Novel Rehabilitative Approaches for Recovery from TBI

描述(申请人提供)：创伤性脑损伤(TBI)在美国每年影响150至200万人。大约100,000名重型颅脑损伤幸存者忍受着长期记忆和/或身体损伤，需要严格而昂贵的康复治疗。虽然目前还没有公认的治疗人类脑损伤的方法，但我们有数据表明，早期(脑损伤后15分钟)给予5-羟色胺/α受体(5-HT1AR)激动剂-一种治疗脑损伤的药物新药，但通常用于治疗人类的焦虑和抑郁-减轻脑损伤导致的实验性行为缺陷。虽然这种早期治疗的好处是令人信服的，但脑损伤后延迟和慢性5-HT1AR激动剂治疗的潜在疗效尚不清楚。考虑到继发性后遗症在颅脑损伤后几小时到几天内普遍存在，并扰乱了康复进程，这个问题是至关重要的。对恢复和/或增强神经调节的药物干预进行经验性研究，这些干预在脑损伤后几小时而不是几分钟内给予，对于成功的康复至关重要。也有必要进一步调查环境浓缩(EE)对回收的影响。与标准环境相比，EE可提高脑外伤后的预后，是康复范例的相关实验模拟，可单独提供临床实用价值，或作为药物治疗的辅助工具。因此，这项建议的目标是进一步研究5-HT1AR激动剂丁螺环酮和EE单独或联合使用的效果。据推测，胡螺环酮和EE将促进脑外伤后记忆和运动的恢复，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：目标1将调查丁螺环酮延迟和慢性治疗方案(损伤后1-20天)对脑挫伤后功能恢复的潜在疗效。目的2将确定EE对脑外伤后功能结局的影响。目的3探讨EE联合丁螺环酮治疗对颅脑损伤后康复的影响。这两种治疗方法都能增强胆碱能功能，胆碱能功能与记忆密切相关，但在脑损伤后会降低，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一种潜在的机制。该项目是首次系统研究延迟性和慢性5-HT1AR激动剂治疗及其联合治疗对脑外伤后记忆和运动功能的影响，并将为进一步的可能机制的实证研究提供一个框架。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.