Mechanisms of structural neuronal plasticity and functional remapping after strok

描述（由申请人提供）：中风引起的一些感觉、运动和认知障碍最终会得到改善，这表明大脑有自我修复和恢复失去功能的能力。但是在脑卒中后的结构重新布线和功能重新映射机制方面仍然存在很大的知识空白。这种大脑可塑性大部分发生在缺血病灶核心周围的组织中，即梗死周围皮层，但这些变化究竟何时发生以及哪些细胞参与其中尚不清楚。此外，回路重塑在多大程度上与功能改善相关尚不清楚。最近体内成像的发展可以帮助克服以前用于记录神经元结构变化和功能重新映射的实验技术的局限性。特别是，脑卒中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，该方法使研究者能够在中风前后以精确的空间和时间分辨率跟踪神经元结构和功能的动态。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，来监测轴突/树突结构，记录丢失功能的重新映射，以及光遗传学和药理学操作来干扰这种重新映射。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)脑梗死周围皮层gaba能中间神经元的锥体细胞轴突和树突也在脑卒中后神经修复中发挥作用；2)结构塑性程度与功能恢复相关；3)根据中风后预先建立的电路，丢失的功能始终如一地重新映射；4)阻断强直抑制或使用约束疗法通过增强可塑性来促进恢复。我们的研究将集中于临床相关的成年小鼠脑卒中大脑中动脉闭塞模型，并将直接研究血流动力学、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层回路可塑性的新知识，希望这将导致更好的康复策略，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.