Neurovascular Mechanisms of Time-Dependencies in Stroke Rehabilitation

中风康复中时间依赖性的神经血管机制

• 批准号: 8439596
• 负责人: Andrew K Dunn
• 金额: $ 34.69万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8439596
• 关键词: Abbreviations; Age; Angiostatins; Animals; Area; Automobile Driving; Awareness; Behavior; Behavior Control; Behavior Therapy; Behavioral; Blood Vessels; Blood flow; Brain; Cells; Cerebrovascular Circulation; Characteristics; Chronic; Dendritic Spines; Dependency; Development; Effectiveness; Electron Microscopy; Elements; Endostatins; Event; Forelimb; Functional disorder; Goals; Growth; Hand; Image; Impairment; Infarction; Injury; Intervention; Ischemia; Knowledge; Learning; Lesion; Limb structure; Link; Maps; Motor; Motor Cortex; Mus; Nature; Neuronal Plasticity; Neurons; Occipital lobe; Outcome; Patients; Procedures; Process; Proteins; Reaction; Rehabilitation therapy; Relative (related person); Reliance; Residual state; Resolution; Shapes; Staging; Stroke; Structure; Synapses; Testing; Time; Training; Transmission Electron Microscopy; Upper Extremity; Vascular remodeling; Vertebral column; age related; aged; angiogenesis; arm; behavior influence; behavior measurement; brain remodeling; density; disability; experience; functional disability; functional improvement; hippocampal pyramidal neuron; improved; improved functioning; in vivo; injured; light microscopy; light transmission; microstimulation; motor impairment; mouse model; neuronal growth; post stroke; rehabilitation strategy; relating to nervous system; response; skills; stroke rehabilitation; tool; two-photon

DESCRIPTION (provided by applicant): Timing is likely to be critical in attempts to promote restorative brain plasticity after stroke. Animal studies of stroke have revealed that ischemic injury triggers cascades of growth promoting and inhibiting cellular reactions and prolonged periods of neuroanatomical reorganization. Many ischemia-triggered remodeling events are activity-dependent and sensitive to behavioral manipulations. There is a growing awareness that rehabilitation strategies might capitalize on this sensitivity to optimize stroke outcome, and that this is likely to require that interventions be timed to coincide with more dynamic stages of remodeling, a timing likely to vary with stroke and patient characteristics, including age. However, the specific cellular events underlying time- dependencies in post-stroke rehabilitation continue to be poorly understood, making it impossible to clearly target them to optimize and tailor rehabilitation strategies. This project is focused on understanding how behavioral experiences differentially impact, depending on timing, post-ischemic neural and vascular remodeling events and their coordination, and the relevance of these time-dependencies for long-term outcome. This will be studied in a mouse model of chronic upper extremity (forelimb) impairments resulting from unilateral ischemic motor cortical damage in which functional impairments are improved by motor rehabilitative training of the paretic limb or exacerbated by compensatory skill learning with the nonparetic limb. Repeated in vivo imaging of synaptic elements, vascular microstructure and blood flow will be used together with sensitive behavioral measures, high resolution mapping of motor cortical organization and quantitative light and electron microscopy to reveal time- and age-dependencies in the effects of functionally beneficial and detrimental experiences on neural and vascular remodeling in peri-infarct cortex, and the consequences of these effects for cortical reorganization and behavioral outcome. The central hypothesis of this project is that behavioral experience- and injury-induced neural and vascular plasticity interact in a time- and age-dependent manner to remodel neural connections and vasculature in remaining motor cortex and to influence behavioral outcome. The specific aims are to test the hypotheses that motor rehabilitative training (1) interacts with post-ischemic neural and vascular plasticity to promote functionally beneficial remodeling of peri-infarct cortex but that this interaction is dependent upon (2) angiogenesis, (3) on its specific timing and duration relative to the onset of ischemic injury, (4) on its timing relative to the development of compensatory skill learning with the nonparetic limb and (5) on the age during which ischemic damage is incurred. The long-term goal of this project is to identify neural and vascular events that create time-dependencies in motor rehabilitative training efficacy so that these events can be targeted to tailor and facilitate the effects of rehabilitative training and to improve long-ter outcome after stroke. PUBLIC HEALTH RELEVANCE: Rehabilitative training approaches remain the primary means of improving function in the chronic period after stroke, but they are far from perfect and there i insufficiently detailed knowledge of their mechanisms to understand what needs to be changed to improve them. This project will reveal neural and vascular events that underlie time- and age-dependencies in motor rehabilitative training effects after stroke. The results will improve our understanding of the brain changes underlying rehabilitation efficacy and reveal new targets for optimizing and tailoring treatments for post-stroke disabilities.

描述（由申请人提供）：时间对于促进中风后恢复性脑可塑性的尝试可能至关重要。中风的动物研究表明，缺血性损伤触发了促进和抑制细胞反应的生长级联，并延长了神经解剖学重组的时期。许多由缺血触发的重塑事件依赖于活动，并且对行为操纵敏感。人们越来越意识到，康复策略可能利用这种敏感性以优化中风结果，并且 这很可能要求将干预措施定时与更具动态的重塑阶段相吻合，这个时间可能会随着中风和患者特征（包括年龄）的变化而变化。但是，势头康复中的时间依赖性的特定细胞事件继续被鲜为人知，这使得不可能明确针对它们以优化和量身定制康复策略。该项目的重点是理解行为经历如何差异化影响，具体取决于时间，缺血后的神经和血管重塑事件及其协调性以及这些时间依赖性与长期结果的相关性。这将在单侧缺血性运动皮质损伤引起的慢性上肢（前肢）损伤的小鼠模型中进行研究，在这种损害中，通过对副肢体的运动康复训练或通过非顾问肢体的补偿技巧来改善功能障碍。突触元件的体内反复成像，血管显微结构和血流将与敏感的行为措施一起使用，运动皮质组织的高分辨率映射以及定量光和电子显微镜，以揭示功能上有益的和年龄的依赖性对侵入周围皮质的神经和血管重塑的有害经历，以及这些作用对皮质重组和行为结果的后果。 该项目的核心假设是，行为经验和损伤引起的神经和血管可塑性以时间和年龄的方式相互作用，以重塑剩余运动皮层的神经联系和脉管系统，并影响行为结果。具体目的是测试运动康复训练（1）与缺血后相互作用的假设 神经和血管可塑性以促进侵袭性皮质的功能有益的重塑，但这种相互作用取决于（2）血管生成，（3）相对于缺血性损伤发作的其特定时间和持续时间（4）发展 通过非准四肢和（5）在发生缺血性损害的年龄上学习的补偿技巧。该项目的长期目标是确定神经和血管事件，这些事件在运动康复训练功效中创造时间依赖性，以便可以针对这些事件来量身定制和促进康复训练的影响，并改善中风后的长期结果。 公共卫生相关性：康复培训方法仍然是中风后慢性时期改善功能的主要手段，但它们远非完美，在那里我对他们的机制的详细知识不足以了解需要更改的方法来改善它们。该项目将揭示神经和血管事件，这些事件是中风后运动康复训练效果的时间和年龄依赖性的基础。结果将提高我们对康复功效的大脑变化的理解，并揭示用于优化和量身定制势力障碍治疗方法的新目标。