Exercise and Antidepressant Treatment in Brain Injury

脑损伤中的运动和抗抑郁治疗

• 批准号: 7017765
• 负责人: THOMAS Hugh MCNEILL
• 金额: $ 18.54万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-02-15 至 2008-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7017765
• 关键词: SDS polyacrylamide gel electrophoresis; antidepressants; biological signal transduction; brain derived neurotrophic factor; brain disorder chemotherapy; brain injury; cell growth regulation; dendrites; depression; exercise; functional ability; gene expression; growth inhibitors; hippocampus; laboratory rat; nervous system regeneration; neural plasticity; neuronal guidance; norepinephrine; silver impregnation; synaptogenesis; western blottings

DESCRIPTION (provided by applicant): The proposed studies are intended to further our understanding of the cellular events underlying neural plasticity and treatment strategies that can promote the recovery of function after brain damage. Specifically, we will determine whether exercise and the norepinephrine-selective antidepressant reboxetine, used in the treatment of post-stroke depression can enhance neurite outgrowth and synapse replacement after brain injury. The rationale for the study is based on previous reports from our laboratories and those of others that show: 1) neural plasticity plays a critical role in the recovery of function after brain injury; 2) exercise and reboxetine stimulate neurotrophin (BDNF) and intracellular signaling pathways that regulate cell survival and plasticity in the nervous system; 3) the increase in hippocampal BDNF following reboxetine treatment is enhanced and accelerated by exercise; and 4) exercise-induced increases in hippocampal BDNF expression are dependent upon noradrenergic activation. The specific hypotheses to be tested are: 1) that exercise and reboxetine act in a convergent manner to facilitate synapse replacement after brain injury by activation of intracellular signaling pathways that promote neurite outgrowth, svnaptogenesis and cell survival, and 2) a key mediator in the convergent effect of exercise and reboxetine treatment is BDNF. The experimental design integrates the research expertise on neural plasticity from Dr. McNeill's laboratory with that of Dr. Russo-Neustadt who has examined the effect of antidepressant treatment and exercise on the induction of neurotrophin (BDNF) and intracellular signaling pathways that regulate cell survival and plasticity in rat models of depression. While both labs have ample background data to support the major aspects of the project independently, we lack pilot data for the effect of reboxetine treatment and exercise on the anatomical and molecular changes that underlie neural plasticity after brain injury. We wish to use this R21 application to develop the necessary pilot data to support our overarching hypotheses and to form a solid base of preliminary data to justify the submission of a R01 application in the future. Data from these studies are fundamental for broadening our understanding of the capacity of the brain to compensate for damage, and central to the development of new treatment strategies that can translate the basic principles of neuroplasticity into effective interventions in the treatment of brain injury.

描述（由申请人提供）： 拟议的研究旨在进一步了解我们对可以促进脑损伤后功能恢复的神经可塑性和治疗策略的细胞事件的理解。具体而言，我们将确定用于治疗势后抑郁症的运动和去甲肾上腺素选择性抗抑郁剂是否可以增强脑损伤后神经突的产物和突触替代。该研究的基本原理是基于我们实验室的先前报道以及其他显示的：1）神经可塑性在脑损伤后功能的恢复中起着至关重要的作用； 2）运动和重替丁刺激神经营养蛋白（BDNF）和细胞内信号通路，这些途径调节神经系统中细胞的存活和可塑性； 3）通过运动后，重甲替丁治疗后海马BDNF的增加得到增强和加速； 4）运动引起的海马BDNF表达增加取决于去肾上腺素能激活。要测试的具体假设是：1）运动和重替丁的作用方式，以促进脑损伤后突触替换，通过激活细胞内信号传导途径，从而促进神经突生殖，svnaptogened和细胞存活，以及2）在锻炼和重生辅助治疗的关键介体效应中是bdnf的关键介体。实验设计将McNeill博士实验室神经可塑性的研究专业知识与Russo-Neustadt博士的研究专业知识融为一体，后者研究了抗抑郁药治疗和运动对诱导神经营养素（BDNF）的诱导和细胞内信号通路的诱导影响，从而调节抑郁症大鼠模型中的细胞存活和可塑性。尽管两个实验室都有足够的背景数据来独立支持该项目的主要方面，但我们缺乏试点数据，无法重新处理和运动对脑损伤后神经可塑性的解剖学和分子变化的影响。我们希望使用此R21应用程序来开发必要的试点数据来支持我们的总体假设，并构成稳固的初步数据基础，以证明将来提交R01应用程序的合理性。这些研究的数据是扩大我们对大脑能力弥补损害能力的理解的基本基础，这是开发新的治疗策略的核心，这些策略可以将神经可塑性的基本原理转化为有效的脑损伤治疗干预措施。