External Light-dark Cycle Research Articles

Time Adjustment of Hydrocortisone Doses During Shift Work in Patients with Adrenal Insufficiency.

Shift work causes a disruption between the circadian system and the external light-dark cycle, but also a misalignment between various levels of the circadian system. There is no information on patients with adrenal insufficiency (AI) who are working shifts. The objective of the study was to analyze the hormone replacement therapy with hydrocortisone (HC) and the adaptation scheme in patients with AI on shifts. Patients working on shifts (n=15) from two German endocrine centers received a questionnaire regarding their therapy scheme, dose adaptations, working shifts, dose adaptations during working shifts, and occurrence of adrenal crisis. We observed that 20% of patients stated that they experience difficulties taking glucocorticoid replacement on time, 40% of patients reported these difficulties to occur only occasionally. Consequently, nearly half of the patients had forgotten to take their replacement therapy at some point. More than 50% of patients reported an adrenal crisis during the last two years. The timely adaptation of HC or of modified-release HC during shifts was very inhomogeneous. In conclusion, the adaptation schemes for HC dosing during shift work are currently not evidence-based but opinion-driven. Our findings highlight the need for further investigations of shift workers with AI.

Circadian clock communication during homeostasis and ageing.

Maintaining homeostasis is essential for continued health, and the progressive decay of homeostatic processes is a hallmark of ageing. Daily environmental rhythms threaten homeostasis, and circadian clocks have evolved to execute physiological processes in a manner that anticipates, and thus mitigates, their effects on the organism. Clocks are active in almost all cell types; their rhythmicity and functional output are determined by a combination of tissue-intrinsic and systemic inputs. Numerous inputs for a specific tissue are produced by the activity of circadian clocks of other tissues or cell types, generating a form of crosstalk known as clock communication. In mammals, the central clock in the hypothalamus integrates signals from external light-dark cycles to align peripheral clocks elsewhere in the body. This regulation is complemented by a tissue-specific milieu of external, systemic and niche inputs that modulate and cooperate with the cellular circadian clock machinery of a tissue to tailor its functional output. These mechanisms of clock communication decay during ageing, and growing evidence suggests that this decline might drive ageing-related morbidities. Dietary, behavioural and pharmacological interventions may offer the possibility to overcome these changes and in turn improve healthspan.

Adaptive coupling between neurons widens the entrainment range of the suprachiasmatic nucleus.

In many realistic systems, such as neural networks in the brain, the coupling strength between neurons is not fixed, but adaptively adjusts according to their activities. The suprachiasmatic nucleus (SCN), as the main clock in the mammalian brain, has been found to be a plastic neural network, and the coupling strength between neurons is highly dynamical. An important function of the SCN is entrainment, reflecting the ability of the SCN to synchronize with the external light-dark cycle. The entrainment ability is reflected by the entrainment range, which is a period range for the external light-dark cycle to which the SCN can entrain. In this article, we investigated whether the entrainment range of the SCN is affected by the adaptive coupling. We use a modified Kuramoto model with external light-dark cycle. We found that when the light sensitivity is larger than the fixed coupling strength (the coupling strength without adaptive rules), adaptive coupling can widen the entrainment range. Our findings help to understand the impact of the adaptive coupling between oscillatorty neurons on the collective behavior of the SCN, and provides a possible explanation for the plasticity of coupling in the master clock network.

Usability and Acceptability of a Corneal-Plane α-Opic Light Logger in a 24-h Field Trial

Introduction: Exposure to light fundamentally influences human physiology and behaviour by synchronising our biological clock to the external light-dark cycle and controlling melatonin production. In addition to well-controlled laboratory studies, more naturalistic approaches to examining these “non-visual” effects of light have been developed in recent years. As naturalistic light exposure is quite unlike well-controlled stimulus conditions in the laboratory, it is critical to measure light exposure in a person-referenced way, the “spectral diet.” To this end, light loggers have been developed to capture personalised light exposure. As an alternative to light sensors integrated into wrist-worn actimeters, pendants, or brooch-based light loggers, a recently developed wearable light logger laterally attached to spectacle frames enables the measurement of biologically relevant quantities in the corneal plane. Methods: Here, we examine the usability and acceptability of using the light logger in an undergraduate student sample (n = 18, mean±1SD: 20.1 ± 1.7 years; 9 female; Oxford, UK) in real-world conditions during a 24-h measurement period. We probed the acceptability of the light logger using rating questionnaires and open-ended questions. Results: Our quantitative results show a modest acceptability of the light logger. A thematic analysis of the open-ended questions reveals that the form factor of the device, in particular, size, weight, and stability, and reactions from other people to the wearer of the light logger, were commonly mentioned aspects. Conclusion: In sum, the results indicate the miniaturisation of light loggers and “invisible” integration into extant everyday objects as key areas for future technological development, facilitating the availability of light exposure data for developing personalised intervention strategies in both research, clinical and consumer contexts.

Structural properties and binding mechanism of DNA aptamers sensing saliva melatonin for diagnosis and monitoring of circadian clock and sleep disorders

Structural properties and binding mechanism of DNA aptamers sensing saliva melatonin for diagnosis and monitoring of circadian clock and sleep disorders

Light-induced synchronization of the SCN coupled oscillators and implications for entraining the HPA axis.

The suprachiasmatic nucleus (SCN) synchronizes the physiological rhythms to the external light-dark cycle and tunes the dynamics of circadian rhythms to photoperiod fluctuations. Changes in the neuronal network topologies are suggested to cause adaptation of the SCN in different photoperiods, resulting in the broader phase distribution of neuron activities in long photoperiods (LP) compared to short photoperiods (SP). Regulated by the SCN output, the level of glucocorticoids is elevated in short photoperiod, which is associated with peak disease incidence. The underlying coupling mechanisms of the SCN and the interplay between the SCN and the HPA axis have yet to be fully elucidated. In this work, we propose a mathematical model including a multiple-cellular SCN compartment and the HPA axis to investigate the properties of the circadian timing system under photoperiod changes. Our model predicts that the probability-dependent network is more energy-efficient than the distance-dependent network. Coupling the SCN network by intra-subpopulation and inter-subpopulation forces, we identified the negative correlation between robustness and plasticity of the oscillatory network. The HPA rhythms were predicted to be strongly entrained to the SCN rhythms with a pro-inflammatory high-amplitude glucocorticoid profile under SP. The fast temporal topology switch of the SCN network was predicted to enhance synchronization when the synchronization is not complete. These synchronization and circadian dynamics alterations might govern the seasonal variation of disease incidence and its symptom severity.

A real-time measurement system for gene expression rhythms from deep tissues of freely moving mice under light-dark conditions

A real-time measurement system for gene expression rhythms from deep tissues of freely moving mice under light-dark conditions

Single cell model for re-entrainment to a shifted light cycle.

Our daily 24‐h rhythm is synchronized to the external light–dark cycle resulting from the Earth's daily rotation. In the mammalian brain, the suprachiasmatic nucleus (SCN) serves as the master clock and receives light‐mediated input via the retinohypothalamic tract. Abrupt changes in the timing of the light–dark cycle (e.g., due to jet lag) cause a phase shift in the circadian rhythms in the SCN. Here, we investigated the effects of a 6‐h delay in the light–dark cycle on PERIOD2::LUCIFERASE expression at the single‐cell level in mouse SCN organotypic explants. The ensemble pattern in phase shift response obtained from individual neurons in the anterior and central SCN revealed a bimodal distribution; specifically, neurons in the ventrolateral SCN responded with a rapid phase shift, while neurons in the dorsal SCN generally did not respond to the shift in the light–dark cycle. We also stimulated the hypothalamic tract in acute SCN slices to simulate light‐mediated input to the SCN; interestingly, we found similarities between the distribution and fraction of rapid shifting neurons (in response to the delay) and neurons that were excited in response to electrical stimulation. These results suggest that a subpopulation of neurons in the ventral SCN that have an excitatory response to light input, shift their clock more readily than dorsal located neurons, and initiate the SCN's entrainment to the new light–dark cycle. Thus, we propose that light‐excited neurons in the anterior and central SCN play an important role in the organism's ability to adjust to changes in the external light–dark cycle.

The circadian clock mutant lhy cca1 elf3 paces starch mobilization to dawn despite severely disrupted circadian clock function.

Many plants, including Arabidopsis (Arabidopsis thaliana), accumulate starch in the daytime and remobilize it to support maintenance and growth at night. Starch accumulation is increased when carbon is in short supply, for example, in short photoperiods. Mobilization is paced to exhaust starch around dawn, as anticipated by the circadian clock. This diel pattern of turnover is largely robust against loss of day, dawn, dusk, or evening clock components. Here, we investigated diel starch turnover in the triple circadian clock mutant lhy cca1 elf3, which lacks the LATE ELONGATED HYPOCOTYL and the CIRCADIAN CLOCK-ASSOCIATED1 (CCA1) dawn components and the EARLY FLOWERING3 (ELF3) evening components of the circadian clock. The diel oscillations of transcripts for the remaining clock components and related genes like REVEILLE and PHYTOCHROME-INTERACING FACTOR family members exhibited attenuated amplitudes and altered peak time, weakened dawn dominance, and decreased robustness against changes in the external light-dark cycle. The triple mutant was unable to increase starch accumulation in short photoperiods. However, it was still able to pace starch mobilization to around dawn in different photoperiods and growth irradiances and to around 24 h after the previous dawn in T17 and T28 cycles. The triple mutant was able to slow down starch mobilization after a sudden low-light day or a sudden early dusk, although in the latter case it did not fully compensate for the lengthened night. Overall, there was a slight trend to less linear mobilization of starch. Thus, starch mobilization can be paced rather robustly to dawn despite a major disruption of the transcriptional clock. It is proposed that temporal information can be delivered from clock components or a semi-autonomous oscillator.

External light-dark cycle shapes gut microbiota through intrinsically photosensitive retinal ganglion cells.

Gut microbiota are involved in many physiological functions such as metabolism, brain development, and neurodegenerative diseases. Many microbes in the digestive tract do not maintain a constant level of their relative abundance but show daily oscillations under normal conditions. Recent evidence indicates that chronic jetlag, constant darkness, or deletion of the circadian core gene can alter the composition of gut microbiota and dampen the daily oscillation of gut microbes. However, the neuronal circuit responsible for modulating gut microbiota remained unclear. Using genetic mouse models and 16s rRNA metagenomic analysis, we find that light-dark cycle information transmitted by the intrinsically photosensitive retinal ganglion cells (ipRGCs) is essential for daily oscillations of gut microbes under temporal restricted high-fat diet conditions. Furthermore, aberrant light exposure such as dim light at night (dLAN) can alter the composition, relative abundance, and daily oscillations of gut microbiota. Together, our results indicate that external light-dark cycle information can modulate gut microbiota in the direction from the brain to the gut via the sensory system.

Disturbance of the Circadian System in Shift Work and Its Health Impact

The various non-standard schedules required of shift workers force abrupt changes in the timing of sleep and light-dark exposure. These changes result in disturbances of the endogenous circadian system and its misalignment with the environment. Simulated night-shift experiments and field-based studies with shift workers both indicate that the circadian system is resistant to adaptation from a day- to a night-oriented schedule, as determined by a lack of substantial phase shifts over multiple days in centrally controlled rhythms, such as those of melatonin and cortisol. There is evidence that disruption of the circadian system caused by night-shift work results not only in a misalignment between the circadian system and the external light-dark cycle, but also in a state of internal desynchronization between various levels of the circadian system. This is the case between rhythms controlled by the central circadian pacemaker and clock genes expression in tissues such as peripheral blood mononuclear cells, hair follicle cells, and oral mucosa cells. The disruptive effects of atypical work schedules extend beyond the expression profile of canonical circadian clock genes and affects other transcripts of the human genome. In general, after several days of living at night, most rhythmic transcripts in the human genome remain adjusted to a day-oriented schedule, with dampened group amplitudes. In contrast to circadian clock genes and rhythmic transcripts, metabolomics studies revealed that most metabolites shift by several hours when working nights, thus leading to their misalignment with the circadian system. Altogether, these circadian and sleep-wake disturbances emphasize the all-encompassing impact of night-shift work, and can contribute to the increased risk of various medical conditions. Here, we review the latest scientific evidence regarding the effects of atypical work schedules on the circadian system, sleep and alertness of shift-working populations, and discuss their potential clinical impacts.

The Importance of Being a 'Lark' in Post-Menopausal Women with Obesity: A Ploy to Prevent Type 2 Diabetes Mellitus?

Chronotype is defined as the behavioral manifestation of circadian rhythms related to the external light–dark cycle. Evening chronotype has been associated with an increased risk of developing cardiometabolic diseases in obesity. Menopause is a lifestage associated with an increased risk of developing cardiometabolic diseases and a change in circadian rhythmicity compared to pre-menopause. However, the prevalence of chronotype categories in menopause and their role in determining menopause-related cardiometabolic risk, mostly in obesity, have not been investigated. Thus, we aimed to investigate the prevalence of chronotype categories in post-menopausal women with obesity and their role in menopause-related cardiometabolic risk. In this cross-sectional study we enrolled 49 pre-menopausal and 74 post-menopausal women with obesity. Anthropometric parameters, lifestyle habits, adherence to the Mediterranean Diet (MD), sleep quality, chronotype and the presence of type 2 diabetes mellitus (T2DM) and cardiovascular diseases (CVD) were studied. No significance differences were detected in terms of lifestyle and adherence to the MD between pre- and post-menopausal women. Chronotype was classified as morning in 66 (53.6%), evening in 20 (16.3%) and intermediate in 37 (30.1%) women. In addition, pre-menopausal women with obesity showed a significantly higher chance to have an intermediate chronotype (OR = 2.21, 95% CI 1.28–3.83; p = 0.004), whereas post-menopausal women with obesity showed a trend to have a higher morning chronotype (OR = 1.42, 95% CI 0.98–2.06; p = 0.051), although this did not reach statistical significance. No significant differences were detected in terms of prevalence of evening chronotype between the two groups. However, the evening chronotype had a significantly higher risk to have T2DM compared to the morning (OR = 17.29, 95% CI 2.40–124.27; p = 0.005) and intermediate chronotypes (OR = 30.86, 95% CI 2.05–464.32; p = 0.013) in both pre- and post-menopausal women with obesity. In conclusion, the intermediate chronotype was significantly more prevalent in pre-menopausal women with obesity compared to post-menopausal women. Evening chronotype was associated to T2DM in both pre- and post-menopause. These results support the importance of including the assessment of chronotype in the management of women with obesity in post-menopause.

The importance of being a “lark” in menopause

The importance of being a “lark” in menopause

Network Structure of the Master Clock Is Important for Its Primary Function.

A master clock located in the suprachiasmatic nucleus (SCN) regulates the circadian rhythm of physiological and behavioral activities in mammals. The SCN has two main functions in the regulation: an endogenous clock produces the endogenous rhythmic signal in body rhythms, and a calibrator synchronizes the body rhythms to the external light-dark cycle. These two functions have been determined to depend on either the dynamic behaviors of individual neurons or the whole SCN neuronal network. In this review, we first introduce possible network structures for the SCN, as revealed by time series analysis from real experimental data. It was found that the SCN network is heterogeneous and sparse, that is, the average shortest path length is very short, some nodes are hubs with large node degrees but most nodes have small node degrees, and the average node degree of the network is small. Secondly, the effects of the SCN network structure on the SCN function are reviewed based on mathematical models of the SCN network. It was found that robust rhythms with large amplitudes, a high synchronization between SCN neurons and a large entrainment ability exists mainly in small-world and scale-free type networks, but not other types. We conclude that the SCN most probably is an efficient small-world type or scale-free type network, which drives SCN function.

Differential response of diurnal and nocturnal mammals to prolonged altered light-dark cycle: a possible role of mood associated endocrine, inflammatory and antioxidant system

ABSTRACT The circadian system maintains internal 24 h oscillation of behavior and physiology, and its misalignment with external light-dark (LD) cycle results in negative health outcomes. In order to elucidate the effect of prolonged constant condition and the differences in the response between nocturnal and diurnal species, we studied the effects of constant light (LL) and constant darkness (DD) on a diurnal (squirrel) and a nocturnal (mouse) rodent species, focusing on the endocrine, inflammatory and antioxidant systems associated with depression-like behavior. Squirrels and mice (n = 10/group) were placed in chronocubicle under 12:12 h LD cycle, LL and DD. After 4 weeks, animals were subjected to sucrose preference test and blood and brain tissues were collected for measuring melatonin, corticosterone, proinflammatory cytokine, tumor necrosis factor-α (TNF-α) and the activity of primary antioxidant enzymes, catalase (CAT) and superoxide dismutase (SOD). The results show that in diurnal squirrels, prolonged constant darkness reduced sucrose preference, CAT, and SOD, increased corticosterone and TNF-α levels, but caused no significant change in the melatonin compared to LD condition. In contrast, in nocturnal mice constant darkness caused no significant changes in sucrose preference and corticosterone levels, increased melatonin, CAT and SOD levels but decreased TNF-α levels. Chronic LL caused a similar response in both squirrels and mice: it decreased sucrose preference, melatonin, CAT and SOD levels but increased corticosterone and TNF-α levels. Together, the study demonstrates differential effects of altered light-dark cycle in a diurnal and a nocturnal rodent on interrelated endocrine, inflammatory and antioxidant systems associated with depression-like behavior, with constant light having adverse effects on both species but constant darkness having a negative effect mainly in the diurnal squirrels.

Chronotype and Adherence to the Mediterranean Diet in Obesity: Results from the Opera Prevention Project.

Chronotype is the attitude of a subject in determining individual circadian preference in behavioral and biological rhythm relative to the external light–dark cycle. Obesity and unhealthy eating habits have been associated with evening chronotype. The Mediterranean diet (MD) is a healthy nutritional pattern that has been reported to be associated with better health and quality of sleep. Thus, the aim of the study was to investigate the association of chronotype categories with adherence to the MD in a population of middle-aged Italian adults. This cross-sectional study included 172 middle-aged adults (71.5% females; 51.8 ± 15.7 years) that were consecutively enrolled in a campaign to prevent obesity called the OPERA (obesity, programs of nutrition, education, research and assessment of the best treatment) Prevention Project that was held in Naples on 11–13 October 2019. Anthropometric parameters, adherence to the MD and chronotype were studied. Chronotype was classified as morning in 58.1% of subjects, evening in 12.8% and intermediate in 28.1%. Our results demonstrated that individuals with evening chronotype, when compared to intermediate (p < 0.001) and morning chronotype (p < 0.001), were more prone to follow unhealthy lifestyle, performing less regular activity and being more frequently smokers. In addition, they showed the lowest adherence to the MD compared to morning (p < 0.001) and intermediate chronotypes (p < 0.001). The lower the chronotype score, the higher body mass index (BMI) values in the whole population (r = −0.158; p = 0.038), thus suggesting that evening chronotype was a common finding in subjects with obesity. In addition, positive correlations of chronotype score with age (r = 0.159; p = 0.037) and PREDIMED score (r = 0.656; p < 0.001) were found. The adherence to the MD, more than the intake of the single food items, was found to predict morning and evening chronotypes. In conclusion, evening chronotype was associated with unhealthy lifestyle and low adherence to the MD. Chronotype score was inversely associated to BMI and positively associated to age and adherence to the MD. Thus, the assessment of chronotype should be taken into account in the management of obesity and in the development of nutritional strategies.

Regulation of Rest, Rather Than Activity, Underlies Day-Night Activity Differences in Mice.

The suprachiasmatic nucleus (SCN), which serves as the central pacemaker in mammals, regulates the 24-h rhythm in behavioral activity. However, it is currently unclear whether and how bouts of activity and rest are regulated within the 24-h cycle (i.e., over ultradian time scales). Therefore, we used passive infrared sensors to measure temporal behavior in mice housed under either a light–dark (LD) cycle or continuous darkness (DD). We found that a probabilistic Markov model captures the ultradian changes in the behavioral state over a 24-h cycle. In this model, the animal’s behavioral state in the next time interval is determined solely by the animal’s current behavioral state and by the “toss” of a proverbial “biased coin.” We found that the bias of this “coin” is regulated by light input and by the phase of the clock. Moreover, the bias of this “coin” for an animal is related to the average length of rest and activity bouts in that animal. In LD conditions, the average length of rest bouts was greater during the day compared to during the night, whereas the average length of activity bouts was greater during the night compared to during the day. Importantly, we also found that day-night changes in the rest bout lengths were significantly greater than day-night changes in the activity bout lengths. Finally, in DD conditions, the activity and rest bouts also differed between subjective night and subjective day, albeit to a lesser extent compared to LD conditions. The ultradian regulation represented by the model does not result in ultradian rhythms, although some weak ultradian rhythms are present in the data. The persistent differences in bout length over the circadian cycle following loss of the external LD cycle indicate that the central pacemaker plays a role in regulating rest and activity bouts on an ultradian time scale.

Differentiating external zeitgeber impact on peripheral circadian clock resetting

Circadian clocks regulate physiological functions, including energy metabolism, along the 24-hour day cycle. The mammalian clock system is organized in a hierarchical manner with a coordinating pacemaker residing in the hypothalamic suprachiasmatic nucleus (SCN). The SCN clock is reset primarily by the external light-dark cycle while other zeitgebers such as the timing of food intake are potent synchronizers of many peripheral tissue clocks. Under conflicting zeitgeber conditions, e.g. during shift work, phase synchrony across the clock network is disrupted promoting the development of metabolic disorders. We established a zeitgeber desynchrony (ZD) paradigm to quantify the differential contributions of the two main zeitgebers, light and food, to the resetting of specific tissue clocks and the effect on metabolic homeostasis in mice. Under 28-hour light-dark and 24-hour feeding-fasting conditions SCN and peripheral clock, as well as activity and hormonal rhythms showed specific periodicities aligning in-between those of the two zeitgebers. During ZD, metabolic homeostasis was cyclic with mice gaining weight under synchronous and losing weight under conflicting zeitgeber conditions. In summary, our study establishes an experimental paradigm to compare zeitgeber input in vivo and study the physiological consequences of chronodisruption.

Effects of light on human circadian rhythms, sleep and mood.

Humans live in a 24-hour environment, in which light and darkness follow a diurnal pattern. Our circadian pacemaker, the suprachiasmatic nuclei (SCN) in the hypothalamus, is entrained to the 24-hour solar day via a pathway from the retina and synchronises our internal biological rhythms. Rhythmic variations in ambient illumination impact behaviours such as rest during sleep and activity during wakefulness as well as their underlying biological processes. Rather recently, the availability of artificial light has substantially changed the light environment, especially during evening and night hours. This may increase the risk of developing circadian rhythm sleep–wake disorders (CRSWD), which are often caused by a misalignment of endogenous circadian rhythms and external light–dark cycles. While the exact relationship between the availability of artificial light and CRSWD remains to be established, nocturnal light has been shown to alter circadian rhythms and sleep in humans. On the other hand, light can also be used as an effective and noninvasive therapeutic option with little to no side effects, to improve sleep, mood and general well-being. This article reviews our current state of knowledge regarding the effects of light on circadian rhythms, sleep, and mood.

Lifespan is unaffected by size and direction of daily phase shifts in Nasonia, a hymenopteran insect with strong circadian light resetting

Lifespan is unaffected by size and direction of daily phase shifts in Nasonia, a hymenopteran insect with strong circadian light resetting