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The role of traumatic brain injury stress response on exercise therapy

创伤性脑损伤应激反应在运动治疗中的作用

基本信息

批准号：
8247106
负责人：
GRACE S. GRIESBACH
金额：
$ 33.01万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-25 至 2013-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8247106
关键词：
Acute Address Adrenal Glands Affect Antidepressive Agents Behavioral Brain Injuries Brain-Derived Neurotrophic Factor CREB1 gene Corticosterone Diagnosis Disease Exercise Exertion Functional disorder Glucocorticoids Health Hypothalamic structure Impaired cognition Impairment Injury Knowledge Laboratory Study Lead Learning Mediating Mental Depression Modeling Neuronal Plasticity Norepinephrine Outcome Patients Physical therapy Physical therapy exercises Pituitary Gland Play Post-Traumatic Stress Disorders Prevalence Proteins Quality of life Rattus Recovery Recovery of Function Regimen Rehabilitation therapy Research Role Serotonin Severities Stress Synapsin I Testing Therapeutic Time Traumatic Brain Injury Up-Regulation base biological adaptation to stress hypothalamic-pituitary-adrenal axis inhibitor/antagonist molecular marker research study response reuptake uptake

项目摘要

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.

描述(申请人提供)：物理疗法在创伤性脑损伤(TBI)康复中得到广泛应用。然而，关于运动对脑损伤康复影响的大部分知识都是建立在观察的基础上的，而关于运动对脑损伤恢复的影响的科学研究很少。以前的研究表明，自愿锻炼可以促进脑震荡损伤的恢复。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，当在受伤后进行剧烈运动时，脑源性神经营养因子没有增加，行为结果恶化。这项建议将继续这一系列研究，通过检验这一假设，即早期创伤后应激反应诱导的糖皮质激素升高会削弱运动诱导的BDNF上调的影响。应激对大鼠脑损伤后第一周(急性)和后几周的脑源性神经营养因子的影响将通过采用不同的运动方案进行研究。由于持续的应激可能会减少BDNF及其下游分子，一些形式的运动可能会阻碍脑外伤后功能的恢复。该方案中的第一个实验将确定损伤诱导的皮质酮(CORT)水平的变化是否在脑创伤后不同时间段BDNF介导的神经可塑性中断中发挥关键作用。皮质醇是大鼠体内主要的循环糖皮质激素。这些实验将提供框架，以确定一些运动方案是否可以延长或煽动由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)运动的效果将在颅脑损伤后的急性期和后期进行比较。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。强迫运动的强度更大，因为它是在相对较短的时间内进行的，这使得它更类似于目前的物理疗法。相比之下，自愿性锻炼贯穿了一天的活动时段。最后，这项建议将确定通过使用抗抑郁剂治疗来缓解压力是否可以逆转应激诱导的BDNF变化。相当数量的脑损伤患者被诊断和治疗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)。在康复期广泛使用的抗抑郁药与上调BDNF和降低糖皮质激素水平有关。将研究选择性去甲肾上腺素和5-羟色胺能摄取抑制剂的效果。预计抗抑郁治疗将降低皮质醇水平，并增强运动依赖性BDNF的增加。最终，这些研究将有助于开发适当的运动方案，在与康复时间相关的时间内内源性增加BDNF和相关分子的水平。公共卫生相关性：那些受脑损伤影响的人承受着对生活质量有强烈影响的长期损伤。我们将调查不同的创伤后锻炼方案对恢复的影响，以及这些影响如何受到压力的影响。这项建议将提供机械基础的信息，将有助于开发出一个最佳的运动方案后脑损伤。