Remodeling of the Corticospinal Innervation and Spontaneous Behavioral Recovery After Ischemic Stroke in Adult Mice

Abstract

Background and Purpose— To elucidate how the motor pathways rewire the denervated tissue after stroke, we investigated remodeling of the corticospinal tract (CST) in transgenic mice with yellow fluorescent protein CST labeling in conjunction with transsynaptic pseudorabies virus retrograde tracing. Methods— Adult male CST-yellow fluorescent protein mice were subjected to permanent right middle cerebral artery occlusion (n=8/group). Foot-fault test was performed to monitor functional deficit and recovery. Pseudorabies virus tracer was injected into the left forelimb muscles at 1 or 4 weeks after middle cerebral artery occlusion (4 days before euthanasia), respectively. A third group of CST-yellow fluorescent protein mice without middle cerebral artery occlusion was used for normal control (n=6). The yellow fluorescent protein labeling of CST in the cervical cord and pseudorabies virus labeling of pyramidal neurons in the bilateral cortices were measured on vibratome sections using a confocal imaging system. Results— Compared with normal animals, axonal density in the stroke-affected side of the cervical cord was significantly decreased at 11 days ( P <0.001) and significantly increased at 32 days after stroke compared with the Day 11 values ( P <0.05). Pseudorabies virus labeling was significantly decreased in the ischemic hemisphere 11 days after middle cerebral artery occlusion ( P <0.001). In contrast, a significant increase was observed in pseudorabies virus labeling of bilateral cortices 32 days after stroke compared with 11 days ( P <0.05). The CST axonal density in the denervated spinal cord and pyramidal neuron labeling in the bilateral cortices were significantly correlated with behavioral recovery ( P <0.05). Conclusions— Spontaneous functional recovery after stroke may, at least in part, be attributed to neuronal remodeling in the corticospinal system.