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大脑可塑性时，时机可能是至关重要的。对中风的动物研究表明，缺血性损伤触发了促生长和抑制细胞反应的级联反应，并延长了神经解剖重组的时间。许多缺血触发的重塑事件是活动依赖的，对行为操作敏感。人们越来越意识到，康复策略可能会利用这种敏感性来优化中风的结果，这可能需要干预措施的时机与更动态的重塑阶段相吻合，这一时机可能会因中风和患者特征(包括年龄)而异。然而，卒中后康复中潜在的时间依赖性的特定细胞事件仍然知之甚少，使其不可能明确地针对它们来优化和定制康复策略。这个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情况产生不同的影响，以及这些时间依赖关系与长期结果的相关性。这将在由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，在该模型中，功能损伤通过偏瘫肢体的运动康复训练得到改善，或通过非偏瘫肢体的代偿性技能学习而加剧。重复的突触元素、血管微结构和血流的活体成像将与敏感的行为测量、高分辨率的运动皮质组织图和定量光学和电子显微镜一起使用，以揭示有益和有害经验对梗死区周围皮质神经和血管重构的影响的时间和年龄依赖性，以及这些影响对皮质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的方式相互作用，以重塑剩余运动皮质中的神经连接和血管系统，并影响行为结果。具体目的是验证以下假设：运动康复训练(1)与缺血后神经和血管可塑性相互作用，促进梗塞周围皮质有益的功能重建，但这种相互作用取决于(2)血管生成，(3)相对于缺血损伤发生的特定时间和持续时间，(4)相对于非瘫痪肢体的代偿性技能学习的发展时间，以及(5)造成缺血损伤的年龄。该项目的长期目标是确定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，以便这些事件能够有针对性地调整和促进康复训练的效果，并改善中风后的长期结果。

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.