Mechanisms of structural neuronal plasticity and functional remapping after strok

描述（由申请人提供）：由中风引起的一些感觉、运动和认知障碍最终得到改善，表明大脑具有自我修复和恢复失去的功能的能力。但是，关于中风后结构重新布线和功能重新映射的机制仍然存在很大的知识差距。这种大脑可塑性的大部分发生在缺血性病变核心周围的组织中，称为梗死周围皮层，但这些变化确切发生的时间以及哪些细胞参与尚不清楚。此外，回路重塑与功能改善的相关程度尚不清楚。最近在体内成像的发展，可以帮助克服以前的限制，用于记录神经元结构和功能重新映射的变化的实验技术。特别是，中风可塑性及其在功能恢复中的作用的研究将受益于纵向体内成像方法的使用，使研究人员能够跟踪神经元结构和功能的动态与精致的空间和时间分辨率，在中风前后相同的神经元或电路。我们建议使用一种创新的方法和尖端的成像技术，包括慢性体内双光子显微镜，监测轴突/树突结构，并记录丢失的功能的重新映射，以及光遗传学和药理学操作来扰乱这种重新映射。我们想验证锥体细胞轴突或GABA能中间神经元的突触重塑在脑修复中也起作用的假设。我们想验证四个假设：1）梗死周围皮层的锥体细胞轴突和GABA能中间神经元的树突在卒中后神经修复中也起作用; 2）结构可塑性的程度与功能恢复相关; 3）卒中后丢失的功能根据预先建立的回路一致地重新映射; 4）阻断紧张性抑制或采用限制性治疗可通过增强可塑性来促进恢复。我们的研究将集中在临床相关的成年小鼠大脑中动脉闭塞中风模型，并将直接检查血流动力学，侧支血流和回路可塑性的相关问题。我们提出的工作旨在产生关于中风和其他类型脑损伤后皮质回路可塑性的新知识，希望这将导致更好的康复策略，以增强功能恢复。

DESCRIPTION (provided by applicant): Some of the sensory, motor and cognitive impairments caused by stroke eventually improve, suggesting that the brain has the ability to repair itself and restore lost functionalities. But large knowledge gaps still exist regarding the mechanisms of structural rewiring and functional remapping after stroke. Much of this brain plasticity takes place in the tissue surrounding the core of the ischemic lesion, known as the peri-infarct cortex, but when exactly these changes occur and which cells participate is not clear. In addition, the extent to which circuit remodeling correlates with functional improvement is not known. Recent in vivo imaging developments could help overcome previous limitations in experimental techniques used to record changes in neuronal structure and functional remapping. In particular, research on stroke plasticity and its role in functional recovery would benefit from the use of longitudinal in vivo imaging approaches that allow the investigator to track the dynamics of neuronal structure and function with exquisite spatial and temporal resolution, in the same neurons or circuits before and after stroke. We propose to use an innovative approach and cutting edge imaging techniques, including chronic in vivo two-photon microscopy, to monitor axonal/dendritic structure and record the remapping of lost functionalities, as well as optogenetics and pharmacological manipulations to perturb such remapping. We want to test the hypothesis that synaptic remodeling in pyramidal cell axons or GABAergic interneurons, also plays a role in brain repair. We want to test four hypotheses: 1) that pyramidal cell axons and dendrites of GABAergic interneurons in peri-infarct cortex also play a role in neural repair after stroke; 2) that the degree of structural plasticity correlates wth functional recovery; 3) that lost functionalities are consistently remapped according to pre-established circuits after stroke; and 4) that blocking tonic inhibition or using constraint therap improve recovery by enhancing plasticity. Our studies will focus on the clinically relevant middle cerebral artery occlusion model of stroke in adult mice and will directly examine the related issues of hemodynamics, collateral blood flow, and circuit plasticity. Our proposed work is intended to generate new knowledge about cortical circuit plasticity after stroke and other types of brain injury, with the hope that this will lead to better strategies for rehabilitation that enhnce functional recovery.