Mapping Neural Recovery: Visualizing Peripheral Nerve Regeneration and Brain Plasticity Post-Peripheral Nerve Injury - SUMMARY Traumatic peripheral nerve injuries (PNI) lead to functional loss and incomplete recovery of peripheral nerve function while also impacting the corresponding brain regions that receive, process, and send out signals to and from the affected nerves. A prolonged duration of denervation due to PNI have adverse implications for both the nerve's prognosis and the associated brain regions. Over time, the absence of normal nerve signaling can cause corresponding brain regions to adapt to the loss, making reintegration more challenging after nerve recovery. This long-term disconnection between the nerve and brain can lead to motor and sensory skill impairments that require retraining that takes many years and might often be unsuccessful. To date, a significant amount of work has been focused on improving accuracy and speed of axonal regeneration, but little has been done to better understand the implications of simultaneous cortical remapping on nerve regeneration. Since the compensatory and regenerative processes associated with damaged PNs and their effect on brain plasticity are poorly characterized there is a critical need to develop novel techniques that can monitor both processes with high spatial resolution. To address this need, we have developed an optical imaging method capable of simultaneous imaging of the sciatic nerve and cerebral cortex structure and function in individual mice longitudinally using an implanted cortical and hindlimb windows. In combination with Thy1-GCaMP6 mice these windows enable visualizing a variety of calcium related processes in live animal both in the cortex and peripheral nerves over the entire nerve regeneration process. The goal of this project is to characterize the synchrony between PN post- injury activity and brain plasticity. To achieve this goal in Aim 1 we will test whether the acute injury evokes immediate response from the sciatic nerve to the corresponding cortical regions. In Aim 2 we will characterize longitudinal response of cortical activation and connectivity after sciatic injury and their relationship to nerve regrowth. Using Arc knockout models, we will investigate how cortical plasticity reflects the sciatic nerve recovery in the injury and repair models. In Aim 3 we will establish the effect of therapeutic electrical and optogenetic stimulation on axonal regrowth, and cortical activation. In this aim we will test whether electrical stimulation on the nerve could modulate functional connectivity and whether cortical stimulation could affect nerve recovery. Overall, this research will bridge the gap in our understanding of how the central and peripheral nervous systems interact during the recovery from PNI. By developing a deeper understanding and providing new treatment approaches, we can significantly improve outcomes for individuals suffering from traumatic PNI.
