The Influence of Arc on Remapping, Network Repair, and Functional Recovery After Stroke

电弧对中风后重新映射、网络修复和功能恢复的影响

• 批准号: 10389115
• 负责人: Ryan Bowen
• 金额: $ 4.68万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10389115
• 关键词: AMPA Receptors; Adult; Affect; Axon; Behavioral; Brain; Brain Injuries; Contralateral; Cytoskeleton; Data; Grant; Healthcare; Hemoglobin; Hippocampus (Brain); Image; Impairment; In Vitro; Infarction; Ischemia; Ischemic Stroke; Knockout Mice; Long-Term Depression; Long-Term Potentiation; Mediating; Mentors; Molecular Target; Mus; Neurons; Optics; Pattern; Persons; Positioning Attribute; Process; Proteins; Recovery; Recovery of Function; Rest; Role; Sensory; Sensory Deprivation; Signal Transduction; Somatosensory Cortex; Stroke; Synapses; Synaptic plasticity; Therapeutic Intervention; United States; Vibrissae; Visual Cortex; barrel cortex; brain repair; calcium indicator; cost; critical period; developmental plasticity; disability; experience; experimental study; fluorescence imaging; imaging system; improved; insight; memory consolidation; neuronal circuitry; neurovascular; overexpression; post stroke; repaired; somatosensory; stroke recovery; stroke survivor; synaptogenesis

PROJECT SUMMARY/ABSTRACT Although some stroke survivors experience spontaneous recovery in the weeks to months following stroke, it is often incomplete. This critical period after stroke, when brain plasticity is heightened, provides a window of opportunity to enhance recovery. However, the precise mechanisms underlying this post-stroke plasticity will need to be better understood before therapeutic interventions can be developed to take advantage of this critical period of recovery. Some of the mechanisms involved in brain repair appear to recapitulate mechanisms involved in developmental plasticity. Exploiting similar processes that enhance plasticity, the Lee lab has recently demonstrated that recovery after stroke in adult mice can be enhanced by focal sensory deprivation, targeted to peri-infarct cortex. Enhanced recovery was mediated by activity-regulated cytoskeleton- associated protein (Arc) – a protein with critical roles in synaptic plasticity. Furthermore, remapping and functional recovery following stroke were absent in Arc knockout mice. Previous studies have shown that Arc overexpression can reopen developmental plasticity in adult visual cortex, raising the possibility of therapeutic intervention for enhancing post-stroke plasticity and repair. The Lee lab has also demonstrated that focal ischemia leads to disruption of functional connectivity (FC) in several brain networks. Here, FC was assessed using optical intrinsic signal imaging (OIS), relying on a neurovascular signal (intrinsic hemoglobin contrast) as a readout for remapping. Therefore, the true assessment of neuronal circuit repair was not determined. Using a wide-field fluorescent imaging system in combination with mice with genetically encoded calcium indicators (GECI), I have collected preliminary data demonstrating neuronal remapping after focal stroke. Furthermore, using FC analyses to examine resting state spontaneous activity, I have shown rapid changes in global brain networks following stroke. It is likely that complete recovery from stroke requires not only local thalamocortical circuit repair, but reintegration of this repaired local circuit into larger brain networks, as well as the temporal coordination of these two processes. The two specific aims of the project are therefore as follows: Aim 1: To determine the relationship between neuronal circuit repair, reintegration of repaired circuits into global brain networks, and behavioral recovery after stroke. Aim 2: To determine the effects of Arc on spatially directing neuronal circuit repair and reintegrating remapped circuits into brain networks, enhancing functional recovery.

项目概要/摘要 尽管一些中风幸存者在接下来的几周到几个月内会自然康复 中风后的这个关键时期，大脑的可塑性是可呼吸的，它通常是不完全的。 然而，中风后的确切机制。 在开发治疗干预措施以利用可塑性之前，需要更好地理解可塑性 这个关键的恢复时期的一些涉及大脑修复的机制似乎得到了重述。 Lee利用类似的过程来增强可塑性。 实验室最近证明，通过局部感觉可以增强成年小鼠中风后的恢复 剥夺，针对梗塞周围皮层的增强恢复是由活性调节的细胞骨架介导的。 相关蛋白（Arc）——一种在突触可塑性中发挥关键作用的蛋白质。 先前的研究表明，Arc 基因敲除小鼠中风后功能恢复不存在。 过度表达可以重新恢复成人视觉皮层的发育可塑性，从而提高治疗的可能性 增强中风后可塑性和修复的干预措施。 Lee 实验室还证明局灶性缺血会导致功能连接 (FC) 中断 在这里，FC 使用光学内在信号成像 (OIS) 进行评估，依赖于 神经血管信号（固有血红蛋白对比度）作为重映射的读数因此是真正的评估。 神经回路修复的效果尚未确定。 具有基因编码钙指示剂（GECI）的小鼠，我收集了初步数据证明 此外，使用 FC 分析来检查静息态自发性。 活动中，我发现中风后全球大脑网络发生了快速变化，很可能完全康复。 中风的治疗不仅需要局部丘脑皮质回路修复，还需要将修复后的局部回路重新整合到 更大的大脑网络，以及这两个过程的时间协调。 因此，该项目的两个具体目标如下： 目标 1：确定神经回路修复、修复后的回路重新整合到全局之间的关系 大脑网络和中风后的行为恢复。 目标 2：确定 Arc 对空间定向神经回路修复和重新整合重新映射的影响 电路进入大脑网络，增强功能恢复。