Single-cell analysis of innate spinal cord regeneration identifies intersecting modes of neuronal repair

Adult zebrafish have an innate ability to recover from severe spinal cord injury. Here, we report a comprehensive single nuclear RNA sequencing atlas that spans 6 weeks of regeneration. We identify cooperative roles for adult neurogenesis and neuronal plasticity during spinal cord repair. Neurogenesis of glutamatergic and GABAergic neurons restores the excitatory/inhibitory balance after injury. In addition, transient populations of injury-responsive neurons (iNeurons) show elevated plasticity between 1 and 3 weeks post-injury. Using cross-species transcriptomics and CRISPR/Cas9 mutagenesis, we found iNeurons are injury-surviving neurons that share transcriptional similarities with a rare population of spontaneously plastic mouse neurons. iNeurons are required for functional recovery and employ vesicular trafficking as an essential mechanism that underlies neuronal plasticity. This study provides a comprehensive resource of the cells and mechanisms that direct spinal cord regeneration and establishes zebrafish as a model of plasticity-driven neural repair.