Mechanisms of structural neuronal plasticity and functional remapping after strok

中风后结构神经元可塑性和功能重映射的机制

基本信息

批准号：
8823835
负责人：
Carlos Portera-Cailliau
金额：
$ 33.69万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-04-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8823835
关键词：
Adult Animals Area Axon Blood flow Brain Brain Injuries Calcium Cells Cerebral cortex Chronic Contralateral Data Dendrites Dendritic Spines Development Experimental Models Health Human Image Imaging Techniques Impaired cognition Infarction Interneurons Investigation Knowledge Lead Location Microscopy Middle Cerebral Artery Occlusion Modeling Monitor Motor Mus Neuronal Plasticity Neurons Optics Patients Play Pyramidal Cells Recovery Recovery of Function Rehabilitation therapy Research Research Personnel Resolution Role Sensory Signal Transduction Stroke Structure Synapses Techniques Testing Time Tissues United States Vibrissae Work arm behavior test brain repair clinically relevant constraint induced movement therapy design disability functional improvement functional plasticity hemodynamics hippocampal pyramidal neuron improved in vivo in vivo imaging innovation ischemic lesion motor impairment optogenetics post stroke rehabilitation strategy relating to nervous system repaired research study temporal measurement tissue fixing two-photon

项目摘要

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.

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会得到改善，这表明大脑具有自我修复和恢复失去的功能的能力。但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巨大的知识差距。这种大脑可塑性大部分发生在缺血性病变核心周围的组织中，即梗塞周围皮层，但这些变化何时发生以及哪些细胞参与尚不清楚。此外，电路改造与功能改进的相关程度尚不清楚。最近的体内成像发展可以帮助克服以前用于记录神经元结构和功能重映射变化的实验技术的局限性。特别是，对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，该方法使研究人员能够在相同的神经元或回路中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。中风之前和之后。我们建议使用创新方法和尖端成像技术，包括慢性体内双光子显微镜，来监测轴突/树突结构并记录丢失功能的重新映射，以及光遗传学和药理学操作来扰乱这种重新映射。我们想要检验这样的假设：锥体细胞轴突或 GABA 能中间神经元的突触重塑也在大脑修复中发挥作用。我们想要检验四个假设：1）梗死周围皮质中的锥体细胞轴突和 GABA 能中间神经元的树突也在中风后的神经修复中发挥作用； 2）结构可塑性程度与功能恢复相关； 3) 中风后根据预先建立的回路一致地重新映射丢失的功能； 4）阻断强直抑制或使用约束疗法通过增强可塑性来改善恢复。我们的研究将重点关注成年小鼠中风的临床相关大脑中动脉闭塞模型，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有关中风和其他类型脑损伤后皮质回路可塑性的新知识，希望这将带来更好的康复策略，从而增强功能恢复。