Constraint‐Induced Movement Therapy Promotes Contralesional Red Nucleus Plasticity and Increases Bilateral Motor Cortex‐to‐Red Nucleus Projections After a Large‐Area Stroke

For decades, scientists have explored the patterns of neural network remodeling that occur after a stroke. Several studies have shown that both motor cortexes (MCs) undergo crucial remodeling after cerebral ischemia. However, the mechanism by which corticofugal fibers are remodeled is not well understood. Therefore, this study was aimed at investigating the changes in the bilateral red nucleus (RN) and MC-RN projections during recovery from a large-area stroke in a rat stroke model with or without constraint-induced movement therapy (CIMT). A large-area middle cerebral artery occlusion (MCAO) model was established in rats using the Longa method. CIMT was initiated 7 days after MCAO and continued for 1, 2, or 3 weeks. Rats in the control group underwent spontaneous recovery. Locomotor impairment was evaluated using the CatWalk automated gait analysis system, and overall neurological function was evaluated with the modified neurological severity score. Bilateral MC-RN projections were visualized by labeling fiber tracts with an anterograde tracer. Postsynaptic density 95 (PSD95), growth-associated protein 43 (GAP43), and synaptophysin expression levels in the RN were detected using western blotting and immunohistochemistry. The results showed that CIMT promoted motor recovery after a stroke, increased levels of GAP43 and PSD95 in the contralesional but not ipsilesional RN, and increased projections from the MC to the bilateral RN. Thus, CIMT promotes neuroplasticity after a large-area stroke by stimulating axon outgrowth, improving postsynaptic membrane function in the contralesional RN, and increasing bilateral projections of the MC-RN. These results provide evidence for the therapeutic efficacy of CIMT in restoring motor function and help with understanding RN plasticity after a large-area stroke.