Optimizing Environmental Enrichment to Model Preclinical Neurorehabilitation

创伤性脑损伤每年影响全球1000多万人(约280万人 美国)，并导致长期的运动和认知缺陷(例如，参考学习和执行功能)。至 与这一重大的医疗保健问题作斗争的各种相对侵入性的实验性治疗策略 已经尝试过，但翻译到临床的效果有限。环境浓缩(EE)是一种 非侵入性范式，促进显著的认知恢复和组织学保护 实验性脑外伤，并有可能模拟脑外伤后的临床康复。父R01是为 开始提炼和优化颅脑损伤后的EE，使其暂时符合临床神经康复的要求。这个 丰富的数据导致了神经康复的临床前模型，从某种意义上说，它在时间上类似于临床 将EE推迟一周(即康复)，每天只提供4小时(如诊所中常见的)显示 显著的好处。总体而言，这些发现为EE作为一种潜在的 神经康复，但额外的实证研究对于更多地了解其能力和 最终加强其有效性和适用性的局限性。因此，这次续签的目标是利用我们的 延迟(7天)和缩短(4小时)的EE神经康复模型，我们称之为Rehab，to 解答理疗师关心的问题。五个具体目标，这些目标是对 建议家长拨款：目标1a确定运动(波束和旋转杆)、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定势转移测试 卡片分类任务)和情感(公开现场测试)好处可以在EE取消后持续，如果是这样，对于 多长时间，目标1b确定在EE诱导的好处开始消退后提供“恢复康复”是否将 稳定或重新加强收益，AIMS 2abc确定是否会延迟EE，这是在7- 伤后数天，a)[金刚烷胺(10 mg/kg/d；ip)]，b)水疗[两次90次S游泳治疗]，或c) 音乐接触[(《新时代》、《环境》或《古典》-莫扎特的双钢琴奏鸣曲，每晚3小时， K.448)]作为脑损伤后一周的辅助治疗，相对于非强化治疗或康复治疗，将促进恢复 目的3评估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，模拟现实世界，同时解决以下问题 继续关注理疗师，例如一旦停止，康复福利能持续多长时间？ 通过补充康复来维持或进一步改善吗？在完全康复前可以补充治疗吗？ 提供更好的结果？观察到的影响涉及哪些机制？精致的模型将 显著影响和推进以康复为基础的研究。调查结果的可译性将得到促进 此外，通过优化成年大鼠的EE模型，并通过评估敏感和 临床相关的运动和执行功能测试，包括急性和长期的。

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.