Development of Animal Models of Local Retinal Degeneration

Lorach, Henri; Kung, Jennifer; Beier, Corinne; Mandel, Yossi; Dalal, Roopa; Huie, Philip; Wang, Jenny; Lee, Seungjun; Sher, Alexander; Jones, Bryan W.; Palanker, Daniel

doi:10.1167/iovs.14-16011

Cited by 22 publications

(23 citation statements)

References 53 publications

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“…The latter has revealed a robust and underappreciated plasticity at the level of outer retina in mammals, where photoreceptors adjacent to those killed form new connections within the wound and appear to eventually spread to occupy the vacated space. The recovery of retinal photoreception in the rabbit system has been demonstrated using electrophysiology [56, 57]. The plasticity in such instances occurs over the course of days, not disparate from our observations in zebrafish.…”

Section: Discussionsupporting

confidence: 60%

“…Damage that is acute, such as surgery, delivery of toxic pharmacology or a toxic light dose, rarely offers specificity in regards to the type(s) of photoreceptors ablated. Conditional ablation strategies promising specificity of which photoreceptors are ablated include using precise doses of short wavelength light to bias the damage towards UV cones of adult zebrafish [55], using thyroid hormone to precociously induce the loss of UV cones during the natural ontogeny of trout, using MTZ-nitroreductase system to ablate rods [17] or UV cones [16], and using lasers to ablate localized regions of photoreceptors in rabbit [56, 57]. The latter has revealed a robust and underappreciated plasticity at the level of outer retina in mammals, where photoreceptors adjacent to those killed form new connections within the wound and appear to eventually spread to occupy the vacated space.…”

Section: Discussionmentioning

confidence: 99%

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Rapid Recovery of Visual Function Associated with Blue Cone Ablation in Zebrafish

et al. 2016

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Hurdles in the treatment of retinal degeneration include managing the functional rewiring of surviving photoreceptors and integration of any newly added cells into the remaining second-order retinal neurons. Zebrafish are the premier genetic model for such questions, and we present two new transgenic lines allowing us to contrast vision loss and recovery following conditional ablation of specific cone types: UV or blue cones. The ablation of each cone type proved to be thorough (killing 80% of cells in each intended cone class), specific, and cell-autonomous. We assessed the loss and recovery of vision in larvae via the optomotor behavioural response (OMR). This visually mediated behaviour decreased to about 5% or 20% of control levels following ablation of UV or blue cones, respectively (P<0.05). We further assessed ocular photoreception by measuring the effects of UV light on body pigmentation, and observed that photoreceptor deficits and recovery occurred (p<0.01) with a timeline coincident to the OMR results. This corroborated and extended previous conclusions that UV cones are required photoreceptors for modulating body pigmentation, addressing assumptions that were unavoidable in previous experiments. Functional vision recovery following UV cone ablation was robust, as measured by both assays, returning to control levels within four days. In contrast, robust functional recovery following blue cone ablation was unexpectedly rapid, returning to normal levels within 24 hours after ablation. Ablation of cones led to increased proliferation in the retina, though the rapid recovery of vision following blue cone ablation was demonstrated to not be mediated by blue cone regeneration. Thus rapid visual recovery occurs following ablation of some, but not all, cone subtypes, suggesting an opportunity to contrast and dissect the sources and mechanisms of outer retinal recovery during cone photoreceptor death and regeneration.

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Section: Discussionsupporting

confidence: 60%

Section: Discussionmentioning

confidence: 99%

Rapid Recovery of Visual Function Associated with Blue Cone Ablation in Zebrafish

et al. 2016

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“…This can be done, for example, by chronically introducing a subretinal implant in healthy animals [55, 97, 48, 100], resulting in the degeneration of photoreceptors above the implant in a few weeks (Figure 6). …”

Section: Pre-clinical Evaluation Of Prosthetic Visionmentioning

confidence: 99%

Electronic approaches to restoration of sight

Goetz

Palanker

2016

Rep. Prog. Phys.

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Retinal prostheses are a promising means for restoring sight to patients blinded by the gradual atrophy of photoreceptors due to retinal degeneration. They are designed to reintroduce information into the visual system by electrically stimulating surviving neurons in the retina. This review outlines the concepts and technologies behind two major approaches to retinal prosthetics: epiretinal and subretinal. We describe how the visual system responds to electrical stimulation. We highlight major differences between direct encoding of the retinal output with epiretinal stimulation, and network-mediated response with subretinal stimulation. We summarize results of pre-clinical evaluation of prosthetic visual functions in- and ex-vivo, as well as the outcomes of current clinical trials of various retinal implants. We also briefly review alternative, non-electronic, approaches to restoration of sight to the blind, and conclude by suggesting some perspectives for future advancement in the field.

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“…Near-infrared (915 nm) illumination was used to activate the photovoltaic pixels while avoiding any visual response in rats. 15,19 The subretinal implantation triggered the loss of photoreceptor outer segments above the implant within a month and a subsequent loss of the outer nuclear layer after 3 months 20 ( Fig. 2A).…”

Section: Subretinal Implantations and Local Degeneration Of Photorecementioning

confidence: 99%

Interactions of Prosthetic and Natural Vision in Animals With Local Retinal Degeneration

Lorach

Lei

Galambos

et al. 2015

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. Prosthetic restoration of partial sensory loss leads to interactions between artificial and natural inputs. Ideally, the rehabilitation should allow perceptual fusion of the two modalities. Here we studied the interactions between normal and prosthetic vision in a rodent model of local retinal degeneration.METHODS. Implantation of a photovoltaic array in the subretinal space of normally sighted rats induced local degeneration of the photoreceptors above the chip, and the inner retinal neurons in this area were electrically stimulated by the photovoltaic implant powered by near-infrared (NIR) light. We studied prosthetic and natural visually evoked potentials (VEP) in response to simultaneous stimulation by NIR and visible light patterns. RESULTS.We demonstrate that electrical and natural VEPs summed linearly in the visual cortex, and both responses decreased under brighter ambient light. Responses to visible light flashes increased over 3 orders of magnitude of contrast (flash/background), while for electrical stimulation the contrast range was limited to 1 order of magnitude. The maximum amplitude of the prosthetic VEP was three times lower than the maximum response to a visible flash over the same area on the retina.CONCLUSIONS. Ambient light affects prosthetic responses, albeit much less than responses to visible stimuli. Prosthetic representation of contrast in the visual scene can be encoded, to a limited extent, by the appropriately calibrated stimulus intensity, which also depends on the ambient light conditions. Such calibration will be important for patients combining central prosthetic vision with natural peripheral sight, such as in age-related macular degeneration.

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Development of Animal Models of Local Retinal Degeneration

Cited by 22 publications

References 53 publications

Rapid Recovery of Visual Function Associated with Blue Cone Ablation in Zebrafish

Rapid Recovery of Visual Function Associated with Blue Cone Ablation in Zebrafish

Electronic approaches to restoration of sight

Interactions of Prosthetic and Natural Vision in Animals With Local Retinal Degeneration

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