Neurovascular Mechanisms of Time-Dependencies in Stroke Rehabilitation

描述（由申请人提供）：在尝试促进中风后恢复性脑可塑性时，时机可能至关重要。中风的动物研究已经揭示，缺血性损伤触发级联的生长促进和抑制细胞反应以及延长的神经解剖重组期。许多缺血触发的重塑事件是活动依赖性的，并且对行为操纵敏感。越来越多的人意识到，康复策略可能会利用这种敏感性来优化卒中结局， 这可能需要对干预进行定时，以与重塑的更动态阶段相一致，定时可能随中风和患者特征（包括年龄）而变化。然而，中风后康复中的时间依赖性的具体细胞事件仍然知之甚少，使得不可能明确地靶向它们以优化和定制康复策略。该项目的重点是了解行为体验如何根据时间、缺血后神经和血管重塑事件及其协调以及这些时间依赖性与长期结果的相关性产生差异性影响。这将在单侧缺血性运动皮质损伤导致的慢性上肢（前肢）损伤的小鼠模型中进行研究，其中功能损伤通过瘫痪肢体的运动康复训练得到改善，或通过非瘫痪肢体的代偿性技能学习加重。突触元件、血管微观结构和血流的重复体内成像将与敏感的行为测量、运动皮层组织的高分辨率映射以及定量光学和电子显微镜一起使用，以揭示功能上有益和有害的经历对梗死周围皮层的神经和血管重塑的影响的时间和年龄依赖性，以及这些效应对皮层重组和行为结果的影响。 该项目的中心假设是，行为经验和损伤诱导的神经和血管可塑性以时间和年龄依赖性的方式相互作用，以重塑剩余运动皮层中的神经连接和血管，并影响行为结果。具体目的是检验运动康复训练（1）与缺血后 神经和血管的可塑性，以促进功能上有益的重构周围梗死皮层，但这种相互作用是依赖于（2）血管生成，（3）其具体的时间和持续时间相对于缺血性损伤的发病，（4）其时间相对于发展， 非瘫痪肢体的补偿性技能学习和（5）缺血性损伤发生的年龄。该项目的长期目标是识别在运动康复训练效果中产生时间依赖性的神经和血管事件，以便这些事件可以有针对性地定制和促进康复训练的效果，并改善卒中后的长期结果。

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.