, critical hypotheses concerning the functional relationship between hippocampal cell proliferation and the behavioral consequences of antidepressant drug treatments will be tested by employing novel genetic models. Finally, potentially novel classes of antidepressant drugs will be tested using the developed procedures. Because stress may contribute to the pathophysiology of mood disorders by causing neuronal atrophy and altering cell morphology, increased neurogenesis could contribute to the actions of antidepressant treatment by facilitating neural plasticity and remodeling critical for behavioral recovery from stress. The development of protocols demonstrating that reversal of the functional consequences of neuronal remodeling in animals subjected to stress leads to behavioral recovery will enable the discovery of potentially novel antidepressant drugs.

描述（由申请人提供）：本提案的目的是在大学神经生物学和行为中心和部门的研究人员之间建立一个治疗情绪障碍的国家合作药物发现小组（NCDDG-MD）惠氏研究实验室神经药理学博士。该计划的目标是通过集中和结合来自每个机构的研究人员的专业知识来解决该领域共同感兴趣和重要的问题，从而在治疗情绪障碍的药物发现方面取得重大进展。该项目的基础是形态学和分子证据，即长期暴露于压力和抑郁会导致神经元萎缩，而长期给动物服用抗抑郁药物会导致神经元增殖和海马神经营养因子分子标记的变化，而这些变化是最近才发现的。这些形态学效应可能是在患者长期服用抗抑郁药后缓解期间产生或维持行为恢复的关键生理因素。 NCDDG 研究计划的重点将是将这一关键想法发展为情绪障碍药物发现的范例。这将通过确定长期抗抑郁药物治疗产生的神经可塑性变化的功能后果对于扭转压力对神经重塑和维持行为恢复的有害影响非常重要来实现。该实验计划将检查对暴露于压力源的大鼠和小鼠进行多种类型的抗抑郁药物治疗的形态学和行为后果之间的关系，这些压力源已被证明与测量抗抑郁药物反应相关。其次，关于海马细胞增殖与抗抑郁药物治疗的行为后果之间功能关系的关键假设将通过采用新的遗传模型进行测试。最后，将使用已开发的程序测试潜在的新型抗抑郁药物。由于压力可能通过引起神经元萎缩和改变细胞形态来促进情绪障碍的病理生理学，因此增加的神经发生可能通过促进神经可塑性和重塑来促进抗抑郁治疗的作用，而神经可塑性和重塑对于从压力中恢复行为至关重要。实验方案的开发表明，在遭受压力的动物中，神经元重塑的功能性后果的逆转会导致行为恢复，这将使潜在的新型抗抑郁药物的发现成为可能。