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^1,2,3 applied during neurorehabilitation^4,5 (EES^REHAB) restored walking in nine individuals 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 EES^REHAB in mice. We applied single-nucleus RNA sequencing^6,7,8,9 and spatial transcriptomics^10,11 to the spinal cords of these mice to chart a spatially resolved molecular atlas of recovery from paralysis. We then employed cell type^12,13 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 EES^REHAB, 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.

脊髓损伤会中断从大脑和脑干投射到腰椎脊髓的通路，从而导致瘫痪。^{在这里，我们展示了在神经康复4,5} (EES ^REHAB )期间应用的腰椎脊髓^1,2,3时空硬膜外电刺激 (EES) 使9 名慢性脊髓损伤患者恢复了行走。这种恢复涉及行走过程中人类腰脊髓神经元活动的减少。我们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，这些神经元亚群对于脊髓损伤后患者行走至关重要。为了识别这些假定的神经元，我们模拟了 EES 的技术和治疗特征小鼠^康复。我们将单核 RNA 测序^6,7,8,9和空间转录组学^10,11应用于这些小鼠的脊髓，以绘制瘫痪恢复的空间分辨分子图谱。然后，我们使用细胞类型^12,13和空间优先化来识别参与步行恢复的神经元。嵌套在中间层内的单个兴奋性中间神经元群出现了。尽管在脊髓损伤前行走不需要这些神经元，但我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表型复制了 EES ^{REHAB实现的步行恢复}，而消融它们阻止了中度脊髓损伤后自发行走的恢复。因此，我们确定了一个恢复组织神经元亚群，它是瘫痪后恢复行走所必需且充分的。此外，我们的方法建立了一个框架，用于使用分子制图来识别产生复杂行为的神经元。