Optimizing environmental enrichment to model preclinical neurorehabilitation

优化环境富集以模拟临床前神经康复

• 批准号: 9057393
• 负责人: ANTHONY E. KLINE
• 金额: $ 33.03万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-15 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9057393
• 关键词: Affect; Behavior; Behavior assessment; Behavioral; Bromodeoxyuridine; Buspirone; Caring; Cell Survival; Clinic; Clinical; Cognitive; Combined Modality Therapy; Critical Care; Data; Dose; Female; Figs - dietary; Gender; Health; Healthcare; Histopathology; Home environment; Hour; Housing; Immunohistochemistry; Individual; Investigational Therapies; Laboratories; Lead; Lesion; Long-Term Effects; Modeling; Motor; Neuronal Plasticity; Neurorehabilitation; Outcome; Patients; Pharmacotherapy; Physical therapy; Pre-Clinical Model; Rattus; Recovery; Regimen; Rehabilitation Research; Rehabilitation therapy; Research; Synaptophysin; Testing; Therapeutic; Time; Translations; Traumatic Brain Injury; Traumatic Brain Injury recovery; United States; Western Blotting; Withdrawal; base; clinical practice; clinically relevant; cognitive disability; cognitive performance; cognitive recovery; combat; design; environmental enrichment for laboratory animals; improved; insight; male; morris water maze; natural hypothermia; neurobehavioral; neurogenesis; novel; object recognition; therapy duration

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.

描述（由申请人提供）：每年在美国影响170万人的脑损伤（TBI），导致长期运动和认知障碍。为了解决这个重要的医疗保健问题，各种相对侵入性的实验治疗 策略已尝试，但对诊所的翻译有限。环境富集（EE）是一种非侵入性范式，可在实验性TBI后促进明显的认知恢复和组织学保护，并有可能模仿TBI后临床康复后。但是，典型的EE范式的缺点是，它由TBI后立即和连续暴露组成，这与临床康复的时间范围不一致，在TBI之后，在TBI之后启动了物理疗法（即重症监护之后 治疗）且暴露量有限。因此，在TBI之后的启动时间和物理治疗暴露的时间上，完善典型的EE范式，以使其更符合临床康复实践，这对于促进相关的神经疗法模型的临床康复实践至关重要，该模型可以应用于TBI设置，以促进TBI设置，以促进可容纳Transiletate的翻译研究。这 通过在男性和女性中开发模型，以及增加药物疗法以增加康复，可以进一步增强可翻译性。为此，提出了四个具体目标。 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体积），以及诱导与神经组织相关的免疫组织化学和/或Western blot量化的神经可塑性（突触蛋白，PSD-95和神经发生）。 AIM 2将在完成初始行为评估（即3周）之前撤回EE，然后在3、6和12个月的时间对所有行为进行重新测试，从而评估该方法的长期影响。 AIM 3将评估EE范式赋予AIM 2的最长有效时间延迟的EE范式是否可以通过提供“复习康复” 2周，然后在3、6和12个月重新测试，从而增强或维持AIM 2的最长有效时间延迟。 AIM 4A将确定合并丁螺酮，临床上相关的药物疗法和缩短2或4小时的EE范式是否能够赋予益处，而AIM 4B将评估这种组合方法的长期影响。拟议的目标的完成将产生临床前的康复模型，该模型模仿了TBI患者的现实世界状况1）1）直到批评后才进行康复，并且一旦进行治疗，并且每天进行治疗量有限，而2）将获得康复和康复治疗，以及在临床中常见的药物治疗。精致的模型将通过洞悉临床相关的时间和治疗参数，从而显着影响和提高康复研究。