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.

Attention deficit hyperactivity disorder (ADHD) is one of the most prevalent psychiatric disorders in children, and ADHD patients always display circadian abnormalities. While, the ADHD drugs currently used in clinic have strong side effects, such as psychosis, allergic reactions, and heart problems. Here, we demonstrated carbon dots derived from the ascorbic acid (VCDs) could strongly rescue the hyperactive and impulsive behaviour of a zebrafish ADHD disease model caused by per1b mutation. VCDs prolonged the circadian period of zebrafish for more than half an hour. In addition, the amplitude and circadian phase were also changed. The dopamine level was specifically increased, which may be caused by stimulation of the dopaminergic neuron development in the midbrain. Notably, it was found that the serotonin level was not altered by VCDs treatments. Also, the gene transcriptome effects of VCDs were discussed in present work. Our results provided the dynamic interactions of carbon dots with circadian system and dopamine signaling pathway, which illustrates a potential application of degradable and bio-safe VCDs for the treatment of the attention deficient and hyperactive disorder through circadian intervention.