Related Experiment Video
Updated: Sep 19, 2025
Transconjunctival Approach for Injection into the Rat Optic Nerve
Published on: April 4, 2025
Serotonin neuromodulation directs optic nerve regeneration
Kristian Saied-Santiago1, Melissa Baxter1, Jaffna Mathiaparanam1
1Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
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.
Insights
Serotonin (5-HT) signaling inhibits optic nerve regeneration in zebrafish. Activating serotonin type-1 (5-HT1) receptors promotes axonal regrowth, revealing a novel pro-regenerative pathway for optic nerve repair.
Area of Science:
- Neuroscience
- Regenerative Medicine
- Molecular Biology
Background:
- Mammalian optic nerve regeneration is hindered by inhibitory factors, limiting pro-regenerative pathway discovery.
- Larval zebrafish possess inherent regenerative capabilities, making them an ideal model for identifying pro-regenerative mechanisms.
Purpose of the Study:
- To identify pathways that promote optic nerve regeneration using larval zebrafish.
- To investigate the role of serotonin (5-HT) signaling in optic nerve regeneration.
Main Methods:
- Conducted a small molecule screen to identify modulators of serotonin signaling.
- Utilized gene expression analysis to examine serotonin type-1 (5-HT1) receptor expression in retinal ganglion cells.
- Performed experiments involving inhibition and activation of 5-HT1 receptors and the 5-HT pathway.
Main Results:
- Identified serotonin (5-HT) signaling modulators that inhibit optic nerve regeneration.
- Found that 5-HT1 receptor genes are expressed in retinal ganglion cells during regeneration.
- Demonstrated that inhibiting 5-HT1 receptors impedes optic nerve regeneration, while activation enhances axonal regrowth.
Conclusions:
- Serotonin (5-HT) signaling, specifically through 5-HT1 receptors, plays a critical role in promoting optic nerve regeneration in zebrafish.
- 5-HT1 receptor signaling is essential for regenerating axons to emerge from the injury site but not for later stages of regeneration.
- Findings suggest serotonin-dependent neuromodulation as a key mechanism directing optic nerve regeneration in vivo.
