Ma Yuan-Huan, Chen Hong-Ying, Wei Qing-Shuai, Peng Li-Zhi, Zhang Ke-Jun, Deng Qing-Wen, Wang Lai-Jian, Liu Zhou, Lai Bi-Qin, Ding Ying, Li Ge, Jiang Bin, Lan Yue, Zeng Xiang, Zeng Yuan-Shan
Key Laboratory for Stem Cells and Tissue Engineering, Sun Yat-sen University, Ministry of Education, Guangzhou, China.
Department of Rehabilitation Medicine, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, China.
Neurospine. 2025 Jun;22(2):311-328. doi: 10.14245/ns.2449312.656. Epub 2025 Jun 30.
Regeneration of corticospinal tract (CST) axons after spinal cord injury (SCI) is a key element in rebuilding neuronal connections to restore voluntary motor function. 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.
A novel optogenetic light emitting diode (LED) device was used to stimulate the brain motor cortex in channelrhodopsin-2-yellow 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.
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.
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.
脊髓损伤（SCI）后皮质脊髓束（CST）轴突的再生是重建神经元连接以恢复自主运动功能的关键因素。然而，由于有效的干预措施有限，这仍然具有挑战性。本研究采用改良的经颅光遗传学技术来刺激CST轴突再生进入完全横断性SCI的损伤部位，并探索其潜在的分子机制。
使用一种新型的光遗传学发光二极管（LED）装置刺激表达通道视紫红质-2-黄色荧光蛋白（ChR2-YFP）的转基因小鼠的脑运动皮层，以观察完全性SCI损伤部位CST轴突的再生情况。该LED装置还用于体外刺激转基因小鼠脑的运动皮层切片，以观察其神经突的生长情况。
经颅光遗传学刺激后，ChR2-YFP转基因小鼠双侧大脑运动皮层的锥体神经元被激活，CST轴突再生进入脊髓损伤部位，瘫痪后肢的运动功能得到改善。蛋白质组学分析显示，CST轴突再生与大脑运动皮层中Janus激酶2/信号转导和转录激活因子3（JAK2/STAT3）通路的激活有关。体外LED蓝光照射增强了转基因小鼠脑切片神经突的生长。用JAK2/STAT3抑制剂处理导致神经突生长显著减弱。
改良的经颅光遗传学技术刺激了ChR2-YFP转基因小鼠大脑中的双侧运动皮层。它增加了运动皮层中锥体神经元的兴奋性，并通过激活JAK2/STAT3通路促进CST轴突再生，修复完全性SCI。
