Objective To observe the effect of increasing brain cortical neuronal activity in mice on axon remyelination and motor function recovery after mild spinal cord contusion injury by chemical genetics technology (DREADDs). Methods 33 C57/BL male adult mice accepted stereotactic injection of adeno-associated virus with activated receptor [AAV-hM3D(Gq)-mCitrine] into the right cerebral cortex. Then all of the mice were randomly divided into three groups: sham group (n=11), SCI group (n=11) and activated group (n=11). SCI spinal cord injury model was established in SCI group and activation group. Two weeks later, activation group was intraperitoneally injected with 1 mg/(kg·d) clozapine N-oxide (CNO) to activate the electrical activity of cortical neurons. Sham group and SCI group were intraperitoneally injected with the same amount of normal saline once a day for 4 weeks. Animals were perfused at last, using immunofluorescence to observe the results of infection of virus, the expression of cellular Fos (cFos) within neurons and myelin basic protein (MBP) in dorsal corticospinal tract; transmission electron microscopy to show the result of axonal myelination; BMS scale and irregular horizontal ladders were used to evaluate the motor function of mice. Results Immunofluorescence microscopy confirmed successful transfection of virus into neurons at mice motor cortex, and there was no statistical significance of number of neurons infected by GFP labled adeno-associated virus between the three groups. Neuronal cFos fluorescence intensity at the transfection site in activated group was significantly higher than that in SCI group(P<0.001); MBP fluorescence intensity in the spinal cord injury center in activated group and sham group were significantly higher than that in SCI group (P<0.001). The G-ration value in activated group was apparently lower than that in SCI group (P<0.001). For the BMS score, there was no statistical significance between activated group and SCI group; the evaluation of irregular horizontal ladders found that after 2 weeks intraperitoneal injection, the error rate in activated group and SCI group decrease, and the error rate in activated group was significantly lower than that in SCI group (P<0.001); after 4 weeks intraperitoneal injection, the error rate in activated group and SCI group continued to decline, and the error rate in activated group was significantly lower than that in SCI group (P<0.001). Conclusion Using DREADDs strategies to improve the neuronal activity of cerebral cortical neurons can effectively promote the axon remyelination and the recovery of motor function after mild spinal cord contusion injury in mice.