Melanopsin Activation Research Articles

In-silico predicted mouse melanopsins with blue spectral shifts deliver efficient subcellular signaling

Melanopsin is a photopigment belonging to the G Protein-Coupled Receptor (GPCR) family expressed in a subset of intrinsically photosensitive retinal ganglion cells (ipRGCs) and responsible for a variety of processes. The bistability and, thus, the possibility to function under low retinal availability would make melanopsin a powerful optogenetic tool. Here, we aim to utilize mouse melanopsin to trigger macrophage migration by its subcellular optical activation with localized blue light, while simultaneously imaging the migration with red light. To reduce melanopsin’s red light sensitivity, we employ a combination of in silico structure prediction and automated quantum mechanics/molecular mechanics modeling to predict minimally invasive mutations to shift its absorption spectrum towards the shorter wavelength region of the visible spectrum without compromising the signaling efficiency. The results demonstrate that it is possible to achieve melanopsin mutants that resist red light-induced activation but are activated by blue light and display properties indicating preserved bistability. Using the A333T mutant, we show that the blue light-induced subcellular melanopsin activation triggers localized PIP3 generation and macrophage migration, which we imaged using red light, demonstrating the optogenetic utility of minimally engineered melanopsins.

Melanopsin-mediated amplification of cone signals in the human visual cortex.

The ambient daylight variation is coded by melanopsin photoreceptors and their luxotonic activity increases towards midday when colour temperatures are cooler, and irradiances are higher. Although melanopsin and cone photoresponses can be mediated via separate pathways, the connectivity of melanopsin cells across all levels of the retina enables them to modify cone signals. The downstream effects of melanopsin-cone interactions on human vision are however, incompletely understood. Here, we determined how the change in daytime melanopsin activation affects the human cone pathway signals in the visual cortex. A 5-primary silent-substitution method was developed to evaluate the dependence of cone-mediated signals on melanopsin activation by spectrally tuning the lights and stabilizing the rhodopsin activation under a constant cone photometric luminance. The retinal (white noise electroretinogram) and cortical responses (visual evoked potential) were simultaneously recorded with the photoreceptor-directed lights in 10 observers. By increasing the melanopsin activation, a reverse response pattern was observed with cone signals being supressed in the retina by 27% (p = 0.03) and subsequently amplified by 16% (p = 0.01) as they reach the cortex. We infer that melanopsin activity can amplify cone signals at sites distal to retinal bipolar cells to cause a decrease in the psychophysical Weber fraction for cone vision.

Melanopsin-driven surround induction on the red/green balance of yellow.

To test the potential role of melanopsin-dependent ipRGCs in surround induction effects, we used a four-channel projector apparatus to hold the cone activity in a surround constant while varying the amount of melanopsin activity between two levels: low (baseline) and high (136% of the baseline). Rods were partially controlled by having the subjects complete conditions after either adapting to a bright field or darkness. The subjects adjusted the red/green balance of a 2.5° central target that varied in its ratio of L and M cones, but was equiluminant with the surround, to a perceptual null point (neither reddish nor greenish). When the surround melanopsin activity was higher, the subjects set their yellow balances at significantly higher L/(L+M) ratios, suggesting the high melanopsin surround was inducing greenishness into the central yellow stimulus. This is consistent with surround brightness effects that show the induction of greenishness into a central yellow test by high luminance surrounds. This potentially provides further evidence for a general role of melanopsin activity in brightness perception.

Review on the study of potential health hazards caused by blue light due to Melanopsin activity

Humans live in a 24-hour environment, in which light and darkness follow a diurnal pattern. In humans, the known effects of light on circadian rhythms and sleep are all, without exception, mediated by the retina. The retina is a fine layer of nerve tissue at the back of our eyes, containing specialized photoreceptors. Melanopsin RGCs are extremely sensitive to blue light and even exposure to light levels as low as the one from a smart-phone or light emitting e-readers are associated with disruptions of circadian rhythm. Melanopsin absorbs light in the short-wavelength range of the visible spectrum, with λmax at or near 480 nm. High-intensity blue light from any source is potentially hazardous to the eye. Industry sources of blue light are purposely filtered or shielded to protect users. However, it may be harmful to look directly at many high-power consumer LEDs simply because they are very bright. When Melanopsin is activated by the short wavelength component of light, it suppresses Melatonin synthesis. This action is controlled mainly by light could affect several functions including the regulation of intraocular pressure. Blue light or blue-violet light can be damaging to delicate retinal cells deep in the eye. No one knows exactly what causes dry macular degeneration. Research indicates that it may be a combination of family genes and environmental factors, including smoking, obesity and diet. The condition develops as the eye ages. Additionally, our studies have shown blue light is a risk factor for the onset of age-related macular degeneration, which is a progressive condition that can lead to vision loss over.

Occipital cortex activity in response to melanopsin in healthy humans

AbstractPurpose: Melanopsin‐expressing retinal ganglion cells (mRGCs) signal light information to the brain and mediate non‐visual physiologic responses. Animal studies suggest that melanopsin also influences the visual pathway via synaptic contacts in the lateral geniculate nucleus and the superior colliculus. In healthy and blind humans, blue light exposure results in modulation of occipital activity in neuroimaging studies, presumably from melanopsin interaction with photoreceptors. This study examined if melanopsin activation influences the visual evoked potential (VEP).Methods: We recorded VEPs to light flash stimuli to activate cones, rods and melanopsin in 30 healthy volunteers (red: 630 nm, blue: 445 nm, intensities: 0.00003 to 150 cd/m2). Dark adaptation was used to sensitize rods. At 2 log cd/m2, rods are saturated, and bright blue lights are considered more melanopsin activating. Under photopic conditions, red light activates M‐L cones. Amplitude and latency of the N2 and P2 components of the VEP were evaluated.Results: P2 obtained from the melanopsin stimulus presented under dark‐adaptation (MEL1) had the largest amplitude and shortest latency of all VEPs including the melanopsin stimulus presented non‐dark adapted condition (MEL2). There was no difference of N2 between MEL1 and MEL2 conditions. The latency of N2 and P2 from rods was longer than that from MEL1 and MEL2. P2 from MEL2 was equivalent in amplitude and latency to the P2 of the brightest cone stimulus (30 cd/m2 red light).Conclusion: Under non‐dark‐adapted conditions, bright blue light evokes a similar VEP as bright red light, suggesting that cones are the predominant influence in these conditions. However, bright blue light presented under dark adaptation modified the VEP latency and amplitude. As rod VEPs are distinguished by slow latencies, then we propose that these changes arise from mRGCs influence on cone‐mediated visual pathways to the occipital cortex.

Is melanopsin activation affecting large field color-matching functions?

Color theory is based on the exclusive activation of cones. However, since the discovery of melanopsin expressing cells in the human retina, evidence of its intrusion in brightness and color vision is increasing. We aimed to assess if differences between peripheral or large field and foveal color matches can be accounted for by melanopsin activation or rod intrusion. Photopic color matches by young observers showed that differences between extrafoveal and foveal results cannot be explained by rod intrusion. Furthermore, statistical analyses on existing color-matching functions suggest a role of melanopsin activation, particularly, in large field S fundamentals.

The role of melanopsin photoreception on visual attention linked pupil responses.

A decision during a visual task is marked by a task‐evoked pupil dilation (TEPD) that is linked to the global cortical arousal state. Melanopsin expressing intrinsically photosensitive retinal ganglion cells (ipRGCs) form the afferent pathway for this pupil response. Melanopsin activation also influences mood and arousal and increases activity in decision‐making brain areas that receive direct ipRGC projections. Here, an optical photostimulation method controlled the excitations of all five photoreceptor classes in the human eye to isolate melanopsin‐mediated photoreception. We hypothesised that the TEPD can be driven by directing active visual covert attention through the ipRGC pathway. When observers are completely certain of the stimulus presence, melanopsin‐directed stimulation produces a TEPD of similar amplitude to a cone‐directed stimulation, with their combination producing larger amplitudes. This dilation is satisfactorily modelled by linear addition with a higher melanopsin weighting in ipRGCs. Visual reaction times were longest in response to melanopsin‐directed lights. Next, we asked whether the afferent photoreceptor input and decision certainty, controlled by priming the observer's a priori expectation, interact to drive the TEPD. Signal detection analysis showed that by fixing the predecision certainty (bias), the phasic arousal and TEPD amplitude vary with observer criterion (c′) and sensitivity (d′) but not with preferential activation of melanopsin. The signature feature of the melanopsin response during attention was a biphasic TEPD. We conclude that active covert attention can be modulated by visual information mediated via ipRGCs, but that phasic arousal responses marked using the TEPD are not increased by higher levels of melanopsin activation.

Sleep disturbance associated with Smith-Magenis syndrome

Smith-Magenis syndrome (SMS) (OMIM #182290) is a rare genetic disorder with a prevalence of 1 in 25 000 live births. Approximately 90% of SMS patients have harbored a 3.7 Mb interstitial 17p11.2 deletion involving the RAI1 gene, while 10% of cases have carried pathogenic variants of the RAI1 gene. SMS is characterized by sleep disturbance, intellectual impairment, developmental delay, craniofacial and cardiovascular anomalies, obesity, self injury, aggressive and autistic-like behaviors. Most SMS patients have sleep disorders such as short total sleep time, frequent night waking, short sleep onset, and early morning waking. The sleep disturbance may aggravate with age and persist throughout life. Three mechanisms have been delineated. The first concern was the abnormal secretion of melatonin, with high levels during daytime and low levels at night. Evaluation of the integrity of the intrinsically photosensitive retinal ganglion cell (ipRGC)/melanopsin system has found that SMS patients showed dysfunction in the sustained component of the pupillary light responses to blue light. Synchronization of daily melatonin profile and its photoinhibition are dependent on the activation of melanopsin. Dysfunction of the retina-melanin system may be one of the causes of melatonin spectrum disorders. Secondly, dysregulation of circadian rhythm gene expression has also been noted in mice and SMS patients. Finally, there may be association between sleep deprivation symptoms and DNA methylation patterns, which has provided new insights for SMS-associated sleep disorders and symptoms alike. Treatment for SMS-related sleep disorders is administered primarily through medications like melatonin tablets, which can alleviate insomnia-related sleep difficulties, in particular externalizing behavior in children. Researchers are also actively exploring other treatments for SMS currently.

The Effect of Light Colour During Night Time to Sleep Quality

<div class="WordSection1"><p><strong>Introduction: </strong>Sleep is one of the basic human needs, where human uses one third of their time only for sleeping. Some contributing factors towards bad sleep quality are stress, depression, surrounding noise, and the use of a bright light. It is known that white lights cause the activation of melanopsin, causing circadian cycle shift, whereas using yellow light does not. The aim of this research was to analyze whether there is an effect of using either white or yellow light towards sleep quality</p><p><strong>Method: </strong>This is RCT on 81 subjects. Sleep quality was measured using PSQI questionnaire on 3 measurements with each measurement taken every week. Result of the analyzed data using the General Linear Model – Repeated Measurement (GLM-RM) method<strong> </strong></p><p><strong>Result: </strong>There were significant differences on PSQI score between group that used white light during sleep (7.6 ± 2.3) in comparison to the control group (5.2 ± 1.8) (p = 0.02), but result also showed that there were no significant difference between the group that used yellow light (6.1 ± 1.7) during sleep in comparison with the control group (p = 0.14). Conclusion: There is a significant difference between the uses of white lights during sleep towards sleep quality, but there has not been any significant difference between the uses of yellow light during sleep towards sleep quality</p></div>

Endogenous Opioid Signaling in the Mouse Retina Modulates Pupillary Light Reflex.

Opioid peptides and their receptors are expressed in the mammalian retina; however, little is known about how they might affect visual processing. The melanopsin-expressing intrinsically photosensitive retinal ganglion cells (ipRGCs), which mediate important non-image-forming visual processes such as the pupillary light reflex (PLR), express β-endorphin-preferring, µ-opioid receptors (MORs). The objective of the present study was to elucidate if opioids, endogenous or exogenous, modulate pupillary light reflex (PLR) via MORs expressed by ipRGCs. MOR-selective agonist [D-Ala2, MePhe4, Gly-ol5]-enkephalin (DAMGO) or antagonist D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 (CTAP) was administered via intravitreal injection. PLR was recorded in response to light stimuli of various intensities. DAMGO eliminated PLR evoked by light with intensities below melanopsin activation threshold but not that evoked by bright blue irradiance that activated melanopsin signaling, although in the latter case, DAMGO markedly slowed pupil constriction. CTAP or genetic ablation of MORs in ipRGCs slightly enhanced dim-light-evoked PLR but not that evoked by a bright blue stimulus. Our results suggest that endogenous opioid signaling in the retina contributes to the regulation of PLR. The slowing of bright light-evoked PLR by DAMGO is consistent with the observation that systemically applied opioids accumulate in the vitreous and that patients receiving chronic opioid treatment have slow PLR.

Relative contributions of melanopsin to brightness discrimination when hue and luminance also vary.

A large number of studies have shown the effect of melanopsin-dependent retinal ganglion cells on humans performing brightness discrimination tasks. These studies often utilized targets that only differ in their melanopsin activation levels, and not in their luminance or hue, which are both factors that make large contributions to brightness discrimination. The purpose of the present study was to evaluate the relative contribution of melanopsin activation to brightness discrimination when luminance and hue are also varying in addition to melanopsin activation. Using an apparatus consisting of three separate high luminance projectors, we were able to manipulate melanopsin-isolating stimulation, and L-, M-, and S-cone stimulation separately, thus allowing us to vary stimuli in their melanopsin activation, luminance, and hue category independently. We constructed three sets of target stimuli with three different levels of melanopsin activation (100%, 131%, and 167% relative melanopsin excitation) and five levels of luminance. We then had subjects do a two-alternative forced choice task where they compared the previously described target stimuli set to a set of four comparison stimuli that varied in their hue category but had identical luminances. We found that in our stimuli set the overall contribution of melanopsin activity to brightness discrimination was small (an average of 6% increase in likelihood to call a high melanopsin activity stimulus brighter compared to a low melanopsin activity stimulus) when luminance and hue also varied. However, a significant interaction showed that when the comparison was between stimuli differing only in melanopsin stimulation (with luminance and hue unchanged) the contribution of melanopsin to brightness judgments was about 3 times larger (an average of 18% increase in likelihood to call a high melanopsin activity stimulus brighter compared to a low melanopsin activity stimulus). This suggests that although luminance and hue have large effects on brightness discrimination such that the melanopsin contribution can become hard to detect, when there are minimal cone-dependent signals available, melanopsin can make a large contribution to brightness discrimination.

Construction of a Multiwell Light-Induction Platform for Traceless Control of Gene Expression in Mammalian Cells.

Mammalian cells can be engineered to incorporate light-responsive elements that reliably sense stimulation by light and activate endogenous pathways, such as the cAMP or Ca2+ pathway, to control gene expression. Light-inducible gene expression systems offer high spatiotemporal resolution, and are also traceless, reversible, tunable, and inexpensive. Melanopsin, a well-known representative of the animal opsins, is a G-protein-coupled receptor that triggers a Gαq-dependent signaling cascade upon activation with blue light (≈470nm). Here, we describe how to rewire melanopsin activation by blue light to transgene expression in mammalian cells, with detailed instructions for constructing a 96-LED array platform with multiple tunable parameters for illumination of the engineered cells in multiwell plates.

Visual and non-visual properties of filters manipulating short-wavelength light.

PurposeOptical filters and tints manipulating short‐wavelength light (sometimes called ‘blue‐blocking’ or ‘blue‐attenuating’ filters) are used in the management of a range of ocular, retinal, neurological and psychiatric disorders. In many cases, the only available quantification of the optical effects of a given optical filter is the spectral transmittance, which specifies the amount of light transmitted as a function of wavelength.MethodsWe propose a novel physiologically relevant and retinally referenced framework for quantifying the visual and non‐visual effects of these filters, incorporating the attenuation of luminance (luminous transmittance), the attenuation of melanopsin activation (melanopsin transmittance), the colour shift, and the reduction of the colour gamut (gamut reduction). Using these criteria, we examined a novel database of spectral transmittance functions of optical filters (n = 121) which were digitally extracted from a variety of sources.ResultsWe find a large diversity in the alteration of visual and non‐visual properties. The spectral transmittance properties of the examined filters vary widely, in terms of shapes and cut‐off wavelengths. All filters show relatively more melanopsin attenuation than luminance attenuation (lower melanopsin transmittance than luminous transmittance). Across the data set, we find that melanopsin transmittance and luminous transmittance are correlated.ConclusionsWe suggest that future studies and examinations of the physiological effects of optical filters quantify the visual and non‐visual effects of the filters beyond the spectral transmittance, which will eventually aid in developing a mechanistic understanding of how different filters affect physiology. We strongly discourage comparing the downstream effects of different filters on, e.g. sleep or circadian responses, without considering their effects on the retinal stimulus.

Melanopsin driven enhancement of cone-mediated visual processing

The precise control of visual sensitivity to variations in external lighting is critical for optimising human visual function in a changing environment. In photopic illumination, the cone photoreceptors and their post-receptoral pathways have a primary role in regulating these adjustments; it is not fully understood how a small population of melanopsin-expressing, intrinsically photosensitive retinal ganglion cells (ipRGCs) can interact with the three cone photoreceptor classes to modulate human visual function. Here we investigated interactions between these inner and outer retinal photoreceptor classes in participants with trichromatic colour vision under conditions that independently controlled the excitations of ipRGCs, cones and rods in the retina. In the peripheral retina, we show that interaction between melanopsin- and cone-directed signals affect conscious, image-forming vision. The interaction patterns are inconsistent with any potential effects arising from artefacts due to open-field and penumbral-cone contrasts, or rod intrusion. For cone signals mediated via each of the three primary visual pathways, melanopsin activation enhances contrast sensitivity. The contrast response functions indicate this enhancement is a more generalised facilitation effect that onsets at ∼9% melanopsin contrast. The implication for human vision is that the contrast sensitivity of cone-mediated visual processes can be modulated by the level of melanopsin excitation in the stimulus light.

Yellow Filter Effect on Melatonin Secretion in the Eye: Role in IOP Regulation

ABSTRACTPurpose: Melatonin is a neurohormone mainly synthesized in the pineal gland; however, it is also present in the aqueous humor. One of melatonins’ functions in the eye is the regulation of intraocular pressure (IOP). Melatonin is known to be sensitive to light. Recently, the photopigment which controls melatonin synthesis, melanopsin, was found in the crystalline lens. Therefore, light conditions are an interesting possible way of regulating melatonin levels in the aqueous humor. The current study used yellow filters, since melanopsin is activated by short wavelength (blue light).Methods: New Zealand white rabbits were used, divided in two groups, one under controlled 12 h light/dark cycles, while the rest had their cages encased with a yellow filter (λ 465–480). IOP measurements were taken every week at the same time before they were anesthetized for aqueous humor extraction.Results: Keeping the rabbits under the yellow filter resulted in a decrease in IOP up to 43.8 ± 7.8% after 3 weeks. This effect was reversed after the topical application of selective and nonselective melatonin receptors antagonists, 4PPDOT and luzindole. Also, blocking melanopsin by its antagonist AA92593 under white light condition decreased IOP. Finally, melatonin levels were found significantly higher in the aqueous humor of rabbits developed under yellow filter compared to controls (37.4 ± 4.2 and 15.3 ± 3.1 ng/ml, respectively).Conclusion: Yellow filters modulate melatonin levels in the aqueous humor due to deactivating melanopsin activity. This effect leads to a decrease in IOP mediated by melatonin receptors.

Regulation of Melanopsin Signaling: Key Interactions of the Nonvisual Photopigment.

Melanopsin is a G protein-coupled receptor with a peak sensitivity in the blue part of the spectrum, which plays a key role in nonvisual light-mediated signaling. Recently, its importance in forming visual pathway as well as its role in blood vessels photorelaxation was also revealed. Melanopsin was discovered in 1998 in Xenopus leavis. Since then, the melanopsin presence was demonstrated across the species. The existence of two melanopsin genes (opn4m and opn4x) as well as melanopsin isoforms resulting from alternative splicing contributes to the variety in melanopsin-regulated processes. In this review, the diversity in melanopsin-induced signaling, regulation of melanopsin activity by phosphorylation and regulation of melanopsin mRNA are discussed.

Effect of background melanopsin activation levels on contrast sensitivity mediated by postreceptoral pathways

Effect of background melanopsin activation levels on contrast sensitivity mediated by postreceptoral pathways

Chromatic Pupillometry in Children.

Chromatic pupillometry is a technique that is increasingly used to assess retinal disorders. As age may be one of the various factors which can influence the pupillary light reaction, this study aimed to evaluate the pupil responses to colored light stimuli in the pediatric population. Fifty-three children with normal vision and without any history of ocular disorders were tested with a portable pupillometer. Four test sequences were used: five dim blue (470 nm) stimuli presented in half log steps ranging from −3.15 to −1.15 log cd/m2 after 3 min of dark adaptation, five red (622 nm) stimuli of −1.15, −0.7, −0.15, 0.3, and 0.85 log cd/m2 after 1 min light adaptation, one bright blue stimulus of 2.2 log cd/m2 and one bright red of 2 log cd/m2. The results were grouped by age: a younger group included 27 children aged from 3 to 10 years old and an older group included 26 from 10 and 1 month to 18 years old. The younger group had a smaller pupil diameter after dark adaptation compared with the older group. A linear regression defining the photopic threshold showed that younger subjects had a higher threshold, e.g., needed a brighter red stimulus to evoke a threshold pupil response comparable that of subjects. Age thus seems to influence outer retinal sensitivity at least as evaluated by the pupillary photopic threshold intensity. The post-illumination pupillary reaction was used as a marker of intrinsic melanopsin activity and did not show any difference between the two age groups.

Circadian rhythms, refractive development, and myopia.

Despite extensive research, mechanisms regulating postnatal eye growth and those responsible for ametropias are poorly understood. With the marked recent increases in myopia prevalence, robust and biologically-based clinical therapies to normalize refractive development in childhood are needed. Here, we review classic and contemporary literature about how circadian biology might provide clues to develop a framework to improve the understanding of myopia etiology, and possibly lead to rational approaches to ameliorate refractive errors developing in children. Increasing evidence implicates diurnal and circadian rhythms in eye growth and refractive error development. In both humans and animals, ocular length and other anatomical and physiological features of the eye undergo diurnal oscillations. Systemically, such rhythms are primarily generated by the 'master clock' in the surpachiasmatic nucleus, which receives input from the intrinsically photosensitive retinal ganglion cells (ipRGCs) through the activation of the photopigment melanopsin. The retina also has an endogenous circadian clock. In laboratory animals developing experimental myopia, oscillations of ocular parameters are perturbed. Retinal signaling is now believed to influence refractive development; dopamine, an important neurotransmitter found in the retina, not only entrains intrinsic retinal rhythms to the light:dark cycle, but it also modulates refractive development. Circadian clocks comprise a transcription/translation feedback control mechanism utilizing so-called clock genes that have now been associated with experimental ametropias. Contemporary clinical research is also reviving ideas first proposed in the nineteenth century that light exposures might impact refraction in children. As a result, properties of ambient lighting are being investigated in refractive development. In other areas of medical science, circadian dysregulation is now thought to impact many non-ocular disorders, likely because the patterns of modern artificial lighting exert adverse physiological effects on circadian pacemakers. How, or if, such modern light exposures and circadian dysregulation contribute to refractive development is not known. The premise of this review is that circadian biology could be a productive area worthy of increased investigation, which might lead to the improved understanding of refractive development and improved therapeutic interventions.

Evidence for an impact of melanopsin activation on unique white perception.

Current models of human color vision only consider cone inputs at photopic light levels, yet it is unclear whether the recently discovered melanopsin-expressing intrinsically photosensitive retinal ganglion cells (ipRGCs) contribute to color perception. Using a lab-made five-primary photostimulator that can independently control the stimulations of rods, cones, and ipRGCs in human retina, we determined the observer's unique white perception, an equilibrium point for signals arising from the opponent mechanisms of color vision, under different levels of melanopsin activation. We found changing melanopsin activation levels shifts the equilibrium point in the chromatic pathways. Our results suggest potential evidence for an impact of melanopsin activation on unique white perception and the existing color vision model for the periphery may need to be revised by incorporating melanopsin signaling.