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和惠氏研究实验室神经药理学部门的研究人员之间发展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集中和结合来自每个机构的研究人员的专业知识，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。该计划的基础来自形态学和分子证据，这些证据表明，长期暴露于压力和抑郁会导致神经元萎缩，而动物长期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，这是最近才发现的。这些形态效应可能是产生或维持患者慢性抗抑郁药缓解期行为恢复的关键生理因素。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逆转压力对神经重塑的有害影响和维持行为恢复很重要来实现。实验项目将检验多种抗抑郁药物治疗对暴露于压力源的大鼠和小鼠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有关。其次，关于海马细胞增殖与抗抑郁药物治疗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验证。最后，潜在的新型抗抑郁药物将使用开发的程序进行测试。由于压力可能通过引起神经元萎缩和改变细胞形态而促进情绪障碍的病理生理，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。研究方案的发展表明，应激动物神经元重塑的功能结果逆转会导致行为恢复，这将有助于发现潜在的新型抗抑郁药物。

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.