De novo establishment of circuit modules restores locomotion after spinal cord injury in adult zebrafish.

Mechanisms underlying spontaneous locomotor recovery after spinal cord injury (SCI) remain unclear. Using adult zebrafish with complete SCI, we show that V2a interneurons regrow their axon to bridge the lesioned spinal segments in a subclass-specific and chronological order. Early after SCI, reestablishment of a unitary high-rhythm locomotor circuit is driven merely by axon-regrown fast V2a interneurons. Later, the reestablished intraspinal de novo circuit is organized into a modular design by axon-regrown fast and slow V2a interneurons rostral to the lesion, selectively driving caudal fast V2a/motor neurons and slow V2a/motor neurons, respectively. This orderly circuitry reestablishment determines the stepwise restoration of locomotor repertoire and recapitulates developmental processes. This progress can be interrupted by ablation of calretinin, a fast module-related protein, and accelerated by physical training. These findings suggest that promotion of axon regrowth of propriospinal V2a interneurons and establishment of de novo intraspinal circuits underpin the effectiveness of physical training in patients after SCI.