Franck P. Martial

Melanopsin-driven light adaptation in mouse vision.

Summary Background In 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”). Results We 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. Conclusions The 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.

Colour as a signal for entraining the Mammalian circadian clock.

Twilight is characterised by changes in both quantity (“irradiance”) and quality (“colour”) of light. Animals use the variation in irradiance to adjust their internal circadian clocks, aligning their behaviour and physiology with the solar cycle. However, it is currently unknown whether changes in colour also contribute to this entrainment process. Using environmental measurements, we show here that mammalian blue–yellow colour discrimination provides a more reliable method of tracking twilight progression than simply measuring irradiance. We next use electrophysiological recordings to demonstrate that neurons in the mouse suprachiasmatic circadian clock display the cone-dependent spectral opponency required to make use of this information. Thus, our data show that some clock neurons are highly sensitive to changes in spectral composition occurring over twilight and that this input dictates their response to changes in irradiance. Finally, using mice housed under photoperiods with simulated dawn/dusk transitions, we confirm that spectral changes occurring during twilight are required for appropriate circadian alignment under natural conditions. Together, these data reveal a new sensory mechanism for telling time of day that would be available to any mammalian species capable of chromatic vision.

Melanopsin contributions to the representation of images in the early visual system

Summary Melanopsin photoreception enhances retinal responses to variations in ambient light (irradiance) and drives non-image-forming visual reflexes such as circadian entrainment [1, 2, 3, 4, 5, 6]. Melanopsin signals also reach brain regions responsible for form vision [7, 8, 9], but melanopsin’s contribution, if any, to encoding visual images remains unclear. We addressed this deficit using principles of receptor silent substitution to present images in which visibility for melanopsin versus rods+cones was independently modulated, and we recorded evoked responses in the mouse dorsal lateral geniculate nucleus (dLGN; thalamic relay for cortical vision). Approximately 20% of dLGN units responded to patterns visible only to melanopsin, revealing that melanopsin signals alone can convey spatial information. Spatial receptive fields (RFs) mapped using melanopsin-isolating stimuli had ON centers with diameters ∼13°. Melanopsin and rod+cone responses differed in the temporal domain, and responses to slow changes in radiance (<0.9 Hz) and stationary images were deficient when stimuli were rendered invisible for melanopsin. We employed these data to devise and test a mathematical model of melanopsin’s involvement in form vision and applied it, along with further experimental recordings, to explore melanopsin signals under simulated active view of natural scenes. Our findings reveal that melanopsin enhances the thalamic representation of scenes containing local correlations in radiance, compensating for the high temporal frequency bias of cone vision and the negative correlation between magnitude and frequency for changes in direction of view. Together, these data reveal a distinct melanopsin contribution to encoding visual images, predicting that, under natural view, melanopsin augments the early visual system’s ability to encode patterns over moderate spatial scales.

Modulation of Fast Narrowband Oscillations in the Mouse Retina and dLGN According to Background Light Intensity.

Background light intensity (irradiance) substantially impacts the visual code in the early visual system at synaptic and single-neuron levels, but its influence on population activity is largely unexplored. We show that fast narrowband oscillations, an important feature of population activity, systematically increase in amplitude as a function of irradiance in both anesthetized and awake, freely moving mice and at the level of the retina and dorsal lateral geniculate nucleus (dLGN). Narrowband coherence increases with irradiance across large areas of the dLGN, but especially for neighboring units. The spectral sensitivity of these effects and their substantial reduction in melanopsin knockout animals indicate a contribution from inner retinal photoreceptors. At bright backgrounds, narrowband coherence allows pooling of single-unit responses to become a viable strategy for enhancing visual signals within its frequency range.

Melanopsin-driven increases in maintained activity enhance thalamic visual response reliability across a simulated dawn

Significance Irradiance-dependent (“luxotonic”) changes in baseline firing were first described in neurones of the early visual system decades ago. However, the origin and function (if any) of this visual response is still poorly understood. Here we address both questions by recording electrophysiological activity in mouse dorsal lateral geniculate nucleus over a simulated dawn. First, we show that in the photopic regime luxotonic activity becomes increasingly driven by inner-retinal melanopsin photoreceptors as irradiance increases. Then, that irradiance-dependent increases in activity apply not only to baseline firing but also to the amplitude of fast visual responses, producing increases in signal:noise across the simulated dawn, revealing a function for luxotonic activity and a new way in which inner retinal photoreceptors support conventional vision. Twice a day, at dawn and dusk, we experience gradual but very high amplitude changes in background light intensity (irradiance). Although we perceive the associated change in environmental brightness, the representation of such very slow alterations in irradiance by the early visual system has been little studied. Here, we addressed this deficit by recording electrophysiological activity in the mouse dorsal lateral geniculate nucleus under exposure to a simulated dawn. As irradiance increased we found a widespread enhancement in baseline firing that extended to units with ON as well as OFF responses to fast luminance increments. This change in baseline firing was equally apparent when the slow irradiance ramp appeared alone or when a variety of higher-frequency artificial or natural visual stimuli were superimposed upon it. Using a combination of conventional knockout, chemogenetic, and receptor-silent substitution manipulations, we continued to show that, over higher irradiances, this increase in firing originates with inner-retinal melanopsin photoreception. At the single-unit level, irradiance-dependent increases in baseline firing were strongly correlated with improvements in the amplitude of responses to higher-frequency visual stimuli. This in turn results in an up to threefold increase in single-trial reliability of fast visual responses. In this way, our data indicate that melanopsin drives a generalized increase in dorsal lateral geniculate nucleus excitability as dawn progresses that both conveys information about changing background light intensity and increases the signal:noise for fast visual responses.

The impact of temporal modulations in irradiance under light adapted conditions on the mouse suprachiasmatic nuclei (SCN)

Electrophysiological responses of SCN neurons to light steps are well established, but responses to more natural modulations in irradiance have been much less studied. We address this deficit first by showing that variations in irradiance for human subjects are biased towards low temporal frequencies and small magnitudes. Using extracellular recordings we show that neurons in the mouse SCN are responsive to stimuli with these characteristics, tracking sinusoidal modulations in irradiance best at lower temporal frequencies and responding to abrupt changes in irradiance over a range of commonly encountered contrasts. The spectral sensitivity of these light adapted responses indicates that they are driven primarily by cones, but with melanopsin (and/or rods) contributing under more gradual changes. Higher frequency modulations in irradiance increased time averaged firing of SCN neurons (typically considered to encode background light intensity) modestly over that encountered during steady exposure, but did not have a detectable effect on the circadian phase resetting efficiency of light. Our findings highlight the SCN’s ability to encode naturalistic temporal modulations in irradiance, while revealing that the circadian system can effectively integrate such signals over time such that phase-resetting responses remain proportional to the mean light exposure.

‘In a dark place, we find ourselves’: light intensity in critical care units

Intensive care units provide specialised care for critically ill patients around the clock. However, intensive care unit patients have disrupted circadian rhythms. Furthermore, disrupted circadian rhythms are associated with worse outcome. As light is the most powerful ‘re-setter’ of circadian rhythm, we measured light intensity on intensive care unit. Light intensity was low compared to daylight during the ‘day’; frequent bright light interruptions occurred over ‘night’. These findings are predicted to disrupt circadian rhythms and impair entrainment to external time. Bright lighting during daytime and black out masks at night might help maintain biological rhythms in critically ill patients and improve clinical outcomes.

Pupil responses to hidden photoreceptor-specific modulations in movies

Under daylight light levels, the human pupillary light response (PLR) is driven by the activity of the L, M, and S cones, and melanopsin expressed in the so-called intrinsically photosensitive retinal ganglion cells (ipRGCs). However, the importance of each of these photoreceptive mechanisms in defining pupil size during natural viewing conditions remains to be established. To address this question, we embedded photoreceptor-specific modulations in a movie projected using a novel projector-based five-primary spatial stimulation system, which allowed for the precise control of photoreceptor activations in time and space. We measured the sensitivity of the PLR in eleven observers, who viewed short cartoon movies which contained hidden low-frequency (0.25 Hz) modulations of the L, M and S cones (no stimulation of melanopsin), melanopsin (no stimulation of L, M and S cones), both L, M, and S cones and melanopsin or no modulation at all. We find that all photoreceptors active at photopic light levels regulate pupil size under this condition. Our data imply that embedding modulations in photoreceptor contrast could provide a method to manipulate key aspects of the human visual system in everyday activities such as a movie watching.

Exploiting metamerism to regulate the impact of a visual display on alertness and melatonin suppression independent of visual appearance

Abstract Objectives Artificial 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. Methods We 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. Results Our 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. Conclusions Our 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.