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However, it remains challenging owing to limited effective interventions. This study adopted a modified transcranial optogenetic technique to stimulate CST axon regeneration into the injury site of completely transected SCI and explore the underlying molecular mechanisms.Methods: A novel optogenetic light emitting diode (LED) device was used to stimulate the brain motor cortex in channelrhodopsin-2\u2013yellow fluorescent protein (ChR2-YFP) transgenic mice to observe the regeneration of CST axons in the injury site of a complete SCI. The LED device was also used In vitro to stimulate the motor cortex slices of the transgenic mouse brain for observing the outgrowth of their neurites.Results: After transcranial optogenetic stimulation, the pyramidal neurons of bilateral cerebral motor cortices, in ChR2-YFP transgenic mice were activated, CST axons regenerated into the injury site of the spinal cord, and the motor function of the paralyzed hindlimbs improved. Proteomic analysis revealed that CST axon regeneration was associated with the activation of the Janus kinase 2\/signal transducer and activator of transcription 3 (JAK2\/STAT3) pathway in the cerebral motor cortices. In vitro LED blue light illumination enhanced the outgrowth of neurites from the brain slices of transgenic mice. Treatment with a JAK2\/STAT3 inhibitor led to a significant attenuation of neurite outgrowth.Conclusion: The modified transcranial optogenetic technique stimulated bilateral motor cortices, in the brains of ChR2-YFP transgenic mice. It increased the excitability of pyramidal neurons in the motor cortices, and promoted CST axon regeneration by activating the JAK2\/STAT3 pathway, repairing complete SCI.<\/jats:p>","DOI":"10.14245\/ns.2449312.656","type":"journal-article","created":{"date-parts":[[2025,6,29]],"date-time":"2025-06-29T21:42:51Z","timestamp":1751233371000},"page":"311-328","update-policy":"https:\/\/doi.org\/10.14245\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Transcranial Optogenetic Stimulation Promotes Corticospinal Tract Axon Regeneration to Repair Spinal Cord Injury by Activating the JAK2\/STAT3 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