Department of Orthopedic Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 31003, China; Department of Orthopedics, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, China.
Department of Neurosurgery, The 904(th) Hospital of PLA, School of Medicine of Anhui Medical University, Wuxi, Jiangsu 214044, China.
Mol Ther. 2021 Aug 4;29(8):2483-2498. doi: 10.1016/j.ymthe.2021.04.023. Epub 2021 Apr 23.
Motor recovery after severe spinal cord injury (SCI) is limited due to the disruption of direct descending commands. Despite the absence of brain-derived descending inputs, sensory afferents below injury sites remain intact. Among them, proprioception acts as an important sensory source to modulate local spinal circuits and determine motor outputs. Yet, it remains unclear whether enhancing proprioceptive inputs promotes motor recovery after severe SCI. Here, we first established a viral system to selectively target lumbar proprioceptive neurons and then introduced the excitatory Gq-coupled Designer Receptors Exclusively Activated by Designer Drugs (DREADD) virus into proprioceptors to achieve specific activation of lumbar proprioceptive neurons upon CNO administration. We demonstrated that chronic activation of lumbar proprioceptive neurons promoted the recovery of hindlimb stepping ability in a bilateral hemisection SCI mouse model. We further revealed that chemogenetic proprioceptive stimulation led to coordinated activation of proprioception-receptive spinal interneurons and facilitated transmission of supraspinal commands to lumbar motor neurons, without affecting the regrowth of proprioceptive afferents or brain-derived descending axons. Moreover, application of 4-aminopyridine-3-methanol (4-AP-MeOH) that enhances nerve conductance further improved the transmission of supraspinal inputs and motor recovery in proprioception-stimulated mice. Our study demonstrates that proprioception-based combinatorial modality may be a promising strategy to restore the motor function after severe SCI.
严重脊髓损伤 (SCI) 后的运动功能恢复受到限制，这是由于直接下行指令的中断。尽管没有来自大脑的下行输入，但损伤部位以下的感觉传入仍然完整。其中，本体感觉作为一种重要的感觉来源，可以调节局部脊髓回路并决定运动输出。然而，增强本体感觉输入是否能促进严重 SCI 后的运动功能恢复仍不清楚。在这里，我们首先建立了一个病毒系统来选择性地靶向腰本体感觉神经元，然后将兴奋性 Gq 偶联 Designer Receptors Exclusively Activated by Designer Drugs (DREADD) 病毒引入本体感觉神经元，以实现 CNO 给药时对腰本体感觉神经元的特异性激活。我们证明，慢性激活腰本体感觉神经元可促进双侧半横断 SCI 小鼠模型后后肢步幅能力的恢复。我们进一步揭示，化学遗传本体感觉刺激导致本体感觉接受性脊髓中间神经元的协调激活，并促进了来自大脑的下行命令向腰运动神经元的传递，而不影响本体感觉传入纤维或大脑衍生的下行轴突的再生。此外，应用增强神经传导的 4-氨基吡啶-3-甲醇 (4-AP-MeOH) 进一步改善了本体感觉刺激小鼠中来自大脑的输入的传递和运动功能恢复。我们的研究表明，基于本体感觉的组合方式可能是恢复严重 SCI 后运动功能的一种有前途的策略。
