Brain injury rehabilitation modality, regulation, & structural plasticity

脑损伤康复方式、调节、

• 批准号: 9763360
• 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 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9763360
• 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; 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; 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)是由于机械力作用于头部造成的。随之而来的是 复杂的病理生理学将损伤事件转化为疾病过程。疾病的长期性 劝阻持续的药物干预，转而采用康复策略来缓解神经疾病 减损。持久的情绪、躯体和认知障碍会降低生活质量。 对于数百万患有长期神经症状的脑外伤幸存者来说，还有无数人留下来 未确诊。对于这些人，包括我们的相当一部分退伍军人，有效的治疗 我们迫切需要进行干预。考虑到这一临床问题，康复策略已有报道 结果好坏参半，因为大多数人没有关注特定的症状或探索细胞过程。在啮齿动物中 弥漫性脑损伤的模型是一种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， 类似于脑外伤幸存者迟发性的光和声敏感性。此外，实验性弥漫性脑损伤 导致临床相关的短期、长期和工作记忆损害。因此，实验室 研究为评估康复策略缓解神经功能障碍的疗效和机制提供了一个平台 弥漫性脑损伤后的症状。在这项建议中，我们检验了脑外伤治疗效果的假设 康复依赖于康复任务执行过程中的区域激活。由此可以得出结论 在康复过程中暂时停用药物会消除治疗效果并与 转化为相关的大脑回路。为了验证这一假设，成年、雄性和雌性大鼠接受了一种弥漫性 中线液体撞击致脑损伤或假性损伤。目标1解决了触觉探索和空间探索 在损伤后1个月后通过peg森林恢复环境航行三周可缓解 伤后2个月和3个月的感觉敏感度和认知损害。初步数据显示盯住美元 森林康复改善了这两种神经症状，而野外康复只改善了 感官敏感度。目标2确定康复激活的大脑区域，并演示失活 通过局部给予GABA-A激动剂麝香酚，通过CFOS表达水平来衡量。AIM 3停用 相关的大脑区域(S1BF，海马体)，以确定区域激活是否是必要的 康复治疗效果。目标4量化与康复相关的神经病理和细胞形态 在相关的感觉和认知回路中。预期结果将显示佩格森林的治疗效果 开放式康复和笼式康复对躯体感觉和认知功能的影响 对照动物，依赖于局部激活和潜在的电路结构重塑。其影响 这些研究中的一个坚实的基础是促进康复战略，而不是休息，在从 TBI。