Optic neuropathies can lead to the loss of retinal ganglion cells and axonal damage. Glaucoma, one of the main optic neuropathies causing blindness, can be modeled using the optic nerve crush (ONC) injury model. Zebrafish have a high regenerative capacity after nerve injury, and their optic nerves can regenerate after ONC. Microglia mediate this regenerative process, and depletion of microglia impairs this capability. In rodents, microglia respond positively to 40-Hz light-flicker stimulation, producing cytokines that have a neuroprotective effect. However, the effect of 40-Hz light-flicker stimulation on zebrafish optic nerve regeneration is still unknown.

ONC was performed on adult zebrafish. After establishing that zebrafish can regenerate their optic nerve and restore visual function in around 14 days, the team saw that 40-Hz light-flicker stimulation accelerated the recovery of retinal structure and visual function in around 7 days. The number of microglia increased in ONC animals for the first 7 days and decreased after 14 days, aligning with the timeline of regeneration of visual function. When stimulated with a 40-Hz flickering light, microglia were significantly more activated when compared to the control group and showed a larger cell size at day 7. Transcriptomics analysis of the retina on the 4th and 7th days after ONC revealed a significant difference between healthy fish and ONC fish, with around 4,000 genes differentially expressed on both time points and most enriched genes being associated with axon regeneration. When comparing animals treated with 40-Hz light-flicker stimulation, there were fewer differences in ONC fish compared to healthy animals, but many differences were related to neuronal plasticity, including an increase in bdnf expression. This gene encodes Brain-derived neurotrophic factor (BDNF), which is a key regulatory factor in the neuroimmune response. To summarize, 40-Hz light-flicker stimulation modulated microglia in the zebrafish retina after ONC, promoted dendritic remodeling and axonal regeneration of retinal ganglion cells and restored visual function.

These results show that specific frequency light stimulation can be of potential use for future therapies, considering that it activates microglia and enhances neural plasticity, opening avenues to treat visual neuropathies such as glaucoma.

Original reference: Hu H. et al. Invest. Ophthalmol. Vis. Sci. 65, 3 (2024)