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 lesions. To assess functional recovery of cones and downstream outer retinal circuits, we exploited color 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- vs. On-responses and found 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. [Display omitted] • UV cones in the adult zebrafish retina are color opponent • Regenerating UV cones progressively recover to normal physiological light responses • Regenerating UV cones recover color-opponent responses • Endogenously regenerating neurons can achieve physiological circuit functionality Abraham et al. use two-photon calcium imaging to gauge the single-cell and circuit functionality of regenerating photoreceptors in adult zebrafish retina after light lesion. They show that UV-cone Off-responses to blue light and On-responses to green light are regenerated, resulting in endogenous restoration of normal photoreceptor physiology and circuit functionality. [ABSTRACT FROM AUTHOR]