Exercise and Antidepressant Treatment in Brain Injury

描述(由申请人提供)： 建议的研究旨在加深我们对神经可塑性背后的细胞事件的了解，以及可以促进脑损伤后功能恢复的治疗策略。具体地说，我们将确定运动和用于治疗中风后抑郁的去甲肾上腺素选择性抗抑郁药瑞波西汀是否可以促进脑损伤后的轴突生长和突触替换。此项研究的基本原理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关键作用；2)运动和瑞波西汀刺激神经营养素(BDNF)和调节神经系统细胞生存和可塑性的细胞内信号通路；3)瑞波西汀治疗后海马区BDNF的增加可被运动增强和加速；4)运动诱导的海马区BDNF表达的增加依赖于去甲肾上腺素能的激活。需要检验的具体假设是：1)运动和瑞波西汀通过激活细胞内促进突起生长、血管发生和细胞存活的信号通路，以一种趋同的方式作用于脑损伤后的突触替换；2)运动和瑞波西汀治疗的融合效应的关键中介是BDNF。该实验设计结合了麦克尼尔博士实验室和Russo-Neustadt博士在神经可塑性方面的研究专业知识，Russo-Neustadt博士研究了抗抑郁治疗和运动对调节抑郁症大鼠模型细胞存活和可塑性的神经营养因子(BDNF)和细胞内信号通路的诱导的影响。虽然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，但我们缺乏瑞波西汀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初步数据。我们希望利用这一R21申请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，以证明未来提交R01申请是合理的。来自这些研究的数据是扩大我们对大脑补偿损伤能力的理解的基础，也是开发新的治疗策略的核心，这些治疗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.