# Serotonin neuromodulation directs optic nerve regeneration

## TL;DR

The study shows that serotonin signaling helps guide optic nerve regeneration in zebrafish, especially during early stages.

## Contribution

The paper identifies serotonin type-1 receptors as key modulators of optic nerve regeneration in zebrafish.

## Key findings

- Serotonin signaling modulates optic nerve regeneration in larval zebrafish.
- Blocking 5-HT1 receptors impairs optic nerve regeneration but is not needed during development.
- Activation of 5-HT1 receptors enhances axonal regrowth.

## Abstract

Optic nerve (ON) regeneration in mammalian systems is limited by an overshadowing dominance of inhibitory factors. This has severely hampered the identification of pro-regenerative pathways. Here, we take advantage of the regenerative capacity of larval zebrafish to identify pathways that promote ON regeneration. From a small molecule screen, we identified modulators of serotonin (5-HT) signaling that inhibit ON regeneration. We find that several serotonin type-1 (5-HT1) receptor genes are expressed in retinal ganglion cells during regeneration and that inhibiting 5-HT1 receptors or components of the 5-HT pathway selectively impedes ON regeneration. We show that 5-HT1 receptor signaling is dispensable during ON development yet is required for regenerating axons to emerge from the injury site. Blocking 5-HT receptors once ON axons have crossed the chiasm does not inhibit regeneration, suggesting a selective role for 5-HT receptor signaling early during ON regeneration. Finally, we show that agonist-mediated activation of 5-HT1 receptors leads to enhanced and ectopic axonal regrowth. Combined, our results provide evidence for mechanisms through which serotonin-dependent neuromodulation directs ON regeneration in vivo.

Summary: 5-HT1 receptors selectively promote early optic nerve regrowth in zebrafish and are dispensable during development, and serotonin receptor-dependent modulation instructs regenerating optic nerve axons toward the brain in vivo.