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

项目总结/摘要 尽管一些中风幸存者在中风后的几周到几个月内经历了自发恢复， 中风，它往往是不完整的。中风后的这一关键时期，大脑的可塑性提高， 机会之窗，促进复苏。然而，这种中风后的确切机制 可塑性需要更好地理解，然后才能开发治疗干预措施， 在这个关键的复苏时期。大脑修复中的一些机制似乎概括了 参与发育可塑性的机制。利用类似的过程，提高可塑性，李 一个实验室最近证明，成年小鼠中风后的恢复可以通过局部感觉增强， 剥夺，靶向梗死周围皮层。增强的恢复是由活性调节的细胞骨架介导的， 相关蛋白（Arc）-在突触可塑性中具有关键作用的蛋白质。此外，重新映射和 中风后的功能恢复在Arc敲除小鼠中不存在。先前的研究表明，Arc 过表达可以重新打开成人视皮层的发育可塑性，提高治疗的可能性。 干预以增强中风后的可塑性和修复。 Lee实验室还证明了局灶性缺血导致功能连接（FC）中断 在几个大脑网络中。在这里，FC是使用光学固有信号成像（OIS）进行评估的，依赖于一个 神经血管信号（固有血红蛋白对比度）作为重新映射的读数。因此，真正的评估 神经元回路修复的能力尚未确定。使用宽视场荧光成像系统结合 小鼠与遗传编码钙指标（GECI），我已经收集了初步数据，证明 局灶性卒中后的神经元再映射此外，使用FC分析来检查静息态自发性， 活动，我已经显示了中风后全球大脑网络的快速变化。很可能完全康复 不仅需要局部丘脑皮层回路修复，而且需要将修复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： 目的1：确定神经元回路修复，修复回路重新整合到全局之间的关系。 脑网络和中风后的行为恢复。 目的2：研究Arc对空间定向神经元回路修复和再整合的影响 神经回路进入大脑网络，促进功能恢复

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.