Mechanisms of structural neuronal plasticity and functional remapping after strok

描述(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，这表明大脑有能力自我修复和恢复失去的功能。但关于卒中后结构重连和功能重绘的机制仍存在很大的知识空白。这种大脑的可塑性大部分发生在缺血损伤核心周围的组织中，也就是所谓的梗死区周围皮质，但这些变化具体发生在什么时候，以及哪些细胞参与尚不清楚。此外，电路重塑与功能改善之间的关联程度尚不清楚。活体成像的最新进展可能有助于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，中风可塑性及其在功能恢复中作用的研究将受益于体内纵向成像方法的使用，这种方法使研究人员能够以精细的空间和时间分辨率跟踪中风前后相同神经元或回路中神经元结构和功能的动态变化。我们建议使用一种创新的方法和尖端的成像技术，包括慢性活体双光子显微镜，来监测轴突/树突状结构，记录丢失功能的重新映射，以及光遗传学和药物操纵来干扰这种重新映射。我们想验证这样一个假设，即锥体细胞轴突或GABA能中间神经元的突触重构也在大脑修复中发挥作用。我们想要检验四个假设：1)梗塞周围皮质内GABA能中间神经元的锥体细胞轴突和树突也在卒中后的神经修复中发挥作用；2)结构可塑性的程度与功能恢复有关；3)卒中后失去的功能一直按照预先建立的回路重新映射；以及4)阻断紧张性抑制或使用束缚抑制可以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模型上，并将直接检查血流动力学、侧支循环血流和电路可塑性的相关问题。我们拟议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，以加强功能恢复。

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.