Novel Rehabilitative Approaches for Recovery from TBI

描述（由申请人提供）：创伤性脑损伤（TBI）每年影响美国150万至200万人。大约10万名严重TBI幸存者忍受着长期记忆和/或身体损伤，需要严格和昂贵的康复治疗。虽然目前没有可接受的人TBI治疗，但我们有数据显示早期（TBI后15分钟）给予5-羟色胺/1A受体（5-HT 1AR）激动剂-一种对TBI新颖的药物疗法，但常规用于治疗人类的焦虑和抑郁-减弱了实验性TBI诱导的行为缺陷。虽然这种早期治疗的好处是引人注目的，但TBI后延迟和慢性5-HT 1AR激动剂治疗的潜在疗效尚不清楚。考虑到TBI后数小时至数天内普遍存在的继发性后遗症并干扰恢复过程，该问题至关重要。当TBI后数小时与数分钟时，恢复和/或增强神经调节的药理学干预的经验性研究对于成功康复至关重要。还需要进一步调查环境富集对恢复的影响。EE与标准环境相比可增强TBI后的结局，是康复范例的相关实验模拟物，可单独或作为药物治疗的辅助手段提供临床效用。因此，本提案的目的是进一步研究5-HT 1AR激动剂丁螺环酮和EE单独或相互结合的作用。据推测，胡螺环酮和EE将促进TBI后的记忆和运动恢复，但联合治疗将比单独治疗更有效。为了检验这一假设，提出了一系列合乎逻辑的目标：目标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由完善的皮质撞击损伤模型产生，该模型产生类似于临床观察到的缺陷。目的2将确定EE对TBI后功能结局的影响。目的3探讨EE联合丁螺环酮治疗对TBI后恢复的影响。这两种治疗都增强了胆碱能功能，这与记忆密切相关，在TBI后降低，因此目标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作为潜在机制。该项目代表了延迟和慢性5-HT 1AR激动剂治疗，EE及其组合对TBI后记忆和运动功能的首次系统研究，并将为进一步的潜在机制的实证研究提供框架。我们的长期目标是开发促进人类TBI后功能恢复的疗法。

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.