How to trick mother nature into letting you fly around or stay up all night

Night shift work and rapid transmeridian travel result in a misalignment between circadian rhythms and the new times for sleep, wake, and work, which has health and safety implications for both the individual involved and the general public. Entrainment to the new sleep/wake schedule requires circadian rhythms to be phase-shifted, but this is often slow or impeded. The authors show superimposed light and melatonin PRCs to explain how to appropriately time these zeitgebers to promote circadian adaptation. They review studies in which bright light and melatonin were administered to try to counteract jet lag or to produce circadian adaptation to night work. They demonstrate how jet lag could be prevented entirely if rhythms are shifted before the flight using their preflight plan and discuss the combination of interventions that they now recommend for night shift workers.     

Circadian rhythm disruption: health consequences

Circadian rhythms control many facets of biology and their disruption can be associated with severe pathological conditions. In healthy individuals, disturbances to the sleep-wake cycle can be the root cause of many problems. In the present review, we explore the major factors contributing to circadian rhythm disruption, including sleep disorders, jet lag, and shift work. The consequences of these disruptions on central and peripheral clocks and the important areas of the body controlled by them involve immune function and metabolism, as well as alterations in cognitive abilities, thereby impairing social and occupational behavior. Further work exploring clock genes, light exposure, and cellular changes will be critical for identifying how these factors interact to affect health and behavior.     

Chronodisruption and ageing

Modern life leads to a more active nocturnal lifestyle, reduced sleep hours and sometimes abrupt shifts across time zones (such as jet lag and shift work) that generate chronodisruption (CD) which can result in premature ageing. CD is defined as a significant disturbance of the internal temporal order of biochemical, physiological and behavioural circadian rhythms. Epidemiological studies show that CD induced by shift work, chronic jet lag, social jet lag and excessive exposure of bright light at night is associated with an increased incidence of metabolic syndrome, cardiovascular disease, cognitive and affective impairment, sleep disorders, some cancers and premature ageing. CD may be the result of disturbances in different components of the circadian system (central pacemaker and peripheral oscillators, inputs to central clock, mainly due to visual deficiencies, and output signals from the pacemaker and oscillators). Exposure to different synchronizers (light, meal times, physical and social activities) with a regular pattern results in a chronoenhacement that can prevent age-related CD.     

Circadian disruption alters mouse lung clock gene expression and lung mechanics

Most aspects of human physiology and behavior exhibit 24-h rhythms driven by a master circadian clock in the brain, which synchronizes peripheral clocks. Lung function and ventilation are subject to circadian regulation and exhibit circadian oscillations. Sleep disruption, which causes circadian disruption, is common in those with chronic lung disease, and in the general population; however, little is known about the effect on the lung of circadian disruption. We tested the hypothesis circadian disruption alters expression of clock genes in the lung and that this is associated with altered lung mechanics. Female and male mice were maintained on a 12:12-h light/dark cycle (control) or exposed for 4 wk to a shifting light regimen mimicking chronic jet lag (CJL). Airway resistance (Rn), tissue damping (G), and tissue elastance (H) did not differ between control and CJL females. Rn at positive end-expiratory pressure (PEEP) of 2 and 3 cmH(2)O was lower in CJL males compared with controls. G, H, and G/H did not differ between CJL and control males. Among CJL females, expression of clock genes, Bmal1 and Rev-erb alpha, was decreased; expression of their repressors, Per2 and Cry 2, was increased. Among CJL males, expression of Clock was decreased; Per 2 and Rev-erb alpha expression was increased. We conclude circadian disruption alters lung mechanics and clock gene expression and does so in a sexually dimorphic manner.     

Modeling the circadian regulation of the immune system: Sexually dimorphic effects of shift work

The circadian clock exerts significance influence on the immune system and disruption of circadian rhythms has been linked to inflammatory pathologies. Shift workers often experience circadian misalignment as their irregular work schedules disrupt the natural light-dark cycle, which in turn can cause serious health problems associated with alterations in genetic expressions of clock genes. In particular, shift work is associated with impairment in immune function, and those alterations are sex-specific. The goal of this study is to better understand the mechanisms that explain the weakened immune system in shift workers. To achieve that goal, we have constructed a mathematical model of the mammalian pulmonary circadian clock coupled to an acute inflammation model in the male and female rats. Shift work was simulated by an 8h-phase advance of the circadian system with sex-specific modulation of clock genes. The model reproduces the clock gene expression in the lung and the immune response to various doses of lipopolysaccharide (LPS). Under normal conditions, our model predicts that a host is more sensitive to LPS at circadian time (CT) CT12 versus CT0 due to a dynamic change of Interleukin 10 (IL-10), an anti-inflammatory cytokine. We identify REV-ERB as a key modulator of IL-10 activity throughout the circadian day. The model also predicts a reversal of the times of lowest and highest sensitivity to LPS, with males and females exhibiting an exaggerated response to LPS at CT0, which is countered by a blunted immune response at CT12. Overall, females produce fewer pro-inflammatory cytokines than males, but the extent of sequelae experienced by males and females varies across the circadian day. This model can serve as an essential component in an integrative model that will yield mechanistic understanding of how shift work-mediated circadian disruptions affect the inflammatory and other physiological responses.     

Phase-dependent effect of room light exposure in a 5-h advance of the sleep-wake cycle: implications for jet lag

The acute disruption in sleep quality, vigilance levels, and cognitive and athletic performance observed after transmeridian flights is presumed to be the result of a transient misalignment between the endogenous circadian pacemaker and the shifted sleep schedule. Several laboratory and field experiments have demonstrated that exposure to bright artificial light can accelerate circadian entrainment to a shifted sleep-wake schedule. In the present study, the authors investigated whether the schedule of exposure to indoor room light, to which urban dwellers are typically exposed, can substantially affect circadian adaptation to a simulated eastward voyage. We enrolled 15 healthy young men in a laboratory simulation of a Montreal-to-London voyage. Subjects were exposed to 6 h of room light (mean +/- SD: 379+/-10) prior to bedtime (n = 7) or when on a progressively advancing schedule (n = 8) early in the day. The remaining 10 hours of wakefulness were spent in dim light (4+/-1 lux). Circadian assessments, performed via the constant routine procedure, evaluated the phase of the endogenous circadian rhythms of core body temperature and plasma melatonin before and after 1 week on the shifted schedule. At the end of the study, only subjects exposed to room light on the advancing schedule expressed oscillations of the endogenous circadian pacemaker in phase with the new sleep-wake cycle. In this group, a mean advance shift of the nadir of core body temperature of +5:22+/-0:15 h was observed, with parallel shifts in plasma melatonin concentration and subjective alertness. The circadian rhythms of subjects exposed to room light later in the day remained much more adjusted to the departure than to the destination time zone. These results demonstrate that the schedule of exposure to room light can substantially affect circadian adaptation to a shifted sleep-wake schedule.     

Modeling the circadian clock: from molecular mechanism to physiological disorders

Based on genetic and biochemical advances on the molecular mechanism of circadian rhythms, a computational model for the mammalian circadian clock is used to examine the dynamical bases of circadian-clock-related physiological disorders in humans. Entrainment by the light-dark cycle with a phase advance or a phase delay is associated with the Familial advanced sleep phase syndrome (FASPS) or the Delayed sleep phase syndrome (DSPS), respectively. Lack of entrainment corresponding to the occurrence of quasiperiodic oscillations with or without phase jump can be associated with the non-24 h sleep-wake syndrome. In the close vicinity of the entrainment domain, the model uncovers the possibility of infradian oscillations of very long period. Perturbation in the form of chronic jet lag, as used in mice, prevents entrainment of the circadian clock and results in chaotic or quasiperiodic oscillations. It is important to clarify the conditions for entrainment and for its failure because dysfunctions of the circadian clock may lead to physiological disorders, which pertain not only to the sleep-wake cycle but also to mood and cancer.     

Rapid Changes in the Light/Dark Cycle Disrupt Memory of Conditioned Fear in Mice

Background

Circadian rhythms govern many aspects of physiology and behavior including cognitive processes. Components of neural circuits involved in learning and memory, e.g., the amygdala and the hippocampus, exhibit circadian rhythms in gene expression and signaling pathways. The functional significance of these rhythms is still not understood. In the present study, we sought to determine the impact of transiently disrupting the circadian system by shifting the light/dark (LD) cycle. Such “jet lag” treatments alter daily rhythms of gene expression that underlie circadian oscillations as well as disrupt the synchrony between the multiple oscillators found within the body.

Methodology/Principal Findings

We subjected adult male C57Bl/6 mice to a contextual fear conditioning protocol either before or after acute phase shifts of the LD cycle. As part of this study, we examined the impact of phase advances and phase delays, and the effects of different magnitudes of phase shifts. Under all conditions tested, we found that recall of fear conditioned behavior was specifically affected by the jet lag. We found that phase shifts potentiated the stress-evoked corticosterone response without altering baseline levels of this hormone. The jet lag treatment did not result in overall sleep deprivation, but altered the temporal distribution of sleep. Finally, we found that prior experience of jet lag helps to compensate for the reduced recall due to acute phase shifts.

Conclusions/Significance

Acute changes to the LD cycle affect the recall of fear-conditioned behavior. This suggests that a synchronized circadian system may be broadly important for normal cognition and that the consolidation of memories may be particularly sensitive to disruptions of circadian timing.     

Failure of extraocular light to facilitate circadian rhythm reentrainment in humans

Although extraocular light can entrain the circadian rhythms of invertebrates and nonmammalian vertebrates, almost all studies show that the mammalian circadian system can only be affected by light to the eyes. The exception is a recent study by Campbell and Murphy that reported phase shifts in humans to bright light applied with fiber-optic pads behind the knees (popliteal region). We tested whether this extraocular light stimulus could accelerate the entrainment of circadian rhythms to a shift of the sleep schedule, as occurs in shift work or jet lag. In experiment 1, the sleep/dark episodes were delayed 8h from baseline for 2 days, and 3h light exposures were timed to occur before the temperature minimum to help delay circadian rhythms. There were three groups: (1) bright (about 13,000 lux) extraocular light from fiber-optic pads, (2) control (dim light, 10-20 lux), and (3) medium-intensity (about 1000 lux) ocular light from light boxes. In experiment 2, the sleep/dark episodes were inverted, and extraocular light was applied either before the temperature minimum to help delay circadian rhythms or after the temperature minimum to help advance rhythms. Circadian phase markers were the salivary dim light melatonin onset (DLMO) and the rectal temperature minimum. There was no evidence that the popliteal extraocular light had a phase-shifting effect in either experiment. Possible reasons for phase shifts in the Campbell and Murphy study and not the current study include the many differences between the protocols. In the current study, there was substantial sleep deprivation before the extraocular light was applied. There was a large shift in the sleep/dark schedule, rather than allowing subjects to sleep each day from midnight to noon, as in the Campbell and Murphy study. Also, when extraocular light was applied in the current protocol, subjects did not experience a change from sleeping to awake, a change in posture (from lying in bed to sitting in a chair), or a change in ocular light (from dark to dim light). Further research is necessary to determine the conditions under which extraocular light might produce phase shifts in human circadian rhythms. (Chronobiology International, 17(6), 807-826, 2000).     

Behavioral responses of Vipr2-/- mice to light

Vasoactive intestinal polypeptide and its receptor, VPAC2, play important roles in the functioning of the dominant circadian pacemaker, located in the hypothalamic suprachiasmatic nuclei (SCN). Mice lacking VPAC2 receptors (Vipr2-/-) show altered circadian rhythms and impaired synchronization to environmental lighting cues. However, light can increase phosphoprotein and immediate early gene expression in the Vipr2-/- SCN demonstrating that the circadian clock is readily responsive to light in these mice. It is not clear whether these neurochemical responses to light can be transduced to behavioral changes as seen in wild-type (WT) animals. In this study we investigated the diurnal and circadian wheel-running profile of WT (C57BL/6J) and Vipr2-/- mice under a 12-h light:12-h complete darkness (LD) lighting schedule and in constant darkness (DD) and used 1-h light pulses to shift the activity of mice in DD. Unlike WT mice, Vipr2-/- mice show grossly altered locomotor patterns making the analysis of behavioral responses to light problematic. However, analyses of both the onset and the offset of locomotor activity reveal that in a subset of these mice, light can reset the offset of behavioral rhythms during the subjective night. This suggests that the SCN clock of Vipr2-/- mice and the rhythms it generates are responsive to photic stimulation and that these responses can be integrated to whole animal behavioral changes.     

FAILURE OF EXTRAOCULAR LIGHT TO FACILITATE CIRCADIAN RHYTHM REENTRAINMENT IN HUMANS

Although extraocular light can entrain the circadian rhythms of invertebrates and nonmammalian vertebrates, almost all studies show that the mammalian circadian system can only be affected by light to the eyes. The exception is a recent study by Campbell and Murphy that reported phase shifts in humans to bright light applied with fiber-optic pads behind the knees (popliteal region). We tested whether this extraocular light stimulus could accelerate the entrainment of circadian rhythms to a shift of the sleep schedule, as occurs in shift work or jet lag. In experiment 1, the sleep/dark episodes were delayed 8h from baseline for 2 days, and 3h light exposures were timed to occur before the temperature minimum to help delay circadian rhythms. There were three groups: (1) bright (about 13,000 lux) extraocular light from fiber-optic pads, (2) control (dim light, 10–20 lux), and (3) medium-intensity (about 1000 lux) ocular light from light boxes. In experiment 2, the sleep/dark episodes were inverted, and extraocular light was applied either before the temperature minimum to help delay circadian rhythms or after the temperature minimum to help advance rhythms. Circadian phase markers were the salivary dim light melatonin onset (DLMO) and the rectal temperature minimum. There was no evidence that the popliteal extraocular light had a phase-shifting effect in either experiment. Possible reasons for phase shifts in the Campbell and Murphy study and not the current study include the many differences between the protocols. In the current study, there was substantial sleep deprivation before the extraocular light was applied. There was a large shift in the sleep/dark schedule, rather than allowing subjects to sleep each day from midnight to noon, as in the Campbell and Murphy study. Also, when extraocular light was applied in the current protocol, subjects did not experience a change from sleeping to awake, a change in posture (from lying in bed to sitting in a chair), or a change in ocular light (from dark to dim light). Further research is necessary to determine the conditions under which extraocular light might produce phase shifts in human circadian rhythms. (Chronobiology International, 17(6), 807–826, 2000).     

Changing the dosing schedule minimizes the disruptive effects of interferon on clock function

The effectiveness and toxicity of many drugs vary depending on the relationship between the dosing schedule and the 24-hour rhythms of biochemical, physiological and behavioral processes. In addition, several drugs can cause alterations to the 24-hour rhythms leading to illness and altered homeostatic regulation. However, the mechanisms of this drug-based disruption of circadian 'clock' genes remain unclear. Here, we show the disruptive effect of interferon-alpha on the rhythm of locomotor activity, body temperature and clock-gene mRNA expression in the periphery and suprachiasmatic nuclei, a primary circadian pacemaker. The rhythmicity of clock genes and the photic induction of the Per gene in suprachiasmatic nuclei were disturbed by the repetitive administration of interferon-alpha. Moreover, alteration of clock function, a new concept of adverse effects, can be overcome by optimizing the dosing schedule to minimize adverse drug effects.     

Adjustment of the Sleep-Wake Cycle to Small (1-2h) Changes in Schedule

Changes of schedules larger than 3 h, such as jet lag and shift work, require an adjustment period of several days to resynchronize the sleep-wake cycle and several weeks to resynchronize other circadian rhythms to the new schedule. Initial studies on adaptation to small changes of schedule (1-2 h) found that the sleep-wake cycle adapts to the new schedule in less than 48 h, and such modifications are generally not studied because they may be confounded by a potential masking effect. This article summarizes the few published studies on Daylight Saving Time (DST) and sleep during weekends, two examples of small changes in schedule. There are individual differences in adaptation to daylight saving time, while some persons adjust immediately; other persons require more than 2 weeks. During weekends, people tend to go to bed and wake up later, and to extend their sleep. Delay and extension of sleep depend on factors such as shift of work during weekdays and chronotype (morningness-eveningness). Both DST and sleep during weekends offer the opportunity to study adaptation of the sleep-wake cycle in recurrent, social conditions. Studying these phenomena is also relevant to some socioeconomic issues, like the reportedincrease of traffic accidents and complaints from the population during daylight saving time; or the possible decrease in productivity and absenteeism during the 'Blue Monday'.     

Preflight adjustment to eastward travel: 3 days of advancing sleep with and without morning bright light

Jet lag is caused by a misalignment between circadian rhythms and local destination time. As humans typically take longer to re-entrain after a phase advance than a phase delay, eastward travel is often more difficult than westward travel. Previous strategies to reduce jet lag have focused on shaping the perceived light-dark cycle after arrival, in order to facilitate a phase shift in the appropriate direction. Here we tested treatments that travelers could use to phase advance their circadian rhythms prior to eastward flight. Thus, travelers would arrive with their circadian rhythms already partially re-entrained to local time. We determined how far the circadian rhythms phase advanced, and the associated side effects related to sleep and mood. Twenty-eight healthy young subjects participated in 1 of 3 different treatments, which all phase advanced each subject's habitual sleep schedule by 1 h/day for 3 days. The 3 treatments differed in morning light exposure for the 1st 3.5 h after waking on each of the 3 days: continuous bright light (> 3000 lux), intermittent bright light (> 3000 lux, 0.5 h on, 0.5 off, etc.), or ordinary dim indoor light (< 60 lux). A phase assessment in dim light (< 10 lux) was conducted before and after the treatments to determine the endogenous salivary dim light melatonin onset (DLMO). The mean DLMO phase advances in the dim, intermittent, and continuous light groups were 0.6, 1.5, and 2.1 h, respectively. The intermittent and continuous light groups advanced significantly more than the dim light group (p < 0.01) but were not significantly different from each other. The side effects as assessed with actigraphy and logs were small. A 2-h phase advance may seem small compared to a 6- to 9-h time zone change, as occurs with eastward travel from the USA to Europe. However, a small phase advance will not only reduce the degree of re-entrainment required after arrival, but may also increase postflight exposure to phase-advancing light relative to phase-delaying light, thereby reducing the risk of antidromic re-entrainment. More days of preflight treatment could be used to produce even larger phase advances and potentially eliminate jet lag.     

Evening Alcohol Consumption Alters the Circadian Rhythm of Body Temperature

To the Editor: Recordings of body temperature rhythms are used as a marker of the circadian system in many fields of study, including shift work, jet lag, affective disorders, gerontology, and sleep disorders. In our studies of circadian rhythms, we routinely prohibit subjects from drinking alcohol because of findings published in 1933 (1). That study found that after alcohol consumption the nocturnal temperature minimum during sleep occurred earlier, and was higher, than on control nights. In the years since that report, there have been no other studies of how alcohol changes the temperature waveform during sleep, despite other studies of the dose- and time-dependent effects of ethanol in humans (2). We decided to investigate whether the results of the 1933 report would generalize to other subjects and to women.     

Long-Lasting Effects of Sepsis on Circadian Rhythms in the Mouse

Daily patterns of activity and physiology are termed circadian rhythms and are driven primarily by an endogenous biological timekeeping system, with the master clock located in the suprachiasmatic nucleus. Previous studies have indicated reciprocal relationships between the circadian and the immune systems, although to date there have been only limited explorations of the long-term modulation of the circadian system by immune challenge, and it is to this question that we addressed ourselves in the current study. Sepsis was induced by peripheral treatment with lipopolysaccharide (5 mg/kg) and circadian rhythms were monitored following recovery. The basic parameters of circadian rhythmicity (free-running period and rhythm amplitude, entrainment to a light/dark cycle) were unaltered in post-septic animals compared to controls. Animals previously treated with LPS showed accelerated re-entrainment to a 6 hour advance of the light/dark cycle, and showed larger phase advances induced by photic stimulation in the late night phase. Photic induction of the immediate early genes c-FOS, EGR-1 and ARC was not altered, and neither was phase-shifting in response to treatment with the 5-HT-1a/7 agonist 8-OH-DPAT. Circadian expression of the clock gene product PER2 was altered in the suprachiasmatic nucleus of post-septic animals, and PER1 and PER2 expression patterns were altered also in the hippocampus. Examination of the suprachiasmatic nucleus 3 months after treatment with LPS showed persistent upregulation of the microglial markers CD-11b and F4/80, but no changes in the expression of various neuropeptides, cytokines, and intracellular signallers. The effects of sepsis on circadian rhythms does not seem to be driven by cell death, as 24 hours after LPS treatment there was no evidence for apoptosis in the suprachiasmatic nucleus as judged by TUNEL and cleaved-caspase 3 staining. Overall these data provide novel insight into how septic shock exerts chronic effects on the mammalian circadian system.     

Does the compromised sleep and circadian disruption of night and shiftworkers make them highly vulnerable to 2019 coronavirus disease (COVID-19)?

ABSTRACT

Rotating and permanent night shiftwork schedules typically result in acute and sometimes chronic sleep deprivation plus acute and sometimes chronic disruption of the circadian time structure. Immune system processes and functionalities are organized as circadian rhythms, and they are also strongly influenced by sleep status. Sleep is a vital behavioral state of living beings and a modulator of immune function and responsiveness. Shiftworkers show increased risk for developing viral infections due to possible compromise of both innate and acquired immunity responses. Short sleep and sleep loss, common consequences of shiftwork, are associated with altered integrity of the immune system. We discuss the possible excess risk for COVID-19 infection in the context of the common conditions among shiftworkers, including nurses, doctors, and first responders, among others of high exposure to the contagion, of sleep imbalance and circadian disruption.