Novel Rehabilitative Approaches for Recovery from TBI

描述（由申请人提供）：在美国，创伤性脑损伤（TBI）每年影响150万至200万人。大约10万名严重创伤性脑损伤幸存者忍受长期记忆和/或身体损伤，需要严格和昂贵的康复治疗。虽然目前还没有公认的治疗人类TBI的方法，但我们有数据显示，早期（TBI后15分钟）给予5-羟色胺/lA受体（5-HT1AR）激动剂-一种新的TBI药物治疗方法，但通常用于治疗人类的焦虑和抑郁-减轻实验性TBI诱导的行为缺陷。虽然这种早期治疗的益处是令人信服的，但TBI后延迟和慢性5-HT1AR激动剂治疗的潜在疗效尚不清楚。这个问题是最重要的考虑到继发性后遗症是普遍的数小时至数天后的创伤性脑损伤，扰乱恢复过程。对创伤后几小时和几分钟内恢复和/或增强神经调节的药物干预进行实证研究对于成功康复至关重要。此外，还需要进一步研究环境富集（EE）对回收的影响。与标准环境相比，情感表达增强了脑外伤后的预后，是一种与康复范例相关的实验模拟，可以单独或作为药物治疗的辅助手段提供临床效用。因此，本提案的目标是进一步研究5-HT1AR激动剂丁螺环酮和EE单独或相互联合的作用。据推测，huspirone和EE将促进脑外伤后的记忆和运动恢复，但联合治疗将比单独治疗更有效。为了验证这一假设，我们提出了一系列合乎逻辑的目标：目的1将研究丁螺环酮延迟和慢性治疗方案（损伤后1-20天）对TBI后功能恢复的潜在疗效，TBI是由一个成熟的皮质撞击损伤模型造成的，该模型产生的缺陷与临床所见的相似。目的2将确定情感表达对脑外伤后功能结局的影响。目的3将研究EE加丁螺环酮治疗对TBI后恢复的影响。这两种治疗方法都增强了胆碱能功能，这与记忆密切相关，并在TBI后下降，因此Aim 4将通过量化胆碱能神经传递的生化和免疫组织化学介质来探索这一途径的潜在机制。该项目首次系统研究了延迟和慢性5-HT1AR激动剂治疗、EE及其联合治疗对TBI后记忆和运动功能的影响，并将为进一步的潜在机制实证研究提供框架。我们的长期目标是开发促进人类脑外伤后功能恢复的治疗方法。

DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) affects 1.5 to 2 million individuals in the United States each year. Approximately 100,000 severe-TBI survivors endure long-term memory and/or physical impairments that require rigorous and costly rehabilitative therapy. While there are currently no accepted treatments for human TBI, we have data showing that early (15 min after TBI) administration of serotonin/lA receptor (5-HT1AR) agonists - a pharmacotherapy novel to TBI, but used routinely to treat anxiety and depression in humans - attenuate experimental TBI-induced behavioral deficits. While the benefits of this early treatment are compelling, the potential efficacy of delayed and chronic 5-HT1AR agonist treatments after TBI is unknown. This issue is paramount given the secondary sequelae that are prevalent hours to days after TBI and that perturb the recovery process. Empirical investigation of pharmacological interventions that restore and/or enhance neuromodulation when given hours vs. minutes post-TBI is essential for successful rehabilitation. Also warranted is further investigation of environmental enrichment (EE) on recovery. EE enhances outcome after TBI vs. standard environments, is a relevant experimental analogue of the rehabilitation paradigm, and may provide clinical utility alone or as an adjunct to pharmacotherapy. Thus, the goals of this proposal are to further examine the effects of the 5-HT1AR agonist buspirone and EE alone or in conjunction with each other. It is hypothesized that huspirone and EE will facilitate memory and motor recovery after TBI, but the combination of treatments will be more efficacious than either alone. To test this hypothesis, a logical series of aims are proposed: Aim 1 will investigate the potential efficacy of a delayed and chronic treatment regimen (1-20 days post-injury) with buspirone on functional recovery after TBI produced by a well-established cortical impact injury model that produces deficits resembling those seen clinically. Aim 2 will determine the effects of EE on functional outcome after TBI. Aim 3 will investigate the effects of EE plus buspirone treatment on recovery after TBI. Both treatments augment cholinergic function, which is strongly implicated in memory and decreased after TBI, and thus Aim 4 will explore this avenue as a potential mechanism by quantifying biochemical and immunohistochemical mediators of cholinergic neurotransmission. This project represents the first systematic investigation of delayed and chronic 5-HT1AR agonist treatments, EE, and their combination on memory and motor function after TBI, and will provide a framework for further empirical research of potential mechanisms. Our long-term goal is to develop therapies that facilitate functional recovery after human TBI.