科学家发现支持“脊髓损伤后”瘫痪患者重新获得行走能力的关键神经元亚群

中文摘要

脊髓损伤中断了从大脑和脑干到腰椎的通路，导致瘫痪。在这里，研究人员发现在神经康复（EESREHAB）期间对9名慢性脊髓损伤患者施加腰脊髓的时空硬膜外电刺激（EES）恢复了他们的行走能力。这种恢复包括在行走过程中人类腰椎脊髓神经元活动的减少。研究人员假设，这种意外的减少反映了特定神经元亚群的活动依赖性选择，这些被选择的神经元亚群在脊髓损伤后对患者行走至关重要。为了识别这些假定的神经元，研究人员对小鼠EESREHAB的技术和治疗特征进行了建模。他们将单核RNA测序和空间转录组学应用于这些小鼠的脊髓，以绘制瘫痪恢复的空间分子图谱。然后，他们使用细胞类型和空间优先级来识别参与行走恢复的神经元，并发现了嵌套在中间层中的单个兴奋性中间神经元群。尽管这些神经元在脊髓损伤前不需要行走，但他们证明它们对于脊髓损伤后EES行走的恢复至关重要。增强这些神经元的活动可复制EESREHAB所能实现的行走恢复，而删除这些神经元可阻止中度脊髓损伤后自发发生的行走恢复。因此，研究人员确定了一个恢复-重组神经元亚群，这是瘫痪后恢复行走所必需的。此外，他们的方法为使用分子制图来识别产生复杂行为的神经元建立了一个框架。

英文摘要

A spinal cord injury interrupts pathways from the brain and brainstem that project to the lumbar spinal cord, leading to paralysis. Here we show that spatiotemporal epidural electrical stimulation (EES) of the lumbar spinal cord applied during neurorehabilitation (EESREHAB) restored walking in nine inpiduals with chronic spinal cord injury. This recovery involved a reduction in neuronal activity in the lumbar spinal cord of humans during walking. We hypothesized that this unexpected reduction reflects activity-dependent selection of specific neuronal subpopulations that become essential for a patient to walk after spinal cord injury. To identify these putative neurons, we modelled the technological and therapeutic features underlying EESREHAB in mice. We applied single-nucleus RNA sequencing and spatial transcriptomics to the spinal cords of these mice to chart a spatially resolved molecular atlas of recovery from paralysis. We then employed cell type12,13 and spatial prioritization to identify the neurons involved in the recovery of walking. A single population of excitatory interneurons nested within intermediate laminae emerged. Although these neurons are not required for walking before spinal cord injury, we demonstrate that they are essential for the recovery of walking with EES following spinal cord injury. Augmenting the activity of these neurons phenocopied the recovery of walking enabled by EESREHAB, whereas ablating them prevented the recovery of walking that occurs spontaneously after moderate spinal cord injury. We thus identified a recovery-organizing neuronal subpopulation that is necessary and sufficient to regain walking after paralysis. Moreover, our methodology establishes a framework for using molecular cartography to identify the neurons that produce complex behaviours.