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

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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.