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.

项目摘要 创伤性脑损伤（TBI）是由施加在头部的机械力引起的。随之而来的是 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 劝阻继续药物干预，支持康复策略，以减轻神经系统疾病， 损伤情感、身体和认知障碍的持久组合降低了生活质量 对于数百万患有长期神经系统症状的TBI幸存者来说， 未确诊对于这些人，包括我们的退伍军人的显着比例，有效的治疗 迫切需要采取干预措施。考虑到这一临床问题，康复策略已报告 混合的结果，因为大多数没有集中在特定的肿瘤学或探索细胞过程。在啮齿类动物 弥漫性TBI模型，随着时间的推移，对胡须刺激的迟发性、持久的感觉敏感性， 类似于TBI幸存者对光和声音敏感的延迟发作。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，以评估康复策略的疗效和机制，以减轻神经系统疾病 弥漫性脑损伤后的症状在这个建议中，我们测试的假设，TBI的治疗效果 康复依赖于在康复任务执行期间的区域激活。它遵循 康复期间暂时的药理学失活将消除治疗效果和相关的 转换到相关的大脑回路。为了验证这一假设，成年大鼠、雄性大鼠和雌性大鼠接受了弥漫性的 通过中线液压冲击造成脑或假损伤。目标1解决触觉探索和空间 在损伤后1个月，通过钉森林恢复环境航行三周， 感觉灵敏度和认知障碍在两个和三个月后受伤。初步数据显示， 森林康复改善了神经系统症状，而开放的领域康复只改善了 感觉灵敏度目的2识别出康复激活的脑区，并证明了失活 通过局部GABA-A激动剂蝇蕈醇给药，如通过cFos表达水平测量的。目标3失活 相关的脑区（S1 BF，海马），以确定区域激活是否是必要的， 康复治疗效果目的4量化康复相关的神经病理学和细胞形态学 在相关的感觉和认知回路中。预期结果将显示peg forest的治疗效果 康复对躯体感觉和认知结果的测量高于开放场地康复和笼舍康复 控制动物，这取决于区域激活和潜在的电路结构重塑。的影响 这些研究是一个坚实的基础，以促进康复战略，而不是休息，在恢复从 创伤性脑损伤