Preschool children, who spend most of their time indoors, and the effects of artificial light on children's health and performance are important. Previous studies show that blue-enriched white light (BWL) has significant effects on human bodies, but only a few studies have specifically examined its effects in young children. Moreover, due to the significant physiological differences between children and adults, findings from BWL studies in adults cannot be directly applied to children. Therefore, investigating the effects of BWL on young children living in indoor environments is crucial. We recruited 24 preschool children (age: 5 ± 0.8 years; 12 girls and 12 boys) to participate in a within-subject, randomized crossover study involving common white light (CWL) (450 lx, Melanopic EDI: 354.04 lx) and BWL (450 lx, Melanopic EDI: 746.05 lx) in a kindergarten playroom. Under different light conditions, the children underwent tests for cardiac activity and critical flicker fusion frequency (CFF), as well as psychomotor vigilance task (PVT) and ruler drop test (RDT). The results indicated that BWL had significant effects on preschool children. Compared to CWL exposure, BWL exposure significantly improved cardiac activity, alertness, and neuromuscular response but slightly increased visual fatigue. Our study reveals that BWL has significant potential to improve children's physiological and cognitive functions, particularly to improve cardiac activity, alertness, and neuromuscular response. This study broadens the understanding of the effects of indoor lighting on children and provides a theoretical basis for designing a healthy indoor environment for children.

This paper synthesises literature on non-visual effects of light in prison environments, drawing attention to disconnect between research evidence and current practices. This paper aims to guide prison designers and decision-makers towards lighting strategies that better support inmates' mental health and rehabilitation.

A focused literature search was conducted from June to October 2024 using Google Scholar and PubMed, targeting peer-reviewed studies published between 1985 and 2024. Included studies addressed the non-visual effects of light related to circadian rhythm, mental health, artificial and natural lighting, stress, aggression and hormonal regulation. Only English-language studies providing empirical or theoretical insights relevant to confinement settings were considered. Studies focused solely on visual performance, non-human subjects or lacking health implications were excluded. Keyword combinations were refined iteratively, although some relevant interdisciplinary work may have been missed due to indexing or terminological variations.

Neglecting the role of lighting in prison design contributes to poor psychological outcomes. Limited access to daylight and the overuse of artificial lighting with high blue light content disrupt circadian regulation, worsening sleep, mood and mental health. Conversely, designs that maximise daylight exposure and use adjustable artificial lighting with appropriate spectral qualities can promote emotional stability, reduce aggression and support rehabilitation.

Relevant interdisciplinary studies may still have been missed due to database indexing limitations or terminological variations across fields.

This paper bridges the gap between lighting design, environmental psychology and prison reform. By focusing on how light affects inmates' psychological health and rehabilitation, it offers insights into how prison design can be improved to foster well-being.

This contribution highlights the scientific development of two intertwined disciplines, photoneuroendocrinology and circadian biology. Photoneuroendocrinology has focused on nonvisual photoreceptors that translate light stimuli into neuroendocrine signals and serve rhythm entrainment. Nonvisual photoreceptors first described in the pineal complex and brain of nonmammalian species are luminance detectors. In the pineal, they control the formation of melatonin, the highly conserved hormone of darkness which is synthesized night by night. Pinealocytes endowed with both photoreceptive and neuroendocrine capacities function as "photoneuroendocrine cells." In adult mammals, nonvisual photoreceptors controlling pineal melatonin biosynthesis and pupillary reflexes are absent from the pineal and brain and occur only in the inner layer of the retina. Encephalic photoreceptors regulate seasonal rhythms, such as the reproductive cycle. They are concentrated in circumventricular organs, the lateral septal organ and the paraventricular organ, and represent cerebrospinal fluid contacting neurons. Nonvisual photoreceptors employ different photopigments such as melanopsin, pinopsin, parapinopsin, neuropsin, and vertebrate ancient opsin. After identification of clock genes and molecular clockwork, circadian biology became cutting-edge research with a focus on rhythm generation. Molecular clockworks tick in every nucleated cell and, as shown in mammals, they drive the expression of more than 3000 genes and are of overall importance for regulation of cell proliferation and metabolism. The mammalian circadian system is hierarchically organized; the central rhythm generator is located in the suprachiasmatic nuclei which entrain peripheral circadian oscillators via multiple neuronal and neuroendocrine pathways. Disrupted molecular clockworks may cause various diseases, and investigations of this interplay will establish a new discipline: circadian medicine.

The C-terminal binding protein 2 (CTBP2) gene (translational isoforms: CTBP2-L/S, RIBEYE) had been identified by a cross-trait analysis of genome-wide association studies for anorexia nervosa (AN) and body mass index (BMI). Here, we did a mutation analysis in CTBP2 by performing polymerase chain reactions with subsequent Sanger-sequencing to identify variants relevant for AN and body weight regulation and ensued functional studies. Analysis of the coding regions of CTBP2 in 462 female patients with AN (acute or recovered), 490 children and adolescents with severe obesity, 445 healthy-lean adult individuals and 168 healthy adult individuals with normal body weight detected 24 variants located in the specific exon of RIBEYE. In the initial analysis, three of these were rare non-synonymous variants (NSVs) detected heterozygously in patients with AN (p.Arg72Trp - rs146900874; p.Val289Met -rs375685611 and p.Gly362Arg - rs202010294). Four NSVs and one heterozygous frameshift variant were exclusively detected in children and adolescents with severe obesity (p.Pro53Ser - rs150867595; p.Gln175ArgfsTer45 - rs141864737; p.Leu310Val - rs769811964; p.Pro397Ala - rs76134089 and p.Pro402Ser - rs113477585). Ribeye mRNA was detected in mouse hypothalamus. No effect of fasting or overfeeding on murine hypothalamic Ribeye expression was determined. Yet, increased Ribeye expression was detected in hypothalami of leptin-treated Lepob/ob mice. This increase was not related to reduced food intake and leptin-induced weight loss. We detected rare and frequent variants in the RIBEYE specific exon in both patients with AN and in children and adolescents with severe obesity. Our data suggest RIBEYE as a relevant gene for weight regulation.

The Trial of External trigeminal nerve stimulation (eTNS) for the Acute treatment of Migraine (TEAM) study demonstrated that eTNS use during active migraine resulted in significantly higher rates of resolution of migraine-associated most bothersome symptom (MBS) compared to sham. However, no previous studies have examined the association between pretreatment MBS subtype and efficacy of eTNS treatment for active migraine.

We conducted a post hoc analysis examining efficacy of eTNS for different pretreatment MBS subtypes using TEAM study data.

Pretreatment MBS subtypes included photophobia (n = 345), nausea (n = 109), phonophobia (n = 73), and vomiting (n = 11). We examined MBS sub-group × treatment group (verum n = 259; sham n = 279) interaction for each post-treatment outcome to explore differential effects conditional on the total sample. We further explored direct, between treatment group comparisons for each MBS subtype, as well as compared treatment outcomes among all MBS subtypes within the sham, verum, and total sample. Finally, clinical heterogeneity of treatment effect (HTE) was assessed using a 1% absolute treatment effect difference as the clinically important threshold.

Significant sub-group × treatment interactions were found for resolution of MBS at 2 h (p = 0.008), pain relief at 2 h (p = 0.001), rescue medication between 2 and 24 h (p = 0.012), sustained pain freedom at 24 h (p = 0.033), and sustained pain relief at 24 h (p = 0.003). Significant sub-group × treatment interactions were not found for pain freedom at 2 h (p = 0.054) or absence of all symptoms at 2 h (p = 0.265). Between treatment group comparisons indicated that pain freedom after 2 h of eTNS was not significantly different between the verum and sham groups for any pretreatment MBS. The verum group had a significantly greater proportion of participants who had resolution of nausea MBS after 2 h of treatment compared to sham (37/55 [67.3%] vs. 25/54 [46.3%], respectively; p = 0.028) and resolution of photophobia MBS compared to sham (85/162 [52.5] vs. 71/183 [38.8%], respectively; p = 0.011). There were no significant differences between treatment groups for phonophobia or vomiting. Pain freedom after 2 h of eTNS was not significantly different among pretreatment MBS groups. Within the sham group and total sample, a greater proportion of participants who had vomiting MBS had resolution of their MBS compared to any other pretreatment MBS (p < 0.05 after Bonferroni adjustment). A greater proportion of participants with nausea MBS used rescue medications between 2 and 24 h after eTNS compared to participants with photophobia or phonophobia MBS within the verum and total sample (p < 0.05 after Bonferroni adjustment). No statistical differences were found among MBS groups for any other treatment outcomes. Clinically important HTE was present in vomiting MBS for resolution of MBS and present in nausea MBS for pain freedom and pain relief after 2 h, need for rescue medication, and sustained pain freedom at 24 h post-treatment. There was no clinically relevant HTE in the nausea MBS group for resolution of MBS at 2 h, absence of all migraine-associated symptoms and sustained pain relief at 24 h, or for any endpoint for other MBS subtypes.

Our results suggest the presence of both statistically significant HTE as well as clinically meaningful HTE. Statistical differences were primarily found for photophobia MBS, while clinically meaningful HTE was primarily found for nausea MBS. These findings may be clinically relevant for patients and clinicians when developing a treatment plan for acute treatment of migraine. Further studies are needed to elucidate the underlying pathophysiological differences between MBS subtypes and treatment optimization, particularly for patients with nausea MBS subtypes.

Mammalian cryptochrome 1 (CRY1) is a central player in the circadian transcription-translation feedback loop, crucial for maintaining a roughly 24-h rhythm. CRY1 was suggested to also function as a blue-light photoreceptor in humans and has been found to be expressed at the mRNA level in various cell types of the inner retina. However, attempts to detect CRY1 at the protein level in the human retina have remained unsuccessful so far. Using various C-terminal specific antibodies recognizing full-length CRY1 protein, we consistently detected selective labeling in the outer segments of short wavelength-sensitive (SWS1, "blue") cone photoreceptor cells across human, bonobo, and gorilla retinae. No other retinal cell types were stained, which is in contrast to what would be expected of a ubiquitous clock protein. Subcellular fractionation experiments in transfected HEK cells using a C-terminal specific antibody located full-length CRY1 in the cytosol and membrane fractions. Our findings indicate that human CRY1 has several different functions including at least one nonclock function. Our results also raise the likely possibility that several different versions of CRY1 exist in humans. We suggest that truncation of the C-terminal tail, maybe to different degrees, may affect the localization and function of human CRY1.

Gambling behaviour is a persistent and growing societal problem. An unexplored factor that may encourage gambling behaviour is the impact of circadian photoreception on cognitive processes underlying the behaviour. We investigated the influence of circadian photoreception on loss aversion in gambling by altering the blue content of light while maintaining the same visual brightness. Fifteen participants (age 18-27 years, M = 20.40, SD = 2.03) completed an economic decision-making task under blue-enriched and blue-depleted light, of equivalent visual brightness, on separate occasions in a randomised order. The task required participants to choose between taking a risky gamble of a positive and negative outcome, or a less risky guaranteed outcome. Hierarchical Bayesian Modelling was conducted to derive individual parameter estimates for loss aversion, and trial-by-trial performance was analysed using linear mixed models. The findings demonstrated that individuals were significantly less loss averse under blue-enriched light compared to blue-depleted light (β = - .43, 95% CI [- .82, - .04], p = .03). This study shows that exposure to light that preferentially targets circadian photoreception reduces loss aversion, which may encourage gambling behaviour.

The biological clock synchronizes with the environmental light-dark cycle through circadian photoentrainment. While intracellular pathways regulating clock gene expression after light exposure in the suprachiasmatic nucleus are well studied in mammals, the neuronal circuits driving phase shifts remain unclear. Here, using a mouse model, we show that chemogenetic activation of early-night light-responsive neurons induces phase delays at any circadian time, potentially breaking the photoentrainment dead zone. In contrast, activating late-night light-responsive neurons mimics light-induced phase shifts. Using in vivo two-photon microscopy, we found that most neurons in the suprachiasmatic nucleus exhibit stochastic light responses, while a small subset is consistently activated in the early subjective night and another is inhibited in the late subjective night. Our findings suggest a dynamic bi-stable network model for circadian photoentrainment, where phase shifts arise from a functional circuit integrating signals to groups of outcome neurons, rather than a labeled-line principle seen in sensory systems.

We investigated the association between outdoor artificial light-at-night (ALAN) exposure and cardiometabolic risk in the GCAT study. We included 9752 participants from Barcelona (59% women) and used satellite images (30 m resolution) and estimated photopic illuminance and the circadian regulation-relevant melanopic equivalent daylight illuminance (melanopic EDI). We explored the association between ALAN exposure and prevalent obesity, hypertension, and diabetes with logistic regressions and assessed the relationship with incident cardiometabolic diseases ascertained through electronic health records (mean follow-up 6.5 years) with Cox proportional hazards regressions. We observed an association between photopic illuminance and melanopic EDI and prevalent hypertension, odds ratio (OR) = 1.09 (95% CI, 1.01-1.16) and 1.08 (1.01-1.14) per interquartile range increase (0.59 and 0.16 lux, respectively). Both ALAN indicators were linked to incident obesity (hazard ratio [HR] = 1.29, 1.11-1.48 and 1.19, 1.05-1.34) and hemorrhagic stroke (HR = 1.73, 1.00-3.02 and 1.51, 0.99-2.29). Photopic illuminance was associated with incident hypercholesterolemia in all participants (HR = 1.17, 1.05-1.31) and with angina pectoris only in women (HR = 1.55, 1.03-2.33). Further research in this area and increased awareness on the health impacts of light pollution are needed. Results should be interpreted carefully since satellite-based ALAN data do not estimate total individual exposure. This article is part of a Special Collection on Environmental Epidemiology.

The anterior region of the hypothalamus accommodates a bilateral structure called the suprachiasmatic nucleus (SCN), which controls, modulates, and perpetuates the homeostasis of circadian rhythm and sleep hormone release. These SCN have a predominance over multitudinous peripheral tissues like the uterus, liver, intestine, pancreas, endocrine system, immune system, reproductive system, and cardiovascular system. This peripheral clock acts as a pacemaker for circadian rhythm timing, which regulates crucial metabolic pathways and organizes numerous activities in the female reproductive network of mammals. The circadian CLOCK genes are expressed in various reproductive organs. The CLOCK, BMAL1, CRY, and PER genes harmonize the balance and manifestation of nuclear receptors (NRs) expression, and the other way round, NRs regulate these circadian genes. Several NRs, in particular estrogen, progesterone, androgen, and PPARs, nurture the ovary and uterus. Bidirectional coordination between SCN and NRs maintains the circadian rhythm of the hypothalamic-pituitary-gonadal (HPG) axis of the female reproductive organs.

The mesolimbic dopamine system is a set of subcortical brain circuits that plays a key role in reward processing, reinforcement, associative learning, and behavioral responses to salient environmental events. In our previous studies of the dopaminergic response to salient visual stimuli, we observed that dopamine release in the lateral nucleus accumbens (LNAc) of mice encoded information about the rate and magnitude of rapid environmental luminance changes from darkness. Light-evoked dopamine responses were rate-dependent, robust to the time of testing or stimulus novelty, and required phototransduction by rod and cone opsins. However, it is unknown if these dopaminergic responses also involve non-visual opsins, such as melanopsin, the primary photopigment expressed by intrinsically photosensitive retinal ganglion cells (ipRGCs). In the current study, we evaluated the role of melanopsin in the dopaminergic response to light in the LNAc using the genetically encoded dopamine sensor dLight1 and fiber photometry. By measuring light-evoked dopamine responses across a broad irradiance and wavelength range in constitutive melanopsin (Opn4) knockout mice, we were able to provide new insights into the ability of non-visual opsins to regulate the mesolimbic dopamine response to visual stimuli.

Although the sensitivity of the circadian system to the characteristics of light (e.g., biological timing, intensity, duration, spectrum) has been well studied in adults, data in early childhood remain limited. Utilizing a crossover, within-subjects design, we examined differences in the circadian response to evening light exposure at two different correlated color temperatures (CCT) in preschool-aged children. Healthy, good sleeping children (n = 10, 3.0-5.9 years) completed two 10-day protocols. In each protocol, after maintaining a stable sleep schedule for 7 days, a 3-day in-home dim-light circadian assessment was performed. On the first and third evenings of the in-home protocol, dim-light melatonin onset (DLMO) was assessed. On the second evening, children received a 1-h light exposure of 20 lux from either 2700 K (low CCT) or 5000 K (high CCT) (~9 and ~16 melanopic equivalent daylight illuminance (mEDI lux), respectively) centered around their habitual bedtime. Children received the remaining light condition during their second protocol, with the order counterbalanced across participants. Salivary melatonin was collected to compute melatonin suppression and circadian phase shift resulting from each experimental light condition. Melatonin suppression across the 1-h light stimulus was significantly greater during exposure to the high CCT light (M = 56.3%, SD = 19.25%) than during the low CCT light (M = 23.90%, SD = 41.06%). Both light conditions resulted in marked delays of circadian timing, but only a small difference (d = -0.25) was observed in the delay between the 5000 K (M = 35.3 min, SD = 34.3 min) and 2700 K (M = 26.7 min, SD = 15.9 min) conditions. Together, these findings add to a growing literature demonstrating high responsivity of the circadian clock to evening light exposure in early childhood and provide preliminary evidence of melatonin suppression sensitivity to differences in light spectrum in preschool-aged children.

Photoperiod is the main environmental signal that affects animal behavior and reproduction. Light stimulus is traduced by a neural pathway that modulates pineal gland melatonin release, which synchronizes physiologic functions with day duration, highly influencing seasonal reproduction. The plains vizcacha (Lagostomus maximus) is a Hystricomorph rodent with seasonal reproduction that inhabits the Neotropic in South America. The aim of this work was to elucidate the effect of light/darkness exposition on the reproductive hypothalamic-pituitary-ovarian (HPO) axis in the female plains vizcacha. During 15 days, animals were subjected to different light/darkness regimens (Control group, CTL: 12:12 h dark:light; Darkness group, DARK: continuous darkness; Light group, LIGHT: continuous light). The melatoninergic system and reproductive hormones were evaluated. Plasma melatonin levels significantly decreased in DARK whereas both melatonin receptors (MT1 and MT2) expression significantly increased in the hypothalamus and decreased in the pituitary gland, and only MT1 expression increased in the ovaries. Continuous light did not induce significant variations in melatonin levels related to CTL, however, MTs expression changed at pituitary and ovary levels. Strikingly, both light/darkness regimens increased reproductive hormone expression. While darkness induced hypothalamic gonadotropin-releasing hormone (GnRH) expression and estradiol (E2) secretion, light increased LH and progesterone (P4) secretion. In conclusion, light availability may impact the reproductive axis of plains vizcacha inducing hormonal changes, with an organ-specific response, and sustaining HPO axis activity, thus ensuring reproduction. Environmental light and darkness, their availability and exposure length, could synchronize the reproductive axis in seasonal breeding species like the plains vizcacha. New & Noteworthy: Hypothalamic, pituitary, and ovarian variations were induced by continuous light or darkness in the plains vizcacha. Plasma melatonin decreased by continuous darkness-inducing hypothalamic, pituitary, and ovarian melatonin receptors variations. Fifteen days of continuous darkness induced GnRH, LH, and estradiol secretion, while 15 days of continuous light induced LH and P4 secretion. Environmental light/darkness would synchronize the reproductive axis in seasonal breeding species like the plains vizcacha.

The non-visual photoreceptor opsin 3 (OPN3) performs various functions by directly accepting light and activating G protein-coupled receptor signalling in non-visual tissues. OPN3, which is expressed in brown adipocytes, induces the expression of uncoupling protein 1 to generate heat upon exposure to blue light. There have been few reports on OPN3 expression in ruminants, and the mRNA sequence registered in a database as bovine OPN3 is the only predicted sequence. Therefore, we examined OPN3 expression in cattle. In the bovine retina, amplified fragments of the visual opsins, rhodopsin and opsin 1 and the non-visual opsins, opsin 4 and opsin 5, were detected using reverse transcription PCR, whereas no amplified PCR products of OPN3 were detected. Eleven tissues were used to analyse OPN3 expression in the entire body of bovines, including the testis and placenta, where OPN3 is highly expressed in humans and mice. No amplified PCR products were detected in any of the tissues. In a comparison among animal species, OPN3 was found to be expressed in mouse and horse testes, whereas no expression was observed in cattle and goat tissues. RNA sequencing revealed no OPN3 transcripts in the bovine placenta. Direct genomic DNA sequencing revealed a stop codon in the middle of the bovine OPN3 sequence. These results suggest that bovine OPN3 is pseudogenic as it does not encode a complete receptor protein. They also indicated that OPN3 is pseudogenic not only in cattle but also in other Cetartiodactyla, including goats.

Intrinsically photosensitive retinal ganglion cells are photoreceptors discovered in the last 20 years. These cells project to the suprachiasmatic nucleus of the brain to drive circadian rhythms, regulated by ambient light levels. The photopigment responsible for photoactivation in these cells, melanopsin, has been shown to exhibit many unique activation features among opsins. Notably, the photopigment can exist in three states dependent on the intensity and spectrum of ambient light, which affects its function. Despite increasing knowledge about these cells and melanopsin, tools that can manipulate their three states, and do so with single-cell precision, are limited. This reduces the extent to which circuit-level phenomena, and studying the implications of melanopsin tri-stability in living systems, can be pursued. In this report, we evoke and modulate calcium transients in live cells and intrinsically photosensitive retinal ganglion cells from isolated retinal tissues following two-photon excitation using near-infrared light pulses. We demonstrate that two-photon activation of melanopsin can successfully stimulate melanopsin-expressing cells with high spatio-temporal precision. Moreover, we demonstrate that the functional tri-stability of the photopigment can be interrogated by multiphoton excitation using spectral-temporal modulation of a broadband, ultrafast laser source.

Lighting environments with different correlated colour temperatures (CCTs) and illuminance levels not only give different subjective perceptions but also affect physiological parameters. However, previous studies have rarely considered the interaction between participants' physiological state and psychological feelings under different lighting environments. To address this gap, this study aimed to investigate the impact of different CCTs (6500 K and 3000 K) and illuminances (300 lx and 900 lx) on participants' visual perception, considering heart rate changes as a key variable. Through physiological and psychological questionnaire assessments, it was found that changes in heart rate significantly influenced participants' subjective evaluations. Heart rate variations affected participants' physiological perception of the lighting environment, such as respiration and thermal sensation. The results of this study can be used as a reference for future indoor lighting design, providing a scientific basis for creating a more comfortable and efficient lighting environment.

Hair follicles, unique skin appendages, undergo cyclic phases (anagen, catagen, telogen) governed by melatonin and associated molecular pathways. Melatonin, synthesized in the pineal gland, skin, and gut, orchestrates these cycles through antioxidant activity and signaling cascades (e.g., Wnt, BMP). This review examines melatonin's biosynthesis across tissues, its regulation of cashmere growth patterns, and its interplay with non-coding RNAs and the gut-skin axis. Recent advances highlight melatonin's dual role in enhancing antioxidant capacity (via Keap1-Nrf2) and modulating gene expression (e.g., Wnt10b, CTNNB1) to promote hair follicle proliferation. By integrating multi-omics insights, we construct a molecular network of melatonin's regulatory mechanisms, offering strategies to improve cashmere yield and quality while advancing therapies for human alopecia.

Extra-retinal photoreception is common across fish and avian species. In birds, the hypothalamus contains non-visual photoreceptors that detect light and regulate multiple endocrine systems. To date, light-dependent control of seasonal reproduction is one of the most well-studied systems that require deep brain photoreception. However, the precise photoreceptor(s) that detect light and the neuroendocrine connection between opsin-expressing cells and the gonadotropin-releasing hormone-1 (GnRH1) system remain poorly defined. In the past couple of decades, two opsin molecules have been proposed to link light detection with seasonal reproduction in birds: neuropsin (Opn5) and vertebrate ancient opsin (VA opsin). Only VA opsin is expressed in GnRH1 cells and has an absorption spectrum that matches the action spectrum of the avian photoperiodic reproductive response. This perspective describes how the annual change in daylength, referred to as photoperiod, regulates the neuroendocrine control of seasonal reproduction. The opsin genes are then outlined, and the cellular phototransduction cascade is described, highlighting the common feature of hyperpolarization in response to light stimulation. We then discuss the latest evidence using short-hairpin RNA to temporarily knock down VA opsin and Opn5 on transcripts involved in the neuroendocrine regulation of reproduction. Based on emerging data, we outline three theoretical scenarios in which VA opsin might regulate GnRH1 synthesis and release in birds. The models proposed provide a series of testable hypotheses that can be used to improve our understanding of avian light detection by VA opsin or other opsin-expressing cells in the brain.

Light is an environmental feature important for human physiology. Investigation of how light affects population health requires exposure assessment and personal biomonitoring efforts. Here, we derived measures of amount, duration, regularity, and timing from objective personal light (lux) measurement in >4000 participants across two United States (US)-based cohort studies, the Multi-Ethnic Study of Atherosclerosis (MESA) and the Hispanic Community Health Study / Study of Latinos (HCHS/SOL), encompassing eight geographic regions. Objective light and actigraphy data were collected over a week using wrist-worn devices (Actiwatch Spectrum). Cohort-stratified light exposure metrics were analyzed in relation to sex, season, time-of-day, location, and demographic and sleep health characteristics using Spearman correlation and linear and logistic regressions (separately by cohort) adjusted for age, sex (where applicable), and exam site. Light exposure showed sex-specific patterns and had seasonal, diurnal, geographic, and demographic and sleep health-related correlates. Results between independent cohorts were strongly consistent, supporting the utility and feasibility of light biomonitoring. These findings provide a fundamental first characterization of light exposure patterns in a large US sample and will inform future work to incorporate light as a biologically relevant exposure in environmental public health and key component of the human exposome.

Light is a crucial environmental factor that influences various aspects of life, including physiological and psychological processes. While light is well-known for its role in enabling humans and other animals to perceive their surroundings, its influence extends beyond vision. Importantly, light affects our internal time-keeping system, the circadian clock, which regulates daily rhythms of biochemical and physiological processes, ultimately impacting mood and behaviour. The 24-h availability of light can have profound effects on our well-being, both physically and mentally, as seen in cases of jet lag and shift work. This review summarizes the intricate relationships between light, the circadian clock, and mood-related behaviours, exploring the underlying mechanisms and its implications for health.

Retinitis pigmentosa (RP) is a leading cause of blindness and genetically induces impairment of the retinal epithelium and photoreceptors. In this study, we investigated the decline in the visual response and visual ability during disease progression. This understanding is crucial for disease staging in patients, establishing therapeutic plans in advance, and evaluating the effects of interventional treatments.

We used a rat model of inherited RP (Royal College of Surgeons [RCS] rats) and evaluated form visual acuity and light perception using behavioral tests and electrophysiological recordings in the dorsal lateral geniculate nucleus, superior colliculus, and primary visual cortex.

The perceptual form vision (detection of grating stimulus) was attenuated by 9 weeks old. The neural responses in the three early visual areas to flashing grating stimuli with various contrasts and spatial frequencies showed similar degeneration progress as the behavioral evaluations. Light perception (detection of a bright uniform light source) was maintained until at least 11 weeks old. The neural responses to the uniform flashlight stimulus in the three early visual areas were maintained during the same period.

Our findings suggest that form vision is primarily affected by the progression of RP, whereas non-form vision is potentially robust to retinal degeneration. This maintenance of light perception is likely due to the preserved function of intrinsically photosensitive retinal ganglion cells. These results provide useful and fundamental knowledge for evaluating the protective or restorative effects of experimental treatments for RP.

In this review, we introduce the concept of "dual thermosensing mechanisms," highlighting the functional collaboration between G protein-coupled receptors (GPCRs) and transient receptor potential (TRP) channels that enable sophisticated cellular thermal responsiveness. GPCRs have been implicated in thermosensory processes, with recent findings identifying several candidates across species, including mammals, fruit flies, and nematodes. In many cases, these GPCRs work in conjunction with another class of thermosensors, TRP channels, offering insights into the complex mechanisms underlying thermosensory signaling. We examine how GPCRs function as thermosensors and how their signaling regulates cellular thermosensation, illustrating the complexity of thermosensory systems. Understanding these dual thermosensory mechanisms would advance our comprehension of cellular thermosensation and its regulatory pathways.

The retina contains distinct types of ganglion cells, which form mosaics with cells of each type at each position of the visual field. Displaced retinal ganglion cells (dRGCs) occur with cell bodies in the inner nuclear layer (INL), and regularly placed RGCs with cell bodies in the ganglion cell layer. An example of mammalian dRGCs are M1-type intrinsically photosensitive ganglion cells (ipRGCs). Little is known, however, about their relationship with regularly placed ipRGCs. We identified mouse ipRGC types M1, M2, and M4/sONɑ by immunohistochemistry and light microscopy. Reconstruction of immunolabeled mosaics from M1 and sONɑ RGCs indicated that dRGCs tiled the retina with their regular RGC partners. Multi-electrode array recordings revealed conventional receptive fields of displaced sONɑ RGCs which fit into the mosaic of their regular counterparts. An RGC distribution analysis showed type-specific dRGC patterns which followed neither the global density distribution of all RGCs nor the local densities of corresponding cell types. The displacement of RGC bodies into the INL occurs in a type-dependent manner, where dRGCs are positioned to form complete mosaics with their regular partners. Our data suggest that dRGCs and regular RGCs serve the same functional role within their corresponding population of RGCs.

Glutamate represents the dominant neurotransmitter that conveys the light information to the brain, including the suprachiasmatic nucleus (SCN), the central pacemaker for the circadian system. The neuronal and astrocytic glutamate transporters are crucial for maintaining efficient glutamatergic signaling. In the SCN, glutamatergic nerve terminals from the retina terminate on vasoactive intestinal polypeptide (VIP) neurons, which are essential for circadian functions. To date, little is known about the role of the core circadian clock gene, Bmal1, in glutamatergic neurotransmission of light signal to various brain regions.

The aim of this study was to further elucidate the role of Bmal1 in glutamatergic neurotransmission from the retina to the SCN. We therefore examined the spontaneous rhythmic locomotor activity, neuronal and glial glutamate transporters, as well as the ultrastructure of the synapse between the retinal ganglion cells (RGCs) and the SCN in adult male Bmal1-/- mice.

We found that the deletion of Bmal1 affects the light-mediated behavior in mice, decreases the retinal thickness and affects the vesicular glutamate transporters (vGLUT1, 2) in the retina. Within the SCN, the immunoreaction of vGLUT1, 2, glial glutamate transporters (GLAST) and VIP was decreased while the glutamate concentration was elevated. At the ultrastructure level, the presynaptic terminals were enlarged and the distance between the synaptic vesicles and the synaptic cleft was increased, indicative of a decrease in the readily releasable pool at the excitatory synapses in Bmal1-/-.

Our data suggests that Bmal1 deletion affects the glutamate transmission in the retina and the SCN and affects the behavioral responses to light.

Mammalian opsin 3 (OPN3) is a member of the opsin family of G-protein-coupled receptors with ambiguous light sensitivity. OPN3 was first identified in the brain (and named encephalopsin) and subsequently found to be expressed in other tissues. In adipocytes, OPN3 is necessary for light responses that modulate lipolysis and glucose uptake, while OPN3 in human skin melanocytes regulates pigmentation in a light-independent manner. Despite its initial discovery in the brain, OPN3 functional mechanisms in the brain remain elusive. Here, we investigated the molecular mechanism of OPN3 function in the paraventricular nucleus (PVN) of the hypothalamus. We show that Opn3 is coexpressed with the melanocortin 4 receptor (Mc4r) in a population of PVN neurons, where it negatively regulates MC4R-mediated cAMP signaling in a specific and Gαi/o-dependent manner. Under baseline conditions, OPN3 via Gαi/o potentiates the activity of the inward rectifying Kir7.1 channel, previously shown to be closed in response to agonist-mediated activation of MC4R in a Gαs-independent manner. In mice, we found that Opn3 in Mc4r-expressing neurons regulates food consumption. Our results reveal the first mechanistic insight into OPN3 function in the hypothalamus, uncovering a unique mechanism by which OPN3 functions to potentiate Kir7.1 activity and negatively regulate MC4R-mediated cAMP signaling, thereby promoting food intake.

Circadian rhythms play an important role in many physiological processes. We have previously reported that no periodic fluctuation in the Bmal1 mRNA is observed in the liver of the chipmunk, a mammalian hibernator, in the hibernation season, suggesting that peripheral circadian clocks are not functional during hibernation. In contrast, the Per2 mRNA levels are transiently increased by elevated body temperature during interbout arousal and showed periodic fluctuations in the hibernation season, suggesting that periodic expression of the Per2 mRNA may be restored during interbout arousal. In the present study, we analyzed Per1 gene expression in the chipmunk liver. The Per1 mRNA showed circadian fluctuations with a peak during the late sleep period in the non-hibernation season and periodic fluctuations with a peak during the early interbout arousal in the hibernation season. In both the non-hibernation and hibernation seasons, Per1 gene expression was phase-advanced relative to Per2 gene expression, and the phase relationship between the two genes was maintained, suggesting that for some genes, periodic gene expression, similar to circadian expression in the non-hibernation season, may be restored during interbout arousal. Interestingly, Per1 gene transcription was differentially activated by BMAL1 in the non-hibernation season and possibly by CREB1 in the hibernation season.

The pupillary light reflex (PLR) is crucial for protecting the retina from excess light. The intrinsically photosensitive retinal ganglion cells (ipRGCs) in the retina are neurons that are critical to generating the PLR, receiving rod/cone photoreceptor signals and directly sensing light through melanopsin. Previous studies have investigated the roles of photoreceptors and ipRGCs in PLR using genetically-modified mouse models. Herein, we acutely ablated photoreceptors using N-nitroso-N-methylurea (MNU) to examine the roles of ipRGCs in the PLR. We conducted PLR and multiple electrode array (MEA) recordings evoked by three levels of light stimuli before and 5 days after MNU intraperitoneal (i.p..) injection using C57BL6/J wildtype (WT) mice. We also conducted these measurements using the rod & cone dysfunctional mice (Gnat1-/- & Cnga3-/-:dKO) to compare the results to published studies in which mutant mice were used to show the role of photoreceptors and ipRGCs in PLR. PLR pupil constriction increased as the light stimulus intensified in WT mice. In MNU mice, PLR was not induced by the low light stimulus, suggesting that photoreceptors induced the PLR at this light intensity. By contrast, the high light stimulus fully induced PLR, similar to the response in WT mice. In dKO mice, no PLR was evoked by the low-light stimulus and a slow-onset PLR was evoked by the high-light stimulus, consistent with previous reports. Ex vivo MEA recording in the MNU tissue revealed a population of ipRGCs with a fast onset and peak time, suggesting that they drove the fast PLR response. These results suggest that ipRGCs primarily contribute to the PLR at a high light intensity, which does not agree with the previous results shown by mutant mouse models. Our results indicate that the melanopsin response in ipRGCs generate fast and robust PLR when induced by high light.

It has long been a decades-old dogma that image perception is mediated solely by rods and cones, while intrinsically photosensitive retinal ganglion cells (ipRGCs) are responsible only for non-image-forming vision, such as circadian photoentrainment and pupillary light reflexes. Surprisingly, we discovered that ipRGC activation enhances the orientation selectivity of layer 2/3 neurons in the primary visual cortex (V1) of mice by both increasing preferred-orientation responses and narrowing tuning bandwidth. Mechanistically, we found that the tuning properties of V1 excitatory and inhibitory neurons are differentially influenced by ipRGC activation, leading to a reshaping of the excitatory/inhibitory balance that enhances visual cortical orientation selectivity. Furthermore, light activation of ipRGCs improves behavioral orientation discrimination in mice. Importantly, we found that specific activation of ipRGCs in human participants through visual spectrum manipulation significantly enhances visual orientation discriminability. Our study reveals a visual channel originating from "non-image-forming photoreceptors" that facilitates visual orientation feature perception.

Melanopsin-expressing intrinsically photosensitive (ip) retinal ganglion cells (RGCs) can be divided into six different subtypes (M1 - M6). Yet, specific markers exist for only some of these subtypes that could be employed to study the function of individual subtypes. Osteopontin (Spp1) marks αRGC, suggesting that, across ipRGCs, it would only mark the M4-ipRGC subtype (synonymous to ON-sustained αRGCs). Recent evidence suggests that osteopontin expression could spread to other ipRGC subtypes. Therefore, this study aims to characterize the expression pattern of osteopontin across ipRGC subtypes in mice.

Single-cell RNA (scRNA-seq) sequencing data from murine RGCs were analyzed to identify expression patterns of Spp1 across ipRGCs. Immunohistochemistry (IHC) was performed on retinal cryosections and flatmounts from C57BL/6J mice to characterize the localization of osteopontin across ipRGCs. Neurite tracing was employed to study dendritic morphology and identify individual ipRGC subtypes.

scRNA-seq analysis revealed Spp1 expression in two distinct clusters of ipRGCs. IHC confirmed osteopontin colocalization with neurofilament heavy chain, an established marker for αRGCs, including M4-ipRGCs. Spp1 immunoreactivity was moreover identified in one additional group of ipRGCs. By dendritic morphology and stratification, those cells were clearly identified as M2-ipRGCs.

Our findings demonstrate that osteopontin is expressed in both M2- and M4-ipRGCs, challenging the notion of osteopontin as a marker exclusively for αRGCs. IHC double-labeling for osteopontin and melanopsin provides a novel method to identify and differentiate M2 ipRGCs from other subtypes. This will support the study of ipRGC physiology in a subtype -specific manner and may, for instance, foster research in the field of optic nerve injury.

Humans spend a third of their lives asleep. While the sleep-wake behaviors are primarily modulated by homeostasis and circadian rhythm, several ambient chemical and physical factors, including light, sound, odor, vibration, temperature, electromagnetic radiation, and ultrasound, also affect sleep and wakefulness. Light at different wavelengths has different effects on sleep and wakefulness. Sound not only promotes but also suppresses sleep; this effect is mediated by certain nuclei, including the pedunculopontine nucleus and inferior colliculus. Certain sleep-promoting odorants regulate sleep through the involvement of the olfactory bulb and olfactory tubercle. In addition, vibrations may induce sleep through the vestibular system. A modest increase in ambient temperature leads to an increase in sleep duration through the involvement of the preoptic area. Electromagnetic radiation has a dual effect on sleep-wake behaviors. The stimulation produced by the ambient chemical and physical factors activates the peripheral sensory system, which converts the chemical and physical stimuli into nerve impulses. This signal is then transmitted to the central nervous system, including several nuclei associated with the modulation of sleep-wake behaviors. This review summarizes the effects of ambient chemical and physical factors on the regulation of sleep and wakefulness, as well as the underlying neurobiological mechanisms.

Hospitalized stroke patients are at high risk of developing circadian disruption due to lack of natural sunlight. This may affect the circadian rhythm of the calcium metabolism. This study is a secondary explorative analysis from a Randomized Controlled Trial. Acute stroke patients requiring a minimum of two weeks of rehabilitation were randomized to an Intervention unit (IU) equipped with naturalistic light or a Control unit (CU) with standard indoor lighting. Blood was drawn across 24 h at inclusion and discharge in 45 patients, 25 from the IU and 20 from the CU. Calcium showed significant rhythmicity at inclusion and discharge in both groups. Alkaline phosphatase, parathyroid hormone (PTH), and Vitamin D exhibited no significant rhythmicity at inclusion or discharge in either group while phosphate exhibited rhythmicity at discharge in the CU. PTH levels were elevated in the CU group compared to the IU group at time of discharge. Of the measured parameters, only calcium exhibited circadian rhythmicity after stroke. Naturalistic light did not have any influence on the rhythmicity, indicating that light may not be the main circadian regulator of the circadian oscillations that regulate calcium metabolism. PTH seems to be decreased by naturalistic light.

The eye is an immune-protected organ, which is driven by factors such as cytokines, chemicals, light, and mechanical stimuli. The circadian clock is an intrinsic timing mechanism that influences the immune activities, such as immune cell count and activity, as well as inflammatory responses. Recent studies have demonstrated that the eye also possesses an intrinsic circadian rhythm, and this rhythmic regulation participates in ocular immune modulation. In this review, we discuss the immunoregulatory mechanisms of the circadian clock within the eye, and reveal new perspectives for the prevention and treatment of ocular diseases.

Visible light influences a range of physiological processes, yet how animals respond to it independently of the visual system remains largely unknown. Here, we uncover a previously undescribed light-induced transcriptional pathway that modulates behavioral plasticity in C. elegans, a roundworm without eyes. We demonstrate that ambient visible light or controlled-intensity visible-spectrum LED activates an effector gene cyp-14A5 in non-neuronal tissues through the bZIP transcription factors ZIP-2 and CEBP-2. Light induction of cyp-14A5 is more prominent at shorter wavelengths but is independent of the known blue light receptors LITE-1 and GUR-3 in C. elegans. This bZIP-dependent genetic pathway in non-neuronal tissues enhances behavioral adaptability and olfactory memory, suggesting a body-brain communication axis. Furthermore, we use the light-responsive cyp-14A5 promoter to drive ectopic gene expression, causing synthetic light-induced sleep and rapid aging phenotypes in C. elegans. These findings advance our understanding of light-responsive mechanisms outside the visual system and offer a new genetic tool for visible light-inducible gene expression in non-neuronal tissues.

In healthy individuals, the majority of cortisol secretion occurs within several hours surrounding morning awakening. A highly studied component of this secretory period is the cortisol awakening response (CAR), the rapid increase in cortisol levels across the first 30 to 45 minutes after morning awakening. This strong cortisol burst at the start of the active phase has been proposed to be functional in preparing the organism for the challenges of the upcoming day. Here, we review evidence on key regulatory and functional processes of the CAR and develop an integrative model of its functional role. Specifically, we propose that, in healthy individuals, the CAR is closely regulated by an intricate dual-control system, which draws upon key circadian, environmental, and neurocognitive processes to best predict the daily need for cortisol-related action. Fine-tuned CAR expression, in turn, is then assumed to induce potent glucocorticoid action via rapid nongenomic and slower genomic pathways (eg, affecting circadian clock gene expression) to support and modulate daily activity through relevant metabolic, immunological, and neurocognitive systems. We propose that this concerted action is adaptive in mediating two main functions: a primary process to mobilize resources to meet activity-related demands and a secondary process to help the organism counterregulate adverse prior-day emotional experiences.

Environmental light serves as the main entraining signal for the central circadian pacemaker, the suprachiasmatic nucleus of the hypothalamus (SCN). To shift clock timing with the changing environment, minute adjustments are necessary and the endocannabinoid system (ECS) acts as a neuromodulatory signaling mechanism in the SCN. These systems exert bidirectional effects on one another, still, limited knowledge exists about the role of endocannabinoids in circadian rhythm regulation. Therefore, we investigated the temporal and spatial molecular layouts of the ECS in the SCN of male and female C57BL/6J mice. We utilized laser capture microdissection and quantitative RT-PCR to investigate the ECS temporal layout in the SCN, detected 13 of 19 examined ECS components, and followed up with two 24-hour time course experiments, one under 12:12 light/dark and one under constant dark conditions. All enzymatic machinery related to endocannabinoid synthesis and degradation investigated were found present; however, only cannabinoid receptor 1 (Cnr1) was detected from the 6 ECS related receptors investigated. Cosinor analysis revealed circadian rhythms in many components in both sexes and lighting conditions. Next, we investigated the spatial localization of ECS components in the SCN with RNAscope in situ hybridization. Some genes, such as Cnr1, were more highly expressed in neurons with others, such as Fabp7, were elevated in astrocytes. Cnr1 levels were highest in neurons that do not express the neuropeptides Avp or Vip, and lowest in Vip neurons. Our results support the idea that locally regulated ECS signaling through neuronal CB1 modulates circadian clock function.

The circadian clock regulates physiological and biochemical processes in nearly every species. Sexual and reproductive behaviors are two processes controlled by the circadian timing system. Evidence supporting the importance of proper clock function on fertility comes from several lines of work demonstrating that misalignment of biological rhythms or disrupted function of the body's master clock, such as occurs from repeated shift work or chronic jet lag, negatively impacts reproduction by interfering with both male and female fertility. Along these lines, dysregulation of clock genes leads to impairments in fertility within mammals, and disruption of circadian clock timing negatively impacts sex hormone levels and semen quality in males, and it leads to ovulatory deficiencies in females. Here, we review the current understanding of the circadian modulation of both male and female reproductive hormones-from animal models to humans. Further, we discuss neural circuits within the hypothalamus that may regulate circadian changes in mammalian sexual behavior and reproduction, and we explore how knowledge of such circuits in animal models may help to improve human sexual function, fertility, and reproduction.