Cone Signals Research Articles

Adaptation in cone photoreceptors contributes to an unexpected insensitivity of primate On parasol retinal ganglion cells to spatial structure in natural images.

Neural circuits are constructed from nonlinear building blocks, and not surprisingly overall circuit behavior is often strongly nonlinear. But neural circuits can also behave near linearly, and some circuits shift from linear to nonlinear behavior depending on stimulus conditions. Such control of nonlinear circuit behavior is fundamental to neural computation. Here, we study a surprising stimulus dependence of the responses of macaque On (but not Off) parasol retinal ganglion cells: these cells respond nonlinearly to spatial structure in some stimuli but near linearly to spatial structure in others, including natural inputs. We show that these differences in the linearity of the integration of spatial inputs can be explained by a shift in the balance of excitatory and inhibitory synaptic inputs that originates at least partially from adaptation in the cone photoreceptors. More generally, this highlights how subtle asymmetries in signaling - here in the cone signals - can qualitatively alter circuit computation.

Invited Session II: Retinal mechanisms mediating vision: Light adaptation in primate fovea

Our visual performance varies remarkably across space. For instance, our central vision exhibits the highest spatial and chromatic sensitivity, whereas temporal sensitivity is higher for our peripheral than central vision. Our high-acuity central vision is initiated in the cone photoreceptors which are packed in a dense array in the fovea. The density and morphology of cones differ remarkably between foveal and peripheral primate retina, but our knowledge about their functional differences remain quite poor. In the past we have shown that cone signals in the fovea are two-fold slower than in the peripheral retina consistent with the difference in the temporal sensitivity of cone-mediated vision to high-frequency flicker. But we are far from understanding the full breadth of these topographic differences in cone signaling across primate retina over a wide range of light inputs. I will present recent results of a detailed comparison of functional properties - such as kinetics, gain and cellular noise - of cones in the fovea with that in rest of the primate retina. I will show how foveal cones adapt across a wide range of lumice and if they exhibit differences in the amplitude, kinetics or timescales of adaptation when compared to cones in the peripheral primate retina. Lastly, I will share our findings on the relative contribution of cone vs circuit mechanisms towards lumice adaptation in the domit neural circuit in the fovea - the midget ganglion cell pathway.

Beyond irradiance: Visual signals influencing mammalian circadian function.

Daily changes in ambient illumination act as important time of day cues which are pivotal for aligning internal circadian clocks to external time. Melanopsin-expressing intrinsically photosensitive retinal ganglion cells (ipRGCs), generally considered specialized for encoding light intensity (irradiance), are critical to this photoentrainment process. However, ipRGCs also convey information from conventional photoreceptor cells, the rods and cones. Here we review data from animal studies identifying the nature and roles of rod and cone signaling to the suprachiasmatic nucleus (SCN) circadian clock including evidence that visual features other than irradiance (color, spatiotemporal variations in light intensity) may influence photoentrainment or other SCN-dependent functions. Finally we consider the extent to which these findings from animal studies might similarly apply to human circadian function.

Differential impact of Kv8.2 loss on rod and cone signaling and degeneration.

Heteromeric Kv2.1/Kv8.2 channels are voltage-gated potassium channels localized to the photoreceptor inner segment. They carry IKx, which is largely responsible for setting the photoreceptor resting membrane potential. Mutations in Kv8.2 result in childhood-onset cone dystrophy with supernormal rod response (CDSRR). We generated a Kv8.2 knockout (KO) mouse and examined retinal signaling and photoreceptor degeneration to gain deeper insight into the complex phenotypes of this disease. Using electroretinograms, we show that there were delayed or reduced signaling from rods depending on the intensity of the light stimulus, consistent with reduced capacity for light-evoked changes in membrane potential. The delayed response was not seen ex vivo where extracellular potassium levels were controlled by the perfusion buffer, so we propose the in vivo alteration is influenced by genotype-associated ionic imbalance. We observed mild retinal degeneration. Signaling from cones was reduced but there was no loss of cone density. Loss of Kv8.2 altered responses to flickering light with responses attenuated at high frequencies and altered in shape at low frequencies. The Kv8.2 KO line on an all-cone retina background had reduced cone-driven ERG b wave amplitudes and underwent degeneration. Altogether, we provide insight into how a deficit in the dark current affects the health and function of photoreceptors.

Spectral inference reveals principal cone-integration rules of the zebrafish inner retina

SummaryRetinal bipolar cells integrate cone signals at dendritic and axonal sites. The axonal route, involving amacrine cells, remains largely uncharted. However, because cone types differ in their spectral sensitivities, insights into bipolar cells’ cone integration might be gained based on their spectral tunings. We therefore recorded in vivo responses of bipolar cell presynaptic terminals in larval zebrafish to widefield but spectrally resolved flashes of light and mapped the results onto spectral responses of the four cones. This “spectral circuit mapping” allowed explaining ∼95% of the spectral and temporal variance of bipolar cell responses in a simple linear model, thereby revealing several notable integration rules of the inner retina. Bipolar cells were dominated by red-cone inputs, often alongside equal sign inputs from blue and green cones. In contrast, UV-cone inputs were uncorrelated with those of the remaining cones. This led to a new axis of spectral opponency where red-, green-, and blue-cone “Off” circuits connect to “natively-On” UV-cone circuits in the outermost fraction of the inner plexiform layer—much as how key color opponent circuits are established in mammals. Beyond this, and despite substantial temporal diversity that was not present in the cones, bipolar cell spectral tunings were surprisingly simple. They either approximately resembled both opponent and non-opponent spectral motifs already present in the cones or exhibited a stereotyped non-opponent broadband response. In this way, bipolar cells not only preserved the efficient spectral representations in the cones but also diversified them to set up a total of six dominant spectral motifs, which included three axes of spectral opponency.

Transformations from cone responses to opponent color spaces

AbstractWe have described a number of transformations by mapping the cone signal vector , formed by , to opponent space , formed by achromatic signal , red‐green signal and yellow‐blue signal . Two new transformations, and , are proposed, based on the CIE 2006 spectral luminous efficiency function, , and Hurvich's opponent spectral red‐green and yellow‐blue responses, and , without and with constraints, respectively. is better than in terms of best fit of and , and both transformations improved previously proposed ones. Finally, we discuss the neutral conditions in cone space using each of the new and some of the extant transformations, as well as choosing scaling factors so that the neutral conditions in cone space are satisfied.

Electrophysiological evidence for higher-level chromatic mechanisms in humans.

Color vision in humans starts with three types of cones (short [S], medium [M], and long [L] wavelengths) in the retina and three retinal and subcortical cardinal mechanisms, which linearly combine cone signals into the luminance channel (L + M), the red-green channel (L – M), and the yellow-blue channel (S-(L + M)). Chromatic mechanisms at the cortical level, however, are less well characterized. The present study investigated such higher-order chromatic mechanisms by recording electroencephalograms (EEGs) on human observers in a noise masking paradigm. Observers viewed colored stimuli that consisted of a target embedded in noise. Color directions of the target and noise varied independently and systematically in an isoluminant plane of color space. The target was flickering on-off at 3 Hz, eliciting steady-state visual evoked potential (SSVEP) responses. As a result, the masking strength could be estimated from the SSVEP amplitude in the presence of 6 Hz noise. Masking was strongest (i.e. target eliciting smallest SSVEPs) when the target and noise were along the same color direction, and was weakest (i.e. target eliciting highest SSVEPs) when the target and noise were along orthogonal directions. This pattern of results was observed both when the target color varied along the cardinal and intermediate directions, which is evidence for higher-order chromatic mechanisms tuned to intermediate axes. The SSVEP result can be well predicted by a model with multiple broadly tuned chromatic mechanisms. In contrast, a model with only cardinal mechanisms failed to account for the data. These results provide strong electrophysiological evidence for multiple chromatic mechanisms in the early visual cortex of humans.

Light adaptation characteristics of melanopsin

Following photopigment bleaching, the rhodopsin and cone-opsins show a characteristic exponential regeneration in the dark with a photocycle dependent on the retinal pigment epithelium. Melanopsin pigment regeneration in animal models requires different pathways to rods and cones. To quantify melanopsin-mediated light adaptation in humans, we first estimated its photopigment regeneration kinetics through the photo-bleach recovery of the intrinsic melanopsin pupil light response (PLR). An intense broadband light (~120,000 Td) bleached 43% of melanopsin compared to 86% of the cone-opsins. Recovery from a 43% bleach was 3.4X slower for the melanopsin than cone-opsin. Post-bleach melanopsin regeneration followed an exponential growth with a 2.5 min time-constant (τ) that required 11.2 min for complete recovery; the half-bleaching level (Ip) was ~ 4.47 log melanopic Td (16.10 log melanopsin effective photons.cm−2.s−1; 8.25 log photoisomerisations.photoreceptor−1.s−1). The effect on the cone-directed PLR of the level of the melanopsin excitation during continuous light adaptation was then determined. We observed that cone-directed pupil constriction amplitudes increased by ~ 10% when adapting lights had a higher melanopic excitation but the same mean photometric luminance. Our findings suggest that melanopsin light adaptation enhances cone signalling along the non-visual retina-brain axis. Parameters τ and Ip will allow estimation of the level of melanopsin bleaching in any light units; the data have implications for quantifying the relative contributions of putative melanopsin pathways to regulate the post-bleach photopigment regeneration and adaptation.

Validated Filter-Based Photoreceptor Count Algorithm on Retinal Heidelberg High Magnification Module™ Images in Healthy and Pathological Conditions

Recently introduced, the Heidelberg Engineering™ high magnification module enables in vivo visualization of cone photoreceptor cells. Currently, a reliable analysis of cone mosaic on high magnification module images is hindered by an unfavorable signal-to-noise ratio. In this paper, we describe how a novel high magnification module high-pass filter may enhance cone signals in healthy participants and patients. We compared the cone counts of our filter-based algorithm to the counts of two human graders. We found a good to excellent intragrader and intergrader correlation in both patients and healthy participants. We identified a good correlation between the average cone counts of both graders and high-pass filter cone counts in patients and healthy participants. We observed no significant difference between manual and filter-based counts via the Bland–Altman analysis. In conclusion, a quantitative cone analysis on high magnification module images is feasible manually by human graders and automatically by a filter-based algorithm. However, larger datasets are needed to improve repeatability and consistency by training human graders.

S-cone contribution to the acute melatonin suppression response in humans.

Light influences diverse aspects of human physiology and behaviour including neuroendocrine function, the circadian system and sleep. A role for melanopsin-expressing intrinsically photosensitive retinal ganglion cells (ipRGCs) in driving such effects is well established. However, rod and/or cone signals routed through ipRGCs could also influence "non-visual" spectral sensitivity. In humans, this has been most extensively studied for acute, light-dependent, suppression of nocturnal melatonin production. Of the published action spectra for melatonin suppression, one demonstrates a spectral sensitivity consistent with that expected for melanopsin while our own (using briefer 30minute light exposures) displays very high sensitivity to short wavelength light, suggesting a contribution of S-cones. To clarify that possibility, six healthy young male participants were each exposed to 30minutes of five irradiances of 415nm monochromatic light (1-40µW/cm2 ) across different nights. These data were then combined with the original action spectrum. The aggregated data are incompatible with the involvement of any single-opsin and multi-opsin models based on the original action spectrum (including Circadian Stimulus) fail to predict the responses to 415nm stimuli. Instead, the extended action spectrum can be most simply approximated by an ~2:1 combination of melanopsin and S-cone signals. Such a model also better describes the magnitude of melatonin suppression observed in other studies using an equivalent 30minute mono- or polychromatic light paradigm but not those using longer (90minute) light exposures. In sum, these data provide evidence for an initial S-cone contribution to melatonin suppression that rapidly decays under extended light exposure.

Modulations in irradiance directed at melanopsin, but not cone photoreceptors, reliably alter electrophysiological activity in the suprachiasmatic nucleus and circadian behaviour in mice.

Intrinsically photosensitive retinal ganglion cells convey intrinsic, melanopsin-based, photoreceptive signals alongside those produced by rods and cones to the suprachiasmatic nucleus (SCN) circadian clock. To date, experimental data suggest that melanopsin plays a more significant role in measuring ambient light intensity than cone photoreception. Such studies have overwhelmingly used diffuse light stimuli, whereas light intensity in the world around us varies across space and time. Here, we investigated the extent to which melanopsin or cone signals support circadian irradiance measurements in the presence of naturalistic spatiotemporal variations in light intensity. To address this, we first presented high- and low-contrast movies to anaesthetised mice whilst recording extracellular electrophysiological activity from the SCN. Using a mouse line with altered cone sensitivity (Opn1mwR mice) and multispectral light sources we then selectively varied irradiance of the movies for specific photoreceptor classes. We found that steps in melanopic irradiance largely account for the light induced-changes in SCN activity over a range of starting light intensities and in the presence of spatiotemporal modulation. By contrast, cone-directed changes in irradiance only influenced SCN activity when spatiotemporal contrast was low. Consistent with these findings, under housing conditions where we could independently adjust irradiance for melanopsin versus cones, the period lengthening effects of constant light on circadian rhythms in behaviour were reliably determined by melanopic irradiance, regardless of irradiance for cones. These data add to the growing evidence that modulating effective irradiance for melanopsin is an effective strategy for controlling the circadian impact of light.

Three-dimensional composition of the photoreceptor cone layers in healthy eyes using adaptive-optics optical coherence tomography (AO-OCT).

To assess the signal composition of cone photoreceptors three-dimensionally in healthy retinas using adaptive optics optical coherence tomography (AO-OCT). Study population. Twenty healthy eyes of ten subjects (age 23 to 67). Procedures. After routine ophthalmological assessments, eyes were examined using AO-OCT. Three-dimensional volumes were acquired at 2.5° and 6.5° foveal eccentricity in four main meridians (superior, nasal, inferior, temporal). Cone densities and signal compositions were investigated in four different planes: the cone inner segment outer segment junction (IS/OS), the cone outer segment combined with the IS/OS (ISOS+), the cone outer segment tips (COST) and full en-face plane (FEF) combining signals from all mentioned cone layers. Additionally, reliability of a simple semi-automated approach for assessment of cone density was tested. Main outcome measures. Cone density of IS/OS, IS/OS+, COST and FEF. Qualitative depiction and composition of each cone layer. Inter-rater agreement of cone density measurements. Mean overall cone density at all eccentricities was highest at the FEF plane (21.160/mm2), followed by COST (20.450/mm2), IS/OS+ (19.920/mm2) and IS/OS (19.530/mm2). The different meridians and eccentricities had a significant impact on cone density, with lower eccentricity resulting in higher cone densities (p≤.001), which were highest at the nasal, then temporal, then inferior and then superior meridian. Depiction of the cone mosaic differed between all 4 layers regarding signal size and packing density. Therefore, different cone layers showed evident but not complete signal overlap. Using the semi-automated technique for counting of cone signals achieved high inter-rater reliability (ICC > .99). In healthy individuals qualitative and quantitative changes in cone signals are found not only in different eccentricities and meridians, but also within different photoreceptor layers. The variation between cone planes has to be considered when assessing the integrity of cone photoreceptors in healthy and diseased eyes using adaptive optics technology.

Glycinergic Inhibition Targets Specific Off Cone Bipolar Cells in Primate Retina.

Adapting between scotopic and photopic illumination involves switching the routing of retinal signals between rod and cone-dominated circuits. In the daytime, cone signals pass through parallel On and Off cone bipolar cells (CBCs), that are sensitive to increments and decrements in luminance, respectively. At night, rod signals are routed into these cone-pathways via a key glycinergic interneuron, the AII amacrine cell (AII-AC). AII-ACs also provide On-pathway-driven crossover inhibition to Off-CBCs under photopic conditions. In primates, it is not known whether all Off-bipolar cell types receive functional inputs from AII-ACs. Here, we show that select Off-CBC types receive significantly higher levels of On-pathway-driven glycinergic input than others. The rise and decay kinetics of the glycinergic events are consistent with involvement of the α1 glycine receptor (GlyR) subunit, a result supported by a higher level of GLRA1 transcript in these cells. The Off-bipolar types that receive glycinergic input have sustained physiological properties and include the flat midget bipolar (FMB) cells, which provide excitatory input to the Off-midget ganglion cells (GCs; parvocellular pathway). Our results suggest that only a subset of Off-bipolar cells have the requisite receptors to respond to AII-AC input. Taken together with results in mouse retina, our findings suggest a conserved motif whereby signal output from AII-ACs is preferentially routed into sustained Off-bipolar signaling pathways.

Bayesian Image Reconstruction from Retinal Cone Signals

Bayesian Image Reconstruction from Retinal Cone Signals

Interplay between cell-adhesion molecules governs synaptic wiring of cone photoreceptors

Establishment of functional synaptic connections in a selective manner is essential for nervous system operation. In mammalian retinas, rod and cone photoreceptors form selective synaptic connections with different classes of bipolar cells (BCs) to propagate light signals. While there has been progress in elucidating rod wiring, molecular mechanisms used by cones to establish functional synapses with BCs have remained unknown. Using an unbiased proteomic strategy in cone-dominant species, we identified the cell-adhesion molecule ELFN2 to be pivotal for the functional wiring of cones with the ON type of BC. It is selectively expressed in cones and transsynaptically recruits the key neurotransmitter receptor mGluR6 in ON-BCs to enable synaptic transmission. Remarkably, ELFN2 in cone terminals functions in synergy with a related adhesion molecule, ELFN1, and their concerted interplay during development specifies selective wiring and transmission of cone signals. These findings identify a synaptic connectivity mechanism of cones and illustrate how interplay between adhesion molecules and postsynaptic transmitter receptors orchestrates functional synaptic specification in a neural circuit.

Selective amplification of ipRGC signals accounts for interictal photophobia in migraine

Second only to headache, photophobia is the most debilitating symptom reported by people with migraine. While the melanopsin-containing intrinsically photosensitive retinal ganglion cells (ipRGCs) are thought to play a role, how cone and melanopsin signals are integrated in this pathway to produce visual discomfort is poorly understood. We studied 60 people: 20 without headache and 20 each with interictal photophobia from migraine with or without visual aura. Participants viewed pulses of spectral change that selectively targeted melanopsin, the cones, or both and rated the degree of visual discomfort produced by these stimuli while we recorded pupil responses. We examined the data within a model that describes how cone and melanopsin signals are weighted and combined at the level of the retina and how this combined signal is transformed into a rating of discomfort or pupil response. Our results indicate that people with migraine do not differ from headache-free controls in the manner in which melanopsin and cone signals are combined. Instead, people with migraine demonstrate an enhanced response to integrated ipRGC signals for discomfort. This effect of migraine is selective for ratings of visual discomfort, in that an enhancement of pupil responses was not seen in the migraine group, nor were group differences found in surveys of other behaviors putatively linked to ipRGC function (chronotype, seasonal sensitivity, presence of a photic sneeze reflex). By revealing a dissociation in the amplification of discomfort vs. pupil response, our findings suggest a postretinal alteration in processing of ipRGC signals for photophobia in migraine.

Thyroid hormone receptor beta mutations alter photoreceptor development and function in Danio rerio(zebrafish).

We investigate mutations in trβ2, a splice variant of thrb, identifying changes in function, structure, and behavior in larval and adult zebrafish retinas. Two N-terminus CRISPR mutants were identified. The first is a 6BP+1 insertion deletion frameshift resulting in a truncated protein. The second is a 3BP in frame deletion with intact binding domains. ERG recordings of isolated cone signals showed that the 6BP+1 mutants did not respond to red wavelengths of light while the 3BP mutants did respond. 6BP+1 mutants lacked optomotor and optokinetic responses to red/black and green/black contrasts. Both larval and adult 6BP+1 mutants exhibit a loss of red-cone contribution to the ERG and an increase in UV-cone contribution. Transgenic reporters show loss of cone trβ2 activation in the 6BP+1 mutant but increase in the density of cones with active blue, green, and UV opsin genes. Antibody reactivity for red-cone LWS1 and LWS2 opsin was absent in the 6BP+1 mutant, as was reactivity for arrestin3a. Our results confirm a critical role for trβ2 in long-wavelength cone development.

Short-Wavelength (Violet) Light Protects Mice From Myopia Through Cone Signaling.

PurposeExposure to short-wavelength light influences refractive development and inhibits myopic development in many animal models. Retinal mechanisms underlying this response remain unknown. This study used a mouse model of lens-induced myopia to evaluate the effect of different wavelength light on refractive development and dopamine levels in the retina. A possible retinal pathway is tested using a mutant mouse with dysfunctional cones.MethodsWild-type C57BL/6J (WT) and ALS/LtJ/Gnat2cpfl3 (Gnat2−/−) mice were exposed to one of three different light conditions beginning at postnatal day 28: broad-spectrum “white” (420-680 nm), medium wavelength “green” (525 ± 40 nm), and short wavelength “violet” (400 ± 20 nm). One-half of the mice received hyperopic lens defocus. All mice were exposed to the light for 4 weeks; animals were measured weekly for refractive error and axial parameters. Retinal dopamine and the dopamine metabolite 3,4-dihydroxyphenylacetic acid were measured by HPLC.ResultsIn WT mice, short-wavelength violet light induced hyperopia and violet light inhibited lens-induced myopia when compared with mice exposed to white light. Hyperopia could be attributed to shallower vitreous chambers in WT animals. There were no changes in the levels of dopamine or its metabolite. In Gnat2−/− mice, violet light did not induce hyperopia or inhibit lens-induced myopia.ConclusionsThese findings show that short-wavelength light slows refractive eye growth, producing hyperopic responses in mice and inhibiting lens-induced myopia. The lack of inhibition in mice with dysfunctional cones suggests that cone signaling plays a role in the hyperopic response to short-wavelength (violet) light.

Degenerated Cones in Cultured Human Retinas Can Successfully Be Optogenetically Reactivated.

Biblical references aside, restoring vision to the blind has proven to be a major technical challenge. In recent years, considerable advances have been made towards this end, especially when retinal degeneration underlies the vision loss such as occurs with retinitis pigmentosa. Under these conditions, optogenetic therapies are a particularly promising line of inquiry where remaining retinal cells are made into “artificial photoreceptors”. However, this strategy is not without its challenges and a model system using human retinal explants would aid its continued development and refinement. Here, we cultured post-mortem human retinas and show that explants remain viable for around 7 days. Within this period, the cones lose their outer segments and thus their light sensitivity but remain electrophysiologically intact, displaying all the major ionic conductances one would expect for a vertebrate cone. We optogenetically restored light responses to these quiescent cones using a lentivirus vector constructed to express enhanced halorhodopsin under the control of the human arrestin promotor. In these ‘reactivated’ retinas, we show a light-induced horizontal cell to cone feedback signal in cones, indicating that transduced cones were able to transmit their light response across the synapse to horizontal cells, which generated a large enough response to send a signal back to the cones. Furthermore, we show ganglion cell light responses, suggesting the cultured explant’s condition is still good enough to support transmission of the transduced cone signal over the intermediate retinal layers to the final retinal output level. Together, these results show that cultured human retinas are an appropriate model system to test optogenetic vision restoration approaches and that cones which have lost their outer segment, a condition occurring during the early stages of retinitis pigmentosa, are appropriate targets for optogenetic vision restoration therapies.

Age‐related changes in flicker sensitivity with rod‐ and cone‐enhanced stimuli

AbstractPurposeCone and rod photoreceptors are usually isolated using high light levels for cone vision and full dark‐adaptation, when only rods respond to light. Such methods are not ideal for clinical use. A new rod/cone flicker test has been designed to isolate and measure rod‐ and cone‐mediated signals in the absence of colour signals with one minute adaptation.Methods118 healthy adults (Mean age ± standard deviation: 40 ± 15 years), were investigated. None of the participants had a history of or exhibited signs of ocular disease. Rod and cone thresholds were measured monocularly in central vision and in each of the four quadrants (superonasal, superotemporal, inferonasal and inferotemporal) at an eccentricity of 5°. Temporal frequencies, stimulus sizes, background luminances and spectral composition were adjusted appropriately to achieve approximately equal thresholds with ~ 10‐fold separation in sensitivity between the rod‐ and cone‐enhanced stimuli. Flicker thresholds were measured using five adaptive (two‐down, one‐up), interleaved staircases. Spectrally calibrated, ‘neutral density’ glasses were used to enable adequate control of display luminance at low levels.ResultsThe superotemporal quadrant had the lowest mean rod and cone thresholds compared to other tested quadrants. For participants, above 50 years of age, the central rod thresholds increased 0.53% per year, whereas cone thresholds increased 0.29% per year and this decline was faster than other respective quadrants. Overall, among the locations tested, the central rod (ρ = 0.547; p < 0.005) and cone (ρ = 0.504, p < 0.005) thresholds demonstrated the strongest correlation with age.ConclusionsThe new test isolates rod and cone signals sufficiently well to detect selective loss of photoreceptor function in normal ageing. The potential use of rod‐ and cone‐enhanced tests in patients with selective loss of photoreceptors and other retinal diseases (e.g., AMD, glaucoma, diabetes) remains to be explored.