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: 10661599
• 负责人: ANTHONY E. KLINE
• 金额: $ 40.76万
• 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 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10661599
• 关键词: Abbreviations; Acute; Address; Adult; Affect; Affective; Age; Amantadine; Attention; Auditory; Behavior; Behavior assessment; Behavioral Mechanisms; Budgets; Chronic; Clinic; Clinical; Cognitive; Cognitive deficits; Data; Dose; Empirical Research; Equilibrium; Exhibits; Galantamine; Goals; Healthcare; Histologic; Histology; Home; Housing; Individual; Investigational Therapies; Knowledge; Lead; Learning; Longevity; Manuscripts; Mediating; Memory; Modeling; Motor; Music; Outcome; Parents; Patient Care; Patients; Performance; Play; Pre-Clinical Model; Productivity; Publishing; Rattus; Recovery; Regimen; Rehabilitation therapy; Research; Role; Sensory; Sorting; Swimming; Testing; Therapeutic; Time; Translations; Traumatic Brain Injury; United States; Walking; Wisconsin; Withdrawal; Zaleplon; behavioral outcome; clinical application; clinical translation; clinically relevant; cognitive recovery; combat; critical period; environmental enrichment for laboratory animals; executive function; field study; improved; innovation; motor deficit; nano-string; neurogenesis; neuroinflammation; neurological rehabilitation; neurotransmission; parent grant; pharmacologic; sex; success

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.

脑外伤（TBI）每年影响全球超过1000万个人（约280万 美国）并导致长期运动和认知缺陷（例如，参考学习和执行功能）。到 对抗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 已尝试并将其转换为诊所。环境丰富（EE）是 非侵入性范式，促进了重大认知恢复和组织学保护 实验性TBI，有可能模仿TBI后临床康复。父母R01被制作为 在TBI之后开始精炼和优化EE，以便暂时符合临床神经居住。这 大量数据导致神经康复的临床前模型，它在某种意义上暂时像诊所一样 延迟EE一周（即康复），每天仅提供4小时（在诊所中常见） 重大好处。总体而言，这些发现为EE提供了重大支持，作为潜在模型 神经居住，但是其他实证研究对于了解其能力和 最终增强其有效性和适用性的局限性。因此，这种更新的目标是利用我们 延迟（7天）和缩写（4 h天）神经康复的EE模型，我们称为康复， 解决与生理学家有关的问题。五个具体目标是逻辑和关键的扩展 提出了父授予：AIM 1A确定运动（梁和旋转rod）是否认知（空间学习和 记忆和执行功能使用类似于临床威斯康星的注意力集转换测试 撤回EE后，可以维持卡片分类任务）和情感（开放测试）的好处，如果是这样，则可以持续 目标1B确定在EE引起的福利开始下降之后是否提供“恢复康复” 稳定或重新强度的福利，目标2ABC确定“桥接”延迟EE是否在7-- TBI之后的几天，a）[amantadine {10 mg/kg/day; i.p.}]，b）水上治疗[{两个90 s游泳课}]或c） 音乐曝光[（新时代的每晚3小时，环境或古典 - 莫扎特的奏鸣曲，两把钢琴， k.448）]作为辅助疗法在TBI后的一周中，相对于未富含或康复的恢复 组，AIM 3评估桥梁和康复疗法的机制。目标的完成将 进一步促进神经康复的模型，该模型模仿现实世界，同时解决问题 继续关注物理学家，例如，康复一旦停产多久了，他们可以 通过补充康复进行维护或进一步改善？可以在完全康复之前补充疗法 提供更好的结果？观察到的效果涉及哪些机制？精制模型将 显着影响并提高基于康复的研究。调查结果的翻译性将准备好 进一步通过优化性别的成年大鼠的EE模型，并通过敏感和 急性和长期的运动和执行功能与临床相关的测试。