OPTOGENETIC MAPPING OF CELL SPECIFIC CONNECTIONS IN THE MOUSE BRAIN AFTER STROKE

中风后小鼠大脑中细胞特异性连接的光遗传学图谱

• 批准号: 10201764
• 负责人: ADAM Q BAUER
• 金额: $ 41.89万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10201764
• 关键词: Adult; Affect; Anatomy; Animal Model; Area; Automobile Driving; Axon; Behavioral; Biological Markers; Brain; Brain region; Cells; Complement; Contralateral; Data; Distant; Evolution; Exhibits; Functional Magnetic Resonance Imaging; Genes; Global Change; Goals; Growth Associated Protein 43; Growth Cones; Image; Impairment; Incidence; Individual; Infarction; Injury; Integral Membrane Protein; Ischemia; Ischemic Stroke; Knockout Mice; Knowledge; Left; Maps; Measures; Molecular; Motor; Motor Cortex; Mus; Neuronal Plasticity; Optics; Pathway interactions; Patients; Pattern; Physical therapy; Population; Prevalence; Process; Proteins; Recovery; Recovery of Function; Rehabilitation therapy; Reporting; Rest; Role; Signal Transduction; Site; Stimulus; Stroke; Structure; Synapses; System; Technology; Testing; Time; Tissues; United States; Vertebral column; awake; axon growth; axonal sprouting; behavior influence; brain repair; density; disability; experience; functional restoration; human model; improved; in vivo; ischemic lesion; knock-down; motor recovery; neurobehavioral; neuroimaging; optogenetics; overexpression; post stroke; relating to nervous system; repaired; restoration; stroke recovery; stroke survivor; therapeutic target; transcriptome

PROJECT SUMMARY/ABSTRACT The goal of the current proposal is to determine how molecular- and systems-level mechanisms of brain repair interact to influence behavioral recovery after focal ischemia in mice. Stroke causes direct structural damage to local circuits and indirect functional damage to global networks that can result in behavioral deficits spanning multiple domains. Neuroplasticity after stroke involves molecular changes within perilesional tissue that can be influenced by distant regions spared from injury. At the systems level, functional magnetic resonance imaging has revealed that recovery from stroke is associated with functional reorganization of the brain through the formation of new or alternative circuits. Directly impacted brain regions remap to adjacent tissue in concert with behavioral recovery. More globally, patterns of resting-state functional connectivity gradually normalize in patients experiencing good recovery. While functional neuroimaging studies in humans and animal models consistently demonstrate local and global changes in functional brain organization after stroke, it is unknown how these processes interrelate to support behavioral recovery. Understanding how (or if) remapped brain regions reintegrate into global networks to support recovery after stroke requires more direct examination of evolving local and global connectivity structure. At the molecular level, limited data suggest that new axons appear after stroke in periinfarct cortex and distant, homotopic contralateral cortex. Increased expression of plasticity-associated genes are found in perilesional tissue including those involved in axonal sprouting. Growth Associated Protein 43 (GAP-43) is an integral membrane protein found in axonal growth cones, synapses, and widely induced after focal ischemia. This protein might drive anatomical connections within the periinfarct that support functional restoration after stroke. However, the role of axonal sprouting in functional neuroplasticity following focal ischemia has not been examined. We hypothesize that GAP-43-dependent axonal sprouting is required for local circuit repair and reintegration into global networks, and this evolving process drives the degree of behavioral recovery after stroke. We further hypothesize that axonal sprouting can be modulated by neural activity in excitatory nodes functionally-connected to the site of injury, and these activity-dependent processes depend on GAP-43. Critical barriers to testing this hypothesis in vivo have been the inability to serially examine global network connectivity as it evolves with recovery, and longitudinally examine subunits of remapped circuits as they change over time. We have overcome these barriers by integrating optical intrinsic signal imaging with optogenetics to probe local circuit connectivity more directly. We will use this technology to determine: 1) how the reemergence of local circuits and global networks relate to functional recovery following focal ischemia, 2) if GAP-43-dependent axonal sprouting is required for local and/or global motor network repair and behavioral recovery, and 3) if activity in excitatory motor nodes modulates local/global motor network repair and behavioral recovery, and if these changes rely on GAP-43.

项目摘要/摘要 当前建议的目的是确定分子 - 和系统级别修复机制如何 相互作用以影响小鼠局灶性缺血后的行为恢复。中风会直接造成结构性损害 本地电路和对全球网络的间接功能损害，可能导致行为缺陷跨越 多个域。中风后的神经可塑性涉及周围组织内的分子变化 受伤害的遥远地区的影响。在系统级别，功能磁共振成像 已经揭示了中风的恢复与大脑的功能重组有关 新电路或替代电路的形成。直接影响大脑区域，与 行为恢复。在全球范围内，静止状态功能连通性的模式逐渐正常化 康复良好的患者。同时在人类和动物模型中的功能性神经影像学研究 始终证明中风后功能性脑组织的本地和全球变化，这是未知的 这些过程如何相互关联以支持行为恢复。了解如何（或是否）重塑大脑 区域重新融入全球网络以支持中风后的恢复 不断发展的本地和全球连接结构。在分子水平上，有限的数据表明新轴突 中风后出现在侧周围皮层和远处，同位对侧皮层中。增加表达 在周围组织中发现了与塑性相关的基因，包括参与轴突发芽的基因。生长 相关蛋白43（GAP-43）是在轴突生长锥，突触和 局灶性缺血后广泛诱导。该蛋白质可能会在周围的围绕中引起解剖学连接 支持中风后的功能恢复。但是，轴突发芽在功能性神经塑性中的作用 尚未检查以下局部缺血。我们假设GAP-43依赖性轴突发芽是 本地电路维修和重新融合到全球网络所必需的，并且这种不断发展的过程推动了学位 中风后行为恢复。我们进一步假设可以通过神经调节轴突发芽 与损伤部位相关的兴奋性节点的活性，这些依赖于活动的过程 取决于GAP-43。在体内检验这一假设的关键障碍是无法串行检查的 随着恢复的发展，全球网络连接性随着恢复的发展而演变，并纵向检查了重新映射电路的亚基 随着时间的流逝而改变。我们通过将光学固有信号成像与 光遗传学以更直接地探测局部电路连接。我们将使用这项技术来确定：1） 本地电路和全球网络的重新出现与局灶性缺血后的功能恢复有关，2）如果 GAP-43依赖性轴突发芽是本地和/或全球运动网络修复以及行为的需要的 恢复，3）如果兴奋性电机节点中的活动调节本地/全球运动网络修复和行为 恢复，如果这些更改依赖于GAP-43。