Restoration of cone circuit functionality in the regenerating adult zebrafish retina

Unlike humans, teleosts like zebrafish exhibit robust retinal regeneration after injury from endogenous stem cells. However, it is unclear if regenerating cone-photoreceptors regain physiological function and integrate correctly into post-synaptic circuits. We used two-photon calcium imaging of living adult retina to examine photoreceptor responses before and after light-induced lesion. To assess functional recovery of cones and downstream outer retinal circuits, we exploited colour opponency; UV cones exhibit intrinsic Off-response to blue light, but On-response to green light, which depends on feedback signals from outer retinal circuits. Accordingly, we assessed the presence and quality of Off- versus On-responses and find that regenerated UV cones regain both Off-responses to short-wavelength, and On-responses to long-wavelength light within 3 months after lesion. Therefore, physiological circuit functionality is restored in regenerated cone photoreceptors, suggesting that inducing endogenous regeneration is a promising strategy for human retinal repair.

Methods
All imaging data in this work is collected by Evelyn Abraham (Research group: Michael Brand) under Leica SP5 MP inverse two-photon microscope at the CRTD - Center for Regenerative Therapies TU Dresden, CMCB, Technische Universität Dresden, Fetscherstraße 105, 01307 Dresden, Germany. This imaging data is pre-processed using custom-written scripts in Igor Pro (Yoshimatsu et al 2020, 2021). Pre-processed functional 2P imaging data, input files and codes used for quantification are provided. 

Associated Zenodo submission: Abraham, E. (2024). External Matlab codes_Abraham et al. Zenodo. https://doi.org/10.5281/zenodo.12790225