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Gordon Hagerman, A Phil Oel, Michele DuVal, Nicole Noel, W Ted Allison; Functional regeneration of cone photoreceptors following cone-specific ablation. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):989.
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© ARVO (1962-2015); The Authors (2016-present)
Zebrafish are the preeminent genetic model of regenerating daytime vision because they possess a diversity of cone photoreceptors and an innate ability to regenerate photoreceptors from intrinsic retinal stem cells. Using our novel model of cone photoreceptor specific ablation we will assess functional integration of regenerated photoreceptors and recovery of vision following ablation.
Our latest transgenic models of conditional cone photoreceptor ablation are tailored to death and regeneration of blue or ultraviolet (UV) cones. These zebrafish were engineered to express nitroreductase in UV or blue cones, and these cones were ablated by addition of the prodrug metronidazole. Our previous work demonstrated the fate of regenerating cones is biased towards the ablated cone subtype (Fraser et al, PloS One 2013). Defects in vision due to cone photoreceptor ablation were identified with a behavioral assay, the optomotor response (OMR), a visually mediated behavior in larval zebrafish, wherein larvae pursue a moving stimulus. With this behavioural assay we detected defects in colour vision using stimuli of different colors. The OMR of transgenic zebrafish at various timepoints following prodrug application was compared to a vehicle and wild-type with prodrug controls.
The stimulus optimized to detect defects in vision after blue cone ablation revealed a >5-fold (p<0.05) response reduction. Near-complete recovery of visually mediated behavior occurred within 24 and 48 hours of prodrug removal (p<0.05 & <0.005, respectively). Recovery was faster than the predicted timeline of photoreceptor regeneration. Extended prodrug treatment inhibited blue cone regeneration, yet visual recovery still occurred (p<0.005). In contrast, after UV cone ablation visually mediated behavior was not recovered in 48 hours regardless of prodrug treatment duration.
Our methods assessed functional restoration of visually mediated behavior in our model of conditional ablation for blue or UV cone photoreceptors in zebrafish. Recovery of visually mediated behavior was independent of blue cone generation or regeneration. Our alternate hypothesis is that neural plasticity is the underlying source of functional vision recovery, which electroretinograms and outer retinal connectomics are expected to resolve. Our novel models enable functional study of retinal plasticity in the context of cone death and regeneration.
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