Regulation of Neurogenesis by Stress and Antidepressants

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以及惠氏研究实验室神经药理学部门的研究者之间开发和建立一个治疗情绪障碍的国家合作药物发现小组（NCDDG-MD）。该计划的目标是通过将每个机构的研究人员的专业知识集中和结合在共同感兴趣和对该领域重要的问题上，为情绪障碍的药物发现提供关键的进展。该计划的基础出现从形态学和分子证据表明，长期暴露于压力和抑郁症产生神经元萎缩，慢性给药的抗抑郁药物的动物产生的变化，神经元增殖和神经营养因子的分子标记物在海马体中，最近才被发现。这些形态学的影响可能是关键的生理因素，产生或维持行为恢复缓解期后，长期服用抗抑郁药的患者。NCDDG研究计划的重点将是发展这一关键思想，作为情绪障碍药物发现的范例。这将通过确定慢性抗抑郁药物治疗产生的神经可塑性变化的功能后果对于逆转应激对神经重塑的有害影响和维持行为恢复是重要的来完成。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，关键假设海马细胞增殖和抗抑郁药物治疗的行为后果之间的功能关系将采用新的遗传模型进行测试。最后，潜在的新型抗抑郁药物将使用开发的程序进行测试。由于应激可能通过引起神经元萎缩和改变细胞形态而导致心境障碍的病理生理学，因此增加的神经发生可能通过促进神经可塑性和重塑而有助于抗抑郁药治疗的作用，神经可塑性和重塑对于从应激中恢复行为至关重要。开发实验方案证明，在受到压力的动物中，神经元重塑的功能性后果的逆转导致行为恢复，这将使潜在的新型抗抑郁药物的发现成为可能。

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.