Physical Activity, Antidepressants and BDNF Induction

身体活动、抗抑郁药和 BDNF 诱导

• 批准号: 7070496
• 负责人: AMELIA A RUSSO-NEUSTADT
• 金额: $ 28.22万
• 依托单位: CALIFORNIA STATE UNIVERSITY LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-01 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7070496
• 关键词: antidepressants; biological signal transduction; brain derived neurotrophic factor; cAMP response element binding protein; combination therapy; enzyme activity; exercise; fluoxetine; gene induction /repression; hippocampus; laboratory mouse; laboratory rat; learning; mental disorder chemotherapy; messenger RNA; neural plasticity; neuroendocrine system; neurophysiology; neuropsychology; neuroregulation; nitric oxide; norepinephrine; phosphatidylinositol 3 kinase; physiologic stressor; restraint; serotonin; tissue /cell culture

DESCRIPTION (provided by applicant): An understanding of the mechanisms of treatments for depression and other chronic neurodegenerative processes is an essential goal. Chronic, recurrent depression involves hippocampal atrophy, which can result from chronic stress. Chronic antidepressant treatment restores neurotrophin (BDNF) expression. During our preliminary funding period, we demonstrated that the enhancement of hippocampai BDNF expression resulting from antidepressant treatment is enhanced and accelerated by exercise. We have found evidence, at the transcriptional level, for overlap and synergy between these two interventions, and have demonstrated, using systemic lesions, receptor blockade and neurotransmitter-selective antidepressants, that the noradrenergic system is essential for the observed BDNF changes. Considering the essential role of BDNF for neuronal maintenance and plasticity, our results suggest that exercise may enhance antidepressant treatment response, and repair neuronal degeneration brought about by stress. We now wish to test the hypothesis that exercise and antidepressant treatment converge upon intracellular signaling pathways associated with neuronal survival and plasticity in the hippocampus. Our preliminary evidence suggests that exercise activates the cell survival-enhancing phosphatidylinositol-3 kinase and nitric oxide signaling pathways, in whole animal and hippocampal cell culture models, we will assess the activation of several signaling molecules along these intracellular pathways, and specifically test their involvement in the enhancement of hippocampal BDNF expression following exercise, antidepressant treatment, and noradrenergic activation. We will also test the involvement of other specific survival-promoting pathways (such as cAMP and calcium-mediated) that can be activated by exercise or antidepressant, and where convergence of these two interventions might be demonstrated. With the currently proposed experiments, we also wish to test the hypothesis that our combined interventions will repair stress-induced impairments in hippocampal function (spatial learning deficits), as well as damage to neuronal cytoarchitecture following stress. Our experiments will yield important information about the intracellular, cooperative mechanisms of improved treatment response resulting from exercise. Knowledge about the mechanisms responsible for the enhancement of antidepressant response will inform the development of novel, more efficacious and rapid treatments.

描述（由申请人提供）：了解抑郁症和其他慢性神经退行性过程的治疗机制是一个基本目标。慢性、复发性抑郁症涉及海马萎缩，这可能是由慢性压力引起的。长期抗抑郁治疗可恢复神经营养素（BDNF）的表达。 在我们的初步资助期间，我们证明了抗抑郁治疗引起的海马 BDNF 表达的增强可以通过运动得到增强和加速。我们在转录水平上发现了这两种干预措施之间重叠和协同作用的证据，并通过使用全身性病变、受体阻断和神经递质选择性抗抑郁药证明，去甲肾上腺素能系统对于观察到的 BDNF 变化至关重要。考虑到 BDNF 对于神经元维持和可塑性的重要作用，我们的结果表明运动可以增强抗抑郁治疗反应，并修复压力引起的神经元退化。我们现在希望检验这样的假设：运动和抗抑郁治疗会集中于与海马神经元存活和可塑性相关的细胞内信号通路。我们的初步证据表明，运动会激活增强细胞存活的磷脂酰肌醇-3激酶和一氧化氮信号通路，在整个动物和海马细胞培养模型中，我们将评估这些细胞内通路上几种信号分子的激活，并专门测试它们的参与运动、抗抑郁治疗和去甲肾上腺素能激活后海马 BDNF 表达增强。我们还将测试可通过运动或抗抑郁药激活的其他特定的促进生存的途径（例如 cAMP 和钙介导的途径）的参与情况，以及可能证明这两种干预措施的融合的地方。通过目前提出的实验，我们还希望检验这样的假设：我们的联合干预措施将修复压力引起的海马功能损伤（空间学习缺陷），以及压力后神经元细胞结构的损伤。我们的实验将产生关于运动引起的改善治疗反应的细胞内协作机制的重要信息。了解增强抗抑郁反应的机制将为开发新颖、更有效和快速的治疗方法提供信息。