Circadian Photoreceptor Research Articles

LIGHT SPECTRA: AN IMPORTANT CONSIDERATION FOR CIRCADIAN ALIGNMENT IN THE MEDICAL ICU

TOPIC: Sleep Disorders TYPE: Original Investigations PURPOSE: Human circadian rhythms are regulated by a central ‘master clock’ which is entrained (i.e., aligned) to the 24-hour day primarily by light. Bright daytime light and lack of nighttime light are key entrainment signals. Light is detected via retinal photoreceptors, of which melanopsin is the primary circadian receptor. Circadian rhythms are best entrained by light wavelengths between 446 and 477 nanometers (nm), which are dominant in sunlight. Light wavelengths outside of this range will fail to optimally activate circadian photoreceptors and thus will not promote circadian alignment. A lack of activating wavelengths in hospital settings may potentiate circadian misalignment; circadian misalignment is associated with poor outcomes in critically ill patients.Light spectra measurements provide the intensity, or relative presence, of wavelengths within a defined range. Our study aims to determine the intensity of wavelengths within the approximate visible light range (380-780 nm) in patient rooms in two medical intensive care unit (MICU) campuses in a tertiary academic hospital system. We hypothesized that, during the day, MICU room lighting lacks significant presence of wavelengths between 446 and 477 nm. METHODS: To test this, we conducted an observational study of the visible spectra in 13 MICU rooms. Spectra were captured at 09:00, 13:00, and 17:00 on a sunny and cloudy day each month for 3 months, with a plan to continue for a full year. To test the contribution of artificial light, the spectra of each light source in the room was measured at night. All readings were taken from a standard location at the head of the patient bed. RESULTS: Rooms in both MICUs revealed common peak light intensities at 545 nm and 611 nm at all time points. These wavelengths align with the two wavelengths of greatest intensity emitted by artificial lights in the MICU. On average, 40% of measured intensities came from artificial room lighting, with MICU 1 having a higher percentage (46%) than MICU 2 (31%). Within the total visible spectrum, wavelengths between 446 and 477 nm had a greater daily contribution in MICU 2 (12%) than MICU 1 (8%). MICU rooms with west facing windows had a higher percentage of artificial light present in their spectra (52%) compared to rooms with east facing windows (35%). Similarly, rooms with east-facing windows demonstrated greater relative intensity of wavelengths between 446 and 477 nm (11%) compared to west-facing windows (7%). Over the day, as expected, room light spectra progressively shifted away from natural light, with late afternoon having a strong percentage of artificial spectra. CONCLUSIONS: The wavelengths of greatest intensity present during the day in MICU rooms are outside of the range known to optimally activate retinal photoreceptors that signal day-night orientation. Patients receive insufficient light reflecting natural sunlight, thus, our MICU room lighting likely fails to entrain patient circadian rhythms. CLINICAL IMPLICATIONS: Circadian misalignment has been associated with cardiovascular, immune, metabolic, and neurologic dysfunction, and in critically ill patients, death. ICUs contain myriad factors that disrupt circadian rhythms. The particular wavelengths of light patients are exposed to must be closely considered in the environment of care so that patients have the opportunity to remain entrained in order to heal. DISCLOSURES: No relevant relationships by Taylor Intihar, source=Web Response No relevant relationships by Melissa Knauert, source=Web Response No relevant relationships by Katherine Wasden, source=Web Response

Behaviorally and environmentally induced non-24-hour sleep-wake rhythm disorder in sighted patients.

To determine whether there was evidence of circadian or sleep-regulatory dysfunction in sighted individuals with non-24-hour sleep-wake rhythm disorder. Three sighted individuals with signs and/or symptoms of non-24-hour sleep-wake rhythm disorder were studied. Thirty-five- to 332-day laboratory and home-based assessments of sleep-wake and circadian timing, endogenous circadian period, photic input to the circadian pacemaker, and/or circadian and sleep-wake-dependent regulation of sleep were conducted. No evidence of circadian dysfunction was found in these individuals. Instead, sleep-wake timing appeared to dissociate from the circadian timing system, and/or self-selected sleep-wake and associated light/dark timing shifted the circadian pacemaker later, rather than the circadian pacemaker determining sleep-wake timing. These findings suggest that the etiology of this disorder may be light- and/or behaviorally induced in some sighted people, which has implications for the successful treatment of this disorder. Emens JS, St Hilaire MA, Klerman EB, etal. Behaviorally and environmentally induced non-24-hour sleep-wake rhythm disorder in sighted patients. J Clin Sleep Med. 2022;18(2):453-459.

Comparative Neurology of Circadian Photoreception: The Retinohypothalamic Tract (RHT) in Sighted and Naturally Blind Mammals.

The mammalian eye contains two systems for light perception: an image detecting system constituted primarily of the classical photoreceptors, rods and cones, and a non-image forming system (NIF) constituted of a small group of intrinsically photosensitive retinal ganglion cells driven by melanopsin (mRGCs). The mRGCs receive input from the outer retina and NIF mediates light entrainment of circadian rhythms, masking behavior, light induced inhibition of nocturnal melatonin secretion, pupillary reflex (PLR), and affect the sleep/wake cycle. This review focuses on the mammalian NIF and its anatomy in the eye as well as its neuronal projection to the brain. This pathway is known as the retinohypothalamic tract (RHT). The development and functions of the NIF as well as the knowledge gained from studying gene modified mice is highlighted. Furthermore, the similarities of the NIF between sighted (nocturnal and diurnal rodent species, monkeys, humans) and naturally blind mammals (blind mole rats Spalax ehrenbergi and the Iberian mole, Talpa occidentalis) are discussed in relation to a changing world where increasing exposure to artificial light at night (ALAN) is becoming a challenge for humans and animals in the modern society.

Weekend Light Shifts Evoke Persistent Drosophila Circadian Neural Network Desynchrony.

We developed a method for single-cell resolution longitudinal bioluminescence imaging of PERIOD (PER) protein and TIMELESS (TIM) oscillations in cultured male adult Drosophila brains that captures circadian circuit-wide cycling under simulated day/night cycles. Light input analysis confirms that CRYPTOCHROME (CRY) is the primary circadian photoreceptor and mediates clock disruption by constant light (LL), and that eye light input is redundant to CRY; 3-h light phase delays (Friday) followed by 3-h light phase advances (Monday morning) simulate the common practice of staying up later at night on weekends, sleeping in later on weekend days then returning to standard schedule Monday morning [weekend light shift (WLS)]. PER and TIM oscillations are highly synchronous across all major circadian neuronal subgroups in unshifted light schedules for 11 d. In contrast, WLS significantly dampens PER oscillator synchrony and rhythmicity in most circadian neurons during and after exposure. Lateral ventral neuron (LNv) oscillations are the first to desynchronize in WLS and the last to resynchronize in WLS. Surprisingly, the dorsal neuron group-3 (DN3s) increase their within-group synchrony in response to WLS. In vivo, WLS induces transient defects in sleep stability, learning, and memory that temporally coincide with circuit desynchrony. Our findings suggest that WLS schedules disrupt circuit-wide circadian neuronal oscillator synchrony for much of the week, thus leading to observed behavioral defects in sleep, learning, and memory.

Light/Clock Influences Membrane Potential Dynamics to Regulate Sleep States.

The circadian rhythm is a fundamental process that regulates the sleep–wake cycle. This rhythm is regulated by core clock genes that oscillate to create a physiological rhythm of circadian neuronal activity. However, we do not know much about the mechanism by which circadian inputs influence neurons involved in sleep–wake architecture. One possible mechanism involves the photoreceptor cryptochrome (CRY). In Drosophila, CRY is receptive to blue light and resets the circadian rhythm. CRY also influences membrane potential dynamics that regulate neural activity of circadian clock neurons in Drosophila, including the temporal structure in sequences of spikes, by interacting with subunits of the voltage-dependent potassium channel. Moreover, several core clock molecules interact with voltage-dependent/independent channels, channel-binding protein, and subunits of the electrogenic ion pump. These components cooperatively regulate mechanisms that translate circadian photoreception and the timing of clock genes into changes in membrane excitability, such as neural firing activity and polarization sensitivity. In clock neurons expressing CRY, these mechanisms also influence synaptic plasticity. In this review, we propose that membrane potential dynamics created by circadian photoreception and core clock molecules are critical for generating the set point of synaptic plasticity that depend on neural coding. In this way, membrane potential dynamics drive formation of baseline sleep architecture, light-driven arousal, and memory processing. We also discuss the machinery that coordinates membrane excitability in circadian networks found in Drosophila, and we compare this machinery to that found in mammalian systems. Based on this body of work, we propose future studies that can better delineate how neural codes impact molecular/cellular signaling and contribute to sleep, memory processing, and neurological disorders.

BDBT in the <i>Drosophila</i> Eye is Regulated by Visual and Circadian Pathways and Regulates Distinct Nuclear Localization Pathways for DBT and PER

BDBT interacts with the circadian kinase DBT and accumulates in eye foci during the dark of a light:dark cycle. BDBT is shown here to be constitutively high in the dark and constitutively low in the light. Analysis of circadian photoreceptor cry and visual photoreceptor ninaE mutants showed that disappearance of eye BDBT foci depends upon both the CRY and the RHODOPSIN-1 pathways. The Arr1 and Arr2 mutants which affect rhodopsin quenching eliminated the accumulation of BDBT foci under dark conditions.Arr1 and Arr2 mutants also lead to increased nuclear accumulation of PER protein. Knock-down of BDBT specifically in the eye produced a loss of coupled circadian localization oscillations for both PER and DBT. PER was constitutively nuclear and DBT was constitutively cytosolic. The results show that BDBT is necessary for co-transport of DBT and PER into the nucleus and suggest that this process is regulated by a light dependent mechanism.

Disrupted Glutamate Signaling in Drosophila Generates Locomotor Rhythms in Constant Light

We have used the Cambridge Protein Trap resource (CPTI) to screen for flies whose locomotor rhythms are rhythmic in constant light (LL) as a means of identifying circadian photoreception genes. From the screen of ∼150 CPTI lines, we obtained seven hits, two of which targeted the glutamate pathway, Got1 (Glutamate oxaloacetate transaminase 1) and Gs2 (Glutamine synthetase 2). We focused on these by employing available mutants and observed that variants of these genes also showed high levels of LL rhythmicity compared with controls. It was also clear that the genetic background was important with a strong interaction observed with the common and naturally occurring timeless (tim) polymorphisms, ls-tim and s-tim. The less circadian photosensitive ls-tim allele generated high levels of LL rhythmicity in combination with Got1 or Gs2, even though ls-tim and s-tim alleles do not, by themselves, generate the LL phenotype. The use of dsRNAi for both genes as well as for Gad (Glutamic acid decarboxylase) and the metabotropic glutamate receptor DmGluRA driven by clock gene promoters also revealed high levels of LL rhythmicity compared to controls. It is clear that the glutamate pathway is heavily implicated in circadian photoreception. TIM levels in Got1 and Gs2 mutants cycled and were more abundant than in controls under LL. Got1 but not Gs2 mutants showed diminished phase shifts to 10 min light pulses. Neurogenetic dissection of the LL rhythmic phenotype using the gal4/gal80 UAS bipartite system suggested that the more dorsal CRY-negative clock neurons, DNs and LNds were responsible for the LL phenotype. Immunocytochemistry using the CPTI YFP tagged insertions for the two genes revealed that the DN1s but not the DN2 and DN3s expressed Got1 and Gs2, but expression was also observed in the lateral neurons, the LNds and s-LNvs. Expression of both genes was also found in neuroglia. However, downregulation of glial Gs2 and Got1 using repo-gal4 did not generate high levels of LL rhythmicity, so it is unlikely that this phenotype is mediated by glial expression. Our results suggest a model whereby the DN1s and possibly CRY-negative LNds use glutamate signaling to supress the pacemaker s-LNvs in LL.

Identification and Expression Patterns of Opsin Genes in a Forest Insect, Dendrolimus punctatus.

Dendrolimus punctatus walker (Lepidoptera: Lasiocampidae) is the most serious coniferous forest defoliator in China. This species has long life history, and shows different activity rhythms and light response behaviors at larval and adult stages. Insect vision system play important roles for survival and reproduction, and disturbance of photoreception may help us to control this pest. However, we know little about the visual system of D. punctatus. As opsins are the most important genes determining photoreceptor sensitivity of insects, we identified opsins of D. punctatus and analyzed their expression patterns at different development stages in this study. Four opsin genes were identified based on our transcriptome data. Phylogenetic analysis showed that there are three classical ultraviolet (UV), blue, and long-wavelength (LW) light sensitive opsin genes, and another UV-like opsin as homolog of a circadian photoreceptor, Rh7, in Drosophila melanogaster and other insects. Expression analysis indicated that the UV and UV-like opsins expression levels only fluctuated slightly during whole life stages of D. punctatus, while Blue and LW opsins were up-regulated many times at adult stage. Interestingly, the ratio of UV-opsin was much higher in eggs and larvae stages, and lower in pupa and adult stages; reversely, LW-opsin showed extremely high relative ratio in pupa and adult stages. High expression level of LW opsin in the adult stage may correlate to the nocturnal lifestyles of this species at adult stage, and different ratios of UV and LW opsins in larval and adult stages may help to explain the different visual ecologies of these two development stages of D. punctatus. This work is the foundation for further research of opsin functions and vision mechanisms of D. punctatus.

Applications in sleep: How light affects sleep.

Sleep is an active physiological state that plays a critical role in our physical and mental health and well-being. It is generated by a complex interplay between two oscillators, namely, the circadian oscillator and the sleep-wake homeostat. Sleep propensity is a function of wakefulness, that is, the longer one is awake the greater the homeostatic sleep pressure. Sleep onset occurs as a wake promoting circadian signal subsides, coinciding with an evening rise in melatonin and drop in core temperature. Light is one of the strongest time signals for the circadian oscillator. Poor sleep is a prevalent complaint today, attributable, in part, to our easy access to artificial light, especially after dusk. This non-visual effect of light is mediated by a multi-component photoreceptive system, consisting of rods, cones and melanopsin-expressing intrinsically-photosensitive retinal ganglion cells (ipRGC). Perhaps, with this available biological knowledge we can engineer artificial light to minimize its disruptive effect on sleep. We will highlight this by discussing circadian photoreception and its effect on sleep, in the blind population.

Entrainment of the Drosophila clock by the visual system.

Circadian clocks evolved as an adaptation to the cyclic change of day and night. To precisely adapt to this environment, the endogenous period has to be adjusted every day to exactly 24 hours by a process called entrainment. Organisms can use several external cues, called zeitgebers, to adapt. These include changes in temperature, humidity, or light. The latter is the most powerful signal to synchronize the clock in animals. Research shows that a complex visual system and circadian photoreceptors work together to adjust animal physiology to the outside world. This review will focus on the importance of the visual system for clock synchronization in the fruit fly Drosophila melanogaster. It will cover behavioral and physiological evidence that supports the importance of the visual system in light entrainment.

Light Pollution, Circadian Photoreception, and Melatonin in Vertebrates

Artificial light at night (ALAN) is increasing exponentially worldwide, accelerated by the transition to new efficient lighting technologies. However, ALAN and resulting light pollution can cause unintended physiological consequences. In vertebrates, production of melatonin—the “hormone of darkness” and a key player in circadian regulation—can be suppressed by ALAN. In this paper, we provide an overview of research on melatonin and ALAN in vertebrates. We discuss how ALAN disrupts natural photic environments, its effect on melatonin and circadian rhythms, and different photoreceptor systems across vertebrate taxa. We then present the results of a systematic review in which we identified studies on melatonin under typical light-polluted conditions in fishes, amphibians, reptiles, birds, and mammals, including humans. Melatonin is suppressed by extremely low light intensities in many vertebrates, ranging from 0.01–0.03 lx for fishes and rodents to 6 lx for sensitive humans. Even lower, wavelength-dependent intensities are implied by some studies and require rigorous testing in ecological contexts. In many studies, melatonin suppression occurs at the minimum light levels tested, and, in better-studied groups, melatonin suppression is reported to occur at lower light levels. We identify major research gaps and conclude that, for most groups, crucial information is lacking. No studies were identified for amphibians and reptiles and long-term impacts of low-level ALAN exposure are unknown. Given the high sensitivity of vertebrate melatonin production to ALAN and the paucity of available information, it is crucial to research impacts of ALAN further in order to inform effective mitigation strategies for human health and the wellbeing and fitness of vertebrates in natural ecosystems.

Identification and Characterization of a New Class of (6–4) Photolyase from Vibrio cholerae

Light is crucial for many biological activities of most organisms, including vision, resetting of circadian rhythm, photosynthesis, and DNA repair. The cryptochrome/photolyase family (CPF) represents an ancient group of UV-A/blue light sensitive proteins that perform different functions such as DNA repair, circadian photoreception, and transcriptional regulation. The CPF is widely distributed throughout all organisms, including marine prokaryotes. The bacterium Vibrio cholerae was previously shown to have a CPD photolyase that repairs UV-induced thymine dimers and two CRY-DASHs that repair UV-induced single-stranded DNA damage. Here, we characterize a hypothetical gene Vca0809 encoding a new member of CPF in this organism. The spectroscopic analysis of the purified protein indicated that this enzyme possessed a catalytic cofactor, FAD, and photoantenna chromophore 6,7-dimethyl 8-ribityl-lumazin. With a slot blot-based DNA repair assay, we showed that it possessed (6-4) photolyase activity. Further phylogenetic and computational analyses enabled us to classify this gene as a member of the family of iron-sulfur bacterial cryptochromes and photolyases (FeS-BCP). Therefore, we named this gene Vc(6-4) FeS-BCP.

Artificial light sources as light pollutant of humans melatonin suppression

Blue light emitted by LEDs might influence on natural biological rhythm of human being, what can be considered as environment pollution. In this paper the effect of the latest commercially available LEDs on melatonin suppression index (MSI) was analyzed. Research was done based on spectral power distribution of given LED (SPD) and melatonin suppression function in reference to melatonin suppression under daylight (illuminant D65). Results of calculations shows strong correlation between CCT and MSI, however MSI factor might vary for different LEDs with same CCT. Full Text: PDF ReferencesC. C. Sun, et al., Packaging efficiency in phosphor-converted white LEDs and its impact to the limit of luminous efficacy, Journal of Solid State Lighting, 1:19, (2014). CrossRef M. S. Rea, M. G. Figueiro, J. D. Bullough, "Circadian photobiology: An emerging framework for lighting practice and research", Light Research Technology Vol. 34(3), (2002). CrossRef I. Fryc, P. Jakubowski, K. Kołacz, Analysis of optical radiation parameters of compact discharge HID lamps and LED COB modules used for illuminating shop windows, Przeglad Elektrotechniczny, R. 93, No. 11, (2017). CrossRef G. C. Brainard, J. P. Hanifin, J.M. Greeson, B. Byrne, E. Gerner, D. D. Rollang, "Action spectrum for melatonin regulation in humans: evidence for a novel circadian photoreceptor", Journal of Neuroscience vol. 21, (2001). CrossRef K. Thapan, J. Arendt, D. J. Skene, "An action spectrum for melatonin supression: evidence for a novel non-rod, non-cone photoreceptor system in humans," Journal of Physiology vol. 535, (2001). CrossRef I. Fryc, J. Fryc, P. Jakubowski, K. A. Wąsowski, Technical, medical and legal aspects of domestic light sources photobiological safety, Przeglad Elektrotechniczny, R. 93, No. 3, (2017). CrossRef J. Enzi et. al, A "Melanopic" Spectral Efficiency Function Predicts the Sensitivity of Melanopsin Photoreceptors to Polychromatic Lights Journal of biological rhytms, Vol. 26 No. 4, (2011). CrossRef M. Aube, J. Roby J, M. Kocifaj, Evaluating Potential Spectral Impacts of Various Artificial Lights on Melatonin Suppression, Photosynthesis, and Star Visibility. PLOS ONE, Vol. 8, (2013). CrossRef P. Jakubowski, I. Fryc, Metrological requirements for measurements of circadian radiation, Optica Applicata, Vol. 48 Issue 4, (2018). CrossRef P. Jakubowski, I. Fryc, Measurement methods of optical radiation in circadian active range, Zeszyty Naukowe Wydziału Elektrotechniki i Automatyki Politechniki Gdańskiej, nr 54 (2017). DirectLink P. Jakubowski, Comparative analysis of light parameters of LEDs and OLEDs in context of blue light emission, Polish Journal for Sustainable Development 21 (2), (2017). CrossRef CIE TN003:2015, "Report on the First International Workshop on Circadian and neurophysiological Photometry", (2015). DirectLink

Circadian Network Interactions with Jasmonate Signaling and Defense.

Plants experience specific stresses at particular, but predictable, times of the day. The circadian clock is a molecular oscillator that increases plant survival by timing internal processes to optimally match these environmental challenges. Clock regulation of jasmonic acid (JA) action is important for effective defenses against fungal pathogens and generalist herbivores in multiple plant species. Endogenous JA levels are rhythmic and under clock control with peak JA abundance during the day, a time when plants are more likely to experience certain types of biotic stresses. The expression of many JA biosynthesis, signaling, and response genes is transcriptionally controlled by the clock and timed through direct connections with core clock proteins. For example, the promoter of Arabidopsis transcription factor MYC2, a master regulator for JA signaling, is directly bound by the clock evening complex (EC) to negatively affect JA processes, including leaf senescence, at the end of the day. Also, tobacco ZEITLUPE, a circadian photoreceptor, binds directly to JAZ proteins and stimulates their degradation with resulting effects on JA root-based defenses. Collectively, a model where JA processes are embedded within the circadian network at multiple levels is emerging, and these connections to the circadian network suggest multiple avenues for future research.

SAT-460 Perceived Well-Being and Light-Reactive Hormones: An Exploratory Study

Light can impact psychobiological processes in a healthy or harmful way, challenging designers to better understand the resources they are manipulating. The present exploratory study compared two forms of office lighting which differed in correlated colour temperatures and light level. A holistic approach, comprising visual, emotional and biological dimensions, was used to assess the lighting conditions that could favour productivity and well-being by means of the identification of congruent relationships between objective and subjective measurements in response to light stimuli. The former included analyses of melatonin and cortisol, and the latter were psychological instruments for measuring transitory mood, somnolence, and visual comfort. Controlled experiments were run in a laboratory with a repeated measures design, which yielded fifty-six evaluations. Although no extreme ranges of correlated colour temperatures were used in this study, the spectral blue component present in the correlated colour temperature of approximately 4000 K, and also provided by the light-emitting diodes system at a higher light level, could have contributed to render most of the strong effects on the inter and intra correlations among the psychobiological responses. The mediator role of the psychological profile of the individuals was demonstrated by the significant predictive value of the perceived stress measures. References Brainard GC, Hanifin JP, Greeson JM, Byrne B, Glickman G, Gerner E, Rollag MD. Action spectrum for melatonin regulation in humans: Evidence for a novel circadian photoreceptor. Journal of Neuroscience 2001; 21: 6405–6412. Lucas RJ, Peirson SN, Berson DM, Brown TM, Cooper HM, Czeisler CA, Figueiro MG, Gamlin PD, Lockley SW, O’Hagan HB, Price LLA, Provencio I, Skene DJ, Brainard GC. Measuring and using light in the melanopsin age. Trends in Neurosciences 2014; 37: 1–9. Rea MS, Figueiro MG. A working threshold for acute nocturnal melatonin suppression from ‘white’ light sources used in architectural applications. Journal of Carcinogenesis and Mutagenesis 2013. DOI: 10.4172/2157-2518- 1000150. Rea MS, Figueiro MG. Light as a circadian stimulus for architectural lighting. Lighting Research and Technology First published 6 December 2016. DOI: 1477153516682368. Rea MS. The lumen seen in a new light: Making distinctions between light, lighting and neuroscience. Lighting Research and Technology 2015; 47: 259–280

Role of Rhodopsins as Circadian Photoreceptors in the Drosophila melanogaster.

Light profoundly affects the circadian clock and the activity levels of animals. Along with the systematic changes in intensity and spectral composition, over the 24-h day, light shows considerable irregular fluctuations (noise). Using light as the Zeitgeber for the circadian clock is, therefore, a complex task and this might explain why animals utilize multiple photoreceptors to entrain their circadian clock. The fruit fly Drosophila melanogaster possesses light-sensitive Cryptochrome and seven Rhodopsins that all contribute to light detection. We review the role of Rhodopsins in circadian entrainment, and of direct light-effects on the activity, with a special emphasis on the newly discovered Rhodopsin 7 (Rh7). We present evidence that Rhodopsin 6 in receptor cells 8 of the compound eyes, as well as in the extra retinal Hofbauer-Buchner eyelets, plays a major role in entraining the fly’s circadian clock with an appropriate phase-to-light–dark cycles. We discuss recent contradictory findings regarding Rhodopsin 7 and report original data that support its role in the compound eyes and in the brain. While Rhodopsin 7 in the brain appears to have a minor role in entrainment, in the compound eyes it seems crucial for fine-tuning light sensitivity to prevent overshooting responses to bright light.

A Distinct Visual Pathway Mediates High-Intensity Light Adaptation of the Circadian Clock in Drosophila.

To provide organisms with a fitness advantage, circadian clocks have to react appropriately to changes in their environment. High-intensity (HI) light plays an essential role in the adaptation to hot summer days, which especially endanger insects of desiccation or prey visibility. Here, we show that solely increasing light intensity leads to an increased midday siesta in Drosophila behavior. Interestingly, this change is independent of the fly's circadian photoreceptor cryptochrome and is solely caused by a small visual organ, the Hofbauer-Buchner eyelets. Using receptor knock-downs, immunostaining, and recently developed calcium tools, we show that the eyelets activate key core clock neurons, namely the s-LNvs, at HI. This activation delays the decrease of PERIOD (PER) in the middle of the day and propagates to downstream target clock neurons that prolong the siesta. We show a new pathway for integrating light-intensity information into the clock network, suggesting new network properties and surprising parallels between Drosophila and the mammalian system.SIGNIFICANCE STATEMENT The ability of animals to adapt to their ever-changing environment plays an important role in their fitness. A key player in this adaptation is the circadian clock. For animals to predict the changes of day and night, they must constantly monitor, detect and incorporate changes in the environment. The appropriate incorporation and reaction to high-intensity (HI) light is of special importance for insects because they might suffer from desiccation during hot summer days. We show here that different photoreceptors have specialized functions to integrate low-intensity, medium-intensity, or HI light into the circadian system in Drosophila These results show surprising parallels to mammalian mechanisms, which also use different photoreceptor subtypes to respond to different light intensities.

Integration of color and intensity increases time signal stability for the human circadian system when sunlight is obscured by clouds

The mammalian circadian system encodes both absolute levels of light intensity and color to phase-lock (entrain) its rhythm to the 24-h solar cycle. The evolutionary benefits of circadian color-coding over intensity-coding per se are yet far from understood. A detailed characterization of sunlight is crucial in understanding how and why circadian photoreception integrates color and intensity information. To this end, we continuously measured 100 days of sunlight spectra over the course of a year. Our analyses suggest that circadian color-coding may have evolved to cope with cloud-induced variation in light intensity. We proceed to show how an integration of intensity and spectral composition reduces day-to-day variability in the synchronizing signal (Zeitgeber). As a consequence, entrained phase angle of the circadian clock will be more stable, which will be beneficial for the organism. The presented characterization of sunlight dynamics may become important in designing lighting solutions aimed at minimizing the detrimental effects of light at night in modern societies.

Impaired Circadian Photoentrainment in Opn5-Null Mice

SummaryThe master circadian pacemaker in mammals resides in the hypothalamic suprachiasmatic nuclei (SCN) and is synchronized to ambient light/dark cycles (i.e., photoentrainment). Melanopsin (Opn4) and classical rod-cone photoreceptors are believed to provide all the photic input necessary for circadian photoentrainment. Although the UVA-sensitive photopigment Opn5 is known to be expressed in retinal ganglion cells, its physiological role remains unclear and a potential role for Opn5 in the photoentrainment of the master clock has not been addressed. Here we report impaired photoentrainment and phase shifting to UVA light in Opn5-null mice. However, triple-knockout mice lacking all known functional circadian photoreceptors (i.e., rods, cones, and melanopsin) failed to entrain to UVA-light/dark cycles, despite the presence of Opn5, demonstrating that Opn5 alone is not sufficient for photoentrainment of the SCN clock. Since Opn5 is involved in the regulation of the retinal circadian clock, disrupted retinal function may cause impaired circadian photoentrainment in Opn5-null mice.

Neural Network Interactions Modulate CRY-Dependent Photoresponses in Drosophila.

Light is one of the chief environmental cues that reset circadian clocks. In Drosophila, CRYPTOCHROME (CRY) mediates acute photic resetting of circadian clocks by promoting the degradation of TIMELESS in a cell-autonomous manner. Thus, even circadian oscillators in peripheral organs can independently perceive light in Drosophila However, there is substantial evidence for nonautonomous mechanisms of circadian photoreception in the brain. We have previously shown that the morning (M) and evening (E) oscillators are critical light-sensing neurons that cooperate to shift the phase of circadian behavior in response to light input. We show here that light can efficiently phase delay or phase advance circadian locomotor behavior in male Drosophila even when either the M- or the E-oscillators are ablated, suggesting that behavioral phase shifts and their directionality are largely a consequence of the cell-autonomous nature of CRY-dependent photoreception. Our observation that the phase response curves of brain and peripheral oscillators are remarkably similar further supports this idea. Nevertheless, the neural network modulates circadian photoresponses. We show that the M-oscillator neurotransmitter pigment dispersing factor plays a critical role in the coordination between M- and E-oscillators after light exposure, and we uncover a potential role for a subset of dorsal neurons in the control of phase advances. Thus, neural modulation of autonomous light detection might play an important role in the plasticity of circadian behavior.SIGNIFICANCE STATEMENT Input pathways provide circadian rhythms with the flexibility needed to harmonize their phase with environmental cycles. Light is the chief environmental cue that synchronizes circadian clocks. In Drosophila, the photoreceptor CRYPTOCHROME resets circadian clocks cell-autonomously. However, recent studies indicate that, in the brain, interactions between clock neurons are critical to reset circadian locomotor behavior. We present evidence supporting the idea that the ability of flies to advance or delay their rhythmic behavior in response to light input essentially results from cell-autonomous photoreception. However, because of their networked organization, we find that circadian neurons have to cooperate to reset the phase of circadian behavior in response to photic cues. Our work thus helps to reconcile cell-autonomous and non-cell-autonomous models of circadian entrainment.