Rejuvenation of corticospinal neurons enhances rehabilitation-associated corticospinal tract axon sprouting and functional recovery post photothrombotic ischemic stroke in mice

Spontaneous recovery following an ischemic stroke is often limited, largely attributed to age-related decline in neuroplasticity. To overcome this, we demonstrated that ectopic expression of a cocktail of transcriptional factors (Oct4, Sox2, and Klf4, referred to as OSKTFs) reset developmental decline of epigenetic signatures in adult corticospinal neurons, without affecting their spinal projection patterns and function in controlling skilled locomotion. Corticospinal expression of OSKTFs had moderate effects on promoting collateral sprouting of the corticospinal tract axons and recovery of skilled motor function following a photothrombotic stroke. When combined with task-dependent rehabilitative training, OSKTFs treatment significantly enhanced its efficacy, suggesting that rejuvenating corticospinal neurons substantially amplifies the beneficial outcomes of rehabilitative training. Mechanistically, pharmacological perturbations and intersectional chemogenetic inhibition establish that both axon sprouting and functional recovery require mTOR activation and are mediated by newly sprouted corticospinal tract axons. Together, these findings identify a novel strategy to rejuvenate adult corticospinal neurons, which improves the otherwise modest benefits typically gained from rehabilitative training after traumatic brain injuries.