The role of traumatic brain injury stress response on exercise therapy

描述（申请人提供）：物理治疗在创伤性脑损伤（TBI）康复中应用广泛。然而，大多数关于运动对创伤性脑损伤后恢复的影响的知识都是基于观察，关于运动对创伤性脑损伤后恢复的影响的科学研究很少。先前的研究表明，自愿运动可以促进脑震荡脑损伤的恢复。特别是，脑外伤后的自愿运动增加了脑源性神经营养因子（BDNF）和其他参与神经可塑性的关键分子的水平。然而，当损伤后立即进行运动时，BDNF没有增加，行为结果反而恶化。该提案将通过测试早期创伤后应激反应诱导的糖皮质激素升高会减弱运动诱导的BDNF上调的作用这一假设来继续这一研究路线。在大鼠创伤后第一周（急性）和后几周，我们将通过不同的运动方案来研究应激对BDNF的影响。因为持续的压力可能会降低BDNF和下游分子，某些形式的运动可能会阻碍TBI后功能的恢复。本提案中的第一个实验将确定损伤引起的皮质酮（CORT）水平的改变是否在脑外伤后不同时期BDNF介导的神经可塑性破坏中起关键作用。CORT是大鼠体内主要的循环糖皮质激素。这些实验将提供一个框架，以确定某些运动方案是否可以延长或加剧损伤引起的糖皮质激素紊乱。非自我调节（强迫）和自我调节（自愿）运动的效果将在急性期和TBI后几周进行比较。这些形式的运动可能会产生不同的应激反应，从而影响BDNF的上调，并最终对恢复或结果产生影响。强制锻炼强度更大，因为它在相对较短的时间内进行，使其更类似于目前的物理治疗。相比之下，自愿运动在一天的活动期间间隔进行。最后，该建议将确定通过使用抗抑郁药物治疗来缓解压力是否可以逆转压力引起的BDNF变化。相当数量的TBI患者被诊断和治疗为与糖皮质激素失调相关的疾病，如抑郁症和创伤后应激障碍（PTSD）。在康复期间广泛使用的抗抑郁药与BDNF上调和糖皮质激素水平降低有关。选择性去甲肾上腺素和血清素摄取抑制剂的作用将被研究。预计抗抑郁治疗将降低CORT水平，并增强运动依赖性BDNF的增加。最终，这些研究将有助于制定适当的运动方案，内源性增加BDNF和相关分子的水平，这与康复期有关。公共卫生相关性：脑损伤患者承受长期损伤，对生活质量产生强烈影响。我们将研究不同的损伤后运动方案对恢复的影响，以及压力如何影响这些。该建议将提供基于机械的信息，有助于制定最佳的TBI后运动方案。

DESCRIPTION (provided by applicant): Physical therapy is widely used during traumatic brain injury (TBI) rehabilitation. However most of the knowledge concerning the effects of exercise on recovery from TBI has been based on observation, and scientifically based research regarding the effects of exercise on recovery from TBI is scant. Previous studies have indicated that voluntary exercise promotes recovery from concussive brain injury. In particular, post-TBI voluntary exercise increases levels of brain derived neurotrophic factor (BDNF) and other key molecules involved in neuroplasticity. However, when exercise is provided acutely after injury there is no increase in BDNF and behavioral outcome worsens. This proposal will continue this line of research by testing the hypothesis that early post-traumatic stress response-induced elevation in glucocorticoids blunts the effects of exercise-induced BDNF upregulation. The effects of stress on BDNF will be investigated in rats through utilizing different exercise regimens during the first week (acute) and later-weeks after TBI. Because sustained stress is likely to decrease BDNF and downstream molecules, some forms of exercise may encumber recovery of function after TBI. The first experiments within this proposal will determine if injury induced alterations in levels of corticosterone (CORT) play a key role in the disruption of BDNF mediated neuroplasticity during different post-TBI time periods. CORT is the main circulating glucocorticoid in rats. These experiments will provide the framework to determine if some exercise regimens can prolong or foment injury-induced disruptions in glucocorticoids. The effects of non-self-regulated (forced) and self-regulated (voluntary) exercise will be compared during the acute and later-weeks after TBI. These forms of exercise are likely to produce different stress responses that will consequentially influence BDNF upregulation and ultimately have an effect on recovery or outcome. Forced exercise is more intensive in that it is administered in relatively short sessions, making it more akin to current physical therapy. In contrast voluntary exercise is spaced throughout the active period of the day. Finally this proposal will determine if stress alleviation through the use of antidepressant treatment can reverse stress-induced changes in BDNF. A substantial number of TBI patients are diagnosed and treated for disorders that are associated with glucocorticoid disregulation, such as depression and post- traumatic stress disorder (PTSD). Antidepressants, which are widely administered in the rehabilitative period, are associated with upregulating BDNF and decreasing levels of glucocorticoids. The effects of a selective norepinephrine and serootonergic uptake inhibitors will be studied. It is expected that antidepressant treatment will decrease levels of CORT and enhance exercise-dependent BDNF increases. Ultimately these studies will aid in developing adequate exercise regimens that endogenously increase levels of BDNF and associated molecules at a time that is pertinent to the rehabilitative time-period. PUBLIC HEALTH RELEVANCE: Those affected with brain injury endure long-lasting impairments that have a strong impact on life quality. We will investigate the effects of different post-injury exercise regimens on recovery and how these can be influenced by stress. This proposal will provide mechanistically based information that will aid in developing an optimal exercise regimen after TBI.