Chemogenetic stimulation of intact corticospinal tract during rehabilitative training promotes circuit rewiring and functional recovery after stroke

Neuromodulatory techniques have been proven to enhance functional recovery after stroke in patients and animals, such as repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS). However, the success and feasibility of these approaches were often variable, largely due to a lack of target specificity. We explored the effects of specific chemogenetic stimulation of intact corticospinal tract during rehabilitative training on functional recovery after stroke in mice. We developed a viral-based intersectional targeting approach that allows specific chemogentic activation of contralateral hindlimb corticospinal neurons (CSNs) in a photothrombotic stroke model. We demonstrated that specific chemogenetic activation of CSNs, when combined with daily rehabilitation training, leads to significant skilled motor functional recovery via promoting corticospinal tract (CST) axons midline crossing sprouting from intact to the denervated spinal hemicord, and rewiring new functional circuits by new synapse formation. Mechanistically, we revealed that combined chemogenetic stimulation of CSNs and daily rehabilitation training significantly enhanced the mTOR activity of CSNs. Our findings highlight the great potential of specific neural activation protocols in combination with motor training for the recovery of skilled motor functions after stroke.