Exercise and Antidepressant Treatment in Brain Injury

描述（由申请人提供）： 拟议的研究旨在进一步了解神经可塑性和治疗策略的细胞事件，可以促进脑损伤后功能的恢复。具体来说，我们将确定运动和用于治疗中风后抑郁症的去甲肾上腺素选择性抗抑郁药reboxalone是否能促进脑损伤后神经突生长和突触替代。这项研究的基本原理是基于我们实验室和其他实验室以前的报告，这些报告表明：1）神经可塑性在脑损伤后的功能恢复中起着关键作用; 2）运动和恢复刺激神经营养因子（BDNF）和调节神经系统细胞存活和可塑性的细胞内信号通路; 3）运动增强并加速了再博替丁治疗后海马BDNF的增加; 4）运动诱导的海马BDNF表达的增加依赖于去甲肾上腺素能激活。待检验的具体假设是：1）运动和再灌流以会聚的方式起作用，以通过激活促进神经突生长、突触发生和细胞存活的细胞内信号传导途径来促进脑损伤后的突触替换，以及2）运动和再灌流治疗的会聚效应中的关键介质是BDNF。实验设计整合了麦克尼尔博士实验室的神经可塑性研究专业知识和Russo-Neustadt博士的研究专业知识，Russo-Neustadt博士研究了抗抑郁治疗和运动对诱导神经营养因子（BDNF）和调节抑郁症大鼠模型中细胞存活和可塑性的细胞内信号通路的影响。虽然这两个实验室都有充足的背景数据来独立支持该项目的主要方面，但我们缺乏关于reboxetrin治疗和运动对脑损伤后神经可塑性基础的解剖学和分子变化的影响的试点数据。我们希望使用此R21应用程序来开发必要的试点数据，以支持我们的总体假设，并形成坚实的初步数据基础，以证明将来提交R01应用程序的合理性。这些研究的数据对于扩大我们对大脑补偿损伤能力的理解至关重要，并且对于开发新的治疗策略至关重要，这些策略可以将神经可塑性的基本原理转化为治疗脑损伤的有效干预措施。

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.