Voluntary Exercise Therapy after Traumatic Brain Injury

描述（由申请人提供）：创伤性脑损伤（TBI）是我们社会中残疾的主要原因之一。不幸的是，TBI没有具体的治疗方法。脑源性神经营养因子（BDNF）是神经元存活、生长和可塑性的关键因子。这些品质为它提供了治疗能力。然而，基于BDNF的治疗受到递送问题的限制。我建议内源性上调脑源性神经营养因子和相关的分子系统与运动后TBI。TBI后内源性上调突触可塑性重要分子的概念是一个未知的研究领域，可能会对康复启动产生影响。然而，在TBI后的最初几天到几周内，大脑处于能量危机状态，这可能会损害分子系统对运动引起的生理刺激的反应性。我想确定脑源性神经营养因子和相关的分子系统在多大程度上对创伤性脑损伤和随后的自愿运动做出反应。为了解决这一问题，提出了以下具体目标： 具体目标1：确定损伤诱导的BDNF和与突触可塑性有关的相关蛋白的变化是否是时间和严重程度依赖性的。在这个目标，我将确定的影响，横向液压冲击损伤（FPI）对海马和皮质BDNF（和相关分子）在伤后的时间，是有关的恢复和康复期。 具体目标二：确定创伤后时间窗，在此时间窗内，运动可以产生BDNF（及其相关分子系统）的内源性上调。在这个目标下，我将确定受伤后自愿运动不会导致BDNF上调的时间段，并确定这个时间窗是否依赖于损伤的严重程度。 具体目标3：确定运动对认知结果的短期和长期影响，并确定任何运动引起的改善是否依赖于BDNF。Morris水迷宫（MWM）将用于评估学习获得和记忆表现。为了解决这些具体的目标，我将利用大鼠的侧向液压冲击损伤模型和自愿运行轮暴露。将进行蛋白质、基因、组织学和行为学研究。

DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) is one of the leading causes of disability in our society. Unfortunately, there is no specific treatment for TBI. Brain derived neurotrohic factor (BDNF) is a key player in neuronal survival, growth and plasticity. These qualities provide it with therapeutic capabilities. However, BDNF-based treatments have been limited by delivery problems. I propose to endogenously upregulate BDNF and associated molecular systems with exercise following TBI. The concept of endogenously upregulating molecules important in synaptic plasticity after TBI is an uncharted area of research that could have an impact on rehabilitative startegies. However, during the first days to weeks following TBI, the brain is in a state of energy crisis that may compromise the reactivity of molecular systems to physiological stimulation as a result of exercise. I would like to determine to what degree BDNF and associated molecular systems respond to TBI and subsequent voluntary exercise. In order to address this topic the following specific aims are proposed to: Specific Aim 1: Determine if injury-induced changes in BDNF and associated proteins involved with synaptic plasticity are time and severity dependent. Within this aim I will determine the effects of a lateral fluid percussion injury (FPI) on hipppocampal and cortical BDNF (and associated molecules) at postinjury times that are pertinent to the recovery and rehabilitative period. Specific Aim 2: Determine the post-traumatic time window in which exercise can produce an endogenous up-regulation of BDNF (and its associated molecular systems). Within this aim I will determine the period of time following injury when voluntary exercise does not result in an up-regulation of BDNF and determine if this time window is injury-severity dependent. Specific Aim 3: Determine the short and long-term effects of exercise on cognitive outcome and determine if any exercise-induced improvement is dependent on BDNF. The Morris Water Maze (MWM) will be used to assess learning acquisition and memory performance. In order to address these specific aims, I will utilize the lateral fluid-percussion injury model in rats and voluntary running wheel exposure. Protein, gene, histological and behavioral studies will be conducted.