运动皮层线粒体分裂融合异常对脊髓损伤后神经病理性痛的作用和机制研究

脊髓损伤(SCI)是一类常见的创伤性疾病，约2/3患者罹患神经病理性痛(NP)，但机制尚不明确，治疗效果有限。研究证实皮层兴奋性失衡在NP发生中发挥重要作用。我们临床研究表明重复经颅磁刺激(rTMS)靶向患者运动皮层(M1区)可改善SCI后NP，并抑制M1区的过度兴奋。预实验发现：SCI后NP小鼠M1区线粒体分裂蛋白Drp1表达升高伴中间神经元线粒体分裂融合异常，而rTMS可改善上述变化，提示M1区线粒体功能紊乱可能参与SCI后NP发生。本课题将利用线粒体荧光报告小鼠及GABA Cre小鼠，结合形态学、电生理等技术，系统研究SCI后NP皮层线粒体分裂融合规律，探讨靶向调控Drp1对SCI后NP线粒体分裂融合、皮层兴奋性、分子网络及行为学的作用，最后探索调控Drp1对rTMS治疗NP效果的影响。本课题将揭示SCI后NP发生的皮层机制，阐明rTMS治疗的机理，为临床改善NP提供新的靶点和思路。

Spinal cord injury (SCI) is a common traumatic disease. About 2 / 3 of SCI patients suffer from neuropathic pain (NP). Since the mechanism is unclear, the therapeutic effect is limited. Growing studies have confirmed that cortical excitability imbalance plays a critical role in the development of NP. Our clinical studies reveal that repeated transcranial magnetic stimulation (rTMS) targeting the motor cortex (M1 region) of SCI patients can improve NP, and suppress excessive activation in M1 region. Our preliminary experiment showed that the expression of mitochondrial fission protein Drp1 in the M1 region of NP mice after SCI was increased with abnormal fission and fusion of mitochondria in interneuron, while rTMS could improve the above changes, suggesting that mitochondrial dysfunction in M1 region may be involved in the occurrence of NP after SCI. In this study, we will use mitochondrial fluorescence reporter mice and GABA Cre mice, with comprehensive applications of morphological and electrophysiological techniques, to systematically study the pattern of mitochondrial fission and fusion in the cortex of NP mice after SCI, to explore the effects of targeted regulation of Drp1 on mitochondrial fission and fusion, cortical excitability, molecular network and behavior of SCI mice, and finally to explore the effect of regulation of Drp1 on the efficacy of rTMS in the treatment of NP. This project will reveal the cortical mechanism of NP after SCI, clarify the mechanism of rTMS treatment, and provide new targets and ideas for the clinical improvement of NP.