Selective cell-type-specific stimulation for functional recovery in chronic subcortical stroke

Abstract

Stroke is a leading cause of motor disability, yet, treatment options are very limited. Cortical electrical stimulation (CES) has been widely studied to promote functional recovery after stroke. Despite promising result, CES is difficult to determine the cell types and associated networks contributing to functional recovery after stimulation. In this study, we used optogenetics for selective cell-type specific stimulation on sensory-parietal cortex in chronic subcortical capsular infarct model, which produces prolonged motor deficit, to explore how different cell types of brain contribute to post-stroke recovery. For selective cell-type-specific stimulation, rats were transduced with CamKII-ChR2 (pyramidal neurons), PV-ChR2 (PV-expressing inhibitory neurons), GFAP-ChR2 (astrocyte), or hsyn-ChR2 (pan-neuronal population). The rats with persist motor deficit were subject to optogenetic stimulation for 2 weeks. Single pellet reaching task (SPRT) was performed daily for motor function evaluation. Longitudinal 2-deoxy-2-[18F]fluoroglucose-microPET (FDG-micoPET) imaging was used to explore changes in brain networks following stimulation. In addition, brain-derived neurotropic factor (BDNF) expression was examined to observe activity-dependent plastic changes according to selective stimulation. The selective stimulation of inhibitory neuron resulted in the greatest motor recovery followed by stimulation of astroctye, excitatory neuron, and pan-neuronal population. In FDG-microPET, both cortical and subcortical activations were observed with behavioral recovery; the inhibitory neuronal or astrocyte stimulation activated cortico-striatal network or cortico-thalamic network, respectively. In addition, selective cell-type-specific stimulation decreased diaschisis occurred after stroke. The degree of reduction of cortical diaschisis was correlated with behavioral outcome. Furthermore, the expression of BDNF-positive cells was consistent with activation patterns observed in microPET and it was correlated with behavioral recovery. As a result, inhibitory neurons and glia play an important role in synaptic plasticity to promote functional recovery after capsular infarct. It suggests that neuromodulation parameters targeting inhibitory neurons and glia may lead to better functional recovery after stroke even for chronic patients.