Voluntary Exercise Therapy after Traumatic Brain Injury

描述（由申请人提供）：创伤性脑损伤（TBI）是我们社会致残的主要原因之一。不幸的是，对于创伤性脑损伤没有特殊的治疗方法。脑源性神经营养因子（BDNF）在神经元的存活、生长和可塑性中起着关键作用。这些特性使它具有治疗能力。然而，基于bdnf的治疗一直受到递送问题的限制。我建议内源性上调脑损伤后的BDNF和相关分子系统。内源性上调分子在脑损伤后突触可塑性中的重要作用是一个未知的研究领域，可能对康复策略产生影响。然而，在创伤性脑损伤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。我想确定BDNF和相关分子系统对创伤性脑损伤和随后的自主运动的反应程度。为解决这一问题，提出以下具体目标：

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.