Optimizing Environmental Enrichment to Model Preclinical Neurorehabilitation

创伤性脑损伤（TBI）每年影响全球超过1000万人（约280万人）。 USA）并导致长期运动和认知缺陷（例如，参考学习和执行功能）。到 为了解决这一重大的卫生保健问题， 已经尝试过，并且在临床上的转化有限。环境富集（EE）是一种 非侵入性范例，促进显著的认知恢复和组织保护， 实验性TBI，并有可能模仿TBI后的临床康复。父R 01被精心制作， 开始细化和优化TBI后EE，使其暂时符合临床神经康复。的 丰富的数据导致神经康复的临床前模型，在某种意义上， 延迟EE一周（即，康复）和每天只提供4小时（如在诊所常见）显示 重大利益。总的来说，研究结果为EE作为一种潜在的模型提供了重要的支持。 神经康复，但额外的实证研究是必不可少的，以了解更多关于其能力， 这些限制最终加强了其有效性和适用性。因此，这次更新的目标是利用我们的 延迟（7天）和缩短（4小时天）神经康复EE模型，我们称之为康复， 解决有关理疗师的问题。这五个具体目标是《公约》的逻辑和关键延伸， 父母补助金提出：目标1a确定是否运动（梁和旋转棒），认知（空间学习和 记忆和执行功能，使用类似于临床威斯康星州的注意力转移测试 卡片分类任务）和情感（开放领域测试）的好处可以维持后EE撤回，如果是这样， 目标1b确定在EE引起的利益开始衰退后提供“更新康复”是否 稳定或重新加强福利，目标2abc确定是否“桥接”延迟EE，这是在7- TBI后10天，用a）[金刚烷胺{10 mg/kg/天; i. p.}]，B）水疗[{两个90年代游泳课程}]，或c） 音乐接触[（每晚3小时的新时代，环境，或古典-莫扎特的奏鸣曲为双钢琴， K.448）]作为TBI后一周内的辅助治疗，相对于非强化或康复治疗， 目标3评估了桥接加康复疗法的机制。目标的实现将 进一步推进神经康复模型，模仿现实世界，同时解决问题， 继续关注物理学家，如多久做康复福利持续一旦中断，他们可以 是否可以通过补充康复来维持或进一步改善？完全康复前的补充疗法 提供更好的结果？观察到的影响涉及哪些机制？改进后的模型将 显著影响和推进基于康复研究。将促进调查结果的可翻译性 进一步通过优化成年雄性大鼠的EE模型，并通过用敏感和 急性和长期的运动和执行功能的临床相关测试。

Traumatic brain injury (TBI) affects more than 10 million individuals worldwide each year (~ 2.8 million in the USA) and results in long-term motor and cognitive deficits (e.g., reference learning and executive function). To combat this significant health care issue a variety of relatively invasive experimental therapeutic strategies have been attempted and 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. The parent R01 was crafted to begin refining and optimizing EE after TBI so that it conformed temporally to clinical neurorehabilitation. The wealth of data lead to a preclinical model of neurorehabilitation that is temporally like the clinic in the sense that delaying EE for a week (i.e., rehabilitation) and providing only 4-hr per day (as common in the clinic) shows significant benefits. Overall, the findings provided significant support for EE as a potential model of neurorehabilitation, but additional empirical research is essential to learn more about its capabilities and limitations that ultimately strengthen its validity and applicability. Hence, the goal of this renewal is to utilize our delayed (7 day) and abbreviated (4 h day) EE model of neurorehabilitation, which we refer to as Rehab, to address questions that concern physiatrists. Five specific aims that are logical and crucial extensions of the parent grant are proposed: Aim 1a determine whether motor (beam and rotarod), cognitive (spatial learning & memory, and executive function using the attentional set shifting test that is analogous to the clinical Wisconsin card sorting task), and affective (open field test) benefits can be sustained after EE is withdrawn, and if so, for how long, Aim 1b determine if providing “refresher rehab” after the EE-induced benefits begin to wane will stabilize or re-strengthen benefits, Aims 2abc determine whether “bridging” delayed EE, which is initiated at 7- days after TBI, with a) [amantadine {10 mg/kg/day; i.p.}], b) aqua therapy [{two 90 s swim sessions}], or c) music exposure [(3 h per night of New Age, Ambient, or Classical - Mozart’s sonata for two pianos, K.448)] as adjunct therapies during the week after TBI will augment recovery relative to non-enriched or Rehab groups, and Aim 3 evaluate mechanisms for the bridge plus Rehab therapies. Completion of the aims will further advance a model of neurorehabilitation that mimics the real-world while addressing questions that continue to concern physiatrists, such as how long do the rehab benefits last once discontinued and can they be maintained or improved further with supplemental rehab? Can supplemental therapies before full rehab provide a better outcome? What mechanisms are involved in the effects observed? The refined model will significantly impact and advance rehabilitation-based research. Translatability of the findings will be facilitated further by optimizing the EE model in adult rats of both sexes and by assessing behavior with sensitive and clinically-relevant tests of motor and executive function both acutely and long-term.