Optimizing environmental enrichment to model preclinical neurorehabilitation

描述(申请人提供)：创伤性脑损伤(TBI)在美国每年影响170万人，导致长期的运动和认知障碍。为了应对这一重大的医疗保健问题，各种相对侵入性的实验性治疗方法 已经尝试了一些策略，但在临床上的翻译效果有限。环境丰富(EE)是一种非侵入性范式，可促进实验性脑损伤后认知功能的显著恢复和组织学保护，并有可能模拟脑损伤后的临床康复。然而，典型EE范式的缺点是它包括在脑损伤后立即和持续暴露，这与临床康复的时间框架不一致，其中在脑损伤后(即在危重护理之后)开始物理治疗 治疗)和有限的暴露。因此，就脑损伤后物理治疗暴露的开始时间和持续时间而言，完善典型的EE范式，使其更符合临床康复实践，对于推进可应用于脑损伤环境的相关临床前神经康复模式，以促进可翻译的研究至关重要。这个 通过在男性和女性中开发该模型，并通过增加药物疗法来加强康复，可译性将进一步增强。为此，提出了四个具体目标。目的1将确定中度颅脑损伤(即3、7或10天；临床相关的时间窗口)后的最晚时间，此时与康复相关的简短6小时剂量的EE可以有效改善运动(Rotarod)、认知(Morris水迷宫和新物体识别)和组织结果(CA1/3细胞存活率和皮质损伤体积)，并诱导神经可塑性(突触素、PSD-95和免疫组织化学和/或Western印迹定量的神经发生)，这将与神经行为结果相关。目标2将评估这种方法的长期效果，方法是在初始行为评估完成时(即3周)取消EE，然后在3、6和12个月重新测试所有行为。AIM 3将评估是否可以通过在3个月、6个月和12个月重新测试之前提供2周的“复习康复”来增强或保持从AIM 2获得的具有最长有效时间延迟的EE范例所带来的益处。目标4a将确定丁螺环酮(一种临床相关的药物疗法)与2或4小时的缩短EE范例相结合是否能够带来益处，目标4b将评估这一组合方法的长期效果。完成拟议的目标将产生一种临床前康复模式，模拟脑外伤患者的真实情况：1)在危重护理后才进行康复，一旦进行治疗，每天将获得有限的量；2)将接受康复加药物治疗，这在临床上很常见。改进的模型将通过提供对临床相关的时机和治疗参数的洞察，显著影响和推进康复研究。

DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) affects 1.7 million individuals in the United States each year causing long- term motor and cognitive disabilities. To combat this significant health care issue a variety of relatively invasive experimental therapeutic strategies have been attempted, but have yielded limited translation to the clinic. Environmental enrichment (EE) is a non-invasive paradigm that promotes significant cognitive recovery and histological protection after experimental TBI and has the potential to mimic post-TBI clinical rehabilitation. However, a shortcoming of the typical EE paradigm is that it consists of immediate and continuous exposure after TBI, which is inconsistent with the time frame of clinical rehabilitation where physiotherapy is initiated later after TBI (i.e., after critical care treatment) and with limited exposure. Hence, refining the typical EE paradigm in terms of time of initiation and duration of physiotherapeutic exposure after TBI so that it conforms closer to clinical rehabilitation practice is paramount for advancement of a relevant preclinical model of neurorehabilitation that can be applied to the TBI setting to facilitate translatable research. The translatability will be strengthened further by developing the model in both males and females and by adding a pharmacotherapy to augment rehabilitation. To this end, four specific aims are proposed. Aim 1 will determine the latest time after moderate TBI (i.e., 3, 7, or 10 days; clinically-relevant temporal window) when an abbreviated 6-hr dose of EE, which is rehabilitation-relevant, can be administered and still effectively improve motor (rotarod), cognitive (Morris water maze and novel object recognition), and histological outcome (CA1/3 cell survival and cortical lesion volume), as well as induce neuroplasticity (synaptophysin, PSD-95, and neurogenesis quantified with immunohistochemistry and/or Western blot) that will correlate with neurobehavioral outcomes. Aim 2 will evaluate the long term effects of this approach by withdrawing EE at the completion of the initial behavioral assessments (i.e., 3 weeks) and then retesting for all behaviors at 3, 6, and 12 months. Aim 3 will evaluate whether the benefits conferred by the EE paradigm with the longest effective time delay post-TBI from Aim 2 can be enhanced or maintained by providing "refresher rehab" for 2 weeks before retesting at 3, 6, & 12 months. Aim 4a will determine whether combining buspirone, a clinically-relevant pharmacotherapy and shortened EE paradigms of 2 or 4 hours is capable of conferring benefits and Aim 4b will evaluate the long-term effects of this combinational approach. Completion of the proposed aims will yield a preclinical model of rehabilitation that mimics the real world situation of the TBI patient who 1) will not engage in rehabilitation until after criticl care and once engaged in therapy will receive limited amounts each day, and 2) will receive rehabilitation plus a pharmacotherapy, which is common in the clinic. The refined model will significantly impact and advance rehabilitation research by providing insight into timing and therapeutic parameters that are clinically relevant.