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Vehicle headlights create pulsed artificial light at night (pALAN) that is unpredictable, intense and extends into previously dark areas. Nocturnal insects often have remarkable low-light vision, but their slow pupillary light responses may leave them vulnerable to pALAN, which has important ecological consequences. To test this, we exposed nocturnal moths-important pollinators and prey-to four pALAN treatments. These comprised 'cool' and 'warm' lights, either emitted from phosphor-coated light-emitting diodes (LEDs) or RGB (red-green-blue) LEDs, matched in colour (CCT) and intensity to human vision. We assessed the initial behavioural response, likely crucial to the survival of an organism, of 428 wild-caught moths comprising 64 species. We found that exposure to a cool phosphor-coated LED light pulse increased instances of erratic flight and flight-to-light that are likely detrimental as they increase the risks of impact with a vehicle, predation or excess energy expenditure. Our findings suggest that pALAN can cause a wide range of behavioural responses in nocturnal moths, but that the most harmful effects could be minimized by reversing the current shift towards high CCT (cool) phosphor-coated LED car headlights. Lower CCT or RGB alternatives are likely to provide benefits for road safety while reducing ecological harm.

There is growing interest in developing artificial lighting that stimulates intrinsically photosensitive retinal ganglion cells (ipRGCs) to entrain circadian rhythms to improve mood, sleep, and health. Efforts have focused on stimulating the intrinsic photopigment, melanopsin; however, specialized color vision circuits have been elucidated in the primate retina that transmit blue-yellow cone-opponent signals to ipRGCs. We designed a light that stimulates color-opponent inputs to ipRGCs by temporally alternating short- and long-wavelength components that strongly modulate short-wavelength sensitive (S) cones. Two-hour exposure to this S-cone modulating light produced an average circadian phase advance of 1 h and 20 min in 6 subjects (mean age = 30 years) compared to no phase advance for the subjects after exposure to a 500 lux white light equated for melanopsin effectiveness. These results are promising for developing artificial lighting that is highly effective in controlling circadian rhythms by invisibly modulating cone-opponent circuits., Competing Interests: Conflict of interest statementThe authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: The University of Washington has filed U.S. Patent Application, entitled “LIGHTING DEVICES, SYSTEMS, METHODS FOR STIMULATING CIRCADIAN RHYTHMS” serial number 17/612,061 for which authors A.N., M.N., J.N., and J.A.K. receive licensing fees.

Human cone phototropism is a key mechanism underlying the Stiles-Crawford effect, a psychophysiological phenomenon according to which photoreceptor outer/inner segments are aligned along with the direction of incoming light. However, such photomechanical movements of photoreceptors remain elusive in mammals. We first show here that primate cone photoreceptors have a planar polarity organized radially around the optical center of the eye. This planar polarity, based on the structure of the cilium and calyceal processes, is highly reminiscent of the planar polarity of the hair cells and their kinocilium and stereocilia. Secondly, we observe under super-high resolution expansion microscopy the cytoskeleton and Usher proteins architecture in the photoreceptors, which appears to establish a mechanical continuity between the outer and inner segments. Taken together, these results suggest a comprehensive cellular mechanism consistent with an active phototropism of cones toward the optical center of the eye, and thus with the Stiles-Crawford effect., (© 2022. The Author(s).)

Mitochondrial decline in ageing robs cells of ATP. However, animal studies show that long wavelength exposure (650-900 nm) over weeks partially restores ATP and improves function. The likely mechanism is via long wavelengths reducing nanoscopic interfacial water viscosity around ATP rota pumps, improving their efficiency. Recently, repeated 670 nm exposures have been used on the aged human retina, which has high-energy demands and significant mitochondrial and functional decline, to improve vision. We show here that single 3 min 670 nm exposures, at much lower energies than previously used, are sufficient to significantly improve for 1 week cone mediated colour contrast thresholds (detection) in ageing populations (37-70 years) to levels associated with younger subjects. But light needs to be delivered at specific times. In environments with artificial lighting humans are rarely dark-adapted, hence cone function becomes critical. This intervention, demonstrated to improve aged mitochondrial function can be applied to enhance colour vision in old age., (© 2021. The Author(s).)

Retinitis pigmentosa (RP) is a major cause of blindness that is difficult to diagnose and treat. PKM2, a subtype of pyruvate kinase, is strongly associated with oxidative stress and is expressed in photoreceptors. We investigated whether PKM2 reduces photoreceptor cell apoptosis and evaluated possible antiapoptotic mechanisms in RP. We established RP models by exposing 661W cells to blue light and modulated PKM2 activity using a PKM2 inhibitor. We measured the apoptosis rates using calcein-acetoxymethyl ester/propidium iodide double staining and Cell Counting Kit-8, the oxidative stress levels using a reactive oxygen species assay, and the changes in protein expression by western blotting. Photodamage increased PKM2 expression, cellular oxidative stress, and apoptosis of 661W cells. PKM2 inhibition significantly reduced the levels of apoptosis and oxidative stress induced by photodamage. Our data suggest that PKM2 is a potential disease marker and therapeutic target for RP., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 Peiwen Zhu et al.)

Purpose: To develop a model of focal injury by blue light-emitting diode (LED)-induced phototoxicity (LIP) in pigmented mouse retinas and to study the effects on cone, Iba-1 + cells and retinal pigment epithelium (RPE) cell populations after administration of basic fibroblast growth factor (bFGF) and minocycline, alone or combined., Methods: In anesthetized dark-adapted adult female pigmented C57BL/6 mice, left pupils were dilated and the eye exposed to LIP (500 lux, 45 s). The retina was monitored longitudinally in vivo with SD-OCT for 7 days (d). Ex vivo, the effects of LIP and its protection with bFGF (0.5 μg) administered alone or combined with minocycline (45 mg/kg) were studied in immunolabeled arrestin-cone outer segments (a + OS) and quantified within a predetermined fixed-size circular area (PCA) centered on the lesion in flattened retinas at 1, 3, 5 or 7d. Moreover, Iba-1 + cells and RPE cell morphology were analysed with Iba-1 and ZO-1 antibodies, respectively., Results: LIP caused a focal lesion within the superior-temporal retina with retinal thinning, particularly the outer retinal layers (116.5 ± 2.9 μm to 36.8 ± 6.3 μm at 7d), and with progressive diminution of a + OS within the PCA reaching minimum values at 7d (6218 ± 342 to 3966 ± 311). Administration of bFGF alone (4519 ± 320) or in combination with minocycline (4882 ± 446) had a significant effect on a + OS survival at 7d and Iba-1 + cell activation was attenuated in the groups treated with minocycline. In parallel, the RPE cell integrity was progressively altered after LIP and administration of neuroprotective components had no restorative effect at 7d., Conclusions: LIP resulted in progressive outer retinal damage affecting the OS cone population and RPE. Administration of bFGF increased a + OS survival but did not prevent RPE deterioration., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Eukaryotes generally display a circadian rhythm as an adaption to the reoccurring day/night cycle. This is particularly true for visual physiology that is directly affected by changing light conditions. Here we investigate the influence of the circadian rhythm on the expression and function of visual transduction cascade regulators in diurnal zebrafish and nocturnal mice. We focused on regulators of shut-off kinetics such as Recoverins , Arrestins , Opsin kinases , and Regulator of G-protein signaling that have direct effects on temporal vision. Transcript as well as protein levels of most analyzed genes show a robust circadian rhythm-dependent regulation, which correlates with changes in photoresponse kinetics. Electroretinography demonstrates that photoresponse recovery in zebrafish is delayed in the evening and accelerated in the morning. Functional rhythmicity persists in continuous darkness, and it is reversed by an inverted light cycle and disrupted by constant light. This is in line with our finding that orthologous gene transcripts from diurnal zebrafish and nocturnal mice are often expressed in an anti-phasic daily rhythm., Competing Interests: JZ, MG, JK, MS, CG, SN No competing interests declared, (© 2021, Zang et al.)

Background: In adult rats we study the short- and long-term effects of focal blue light-emitting diode (LED)-induced phototoxicity (LIP) on retinal thickness and Iba-1 + activation., Methods: The left eyes of previously dark-adapted Sprague Dawley (SD) rats were photoexposed to a blue LED (20 s, 200 lux). In vivo longitudinal monitoring of retinal thickness, fundus images, and optical retinal sections was performed from 1 to 30 days (d) after LIP with SD-OCT. Ex vivo, we analysed the population of S-cone and Iba-1 + cells within a predetermined fixed-size circular area (PCA) centred on the lesion., Results: LIP resulted in a circular focal lesion readily identifiable in vivo by fundus examination, which showed within the PCAs a progressive thinning of the outer retinal layer, and a diminution of the S-cone population to 19% by 30 d. In parallel to S-cone loss, activated Iba-1 + cells delineated the lesioned area and acquired an ameboid morphology with peak expression at 3 d after LIP. Iba-1 + cells adopted a more relaxed-branched morphology at 7 d and by 14-30 d their morphology was fully branched., Conclusion: LIP caused a progressive reduction of the outer retina with loss of S cones and a parallel dynamic activation of microglial cells in the lesioned area.

Iron is implicated in ocular diseases such as in age-related macular degeneration. Light is also considered as a pathological factor in this disease. Earlier, two studies reported the influence of constant light environment on the pattern of expressions of iron-handling proteins. Here, we aimed to see the influence of light in 12-h light-12-h dark (12L:12D) cycles on the expression of iron-handling proteins in chick retina. Chicks were exposed to 400 lx (control) and 5000 lx (experimental) light at 12L:12D cycles and sacrificed at variable timepoints. Retinal ferrous ion (Fe 2+ ) level, ultrastructural changes, lipid peroxidation level, immunolocalization and expression patterns of iron-handling proteins were analysed after light exposure. Both total Fe 2+ level (p = 0.0004) and lipid peroxidation (p = 0.002) significantly increased at 12-, 48- and 168-h timepoint (for Fe 2+ ) and 48- and 168-h timepoint (for lipid peroxidation), and there were degenerative retinal changes after 168 h of light exposure. Intense light exposure led to an increase in the levels of transferrin and transferrin receptor-1 (at 168-h) and ferroportin-1, whereas the levels of ferritins, hephaestin, (at 24-, 48- and 168-h timepoint) and ceruloplasmin (at 168-h timepoint) were decreased. These changes in iron-handling proteins after light exposure are likely due to a disturbance in the iron storage pool evident from decreased ferritin levels, which would result in increased intracellular Fe 2+ levels. To counteract this, Fe 2+ is released into the extracellular space, an observation supported by increased expression of ferroportin-1. Ceruloplasmin was able to convert Fe 2+ into Fe 3+ until 48 h of light exposure, but its decreased expression with time (at 168-h timepoint) resulted in increased extracellular Fe 2+ that might have caused oxidative stress and retinal cell damage., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

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 30 minute 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 30 minutes of five irradiances of 415 nm monochromatic light (1-40 µW/cm 2 ) 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 415 nm 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 30 minute mono- or polychromatic light paradigm but not those using longer (90 minute) light exposures. In sum, these data provide evidence for an initial S-cone contribution to melatonin suppression that rapidly decays under extended light exposure., (© 2021 The Authors. Journal of Pineal Research published by John Wiley & Sons Ltd.)

The intrinsic melanopsin photoresponse may initiate visual signals that differ in spatiotemporal characteristics from the cone-opsin- and rhodopsin-mediated signals. Applying the CIE standard observer functions in silent-substitution methods can require individual differences in photoreceptor spectral sensitivities and pre-receptoral filtering to be corrected; failure to do so can lead to the intrusion of more sensitive cone processes with putative melanopsin-directed stimuli. Here we evaluate heterochromatic flicker photometry (HFP) and photoreceptor-directed temporal white noise as techniques to limit the effect of these individual differences. Individualized luminous efficiency functions ( V ( λ )) were compared to the CIE standard observer functions. We show that adapting chromaticities used in silent-substitution methods can deviate by up to 54% in luminance when estimated with the individual and standard observer functions. These deviations lead to inadvertent cone intrusions in the visual functions measured with melanopsin-directed stimuli. To eliminate the intrusions, individual HFP corrections are sufficient at low frequencies (∼1 H z ) but temporal white noise is also required at higher frequencies to desensitize penumbral cones. We therefore recommend the selective application of individualized observer calibration and/or temporal white noise in silent-substitution paradigms when studying melanopsin-directed photoresponses.

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 (Opn1mw R 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., (© 2021 The Authors. Journal of Pineal Research published by John Wiley & Sons Ltd.)

Retinal rod and cone photoreceptors mediate vision in dim and bright light, respectively, by transducing absorbed photons into neural electrical signals. Their phototransduction mechanisms are essentially identical. However, one difference is that, whereas a rod visual pigment remains stable in darkness, a cone pigment has some tendency to dissociate spontaneously into apo-opsin and retinal (the chromophore) without isomerization. This cone-pigment property is long known but has mostly been overlooked. Importantly, because apo-opsin has weak constitutive activity, it triggers transduction to produce electrical noise even in darkness. Currently, the precise dark apo-opsin contents across cone subtypes are mostly unknown, as are their dark activities. We report here a study of goldfish red (L), green (M), and blue (S) cones, finding with microspectrophotometry widely different apo-opsin percentages in darkness, being ∼30% in L cones, ∼3% in M cones, and negligible in S cones. L and M cones also had higher dark apo-opsin noise than holo-pigment thermal isomerization activity. As such, given the most likely low signal amplification at the pigment-to-transducin/phosphodiesterase phototransduction step, especially in L cones, apo-opsin noise may not be easily distinguishable from light responses and thus may affect cone vision near threshold., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

We had previously found that M to L cone abundancy ratios in the chicken retina are correlated with vitreous chamber depth and refractive state in chickens eyes, when they have normal visual exposure but not when they develop deprivation myopia. The finding suggests an interaction between cone abundancies and emmetropization. In the current study, we analyzed how stable this correlation was against changes in environmental variables and strain differences. We found that the correlation was preserved in two chicken strains, as long as they were raised in the laboratory facilities and not in the animal facilities of the institute. To determine the reasons for this difference, spectral and temporal lighting parameters were better adjusted in both places, whereas temperature, humidity, food, diurnal lighting cycles and illuminance were already matched. It was also verified that both strains of chickens had the same cone opsin amino acid sequences. The correlation between M to L cone abundancy and ocular biometry is highly susceptible to changes in environmental variables. Yet undetermined differences in lighting parameters were the most likely reasons. Other striking findings were that green cone opsin mRNA expression was downregulated when deprivation myopia developed. Similarly, red opsin mRNA was downregulated when chicks wore red spectacles, which made them more hyperopic. In summary, our experiments show that photoreceptor abundancies, opsin expression, and the responses to deprivation, and therefore emmetropization, are surprisingly dependent on subtle differences in lighting parameters., (Copyright © 2020. Published by Elsevier Ltd.)

The crumbs ( crb ) apical polarity genes are essential for the development and functions of epithelia. Adult zebrafish retinal neuroepithelium expresses three crb genes ( crb1 , crb2a , and crb2b ); however, it is unknown whether and how Crb1 differs from other Crb proteins in expression, localization, and functions. Here, we show that, unlike zebrafish Crb2a and Crb2b as well as mammalian Crb1 and Crb2, zebrafish Crb1 does not localize to the subapical regions of photoreceptors and Müller glial cells; rather, it localizes to a small region of cone outer segments: the cell membranes surrounding the axonemes. Moreover, zebrafish Crb1 is not required for retinal morphogenesis and photoreceptor patterning. Interestingly, Crb1 promotes rod survival under strong white light irradiation in a previously unreported non--cell-autonomous fashion; in addition, Crb1 delays UV and blue cones' chromatin condensation caused by UV light irradiation. Finally, Crb1 plays a role in cones' responsiveness to light through an arrestin-translocation-independent mechanism. The localization of Crb1 and its functions do not differ between male and female fish. We conclude that zebrafish Crb1 has diverged from other vertebrate Crb proteins, representing a neofunctionalization in Crb biology during evolution. SIGNIFICANCE STATEMENT Apicobasal polarity of epithelia is an important property that underlies the morphogenesis and functions of epithelial tissues. Epithelial apicobasal polarity is controlled by many polarity genes, including the crb genes. In vertebrates, multiple crb genes have been identified, but the differences in their expression patterns and functions are not fully understood. Here, we report a novel subcellular localization of zebrafish Crb1 in retinal cone photoreceptors and evidence for its new functions in photoreceptor maintenance and light responsiveness. This study expands our understanding of the biology of the crb genes in epithelia, including retinal neuroepithelium., (Copyright © 2020 the authors.)

Noninvasive, objective measurement of rod function is as significant as that of cone function, and for retinal diseases such as retinitis pigmentosa and age-related macular degeneration, rod function may be a more sensitive biomarker of disease progression and efficacy of treatment than cone function. Functional imaging of single human rod photoreceptors, however, has proven difficult because their small size and rapid functional response pose challenges for the resolution and speed of the imaging system. Here, we describe light-evoked, functional responses of human rods and cones, measured noninvasively using a synchronized adaptive optics optical coherence tomography (OCT) and scanning light ophthalmoscopy (SLO) system. The higher lateral resolution of the SLO images made it possible to confirm the identity of rods in the corresponding OCT volumes.

Lighting is rapidly changing with the introduction of light-emitting diodes (LEDs) in our homes, workplaces, and cities. This evolution of our optical landscape raises major concerns regarding phototoxicity to the retina since light exposure is an identified risk factor for the development of age-related macular degeneration (AMD). In this disease, cone photoreceptors degenerate while the retinal pigment epithelium (RPE) is accumulating lipofuscin containing phototoxic compounds such as A2E. Therefore, it remains unclear if the light-elicited degenerative process is initiated in cones or in the RPE. Using purified cone photoreceptors from pig retina, we here investigated the effect of light on cone survival from 390 to 510 nm in 10 nm steps, plus the 630 nm band. If at a given intensity (0.2 mW/cm²), the most toxic wavelengths are comprised in the visible-to-near-UV range, they shift to blue-violet light (425-445 nm) when exposing cells to a solar source filtered by the eye optics. In contrast to previous rodent studies, this cone photoreceptor phototoxicity is not related to light absorption by the visual pigment. Despite bright flavin autofluorescence of cone inner segment, excitation-emission matrix of this inner segment suggested that cone phototoxicity was instead caused by porphyrin. Toxic light intensities were lower than those previously defined for A2E-loaded RPE cells indicating cones are the first cells at risk for a direct light insult. These results are essential to normative regulations of new lighting but also for the prevention of human retinal pathologies since toxic solar light intensities are encountered even at high latitudes.

Enabling near-infrared light sensitivity in a blind human retina may supplement or restore visual function in patients with regional retinal degeneration. We induced near-infrared light sensitivity using gold nanorods bound to temperature-sensitive engineered transient receptor potential (TRP) channels. We expressed mammalian or snake TRP channels in light-insensitive retinal cones in a mouse model of retinal degeneration. Near-infrared stimulation increased activity in cones, ganglion cell layer neurons, and cortical neurons, and enabled mice to perform a learned light-driven behavior. We tuned responses to different wavelengths, by using nanorods of different lengths, and to different radiant powers, by using engineered channels with different temperature thresholds. We targeted TRP channels to human retinas, which allowed the postmortem activation of different cell types by near-infrared light., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Photoreceptors are specialized neurons that rely on Ca 2+ to regulate phototransduction and neurotransmission. Photoreceptor dysfunction and degeneration occur when intracellular Ca 2+ homeostasis is disrupted. Ca 2+ homeostasis is maintained partly by mitochondrial Ca 2+ uptake through the mitochondrial Ca 2+ uniporter (MCU), which can influence cytosolic Ca 2+ signals, stimulate energy production, and trigger apoptosis. Here we discovered that zebrafish cone photoreceptors express unusually low levels of MCU. We expected that this would be important to prevent mitochondrial Ca 2+ overload and consequent cone degeneration. To test this hypothesis, we generated a cone-specific model of MCU overexpression. Surprisingly, we found that cones tolerate MCU overexpression, surviving elevated mitochondrial Ca 2+ and disruptions to mitochondrial ultrastructure until late adulthood. We exploited the survival of MCU overexpressing cones to additionally demonstrate that mitochondrial Ca 2+ uptake alters the distributions of citric acid cycle intermediates and accelerates recovery kinetics of the cone response to light. Cones adapt to mitochondrial Ca 2+ stress by decreasing MICU3, an enhancer of MCU-mediated Ca 2+ uptake, and selectively transporting damaged mitochondria away from the ellipsoid toward the synapse. Our findings demonstrate how mitochondrial Ca 2+ can influence physiological and metabolic processes in cones and highlight the remarkable ability of cone photoreceptors to adapt to mitochondrial stress.

Retinal ganglion cells (GCs) are important visual neurons which carry complex spatiotemporal information from the retina to higher visual centers in the brain. By taking advantage of pathway-specific knockout/mutant mice and multi-electrode array (MEA) recording techniques, we analyze contributions of rod and cone pathways to responsiveness, kinetics and receptive field profiles of GCs under scotopic and photopic conditions. Our data suggest: (1) Scotopic responses of some GCs require all three rod pathways, some require only the secondary and tertiary rod pathways, and others require only the tertiary rod pathway. (2) There are more responsive GCs in photopic conditions than responsive GCs in scotopic conditions. (3) Gap junctions slow down GCs' scotopic light responses and increase GCs' ratio of antagonistic to center inputs. (4) Cone pathways do not affect the kinetics but alter the ratio of antagonistic to center inputs of scotopic GC responses, and they speed up GCs photopic responses and alter the ratio of GCs' antagonistic to center synaptic inputs and receptive field profiles. (5) Rod bipolar cells shorten response latency of ON GCs and increase the ratio of GCs' antagonistic to center synaptic inputs. (6) Light adaptation speeds up GCs' temporal processing and tunes GC photopic responses to higher frequencies, and the tertiary rod pathway plays a significant role in adaptation-induced TTP changes in some GCs. (7) GC RF center sizes are partially mediated by AIIACs and GC-GC coupling. (8) Connexin36 gap junctions and cone pathways alter synaptic circuits underlying antagonistic surround inputs to GCs in photopic conditions., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Stimuli that modulate neuronal activity are not always detectable, indicating a loss of information between the modulated neurons and perception. To identify where in the macaque visual system information about periodic light modulations is lost, signal-to-noise ratios were compared across simulated cone photoreceptors, lateral geniculate nucleus (LGN) neurons, and perceptual judgements. Stimuli were drifting, threshold-contrast Gabor patterns on a photopic background. The sensitivity of LGN neurons, extrapolated to populations, was similar to the monkeys' at low temporal frequencies. At high temporal frequencies, LGN sensitivity exceeded the monkeys' and approached the upper bound set by cone photocurrents. These results confirm a loss of high-frequency information downstream of the LGN. However, this loss accounted for only about 5% of the total. Phototransduction accounted for essentially all of the rest. Together, these results show that low temporal frequency information is lost primarily between the cones and the LGN, whereas high-frequency information is lost primarily within the cones, with a small additional loss downstream of the LGN., Competing Interests: The author has declared that no competing interests exist.

Cryptochromes (Cry) are ancient flavoproteins known to regulate circadian rhythms. In plants and some animals, Cry is sensitive to blue light due to its ability to bind the chromophore flavin adenine dinucleotide (FAD). Cry is also suggested to function in magnetoreception, since it can create light-dependent radical pairs with FAD that are sensitive to magnetic fields (Ritz2000; Liedvogel et al., 2007; Solov'yov et al., 2014). Cry is expressed in the visual system of various animals and specifically co-localizes with both short- and long-wavelength cone photoreceptors in birds (Bischof et al., 2011; Günther et al., 2018). However, magnetoreception is not limited to birds and the expression of cry genes in the photoreceptors of other vertebrates is unknown. Here, we use zebrafish to examine the retinal expression pattern of cry family genes. Zebrafish have seven cry genes and while most are known regulators of the circadian clock, relatively little is known about cry2 and cry4 (Haug et al., 2015; Liu et al., 2015). Therefore, we explored cry2 and cry4 expression in the larval and adult zebrafish retina. We demonstrate that cry4 is predominantly expressed in the short-wavelength ultraviolet (UV)-sensitive cone photoreceptors, while cry2 is expressed in UV cones and additional retinal photoreceptors during the day. Using Nitroreductase (NTZ)-mediated cell ablation and qRT-PCR, we find that cry4 expression significantly decreases when UV cones are ablated, but not when the neighboring short-wavelength sensitive blue cones are ablated. cry2 expression decreases after UV cone ablation but is still significantly detectable, while blue cone ablation does not alter cry2 expression. This study provides a more detailed annotation of cry2 and cry4 expression in the zebrafish retina and highlights the feasibility of a well-established ablation paradigm to test if photoreceptors are required for magnetoreception in fish. Although evidence of magnetoreception in adult zebrafish has gained considerable evidence over the last decade (Shcherbakov et al., 2005; Takebe et al., 2012; Krylov et al., 2016; Myklatun et al., 2018) the mediating mechanism(s) remain unknown. Additionally, despite limited evidence that larval zebrafish are magnetoreceptive, many other larval fish have a characterized magnetic sense; sockeye salmon fry, larval coral reef fish, larval medaka and larval Atlantic haddock have been shown to be responsive to magnetic fields (Quinn; 1980; Bottesch et al., 2016; O'Connor and Muheim. 2017; Myklatun et al., 2018; Cresci, et al. 2019). If cry-cone interactions are conserved within fish, our findings may suggest one potential mechanism, such that UV cones appear poised for light-dependent magnetoreception via photoreceptor subtype-specific expression of cry., Competing Interests: Declaration of competing interest The authors have no competing interests., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Purpose: The purpose of this paper is to describe the extent to which scotopic and photopic measures of visual function predict color fundus photograph (CFP) and fundus autofluorescence (FAF) changes in early and intermediate nonexudative AMD., Methods: Sixty-nine observers were recruited: 56 AMD patients (mean age, 73 ± 12.98 years) and 13 controls (mean age, 67.77 ± 9.72 years). A nonmydriatic retinal camera was used to obtain stereo fundus photographs and FAF images were recorded with a cSLO Heidelberg Spectralis HRA+OCT. Visual acuity (VA) was measured using an Early Treatment of Diabetic Retinopathy Study chart. Contrast sensitivity (CS) was assessed with a Pelli-Robson chart. Dark adaptation (DA) curves were recorded at 3° eccentricity using a PC-based technique. Analysis of these curves yielded five parameters: cone threshold (CT), cone time constant (CC), cone-rod break (α), slope of the second rod component (S2), and rod-rod break (β)., Results: Both cone and rod sensitivity recovery were grossly abnormal in the patients. The rod recovery slope (S2) most accurately predicted the fundus photograph-based grade and the FAF classification (ρ = 0.61 and ρ = 0.60, respectively; both P < 0.0001). CS showed a strong association with FAF (ρ = 0.50, P < 0.0001) and with fundus photograph-based grade (ρ = 0.38, P < 0.002). There was no correlation between VA and either imaging method., Conclusions: Dynamic, rod-based measures most accurately reflect the severity of early AMD. Although less specific to AMD than DA changes, static photopic abnormalities such as CS also correspond with morphologic changes. Assessment of function in early AMD should include dynamic rod- and cone-mediated measurements of sensitivity recovery.

Although it is well established that the vertebrate retina contains endogenous circadian clocks that regulate retinal physiology and function during day and night, the processes that the clocks affect and the means by which the clocks control these processes remain unresolved. We previously demonstrated that a circadian clock in the goldfish retina regulates rod-cone electrical coupling so that coupling is weak during the day and robust at night. The increase in rod-cone coupling at night introduces rod signals into cones so that the light responses of both cones and cone horizontal cells, which are post-synaptic to cones, become dominated by rod input. By comparing the light responses of cones, cone horizontal cells and rod horizontal cells, which are post-synaptic to rods, under dark-adapted conditions during day and night, we determined whether the daily changes in the strength of rod-cone coupling could account entirely for rhythmic changes in the light response properties of cones and cone horizontal cells. We report that although some aspects of the day/night changes in cone and cone horizontal cell light responses, such as response threshold and spectral tuning, are consistent with modulation of rod-cone coupling, other properties cannot be solely explained by this phenomenon. Specifically, we found that at night compared to the day the time course of spectrally-isolated cone photoresponses was slower, cone-to-cone horizontal cell synaptic transfer was highly non-linear and of lower gain, and the delay in cone-to-cone horizontal cell synaptic transmission was longer. However, under bright light-adapted conditions in both day and night, cone-to-cone horizontal cell synaptic transfer was linear and of high gain, and no additional delay was observed at the cone-to-cone horizontal cell synapse. These findings suggest that in addition to controlling rod-cone coupling, retinal clocks shape the light responses of cone horizontal cells by modulating cone-to-cone horizontal cell synaptic transmission., Competing Interests: The authors have declared that no competing interests exist.

Staphylococcal nuclease and tudor domain containing 1 (SND1) has multiple functions in a variety of cellular processes. Here, we assessed the effects of SND1 in cellular DNA damage after ionizing radiation (IR). Knocking down SND1 in the mouse-derived photoreceptor 661 W cell line markedly inhibited cell proliferation and increased apoptosis after IR treatment. After DNA damage, SND1 induced Ataxia telangiectasia mutated kinase (ATM) signaling to launch DNA repair. Defects of SND1 were associated with missing response to DNA damage signal to cell cycle checkpoints or DNA repair. The current findings reveal SND1 as a new regulatory factor in DNA damage response., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

While rods in the mammalian retina regenerate rhodopsin through a well-characterized pathway in cells of the retinal pigment epithelium (RPE), cone visual pigments are thought to regenerate in part through an additional pathway in Müller cells of the neural retina. The proteins comprising this intrinsic retinal visual cycle are unknown. Here, we show that RGR opsin and retinol dehydrogenase-10 (Rdh10) convert all-trans-retinol to 11-cis-retinol during exposure to visible light. Isolated retinas from Rgr+/+ and Rgr-/- mice were exposed to continuous light, and cone photoresponses were recorded. Cones in Rgr-/- retinas lost sensitivity at a faster rate than cones in Rgr+/+ retinas. A similar effect was seen in Rgr+/+ retinas following treatment with the glial cell toxin, α-aminoadipic acid. These results show that RGR opsin is a critical component of the Müller cell visual cycle and that regeneration of cone visual pigment can be driven by light., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: To study rod- and cone-driven adaptation dynamics separately, we used the silent substitution technique to selectively stimulate rods or cones in the Opn1lwLIAIS (LIAIS) mouse, in which the native M-cone pigment is replaced by a human L-cone pigment (L*)., Methods: ERG recordings were performed on anesthetized LIAIS mice. ERG stimuli were sinusoidally modulated. After 10 minutes of adaptation to 0.4 candela per square meter (cd/m2) ERGs were measured, followed by 11-minute adaptation to 8.8 cd/m2 background and recordings directly after the luminance increase and every second minute. Finally, during adaptation to 0.4 cd/m2 for 32 minutes, ERG responses were recorded directly after the change in background and every second minute. This protocol was repeated with rod-isolating stimuli (8 Hz; 75% rod contrast), L*-cone-isolating stimuli (12 Hz; 55% cone contrast) and white light (8 Hz and 12 Hz; 100% Michelson contrast)., Results: At 8.8 cd/m2, responses directly displayed photopic response properties without further changes in either cone or white light responses. Rod-driven responses were very small. After the return to 0.4 cd/m2, both rod-driven and white light responses increased over a time course of about 30 minutes. Cone-driven responses were very small. Response phases changed directly after a change in background without further alterations., Conclusions: Rod- and cone-driven signal pathways display strongly different adaptation characteristics: adaptation of cone-driven responses to photopic conditions is very fast, whereas rod-driven responses change with a time course up to 30 minutes during scotopic conditions. Luminance responses are cone-driven at 8.8 cd/m2 and rod-driven at 0.4 cd/m2.

Purpose: The clinical standards for multifocal electroretinograms (mfERG) call for adaption to normal room lighting before the mfERG begins. They specify that any assessments where bright lights are used, should be done after the mfERG to prevent excess stimulation of retinal cells. However, full-field electroretinograms (FFERG) are performed prior to mfERGs in some clinical settings. It is unclear from the literature whether the FFERG has an impact on the mfERG. This study seeks to examine the effect of the FFERG on the mfERG when performed sequentially., Methods: Thirty young healthy subjects (age 27.1 ± 3.5 years) were included. Patients reported for two visits and were fully dilated at both visits. At visit one, a FFERG was recorded (VERIS 6.2) using our clinical protocol which includes an ISCEV standard flash sequence; each flash condition was repeated 4-6 times. Following the FFERG, an mfERG was recorded using a 4-min m-sequence at near 100% contrast. At visit two, only the mfERG was recorded. A Burian-Allen contact lens electrode filled with celluvisc was used for all recordings. The two mfERGs were compared for foveal, peripheral, and overall implicit time (IT) and amplitudes (amp). Paired t tests were used to evaluate the data. Coefficient of variation and Bland-Altman analysis was also reported for this patient group., Results: There was a small but statistically significant difference in foveal amplitudes (amp) (p = 0.004) wherein the amp was larger following the FFERG stimuli. The mean difference was 11.1 nV/deg 2 (100.9 nV vs 89.8 nV). There was no difference in foveal IT (p = 0.66). There was no difference in overall IT or amp when averaging the entire eye (p = 0.44 amp and p = 0.54 IT) or just evaluating the periphery (p = 0.87 amp and p = 0.051 IT). Bland-Altman analysis found a coefficient of repeatability overall was 1.57 ms (IT) and 10.7 nV/deg 2 (amp)., Conclusions: The difference in foveal amplitude is likely the result of a small long-term cone adaptation, but further studies are needed. While it is statistically significant, the small difference is unlikely to be clinically important. These results should help increase clinical confidence in mfERG results when recorded following a FFERG.

Retinal dopamine is a critical modulator of high acuity, light-adapted vision and photoreceptor coupling in the retina. Dopaminergic amacrine cells (DACs) serve as the sole source of retinal dopamine, and dopamine release in the retina follows a circadian rhythm and is modulated by light exposure. However, the retinal circuits through which light influences the development and function of DACs are still unknown. Intrinsically photosensitive retinal ganglion cells (ipRGCs) have emerged as a prime target for influencing retinal dopamine levels because they costratify with DACs in the inner plexiform layer and signal to them in a retrograde manner. Surprisingly, using genetic mouse models lacking specific phototransduction pathways, we find that while light influences the total number of DACs and retinal dopamine levels, this effect does not require ipRGCs. Instead, we find that the rod pathway is a critical modulator of both DAC number and retinal dopamine levels., Competing Interests: TM, KN, AL, SP, JL, TS No competing interests declared, (© 2018, Munteanu et al.)

Vision is mediated by two types of photoreceptors: rods, enabling vision in dim light; and cones, which function in bright light. Despite many similarities in the components of their respective phototransduction cascades, rods and cones have distinct sensitivity, response kinetics, and adaptation capacity. Cones are less sensitive and have faster responses than rods. In addition, cones can function over a wide range of light conditions whereas rods saturate in moderately bright light. Calcium plays an important role in regulating phototransduction and light adaptation of rods and cones. Notably, the two dominant Ca 2+ -feedbacks in rods and cones are driven by the identical calcium-binding proteins: guanylyl cyclase activating proteins 1 and 2 (GCAPs), which upregulate the production of cGMP; and recoverin, which regulates the inactivation of visual pigment. Thus, the mechanisms producing the difference in adaptation capacity between rods and cones have remained poorly understood. Using GCAPs/recoverin-deficient mice, we show that mammalian cones possess another Ca 2+ -dependent mechanism promoting light adaptation. Surprisingly, we also find that, unlike in mouse rods, a unique Ca 2+ -independent mechanism contributes to cone light adaptation. Our findings point to two novel adaptation mechanisms in mouse cones that likely contribute to the great adaptation capacity of cones over rods.

Stimulus- or context-dependent routing of neural signals through parallel pathways can permit flexible processing of diverse inputs. For example, work in mouse shows that rod photoreceptor signals are routed through several retinal pathways, each specialized for different light levels. This light-level-dependent routing of rod signals has been invoked to explain several human perceptual results, but it has not been tested in primate retina. Here, we show, surprisingly, that rod signals traverse the primate retina almost exclusively through a single pathway - the dedicated rod bipolar pathway. Identical experiments in mouse and primate reveal substantial differences in how rod signals traverse the retina. These results require reevaluating human perceptual results in terms of flexible computation within this single pathway. This includes a prominent speeding of rod signals with light level - which we show is inherited directly from the rod photoreceptors themselves rather than from different pathways with distinct kinetics., Competing Interests: WG, JB, AA No competing interests declared, FR Reviewing editor, eLife

Birds seem to use a light-dependent, radical-pair-based magnetic compass. In vertebrates, cryptochromes are the only class of proteins that form radical pairs upon photo-excitation. Therefore, they are currently the only candidate proteins for light-dependent magnetoreception. Cryptochrome 4 (Cry4) is particularly interesting because it has only been found in vertebrates that use a magnetic compass. However, its structure and localization within the retina has remained unknown. Here, we sequenced night-migratory European robin (Erithacus rubecula) Cry4 from the retina and predicted the currently unresolved structure of the erCry4 protein, which suggests that erCry4 should bind Flavin. We also found that Cry1a, Cry1b, and Cry2 mRNA display robust circadian oscillation patterns, whereas Cry4 shows only a weak circadian oscillation. When we compared the relative mRNA expression levels of the cryptochromes during the spring and autumn migratory seasons relative to the non-migratory seasons in European robins and domestic chickens (Gallus gallus), the Cry4 mRNA expression level in European robin retinae, but not in chicken retinae, is significantly higher during the migratory season compared to the non-migratory seasons. Cry4 protein is specifically expressed in the outer segments of the double cones and long-wavelength single cones in European robins and chickens. A localization of Cry4 in double cones seems to be ideal for light-dependent magnetoreception. Considering all of the data presented here, especially including its localization within the European robin retina, its likely binding of Flavin, and its increased expression during the migratory season in the migratory bird but not in chicken, Cry4 could be the magnetoreceptive protein., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Retbindin (Rtbdn) is a novel protein of unknown function found exclusively in the retina. Recently, our group has suggested, from in silico analysis of the peptide sequence and in vitro binding data, that Rtbdn could function to bind riboflavin (RF) and its derivatives flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN), collectively known as flavins. Here we confirm that Rtbdn is capable of flavin binding and that this characteristic can protect photoreceptors from flavin-sensitized light damage.

The conventional view was that cones are responsible for pupil constriction in photopic lighting conditions. With the discovery of intrinsically photosensitive retinal ganglion cells (ipRGC), it was found that signals from ipRGCs along with cones mediated the pupil light reflex in photopic lighting conditions. Although both signals contributed, it was unclear how these signals were summed. In the work reported here, steady-state pupil size was measured with an infrared camera under LED lighting conditions with different color temperatures and luminance. A formula was then derived for pupil size according to the linear summation of cirtopic and photopic luminance. This formula allowed direct calculations to predict pupil size well when LED photopic luminance ranged from about 50cd/m 2 to 300cd/m 2 , which is the general luminance level range for computer and smartphone screens., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Hallmarks of Retinitis Pigmentosa (RP), a family of genetic diseases, are a typical rod-cone-degeneration with initial night blindness and loss of peripheral vision, followed by decreased daylight sight and progressive visual acuity loss up to legal blindness. Great heterogeneity in nature and function of mutated genes, variety of mutations for each of them, variability in phenotypic appearance and transmission modality contribute to make RP a still incurable disease. Translational research relies on appropriate animal models mimicking the genetic and phenotypic diversity of the human pathology. Here, we provide a systematic, morphological and functional analysis of Rho Tvrm4 /Rho + rhodopsin mutant mice, originally described in 2010 and portraying several features of common forms of autosomal dominant RP caused by gain-of-function mutations. These mice undergo photoreceptor degeneration only when exposed briefly to strong, white light and allow controlled timing of induction of rod and cone death, which therefore can be elicited in adult animals, as observed in human RP. The option to control severity and retinal extent of the phenotype by regulating intensity and duration of the inducing light opens possibilities to exploit this model for multiple experimental purposes. Altogether, the unique features of this mutant make it an excellent resource for retinal degeneration research.

The endocannabinoid system is involved in some neurodegenerative diseases such as Alzheimer's disease. An endogenous constellation of proteins related to cannabinoid 1 receptor signaling, including free fatty acids, diacylglycerol lipase, and N-acylethanolamine-hydrolyzing acid amidase, are localized in the murine retina. Moreover, the expression levels of endogenous agonists of cannabinoid receptors are changed in the vitreous fluid. However, the role of the endocannabinoid system in the retina, particularly in the light-induced photoreceptor degeneration, remains unknown. Therefore, we investigated involvement of the cannabinoid 1 receptor in light-induced retinal degeneration using in vitro and in vivo models. To evaluate the effect of cannabinoid 1 receptors in light irradiation-induced cell death, the mouse retinal cone-cell line (661W) was treated with a cannabinoid 1 receptor antagonist, rimonabant. Time-dependent changes of expression and localization of retinal cannabinoid 1 receptors were measured using Western blot and immunostaining. Retinal damage was induced in mice by exposure to light, followed by intravitreal injection of rimonabant. Electroretinograms and histologic analyses were performed. Rimonabant suppressed light-induced photoreceptor cell death. Cannabinoid 1 receptor expression was upregulated by light exposure. Treatment with rimonabant improved both a- and b-wave amplitudes and the thickness of the outer nuclear layer. These results suggest that the cannabinoid 1 receptor is involved in light-induced retinal degeneration and it may represent a therapeutic target in the light-induced photoreceptor degeneration related diseases., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The light absorbing chromophore in opsin visual pigments is the protonated Schiff base of 11-cis-retinaldehyde (11cRAL). Absorption of a photon isomerizes 11cRAL to all-trans-retinaldehyde (atRAL), briefly activating the pigment before it dissociates. Light sensitivity is restored when apo-opsin combines with another 11cRAL to form a new visual pigment. Conversion of atRAL to 11cRAL is carried out by enzyme pathways in neighboring cells. Here we show that blue (450-nm) light converts atRAL specifically to 11cRAL through a retinyl-phospholipid intermediate in photoreceptor membranes. The quantum efficiency of this photoconversion is similar to rhodopsin. Photoreceptor membranes synthesize 11cRAL chromophore faster under blue light than in darkness. Live mice regenerate rhodopsin more rapidly in blue light. Finally, whole retinas and isolated cone cells show increased photosensitivity following exposure to blue light. These results indicate that light contributes to visual-pigment renewal in mammalian rods and cones through a non-enzymatic process involving retinyl-phospholipids.It is currently thought that visual pigments in vertebrate photoreceptors are regenerated exclusively through enzymatic cycles. Here the authors show that mammalian photoreceptors also regenerate opsin pigments in light through photoisomerization of N-ret-PE (N-retinylidene-phosphatidylethanolamine.

An animal's ability to survive depends on its sensory systems being able to adapt to a wide range of environmental conditions, by maximizing the information extracted and reducing the noise transmitted. The visual system does this by adapting to luminance and contrast. While luminance adaptation can begin at the retinal photoreceptors, contrast adaptation has been shown to start at later stages in the retina. Photoreceptors adapt to changes in luminance over multiple time scales ranging from tens of milliseconds to minutes, with the adaptive changes arising from processes within the phototransduction cascade. Here we show a new form of adaptation in cones that is independent of the phototransduction process. Rather, it is mediated by voltage-gated ion channels in the cone membrane and acts by changing the frequency response of cones such that their responses speed up as the membrane potential modulation depth increases and slow down as the membrane potential modulation depth decreases. This mechanism is effectively activated by high-contrast stimuli dominated by low frequencies such as natural stimuli. However, the more generally used Gaussian white noise stimuli were not effective since they did not modulate the cone membrane potential to the same extent. This new adaptive process had a time constant of less than a second. A critical component of the underlying mechanism is the hyperpolarization-activated current, Ih, as pharmacologically blocking it prevented the long- and mid- wavelength sensitive cone photoreceptors (L- and M-cones) from adapting. Consistent with this, short- wavelength sensitive cone photoreceptors (S-cones) did not show the adaptive response, and we found they also lacked a prominent Ih. The adaptive filtering mechanism identified here improves the information flow by removing higher-frequency noise during lower signal-to-noise ratio conditions, as occurs when contrast levels are low. Although this new adaptive mechanism can be driven by contrast, it is not a contrast adaptation mechanism in its strictest sense, as will be argued in the Discussion.

We established a protocol using a well-established LED stimulator to measure temporal contrast sensitivities driven by sine-wave modulation of L- and M-cones in the perifovea using triple silent substitution. The stimulus was presented in an annular field (2° inner diameter, 13° outer diameter). We validated this technique by studying the contrast sensitivity of three color normal observers at 10 different temporal frequencies (between 1 and 28 Hz) over a large range of retinal illuminances (between 0.07 and 587 phot Td), spanning the complete mesopic range. In one subject, sensitivities to counterphase modulation of L- and M-cones and in-phase modulation of L, M, and S-cones were additionally measured, which putatively reflected the parvo- and magnocellular retinogeniculate pathways, respectively. Furthermore, we performed measurements of temporal contrast sensitivities as a function of frequency at 294 phot Td in two protanopes, in two deuteranopes, and in one subject with S-cone monochromacy. Quality of isolation was satisfactory and we were able to reproduce known physiological patterns of temporal vision, such as the typical temporal contrast sensitivity functions of the L- and M-cone, the parvo- and magnocellular retinogeniculate pathways, as well as the light adaptation curves. These results will help determine optimal stimulus conditions in future studies. Results from the dichromats and the S-cone monochromat also support the quality of isolation of our protocol and underpin its potential clinical value.

Melanopsin phototransduction allows intrinsically photosensitive retinal ganglion cells (ipRGCs) to maintain firing under sustained illumination and to encode irradiance. ipRGCs project to different parts of the visual system, including the superficial superior colliculus (sSC), but to date there is no description of melanopsin contributions to the activity of that nucleus. We sought to fill that gap using extracellular recordings to describe light response in the sSC. We failed to observe light responses in the sSC of mice lacking rod and cone function, in which melanopsin provides the only photoreception. Nor did the sSC of intact animals track very gradual ramps in irradiance, a stimulus encoded by melanopsin for other brain regions. However, in visually intact mice we did find maintained responses to extended light steps (30 s) and to an irradiance ramp upon which a high frequency (20 Hz) temporal white noise was superimposed. Both of these responses were deficient when the spectral composition of the stimulus was changed to selectively reduce its effective irradiance for melanopsin. Such maintained activity was also impaired in mice lacking melanopsin, and this effect was specific, as responses of this genotype to higher spatiotemporal frequency stimuli were normal. We conclude that ipRGCs contribute to irradiance-dependent modulations in maintained activity in the sSC, but that this effect is less robust than for other brain regions receiving ipRGC input., (© 2016 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Melanopsin expressing intrinsically photosensitive Retinal Ganglion Cells (ipRGCs) entirely control the post-illumination pupil response (PIPR) from 6 s post-stimulus to the plateau during redilation after light offset. However, the photoreceptor contributions to the early redilation phase of the PIPR (< 6 s post-stimulus) have not been reported. Here, we evaluated the photoreceptor contributions to the early phase PIPR (0.6 s to 5.0 s) by measuring the spectral sensitivity of the criterion PIPR amplitude in response to 1 s light pulses at five narrowband stimulus wavelengths (409, 464, 508, 531 and 592 nm). The retinal irradiance producing a criterion PIPR was normalised to the peak and fitted by either a single photopigment nomogram or the combined melanopsin and rhodopsin spectral nomograms with the +L+M cone photopic luminous efficiency (Vλ) function. We show that the PIPR spectral sensitivity at times ≥ 1.7 s after light offset is best described by the melanopsin nomogram. At times < 1.7 s, the peak PIPR sensitivity shifts to longer wavelengths (range: 482 to 498 nm) and is best described by the combined photoreceptor nomogram, with major contributions from melanopsin and rhodopsin. This first report of melanopsin and rhodopsin contributions to the early phase PIPR is in line with the electrophysiological findings of ipRGC and rod signalling after the cessation of light stimuli and provides a cut-off time for isolating photoreceptor specific function in healthy and diseased eyes., Competing Interests: The authors have declared that no competing interests exist.

Color vision in birds is mediated by four types of cone photoreceptors whose maximal sensitivities (λmax) are evenly spaced across the light spectrum. In the course of avian evolution, the λmax of the most shortwave-sensitive cone, SWS1, has switched between violet (λmax > 400 nm) and ultraviolet (λmax < 380 nm) multiple times. This shift of the SWS1 opsin is accompanied by a corresponding short-wavelength shift in the spectrally adjacent SWS2 cone. Here, we show that SWS2 cone spectral tuning is mediated by modulating the ratio of two apocarotenoids, galloxanthin and 11’,12’-dihydrogalloxanthin, which act as intracellular spectral filters in this cell type. We propose an enzymatic pathway that mediates the differential production of these apocarotenoids in the avian retina, and we use color vision modeling to demonstrate how correlated evolution of spectral tuning is necessary to achieve even sampling of the light spectrum and thereby maintain near-optimal color discrimination.

Vertebrate ancestors had only cone-like photoreceptors. The duplex retina evolved in jawless vertebrates with the advent of highly photosensitive rod-like photoreceptors. Despite cones being the arbiters of high-resolution color vision, rods emerged as the dominant photoreceptor in mammals during a nocturnal phase early in their evolution. We investigated the evolutionary and developmental origins of rods in two divergent vertebrate retinas. In mice, we discovered genetic and epigenetic vestiges of short-wavelength cones in developing rods, and cell-lineage tracing validated the genesis of rods from S cones. Curiously, rods did not derive from S cones in zebrafish. Our study illuminates several questions regarding the evolution of duplex retina and supports the hypothesis that, in mammals, the S-cone lineage was recruited via the Maf-family transcription factor NRL to augment rod photoreceptors. We propose that this developmental mechanism allowed the adaptive exploitation of scotopic niches during the nocturnal bottleneck early in mammalian evolution., (Published by Elsevier Inc.)

In bright light, cone-photoreceptors are active and colour vision derives from a comparison of signals in cones with different visual pigments. This comparison begins in the retina, where certain retinal ganglion cells have 'colour-opponent' visual responses-excited by light of one colour and suppressed by another colour. In dim light, rod-photoreceptors are active, but colour vision is impossible because they all use the same visual pigment. Instead, the rod signals are thought to splice into retinal circuits at various points, in synergy with the cone signals. Here we report a new circuit for colour vision that challenges these expectations. A genetically identified type of mouse retinal ganglion cell called JAMB (J-RGC), was found to have colour-opponent responses, OFF to ultraviolet (UV) light and ON to green light. Although the mouse retina contains a green-sensitive cone, the ON response instead originates in rods. Rods and cones both contribute to the response over several decades of light intensity. Remarkably, the rod signal in this circuit is antagonistic to that from cones. For rodents, this UV-green channel may play a role in social communication, as suggested by spectral measurements from the environment. In the human retina, all of the components for this circuit exist as well, and its function can explain certain experiences of colour in dim lights, such as a 'blue shift' in twilight. The discovery of this genetically defined pathway will enable new targeted studies of colour processing in the brain.

We explored the color constancy mechanisms of color-deficient observers under red, green, blue, and yellow illuminations. The red and green illuminations were defined individually by the longer axis of the color discrimination ellipsoid measured by the Cambridge Colour Test. Four dichromats (3 protanopes and 1 deuteranope), two anomalous trichromats (2 deuteranomalous observers), and five color-normal observers were asked to complete the color constancy task by making a simultaneous paper match under asymmetrical illuminations in haploscopic view on a monitor. The von Kries adaptation model was applied to estimate the cone responses. The model fits showed that for all color-deficient observers under all illuminations, the adjustment of the S-cone response or blue-yellow chromatically opponent responses modeled with the simple assumption of cone deletion in a certain type (S-M, S-L or S-(L+M)) was consistent with the principle of the von Kries model. The degree of adaptation was similar to that of color-normal observers. The results indicate that the color constancy of color-deficient observers is mediated by the simplified blue-yellow color system with a von Kries-type adaptation effect, even in the case of brightness match, as well as by a possible cone-level adaptation to the S-cone when the illumination produces a strong S-cone stimulation, such as blue illumination.

The Rayleigh match is defined by the range of mixtures of red and green lights that appear the same as an intensity-adjustable monochromatic yellow light. The perceptual match indicates that the red-green mixture and the yellow light have evoked the same respective cone absorptions in the L- and M-cone pathways. Going beyond the existing models, the Poisson noise in cone absorptions is proposed to make the matching proportion of red-green mixtures span a finite range because any mixture in that range evokes cone absorptions that do not differ from those by a yellow light by more than the variations in the absorption noise. We derive a mathematical formula linking the match midpoint or match range with the sensitivities and numerosities of the two cones. The noise-free, exact, matching point, close to the midpoint of the matching range, depends only on the L- and M-cone sensitivities to each of the red, green, and yellow lights [these sensitivities, in turn, depend on the preferred wavelengths (λmax) and optical densities of the cone pigments and the properties of prereceptoral light filtering]. Meanwhile, the matching range depends on both these cone sensitivities and the relative numerosity of the L and M cones. The model predicts that, in normal trichromats, all other things being equal, the match range is smallest when the ratio r between L and M cone densities is r=R(-1/2) with R as the ratio between the sensitivities of the L and M cones to the yellow light, i.e., when L and M cones are similarly abundant in typical cases, and, as r departs from R(-1/2), the match range increases. For example, when one cone type is 10 times more numerous, the match range increases two- to threefold, depending on the sensitivities of the cones. Testing these model predictions requires either a large data set to identify the effect of one factor (e.g., cone numerosity) while averaging out the effects of the other factors (e.g., cone sensitivities) or for all factors to be known. A corollary of this prediction is that, because they are more likely than usual to have L:M cone ratios skewed, the matching ranges of normal female trichromats who are carriers of dichromacy (but not anomalous trichromacy) are likely to have a larger matching range than usual, particularly for the deutan carriers. In addition, the model predicts that, in strong tetrachromats (whose four dimensions of color are preserved post-receptorally), either the Rayleigh matching is impossible or the matching range is typically smaller than usual.

We investigated the brightness (i.e., perceived luminance) of isolated L- and M-cone pulses to seek a perceptual correlate of our previous reports that M-on electroretinograms resemble L-off responses, implying the operation of post-receptoral opponent processing. Using triple silent substitutions, cone increments were generated in a 4-primary ganzfeld, masked by random positive or negative luminance bias. The results show that M-cone increments decrease in brightness, while L-cone increments increase. These differences became smaller as field size reduced; this was not eccentricity or area dependent. We speculate about early retinal input into brightness perception.

An important goal in characterizing human color vision is to order color percepts in a way that captures their similarities and differences. This has resulted in the continuing evolution of "uniform color spaces," in which the distances within the space represent the perceptual differences between the stimuli. While these metrics are now very successful in predicting how color percepts are scaled, they do so in largely empirical, ad hoc ways, with limited reference to actual mechanisms of color vision. In this article our aim is to instead begin with general and plausible assumptions about color coding, and then develop a model of color appearance that explicitly incorporates them. We show that many of the features of empirically defined color order systems (those of Munsell, Pantone, NCS, and others) as well as many of the basic phenomena of color perception, emerge naturally from fairly simple principles of color information encoding in the visual system and how it can be optimized for the spectral characteristics of the environment.

There is theoretical and empirical support for long-term adaptation of human vision to chromatic regularities in the environment. The current study investigates whether relationships of luminance and chromaticity in the natural environment could drive chromatic adaptation independently and differently for bright and dark colors. This is motivated by psychophysical evidence of systematic difference shifts in red-green chromatic sensitivities between contextually bright- versus dark-colored stimuli. For some broad classes of scene content, consistent shifts in chromaticity are found between high and low light levels within images. Especially in those images in which sky and terrain are juxtaposed, this shift has direction and magnitude consistent with the observed psychophysical shifts in the red-green balance between bright and dark colors. Taken together, these findings suggest that relative weighting of M- and L-cone signals could be adapted, in a luminance-dependent fashion, to regularities in the natural environment.