The neurons that restore walking after paralysis

Claudia Kathe, Michael A. Skinnider, Thomas H. Hutson, Nicola Regazzi, Matthieu Gautier, Robin Demesmaeker, Salif Komi, Steven Ceto, Nicholas D. James, Newton Cho, Laetitia Baud, Katia Galan, Kaya J. E. Matson, Andreas Rowald, Kyungjin Kim, Ruijia Wang, Karen Minassian, John O. Prior, Leonie Asboth, Quentin Barraud, Stéphanie P. Lacour, Ariel J. Levine, Fabien Wagner, Jocelyne Bloch (), Jordan W. Squair () and Grégoire Courtine ()
Additional contact information
Claudia Kathe: EPFL/CHUV/UNIL
Michael A. Skinnider: EPFL/CHUV/UNIL
Thomas H. Hutson: EPFL/CHUV/UNIL
Nicola Regazzi: EPFL/CHUV/UNIL
Matthieu Gautier: EPFL/CHUV/UNIL
Robin Demesmaeker: EPFL/CHUV/UNIL
Salif Komi: EPFL/CHUV/UNIL
Steven Ceto: EPFL/CHUV/UNIL
Nicholas D. James: EPFL/CHUV/UNIL
Newton Cho: EPFL/CHUV/UNIL
Laetitia Baud: EPFL/CHUV/UNIL
Katia Galan: EPFL/CHUV/UNIL
Kaya J. E. Matson: National Institute of Neurological Disorders and Stroke
Andreas Rowald: EPFL/CHUV/UNIL
Kyungjin Kim: Institute of Electrical and Microengineering, Institute of Bioengineering, NeuroX Institute, EPFL
Ruijia Wang: EPFL/CHUV/UNIL
Karen Minassian: Medical University of Vienna
John O. Prior: Lausanne University Hospital (CHUV) and University of Lausanne (UNIL)
Leonie Asboth: EPFL/CHUV/UNIL
Quentin Barraud: EPFL/CHUV/UNIL
Stéphanie P. Lacour: Institute of Electrical and Microengineering, Institute of Bioengineering, NeuroX Institute, EPFL
Ariel J. Levine: National Institute of Neurological Disorders and Stroke
Fabien Wagner: EPFL/CHUV/UNIL
Jocelyne Bloch: EPFL/CHUV/UNIL
Jordan W. Squair: EPFL/CHUV/UNIL
Grégoire Courtine: EPFL/CHUV/UNIL

Nature, 2022, vol. 611, issue 7936, 540-547

Abstract: Abstract 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 cord1–3 applied during neurorehabilitation4,5 (EESREHAB) 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 EESREHAB in mice. We applied single-nucleus RNA sequencing6–9 and spatial transcriptomics10,11 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.

Date: 2022
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DOI: 10.1038/s41586-022-05385-7

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