Abstract 24: Optogenetic Stimulation of Excitatory Motor Cortex Neurons Promotes Functional Recovery After Stroke

Abstract

Objective: Post-stroke brain stimulations have been shown to successfully enhance functional recovery. Previously we have demonstrated that optogenetic pan-neuronal stimulations in the ipsilesional primary motor cortex (iM1) promote functional recovery after stroke, however, the specific neuronal cell types involved (excitatory or inhibitory) remain unclear. Here we use optogenetic techniques to specifically stimulate excitatory neurons in layer V ipsilesional motor cortex and investigate the effects on functional recovery. Methods: C57BL/6 wild type mice were used (7-9 weeks). Mice underwent stereotaxic surgery to inject AAV1-CAMKIIa-ChR2-eYFP and implant a fiber cannula in the iM1. Six weeks later, all mice were subjected to an intraluminal middle cerebral artery suture occlusion (30 minutes). Optogenetic stimulation began at post-stroke (PD) day 5 and continued until PD14. Sensorimotor tests were used to assess behavioral recovery at PD4, 7 and 14. Mice were sacrificed at PD14 and their brains were processed for immunohistochemistry with CD68 and MAP2 for infarct analysis. Results: High expression of ChR2-YFP was detected in excitatory neurons of ipsilesional layer V motor cortex. Optogenetic excitatory stimulations in iM1 resulted in significant forelimb movements. Horizontal rotating beam test demonstrated that iM1-stimulated mice recovered significantly faster than non-stimulated mice in both speed and distance at PD14 after stroke. In particular, iM1-stimulated mice exhibited robust recovery in distance traveled at PD14 (p<0.01), with most mice performed similar to pre-stroke baseline. Furthermore, iM1-stimulated mice also exhibited faster regain of body weight loss after stroke. Infarct analysis using immunohistochemistry showed that there was no difference in lesion size between groups. Conclusions: These data highlight excitatory neurons as key cell type for brain stimulation-induced functional recovery after stroke. Current studies examine the molecular and circuit mechanisms underlying this recovery, including the role of neurotrophins in both the ipsilesional and contralesional sensory and motor cortices.