Brain injury rehabilitation modality, regulation, & structural plasticity

脑损伤康复方式、调节、

• 批准号: 10226791
• 负责人: JONATHAN LIFSHITZ
• 金额: --
• 依托单位: PHOENIX VA HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10226791
• 关键词: Address; Adult; Affect; Agonist; Animals; Attenuated; Brain; Brain Concussion; Brain Injuries; Brain region; Cell physiology; Cellular Morphology; Clinical; Cognitive; Complex; Conflict (Psychology); Control Animal; Control Groups; Data; Development; Diffuse; Diffuse Brain Injury; Disease; Drug Prescriptions; Effectiveness; Emotional; Environment; Event; Exercise; Exposure to; Female; Foundations; Functional disorder; Goals; Head; Hippocampus (Brain); Immunohistochemistry; Impaired cognition; Impairment; Individual; Infusion procedures; Injury; Intervention; Label; Laboratories; Laboratory Study; Light; Liquid substance; Measures; Mediating; Medical; Microglia; Mind; Mission; Modality; Modeling; Morphology; Muscimol; Nature; Nervous System Physiology; Neurologic; Neurologic Symptoms; Neurons; Outcome; Outcome Measure; Percussion; Pharmacology; Post-Concussion Syndrome; Process; Protocols documentation; Public Health; Quality of life; Rattus; Recovery; Regulation; Rehabilitation therapy; Reporting; Research; Rest; Rodent Model; Sensory; Short-Term Memory; Silver Staining; Skeleton; Structure; Survivors; Tactile; Task Performances; Testing; Therapeutic Intervention; Time; Training; Traumatic Brain Injury; Traumatic Brain Injury recovery; Treatment Efficacy; United States; Veterans; Vibrissae; clinically relevant; cognitive performance; diagnostic biomarker; efficacy evaluation; environmental enrichment for laboratory animals; fluid percussion injury; forest; gamma-Aminobutyric Acid; improved; improved outcome; long term memory; male; mechanical force; mild traumatic brain injury; neuropathology; novel; object recognition; pre-clinical; preservation; rehabilitation strategy; response; somatosensory; sound; symptomatology; therapeutic biomarker; therapeutically effective; way finding

Project Summary Traumatic brain injury (TBI) results from mechanical forces applied to the head. Ensuing cascades of complex pathophysiology transition the injury event into a disease process. The protracted nature of disease dissuades continued pharmacological interventions in favor of rehabilitation strategies to alleviate neurological impairment. The enduring constellation of emotional, somatic, and cognitive impairments degrade quality of life for the millions of TBI survivors suffering from long-term neurological symptoms, and countless more remain undiagnosed. For these individuals, including a significant percentage of our Veterans, effective therapeutic interventions are desperately needed. With this clinical problem in mind, rehabilitation strategies have reported mixed results, as most have not focused on specific symptomatology or explored cellular processes. In rodent models of diffuse TBI, a late-onset, long-lasting sensory sensitivity to whisker stimulation develops over time, similar to the protracted onset of light and sound sensitivity in TBI survivors. In addition, experimental diffuse TBI causes clinically-relevant impairment in short term, long term, and working memory. Therefore, laboratory studies provide a platform to evaluate efficacy and mechanism of rehabilitation strategies to mitigate neurological symptoms after diffuse brain injury. In this proposal, we test the hypothesis that therapeutic efficacy of TBI rehabilitation depends on regional activation during rehabilitation task performance. It follows that temporary pharmacological inactivation during rehabilitation would eliminate therapeutic efficacy and associated transformations to relevant brain circuits. To test the hypothesis, adult, male and female rats receive a diffuse brain or sham injury by midline fluid percussion. Aim 1 addresses whether tactile exploration and spatial navigation through a peg forest rehabilitation environment for three weeks after 1 month post-injury alleviates sensory sensitivity and cognitive impairment at two and three months post-injury. Preliminary data indicate peg forest rehabilitation improves both neurological symptoms, whereas an open field rehabilitation only improves sensory sensitivity. Aim 2 identifies brain regions activated by rehabilitation and demonstrates the inactivation by local GABA-A agonist muscimol administration as measured by cFos expression levels. Aim 3 inactivates associated brain regions (S1BF, hippocampus) to determine whether regional activation is necessary for rehabilitation therapeutic efficacy. Aim 4 quantifies rehabilitation-related neuropathology and cellular morphology in associated sensory and cognitive circuitry. Expected outcomes would show therapeutic efficacy of peg forest rehabilitation on somatosensory and cognitive outcome measures above open field rehabilitation and caged control animals, which depended on regional activation and underlying remodeling of circuit structure. The impact of these studies is a firm foundation to promote rehabilitation strategies, rather than rest, in the recovery from TBI.

项目概要 创伤性脑损伤 (TBI) 是由施加到头部的机械力引起的。随后发生的级联 复杂的病理生理学将损伤事件转变为疾病过程。疾病的长期性质 劝阻继续进行药物干预，转而采用康复策略来缓解神经功能障碍 损害。一系列持久的情感、躯体和认知障碍降低了生活质量 对于数百万患有长期神经系统症状的 TBI 幸存者，以及无数的幸存者 未确诊。对于这些人，包括我们很大比例的退伍军人，有效的治疗 迫切需要干预措施。考虑到这一临床问题，康复策略已报告 结果好坏参半，因为大多数人没有关注特定的症状学或探索细胞过程。在啮齿动物中 弥漫性 TBI 模型，对胡须刺激的迟发性、持久的感觉敏感性随着时间的推移而发展， 类似于 TBI 幸存者长期出现的光和声音敏感性。此外，实验性弥漫性 TBI 导致短期、长期和工作记忆的临床相关损伤。因此，实验室 研究提供了一个平台来评估康复策略的功效和机制，以减轻神经功能障碍 弥漫性脑损伤后的症状。在本提案中，我们检验了以下假设：TBI 的治疗效果 康复取决于康复任务执行过程中的区域激活。由此可见 康复期间暂时的药理失活将消除治疗效果和相关的 相关脑回路的转变。为了检验这一假设，成年、雄性和雌性大鼠均接受了弥漫性 中线液体冲击造成脑损伤或假损伤。目标 1 解决触觉探索和空间探索是否 受伤后 1 个月后，在钉子森林康复环境中导航三周，症状缓解 受伤后两三个月的感觉敏感性和认知障碍。初步数据表明挂钩 森林康复可以改善两种神经症状，而露天康复只能改善 感官敏感性。目标 2 识别康复激活的大脑区域并展示失活情况 通过局部 GABA-A 激动剂蝇蕈醇施用（通过 cFos 表达水平测量）。目标 3 失效 相关的大脑区域（S1BF、海马体）以确定区域激活是否是必要的 康复治疗功效。目标 4 量化康复相关的神经病理学和细胞形态 相关的感觉和认知电路。预期结果将显示钉林的治疗功效 体感和认知结果测量的康复高于露天康复和笼养康复 控制动物，这取决于区域激活和回路结构的潜在重塑。影响 这些研究为促进康复策略（而不是休息）奠定了坚实的基础 创伤性脑损伤。