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: 9096913
• 负责人: Andrew K Dunn
• 金额: $ 33.58万
• 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 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9096913
• 关键词: 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; Learning Skill; Lesion; Limb structure; Link; Maps; Motor; Motor Cortex; Mus; Nature; Neuronal Plasticity; Neurons; Outcome; Paresis; Patients; Procedures; Process; Proteins; Reaction; Rehabilitation therapy; 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 measurement; behavioral outcome; behavioral plasticity; brain remodeling; density; disability; experience; functional disability; functional improvement; hippocampal pyramidal neuron; improved; improved functioning; in vivo; in vivo imaging; individualized medicine; injured; light microscopy; light transmission; microstimulation; motor impairment; mouse model; neuronal growth; neurovascular; post stroke; rehabilitation strategy; relating to nervous system; response; 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.

描述（由申请人提供）：在尝试促进中风后恢复大脑可塑性时，时机可能很关键。中风的动物研究表明，缺血性损伤会引发一系列促进生长和抑制细胞反应以及长时间的神经解剖重组。许多缺血触发的重塑事件是活动依赖性的并且对行为操作敏感。人们越来越认识到，康复策略可能会利用这种敏感性来优化中风结果，并且这可能需要干预措施的时间安排与重塑的动态阶段相一致，时间可能会因中风和患者特征而异，包括年龄。然而，人们对中风后康复中时间依赖性背后的特定细胞事件仍然知之甚少，因此不可能明确地针对它们来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不同的影响。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，其中功能损伤通过瘫痪肢体的运动康复训练得到改善，或者通过非瘫痪肢体的代偿技能学习而加剧。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、运动皮质组织的高分辨率绘图以及定量光学和电子显微镜一起使用，以揭示功能有益和功能影响的时间和年龄依赖性。对梗塞周围皮层神经和血管重塑的有害经历，以及这些影响对皮层重组和行为结果的影响。 该项目的中心假设是，行为经历和损伤引起的神经和血管可塑性以时间和年龄依赖性方式相互作用，重塑剩余运动皮层的神经连接和脉管系统，并影响行为结果。具体目的是检验以下假设：运动康复训练 (1) 与缺血后神经和血管可塑性相互作用，以促进梗塞周围皮层的功能性有益重塑，但这种相互作用取决于 (2) 血管生成，(3)其相对于缺血性损伤发生的具体时间和持续时间，（4）其相对于非麻痹肢体代偿技能学习发展的时间，以及（5）其期间的年龄发生缺血性损伤。该项目的长期目标是确定运动康复训练效果具有时间依赖性的神经和血管事件，以便可以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。

项目成果

Postnatal Ablation of Synaptic Retinoic Acid Signaling Impairs Cortical Information Processing and Sensory Discrimination in Mice.

出生后突触视黄酸信号的消除会损害小鼠的皮质信息处理和感觉辨别。

• 发表时间: 2018
• 作者: Park, Esther;Tjia, Michelle;Zuo, Yi;Chen, Lu
• 通讯作者: Chen, Lu

Chronic imaging of cortical blood flow using Multi-Exposure Speckle Imaging.

使用多重曝光散斑成像对皮质血流进行慢性成像。

• 发表时间: 2013-06
• 作者: Kazmi, Syed Mohammad Shams;Parthasarthy, Ashwin B;Song, Nelly E;Jones, Theresa A;Dunn, Andrew K
• 通讯作者: Dunn, Andrew K

Dynamic light scattering Monte Carlo: a method for simulating time-varying dynamics for ordered motion in heterogeneous media.

动态光散射蒙特卡罗：一种模拟异质介质中有序运动的时变动力学的方法。

• 发表时间: 2015-06-29
• 影响因子: 3.8
• 作者: Davis, Mitchell A;Dunn, Andrew K
• 通讯作者: Dunn, Andrew K

Astrocytic Contributions to Synaptic and Learning Abnormalities in a Mouse Model of Fragile X Syndrome.

脆性 X 综合征小鼠模型中星形胶质细胞对突触和学习异常的贡献。

• 发表时间: 2017-07-15
• 影响因子: 10.6
• 作者: Hodges, Jennifer L;Yu, Xinzhu;Gilmore, Anthony;Bennett, Hannah;Tjia, Michelle;Perna, James F;Chen, Chia;Li, Xiang;Lu, Ju;Zuo, Yi
• 通讯作者: Zuo, Yi

Sensitivity of laser speckle contrast imaging to flow perturbations in the cortex.

激光散斑对比成像对皮层流动扰动的敏感性。

• DOI: 10.1364/boe.7.000759
• 发表时间: 2016-03-01
• 期刊: Biomedical optics express
• 影响因子: 3.4
• 作者: Mitchell A. Davis;L. Gagnon;D. Boas;A. Dunn
• 通讯作者: A. Dunn