Optimizing environmental enrichment to model preclinical neurorehabilitation

描述（由申请人提供）：创伤性脑损伤（TBI）每年影响美国170万人，造成长期运动和认知残疾。为了解决这一重大的卫生保健问题，各种相对侵入性的实验性治疗方法， 已经尝试了一些策略，但在临床上的应用有限。环境富集（EE）是一种非侵入性范例，其促进实验性TBI后显著的认知恢复和组织学保护，并且具有模仿TBI后临床康复的潜力。然而，典型的EE范例的缺点在于其包括TBI之后的立即和连续暴露，这与临床康复的时间框架不一致，其中物理治疗在TBI之后稍后开始（即，重症监护后 治疗）和有限的暴露。因此，在TBI后物理治疗暴露的开始时间和持续时间方面改进典型的EE范例，使其更接近临床康复实践，对于推进可应用于TBI环境的相关临床前神经康复模型以促进可翻译研究至关重要。的 将通过在男性和女性中开发模型并通过增加药物治疗来加强康复，进一步加强可翻译性。为此，提出了四个具体目标。目标1将确定中度TBI后的最晚时间（即，3、7或10天;临床相关的时间窗），此时可以施用缩短的6小时剂量的EE，其与康复相关，并且仍然有效地改善运动（旋转杆）、认知（Morris水迷宫和新物体识别）和组织学结果（CA 1/3细胞存活和皮质病变体积），以及诱导神经可塑性（突触素、PSD-95和用免疫组织化学和/或蛋白质印迹定量的神经发生），其将与神经行为结果相关。目标2将通过在完成初始行为评估（即，3周），然后在3、6和12个月时重新测试所有行为。目标3将评估目标2中TBI后有效时间延迟最长的EE范式所带来的益处是否可以通过在3、6和12个月重新测试之前提供2周的“复习康复”来增强或维持。目标4a将确定丁螺环酮（一种临床相关药物治疗）和缩短的EE模式（2或4小时）联合治疗是否能够带来获益，目标4 b将评价这种联合治疗方法的长期效果。所提出的目标的完成将产生临床前康复模型，其模拟TBI患者的真实的世界情况，所述TBI患者1）将不参与康复直到在重症护理之后，并且一旦参与治疗将每天接受有限的量，以及2）将接受康复加药物治疗，这在临床中是常见的。改进的模型将通过提供与临床相关的时间和治疗参数的洞察力来显着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.