SummaryPhotoreception in the mammalian retina is not restricted to rods and cones but extends to a small number of intrinsically photoreceptive retinal ganglion cells (ipRGCs), expressing the photopigment melanopsin [1–4]. ipRGCs are known to support various accessory visual functions including circadian photoentrainment and pupillary reflexes. However, despite anatomical and physiological evidence that they contribute to the thalamocortical visual projection [5–7], no aspect of visual discrimination has been shown to rely upon ipRGCs. Based on their currently known roles, we hypothesized that ipRGCs may contribute to distinguishing brightness. This percept is related to an object's luminance—a photometric measure of light intensity relevant for cone photoreceptors. However, the perceived brightness of different sources is not always predicted by their respective luminance [8–12]. Here, we used parallel behavioral and electrophysiological experiments to first show that melanopsin contributes to brightness discrimination in both retinally degenerate and fully sighted mice. We continued to use comparable paradigms in psychophysical experiments to provide evidence for a similar role in healthy human subjects. These data represent the first direct evidence that an aspect of visual discrimination in normally sighted subjects can be supported by inner retinal photoreceptors.

SummaryMany retinal dystrophies result in photoreceptor loss, but the inner retinal neurons can survive, making them potentially amenable to emerging optogenetic therapies. Here, we show that ectopically expressed human rod opsin, driven by either a non-selective or ON-bipolar cell-specific promoter, can function outside native photoreceptors and restore visual function in a mouse model of advanced retinal degeneration. Electrophysiological recordings from retinal explants and the visual thalamus revealed changes in firing (increases and decreases) induced by simple light pulses, luminance increases, and naturalistic movies in treated mice. These responses could be elicited at light intensities within the physiological range and substantially below those required by other optogenetic strategies. Mice with rod opsin expression driven by the ON-bipolar specific promoter displayed behavioral responses to increases in luminance, flicker, coarse spatial patterns, and elements of a natural movie at levels of contrast and illuminance (≈50–100 lux) typical of natural indoor environments. These data reveal that virally mediated ectopic expression of human rod opsin can restore vision under natural viewing conditions and at moderate light intensities. Given the inherent advantages in employing a human protein, the simplicity of this intervention, and the quality of vision restored, we suggest that rod opsin merits consideration as an optogenetic actuator for treating patients with advanced retinal degeneration.

SummaryBackgroundIn bright light, mammals use a distinct photopigment (melanopsin) to measure irradiance for centrally mediated responses such as circadian entrainment. We aimed to determine whether the information generated by melanopsin is also used by the visual system as a signal for light adaptation. To this end, we compared retinal and thalamic responses to a range of artificial and natural visual stimuli presented using spectral compositions that either approximate the mouse’s experience of natural daylight (“daylight”) or are selectively depleted of wavelengths to which melanopsin is most sensitive (“mel-low”).ResultsWe found reproducible and reversible changes in the flash electroretinogram between daylight and mel-low. Simultaneous recording in the dorsal lateral geniculate nucleus (dLGN) revealed that these reflect changes in feature selectivity of visual circuits in both temporal and spatial dimensions. A substantial fraction of units preferred finer spatial patterns in the daylight condition, while the population of direction-sensitive units became tuned to faster motion. The dLGN contained a richer, more reliable encoding of natural scenes in the daylight condition. These effects were absent in mice lacking melanopsin.ConclusionsThe feature selectivity of many neurons in the mouse dLGN is adjusted according to a melanopsin-dependent measure of environmental brightness. These changes originate, at least in part, within the retina. Melanopsin performs a role analogous to a photographer’s light meter, providing an independent measure of irradiance that determines optimal setting for visual circuits.

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The collective activity pattern of retinal ganglion cells, the retinal code, underlies higher visual processing. How does the ambient illuminance of the visual scene influence this retinal output? We recorded from isolated mouse and pig retina and from mouse dLGN in-vivo at up to seven ambient light levels covering the scotopic to photopic regimes. Across each luminance transition, the majority of ganglion cells exhibited qualitative response changes, while maintaining stable responses within each luminance. Strikingly, we commonly observed the appearance and disappearance of ON responses in OFF cells and vice versa. Such qualitative response changes occurred for a variety of stimuli, including full-field and localized contrast steps, and naturalistic movies. Our results suggest that the retinal code is not fixed but varies with every change of ambient luminance. This finding raises new questions about signal processing within the retina and has intriguing implications for visual processing in higher brain areas.

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Melanopsin-expressing intrinsically photosensitive retinal ganglion cells (ipRGCs) combine inputs from outer-retinal rod/cone photoreceptors with their intrinsic phototransduction machinery to drive a wide range of so-called non-image-forming (NIF) responses to light. Defining the contribution of each photoreceptor class to evoked responses is vital for determining the degree to which our sensory capabilities depend on melanopsin and for optimizing NIF responses to benefit human health. We addressed this problem by recording electrophysiological responses in the mouse pretectal olivary nucleus (PON) (a target of ipRGCs and origin of the pupil light reflex) to a range of gradual and abrupt changes in light intensity. Dim stimuli drove minimal changes in PON activity, suggesting that rods contribute little under these conditions. To separate cone from melanopsin influences, we compared responses to short (460 nm) and longer (600/655 nm) wavelengths in mice carrying a red shifted cone population (Opn1mw R ) or lacking melanopsin (Opn4 ؊ /؊ ). Our data reveal a surprising difference in the quality of information available from medium-and short-wavelength-sensitive cones. The majority cone population (responsive to 600/655 nm) supported only transient changes in firing and responses to relatively sudden changes in light intensity. In contrast, cones uniquely sensitive to the shorter wavelength (S-cones) were better able to drive responses to gradual changes in illuminance, contributed a distinct off inhibition, and at least partially recapitulated the ability of melanopsin to sustain responses under continuous illumination. These data reveal a new role for S-cones unrelated to color vision and suggest renewed consideration of cone contributions to NIF vision at shorter wavelengths.

ObjectivesArtificial light sources such as visual display units (VDUs) elicit a range of subconscious and reflex light responses, including increases in alertness and suppression of pineal melatonin. Such responses employ dedicated retinal circuits encompassing melanopsin photoreceptors. Here, we aimed to determine whether this arrangement can be exploited to modulate the impact of VDUs on melatonin onset and alertness without altering visual appearance.MethodsWe generated a five-primary VDU capable of presenting metameric movies (matched for color and luminance) but varying in melanopic-irradiance. Healthy human participants (n = 11) were exposed to the VDU from 18:00 to 23:00 hours at high- or low-melanopic setting in a randomized cross-over design and measured salivary melatonin and self-reported sleepiness at 30-minute intervals.ResultsOur VDU presented a 3× adjustment in melanopic-irradiance for images matched photometrically for color and luminance. Participants reported no significant difference in visual appearance (color and glare) between conditions. During the time in which the VDU was viewed, self-reported sleepiness and salivary melatonin levels increased significantly, as would be expected in this phase of the diurnal cycle. The magnitude of the increase in both parameters was significantly enhanced when melanopic-irradiance was reduced.ConclusionsOur data demonstrate that melatonin onset and self-reported sleepiness can be modulated independent of photometric parameters (color and luminance) under a commonly encountered light exposure scenario (evening use of a VDU). They provide the first demonstration that the impact of light on alertness and melatonin production can be controlled independently of visual experience, and establish a VDU capable of achieving this objective.