Patterned Neuronal Activities Dictate Cell Type-specific Axon Regeneration

Injured neurons exhibit cell type-specific axon regeneration, but the underlying mechanisms remain elusive. Two subtypes of sensory neurons show distinct regenerative competence. Here, we show that axotomy induces long-lasting burst firing and Ca spikes specifically in the regenerative subtype. Genetic silencing of firing in the regenerative subtype inhibits regeneration. Optogenetic stimulation of the non-regenerative subtype reveals that activity patterns critically determine regeneration; burst firing triggers Ca spikes and suffices to induce regeneration, while tonic firing fails to induce Ca spikes and regeneration. We further show the L-type Ca channel, Dmca1D, regulates Ca spikes and regeneration. Intriguingly, the regenerative neuronal subtype expresses higher levels of Dmca1D, and overexpression of Dmca1D in the non-regenerative subtype facilitates regeneration. Our studies indicate that injury induces cell type-specific neuronal activities, which act through Ca spikes to govern regeneration, and suggest that precise control of neuronal activity patterns is an effective way to promote regeneration.