Olcese, James; Lozier, Stephen; Paradise, Courtney
Although the onset of spontaneous human parturition has long been known to occur preferentially during the nighttime and early morning hours, no convincing physiological explanation for this pattern has yet been proposed. This review focuses on the circadian timing of mammalian parturition, particularly in the human. It is proposed that differences in the phasing of parturition among different species are likely a function of opposite uterine responses to humoral cues, in particular those coding for time of day. The brain hormone melatonin fulfills many of the prerequisites to serve as a circadian signal for initiating uterine contractions that lead to human parturition. These encompass direct actions of melatonin on myometrial smooth muscle cells that are synergistic with oxytocin in facilitating greater uterine contractions at night. This may not only help to explain the nocturnal phasing of human parturition but also open new avenues for the management of term and preterm labor.
Duffy, Jeanne F.; Cain, Sean W.; Chang, Anne-Marie; Phillips, Andrew J. K.; Münch, Mirjam Y.; Gronfier, Claude; Wyatt, James K.; Dijk, Derk-Jan; Czeisler, Charles A.
The circadian rhythms of melatonin and body temperature are set to an earlier hour in women than in men, even when the women and men maintain nearly identical and consistent bedtimes and wake times. Moreover, women tend to wake up earlier than men and exhibit a greater preference for morning activities than men. Although the neurobiological mechanism underlying this sex difference in circadian alignment is unknown, multiple studies in nonhuman animals have demonstrated a sex difference in circadian period that could account for such a difference in circadian alignment between women and men. Whether a sex difference in intrinsic circadian period in humans underlies the difference in circadian alignment between men and women is unknown. We analyzed precise estimates of intrinsic circadian period collected from 157 individuals (52 women, 105 men; aged 18–74 y) studied in a month-long inpatient protocol designed to minimize confounding influences on circadian period estimation. Overall, the average intrinsic period of the melatonin and temperature rhythms in this population was very close to 24 h [24.15 ± 0.2 h (24 h 9 min ± 12 min)]. We further found that the intrinsic circadian period was significantly shorter in women [24.09 ± 0.2 h (24 h 5 min ± 12 min)] than in men [24.19 ± 0.2 h (24 h 11 min ± 12 min); P < 0.01] and that a significantly greater proportion of women have intrinsic circadian periods shorter than 24.0 h (35% vs. 14%; P < 0.01). The shorter average intrinsic circadian period observed in women may have implications for understanding sex differences in habitual sleep duration and insomnia prevalence. PMID:21536890
Martinez-Lozano Sinues, Pablo; Tarokh, Leila; Li, Xue; Kohler, Malcolm; Brown, Steven A.; Zenobi, Renato; Dallmann, Robert
Circadian clocks play a significant role in the correct timing of physiological metabolism, and clock disruption might lead to pathological changes of metabolism. One interesting method to assess the current state of metabolism is metabolomics. Metabolomics tries to capture the entirety of small molecules, i.e. the building blocks of metabolism, in a given matrix, such as blood, saliva or urine. Using mass spectrometric approaches we and others have shown that a significant portion of the human metabolome in saliva and blood exhibits circadian modulation; independent of food intake or sleep/wake rhythms. Recent advances in mass spectrometry techniques have introduced completely non-invasive breathprinting; a method to instantaneously assess small metabolites in human breath. In this proof-of-principle study, we extend these findings about the impact of circadian clocks on metabolomics to exhaled breath. As previously established, our method allows for real-time analysis of a rich matrix during frequent non-invasive sampling. We sampled the breath of three healthy, non-smoking human volunteers in hourly intervals for 24 hours during total sleep deprivation, and found 111 features in the breath of all individuals, 36–49% of which showed significant circadian variation in at least one individual. Our data suggest that real-time mass spectrometric "breathprinting" has high potential to become a useful tool to understand circadian metabolism, and develop new biomarkers to easily and in real-time assess circadian clock phase and function in experimental and clinical settings. PMID:25545545
Burke, Tina M.; Markwald, Rachel R.; Chinoy, Evan D.; Snider, Jesse A.; Bessman, Sara C.; Jung, Christopher M.; Wright, Kenneth P.
Study Objectives: Photic and non-photic stimuli have been shown to shift the phase of the human circadian clock. We examined how photic and non-photic time cues may be combined by the human circadian system by assessing the phase advancing effects of one evening dose of exogenous melatonin, alone and in combination with one session of morning bright light exposure. Design: Randomized placebo-controlled double-blind circadian protocol. The effects of four conditions, dim light (∼1.9 lux, ∼0.6 Watts/m2)-placebo, dim light-melatonin (5 mg), bright light (∼3000 lux, ∼7 Watts/m2)-placebo, and bright light-melatonin on circadian phase was assessed by the change in the salivary dim light melatonin onset (DLMO) prior to and following treatment under constant routine conditions. Melatonin or placebo was administered 5.75 h prior to habitual bedtime and 3 h of bright light exposure started 1 h prior to habitual wake time. Setting: Sleep and chronobiology laboratory environment free of time cues. Participants: Thirty-six healthy participants (18 females) aged 22 ± 4 y (mean ± SD). Results: Morning bright light combined with early evening exogenous melatonin induced a greater phase advance of the DLMO than either treatment alone. Bright light alone and melatonin alone induced similar phase advances. Conclusion: Information from light and melatonin appear to be combined by the human circadian clock. The ability to combine circadian time cues has important implications for understanding fundamental physiological principles of the human circadian timing system. Knowledge of such principles is important for designing effective countermeasures for phase-shifting the human circadian clock to adapt to jet lag, shift work, and for designing effective treatments for circadian sleep-wakefulness disorders. Citation: Burke TM; Markwald RR; Chinoy ED; Snider JA; Bessman SC; Jung CM; Wright Jr KP. Combination of light and melatonin time cues for phase advancing the human circadian
Duffy, J. F.; Kronauer, R. E.; Czeisler, C. A.
1. Both the timing of behavioural events (activity, sleep and social interactions) and the environmental light-dark cycle have been reported to contribute to entrainment of human circadian rhythms to the 24 h day. Yet, the relative contribution of those putative behavioural synchronizers to that of light exposure remains unclear. 2. To investigate this, we inverted the schedule of rest, sedentary activity and social contact of thirty-two young men either with or without exposure to bright light. 3. On this inverted schedule, the endogenous component of the core temperature rhythm of subjects who were exposed to bright light showed a significant phase shift, demonstrating that they were adapting to the new schedule. In contrast, the core temperature rhythm of subjects who were not exposed to bright light moved on average 0.2 h later per day and after 10 days had not significantly adapted to the new schedule. 4. The direction of phase shift in the groups exposed to bright light was dependent on the time of bright light exposure, while control subjects drifted to a later hour regardless of the timing of their schedule of sleep timing, social contact and meals. 5. These results support the concept that the light-dark cycle is the most important synchronizer of the human circadian system. They suggest that inversion of the sleep-wake, rest-activity and social contact cycles provides relatively minimal drive for resetting the human circadian pacemaker. 6. These data indicate that interventions designed to phase shift human circadian rhythms for adjustment to time zone changes or altered work schedules should focus on properly timed light exposure.
Micó, Víctor; Díez-Ricote, Laura; Daimiel, Lidia
Even though the rhythmic oscillations of life have long been known, the precise molecular mechanisms of the biological clock are only recently being explored. Circadian rhythms are found in virtually all organisms and affect our lives. Thus, it is not surprising that the correct running of this clock is essential for cellular functions and health. The circadian system is composed of an intricate network of genes interwined in an intrincated transcriptional/translational feedback loop. The precise oscillation of this clock is controlled by the circadian genes that, in turn, regulate the circadian oscillations of many cellular pathways. Consequently, variations in these genes have been associated with human diseases and metabolic disorders. From a nutrigenetics point of view, some of these variations modify the individual response to the diet and interact with nutrients to modulate such response. This circadian feedback loop is also epigenetically modulated. Among the epigenetic mechanisms that control circadian rhythms, microRNAs are the least studied ones. In this paper, we review the variants of circadian-related genes associated to human disease and nutritional response and discuss the current knowledge about circadian microRNAs. Accumulated evidence on the genetics and epigenetics of the circadian system points to important implications of chronotherapy in the clinical practice, not only in terms of pharmacotherapy, but also for dietary interventions. However, interventional studies (especially nutritional trials) that include chronotherapy are scarce. Given the importance of chronobiology in human health such studies are warranted in the near future.
Micó, Víctor; Díez-Ricote, Laura; Daimiel, Lidia
Even though the rhythmic oscillations of life have long been known, the precise molecular mechanisms of the biological clock are only recently being explored. Circadian rhythms are found in virtually all organisms and affect our lives. Thus, it is not surprising that the correct running of this clock is essential for cellular functions and health. The circadian system is composed of an intricate network of genes interwined in an intrincated transcriptional/translational feedback loop. The precise oscillation of this clock is controlled by the circadian genes that, in turn, regulate the circadian oscillations of many cellular pathways. Consequently, variations in these genes have been associated with human diseases and metabolic disorders. From a nutrigenetics point of view, some of these variations modify the individual response to the diet and interact with nutrients to modulate such response. This circadian feedback loop is also epigenetically modulated. Among the epigenetic mechanisms that control circadian rhythms, microRNAs are the least studied ones. In this paper, we review the variants of circadian-related genes associated to human disease and nutritional response and discuss the current knowledge about circadian microRNAs. Accumulated evidence on the genetics and epigenetics of the circadian system points to important implications of chronotherapy in the clinical practice, not only in terms of pharmacotherapy, but also for dietary interventions. However, interventional studies (especially nutritional trials) that include chronotherapy are scarce. Given the importance of chronobiology in human health such studies are warranted in the near future. PMID:26927084
Paschos, Georgios K.
Metabolic processes exhibit diurnal variation from cyanobacteria to humans. The circadian clock is thought to have evolved as a time keeping system for the cell to optimize the timing of metabolic events according to physiological needs and environmental conditions. Circadian rhythms temporally separate incompatible cellular processes and optimize cellular and organismal fitness. A modern 24 h lifestyle can run at odds with the circadian rhythm dictated by our molecular clocks and create desynchrony between internal and external timing. It has been suggested that this desynchrony compromises metabolic homeostasis and may promote the development of obesity (Morris et al., 2012). Here we review the evidence supporting the association between circadian misalignment and metabolic homeostasis and discuss the role of feeding time. PMID:26082718
Yamanaka, Yujiro; Hashimoto, Satoko; Masubuchi, Satoru; Natsubori, Akiyo; Nishide, Shin-Ya; Honma, Sato; Honma, Ken-Ichi
Our previous study demonstrated that physical exercise under dim lights (<10 lux) accelerated reentrainment of the sleep-wake cycle but not the circadian melatonin rhythm to an 8-h phase-advanced sleep schedule, indicating differential effects of physical exercise on the human circadian system. The present study examined the effects of bright light (>5,000 lux) on exercise-induced acceleration of reentrainment because timed bright lights are known to reset the circadian pacemaker. Fifteen male subjects spent 12 days in temporal isolation. The sleep schedule was advanced from habitual sleep times by 8 h for 4 days, which was followed by a free-run session. In the shift session, bright lights were given during the waking time. Subjects in the exercise group performed 2-h bicycle running twice a day. Subjects in the control kept quiet. As a result, the sleep-wake cycle was fully entrained by the shift schedule in both groups. Bright light may strengthen the resetting potency of the shift schedule. By contrast, the circadian melatonin rhythm was phase-advanced by 6.9 h on average in the exercise group but only by 2.0 h in the control. Thus physical exercise prevented otherwise unavoidable internal desynchronization. Polysomnographical analyses revealed that deterioration of sleep quality by shift schedule was protected by physical exercise under bright lights. These findings indicate differential regulation of sleep-wake cycle and circadian melatonin rhythm by physical exercise in humans. The melatonin rhythm is regulated primarily by bright lights, whereas the sleep-wake cycle is by nonphotic time cues, such as physical exercise and shift schedule.
Skeldon, Anne C; Phillips, Andrew J K; Dijk, Derk-Jan
Why do we go to sleep late and struggle to wake up on time? Historically, light-dark cycles were dictated by the solar day, but now humans can extend light exposure by switching on artificial lights. We use a mathematical model incorporating effects of light, circadian rhythmicity and sleep homeostasis to provide a quantitative theoretical framework to understand effects of modern patterns of light consumption on the human circadian system. The model shows that without artificial light humans wakeup at dawn. Artificial light delays circadian rhythmicity and preferred sleep timing and compromises synchronisation to the solar day when wake-times are not enforced. When wake-times are enforced by social constraints, such as work or school, artificial light induces a mismatch between sleep timing and circadian rhythmicity ('social jet-lag'). The model implies that developmental changes in sleep homeostasis and circadian amplitude make adolescents particularly sensitive to effects of light consumption. The model predicts that ameliorating social jet-lag is more effectively achieved by reducing evening light consumption than by delaying social constraints, particularly in individuals with slow circadian clocks or when imposed wake-times occur after sunrise. These theory-informed predictions may aid design of interventions to prevent and treat circadian rhythm-sleep disorders and social jet-lag.
Skeldon, Anne C.; Phillips, Andrew J. K.; Dijk, Derk-Jan
Why do we go to sleep late and struggle to wake up on time? Historically, light-dark cycles were dictated by the solar day, but now humans can extend light exposure by switching on artificial lights. We use a mathematical model incorporating effects of light, circadian rhythmicity and sleep homeostasis to provide a quantitative theoretical framework to understand effects of modern patterns of light consumption on the human circadian system. The model shows that without artificial light humans wakeup at dawn. Artificial light delays circadian rhythmicity and preferred sleep timing and compromises synchronisation to the solar day when wake-times are not enforced. When wake-times are enforced by social constraints, such as work or school, artificial light induces a mismatch between sleep timing and circadian rhythmicity (‘social jet-lag’). The model implies that developmental changes in sleep homeostasis and circadian amplitude make adolescents particularly sensitive to effects of light consumption. The model predicts that ameliorating social jet-lag is more effectively achieved by reducing evening light consumption than by delaying social constraints, particularly in individuals with slow circadian clocks or when imposed wake-times occur after sunrise. These theory-informed predictions may aid design of interventions to prevent and treat circadian rhythm-sleep disorders and social jet-lag. PMID:28345624
Dijk, D. J.; Duffy, J. F.
The light-entrainable circadian pacemaker located in the suprachiasmatic nucleus of the hypothalamus regulates the timing and consolidation of sleep by generating a paradoxical rhythm of sleep propensity; the circadian drive for wakefulness peaks at the end of the day spent awake, ie close to the onset of melatonin secretion at 21.00-22.00 h and the circadian drive for sleep crests shortly before habitual waking-up time. With advancing age, ie after early adulthood, sleep consolidation declines, and time of awakening and the rhythms of body temperature, plasma melatonin and cortisol shift to an earlier clock hour. The variability of the phase relationship between the sleep-wake cycle and circadian rhythms increases, and in old age sleep is more susceptible to internal arousing stimuli associated with circadian misalignment. The propensity to awaken from sleep advances relative to the body temperature nadir in older people, a change that is opposite to the phase delay of awakening relative to internal circadian rhythms associated with morningness in young people. Age-related changes do not appear to be associated with a shortening of the circadian period or a reduction of the circadian drive for wake maintenance. These changes may be related to changes in the sleep process itself, such as reductions in slow-wave sleep and sleep spindles as well as a reduced strength of the circadian signal promoting sleep in the early morning hours. Putative mediators and modulators of circadian sleep regulation are discussed.
Zeitzer, J. M.; Kronauer, R. E.; Czeisler, C. A.
Despite the preeminence of light as the synchronizer of the circadian timing system, the phototransductive machinery in mammals which transmits photic information from the retina to the hypothalamic circadian pacemaker remains largely undefined. To determine the class of photopigments which this phototransductive system uses, we exposed a group (n = 7) of human subjects to red light below the sensitivity threshold of a scotopic (i.e. rhodopsin/rod-based) system, yet of sufficient strength to activate a photopic (i.e. cone-based) system. Exposure to this light stimulus was sufficient to reset significantly the human circadian pacemaker, indicating that the cone pigments which mediate color vision can also mediate circadian vision.
Stenvers, Dirk Jan; Jonkers, Cora F; Fliers, Eric; Bisschop, Peter H L T; Kalsbeek, Andries
Life on earth has evolved under the daily rhythm of light and dark. Consequently, most creatures experience a daily rhythm in food availability. In this review, we first introduce the mammalian circadian timing system, consisting of a central clock in the suprachiasmatic nucleus (SCN) and peripheral clocks in various metabolic tissues including liver, pancreas, and intestine. We describe how peripheral clocks are synchronized by the SCN and metabolic signals. Second, we review the influence of the circadian timing system on food intake behavior, activity of the gastrointestinal system, and several aspects of glucose and lipid metabolism. Third, the circadian control of digestion and metabolism may have important implications for several aspects of food intake in humans. Therefore, we review the human literature on health aspects of meal timing, meal frequency, and breakfast consumption, and we describe the potential implications of the clock system for the timing of enteral tube feeding and parenteral nutrition. Finally, we explore the connection between type 2 diabetes and the circadian timing system. Although the past decade has provided exciting knowledge about the reciprocal relation between biological clocks and feeding/energy metabolism, future research is necessary to further elucidate this fascinating relationship in order to improve human health.
Shanahan, T. L.; Czeisler, C. A.
The physiology of the human circadian pacemaker and its influence and on the daily organization of sleep, endocrine and behavioral processes is an emerging interest in science and medicine. Understanding the development, organization and fundamental properties underlying the circadian timing system may provide insight for the application of circadian principles to the practice of clinical medicine, both diagnostically (interpretation of certain clinical tests are dependent on time of day) and therapeutically (certain pharmacological responses vary with the time of day). The light-dark cycle is the most powerful external influence acting upon the human circadian pacemaker. It has been shown that timed exposure to light can both synchronize and reset the phase of the circadian pacemaker in a predictable manner. The emergence of detectable circadian rhythmicity in the neonatal period is under investigation (as described elsewhere in this issue). Therefore, the pattern of light exposure provided in the neonatal intensive care setting has implications. One recent study identified differences in both amount of sleep time and weight gain in infants maintained in a neonatal intensive care environment that controlled the light-dark cycle. Unfortunately, neither circadian phase nor the time of day has been considered in most clinical investigations. Further studies with knowledge of principles characterizing the human circadian timing system, which governs a wide array of physiological processes, are required to integrate these findings with the practice of clinical medicine.
Markova-Car, Elitza P; Jurišić, Davor; Ilić, Nataša; Kraljević Pavelić, Sandra
Circadian timing system includes an input pathway transmitting environmental signals to a core oscillator that generates circadian signals responsible for the peripheral physiological or behavioural events. Circadian 24-h rhythms regulate diverse physiologic processes. Deregulation of these rhythms is associated with a number of pathogenic conditions including depression, diabetes, metabolic syndrome and cancer. Melanoma is a less common type of skin cancer yet more aggressive often with a lethal ending. However, little is known about circadian control in melanoma and exact functional associations between core clock genes and development of melanoma skin cancer. This paper, therefore, comprehensively analyses current literature data on the involvement of circadian clock components in melanoma development. In particular, the role of circadian rhythm deregulation is discussed in the context of DNA repair mechanisms and influence of UV radiation and artificial light exposure on cancer development. The role of arylalkylamine N-acetyltransferase (AANAT) enzyme and impact of melatonin, as a major output factor of circadian rhythm, and its protective role in melanoma are discussed in details. We hypothesise that further understanding of clock genes' involvement and circadian regulation might foster discoveries in the field of melanoma diagnostics and treatment.
Dijk, Derk-Jan; Lockley, Steven W.
The human sleep-wake cycle is generated by a circadian process, originating from the suprachiasmatic nuclei, in interaction with a separate oscillatory process: the sleep homeostat. The sleep-wake cycle is normally timed to occur at a specific phase relative to the external cycle of light-dark exposure. It is also timed at a specific phase relative to internal circadian rhythms, such as the pineal melatonin rhythm, the circadian sleep-wake propensity rhythm, and the rhythm of responsiveness of the circadian pacemaker to light. Variations in these internal and external phase relationships, such as those that occur in blindness, aging, morning and evening, and advanced and delayed sleep-phase syndrome, lead to sleep disruptions and complaints. Changes in ocular circadian photoreception, interindividual variation in the near-24-h intrinsic period of the circadian pacemaker, and sleep homeostasis can contribute to variations in external and internal phase. Recent findings on the physiological and molecular-genetic correlates of circadian sleep disorders suggest that the timing of the sleep-wake cycle and circadian rhythms is closely integrated but is, in part, regulated differentially.
Jones, Christopher R; Huang, Angela L; Ptáček, Louis J; Fu, Ying-Hui
Circadian rhythm disorders constitute a group of phenotypes that usually present as altered sleep-wake schedules. Until a human genetics approach was applied to investigate these traits, the genetic components regulating human circadian rhythm and sleep behaviors remained mysterious. Steady advances in the last decade have dramatically improved our understanding of the genes involved in circadian rhythmicity and sleep regulation. Finding these genes presents new opportunities to use a wide range of approaches, including in vitro molecular studies and in vivo animal modeling, to elevate our understanding of how sleep and circadian rhythms are regulated and maintained. Ultimately, this knowledge will reveal how circadian and sleep disruption contribute to various ailments and shed light on how best to maintain and recover good health.
de Pedro, M A; Morán, J; Díaz, I; Murias, L; Fernández-Plaza, C; González, C; Díaz, E
Kisspeptin is an essential gatekeeper of reproductive function. During pregnancy high circulating levels of kisspeptin have been described, however the clear role of this neuropeptide in pregnancy remains unknown. We tested the existence of rhythmic kisspeptin expression in human full-term placenta from healthy pregnant women at six different time points during the day. The data obtained by Western blotting were fitted to a mathematical model (Fourier series), demonstrating, for the first time, the existence of a circadian rhythm in placental kisspeptin expression.
Klerman, E. B.; Rimmer, D. W.; Dijk, D. J.; Kronauer, R. E.; Rizzo, J. F. 3rd; Czeisler, C. A.
In organisms as diverse as single-celled algae and humans, light is the primary stimulus mediating entrainment of the circadian biological clock. Reports that some totally blind individuals appear entrained to the 24-h day have suggested that nonphotic stimuli may also be effective circadian synchronizers in humans, although the nonphotic stimuli are probably comparatively weak synchronizers, because the circadian rhythms of many totally blind individuals "free run" even when they maintain a 24-h activity-rest schedule. To investigate entrainment by nonphotic synchronizers, we studied the endogenous circadian melatonin and core body temperature rhythms of 15 totally blind subjects who lacked conscious light perception and exhibited no suppression of plasma melatonin in response to ocular bright-light exposure. Nine of these fifteen blind individuals were able to maintain synchronization to the 24-h day, albeit often at an atypical phase angle of entrainment. Nonphotic stimuli also synchronized the endogenous circadian rhythms of a totally blind individual to a non-24-h schedule while living in constant near darkness. We conclude that nonphotic stimuli can entrain the human circadian pacemaker in some individuals lacking ocular circadian photoreception.
Ly, Julien Q. M.; Gaggioni, Giulia; Chellappa, Sarah L.; Papachilleos, Soterios; Brzozowski, Alexandre; Borsu, Chloé; Rosanova, Mario; Sarasso, Simone; Middleton, Benita; Luxen, André; Archer, Simon N.; Phillips, Christophe; Dijk, Derk-Jan; Maquet, Pierre; Massimini, Marcello; Vandewalle, Gilles
Prolonged wakefulness alters cortical excitability, which is essential for proper brain function and cognition. However, besides prior wakefulness, brain function and cognition are also affected by circadian rhythmicity. Whether the regulation of cognition involves a circadian impact on cortical excitability is unknown. Here, we assessed cortical excitability from scalp electroencephalography (EEG) responses to transcranial magnetic stimulation in 22 participants during 29 h of wakefulness under constant conditions. Data reveal robust circadian dynamics of cortical excitability that are strongest in those individuals with highest endocrine markers of circadian amplitude. In addition, the time course of cortical excitability correlates with changes in EEG synchronization and cognitive performance. These results demonstrate that the crucial factor for cortical excitability, and basic brain function in general, is the balance between circadian rhythmicity and sleep need, rather than sleep homoeostasis alone. These findings have implications for clinical applications such as non-invasive brain stimulation in neurorehabilitation. PMID:27339884
Fuhr, Luise; Abreu, Mónica; Pett, Patrick; Relógio, Angela
The circadian clock is a powerful endogenous timing system, which allows organisms to fine-tune their physiology and behaviour to the geophysical time. The interplay of a distinct set of core-clock genes and proteins generates oscillations in expression of output target genes which temporally regulate numerous molecular and cellular processes. The study of the circadian timing at the organismal as well as at the cellular level outlines the field of chronobiology, which has been highly interdisciplinary ever since its origins. The development of high-throughput approaches enables the study of the clock at a systems level. In addition to experimental approaches, computational clock models exist which allow the analysis of rhythmic properties of the clock network. Such mathematical models aid mechanistic understanding and can be used to predict outcomes of distinct perturbations in clock components, thereby generating new hypotheses regarding the putative function of particular clock genes. Perturbations in the circadian timing system are linked to numerous molecular dysfunctions and may result in severe pathologies including cancer. A comprehensive knowledge regarding the mechanistic of the circadian system is crucial to develop new procedures to investigate pathologies associated with a deregulated clock. In this manuscript we review the combination of experimental methodologies, bioinformatics and theoretical models that have been essential to explore this remarkable timing-system. Such an integrative and interdisciplinary approach may provide new strategies with regard to chronotherapeutic treatment and new insights concerning the restoration of the circadian timing in clock-associated diseases. PMID:26288701
Cordes, Sara; Gallistel, C. R.
While progress has been made in determining the molecular basis for the circadian clock, the mechanism by which mammalian brains time intervals measured in seconds to minutes remains a mystery. An obvious question is whether the interval timing mechanism shares molecular machinery with the circadian timing mechanism. In the current study, we trained circadian CLOCK +/− and −/− mutant male mice in a peak-interval procedure with 10 and 20-s criteria. The mutant mice were more active than their wild-type littermates, but there were no reliable deficits in the accuracy or precision of their timing as compared with wild-type littermates. This suggests that expression of the CLOCK protein is not necessary for normal interval timing. PMID:18602902
Akashi, Makoto; Soma, Haruhiko; Yamamoto, Takuro; Tsugitomi, Asuka; Yamashita, Shiko; Yamamoto, Takuya; Nishida, Eisuke; Yasuda, Akio; Liao, James K.; Node, Koichi
A thorough understanding of the circadian clock requires qualitative evaluation of circadian clock gene expression. Thus far, no simple and effective method for detecting human clock gene expression has become available. This limitation has greatly hampered our understanding of human circadian rhythm. Here we report a convenient, reliable, and less invasive method for detecting human clock gene expression using biopsy samples of hair follicle cells from the head or chin. We show that the circadian phase of clock gene expression in hair follicle cells accurately reflects that of individual behavioral rhythms, demonstrating that this strategy is appropriate for evaluating the human peripheral circadian clock. Furthermore, using this method, we indicate that rotating shift workers suffer from a serious time lag between circadian gene expression rhythms and lifestyle. Qualitative evaluation of clock gene expression in hair follicle cells, therefore, may be an effective approach for studying the human circadian clock in the clinical setting. PMID:20798039
Ercolani, Luisa; Ferrari, Alessio; De Mei, Claudia; Parodi, Chiara; Wade, Mark; Grimaldi, Benedetto
Disruption of the circadian clock is associated with a variety of human pathologies, including cancer. Rather than being a mere consequence of a global changes associated with the cancer cell transcriptome, the aberrant clock gene expression observed in many tumors may serve for cancer cell survival. This scenario suggests the provocative hypothesis that pharmacological modulation of clock-related proteins may be suitable as an effective anticancer strategy. In this review, we focus on the functions of the druggable circadian nuclear receptors, REV-ERBα and REV-ERBβ, in cancer cell survival and describe the potential development of small molecule compounds that modulate REV-ERB activity as novel anticancer therapeutics. In addition, we debate the use of circadian rhythm-based synthetic lethal approaches to identify yet unexplored anticancer strategies.
Melatonin(N-acetyl-5-methoxytryptamine) is synthesized from tryptophan and is intensively secreted into the blood only in darkness (nighttime) by the pineal gland. Melatonin is not only the most reliable marker of internal circadian phase but also a potent sleep-promoting and circadian phase regulatory agent in humans. There is evidence that daytime administered melatonin is able to exhibit short-acting hypnagogic effect and phase-shifting of the circadian rhythms such that sleep timing and associated various physiological functions realign at a new desired phase. Under favor of these properties, melatonin and melatonin receptor agonists have been shown to be potent therapeutic agents for the treatment of circadian rhythm sleep disorders and some type of insomnia.
Jewett, Megan; Czeisler, Charles A.; Kronauer, Richard E.
A recent demonstration that the phase of the human circadian pacemaker could be inverted using an unconventional three-cycle stimulus has led to an investigation of whether critically timed exposure to a more moderate stimulus could drive that oscillator toward its singularity, a phaseless position at which the amplitude of circadian oscillation is zero. It is reported here that exposure of humans to fewer cycles of bright light, centered around the time at which the human circadian pacemaker is most sensitive to light-induced phase shifts, can markedly attenuate endogenous cicadian amplitude. In some cases this results in an apparent loss of rhythmicity, as expected to occur in the region of singularity.
Arble, Deanna M.; Bass, Joseph; Laposky, Aaron D.; Vitaterna, Martha H.; Turek, Fred W.
Studies of body weight regulation have focused almost entirely on caloric intake and energy expenditure. However, a number of recent studies in animals linking energy regulation and the circadian clock at the molecular, physiological and behavioral levels raise the possibility that the timing of food intake itself may play a significant role in weight gain. The present study focused on the role of the circadian phase of food consumption in weight gain. We provide evidence that nocturnal mice fed a high fat diet only during the 12 hour light phase gain significantly more weight than mice fed only during the 12 hour dark phase. A better understanding of the role of the circadian system for weight gain could have important implications for developing new therapeutic strategies for combating the obesity epidemic facing the human population today. PMID:19730426
Arble, Deanna M; Bass, Joseph; Laposky, Aaron D; Vitaterna, Martha H; Turek, Fred W
Studies of body weight regulation have focused almost entirely on caloric intake and energy expenditure. However, a number of recent studies in animals linking energy regulation and the circadian clock at the molecular, physiological, and behavioral levels raise the possibility that the timing of food intake itself may play a significant role in weight gain. The present study focused on the role of the circadian phase of food consumption in weight gain. We provide evidence that nocturnal mice fed a high-fat diet only during the 12-h light phase gain significantly more weight than mice fed only during the 12-h dark phase. A better understanding of the role of the circadian system for weight gain could have important implications for developing new therapeutic strategies for combating the obesity epidemic facing the human population today.
Although it is well established that human adipose tissue (AT) shows circadian rhythmicity, published studies have been discussed as if tissues or systems showed only one or few circadian rhythms at a time. To provide an overall view of the internal temporal order of circadian rhythms in human AT in...
Duffy, J. F.; Rimmer, D. W.; Czeisler, C. A.
The biological basis of preferences for morning or evening activity patterns ("early birds" and "night owls") has been hypothesized but has remained elusive. The authors reported that, compared with evening types, the circadian pacemaker of morning types was entrained to an earlier hour with respect to both clock time and wake time. The present study explores a chronobiological mechanism by which the biological clock of morning types may be set to an earlier hour. Intrinsic period, a fundamental property of the circadian system, was measured in a month-long inpatient study. A subset of participants also had their circadian phase assessed. Participants completed a morningness-eveningness questionnaire before study. Circadian period was correlated with morningness-eveningness, circadian phase, and wake time, demonstrating that a fundamental property of the circadian pacemaker is correlated with the behavioral trait of morningness-eveningness.
Jewett, M. E.; Duffy, J. F.; Czeisler, C. A.
A double-stimulus experiment was conducted to evaluate the phase of the underlying circadian clock following light-induced phase shifts of the human circadian system. Circadian phase was assayed by constant routine from the rhythm in core body temperature before and after a three-cycle bright-light stimulus applied near the estimated minimum of the core body temperature rhythm. An identical, consecutive three-cycle light stimulus was then applied, and phase was reassessed. Phase shifts to these consecutive stimuli were no different from those obtained in a previous study following light stimuli applied under steady-state conditions over a range of circadian phases similar to those at which the consecutive stimuli were applied. These data suggest that circadian phase shifts of the core body temperature rhythm in response to a three-cycle stimulus occur within 24 h following the end of the 3-day light stimulus and that this poststimulus temperature rhythm accurately reflects the timing of the underlying circadian clock.
Gibbs, J. E.; Beesley, S.; Plumb, J.; Singh, D.; Farrow, S.; Ray, D. W.; Loudon, A. S. I.
In addition to the core circadian oscillator, located within the suprachiasmatic nucleus, numerous peripheral tissues possess self-sustaining circadian timers. In vivo these are entrained and temporally synchronized by signals conveyed from the core oscillator. In the present study, we examine circadian timing in the lung, determine the cellular localization of core clock proteins in both mouse and human lung tissue, and establish the effects of glucocorticoids (widely used in the treatment of asthma) on the pulmonary clock. Using organotypic lung slices prepared from transgenic mPER2::Luc mice, luciferase levels, which report PER2 expression, were measured over a number of days. We demonstrate a robust circadian rhythm in the mouse lung that is responsive to glucocorticoids. Immunohistochemical techniques were used to localize specific expression of core clock proteins, and the glucocorticoid receptor, to the epithelial cells lining the bronchioles in both mouse and human lung. In the mouse, these were established to be Clara cells. Murine Clara cells retained circadian rhythmicity when grown as a pure population in culture. Furthermore, selective ablation of Clara cells resulted in the loss of circadian rhythm in lung slices, demonstrating the importance of this cell type in maintaining overall pulmonary circadian rhythmicity. In summary, we demonstrate that Clara cells are critical for maintaining coherent circadian oscillations in lung tissue. Their coexpression of the glucocorticoid receptor and core clock components establishes them as a likely interface between humoral suprachiasmatic nucleus output and circadian lung physiology. PMID:18787022
Spengler, Christina M; Czeisler, Charles A; Shea, Steven A
respiratory control in awake humans even when at rest under constant environmental and behavioural conditions. The characteristic change in PET,CO2 during non-rapid eye movement sleep was shown to be independent of circadian variations in PET,CO2, and probably reflects a change from predominantly behavioural to predominantly chemosensory respiratory control. This study has documented the existence and magnitude of circadian variations in respiration and respiratory control in awake humans for the first time under constant behavioural and environmental conditions. These results provide unique insights into respiratory control in awake humans, and highlight the importance of considering the phase of the circadian cycle in studies of respiratory control. PMID:10922018
Emens, Jonathan S; Burgess, Helen J
Circadian (body clock) timing has a profound influence on mental health, physical health, and health behaviors. This review focuses on how light, melatonin, and other melatonin receptor agonist drugs can be used to shift circadian timing in patients with misaligned circadian rhythms. A brief overview of the human circadian system is provided, followed by a discussion of patient characteristics and safety considerations that can influence the treatment of choice. The important features of light treatment, light avoidance, exogenous melatonin, and other melatonin receptor agonists are reviewed, along with some of the practical aspects of light and melatonin treatment.
Emens, Jonathan S.
Synopsis Circadian (body clock) timing has a profound influence on mental health, physical health, and health behaviors. This review focuses on how light, melatonin and other melatonin receptor agonist drugs can be used to shift circadian timing in patients with misaligned circadian rhythms. A brief overview of the human circadian system is provided, followed by a discussion of patient characteristics and safety considerations that can influence the treatment of choice. The important features of light treatment, light avoidance, exogenous melatonin and other melatonin receptor agonists are reviewed, along with some of the practical aspects of light and melatonin treatment. PMID:26568121
Carrasco-Benso, Maria P; Rivero-Gutierrez, Belen; Lopez-Minguez, Jesus; Anzola, Andrea; Diez-Noguera, Antoni; Madrid, Juan A; Lujan, Juan A; Martínez-Augustin, Olga; Scheer, Frank A J L; Garaulet, Marta
In humans, insulin sensitivity varies according to time of day, with decreased values in the evening and at night. Mechanisms responsible for the diurnal variation in insulin sensitivity are unclear. We investigated whether human adipose tissue (AT) expresses intrinsic circadian rhythms in insulin sensitivity that could contribute to this phenomenon. Subcutaneous and visceral AT biopsies were obtained from extremely obese participants (body mass index, 41.8 ± 6.3 kg/m(2); 46 ± 11 y) during gastric-bypass surgery. To assess the rhythm in insulin signaling, AKT phosphorylation was determined every 4 h over 24 h in vitro in response to different insulin concentrations (0, 1, 10, and 100 nM). Data revealed that subcutaneous AT exhibited robust circadian rhythms in insulin signaling (P < 0.00001). Insulin sensitivity reached its maximum (acrophase) around noon, being 54% higher than during midnight (P = 0.009). The amplitude of the rhythm was positively correlated with in vivo sleep duration (r = 0.53; P = 0.023) and negatively correlated with in vivo bedtime (r = -0.54; P = 0.020). No circadian rhythms were detected in visceral AT (P = 0.643). Here, we demonstrate the relevance of the time of the day for how sensitive AT is to the effects of insulin. Subcutaneous AT shows an endogenous circadian rhythm in insulin sensitivity that could provide an underlying mechanism for the daily rhythm in systemic insulin sensitivity.-Carrasco-Benso, M. P., Rivero-Gutierrez, B., Lopez-Minguez, J., Anzola, A., Diez-Noguera, A., Madrid, J. A., Lujan, J. A., Martínez-Augustin, O., Scheer, F. A. J. L., Garaulet, M. Human adipose tissue expresses intrinsic circadian rhythm in insulin sensitivity.
Yan, Lily; Silver, Rae
There are compelling reasons to study the role of steroids and sex differences in the circadian timing system. A solid history of research demonstrates the ubiquity of circadian changes that impact virtually all behavioral and biological responses. Furthermore, steroid hormones can modulate every attribute of circadian responses including the period, amplitude and phase. Finally, desynchronization of circadian rhythmicity, and either enhancing or damping amplitude of various circadian responses can produce different effects in the sexes. Studies of the neuroendocrine underpinnings of circadian timing systems and underlying sex differences have paralleled the overall development of the field as a whole. Early experimental studies established the ubiquity of circadian rhythms by cataloging daily and seasonal changes in whole organism responses. The next generation of experiments demonstrated that daily changes are not a result of environmental synchronizing cues, and are internally orchestrated, and that these differ in the sexes. This work was followed by the revelation of molecular circadian rhythms within individual cells. At present, there is a proliferation of work on the consequences of these daily oscillations in health and in disease, and awareness that these may differ in the sexes. In the present discourse we describe the paradigms used to examine circadian oscillation, to characterize how these internal timing signals are synchronized to local environmental conditions, and how hormones of gonadal and/or adrenal origin modulate circadian responses. Evidence pointing to endocrinologically and genetically mediated sex differences in circadian timing systems can be seen at many levels of the neuroendocrine and endocrine systems, from the cell, the gland and organ, and to whole animal behavior, including sleep/wake or rest/activity cycles, responses to external stimuli, and responses to drugs. We review evidence indicating that the analysis of the circadian
Manoogian, Emily N C; Panda, Satchidananda
Circadian rhythms optimize physiology and health by temporally coordinating cellular function, tissue function, and behavior. These endogenous rhythms dampen with age and thus compromise temporal coordination. Feeding-fasting patterns are an external cue that profoundly influence the robustness of daily biological rhythms. Erratic eating patterns can disrupt the temporal coordination of metabolism and physiology leading to chronic diseases that are also characteristic of aging. However, sustaining a robust feeding-fasting cycle, even without altering nutrition quality or quantity, can prevent or reverse these chronic diseases in experimental models. In humans, epidemiological studies have shown erratic eating patterns increase the risk of disease, whereas sustained feeding-fasting cycles, or prolonged overnight fasting, is correlated with protection from breast cancer. Therefore, optimizing the timing of external cues with defined eating patterns can sustain a robust circadian clock, which may prevent disease and improve prognosis.
Simonneaux, Valérie; Bahougne, Thibault
Rhythms in female reproduction are critical to insure that timing of ovulation coincides with oocyte maturation and optimal sexual arousal. This fine tuning of female reproduction involves both the estradiol feedback as an indicator of oocyte maturation, and the master circadian clock of the suprachiasmatic nuclei (SCN) as an indicator of the time of the day. Herein, we are providing an overview of the state of knowledge regarding the differential inhibitory and stimulatory effects of estradiol at different stages of the reproductive axis, and the mechanisms through which the two main neurotransmitters of the SCN, arginine vasopressin, and vasoactive intestinal peptide, convey daily time cues to the reproductive axis. In addition, we will report the most recent findings on the putative functions of peripheral clocks located throughout the reproductive axis [kisspeptin (Kp) neurons, gonadotropin-releasing hormone neurons, gonadotropic cells, the ovary, and the uterus]. This review will point to the critical position of the Kp neurons of the anteroventral periventricular nucleus, which integrate both the stimulatory estradiol signal, and the daily arginine vasopressinergic signal, while displaying a circadian clock. Finally, given the critical role of the light/dark cycle in the synchronization of female reproduction, we will discuss the impact of circadian disruptions observed during shift-work conditions on female reproductive performance and fertility in both animal model and humans.
Simonneaux, Valérie; Bahougne, Thibault
Rhythms in female reproduction are critical to insure that timing of ovulation coincides with oocyte maturation and optimal sexual arousal. This fine tuning of female reproduction involves both the estradiol feedback as an indicator of oocyte maturation, and the master circadian clock of the suprachiasmatic nuclei (SCN) as an indicator of the time of the day. Herein, we are providing an overview of the state of knowledge regarding the differential inhibitory and stimulatory effects of estradiol at different stages of the reproductive axis, and the mechanisms through which the two main neurotransmitters of the SCN, arginine vasopressin, and vasoactive intestinal peptide, convey daily time cues to the reproductive axis. In addition, we will report the most recent findings on the putative functions of peripheral clocks located throughout the reproductive axis [kisspeptin (Kp) neurons, gonadotropin-releasing hormone neurons, gonadotropic cells, the ovary, and the uterus]. This review will point to the critical position of the Kp neurons of the anteroventral periventricular nucleus, which integrate both the stimulatory estradiol signal, and the daily arginine vasopressinergic signal, while displaying a circadian clock. Finally, given the critical role of the light/dark cycle in the synchronization of female reproduction, we will discuss the impact of circadian disruptions observed during shift-work conditions on female reproductive performance and fertility in both animal model and humans. PMID:26539161
Najjar, Raymond P.; Zeitzer, Jamie M.
BACKGROUND. Beyond image formation, the light that is detected by retinal photoreceptors influences subcortical functions, including circadian timing, sleep, and arousal. The physiology of nonimage-forming (NIF) photoresponses in humans is not well understood; therefore, the development of therapeutic interventions based on this physiology, such as bright light therapy to treat chronobiological disorders, remains challenging. METHODS. Thirty-nine participants were exposed to 60 minutes of either continuous light (n = 8) or sequences of 2-millisecond light flashes (n = 31) with different interstimulus intervals (ISIs; ranging from 2.5 to 240 seconds). Melatonin phase shift and suppression, along with changes in alertness and sleepiness, were assessed. RESULTS. We determined that the human circadian system integrates flash sequences in a nonlinear fashion with a linear rise to a peak response (ISI = 7.6 ± 0.53 seconds) and a power function decrease following the peak of responsivity. At peak ISI, flashes were at least 2-fold more effective in phase delaying the circadian system as compared with exposure to equiluminous continuous light 3,800 times the duration. Flashes did not change melatonin concentrations or alertness in an ISI-dependent manner. CONCLUSION. We have demonstrated that intermittent light is more effective than continuous light at eliciting circadian changes. These findings cast light on the phenomenology of photic integration and suggest a dichotomous retinohypothalamic network leading to circadian phase shifting and other NIF photoresponses. Further clinical trials are required to judge the practicality of light flash protocols. TRIAL REGISTRATION. Clinicaltrials.gov NCT01119365. FUNDING. National Heart, Lung, and Blood Institute (1R01HL108441-01A1) and Department of Veterans Affairs Sierra Pacific Mental Illness Research, Education, and Clinical Center. PMID:26854928
Folkard, Simon; Monk, Timothy H.
Two experiments are described that examined the influence of time-of-day of presentation on immediate and delayed retention and its potential effects on retrieval from long-term memory. Time of presentation was found to influence both immediate and delayed (28 day) retention, but not retrieval from long-term memory. (Author/SJL)
Watts, Barbara L.
Many physiological and psychological processes fluctuate throughout the day in fairly stable, rhythmic patterns. The relationship between individual differences in circadian activity rhythms and a sense of time urgency were explored as well as a number of achievement-related variables. Undergraduates (N=308), whose circadian activity rhythms were…
Bailey, Matthew; Silver, Rae
Virtually every eukaryotic cell has an endogenous circadian clock and a biological sex. These cell-based clocks have been conceptualized as oscillators whose phase can be reset by internal signals such as hormones, and external cues such as light. The present review highlights the inter-relationship between circadian clocks and sex differences. In mammals, the suprachiasmatic nucleus (SCN) serves as a master clock synchronizing the phase of clocks throughout the body. Gonadal steroid receptors are expressed in almost every site that receives direct SCN input. Here we review sex differences in the circadian timing system in the hypothalamic-pituitary-gonadal axis (HPG), the hypothalamicadrenal-pituitary (HPA) axis, and sleep-arousal systems. We also point to ways in which disruption of circadian rhythms within these systems differs in the sexes and is associated with dysfunction and disease. Understanding sex differentiated circadian timing systems can lead to improved treatment strategies for these conditions. PMID:24287074
Mulder, C. K.; Gerkema, M. P.; Van der Zee, E. A.
Time-Place learning (TPL) refers to the ability of animals to remember important events that vary in both time and place. This ability is thought to be functional to optimize resource localization and predator avoidance in a circadian changing environment. Various studies have indicated that animals use their circadian system for TPL. However, not much is known about this specific role of the circadian system in cognition. This review aims to put TPL in a broader context and to provide an overview of historical background, functional aspects, and future perspectives of TPL. Recent advances have increased our knowledge on establishing TPL in a laboratory setting, leading to the development of a behavioral paradigm demonstrating the circadian nature of TPL in mice. This has enabled the investigation of circadian clock components on a functional behavioral level. Circadian TPL (cTPL) was found to be Cry clock gene dependent, confirming the essential role of Cry genes in circadian rhythms. In contrast, preliminary results have shown that cTPL is independent of Per genes. Circadian system decline with aging predicts that cTPL is age sensitive, potentially qualifying TPL as a functional model for episodic memory and aging. The underlying neurobiological mechanism of TPL awaits further examination. Here we discuss some putative mechanisms. PMID:23596390
Winget, C. M.; Deroshia, C. W.; Vernikos-Danellis, J.; Rosenblatt, W. S.; Hetherington, N. W.
Heart rate (HR) and rectal temperature (RT) data were obtained from 12 female and 27 male subjects. The subjects were housed in a facility where the environment was controlled. Human male and female RT and HR exhibit a circadian rhythm with an excursion of about 1.2 C and 30 beats/min, respectively. The acrophases, amplitudes, and level crossings are only slightly different between the sexes. The male HR and RT circadian wave forms are more stable than those of the females. However, the actual RT and HR of males were always lower than that of females at all time points around the clock. The HR during sleep in females is 15 per cent below the daily mean heart rate and in males, 22 per cent.
Matsumura, Ritsuko; Node, Koichi; Akashi, Makoto
Almost all living organisms, including humans, exhibit diurnal rhythms of physiology and behavior, which are driven by the circadian clock. Many studies have found that chronic misalignment between circadian and environmental/social rhythms carries a significant risk of various disorders, including sleep disorders, metabolic syndrome, cardiovascular diseases and cancer. However, irregular sleep-wake cycles and circadian maladjustment often cause 'social jet lag', which is minor but chronic jet-lag in our daily lives. Establishment of objective and convenient circadian-phase estimation methods in the clinical setting would therefore greatly contribute not only to resolving this global health problem but also to developing chronomedicine, a clinical approach for optimizing the time of day of treatments. Traditional melatonin-based methods have limitations with respect to circadian-phase evaluation; however, estimation methods based on clock gene expression may be able to compensate for these limitations. As a representative application of circadian-phase estimation based on clock gene expression, our method of using hair follicle cells may aid in the rapid clinical detection of circadian-related sleep problems, especially circadian rhythm sleep disorders that are masked because of forced adaptation to social time schedules.
Perrin, Laurent; Loizides-Mangold, Ursula; Skarupelova, Svetlana; Pulimeno, Pamela; Chanon, Stephanie; Robert, Maud; Bouzakri, Karim; Modoux, Christine; Roux-Lombard, Pascale; Vidal, Hubert; Lefai, Etienne; Dibner, Charna
Objective Circadian clocks are functional in all light-sensitive organisms, allowing an adaptation to the external world in anticipation of daily environmental changes. In view of the potential role of the skeletal muscle clock in the regulation of glucose metabolism, we aimed to characterize circadian rhythms in primary human skeletal myotubes and investigate their roles in myokine secretion. Methods We established a system for long-term bioluminescence recording in differentiated human myotubes, employing lentivector gene delivery of the Bmal1-luciferase and Per2-luciferase core clock reporters. Furthermore, we disrupted the circadian clock in skeletal muscle cells by transfecting siRNA targeting CLOCK. Next, we assessed the basal secretion of a large panel of myokines in a circadian manner in the presence or absence of a functional clock. Results Bioluminescence reporter assays revealed that human skeletal myotubes, synchronized in vitro, exhibit a self-sustained circadian rhythm, which was further confirmed by endogenous core clock transcript expression. Moreover, we demonstrate that the basal secretion of IL-6, IL-8 and MCP-1 by synchronized skeletal myotubes has a circadian profile. Importantly, the secretion of IL-6 and several additional myokines was strongly downregulated upon siClock-mediated clock disruption. Conclusions Our study provides for the first time evidence that primary human skeletal myotubes possess a high-amplitude cell-autonomous circadian clock, which could be attenuated. Furthermore, this oscillator plays an important role in the regulation of basal myokine secretion by skeletal myotubes. PMID:26629407
Hoban-Higgins, T. M.; Murakami, D. M.; Tandon, T.; Fuller, C. A.
The circadian timing system (CTS) provides internal and external temporal coordination of an animal's physiology and behavior. In mammals, the generation and coordination of these circadian rhythms is controlled by a neural pacemaker, the suprachiasmatic nucleus (SCN), located within the hypothalamus. The pacemaker is synchronized to the 24 hour day by time cures (zeitgebers) such as the light/dark cycle. When an animal is exposed to an environment without time cues, the circadian rhythms maintain internal temporal coordination, but exhibit a 'free-running' condition in which the period length is determined by the internal pacemaker. Maintenance of internal and external temporal coordination are critical for normal physiological and psychological function in human and non-human primates. Exposure to altered gravitational environments has been shown to affect the amplitude, mean, and timing of circadian rhythms in species ranging from unicellular organisms to man. However, it has not been determined whether altered gravitational fields have a direct effect on the neural pacemaker, or affect peripheral parameters. In previous studies, the ability of a stimulus to phase shift circadian rhythms was used to determine whether a stimulus has a direct effect on the neural pacemaker. The present experiment was performed in order to determine whether acute exposure to a hyperdynamic field could phase shift circadian rhythms.
Fuller, C. A.; Sulzman, F. M.; Moore-Ede, M. C.
Thirteen adult male squirrel monkeys were restrained to a metabolism chair for periods of two or more weeks within an isolation chamber having controlled environmental lighting and ambient temperature. The monkeys were subjected to mild 6-hour cold exposures at all circadian phases of the day. It was found that a prominent circadian rhythm in body temperature, regulated against mild cold exposure, was present in those monkeys synchronized in a 24-hour light-dark cycle. Cold exposures were found to produce decreased core body temperatures when the circadian rhythms were free running or when environmental time indicators were not present. It is concluded that the thermoregulating system depends on the internal synchronization of the circadian time-keeping system.
Vetter, Céline; Fischer, Dorothee; Matera, Joana L; Roenneberg, Till
Sleep loss and circadian disruption-a state of misalignment between physiological functions and imposed sleep/wake behavior-supposedly play central roles in the etiology of shift work-related pathologies [1-4]. Circadian entrainment is, however, highly individual , resulting in different chronotypes [6, 7]. Chronotype in turn modulates the effects of working times: compared to late chronotypes, earlier ones sleep worse and shorter and show higher levels of circadian misalignment during night shifts, while late types experience more sleep and circadian disruption than early types when working morning shifts . To promote sleep and reduce the mismatch between circadian and working time, we implemented a chronotype-adjusted (CTA) shift schedule in a factory. We abolished the most strenuous shifts for extreme chronotypes (i.e., mornings for late chronotypes, nights for early ones) and examined whether sleep duration and quality, social jetlag [9, 10], wellbeing, subjective stress perception, and satisfaction with leisure time improved in this schedule. Intermediate chronotypes (quartiles 2 and 3) served as a control group, still working morning (6:00-14:00), evening (14:00-22:00), and night (22:00-6:00) shifts, with two strenuous shifts (out of twelve per month) replaced by evening ones. We observed a significant increase of self-reported sleep duration and quality, along with increased wellbeing ratings on workdays among extreme chronotypes. The CTA schedule reduced overall social jetlag by 1 hr, did not alter stress levels, and increased satisfaction with leisure time (early types only). Chronotype-based schedules thus can reduce circadian disruption and improve sleep; potential long-term effects on health and economic indicators need to be elucidated in future studies.
Duffy, Jeanne F.; Zitting, Kirsi-Marja; Chinoy, Evan D.
Aging is associated with numerous changes, including changes in sleep timing, duration, and quality. The circadian timing system interacts with a sleep-wake homeostatic system to regulate human sleep, including sleep timing and structure. Here, we review key features of the human circadian timing system, age-related changes in the circadian timing system, and how those changes may contribute to the observed alterations in sleep. PMID:26568120
Agostino, Patricia V.; Golombek, Diego A.; Meck, Warren H.
Neural timing mechanisms range from the millisecond to diurnal, and possibly annual, frequencies. Two of the main processes under study are the interval timer (seconds-to-minute range) and the circadian clock. The molecular basis of these two mechanisms is the subject of intense research, as well as their possible relationship. This article summarizes data from studies investigating a possible interaction between interval and circadian timing and reviews the molecular basis of both mechanisms, including the discussion of the contribution from studies of genetically modified animal models. While there is currently no common neurochemical substrate for timing mechanisms in the brain, circadian modulation of interval timing suggests an interaction of different frequencies in cerebral temporal processes. PMID:22022309
Facer-Childs, Elise; Brandstaetter, Roland
Circadian rhythms, among other factors, have been shown to regulate key physiological processes involved in athletic performance. Personal best performance of athletes in the evening was confirmed across different sports. Contrary to this view, we identified peak performance times in athletes to be different between human "larks" and "owls" (also called "morningness/eveningness types" or "chronotypes" and referred to as circadian phenotypes in this paper), i.e., individuals with well-documented genetic and physiological differences that result in disparities between their biological clocks and how they entrain to exogenous cues, such as the environmental light/dark cycle and social factors. We found time since entrained awakening to be the major predictor of peak performance times, rather than time of day, as well as significant individual performance variations as large as 26% in the course of a day. Our novel approach combining the use of an athlete-specific chronometric test, longitudinal circadian analysis, and physical performance tests to characterize relevant sleep/wake and performance parameters in athletes allows a comprehensive analysis of the link between the circadian system and diurnal performance variation. We establish that the evaluation of an athlete's personal best performance requires consideration of circadian phenotype, performance evaluation at different times of day, and analysis of performance as a function of time since entrained awakening.
Burke, Tina M; Markwald, Rachel R; McHill, Andrew W; Chinoy, Evan D; Snider, Jesse A; Bessman, Sara C; Jung, Christopher M; O'Neill, John S; Wright, Kenneth P
Caffeine's wakefulness-promoting and sleep-disrupting effects are well established, yet whether caffeine affects human circadian timing is unknown. We show that evening caffeine consumption delays the human circadian melatonin rhythm in vivo and that chronic application of caffeine lengthens the circadian period of molecular oscillations in vitro, primarily with an adenosine receptor/cyclic adenosine monophosphate (AMP)-dependent mechanism. In a double-blind, placebo-controlled, ~49-day long, within-subject study, we found that consumption of a caffeine dose equivalent to that in a double espresso 3 hours before habitual bedtime induced a ~40-min phase delay of the circadian melatonin rhythm in humans. This magnitude of delay was nearly half of the magnitude of the phase-delaying response induced by exposure to 3 hours of evening bright light (~3000 lux, ~7 W/m(2)) that began at habitual bedtime. Furthermore, using human osteosarcoma U2OS cells expressing clock gene luciferase reporters, we found a dose-dependent lengthening of the circadian period by caffeine. By pharmacological dissection and small interfering RNA knockdown, we established that perturbation of adenosine receptor signaling, but not ryanodine receptor or phosphodiesterase activity, was sufficient to account for caffeine's effects on cellular timekeeping. We also used a cyclic AMP biosensor to show that caffeine increased cyclic AMP levels, indicating that caffeine influenced a core component of the cellular circadian clock. Together, our findings demonstrate that caffeine influences human circadian timing, showing one way that the world's most widely consumed psychoactive drug affects human physiology.
Lee, Boyoung; Li, Aiqing; Hansen, Katelin F; Cao, Ruifeng; Yoon, Jae Hwa; Obrietan, Karl
The transcriptional feedback circuit, which is at the core of the suprachiasmatic nucleus (SCN) circadian (i.e., 24 h) clock, is tightly coupled to both external entrainment cues, such as light, as well as rhythmic cues that arise on a system-wide level within the SCN. One potential signaling pathway by which these cues are conveyed to the molecular clock is the CREB/CRE transcriptional cascade. In this study, we employed a tetracycline-inducible CREB repressor mouse strain, in which approximately 60% of the SCN neurons express the transgene, to test CREB functionality in the clock and its effects on overt rhythmicity. We show that attenuated CREB signaling in the SCN led to a significant reduction in light-evoked clock entrainment. An examination of circadian timing revealed that CREB repressor mice exhibited normal free-running rhythms in the absence of external lighting cues. However, under conditions of constant light, which typically leads to a lengthening of the circadian period, CREB repressor mice exhibited a dramatic arrhythmic phenotype, which could be reversed with doxycycline. At a cellular level, the repression of CREB led to a significant reduction in both the expression of the circadian clock proteins PERIOD1 and PERIOD2 and the clock output hormones AVP and VIP. Together, these data support the idea that the CRE transcriptional pathway orchestrates transcriptional events that are essential for both the maintenance of SCN timing and light entrainment of the circadian clock.
Mammalian circadian timekeeping arises from a transcription-based feedback loop driven by a set of dedicated clock proteins. At its core, the heterodimeric transcription factor CLOCK:BMAL1 activates expression of Period, Cryptochrome, and Rev-Erb genes, which feed back to repress transcription and create oscillations in gene expression that confer circadian timing cues to cellular processes. The formation of different clock protein complexes throughout this transcriptional cycle helps to establish the intrinsic ∼24 h periodicity of the clock; however, current models of circadian timekeeping lack the explanatory power to fully describe this process. Recent studies confirm the presence of at least three distinct regulatory complexes: a transcriptionally active state comprising the CLOCK:BMAL1 heterodimer with its coactivator CBP/p300, an early repressive state containing PER:CRY complexes, and a late repressive state marked by a poised but inactive, DNA-bound CLOCK:BMAL1:CRY1 complex. In this review, we analyze high-resolution structures of core circadian transcriptional regulators and integrate biochemical data to suggest how remodeling of clock protein complexes may be achieved throughout the 24 h cycle. Defining these detailed mechanisms will provide a foundation for understanding the molecular basis of circadian timing and help to establish new platforms for the discovery of therapeutics to manipulate the clock. PMID:25303119
Harrison, Elizabeth M; Gorman, Michael R
Daily rhythms in mammalian physiology and behavior are generated by a central pacemaker located in the hypothalamic suprachiasmatic nuclei (SCN), the timing of which is set by light from the environment. When the ambient light-dark cycle is shifted, as occurs with travel across time zones, the SCN and its output rhythms must reset or re-entrain their phases to match the new schedule-a sluggish process requiring about 1 day per hour shift. Using a global assay of circadian resetting to 6 equidistant time-zone meridians, we document this characteristically slow and distance-dependent resetting of Syrian hamsters under typical laboratory lighting conditions, which mimic summer day lengths. The circadian pacemaker, however, is additionally entrainable with respect to its waveform (i.e., the shape of the 24-h oscillation) allowing for tracking of seasonally varying day lengths. We here demonstrate an unprecedented, light exposure-based acceleration in phase resetting following 2 manipulations of circadian waveform. Adaptation of circadian waveforms to long winter nights (8 h light, 16 h dark) doubled the shift response in the first 3 days after the shift. Moreover, a bifurcated waveform induced by exposure to a novel 24-h light-dark-light-dark cycle permitted nearly instant resetting to phase shifts from 4 to 12 h in magnitude, representing a 71% reduction in the mismatch between the activity rhythm and the new photocycle. Thus, a marked enhancement of phase shifting can be induced via nonpharmacological, noninvasive manipulation of the circadian pacemaker waveform in a model species for mammalian circadian rhythmicity. Given the evidence of conserved flexibility in the human pacemaker waveform, these findings raise the promise of flexible resetting applicable to circadian disruption in shift workers, frequent time-zone travelers, and any individual forced to adjust to challenging schedules.
Kaiser, Tobias S; Poehn, Birgit; Szkiba, David; Preussner, Marco; Sedlazeck, Fritz J; Zrim, Alexander; Neumann, Tobias; Nguyen, Lam-Tung; Betancourt, Andrea J; Hummel, Thomas; Vogel, Heiko; Dorner, Silke; Heyd, Florian; von Haeseler, Arndt; Tessmar-Raible, Kristin
Organisms use endogenous clocks to anticipate regular environmental cycles, such as days and tides. Natural variants resulting in differently timed behaviour or physiology, known as chronotypes in humans, have not been well characterized at the molecular level. We sequenced the genome of Clunio marinus, a marine midge whose reproduction is timed by circadian and circalunar clocks. Midges from different locations show strain-specific genetic timing adaptations. We examined genetic variation in five C. marinus strains from different locations and mapped quantitative trait loci for circalunar and circadian chronotypes. The region most strongly associated with circadian chronotypes generates strain-specific differences in the abundance of calcium/calmodulin-dependent kinase II.1 (CaMKII.1) splice variants. As equivalent variants were shown to alter CaMKII activity in Drosophila melanogaster, and C. marinus (Cma)-CaMKII.1 increases the transcriptional activity of the dimer of the circadian proteins Cma-CLOCK and Cma-CYCLE, we suggest that modulation of alternative splicing is a mechanism for natural adaptation in circadian timing.
Bee, Leonardo; Marini, Selena; Pontarin, Giovanna; Ferraro, Paola; Costa, Rodolfo; Albrecht, Urs; Celotti, Lucia
The efficiency of Nucleotide Excision Repair (NER)process is crucial for maintaining genomic integrity because in many organisms, including humans, it represents the only system able to repair a wide range of DNA damage. The aim of the work was to investigate whether the efficiency of the repair of photoproducts induced by UV-light is affected by the circadian phase at which irradiation occurred. NER activity has been analyzed in human quiescent fibroblasts (in the absence of the cell cycle effect), in which circadian rhythmicity has been synchronized with a pulse of dexamethasone. Our results demonstrate that both DNA damage induction and repair efficiency are strictly dependent on the phase of the circadian rhythm at which the cells are UV-exposed. Furthermore, the differences observed between fibroblasts irradiated at different circadian times (CTs) are abolished when the clock is obliterated. In addition, we observe that chromatin structure is regulated by circadian rhythmicity. Maximal chromatin relaxation occurred at the same CT when photoproduct formation and removal were highest. Our data suggest that the circadian clock regulates both the DNA sensitivity to UV damage and the efficiency of NER by controlling chromatin condensation mainly through histone acetylation. PMID:25662220
Wright, Kenneth P; McHill, Andrew W; Birks, Brian R; Griffin, Brandon R; Rusterholz, Thomas; Chinoy, Evan D
The electric light is one of the most important human inventions. Sleep and other daily rhythms in physiology and behavior, however, evolved in the natural light-dark cycle , and electrical lighting is thought to have disrupted these rhythms. Yet how much the age of electrical lighting has altered the human circadian clock is unknown. Here we show that electrical lighting and the constructed environment is associated with reduced exposure to sunlight during the day, increased light exposure after sunset, and a delayed timing of the circadian clock as compared to a summer natural 14 hr 40 min:9 hr 20 min light-dark cycle camping. Furthermore, we find that after exposure to only natural light, the internal circadian clock synchronizes to solar time such that the beginning of the internal biological night occurs at sunset and the end of the internal biological night occurs before wake time just after sunrise. In addition, we find that later chronotypes show larger circadian advances when exposed to only natural light, making the timing of their internal clocks in relation to the light-dark cycle more similar to earlier chronotypes. These findings have important implications for understanding how modern light exposure patterns contribute to late sleep schedules and may disrupt sleep and circadian clocks.
Rimmer, D. W.; Boivin, D. B.; Shanahan, T. L.; Kronauer, R. E.; Duffy, J. F.; Czeisler, C. A.
In humans, experimental studies of circadian resetting typically have been limited to lengthy episodes of exposure to continuous bright light. To evaluate the time course of the human endogenous circadian pacemaker's resetting response to brief episodes of intermittent bright light, we studied 16 subjects assigned to one of two intermittent lighting conditions in which the subjects were presented with intermittent episodes of bright-light exposure at 25- or 90-min intervals. The effective duration of bright-light exposure was 31% or 63% compared with a continuous 5-h bright-light stimulus. Exposure to intermittent bright light elicited almost as great a resetting response compared with 5 h of continuous bright light. We conclude that exposure to intermittent bright light produces robust phase shifts of the endogenous circadian pacemaker. Furthermore, these results demonstrate that humans, like other species, exhibit an enhanced sensitivity to the initial minutes of bright-light exposure.
Johnston, Jonathan D; Scheer, Frank A; Turek, Fred W
Chrononutrition is an emerging discipline that builds on the intimate relation between endogenous circadian (24-h) rhythms and metabolism. Circadian regulation of metabolic function can be observed from the level of intracellular biochemistry to whole-organism physiology and even postprandial responses. Recent work has elucidated the metabolic roles of circadian clocks in key metabolic tissues, including liver, pancreas, white adipose, and skeletal muscle. For example, tissue-specific clock disruption in a single peripheral organ can cause obesity or disruption of whole-organism glucose homeostasis. This review explains mechanistic insights gained from transgenic animal studies and how these data are being translated into the study of human genetics and physiology. The principles of chrononutrition have already been demonstrated to improve human weight loss and are likely to benefit the health of individuals with metabolic disease, as well as of the general population. PMID:26980824
Johnston, Jonathan D; Ordovás, José M; Scheer, Frank A; Turek, Fred W
Chrononutrition is an emerging discipline that builds on the intimate relation between endogenous circadian (24-h) rhythms and metabolism. Circadian regulation of metabolic function can be observed from the level of intracellular biochemistry to whole-organism physiology and even postprandial responses. Recent work has elucidated the metabolic roles of circadian clocks in key metabolic tissues, including liver, pancreas, white adipose, and skeletal muscle. For example, tissue-specific clock disruption in a single peripheral organ can cause obesity or disruption of whole-organism glucose homeostasis. This review explains mechanistic insights gained from transgenic animal studies and how these data are being translated into the study of human genetics and physiology. The principles of chrononutrition have already been demonstrated to improve human weight loss and are likely to benefit the health of individuals with metabolic disease, as well as of the general population.
Korenčič, Anja; Košir, Rok; Bordyugov, Grigory; Lehmann, Robert; Rozman, Damjana; Herzel, Hanspeter
Circadian clocks are endogenous oscillators driving daily rhythms in physiology. The cell-autonomous clock is governed by an interlocked network of transcriptional feedback loops. Hundreds of clock-controlled genes (CCGs) regulate tissue specific functions. Transcriptome studies reveal that different organs (e.g. liver, heart, adrenal gland) feature substantially varying sets of CCGs with different peak phase distributions. To study the phase variability of CCGs in mammalian peripheral tissues, we develop a core clock model for mouse liver and adrenal gland based on expression profiles and known cis-regulatory sites. ‘Modulation factors’ associated with E-boxes, ROR-elements, and D-boxes can explain variable rhythms of CCGs, which is demonstrated for differential regulation of cytochromes P450 and 12 h harmonics. By varying model parameters we explore how tissue-specific peak phase distributions can be generated. The central role of E-boxes and ROR-elements is confirmed by analysing ChIP-seq data of BMAL1 and REV-ERB transcription factors. PMID:25048020
Morris, Christopher J.; Purvis, Taylor E.; Hu, Kun; Scheer, Frank A. J. L.
Shift work is a risk factor for hypertension, inflammation, and cardiovascular disease. This increased risk cannot be fully explained by classic risk factors. One of the key features of shift workers is that their behavioral and environmental cycles are typically misaligned relative to their endogenous circadian system. However, there is little information on the impact of acute circadian misalignment on cardiovascular disease risk in humans. Here we show—by using two 8-d laboratory protocols—that short-term circadian misalignment (12-h inverted behavioral and environmental cycles for three days) adversely affects cardiovascular risk factors in healthy adults. Circadian misalignment increased 24-h systolic blood pressure (SBP) and diastolic blood pressure (DBP) by 3.0 mmHg and 1.5 mmHg, respectively. These results were primarily explained by an increase in blood pressure during sleep opportunities (SBP, +5.6 mmHg; DBP, +1.9 mmHg) and, to a lesser extent, by raised blood pressure during wake periods (SBP, +1.6 mmHg; DBP, +1.4 mmHg). Circadian misalignment decreased wake cardiac vagal modulation by 8–15%, as determined by heart rate variability analysis, and decreased 24-h urinary epinephrine excretion rate by 7%, without a significant effect on 24-h urinary norepinephrine excretion rate. Circadian misalignment increased 24-h serum interleukin-6, C-reactive protein, resistin, and tumor necrosis factor-α levels by 3–29%. We demonstrate that circadian misalignment per se increases blood pressure and inflammatory markers. Our findings may help explain why shift work increases hypertension, inflammation, and cardiovascular disease risk. PMID:26858430
Morris, Christopher J; Purvis, Taylor E; Hu, Kun; Scheer, Frank A J L
Shift work is a risk factor for hypertension, inflammation, and cardiovascular disease. This increased risk cannot be fully explained by classic risk factors. One of the key features of shift workers is that their behavioral and environmental cycles are typically misaligned relative to their endogenous circadian system. However, there is little information on the impact of acute circadian misalignment on cardiovascular disease risk in humans. Here we show-by using two 8-d laboratory protocols-that short-term circadian misalignment (12-h inverted behavioral and environmental cycles for three days) adversely affects cardiovascular risk factors in healthy adults. Circadian misalignment increased 24-h systolic blood pressure (SBP) and diastolic blood pressure (DBP) by 3.0 mmHg and 1.5 mmHg, respectively. These results were primarily explained by an increase in blood pressure during sleep opportunities (SBP, +5.6 mmHg; DBP, +1.9 mmHg) and, to a lesser extent, by raised blood pressure during wake periods (SBP, +1.6 mmHg; DBP, +1.4 mmHg). Circadian misalignment decreased wake cardiac vagal modulation by 8-15%, as determined by heart rate variability analysis, and decreased 24-h urinary epinephrine excretion rate by 7%, without a significant effect on 24-h urinary norepinephrine excretion rate. Circadian misalignment increased 24-h serum interleukin-6, C-reactive protein, resistin, and tumor necrosis factor-α levels by 3-29%. We demonstrate that circadian misalignment per se increases blood pressure and inflammatory markers. Our findings may help explain why shift work increases hypertension, inflammation, and cardiovascular disease risk.
Laing, Emma E; Möller-Levet, Carla S; Poh, Norman; Santhi, Nayantara; Archer, Simon N; Dijk, Derk-Jan
Diagnosis and treatment of circadian rhythm sleep-wake disorders both require assessment of circadian phase of the brain's circadian pacemaker. The gold-standard univariate method is based on collection of a 24-hr time series of plasma melatonin, a suprachiasmatic nucleus-driven pineal hormone. We developed and validated a multivariate whole-blood mRNA-based predictor of melatonin phase which requires few samples. Transcriptome data were collected under normal, sleep-deprivation and abnormal sleep-timing conditions to assess robustness of the predictor. Partial least square regression (PLSR), applied to the transcriptome, identified a set of 100 biomarkers primarily related to glucocorticoid signaling and immune function. Validation showed that PLSR-based predictors outperform published blood-derived circadian phase predictors. When given one sample as input, the R(2) of predicted vs observed phase was 0.74, whereas for two samples taken 12 hr apart, R(2) was 0.90. This blood transcriptome-based model enables assessment of circadian phase from a few samples.
Laing, Emma E; Möller-Levet, Carla S; Poh, Norman; Santhi, Nayantara; Archer, Simon N; Dijk, Derk-Jan
Diagnosis and treatment of circadian rhythm sleep-wake disorders both require assessment of circadian phase of the brain’s circadian pacemaker. The gold-standard univariate method is based on collection of a 24-hr time series of plasma melatonin, a suprachiasmatic nucleus-driven pineal hormone. We developed and validated a multivariate whole-blood mRNA-based predictor of melatonin phase which requires few samples. Transcriptome data were collected under normal, sleep-deprivation and abnormal sleep-timing conditions to assess robustness of the predictor. Partial least square regression (PLSR), applied to the transcriptome, identified a set of 100 biomarkers primarily related to glucocorticoid signaling and immune function. Validation showed that PLSR-based predictors outperform published blood-derived circadian phase predictors. When given one sample as input, the R2 of predicted vs observed phase was 0.74, whereas for two samples taken 12 hr apart, R2 was 0.90. This blood transcriptome-based model enables assessment of circadian phase from a few samples. DOI: http://dx.doi.org/10.7554/eLife.20214.001 PMID:28218891
Agostinelli, Forest; Ceglia, Nicholas; Shahbaba, Babak; Sassone-Corsi, Paolo; Baldi, Pierre
Motivation: Circadian rhythms date back to the origins of life, are found in virtually every species and every cell, and play fundamental roles in functions ranging from metabolism to cognition. Modern high-throughput technologies allow the measurement of concentrations of transcripts, metabolites and other species along the circadian cycle creating novel computational challenges and opportunities, including the problems of inferring whether a given species oscillate in circadian fashion or not, and inferring the time at which a set of measurements was taken. Results: We first curate several large synthetic and biological time series datasets containing labels for both periodic and aperiodic signals. We then use deep learning methods to develop and train BIO_CYCLE, a system to robustly estimate which signals are periodic in high-throughput circadian experiments, producing estimates of amplitudes, periods, phases, as well as several statistical significance measures. Using the curated data, BIO_CYCLE is compared to other approaches and shown to achieve state-of-the-art performance across multiple metrics. We then use deep learning methods to develop and train BIO_CLOCK to robustly estimate the time at which a particular single-time-point transcriptomic experiment was carried. In most cases, BIO_CLOCK can reliably predict time, within approximately 1 h, using the expression levels of only a small number of core clock genes. BIO_CLOCK is shown to work reasonably well across tissue types, and often with only small degradation across conditions. BIO_CLOCK is used to annotate most mouse experiments found in the GEO database with an inferred time stamp. Availability and Implementation: All data and software are publicly available on the CircadiOmics web portal: circadiomics.igb.uci.edu/. Contacts: firstname.lastname@example.org or email@example.com Supplementary information: Supplementary data are available at Bioinformatics online. PMID:27307647
Fuller, C. A.; Hoban-Higgins, T. M.; Griffin, D. W.; Murakami, D. M.
The circadian timing system (CTS) is responsible for daily temporal coordination of physiological and behavioral functions both internally and with the external environment. Experiments in altered gravitational environments have revealed changes in circadian rhythms of species ranging from fungi to primates. The altered gravitational environments examined included both the microgravity environment of spaceflight and hyperdynamic environments produced by centrifugation. Acute exposure to altered gravitational environments changed homeostatic parameters such as body temperature. These changes were time of day dependent. Exposure to gravitational alterations of relatively short duration produced changes in both the homeostatic level and the amplitude of circadian rhythms. Chronic exposure to a non-earth level of gravity resulted in changes in the period of the expressed rhythms as well as in the phase relationships between the rhythms and between the rhythms and the external environment. In addition, alterations in gravity appeared to act as a time cue for the CTS. Altered gravity also affected the sensitivity of the pacemaker to other aspects of the environment (i.e., light) and to shifts of time cues. Taken together, these studies lead to the conclusion that the CTS is indeed sensitive to gravity and its alterations. This finding has implications for both basic biology and space medicine.
Fuller, C. A.; Hoban-Higgins, T. M.; Griffin, D. W.; Murakami, D. M.
The circadian timing system (CTS) is responsible for daily temporal coordination of physiological and behavioral functions both internally and with the external environment. Experiments in altered gravitational environments have revealed changes in circadian rhythms of species ranging from fungi to primates. The altered gravitational environments examined included both the microgravity environment of spaceflight and hyperdynamic environments produced by centrifugation. Acute exposure to altered gravitational environments changed homeostatic parameters such as body temperature. These changes were time of day dependent. Exposure to gravitational alterations of relatively short duration produced changes in both the homeostatic level and the amplitude of circadian rhythms. Chronic exposure to a non-earth level of gravity resulted in changes in the period of the expressed rhythms as well as in the phase relationships between the rhythms and between the rhythms and the external environment. In addition, alterations in gravity appeared to act as a time cue for the CTS. Altered gravity also affected the sensitivity of the pacemaker to other aspects of the environment (i.e., light) and to shifts of time cues. Taken together, these studies lead to the conclusion that the CTS is indeed sensitive to gravity and its alterations. This finding has implications for both basic biology and space medicine.
Bonmati-Carrion, Maria Angeles; Hild, Konstanze; Isherwood, Cheryl; Sweeney, Stephen J.; Revell, Victoria L.; Skene, Debra J.; Rol, Maria Angeles; Madrid, Juan Antonio
Intrinsically photosensitive retinal ganglion cells (ipRGCs), whose photopigment melanopsin has a peak of sensitivity in the short wavelength range of the spectrum, constitute a common light input pathway to the olivary pretectal nucleus (OPN), the pupillary light reflex (PLR) regulatory centre, and to the suprachiasmatic nuclei (SCN), the major pacemaker of the circadian system. Thus, evaluating PLR under short wavelength light (λmax ≤ 500 nm) and creating an integrated PLR parameter, as a possible tool to indirectly assess the status of the circadian system, becomes of interest. Nine monochromatic, photon-matched light stimuli (300 s), in 10 nm increments from λmax 420 to 500 nm were administered to 15 healthy young participants (8 females), analyzing: i) the PLR; ii) wrist temperature (WT) and motor activity rhythms (WA), iii) light exposure (L) pattern and iv) diurnal preference (Horne-Östberg), sleep quality (Pittsburgh) and daytime sleepiness (Epworth). Linear correlations between the different PLR parameters and circadian status index obtained from WT, WA and L recordings and scores from questionnaires were calculated. In summary, we found markers of robust circadian rhythms, namely high stability, reduced fragmentation, high amplitude, phase advance and low internal desynchronization, were correlated with a reduced PLR to 460–490 nm wavelengths. Integrated circadian (CSI) and PLR (cp-PLR) parameters are proposed, that also showed an inverse correlation. These results demonstrate, for the first time, the existence of a close relationship between the circadian system robustness and the pupillary reflex response, two non-visual functions primarily under melanopsin-ipRGC input. PMID:27636197
Circadian variability of circulating leptin levels has been well established over the last decade. However, the circadian behavior of leptin in human adipose tissue remains unknown. This also applies to the soluble leptin receptor. We investigated the ex vivo circadian behavior of leptin and its rec...
Moore, Robert Y
The circadian timing system (CTS) in mammals may be defined as a network of interconnected diencephalic structures that regulate the timing of physiological processes and behavioral state. The central feature of the CTS is the suprachiasmatic nucleus (SCN) of the hypothalamus, a self-sustaining circadian oscillator entrained by visual afferents, input from other brain and peripheral oscillators. The SCN was first noted as a distinct component of the hypothalamus during the late nineteenth century and recognized soon after as a uniform feature of the mammalian and lower vertebrate brain. But, as was true for so many brain components identified in that era, its function was unknown and remained so for nearly a century. In the latter half of the twentieth century, numerous tools for studying the brain were developed including neuroanatomical tracing methods, electrophysiological methods including long-term recording in vivo and in vitro, precise methods for producing localized lesions in the brain, and molecular neurobiology. Application of these methods provided a body of data strongly supporting the view that the SCN is a circadian pacemaker in the mammalian brain. This chapter presents an analysis of the functional organization of the SCN as a component of a neural network, the CTS. This network functions as a coordinator of hypothalamic regulatory systems imposing a temporal organization of physiological processes and behavioral state to promote environmental adaptation.
ABSTRACT Circadian clocks are a near-ubiquitous feature of biology, allowing organisms to optimise their physiology to make the most efficient use of resources and adjust behaviour to maximise survival over the solar day. To fulfil this role, circadian clocks require information about time in the external world. This is most reliably obtained by measuring the pronounced changes in illumination associated with the earth's rotation. In mammals, these changes are exclusively detected in the retina and are relayed by direct and indirect neural pathways to the master circadian clock in the hypothalamic suprachiasmatic nuclei. Recent work reveals a surprising level of complexity in this sensory control of the circadian system, including the participation of multiple photoreceptive pathways conveying distinct aspects of visual and/or time-of-day information. In this Review, I summarise these important recent advances, present hypotheses as to the functions and neural origins of these sensory signals, highlight key challenges for future research and discuss the implications of our current knowledge for animals and humans in the modern world. PMID:27307539
Fujihara, Yuko; Kondo, Hisataka; Noguchi, Toshihide; Togari, Akifumi
Circadian rhythms are prevalent in bone metabolism. However, the molecular mechanisms involved are poorly understood. Recently, we suggested that output signals from the suprachiasmatic nucleus (SCN) are transmitted from the master circadian rhythm to peripheral osteoblasts through β-adrenergic and glucocorticoid signaling. In this study, we examined how the master circadian rhythm is transmitted to peripheral osteoclasts and the role of clock gene in osteoclast. Mice were maintained under 12-hour light/dark periods and sacrificed at Zeitgeber times 0, 4, 8, 12, 16 and 20. mRNA was extracted from femur (cancellous bone) and analyzed for the expression of osteoclast-related genes and clock genes. Osteoclast-related genes such as cathepsin K (CTSK) and nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1) showed circadian rhythmicity like clock genes such as period 1 (PER1), PER2 and brain and muscle Arnt-like protein 1 (BMAL1). In an in vitro study, not β-agonist but glucocorticoid treatment remarkably synchronized clock and osteoclast-related genes in cultured osteoclasts. Chromatin immunoprecipitation (ChIP) assay showed the interaction between BMAL1 proteins and promoter region of CTSK and NFATc1. To examine whether endogenous glucocorticoids influence the osteoclast circadian rhythms, mice were adrenalectomized (ADX) and maintained under 12-hour light/dark periods at least two weeks before glucocorticoid injection. A glucocorticoid injection restarted the circadian expression of CTSK and NFATc1 in ADX mice. These results suggest that glucocorticoids mediate circadian timing to peripheral osteoclasts and osteoclast clock contributes to the circadian expression of osteoclast-related genes such as CTSK and NFATc1.
1. Unstimulated whole saliva and parotid saliva stimulated at a constant flow rate of 1·0 ml./min were collected from eight subjects at about 07.00, 11.00, 14.00, 17.00 and 22.00 hr and oral temperature was recorded several times daily for time spans of between 4 and 26 days. A least-squares cosine wave was fitted to the data to test for the presence and characteristics of circadian rhythms. 2. Estimates of mean level, amplitude, acrophase and period were obtained for different components and the results were subjected to cosinor analysis. 3. Unstimulated whole saliva showed significant circadian rhythms in flow rate and in the concentrations of sodium and chloride but not in protein, potassium, calcium, phosphate or urea. 4. Stimulated parotid saliva showed significant circadian rhythms in the concentrations of protein, sodium, potassium, calcium and chloride but not in phosphate or urea 5. Oral temperature showed a circadian rhythm which, like the salivary rhythms, was of a 24.0 hr periodicity. PMID:5016036
Truong, Kimberly K; Lam, Michael T; Grandner, Michael A; Sassoon, Catherine S; Malhotra, Atul
Physiological and cellular functions operate in a 24-hour cyclical pattern orchestrated by an endogenous process known as the circadian rhythm. Circadian rhythms represent intrinsic oscillations of biological functions that allow for adaptation to cyclic environmental changes. Key clock genes that affect the persistence and periodicity of circadian rhythms include BMAL1/CLOCK, Period 1, Period 2, and Cryptochrome. Remarkable progress has been made in our understanding of circadian rhythms and their role in common medical conditions. A critical review of the literature supports the association between circadian misalignment and adverse health consequences in sepsis, obstructive lung disease, obstructive sleep apnea, and malignancy. Circadian misalignment plays an important role in these disease processes and can affect disease severity, treatment response, and survivorship. Normal inflammatory response to acute infections, airway resistance, upper airway collapsibility, and mitosis regulation follows a robust circadian pattern. Disruption of normal circadian rhythm at the molecular level affects severity of inflammation in sepsis, contributes to inflammatory responses in obstructive lung diseases, affects apnea length in obstructive sleep apnea, and increases risk for cancer. Chronotherapy is an underused practice of delivering therapy at optimal times to maximize efficacy and minimize toxicity. This approach has been shown to be advantageous in asthma and cancer management. In asthma, appropriate timing of medication administration improves treatment effectiveness. Properly timed chemotherapy may reduce treatment toxicities and maximize efficacy. Future research should focus on circadian rhythm disorders, role of circadian rhythm in other diseases, and modalities to restore and prevent circadian disruption.
Hut, R A; Van der Zee, E A
This review provides an overview of the interaction between the mammalian cholinergic system and circadian system, and its possible role in time memory. Several studies made clear that circadian (daily) fluctuations in acetylcholine (ACh) release, cholinergic enzyme activity and cholinergic receptor expression varies remarkably between species and even strains. Apparently, cholinergic features can be flexibly adjusted to the needs of a species or strain. Nevertheless, it can be generalized that circadian rhythmicity in the cholinergic system is characterized by high ACh release during the active phase of an individual. During the active phase, the activity of the ACh synthesizing enzyme Choline Acetyltransferase (ChAT) is enhanced, and the activity of the ACh degrading enzyme Acetylcholinesterase (AChE) is reduced. The number of free, unbound and thus available muscarinic acetylcholine receptors (mAChRs) is highest when ACh release is lowest. The cholinergic innervation of the suprachiasmatic nucleus (SCN), the hypothalamic circadian master clock, arises from the cholinergic forebrain and brain stem nuclei. The density of cholinergic fibers and terminals is modest as compared to other hypothalamic nuclei. This is the case for rat, hamster and mouse, three chronobiological model rodent species studied by us. A new finding is that the rat SCN contains some local cholinergic neurons. Hamster SCN contains less cholinergic neurons, whereas the mouse SCN is devoid of such cells. ACh has an excitatory effect on SCN cells (at least in vivo), and functions in close interaction with other neurotransmitters. Originally it was thought that ACh transferred retinal light information to the SCN. This turned out to be wrong. Thereafter, the phase shifting effects of ACh prompted researches to view ACh as an agent for nocturnal clock resetting. It is still not clear, however, what the function consequence is of SCN cholinergic neurotransmission. Here, we postulate the hypothesis
Fuller, Charles A.
All vertebrates have a physiological control system that regulates the timing of the rhythms of their daily life. Dysfunction of this system, the circadian timing system (CTS), adversely affects an organism's ability to respond to environmental challenges and has been linked to physiological and psychological disorders. Exposure to altered gravitational environments (the microgravity of space and hyperdynamic environments produced via centrifugation) produces changes in both the functioning of the CTS and the rhythmic variables it controls. The earliest record of primate rhythms in a spaceflight environment come from Biosatellite III. The subject, a pig-tailed macaque, showed a loss of synchronization of the body temperature rhythm and a fragmented sleep-wake cycle. Alterations in the rhythm of body temperature were also seen in rhesus macaques flown on COSMOS 1514. Squirrel monkeys exposed to chronic centrifugation showed an initial decrease in the amplitude and mean of their body temperature and activity rhythms. In a microgravity environment, Squirrel monkeys on Spacelab-3 showed a reduction in the mean and amplitude of their feeding rhythms. Since 1992 we have had the opportunity to participate on three US/Russian sponsored biosatellite missions on which a total of six juvenile male rhesus macaques were flown. These animals uniformly exhibited delays in the phasing of their temperature rhythms, but not their heart rate or activity rhythms during spaceflight. There was also a tendency for changes in waveform mean and amplitude. These data suggest that the spaceflight environment may have a differential effect on the different oscillators controlling different rhythmic variables. Ongoing studies are examining the effects of +G on the CTS. The long-term presence of humans in space highlights the need for effective countermeasures to gravitational effects on the CTS.
Wright, K. P. Jr; Hughes, R. J.; Kronauer, R. E.; Dijk, D. J.; Czeisler, C. A.
Endogenous circadian clocks are robust regulators of physiology and behavior. Synchronization or entrainment of biological clocks to environmental time is adaptive and important for physiological homeostasis and for the proper timing of species-specific behaviors. We studied subjects in the laboratory for up to 55 days each to determine the ability to entrain the human clock to a weak circadian synchronizing stimulus [scheduled activity-rest cycle in very dim (approximately 1.5 lux in the angle of gaze) light-dark cycle] at three approximately 24-h periods: 23.5, 24.0, and 24.6 h. These studies allowed us to test two competing hypotheses as to whether the period of the human circadian pacemaker is near to or much longer than 24 h. We report here that imposition of a sleep-wake schedule with exposure to the equivalent of candle light during wakefulness and darkness during sleep is usually sufficient to maintain circadian entrainment to the 24-h day but not to a 23.5- or 24.6-h day. Our results demonstrate functionally that, in normally entrained sighted adults, the average intrinsic circadian period of the human biological clock is very close to 24 h. Either exposure to very dim light and/or the scheduled sleep-wake cycle itself can entrain this near-24-h intrinsic period of the human circadian pacemaker to the 24-h day.
Gundel, A; Polyakov, V V; Zulley, J
Numerous anecdotes in the past suggest the concept that sleep disturbances in astronauts occur more frequently during spaceflight than on ground. Such disturbances may be caused in part by exogenous factors, but also an altered physiological state under microgravity may add to reducing sleep quality in a spacecraft. The present investigation aims at a better understanding of possible sleep disturbances under microgravity. For the first time, experiments were conducted in which sleep and circadian regulation could be simultaneously assessed in space. Four astronauts took part in this study aboard the Russian MIR station. Sleep was recorded polygraphically on tape together with body temperature. For a comparison, the same parameters were measured during baseline periods preceding the flights. The circadian phase of body temperature was found to be delayed by about 2 h in space compared with baseline data. A free-run was not observed during the first 30 d in space. Sleep was shorter and more disturbed than on earth. In addition, the structure of sleep was significantly altered. In space, the latency to the first REM episode was shorter, and slow-wave sleep was redistributed from the first to the second sleep cycle. Several mechanisms may be responsible for these alterations in sleep regulation and circadian phase. Most likely, altered circadian zeitgebers on MIR and a deficiency in the process S of Borbély's sleep model cause the observed findings. The change in process S may be related to changes in physical activity as a result of weightlessness.
Abellán, P. Gómez; Santos, C. Gómez; Madrid, J. A.; Milagro, F. I.; Campion, J.; Martínez, J. A.; Luján, J. A.; Ordovás, J. M.; Garaulet, M.
Introduction Circadian variability of circulating leptin levels has been well established over the last decade. However, the circadian behavior of leptin in human adipose tissue remains unknown. This also applies to the soluble leptin receptor. Objective We investigated the ex vivo circadian behavior of leptin and its receptor expression in human adipose tissue (AT). Subjects and methods Visceral and subcutaneous abdominal AT biopsies (n = 6) were obtained from morbid obese women (BMI ≥ 40 kg/m2). Anthropometric variables and fasting plasma glucose, leptin, lipids and lipoprotein concentrations were determined. In order to investigate rhythmic expression pattern of leptin and its receptor, AT explants were cultured during 24-h and gene expression was analyzed at the following times: 08:00, 14:00, 20:00, 02:00 h, using quantitative real-time PCR. Results Leptin expression showed an oscillatory pattern that was consistent with circadian rhythm in cultured AT. Similar patterns were noted for the leptin receptor. Leptin showed its achrophase (maximum expression) during the night, which might be associated to a lower degree of fat accumulation and higher mobilization. When comparing both fat depots, visceral AT anticipated its expression towards afternoon and evening hours. Interestingly, leptin plasma values were associated with decreased amplitude of LEP rhythm. This association was lost when adjusting for waist circumference. Conclusion Circadian rhythmicity has been demonstrated in leptin and its receptor in human AT cultures in a site-specific manner. This new knowledge paves the way for a better understanding of the autocrine/paracrine role of leptin in human AT. PMID:22411388
Pellman, Blake A.; Kim, Earnest; Reilly, Melissa; Kashima, James; Motch, Oleksiy; de la Iglesia, Horacio O.; Kim, Jeansok J.
Virtually all animals have endogenous clock mechanisms that “entrain” to the light-dark (LD) cycle and synchronize psychophysiological functions to optimal times for exploring resources and avoiding dangers in the environment. Such circadian rhythms are vital to human mental health, but it is unknown whether circadian rhythms “entrained” to the LD cycle can be overridden by entrainment to daily recurring threats. We show that unsignaled nocturnal footshock caused rats living in an “ethological” apparatus to switch their natural foraging behavior from the dark to the light phase and that this switch was maintained as a free-running circadian rhythm upon removal of light cues and footshocks. Furthermore, this fear-entrained circadian behavior was dependent on an intact amygdala and suprachiasmatic nucleus. Thus, time-specific fear can act as a non-photic entraining stimulus for the circadian system, and limbic centers encoding aversive information are likely part of the circadian oscillator network that temporally organizes behavior. PMID:26468624
Zeitzer, J. M.; Dijk, D. J.; Kronauer, R.; Brown, E.; Czeisler, C.
Ocular exposure to early morning room light can significantly advance the timing of the human circadian pacemaker. The resetting response to such light has a non-linear relationship to illuminance. The dose-response relationship of the human circadian pacemaker to late evening light of dim to moderate intensity has not been well established. Twenty-three healthy young male and female volunteers took part in a 9 day protocol in which a single experimental light exposure6.5 h in duration was given in the early biological night. The effects of the light exposure on the endogenous circadian phase of the melatonin rhythm and the acute effects of the light exposure on plasma melatonin concentration were calculated. We demonstrate that humans are highly responsive to the phase-delaying effects of light during the early biological night and that both the phase resetting response to light and the acute suppressive effects of light on plasma melatonin follow a logistic dose-response curve, as do many circadian responses to light in mammals. Contrary to expectations, we found that half of the maximal phase-delaying response achieved in response to a single episode of evening bright light ( approximately 9000 lux (lx)) can be obtained with just over 1 % of this light (dim room light of approximately 100 lx). The same held true for the acute suppressive effects of light on plasma melatonin concentrations. This indicates that even small changes in ordinary light exposure during the late evening hours can significantly affect both plasma melatonin concentrations and the entrained phase of the human circadian pacemaker.
Harano, Tomohiro; Miyatake, Takahisa
A positive genetic correlation between periods of circadian rhythm and developmental time supports the hypothesis that circadian clocks are implicated in the timing of development. Empirical evidence for this genetic correlation in insects has been documented in two fly species. In contrast, here we show that there is no evidence of genetic correlation between circadian rhythm and development time in the adzuki bean beetle, Callosobruchus chinensis. This species has variation that is explained by a major gene in the expression and period length of circadian rhythm between strains. In this study, we found genetic variation in development time between the strains. The development time was not covaried with either the incidence or the period length of circadian rhythm among the strains. Crosses between strains suggest that development time is controlled by a polygene. In the F(2) individuals from the crosses, the circadian rhythm is attributable to allelic variation in the major gene. Across the F(2) individuals, development time was not correlated with either the expression or the period length of circadian rhythm. Thus, we found no effects of major genes responsible for variation in the circadian rhythm on development time in C. chinensis. Our findings collectively give no support to the hypothesis that the circadian clock is involved in the regulation of development time in this species.
Fuller, Charles A.; Murakami, Dean M.; Hoban-Higgins, Tana M.; Fuller, Patrick M.; Robinson, Edward L.; Tang, I.-Hsiung
Two fundamental environmental influences that have shaped the evolution of life on Earth are gravity and the cyclic changes occurring over the 24-hour day. Light levels, temperature, and humidity fluctuate over the course of a day, and organisms have adapted to cope with these variations. The primary adaptation has been the evolution of a biological timing system. Previous studies have suggested that this system, named the circadian (circa - about; dies - a day) timing system (CTS), may be sensitive to changes in gravity. The NASA Neurolab spaceflight provided a unique opportunity to evaluate the effects of microgravity on the mammalian CTS. Our experiment tested the hypotheses that microgravity would affect the period, phasing, and light sensitivity of the CTS. Twenty-four Fisher 344 rats were exposed to 16 days of microgravity on the Neurolab STS-90 mission, and 24 Fisher 344 rats were also studied on Earth as one-G controls. Rats were equipped with biotelemetry transmitters to record body temperature (T(sub b)) and heart rate (HR) continuously while the rats moved freely. In each group, 18 rats were exposed to a 24-hour light-dark (LD 12:12) cycle, and six rats were exposed to constant dim red-light (LL). The ability of light to induce a neuronal activity marker (c-fos) in the circadian pacemaker of the brain, the suprachiasmatic nucleus (SCN), was examined in rats studied on flight days two (FD2) and 14 (FD14), and postflight days two (R+1) and 14 (R+13). The flight rats in LD remained synchronized with the LD cycle. However, their T(sub b), rhythm was markedly phase-delayed relative to the LD cycle. The LD flight rats also had a decreased T(sub b) and a change in the waveform of the T(sub b) rhythm compared to controls. Rats in LL exhibited free-running rhythms of T(sub b), and HR; however, the periods were longer in microgravity. Circadian period returned to preflight values after landing. The internal phase angle between rhythms was different in flight than
Ivanov, Plamen Ch; Hu, Kun; Hilton, Michael F; Shea, Steven A; Stanley, H Eugene
The endogenous circadian pacemaker influences key physiologic functions, such as body temperature and heart rate, and is normally synchronized with the sleep/wake cycle. Epidemiological studies demonstrate a 24-h pattern in adverse cardiovascular events with a peak at approximately 10 a.m. It is unknown whether this pattern in cardiac risk is caused by a day/night pattern of behaviors, including activity level and/or influences from the internal circadian pacemaker. We recently found that a scaling index of cardiac vulnerability has an endogenous circadian peak at the circadian phase corresponding to approximately 10 a.m., which conceivably could contribute to the morning peak in cardiac risk. Here, we test whether this endogenous circadian influence on cardiac dynamics is caused by circadian-mediated changes in motor activity or whether activity and heart rate dynamics are decoupled across the circadian cycle. We analyze high-frequency recordings of motion from young healthy subjects during two complementary protocols that decouple the sleep/wake cycle from the circadian cycle while controlling scheduled behaviors. We find that static activity properties (mean and standard deviation) exhibit significant circadian rhythms with a peak at the circadian phase corresponding to 5-9 p.m. ( approximately 9 h later than the peak in the scale-invariant index of heartbeat fluctuations). In contrast, dynamic characteristics of the temporal scale-invariant organization of activity fluctuations (long-range correlations) do not exhibit a circadian rhythm. These findings suggest that endogenous circadian-mediated activity variations are not responsible for the endogenous circadian rhythm in the scale-invariant structure of heartbeat fluctuations and likely do not contribute to the increase in cardiac risk at approximately 10 a.m.
Time-of-day effects in human psychological functioning have been known of since the 1800s. However, outside of research specifically focused on the quantification of circadian rhythms, their study has largely been neglected. Moves toward online data collection now mean that psychological investigations take place around the clock, which affords researchers the ability to easily study time-of-day effects. Recent analyses have shown, for instance, that implicit attitudes have time-of-day effects. The plausibility that these effects indicate circadian rhythms rather than selection effects is considered in the current study. There was little evidence that the time-of-day effects in implicit attitudes shifted appropriately with factors known to influence the time of circadian rhythms. Moreover, even variables that cannot logically show circadian rhythms demonstrated stronger time-of-day effects than did implicit attitudes. Taken together, these results suggest that time-of-day effects in implicit attitudes are more likely to represent processes of selection rather than circadian rhythms, but do not rule out the latter possibility. PMID:27114886
Schofield, Timothy P
Time-of-day effects in human psychological functioning have been known of since the 1800s. However, outside of research specifically focused on the quantification of circadian rhythms, their study has largely been neglected. Moves toward online data collection now mean that psychological investigations take place around the clock, which affords researchers the ability to easily study time-of-day effects. Recent analyses have shown, for instance, that implicit attitudes have time-of-day effects. The plausibility that these effects indicate circadian rhythms rather than selection effects is considered in the current study. There was little evidence that the time-of-day effects in implicit attitudes shifted appropriately with factors known to influence the time of circadian rhythms. Moreover, even variables that cannot logically show circadian rhythms demonstrated stronger time-of-day effects than did implicit attitudes. Taken together, these results suggest that time-of-day effects in implicit attitudes are more likely to represent processes of selection rather than circadian rhythms, but do not rule out the latter possibility.
Hughey, Jacob J.; Butte, Atul J.
The daily timing of mammalian physiology is coordinated by circadian clocks throughout the body. Although measurements of clock gene expression indicate that these clocks in mice are normally in phase with each other, the situation in humans remains unclear. We used publicly available data from five studies, comprising over 1000 samples, to compare the phasing of circadian gene expression in human brain and human blood. Surprisingly, after controlling for age, clock gene expression in brain was phase-delayed by ~8.5 h relative to that of blood. We then examined clock gene expression in two additional human organs and in organs from nine other mammalian species, as well as in the suprachiasmatic nucleus (SCN). In most tissues outside the SCN, the expression of clock gene orthologs showed a phase difference of ~12 h between diurnal and nocturnal species. The exception to this pattern was human brain, whose phasing resembled that of the SCN. Our results highlight the value of a multi-tissue, multi-species meta-analysis, and have implications for our understanding of the human circadian system. PMID:27702781
Buxton, Orfeu M.; Cain, Sean W.; O’Connor, Shawn P.; Porter, James H.; Duffy, Jeanne F.; Wang, Wei; Czeisler, Charles A.; Shea, Steven A.
Epidemiological studies link short sleep and circadian disruption with risk of metabolic syndrome and diabetes. We tested the hypotheses that prolonged sleep restriction with concurrent circadian disruption, as can occur with shift work, impairs glucose regulation and metabolism. Healthy adults spent >5 weeks in controlled laboratory conditions including: sleep extension (baseline), 3-week sleep restriction (5.6 h sleep/24 h) combined with circadian disruption (recurring 28-h ‘days’), and 9-day recovery sleep with circadian re-entrainment. Prolonged sleep restriction with concurrent circadian disruption significantly decreased resting metabolic rate, and increased postprandial plasma via inadequate pancreatic beta cell responsivity; these normalized with 9 days of recovery sleep and stable circadian reentrainment. Thus, in humans, prolonged sleep restriction with concurrent circadian disruption alters metabolism and could increase risk of obesity and diabetes. PMID:22496545
Debarnot, Ursula; Sahraoui, Djafar; Champely, Stephane; Collet, Christian; Guillot, Aymeric
In this study, we examined the effect of circadian modulation on motor imagery (MI) time while also considering the effects of task complexity and duration. The ability to imagine in real time was influenced by circadian modulation in a simple walking condition, with longer MI times in the morning and evening sessions. By contrast, there was no…
Morris, Christopher J.; Yang, Jessica N.; Garcia, Joanna I.; Myers, Samantha; Bozzi, Isadora; Wang, Wei; Buxton, Orfeu M.; Shea, Steven A.; Scheer, Frank A. J. L.
Glucose tolerance is lower in the evening and at night than in the morning. However, the relative contribution of the circadian system vs. the behavioral cycle (including the sleep/wake and fasting/feeding cycles) is unclear. Furthermore, although shift work is a diabetes risk factor, the separate impact on glucose tolerance of the behavioral cycle, circadian phase, and circadian disruption (i.e., misalignment between the central circadian pacemaker and the behavioral cycle) has not been systematically studied. Here we show—by using two 8-d laboratory protocols—in healthy adults that the circadian system and circadian misalignment have distinct influences on glucose tolerance, both separate from the behavioral cycle. First, postprandial glucose was 17% higher (i.e., lower glucose tolerance) in the biological evening (8:00 PM) than morning (8:00 AM; i.e., a circadian phase effect), independent of the behavioral cycle effect. Second, circadian misalignment itself (12-h behavioral cycle inversion) increased postprandial glucose by 6%. Third, these variations in glucose tolerance appeared to be explained, at least in part, by different mechanisms: during the biological evening by decreased pancreatic β-cell function (27% lower early-phase insulin) and during circadian misalignment presumably by decreased insulin sensitivity (elevated postprandial glucose despite 14% higher late-phase insulin) without change in early-phase insulin. We explored possible contributing factors, including changes in polysomnographic sleep and 24-h hormonal profiles. We demonstrate that the circadian system importantly contributes to the reduced glucose tolerance observed in the evening compared with the morning. Separately, circadian misalignment reduces glucose tolerance, providing a mechanism to help explain the increased diabetes risk in shift workers. PMID:25870289
Morris, Christopher J; Yang, Jessica N; Garcia, Joanna I; Myers, Samantha; Bozzi, Isadora; Wang, Wei; Buxton, Orfeu M; Shea, Steven A; Scheer, Frank A J L
Glucose tolerance is lower in the evening and at night than in the morning. However, the relative contribution of the circadian system vs. the behavioral cycle (including the sleep/wake and fasting/feeding cycles) is unclear. Furthermore, although shift work is a diabetes risk factor, the separate impact on glucose tolerance of the behavioral cycle, circadian phase, and circadian disruption (i.e., misalignment between the central circadian pacemaker and the behavioral cycle) has not been systematically studied. Here we show--by using two 8-d laboratory protocols--in healthy adults that the circadian system and circadian misalignment have distinct influences on glucose tolerance, both separate from the behavioral cycle. First, postprandial glucose was 17% higher (i.e., lower glucose tolerance) in the biological evening (8:00 PM) than morning (8:00 AM; i.e., a circadian phase effect), independent of the behavioral cycle effect. Second, circadian misalignment itself (12-h behavioral cycle inversion) increased postprandial glucose by 6%. Third, these variations in glucose tolerance appeared to be explained, at least in part, by different mechanisms: during the biological evening by decreased pancreatic β-cell function (27% lower early-phase insulin) and during circadian misalignment presumably by decreased insulin sensitivity (elevated postprandial glucose despite 14% higher late-phase insulin) without change in early-phase insulin. We explored possible contributing factors, including changes in polysomnographic sleep and 24-h hormonal profiles. We demonstrate that the circadian system importantly contributes to the reduced glucose tolerance observed in the evening compared with the morning. Separately, circadian misalignment reduces glucose tolerance, providing a mechanism to help explain the increased diabetes risk in shift workers.
Gyllenstrand, Niclas; Karlgren, Anna; Clapham, David; Holm, Karl; Hall, Anthony; Gould, Peter D; Källman, Thomas; Lagercrantz, Ulf
The identification and cloning of full-length homologs of circadian clock genes from Picea abies represent a first step to study the function and evolution of the circadian clock in gymnosperms. Phylogenetic analyses suggest that the sequences of key circadian clock genes are conserved between angiosperms and gymnosperms. though fewer homologous copies were found for most gene families in P. abies. We detected diurnal cycling of circadian clock genes in P. abies using quantitative real-time PCR; however, cycling appeared to be rapidly dampened under free-running conditions. Given the unexpected absence of transcriptional cycling during constant conditions, we employed a complementary method to assay circadian rhythmic outputs and measured delayed fluorescence in seedlings of Norway spruce. Neither of the two approaches to study circadian rhythms in Norway spruce could detect robust ∼24 h cycling behavior under constant conditions. These data suggest gene conservation but fundamental differences in clock function between gymnosperms and other plant taxa.
Indic, Premananda; Forger, Daniel B.; St. Hilaire, Melissa A.; Dean, Dennis A.; Brown, Emery N.; Kronauer, Richard E.; Klerman, Elizabeth B.; Jewett, Megan E.
At an organism level, the mammalian circadian pacemaker is a two-dimensional system. For these two dimensions, phase (relative timing) and amplitude of the circadian pacemaker are commonly used. Both the phase and the amplitude (A) of the human circadian pacemaker can be observed within multiple physiological measures—including plasma cortisol, plasma melatonin, and core body temperature (CBT)—all of which are also used as markers of the circadian system. Although most previous work has concentrated on changes in phase of the circadian system, critically timed light exposure can significantly reduce the amplitude of the pacemaker. The rate at which the amplitude recovers to its equilibrium level after reduction can have physiological significance. Two mathematical models that describe the phase and amplitude dynamics of the pacemaker have been reported. These models are essentially equivalent in predictions of phase and in predictions of amplitude recovery for small changes from an equilibrium value (A = 1), but are markedly different in the prediction of recovery rates when A < 0.6. To determine which dynamic model best describes the amplitude recovery observed in experimental data; both models were fit to CBT data using a maximum likelihood procedure and compared using Akaike’s Information Criterion (AIC). For all subjects, the model with the lower recovery rate provided a better fit to data in terms of AIC, supporting evidence that the amplitude recovery of the endogenous pacemaker is slow at low amplitudes. Experiments derived from model predictions are proposed to test the influence of low amplitude recovery on the physiological and neurobehavioral functions. PMID:16147894
Zhdanova, Irina V; Rogers, Jeffrey; González-Martínez, Janis; Farrer, Lindsay A
The circadian clock disorders in humans remain poorly understood. However, their impact on the development and progression of major human conditions, from cancer to insomnia, metabolic or mental illness becomes increasingly apparent. Addressing human circadian disorders in animal models is, in part, complicated by inverse temporal relationship between the core clock and specific physiological or behavioral processes in diurnal and nocturnal animals. Major advantages of a macaque model for translational circadian research, as a diurnal vertebrate phylogenetically close to humans, are further emphasized by the discovery of the first familial circadian disorder in non-human primates among the rhesus monkeys originating from Cayo Santiago. The remarkable similarity of their pathological phenotypes to human Delayed Sleep Phase Disorder (DSPD), high penetrance of the disorder within one branch of the colony and the large number of animals available provide outstanding opportunities for studying the mechanisms of circadian disorders, their impact on other pathological conditions, and for the development of novel and effective treatment strategies.
Czeisler, C. A.; Klerman, E. B.
Daily oscillations characterize the release of nearly every hormone. The circadian pacemaker, located in the suprachiasmatic nucleus of the hypothalamus, generates circadian, approximately 24-hour rhythms in many physiologic functions. However, the observed hormonal oscillations do not simply reflect the output of this internal clock. Instead, daily hormonal profiles are the product of a complex interaction between the output of the circadian pacemaker, periodic changes in behavior, light exposure, neuroendocrine feedback mechanisms, gender, age, and the timing of sleep and wakefulness. The interaction of these factors can affect hormonal secretory pulse frequency and amplitude, with each endocrine system differentially affected by these factors. This chapter examines recent advances in understanding the effects on endocrine rhythms of a number of these factors. Sleep exerts a profound effect on endocrine secretion. Sleep is a dynamic process that is characterized by periodic changes in electrophysiologic activity. These electrophysiologic changes, which are used to mark the state and depth of sleep, are associated with periodic, short-term variations in hormonal levels. The secretion of hormones such as renin and human growth hormone are strongly influenced by sleep or wake state, while melatonin and cortisol levels are relatively unaffected by sleep or wake state. In addition, sleep is associated with changes in posture, behavior, and light exposure, each of which is known to affect endocrine secretion. Furthermore, the tight concordance of habitual sleep and wake times with certain circadian phases has made it difficult to distinguish sleep and circadian effects on these hormones. Specific protocols, designed to extract circadian and sleep information semi-independently, have been developed and have yielded important insights into the effects of these regulatory processes. These results may help to account for changes in endocrine rhythms observed in circadian
Rea, Mark S; Figueiro, Mariana G
Although circadian disruption is an accepted term, little has been done to develop methods to quantify the degree of disruption or entrainment individual organisms actually exhibit in the field. A variety of behavioral, physiological and hormonal responses vary in amplitude over a 24-h period and the degree to which these circadian rhythms are synchronized to the daily light-dark cycle can be quantified with a technique known as phasor analysis. Several studies have been carried out using phasor analysis in an attempt to measure circadian disruption exhibited by animals and by humans. To perform these studies, species-specific light measurement and light delivery technologies had to be developed based upon a fundamental understanding of circadian phototransduction mechanisms in the different species. When both nocturnal rodents and diurnal humans, experienced different species-specific light-dark shift schedules, they showed, based upon phasor analysis of the light-dark and activity-rest patterns, similar levels of light-dependent circadian disruption. Indeed, both rodents and humans show monotonically increasing and quantitatively similar levels of light-dependent circadian disruption with increasing shift-nights per week. Thus, phasor analysis provides a method for quantifying circadian disruption in the field and in the laboratory as well as a bridge between ecological measurements of circadian entrainment in humans and parametric studies of circadian disruption in animal models, including nocturnal rodents.
Späti, Jakub; Aritake, Sayaka; Meyer, Andrea H.; Kitamura, Shingo; Hida, Akiko; Higuchi, Shigekazu; Moriguchi, Yoshiya; Mishima, Kazuo
Short-term interval timing i.e., perception and action relating to durations in the seconds range, has been suggested to display time-of-day as well as wake dependent fluctuations due to circadian and sleep-homeostatic changes to the rate at which an underlying pacemaker emits pulses; pertinent human data being relatively sparse and lacking in consistency however, the phenomenon remains elusive and its mechanism poorly understood. To better characterize the putative circadian and sleep-homeostatic effects on interval timing and to assess the ability of a pacemaker-based mechanism to account for the data, we measured timing performance in eighteen young healthy male subjects across two epochs of sustained wakefulness of 38.67 h each, conducted prior to (under entrained conditions) and following (under free-running conditions) a 28 h sleep-wake schedule, using the methods of duration estimation and duration production on target intervals of 10 and 40 s. Our findings of opposing oscillatory time courses across both epochs of sustained wakefulness that combine with increasing and, respectively, decreasing, saturating exponential change for the tasks of estimation and production are consistent with the hypothesis that a pacemaker emitting pulses at a rate controlled by the circadian oscillator and increasing with time awake determines human short-term interval timing; the duration-specificity of this pattern is interpreted as reflecting challenges to maintaining stable attention to the task that progressively increase with stimulus magnitude and thereby moderate the effects of pacemaker-rate changes on overt behavior. PMID:25741253
Chen, Cho-Yi; Logan, Ryan W.; Ma, Tianzhou; Lewis, David A.; Tseng, George C.; Sibille, Etienne; McClung, Colleen A.
With aging, significant changes in circadian rhythms occur, including a shift in phase toward a “morning” chronotype and a loss of rhythmicity in circulating hormones. However, the effects of aging on molecular rhythms in the human brain have remained elusive. Here, we used a previously described time-of-death analysis to identify transcripts throughout the genome that have a significant circadian rhythm in expression in the human prefrontal cortex [Brodmann’s area 11 (BA11) and BA47]. Expression levels were determined by microarray analysis in 146 individuals. Rhythmicity in expression was found in ∼10% of detected transcripts (P < 0.05). Using a metaanalysis across the two brain areas, we identified a core set of 235 genes (q < 0.05) with significant circadian rhythms of expression. These 235 genes showed 92% concordance in the phase of expression between the two areas. In addition to the canonical core circadian genes, a number of other genes were found to exhibit rhythmic expression in the brain. Notably, we identified more than 1,000 genes (1,186 in BA11; 1,591 in BA47) that exhibited age-dependent rhythmicity or alterations in rhythmicity patterns with aging. Interestingly, a set of transcripts gained rhythmicity in older individuals, which may represent a compensatory mechanism due to a loss of canonical clock function. Thus, we confirm that rhythmic gene expression can be reliably measured in human brain and identified for the first time (to our knowledge) significant changes in molecular rhythms with aging that may contribute to altered cognition, sleep, and mood in later life. PMID:26699485
Akacem, Lameese D.; Wright, Kenneth P.; LeBourgeois, Monique K.
Light exposure and sleep timing are two factors that influence inter-individual variability in the timing of the human circadian clock. The aim of this study was to quantify the degree to which evening light exposure predicts variance in circadian timing over and above bedtime alone in preschool children. Participants were 21 children ages 4.5–5.0 years (4.7 ± 0.2 years; 9 females). Children followed their typical sleep schedules for 4 days during which time they wore a wrist actigraph to assess sleep timing and a pendant light meter to measure minute-by-minute illuminance levels in lux. On the 5th day, children participated in an in-home dim-light melatonin onset (DLMO) assessment. Light exposure in the 2 h before bedtime was averaged and aggregated across the 4 nights preceding the DLMO assessment. Mean DLMO and bedtime were 19:22 ± 01:04 and 20:07 ± 00:46, respectively. Average evening light exposure was 710.1 ± 1418.2 lux. Children with later bedtimes (lights-off time) had more delayed melatonin onset times (r=0.61, p=0.002). Evening light exposure was not independently associated with DLMO (r=0.32, p=0.08); however, a partial correlation between evening light exposure and DLMO when controlling for bedtime yielded a positive correlation (r=0.46, p=0.02). Bedtime explained 37.3% of the variance in the timing of DLMO, and evening light exposure accounted for an additional 13.3% of the variance. These findings represent an important step in understanding factors that influence circadian phase in preschool-age children and have implications for understanding a modifiable pathway that may underlie late sleep timing and the development of evening settling problems in early childhood. PMID:28042611
Duffy, J. F.; Dijk, D. J.; Klerman, E. B.; Czeisler, C. A.
The contribution of the circadian timing system to the age-related advance of sleep-wake timing was investigated in two experiments. In a constant routine protocol, we found that the average wake time and endogenous circadian phase of 44 older subjects were earlier than that of 101 young men. However, the earlier circadian phase of the older subjects actually occurred later relative to their habitual wake time than it did in young men. These results indicate that an age-related advance of circadian phase cannot fully account for the high prevalence of early morning awakening in healthy older people. In a second study, 13 older subjects and 10 young men were scheduled to a 28-h day, such that they were scheduled to sleep at many circadian phases. Self-reported awakening from scheduled sleep episodes and cognitive throughput during the second half of the wake episode varied markedly as a function of circadian phase in both groups. The rising phase of both rhythms was advanced in the older subjects, suggesting an age-related change in the circadian regulation of sleep-wake propensity. We hypothesize that under entrained conditions, these age-related changes in the relationship between circadian phase and wake time are likely associated with self-selected light exposure at an earlier circadian phase. This earlier exposure to light could account for the earlier clock hour to which the endogenous circadian pacemaker is entrained in older people and thereby further increase their propensity to awaken at an even earlier time.
Monk, T. H.; Buysse, D. J.; Reynolds, C. F. 3rd; Berga, S. L.; Jarrett, D. B.; Begley, A. E.; Kupfer, D. J.
This study explored the relationship between circadian performance rhythms and rhythms in rectal temperature, plasma cortisol, plasma melatonin, subjective alertness and well-being. Seventeen healthy young adults were studied under 36 h of 'unmasking' conditions (constant wakeful bedrest, temporal isolation, homogenized 'meals') during which rectal temperatures were measured every minute, and plasma cortisol and plasma melatonin measured every 20 min. Hourly subjective ratings of global vigour (alertness) and affect (well-being) were obtained followed by one of two performance batteries. On odd-numbered hours performance (speed and accuracy) of serial search, verbal reasoning and manual dexterity tasks was assessed. On even-numbered hours, performance (% hits, response speed) was measured at a 25-30 min visual vigilance task. Performance of all tasks (except search accuracy) showed a significant time of day variation usually with a nocturnal trough close to the trough in rectal temperature. Performance rhythms appeared not to reliably differ with working memory load. Within subjects, predominantly positive correlations emerged between good performance and higher temperatures and better subjective alertness; predominantly negative correlations between good performance and higher plasma levels of cortisol and melatonin. Temperature and cortisol rhythms correlated with slightly more performance measures (5/7) than did melatonin rhythms (4/7). Global vigour correlated about as well with performance (5/7) as did temperature, and considerably better than global affect (1/7). In conclusion: (1) between-task heterogeneity in circadian performance rhythms appeared to be absent when the sleep/wake cycle was suspended; (2) temperature (positively), cortisol and melatonin (negatively) appeared equally good as circadian correlates of performance, and (3) subjective alertness correlated with performance rhythms as well as (but not better than) body temperature, suggesting that
Adiponectin is one of the most clinically relevant cytokines associated with obesity. However, circadian rhythmicity of adiponectin in human adipose tissue (AT) has not been analyzed. To assess whether the mRNA levels of adiponectin and its receptors (ADIPOR1 and ADIPOR2) might show daily circadian ...
Klerman, E. B.; Dijk, D. J.; Kronauer, R. E.; Czeisler, C. A.
The sensitivity of the human circadian system to light has been the subject of considerable debate. Using computer simulations of a recent quantitative model for the effects of light on the human circadian system, we investigated these effects of light during different experimental protocols. The results of the simulations indicate that the nonuniform distribution over the circadian cycle of exposure to ordinary room light seen in classical free-run studies, in which subjects select their exposure to light and darkness, can result in an observed period of approximately 25 h, even when the intrinsic period of the subject's endogenous circadian pacemaker is much closer to 24 h. Other simulation results suggest that accurate assessment of the true intrinsic period of the human circadian pacemaker requires low ambient light intensities (approximately 10-15 lx) during scheduled wake episodes, desynchrony of the imposed light-dark cycle from the endogenous circadian oscillator, and a study length of at least 20 days. Although these simulations await further experimental substantiation, they highlight the sensitivity to light of the human circadian system and the potential confounding influence of light on the assessment of the intrinsic period of the circadian pacemaker.
E. A twin study of the circadian and pulsatile variations of plasma cortisol: evidence for genetic control of the human circadian clock. Am J Physiol...Conference on Chronobiology , Irsee, Germany, September 29-October 4, 1991. Van Cauter, E. Effects of sleep on glucose regulation. Invited Speaker. Founding
Dewan, Karuna; Benloucif, Susan; Reid, Kathryn; Wolfe, Lisa F.; Zee, Phyllis C.
Study Objectives: To evaluate the effect of increasing the intensity and/or duration of exposure on light-induced changes in the timing of the circadian clock of humans. Design: Multifactorial randomized controlled trial, between and within subject design Setting: General Clinical Research Center (GCRC) of an academic medical center Participants: 56 healthy young subjects (20-40 years of age) Interventions: Research subjects were admitted for 2 independent stays of 4 nights/3 days for treatment with bright or dim-light (randomized order) at a time known to induce phase delays in circadian timing. The intensity and duration of the bright light were determined by random assignment to one of 9 treatment conditions (duration of 1, 2, or 3 hours at 2000, 4000, or 8000 lux). Measurements and Results: Treatment-induced changes in the dim light melatonin onset (DLMO) and dim light melatonin offset (DLMOff) were measured from blood samples collected every 20-30 min throughout baseline and post-treatment nights. Comparison by multi-factor analysis of variance (ANOVA) of light-induced changes in the time of the circadian melatonin rhythm for the 9 conditions revealed that changing the duration of the light exposure from 1 to 3 h increased the magnitude of light-induced delays. In contrast, increasing from moderate (2,000 lux) to high (8,000 lux) intensity light did not alter the magnitude of phase delays of the circadian melatonin rhythm. Conclusions: Results from the present study suggest that for phototherapy of circadian rhythm sleep disorders in humans, a longer period of moderate intensity light may be more effective than a shorter exposure period of high intensity light. Citation: Dewan K; Benloucif S; Reid K; Wolfe LF; Zee PC. Light-induced changes of the circadian clock of humans: increasing duration is more effective than increasing light intensity. SLEEP 2011;34(5):593-599. PMID:21532952
Ivanov, Plamen Ch.
Cardiovascular vulnerability displays a 24-hour pattern with a peak between 9AM and 11AM. This daily pattern in cardiac risk is traditionally attributed to external factors including activity levels and sleep-wake cycles. However,influences from the endogenous circadian pacemaker independent from behaviors may also affect cardiac control. We investigate heartbeat dynamics in healthy subjects recorded throughout a 10-day protocol wherein the sleep/wake and behavior cycles are desynchronized from the endogenous circadian cycle,enabling assessment of circadian factors while controlling for behavior-related factors. We demonstrate that the scaling exponent characterizing temporal correlations in heartbeat dynamics over multiple time scales does exhibit a significant circadian rhythm with a sharp peak at the circadian phase corresponding to the period 9-11AM, and that this rhythm is independent from scheduled behaviors and mean heart rate. Our findings of strong circadian rhythms in the multi-scale heartbeat dynamics of healthy young subjects indicate that the underlying mechanism of cardiac regulation is strongly influenced by the endogenous circadian pacemaker. A similar circadian effect in vulnerable individuals with underlying cardiovascular disease would contribute to the morning peak of adverse cardiac events observed in epidemiological studies.
Baumann, Anja; Feilhauer, Katharina; Bischoff, Stephan C; Froy, Oren; Lorentz, Axel
Symptoms of allergic attacks frequently exhibit diurnal variations. Accordingly, we could recently demonstrate that mast cells and eosinophils - known as major effector cells of allergic diseases - showed an intact circadian clock. Here, we analyzed the role of the circadian clock in the functionality of mast cells and eosinophils. Human intestinal mast cells (hiMC) were isolated from intestinal mucosa; human eosinophils were isolated from peripheral blood. HiMC and eosinophils were synchronized by dexamethasone before stimulation every 4h around the circadian cycle by FcɛRI crosslinking or fMLP, respectively. Signaling molecule activation was examined using Western blot, mRNA expression by real-time RT-PCR, and mediator release by multiplex analysis. CXCL8 and CCL2 were expressed and released in a circadian manner by both hiMC and eosinophils in response to activation. Moreover, phosphorylation of ERK1/2, known to be involved in activation of hiMC and eosinophils, showed circadian rhythms in both cell types. Interestingly, all clock genes hPer1, hPer2, hCry1, hBmal1, and hClock were expressed in a similar circadian pattern in activated and unstimulated cells indicating that the local clock controls hiMC and eosinophils and subsequently allergic reactions but not vice versa.
Ho Mien, Ivan; Chua, Eric Chern-Pin; Lau, Pauline; Tan, Luuan-Chin; Lee, Ivan Tian-Guang; Yeo, Sing-Chen; Tan, Sara Shuhui; Gooley, Joshua J.
Exposure to light is a major determinant of sleep timing and hormonal rhythms. The role of retinal cones in regulating circadian physiology remains unclear, however, as most studies have used light exposures that also activate the photopigment melanopsin. Here, we tested the hypothesis that exposure to alternating red light and darkness can enhance circadian resetting responses in humans by repeatedly activating cone photoreceptors. In a between-subjects study, healthy volunteers (n = 24, 21–28 yr) lived individually in a laboratory for 6 consecutive days. Circadian rhythms of melatonin, cortisol, body temperature, and heart rate were assessed before and after exposure to 6 h of continuous red light (631 nm, 13 log photons cm−2 s−1), intermittent red light (1 min on/off), or bright white light (2,500 lux) near the onset of nocturnal melatonin secretion (n = 8 in each group). Melatonin suppression and pupillary constriction were also assessed during light exposure. We found that circadian resetting responses were similar for exposure to continuous versus intermittent red light (P = 0.69), with an average phase delay shift of almost an hour. Surprisingly, 2 subjects who were exposed to red light exhibited circadian responses similar in magnitude to those who were exposed to bright white light. Red light also elicited prolonged pupillary constriction, but did not suppress melatonin levels. These findings suggest that, for red light stimuli outside the range of sensitivity for melanopsin, cone photoreceptors can mediate circadian phase resetting of physiologic rhythms in some individuals. Our results also show that sensitivity thresholds differ across non-visual light responses, suggesting that cones may contribute differentially to circadian resetting, melatonin suppression, and the pupillary light reflex during exposure to continuous light. PMID:24797245
Burgess, Helen J; Rizvydeen, Muneer; Fogg, Louis F; Keshavarzian, Ali
Central circadian timing influences mental and physical health. Research in nocturnal rodents has demonstrated that when alcohol is consumed, it reaches the central hypothalamic circadian pacemaker (suprachiasmatic nuclei) and can directly alter circadian phase shifts to light. In two separate studies, we examined, for the first time, the effects of a single dose of alcohol on circadian phase advances and phase delays to light in humans. Two 23-day within-subjects placebo-controlled counterbalanced design studies were conducted. Both studies consisted of 6 days of fixed baseline sleep to stabilize circadian timing, a 2-day laboratory session, a 6-day break, and a repeat of 6 days of fixed sleep and a 2-day laboratory session. In the phase advance study (n= 10 light drinkers, 24-45 yr), the laboratory sessions consisted of a baseline dim light phase assessment, sleep episode, alcohol (0.6 g/kg) or placebo, 2-h morning bright light pulse, and final phase assessment. In the phase-delay study (n= 14 light drinkers, 22-44 yr), the laboratory sessions consisted of a baseline phase assessment, alcohol (0.8 g/kg) or placebo, 2-h late night bright light pulse, sleep episode, and final phase assessment. In both studies, alcohol either increased or decreased the observed phase shifts to light (interaction P≥ 0.46), but the effect of alcohol vs. placebo on phase shifts to light was always on average smaller than 30 min. Thus, no meaningful effects of a single dose of alcohol vs. placebo on circadian phase shifts to light in humans were observed.
Fuller, C. A.
The physiological system responsible for the temporal coordination of an organism is the circadian timing system (CTS). This system provides two forms of temporal coordination. First, the CTS provides for synchronization of the organism with the 24 hour period of the external environment. This synchronization of the organism with the environment is termed entrainment. Second, this system also provides for internal coordination of the various physiological, behavioral, and biochemical events within the organism. When either of these two temporal relationships are disturbed, various dysfunctions can be manifest within the organism. Homeostatic capacity of other physiological systems may be reduced. Performance is decreased and sleep disorders, mental health impairment (e.g., depression), jet lag syndrome, and shift work maladaptation frequently occur. Over the last several years, several studies have evaluated the potential influence of gravity on this physiological control system by examining changes in rhythmic characteristics of organisms exposed to altered gravitational environments. The altered gravitational environments have included the microgravity of spaceflight as well as hyperdynamic fields produced via centrifugation.
Reppert, S M
The circadian clock has a vital role in monarch butterfly (Danaus plexippus) migration by providing the timing component of time-compensated sun compass orientation, which contributes to navigation to the overwintering grounds. The location of circadian clock cells in monarch brain has been identified in the dorsolateral protocerebrum (pars lateralis); these cells express PERIOD, TIMELESS, and a Drosophila-like cryptochrome designated CRY1. Monarch butterflies, like all other nondrosophilid insects examined so far, express a second cry gene (designated insect CRY2) that encodes a vertebrate-like CRY that is also expressed in pars lateralis. An ancestral circadian clock mechanism has been defined in monarchs, in which CRY1 functions as a blue light photoreceptor for photic entrainment, whereas CRY2 functionswithin the clockwork as themajor transcriptional repressor of an intracellular negative transcriptional feedback loop. A CRY1-staining neural pathway has been identified that may connect the circadian (navigational) clock to polarized light input important for sun compass navigation, and a CRY2-positive neural pathway has been discovered that may communicate circadian information directly from the circadian clock to the central complex, the likely site of the sun compass. The monarch butterfly may thus use the CRY proteins as components of the circadian mechanism and also as output molecules that connect the clock to various aspects of the sun compass apparatus.
Debarnot, Ursula; Sahraoui, Djafar; Champely, Stéphane; Collet, Christian; Guillot, Aymeric
In this study, we examined the effect of circadian modulation on motor imagery (MI) time while also considering the effects of task complexity and duration. The ability to imagine in real time was influenced by circadian modulation in a simple walking condition, with longer MI times in the morning and evening sessions. By contrast, there was no effect of circadian rhythm in the complex, short or long walking conditions. We concluded that motor imagery time is modulated during the course of the day, but the effect of task difficulty is stronger than circadian modulation in altering the temporal congruence between physical practice and MI performance. Practical applications in motor learning and rehabilitation are discussed.
Barnard, Alun R; Nolan, Patrick M
Progress in unravelling the cellular and molecular basis of mammalian circadian regulation over the past decade has provided us with new avenues through which we can explore central nervous system disease. Deteriorations in measurable circadian output parameters, such as sleep/wake deficits and dysregulation of circulating hormone levels, are common features of most central nervous system disorders. At the core of the mammalian circadian system is a complex of molecular oscillations within the hypothalamic suprachiasmatic nucleus. These oscillations are modifiable by afferent signals from the environment, and integrated signals are subsequently conveyed to remote central neural circuits where specific output rhythms are regulated. Mutations in circadian genes in mice can disturb both molecular oscillations and measurable output rhythms. Moreover, systematic analysis of these mutants indicates that they can express an array of abnormal behavioural phenotypes that are intermediate signatures of central nervous system disorders. Furthermore, the response of these mutants to psychoactive drugs suggests that clock genes can modify a number of the brain's critical neurotransmitter systems. This evidence has led to promising investigations into clock gene polymorphisms in psychiatric disease. Preliminary indications favour the systematic investigation of the contribution of circadian genes to central nervous system disease.
Kronauer, R E; Forger, D B; Jewett, M E
The authors' previous models have been able to describe accurately the effects of extended (approximately 5 h) bright-light (>4000 lux) stimuli on the phase and amplitude of the human circadian pacemaker, but they are not sufficient to represent the surprising human sensitivity to both brief pulses of bright light and light of more moderate intensities. Therefore, the authors have devised a new model in which a dynamic stimulus processor (Process L) intervenes between the light stimuli and the traditional representation of the circadian pacemaker as a self-sustaining limit-cycle oscillator (Process P). The overall model incorporating Process L and Process P is intended to allow the prediction of phase shifts to photic stimuli of any temporal pattern (extended and brief light episodes) and any light intensity in the photopic range. Two time constants emerge in the Process L model: the characteristic duration for necessary bright-light pulses to achieve their full effect (5-10 min) and the characteristic stimulus-free (dark) interval that can be tolerated without incurring an excessive penalty in phase shifting (30-80 min). The effect of reducing light intensity is incorporated in Process L as an extension of the time necessary for the light pulse to be fully realized (a power-law relation between time and intensity). This new model generates a number of new testable hypotheses, including the surprising prediction that 24-h cycles consisting of 8 h of darkness and 16 h of only approximately 3.5 lux would be capable of entraining a large fraction of the adult population (approximately 45%). Experimental data on the response of the human circadian system to lower light intensities and briefer stimuli are needed to allow for further refinement and validation of the model proposed here.
Muto, Vincenzo; Jaspar, Mathieu; Meyer, Christelle; Kussé, Caroline; Chellappa, Sarah L; Degueldre, Christian; Balteau, Evelyne; Shaffii-Le Bourdiec, Anahita; Luxen, André; Middleton, Benita; Archer, Simon N; Phillips, Christophe; Collette, Fabienne; Vandewalle, Gilles; Dijk, Derk-Jan; Maquet, Pierre
Human performance is modulated by circadian rhythmicity and homeostatic sleep pressure. Whether and how this interaction is represented at the regional brain level has not been established. We quantified changes in brain responses to a sustained-attention task during 13 functional magnetic resonance imaging sessions scheduled across the circadian cycle, during 42 hours of wakefulness and after recovery sleep, in 33 healthy participants. Cortical responses showed significant circadian rhythmicity, the phase of which varied across brain regions. Cortical responses also significantly decreased with accrued sleep debt. Subcortical areas exhibited primarily a circadian modulation that closely followed the melatonin profile. These findings expand our understanding of the mechanisms involved in maintaining cognition during the day and its deterioration during sleep deprivation and circadian misalignment.
Summary of recent advances Plants possess a circadian clock that enables them to coordinate internal biological events with external daily changes. Recent studies in Arabidopsis revealed that tissue specific clock components exist and that the clock network architecture also varies within different organs. These findings indicate that the makeup of circadian clock(s) within a plant is quite variable. Plants utilize the circadian clock to measure day-length changes for regulating seasonal responses, such as flowering. To ensure that flowering occurs under optimum conditions, the clock regulates diurnal CONSTANS (CO) expression. Subsequently, CO protein induces FLOWERING LOCUS T (FT) expression which leads to flowering. It is emerging that both CO and FT expression are intricately controlled by groups of transcription factors with overlapping functions. PMID:19836294
Buxton, Orfeu M; Cain, Sean W; O'Connor, Shawn P; Porter, James H; Duffy, Jeanne F; Wang, Wei; Czeisler, Charles A; Shea, Steven A
Epidemiological studies link short sleep duration and circadian disruption with higher risk of metabolic syndrome and diabetes. We tested the hypotheses that prolonged sleep restriction with concurrent circadian disruption, as can occur in people performing shift work, impairs glucose regulation and metabolism. Healthy adults spent >5 weeks under controlled laboratory conditions in which they experienced an initial baseline segment of optimal sleep, 3 weeks of sleep restriction (5.6 hours of sleep per 24 hours) combined with circadian disruption (recurring 28-hour "days"), followed by 9 days of recovery sleep with circadian re-entrainment. Exposure to prolonged sleep restriction with concurrent circadian disruption, with measurements taken at the same circadian phase, decreased the participants' resting metabolic rate and increased plasma glucose concentrations after a meal, an effect resulting from inadequate pancreatic insulin secretion. These parameters normalized during the 9 days of recovery sleep and stable circadian re-entrainment. Thus, in humans, prolonged sleep restriction with concurrent circadian disruption alters metabolism and could increase the risk of obesity and diabetes.
Fuller, Charles A.; Murakami, Dean M.; Sulzman, Frank M.
Using published reports, this paper compares and contrasts results on the effects of altered gravitational fields on the regulation in mammals of several physiological and behavioral variables with the circadian regulation of the same variables. The variables considered include the temperature regulation, heart rate, activity, food intake, and calcium balance. It is shown that, in rats, the homeostatic regulation of the body temperature, heart rate, and activity becomes depressed following exposure to a 2 G hyperdynamic field, and recovers within 6 days of 1 G condition. In addition, the circadian rhythms of these variables exhibit a depression of the rhythm amplitude; a recovery of this condition requires a minimum of 7 days.
Czeisler, C. A.; Duffy, J. F.; Shanahan, T. L.; Brown, E. N.; Mitchell, J. F.; Rimmer, D. W.; Ronda, J. M.; Silva, E. J.; Allan, J. S.; Emens, J. S.; Dijk, D. J.; Kronauer, R. E.
Regulation of circadian period in humans was thought to differ from that of other species, with the period of the activity rhythm reported to range from 13 to 65 hours (median 25.2 hours) and the period of the body temperature rhythm reported to average 25 hours in adulthood, and to shorten with age. However, those observations were based on studies of humans exposed to light levels sufficient to confound circadian period estimation. Precise estimation of the periods of the endogenous circadian rhythms of melatonin, core body temperature, and cortisol in healthy young and older individuals living in carefully controlled lighting conditions has now revealed that the intrinsic period of the human circadian pacemaker averages 24.18 hours in both age groups, with a tight distribution consistent with other species. These findings have important implications for understanding the pathophysiology of disrupted sleep in older people.
Paulose, Jiffin K.; Wright, John M.; Patel, Akruti G; Cassone, Vincent M.
Circadian rhythms are fundamental properties of most eukaryotes, but evidence of biological clocks that drive these rhythms in prokaryotes has been restricted to Cyanobacteria. In vertebrates, the gastrointestinal system expresses circadian patterns of gene expression, motility and secretion in vivo and in vitro, and recent studies suggest that the enteric microbiome is regulated by the host’s circadian clock. However, it is not clear how the host’s clock regulates the microbiome. Here, we demonstrate at least one species of commensal bacterium from the human gastrointestinal system, Enterobacter aerogenes, is sensitive to the neurohormone melatonin, which is secreted into the gastrointestinal lumen, and expresses circadian patterns of swarming and motility. Melatonin specifically increases the magnitude of swarming in cultures of E. aerogenes, but not in Escherichia coli or Klebsiella pneumoniae. The swarming appears to occur daily, and transformation of E. aerogenes with a flagellar motor-protein driven lux plasmid confirms a temperature-compensated circadian rhythm of luciferase activity, which is synchronized in the presence of melatonin. Altogether, these data demonstrate a circadian clock in a non-cyanobacterial prokaryote and suggest the human circadian system may regulate its microbiome through the entrainment of bacterial clocks. PMID:26751389
Lech, Karolina; Ackermann, Katrin; Revell, Victoria L; Lao, Oscar; Skene, Debra J; Kayser, Manfred
The identification and investigation of novel clock-controlled genes (CCGs) has been conducted thus far mainly in model organisms such as nocturnal rodents, with limited information in humans. Here, we aimed to characterize daily and circadian expression rhythms of CCGs in human peripheral blood during a sleep/sleep deprivation (S/SD) study and a constant routine (CR) study. Blood expression levels of 9 candidate CCGs (SREBF1, TRIB1, USF1, THRA1, SIRT1, STAT3, CAPRIN1, MKNK2, and ROCK2), were measured across 48 h in 12 participants in the S/SD study and across 33 h in 12 participants in the CR study. Statistically significant rhythms in expression were observed for STAT3, SREBF1, TRIB1, and THRA1 in samples from both the S/SD and the CR studies, indicating that their rhythmicity is driven by the endogenous clock. The MKNK2 gene was significantly rhythmic in the S/SD but not the CR study, which implies its exogenously driven rhythmic expression. In addition, we confirmed the circadian expression of PER1, PER3, and REV-ERBα in the CR study samples, while BMAL1 and HSPA1B were not significantly rhythmic in the CR samples; all 5 genes previously showed significant expression in the S/SD study samples. Overall, our results demonstrate that rhythmic expression patterns of clock and selected clock-controlled genes in human blood cells are in part determined by exogenous factors (sleep and fasting state) and in part by the endogenous circadian timing system. Knowledge of the exogenous and endogenous regulation of gene expression rhythms is needed prior to the selection of potential candidate marker genes for future applications in medical and forensic settings.
Adamovich, Yaarit; Rousso-Noori, Liat; Zwighaft, Ziv; Neufeld-Cohen, Adi; Golik, Marina; Kraut-Cohen, Judith; Wang, Miao; Han, Xianlin; Asher, Gad
Circadian clocks play a major role in orchestrating daily physiology, and their disruption can evoke metabolic diseases such as fatty liver and obesity. To study the role of circadian clocks in lipid homeostasis, we performed an extensive lipidomic analysis of liver tissues from wild-type and clock-disrupted mice either fed ad libitum or night fed. To our surprise, a similar fraction of lipids (∼17%) oscillated in both mouse strains, most notably triglycerides, but with completely different phases. Moreover, several master lipid regulators (e.g., PPARα) and enzymes involved in triglyceride metabolism retained their circadian expression in clock-disrupted mice. Nighttime restricted feeding shifted the phase of triglyceride accumulation and resulted in ∼50% decrease in hepatic triglyceride levels in wild-type mice. Our findings suggest that circadian clocks and feeding time dictate the phase and levels of hepatic triglyceride accumulation; however, oscillations in triglycerides can persist in the absence of a functional clock.
Saini, Camille; Brown, Steven A.; Dibner, Charna
Most light-sensitive organisms on earth have acquired an internal system of circadian clocks allowing the anticipation of light or darkness. In humans, the circadian system governs nearly all aspects of physiology and behavior. Circadian phenotypes, including chronotype, vary dramatically among individuals and over individual lifespan. Recent studies have revealed that the characteristics of human skin fibroblast clocks correlate with donor chronotype. Given the complexity of circadian phenotype assessment in humans, the opportunity to study oscillator properties by using cultured primary cells has the potential to uncover molecular details difficult to assess directly in humans. Since altered properties of the circadian oscillator have been associated with many diseases including metabolic disorders and cancer, clock characteristics assessed in additional primary cell types using similar technologies might represent an important tool for exploring the connection between chronotype and disease, and for diagnostic purposes. Here, we review implications of this approach for gathering insights into human circadian rhythms and their function in health and disease. PMID:26029154
Nagy, Andras D; Reddy, Akhilesh B
Since the advent of modern molecular tools, researchers have extensively shown that essential cellular machineries have robust circadian (roughly 24 hours) variations in their pace. This molecular rhythmicity translates directly into time-of-day-dependent variation in physiology in most organ systems, which in turn provides the mechanistic rationale for why timing on a daily basis should matter in many aspects of human health. However, these basic science findings have been slow to move from bench to bedside because clinical studies are still lacking to demonstrate the importance of timing. Therefore, it has not been clear how physicians should incorporate knowledge of natural 24-hour rhythms into routine practice. This review is a brief summary of results from recently completed clinical studies on hypertension, myocardial infarction, diabetes mellitus, and adrenal dysfunction that highlights new evidence for the emerging importance of circadian rhythms in diagnosis, prognosis and treatment of disease.
Santhi, Nayantara; Lazar, Alpar S.; McCabe, Patrick J.; Lo, June C.; Groeger, John A.; Dijk, Derk-Jan
The sleep–wake cycle and circadian rhythmicity both contribute to brain function, but whether this contribution differs between men and women and how it varies across cognitive domains and subjective dimensions has not been established. We examined the circadian and sleep–wake-dependent regulation of cognition in 16 men and 18 women in a forced desynchrony protocol and quantified the separate contributions of circadian phase, prior sleep, and elapsed time awake on cognition and sleep. The largest circadian effects were observed for reported sleepiness, mood, and reported effort; the effects on working memory and temporal processing were smaller. Although these effects were seen in both men and women, there were quantitative differences. The amplitude of the circadian modulation was larger in women in 11 of 39 performance measures so that their performance was more impaired in the early morning hours. Principal components analysis of the performance measures yielded three factors, accuracy, effort, and speed, which reflect core performance characteristics in a range of cognitive tasks and therefore are likely to be important for everyday performance. The largest circadian modulation was observed for effort, whereas accuracy exhibited the largest sex difference in circadian modulation. The sex differences in the circadian modulation of cognition could not be explained by sex differences in the circadian amplitude of plasma melatonin and electroencephalographic slow-wave activity. These data establish the impact of circadian rhythmicity and sex on waking cognition and have implications for understanding the regulation of brain function, cognition, and affect in shift-work, jetlag, and aging. PMID:27091961
Santhi, Nayantara; Lazar, Alpar S; McCabe, Patrick J; Lo, June C; Groeger, John A; Dijk, Derk-Jan
The sleep-wake cycle and circadian rhythmicity both contribute to brain function, but whether this contribution differs between men and women and how it varies across cognitive domains and subjective dimensions has not been established. We examined the circadian and sleep-wake-dependent regulation of cognition in 16 men and 18 women in a forced desynchrony protocol and quantified the separate contributions of circadian phase, prior sleep, and elapsed time awake on cognition and sleep. The largest circadian effects were observed for reported sleepiness, mood, and reported effort; the effects on working memory and temporal processing were smaller. Although these effects were seen in both men and women, there were quantitative differences. The amplitude of the circadian modulation was larger in women in 11 of 39 performance measures so that their performance was more impaired in the early morning hours. Principal components analysis of the performance measures yielded three factors, accuracy, effort, and speed, which reflect core performance characteristics in a range of cognitive tasks and therefore are likely to be important for everyday performance. The largest circadian modulation was observed for effort, whereas accuracy exhibited the largest sex difference in circadian modulation. The sex differences in the circadian modulation of cognition could not be explained by sex differences in the circadian amplitude of plasma melatonin and electroencephalographic slow-wave activity. These data establish the impact of circadian rhythmicity and sex on waking cognition and have implications for understanding the regulation of brain function, cognition, and affect in shift-work, jetlag, and aging.
Brown, E. N.; Choe, Y.; Luithardt, H.; Czeisler, C. A.
We formulate a statistical model of the human core-temperature circadian rhythm in which the circadian signal is modeled as a van der Pol oscillator, the thermoregulatory response is represented as a first-order autoregressive process, and the evoked effect of activity is modeled with a function specific for each circadian protocol. The new model directly links differential equation-based simulation models and harmonic regression analysis methods and permits statistical analysis of both static and dynamical properties of the circadian pacemaker from experimental data. We estimate the model parameters by using numerically efficient maximum likelihood algorithms and analyze human core-temperature data from forced desynchrony, free-run, and constant-routine protocols. By representing explicitly the dynamical effects of ambient light input to the human circadian pacemaker, the new model can estimate with high precision the correct intrinsic period of this oscillator ( approximately 24 h) from both free-run and forced desynchrony studies. Although the van der Pol model approximates well the dynamical features of the circadian pacemaker, the optimal dynamical model of the human biological clock may have a harmonic structure different from that of the van der Pol oscillator.
Miyawaki, T; Taga, K; Nagaoki, T; Seki, H; Suzuki, Y; Taniguchi, N
The circadian variations in circulating T cell subsets defined by monoclonal antibodies in eight healthy male volunteers were evaluated in whole blood using a flow cytometry. In all subjects, the number of lymphocytes showed a clear rhythmicity with high values at night and low values during the day. This circadian variation in circulating lymphocytes appeared to reflect largely a change in the number of T cells rather than B cells. The percentage of OKT3+ and OKT11+ cells showed a similar fluctuation with a peak at night and a depression during the day. It was found that the percentage of OKT4+ cells varied in parallel with that of T cells, particularly of OKT3+ cells, but the OKT8+ subset was not appreciably altered over a 24 h period. Thus, a circadian variation of T cells could be largely accounted for by a circadian change of OKT4+ cells. Plasma cortisol levels showed an expected circadian variation. It was also shown that there might be an intimate relationship between these circadian changes of T cell subsets and plasma cortisol levels. PMID:6608426
Monk, T. H.; Kennedy, K. S.; Rose, L. R.; Linenger, J. M.
OBJECTIVE: The objectives of this study were (1) to assess the circadian rhythms and sleep of a healthy, 42-year-old male astronaut experiencing microgravity (weightlessness) for nearly 5 months while living aboard Space Station Mir as it orbited Earth and (2) to determine the effects of prolonged space flight on the endogenous circadian pacemaker, as indicated by oral temperature and subjective alertness rhythms, and their ramifications for sleep, alertness, and performance. METHODS: For three 12- to 14-day blocks of time (spread throughout the mission), oral temperatures were taken and subjective alertness was self-rated five times per day. Sleep diaries and performance tests were also completed daily during each block. RESULTS: Examination of the subject's circadian alertness and oral temperature rhythms suggested that the endogenous circadian pacemaker seemed to function quite well up to 90 days in space. Thereafter (on days 110-122), the influence of the endogenous circadian pacemaker on oral temperature and subjective alertness circadian rhythms was considerably weakened, with consequent disruptions in sleep. CONCLUSIONS: Space missions lasting more than 3 months might result in diminished circadian pacemaker influence in astronauts, leading to eventual sleep problems.
Smadja Storz, Sima; Tovin, Adi; Mracek, Philipp; Alon, Shahar; Foulkes, Nicholas S; Gothilf, Yoav
Zebrafish have become a popular model for studies of the circadian timing mechanism. Taking advantage of its rapid development of a functional circadian clock and the availability of light-entrainable clock-containing cell lines, much knowledge has been gained about the circadian clock system in this species. However, the post-translational modifications of clock proteins, and in particular the phosphorylation of PER proteins by Casein kinase I delta and epsilon (CK1δ and CK1ε), have so far not been examined in the zebrafish. Using pharmacological inhibitors for CK1δ and CK1ε, a pan-CK1δ/ε inhibitor PF-670462, and a CK1ε -selective inhibitor PF-4800567, we show that CK1δ activity is crucial for the functioning of the circadian timing mechanism of zebrafish, while CK1ε plays a minor role. The CK1δ/ε inhibitor disrupted circadian rhythms of promoter activity in the circadian clock-containing zebrafish cell line, PAC-2, while the CK1ε inhibitor had no effect. Zebrafish larvae that were exposed to the CK1δ/ε inhibitor showed no rhythms of locomotor activity while the CK1ε inhibitor had only a minor effect on locomotor activity. Moreover, the addition of the CK1δ/ε inhibitor disrupted rhythms of aanat2 mRNA expression in the pineal gland. The pineal gland is considered to act as a central clock organ in fish, delivering a rhythmic hormonal signal, melatonin, which is regulated by AANAT2 enzymatic activity. Therefore, CK1δ plays a key role in the circadian timing system of the zebrafish. Furthermore, the effect of CK1δ inhibition on rhythmic locomotor activity may reflect its effect on the function of the central clock in the pineal gland as well as its regulation of peripheral clocks.
Kolodyazhniy, Vitaliy; Späti, Jakub; Frey, Sylvia; Götz, Thomas; Wirz-Justice, Anna; Kräuchi, Kurt; Cajochen, Christian; Wilhelm, Frank H
Reliable detection of circadian phase in humans using noninvasive ambulatory measurements in real-life conditions is challenging and still an unsolved problem. The masking effects of everyday behavior and environmental input such as physical activity and light on the measured variables need to be considered critically. Here, we aimed at developing techniques for estimating circadian phase with the lowest subject burden possible, that is, without the need of constant routine (CR) laboratory conditions or without measuring the standard circadian markers, (rectal) core body temperature (CBT), and melatonin levels. In this validation study, subjects (N = 16) wore multi-channel ambulatory monitoring devices and went about their daily routine for 1 week. The devices measured a large number of physiological, behavioral, and environmental variables, including CBT, skin temperatures, cardiovascular and respiratory function, movement/posture, ambient temperature, and the spectral composition and intensity of light received at eye level. Sleep diaries were logged electronically. After the ambulatory phase, subjects underwent a 32-h CR procedure in the laboratory for measuring unmasked circadian phase based on the "midpoint" of the salivary melatonin profile. To overcome the complex masking effects of confounding variables during ambulatory measurements, multiple regression techniques were applied in combination with the cross-validation approach to subject-independent prediction of circadian phase. The most accurate estimate of circadian phase was achieved using skin temperatures, irradiance for ambient light in the blue spectral band, and motion acceleration as predictors with lags of up to 24 h. Multiple regression showed statistically significant improvement of variance of prediction error over the traditional approaches to determining circadian phase based on single predictors (motion acceleration or sleep log), although CBT was intentionally not included as the predictor
Stevens, Richard G.; Zhu, Yong
Over the past 3 billion years, an endogenous circadian rhythmicity has developed in almost all life forms in which daily oscillations in physiology occur. This allows for anticipation of sunrise and sunset. This physiological rhythmicity is kept at precisely 24 h by the daily cycle of sunlight and dark. However, since the introduction of electric lighting, there has been inadequate light during the day inside buildings for a robust resetting of the human endogenous circadian rhythmicity, and too much light at night for a true dark to be detected; this results in circadian disruption and alters sleep/wake cycle, core body temperature, hormone regulation and release, and patterns of gene expression throughout the body. The question is the extent to which circadian disruption compromises human health, and can account for a portion of the modern pandemics of breast and prostate cancers, obesity, diabetes and depression. As societies modernize (i.e. electrify) these conditions increase in prevalence. There are a number of promising leads on putative mechanisms, and epidemiological findings supporting an aetiologic role for electric lighting in disease causation. These include melatonin suppression, circadian gene expression, and connection of circadian rhythmicity to metabolism in part affected by haem iron intake and distribution. PMID:25780233
Stevens, Richard G; Zhu, Yong
Over the past 3 billion years, an endogenous circadian rhythmicity has developed in almost all life forms in which daily oscillations in physiology occur. This allows for anticipation of sunrise and sunset. This physiological rhythmicity is kept at precisely 24 h by the daily cycle of sunlight and dark. However, since the introduction of electric lighting, there has been inadequate light during the day inside buildings for a robust resetting of the human endogenous circadian rhythmicity, and too much light at night for a true dark to be detected; this results in circadian disruption and alters sleep/wake cycle, core body temperature, hormone regulation and release, and patterns of gene expression throughout the body. The question is the extent to which circadian disruption compromises human health, and can account for a portion of the modern pandemics of breast and prostate cancers, obesity, diabetes and depression. As societies modernize (i.e. electrify) these conditions increase in prevalence. There are a number of promising leads on putative mechanisms, and epidemiological findings supporting an aetiologic role for electric lighting in disease causation. These include melatonin suppression, circadian gene expression, and connection of circadian rhythmicity to metabolism in part affected by haem iron intake and distribution.
Dodd, Antony N; Dalchau, Neil; Gardner, Michael J; Baek, Seong-Jin; Webb, Alex A R
A circadian rhythm matched to the phase and period of the day-night cycle has measurable benefits for land plants. We assessed the contribution of circadian period to the phasing of cellular events with the light : dark cycle. We also investigated the plasticity of circadian period within the Arabidopsis circadian oscillator. We monitored the circadian oscillator in wild-type and circadian period mutants under light : dark cycles of varying total duration. We also investigated changes in oscillator dynamics during and after the transition from light : dark cycles to free running conditions. Under light : dark cycles, dawn and dusk were anticipated differently when the circadian period was not resonant with the environmental period ('T cycle'). Entrainment to T cycles differing from the free-running period caused a short-term alteration in oscillator period. The transient plasticity of period was described by existing mathematical models of the Arabidopsis circadian network. We conclude that a circadian period resonant with the period of the environment is particularly important for anticipation of dawn and the timing of nocturnal events; and there is short-term and transient plasticity of period of the Arabidopsis circadian network.
Mheid, Ibhar Al; Corrigan, Frank; Shirazi, Farheen; Veledar, Emir; Li, Qunna; Alexander, Wayne R.; Taylor, W. Robert; Waller, Edmund K.; Quyyumi, Arshed A.
Background Progenitor cells (PCs) are mobilized in response to vascular injury to effect regeneration and repair. Recruitment of PCs requires intact nitric oxide (NO) synthesis by endothelial cells, and their number and activity correlate with cardiovascular disease risk burden and future outcomes. Whereas cardiovascular vulnerability exhibits a robust circadian rhythm, the 24‐hour variation of PCs and their inter‐relation with vascular function remain unknown. We investigated the circadian variation of PCs and vascular function with the hypothesis that this will parallel the pattern observed for cardiovascular events (CVEs). Methods and Results In 15 healthy subjects (9 men, 37±16 years), circulating PCs and vascular function were measured at 8 am, noon, 4 pm, 8 pm, midnight, 4 am (only PCs counts), and 8 am the following day. Circulating PCs were enumerated as mononuclear cells (MNCs; CD45med) that express CD34 as well as CD133, and their activity was assessed as the number of colonies formed by culturing MNCs. Vascular function was evaluated by measurement of endothelium‐dependent, flow‐mediated vasodilation (FMD) of the brachial artery and tonometry‐derived indices of arterial stiffness. Higher CD34+ and CD34+/CD133+ cell counts were observed at 8 pm than any other time of the day (P‐ANOVA=0.038 and <0.001; respectively) and were lowest at 8 am. PC colony formation was highest at midnight (P‐ANOVA=0.045) and lowest in the morning hours. FMD was highest at midnight and lowest at 8 am and 8 pm, and systemic arterial stiffness was greatest at 8 am and lowest at 4 pm and midnight (P‐ANOVA=0.03 and 0.01; respectively). Conclusion A robust circadian variation in PC counts and vascular function occurs in healthy humans and both exhibit an unfavorable profile in the morning hours that parallels the preponderance of CVEs at these times. Whether these changes are precipitated by awakening and time‐dependent physical activity or governed by the
Boivin, D. B.; Duffy, J. F.; Kronauer, R. E.; Czeisler, C. A.
Since the first report in unicells, studies across diverse species have demonstrated that light is a powerful synchronizer which resets, in an intensity-dependent manner, endogenous circadian pacemakers. Although it is recognized that bright light (approximately 7,000 to 13,000 lux) is an effective circadian synchronizer in humans, it is widely believed that the human circadian pacemaker is insensitive to ordinary indoor illumination (approximately 50-300 lux). It has been proposed that the relationship between the resetting effect of light and its intensity follows a compressive nonlinear function, such that exposure to lower illuminances still exerts a robust effect. We therefore undertook a series of experiments which support this hypothesis and report here that light of even relatively low intensity (approximately 180 lux) significantly phase-shifts the human circadian pacemaker. Our results clearly demonstrate that humans are much more sensitive to light than initially suspected and support the conclusion that they are not qualitatively different from other mammals in their mechanism of circadian entrainment.
Jewett, M. E.; Rimmer, D. W.; Duffy, J. F.; Klerman, E. B.; Kronauer, R. E.; Czeisler, C. A.
Fifty-six resetting trials were conducted across the subjective day in 43 young men using a three-cycle bright-light (approximately 10,000 lx). The phase-response curve (PRC) to these trials was assessed for the presence of a "dead zone" of photic insensitivity and was compared with another three-cycle PRC that had used a background of approximately 150 lx. To assess possible transients after the light stimulus, the trials were divided into 43 steady-state trials, which occurred after several baseline days, and 13 consecutive trials, which occurred immediately after a previous resetting trial. We found that 1) bright light induces phase shifts throughout subjective day with no apparent dead zone; 2) there is no evidence of transients in constant routine assessments of the fitted temperature minimum 1-2 days after completion of the resetting stimulus; and 3) the timing of background room light modulates the resetting response to bright light. These data indicate that the human circadian pacemaker is sensitive to light at virtually all circadian phases, implying that the entire 24-h pattern of light exposure contributes to entrainment.
Dijk, D J; Beersma, D G; Daan, S; Lewy, A J
Eight male subjects were exposed to either bright light or dim light between 0600 and 0900 h for 3 consecutive days each. Relative to the dim light condition, the bright light treatment advanced the evening rise in plasma melatonin and the time of sleep termination (sleep onset was held constant) for an average approximately 1 h. The magnitude of the advance of the plasma melatonin rise was dependent on its phase in dim light. The reduction in sleep duration was at the expense of rapid-eye-movement (REM) sleep. Spectral analysis of the sleep electroencephalogram (EEG) revealed that the advance of the circadian pacemaker did not affect EEG power densities between 0.25 and 15.0 Hz during either non-REM or REM sleep. The data show that shifting the human circadian pacemaker by 1 h does not affect non-REM sleep homeostasis. These findings are in accordance with the predictions of the two-process model of sleep regulation.
Zmrzljak, Ursula Prosenc; Rozman, Damjana
Metabolic processes have to be regulated tightly to prevent waste of energy and to ensure sufficient detoxification. Most anabolic processes operate in a timely manner when energy intake is the highest, while catabolism takes place in energy spending periods. Endobiotic and xenobiotic metabolism are therefore under circadian control. Circadian regulation is mediated through the suprachiasmatic nucleus (SCN), a master autonomous oscillator of the brain. Although many peripheral organs have their own oscillators, the SCN is important in orchestrating and entraining organs according to the environmental light cues. However, light is not the only signal for entrainment of internal clocks. For endobiotic and xenobitoic detoxification pathways, the food composition and intake regime are equally important. The rhythm of the liver as an organ where the major metabolic pathways intersect depends on SCN signals, signals from endocrine tissues, and, importantly, the type and time of feeding or xenobiotics ingestion. Several enzymes are involved in detoxification processes. Phase I is composed mainly of cytochromes P450, which are regulated by nuclear receptors. Phase II enzymes modify the phase I metabolites, while phase III includes membrane transporters responsible for the elimination of modified xenobiotics. Phases I-III of drug metabolism are under strong circadian regulation, starting with the drug-sensing nuclear receptors and ending with drug transporters. Disturbed circadian regualtion (jet-lag, shift work, and dysfunction of core clock genes) leads to changed periods of activity, sleep disorders, disturbed glucose homeostasis, breast or colon cancer, and metabolic syndrome. As many xenobiotics influence the circadian rhythm of the liver, bad drug administration timing can worsen the above listed effects. This review will cover the major hepatic circadian regulation of endogenous and xenobiotic metabolic pathways and will provide examples of how good timing of drug
Butler, Matthew P.; Karatsoreos, Ilia N.; LeSauter, Joseph
The hypothalamic suprachiasmatic nucleus (SCN) is the locus of a master clock that regulates circadian rhythms in physiology and behavior. Gonadectomy in male mice lengthens the period of circadian rhythms and increases the day-to-day variability of activity onset time. Both of these responses are rescued by the nonaromatizable androgen dihydrotestosterone. Androgen receptors (AR) are localized in SCN neurons that receive direct retinal input. To explore how androgens affect circadian clock function and its responsiveness to photic cues, we measured wheel-running behavior and SCN AR expression in intact, gonadectomized, and testosterone-replaced mice, held under various photic conditions. Gonadectomy lengthened circadian period in constant dim light but not in constant darkness. Increasing intensities of constant light parametrically increased circadian period, and this was potentiated at all intensities by gonadectomy. In contrast, gonadectomy did not alter light-induced pupil constriction, suggesting a nonretinal locus of hormone action. In hormone-replaced animals housed in constant darkness, T concentration was positively correlated with precision of activity onset and with SCN AR expression and negatively correlated with duration of activity. We infer the existence of two androgenic mechanisms: one modulates SCN responsiveness to light, and the second modulates SCN timekeeping and locomotor activity in a dose-dependent manner. Finally, the effects of androgens on period are a result of hormonal modulation of the SCN's response to photic input rather than to a change in the inherent period of oscillators in the absence of light. PMID:22492303
Gil, Enrique A; Aubert, Xavier L; Beersma, Domien G M
In this work, we introduce a number of models for human circadian phase estimation in ambulatory conditions using various sensor modalities. Machine learning techniques have been applied to ambulatory recordings of wrist actigraphy, light exposure, electrocardiograms (ECG), and distal and proximal skin temperature to develop ARMAX models capturing the main signal dependencies on circadian phase and evaluating them versus melatonin onset times. The most accurate models extracted heart rate variability features from an ECG coupled with wrist activity information to produce phase estimations with prediction errors of ~30 minutes. Replacing the ECG features with skin temperature from the upper leg led to a slight degradation, while less accurate results, in the order of 1 hour, were obtained from wrist activity and light measurements. The trade-off between highest precision and least obtrusive configuration is discussed for applications to sleep and mood disorders caused by a misalignment of the internal phase with the external solar and social times.
Wu, Xiying; Yu, Gang; Parks, Helen; Hebert, Teddi; Goh, Brian C.; Dietrich, Marilyn A.; Pelled, Gadi; Izadpanah, Reza; Gazit, Dan; Bunnell, Bruce A.; Gimble, Jeffrey M.
A core group of transcriptional regulatory factors regulate circadian rhythms in mammalian cells. While the suprachiasmatic nucleus in the brain serves as the central core circadian oscillator, circadian clocks also exist within peripheral tissues and cells. A growing body of evidence has demonstrated that >20% of expressed mRNAs in bone and adipose tissues oscillate in a circadian manner. The current manuscript reports evidence of the core circadian transcriptional apparatus within primary cultures of murine and human bone marrow-derived mesenchymal stem cells (BMSCs). Exposure of confluent, quiescent BMSCs to dexamethasone synchronized the oscillating expression of the mRNAs encoding the albumin D binding protein (dbp), brain-muscle arnt-like 1 (bmal1), period 3 (per3), rev-erb α, and rev-erb β. The genes displayed a mean oscillatory period of 22.2 to 24.3 hours. The acrophase or peak expression of mRNAs encoding “positive” (bmal1) and “negative” (per3) transcriptional regulatory factors were out of phase with each other by ∼8-12 hours, consistent with in vivo observations. In vivo, glycogen synthase kinase 3β (GSK3β) mediated phosphorylation regulates the turnover of per3 and core circadian transcriptional apparatus. In vitro addition of lithium chloride, a GSK3β inhibitor, significantly shifted the acrophase of all genes by 4.2-4.7 hours oscillation in BMSCs; however, only the male murine BMSCs displayed a significant increase in the length of the period of oscillation. We conclude that human and murine BMSCs represent a valid in vitro model for the analysis of circadian mechanisms in bone metabolism and stem cell biology. PMID:18302991
Gooley, Joshua J
The circadian system temporally coordinates daily rhythms in feeding behaviour and energy metabolism. The objective of the present paper is to review the mechanisms that underlie circadian regulation of lipid metabolic pathways. Circadian rhythms in behaviour and physiology are generated by master clock neurons in the suprachiasmatic nucleus (SCN). The SCN and its efferent targets in the hypothalamus integrate light and feeding signals to entrain behavioural rhythms as well as clock cells located in peripheral tissues, including the liver, adipose tissue and muscle. Circadian rhythms in gene expression are regulated at the cellular level by a molecular clock comprising a core set of clock genes/proteins. In peripheral tissues, hundreds of genes involved in lipid biosynthesis and fatty acid oxidation are rhythmically activated and repressed by clock proteins, hence providing a direct mechanism for circadian regulation of lipids. Disruption of clock gene function results in abnormal metabolic phenotypes and impaired lipid absorption, demonstrating that the circadian system is essential for normal energy metabolism. The composition and timing of meals influence diurnal regulation of metabolic pathways, with food intake during the usual rest phase associated with dysregulation of lipid metabolism. Recent studies using metabolomics and lipidomics platforms have shown that hundreds of lipid species are circadian-regulated in human plasma, including but not limited to fatty acids, TAG, glycerophospholipids, sterol lipids and sphingolipids. In future work, these lipid profiling approaches can be used to understand better the interaction between diet, mealtimes and circadian rhythms on lipid metabolism and risk for obesity and metabolic diseases.
Voigt, Robin M.; Forsyth, Christopher B.; Green, Stefan J.; Mutlu, Ece; Engen, Phillip; Vitaterna, Martha H.; Turek, Fred W.; Keshavarzian, Ali
Intestinal dysbiosis and circadian rhythm disruption are associated with similar diseases including obesity, metabolic syndrome, and inflammatory bowel disease. Despite the overlap, the potential relationship between circadian disorganization and dysbiosis is unknown; thus, in the present study, a model of chronic circadian disruption was used to determine the impact on the intestinal microbiome. Male C57BL/6J mice underwent once weekly phase reversals of the light:dark cycle (i.e., circadian rhythm disrupted mice) to determine the impact of circadian rhythm disruption on the intestinal microbiome and were fed either standard chow or a high-fat, high-sugar diet to determine how diet influences circadian disruption-induced effects on the microbiome. Weekly phase reversals of the light:dark (LD) cycle did not alter the microbiome in mice fed standard chow; however, mice fed a high-fat, high-sugar diet in conjunction with phase shifts in the light:dark cycle had significantly altered microbiota. While it is yet to be established if some of the adverse effects associated with circadian disorganization in humans (e.g., shift workers, travelers moving across time zones, and in individuals with social jet lag) are mediated by dysbiosis, the current study demonstrates that circadian disorganization can impact the intestinal microbiota which may have implications for inflammatory diseases. PMID:24848969
McElroy, Todd; Mosteller, Lynn
Introduction: In this paper we investigate how students' class grades are affected by individual differences in circadian rhythm, class time-of-day and class difficulty. Method: Using a sample of university students, we assessed morningness and eveningness personality type, and then obtained students recalled classes as well as their…
Fuller, Charles A.
Ten pregnant Sprague Dawley rat dams were exposed to spaceflight aboard the Space Shuttle (STS-70) for gestational days 11-20 (G 11-20; FILT group). Control dams were maintained in either a flight-like (FIDS group) or vivarium cage environment (VIV group) on earth. All dams had ad lib access to food and water and were exposed to a light-dark cycle consisting of 12 hours of light (- 30 lux) followed by 12 hours of darkness. The dams were closely monitored from G 22 until parturition. All pups were cross-fostered at birth; each foster dam had a litter of 10 pups. Pups remained with their foster dam until post-natal day 21 (PN 21). Pup body mass was measured twice weekly. At PN14 FILT pups had a smaller body mass than did the VIV pups (p < 0.01). Circadian rhythms of body temperature and activity of pups from two FILT dams (n = 8), two FIDS dams (n = 9) and two VIV dams (n = 7) were studied starting from age PN 21. All pups had circadian rhythms of temperature and activity at this age. There were no significant differences in rhythms between groups that could be attributed to microgravity exposure. We also examined the development of neural structures involved in circadian rhythmicity: the retina, the intergeniculate leaflet (IGL) and the circadian pacemaker, the suprachiasmatic nucleus (SCN). There were small differences between the flight and control groups at very early stages of development (G 20 and PN3) which indicated that the development of both the SCN and the IGL. These results indicate that exposure to the microgravity environment of spaceflight during this embryonic development period does not affect the development of the circadian rhythms of body temperature and activity, but may affect the early development of the neural structures involved in circadian timing.
Hodkinson, Duncan J; O'Daly, Owen; Zunszain, Patricia A; Pariante, Carmine M; Lazurenko, Vitaly; Zelaya, Fernando O; Howard, Matthew A; Williams, Steven C R
Diurnal rhythms have been observed in human behaviors as diverse as sleep, olfaction, and learning. Despite its potential impact, time of day is rarely considered when brain responses are studied by neuroimaging techniques. To address this issue, we explicitly examined the effects of circadian and homeostatic regulation on functional connectivity (FC) and regional cerebral blood flow (rCBF) in healthy human volunteers, using whole-brain resting-state functional magnetic resonance imaging (rs-fMRI) and arterial spin labeling (ASL). In common with many circadian studies, we collected salivary cortisol to represent the normal circadian activity and functioning of the hypothalamic-pituitary-adrenal (HPA) axis. Intriguingly, the changes in FC and rCBF we observed indicated fundamental decreases in the functional integration of the default mode network (DMN) moving from morning to afternoon. Within the anterior cingulate cortex (ACC), our results indicate that morning cortisol levels are negatively correlated with rCBF. We hypothesize that the homeostatic mechanisms of the HPA axis has a role in modulating the functional integrity of the DMN (specifically, the ACC), and for the purposes of using fMRI as a tool to measure changes in disease processes or in response to treatment, we demonstrate that time of the day is important when interpreting resting-state data.
The identification of circadian clocks in endocrine tissues has added considerable depth and complexity to our understanding of their physiology. A growing body of research reveals circadian clock gene expression in the uterus of non-pregnant and pregnant rodents. This review will focus on the mammalian uterus and its rhythmicity, particularly as it pertains to the circadian timing of parturition. This key event in the reproductive axis shows dramatic species-specific differences in its circadian phase. It is proposed here that these differences in the phasing of mammalian parturition are likely a function of opposite uterine cell responses to humoral cues. The argument will be made that melatonin fulfills many of the criteria to serve as a circadian signal in the initiation of human parturition, including specific actions on uterine smooth muscle cells that are consistent with a role for this hormone in the circadian timing of parturition.
Guess, Jaclyn; Burch, James B; Ogoussan, Kisito; Armstead, Cheryl A; Zhang, Hongmei; Wagner, Sara; Hebert, James R; Wood, Patricia; Youngstedt, Shawn D; Hofseth, Lorne J; Singh, Udai P; Xie, Dawen; Hrushesky, William J M
Circadian disruption has been linked with inflammation, an established cancer risk factor. Per3 clock gene polymorphisms have also been associated with circadian disruption and with increased cancer risk. Patients completed a questionnaire and provided a blood sample prior to undergoing a colonoscopy (n = 70). Adjusted mean serum cytokine concentrations (IL-6, TNF-alpha, gamma-INF, IL-1ra, IL-1-beta, VEGF) were compared among patients with high and low scores for fatigue (Multidimensional Fatigue Inventory), depressive symptoms (Beck Depression Inventory II), or sleep disruption (Pittsburgh Sleep Quality Index), or among patients with different Per3 clock gene variants. Poor sleep was associated with elevated VEGF, and fatigue-related reduced activity was associated with elevated TNF-alpha concentrations. Participants with the 4/5 or 5/5 Per3 variable tandem repeat sequence had elevated IL-6 concentrations compared to those with the 4/4 genotype. Biological processes linking circadian disruption with cancer remain to be elucidated. Increased inflammatory cytokine secretion may play a role.
Archer, Simon N; Oster, Henrik
The mammalian circadian system is a multi-oscillator, hierarchically organised system where a central pacemaker synchronises behavioural, physiological and gene expression rhythms in peripheral tissues. Epidemiological studies show that disruption of this internal synchronisation by short sleep and shift work is associated with adverse health outcomes through mechanisms that remain to be elucidated. Here, we review recent animal and human studies demonstrating the profound effects of insufficient and mistimed sleep on the rhythms of gene expression in central and peripheral tissues. In mice, sleep restriction leads to an ~80% reduction in circadian transcripts in the brain and profound disruption of the liver transcriptome. In humans, sleep restriction leads to a 1.9% reduction in circadian transcripts in whole blood, and when sleep is displaced to the daytime, 97% of rhythmic genes become arrhythmic and one-third of all genes show changes in temporal expression profiles. These changes in mice and humans include a significant reduction in the circadian regulation of transcription and translation and core clock genes in the periphery, while at the same time rhythms within the suprachiasmatic nucleus are not disrupted. Although the physiological mediators of these sleep disruption effects on the transcriptome have not been established, altered food intake, changes in hormones such as cortisol, and changes in body and brain temperature may play important roles. Processes and molecular pathways associated with these disruptions include metabolism, immune function, inflammatory and stress responses, and point to the molecular mechanisms underlying the established adverse health outcomes associated with short sleep duration and shift work, such as metabolic syndrome and cancer.
Chen, Rongmin; D’Alessandro, Matthew; Lee, Choogon
Background Circadian clocks coordinate an organism’s activities and regulate metabolic homeostasis in relation to daily environmental changes, most notably light/dark cycles. As in other organisms, the timekeeping mechanism in mammals depends on a self-sustaining transcriptional negative feedback loop with a built-in time delay in feedback inhibition. Although the time delay is essential for generating a slow, self-sustaining negative feedback loop with a period close to 24 hours, the exact mechanisms underlying the time delay are not known. Results We show here that RNA interference mediated by microRNAs (miRNAs) is an essential mechanism in generating the time delay. In Dicer-deficient (and thus miRNA-deficient) cells and mice, circadian rhythms were dramatically shortened (by ~2 hours), although the rhythms remained robust. The period shortening was caused by faster PER1 and PER2 translation in the Dicer-deficient cells. We also identified three specific miRNAs that regulate Per expression, and showed that knockdown of these miRNAs in wild-type cells also shortened the circadian period. Conclusions Consistent with the canonical function of miRNAs as translational modulators of target genes and their widespread roles in cell physiology, circadian rhythms are also modulated by miRNA-mediated RNA interference acting on posttranscriptional regulation of key clock genes. Our present study definitively shows that RNA interference is an important modulator of circadian rhythms by controlling the pace of PER synthesis, and presents a novel layer of regulation for the clock. PMID:24094851
Gonnissen, Hanne K. J.; Mazuy, Claire; Rutters, Femke; Martens, Eveline A. P.; Adam, Tanja C.; Westerterp-Plantenga, Margriet S.
Circadian misalignment affects total sleep time, but it may also affect sleep architecture. The objectives of this study were to examine intra-individual effects of circadian misalignment on sleep architecture and inter-individual relationships between sleep stages, cortisol levels and insulin sensitivity. Thirteen subjects (7 men, 6 women, age: 24.3±2.5 y; BMI: 23.6±1.7 kg/m2) stayed in a time blinded respiration chamber during three light-entrained circadian cycles (3x21h and 3x27h) resulting in a phase advance and a phase delay. Sleep was polysomnographically recorded. Blood and salivary samples were collected to determine glucose, insulin and cortisol concentrations. Intra-individually, a phase advance decreased rapid eye movement (REM) sleep and slow-wave sleep (SWS), increased time awake, decreased sleep and REM sleep latency compared to the 24h cycle. A phase delay increased REM sleep, decreased stage 2 sleep, increased time awake, decreased sleep and REM sleep latency compared to the 24h cycle. Moreover, circadian misalignment changed REM sleep distribution with a relatively shorter REM sleep during the second part of the night. Inter-individually, REM sleep was inversely associated with cortisol levels and HOMA-IR index. Circadian misalignment, both a phase advance and a phase delay, significantly changed sleep architecture and resulted in a shift in rem sleep. Inter-individually, shorter REM sleep during the second part of the night was associated with dysregulation of the HPA-axis and reduced insulin sensitivity. Trial Registration: International Clinical Trials Registry Platform NTR2926 http://apps.who.int/trialsearch/ PMID:23951335
Boivin, D. B.; Czeisler, C. A.
The present study was designed to investigate whether a weak photic stimulus can reset the endogenous circadian rhythms of plasma melatonin and plasma cortisol in human subjects. A stimulus consisting of three cycles of 5 h exposures to ordinary room light (approximately 180 lux), centered 1.5 h after the endogenous temperature nadir, significantly phase-advanced the plasma melatonin rhythm in eight healthy young men compared with the phase delays observed in eight control subjects who underwent the same protocol but were exposed to darkness (p < or = 0.003). After light-induced phase advances, the circadian rhythms of plasma melatonin and plasma cortisol maintained stable temporal relationships with the endogenous core body temperature cycle, consistent with the conclusion that exposure to ordinary indoor room light had shifted a master circadian pacemaker.
Pichon, Gaston; Treuil, Jean-Pierre
The larval parasites of the pantropical lymphatic filariasis exhibit two types of circadian behaviour. Typically, they only appear in the human bloodstream at nighttime, synchronised with their mosquito vectors. In Polynesia and parts of Southeast Asia, free of nocturnal vectors, they are found at all hours, and each population biorhythm differs. Through a geometrical approach, we explain this circadian diversity by a single, dominant mutation: the clocks of individual parasites are set at midnight (ubiquitous) or at 2 p.m. Compared to other circadian genes, this mutation must be very old, as it is shared by four biologically remote genera of parasites. This seniority sheds new light on several theoretical and practical aspects of vector-parasite temporal relations.
Vernikos-Danellis, J.; Winget, C. M.; Goodwin, A. E.; Reilly, T.
Circadian rhythm characteristics in healthy male and female humans were studied at 4-hour intervals for urine volume, cortisol, 5-hydroxyindoleacetic acid (5-HIAA), Na, K, Na/K ratios in the urine, as well as plasma cortisol. While plasma and urinary cortisol rhythms were very similar in both sexes, the described rhythms in urine volume, electrolyte, and 5-HIAA excretion differ for the two sexes. The results suggest that sex differences exist in the circadian patterns of important hormone and metabolic functions and that the internal synchrony of circadian rhythms differs for the two sexes. The results seem to indicate that the rhythmical secretion of cortisol does not account for the pattern of Na and K excretion.
Gronfier, Claude; Wright, Kenneth P.; Kronauer, Richard E.; Czeisler, Charles A.
Entrainment of the circadian pacemaker to the light:dark cycle is necessary for rhythmic physiological functions to be appropriately timed over the 24-h day. Nonentrainment results in sleep, endocrine, and neurobehavioral impairments. Exposures to intermittent bright light pulses have been reported to phase shift the circadian pacemaker with great efficacy. Therefore, we tested the hypothesis that a modulated light exposure (MLE) with bright light pulses in the evening would entrain subjects to a light:dark cycle 1 h longer than their own circadian period (τ). Twelve subjects underwent a 65-day inpatient study. Individual subject's circadian period was determined in a forced desynchrony protocol. Subsequently, subjects were released into 30 longer-than-24-h days (daylength of τ + 1 h) in one of three light:dark conditions: (i) ≈25 lux; (ii) ≈100 lux; and (iii) MLE: ≈25 lux followed by ≈100 lux, plus two 45-min bright light pulses of ≈9,500 lux near the end of scheduled wakefulness. We found that lighting levels of ≈25 lux were insufficient to entrain all subjects tested. Exposure to ≈100 lux was sufficient to entrain subjects, although at a significantly wider phase angle compared with baseline. Exposure to MLE was able to entrain the subjects to the imposed sleep–wake cycles but at a phase angle comparable to baseline. These results suggest that MLE can be used to entrain the circadian pacemaker to non-24-h days. The implications of these findings are important because they could be used to treat circadian misalignment associated with space flight and circadian rhythm sleep disorders such as shift-work disorder. PMID:17502598
Dauchy, Robert T; Hoffman, Aaron E; Wren-Dail, Melissa A; Hanifin, John P; Warfield, Benjamin; Brainard, George C; Xiang, Shulin; Yuan, Lin; Hill, Steven M; Belancio, Victoria P; Dauchy, Erin M; Smith, Kara; Blask, David E
Light controls pineal melatonin production and temporally coordinates circadian rhythms of metabolism and physiology in normal and neoplastic tissues. We previously showed that peak circulating nocturnal melatonin levels were 7-fold higher after daytime spectral transmittance of white light through blue-tinted (compared with clear) rodent cages. Here, we tested the hypothesis that daytime blue-light amplification of nocturnal melatonin enhances the inhibition of metabolism, signaling activity, and growth of prostate cancer xenografts. Compared with male nude rats housed in clear cages under a 12:12-h light:dark cycle, rats in blue-tinted cages (with increased transmittance of 462-484 nm and decreased red light greater than 640 nm) evinced over 6-fold higher peak plasma melatonin levels at middark phase (time, 2400), whereas midlight-phase levels (1200) were low (less than 3 pg/mL) in both groups. Circadian rhythms of arterial plasma levels of linoleic acid, glucose, lactic acid, pO2, pCO2, insulin, leptin, and corticosterone were disrupted in rats in blue cages as compared with the corresponding entrained rhythms in clear-caged rats. After implantation with tissue-isolated PC3 human prostate cancer xenografts, tumor latency-to-onset of growth and growth rates were markedly delayed, and tumor cAMP levels, uptake-metabolism of linoleic acid, aerobic glycolysis (Warburg effect), and growth signaling activities were reduced in rats in blue compared with clear cages. These data show that the amplification of nighttime melatonin levels by exposing nude rats to blue light during the daytime significantly reduces human prostate cancer metabolic, signaling, and proliferative activities.
Petrova, Elena S; Afanasova, Anastasia I
This paper is presenting a software development for simulating and processing thermometry data. The motivation of this research is the miniaturization of actuators attached to human body which allow frequent temperature measurements and improve the medical diagnosis procedures related to circadian dynamics.
Van Reen, Eliza; Sharkey, Katherine M; Roane, Brandy M; Barker, David; Seifer, Ronald; Raffray, Tifenn; Bond, Tamara L; Carskadon, Mary A
Sex differences in circadian rhythms have been reported with some conflicting results. The timing of sleep and length of time in bed have not been considered, however, in previous such studies. The current study has 3 major aims: (1) replicate previous studies in a large sample of young adults for sex differences in sleep patterns and dim light melatonin onset (DLMO) phase; (2) in a subsample constrained by matching across sex for bedtime and time in bed, confirm sex differences in DLMO and phase angle of DLMO to bedtime; (3) explore sex differences in the influence of sleep timing and length of time in bed on phase angle. A total of 356 first-year Brown University students (207 women) aged 17.7 to 21.4 years (mean = 18.8 years, SD = 0.4 years) were included in these analyses. Wake time was the only sleep variable that showed a sex difference. DLMO phase was earlier in women than men and phase angle wider in women than men. Shorter time in bed was associated with wider phase angle in women and men. In men, however, a 3-way interaction indicated that phase angles were influenced by both bedtime and time in bed; a complex interaction was not found for women. These analyses in a large sample of young adults on self-selected schedules confirm a sex difference in wake time, circadian phase, and the association between circadian phase and reported bedtime. A complex interaction with length of time in bed occurred for men but not women. We propose that these sex differences likely indicate fundamental differences in the biology of the sleep and circadian timing systems as well as in behavioral choices.
Ding, Zhaojun; Millar, Andrew J.; Davis, Amanda M.; Davis, Seth J.
The plant circadian clock is required for daily anticipation of the diurnal environment. Mutation in Arabidopsis thaliana TIME FOR COFFEE (TIC) affects free-running circadian rhythms. To investigate how TIC functions within the circadian system, we introduced markers for the evening and morning phases of the clock into tic and measured evident rhythms. The phases of evening clock genes in tic were all advanced under light/dark cycles without major expression level defects. With regard to morning-acting genes, we unexpectedly found that TIC has a closer relationship with LATE ELONGATED HYPOCOTYL (LHY) than with CIRCADIAN CLOCK ASSOCIATED1, as tic has a specific LHY expression level defect. Epistasis analysis demonstrated that there were no clear rhythms in double mutants of tic and evening-acting clock genes, although double mutants of tic and morning-acting genes exhibited a similar free-running period as tic. We isolated TIC and found that its mRNA expression is continuously present over the diurnal cycle, and the encoded protein appears to be strictly localized to the nucleus. Neither its abundance nor its cellular distribution was found to be clock regulated. We suggest that TIC encodes a nucleus-acting clock regulator working close to the central oscillator. PMID:17496120
Smarr, Benjamin L.; Morris, Emma
Ovulation in mammals is gated by a master circadian clock in the suprachiasmatic nucleus (SCN). GnRH neurons represent the converging pathway through which the brain triggers ovulation, but precisely how the SCN times GnRH neurons is unknown. We tested the hypothesis that neurons expressing kisspeptin, a neuropeptide coded by the Kiss1 gene and necessary for the activation of GnRH cells during ovulation, represent a relay station for circadian information that times ovulation. We first show that the circadian increase of Kiss1 expression, as well as the activation of GnRH cells, relies on intact ipsilateral neural input from the SCN. Second, by desynchronizing the dorsomedial (dm) and ventrolateral (vl) subregions of the SCN, we show that a clock residing in the dmSCN acts independently of the light-dark cycle, and the vlSCN, to time Kiss1 expression in the anteroventral periventricular nucleus of the hypothalamus and that this rhythm is always in phase with the LH surge. In addition, we show that although the timing of the LH surge is governed by the dmSCN, its amplitude likely depends on the phase coherence between the vlSCN and dmSCN. Our results suggest that whereas dmSCN neuronal oscillators are sufficient to time the LH surge through input to kisspeptin cells in the anteroventral periventricular nucleus of the hypothalamus, the phase coherence among dmSCN, vlSCN, and extra-SCN oscillators is critical for shaping it. They also suggest that female reproductive disorders associated with nocturnal shift work could emerge from the desynchronization between subregional oscillators within the master circadian clock. PMID:22454148
Smarr, Benjamin L; Morris, Emma; de la Iglesia, Horacio O
Ovulation in mammals is gated by a master circadian clock in the suprachiasmatic nucleus (SCN). GnRH neurons represent the converging pathway through which the brain triggers ovulation, but precisely how the SCN times GnRH neurons is unknown. We tested the hypothesis that neurons expressing kisspeptin, a neuropeptide coded by the Kiss1 gene and necessary for the activation of GnRH cells during ovulation, represent a relay station for circadian information that times ovulation. We first show that the circadian increase of Kiss1 expression, as well as the activation of GnRH cells, relies on intact ipsilateral neural input from the SCN. Second, by desynchronizing the dorsomedial (dm) and ventrolateral (vl) subregions of the SCN, we show that a clock residing in the dmSCN acts independently of the light-dark cycle, and the vlSCN, to time Kiss1 expression in the anteroventral periventricular nucleus of the hypothalamus and that this rhythm is always in phase with the LH surge. In addition, we show that although the timing of the LH surge is governed by the dmSCN, its amplitude likely depends on the phase coherence between the vlSCN and dmSCN. Our results suggest that whereas dmSCN neuronal oscillators are sufficient to time the LH surge through input to kisspeptin cells in the anteroventral periventricular nucleus of the hypothalamus, the phase coherence among dmSCN, vlSCN, and extra-SCN oscillators is critical for shaping it. They also suggest that female reproductive disorders associated with nocturnal shift work could emerge from the desynchronization between subregional oscillators within the master circadian clock.
Zhu, Lirong; Zee, Phyllis C.
There have been remarkable advances in our understanding of the molecular, cellular and physiological mechanisms underlying the regulation of circadian rhythms, as well as the impact of circadian dysfunction on health and disease. This information has transformed our understanding of the effect of circadian rhythm sleep disorders (CRSD) on health, performance and safety. CRSDs are caused by alterations of the central circadian time-keeping system, or a misalignment of the endogenous circadian rhythm and the external environment. In this section, we provide a review of circadian biology and discuss the pathophysiology, clinical features, diagnosis, and treatment of the most commonly encountered CRSDs in clinical practice. PMID:23099133
Synchronization of the mammalian circadian timing system: Light can control peripheral clocks independently of the SCN clock: alternate routes of entrainment optimize the alignment of the body's circadian clock network with external time.
Husse, Jana; Eichele, Gregor; Oster, Henrik
A vast network of cellular circadian clocks regulates 24-hour rhythms of behavior and physiology in mammals. Complex environments are characterized by multiple, and often conflicting time signals demanding flexible mechanisms of adaptation of endogenous rhythms to external time. Traditionally this process of circadian entrainment has been conceptualized in a hierarchical scheme with a light-reset master pacemaker residing in the hypothalamus that subsequently aligns subordinate peripheral clocks with each other and with external time. Here we review new experiments using conditional mouse genetics suggesting that resetting of the circadian system occurs in a more "federated" and tissue-specific fashion, which allows for increased noise resistance and plasticity of circadian timekeeping under natural conditions.
Johnston, Jonathan D
Emerging links between circadian rhythms and metabolism promise much for the understanding of metabolic physiology and pathophysiology, in which white adipose tissue (WAT) plays a prominent role. Many WAT endocrine molecules, termed adipokines, display rhythmic plasma concentration. Moreover, similar to most other tissues, WAT exhibits widespread 24-h variation in gene expression, with approximately 20% of the murine adipose transcriptome estimated to undergo daily variation. A major limitation to human chronobiology research is the availability of physiologically defined peripheral tissues. To date most analyses of in vivo human peripheral clocks has been limited to blood leucocytes. However, subcutaneous adipose tissue represents a novel opportunity to study peripheral molecular rhythms that are of clearly defined metabolic relevance. This review summarises basic concepts of circadian and metabolic physiology before then comparing alternative protocols used to analyse the rhythmic properties of human adipose tissue.
Dickmeis, Thomas; Weger, Benjamin D; Weger, Meltem
Glucocorticoids are steroid hormones of the adrenal gland that are an integral component of the stress response and regulate many physiological processes, including metabolism and immune response. Their release into the blood is highly dynamic and occurs in about hourly pulses, the amplitude of which is modulated in a daytime dependent fashion. In addition, in many species seasonal changes in basal glucocorticoid levels have been reported. In their target tissues, glucocorticoids bind to cytoplasmic receptors of the nuclear receptor superfamily. Upon binding, these receptors regulate transcription in a highly dynamic fashion, which involves stochastic binding to regulatory DNA elements on a time scale of seconds and heat shock protein mediated receptor-ligand complex recycling within minutes. The glucocorticoid hormone system interacts with another highly dynamic system, the circadian clock. The circadian clock is an endogenous biological timing mechanism that allows organisms to anticipate regular daily changes in their environment. It regulates daily rhythms of glucocorticoid release by a variety of mechanisms, modulates glucocorticoid signaling and is itself influenced by glucocorticoids. Here, we discuss mechanisms, functions and interactions of the circadian and glucocorticoid systems across time scales ranging from seconds (DNA binding by transcriptional regulators) to years (seasonal rhythms).
Monk, Timothy H.; Buysse, Daniel J.; Billy, Bart D.; Fletcher, Mary E.; Kennedy, Kathy S.; Schlarb, Janet E.; Beach, Scott R.
Study Objectives: Using telephone interview data from retired seniors to explore how inter-individual differences in circadian type (morningness) and bed-timing regularity might be related to subjective sleep quality and quantity. Design: MANCOVA with binary measures of morningness, stability of bedtimes, and stability of rise-times as independent variables; sleep measures as dependent variables; age, former shift work, and gender as covariates. Setting: Telephone interviews using a pseudo-random age-targeted sampling process. Participants: 654 retired seniors (65 y+, 363M, 291F). Intervention: none. Measurements and Results: Independent variables: (1) circadian type (from Composite Scale of Morningness [CSM]), and stability of (2) bedtime and (3) rise-time from the Sleep Timing Questionnaire (STQ). Dependent variables: Pittsburgh Sleep Quality Index (PSQI) score, time in bed, time spent asleep, and sleep efficiency, from Sleep Timing Questionnaire (STQ). Morning-type orientation, stability in bedtimes, and stability in rise-times were all associated with better sleep quality (P < 0.001, for all; effect sizes: 0.43, 0.33, and 0.27). Morningness was associated with shorter time in bed (P < 0.0001, effect size 0.45) and time spent asleep (P < 0.005, effect size 0.26). For bedtime and rise-time stability the direction of effect was similar but mostly weaker. Conclusions: In retired seniors, a morning-type orientation and regularity in bedtimes and rise-times appear to be correlated with improved subjective sleep quality and with less time spent in bed. Citation: Monk TH; Buysse DJ; Billy BD; Fletcher ME; Kennedy KS; Schlarb JE; Beach SR. Circadian type and bed-timing regularity in 654 retired seniors: correlations with subjective sleep measures. SLEEP 2011;34(2):235-239. PMID:21286245
Squarcini, Camila Fabiana Rossi; Pires, Maria Laura Nogueira; Lopes, Cleide; Benedito-Silva, Ana Amélia; Esteves, Andrea Maculano; Cornelissen-Guillaume, Germaine; Matarazzo, Carolina; Garcia, Danilo; da Silva, Maria Stella Peccin; Tufik, Sergio; de Mello, Marco Túlio
Light is the major synchronizer of circadian rhythms. In the absence of light, as for totally blind people, some variables, such as body temperature, have an endogenous period that is longer than 24 h and tend to be free running. However, the circadian rhythm of muscle strength and reaction time in totally blind people has not been defined in the literature. The objective of this study was to determine the period of the endogenous circadian rhythm of the isometric and isokinetic contraction strength and simple reaction time of totally blind people. The study included six totally blind people with free-running circadian rhythms and four sighted people (control group). Although the control group required only a single session to determine the circadian rhythm, the blind people required three sessions to determine the endogenous period. In each session, isometric strength, isokinetic strength, reaction time, and body temperature were collected six different times a day with an interval of at least 8 h. The control group had better performance for strength and reaction time in the afternoon. For the blind, this performance became delayed throughout the day. Therefore, we conclude that the circadian rhythms of strength and simple reaction time of totally blind people are within their free-running periods. For some professionals, like the blind paralympic athletes, activities that require large physiological capacities in which the maximum stimulus should match the ideal time of competition may result in the blind athletes falling short of their expected performance under this free-running condition.
Keller, Jutta; Layer, Peter
It is unknown whether nonparallel pancreatic enzyme output occurs under basal conditions in humans. We aimed to determine whether the circadian or wake-sleep cycle influences the relationship among pancreatic enzymes or between pancreatic secretory and jejunal motor activity. Using orojejunal multilumen intubation, we measured enzyme outputs and proximal jejunal motility index during consecutive daytime and nighttime periods in each of seven fasting, healthy volunteers. Enzyme outputs were correlated tightly during daytime phases of wakefulness and nighttime phases of sleep (r > 0.72, P < 0.001). During nocturnal phases of wakefulness, output of proteases (r = 0.84, P < 0.001), but not of amylase and trypsin (r = 0.12), remained associated. Nocturnally, particularly during sleep, pancreatic secretory activity was directly correlated with jejunal motility index (r > 0.50, P < 0.001). In conclusion, parallel secretion of pancreatic enzymes dominates throughout the circadian cycle. Nonparallel secretion during nocturnal phases of wakefulness may be due to merely circadian effects or to the coupling of the wake-sleep and the circadian cycle. The association between fluctuations of secretory and motor activity appears to be particularly tight during the night.
Husse, Jana; Eichele, Gregor
A vast network of cellular circadian clocks regulates 24‐hour rhythms of behavior and physiology in mammals. Complex environments are characterized by multiple, and often conflicting time signals demanding flexible mechanisms of adaptation of endogenous rhythms to external time. Traditionally this process of circadian entrainment has been conceptualized in a hierarchical scheme with a light‐reset master pacemaker residing in the hypothalamus that subsequently aligns subordinate peripheral clocks with each other and with external time. Here we review new experiments using conditional mouse genetics suggesting that resetting of the circadian system occurs in a more “federated” and tissue‐specific fashion, which allows for increased noise resistance and plasticity of circadian timekeeping under natural conditions. PMID:26252253
Martin-Tryon, Ellen L.; Harmer, Stacey L.
Numerous, varied, and widespread taxa have an internal circadian clock that allows anticipation of rhythmic changes in the environment. We have identified XAP5 CIRCADIAN TIMEKEEPER (XCT), an Arabidopsis thaliana gene important for light regulation of the circadian clock and photomorphogenesis. XCT is essential for proper clock function: xct mutants display a shortened circadian period in all conditions tested. Interestingly, XCT plays opposite roles in plant responses to light depending both on trait and wavelength. The clock in xct plants is hypersensitive to red but shows normal responses to blue light. By contrast, inhibition of hypocotyl elongation in xct is hyposensitive to red light but hypersensitive to blue light. Finally, XCT is important for ribulose-1,5-bisphosphate carboxylase/oxygenase production and plant greening in response to light. This novel combination of phenotypes suggests XCT may play a global role in coordinating growth in response to the light environment. XCT contains a XAP5 domain and is well conserved across diverse taxa, suggesting it has a common function in higher eukaryotes. Downregulation of the XCT ortholog in Caenorhabditis elegans is lethal, suggesting that studies in Arabidopsis may be instrumental to understanding the biochemical activity of XCT. PMID:18515502
Cajochen, C.; Khalsa, S. B.; Wyatt, J. K.; Czeisler, C. A.; Dijk, D. J.
The aim of this study was to quantify the associations between slow eye movements (SEMs), eye blink rate, waking electroencephalogram (EEG) power density, neurobehavioral performance, and the circadian rhythm of plasma melatonin in a cohort of 10 healthy men during up to 32 h of sustained wakefulness. The time course of neurobehavioral performance was characterized by fairly stable levels throughout the first 16 h of wakefulness followed by deterioration during the phase of melatonin secretion. This deterioration was closely associated with an increase in SEMs. Frontal low-frequency EEG activity (1-7 Hz) exhibited a prominent increase with time awake and little circadian modulation. EEG alpha activity exhibited circadian modulation. The dynamics of SEMs and EEG activity were phase locked to changes in neurobehavioral performance and lagged the plasma melatonin rhythm. The data indicate that frontal areas of the brain are more susceptible to sleep loss than occipital areas. Frontal EEG activity and ocular parameters may be used to monitor and predict changes in neurobehavioral performance associated with sleep loss and circadian misalignment.
Miller, D; Bierman, A; Figueiro, Mg; Schernhammer, Es; Rea, Ms
Circadian rhythms are biological rhythms that repeat at approximately 24 hours. In humans, circadian rhythms have an average period of 24.2 hours. The 24-hour patterns of light and dark on the retina synchronize circadian rhythms to the local time on earth. Lighting characteristics affecting circadian rhythms are very different than those affecting visual responses. Lack of synchronization between the endogenous clock and the local time has been associated with a host of maladies. Therefore, it is important to measure circadian light exposures over the course of the 24-hour day and to be able to assess circadian entrainment and disruption in actual living environments. Presented is an overview of the recently developed Daysimeter, a personal measurement device for recording activity and circadian light-exposure. When the Daysimeter is worn on the head, two light sensors near the eye are used to estimate circadian light (CLA) exposures over extended periods of time. Phasor analysis combines the measured periodic activity-rest patterns with the measured periodic light-dark patterns to assess behavioural circadian entrainment/disruption. As shown, day-shift and rotating-shift nurses exhibit remarkably different levels of behavioural circadian entrainment/disruption. These new ecological measurement and analysis techniques may provide important insights into the relationship between circadian disruption and well-being.
Müller, Lisa; Fritzsche, Peter; Weinert, Dietmar
Circadian rhythms have been shown to influence learning and memory. In this study, cognitive functions of Djungarian hamsters revealing different circadian phenotypes were evaluated using a novel object recognition (NOR) task. Wild type (WT) animals show a clear and well-synchronized daily activity rhythm, whereas DAO hamsters are characterized by a delayed activity onset. The phenomenon is caused by a diminished ability of photic synchronization. In arrhythmic (AR) hamsters, the suprachiasmatic nuclei (SCN) do not generate a circadian signal at all. The aim of this study was to investigate consequences of these deteriorations for learning and memory processes. Hamsters were bred and kept under standardized housing conditions with food and water ad libitum and a 14 L/10 D lighting regimen. Experimental animals were assigned to different groups (WT, DAO and AR) according to their activity pattern obtained by means of infrared motion sensors. Activity onset of DAO animals was delayed by 3 ± 0.5 h. NOR tests were performed in an open arena and consisted of habituation, training (two identical objects) and test sessions (one of the two objects being replaced). The training-test interval was 60 min. Tests were performed at different Zeitgeber times (ZT 0 = light-on). Every hamster was tested at all times with an interval of one week between experiments. As activity onset of DAO animals is delaying continuously day by day, they could be tested at only three times (ZT 13, ZT 16 and ZT 19). The times animals did explore the novel and the familiar objects were recorded, and the discrimination index as a measure of cognitive performance was calculated. Behavioral analyzes revealed that, WT hamsters were able to discriminate between familiar and novel objects at ZT 13, ZT 16 and ZT 19, i.e. one hour before and during their activity period. In accordance with their delayed activity onset, DAO hamsters could discriminate between objects only at ZT 16 and ZT 19
Johnston, Jonathan D
Circadian rhythms, metabolism and nutrition are closely interlinked. A great deal of recent research has investigated not only how aspects of metabolic physiology are driven by circadian clocks, but also how these circadian clocks are themselves sensitive to metabolic change. At the cellular level, novel feedback loops have been identified that couple circadian 'clock genes' and their proteins to expression of nuclear receptors, regulation of redox state and other major pathways. Using targeted disruption of circadian clocks, mouse models are providing novel insight into the role of tissue-specific clocks in glucose homeostasis and body weight regulation. The relationship between circadian rhythms and obesity appears complex, with variable alteration of rhythms in obese individuals. However, it is clear from animal studies that the timing and nutritional composition of meals can regulate circadian rhythms, particularly in peripheral tissues. Translation of these findings to human physiology now represents an important goal.
Cavanaugh, Daniel J.; Vigderman, Abigail S.; Dean, Terry; Garbe, David S.; Sehgal, Amita
Study Objectives: Sleep is under the control of homeostatic and circadian processes, which interact to determine sleep timing and duration, but the mechanisms through which the circadian system modulates sleep are largely unknown. We therefore used adult-specific, temporally controlled neuronal activation and inhibition to identify an interaction between the circadian clock and a novel population of sleep-promoting neurons in Drosophila. Methods: Transgenic flies expressed either dTRPA1, a neuronal activator, or Shibirets1, an inhibitor of synaptic release, in small subsets of neurons. Sleep, as determined by activity monitoring and video tracking, was assessed before and after temperature-induced activation or inhibition using these effector molecules. We compared the effect of these manipulations in control flies and in mutant flies that lacked components of the molecular circadian clock. Results: Adult-specific activation or inhibition of a population of neurons that projects to the sleep-promoting dorsal Fan-Shaped Body resulted in bidirectional control over sleep. Interestingly, the magnitude of the sleep changes were time-of-day dependent. Activation of sleep-promoting neurons was maximally effective during the middle of the day and night, and was relatively ineffective during the day-to-night and night-to-day transitions. These time-ofday specific effects were absent in flies that lacked functional circadian clocks. Conclusions: We conclude that the circadian system functions to gate sleep through active inhibition at specific times of day. These data identify a mechanism through which the circadian system prevents premature sleep onset in the late evening, when homeostatic sleep drive is high. Citation: Cavanaugh DJ, Vigderman AS, Dean T, Garbe DS, Sehgal A. The Drosophila circadian clock gates sleep through time-of-day dependent modulation of sleep-promoting neurons. SLEEP 2016;39(2):345–356. PMID:26350473
Emerson, Kevin J; Dake, Sabrina J; Bradshaw, William E; Holzapfel, Christina M
For over 70 years, researchers have debated whether the ability to use day length as a cue for the timing of seasonal events (photoperiodism) is related to the endogenous circadian clock that regulates the timing of daily events. Models of photoperiodism include two components: (1) a photoperiodic timer that measures the length of the day, and (2) a photoperiodic counter that elicits the downstream photoperiodic response after a threshold number of days has been counted. Herein, we show that there is no geographical pattern of genetic association between the expression of the circadian clock and the photoperiodic timer or counter. We conclude that the photoperiodic timer and counter have evolved independently of the circadian clock in the pitcher-plant mosquito Wyeomyia smithii and hence, the evolutionary modification of photoperiodism throughout the range of W. smithii has not been causally mediated by a corresponding evolution of the circadian clock.
Froy, Oren; Chapnik, Nava; Miskin, Ruth
Calorie restriction (CR) resets circadian rhythms and extends life span. Intermittent fasting (IF) also extends life span, but its affect on circadian rhythms has not been studied. To study the effect of IF alongside CR, we imposed IF in FVB/N mice or IF combined with CR using the transgenic FVB/N alphaMUPA mice that, when fed ad libitum, exhibit spontaneously reduced eating and extended life span. Our results show that when food was introduced during the light period, body temperature peak was not disrupted. In contrast, IF caused almost arrhythmicity in clock gene expression in the liver and advanced mPer2 and mClock expression. However, IF restored the amplitudes of clock gene expression under disruptive light condition regardless whether the animals were calorically restricted or not. Unlike daytime feeding, nighttime feeding yielded rhythms similar to those generated during ad libitum feeding. Taken together, our results show that IF can affect circadian rhythms differently depending on the timing of food availability, and suggest that this regimen induces a metabolic state that affects the suprachiasmatic nuclei (SCN) clock.
Cain, Sean W; Rawashdeh, Omar A; Siu, Michael; Kim, Seung Cheol; Ralph, Martin R
Animals learn and remember the time of day that significant conditions occur, and anticipate recurrence at 24-h intervals, even after only one exposure to the condition. On several place-conditioning tasks, animals show context avoidance or preference only near the time of day of the experience. The memory for time of day is registered by a circadian oscillator that is set at the time of the training. We show that manipulations of dopamine (DA) neurotransmission can set a time memory in place preference and avoidance tasks, indicating that time of day is part of the context that is learned. Single injections of the DA agonist, d-amphetamine sulfate given without further exposure to the conditioning apparatus, can reset the timing of anticipatory behavior evoked by previously acquired place-event associations. The data support a model for time memory in which DA signaling sets the phase of a circadian oscillator, which returns to the same state at regular 24-h intervals. The data also raise the possibility that some apparent impairments of memory formation or retention could reflect post-experience resetting of the optimal retrieval time rather than impairment of memory or retrieval per se.
Dijk, D. J.
In humans, EEG power spectra in REM and NREM sleep, as well as characteristics of sleep spindles such as their duration, amplitude, frequency and incidence, vary with circadian phase. Recently it has been hypothesized that circadian variations in EEG spectra in humans are caused by variations in brain or body temperature and may not represent phenomena relevant to sleep regulatory processes. To test this directly, a further analysis of EEG power spectra - collected in a forced desynchrony protocol in which sleep episodes were scheduled to a 28-h period while the rhythms of body temperature and plasma melatonin were oscillating at their near 24-h period - was carried out. EEG power spectra were computed for NREM and REM sleep occurring between 90-120 and 270-300 degrees of the circadian melatonin rhythm, i.e. just after the clearance of melatonin from plasma in the 'morning' and just after the 'evening' increase in melatonin secretion. Average body temperatures during scheduled sleep at these two circadian phases were identical (36.72 degrees C). Despite identical body temperatures, the power spectra in NREM sleep were very different at these two circadian phases. EEG activity in the low frequency spindle range was significantly and markedly enhanced after the evening increase in plasma melatonin as compared to the morning phase. For REM sleep, significant differences in power spectra during these two circadian phases, in particular in the alpha range, were also observed. The results confirm that EEG power spectra in NREM and REM sleep vary with circadian phase, suggesting that the direct contribution of temperature to the circadian variation in EEG power spectra is absent or only minor, and are at variance with the hypothesis that circadian variations in EEG power spectra are caused by variations in temperature.
Akacem, Lameese D; Simpkin, Charles T; Carskadon, Mary A; Wright, Kenneth P; Jenni, Oskar G; Achermann, Peter; LeBourgeois, Monique K
The timing of the internal circadian clock shows large inter-individual variability across the lifespan. Although the sleep-wakefulness pattern of most toddlers includes an afternoon nap, the association between napping and circadian phase in early childhood remains unexplored. This study examined differences in circadian phase and sleep between napping and non-napping toddlers. Data were collected on 20 toddlers (34.2±2.0 months; 12 females; 15 nappers). Children followed their habitual napping and non-napping sleep schedules (monitored with actigraphy) for 5 days before an in-home salivary dim light melatonin onset (DLMO) assessment. On average, napping children fell asleep during their nap opportunities on 3.6±1.2 of the 5 days before the DLMO assessment. For these napping children, melatonin onset time was 38 min later (p = 0.044; d = 0.93), actigraphically-estimated bedtime was 43 min later (p = 0.014; d = 1.24), sleep onset time was 59 min later (p = 0.006; d = 1.46), and sleep onset latency was 16 min longer (p = 0.030; d = 1.03) than those not napping. Midsleep and wake time did not differ by napping status. No difference was observed in the bedtime, sleep onset, or midsleep phase relationships with DLMO; however, the wake time phase difference was 47 min smaller for napping toddlers (p = 0.029; d = 1.23). On average, nappers had 69 min shorter nighttime sleep durations (p = 0.006; d = 1.47) and spent 49 min less time in bed (p = 0.019; d = 1.16) than non-nappers. Number of days napping was correlated with melatonin onset time (r = 0.49; p = 0.014). Our findings indicate that napping influences individual variability in melatonin onset time in early childhood. The delayed bedtimes of napping toddlers likely permits light exposure later in the evening, thereby delaying the timing of the clock and sleep. Whether the early developmental trajectory of circadian phase involves an advance associated with the decline in napping is a question necessitating
Potter, Gregory D M; Cade, Janet E; Grant, Peter J; Hardie, Laura J
The human circadian system anticipates and adapts to daily environmental changes to optimise behaviour according to time of day and temporally partition incompatible physiological processes. At the helm of this system is a master clock in the suprachiasmatic nuclei (SCN) of the anterior hypothalamus. The SCN are primarily synchronised to the 24 hour day by the light/dark cycle; however, feeding/fasting cycles are the primary time cues for clocks in peripheral tissues. Aligning feeding/fasting cycles with clock-regulated metabolic changes optimises metabolism, and studies of other animals suggest that feeding at inappropriate times disrupts circadian system organisation and thereby contributes to adverse metabolic consequences and chronic disease development. ‘High-fat diets’ (HFDs) produce particularly deleterious effects on circadian system organisation in rodents by blunting feeding/fasting cycles. Time-of-day-restricted feeding, where food availability is restricted to a period of several hours, offsets many adverse consequences of HFDs in these animals; however, further evidence is required to assess whether the same is true in humans. Several nutritional compounds have robust effects on the circadian system. Caffeine, for example, can speed synchronisation to new time zones after jetlag. An appreciation of the circadian system has many implications for nutritional science and may ultimately help reduce the burden of chronic diseases. PMID:27221157
Potter, Gregory D M; Cade, Janet E; Grant, Peter J; Hardie, Laura J
The human circadian system anticipates and adapts to daily environmental changes to optimise behaviour according to time of day and temporally partitions incompatible physiological processes. At the helm of this system is a master clock in the suprachiasmatic nuclei (SCN) of the anterior hypothalamus. The SCN are primarily synchronised to the 24-h day by the light/dark cycle; however, feeding/fasting cycles are the primary time cues for clocks in peripheral tissues. Aligning feeding/fasting cycles with clock-regulated metabolic changes optimises metabolism, and studies of other animals suggest that feeding at inappropriate times disrupts circadian system organisation, and thereby contributes to adverse metabolic consequences and chronic disease development. 'High-fat diets' (HFD) produce particularly deleterious effects on circadian system organisation in rodents by blunting feeding/fasting cycles. Time-of-day-restricted feeding, where food availability is restricted to a period of several hours, offsets many adverse consequences of HFD in these animals; however, further evidence is required to assess whether the same is true in humans. Several nutritional compounds have robust effects on the circadian system. Caffeine, for example, can speed synchronisation to new time zones after jetlag. An appreciation of the circadian system has many implications for nutritional science and may ultimately help reduce the burden of chronic diseases.
Yoon, Ji-Ae; Han, Dong-Hee; Noh, Jong-Yun; Kim, Mi-Hee; Son, Gi Hoon; Kim, Kyungjin; Kim, Chang-Ju; Pak, Youngmi Kim; Cho, Sehyung
In modern society, growing numbers of people are engaged in various forms of shift works or trans-meridian travels. Such circadian misalignment is known to disturb endogenous diurnal rhythms, which may lead to harmful physiological consequences including metabolic syndrome, obesity, cancer, cardiovascular disorders, and gastric disorders as well as other physical and mental disorders. However, the precise mechanism(s) underlying these changes are yet unclear. The present work, therefore examined the effects of 6 h advance or delay of usual meal time on diurnal rhythmicities in home cage activity (HCA), body temperature (BT), blood metabolic markers, glucose homeostasis, and expression of genes that are involved in cholesterol homeostasis by feeding young adult male mice in a time-restrictive manner. Delay of meal time caused locomotive hyperactivity in a significant portion (42%) of subjects, while 6 h advance caused a torpor-like symptom during the late scotophase. Accordingly, daily rhythms of blood glucose and triglyceride were differentially affected by time-restrictive feeding regimen with concurrent metabolic alterations. Along with these physiological changes, time-restrictive feeding also influenced the circadian expression patterns of low density lipoprotein receptor (LDLR) as well as most LDLR regulatory factors. Strikingly, chronic advance of meal time induced insulin resistance, while chronic delay significantly elevated blood glucose levels. Taken together, our findings indicate that persistent shifts in usual meal time impact the diurnal rhythms of carbohydrate and lipid metabolisms in addition to HCA and BT, thereby posing critical implications for the health and diseases of shift workers.
Dridi, Dorra; Boughattas, Naceur A; Aouam, Karim; Reinberg, Alain; Ben Attia, Mossadok
Loratadine is a second-generation histamine H(1)-receptor antagonist used in the treatment of allergic diseases. The aim of the study was to assess whether lethal toxicity and motor incoordination (neurotoxicity) of loratadine is circadian rhythm-dependent. A total of 210 male Swiss mice, aged 10 wk, were synchronized for 3 wk to 12 h light (rest span)/12 h dark (activity span). The drug was administered per os. The choice of the sublethal (TD(50) = 82 mg/kg body weight) and the lethal (LD(50) = 4 g/kg body weight) dosage was based on preliminary studies. Each of these two doses was administered to comparable groups of animals at six different circadian time points (1, 5, 9, 13, 17, and 21 Hours After Light Onset [HALO]). The survival duration was dosing time-dependent (chi(2) = 16.96; p < 0.001). Drug dosing at 17 HALO resulted in best (67%) survival rate; whereas, dosing at 9 HALO resulted in poorest (21%) survival rate. Cosinor analyses (with a trial period tau = 24 h) validated a statistically significant circadian rhythm in survival rate (p < 0.04) with an acrophase (peak time Ø of best tolerance to loratadine) being at 17.5 HALO +/- 4.65 h. Troughs of motor incoordination were located at the administration times of 5 and 17 HALO (60% and 32% of animals affected, respectively), whereas peaks were located at 9 and 21 HALO (87% and 68% of animals affected, respectively). The 24 h mean of the motor incoordination was 61%, the mean proportion of animals affected by the treatment for the six different circadian times studies. The extent of this neurotoxic effect varied as a function of loratadine dosing time (p < 0.001). A statistically significant ultradian component rhythm (p < 0.01) with a trial period tau = 12 h was also validated. The obtained results show that the dosing time of loratadine at the mid-activity (dark) span seems to be optimal, since it corresponds to the longest (21 vs. 12 days) survival span and to least neurotoxicity.
Teschke, Mathias; Wendt, Sabrina; Kawaguchi, So; Kramer, Achim; Meyer, Bettina
Antarctic krill, Euphausia superba, shapes the structure of the Southern Ocean ecosystem. Its central position in the food web, the ongoing environmental changes due to climatic warming, and increasing commercial interest on this species emphasize the urgency of understanding the adaptability of krill to its environment. Krill has evolved rhythmic physiological and behavioral functions which are synchronized with the daily and seasonal cycles of the complex Southern Ocean ecosystem. The mechanisms, however, leading to these rhythms are essentially unknown. Here, we show that krill possesses an endogenous circadian clock that governs metabolic and physiological output rhythms. We found that expression of the canonical clock gene cry2 was highly rhythmic both in a light-dark cycle and in constant darkness. We detected a remarkable short circadian period, which we interpret as a special feature of the krill's circadian clock that helps to entrain the circadian system to the extreme range of photoperiods krill is exposed to throughout the year. Furthermore, we found that important key metabolic enzymes of krill showed bimodal circadian oscillations (∼9-12 h period) in transcript abundance and enzymatic activity. Oxygen consumption of krill showed ∼9-12 h oscillations that correlated with the temporal activity profile of key enzymes of aerobic energy metabolism. Our results demonstrate the first report of an endogenous circadian timing system in Antarctic krill and its likely link to metabolic key processes. Krill's circadian clock may not only be critical for synchronization to the solar day but also for the control of seasonal events. This study provides a powerful basis for the investigation into the mechanisms of temporal synchronization in this marine key species and will also lead to the first comprehensive analyses of the circadian clock of a polar marine organism through the entire photoperiodic cycle.
Teschke, Mathias; Wendt, Sabrina; Kawaguchi, So; Kramer, Achim; Meyer, Bettina
Antarctic krill, Euphausia superba, shapes the structure of the Southern Ocean ecosystem. Its central position in the food web, the ongoing environmental changes due to climatic warming, and increasing commercial interest on this species emphasize the urgency of understanding the adaptability of krill to its environment. Krill has evolved rhythmic physiological and behavioral functions which are synchronized with the daily and seasonal cycles of the complex Southern Ocean ecosystem. The mechanisms, however, leading to these rhythms are essentially unknown. Here, we show that krill possesses an endogenous circadian clock that governs metabolic and physiological output rhythms. We found that expression of the canonical clock gene cry2 was highly rhythmic both in a light-dark cycle and in constant darkness. We detected a remarkable short circadian period, which we interpret as a special feature of the krill's circadian clock that helps to entrain the circadian system to the extreme range of photoperiods krill is exposed to throughout the year. Furthermore, we found that important key metabolic enzymes of krill showed bimodal circadian oscillations (∼9–12 h period) in transcript abundance and enzymatic activity. Oxygen consumption of krill showed ∼9–12 h oscillations that correlated with the temporal activity profile of key enzymes of aerobic energy metabolism. Our results demonstrate the first report of an endogenous circadian timing system in Antarctic krill and its likely link to metabolic key processes. Krill's circadian clock may not only be critical for synchronization to the solar day but also for the control of seasonal events. This study provides a powerful basis for the investigation into the mechanisms of temporal synchronization in this marine key species and will also lead to the first comprehensive analyses of the circadian clock of a polar marine organism through the entire photoperiodic cycle. PMID:22022521
Background Circadian clocks have been postulated to regulate development time in several species of insects including fruit flies Drosophila melanogaster. Previously we have reported that selection for faster pre-adult development reduces development time (by ~19 h or ~11%) and clock period (by ~0.5 h), suggesting a role of circadian clocks in the regulation of development time in D. melanogaster. We reasoned that these faster developing flies could serve as a model to study stage-specific interaction of circadian clocks and developmental events with the environmental light/dark (LD) conditions. We assayed the duration of three pre-adult stages in the faster developing (FD) and control (BD) populations under a variety of light regimes that are known to modulate circadian clocks and pre-adult development time of Drosophila to examine the role of circadian clocks in the timing of pre-adult developmental stages. Results We find that the duration of pre-adult stages was shorter under constant light (LL) and short period light (L)/dark (D) cycles (L:D = 10:10 h; T20) compared to the standard 24 h day (L:D = 12:12 h; T24), long LD cycles (L:D = 14:14 h; T28) and constant darkness (DD). The difference in the duration of pre-adult stages between the FD and BD populations was significantly smaller under the three LD cycles and LL compared to DD, possibly due to the fact that clocks of both FD and BD flies are driven at the same pace in the three LD regimes owing to circadian entrainment, or are rendered dysfunctional under LL. Conclusions These results suggest that interaction between light regimes and circadian clocks regulate the duration of pre-adult developmental stages in fruit flies D. melanogaster. PMID:24885932
Martin-Tryon, Ellen L; Kreps, Joel A; Harmer, Stacey L
Circadian clocks are widespread in nature. In higher plants, they confer a selective advantage, providing information regarding not only time of day but also time of year. Forward genetic screens in Arabidopsis (Arabidopsis thaliana) have led to the identification of many clock components, but the functions of most of these genes remain obscure. To identify both new constituents of the circadian clock and new alleles of known clock-associated genes, we performed a mutant screen. Using a clock-regulated luciferase reporter, we isolated new alleles of ZEITLUPE, LATE ELONGATED HYPOCOTYL, and GIGANTEA (GI). GI has previously been reported to function in red light signaling, central clock function, and flowering time regulation. Characterization of this and other GI alleles has helped us to further define GI function in the circadian system. We found that GI acts in photomorphogenic and circadian blue light signaling pathways and is differentially required for clock function in constant red versus blue light. Gene expression and epistasis analyses show that TIMING OF CHLOROPHYLL A/B BINDING PROTEIN1 (TOC1) expression is not solely dependent upon GI and that GI expression is only indirectly affected by TOC1, suggesting that GI acts both in series with and in parallel to TOC1 within the central circadian oscillator. Finally, we found that the GI-dependent promotion of CONSTANS expression and flowering is intact in a gi mutant with altered circadian regulation. Thus GI function in the regulation of a clock output can be biochemically separated from its role within the circadian clock.
Winget, C. M.; Lyman, J.; Beljan, J. R.
Experiments were conducted on six healthy male subjects aged 20-23 yr and exposed for 21 days in a confined regulated environment to 16L:8D light:dark cycle with a view toward determining whether the light environment of 16L:8D at the relatively low light intensity of 15 ft.c. is adequate for the maintenance of circadian synchrony in man. The light intensity was 100 ft.c. during the first seven days, reduced to 15 ft.c. during the next seven days, and increased again to 100 ft.c. during the last seven days. Rectal temperature (RT) and heart rate (HR) were recorded throughout the three phases. In the 100 ft.c. regime, the RT and HR rhythms remained stable and circadian throughout. It is shown that 15 ft.c. light intensity is at or below threshold for maintaining circadian synchrony of human physiologic rhythms marked by instability and internal desynchronization with degradation of performance and well-being.
Al-Turk, Walid; Al-Dujaili, Emad A S
There has been a lot of effort by scientists to elucidate the multi functions of the naturally occurring hormone, dehydroepiandrosterone (DHEA). However, to plan research experiments optimally, it is important first to characterize the diurnal rhythm in healthy individuals. The aim of this research was to investigate the daily circadian rhythms of DHEA among the 2 genders, and the effect of age and exercise on salivary DHEA circadian rhythms. Volunteers (20-39 and 40-60 years) were recruited for 2 studies investigating the salivary DHEA circadian rhythm. The first study looked at the effect of gender and age on DHEA levels on 2 non-consecutive days, and the second study explored the effect of exercise on DHEA circadian rhythm in males. DHEA levels were estimated by a sensitive and specific ELISA method. The results showed a clear daily circadian rhythm in salivary DHEA in all participants groups, however the profile was flatter in the older female group. There was a significant difference between age and gender groups particularly at 8.00 h. In young males DHEA reduced from 541.1 ± 101.3 (mean ± sd) at 8.00 h to 198.9 ± 90.7 pg/mL at 18.00 h; p<0.0001, and young females from 401.6 ± 149.5 to 215.4 ± 95.3 pg/mL; p<0.001. In older males DHEA reduced from 267.5 ± 32.4 to 132.5 ± 46.7 pg/mL; p<0.001, and older females from 147.7 ± 78.1 to 89.5 ± 29.1 pg/mL; p=0.05. DHEA levels on 2 non-consecutive days showed some variations but this was not significant. Aerobic exercise has significantly increased DHEA levels at 2 time points of the day (p=0.05) in male subjects. In conclusion, our study showed a clear daily circadian rhythm in salivary DHEA in all participants was observed, but the profile was flatter in the older groups.
Simpkin, Charles T; Jenni, Oskar G; Carskadon, Mary A; Wright, Kenneth P; Akacem, Lameese D; Garlo, Katherine G; LeBourgeois, Monique K
Chronotype is a construct reflecting individual differences in diurnal preference. Although chronotype has been studied extensively in school-age children, adolescents and adults, data on young children are scarce. This study describes chronotype and its relationship to the timing of the circadian clock and sleep in 48 healthy children aged 30-36 months (33.4 ± 2.1 months; 24 males). Parents completed the Children's Chronotype Questionnaire (CCTQ) ~2 weeks before the start of the study. The CCTQ provides three measures of chronotype: midsleep time on free days, a multi-item morningness/eveningness score and a single item chronotype score. After 5 days of sleeping on their habitual schedule (assessed with actigraphy and sleep diaries), children participated in an in-home salivary dim light melatonin onset assessment. Average midsleep time on free days was 1:47 ± 0:35, and the average morningness/eveningness score was 26.8 ± 4.3. Most toddlers (58.4%) were rated as 'definitely a morning type' or 'rather morning than evening type', while none (0%) were rated as 'definitely evening type'. More morning types (midsleep time on free days and morningness/eveningness score, respectively) had earlier melatonin onset times (r = 0.45, r = 0.26), earlier habitual bedtimes (r = 0.78, r = 0.54), sleep onset times (r = 0.80, r = 0.52), sleep midpoint times (r = 0.90, r = 0.53) and wake times (r = 0.74, r = 0.34). Parent ratings using the single-item chronotype score were associated with melatonin onset (r = 0.32) and habitual bedtimes (r = 0.27), sleep onset times (r = 0.33) and sleep midpoint times (r = 0.27). Morningness may best characterize circadian preference in early childhood. Associations between chronotype and circadian physiology and sleep timing suggest adequate validity for the CCTQ in this age group. These findings have important implications for understanding the marked variability in sleep timing during the early years of life.
Kumar, Vinod; Gwinner, Eberhard
In many birds periodic melatonin secretion by the pineal organ is essential for the high-amplitude self-sustained output of the circadian pacemaker, and thus for the persistence of rhythmicity in 24 h oscillations controlled by it. The elimination of the pineal melatonin rhythm, or a reduction of its amplitude, renders the circadian pacemaker a less self-sustained, often highly damped, oscillatory system. A reduction in the degree of self-sustainment of a rhythm should not only increase its range of entrainment but also shorten the resynchronization times following phase-shifts of the zeitgeber. This hypothesis has not yet been directly tested. We therefore carried out the present study in which house sparrows (Passer domesticus) were subjected to both 6-h advance and 6-h delay phase-shifts of the light-dark cycle before and after the pinealectomy, and the rhythms in locomotion and feeding were recorded. The results indicate that following the delay, but not the advance, phase shift, resynchronization times were significantly shorter after pinealectomy. The dependence of resynchronization times on the presence or absence of the pineal organ is not only of theoretical interest but might also be of functional significance in the natural life of birds. A reduction or elimination of the amplitude of the melatonin secretion rhythm by the pineal organ might be responsible for faster adjustment to changes in zeitgeber conditions in nature.
Myung, Jihwan; Hong, Sungho; DeWoskin, Daniel; De Schutter, Erik; Forger, Daniel B.; Takumi, Toru
The mammalian suprachiasmatic nucleus (SCN) forms not only the master circadian clock but also a seasonal clock. This neural network of ∼10,000 circadian oscillators encodes season-dependent day-length changes through a largely unknown mechanism. We show that region-intrinsic changes in the SCN fine-tune the degree of network synchrony and reorganize the phase relationship among circadian oscillators to represent day length. We measure oscillations of the clock gene Bmal1, at single-cell and regional levels in cultured SCN explanted from animals raised under short or long days. Coupling estimation using the Kuramoto framework reveals that the network has couplings that can be both phase-attractive (synchronizing) and -repulsive (desynchronizing). The phase gap between the dorsal and ventral regions increases and the overall period of the SCN shortens with longer day length. We find that one of the underlying physiological mechanisms is the modulation of the intracellular chloride concentration, which can adjust the strength and polarity of the ionotropic GABAA-mediated synaptic input. We show that increasing day-length changes the pattern of chloride transporter expression, yielding more excitatory GABA synaptic input, and that blocking GABAA signaling or the chloride transporter disrupts the unique phase and period organization induced by the day length. We test the consequences of this tunable GABA coupling in the context of excitation–inhibition balance through detailed realistic modeling. These results indicate that the network encoding of seasonal time is controlled by modulation of intracellular chloride, which determines the phase relationship among and period difference between the dorsal and ventral SCN. PMID:26130804
Brainard, G. C.; Hanifin, J. P.; Greeson, J. M.; Byrne, B.; Glickman, G.; Gerner, E.; Rollag, M. D.
The photopigment in the human eye that transduces light for circadian and neuroendocrine regulation, is unknown. The aim of this study was to establish an action spectrum for light-induced melatonin suppression that could help elucidate the ocular photoreceptor system for regulating the human pineal gland. Subjects (37 females, 35 males, mean age of 24.5 +/- 0.3 years) were healthy and had normal color vision. Full-field, monochromatic light exposures took place between 2:00 and 3:30 A.M. while subjects' pupils were dilated. Blood samples collected before and after light exposures were quantified for melatonin. Each subject was tested with at least seven different irradiances of one wavelength with a minimum of 1 week between each nighttime exposure. Nighttime melatonin suppression tests (n = 627) were completed with wavelengths from 420 to 600 nm. The data were fit to eight univariant, sigmoidal fluence-response curves (R(2) = 0.81-0.95). The action spectrum constructed from these data fit an opsin template (R(2) = 0.91), which identifies 446-477 nm as the most potent wavelength region providing circadian input for regulating melatonin secretion. The results suggest that, in humans, a single photopigment may be primarily responsible for melatonin suppression, and its peak absorbance appears to be distinct from that of rod and cone cell photopigments for vision. The data also suggest that this new photopigment is retinaldehyde based. These findings suggest that there is a novel opsin photopigment in the human eye that mediates circadian photoreception.
Burgess, Helen J.; Legasto, Carlo S.; Fogg, Louis F.; Smith, Mark R.
Small shifts in circadian timing occur frequently as a result of daylight saving time or later weekend sleep. These subtle shifts in circadian phase have been shown to influence subjective sleepiness, but it remains unclear if they can significantly affect performance. In a retrospective analysis we examined performance on the Psychomotor Vigilance Test before bedtime and after wake time in 11 healthy adults on fixed sleep schedules based on their habitual sleep times. The dim light melatonin onset, a marker of circadian timing, was measured on two occasions. An average 1.1 hour shift away from a proposed optimal circadian phase angle (6 hours between melatonin onset and midpoint of sleep) significantly slowed mean, median and fastest 10% reaction times before bedtime and after wake time (p<0.05). These results add to previous reports that suggest that humans may be sensitive to commonly occurring small shifts in circadian timing. PMID:22695081
Burgess, Helen J; Legasto, Carlo S; Fogg, Louis F; Smith, Mark R
Small shifts in circadian timing occur frequently as a result of daylight saving time or later weekend sleep. These subtle shifts in circadian phase have been shown to influence subjective sleepiness, but it remains unclear if they can significantly affect performance. In a retrospective analysis we examined performance on the Psychomotor Vigilance Test before bedtime and after wake time in 11 healthy adults on fixed sleep schedules based on their habitual sleep times. The dim light melatonin onset, a marker of circadian timing, was measured on two occasions. An average 1.1 h shift away from a proposed optimal circadian phase angle (6 h between melatonin onset and midpoint of sleep) significantly slowed mean, median and fastest 10% reaction times before bedtime and after wake time (p < 0.05). These results add to previous reports that suggest that humans may be sensitive to commonly occurring small shifts in circadian timing.
Mendez, Natalia; Abarzua-Catalan, Lorena; Vilches, Nelson; Galdames, Hugo A.; Spichiger, Carlos; Richter, Hans G.; Valenzuela, Guillermo J.; Seron-Ferre, Maria; Torres-Farfan, Claudia
Surprisingly, in our modern 24/7 society, there is scant information on the impact of developmental chronodisruption like the one experienced by shift worker pregnant women on fetal and postnatal physiology. There are important differences between the maternal and fetal circadian systems; for instance, the suprachiasmatic nucleus is the master clock in the mother but not in the fetus. Despite this, several tissues/organs display circadian oscillations in the fetus. Our hypothesis is that the maternal plasma melatonin rhythm drives the fetal circadian system, which in turn relies this information to other fetal tissues through corticosterone rhythmic signaling. The present data show that suppression of the maternal plasma melatonin circadian rhythm, secondary to exposure of pregnant rats to constant light along the second half of gestation, had several effects on fetal development. First, it induced intrauterine growth retardation. Second, in the fetal adrenal in vivo it markedly affected the mRNA expression level of clock genes and clock-controlled genes as well as it lowered the content and precluded the rhythm of corticosterone. Third, an altered in vitro fetal adrenal response to ACTH of both, corticosterone production and relative expression of clock genes and steroidogenic genes was observed. All these changes were reversed when the mother received a daily dose of melatonin during the subjective night; supporting a role of melatonin on overall fetal development and pointing to it as a ‘time giver’ for the fetal adrenal gland. Thus, the present results collectively support that the maternal circadian rhythm of melatonin is a key signal for the generation and/or synchronization of the circadian rhythms in the fetal adrenal gland. In turn, low levels and lack of a circadian rhythm of fetal corticosterone may be responsible of fetal growth restriction; potentially inducing long term effects in the offspring, possibility that warrants further research. PMID
Winget, C. M.; Lyman, J.; Beljan, J. R.
The light-intensity threshold for humans is not known. In past space flights owing to power restrictions, light intensities have been minimal and reported to be as low as 15 ft. c. This study was conducted to determine whether the light (L)/dark (D) environment of 16L : 8D at the relatively low light intensity of 15 ft. c. was adequate for the maintenance of circadian synchrony in human subjects. Six healthy male subjects aged 20-23 years were exposed for 21 days to a 16L : 8D photoperiod. During the first 7 days the light intensity was 100 ft. c.; it was reduced to 15 ft. c. during the next 7 days and increased again to 100 ft. c. during the last 7 days of the study. Rectal temperature (RT) and heart rate (HR) were recorded continuously throughout the 21 days of the study. In the 100 ft. c. 16L : 8D the RT and HR rhythms remained stable and circadian throughout. When the light intensity was decreased to 15 ft. c. the periodicity of the HR rhythm was significantly decreased and this rhythm showed marked instability. In contrast the period of the RT rhythm did not change but a consistent phase delay occurred due to a delay in the lights-on associated rise in RT. These divergent effects on these two rhythms in internal desynchronization and performance decrement during the 15 ft. c. exposure. The data emphasize the need for establishing accurately the minimal lighting requirements for the maintenance of circadian rhythms of humans in confined environments.
Papp, Stephanie J; Huber, Anne-Laure; Jordan, Sabine D; Kriebs, Anna; Nguyen, Madelena; Moresco, James J; Yates, John R; Lamia, Katja A
The circadian transcriptional repressors cryptochrome 1 (Cry1) and 2 (Cry2) evolved from photolyases, bacterial light-activated DNA repair enzymes. In this study, we report that while they have lost DNA repair activity, Cry1/2 adapted to protect genomic integrity by responding to DNA damage through posttranslational modification and coordinating the downstream transcriptional response. We demonstrate that genotoxic stress stimulates Cry1 phosphorylation and its deubiquitination by Herpes virus associated ubiquitin-specific protease (Hausp, a.k.a Usp7), stabilizing Cry1 and shifting circadian clock time. DNA damage also increases Cry2 interaction with Fbxl3, destabilizing Cry2. Thus, genotoxic stress increases the Cry1/Cry2 ratio, suggesting distinct functions for Cry1 and Cry2 following DNA damage. Indeed, the transcriptional response to genotoxic stress is enhanced in Cry1−/− and blunted in Cry2−/− cells. Furthermore, Cry2−/− cells accumulate damaged DNA. These results suggest that Cry1 and Cry2, which evolved from DNA repair enzymes, protect genomic integrity via coordinated transcriptional regulation. DOI: http://dx.doi.org/10.7554/eLife.04883.001 PMID:25756610
Noh, Jong-Yun; Kim, Mi-Hee; Son, Gi Hoon; Kim, Kyungjin; Kim, Chang-Ju; Pak, Youngmi Kim; Cho, Sehyung
In modern society, growing numbers of people are engaged in various forms of shift works or trans-meridian travels. Such circadian misalignment is known to disturb endogenous diurnal rhythms, which may lead to harmful physiological consequences including metabolic syndrome, obesity, cancer, cardiovascular disorders, and gastric disorders as well as other physical and mental disorders. However, the precise mechanism(s) underlying these changes are yet unclear. The present work, therefore examined the effects of 6 h advance or delay of usual meal time on diurnal rhythmicities in home cage activity (HCA), body temperature (BT), blood metabolic markers, glucose homeostasis, and expression of genes that are involved in cholesterol homeostasis by feeding young adult male mice in a time-restrictive manner. Delay of meal time caused locomotive hyperactivity in a significant portion (42%) of subjects, while 6 h advance caused a torpor-like symptom during the late scotophase. Accordingly, daily rhythms of blood glucose and triglyceride were differentially affected by time-restrictive feeding regimen with concurrent metabolic alterations. Along with these physiological changes, time-restrictive feeding also influenced the circadian expression patterns of low density lipoprotein receptor (LDLR) as well as most LDLR regulatory factors. Strikingly, chronic advance of meal time induced insulin resistance, while chronic delay significantly elevated blood glucose levels. Taken together, our findings indicate that persistent shifts in usual meal time impact the diurnal rhythms of carbohydrate and lipid metabolisms in addition to HCA and BT, thereby posing critical implications for the health and diseases of shift workers. PMID:22952870
Jeon, M; Gardner, H F; Miller, E A; Deshler, J; Rougvie, A E
The Caenorhabditis elegans heterochronic genes control the relative timing and sequence of many events during postembryonic development, including the terminal differentiation of the lateral hypodermis, which occurs during the final (fourth) molt. Inactivation of the heterochronic gene lin-42 causes hypodermal terminal differentiation to occur precociously, during the third molt. LIN-42 most closely resembles the Period family of proteins from Drosophila and other organisms, proteins that function in another type of biological timing mechanism: the timing of circadian rhythms. Per mRNA levels oscillate with an approximately 24-hour periodicity. lin-42 mRNA levels also oscillate, but with a faster rhythm; the oscillation occurs relative to the approximately 6-hour molting cycles of postembryonic development.
... chronobiology. Are circadian rhythms the same thing as biological clocks? No, but they are related. Our biological clocks drive our circadian rhythms. What are biological clocks? The biological clocks that control circadian rhythms ...
Papantoniou, Christos; Gerkema, Menno P.; Van Der Zee, Eddy A.
During Time-Place Learning (TPL), animals link biological significant events (e.g. encountering predators, food, mates) with the location and time of occurrence in the environment. This allows animals to anticipate which locations to visit or avoid based on previous experience and knowledge of the current time of day. The TPL task applied in this study consists of three daily sessions in a three-arm maze, with a food reward at the end of each arm. During each session, mice should avoid one specific arm to avoid a foot-shock. We previously demonstrated that, rather than using external cue-based strategies, mice use an internal clock (circadian strategy) for TPL, referred to as circadian TPL (cTPL). It is unknown in which brain region(s) or peripheral organ(s) the consulted clock underlying cTPL resides. Three candidates were examined in this study: (a) the suprachiasmatic nucleus (SCN), a light entrainable oscillator (LEO) and considered the master circadian clock in the brain, (b) the food entrainable oscillator (FEO), entrained by restricted food availability, and (c) the adrenal glands, harboring an important peripheral oscillator. cTPL performance should be affected if the underlying oscillator system is abruptly phase-shifted. Therefore, we first investigated cTPL sensitivity to abrupt light and food shifts. Next we investigated cTPL in SCN-lesioned- and adrenalectomized mice. Abrupt FEO phase-shifts (induced by advancing and delaying feeding time) affected TPL performance in specific test sessions while a LEO phase-shift (induced by a light pulse) more severely affected TPL performance in all three daily test sessions. SCN-lesioned mice showed no TPL deficiencies compared to SHAM-lesioned mice. Moreover, both SHAM- and SCN-lesioned mice showed unaffected cTPL performance when re-tested after bilateral adrenalectomy. We conclude that, although cTPL is sensitive to timing manipulations with light as well as food, neither the SCN nor the adrenals are required for
Rey, G; Reddy, A B
The circadian clock is a cellular timekeeping mechanism that helps organisms from bacteria to humans to organize their behaviour and physiology around the solar cycle. Current models for circadian timekeeping incorporate transcriptional/translational feedback loop mechanisms in the predominant model systems. However, recent evidence suggests that non-transcriptional oscillations such as metabolic and redox cycles may play a fundamental role in circadian timekeeping. Peroxiredoxins, an antioxidant protein family, undergo rhythmic oxidation on the circadian time scale in a variety of species, including bacteria, insects and mammals, but also in red blood cells, a naturally occurring, non-transcriptional system. The profound interconnectivity between circadian and redox pathways strongly suggests that a conserved timekeeping mechanism based on redox cycles could be integral to generating circadian rhythms.
Carrier, J.; Monk, T. H.
This brief review is concerned with how human performance efficiency changes as a function of time of day. It presents an overview of some of the research paradigms and conceptual models that have been used to investigate circadian performance rhythms. The influence of homeostatic and circadian processes on performance regulation is discussed. The review also briefly presents recent mathematical models of alertness that have been used to predict cognitive performance. Related topics such as interindividual differences and the postlunch dip are presented.
Videnovic, Aleksandar; Lazar, Alpar S.; Barker, Roger A.; Overeem, Sebastiaan
Circadian rhythms are physiological and behavioural cycles generated by an endogenous biological clock, the suprachiasmatic nucleus. The circadian system influences the majority of physiological processes, including sleep–wake homeostasis. Impaired sleep and alertness are common symptoms of neurodegenerative disorders, and circadian dysfunction might exacerbate the disease process. The pathophysiology of sleep–wake disturbances in these disorders remains largely unknown, and is presumably multifactorial. Circadian rhythm dysfunction is often observed in patients with Alzheimer disease, in whom it has a major impact on quality of life and represents one of the most important factors leading to institutionalization of patients. Similarly, sleep and circadian problems represent common nonmotor features of Parkinson disease and Huntington disease. Clinical studies and experiments in animal models of neurodegenerative disorders have revealed the progressive nature of circadian dysfunction throughout the course of neurodegeneration, and suggest strategies for the restoration of circadian rhythmicity involving behavioural and pharmacological interventions that target the sleep–wake cycle. In this Review, we discuss the role of the circadian system in the regulation of the sleep–wake cycle, and outline the implications of disrupted circadian timekeeping in neurodegenerative diseases. PMID:25385339
Perrin, Fabien; Peigneux, Philippe; Fuchs, Sonia; Verhaeghe, Stéphane; Laureys, Steven; Middleton, Benita; Degueldre, Christian; Del Fiore, Guy; Vandewalle, Gilles; Balteau, Evelyne; Poirrier, Robert; Moreau, Vincent; Luxen, André; Maquet, Pierre; Dijk, Derk-Jan
The brain processes light information to visually represent the environment but also to detect changes in ambient light level. The latter information induces non-image-forming responses and exerts powerful effects on physiology such as synchronization of the circadian clock and suppression of melatonin. In rodents, irradiance information is transduced from a discrete subset of photosensitive retinal ganglion cells via the retinohypothalamic tract to various hypothalamic and brainstem regulatory structures including the hypothalamic suprachiasmatic nuclei, the master circadian pacemaker. In humans, light also acutely modulates alertness, but the cerebral correlates of this effect are unknown. We assessed regional cerebral blood flow in 13 subjects attending to auditory and visual stimuli in near darkness following light exposures (>8000 lux) of different durations (0.5, 17, 16.5, and 0 min) during the biological night. The bright broadband polychromatic light suppressed melatonin and enhanced alertness. Functional imaging revealed that a large-scale occipito-parietal attention network, including the right intraparietal sulcus, was more active in proportion to the duration of light exposures preceding the scans. Activity in the hypothalamus decreased in proportion to previous illumination. These findings have important implications for understanding the effects of light on human behavior.
Baehr, E K; Fogg, L F; Eastman, C I
Bright light can phase shift human circadian rhythms, and recent studies have suggested that exercise can also produce phase shifts in humans. However, few studies have examined the phase-shifting effects of intermittent bright light, exercise, or the combination. This simulated night work field study included eight consecutive night shifts followed by daytime sleep/dark periods (delayed 9 h from baseline). There were 33 subjects in a 2 x 2 design that compared 1) intermittent bright light (6 pulses, 40-min long each, at 5,000 lx) versus dim light and 2) intermittent exercise (6 bouts, 15-min long each, at 50-60% of maximum heart rate) versus no exercise. Bright light and exercise occurred during the first 6 h of the first three night shifts. The circadian phase marker was the demasked rectal temperature minimum. Intermittent bright-light groups had significantly larger phase delays than dim-light groups, and 94% of subjects who received bright light had phase shifts large enough for the temperature minimum to reach daytime sleep. Exercise did not affect phase shifts; neither facilitating nor inhibiting phase shifts produced by bright light.
Mereness, Amanda L; Murphy, Zachary C; Sellix, Michael T
Circadian clocks play essential roles in the timing of events in the mammalian hypothalamo-pituitary-ovarian (HPO) axis. The molecular oscillator driving these rhythms has been localized to tissues of the HPO axis. It has been suggested that synchrony among these oscillators is a feature of normal reproductive function. The impact of fertility disorders on clock function and the role of the clock in the etiology of endocrine pathology remain unknown. Polycystic ovarian syndrome (PCOS) is a particularly devastating fertility disorder, affecting 5%-10% of women at childbearing age with features including a polycystic ovary, anovulation, and elevated serum androgen. Approximately 40% of these women have metabolic syndrome, marked by hyperinsulinemia, dyslipidemia, and insulin resistance. It has been suggested that developmental exposure to excess androgen contributes to the etiology of fertility disorders, including PCOS. To better define the role of the timing system in these disorders, we determined the effects of androgen-dependent developmental programming on clock gene expression in tissues of the metabolic and HPO axes. Female PERIOD2::luciferase (PER2::LUC) mice were exposed to androgen (dihydrotestosterone [DHT]) in utero (Days 16-18 of gestation) or for 9-10 wk (DHT pellet) beginning at weaning (pubertal androgen excess [PAE]). As expected, both groups of androgen-treated mice had disrupted estrous cycles. Analysis of PER2::LUC expression in tissue explants revealed that excess androgen produced circadian misalignment via tissue-dependent effects on phase distribution. In vitro treatment with DHT differentially affected the period of PER2::LUC expression in tissue explants and granulosa cells, indicating that androgen has direct and tissue-specific effects on clock gene expression that may account for the effects of developmental programming on the timing system.
Steele, Christopher T; Tosini, Gianluca; Siopes, Thomas; Underwood, Herbert
Previous studies have shown that eye removal disrupts the circadian body temperature and activity rhythms of Japanese quail supporting the hypothesis that the eyes act as pacemakers within the quail circadian system. Furthermore, the putative ocular pacemakers are coupled to the rest of the circadian system via neural and hormonal outputs. Although the neural pathway has yet to be identified, experiments suggest that the daily rhythm of ocular melatonin synthesis and release is the hormonal output. We sought to strengthen the hypothesis that the eyes are the loci of circadian pacemakers, and that melatonin output is involved, by examining melatonin secretion in cultured quail retinas. Using an in vitro flow-through system we demonstrated that (1) isolated retinal tissue could exhibit a rhythm of melatonin release, (2) the rhythm of melatonin synthesis is directly entrainable by 24-h light-dark cycles, and (3) supplementation of the culture medium with serotonin is necessary for robust, rhythmic production of melatonin in constant darkness. These results show definitively that the eyes are the loci of a biological clock and, in light of previous studies showing the disruptive effects of blinding on the circadian system, strengthen the hypothesis that the ocular clock is a circadian pacemaker that can affect the rest of the circadian system via the cyclic synthesis and release of melatonin. The quail retina is proving to be a valuable in vitro model for investigating properties of circadian pacemakers.
Arellanes-Licea, Elvira; Caldelas, Ivette; De Ita-Pérez, Dalia; Díaz-Muñoz, Mauricio
Experimental findings and clinical observations have strengthened the association between physio-pathologic aspects of several diseases, as well as aging process, with the occurrence and control of circadian rhythms. The circadian system is composed by a principal pacemaker in the suprachiasmatic nucleus (SNC) which is in coordination with a number of peripheral circadian oscillators. Many pathological entities such as metabolic syndrome, cancer and cardiovascular events are strongly connected with a disruptive condition of the circadian cycle. Inadequate circadian physiology can be elicited by genetic defects (mutations in clock genes or circadian control genes) or physiological deficiencies (desynchronization between SCN and peripheral oscillators). In this review, we focus on the most recent experimental findings regarding molecular defects in the molecular circadian clock and the altered coordination in the circadian system that are related with clinical conditions such as metabolic diseases, cancer predisposition and physiological deficiencies associated to jet-lag and shiftwork schedules. Implications in the aging process will be also reviewed. PMID:25489492
Huang, Wenyu; Ramsey, Kathryn Moynihan; Marcheva, Biliana; Bass, Joseph
The discovery of the genetic basis for circadian rhythms has expanded our knowledge of the temporal organization of behavior and physiology. The observations that the circadian gene network is present in most living organisms from eubacteria to humans, that most cells and tissues express autonomous clocks, and that disruption of clock genes results in metabolic dysregulation have revealed interactions between metabolism and circadian rhythms at neural, molecular, and cellular levels. A major challenge remains in understanding the interplay between brain and peripheral clocks and in determining how these interactions promote energy homeostasis across the sleep-wake cycle. In this Review, we evaluate how investigation of molecular timing may create new opportunities to understand and develop therapies for obesity and diabetes.
McHill, A W; Wright, K P
Weight gain, obesity and diabetes have reached alarming levels in the developed world. Traditional risk factors such as over-eating, poor nutritional choices and lack of exercise cannot fully account for the high prevalence of metabolic disease. This review paper examines the scientific evidence on two novel risk factors that contribute to dys-regulated metabolic physiology: sleep disruption and circadian misalignment. Specifically, fundamental relationships between energy metabolism and sleep and circadian rhythms and the impact of sleep and circadian disruption on metabolic physiology are examined. Millions of individuals worldwide do not obtain sufficient sleep for healthy metabolic function, and many participate in shift work and social activities at times when the internal physiological clock is promoting sleep. These behaviours predispose an individual for poor metabolic health by promoting excess caloric intake in response to reduced sleep, food intake at internal biological times when metabolic physiology is not prepared, decreased energy expenditure when wakefulness and sleep are initiated at incorrect internal biological times, and disrupted glucose metabolism during short sleep and circadian misalignment. In addition to the traditional risk factors of poor diet and exercise, disturbed sleep and circadian rhythms represent modifiable risk factors for prevention and treatment of metabolic disease and for promotion of healthy metabolism.
Bouchard-Cannon, Pascale; Cheng, Hai-Ying M.
Restricted feeding (RF) schedules are potent zeitgebers capable of entraining metabolic and hormonal rhythms in peripheral oscillators in anticipation of food. Behaviorally, this manifests in the form of food anticipatory activity (FAA) in the hours preceding food availability. Circadian rhythms of FAA are thought to be controlled by a food-entrainable oscillator (FEO) outside of the suprachiasmatic nucleus (SCN), the central circadian pacemaker in mammals. Although evidence suggests that the FEO and the SCN are capable of interacting functionally under RF conditions, the genetic basis of these interactions remains to be defined. In this study, using dexras1-deficient (dexras1−/−) mice, the authors examined whether Dexras1, a modulator of multiple inputs to the SCN, plays a role in regulating the effects of RF on activity rhythms and gene expression in the SCN. Daytime RF under 12L:12D or constant darkness (DD) resulted in potentiated (but less stable) FAA expression in dexras1−/− mice compared with wild-type (WT) controls. Under these conditions, the magnitude and phase of the SCN-driven activity component were greatly perturbed in the mutants. Restoration to ad libitum (AL) feeding revealed a stable phase displacement of the SCN-driven activity component of dexras1−/− mice by ~2 h in advance of the expected time. RF in the late night/early morning induced a long-lasting increase in the period of the SCN-driven activity component in the mutants but not the WT. At the molecular level, daytime RF advanced the rhythm of PER1, PER2, and pERK expression in the mutant SCN without having any effect in the WT. Collectively, these results indicate that the absence of Dexras1 sensitizes the SCN to perturbations resulting from restricted feeding. PMID:22928915
Yamaguchi, Mitsue; Kotani, Kazuhiko; Tsuzaki, Kokoro; Takagi, Ayaka; Motokubota, Naoko; Komai, Naho; Sakane, Naoki; Moritani, Toshio; Nagai, Narumi
Background Clock genes regulate circadian rhythm and are involved in various physiological processes, including digestion. We therefore investigated the association between the CLOCK 3111T/C single nucleotide polymorphism and the Period3 (PER3) variable-number tandem-repeat polymorphism (either 4 or 5 repeats 54 nt in length) with morning gastric motility. Methods Lifestyle questionnaires and anthropometric measurements were performed with 173 female volunteers (mean age, 19.4 years). Gastric motility, evaluated by electrogastrography (EGG), blood pressure, and heart rate levels were measured at 8:30 a.m. after an overnight fast. For gastric motility, the spectral powers (% normal power) and dominant frequency (DF, peak of the power spectrum) of the EGG were evaluated. The CLOCK and PER3 polymorphisms were determined by polymerase chain reaction (PCR) restriction fragment length polymorphism analysis. Results Subjects with the CLOCK C allele (T/C or C/C genotypes: n = 59) showed a significantly lower DF (mean, 2.56 cpm) than those with the T/T genotype (n = 114, 2.81 cpm, P < 0.05). Subjects with the longer PER3 allele (PER34/5 or PER35/5 genotypes: n = 65) also showed a significantly lower DF (2.55 cpm) than those with the shorter PER34/4 genotype (n = 108, 2.83 cpm, P < 0.05). Furthermore, subjects with both the T/C or C/C and PER34/5 or PER35/5 genotypes showed a significantly lower DF (2.43 cpm, P < 0.05) than subjects with other combinations of the alleles (T/T and PER34/4 genotype, T/C or C/C and PER34/4 genotypes, and T/T and PER34/5 or PER35/5 genotypes). Conclusions These results suggest that minor polymorphisms of the circadian rhythm genes CLOCK and PER3 may be associated with poor morning gastric motility, and may have a combinatorial effect. The present findings may offer a new viewpoint on the role of circadian rhythm genes on the peripheral circadian systems, including the time-keeping function of the gut. PMID:25775462
Singh, Devraj; Trivedi, Neerja; Malik, Shalie; Rani, Sangeeta; Kumar, Vinod
We tested the hypothesis whether daily food availability period would restore rhythmicity in individuals with disrupted circadian behavior with no effect on appetite regulation. Particularly, we investigated the effects of timed food availability on activity behavior, and Fos and neuropeptide Y expressions in Indian weaverbirds (Ploceus philippinus) under atypical light conditions. Initially, weaverbirds in 3 groups of 7-8 each were entrained to 7L:17D (25: <0.3lx) with food ad libitum. Thereafter, food availability was restricted for 7h such that it overlapped with the light period. After a week, 7L:17D was replaced with 3.5L: 3.5D (T7, group 1), 3.5L: 20.5D (T24, group 2) or constant dim light, LLdim (<0.3lx, group 3) for 5weeks. Food cycles synchronized the circadian activity behavior, albeit with group differences, but did not affect body mass, blood glucose levels or testis size. Further, Fos, not NPY mRNA or peptide, expression measured at ZT2 and ZT14 (ZT0=time of food given) showed significant group differences in the hippocampus, dorsomedial hypothalamus and infundibular nuclear complex. Another identical experiment examined after-effects of the 3 light conditions on persistence of the circadian rhythms. Weaverbirds exposed for 4weeks to identical food but different light conditions, as above, were released into the free-running condition of food ad libitum and LLdim. Circadian rhythms were decayed in birds previously exposed to T7 LD cycle. Overall, these results show that timed meal restores rhythmicity in individuals with circadian rhythm disruptions without involving neuropeptide Y, the key appetite regulatory molecule.
Haydon, Michael J; Hearn, Timothy J; Bell, Laura J; Hannah, Matthew A; Webb, Alex A R
Circadian clocks are 24-h timekeeping mechanisms, which have evolved in plants, animals, fungi and bacteria to anticipate changes in light and temperature associated with the rotation of the Earth. The current paradigm to explain how biological clocks provide timing information is based on multiple interlocking transcription-translation negative feedback loops (TTFL), which drive rhythmic gene expression and circadian behaviour of growth and physiology. Metabolism is an important circadian output, which in plants includes photosynthesis, starch metabolism, nutrient assimilation and redox homeostasis. There is increasing evidence in a range of organisms that these metabolic outputs can also contribute to circadian timing and might also comprise independent circadian oscillators. In this review, we summarise the mechanisms of circadian regulation of metabolism by TTFL and consider increasing evidence that rhythmic metabolism contributes to the circadian network. We highlight how this might be relevant to plant circadian clock function.
Gander, Philippa H.; Myhre, Grete; Graeber, R. Curtis; Lauber, John K.; Andersen, Harald T.
The adjustment of sleep-wake patterns and the circadian temperature rhythm was monitored in nine Royal Norwegian Airforce volunteers operating P-3 aircraft during a westward training deployment across nine time zones. Subjects recorded all sleep and nap times, rated nightly sleep quality, and completed personality inventories. Rectal temperature, heart rate, and wrist activity were continuously monitored. Adjustment was slower after the return eastward flight than after the outbound westward flight. The eastward flight produced slower readjustment of sleep timing to local time and greater interindividual variability in the patterns of adjustment of sleep and temperature. One subject apparently exhibited resynchronization by partition, with the temperature rhythm undergoing the reciprocal 15-h delay. In contrast, average heart rates during sleep were significantly elevated only after westward flight. Interindividual differences in adjustment of the temperature rhythm were correlated with some of the personality measures. Larger phase delays in the overall temperature waveform (as measured on the 5th day after westward flight) were exhibited by extraverts, and less consistently by evening types.
Smarr, Benjamin L.; Jennings, Kimberly J.; Driscoll, Joseph R.; Kriegsfeld, Lance J.
The circadian system has pronounced influence on learning and memory, manifesting as marked changes in memory acquisition and recall across the day. From a mechanistic level, the majority of studies have investigated mammalian hippocampal dependent learning and memory, as this system is highly tractable. The hippocampus plays a major role in learning and memory and has the potential to integrate circadian information in many ways, including information from local, independent oscillators, and through circadian modulation of neurogenesis, synaptic remodeling, intracellular cascades, and epigenetic regulation of gene expression. These local processes are combined with input from other oscillatory systems to synergistically augment hippocampal rhythmic function. This overview presents an account of the current state of knowledge on circadian interactions with learning and memory circuitry and provides a framework for those interested in further exploring these interactions. PMID:24708297
Scheer, Frank A J L; Shea, Steven A
Serious adverse cardiovascular events peak in the morning, possibly related to increased thrombosis in critical vessels. Plasminogen activator inhibitor-1 (PAI-1), which inhibits fibrinolysis, is a key circulating prothrombotic factor that rises in the morning in humans. We tested whether this morning peak in PAI-1 is caused by the internal circadian system or by behaviors that typically occur in the morning, such as altered posture and physical activity. Twelve healthy adults underwent a 2-week protocol that enabled the distinction of endogenous circadian effects from behavioral and environmental effects. The results demonstrated a robust circadian rhythm in circulating PAI-1 with a peak corresponding to ∼6:30 am. This rhythm in PAI-1 was 8-times larger than changes in PAI-1 induced by standardized behavioral stressors, including head-up tilt and 15-minute cycle exercise. If this large endogenous morning peak in PAI-1 persists in vulnerable individuals, it could help explain the morning peak in adverse cardiovascular events.
Gooley, Joshua J; Rajaratnam, Shantha M; Brainard, George C; Kronauer, Richard E; Czeisler, Charles A; Lockley, Steven W
In humans, circadian responses to light are thought to be mediated primarily by melanopsin-containing retinal ganglion cells, not rods or cones. Melanopsin cells are intrinsically blue-light sensitive, but also receive input from visual photoreceptors. We therefore tested in humans whether cone photoreceptors contribute to the regulation of circadian and neuroendocrine light responses. Dose-response curves for melatonin suppression and circadian phase resetting were constructed in subjects exposed to blue (460 nm) or green (555 nm) light near the onset of nocturnal melatonin secretion. At the beginning of the intervention, 555 nm light was just as effective as 460 nm light at suppressing melatonin, suggesting a significant contribution from the three-cone visual system (lambdamax 555 nm). During light exposure, however, the spectral sensitivity to 555 nm light decayed exponentially relative to 460 nm light. For phase-resetting responses, the effects of exposure to low irradiance 555 nm light were too large relative to 460 nm light to be explained solely by the activation of melanopsin. Our findings suggest that cone photoreceptors contribute substantially to non-visual responses at the beginning of a light exposure and at low irradiances, whereas melanopsin appears to be the primary circadian photopigment in response to long-duration light exposure and at high irradiances. These results are consistent with a non-redundant role for visual photoreceptors and melanopsin in mediating human non-visual photoreception and suggest that light therapy for circadian rhythm sleep disorders and other indications might be optimized by stimulating both the melanopsin- and cone-driven photoreceptor systems. PMID:20463367
A majority of mammalian genes exhibit daily fluctuations in expression levels, making circadian expression rhythms the largest known regulatory network in normal physiology. Cell-autonomous circadian clocks interact with daily light-dark and feeding-fasting cycles to generate approximately 24-hour oscillations in the function of thousands of genes. Circadian expression of secreted molecules and signaling components transmits timing information between cells and tissues. Such intra- and intercellular daily rhythms optimize physiology both by managing energy use and by temporally segregating incompatible processes. Experimental animal models and epidemiological data indicate that chronic circadian rhythm disruption increases the risk of metabolic diseases. Conversely, time-restricted feeding, which imposes daily cycles of feeding and fasting without caloric reduction, sustains robust diurnal rhythms and can alleviate metabolic diseases. These findings highlight an integrative role of circadian rhythms in physiology and offer a new perspective for treating chronic diseases in which metabolic disruption is a hallmark.
Sakata-Haga, Hiromi; Fukui, Yoshihiro
Ethanol exposure during gestation can have devastating consequences on the developing organism. Children who have a history of prenatally exposure to ethanol may show morphological and functional alterations, referred to as fetal alcohol spectrum disorders (FASD). Fetal alcohol syndrome (FAS), which is characterized by pre- and postnatal growth deficiency, specific cranial/facial features, and dysfunction of central nervous system, is the most severe end of FASD. FAS or FASD children are known to suffer from disturbance of sleep and/or food intake behaviors. These neuropsychiatric symptoms may be due to impairment of the system regulating circadian rhythms. Recently, animal studies revealed that ethanol exposure during brain development can cause alterations in the circadian rhythm and its regulating system. We examined the effects of pre- or postnatal exposure to ethanol on the circadian rhythm in adulthood by measuring deep body temperature and wheel running activity in rats. After a phase delay in the light/dark cycle, ethanol-exposed rats took longer than control rats to resynchronize to the new light/dark cycle. These results suggest that both pre- and postnatal ethanol exposure impair the development of the circadian clock response to light cue. Because abnormal development of the circadian clock system might contribute to the neuropsychiatric symptoms seen in FASD, it is believed that normalizing the disturbed rhythm improves the symptoms. However, the mechanisms of dysfunction and potential interventions for disturbance of circadian clock system still remain to be elucidated. Further investigations are required to fully understand long-term effects of ethanol on the development of circadian rhythms.
Hrushesky, William; Rich, Ivan N
Circadian rhythms are biological rhythms that occur within a 24-h time cycle. Sleep is a prime example of a circadian rhythm and with it melatonin production. Stem cell systems also demonstrate circadian rhythms. This is particularly the case for the proliferating cells within the system. In fact, all proliferating cell populations exhibit their own circadian rhythm, which has important implications for disease and the treatment of disease. Stem cell chronobiology is particularly important because the treatment of cancer can be significantly affected by the time of day a drug is administered. This protocol provides a basis for measuring hematopoietic stem cell circadian rhythm for future stem cell chronotherapeutic applications.
Jewett, M. E.; Kronauer, R. E.; Brown, E. N. (Principal Investigator)
In 1990, Kronauer proposed a mathematical model of the effects of light on the human circadian pacemaker. Although this model predicted many general features of the response of the human circadian pacemaker to light exposure, additional data now available enable us to refine the original model. We first refined the original model by incorporating the results of a dose response curve to light into the model's predicted relationship between light intensity and the strength of the drive onto the pacemaker. Data from three bright light phase resetting experiments were then used to refine the amplitude recovery characteristics of the model. Finally, the model was tested and further refined using data from an extensive phase resetting experiment in which a 3-cycle bright light stimulus was presented against a background of dim light. In order to describe the results of the four resetting experiments, the following major refinements to the original model were necessary: (i) the relationship between light intensity (I) and drive onto the pacemaker was reduced from I1/3 to I0.23 for light levels between 150 and 10,000 lux; (ii) the van der Pol oscillator from the original model was replaced with a higher-order limit cycle oscillator so that amplitude recovery is slower near the singularity and faster near the limit cycle; (iii) a direct effect of light on circadian period (tau x) was incorporated into the model such that as I increases, tau x decreases, which is in accordance with "Aschoff's rule". This refined model generates the following testable predictions: it should be difficult to enhance normal circadian amplitude via bright light; near the critical point of a type 0 phase response curve (PRC) the slope should be steeper than it is in a type 1 PRC; and circadian period measured during forced desynchrony should be directly affected by ambient light intensity.
Monk, Timothy H.
This review discusses the ways in which the circadian rhythms of older people are different from those of younger adults. After a brief discussion of clinical issues, the review describes the conventional wisdom regarding age-related changes in circadian rhythms. These can be summarized as four assertions regarding what happens to people as they get older: 1) the amplitude of their circadian rhythms reduces, 2) the phase of their circadian rhythms becomes earlier, 3) their natural free-running period (tau) shortens, and 4) their ability to tolerate abrupt phase shifts (e.g., from jet travel or night work) worsens. The review then discusses the empirical evidence for and against these assertions and discusses some alternative explanations. The conclusions are that although older people undoubtedly have earlier circadian phases than younger adults, and have more trouble coping with shift work and jet lag, evidence for the assertions about rhythm amplitude and tau are, at best, mixed.
A growing body of research has identified significant sleep problems in children with autism. Disturbed sleep-wake patterns and abnormal hormone profiles in children with autism suggest an underlying impairment of the circadian timing system. Reviewing normal and dysfunctional relationships between sleep and circadian rhythms will enable comparisons to sleep problems in children with autism, prompt a reexamination of existing literature and offer suggestions for future inquiry. In addition, sleep and circadian rhythms continue to change over the course of development even in typical, healthy humans. Therefore, exploring the dynamic relationship between circadian rhythms and sleep throughout development provides valuable insight into those sleep problems associated with autism. Ultimately, a better understanding of sleep and circadian rhythms in children with autism may help guide appropriate treatment strategies and minimize the negative impact of these disturbances on both the children and their families.
Scheer, Frank A J L; Hu, Kun; Evoniuk, Heather; Kelly, Erin E; Malhotra, Atul; Hilton, Michael F; Shea, Steven A
The risk of adverse cardiovascular events peaks in the morning (≈9:00 AM) with a secondary peak in the evening (≈8:00 PM) and a trough at night. This pattern is generally believed to be caused by the day/night distribution of behavioral triggers, but it is unknown whether the endogenous circadian system contributes to these daily fluctuations. Thus, we tested the hypotheses that the circadian system modulates autonomic, hemodynamic, and hemostatic risk markers at rest, and that behavioral stressors have different effects when they occur at different internal circadian phases. Twelve healthy adults were each studied in a 240-h forced desynchrony protocol in dim light while standardized rest and exercise periods were uniformly distributed across the circadian cycle. At rest, there were large circadian variations in plasma cortisol (peak-to-trough ≈85% of mean, peaking at a circadian phase corresponding to ≈9:00 AM) and in circulating catecholamines (epinephrine, ≈70%; norepinephrine, ≈35%, peaking during the biological day). At ≈8:00 PM, there was a circadian peak in blood pressure and a trough in cardiac vagal modulation. Sympathetic variables were consistently lowest and vagal markers highest during the biological night. We detected no simple circadian effect on hemostasis, although platelet aggregability had two peaks: at ≈noon and ≈11:00 PM. There was circadian modulation of the cardiovascular reactivity to exercise, with greatest vagal withdrawal at ≈9:00 AM and peaks in catecholamine reactivity at ≈9:00 AM and ≈9:00 PM. Thus, the circadian system modulates numerous cardiovascular risk markers at rest as well as their reactivity to exercise, with resultant profiles that could potentially contribute to the day/night pattern of adverse cardiovascular events.
Borisenkov, M F; Perminova, E V; Kosova, A L
The literature and results of own researches concerning the influence of climatic conditions of the North on human organism are analyzed in the paper. Experimental and clinical data are in accordance with a hypothesis of "circadian destruction" covering the mechanism of negative influence of factors of the North on human health. The model to describe the possible mechanism of action of electromagnetic radiations on circadian system of an organism is offered.
Studies on the relationship between stroke incidence and alterations of circadian rhythm are scarce, while pathologically reduced or abolished circadian variation has been described to cause stroke since a long time ago. Although ischemic and hemorrhagic strokes are different entities and are characterized by different pathophysiological mechanisms, they share an identical pattern. A constellation of endogenous circadian rhythms and exogenous cyclic factors are involved. The staging of the circadian rhythms in vascular tone, coagulation balance including platelet function, and blood pressure plus temporal patterns in posture, physical activity, emotional stress, autonomic function, and medication effects play central and/or triggering roles. Features of the circadian rhythm of blood pressure, in terms of their chronic and acute effects on cerebral vessels, and of coagulation are especially important.
The mammalian circadian system, which is comprised of multiple cellular clocks located in the organs and tissues, orchestrates their regulation in a hierarchical manner throughout the 24 hr of the day. At the top of the hierarchy are the suprachiasmatic nuclei, which synchronize subordinate organ and tissue clocks using electrical, endocrine, and metabolic signaling pathways that impact the molecular mechanisms of cellular clocks. The interplay between the central neural and peripheral tissue clocks is not fully understood and remains a major challenge in determining how neurological and metabolic homeostasis is achieved across the sleep-wake cycle. Disturbances in the communication between the plethora of body clocks can desynchronize the circadian system, which is believed to contribute to the development of diseases such as obesity and neuropsychiatric disorders. This review will highlight the relationship between clocks and metabolism, and describe how cues such as light, food, and reward mediate entrainment of the circadian system.
Figueiro, Mariana G; Bierman, Andrew; Rea, Mark S
A model of circadian phototransduction was published in 2005 to predict the spectral sensitivity of the human circadian system to narrow-band and polychromatic light sources by combining responses to light from the spectral-opponent “blue” versus “yellow” cone bipolar pathway with direct responses to light by the intrinsically photosensitive retinal ganglion cells. In the model, depolarizing “blue” responses, but not hyperpolarizing “yellow” responses, from the “blue” versus “yellow” pathway are combined with the intrinsically photosensitive retinal ganglion cell responses. Intrinsically photosensitive retinal ganglion cell neurons are known to be much slower to respond to light than the cone pathway, so an implication of the model is that periodic flashes of “blue” light, but not “yellow” light, would be effective for stimulating the circadian system. A within-subjects study was designed to test the implications of the model regarding retinal exposures to brief flashes of light. The study was also aimed at broadening the foundation for clinical treatment of circadian sleep disorders by delivering flashing light through closed eyelids while people were asleep. In addition to a dark control night, the eyelids of 16 subjects were exposed to three light-stimulus conditions in the phase delay portion of the phase response curve while they were asleep: (1) 2-second flashes of 111 W/m2 of blue (λmax ≈ 480 nm) light once every minute for 1 hour, (2) 131 W/m2 of green (λmax ≈ 527 nm) light, continuously on for 1 hour, and (3) 2-second flashes of the same green light once every minute for 1 hour. Inferential statistics showed that the blue flash light-stimulus condition significantly delayed circadian phase and significantly suppressed nocturnal melatonin. The results of this study further our basic understanding of circadian phototransduction and broaden the technical foundations for delivering light through closed eyelids during sleep
Wisor, J P
The mammalian circadian clock in the suprachiasmatic nuclei (SCN) of the hypothalamus conveys 24-hr rhythmicity to sleep-wake cycles, temperature, locomotor activity and virtually all other behavioral and physiological processes. In order for these cycles to be adaptive, they must be synchronized, or entrained, to the 24-hr light/dark cycle produced by the rotation of the Earth. The timing of circadian variables relative to the light/dark cycle, i.e., the phase angle of entrainment, is influenced by intrinsic circadian clock properties that are to an extent genetically determined, and thus varies between individuals. In extreme cases (advanced or delayed sleep phase syndrome) or during shift work or jet lag, the phase angle of entrainment may be incompatible with work requirements or other social demands, resulting in negative consequences to health and productivity. This review describes the etiology of circadian disorders within the context of formal circadian clock properties and summarizes studies in humans and in other species which link specific genetic loci to circadian clock function and malfunction. The proteins encoded by these genetic loci play key roles in the intracellular feedback loop that generates circadian rhythms, and thus represent therapeutic targets for the treatment of both endogenous and exogenous circadian disorders.
Levi, Francis; Schibler, Ueli
The mammalian circadian system is organized in a hierarchical manner in that a central pacemaker in the suprachiasmatic nucleus (SCN) of the brain's hypothalamus synchronizes cellular circadian oscillators in most peripheral body cells. Fasting-feeding cycles accompanying rest-activity rhythms are the major timing cues in the synchronization of many, if not most, peripheral clocks, suggesting that the temporal coordination of metabolism and proliferation is a major task of the mammalian timing system. The inactivation of noxious food components by hepatic, intestinal, and renal detoxification systems is among the metabolic processes regulated in a circadian manner, with the understanding of the involved clock output pathways emerging. The rhythmic control of xenobiotic detoxification provides the molecular basis for the dosing time-dependence of drug toxicities and efficacy. This knowledge can in turn be used in improving or designing chronotherapeutics for the patients who suffer from many of the major human diseases.
Prosser, Rebecca A.; Stowie, Adam; Amicarelli, Mario; Nackenoff, Alex G.; Blakely, Randy D.; Glass, J. David
Cocaine abuse disrupts reward and homeostatic processes through diverse processes, including those involved in circadian clock regulation. Recently we showed that cocaine administration to mice disrupts nocturnal photic phase resetting of the suprachiasmatic (SCN) circadian clock, whereas administration during the day induces non-photic phase shifts. Importantly, the same effects are seen when cocaine is applied to the SCN in vitro, where it blocks photic-like (glutamate-induced) phase shifts at night and induces phase advances during the day. Furthermore, our previous data suggest that cocaine acts in the SCN by enhancing serotonin (5-HT) signaling. For example, the in vitro actions of cocaine mimic those of 5-HT and are blocked by the 5-HT antagonist, metergoline, but not the dopamine receptor antagonist, fluphenazine. Although our data are consistent with cocaine acting through enhance 5-HT signaling, the nonselective actions of cocaine as an antagonist of monoamine transporters raises the question of whether inhibition of the 5-HT transporter (SERT) is key to its circadian effects. Here we investigate this issue using transgenic mice expressing a SERT that exhibits normal 5-HT recognition and transport but significantly reduced cocaine potency (SERT Met172). Circadian patterns of SCN behavioral and neuronal activity did not differ between WT and SERT Met172 mice, nor did they differ in the ability of the 5-HT1A,2,7 receptor agonist, 8-OH-DPAT to reset SCN clock phase, consistent with the normal SERT expression and activity in the transgenic mice. However, 1) cocaine administration does not induce phase advances when administered in vivo or in vitro in SERT Met172 mice; 2) cocaine does not block photic or glutamate-induced (phase shifts in SERT Met172 mice; and 3) cocaine does not induce long-term changes in free-running period in SERT Met172 mice. We conclude that SERT antagonism is required for the phase shifting of the SCN circadian clock induced by cocaine
Dridi, Dorra; Ben-Attia, Mossadok; Sani, Mamane; Djebli, Nassim; Sauvage, Francois Ludovic; Boughattas, Naceur A
Little is known about the chronopharmacokinetics of loratadine, a long-acting tricyclic antihistamine H(1) widely used in the treatment of allergic diseases. Hence, the pharmacokinetics of loratadine and its major metabolite, desloratadine, were investigated after a 20 mg/kg dose of loratadine had been orally administered to comparable groups of mice (n=33), synchronized for three weeks to 12 h light (rest span)/12 h dark (activity span). The drug was administered at three different circadian times (1, 9, and 17 h after light onset [HALO]). Multiple blood samples were collected over 48 h, and plasma concentrations of loratadine and desloratadine were determined by high performance liquid chromatography. There were no significant differences in T(max) of loratadine and desloratadine between treatment-time different groups. However, the elimination half-life (t1/2) of the parent compound and its metabolite was significantly longer (p<0.01) following administration at 9 HALO (t1/2 loratadine and desloratadine 5.62 and 4.08 h at 9 HALO vs. 4.29 and 2.6 h at 17 HALO vs. 3.26 and 3.27 at 1 HALO). There were relevant (p<0.05) differences in C(max) between the three treated groups for loratadine and desloratadine; 133.05+/-3.55 and 258.07+/-14.45 ng/mL at 9 HALO vs. 104.5+/-2.61 and 188.62+/-7.20 ng/mL at 1 HALO vs. 94.33+/-20 and 187.75+/-10.79 ng/mL at 17 HALO. Drug dosing at 17 HALO resulted in highest loratadine and desloratadine total apparent clearance values: 61.46 and 15.97 L/h/kg, respectively, whereas loratadine and desloratadine clearances (CL) were significantly slower (p<0.05) at the other administration times (loratadine and desloratadine CL was 57.3 and 14.22 L/h/kg at 1 HALO vs. 43.79 and 12.89 L/h/kg at 9 HALO, respectively). The area under the concentration-time curve (AUC) of loratadine and desloratadine was significantly (p<0.05) greater following drug administration at 9 HALO (456.75 and 1550.57 (ng/mL) . h, respectively); it was lowest following
Lee, Kathryn A.; Gay, Caryl; Byun, Eeeseung; Lerdal, Anners; Pullinger, Clive R.; Aouizerat, Bradley E.
Genes involved in circadian regulation, such as circadian locomotor output cycles kaput [CLOCK], cryptochrome [CRY1], and period [PER], have been associated with sleep outcomes in prior animal and human research. However, it is unclear whether polymorphisms in these genes are associated with the sleep disturbances commonly experienced by adults living with human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS). Thus, the purpose of this study was to describe polymorphisms in selected circadian genes that are associated with sleep duration or disruption as well as the sleep-wake rhythm strength and phase timing among adults living with HIV/AIDS. A convenience sample of 289 adults with HIV/AIDS was recruited from HIV clinics and community sites in the San Francisco Bay Area. A wrist actigraph was worn for 72 hours on weekdays to estimate sleep duration or total sleep time (TST), sleep disruption or percentage of wake after sleep onset (WASO), and several circadian rhythm parameters: mesor, amplitude, the ratio of mesor to amplitude (circadian quotient), and 24-hour autocorrelation. Circadian phase measures included clock time for peak activity (acrophase) from actigraphy movement data, and bed time and final wake time from actigraphy and self-report. Genotyping was conducted for polymorphisms in 5 candidate genes involved in circadian regulation: CLOCK, CRY1, PER1, PER2, and PER3. Demographic and clinical variables were evaluated as potential covariates. Interactions between genotype and HIV variables (i.e., viral load, years since HIV diagnosis) were also evaluated. Controlling for potentially confounding variables (e.g., race, gender, CD4+ T-cell count, waist circumference, medication use, smoking, depressive symptoms), CLOCK was associated with WASO, 24-hour autocorrelation, and objectively-measured bed time; CRY1 was associated with circadian quotient; PER1 was associated with mesor and self-reported habitual wake time; PER2 was associated
Lee, Kathryn A; Gay, Caryl; Byun, Eeeseung; Lerdal, Anners; Pullinger, Clive R; Aouizerat, Bradley E
Genes involved in circadian regulation, such as circadian locomotor output cycles kaput [CLOCK], cryptochrome [CRY1] and period [PER], have been associated with sleep outcomes in prior animal and human research. However, it is unclear whether polymorphisms in these genes are associated with the sleep disturbances commonly experienced by adults living with human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS). Thus, the purpose of this study was to describe polymorphisms in selected circadian genes that are associated with sleep duration or disruption as well as the sleep-wake rhythm strength and phase timing among adults living with HIV/AIDS. A convenience sample of 289 adults with HIV/AIDS was recruited from HIV clinics and community sites in the San Francisco Bay Area. A wrist actigraph was worn for 72 h on weekdays to estimate sleep duration or total sleep time (TST), sleep disruption or percentage of wake after sleep onset (WASO) and several circadian rhythm parameters: mesor, amplitude, the ratio of mesor to amplitude (circadian quotient), and 24-h autocorrelation. Circadian phase measures included clock time for peak activity (acrophase) from actigraphy movement data, and bed time and final wake time from actigraphy and self-report. Genotyping was conducted for polymorphisms in five candidate genes involved in circadian regulation: CLOCK, CRY1, PER1, PER2 and PER3. Demographic and clinical variables were evaluated as potential covariates. Interactions between genotype and HIV variables (i.e. viral load, years since HIV diagnosis) were also evaluated. Controlling for potentially confounding variables (e.g. race, gender, CD4+ T-cell count, waist circumference, medication use, smoking and depressive symptoms), CLOCK was associated with WASO, 24-h autocorrelation and objectively-measured bed time; CRY1 was associated with circadian quotient; PER1 was associated with mesor and self-reported habitual wake time; PER2 was associated with TST
Youngstedt, Shawn D; Kripke, Daniel F; Elliott, Jeffrey A
In a within-subjects (n = 18), counterbalanced design, the circadian phase-shifting effects of 3 h of 1) bright light (3,000 lx) alone 2) and bright light combined with vigorous exercise were compared. For each treatment, volunteers spent 3 nights and 2 days in the laboratory, typically receiving the treatment from approximately 2300 to 0200 on night 2. Bedtimes and waketimes were fixed to the volunteers' habits. Illumination was 50 lx during other wake hours and 0 lx during sleep. Bright Light Alone elicited a significant phase delay in rectal temperature minimum (70 min), but not in urinary 6-sulphatoxymelatonin (6-SMT) acrophase (20 min). Bright Light + Exercise elicited a significant phase delay in 6-SMT (68 min), but did not result in a significant difference in shift compared with Bright Light Alone. The study had adequate statistical power (80%) to detect phase-shift differences between treatments of approximately 2-2.5 h. Thus any antagonism of light shifts with exercise could not have been revealed. Within the limited exercise and light parameters of this study, the results suggest that exercise does not reliably modulate phase-shifting effects of late night bright light in humans.
Crowley, Stephanie J.; Eastman, Charmane I.
OBJECTIVE Efficient treatments to phase advance human circadian rhythms are needed to attenuate circadian misalignment and the associated negative health outcomes that accompany early morning shift work, early school start times, jet lag, and delayed sleep phase disorder. This study compared three morning bright light exposure patterns from a single light box (to mimic home treatment) in combination with afternoon melatonin. METHODS Fifty adults (27 males) aged 25.9±5.1 years participated. Sleep/dark was advanced 1 hour/day for 3 treatment days. Participants took 0.5 mg melatonin 5 hours before baseline bedtime on treatment day 1, and an hour earlier each treatment day. They were exposed to one of three bright light (~5000 lux) patterns upon waking each morning: four 30-minute exposures separated by 30 minutes of room light (2 h group); four 15-minute exposures separated by 45 minutes of room light (1 h group), and one 30-minute exposure (0.5 h group). Dim light melatonin onsets (DLMOs) before and after treatment determined the phase advance. RESULTS Compared to the 2 h group (phase shift=2.4±0.8 h), smaller phase advance shifts were seen in the 1 h (1.7±0.7 h) and 0.5 h (1.8±0.8 h) groups. The 2-hour pattern produced the largest phase advance; however, the single 30-minute bright light exposure was as effective as 1 hour of bright light spread over 3.25 h, and produced 75% of the phase shift observed with 2 hours of bright light. CONCLUSIONS A 30-minute morning bright light exposure with afternoon melatonin is an efficient treatment to phase advance human circadian rhythms. PMID:25620199
Monk, T. H.; Buysse, D. J.; Billy, B. D.; Kennedy, K. S.; Kupfer, D. J.
As part of a larger bedrest study involving various life science experiments, a study was conducted on the effects of 17 days of continuous bedrest and elimination of daylight on circadian rectal temperature rhythms, mood, alertness, and sleep (objective and diary) in eight healthy middle-aged men. Sleep was timed from 2300 to 0700 hours throughout. Three 72-hour measurement blocks were compared: ambulatory prebedrest, early bedrest (days 5-7), and late bedrest (days 15-17). Temperature rhythms showed reduced amplitude and later phases resulting from the bedrest conditions. This was associated with longer nocturnal sleep onset latencies and poorer subjectively rated sleep but with no reliable changes in any of the other sleep parameters. Daily changes in posture and/or exposure to daylight appear to be important determinants of a properly entrained circadian system.
Oosterman, Johanneke E; Kalsbeek, Andries; la Fleur, Susanne E; Belsham, Denise D
The suprachiasmatic nucleus (SCN) in the mammalian hypothalamus functions as an endogenous pacemaker that generates and maintains circadian rhythms throughout the body. Next to this central clock, peripheral oscillators exist in almost all mammalian tissues. Whereas the SCN is mainly entrained to the environment by light, peripheral clocks are entrained by various factors, of which feeding/fasting is the most important. Desynchronization between the central and peripheral clocks by, for instance, altered timing of food intake can lead to uncoupling of peripheral clocks from the central pacemaker and is, in humans, related to the development of metabolic disorders, including obesity and Type 2 diabetes. Diets high in fat or sugar have been shown to alter circadian clock function. This review discusses the recent findings concerning the influence of nutrients, in particular fatty acids and glucose, on behavioral and molecular circadian rhythms and will summarize critical studies describing putative mechanisms by which these nutrients are able to alter normal circadian rhythmicity, in the SCN, in non-SCN brain areas, as well as in peripheral organs. As the effects of fat and sugar on the clock could be through alterations in energy status, the role of specific nutrient sensors will be outlined, as well as the molecular studies linking these components to metabolism. Understanding the impact of specific macronutrients on the circadian clock will allow for guidance toward the composition and timing of meals optimal for physiological health, as well as putative therapeutic targets to regulate the molecular clock.
Oosterman, Johanneke E.; Kalsbeek, Andries; la Fleur, Susanne E.
The suprachiasmatic nucleus (SCN) in the mammalian hypothalamus functions as an endogenous pacemaker that generates and maintains circadian rhythms throughout the body. Next to this central clock, peripheral oscillators exist in almost all mammalian tissues. Whereas the SCN is mainly entrained to the environment by light, peripheral clocks are entrained by various factors, of which feeding/fasting is the most important. Desynchronization between the central and peripheral clocks by, for instance, altered timing of food intake can lead to uncoupling of peripheral clocks from the central pacemaker and is, in humans, related to the development of metabolic disorders, including obesity and Type 2 diabetes. Diets high in fat or sugar have been shown to alter circadian clock function. This review discusses the recent findings concerning the influence of nutrients, in particular fatty acids and glucose, on behavioral and molecular circadian rhythms and will summarize critical studies describing putative mechanisms by which these nutrients are able to alter normal circadian rhythmicity, in the SCN, in non-SCN brain areas, as well as in peripheral organs. As the effects of fat and sugar on the clock could be through alterations in energy status, the role of specific nutrient sensors will be outlined, as well as the molecular studies linking these components to metabolism. Understanding the impact of specific macronutrients on the circadian clock will allow for guidance toward the composition and timing of meals optimal for physiological health, as well as putative therapeutic targets to regulate the molecular clock. PMID:25519730
Skene, Debra J.; Arendt, Josephine; Cade, Janet E.; Grant, Peter J.; Hardie, Laura J.
Circadian (∼24-hour) timing systems pervade all kingdoms of life and temporally optimize behavior and physiology in humans. Relatively recent changes to our environments, such as the introduction of artificial lighting, can disorganize the circadian system, from the level of the molecular clocks that regulate the timing of cellular activities to the level of synchronization between our daily cycles of behavior and the solar day. Sleep/wake cycles are intertwined with the circadian system, and global trends indicate that these, too, are increasingly subject to disruption. A large proportion of the world's population is at increased risk of environmentally driven circadian rhythm and sleep disruption, and a minority of individuals are also genetically predisposed to circadian misalignment and sleep disorders. The consequences of disruption to the circadian system and sleep are profound and include myriad metabolic ramifications, some of which may be compounded by adverse effects on dietary choices. If not addressed, the deleterious effects of such disruption will continue to cause widespread health problems; therefore, implementation of the numerous behavioral and pharmaceutical interventions that can help restore circadian system alignment and enhance sleep will be important. PMID:27763782
McCarthy, Michael J; Welsh, David K
Bipolar disorder (BD) and major depressive disorder (MDD) are heritable neuropsychiatric disorders associated with disrupted circadian rhythms. The hypothesis that circadian clock dysfunction plays a causal role in these disorders has endured for decades but has been difficult to test and remains controversial. In the meantime, the discovery of clock genes and cellular clocks has revolutionized our understanding of circadian timing. Cellular circadian clocks are located in the suprachiasmatic nucleus (SCN), the brain's primary circadian pacemaker, but also throughout the brain and peripheral tissues. In BD and MDD patients, defects have been found in SCN-dependent rhythms of body temperature and melatonin release. However, these are imperfect and indirect indicators of SCN function. Moreover, the SCN may not be particularly relevant to mood regulation, whereas the lateral habenula, ventral tegmentum, and hippocampus, which also contain cellular clocks, have established roles in this regard. Dysfunction in these non-SCN clocks could contribute directly to the pathophysiology of BD/MDD. We hypothesize that circadian clock dysfunction in non-SCN clocks is a trait marker of mood disorders, encoded by pathological genetic variants. Because network features of the SCN render it uniquely resistant to perturbation, previous studies of SCN outputs in mood disorders patients may have failed to detect genetic defects affecting non-SCN clocks, which include not only mood-regulating neurons in the brain but also peripheral cells accessible in human subjects. Therefore, reporters of rhythmic clock gene expression in cells from patients or mouse models could provide a direct assay of the molecular gears of the clock, in cellular clocks that are likely to be more representative than the SCN of mood-regulating neurons in patients. This approach, informed by the new insights and tools of modern chronobiology, will allow a more definitive test of the role of cellular circadian clocks
Pauley, Stephen M
The hypothesis that the suppression of melatonin (MLT) by exposure to light at night (LAN) may be one reason for the higher rates of breast and colorectal cancers in the developed world deserves more attention. The literature supports raising this subject for awareness as a growing public health issue. Evidence now exists that indirectly links exposures to LAN to human breast and colorectal cancers in shift workers. The hypothesis begs an even larger question: has medical science overlooked the suppression of MLT by LAN as a contributor to the overall incidence of cancer? The indirect linkage of breast cancer to LAN is further supported by laboratory rat experiments by David E. Blask and colleagues. Experiments involved the implanting of human MCF-7 breast cancer cell xenografts into the groins of rats and measurements were made of cancer cell growth rates, the uptake of linoleic acid (LA), and MLT levels. One group of implanted rats were placed in light-dark (12L:12D) and a second group in light-light (12L:12L) environments. Constant light suppressed MLT, increased cancer cell growth rates, and increased LA uptake into cancer cells. The opposite was seen in the light-dark group. The proposed mechanism is the suppression of nocturnal MLT by exposure to LAN and subsequent lack of protection by MLT on cancer cell receptor sites which allows the uptake of LA which in turn enhances the growth of cancer cells. MLT is a protective, oncostatic hormone and strong antioxidant having evolved in all plants and animals over the millennia. In vertebrates, MLT is normally produced by the pineal gland during the early morning hours of darkness, even in nocturnal animals, and is suppressed by exposure to LAN. Daily entrainment of the human circadian clock is important for good human health. These studies suggest that the proper use and color of indoor and outdoor lighting is important to the health of both humans and ecosystems. Lighting fixtures should be designed to minimize
Martinez-Nicolas, Antonio; Madrid, Juan Antonio; Rol, Maria Angeles
Modern societies are characterized by a 24/7 lifestyle (LS) with no environmental differences between day and night, resulting in weak zeitgebers (weak day light, absence of darkness during night, constant environmental temperature, sedentary LS and frequent snacking), and as a consequence, in an impaired circadian system (CS) through a process known as chronodisruption. Both weak zeitgebers and CS impairment are related to human pathologies (certain cancers, metabolic syndrome and affective and cognitive disorders), but little is known about how to chronoenhance the CS. The aim of this work is to propose practical strategies for chronoenhancement, based on accentuating the day/night contrast. For this, 131 young subjects were recruited, and their wrist temperature (WT), activity, body position, light exposure, environmental temperature and sleep were recorded under free-living conditions for 1 week. Subjects with high contrast (HC) and low contrast (LC) for each variable were selected to analyze the HC effect in activity, body position, environmental temperature, light exposure and sleep would have on WT. We found that HC showed better rhythms than LC for every variable except sleep. Subjects with HC and LC for WT also demonstrated differences in LS, where HC subjects had a slightly advanced night phase onset and a general increase in day/night contrast. In addition, theoretical high day/night contrast calculated using mathematical models suggests an improvement by means of LS contrast. Finally, some individuals classified as belonging to the HC group in terms of WT when they are exposed to the LS characteristic of the LC group, while others exhibit WT arrhythmicity despite their good LS habits, revealing two different WT components: an exogenous component modified by LS and another endogenous component that is refractory to it. Therefore, intensifying day/night contrast in subject's LS has proven to be a feasible measure to chronoenhance the CS.
Circadian rhythm is an internal biological clock which initiates and monitors various physiological processes with a fixed time-related schedule. The master circadian pacemaker is located in the suprachiasmatic nucleus in the hypothalamus. The circadian clock undergoes significant changes throughout the life span, at both the physiological and molecular levels. This cyclical physiological process, which is very complex and multifactorial, may be associated with metabolic alterations, atherosclerosis, impaired cognition, mood disturbances and even development of cancer. Sex differences do exist, and the well-known sleep disturbances associated with menopause are a good example. Circadian rhythm was detected in the daily pattern of hot flushes, with a peak in the afternoons. Endogenous secretion of melatonin decreases with aging across genders, and, among women, menopause is associated with a significant reduction of melatonin levels, affecting sleep. Although it might seem that hot flushes and melatonin secretion are likely related, there are not enough data to support such a hypothesis.
Giebultowicz, Jadwiga M.; Long, Dani M.
Circadian clocks are cell-autonomous molecular feedback loops that generate daily rhythms in gene expression, cellular functions, physiological processes and behavior. The mechanisms of circadian clocks are well understood in young fruit flies Drosophila melanogaster, but less is known about how circadian system changes during organismal aging. Similar as in humans, rest/activity rhythms tend to weaken with age in fruit flies, suggesting conservation of aging-related changes in the circadian system. It has been shown that aging is associated with reduced expression of core clock genes in peripheral head clocks while similar reduction may not occur in central clock neurons regulating behavioral rhythms. Arrhythmic flies with mutations in core clock genes display accelerated aging and shortened lifespan suggesting that weakened circadian rhythms may contribute to aging phenotypes. To understand whether strong circadian clocks support organism’s healthspan and lifespan, future research needs to focus on age-related changes in clock genes as well as clock-controlled genes in specific organs and tissues. PMID:26000238
Chang, Anne-Marie; Aeschbach, Daniel; Duffy, Jeanne F.; Czeisler, Charles A.
In the past 50 y, there has been a decline in average sleep duration and quality, with adverse consequences on general health. A representative survey of 1,508 American adults recently revealed that 90% of Americans used some type of electronics at least a few nights per week within 1 h before bedtime. Mounting evidence from countries around the world shows the negative impact of such technology use on sleep. This negative impact on sleep may be due to the short-wavelength–enriched light emitted by these electronic devices, given that artificial-light exposure has been shown experimentally to produce alerting effects, suppress melatonin, and phase-shift the biological clock. A few reports have shown that these devices suppress melatonin levels, but little is known about the effects on circadian phase or the following sleep episode, exposing a substantial gap in our knowledge of how this increasingly popular technology affects sleep. Here we compare the biological effects of reading an electronic book on a light-emitting device (LE-eBook) with reading a printed book in the hours before bedtime. Participants reading an LE-eBook took longer to fall asleep and had reduced evening sleepiness, reduced melatonin secretion, later timing of their circadian clock, and reduced next-morning alertness than when reading a printed book. These results demonstrate that evening exposure to an LE-eBook phase-delays the circadian clock, acutely suppresses melatonin, and has important implications for understanding the impact of such technologies on sleep, performance, health, and safety. PMID:25535358
Chang, Anne-Marie; Aeschbach, Daniel; Duffy, Jeanne F; Czeisler, Charles A
In the past 50 y, there has been a decline in average sleep duration and quality, with adverse consequences on general health. A representative survey of 1,508 American adults recently revealed that 90% of Americans used some type of electronics at least a few nights per week within 1 h before bedtime. Mounting evidence from countries around the world shows the negative impact of such technology use on sleep. This negative impact on sleep may be due to the short-wavelength-enriched light emitted by these electronic devices, given that artificial-light exposure has been shown experimentally to produce alerting effects, suppress melatonin, and phase-shift the biological clock. A few reports have shown that these devices suppress melatonin levels, but little is known about the effects on circadian phase or the following sleep episode, exposing a substantial gap in our knowledge of how this increasingly popular technology affects sleep. Here we compare the biological effects of reading an electronic book on a light-emitting device (LE-eBook) with reading a printed book in the hours before bedtime. Participants reading an LE-eBook took longer to fall asleep and had reduced evening sleepiness, reduced melatonin secretion, later timing of their circadian clock, and reduced next-morning alertness than when reading a printed book. These results demonstrate that evening exposure to an LE-eBook phase-delays the circadian clock, acutely suppresses melatonin, and has important implications for understanding the impact of such technologies on sleep, performance, health, and safety.
Gooley, Joshua J; Chua, Eric Chern-Pin
The circadian timing system plays a key role in orchestrating lipid metabolism. In concert with the solar cycle, the circadian system ensures that daily rhythms in lipid absorption, storage, and transport are temporally coordinated with rest-activity and feeding cycles. At the cellular level, genes involved in lipid synthesis and fatty acid oxidation are rhythmically activated and repressed by core clock proteins in a tissue-specific manner. Consequently, loss of clock gene function or misalignment of circadian rhythms with feeding cycles (e.g., in shift work) results in impaired lipid homeostasis. Herein, we review recent progress in circadian rhythms research using lipidomics, i.e., large-scale profiling of lipid metabolites, to characterize circadian-regulated lipid pathways in mammals. In mice, novel regulatory circuits involved in fatty acid metabolism have been identified in adipose tissue, liver, and muscle. Extensive diversity in circadian regulation of plasma lipids has also been revealed in humans using lipidomics and other metabolomics approaches. In future studies, lipidomics platforms will be increasingly used to better understand the effects of genetic variation, shift work, food intake, and drugs on circadian-regulated lipid pathways and metabolic health.
Humans as diurnal beings are active during the day and rest at night. This daily oscillation of behavior and physiology is driven by an endogenous circadian clock not environmental cues. In modern societies, changes in lifestyle have led to a frequent disruption of the endogenous circadian homeostas...
Baldwin, Ian T; Meldau, Stefan
The optimal defense hypothesis (ODH) provides a functional explanation for the inhomogeneous distribution of defensive structures and defense metabolites throughout a plant's body: tissues that are most valuable in terms of fitness and have the highest probability of attack are generally the best defended. In a previous review, we argue that ontogenically-controlled accumulations of defense metabolites are likely regulated through an integration of developmental and defense signaling pathways. In this addendum, we extend the discussion of ODH patterns by including the recent discoveries of circadian clock-controlled defenses in plants.
Aguilar-Arnal, Lorena; Sassone-Corsi, Paolo
The molecular circadian clock orchestrates the daily cyclical expression of thousands of genes. Disruption of this transcriptional program leads to a variety of pathologies, including insomnia, depression and metabolic disorders. Circadian rhythms in gene expression rely on specific chromatin transitions which are ultimately coordinated by the molecular clock. As a consequence, a highly plastic and dynamic circadian epigenome can be delineated across different tissues and cell types. Intriguingly, genome topology appears to coordinate cyclic transcription at circadian interactomes, in which circadian genes are in physical contact within the cell nucleus in a time-specific manner. Moreover, the clock machinery shows functional interplays with key metabolic regulators, thereby connecting the circadian epigenome to cellular metabolism. Unraveling the molecular aspects of such interplays is likely to reveal new therapeutic strategies towards the treatment of metabolic disorders. PMID:27014564
Brady, A. K.; Hilton, J. D.; Vize, P. D.
Broadcast spawning corals release gametes into the oceans with extraordinarily accurate timing. While the date of spawning is set by the lunar cycle, the hour/minute of spawning is set by the solar cycle. In this report, we describe experiments that test whether the time of spawning is regulated by an entrained biological clock or whether it is directly controlled by the solar cycle. Montastraea franksi samples were collected on the morning of the predicted spawning. Fragments from colonies were kept under three different lighting conditions and spawning monitored. The three conditions were sunset times of 0, 1 or 2 h earlier than normal. Fragments from the same colony spawned differently under these three conditions, with an early sunset causing a corresponding early shift in spawning. These results indicate that spawn timing is not controlled by a circadian rhythm and that it is directly controlled by local solar light cycle.
Sollars, Patricia J; Pickard, Gary E
There is a growing recognition that the coordinated timing of behavioral, physiologic, and metabolic circadian rhythms is a requirement for a healthy body and mind. In mammals, the primary circadian oscillator is the hypothalamic suprachiasmatic nucleus (SCN), which is responsible for circadian coordination throughout the organism. Temporal homeostasis is recognized as a complex interplay between rhythmic clock gene expression in brain regions outside the SCN and in peripheral organs. Abnormalities in this intricate circadian orchestration may alter sleep patterns and contribute to the pathophysiology of affective disorders.
Lazar, Alpar S; Santhi, Nayantara; Hasan, Sibah; Lo, June C-Y; Johnston, Jonathan D; Von Schantz, Malcolm; Archer, Simon N; Dijk, Derk-Jan
Sleep complaints and irregular sleep patterns, such as curtailed sleep during workdays and longer and later sleep during weekends, are common. It is often implied that differences in circadian period and in entrained phase contribute to these patterns, but few data are available. We assessed parameters of the circadian rhythm of melatonin at baseline and in a forced desynchrony protocol in 35 participants (18 women) with no sleep disorders. Circadian period varied between 23 h 50 min and 24 h 31 min, and correlated positively (n = 31, rs = 0.43, P = 0.017) with the timing of the melatonin rhythm relative to habitual bedtime. The phase of the melatonin rhythm correlated with the Insomnia Severity Index (n = 35, rs = 0.47, P = 0.004). Self-reported time in bed during free days also correlated with the timing of the melatonin rhythm (n = 35, rs = 0.43, P = 0.01) as well as with the circadian period (n = 31, rs = 0.47, P = 0.007), such that individuals with a more delayed melatonin rhythm or a longer circadian period reported longer sleep during the weekend. The increase in time in bed during the free days correlated positively with circadian period (n = 31, rs = 0.54, P = 0.002). Polysomnographically assessed latency to persistent sleep (n = 34, rs = 0.48, P = 0.004) correlated with the timing of the melatonin rhythm when participants were sleeping at their habitual bedtimes in the laboratory. This correlation was significantly stronger in women than in men (Z = 2.38, P = 0.017). The findings show that individual differences in circadian period and phase of the melatonin rhythm associate with differences in sleep, and suggest that individuals with a long circadian period may be at risk of developing sleep problems.
Mallis, M. M.; DeRoshia, C. W.
Maintaining optimal alertness and neurobehavioral functioning during space operations is critical to enable the National Aeronautics and Space Administration's (NASA's) vision "to extend humanity's reach to the Moon, Mars and beyond" to become a reality. Field data have demonstrated that sleep times and performance of crewmembers can be compromised by extended duty days, irregular work schedules, high workload, and varying environmental factors. This paper documents evidence of significant sleep loss and disruption of circadian rhythms in astronauts and associated performance decrements during several space missions, which demonstrates the need to develop effective countermeasures. Both sleep and circadian disruptions have been identified in the Behavioral Health and Performance (BH&P) area and the Advanced Human Support Technology (AHST) area of NASA's Bioastronautics Critical Path Roadmap. Such disruptions could have serious consequences on the effectiveness, health, and safety of astronaut crews, thus reducing the safety margin and increasing the chances of an accident or incident. These decrements oftentimes can be difficult to detect and counter effectively in restrictive operational environments. NASA is focusing research on the development of optimal sleep/wake schedules and countermeasure timing and application to help mitigate the cumulative effects of sleep and circadian disruption and enhance operational performance. Investing research in humans is one of NASA's building blocks that will allow for both short- and long-duration space missions and help NASA in developing approaches to manage and overcome the human limitations of space travel. In addition to reviewing the current state of knowledge concerning sleep and circadian disruptions during space operations, this paper provides an overview of NASA's broad research goals. Also, NASA-funded research, designed to evaluate the relationships between sleep quality, circadian rhythm stability, and
Mallis, M M; DeRoshia, C W
Maintaining optimal alertness and neurobehavioral functioning during space operations is critical to enable the National Aeronautics and Space Administration's (NASA's) vision "to extend humanity's reach to the Moon, Mars and beyond" to become a reality. Field data have demonstrated that sleep times and performance of crewmembers can be compromised by extended duty days, irregular work schedules, high workload, and varying environmental factors. This paper documents evidence of significant sleep loss and disruption of circadian rhythms in astronauts and associated performance decrements during several space missions, which demonstrates the need to develop effective countermeasures. Both sleep and circadian disruptions have been identified in the Behavioral Health and Performance (BH&P) area and the Advanced Human Support Technology (AHST) area of NASA's Bioastronautics Critical Path Roadmap. Such disruptions could have serious consequences on the effectiveness, health, and safety of astronaut crews, thus reducing the safety margin and increasing the chances of an accident or incident. These decrements oftentimes can be difficult to detect and counter effectively in restrictive operational environments. NASA is focusing research on the development of optimal sleep/wake schedules and countermeasure timing and application to help mitigate the cumulative effects of sleep and circadian disruption and enhance operational performance. Investing research in humans is one of NASA's building blocks that will allow for both short- and long-duration space missions and help NASA in developing approaches to manage and overcome the human limitations of space travel. In addition to reviewing the current state of knowledge concerning sleep and circadian disruptions during space operations, this paper provides an overview of NASA's broad research goals. Also, NASA-funded research, designed to evaluate the relationships between sleep quality, circadian rhythm stability, and
Czeisler, Charles A.; Chiasera, August J.; Duffy, Jeanne F.
Disorders of sleep and circadian rhythmicity are characteristic of both advancing age and manned spaceflight. Sleep fragmentation, reduced nocturnal sleep tendency and sleep efficiency, reduced daytime alertness, and increased daytime napping are common to both of these conditions. Recent research on the pathophysiology and treatment of disrupted sleep in older people has led to a better understanding of how the human circadian pacemaker regulates the timing of the daily sleep-wake cycle and how it responds to the periodic changes in the light-dark cycle to which we are ordinarily exposed. These findings have led to new treatments for some of the sleep disorders common to older individuals, using carefully timed exposure to bright light and darkness to manipulate the phase and/or amplitude of the circadian timing system. These insights and treatment approaches have direct applications in the design of countermeasures allowing astronauts to overcome some of the challenges which manned spaceflight poses for the human circadian timing system. We have conducted an operational feasibility study on the use of scheduled exposure to bright light and darkness prior to launch in order to facilitate adaptation of the circadian system of a NASA Space Shuttle crew to the altered sleep-wake schedule required for their mission. The results of this study illustrate how an understanding of the properties of the human circadian timing system and the consequences of circadian disruption can be applied to manned spaceflight.
Winget, C. M.; Deroshia, C. W.; Sandler, H.
Eight females from 35-45 yr of age were subjected to seven days of ambulatory control, seven days of bed rest, and a five day recovery period, with 30 min of centrifugation on day seven of bedrest to determine the effects of weightlessness on the circadian rhythms of females in that age group. Heart rate and rectal temperature (RT) were monitored and each subject was tested in a flight simulator twice a day in conditions of varying levels of turbulence. The flight simulations were run during the morning and acrophase of the circadian RT and performance errors wery monitored for 6 min. No significant differences were detected in the group performance data pre-, during, and post-bedrest, although better performance in the simulator was observed after the centrifuge exposure. An RT phase shift was statistically significant between pre- and during bedrest stages.
Lin, L; Wisor, J; Shiba, T; Taheri, S; Yanai, K; Wurts, S; Lin, X; Vitaterna, M; Takahashi, J; Lovenberg, T W; Koehl, M; Uhl, G; Nishino, S; Mignot, E
The hypocretins (1 and 2) have emerged as key regulators of sleep and wakefulness. We developed a high-throughput enzyme immunoassay (EIA) to measure total brain hypocretin levels from large numbers of mice. Hypocretin levels were not altered by circadian time or age. However, significant differences in one or both hypocretin peptides were observed between different mouse strains. We studied hypocretin levels in knockout and transgenic mouse models with obesity, circadian gene mutations or monoaminergic defects. Compared to controls, only histamine receptor knockouts had lower hypocretin levels. This was most pronounced in H1 receptor knockouts suggesting the existence of a positive feedback loop between hypocretin and histaminergic neurons.
Stevenson, Douglass E; Harris, Marvin K
Mate finding is a key lifecycle event for the pecan nut casebearer, Acrobasis nuxvorella Neunzig, as it is for virtually all Lepidoptera, many of which rely on long-range, species-specific sex pheromones, regulated largely by circadian clocks. Adult male moths were trapped at discrete time intervals during the first two seasonal flights for 6 yr to determine times of peak activity associated with male response to pheromones. From 1997 to 2002, the Harris-Coble automated clockwork timing trap was used for hourly time-segregated sampling. Analysis of variance with linear contrasts determined that circadian response of A. nuxvorella males to pecan nut casebearer pheromone began at approximately 2100 hours, the first hour of total darkness, lasting for 6-7 h. It peaked from midnight to 0400 hours and ended at the onset of morning twilight, approximately 0500 hours. The hours of peak activity are hours of minimal bat predation. The study shows that pecan nut casebearer males become responsive to pheromone several hours before females start calling and remain responsive for at least 1 h after they stop. The extended response period conforms to studies of other polygamous Lepidoptera in which a selective advantage is conferred on early responding males in scramble competition for available females.
Lin, Li-Ling; Huang, Hsuan-Cheng; Juan, Hsueh-Fen
Systems biology, which can be defined as integrative biology, comprises multistage processes that can be used to understand components of complex biological systems of living organisms and provides hierarchical information to decoding life. Using systems biology approaches such as genomics, transcriptomics and proteomics, it is now possible to delineate more complicated interactions between circadian control systems and diseases. The circadian rhythm is a multiscale phenomenon existing within the body that influences numerous physiological activities such as changes in gene expression, protein turnover, metabolism and human behavior. In this review, we describe the relationships between the circadian control system and its related genes or proteins, and circadian rhythm disorders in systems biology studies. To maintain and modulate circadian oscillation, cells possess elaborative feedback loops composed of circadian core proteins that regulate the expression of other genes through their transcriptional activities. The disruption of these rhythms has been reported to be associated with diseases such as arrhythmia, obesity, insulin resistance, carcinogenesis and disruptions in natural oscillations in the control of cell growth. This review demonstrates that lifestyle is considered as a fundamental factor that modifies circadian rhythm, and the development of dysfunctions and diseases could be regulated by an underlying expression network with multiple circadian-associated signals.
Hashimoto, S; Kohsaka, M; Morita, N; Fukuda, N; Honma, S; Honma, K
Eight young males were subjected to a single blind cross-over test to see the effects of vitamin B12 (methylcobalamin; VB12) on the phase-response of the circadian melatonin rhythm to a single bright light exposure. VB12 (0.5 mg/day) or vehicle was injected intravenously at 1230 h for 11 days, which was followed by oral administration (2 mg x 3/day) for 7 days. A serial blood sampling was performed under dim light condition (less than 200 lx) and plasma melatonin rhythm was determined before and after a single bright light exposure (2500 lx for 3 h) at 0700 h. The melatonin rhythm before the light exposure showed a smaller amplitude in the VB12 trial than in the placebo. The light exposure phase-advanced the melatonin rhythm significantly in the VB12 trail, but not in the placebo. These findings indicate that VB12 enhances the light-induced phase-shift in the human circadian rhythm.
De Nobrega, Aliza K; Lyons, Lisa C
Delineating the factors that affect behavioral and neurological responses to alcohol is critical to facilitate measures for preventing or treating alcohol abuse. The high degree of conserved molecular and physiological processes makes Drosophila melanogaster a valuable model for investigating circadian interactions with alcohol-induced behaviors and examining sex-specific differences in alcohol sensitivity. We found that wild-type Drosophila exhibited rhythms in alcohol-induced sedation under light-dark and constant dark conditions with considerably greater alcohol exposure necessary to induce sedation during the late (subjective) day and peak sensitivity to alcohol occurring during the late (subjective) night. The circadian clock also modulated the recovery from alcohol-induced sedation with flies regaining motor control significantly faster during the late (subjective) day. As predicted, the circadian rhythms in sedation and recovery were absent in flies with a mutation in the circadian gene period or arrhythmic flies housed in constant light conditions. Flies lacking a functional circadian clock were more sensitive to the effects of alcohol with significantly longer recovery times. Similar to other animals and humans, Drosophila exhibit sex-specific differences in alcohol sensitivity. We investigated whether the circadian clock modulated the rhythms in the loss-of-righting reflex, alcohol-induced sedation, and recovery differently in males and females. We found that both sexes demonstrated circadian rhythms in the loss-of-righting reflex and sedation with the differences in alcohol sensitivity between males and females most pronounced during the late subjective day. Recovery of motor reflexes following alcohol sedation also exhibited circadian modulation in male and female flies, although the circadian clock did not modulate the difference in recovery times between the sexes. These studies provide a framework outlining how the circadian clock modulates alcohol
De Nobrega, Aliza K.; Lyons, Lisa C.
Delineating the factors that affect behavioral and neurological responses to alcohol is critical to facilitate measures for preventing or treating alcohol abuse. The high degree of conserved molecular and physiological processes make Drosophila melanogaster a valuable model for investigating circadian interactions with alcohol-induced behaviors and examining sex-specific differences in alcohol sensitivity. We found that wild-type Drosophila exhibit rhythms in alcohol-induced sedation under light-dark and constant dark conditions with considerably greater alcohol exposure necessary to induce sedation during the late (subjective) day and peak sensitivity to alcohol occurring during the late (subjective) night. The circadian clock also modulated the recovery from alcohol-induced sedation with flies regaining motor control significantly faster during the late (subjective) day. As predicted, the circadian rhythms in sedation and recovery were absent in flies with a mutation in the circadian gene period or arrhythmic flies housed in constant light conditions. Flies lacking a functional circadian clock were more sensitive to the effects of alcohol with significantly longer recovery times. Similar to other animals and humans, Drosophila exhibit sex-specific differences in alcohol sensitivity. We investigated whether the circadian clock modulated the rhythms in the Loss-of-Righting Reflex, alcohol-induced sedation, and recovery differently in males and females. We found that both sexes demonstrate circadian rhythms in the Loss-of-Righting Reflex and sedation with the differences in alcohol sensitivity between males and females most pronounced during the late subjective day. Recovery of motor reflexes following alcohol sedation also exhibited circadian modulation in male and female flies, although the circadian clock did not modulate the difference in recovery times between the sexes. These studies provide a framework outlining how the circadian clock modulates alcohol
Pomplun, Marc; Silva, Edward J.; Ronda, Joseph M.; Cain, Sean W.; Münch, Mirjam Y.; Czeisler, Charles A.; Duffy, Jeanne F.
Cognitive performance not only differs between individuals, but also varies within them, influenced by factors that include sleep-wakefulness and biological time of day (circadian phase). Previous studies have shown that both factors influence accuracy rather than the speed of performing a visual search task, which can be hazardous in safety-critical tasks such as air-traffic control or baggage screening. However, prior investigations used simple, brief search tasks requiring little use of working memory. In order to study the effects of circadian phase, time awake, and chronic sleep restriction on the more realistic scenario of longer tasks requiring the sustained interaction of visual working memory and attentional control, the present study employed two comparative visual search tasks. In these tasks, participants had to detect a mismatch between two otherwise identical object distributions, with one of the tasks (mirror task) requiring an additional mental image transformation. Time awake and circadian phase both had significant influences on the speed, but not the accuracy of task performance. Over the course of three weeks of chronic sleep restriction, speed but not accuracy of task performance was impacted. The results suggest measures for safer performance of important tasks and point out the importance of minimizing the impact of circadian phase and sleep-wake history in laboratory vision experiments. PMID:22836655
Kettner, Nicole M.; Katchy, Chinenye A.; Fu, Loning
Humans as diurnal beings are active during the day and rest at night. This daily oscillation of behavior and physiology is driven by an endogenous circadian clock not environmental cues. In modern societies, changes in lifestyle have led to a frequent disruption of the endogenous circadian homeostasis leading to increased risk of various diseases including cancer. The clock is operated by the feedback loops of circadian genes and controls daily physiology by coupling cell proliferation and metabolism, DNA damage repair, and apoptosis in peripheral tissues with physical activity, energy homeostasis, immune and neuroendocrine functions at the organismal level. Recent studies have revealed that defects in circadian genes due to targeted gene ablation in animal models or single nucleotide polymorphism, deletion, deregulation and/or epigenetic silencing in humans are closely associated with increased risk of cancer. In addition, disruption of circadian rhythm can disrupt the molecular clock in peripheral tissues in the absence of circadian gene mutations. Circadian disruption has recently been recognized as an independent cancer risk factor. Further study of the mechanism of clock-controlled tumor suppression will have a significant impact on human health by improving the efficiencies of cancer prevention and treatment. PMID:24901356
Halgamuge, Malka N
Electromagnetic fields (EMFs) can increase free radicals, activate the stress response and alter enzyme reactions. Intracellular signalling is mediated by free radicals and enzyme kinetics is affected by radical pair recombination rates. The magnetic field component of an external EMF can delay the "recombination rate" of free radical pairs. Magnetic fields thus increase radical life-times in biological systems. Although measured in nanoseconds, this extra time increases the potential to do more damage. Melatonin regulates the body's sleep-wake cycle or circadian rhythm. The World Health Organization (WHO) has confirmed that prolonged alterations in sleep patterns suppress the body's ability to make melatonin. Considerable cancer rates have been attributed to the reduction of melatonin production as a result of jet lag and night shift work. In this study, changes in circadian rhythm and melatonin concentration are observed due to the external perturbation of chemical reaction rates. We further analyze the pineal melatonin rhythm and investigate the critical time delay or maturation time of radical pair recombination rates, exploring the impact of the mRNA degradation rate on the critical time delay. The results show that significant melatonin interruption and changes to the circadian rhythm occur due to the perturbation of chemical reaction rates, as also reported in previous studies. The results also show the influence of the mRNA degradation rate on the circadian rhythm's critical time delay or maturation time. The results support the hypothesis that exposure to weak EMFs via melatonin disruption can adversely affect human health.
Summa, Keith C; Turek, Fred W
Recent advances in the understanding of the molecular, genetic, neural, and physiologic basis for the generation and organization of circadian clocks in mammals have revealed profound bidirectional interactions between the circadian clock system and pathways critical for the regulation of metabolism and energy balance. The discovery that mice harboring a mutation in the core circadian gene circadian locomotor output cycles kaput (Clock) develop obesity and evidence of the metabolic syndrome represented a seminal moment for the field, clearly establishing a link between circadian rhythms, energy balance, and metabolism at the genetic level. Subsequent studies have characterized in great detail the depth and magnitude of the circadian clock's crucial role in regulating body weight and other metabolic processes. Dietary nutrients have been shown to influence circadian rhythms at both molecular and behavioral levels; and many nuclear hormone receptors, which bind nutrients as well as other circulating ligands, have been observed to exhibit robust circadian rhythms of expression in peripheral metabolic tissues. Furthermore, the daily timing of food intake has itself been shown to affect body weight regulation in mammals, likely through, at least in part, regulation of the temporal expression patterns of metabolic genes. Taken together, these and other related findings have transformed our understanding of the important role of time, on a 24-h scale, in the complex physiologic processes of energy balance and coordinated regulation of metabolism. This research has implications for human metabolic disease and may provide unique and novel insights into the development of new therapeutic strategies to control and combat the epidemic of obesity.
Miyazaki, Yosuke; Watari, Yasuhiko; Tanaka, Kazuhiro; Goto, Shin G
Soil temperature cycles are considered to play an important role in the entrainment of circadian clocks of underground insects. However, because of the low conductivity of soil, temperature cycles are gradually dampened and the phase of the temperature cycle is delayed with increasing soil depth. The onion fly, Delia antiqua, pupates at various soil depths, and its eclosion is timed by a circadian clock. This fly is able to compensate for the depth-dependent phase delay of temperature change by advancing the eclosion time with decreasing amplitude of the temperature cycle. Therefore, pupae can eclose at the appropriate time irrespective of their location at any depth. However, the mechanism that regulates eclosion time in response to temperature amplitude is still unknown. To understand whether this mechanism involves the circadian clock or further downstream physiological processes, we examined the expression patterns of period (per), a circadian clock gene, of D. antiqua under temperature cycles that were square wave cycles of 12-h warm phase (W) and 12-h cool phase (C) with the temperature difference of 8 °C (WC 29:21 °C) and 1 °C (WC 25.5:24.5 °C). The phase of oscillation in per expression was found to commence 3.5h earlier under WC 25.5:24.5 °C as compared to WC 29:21 °C. This difference was in close agreement with the eclosion time difference between the two temperature cycles, suggesting that the mechanism that responds to the temperature amplitude involves the circadian clock.
Kim, Min Ju; Lee, Jung Hie; Duffy, Jeanne F.
Objective To review circadian rhythm sleep disorders, including underlying causes, diagnostic considerations, and typical treatments. Methods Literature review and discussion of specific cases. Results Survey studies 1,2 suggest that up to 3% of the adult population suffers from a circadian rhythm sleep disorder (CRSD). However, these sleep disorders are often confused with insomnia, and an estimated 10% of adult and 16% of adolescent sleep disorders patients may have a CRSD 3-6. While some CRSD (such as jet lag) can be self-limiting, others when untreated can lead to adverse medical, psychological, and social consequences. The International Classification of Sleep Disorders classifies CRSD as dyssomnias, with six subtypes: Advanced Sleep Phase Type, Delayed Sleep Phase Type, Irregular Sleep Wake Type, Free Running Type, Jet Lag Type, and Shift Work Type. The primary clinical characteristic of all CRSD is an inability to fall asleep and wake at the desired time. It is believed that CRSD arise from a problem with the internal biological clock (circadian timing system) and/or misalignment between the circadian timing system and the external 24-hour environment. This misalignment can be the result of biological and/or behavioral factors. CRSD can be confused with other sleep or medical disorders. Conclusions Circadian rhythm sleep disorders are a distinct class of sleep disorders characterized by a mismatch between the desired timing of sleep and the ability to fall asleep and remain asleep. If untreated, CRSD can lead to insomnia and excessive daytime sleepiness, with negative medical, psychological, and social consequences. It is important for physicians to recognize potential circadian rhythm sleep disorders so that appropriate diagnosis, treatment, and referral can be made. PMID:25368503
Dibner, Charna; Sadowski, Samira Mercedes; Triponez, Frederic; Philippe, Jacques
Accumulating evidence suggests that alterations in the molecular clocks underlying the circadian time-keeping system might be connected to changes in cell cycle, resulting in oncogenic transformation. The hypothalamic-pituitary-thyroid axis is driven by a circadian clock at several levels, with an endocrine feedback loop regulating thyroid-stimulating hormone. Changes in the expression levels of circadian and cell cycle markers may correlate with clinic-pathological characteristics in differentiated follicular thyroid carcinomas. Here we summarize recent advances in exploring complex regulation of the thyroid gland transcriptome and function by the circadian oscillator. We particularly focus on clinical implications of the parallel assessment of the circadian clock, cell-cycle and cell functionality markers in human thyroid tissue, which might help improving preoperative diagnostics of thyroid malignancies.
Monk, T. H.; Kupfer, D. J.
Using both previously published findings and entirely new data, we present evidence in support of the argument that the circadian dysfunction of advancing age in the healthy human is primarily one of failing to transduce the circadian signal from the circadian timing system (CTS) to rhythms "downstream" from the pacemaker rather than one of failing to generate the circadian signal itself. Two downstream rhythms are considered: subjective alertness and objective performance. For subjective alertness, we show that in both normal nychthemeral (24 h routine, sleeping at night) and unmasking (36 h of constant wakeful bed rest) conditions, advancing age, especially in men, leads to flattening of subjective alertness rhythms, even when circadian temperature rhythms are relatively robust. For objective performance, an unmasking experiment involving manual dexterity, visual search, and visual vigilance tasks was used to demonstrate that the relationship between temperature and performance is strong in the young, but not in older subjects (and especially not in older men).
Jones, Helen; George, Keith; Edwards, Ben; Atkinson, Greg
Recently, we found that the reactivity of ambulatory blood pressure (BP) to everyday physical activities is highest in the morning. All participants in that study slept normally at night and freely chose their activity levels, which did not allow a separation of any circadian influence on the BP response from the effects of sleep per se. Therefore, the aims of the present study were to investigate whether there is circadian variation in the BP response to a controlled bout of exercise, and whether or not such variation is explained by the residual masking effects of nocturnal sleep. Following 4 h of nocturnal sleep, six normotensive males exercised on a cycle ergometer at 04:00, 06:00, 08:00, and 10:00 h. On a separate day, participants also slept for 4 h in the afternoon and then exercised at 16:00, 18:00, 20:00, and 22:00 h. Mean arterial BP, cardiac output (CO), heart rate (HR), and total peripheral resistance (TPR) were measured for 5 min before and 5, 10, 15, and 20 min after each exercise bout. Post-exercise data were subtracted from pre-exercise baselines and analyzed using general linear modeling with repeated measures. Fifteen min after exercise at 04:00 h, mean arterial BP was 8-14 mm Hg higher (p<0.05) than it was after the corresponding post-exercise time at the other clock-hour trials, including the 16:00 h bout that immediately followed daytime sleep. Significantly (p<0.05) greater responses of TPR and HR were also found after the 04:00 h exercise bout. We conclude that mean arterial BP shows highest reactivity to a controlled bout of exercise when performed in the morning. This phenomenon cannot be attributed simply to the residual effects of sleep, as it was not observed when participants exercised after a period of daytime sleep.
Landry, Glenn J; Kent, Brianne A; Patton, Danica F; Jaholkowski, Mark; Marchant, Elliott G; Mistlberger, Ralph E
The dorsomedial hypothalamus (DMH) is a site of circadian clock gene and immediate early gene expression inducible by daytime restricted feeding schedules that entrain food anticipatory circadian rhythms in rats and mice. The role of the DMH in the expression of anticipatory rhythms has been evaluated using different lesion methods. Partial lesions created with the neurotoxin ibotenic acid (IBO) have been reported to attenuate food anticipatory rhythms, while complete lesions made with radiofrequency current leave anticipatory rhythms largely intact. We tested a hypothesis that the DMH and fibers of passage spared by IBO lesions play a time-of-day dependent role in the expression of food anticipatory rhythms. Rats received intra-DMH microinjections of IBO and activity and body temperature (T(b)) rhythms were recorded by telemetry during ad-lib food access, total food deprivation and scheduled feeding, with food provided for 4-h/day for 20 days in the middle of the light period and then for 20 days late in the dark period. During ad-lib food access, rats with DMH lesions exhibited a lower amplitude and mean level of light-dark entrained activity and T(b) rhythms. During the daytime feeding schedule, all rats exhibited food anticipatory activity and T(b) rhythms that persisted during 2 days without food in constant dark. In some rats with partial or total DMH ablation, the magnitude of the anticipatory rhythm was weak relative to most intact rats. When mealtime was shifted to the late night, the magnitude of the food anticipatory activity rhythms in these cases was restored to levels characteristic of intact rats. These results confirm that rats can anticipate scheduled daytime or nighttime meals without the DMH. Improved anticipation at night suggests a modulatory role for the DMH in the expression of food anticipatory activity rhythms during the daily light period, when nocturnal rodents normally sleep.
Monk, Timothy H.; Buysse, Daniel J.; Billy, Bart D.; Kennedy, Kathy S.; Willrich, Linda M.
INTRODUCTION The study of human sleep and circadian rhythms in space has both operational and scientific significance. Operationally, U.S. Spaceflight is moving away from brief missions with durations of less than one week. Most space shuttle missions now last two weeks or more, and future plans involving space stations, lunar bases and interplanetary missions all presume that people will be living away from the gravity and time cues of earth for months at a time. Thus, missions are moving away from situations where astronauts can "tough it out" for comparatively brief durations, to situations where sleep and circadian disruptions are likely to become chronic, and thus resistant to short term pharmacological or behavioral manipulations. As well as the operational significance, there is a strong theoretical imperative for studying the sleep and circadian rhythms of people who are removed from the gravity and time cues of earth. Like other animals, in humans, the Circadian Timekeeping System (CTS) is entrained to the correct period (24h) and temporal orientation by various time cues ("zeitgebers"), the most powerful of which is the alternation of daylight and darkness. In leaving Earth, astronauts are removing themselves from the prime zeitgeber of their circadian system -- the 24h alternation of daylight and darkness.
Takeuchi, Tomomi; Newton, Linsey; Burkhardt, Alyssa; Mason, Saundra; Farré, Eva M.
In Arabidopsis, the circadian clock regulates UV-B-mediated changes in gene expression. Here it is shown that circadian clock components are able to inhibit UV-B-induced gene expression in a gene-by-gene-specific manner and act downstream of the initial UV-B sensing by COP1 (CONSTITUTIVE PHOTOMORPHOGENIC 1) and UVR8 (UV RESISTANCE LOCUS 8). For example, the UV-B induction of ELIP1 (EARLY LIGHT INDUCIBLE PROTEIN 1) and PRR9 (PSEUDO-RESPONSE REGULATOR 9) is directly regulated by LUX (LUX ARRYTHMO), ELF4 (EARLY FLOWERING 4), and ELF3. Moreover, time-dependent changes in plant sensitivity to UV-B damage were observed. Wild-type Arabidopsis plants, but not circadian clock mutants, were more sensitive to UV-B treatment during the night periods than during the light periods under diel cycles. Experiments performed under short cycles of 6h light and 6h darkness showed that the increased stress sensitivity of plants to UV-B in the dark only occurred during the subjective night and not during the subjective day in wild-type seedlings. In contrast, the stress sensitivity of Arabidopsis mutants with a compromised circadian clock was still influenced by the light condition during the subjective day. Taken together, the results show that the clock and light modulate plant sensitivity to UV-B stress at different times of the day. PMID:25147271
Takeuchi, Tomomi; Newton, Linsey; Burkhardt, Alyssa; Mason, Saundra; Farré, Eva M
In Arabidopsis, the circadian clock regulates UV-B-mediated changes in gene expression. Here it is shown that circadian clock components are able to inhibit UV-B-induced gene expression in a gene-by-gene-specific manner and act downstream of the initial UV-B sensing by COP1 (CONSTITUTIVE PHOTOMORPHOGENIC 1) and UVR8 (UV RESISTANCE LOCUS 8). For example, the UV-B induction of ELIP1 (EARLY LIGHT INDUCIBLE PROTEIN 1) and PRR9 (PSEUDO-RESPONSE REGULATOR 9) is directly regulated by LUX (LUX ARRYTHMO), ELF4 (EARLY FLOWERING 4), and ELF3. Moreover, time-dependent changes in plant sensitivity to UV-B damage were observed. Wild-type Arabidopsis plants, but not circadian clock mutants, were more sensitive to UV-B treatment during the night periods than during the light periods under diel cycles. Experiments performed under short cycles of 6h light and 6h darkness showed that the increased stress sensitivity of plants to UV-B in the dark only occurred during the subjective night and not during the subjective day in wild-type seedlings. In contrast, the stress sensitivity of Arabidopsis mutants with a compromised circadian clock was still influenced by the light condition during the subjective day. Taken together, the results show that the clock and light modulate plant sensitivity to UV-B stress at different times of the day.
Zhdanova, Irina V.; Tucci, Valter
Experimental data show a close relationship among melatonin, circadian rhythms, and sleep. Low-dose melatonin treatment, increasing circulating melatonin levels to those normally observed at night, promotes sleep onset and sleep maintenance without changing sleep architecture. Melatonin treatment can also advance or delay the phase of the circadian clock if administered in the evening or in the morning, respectively. If used in physiologic doses and at appropriate times, melatonin can be helpful for those suffering from insomnia or circadian rhythm disorders. This may be especially beneficial for individuals with low melatonin production, which is established by measuring individual blood or saliva melatonin levels. However, high melatonin doses (over 0.3 mg) may cause side effects and disrupt the delicate mechanism of the circadian system, dissociating mutually dependent circadian body rhythms. A misleading labeling of the hormone melatonin as a "food supplement" and lack of quality control over melatonin preparations on the market continue to be of serious concern.
In 7 men with normal weight and 9 man with overweight and healthy metabolism the resting and fasting energy expenditure was indirectly calorimetrically pursued in the open system over 24 hours. The total energy expenditure over 24 hours revealed an ascertained dependence on body-weight and nutrition. The persons with overweight had a higher absolute energy expenditure, however, the activity of the energy metabolism of the body mass free from fat and the active body mass, respectively, decreased with increasing overweight. The resting and fasting energy expenditure showed in all measured parameters (oxygen consumption, respiratory quotient and nitrogen excretion in the urine) an ascertained daily periodicity (circadian rhythm), which was widely independent of body weight. Only the average daily level C0 (rhythm adjusted level) of the resting and fasting energy expenditure was positively correlated with the body weight and the food energy intake. A negative energy balance (reduction 1.2 MJ/d over 28 days) influenced only the total energy and substrate balance over 24 hours and the daily average level, respectively. The circadian conditions remained unchanged (Chossat's phenomenon). The variability in daily rhythm of the energy expenditure of nearly 25% of the daily average should be taken into consideration in the judgment of exogenically stimulated changes in the energy metabolism.
Bedrosian, Tracy A; Fonken, Laura K; Nelson, Randy J
Disruption of circadian rhythms, provoked by artificial lighting at night, inconsistent sleep-wake schedules, and transmeridian air travel, is increasingly prevalent in modern society. Desynchrony of biological rhythms from environmental light cycles has dramatic consequences for human health. In particular, disrupting homeostatic oscillations in endocrine tissues and the hormones that these tissues regulate can have cascading effects on physiology and behavior. Accumulating evidence suggests that chronic disruption of circadian organization of endocrine function may lead to metabolic, reproductive, sleep, and mood disorders. This review discusses circadian control of endocrine systems and the consequences of distorting rhythmicity of these systems.
Meireles-Filho, Antonio Carlos Alves; Kyriacou, Charalambos Panayiotis
Organisms from bacteria to humans have evolved under predictable daily environmental cycles owing to the Earth’s rotation. This strong selection pressure has generated endogenous circadian clocks that regulate many aspects of behaviour, physiology and metabolism, anticipating and synchronising internal time-keeping to changes in the cyclical environment. In haematophagous insect vectors the circadian clock coordinates feeding activity, which is important for the dynamics of pathogen transmission. We have recently witnessed a substantial advance in molecular studies of circadian clocks in insect vector species that has consolidated behavioural data collected over many years, which provided insights into the regulation of the clock in the wild. Next generation sequencing technologies will facilitate the study of vector genomes/transcriptomes both among and within species and illuminate some of the species-specific patterns of adaptive circadian phenotypes that are observed in the field and in the laboratory. In this review we will explore these recent findings and attempt to identify potential areas for further investigation. PMID:24473802
Circadian rhythm, or daily oscillation, of behaviors and biological processes is a fundamental feature of mammalian physiology that has developed over hundreds of thousands of years under the continuous evolutionary pressure of energy conservation and efficiency. Evolution has fine-tuned the body's clock to anticipate and respond to numerous environmental cues in order to maintain homeostatic balance and promote survival. However, we now live in a society in which these classic circadian entrainment stimuli have been dramatically altered from the conditions under which the clock machinery was originally set. A bombardment of artificial lighting, heating, and cooling systems that maintain constant ambient temperature; sedentary lifestyle; and the availability of inexpensive, high-calorie foods has threatened even the most powerful and ancient circadian programming mechanisms. Such environmental changes have contributed to the recent staggering elevation in lifestyle-influenced pathologies, including cancer, cardiovascular disease, depression, obesity, and diabetes. This review scrutinizes the role of the body's internal clocks in the hard-wiring of circadian networks that have evolved to achieve energetic balance and adaptability, and it discusses potential therapeutic strategies to reset clock metabolic control to modern time for the benefit of human health. PMID:25927923
Valdez, Pablo; Ramírez, Candelaria; García, Aída; Talamantes, Javier; Cortez, Juventino
Human performance is modulated by circadian rhythms and homeostatic changes. Changes in efficiency in the performance of many tasks might be produced by variation in a basic cognitive process, such as sustained attention. This cognitive process is the capacity to respond efficiently to the environment during prolonged periods (from minutes to hours). There are three indices of sustained attention: general stability of efficiency, time on task stability, and short-term stability. The objective of this work was to analyze circadian and homeostatic influences on the indices of sustained attention. Participants were nine undergraduate female student volunteers (mean age 17.67 yrs, SD = 1.00, range 16-19 yrs) who attended school from 07:00-13:30 h, Monday to Friday. They were assessed while adhering to a modified 28 h constant-routine protocol during which feeding, room temperature, motor activity, and room illumination were controlled. Rectal temperature was recorded each minute, and indices of sustained attention were assessed hourly through a continuous performance task (CPT). General stability was measured as standard deviation of correct responses and reaction time, time on task stability was measured as the linear regression of correct responses and reaction time throughout the task, and short-term stability was measured as hit runs and error runs. Rectal temperature showed circadian variation; subjective somnolence and tiredness increased, while general performance and all indices of sustained attention declined throughout the 28 h recording session. General stability exhibited circadian variation, whereas time on task did not. Short-term stability showed circadian variations in short-error runs, long-error runs, and short-hit runs, but long-hit runs did not. There was a 26 sec short interval at the beginning of the task, characterized by a very high efficiency level of performance. Execution during this safe period was not affected by time awake and did not show
Stowie, Adam C; Amicarelli, Mario J; Crosier, Caitlin J; Mymko, Ryan; Glass, J David
Few, if any studies have focused on the daily rhythmic nature of modern industrialized populations. The present study utilized real-time load data from the U.S. Pacific Northwest electrical power grid as a reflection of human operative household activity. This approach involved actigraphic analyses of continuously streaming internet data (provided in 5 min bins) from a human subject pool of approximately 43 million primarily residential users. Rhythm analyses reveal striking seasonal and intra-week differences in human activity patterns, largely devoid of manufacturing and automated load interference. Length of the diurnal activity period (alpha) is longer during the spring than the summer (16.64 h versus 15.98 h, respectively; p < 0.01). As expected, significantly more activity occurs in the solar dark phase during the winter than during the summer (6.29 h versus 2.03 h, respectively; p < 0.01). Interestingly, throughout the year a "weekend effect" is evident, where morning activity onset occurs approximately 1 h later than during the work week (5:54 am versus 6:52 am, respectively; p < 0.01). This indicates a general phase-delaying response to the absence of job-related or other weekday morning arousal cues, substantiating a preference or need to sleep longer on weekends. Finally, a shift in onset time can be seen during the transition to Day Light Saving Time, but not the transition back to Standard Time. The use of grid power load as a means for human actimetry assessment thus offers new insights into the collective diurnal activity patterns of large human populations.
Eckel-Mahan, Kristin; Sassone-Corsi, Paolo
Circadian rhythms take place with a periodicity of 24 hr, temporally following the rotation of the earth around its axis. Examples of circadian rhythms are the sleep/wake cycle, feeding, and hormone secretion. Light powerfully entrains the mammalian clock and assists in keeping animals synchronized to the 24-hour cycle of the earth by activating specific neurons in the "central pacemaker" of the brain, the suprachiasmatic nucleus. Absolute periodicity of an animal can deviate slightly from 24 hr as manifest when an animal is placed into constant dark or "free-running" conditions. Simple measurements of an organism's activity in free-running conditions reveal its intrinsic circadian period. Mice are a particularly useful model for studying circadian rhythmicity due to the ease of genetic manipulation, thus identifying molecular contributors to rhythmicity. Furthermore, their small size allows for monitoring locomotion or activity in their homecage environment with relative ease. Several tasks commonly used to analyze circadian periodicity and plasticity in mice are presented here including the process of entrainment, determination of tau (period length) in free-running conditions, determination of circadian periodicity in response to light disruption (e.g., jet lag studies), and evaluation of clock plasticity in non-24-hour conditions (T-cycles). Studying the properties of circadian periods such as their phase, amplitude, and length in response to photic perturbation, can be particularly useful in understanding how humans respond to jet lag, night shifts, rotating shifts, or other transient or chronic disruption of environmental surroundings.
Obesity has become a serious public health problem and a major risk factor for the development of illnesses, such as insulin resistance and hypertension. Attempts to understand the causes of obesity and develop new therapeutic strategies have mostly focused on caloric intake and energy expenditure. Recent studies have shown that the circadian clock controls energy homeostasis by regulating the circadian expression and/or activity of enzymes, hormones, and transport systems involved in metabolism. Moreover, disruption of circadian rhythms leads to obesity and metabolic disorders. Therefore, it is plausible that resetting of the circadian clock can be used as a new approach to attenuate obesity. Feeding regimens, such as restricted feeding (RF), calorie restriction (CR), and intermittent fasting (IF), provide a time cue and reset the circadian clock and lead to better health. In contrast, high-fat (HF) diet leads to disrupted circadian expression of metabolic factors and obesity. This paper focuses on circadian rhythms and their link to obesity. PMID:24527263
Gafni, Y.; Ptitsyn, A.A.; Zilberman, Y.; Pelled, G.; Gimble, J.M.; Gazit, D.
The human body displays central circadian rhythms of activity. Recent findings suggest that peripheral tissues, such as bone, possess their own circadian clocks. Studies have shown that osteocalcin protein levels oscillate over a 24-hour period, yet the specific skeletal sites involved and its transcriptional profile remain unknown. The current study aimed to test the hypothesis that peripheral circadian mechanisms regulate transcription driven by the osteocalcin promoter. Transgenic mice harboring the human osteocalcin promoter linked to a luciferase reporter gene were used. Mice of both genders and various ages were analyzed non-invasively at sequential times throughout 24-hour periods. Statistical analyses of luminescent signal intensity of osteogenic activity from multiple skeletal sites indicated a periodicity of ~ 24 hrs. The maxillomandibular complex displayed the most robust oscillatory pattern. These findings have implications for dental treatments in orthodontics and maxillofacial surgery, as well as for the mechanisms underlying bone remodeling in the maxillomandibular complex. PMID:19131316
Gander, P. H.; Myhre, G.; Graeber, R. C.; Andersen, H. T.; Lauber, J. K.
Physiological and psychological disruptions caused by transmeridian flights may affect the ability of flight crews to meet operational demands. To study these effects, 9 Royal Norwegian Airforces P3-Orion crewmembers flew from Norway to California (-9 hr), and back (+9 hr). Rectal temperature, heart rate and wrist activity were recorded every 2 min, fatigue and mood were rated every 2 hr during the waking day, and logs were kept of sleep times and ratings. Subjects also completed 4 personality inventories. The time-zone shifts produced negative changes in mood which persisted longer after westward flights. Sleep quality (subjective and objective) and duration were slightly disrupted (more after eastward flights). The circadian rhythms of sleep/wake and temperature both completed the 9-hr delay by day 5 in California, although temperature adjusted more slowly. The size of the delay shift was significantly correlated with scores on extraversion and achievement need personality scales. Response to the 9-hr advance were more variable. One subject exhibited a 15-hr delay in his temperature rhythm, and an atypical sleep/nap pattern. On average, the sleep/wake cycle (but not the temperature rhythm), completed the 9-hr advance by the end of the study. Both rhythms adapted more slowly after the eastward flight.
Rosenwasser, Alan M; Turek, Fred W
Over the past few decades, multilevel research has elucidated the basic neuroanatomy, neurochemistry, and molecular neurobiology of the master circadian pacemaker located in the hypothalamic suprachiasmatic nucleus (SCN). The circadian timing system is composed of a large number of cellular oscillators located in the SCN, in non-SCN brain structures, and throughout the body. Cellular-level oscillations are generated by a molecular feedback loop in which circadian clock genes rhythmically regulate their own transcription, as well as that of hundreds of clock-controlled genes. The maintenance of proper coordination within this network of cellular- and tissue-level clocks is essential for health and well-being.
Mahadevan, Sangeetha K.; Fiorotto, Marta L.; Van den Veyver, Ignatia B.
Offspring of murine dams chronically fed a protein-restricted diet have an increased risk for metabolic and neurobehavioral disorders. Previously we showed that adult offspring, developmentally exposed to a chronic maternal low-protein (MLP) diet, had lower body and hind-leg muscle weights and decreased liver enzyme serum levels. We conducted energy expenditure, neurobehavioral and circadian rhythm assays in male offspring to examine mechanisms for the body-weight phenotype and assess neurodevelopmental implications of MLP exposure. C57BL/6J dams were fed a protein restricted (8%protein, MLP) or a control protein (20% protein, C) diet from four weeks before mating until weaning of offspring. Male offspring were weaned to standard rodent diet (20% protein) and single-housed until 8–12 weeks of age. We examined body composition, food intake, energy expenditure, spontaneous rearing activity and sleep patterns and performed behavioral assays for anxiety (open field activity, elevated plus maze [EPM], light/dark exploration), depression (tail suspension and forced swim test), sociability (three-chamber), repetitive (marble burying), learning and memory (fear conditioning), and circadian behavior (wheel-running activity during light-dark and constant dark cycles). We also measured circadian gene expression in hypothalamus and liver at different Zeitgeber times (ZT). Male offspring from separate MLP exposed dams had significantly greater body fat (P = 0.03), less energy expenditure (P = 0.004), less rearing activity (P = 0.04) and a greater number of night-time rest/sleep bouts (P = 0.03) compared to control. MLP offspring displayed greater anxiety-like behavior in the EPM (P<0.01) but had no learning and memory deficit in fear-conditioning assay (P = 0.02). There was an effect of time on Per1, Per 2 and Clock circadian gene expression in the hypothalamus but not on circadian behavior. Thus, transplacental and early developmental exposure of dams to chronic MLP reduces
Doherty, Colleen J.; Kay, Steve A.
An internal time-keeping mechanism has been observed in almost every organism studied from archaea to humans. This circadian clock provides a competitive advantage in fitness and survival (18, 30, 95, 129, 137). Researchers have uncovered the molecular composition of this internal clock by combining enzymology, molecular biology, genetics, and modeling approaches. However, understanding the mechanistic link between the clock and output responses has been elusive. In three model organisms, Arabidopsis thaliana, Drosophila melanogaster, and Mus musculus, whole-genome expression arrays have enabled researchers to investigate how maintaining a time-keeping mechanism connects to an adaptive advantage. Here, we review the impacts transcriptomics have had on our understanding of the clock and how this molecular clock connects with system-level circadian responses. We explore the discoveries made possible by high-throughput RNA assays, the network approaches used to investigate these large transcript datasets, and potential future directions. PMID:20809800
Marinac, Catherine R.; Sears, Dorothy D.; Natarajan, Loki; Gallo, Linda C.; Breen, Caitlin I.; Patterson, Ruth E.
Emerging evidence suggests that there is interplay between the frequency and circadian timing of eating and metabolic health. We examined the associations of eating frequency and timing with metabolic and inflammatory biomarkers putatively associated with breast cancer risk in women participating in the National Health and Nutrition Examination 2009–2010 Survey. Eating frequency and timing variables were calculated from 24-hour food records and included (1) proportion of calories consumed in the evening (5pm-midnight), (2) number of eating episodes per day, and (3) nighttime fasting duration. Linear regression models examined each eating frequency and timing exposure variable with C-reactive protein (CRP) concentrations and the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR). Each 10 percent increase in the proportion of calories consumed in the evening was associated with a 3 percent increase in CRP. Conversely, eating one additional meal or snack per day was associated with an 8 percent reduction in CRP. There was a significant interaction between proportion of calories consumed in the evening and fasting duration with CRP (p = 0.02). A longer nighttime fasting duration was associated with an 8 percent lower CRP only among women who ate less than 30% of their total daily calories in the evening (p = 0.01). None of the eating frequency and timing variables were significantly associated with HOMA-IR. These findings suggest that eating more frequently, reducing evening energy intake, and fasting for longer nightly intervals may lower systemic inflammation and subsequently reduce breast cancer risk. Randomized trials are needed to validate these associations. PMID:26305095
Lahti, Tuuli; Merikanto, Ilona; Partonen, Timo
Disrupted circadian rhythms may lead to failures in the control of the cell division cycle and the subsequent malignant cell growth. In order to understand the pathogenesis of cancer more in detail, it is crucial to identify those mechanisms of action which contribute to the loss of control of the cell division cycle. This mini-review focuses on the recent findings concerning the links between the human circadian clock and cancer. Clinical implications concern not only feasible methods for the assessment of the circadian time of an individual or for the determination of the best time for administration of a drug of treatment, but also in the future genetic tests for screening and for planning treatment.
Lee, Susie; Donehower, Lawrence A.; Herron, Alan J.; Moore, David D.; Fu, Loning
Background Cell proliferation in all rapidly renewing mammalian tissues follows a circadian rhythm that is often disrupted in advanced-stage tumors. Epidemiologic studies have revealed a clear link between disruption of circadian rhythms and cancer development in humans. Mice lacking the circadian genes Period1 and 2 (Per) or Cryptochrome1 and 2 (Cry) are deficient in cell cycle regulation and Per2 mutant mice are cancer-prone. However, it remains unclear how circadian rhythm in cell proliferation is generated in vivo and why disruption of circadian rhythm may lead to tumorigenesis. Methodology/Principal Findings Mice lacking Per1 and 2, Cry1 and 2, or one copy of Bmal1, all show increased spontaneous and radiation-induced tumor development. The neoplastic growth of Per-mutant somatic cells is not controlled cell-autonomously but is dependent upon extracellular mitogenic signals. Among the circadian output pathways, the rhythmic sympathetic signaling plays a key role in the central-peripheral timing mechanism that simultaneously activates the cell cycle clock via AP1-controlled Myc induction and p53 via peripheral clock-controlled ATM activation. Jet-lag promptly desynchronizes the central clock-SNS-peripheral clock axis, abolishes the peripheral clock-dependent ATM activation, and activates myc oncogenic potential, leading to tumor development in the same organ systems in wild-type and circadian gene-mutant mice. Conclusions/Significance Tumor suppression in vivo is a clock-controlled physiological function. The central circadian clock paces extracellular mitogenic signals that drive peripheral clock-controlled expression of key cell cycle and tumor suppressor genes to generate a circadian rhythm in cell proliferation. Frequent disruption of circadian rhythm is an important tumor promoting factor. PMID:20539819
In recent decades our knowledge of the molecular mechanisms of biological clocks has grown expontentially. This has helped to guide the choice of genes studied to explain inter-individual variations seen in circadian rhythms. In recent years analysis of circadian rhythms has advanced considerably into the study of pathological circadian rhythms in human beings. These findings, combined with those obtained from studying mice whose circadian genes have been rendered incapable, have revealed the role of genetic factors in circadian rhythms. This literature review presents an overview of these findings. Beyond our understanding of the functioning of these biological clocks, this knowledge will be extremely useful to analyse genetic factors involved in morbid conditions involving circadian rhythm abnormalities.
Borisenkov, M F
In the inhabitants of the North during increase of geomagnetic activity and during magnetic calm the decrease of amplitude of circadian rhythm of total antioxidant capacity of saliva is observed. The most favorable conditions to display the circadian rhythm are observed at Kp from 0,5 up to 2. The long residing in the North is connected to influence of irregularly varying geomagnetic activity causing disturbance of function of circadian and antioxidant systems that, probably, is one of the reasons of acceleration of process of aging at northerner and of higher risk of occurrence in them the age associated diseases.
Abbott, Sabra M; Reid, Kathryn J; Zee, Phyllis C
The circadian system regulates the timing and expression of nearly all biological processes, most notably, the sleep-wake cycle, and disruption of this system can result in adverse effects on both physical and mental health. The circadian rhythm sleep-wake disorders (CRSWDs) consist of 5 disorders that are due primarily to pathology of the circadian clock or to a misalignment of the timing of the endogenous circadian rhythm with the environment. This article outlines the nature of these disorders, the association of many of these disorders with psychiatric illness, and available treatment options.
Roenneberg, Till; Merrow, Martha
Circadian clocks control the daily life of most light-sensitive organisms - from cyanobacteria to humans. Molecular processes generate cellular rhythmicity, and cellular clocks in animals coordinate rhythms through interaction (known as coupling). This hierarchy of clocks generates a complex, approximately 24-hour temporal programme that is synchronized with the rotation of the Earth. The circadian system ensures anticipation and adaptation to daily environmental changes, and functions on different levels - from gene expression to behaviour. Circadian research is a remarkable example of interdisciplinarity, unravelling the complex mechanisms that underlie a ubiquitous biological programme. Insights from this research will help to optimize medical diagnostics and therapy, as well as adjust social and biological timing on the individual level.
Reinberg, Alain; Riedel, Marc; Brousse, Eric; Floc'h, Nadine Le; Clarisse, René; Mauvieux, Benoît; Touitou, Yvan; Smolensky, Michael H; Marlot, Michel; Berrez, Stéphane; Mechkouri, Mohamed
We investigated the circadian synchronization/desynchronization (by field-study assessment of differences in period, τ, of 16 coexisting and well-documented rhythms) of 30 healthy firemen (FM) exposed to irregular, difficult, and stressful nocturnal work hours who demonstrated excellent clinical tolerance (allochronism). Three groups of FM were studied (A = 12 FM on 24-h duty at the fire station; B = 9 FM on 24-h duty at the emergency call center; C = 9 day-shift administrative FM) of mostly comparable average age, body mass index, career duration, chronotype-morningness/eveningness, and trait of field dependence/independence. The self-assessed 16 circadian rhythms were (i) physiological ones of sleep-wake (sleep log), activity-rest (actography), body temperature (internal transmitter pill probe), right- and left-hand grip strength (hand dynamometer), systolic and diastolic blood pressure (BP) plus heart rate (ambulatory BP monitoring device); (ii) psychological ones (visual analog self-rating scales) of sleepiness, fatigue, fitness for work, and capacity to cope with aggressive social behavior; and (iii) cognitive ones of eye-hand skill and letter cancellation, entailing performance speed (tasks completed/unit time) and accuracy (errors). Data (4-6 time points/24 h; 2 591 480 values in total) were gathered continuously throughout two 8-d spans, one in winter 2010-2011 and one in summer 2011. Each of the resulting 938 unequal-interval time series was analyzed by a special power spectrum analysis to objectively determine the prominent τ. The desynchronization ratio (DR: number of study variables with τ = 24.0 h/number of study variables × 100) served to ascertain the strength/weakness of each rhythm per individual, group, and season. The field study confirmed, independent of group and season, coexistence of rather strong and weak circadian oscillators. Interindividual differences in DR were detected between groups and seasons (χ(2), correlation tests, analysis
Circadian rhythms in myocardial function and dysfunction are firmly established in both animal models and humans. For example, the incidence of arrhythmias and sudden cardiac death increases when organisms awaken. Such observations have classically been explained by circadian rhythms in neurohumoral...
Hahn, Constanze; Cowell, Jason M.; Wiprzycka, Ursula J.; Goldstein, David; Ralph, Martin; Hasher, Lynn; Zelazo, Philip David
To explore the influence of circadian rhythms on executive function during early adolescence, we administered a battery of executive function measures (including a Go-Nogo task, the Iowa Gambling Task, a Self-ordered Pointing task, and an Intra/Extradimensional Shift task) to Morning-preference and Evening-preference participants (N = 80) between…
Wyatt, J. K.; Ritz-De Cecco, A.; Czeisler, C. A.; Dijk, D. J.
The interaction of homeostatic and circadian processes in the regulation of waking neurobehavioral functions and sleep was studied in six healthy young subjects. Subjects were scheduled to 15-24 repetitions of a 20-h rest/activity cycle, resulting in desynchrony between the sleep-wake cycle and the circadian rhythms of body temperature and melatonin. The circadian components of cognitive throughput, short-term memory, alertness, psychomotor vigilance, and sleep disruption were at peak levels near the temperature maximum, shortly before melatonin secretion onset. These measures exhibited their circadian nadir at or shortly after the temperature minimum, which in turn was shortly after the melatonin maximum. Neurobehavioral measures showed impairment toward the end of the 13-h 20-min scheduled wake episodes. This wake-dependent deterioration of neurobehavioral functions can be offset by the circadian drive for wakefulness, which peaks in the latter half of the habitual waking day during entrainment. The data demonstrate the exquisite sensitivity of many neurobehavioral functions to circadian phase and the accumulation of homeostatic drive for sleep.
Stothard, Ellen R; McHill, Andrew W; Depner, Christopher M; Birks, Brian R; Moehlman, Thomas M; Ritchie, Hannah K; Guzzetti, Jacob R; Chinoy, Evan D; LeBourgeois, Monique K; Axelsson, John; Wright, Kenneth P
Reduced exposure to daytime sunlight and increased exposure to electrical lighting at night leads to late circadian and sleep timing [1-3]. We have previously shown that exposure to a natural summer 14 hr 40 min:9 hr 20 min light-dark cycle entrains the human circadian clock to solar time, such that the internal biological night begins near sunset and ends near sunrise . Here we show that the beginning of the biological night and sleep occur earlier after a week's exposure to a natural winter 9 hr 20 min:14 hr 40 min light-dark cycle as compared to the modern electrical lighting environment. Further, we find that the human circadian clock is sensitive to seasonal changes in the natural light-dark cycle, showing an expansion of the biological night in winter compared to summer, akin to that seen in non-humans [4-8]. We also show that circadian and sleep timing occur earlier after spending a weekend camping in a summer 14 hr 39 min:9 hr 21 min natural light-dark cycle compared to a typical weekend in the modern environment. Weekend exposure to natural light was sufficient to achieve ∼69% of the shift in circadian timing we previously reported after a week's exposure to natural light . These findings provide evidence that the human circadian clock adapts to seasonal changes in the natural light-dark cycle and is timed later in the modern environment in both winter and summer. Further, we demonstrate that earlier circadian timing can be rapidly achieved through natural light exposure during a weekend spent camping.
Wang, Dongni; Liang, Xiaodi; Chen, Xianyun; Guo, Jinhu
Circadian clocks are internal molecular time-keeping mechanisms that enable organisms to adjust their physiology and behavior to the daily surroundings. Misalignment of circadian clocks leads to both physiological and health impairment. Post-transcriptional regulation and translational regulation of circadian clocks have been extensively investigated. In addition, accumulating evidence has shed new light on the involvement of ribonucleoprotein complexes (RNPs) in the post-transcriptional regulation of circadian clocks. Numerous RNA-binding proteins (RBPs) and RNPs have been implicated in the post-transcriptional modification of circadian clock proteins in different model organisms. Herein, we summarize the advances in the current knowledge on the role of RNP complexes in circadian clock regulation.
Iamshanov, V A; Koshelevskiĭ, V K
The circadian rhythms of background gamma-radiation and Ki-indexes of geomagnetic activity (GMF) during August-September 2008, January-February 2010 and March 2011 were studied. The authors show that in summer period the maximum of Ki-indexes and gamma-radiation were at 3 p.m. of local time. In winter these maximums were shifted at more last time. It was suggested that an organism produces the own free radicals as nitric oxide to neutralize radicals from background radiation. They are formed during decay of neutrophiles when GMF-activity falls. On the other side, the production of NO is regulated by melatonin synthesis which has a circadian rhythm.
Deroshia, C. W.; Winget, C. M.; Bond, G. H.
A model developed by Wever (1966) is considered. The model describes the behavior of circadian rhythms in response to photoperiod phase shifts simulating time zone changes, as a function of endogenous periodicity, light intensity, and direction of phase shift. A description is given of an investigation conducted to test the model upon the deep body temperature rhythm in unrestrained subhuman primates. An evaluation is conducted regarding the applicability of the model in predicting the type and duration of desynchronization induced by simulated time zone changes as a function of endogenous periodicity.
Yadav, Pankaj; Choudhury, Deepak; Sadanandappa, Madhumala K; Sharma, Vijay Kumar
Circadian clocks time developmental stages of fruit flies Drosophila melanogaster, while light/dark (LD) cycles delimit emergence of adults, conceding only during the "allowed gate." Previous studies have revealed that time-to-emergence can be altered by mutations in the core clock gene period (per), or by altering the length of LD cycles. Since this evidence came from studies on genetically manipulated flies, or on flies maintained under LD cycles with limited range of periods, inferences that can be drawn are limited. Moreover, the extent of shortening or lengthening of time-to-emergence remains yet unknown. In order to pursue this further, we assayed time-to-emergence of D. melanogaster under 12 different LD cycles as well as in constant light (LL) and constant dark conditions (DD). Time-to-emergence in flies occurred earlier under LL than in LD cycles and DD. Among the LD cycles, time-to-emergence occurred earlier under T4-T8, followed by T36-T48, and then T12-T32, suggesting that egg-to-emergence duration in flies becomes shorter when the length of LD cycles deviates from 24 h, bearing a strong positive and a marginally negative correlation with day length, for values shorter and longer than 24 h, respectively. These results suggest that the extent of mismatch between the period of circadian clocks and environmental cycles determines the time-to-emergence in Drosophila.
Zeruesenay, D; Siegmund, W; Franke, G; Zschiesche, M
The pharmacokinetics of theophylline (TPH, 10 mg/kg i.v.) were assessed in rats (natural light-dark span, June 9-10) after i.p. pretreatment with saline and 80 mg/kg phenobarbital (PB), respectively, for 3 consecutive days at either 07:00 h or at 19:00 h. Serum concentrations of TPH were assayed by high-performance liquid chromatography. No significant differences of the elimination rates of TPH could be found between the times of TPH administration (clearance: 1.17 +/- 0.17 ml/kg/min at 07:00 h vs. 1.23 +/- 0.17 ml/kg/min at 19:00 hours). PB premedication markedly accelerated TPH elimination. The increase in clearance values was more expressed when TPH was injected at 07:00 h than at 19:00 h (2.48 +/- 0.67 vs. 2.06 +/- 0.41 ml/kg/min, p < 0.01).
Husse, J; Leliavski, A; Oster, H
In most species--from cyanobacteria to humans--genetically encoded circadian clocks have evolved to adapt behavioral and physiological processes to environmental changes brought about by the Earth's rotation. Clock disruption, e. g. by shift work, can lead to circadian misalignment, promoting the development of metabolic, immune and cognitive dysfunction. In mammals, a central circadian pacemaker residing in the suprachiasmatic nuclei of the hypothalamus resets subordinate, but semi-independent cellular clocks in tissues such as liver, kidney, adrenal, and many brain areas. Peripheral clocks regulate various endocrine, metabolic and immune processes, whereas central oscillators modulate basic as well as higher brain functions. For the clinical practice it is of major importance to be aware of these physiological rhythms in order to correctly interpret laboratory data and other disease symptoms. Chronomedical therapies can reduce side effects and increase efficacy by optimizing the timing of treatment or directly affect disease state by restoring internal circadian synchrony.
Means, John C.; Venkatesan, Anandakrishnan; Gerdes, Bryan; Fan, Jin-Yuan; Bjes, Edward S.; Price, Jeffrey L.
While circadian dysfunction and neurodegeneration are correlated, the mechanism for this is not understood. It is not known if age-dependent circadian dysfunction leads to neurodegeneration or vice-versa, and the proteins that mediate the effect remain unidentified. Here, we show that the knock-down of a regulator (spag) of the circadian kinase Dbt in circadian cells lowers Dbt levels abnormally, lengthens circadian rhythms and causes expression of activated initiator caspase (Dronc) in the optic lobes during the middle of the day or after light pulses at night. Likewise, reduced Dbt activity lengthens circadian period and causes expression of activated Dronc, and a loss-of-function mutation in Clk also leads to expression of activated Dronc in a light-dependent manner. Genetic epistasis experiments place Dbt downstream of Spag in the pathway, and Spag-dependent reductions of Dbt are shown to require the proteasome. Importantly, activated Dronc expression due to reduced Spag or Dbt activity occurs in cells that do not express the spag RNAi or dominant negative Dbt and requires PDF neuropeptide signaling from the same neurons that support behavioral rhythms. Furthermore, reduction of Dbt or Spag activity leads to Dronc-dependent Drosophila Tau cleavage and enhanced neurodegeneration produced by human Tau in a fly eye model for tauopathy. Aging flies with lowered Dbt or Spag function show markers of cell death as well as behavioral deficits and shortened lifespans, and even old wild type flies exhibit Dbt modification and activated caspase at particular times of day. These results suggest that Dbt suppresses expression of activated Dronc to prevent Tau cleavage, and that the circadian clock defects confer sensitivity to expression of activated Dronc in response to prolonged light. They establish a link between the circadian clock factors, light, cell death pathways and Tau toxicity, potentially via dysregulation of circadian neuronal remodeling in the optic lobes
Hardin, Paul E
Circadian clocks control behavioral, physiological and metabolic rhythms via one or more transcriptional feedback loops. In animals, two conserved feedback loops are thought to keep circadian time by mediating rhythmic transcription in opposite phases of the circadian cycle. Recent work in cyanobacteria nevertheless demonstrates that rhythmic transcription is dispensable for circadian timekeeping, raising the possibility that some features of the transcriptional feedback loops in animals are also expendable. Indeed, one of the two feedback loops is not necessary for circadian timekeeping in animals, but rhythmic transcription and post-translational modifications are both essential for keeping circadian time. These results not only confirm additional requirements within the animal circadian timekeeping mechanism, but also raise important questions about the function of conserved, yet expendable, features of the circadian timekeeping mechanism in animals.
Fischer, Dorothee; Vetter, Céline; Roenneberg, Till
The circadian clock governs virtually all processes in the human body, including sleep-wake behaviour. Circadian misalignment describes the off-set between sleep-wake cycles and clock-regulated physiology. This strain is predominantly caused by external (societal) demands including shift work, early school start times and fast travels across time zones. Sleeping at the ‘wrong’ internal time can jeopardise health and safety, and we therefore need a good quantification of this phenomenon. Here, we propose a novel method to quantify the mistiming of sleep-wake rhythms and demonstrate its versatility in day workers and shift workers. Based on a single time series, our Composite Phase Deviation method unveils distinct, subject- and schedule-specific geometries (‘islands and pancakes’) that illustrate how modern work times interfere with sleep. With increasing levels of circadian strain, the resulting shapes change systematically from small, connected forms to large and fragmented patterns. Our method shows good congruence with published measures of circadian misalignment (i.e., Inter-daily Stability and ‘Behavioural Entrainment’), but offers added value as to its requirements, e.g., being computable for sleep logs and questionnaires. Composite Phase Deviations will help to understand the mechanisms that link ‘living against the clock’ with health and disease on an individual basis. PMID:27929109
Background Hunter syndrome (HS) is a lysosomal storage disease caused by iduronate-2-sulfatase (IDS) deficiency and loss of ability to break down and recycle the glycosaminoglycans, heparan and dermatan sulfate, leading to impairment of cellular processes and cell death. Cell activities and functioning of intracellular organelles are controlled by the clock genes (CGs), driving the rhythmic expression of clock controlled genes (CCGs). We aimed to evaluate the expression of CGs and downstream CCGs in HS, before and after enzyme replacement treatment with IDS. Methods The expression levels of CGs and CCGs were evaluated by a whole transcriptome analysis through Next Generation Sequencing in normal primary human fibroblasts and fibroblasts of patients affected by HS before and 24 h/144 h after IDS treatment. The time related expression of CGs after synchronization by serum shock was also evaluated by qRT-PCR before and after 24 hours of IDS treatment. Results In HS fibroblasts we found altered expression of several CGs and CCGs, with dynamic changes 24 h and 144 h after IDS treatment. A semantic hypergraph-based analysis highlighted five gene clusters significantly associated to important biological processes or pathways, and five genes, AHR, HIF1A, CRY1, ITGA5 and EIF2B3, proven to be central players in these pathways. After synchronization by serum shock and 24 h treatment with IDS the expression of ARNTL2 at 10 h (p = 0.036), PER1 at 4 h (p = 0.019), PER2 at 10 h (p = 0.041) and 16 h (p = 0.043) changed in HS fibroblasts. Conclusion CG and CCG expression is altered in HS fibroblasts and IDS treatment determines dynamic modifications, suggesting a direct involvement of the CG machinery in the physiopathology of cellular derangements that characterize HS. PMID:24083598
LeBourgeois, Monique K; Carskadon, Mary A; Akacem, Lameese D; Simpkin, Charles T; Wright, Kenneth P; Achermann, Peter; Jenni, Oskar G
Circadian phase and its relation to sleep are increasingly recognized as fundamental factors influencing human physiology and behavior. Dim light melatonin onset (DLMO) is a reliable marker of the timing of the circadian clock, which has been used in experimental, clinical, and descriptive studies in the past few decades. Although DLMO and its relationship to sleep have been well documented in school-aged children, adolescents, and adults, very little is known about these processes in early childhood. The purpose of this study was 1) to describe circadian phase and phase angles of entrainment in toddlers and 2) to examine associations between DLMO and actigraphic measures of children's nighttime sleep. Participants were 45 healthy toddlers aged 30 to 36 months (33.5 ± 2.2 months; 21 females). After sleeping on a parent-selected schedule for 5 days (assessed with actigraphy and diaries), children participated in an in-home DLMO assessment involving the collection of saliva samples every 30 minutes for 6 hours. Average bedtime was 2015 ± 0036 h, average sleep onset time was 2043 ± 0043 h, average midsleep time was 0143 ± 0038 h, and average wake time was 0644 ± 0042 h. Average DLMO was 1929 ± 0051 h, with a 3.5-hour range. DLMO was normally distributed; however, the distribution of the bedtime, sleep onset time, and midsleep phase angles of entrainment were skewed. On average, DLMO occurred 47.8 ± 47.6 minutes (median = 39.4 minutes) before bedtime, 74.6 ± 48.0 minutes (median = 65.4 minutes) before sleep onset time, 6.2 ± 0.7 hours (median = 6.1 hours) before midsleep time, and 11.3 ± 0.7 hours before wake time. Toddlers with later DLMOs had later bedtimes (r = 0.46), sleep onset times (r = 0.51), midsleep times (r = 0.66), and wake times (r = 0.65) (all p < 0.001). Interindividual differences in toddlers' circadian phase are large and associated with their sleep timing. The early DLMOs of toddlers indicate a maturational delay in the circadian timing
Eckel-Mahan, Kristin; Sassone-Corsi, Paolo
Circadian rhythms take place with a periodicity of twenty-four hours, temporally following the rotation of the earth around its axis. Examples of circadian rhythms are the sleep/wake cycle, feeding, and hormone secretion. Light powerfully entrains the mammalian clock and assists in keeping animals synchronized to the 24-hour cycle of the earth by activating specific neurons in the “central pacemaker” of the brain, the suprachiasmatic nucleus. Absolute periodicity of an animal can deviate slightly from 24 hours as manifest when an animal is placed into constant dark- or “free running”- conditions. Simple measurements of an organism's activity in free running conditions reveal its intrinsic circadian period. Mice are a particularly useful model for studying circadian rhythmicity due to the ease of genetic manipulation, thus identifying molecular contributors to rhythmicity. Furthermore, their small size allows for monitoring locomotion or activity in their home cage environment with relative ease. Several tasks commonly used to analyze circadian periodicity and plasticity in mice are outlined here including the process of entrainment, determination of tau (period length) in free running conditions, determination of circadian periodicity in response to light disruption (i.e. jet lag studies), and evaluation of clock plasticity in non-twenty-four hour conditions (T-cycles). Studying the properties of circadian periods such as their phase, amplitude, and length in response to photic perturbation, can be particularly useful in understanding how humans respond to jet lag, night shifts, rotating shifts, or other transient or chronic disruption of one's environmental surroundings. PMID:26331760
Dong, Chaohua; Bai, Suhua; Du, Liqiang
As an ectothermic animal, crayfish immunity and their resistance to pathogen can be significantly affected by environmental factors such as light and temperature. It has been found for a long time that multiple immune parameters of animals and human are circadian-regulated by light-entrained circadian rhythm. Whether temperature also affects the immune rhythm of animals still remains unclear. In the present study, we investigated the effect of temperature cycles on the rhythm of crayfish immunity and their resistance. Survival experiments demonstrated that temperature cycles of 24 °C and 18 °C effectively entrained the circadian rhythm of crayfish resistance to Aeromonas hydrophila in constant dark. After being exposed to temperature cycles, the crayfish injected at different time points exhibited significant difference in resistance to A. hydrophila. Bacterial growth and total hemocyte count (THC) also showed circadian variation in crayfish subjected to temperature cycles, but phenoloxidase (PO) activity didn't show rhythmic change under the same conditions. Quantitative real-time PCR revealed that basal expression of crustin1 and astacidin in crayfish subjected to temperature cycles was circadian-rhythmic, but induced expression by A. hydrophila didn't show the same rhythm. In contrast, crayfish maintained at constant temperature showed completely arrhythmic in bacterial resistance, immune parameters mentioned above and the expression of antimicrobial peptides. The results present here collectively indicated that temperature cycles entrained circadian rhythm of some immune parameters and shaped crayfish resistance to bacteria.
Circadian rhythmicity is an important component of physiological processes which provides them with a 24-hour temporal organization and adjustment to cyclical changes in the environment. Circadian rhythms are controlled by a network of endogenous clocks, comprising the main clock in the suprachiasmatic nuclei of the hypothalamus and many secondary clocks in the brain and peripheral tissues. All aspects of energy metabolism, from food intake to intracellular signaling pathways, are strongly influenced by circadian rhythmicity. In turn, meal timing is an efficient synchronizer (time-giver) to set the phase of the peripheral clocks, while the suprachiasmatic clock is synchronized by ambient light. In certain nutritional conditions (i.e., low- or high-calory diets), metabolic factors remaining to be identified modulate the functioning of the suprachiasmatic clock. Animal models of obesity and diabetes show circadian alterations. Conversely, when circadian rhythmicity is disturbed, either due to genetically defective circadian clocks, or to circadian desynchronization (chronic light exposure or repeated meals at odd times of the cycle), lipid and glucose metabolism is deregulated. The metabolic impact of circadian desynchronization justifies the development of preventive or therapeutic strategies that could rely, among others, on dietary interventions combining timed meals and specific composition.
Hida, Akiko; Kitamura, Shingo; Ohsawa, Yosuke; Enomoto, Minori; Katayose, Yasuko; Motomura, Yuki; Moriguchi, Yoshiya; Nozaki, Kentaro; Watanabe, Makiko; Aritake, Sayaka; Higuchi, Shigekazu; Kato, Mie; Kamei, Yuichi; Yamazaki, Shin; Goto, Yu-ichi; Ikeda, Masaaki; Mishima, Kazuo
Evaluation of circadian phenotypes is crucial for understanding the pathophysiology of diseases associated with disturbed biological rhythms such as circadian rhythm sleep disorders (CRSDs). We measured clock gene expression in fibroblasts from individual subjects and observed circadian rhythms in the cells (in vitro rhythms). Period length of the in vitro rhythm (in vitro period) was compared with the intrinsic circadian period, τ, measured under a forced desynchrony protocol (in vivo period) and circadian/sleep parameters evaluated by questionnaires, sleep log, and actigraphy. Although no significant correlation was observed between the in vitro and in vivo periods, the in vitro period was correlated with chronotype, habitual sleep time, and preferred sleep time. Our data demonstrate that the in vitro period is significantly correlated with circadian/sleep preference. The findings suggest that fibroblasts from individual patients can be utilized for in vitro screening of therapeutic agents to provide personalized therapeutic regimens for CRSD patients. PMID:23797865
Lacruz, Rodrigo S.; Hacia, Joseph G.; Bromage, Timothy G.; Boyde, Alan; Lei, Yaping; Xu, Yucheng; Miller, Joseph D.; Paine, Michael L.; Snead, Malcolm L.
Fully mature enamel is about 98% mineral by weight. While mineral crystals appear very early during its formative phase, the newly secreted enamel is a soft gel-like matrix containing several enamel matrix proteins of which the most abundant is amelogenin (Amelx). Histological analysis of mineralized dental enamel reveals markings called cross-striations associated with daily increments of enamel formation, as evidenced by injections of labeling dyes at known time intervals. The daily incremental growth of enamel has led to the hypothesis that the circadian clock might be involved in the regulation of enamel development. To identify daily rhythms of clock genes and Amelx, we subjected murine ameloblast cells to serum synchronization to analyze the expression of the circadian transcription factors Per2 and Bmal1 by real-time PCR. Results indicate that these key genetic regulators of the circadian clock are expressed in synchronized murine ameloblast cell cultures and that their expression profile follows a circadian pattern with acrophase and bathyphase for both gene transcripts in antiphase. Immunohistological analysis confirms the protein expression of Bmal and Cry in enamel cells. Amelx expression in 2-day postnatal mouse molars dissected every 4 hours for a duration of 48 hours oscillated with an approximately 24-hour period, with a significant approximately 2-fold decrease in expression during the dark period compared to the light period. The expression of genes involved in bicarbonate production (Car2) and transport (Slc4a4), as well as in enamel matrix endocytosis (Lamp1), was greater during the dark period, indicating that ameloblasts express these proteins when Amelx expression is at the nadir. The human and mouse Amelx genes each contain a single nonconserved E-box element within 10 kb upstream of their respective transcription start sites. We also found that within 2 kb of the transcription start site of the human NFYA gene, which encodes a positive
Recent studies have demonstrated relationships between the disturbance of circadian rhythm and the development of lifestyle-related diseases. First, epidemiological studies showed that rotating shift workers are more likely to develop obesity, hypertension, type 2 diabetes, coronary heart disease, and cancers than day shift employees. In addition, mice with their circadian rhythm chronically impaired by alteration of the light-dark cycle also develop such diseases. Furthermore, both the genotypes and genetic modifications of the clock genes are associated with the development of lifestyle-related diseases in humans and mice, respectively. Finally, circadian clocks in peripheral tissues are impaired in both patients with type 2 diabetes and obese diabetic mice, probably not due to metabolic abnormalities, but to the lifestyle, aging, and/or genetic factors. Thus, disturbance of the circadian rhythm is an important cause of lifestyle-related diseases, and therefore the circadian clocks are attractive therapeutic targets for preventing and treating these conditions.
Monteleone, Palmiero; Martiadis, Vassilis; Maj, Mario
In humans almost all physiological and behavioural functions occur on a rhythmic basis. Therefore the possibility that delays, advances or desynchronizations of circadian rhythms may play a role in the pathophysiology of psychiatric disorders is an interesting field of research. In particular mood disorders such as seasonal affective disorder and major depression have been linked to circadian rhythms alterations. Furthermore, the antidepressant efficacy of both pharmacological and non-pharmacological strategies affecting endogenous circadian rhythms, such as new antidepressant medications, light-therapy and sleep deprivation, is consistent with the idea that circadian alterations may represent a core component of depression, at least in a subgroup of depressed patients. This paper briefly describes the molecular and genetic mechanisms regulating the endogenous clock system, and reviews the literature supporting the relationships between depression, antidepressant treatments and changes in circadian rhythms.
Boyle, Greg; Richter, Kerstin; Priest, Henry D.; Traver, David; Mockler, Todd C.; Chang, Jeffrey T.; Kay, Steve A.
From photosynthetic bacteria to mammals, the circadian clock evolved to track diurnal rhythms and enable organisms to anticipate daily recurring changes such as temperature and light. It orchestrates a broad spectrum of physiology such as the sleep/wake and eating/fasting cycles. While we have made tremendous advances in our understanding of the molecular details of the circadian clock mechanism and how it is synchronized with the environment, we still have rudimentary knowledge regarding its connection to help regulate diurnal physiology. One potential reason is the sheer size of the output network. Diurnal/circadian transcriptomic studies are reporting that around 10% of the expressed genome is rhythmically controlled. Zebrafish is an important model system for the study of the core circadian mechanism in vertebrate. As Zebrafish share more than 70% of its genes with human, it could also be an additional model in addition to rodent for exploring the diurnal/circadian output with potential for translational relevance. Here we performed comparative diurnal/circadian transcriptome analysis with established mouse liver and other tissue datasets. First, by combining liver tissue sampling in a 48h time series, transcription profiling using oligonucleotide arrays and bioinformatics analysis, we profiled rhythmic transcripts and identified 2609 rhythmic genes. The comparative analysis revealed interesting features of the output network regarding number of rhythmic genes, proportion of tissue specific genes and the extent of transcription factor family expression. Undoubtedly, the Zebrafish model system will help identify new vertebrate outputs and their regulators and provides leads for further characterization of the diurnal cis-regulatory network. PMID:28076377
The circadian clock is a global regulatory system that interfaces with most other regulatory systems and pathways in mammalian organisms. Investigations of the circadian clock–DNA damage response connections have revealed that nucleotide excision repair, DNA damage checkpoints, and apoptosis are appreciably influenced by the clock. Although several epidemiological studies in humans and a limited number of genetic studies in mouse model systems have indicated that clock disruption may predispose mammals to cancer, well-controlled genetic studies in mice have not supported the commonly held view that circadian clock disruption is a cancer risk factor. In fact, in the appropriate genetic background, clock disruption may instead aid in cancer regression by promoting intrinsic and extrinsic apoptosis. Finally, the clock may affect the efficacy of cancer treatment (chronochemotherapy) by modulating the pharmacokinetics and pharmacodynamics of chemotherapeutic drugs as well as the activity of the DNA repair enzymes that repair the DNA damage caused by anticancer drugs. PMID:25302769
analysis of slow wave characteristics, origin and propagation. Circadian rhythm is also assessed, including temperature and salivary melatonin...with some increase in temperature over that time. Temperature and circadian rhythm are closely tied together. Alerting factors from the circadian ... circadian rhythm abnormalities. Overall these 2 findings contribute to an overall picture of potentially lower arousal mechanisms day and night, with
Yang, Wen-Qi; Li, Hong
The time phase of epileptic seizures has attracted more and more attention. Epileptic seizures have their own circadian rhythm. The same type of epilepsy has different seizure frequencies in different time periods and states (such as sleeping/awakening state and natural day/night cycle). The circadian rhythm of epileptic seizures has complex molecular and endocrine mechanisms, and currently there are several hypotheses. Clarification of the circadian rhythm of epileptic seizures and prevention and administration according to such circadian rhythm can effectively control seizures and reduce the adverse effects of drugs. The research on the circadian rhythm of epileptic seizures provides a new idea for the treatment of epilepsy.
Vafopoulou, Xanthe; Steel, Colin G H
The rhythmic phenomena expressed by organisms change over their lifetimes, but little is known of accompanying reorganization of the central circadian timing system in the brain. Especially dramatic changes in overt rhythms and morphology occur during transformation of larval insects into the adult form (metamorphosis). In Rhodnius prolixus, both the physiology of metamorphosis and its hormonal control are known in detail. Here we report changes in the brain timing system as revealed by pigment dispersing factor immunohistochemistry and confocal microscopy. Most of the features of the larval system are retained, but new clock cells differentiate and the arborizations of their axons increase in complexity, as do pathways connecting the lateral (LNs) and dorsal (DNs) groups of clock neurons. Early in metamorphosis, the LNs increase from 8 to 11 in number, becoming five small and six large LNs. Two large LNs then migrate to new positions in the protocerebrum. Another clock cell differentiates in the posterior protocerebrum. Each change occurs at a characteristic concentration of the ecdysteroid molting hormones that regulate metamorphosis. Clock cell axons invade the mushroom body and corpus allatum and travel down the ventral nerve cord. New overt rhythms develop during metamorphosis, in which these structures participate. The neuroendocrine cells of the brain receive more extensive branches of clock cell axons than in larvae. These increases in size and complexity of the circadian system during metamorphosis imply a greater complexity and diversity of outputs from it to both behavioral and hormonal rhythms in the adult.
Trufakin, Valery A; Shurlygina, Anna V
In recent times, a number of diseases involving immune system dysfunction have appeared. This increases the importance of research aimed at finding and developing optimized methods for immune system correction. Numerous studies have found a positive effect in using cytokines to treat a variety of diseases, yet the clinical use of cytokines is limited by their toxicity. Research in the field of chronotherapy, aimed at designing schedules of medicine intake using circadian biorhythms of endogenous production of factors, and receptors' expression to the factors on the target cells, as well as chronopharmacodynamics and chronopharmacokinetics of medicines may contribute to the solution of this problem. Advantages of chronotherapy include a greater effectiveness of treatment, reduced dose of required drugs, and minimized adverse effects. This review presents data on the presence of circadian rhythms of spontaneous and induced cytokine production, as well as the expression of cytokine receptors in the healthy body and in a number of diseases. The article reviews various effects of cytokines, used at different times of the day in humans and experimental animals, as well as possible mechanisms underlying the chronodependent effects of cytokines. The article presents the results of chronotherapeutic modes of administering IL-2, interferons, G-CSF, and GM-CSF in treatment of various types of cancer as well as in experimental models of immune suppression and inflammation, which lead to a greater effectiveness of therapy, the possibility of reducing or increasing the dosage, and reduced drug toxicity. Further research in this field will contribute to the effectiveness and safety of cytokine therapy.
Krishnan, Harini C.
Circadian clocks evolved under conditions of environmental variation, primarily alternating light dark cycles, to enable organisms to anticipate daily environmental events and coordinate metabolic, physiological, and behavioral activities. However, modern lifestyle and advances in technology have increased the percentage of individuals working in phases misaligned with natural circadian activity rhythms. Endogenous circadian oscillators modulate alertness, the acquisition of learning, memory formation, and the recall of memory with examples of circadian modulation of memory observed across phyla from invertebrates to humans. Cognitive performance and memory are significantly diminished when occurring out of phase with natural circadian rhythms. Disruptions in circadian regulation can lead to impairment in the formation of memories and manifestation of other cognitive deficits. This review explores the types of interactions through which the circadian clock modulates cognition, highlights recent progress in identifying mechanistic interactions between the circadian system and the processes involved in memory formation, and outlines methods used to remediate circadian perturbations and reinforce circadian adaptation. PMID:26286653
Depner, Christopher M.; Stothard, Ellen R.; Wright, Kenneth P.
Sleep and circadian rhythms modulate or control daily physiological patterns with importance for normal metabolic health. Sleep deficiencies associated with insufficient sleep schedules, insomnia with short-sleep duration, sleep apnea, narcolepsy, circadian misalignment, shift work, night eating syndrome and sleep-related eating disorder may all contribute to metabolic dysregulation. Sleep deficiencies and circadian disruption associated with metabolic dysregulation may contribute to weight gain, obesity, and type 2 diabetes potentially by altering timing and amount of food intake, disrupting energy balance, inflammation, impairing glucose tolerance and insulin sensitivity. Given the rapidly increasing prevalence of metabolic diseases, it is important to recognize the role of sleep and circadian disruption in the development, progression, and morbidity of metabolic disease. Some findings indicate sleep treatments and countermeasures improve metabolic health, but future clinical research investigating prevention and treatment of chronic metabolic disorders through treatment of sleep and circadian disruption is needed. PMID:24816752
Schick, Sandra; Thakurela, Sudhir; Fournier, David; Hampel, Mareike Hildegard
Organisms adapt their physiology and behavior to the 24-h day-night cycle to which they are exposed. On a cellular level, this is regulated by intrinsic transcriptional-translational feedback loops that are important for maintaining the circadian rhythm. These loops are organized by members of the core clock network, which further regulate transcription of downstream genes, resulting in their circadian expression. Despite progress in understanding circadian gene expression, only a few players involved in circadian transcriptional regulation, including transcription factors, epigenetic regulators, and long noncoding RNAs, are known. Aiming to discover such genes, we performed a high-coverage transcriptome analysis of a circadian time course in murine fibroblast cells. In combination with a newly developed algorithm, we identified many transcription factors, epigenetic regulators, and long intergenic noncoding RNAs that are cyclically expressed. In addition, a number of these genes also showed circadian expression in mouse tissues. Furthermore, the knockdown of one such factor, Zfp28, influenced the core clock network. Mathematical modeling was able to predict putative regulator-effector interactions between the identified circadian genes and may help for investigations into the gene regulatory networks underlying circadian rhythms. PMID:26644408
Martí, María C.; Laurie, David A.; Greenland, Andy J.; Hall, Anthony; Webb, Alex A. R.
Circadian clocks regulate many aspects of plant physiology and development that contribute to essential agronomic traits. Circadian clocks contain transcriptional feedback loops that are thought to generate circadian timing. There is considerable similarity in the genes that comprise the transcriptional and translational feedback loops of the circadian clock in the plant Kingdom. Functional characterisation of circadian clock genes has been restricted to a few model species. Here we provide a functional characterisation of the Hordeum vulgare (barley) circadian clock genes Hv CIRCADIAN CLOCK ASSOCIATED 1 (HvCCA1) and Hv PHOTOPERIODH1, which are respectively most similar to Arabidopsis thaliana CIRCADIAN CLOCK ASSOCIATED 1 (AtCCA1) and PSEUDO RESPONSE REGULATOR 7 (AtPRR7). This provides insight into the circadian regulation of one of the major crop species of Northern Europe. Through a combination of physiological assays of circadian rhythms in barley and heterologous expression in wild type and mutant strains of A. thaliana we demonstrate that HvCCA1 has a conserved function to AtCCA1. We find that Hv PHOTOPERIOD H1 has AtPRR7-like functionality in A. thaliana and that the effects of the Hv photoperiod h1 mutation on photoperiodism and circadian rhythms are genetically separable. PMID:26076005
Yang, Jing; Yang, Ming-Feng; Zhang, Wen-Peng; Chen, Fan; Shen, Shi-Hua
Plant-specific DNA-binding transcription factors with one finger (Dof) perform important roles in several biological processes. A yeast one-hybrid cDNA library of Jatropha curcas was used to identify Dof-type transcription factors. JcDof3, isolated from the library as a full-length cDNA, encoded a protein of 518 amino acids and contained a highly conserved Dof domain. Yeast one-hybrid systems and subcellular localization assays confirmed that JcDof3 was a typical transcription factor. In contrast to arrhythmic expression at basal level in etiolated cotyledons under continuous dark conditions, the circadian oscillations of JcDof3 transcripts were observed under long day, short day or continuous light regimes. A phylogenetic analysis showed that JcDof3 was clustered into the same clade with CYCLING DOF FACTOR (CDF), which interacts with F-box protein to regulate photoperiodic flowering. Moreover, a yeast two-hybrid assay showed that JcDof3 also interacted with F-box proteins. Our results suggest that JcDof3 is a circadian clock regulated gene, and might be involved in the flowering time regulation of J. curcas.
Ramanathan, Chidambaram; Khan, Sanjoy K; Kathale, Nimish D; Xu, Haiyan; Liu, Andrew C
In mammals, many aspects of behavior and physiology such as sleep-wake cycles and liver metabolism are regulated by endogenous circadian clocks (reviewed). The circadian time-keeping system is a hierarchical multi-oscillator network, with the central clock located in the suprachiasmatic nucleus (SCN) synchronizing and coordinating extra-SCN and peripheral clocks elsewhere. Individual cells are the functional units for generation and maintenance of circadian rhythms, and these oscillators of different tissue types in the organism share a remarkably similar biochemical negative feedback mechanism. However, due to interactions at the neuronal network level in the SCN and through rhythmic, systemic cues at the organismal level, circadian rhythms at the organismal level are not necessarily cell-autonomous. Compared to traditional studies of locomotor activity in vivo and SCN explants ex vivo, cell-based in vitro assays allow for discovery of cell-autonomous circadian defects. Strategically, cell-based models are more experimentally tractable for phenotypic characterization and rapid discovery of basic clock mechanisms. Because circadian rhythms are dynamic, longitudinal measurements with high temporal resolution are needed to assess clock function. In recent years, real-time bioluminescence recording using firefly luciferase as a reporter has become a common technique for studying circadian rhythms in mammals, as it allows for examination of the persistence and dynamics of molecular rhythms. To monitor cell-autonomous circadian rhythms of gene expression, luciferase reporters can be introduced into cells via transient transfection or stable transduction. Here we describe a stable transduction protocol using lentivirus-mediated gene delivery. The lentiviral vector system is superior to traditional methods such as transient transfection and germline transmission because of its efficiency and versatility: it permits efficient delivery and stable integration into the host
Bass, Joseph; Takahashi, Joseph S.
Circadian clocks align behavioral and biochemical processes with the day/night cycle. Nearly all vertebrate cells possess self-sustained clocks that couple endogenous rhythms with changes in cellular environment. Genetic disruption of clock genes in mice perturbs metabolic functions of specific tissues at distinct phases of the sleep/wake cycle. Circadian desynchrony, a characteristic of shift work and sleep disruption in humans, also leads to metabolic pathologies. Here we review advances in understanding the interrelationship among circadian disruption, sleep deprivation, obesity and diabetes, and implications for rational therapeutics for these conditions. PMID:21127246
Morris, Christopher J.; Aeschbach, Daniel; Scheer, Frank A.J.L.
Levels of numerous hormones vary across the day and night. Such fluctuations are not only attributable to changes in sleep/wakefulness and other behaviors but also to a biological timing system governed by the suprachiasmatic nucleus of the hypothalamus. Sleep has a strong effect on levels of some hormones such as growth hormone but little effect on others which are more strongly regulated by the biological timing system (e.g., melatonin). Whereas the exact mechanisms through which sleep affects circulating hormonal levels are poorly understood, more is known about how the biological timing system influences the secretion of hormones. The suprachiasmatic nucleus exerts its influence on hormones via neuronal and humoral signals but it is also now apparent that peripheral cells can rhythmically secrete hormones independent of signals from the suprachiasmatic nucleus. Under normal circumstances, behaviors and the biological timing system are synchronized and consequently hormonal systems are exquisitely regulated. However, many individuals (e.g., shift-workers) frequently undergo circadian misalignment by desynchronizing their sleep/wake cycle from the biological timing system. Recent experiments indicate that circadian misalignment has an adverse effect on metabolic and hormonal factors such as glucose and insulin. Further research is needed to determine the underlying mechanisms that cause the negative effects induced by circadian misalignment. Such research could aid the development of countermeasures for circadian misalignment. PMID:21939733
Goldsmith, Charles S; Bell-Pedersen, Deborah
The mitogen-activated protein kinase (MAPK) family of genes aids cells in sensing both extracellular and intracellular stimuli, and emerging data indicate that MAPKs have fundamental, yet diverse, roles in the circadian biological clock. In the mammalian suprachiasmatic nucleus (SCN), MAPK pathways can function as inputs allowing the endogenous clock to entrain to 24h environmental cycles. MAPKs can also interact physically and/or genetically with components of the molecular circadian oscillator, implying that MAPKs can affect the cycling of the clock. Finally, circadian rhythms in MAPK pathway activation exist in many different tissue types and in model organisms, providing a mechanism to coordinately control the expression tissue-specific target genes at the proper time of day. As such, it should probably not come as a surprise that MAPK signaling pathways and circadian clocks affect similar biological processes and defects in either pathway lead to many of the same types of human diseases, highlighting the need to better define the mechanisms that link these two fundamental pathways together.
Lefta, Mellani; Wolff, Gretchen; Esser, Karyn A.
Almost all organisms ranging from single cell bacteria to humans exhibit a variety of behavioral, physiological, and biochemical rhythms. In mammals, circadian rhythms control the timing of many physiological processes over a 24-h period, including sleep-wake cycles, body temperature, feeding, and hormone production. This body of research has led to defined characteristics of circadian rhythms based on period length, phase, and amplitude. Underlying circadian behaviors is a molecular clock mechanism found in most, if not all, cell types including skeletal muscle. The mammalian molecular clock is a complex of multiple oscillating networks that are regulated through transcriptional mechanisms, timed protein turnover, and input from small molecules. At this time, very little is known about circadian aspects of skeletal muscle function/metabolism but some progress has been made on understanding the molecular clock in skeletal muscle. The goal of this chapter is to provide the basic terminology and concepts of circadian rhythms with a more detailed review of the current state of knowledge of the molecular clock, with reference to what is known in skeletal muscle. Research has demonstrated that the molecular clock is active in skeletal muscles and that the muscle-specific transcription factor, MyoD, is a direct target of the molecular clock. Skeletal muscle of clock-compromised mice, Bmal1−/− and ClockΔ19 mice, are weak and exhibit significant disruptions in expression of many genes required for adult muscle structure and metabolism. We suggest that the interaction between the molecular clock, MyoD, and metabolic factors, such as PGC-1, provide a potential system of feedback loops that may be critical for both maintenance and adaptation of skeletal muscle. PMID:21621073
Martin, Tristan; Moussay, Sébastien; Bulla, Ingo; Bulla, Jan; Toupet, Michel; Etard, Olivier; Denise, Pierre; Davenne, Damien; Coquerel, Antoine; Quarck, Gaëlle
Background New insights have expanded the influence of the vestibular system to the regulation of circadian rhythmicity. Indeed, hypergravity or bilateral vestibular loss (BVL) in rodents causes a disruption in their daily rhythmicity for several days. The vestibular system thus influences hypothalamic regulation of circadian rhythms on Earth, which raises the question of whether daily rhythms might be altered due to vestibular pathology in humans. The aim of this study was to evaluate human circadian rhythmicity in people presenting a total bilateral vestibular loss (BVL) in comparison with control participants. Methodology and Principal Findings Nine patients presenting a total idiopathic BVL and 8 healthy participants were compared. Their rest-activity cycle was recorded by actigraphy at home over 2 weeks. The daily rhythm of temperature was continuously recorded using a telemetric device and salivary cortisol was recorded every 3 hours from 6:00AM to 9:00PM over 24 hours. BVL patients displayed a similar rest activity cycle during the day to control participants but had higher nocturnal actigraphy, mainly during weekdays. Sleep efficiency was reduced in patients compared to control participants. Patients had a marked temperature rhythm but with a significant phase advance (73 min) and a higher variability of the acrophase (from 2:24 PM to 9:25 PM) with no correlation to rest-activity cycle, contrary to healthy participants. Salivary cortisol levels were higher in patients compared to healthy people at any time of day. Conclusion We observed a marked circadian rhythmicity of temperature in patients with BVL, probably due to the influence of the light dark cycle. However, the lack of synchronization between the temperature and rest-activity cycle supports the hypothesis that the vestibular inputs are salient input to the circadian clock that enhance the stabilization and precision of both external and internal entrainment. PMID:27341473
Labrecque, Nathalie; Cermakian, Nicolas
The immune system is a complex set of physiological mechanisms whose general aim is to defend the organism against non-self-bodies, such as pathogens (bacteria, viruses, parasites), as well as cancer cells. Circadian rhythms are endogenous 24-h variations found in virtually all physiological processes. These circadian rhythms are generated by circadian clocks, located in most cell types, including cells of the immune system. This review presents an overview of the clocks in the immune system and of the circadian regulation of the function of immune cells. Most immune cells express circadian clock genes and present a wide array of genes expressed with a 24-h rhythm. This has profound impacts on cellular functions, including a daily rhythm in the synthesis and release of cytokines, chemokines and cytolytic factors, the daily gating of the response occurring through pattern recognition receptors, circadian rhythms of cellular functions such as phagocytosis, migration to inflamed or infected tissue, cytolytic activity, and proliferative response to antigens. Consequently, alterations of circadian rhythms (e.g., clock gene mutation in mice or environmental disruption similar to shift work) lead to disturbed immune responses. We discuss the implications of these data for human health and the areas that future research should aim to address.
Brainard, Jason; Gobel, Merit; Bartels, Karsten; Scott, Benjamin; Koeppen, Michael; Eckle, Tobias
The rotation of the earth and associated alternating cycles of light and dark–the basis of our circadian rhythms–are fundamental to human biology and culture. However, it was not until 1971 that researchers first began to describe the molecular mechanisms for the circadian system. During the last few years, groundbreaking research has revealed a multitude of circadian genes affecting a variety of clinical diseases, including diabetes, obesity, sepsis, cardiac ischemia, and sudden cardiac death. Anesthesiologists, in the operating room and intensive care units, manage these diseases on a daily basis as they significantly impact patient outcomes. Intriguingly, sedatives, anesthetics, and the ICU environment have all been shown to disrupt the circadian system in patients. In the current review we will discuss how newly acquired knowledge of circadian rhythms could lead to changes in clinical practice and new therapeutic concepts. PMID:25294583
Lunghi, Laura; Frigato, Elena; Ferretti, Maria Enrica; Biondi, Carla; Bertolucci, Cristiano
Circadian clock controls several physiological processes such as cell proliferation. Extravillous trophoblast proliferation is a tightly regulated function playing a fundamental role in maternal vessel remodeling. We recently demonstrated that clock genes Per2 and Dec1 as well as the clock-controlled genes Dbp and Vegf are rhythmically expressed in human extravillous trophoblast-derived HTR-8/SVneo cells. Analyzing the time course of HTR-8/SVneo cell proliferation, a circadian variation in cell number was found. Moreover, we showed a rhythmic expression of mRNAs for Wee1 and stathmin, two genes involved in cell cycle progression. We suggest that circadian clockwork may orchestrate the functionality of the several factors involved in the control of human trophoblast functions that are fundamental for a successfully pregnancy outcome.
The discovery that inhibition of a circadian regulator enhances autophagy-dependent cancer cell death reveals potential avenues for the development of new multifunctional anticancer agents. Further studies may elucidate novel crosstalk between circadian rhythm, metabolism, and autophagy that determines cancer cell viability.
Forsyth, Christopher B.; Voigt, Rbin M.; Burgess, Helen J.; Swanson, Garth R.; Keshavarzian, Ali
The circadian clock establishes rhythms throughout the body with an approximately 24 hour period that affect expression of hundreds of genes. Epidemiological data reveal chronic circadian misalignment, common in our society, significantly increases the risk for a myriad of diseases, including cardiovascular disease, diabetes, cancer, infertility and gastrointestinal disease. Disruption of intestinal barrier function, also known as gut leakiness, is especially important in alcoholic liver disease (ALD). Several studies have shown that alcohol causes ALD in only a 20–30% subset of alcoholics. Thus, a better understanding is needed of why only a subset of alcoholics develops ALD. Compelling evidence shows that increased gut leakiness to microbial products and especially LPS play a critical role in the pathogenesis of ALD. Clock and other circadian clock genes have been shown to regulate lipid transport, motility and other gut functions. We hypothesized that one possible mechanism for alcohol-induced intestinal hyper-permeability is through disruption of central or peripheral (intestinal) circadian regulation. In support of this hypothesis, our recent data shows that disruption of circadian rhythms makes the gut more susceptible to injury. Our in vitro data show that alcohol stimulates increased Clock and Per2 circadian clock proteins and that siRNA knockdown of these proteins prevents alcohol-induced permeability. We also show that intestinal Cyp2e1-mediated oxidative stress is required for alcohol-induced upregulation of Clock and Per2 and intestinal hyperpermeability. Our mouse model of chronic alcohol feeding shows that circadian disruption through genetics (in ClockΔ19 mice) or environmental disruption by weekly 12h phase shifting results in gut leakiness alone and exacerbates alcohol-induced gut leakiness and liver pathology. Our data in human alcoholics show they exhibit abnormal melatonin profiles characteristic of circadian disruption. Taken together our
Forsyth, Christopher B; Voigt, Robin M; Burgess, Helen J; Swanson, Garth R; Keshavarzian, Ali
The circadian clock establishes rhythms throughout the body with an approximately 24 hour period that affect expression of hundreds of genes. Epidemiological data reveal chronic circadian misalignment, common in our society, significantly increases the risk for a myriad of diseases, including cardiovascular disease, diabetes, cancer, infertility and gastrointestinal disease. Disruption of intestinal barrier function, also known as gut leakiness, is especially important in alcoholic liver disease (ALD). Several studies have shown that alcohol causes ALD in only a 20-30% subset of alcoholics. Thus, a better understanding is needed of why only a subset of alcoholics develops ALD. Compelling evidence shows that increased gut leakiness to microbial products and especially LPS play a critical role in the pathogenesis of ALD. Clock and other circadian clock genes have been shown to regulate lipid transport, motility and other gut functions. We hypothesized that one possible mechanism for alcohol-induced intestinal hyperpermeability is through disruption of central or peripheral (intestinal) circadian regulation. In support of this hypothesis, our recent data shows that disruption of circadian rhythms makes the gut more susceptible to injury. Our in vitro data show that alcohol stimulates increased Clock and Per2 circadian clock proteins and that siRNA knockdown of these proteins prevents alcohol-induced permeability. We also show that intestinal Cyp2e1-mediated oxidative stress is required for alcohol-induced upregulation of Clock and Per2 and intestinal hyperpermeability. Our mouse model of chronic alcohol feeding shows that circadian disruption through genetics (in Clock(▵19) mice) or environmental disruption by weekly 12h phase shifting results in gut leakiness alone and exacerbates alcohol-induced gut leakiness and liver pathology. Our data in human alcoholics show they exhibit abnormal melatonin profiles characteristic of circadian disruption. Taken together our
Klerman, E. B.; Goldenberg, D. L.; Brown, E. N.; Maliszewski, A. M.; Adler, G. K.
Fibromyalgia syndrome is a chronic and debilitating disorder characterized by widespread nonarticular musculoskeletal pain whose etiology is unknown. Many of the symptoms of this syndrome, including difficulty sleeping, fatigue, malaise, myalgias, gastrointestinal complaints, and decreased cognitive function, are similar to those observed in individuals whose circadian pacemaker is abnormally aligned with their sleep-wake schedule or with local environmental time. Abnormalities in melatonin and cortisol, two hormones whose secretion is strongly influenced by the circadian pacemaker, have been reported in women with fibromyalgia. We studied the circadian rhythms of 10 women with fibromyalgia and 12 control healthy women. The protocol controlled factors known to affect markers of the circadian system, including light levels, posture, sleep-wake state, meals, and activity. The timing of the events in the protocol were calculated relative to the habitual sleep-wake schedule of each individual subject. Under these conditions, we found no significant difference between the women with fibromyalgia and control women in the circadian amplitude or phase of rhythms of melatonin, cortisol, and core body temperature. The average circadian phases expressed in hours posthabitual bedtime for women with and without fibromyalgia were 3:43 +/- 0:19 and 3:46 +/- 0:13, respectively, for melatonin; 10:13 +/- 0:23 and 10:32 +/- 0:20, respectively for cortisol; and 5:19 +/- 0:19 and 4:57 +/- 0:33, respectively, for core body temperature phases. Both groups of women had similar circadian rhythms in self-reported alertness. Although pain and stiffness were significantly increased in women with fibromyalgia compared with healthy women, there were no circadian rhythms in either parameter. We suggest that abnormalities in circadian rhythmicity are not a primary cause of fibromyalgia or its symptoms.
Gayraud, Nathalie T H; Manis, George
R-R interval signals that come from different subjects are regularly aligned and averaged according to the horological starting time of the recordings. We argue that the horological time is a faulty alignment criterion and provide evidence in the form of a new alignment method. Our main motivation is that the human heart rate (HR) rhythm follows a circadian cycle, whose pattern can vary among different classes of people. We propose two novel alignment algorithms that consider the HR circadian rhythm, the Puzzle Piece Alignment Algorithm (PPA) and the Event Based Alignment Algorithm (EBA). First, we convert the R-R interval signal into a series of time windows and compute the mean HR per window. Then our algorithms search for matching circadian patterns to align the signals. We conduct experiments using R-R interval signals extracted from two databases in the Physionet Data Bank. Both algorithms are able to align the signals with respect to the circadian rhythmicity of HR. Furthermore, our findings confirm the presence of more than one pattern in the circadian HR rhythm. We suggest an automatic classification of signals according to the three most prominent patterns.
Leder, Ron S.
Our example from nature is two groups of about 10,000 cells in the brain called Suprachiasmatic Nuclei (SCN) and how light can entrain free running endogenous periodic behavior via the retina's connection to the SCN. Our major question is how a complex behavior like this can arise in nature. Finally presented is a mathematical model and simulation showing how simple periodic signals can be coupled to produce spatio-temporal chaotic behavior and how two complex signals can combine to produce simple coherent behavior with a hypothetical analogy to phase resetting in biological circadian pacemakers.
Egli, Marcel; Betram, Richard; Cogoli-Greuter, Marianne; Vadrucci, Sonia; Henggeler, Daniele
Hormone secretion in mammals often displays circadian rhythms. These rhythms usually relay on internal "biological clocks", which adjusts to geophysical parameters like the light/dark cycle, temperature cycle, or gravity force, all functioning as time cues. In humans, synchronized external and internal rhythms are important for good performance. This study focuses on the effect of altered gravity on the rhythmic secretory pattern of prolactin (PRL), a hormone of the hypothalamic-pituitary system. Several studies have shown that space flight disturbs PRL secretion. Further, we will investigate the response of clock gene expression in the suprachiasmatic nucleus (SCN), the central circadian pacemaker implicated in the neural network for timed PRL secretion, under various gravitational fields. The results of this study will demonstrate the vulnerability of mammalian endocrine systems to changes in gravity and may help in the design of counter actions for stabilizing circadian rhythms during long-term manned space flight.
Kettner, Nicole M; Mayo, Sara A; Hua, Jack; Lee, Choogon; Moore, David D; Fu, Loning
Circadian disruption is associated with obesity, implicating the central clock in body weight control. Our comprehensive screen of wild-type and three circadian mutant mouse models, with or without chronic jet lag, shows that distinct genetic and physiologic interventions differentially disrupt overall energy homeostasis and Leptin signaling. We found that BMAL1/CLOCK generates circadian rhythm of C/EBPα-mediated leptin transcription in adipose. Per and Cry mutant mice show similar disruption of peripheral clock and deregulation of leptin in fat, but opposite body weight and composition phenotypes that correlate with their distinct patterns of POMC neuron deregulation in the arcuate nucleus. Chronic jet lag is sufficient to disrupt the endogenous adipose clock and also induce central Leptin resistance in wild-type mice. Thus, coupling of the central and peripheral clocks controls Leptin endocrine feedback homeostasis. We propose that Leptin resistance, a hallmark of obesity in humans, plays a key role in circadian dysfunction-induced obesity and metabolic syndromes.
Circadian rhythms refer to the endogenous rhythms that are generated to synchronize physiology and behavior with 24-h environmental cues. These rhythms are regulated by both external cues and molecular clock mechanisms in almost all cells. Disruption of circadian rhythms, which is called circadian disruption, affects many biological processes within the body and results in different long-term diseases, including cancer. Circadian regulatory pathways result in rhythmic epigenetic modifications and the formation of circadian epigenomes. Aberrant epigenetic modifications, such as hypermethylation, due to circadian disruption may be involved in the transformation of normal cells into cancer cells. Several studies have indicated an epigenetic basis for the carcinogenic effects of circadian disruption. In this review, I first discuss some of the circadian genes and regulatory proteins. Then, I summarize the current evidence related to the epigenetic modifications that result in circadian disruption. In addition, I explain the carcinogenic effects of circadian disruption and highlight its potential role in different human cancers using an epigenetic viewpoint. Finally, the importance of chronotherapy in cancer treatment is highlighted.
Vafopoulou, Xanthe; Steel, Colin G H
Insulin-like peptides (ILPs) regulate numerous functions in insects including growth, development, carbohydrate metabolism and female reproduction. This paper reports the immunohistochemical localization of ILPs in brain neurons of Rhodnius prolixus and their intimate associations with the brain circadian clock system. In larvae, three groups of neurons in the protocerebrum are ILP-positive, and testis ecdysiotropin (TE) is co-localized in two of them. During adult development, the number of ILP groups increased to four. A blood meal initiates transport and release of ILPs, indicating that release is nutrient dependent. Both production and axonal transport of ILPs continue during adult development with clear cytological evidence of a daily rhythm that closely correlates with the daily rhythm of ILPs release from brains in vitro. The same phenomena were observed with TE previously. Double labeling for ILPs and pigment dispersing factor (PDF) (contained in the brain lateral clock cells, LNs) revealed intimate associations between axons of the ILP/TE cells and PDF-positive axons in both central brain and retrocerebral complex, revealing potential neuronal pathways for circadian regulation of ILPs and TE. Similar close associations were found previously between LN axons and axons of the brain neurons producing the neuropeptide prothoracicotropic hormone. Thus, the brain clock system controls rhythmicity in multiple brain neurohormones. It is suggested that rhythms in circulating ILPs and TE act in concert with known rhythms of circulating ecdysteroids in both larvae and adults to orchestrate the timing of cellular responses in diverse tissues of the animal, thereby generating internal temporal order within it.
Williams, Cory T; Barnes, Brian M; Buck, C Loren
Polar organisms must cope with an environment that periodically lacks the strongest time-giver, or zeitgeber, of circadian organization-robust, cyclical oscillations between light and darkness. We review the factors influencing the persistence of circadian rhythms in polar vertebrates when the light-dark cycle is absent, the likely mechanisms of entrainment that allow some polar vertebrates to remain synchronized with geophysical time, and the adaptive function of maintaining circadian rhythms in such environments.
Muranaka, T; Okada, M; Yomo, J; Kubota, S; Oyama, T
The plant circadian clock controls various physiological phenomena that are important for adaptation to natural day-night cycles. Many components of the circadian clock have been identified in Arabidopsis thaliana, the model plant for molecular genetic studies. Recent studies revealed evolutionary conservation of clock components in green plants. Homologues of clock-related genes have been isolated from Lemna gibba and Lemna aequinoctialis, and it has been demonstrated that these homologues function in the clock system in a manner similar to their functioning in Arabidopsis. While clock components are widely conserved, circadian phenomena display diversity even within the Lemna genus. In order to survey the full extent of diversity in circadian rhythms among duckweed plants, we characterised the circadian rhythms of duckweed by employing a semi-transient bioluminescent reporter system. Using a particle bombardment method, circadian bioluminescent reporters were introduced into nine strains representing five duckweed species: Spirodela polyrhiza, Landoltia punctata, Lemna gibba, L. aequinoctialis and Wolffia columbiana. We then monitored luciferase (luc+) reporter activities driven by AtCCA1, ZmUBQ1 or CaMV35S promoters under entrainment and free-running conditions. Under entrainment, AtCCA1::luc+ showed similar diurnal rhythms in all strains. This suggests that the mechanism of biological timing under day-night cycles is conserved throughout the evolution of duckweeds. Under free-running conditions, we observed circadian rhythms of AtCCA1::luc+, ZmUBQ1::luc+ and CaMV35S::luc+. These circadian rhythms showed diversity in period length and sustainability, suggesting that circadian clock mechanisms are somewhat diversified among duckweeds.
This review summarizes the current knowledge about the ontogenetic development of the circadian system in mammals. The developmental changes of overt rhythms are discussed, although the main focus of the review is the underlying neuronal and molecular mechanisms. In addition, the review describes ontogenetic development, not only as a process of morpho-functional maturation. The need of repeated adaptations and readaptations due to changing developmental stage and environmental conditions is also considered. The review analyzes mainly rodent data, obtained from the literature and from the author's own studies. Results from other species, including humans, are presented to demonstrate common features and species-dependent differences. The review first describes the development of the suprachiasmatic nuclei as the central pacemaker system and shows that intrinsic circadian rhythms are already generated in the mammalian fetus. As in adult organisms, the period length is different from 24 h and needs continuous correction by environmental periodicities, or zeitgebers. The investigation of the ontogenetic development of the mechanisms of entrainment reveals that, at prenatal and early postnatal stages, non-photic cues deriving from the mother are effective. Light-dark entrainment develops later. At a certain age, both photic and non-photic zeitgebers may act in parallel, even though the respective time information is 12 h out of phase. That leads to a temporary internal desynchronization. Because rhythmic information needs to be transferred to effector organs, the corresponding neural and humoral signalling pathways are also briefly described. Finally, to be able to transform a rhythmic signal into an overt rhythm, the corresponding effector organs must be functionally mature. As many of these organs are able to generate their own intrinsic rhythms, another aspect of the review is dedicated to the development of peripheral oscillators and mechanisms of their entrainment
Jang, Christopher; Lahens, Nicholas F.; Hogenesch, John B.; Sehgal, Amita
Physiological and behavioral circadian rhythms are driven by a conserved transcriptional/translational negative feedback loop in mammals. Although most core clock factors are transcription factors, post-transcriptional control introduces delays that are critical for circadian oscillations. Little work has been done on circadian regulation of translation, so to address this deficit we conducted ribosome profiling experiments in a human cell model for an autonomous clock. We found that most rhythmic gene expression occurs with little delay between transcription and translation, suggesting that the lag in the accumulation of some clock proteins relative to their mRNAs does not arise from regulated translation. Nevertheless, we found that translation occurs in a circadian fashion for many genes, sometimes imposing an additional level of control on rhythmically expressed mRNAs and, in other cases, conferring rhythms on noncycling mRNAs. Most cyclically transcribed RNAs are translated at one of two major times in a 24-h day, while rhythmic translation of most noncyclic RNAs is phased to a single time of day. Unexpectedly, we found that the clock also regulates the formation of cytoplasmic processing (P) bodies, which control the fate of mRNAs, suggesting circadian coordination of mRNA metabolism and translation. PMID:26338483
Hevia, Montserrat A; Canessa, Paulo; Larrondo, Luis F
You cannot escape time. Therefore, it seems wise to learn how to keep track of it and use it to your advantage. Circadian clocks are molecular circuits that allow organisms to temporally coordinate a plethora of processes, including gene expression, with a close to 24h rhythm, optimizing cellular function in synchrony with daily environmental cycles. The molecular bases of these clocks have been extensively studied in the fungus Neurospora crassa, providing a detailed molecular description. Surprisingly, there is scarce molecular information of clocks in fungi other than Neurospora, despite the existence of rhythmic phenomena in many fungal species, including pathogenic ones. This review will comment on the overall importance of clocks, what is known in Neurospora and what has been described in other fungi including new insights on the evolution of fungal clock components. The molecular description of the circadian system of the phytopathogenic fungus Botrytis cinerea will be revisited, as well as time-of-the-day variation in host-pathogen interaction dynamics, utilizing an Arabidopsis-Botrytis system, including also what is known regarding circadian regulation of defense mechanisms in the Arabidopsis thaliana plant model. Finally, this review will mention how little is known about circadian regulation of human pathogenic fungi, commenting on potential future directions and the overall perspective of fungal circadian studies.
Sommer, B; Montaño, L M; Chávez, J; Gustin, P; Vargas, M H
Increased circadian variability of airway caliber is a key feature of asthmatic patients, but it has not been addressed in animal models of asthma. Furthermore, animal studies on circadian rhythmicity of airway resistance are very scanty. We used a plethysmographic method for unrestrained guinea pigs to monitor a lung resistance index (iRL) during 24 h. We found circadian variability of iRL values, which were fitted by a sinusoidal curve. Acrophase and bathyphase, characterizing the timing of narrowest and widest airway caliber, respectively, were found at 02:03, and 15:34 h. iRL values at these time-points were statistically different (P < 10(-5)). Moreover, average resistance during the dark period was significantly higher (P < 0.0001) than during the light period. Immediately after an acute ozone exposure (3 ppm for 1 h) an increase in iRL was demonstrated (P < 0.01), which lasted for 2 h, and tended to remain high for the next hour. After guinea pigs recovered from this obstruction, the circadian rhythm and variability of airway caliber were unaffected. Our results show that a circadian rhythm of iRL takes place in guinea pigs, greatly resembling what occurs in humans, and that ozone exposure causes a transient airway obstruction, but fails to reproduce the increased variability of airway caliber observed in asthmatic patients.
Leloup, Jean-Christophe; Goldbeter, Albert
Advancing or delaying the light-dark (LD) cycle perturbs the circadian clock, which eventually recovers its original phase with respect to the new LD cycle. Readjustment of the clock occurs by shifting its phase in the same (orthodromic re-entrainment) or opposite direction (antidromic re-entrainment) as the shift in the LD cycle. To investigate circadian clock recovery after phase shifts of the LD cycle we use a detailed computational model previously proposed for the cellular regulatory network underlying the mammalian circadian clock. The model predicts the existence of a sharp threshold separating orthodromic from antidromic re-entrainment. In the vicinity of this threshold, resynchronization of the clock after a phase shift markedly slows down. The type of re-entrainment, the position of the threshold and the time required for resynchronization depend on multiple factors such as the autonomous period of the clock, the direction and magnitude of the phase shift, the clock biochemical kinetic parameters, and light intensity. Partitioning the phase shift into a series of smaller phases shifts decreases the impact on the recovery of the circadian clock. We use the phase response curve to predict the location of the threshold separating orthodromic and antidromic re-entrainment after advanced or delayed phase shifts of the LD cycle. The marked increase in recovery times predicted near the threshold could be responsible for the most severe disturbances of the human circadian clock associated with jet lag.
McGinnis, Graham R; Young, Martin E
Robust circadian rhythms in metabolic processes have been described in both humans and animal models, at the whole body, individual organ, and even cellular level. Classically, these time-of-day-dependent rhythms have been considered secondary to fluctuations in energy/nutrient supply/demand associated with feeding/fasting and wake/sleep cycles. Renewed interest in this field has been fueled by studies revealing that these rhythms are driven, at least in part, by intrinsic mechanisms and that disruption of metabolic synchrony invariably increases the risk of cardiometabolic disease. The objectives of this paper are to provide a comprehensive review regarding rhythms in glucose, lipid, and protein/amino acid metabolism, the relative influence of extrinsic (eg, neurohumoral factors) versus intrinsic (eg, cell autonomous circadian clocks) mediators, the physiologic roles of these rhythms in terms of daily fluctuations in nutrient availability and activity status, as well as the pathologic consequences of dyssynchrony. PMID:27313482
Cell proliferation in all rapidly renewing mammalian tissues follows a circadian rhythm that is often disrupted in advanced-stage tumors. Epidemiologic studies have revealed a clear link between disruption of circadian rhythms and cancer development in humans. Mice lacking the circadian genes Perio...
Hallows, William C.; Ptáček, Louis J.; Fu, Ying-Hui
Sleep behavior remains one of the most enigmatic areas of life. The unanswered questions range from “why do we sleep?” to “how we can improve sleep in today's society?” Identification of mutations responsible for altered circadian regulation of human sleep lead to unique opportunities for probing these territories. In this review, we summarize causative circadian mutations found from familial genetic studies to date. We also describe how these mutations mechanistically affect circadian function and lead to altered sleep behaviors, including shifted or shortening of sleep patterns. In addition, we discuss how the investigation of mutations can not only expand our understanding of the molecular mechanisms regulating the circadian clock and sleep duration, but also bridge the pathways between clock/sleep and other human physiological conditions and ailments such as metabolic regulation and migraine headaches. PMID:24001255
Chen, Zheng; McKnight, Steven L
The circadian clock drives endogenous oscillations of cellular and physiological processes with a periodicity of approximately 24 h. Progression of the cell division cycle (CDC) has been found to be coupled to the circadian clock, and it has been postulated that gating of the CDC by the circadian cycle may have evolved to protect DNA from the mutagenic effects of ultraviolet light. When grown under nutrient-limiting conditions in a chemostat, prototrophic strains of budding yeast, Saccharomyces cerevisiae, adopt a robust metabolic cycle of ultradian dimensions that temporally compartmentalizes essential cellular events. The CDC is gated by this yeast metabolic cycle (YMC), with DNA replication strictly segregated away from the oxidative phase when cells are actively respiring. Mutants impaired in such gating allow DNA replication to take place during the respiratory phase of the YMC and have been found to suffer significantly elevated rates of spontaneous mutation. Analogous to the circadian cycle, the YMC also employs the conserved DNA checkpoint kinase Rad53/Chk2 to facilitate coupling with the CDC. These studies highlight an evolutionarily conserved mechanism that seems to confine cell division to particular temporal windows to prevent DNA damage. We hypothesize that DNA damage itself might constitute a "zeitgeber", or time giver, for both the circadian cycle and the metabolic cycle. We discuss these findings in the context of a unifying theme underlying the circadian and metabolic cycles, and explore the relevance of cell cycle gating to human diseases including cancer.
Haus, E.; Halberg, F.; Loken, M. K.; Kim, Y. S.
In the case of human bone marrow, the largest number of mitoses is seen in the evening in diurnally active men, mitotic activity being at a minimum in the morning. The opposite pattern is observed for nocturnal animals such as rats and mice on a regimen of light during the daytime alternating with darkness during the night hours. The entirety of these rhythms plays an important role in the organism's responses to environmental stimuli, including its resistance to potentially harmful agents. Conditions under which circadian rhythms can be observed and validated by inferential statistical means are discussed while emphasizing how artifacts of the laboratory environment can be shown to obscure circadian periodic variations in radiosensitivity.
Dijk, Derk-Jan; Duffy, Jeanne F.; Silva, Edward J.; Shanahan, Theresa L.; Boivin, Diane B.; Czeisler, Charles A.
Background The phase and amplitude of rhythms in physiology and behavior are generated by circadian oscillators and entrained to the 24-h day by exposure to the light-dark cycle and feedback from the sleep-wake cycle. The extent to which the phase and amplitude of multiple rhythms are similarly affected during altered timing of light exposure and the sleep-wake cycle has not been fully characterized. Methodology/Principal Findings We assessed the phase and amplitude of the rhythms of melatonin, core body temperature, cortisol, alertness, performance and sleep after a perturbation of entrainment by a gradual advance of the sleep-wake schedule (10 h in 5 days) and associated light-dark cycle in 14 healthy men. The light-dark cycle consisted either of moderate intensity ‘room’ light (∼90–150 lux) or moderate light supplemented with bright light (∼10,000 lux) for 5 to 8 hours following sleep. After the advance of the sleep-wake schedule in moderate light, no significant advance of the melatonin rhythm was observed whereas, after bright light supplementation the phase advance was 8.1 h (SEM 0.7 h). Individual differences in phase shifts correlated across variables. The amplitude of the melatonin rhythm assessed under constant conditions was reduced after moderate light by 54% (17–94%) and after bright light by 52% (range 12–84%), as compared to the amplitude at baseline in the presence of a sleep-wake cycle. Individual differences in amplitude reduction of the melatonin rhythm correlated with the amplitude of body temperature, cortisol and alertness. Conclusions/Significance Alterations in the timing of the sleep-wake cycle and associated bright or moderate light exposure can lead to changes in phase and reduction of circadian amplitude which are consistent across multiple variables but differ between individuals. These data have implications for our understanding of circadian organization and the negative health outcomes associated with shift-work, jet
Egan, Kieren J; Knutson, Kristen L; Pereira, Alexandre C; von Schantz, Malcolm
In recent years, strong evidence has emerged suggesting that insufficient duration, quality, and/or timing of sleep are associated with cardiovascular disease (CVD), and various mechanisms for this association have been proposed. Such associations may be related to endophenotypic features of the sleep homeostat and the circadian oscillator, or may be state-like effects of the environment. Here, we review recent literature on sleep, circadian rhythms and CVD with a specific emphasis on differences between racial/ethnic groups. We discuss the reported differences, mainly between individuals of European and African descent, in parameters related to sleep (architecture, duration, quality) and circadian rhythms (period length and phase shifting). We further review racial/ethnic differences in cardiovascular disease and its risk factors, and develop the hypothesis that racial/ethnic health disparities may, to a greater or smaller degree, relate to differences in parameters related to sleep and circadian rhythms. When humans left Africa some 100,000 years ago, some genetic differences between different races/ethnicities were acquired. These genetic differences have been proposed as a possible predictor of CVD disparities, but concomitant differences in culture and lifestyle between different groups may equally explain CVD disparities. We discuss the evidence for genetic and environmental causes of these differences in sleep and circadian rhythms, and their usefulness as health intervention targets.
Wu, Lisa; Reddy, Akhilesh B
Circadian rhythms are a hallmark of living organisms, observable in all walks of life from primitive bacteria to highly complex humans. They are believed to have evolved to co-ordinate the timing of biological and behavioural processes to the changing environmental needs brought on by the progression of day and night through the 24-h cycle. Most of the modern study of circadian rhythms has centred on so-called TTFLs (transcription-translation feedback loops), wherein a core group of 'clock' genes, capable of negatively regulating themselves, produce oscillations with a period of approximately 24 h. Recently, however, the prevalence of the TTFL paradigm has been challenged by a series of findings wherein circadian rhythms, in the form of redox reactions, persist in the absence of transcriptional cycles. We have found that circadian cycles of oxidation and reduction are conserved across all domains of life, strongly suggesting that non-TTFL mechanisms work in parallel with the canonical genetic processes of timekeeping to generate the cyclical cellular and behavioural phenotypes that we commonly recognize as circadian rhythms.
Mistlberger, Ralph E
Circadian rhythms in mammals can be entrained by daily schedules of light or food availability. A master light-entrainable circadian pacemaker located in the suprachiasmatic nucleus (SCN) is comprised of a population of cell autonomous, transcriptionally based circadian oscillators with defined retinal inputs, circadian clock genes and neural outputs. By contrast, the neurobiology of food-entrainable circadian rhythmicity remains poorly understood at the systems and cellular levels. Induction of food-anticipatory activity rhythms by daily feeding schedules does not require the SCN, but these rhythms do exhibit defining properties of circadian clock control. Clock gene rhythms expressed in other brain regions and in peripheral organs are preferentially reset by mealtime, but lesions of specific hypothalamic, corticolimbic and brainstem structures do not eliminate all food anticipatory rhythms, suggesting control by a distributed, decentralized system of oscillators, or the existence of a critical oscillator at an unknown location. The melanocortin system and dorsomedial hypothalamus may play modulatory roles setting the level of anticipatory activity. The metabolic hormones ghrelin and leptin are not required to induce behavioral food anticipatory rhythms, but may also participate in gain setting. Clock gene mutations that disrupt light-entrainable rhythms generally do not eliminate food anticipatory rhythms, suggesting a novel timing mechanism. Recent evidence for non-transcriptional and network based circadian rhythmicity provides precedence, but any such mechanisms are likely to interact closely with known circadian clock genes, and some important double and triple clock gene knockouts remain to be phenotyped for food entrainment. Given the dominant role of food as an entraining stimulus for metabolic rhythms, the timing of daily food intake and the fidelity of food entrainment mechanisms are likely to have clinical relevance.
Kc, Ranjan; Li, Xin; Forsyth, Christopher B; Voigt, Robin M; Summa, Keith C; Vitaterna, Martha Hotz; Tryniszewska, Beata; Keshavarzian, Ali; Turek, Fred W; Meng, Qing-Jun; Im, Hee-Jeong
A variety of environmental factors contribute to progressive development of osteoarthritis (OA). Environmental factors that upset circadian rhythms have been linked to various diseases. Our recent work establishes chronic environmental circadian disruption - analogous to rotating shiftwork-associated disruption of circadian rhythms in humans - as a novel risk factor for the development of OA. Evidence suggests shift workers are prone to obesity and also show altered eating habits (i.e., increased preference for high-fat containing food). In the present study, we investigated the impact of chronic circadian rhythm disruption in combination with a high-fat diet (HFD) on progression of OA in a mouse model. Our study demonstrates that when mice with chronically circadian rhythms were fed a HFD, there was a significant proteoglycan (PG) loss and fibrillation in knee joint as well as increased activation of the expression of the catabolic mediators involved in cartilage homeostasis. Our results, for the first time, provide the evidence that environmental disruption of circadian rhythms plus HFD potentiate OA-like pathological changes in the mouse joints. Thus, our findings may open new perspectives on the interactions of chronic circadian rhythms disruption with diet in the development of OA and may have potential clinical implications.
Drummond, Sean P. A.; McElroy, Todd
Chronic sleep restriction (SR) increases sleepiness, negatively impacts mood, and impairs a variety of cognitive performance measures. The vast majority of work establishing these effects are tightly controlled in-lab experimental studies. Examining commonly-experienced levels of SR in naturalistic settings is more difficult and generally involves observational methods, rather than active manipulations of sleep. The same is true for analyzing behavioral and cognitive outcomes at circadian unfavorable times. The current study tested the ability of an at-home protocol to manipulate sleep schedules (i.e., impose SR), as well as create a mismatch between a subject’s circadian preference and time of testing. Viability of the protocol was assessed via completion, compliance with the SR, and success at manipulating sleepiness and mood. An online survey was completed by 3630 individuals to assess initial eligibility, 256 agreed via email response to participate in the 3-week study, 221 showed for the initial in-person session, and 184 completed the protocol (175 with complete data). The protocol consisted of 1 week at-home SR (5-6 hours in bed/night), 1 week wash-out, and 1 week well-rested (WR: 8-9 hours in bed/night). Sleep was monitored with actigraphy, diary, and call-ins. Risk management strategies were implemented for subject safety. At the end of each experimental week, subjects reported sleepiness and mood ratings. Protocol completion was 83%, with lower depression scores, higher anxiety scores, and morning session assignment predicting completion. Compliance with the sleep schedule was also very good. Subjects spent approximately 2 hours less time in bed/night and obtained an average of 1.5 hours less nightly sleep during SR, relative to WR, with 82% of subjects obtaining at least 60 minutes less average nightly sleep. Sleepiness and mood were impacted as expected by SR. These findings show the viability of studying experimental chronic sleep restriction outside
McClung, C. Robertson; Salomé, Patrice A.; Michael, Todd P.
Rhythms with periods of approximately 24 hr are widespread in nature. Those that persist in constant conditions are termed circadian rhythms and reflect the activity of an endogenous biological clock. Plants, including Arabidopsis, are richly rhythmic. Expression analysis, most recently on a genomic scale, indicates that the Arabidopsis circadian clock regulates a number of key metabolic pathways and stress responses. A number of sensitive and high-throughput assays have been developed to monitor the Arabidopsis clock. These assays have facilitated the identification of components of plant circadian systems through genetic and molecular biological studies. Although much remains to be learned, the framework of the Arabidopsis circadian system is coming into focus. Dedication This review is dedicated to the memory of DeLill Nasser, a wonderful mentor and an unwavering advocate of both Arabidopsis and circadian rhythms research. PMID:22303209
Sarabia, J A; Rol, M A; Mendiola, P; Madrid, J A
Most circadian rhythms are under the control of a major pacemaker located in the hypothalamic suprachiasmatic nucleus. Some of these rhythms, called marker rhythms, serve to characterize the timing of the internal temporal order. A marker rhythm, (e.g., one used in chronotherapy) has to be periodic and easy to measure over long periods using non-invasive methods. The most frequent reference variables for human chronotherapy include salivary melatonin or cortisol, urinary 6-sulfatoximelatonin, actimetry and core body temperature (CBT). Recent evidence suggests that sleepiness may be more closely linked to increased peripheral skin temperature than to a core temperature drop, and that distal skin temperature seems to be correlated and phase-advanced with respect to CBT, suggesting that heat loss from the extremities may drive the circadian CBT rhythm. The aim of the present study was to evaluate whether the wrist skin temperature rhythm could be used as a possible index of the human circadian system. To this end, wrist skin temperature (WT1), as determined by a wireless data logger in healthy normal living subjects, was correlated with sleep-wake diaries and oral temperature (OT) recordings. WT and sleep habits were studied in 99 university students. Each subject wore a wireless iButton sensor attached to the inner side of a sport wristband. Our results show that the WT rhythm exhibits an inverse phase relationship with OT, and it is phase-advanced by 60 min with respect to OT. WT started to increase in association to bed time and dropped sharply after awakening. A secondary WT increase, independent of feeding, was observed in the early afternoon. In conclusion, WT wireless recording can be considered a reliable procedure to evaluate circadian rhythmicity, and an index to establish and follow the effects of chronotherapy in normal living subjects.
Hagenauer, M.H.; Perryman, J.I.; Lee, T.M.; Carskadon, M.A.
Sleep deprivation among adolescents is epidemic. We argue that this sleep deprivation is due in part to pubertal changes in the homeostatic and circadian regulation of sleep. These changes promote a delayed sleep phase that is exacerbated by evening light exposure and incompatible with aspects of modern society, notably early school start times. In this review of human and animal literature, we demonstrate that delayed sleep phase during puberty is likely a common phenomenon in mammals, not specific to human adolescents, and we provide insight into the mechanisms underlying this phenomenon. PMID:19546564
Li, Shujing; Ao, Xiang; Wu, Huijian
The circadian rhythm is an endogenous time keeping system shared by most organisms. The circadian clock is comprised of both peripheral oscillators in most organ tissues of the body and a central pacemaker located in the suprachiasmatic nucleus (SCN) of the central nervous system. The circadian rhythm is crucial in maintaining the normal physiology of the organism including, but not limited to, cell proliferation, cell cycle progression, and cellular metabolism; whereas disruption of the circadian rhythm is closely related to multi-tumorigenesis. In the past several years, studies from different fields have revealed that the genetic or functional disruption of the molecular circadian rhythm has been found in various cancers, such as breast, prostate, and ovarian. In this review, we will investigate and present an overview of the current research on the influence of circadian rhythm regulating proteins on breast cancer.
water intake was not con oiled; meals were taken at about 07.00, 13.00 and 20.00. The subjects’ circadian periodicity was synchronized with light-on at...individuals on earth , at all times, cycles must run with precisely the length of 23, 28 and 33 days; deviations of only minutes or ’ven fractions of...regarded as stress hormones; the other adrenocortical hormones include aldosterone (the hormone that regulates electrolyte and water balance) and several
Logan, Ryan W.; Williams, Wilbur P.; McClung, Colleen A.
Circadian rhythms are prominent in many physiological and behavioral functions. Circadian disruptions either by environmental or molecular perturbation can have profound health consequences, including the development and progression of addiction. Both animal and humans studies indicate extensive bidirectional relationships between the circadian system and drugs of abuse. Addicted individuals display disrupted rhythms, and chronic disruption or particular chronotypes, may increase the risk for substance abuse and relapse. Moreover, polymorphisms in circadian genes and an evening chronotype have been linked to mood and addiction disorders, and recent efforts suggest an association with the function of reward neurocircuitry. Animal studies are beginning to determine how altered circadian gene function results in drug induced neuroplasticity and behaviors. Many studies suggest a critical role for circadian rhythms in reward-related pathways in the brain and indicate that drugs of abuse directly affect the central circadian pacemaker. In this review, we highlight key findings demonstrating the importance of circadian rhythms in addiction, and how future studies will reveal important mechanistic insights into the involvement of circadian rhythms in drug addiction. PMID:24731209
Logan, Ryan W; Williams, Wilbur P; McClung, Colleen A
Circadian rhythms are prominent in many physiological and behavioral functions. Circadian disruptions either by environmental or molecular perturbation can have profound health consequences, including the development and progression of addiction. Both animal and humans studies indicate extensive bidirectional relationships between the circadian system and drugs of abuse. Addicted individuals display disrupted rhythms, and chronic disruption or particular chronotypes may increase the risk for substance abuse and relapse. Moreover, polymorphisms in circadian genes and an evening chronotype have been linked to mood and addiction disorders, and recent efforts suggest an association with the function of reward neurocircuitry. Animal studies are beginning to determine how altered circadian gene function results in drug-induced neuroplasticity and behaviors. Many studies suggest a critical role for circadian rhythms in reward-related pathways in the brain and indicate that drugs of abuse directly affect the central circadian pacemaker. In this review, we highlight key findings demonstrating the importance of circadian rhythms in addiction and how future studies will reveal important mechanistic insights into the involvement of circadian rhythms in drug addiction.
Ptitsyn, Andrey A; Zvonic, Sanjin; Conrad, Steven A; Scott, L Keith; Mynatt, Randall L; Gimble, Jeffrey M
Circadian rhythms are prevalent in most organisms. Even the smallest disturbances in the orchestration of circadian gene expression patterns among different tissues can result in functional asynchrony, at the organism level, and may to contribute to a wide range of physiologic disorders. It has been reported that as many as 5%-10% of transcribed genes in peripheral tissues follow a circadian expression pattern. We have conducted a comprehensive study of circadian gene expression on a large dataset representing three different peripheral tissues. The data have been produced in a large-scale microarray experiment covering replicate daily cycles in murine white and brown adipose tissues as well as in liver. We have applied three alternative algorithmic approaches to identify circadian oscillation in time series expression profiles. Analyses of our own data indicate that the expression of at least 7% to 21% of active genes in mouse liver, and in white and brown adipose tissues follow a daily oscillatory pattern. Indeed, analysis of data from other laboratories suggests that the percentage of genes with an oscillatory pattern may approach 50% in the liver. For the rest of the genes, oscillation appears to be obscured by stochastic noise. Our phase classification and computer simulation studies based on multiple datasets indicate no detectable boundary between oscillating and non-oscillating fractions of genes. We conclude that greater attention should be given to the potential influence of circadian mechanisms on any biological pathway related to metabolism and obesity.
Ptitsyn, Andrey A; Zvonic, Sanjin; Conrad, Steven A; Scott, L. Keith; Mynatt, Randall L; Gimble, Jeffrey M
Circadian rhythms are prevalent in most organisms. Even the smallest disturbances in the orchestration of circadian gene expression patterns among different tissues can result in functional asynchrony, at the organism level, and may to contribute to a wide range of physiologic disorders. It has been reported that as many as 5%–10% of transcribed genes in peripheral tissues follow a circadian expression pattern. We have conducted a comprehensive study of circadian gene expression on a large dataset representing three different peripheral tissues. The data have been produced in a large-scale microarray experiment covering replicate daily cycles in murine white and brown adipose tissues as well as in liver. We have applied three alternative algorithmic approaches to identify circadian oscillation in time series expression profiles. Analyses of our own data indicate that the expression of at least 7% to 21% of active genes in mouse liver, and in white and brown adipose tissues follow a daily oscillatory pattern. Indeed, analysis of data from other laboratories suggests that the percentage of genes with an oscillatory pattern may approach 50% in the liver. For the rest of the genes, oscillation appears to be obscured by stochastic noise. Our phase classification and computer simulation studies based on multiple datasets indicate no detectable boundary between oscillating and non-oscillating fractions of genes. We conclude that greater attention should be given to the potential influence of circadian mechanisms on any biological pathway related to metabolism and obesity. PMID:16532060
Sarkar, Dipak K
The body's internal system to control the daily rhythm of the body's functions (i.e., the circadian system), the body's stress response, and the body's neurobiology are highly interconnected. Thus, the rhythm of the circadian system impacts alcohol use patterns; at the same time, alcohol drinking also can alter circadian functions. The sensitivity of the circadian system to alcohol may result from alcohol's effects on the expression of several of the clock genes that regulate circadian function. The stress response system involves the hypothalamus and pituitary gland in the brain and the adrenal glands, as well as the hormones they secrete, including corticotrophin-releasing hormone, adrenocorticotrophic hormone, and glucocorticoids. It is controlled by brain-signaling molecules, including endogenous opioids such as β-endorphin. Alcohol consumption influences the activity of this system and vice versa. Finally, interactions exist between the circadian system, the hypothalamic-pituitary-adrenal axis, and alcohol consumption. Thus, it seems that certain clock genes may control functions of the stress response system and that these interactions are affected by alcohol.
Souayed, Nouha; Chennoufi, Malek; Boughattas, Fida; Haouas, Zohra; Maaroufi, Khira; Miled, Abdelhedi; Ben-Attia, Mosaddok; Aouam, Karim; Reinberg, Alain; Boughattas, Naceur A
The circadian time is an important process affecting both pharmacokinetics and pharmacodynamics of drugs. Consequently, the desired and/or undesired effects vary according to the time of drug administration in the 24 h scale. This study investigates whether the toxicity in liver as well as oxidative stress varies according to the circadian dosing-time of isoniazid (INH) in mice. A potentially toxic INH dose (120 mg/kg) was injected by i.p. route to different groups of animals at three different circadian times: 1, 9, and 17 Zeitgeber time (ZT). INH administration at 1 ZT resulted in a maximum hepatotoxicity assessed by the significant increase in both serum transaminase (ALAT: alanine aminotransferase) and (ASAT: aspartate aminotransferase) and antioxidant enzyme activities (catalase: CAT and superoxide dismutase: SOD). The highest malondialdehyde (MDA) level indicating an induction of lipid peroxidation resulting in oxidative damage was also observed at 1 ZT. Liver histopathology from INH groups at 9 ZT and at 1 ZT showed moderate to severe cytoplasma vacuolation, hepatocyte hypertrophy, ballooning, and necrosis. The circadian variation in INH toxicity may help realize a chronotherapy protocol in humans based on the selection of the best time associated to optimal tolerance or least side effects.
The circadian clock is crucial for efficient physiological function and drives the temporal regulation of the sleep-wake state, metabolism, and behavior. The timing of food intake and the accompanying behavior are both controlled by the internal clock, which is located in the suprachiasmatic nucleus (SCN) of the anterior hypothalamus. The SCN is considered as the master clock because the circadian rhythms for most physiological and behavioral processes are terminated after SCN ablation. The molecular framework of circadian oscillations can be best studied in the SCN. A "core" set of circadian clock genes form autoregulatory transcription-translation feedback loops that are believed to drive daily rhythms in individual cells. These clock genes are expressed in a circadian manner not only in the SCN but also in other parts of the brain and many peripheral tissues. Mammals can anticipate a predictable daily mealtime through entrainment of circadian oscillators. Because the restriction of food availability to a specific time of the day elicits anticipatory behavior even after ablation of the SCN, such behaviour is assumed to be controlled by another circadian oscillator. In this paper, we have (1) reviewed studies involving the identification of the circadian clock and (2) aimed to elucidate the complex mechanism underlying feeding-associated rhythms by achieving a deep understanding of the circadian phenotypes of the SCN.
Klerman, E. B.; Zeitzer, J. M.; Duffy, J. F.; Khalsa, S. B.; Czeisler, C. A.
The daily rhythm of melatonin influences multiple physiological measures, including sleep tendency, circadian rhythms, and reproductive function in seasonally breeding mammals. The biological signal for photoperiodic changes in seasonally breeding mammals is a change in the duration of melatonin secretion, which in a natural environment reflects the different durations of daylight across the year, with longer nights leading to a longer duration of melatonin secretion. These seasonal changes in the duration of melatonin secretion do not simply reflect the known acute suppression of melatonin secretion by ocular light exposure, but also represent long-term changes in the endogenous nocturnal melatonin episode that persist in constant conditions. As the eyes of totally blind individuals do not transmit ocular light information, we hypothesized that the duration of the melatonin secretory episode in blind subjects would be longer than those in sighted individuals, who are exposed to light for all their waking hours in an urban environment. We assessed the melatonin secretory profile during constant posture, dim light conditions in 17 blind and 157 sighted adults, all of whom were healthy and using no prescription or nonprescription medications. The duration of melatonin secretion was not significantly different between blind and sighted individuals. Healthy blind individuals after years without ocular light exposure do not have a longer duration of melatonin secretion than healthy sighted individuals.
Kowalska, Elzbieta; Ripperger, Juergen A; Hoegger, Dominik C; Bruegger, Pascal; Buch, Thorsten; Birchler, Thomas; Mueller, Anke; Albrecht, Urs; Contaldo, Claudio; Brown, Steven A
Mammalian circadian clocks restrict cell proliferation to defined time windows, but the mechanism and consequences of this interrelationship are not fully understood. Previously we identified the multifunctional nuclear protein NONO as a partner of circadian PERIOD (PER) proteins. Here we show that it also conveys circadian gating to the cell cycle, a connection surprisingly important for wound healing in mice. Specifically, although fibroblasts from NONO-deficient mice showed approximately normal circadian cycles, they displayed elevated cell doubling and lower cellular senescence. At a molecular level, NONO bound to the p16-Ink4A cell cycle checkpoint gene and potentiated its circadian activation in a PER protein-dependent fashion. Loss of either NONO or PER abolished this activation and circadian expression of p16-Ink4A and eliminated circadian cell cycle gating. In vivo, lack of NONO resulted in defective wound repair. Because wound healing defects were also seen in multiple circadian clock-deficient mouse lines, our results therefore suggest that coupling of the cell cycle to the circadian clock via NONO may be useful to segregate in temporal fashion cell proliferation from tissue organization.
Manfredini, Roberto; Sasso, Ferdinando Carlo; Pala, Marco; De Giorgi, Alfredo; Fabbian, Fabio
Chronobiology is a branch of biomedical sciences devoted to the study of biological rhythms. Biological rhythms exist at any level of living organisms and, according to their cycle length, may be divided into three main types: circadian, ultradian, and infradian rhythms. Circadian rhythms are the most commonly and widely studied. The principal circadian clock is located in the suprachiasmatic nucleus of the hypothalamus, and is supposed to regulate peripheral clocks via neurohumoral modulation. Circadian clocks have been identified within almost all mammalian cell types, and circadian clock genes seem to be essential for cardiovascular health. Disturbance of the renal circadian rhythms is increasingly recognized as a risk factor for hypertension, polyuria, and other diseases and may contribute to renal fibrosis. The origin of these rhythms has been attributed to the reactive response of the kidney to circadian changes in volume and/or in the composition of extracellular fluids regulated by rest/activity and feeding/fasting cycles. However, most of the renal excretory rhythms persist for long periods of time, even in the absence of periodic environmental cues. These observations led to the hypothesis of the existence of a self-sustained mechanism, enabling the kidney to anticipate various predictable circadian challenges to homeostasis. The molecular basis of this mechanism remained unknown until the recent discovery of the mammalian circadian clock, comprising a system of autoregulatory transcriptional/translational feedback loops, which have also been found in the kidney.
Kowalska, Elzbieta; Ripperger, Juergen A.; Hoegger, Dominik C.; Bruegger, Pascal; Buch, Thorsten; Birchler, Thomas; Mueller, Anke; Albrecht, Urs; Contaldo, Claudio; Brown, Steven A.
Mammalian circadian clocks restrict cell proliferation to defined time windows, but the mechanism and consequences of this interrelationship are not fully understood. Previously we identified the multifunctional nuclear protein NONO as a partner of circadian PERIOD (PER) proteins. Here we show that it also conveys circadian gating to the cell cycle, a connection surprisingly important for wound healing in mice. Specifically, although fibroblasts from NONO-deficient mice showed approximately normal circadian cycles, they displayed elevated cell doubling and lower cellular senescence. At a molecular level, NONO bound to the p16-Ink4A cell cycle checkpoint gene and potentiated its circadian activation in a PER protein-dependent fashion. Loss of either NONO or PER abolished this activation and circadian expression of p16-Ink4A and eliminated circadian cell cycle gating. In vivo, lack of NONO resulted in defective wound repair. Because wound healing defects were also seen in multiple circadian clock-deficient mouse lines, our results therefore suggest that coupling of the cell cycle to the circadian clock via NONO may be useful to segregate in temporal fashion cell proliferation from tissue organization. PMID:23267082
Xu, Lili; Ruan, Guoxiang; Dai, Heng; Liu, Andrew C.; Penn, John
Purpose To test whether Müller glia of the mammalian retina have circadian rhythms. Methods We used Müller glia cultures isolated from mouse lines or from humans and bioluminescent reporters of circadian clock genes to monitor molecular circadian rhythms. The clock gene dependence of the Müller cell rhythms was tested using clock gene knockout mouse lines or with siRNA for specific clock genes. Results We demonstrated that retinal Müller glia express canonical circadian clock genes, are capable of sustained circadian oscillations in isolation from other cell types, and exhibit unique features of their molecular circadian clock compared to the retina as a whole. Mouse and human Müller cells demonstrated circadian clock function; however, they exhibited species-specific differences in the gene dependence of their clocks. Conclusions Müller cells are the first mammalian retinal cell type in which sustained circadian rhythms have been demonstrated in isolation from other retinal cells. PMID:27081298
Martynhak, Bruno Jacson; Hogben, Alexandra L.; Zanos, Panos; Georgiou, Polymnia; Andreatini, Roberto; Kitchen, Ian; Archer, Simon N.; von Schantz, Malcolm; Bailey, Alexis; van der Veen, Daan R.
Industrialisation greatly increased human night-time exposure to artificial light, which in animal models is a known cause of depressive phenotypes. Whilst many of these phenotypes are ‘direct’ effects of light on affect, an ‘indirect’ pathway via altered sleep-wake timing has been suggested. We have previously shown that the Period3 gene, which forms part of the biological clock, is associated with altered sleep-wake patterns in response to light. Here, we show that both wild-type and Per3−/− mice showed elevated levels of circulating corticosterone and increased hippocampal Bdnf expression after 3 weeks of exposure to dim light at night, but only mice deficient for the PERIOD3 protein (Per3−/−) exhibited a transient anhedonia-like phenotype, observed as reduced sucrose preference, in weeks 2–3 of dim light at night, whereas WT mice did not. Per3−/− mice also exhibited a significantly smaller delay in behavioural timing than WT mice during weeks 1, 2 and 4 of dim light at night exposure. When treated with imipramine, neither Per3−/− nor WT mice exhibited an anhedonia-like phenotype, and neither genotypes exhibited a delay in behavioural timing in responses to dLAN. While the association between both Per3−/− phenotypes remains unclear, both are alleviated by imipramine treatment during dim night-time light. PMID:28071711
Tomioka, Kenji; Abdelsalam, Salaheldin
The circadian system of hemimetabolous insects is reviewed in respect to the locus of the circadian clock and multioscillatory organization. Because of relatively easy access to the nervous system, the neuronal organization of the clock system in hemimetabolous insects has been studied, yielding identification of the compound eye as the major photoreceptor for entrainment and the optic lobe for the circadian clock locus. The clock site within the optic lobe is inconsistent among reported species; in cockroaches the lobula was previously thought to be a most likely clock locus but accessory medulla is recently stressed to be a clock center, while more distal part of the optic lobe including the lamina and the outer medulla area for the cricket. Identification of the clock cells needs further critical studies. Although each optic lobe clock seems functionally identical, in respect to photic entrainment and generation of the rhythm, the bilaterally paired clocks form a functional unit. They interact to produce a stable time structure within individual insects by exchanging photic and temporal information through neural pathways, in which serotonin and pigment-dispersing factor (PDF) are involved as chemical messengers. The mutual interaction also plays an important role in seasonal adaptation of the rhythm.
Fernandes, Pedro A C M; Cecon, Erika; Markus, Regina P; Ferreira, Zulma S
A retino-hypothalamic-sympathetic pathway drives the nocturnal surge of pineal melatonin production that determines the synchronization of pineal function with the environmental light/dark cycle. In many studies, melatonin has been implicated in the modulation of the inflammatory response. However, scant information on the feedback action of molecules present in the blood on the pineal gland during the time course of an inflammatory response is available. Here we analyzed the effect of tumor necrosis factor-alpha (TNF-alpha) and corticosterone on the transcription of the Aa-nat, hiomt and 14-3-3 protein genes in denervated pineal glands of rats stimulated for 5 hr with norepinephrine, using real-time reverse transcription-polymerase chain reaction. The transcription of Aa-nat, a gene encoding the key enzyme in melatonin biosynthesis, together with the synthesis of the melatonin precursor N-acetylserotonin, was inhibited by TNF-alpha. This inhibition was transient, and a preincubation of TNF-alpha for more than 24 hr had no detectable effect. In fact, a protein(s) transcribed, later on, as shown by cycloheximide, was responsible for the reversal of the inhibition of Aa-nat transcription. In addition, corticosterone induced a potentiation of norepinephrine-induced Aa-nat transcription even after 48 hr of incubation. These data support the hypothesis that the nocturnal surge in melatonin is impaired at the beginning of an inflammatory response and restored either during the shutdown of an acute response or in a chronic inflammatory pathology. Here, we introduce a new molecular pathway involved in the feedback of an inflammatory response on pineal activity, and provide a molecular basis for understanding the expression of circadian timing in injured organisms.
Circadian clocks are endogenous timers that enable plants to synchronize biological processes with daily and seasonal environmental conditions in order to allocate resources during the most beneficial times of day and year. The circadian clock regulates a number of central plant activities, includin...
Zámborszky, Judit; Hong, Christian I; Csikász Nagy, Attila
Cell cycle and circadian rhythms are conserved from cyanobacteria to humans with robust cyclic features. Recently, molecular links between these two cyclic processes have been discovered. Core clock transcription factors, Bmal1 and Clock (Clk), directly regulate Wee1 kinase, which inhibits entry into the mitosis. We investigate the effect of this connection on the timing of mammalian cell cycle processes with computational modeling tools. We connect a minimal model of circadian rhythms, which consists of transcription-translation feedback loops, with a modified mammalian cell cycle model from Novak and Tyson (2004). As we vary the mass doubling time (MDT) of the cell cycle, stochastic simulations reveal quantized cell cycles when the activity of Wee1 is influenced by clock components. The quantized cell cycles disappear in the absence of coupling or when the strength of this link is reduced. More intriguingly, our simulations indicate that the circadian clock triggers critical size control in the mammalian cell cycle. A periodic brake on the cell cycle progress via Wee1 enforces size control when the MDT is quite different from the circadian period. No size control is observed in the absence of coupling. The issue of size control in the mammalian system is debatable, whereas it is well established in yeast. It is possible that the size control is more readily observed in cell lines that contain circadian rhythms, since not all cell types have a circadian clock. This would be analogous to an ultradian clock intertwined with quantized cell cycles (and possibly cell size control) in yeast. We present the first coupled model between the mammalian cell cycle and circadian rhythms that reveals quantized cell cycles and cell size control influenced by the clock.
Binkley, S A
In pineal glands melatonin is synthesized daily. Melatonin synthesis in rats kept in most light-dark cycles occurs during the subjective night. This rhythm, which persists in constant dark, is a circadian rhythm which may be a consequence of another circadian rhythm in the pineal gland, of N-acetyltransferase activity (NAT). The NAT rhythm has been studied extensively in rats as a possible component of the system timing circadian rhythms. The NAT rhythm is driven by neural signals transmitted to the pineal gland by the sympathetic nervous system. Environmental lighting exerts precise control over the timing of the NAT rhythm. In rats, there is enough data to describe a daily time course of events in the pineal gland and to describe a pineal "life history." Hypothetical schemes for generation of the NAT rhythm and for its control by light are presented.
Hasegawa, Yoshihiko; Arita, Masanori
Circadian rhythms are acquired through evolution to increase the chances for survival through synchronizing with the daylight cycle. Reliable synchronization is realized through two trade-off properties: regularity to keep time precisely, and entrainability to synchronize the internal time with daylight. We find by using a phase model with multiple inputs that achieving the maximal limit of regularity and entrainability entails many inherent features of the circadian mechanism. At the molecular level, we demonstrate the role sharing of two light inputs, phase advance and delay, as is well observed in mammals. At the behavioral level, the optimal phase-response curve inevitably contains a dead zone, a time during which light pulses neither advance nor delay the clock. We reproduce the results of phase-controlling experiments entrained by two types of periodic light pulses. Our results indicate that circadian clocks are designed optimally for reliable clockwork through evolution.
Arble, Deanna M.; Sandoval, Darleen A.; Turek, Fred W.; Woods, Stephen C.; Seeley, Randy J.
Background/Objectives Mounting evidence supports a link between circadian disruption and metabolic disease. Humans with circadian disruption (e.g., night-shift workers) have an increased risk of obesity and cardiometabolic diseases compared to the non-disrupted population. However, it is unclear if the obesity and obesity-related disorders associated with circadian disruption respond to therapeutic treatments as well as individuals with other types of obesity. Subjects/Methods Here, we test the effectiveness of the commonly used bariatric surgical procedure, Vertical Sleeve Gastrectomy (VSG) in mouse models of genetic and environmental circadian disruption. Results VSG led to a reduction in body weight and fat mass in both ClockΔ19 mutant and constant-light mouse models (P < .05), resulting in an overall metabolic improvement independent of circadian disruption. Interestingly, the decrease in body weight occurred without altering diurnal feeding or activity patterns (P > .05). Within circadian-disrupted models, VSG also led to improved glucose tolerance and lipid handling (P < .05). Conclusions Together these data demonstrate that VSG is an effective treatment for the obesity associated with circadian disruption, and that the potent effects of bariatric surgery are orthogonal to circadian biology. However, since the effects of bariatric surgery are independent of circadian disruption, VSG cannot be considered a cure for circadian disruption. These data have important implications for circadian-disrupted obese patients. Moreover, these results reveal new information about the metabolic pathways governing the effects of bariatric surgery as well as of circadian disruption. PMID:25869599
Jeyaraj, Darwin; Scheer, Frank A.J.L.; Ripperger, Jürgen A.; Haldar, Saptarsi M.; Lu, Yuan; Prosdocimo, Domenick A.; Eapen, Sam J.; Eapen, Betty L.; Cui, Yingjie; Mahabeleshwar, Ganapathi H.; Lee, Hyoung-gon; Smith, Mark A.; Casadesus, Gemma; Mintz, Eric M.; Sun, Haipeng; Wang, Yibin; Ramsey, Kathryn M.; Bass, Joseph; Shea, Steven A.; Albrecht, Urs; Jain, Mukesh K.
SUMMARY Diurnal variation in nitrogen homeostasis is observed across phylogeny. But whether these are endogenous rhythms, and if so, molecular mechanisms that link nitrogen homeostasis to the circadian clock remain unknown. Here, we provide evidence that a clock-dependent peripheral oscillator, Krüppel-like factor15 transcriptionally coordinates rhythmic expression of multiple enzymes involved in mammalian nitrogen homeostasis. In particular, Krüppel-like factor15-deficient mice exhibit no discernable amino acid rhythm, and the rhythmicity of ammonia to urea detoxification is impaired. Of the external cues, feeding plays a dominant role in modulating Krüppel-like factor15 rhythm and nitrogen homeostasis. Further, when all behavioral, environmental and dietary cues were controlled in humans, nitrogen homeostasis still expressed endogenous circadian rhythmicity. Thus, in mammals, nitrogen homeostasis exhibits circadian rhythmicity, and is orchestrated by Krüppel-like factor15. PMID:22405069
Figueiro, Mariana G.; Bullough, John D.; Rea, Mark S.
Light exposure regulates several circadian functions in normal humans including the sleep-wake cycle. Individuals with Alzheimer"s Disease (AD) often do not have regular patterns of activity and rest, but, rather, experience random periods of sleep and agitation during both day and night. Bright light during the day and darkness at night has been shown to consolidate activity periods during the day and rest periods at night in AD patients. The important characteristics of bright light exposure (quantity, spectrum, distribution, timing and duration) for achieving these results in AD patients is not yet understood. Recent research has shown that moderate (~18 lx at the cornea) blue (~470 nm) light is effective at suppressing melatonin in normal humans. It was hypothesized that blue light applied just before AD patients retire to their beds for the night would have a measurable impact on their behavior. A pilot study was conducted for 30 days in a senior health care facility using four individuals diagnosed with mild to moderate levels of dementia. Four AD patients were exposed to arrays of blue light from light emitting diodes (max wavelength = 470 nm) in two-hour sessions (18:00 to 20:00 hours) for 10 days. As a control, they were exposed to red light (max wavelength = 640 nm) in two-hour sessions for 10 days prior to the blue light exposure. Despite the modest sample size, exposure to blue LEDs has shown to affect sleep quality and median body temperature peak of these AD patients. Median body temperature peak was delayed by approximately 2 hours after exposure to blue LEDs compared to exposure to red LEDs and sleep quality was improved. This pilot study demonstrated that light, especially LEDs, can be an important contribution to helping AD patients regulate their circadian functions.
Ferrell, Jessica M; Chiang, John Y L
Mounting research evidence demonstrates a significant negative impact of circadian disruption on human health. Shift work, chronic jet lag and sleep disturbances are associated with increased incidence of metabolic syndrome, and consequently result in obesity, type 2 diabetes and dyslipidemia. Here, these associations are reviewed with respect to liver metabolism and disease.
Ferrell, Jessica M.; Chiang, John Y.L.
Mounting research evidence demonstrates a significant negative impact of circadian disruption on human health. Shift work, chronic jet lag and sleep disturbances are associated with increased incidence of metabolic syndrome, and consequently result in obesity, type 2 diabetes and dyslipidemia. Here, these associations are reviewed with respect to liver metabolism and disease. PMID:26579436
Udoh, Uduak S.; Valcin, Jennifer A.; Gamble, Karen L.; Bailey, Shannon M.
Emerging evidence from both experimental animal studies and clinical human investigations demonstrates strong connections among circadian processes, alcohol use, and alcohol-induced tissue injury. Components of the circadian clock have been shown to influence the pathophysiological effects of alcohol. Conversely, alcohol may alter the expression of circadian clock genes and the rhythmic behavioral and metabolic processes they regulate. Therefore, we propose that alcohol-mediated disruption in circadian rhythms likely underpins many adverse health effects of alcohol that cut across multiple organ systems. In this review, we provide an overview of the circadian clock mechanism and showcase results from new studies in the alcohol field implicating the circadian clock as a key target of alcohol action and toxicity in the liver. We discuss various molecular events through which alcohol may work to negatively impact circadian clock-mediated processes in the liver, and contribute to tissue pathology. Illuminating the mechanistic connections between the circadian clock and alcohol will be critical to the development of new preventative and pharmacological treatments for alcohol use disorders and alcohol-mediated organ diseases. PMID:26473939
Hu, Kun; Hilton, Michael F.
Recent studies have shown that the circadian pacemaker --- an internal body clock located in the brain which is normally synchronized with the sleep/wake behavioral cycles --- influences key physiologic functions such as the body temperature, hormone secretion and heart rate. Surprisingly, no previous studies have investigated whether the circadian pacemaker impacts human motor activity --- a fundamental physiologic function. We investigate high-frequency actigraph recordings of forearm motion from a group of young and healthy subjects during a forced desynchrony protocol which allows to decouple the sleep/wake cycles from the endogenous circadian cycle while controlling scheduled behaviors. We investigate both static properties (mean value, standard deviation), dynamical characteristics (long-range correlations), and nonlinear features (magnitude and Fourier-phase correlations) in the fluctuations of forearm acceleration across different circadian phases. We demonstrate that while the static properties exhibit significant circadian rhythms with a broad peak in the afternoon, the dynamical and nonlinear characteristics remain invariant with circadian phase. This finding suggests an intrinsic multi-scale dynamic regulation of forearm motion the mechanism of which is not influenced by the circadian pacemaker, thus suggesting that increased cardiac risk in the early morning hours is not related to circadian-mediated influences on motor activity.
Smith, Roger S.; Efron, Bradley; Mah, Cheri D.; Malhotra, Atul
Objective: We hypothesized that professional football teams would perform better than anticipated during games occurring close to their circadian peak in performance. Design: We reviewed the past 40 years of evening and daytime professional football games between west coast and east coast United States teams. In order to account for known factors influencing football game outcomes we compared the results to the point spread which addresses all significant differences between opposing teams for sports betting purposes. One sample t-tests, Wilcoxon signed ranked tests, and linear regression were performed. Comparison to day game data was included as a control. Setting: Academic medical center Participants: N/A. Interventions: N/A. Results: The results were strongly in favor of the west coast teams during evening games against east coast teams, with the west coast teams beating the point spread about twice as often (t = 3.95, P < 0.0001) as east coast teams. For similar daytime game match-ups, we observed no such advantage. Conclusions: Sleep and circadian physiology have profound effects on human function including the performance of elite athletes. Professional football players playing close to the circadian peak in performance demonstrate a significant athletic advantage over those who are playing at other times. Application of this knowledge is likely to enhance human performance. Citation: Smith RS; Efron B; Mah CD; Malhotra A. The impact of circadian misalignment on athletic performance in professional football players. SLEEP 2013;36(12):1999-2001. PMID:24293776
Touitou, Yvan; Reinberg, Alain; Touitou, David
Exposure to Artificial Light At Night (ALAN) results in a disruption of the circadian system, which is deleterious to health. In industrialized countries, 75% of the total workforce is estimated to have been involved in shift work and night work. Epidemiologic studies, mainly of nurses, have revealed an association between sustained night work and a 50-100% higher incidence of breast cancer. The potential and multifactorial mechanisms of the effects include the suppression of melatonin secretion by ALAN, sleep deprivation, and circadian disruption. Shift and/or night work generally decreases the time spent sleeping, and it disrupts the circadian time structure. In the long run, this desynchronization is detrimental to health, as underscored by a large number of epidemiological studies that have uncovered elevated rates of several diseases, including cancer, diabetes, cardiovascular risks, obesity, mood disorders and age-related macular degeneration. It amounts to a public health issue in the light of the very substantial number of individuals involved. The IARC has classified shift work in group 2A of "probable carcinogens to humans" since "they involve a circadian disorganization". Countermeasures to the effects of ALAN, such as melatonin, bright light, or psychotropic drugs, have been proposed as a means to combat circadian clock disruption and improve adaptation to shift and night work. We review the evidence for the ALAN impacts on health. Furthermore, we highlight the importance of an in-depth mechanistic understanding to combat the detrimental properties of exposure to ALAN and develop strategies of prevention.
Zanello, Susana; Boyle, Richard
Disruption of the regular environmental circadian cues in addition to stringent and demanding operational schedules are two main factors that undoubtedly impact sleep patterns and vigilant performance in the astronaut crews during spaceflight. Most research is focused on the behavioral aspects of the risk of circadian desynchronization, characterized by fatigue and health and performance decrement. A common countermeasure for circadian re-entrainment utilizes blue-green light to entrain the circadian clock and mitigate this risk. However, an effective countermeasure targeting the photoreceptor system requires that the basic circadian molecular machinery remains intact during spaceflight. The molecular clock consists of sets of proteins that perform different functions within the clock machinery: circadian oscillators (genes whose expression levels cycle during the day, keep the pass of cellular time and regulate downstream effector genes), the effector or output genes (those which impact the physiology of the tissue or organism), and the input genes (responsible for sensing the environmental cues that allow circadian entrainment). The main environmental cue is light. As opposed to the known photoreceptors (rods and cones), the non-visual light stimulus is received by a subset of the population of retinal ganglion cells called intrinsically photosensitive retinal ganglion cells (ipRGC) that express melanopsin (opsin 4 -Opn4-) as the photoreceptor. We hypothesize that spaceflight may affect ipRGC and melanopsin expression, which may be a contributing cause of circadian disruption during spaceflight. To answer this question, eyes from albino Balb/cJ mice aboard STS-133 were collected for histological analysis and gene expression profiling of the retina at 1 and 7 days after landing. Both vivarium and AEM (animal enclosure module) mice were used as ground controls. Opn4 expression was analyzed by real time RT/qPCR and retinal sections were stained for Opn4
REFINETTI, ROBERTO; LISSEN, GERMAINE CORNÉ; HALBERG, FRANZ
This article reviews various procedures used in the analysis of circadian rhythms at the populational, organismal, cellular and molecular levels. The procedures range from visual inspection of time plots and actograms to several mathematical methods of time series analysis. Computational steps are described in some detail, and additional bibliographic resources and computer programs are listed. PMID:23710111
Kumar Jha, Pawan; Challet, Etienne; Kalsbeek, Andries
Most aspects of energy metabolism display clear variations during day and night. This daily rhythmicity of metabolic functions, including hormone release, is governed by a circadian system that consists of the master clock in the suprachiasmatic nuclei of the hypothalamus (SCN) and many secondary clocks in the brain and peripheral organs. The SCN control peripheral timing via the autonomic and neuroendocrine system, as well as via behavioral outputs. The sleep-wake cycle, the feeding/fasting rhythm and most hormonal rhythms, including that of leptin, ghrelin and glucocorticoids, usually show an opposite phase (relative to the light-dark cycle) in diurnal and nocturnal species. By contrast, the SCN clock is most active at the same astronomical times in these two categories of mammals. Moreover, in both species, pineal melatonin is secreted only at night. In this review we describe the current knowledge on the regulation of glucose and lipid metabolism by central and peripheral clock mechanisms. Most experimental knowledge comes from studies in nocturnal laboratory rodents. Nevertheless, we will also mention some relevant findings in diurnal mammals, including humans. It will become clear that as a consequence of the tight connections between the circadian clock system and energy metabolism, circadian clock impairments (e.g., mutations or knock-out of clock genes) and circadian clock misalignments (such as during shift work and chronic jet-lag) have an adverse effect on energy metabolism, that may trigger or enhancing obese and diabetic symptoms.
Sumová, A; Bendová, Z; Sládek, M; El-Hennamy, R; Matejů, K; Polidarová, L; Sosniyenko, S; Illnerová, H
The circadian system controls the timing of behavioral and physiological functions in most organisms studied. The review addresses the question of when and how the molecular clockwork underlying circadian oscillations within the central circadian clock in the suprachiasmatic nuclei of the hypothalamus (SCN) and the peripheral circadian clocks develops during ontogenesis. The current model of the molecular clockwork is summarized. The central SCN clock is viewed as a complex structure composed of a web of mutually synchronized individual oscillators. The importance of development of both the intracellular molecular clockwork as well as intercellular coupling for development of the formal properties of the circadian SCN clock is also highlighted. Recently, data has accumulated to demonstrate that synchronized molecular oscillations in the central and peripheral clocks develop gradually during ontogenesis and development extends into postnatal period. Synchronized molecular oscillations develop earlier in the SCN than in the peripheral clocks. A hypothesis is suggested that the immature clocks might be first driven by external entraining cues, and therefore, serve as "slave" oscillators. During ontogenesis, the clocks may gradually develop a complete set of molecular interlocked oscillations, i.e., the molecular clockwork, and become self-sustained clocks.
Golden, Susan S.
SUMMARY Life on earth is subject to daily and predictable fluctuations in light intensity, temperature, and humidity created by rotation of the earth. Circadian rhythms, generated by a circadian clock, control temporal programs of cellular physiology to facilitate adaptation to daily environmental changes. Circadian rhythms are nearly ubiquitous and are found in both prokaryotic and eukaryotic organisms. Here we introduce the molecular mechanism of the circadian clock in the model cyanobacterium Synechococcus elongatus PCC 7942. We review the current understanding of the cyanobacterial clock, emphasizing recent work that has generated a more comprehensive understanding of how the circadian oscillator becomes synchronized with the external environment and how information from the oscillator is transmitted to generate rhythms of biological activity. These results have changed how we think about the clock, shifting away from a linear model to one in which the clock is viewed as an interactive network of multifunctional components that are integrated into the context of the cell in order to pace and reset the oscillator. We conclude with a discussion of how this basic timekeeping mechanism differs in other cyanobacterial species and how information gleaned from work in cyanobacteria can be translated to understanding rhythmic phenomena in other prokaryotic systems. PMID:26335718
Bloch, Guy; Herzog, Erik D; Levine, Joel D; Schwartz, William J
Daily rhythms of physiology and behaviour are governed by an endogenous timekeeping mechanism (a circadian 'clock'). The alternation of environmental light and darkness synchronizes (entrains) these rhythms to the natural day-night cycle, and underlying mechanisms have been investigated using singly housed animals in the laboratory. But, most species ordinarily would not live out their lives in such seclusion; in their natural habitats, they interact with other individuals, and some live in colonies with highly developed social structures requiring temporal synchronization. Social cues may thus be critical to the adaptive function of the circadian system, but elucidating their role and the responsible mechanisms has proven elusive. Here, we highlight three model systems that are now being applied to understanding the biology of socially synchronized circadian oscillators: the fruitfly, with its powerful array of molecular genetic tools; the honeybee, with its complex natural society and clear division of labour; and, at a different level of biological organization, the rodent suprachiasmatic nucleus, site of the brain's circadian clock, with its network of mutually coupled single-cell oscillators. Analyses at the 'group' level of circadian organization will likely generate a more complex, but ultimately more comprehensive, view of clocks and rhythms and their contribution to fitness in nature.
Clegg, Benjamin A.; Wickens, Christopher D.; Vieane, Alex Z.; Gutzwiller, Robert S.; Sebok, Angelia L.
The goal of this study was to advance understanding and prediction of the impact of circadian rhythm on aspects of complex task performance during unexpected automation failures, and subsequent fault management. Participants trained on two tasks: a process control simulation, featuring automated support; and a multi-tasking platform. Participants then completed one task in a very early morning (circadian night) session, and the other during a late afternoon (circadian day) session. Small effects of time of day were seen on simple components of task performance, but impacts on more demanding components, such as those that occur following an automation failure, were muted relative to previous studies where circadian rhythm was compounded with sleep deprivation and fatigue. Circadian low participants engaged in compensatory strategies, rather than passively monitoring the automation. The findings and implications are discussed in the context of a model that includes the effects of sleep and fatigue factors.
Kondratova, A.A.; Kondratov, R.V.
Ageing leads to functional deterioration of many brain systems, including the circadian clock - an internal time-keeping system that generates 24 hr rhythms in physiology and behaviour. Numerous clinical studies have established a direct correlation between the severity of neurodegenerative disorders, sleep disturbances and weakening of circadian clock functions. The latest data from model organisms, gene expression studies and clinical trials imply that the dysfunction of the circadian clock may contribute to the progression of ageing and age-associated pathologies, suggesting a functional link between the circadian clock, and age-associated decline of brain functions. Potential molecular mechanisms underlying this link include the circadian control of brain metabolism, reactive oxygen species homeostasis, hormone secretion, autophagy and stem cell proliferation. PMID:22395806
Zhang, Chong; Xie, Qiguang; Anderson, Ryan G.; Ng, Gina; Seitz, Nicholas C.; Peterson, Thomas; McClung, C. Robertson; McDowell, John M.; Kong, Dongdong; Kwak, June M.; Lu, Hua
The circadian clock integrates temporal information with environmental cues in regulating plant development and physiology. Recently, the circadian clock has been shown to affect plant responses to biotic cues. To further examine this role of the circadian clock, we tested disease resistance in mutants disrupted in CCA1 and LHY, which act synergistically to regulate clock activity. We found that cca1 and lhy mutants also synergistically affect basal and resistance gene-mediated defense against Pseudomonas syringae and Hyaloperonospora arabidopsidis. Disrupting the circadian clock caused by overexpression of CCA1 or LHY also resulted in severe susceptibility to P. syringae. We identified a downstream target of CCA1 and LHY, GRP7, a key constituent of a slave oscillator regulated by the circadian clock and previously shown to influence plant defense and stomatal activity. We show that the defense role of CCA1 and LHY against P. syringae is at least partially through circadian control of stomatal aperture but is independent of defense mediated by salicylic acid. Furthermore, we found defense activation by P. syringae infection and treatment with the elicitor flg22 can feedback-regulate clock activity. Together this data strongly supports a direct role of the circadian clock in defense control and reveal for the first time crosstalk between the circadian clock and plant innate immunity. PMID:23754942
Dridi, Ichrak; Grissa, Intissar; Ezzi, Lobna; Chakroun, Sana; Ben-Cherif, Wafa; Haouas, Zohra; Aouam, Karim; Ben-Attia, Mossadok; Reinberg, Alain; Boughattas, Naceur A
Immunosuppressive drugs such as Mycophenolate Mofetil (MMF) are used to suppress the immune system activity in transplant patients and reduce the risk of organ rejection. The present study investigates whether the potential cytotoxicity and genotoxicity varied according to MMF dosing-time in Wistar Rat. A potentially toxic MMF dose (300 mg/kg) was acutely administered by the i.p. route in rats at four different circadian stages (1, 7, 13 and 19 hours after light onset, HALO). Rats were sacrificed 3 days following injection, blood and bone marrow were removed for determination of cytotoxicity and genotoxicity analysis. The genotoxic effect of this pro-drug was investigated using the comet assay and the micronucleus test. Hematological changes were also evaluated according to circadian dosing time. MMF treatment induced a significant decrease at 7 HALO in red blood cells, in the hemoglobin rate and in white blood cells. These parameters followed a circadian rhythm in controls or in treated rats with an acrophase located at the end of the light-rest phase. A significant, thrombocytopenia was observed according to MMF circadian dosing time. Furthermore, abnormally shaped red cells, sometimes containing micronuclei, poikilocytotic in red cells and hypersegmented neutrophil nuclei were observed with MMF treatment. The micronucleus test revealed damage to chromosomes in rat bone marrow; the comet assay showed significant DNA damage. This damage varied according to circadian MMF dosing time. The injection of MMF in the middle of the dark-activity phase produced a very mild hematological toxicity and low genotoxicity. Conversely, it induced maximum hematological toxicity and genotoxicity when the administration occurred in the middle of the light-rest phase, which is physiologically analogous to the end of the activity of the diurnal phase in human patients.
Circadian clocks are cell-autonomous timing mechanisms that organize cell functions in a 24-h periodicity. In mammals, the main circadian oscillator consists of transcription–translation feedback loops composed of transcriptional regulators, enzymes, and scaffolds that generate and sustain daily oscillations of their own transcript and protein levels. The clock components and their targets impart rhythmic functions to many gene products through transcriptional, posttranscriptional, translational, and posttranslational mechanisms. This, in turn, temporally coordinates many signaling pathways, metabolic activity, organelles’ structure and functions, as well as the cell cycle and the tissue-specific functions of differentiated cells. When the functions of these circadian oscillators are disrupted by age, environment, or genetic mutation, the temporal coordination of cellular functions is lost, reducing organismal health and fitness. PMID:27738003
Tataroglu, Ozgur; Emery, Patrick
Circadian rhythms have a profound influence on most bodily functions: from metabolism to complex behaviors. They ensure that all these biological processes are optimized with the time-of-day. They are generated by endogenous molecular oscillators that have a period that closely, but not exactly, matches day length. These molecular clocks are synchronized by environmental cycles such as light intensity and temperature. Drosophila melanogaster has been a model organism of choice to understand genetically, molecularly and at the level of neural circuits how circadian rhythms are generated, how they are synchronized by environmental cues, and how they drive behavioral cycles such as locomotor rhythms. This review will cover a wide range of techniques that have been instrumental to our understanding of Drosophila circadian rhythms, and that are essential for current and future research. PMID:24412370
Tataroglu, Ozgur; Emery, Patrick
Circadian rhythms have a profound influence on most bodily functions: from metabolism to complex behaviors. They ensure that all these biological processes are optimized with the time-of-day. They are generated by endogenous molecular oscillators that have a period that closely, but not exactly, matches day length. These molecular clocks are synchronized by environmental cycles such as light intensity and temperature. Drosophila melanogaster has been a model organism of choice to understand genetically, molecularly and at the level of neural circuits how circadian rhythms are generated, how they are synchronized by environmental cues, and how they drive behavioral cycles such as locomotor rhythms. This review will cover a wide range of techniques that have been instrumental to our understanding of Drosophila circadian rhythms, and that are essential for current and future research.
The circadian clock allows plants to anticipate and respond to daily changes in ambient temperature. Mechanisms establishing the timing of circadian rhythms in Arabidopsis thaliana through temperature entrainment remain unclear. Also incompletely understood is the temperature compensation mechanism ...
Farré, Eva M; Liu, Tiffany
Circadian clocks are internal time-keeping mechanisms that provide an adaptive advantage by enabling organisms to anticipate daily changes and orchestrate biological processes accordingly. Circadian regulated pseudo-response regulators are key components of transcription/translation circadian networks in green alga and plants. Recent studies in Arabidopsis thaliana have shown that most of them act as transcriptional repressors and directly regulate output pathways suggesting a close relationship between the central oscillator and circadian regulated processes. Moreover, phylogenetic studies on this small gene family have shed light on the evolution of circadian clocks in the green lineage.
Eissa, M A; Yetman, R J; Poffenbarger, T; Portman, R J
Determining blood pressure (BP) values at different daily time periods is a well recognised measure to assess the risk of end-organ damage. However, the use of various definitions of these periods, eg, day vs night, sleep vs wake or arbitrary definitions, makes clinical decisions based on available data difficult. In the present study, we compared BP loads in actual sleep-wake periods to default day-night definition provided by the ambulatory BP monitoring (ABPM) software (day 06.00 to 22.00; night 22.00 to 06.00) as well as to an arbitrary definition of sleep-wake periods in children published in Soergel et al (J Pediatr 1997; 130: 178-184)1 (awake 08.00 to 20.00 and sleep 00.00 to 06.00. We used an actigraphy, an accelerometer, to define the actual sleep-wake periods in 46 patients with essential hypertension who are on various treatment regimens. BP data was obtained by using Spacelabs 90207 monitors for a full 24 h. There were significant differences between actual sleep-wake and default definition for BP load. No similar finding was noted when arbitrary definition was used. The proportion of hypertensives was not significantly different when default and arbitrary definitions were used. Classification of dippers and non-dippers is greatly affected by the definition of sleep interval using the default method. Although some of the misclassifications were not statistically significant, their clinical importance must be considered. Determination of sleep and wake periods for analysis of ABPM data should be based on careful determination of actual periods. Using other definitions may not provide complete information or accommodate for individual variation.
Eissa, M A; Yetman, R J; Poffenbarger, T; Portman, R J
Determining blood pressure (BP) values at different daily time periods is a well recognised measure to assess the risk of end-organ damage. However, the use of various definitions of these periods, eg, day vs night, sleep vs wake or arbitrary definitions, makes clinical decisions based on available data difficult. In the present study, we compared BP loads in actual sleep-wake periods to default day-night definition provided by the ambulatory BP monitoring (ABPM) software (day 06.00-22.00; night 22.00-06.00) as well as to an arbitrary definition of sleep-wake periods in children published in Journal of Pediatrics (Soergel et al, 1997) (awake 08.00-20:00 and sleep 00.00-06.00). We used an actigraph, an accelerometer, to define the actual sleep-wake periods in 46 patients with essential hypertension who are on various treatment regimens. BP data were obtained by using Spacelabs 90207 monitors for a full 24 hours. There were significant differences between actual sleep-wake and default definition for BP load. No similar findings were noted when arbitrary definition was used. The proportion of hypertensives was not significantly different when default and arbitrary definitions were used. Classification of dippers and non-dippers is greatly affected by the definition of sleep interval using the default method. Although some of the misclassifications were not statistically significant, their clinical importance must be considered. Determination of sleep and wake periods for analysis of ABPM data should be based on careful determination of actual periods. Using other definitions may not provide complete information or accommodate for individual variation.
Lipton, Jonathan O; Yuan, Elizabeth D; Boyle, Lara M; Ebrahimi-Fakhari, Darius; Kwiatkowski, Erica; Nathan, Ashwin; Güttler, Thomas; Davis, Fred; Asara, John M; Sahin, Mustafa
The circadian timing system synchronizes cellular function by coordinating rhythmic transcription via a transcription-translational feedback loop. How the circadian system regulates gene expression at the translational level remains a mystery. Here, we show that the key circadian transcription factor BMAL1 associates with the translational machinery in the cytosol and promotes protein synthesis. The mTOR-effector kinase, ribosomal S6 protein kinase 1 (S6K1), an important regulator of translation, rhythmically phosphorylates BMAL1 at an evolutionarily conserved site. S6K1-mediated phosphorylation is critical for BMAL1 to both associate with the translational machinery and stimulate protein synthesis. Protein synthesis rates demonstrate circadian oscillations dependent on BMAL1. Thus, in addition to its critical role in circadian transcription, BMAL1 is a translation factor that links circadian timing and the mTOR signaling pathway. More broadly, these results expand the role of the circadian clock to the regulation of protein synthesis.
Hasler, Brant P.; Clark, Duncan B.
Background Developmental changes in sleep and circadian rhythms that occur during adolescence may contribute to reward-related brain dysfunction, and consequently increase the risk of alcohol use disorders (AUDs). Methods This review (a) describes marked changes in circadian rhythms, reward-related behavior and brain function, and alcohol involvement that occur during adolescence, (b) offers evidence that these parallel developmental changes are associated, and (c) posits a conceptual model by which misalignment between sleep-wake timing and endogenous circadian timing may increase the risk of adolescent AUDs by altering reward-related brain function. Results The timing of sleep shifts later throughout adolescence, in part due to developmental changes in endogenous circadian rhythms, which tend to become more delayed. This tendency for delayed sleep and circadian rhythms is at odds with early school start times during secondary education, leading to misalignment between many adolescents’ sleep-wake schedules and their internal circadian timing. Circadian misalignment is associated with increased alcohol use and other risk-taking behaviors, as well as sleep loss and sleep disturbance. Growing evidence indicates that circadian rhythms modulate the reward system, suggesting that circadian misalignment may impact adolescent alcohol involvement by altering reward-related brain function. Neurocognitive function is also subject to sleep and circadian influence, and thus circadian misalignment may also impair inhibitory control and other cognitive processes relevant to alcohol use. Specifically, circadian misalignment may further exacerbate the cortical-subcortical imbalance within the reward circuit, an imbalance thought to explain increased risk-taking and sensation-seeking during adolescence. Adolescent alcohol use is highly contexualized, however, and thus studies testing this model will also need to consider factors that may influence both circadian misalignment and
Martorell-Barceló, Martina; Campos-Candela, Andrea
Repeatable between-individual differences in the behavioural manifestation of underlying circadian rhythms determine chronotypes in humans and terrestrial animals. Here, we have repeatedly measured three circadian behaviours, awakening time, rest onset and rest duration, in the free-ranging pearly razorfish, Xyrithchys novacula, facilitated by acoustic tracking technology and hidden Markov models. In addition, daily travelled distance, a standard measure of daily activity as fish personality trait, was repeatedly assessed using a State-Space Model. We have decomposed the variance of these four behavioural traits using linear mixed models and estimated repeatability scores (R) while controlling for environmental co-variates: year of experimentation, spatial location of the activity, fish size and gender and their interactions. Between- and within-individual variance decomposition revealed significant Rs in all traits suggesting high predictability of individual circadian behavioural variation and the existence of chronotypes. The decomposition of the correlations among chronotypes and the personality trait studied here into between- and within-individual correlations did not reveal any significant correlation at between-individual level. We therefore propose circadian behavioural variation as an independent axis of the fish personality, and the study of chronotypes and their consequences as a novel dimension in understanding within-species fish behavioural diversity. PMID:28386434
Stewart, Karen T.; Hayes, Julie
People who must work at night experience a number of physiological and psychological difficulties. These include sleepiness and fatigue at work, poor daytime sleep, gastrointestinal distress, impaired concentration and performance, disturbed mood, and increased health complaints and risk of disease. These difficulties arise because nocturnal work and daytime sleep take place at inappropriate phases of the body's circadian rhythms. Intense artificial light can shift the phase of human circadian rhythms, and can thus be used to promote adaptation to shifted work schedules. The first attempts to investigate the efficacy of light treatment for MSFC POCC shiftworkers took place during USML-1 and ATLAS-2. The findings from these studies led to the development of a Circadian Countermeasures Program that was implemented during USMP-2. Light treatment and other circadian countermeasures were employed to promote adjustment to mission shiftwork in POCC cadre volunteers. Treatment protocols were designed and customized for each volunteer's work hours and personal preferences. Treatment protocols included some or all of the following: scheduled self-administration of intense light, scheduled avoidance or attenuation of sunlight at other times, and sleep schedules. Data from post-mission questionnaires indicated that volunteers found the program to be effective, convenient, and beneficial.
Feillet, Celine; van der Horst, Gijsbertus T J; Levi, Francis; Rand, David A; Delaunay, Franck
Uncontrolled cell proliferation is one of the key features leading to cancer. Seminal works in chronobiology have revealed that disruption of the circadian timing system in mice, either by surgical, genetic, or environmental manipulation, increased tumor development. In humans, shift work is a risk factor for cancer. Based on these observations, the link between the circadian clock and cell cycle has become intuitive. But despite identification of molecular connections between the two processes, the influence of the clock on the dynamics of the cell cycle has never been formally observed. Recently, two studies combining single live cell imaging with computational methods have shed light on robust coupling between clock and cell cycle oscillators. We recapitulate here these novel findings and integrate them with earlier results in both healthy and cancerous cells. Moreover, we propose that the cell cycle may be synchronized or slowed down through coupling with the circadian clock, which results in reduced tumor growth. More than ever, systems biology has become instrumental to understand the dynamic interaction between the circadian clock and cell cycle, which is critical in cellular coordination and for diseases such as cancer.
Curtis, Anne M.; Fagundes, Caio T.; Palsson-McDermott, Eva M.; Wochal, Paulina; McGettrick, Anne F.; Foley, Niamh H.; Early, James O.; Chen, Lihong; Zhang, Hanrui; Xue, Chenyi; Geiger, Sarah S.; Hokamp, Karsten; Reilly, Muredach P.; Coogan, Andrew N.; Vigorito, Elena; FitzGerald, Garret A.; O’Neill, Luke A. J.
The response to an innate immune challenge is conditioned by the time of day, but the molecular basis for this remains unclear. In myeloid cells, there is a temporal regulation to induction by lipopolysaccharide (LPS) of the proinflammatory microRNA miR-155 that correlates inversely with levels of BMAL1. BMAL1 in the myeloid lineage inhibits activation of NF-κB and miR-155 induction and protects mice from LPS-induced sepsis. Bmal1 has two miR-155–binding sites in its 3′-UTR, and, in response to LPS, miR-155 binds to these two target sites, leading to suppression of Bmal1 mRNA and protein in mice and humans. miR-155 deletion perturbs circadian function, gives rise to a shorter circadian day, and ablates the circadian effect on cytokine responses to LPS. Thus, the molecular clock controls miR-155 induction that can repress BMAL1 directly. This leads to an innate immune response that is variably responsive to challenges across the circadian day. PMID:25995365
Duffy, Jeanne F.; Dijk, Derk-Jan
Overt 24-h rhythmicity is composed of both exogenous and endogenous components, reflecting the product of multiple (periodic) feedback loops with a core pacemaker at their center. Researchers attempting to reveal the endogenous circadian (near 24-h) component of rhythms commonly conduct their experiments under constant environmental conditions. However, even under constant environmental conditions, rhythmic changes in behavior, such as food intake or the sleep-wake cycle, can contribute to observed rhythmicity in many physiological and endocrine variables. Assessment of characteristics of the core circadian pacemaker and its direct contribution to rhythmicity in different variables, including rhythmicity in gene expression, may be more reliable when such periodic behaviors are eliminated or kept constant across all circadian phases. This is relevant for the assessment of the status of the circadian pacemaker in situations in which the sleep-wake cycle or food intake regimes are altered because of external conditions, such as in shift work or jet lag. It is also relevant for situations in which differences in overt rhythmicity could be due to changes in either sleep oscillatory processes or circadian rhythmicity, such as advanced or delayed sleep phase syndromes, in aging, or in particular clinical conditions. Researchers studying human circadian rhythms have developed constant routine protocols to assess the status of the circadian pacemaker in constant behavioral and environmental conditions, whereas this technique is often thought to be unnecessary in the study of animal rhythms. In this short review, the authors summarize constant routine methodology and what has been learned from constant routines and argue that animal and human circadian rhythm researchers should (continue to) use constant routines as a step on the road to getting through to central and peripheral circadian oscillators in the intact organism.
Tokizawa, K; Uchida, Y; Nagashima, K
The circadian rhythm of body temperature (T(b)) is a well-known phenomenon. However, it is unknown how the circadian system including the suprachiasmatic nucleus (SCN) and clock genes affects thermoregulation. Food deprivation in mice induces a greater reduction of T(b) particularly in the light phase. We examined the role of Clock, one of key clock genes and the SCN during induced hypothermia. At 20 degrees C with fasting, mice increased their metabolic heat production in the dark phase and maintained T(b), whereas in the light phase, heat production was less, resulting in hypothermia. Under these conditions, neuronal activity in the SCN, assessed by cFos expression, increased only in the light phase. However, such differences in thermoregulatory and neural responses between the phases in Clock mutant mice were less marked. The neural network between the SCN and paraventricular nucleus appeared to be important in hypothermia. These findings suggest that the circadian system per se is influenced by both the feeding condition and environmental temperature and that it modulates thermoregulation.
Arble, Deanna Marie; Ramsey, Kathryn Moynihan; Bass, Joseph
Social opportunities and work demands have caused humans to become increasingly active during the late evening hours, leading to a shift from the predominantly diurnal lifestyle of our ancestors to a more nocturnal one. This voluntarily decision to stay awake long into the evening hours leads to circadian disruption at the system, tissue, and cellular levels. These derangements are in turn associated with clinical impairments in metabolic processes and physiology. The use of animal models for circadian disruption provides an important opportunity to determine mechanisms by which disorganization in the circadian system can lead to metabolic dysfunction in response to genetic, environmental, and behavioral perturbations. Here we review recent key animal studies involving circadian disruption and discuss the possible translational implications of these studies for human health and particularly for the development of metabolic disease. PMID:21112026
Arble, Deanna Marie; Ramsey, Kathryn Moynihan; Bass, Joseph; Turek, Fred W
Social opportunities and work demands have caused humans to become increasingly active during the late evening hours, leading to a shift from the predominantly diurnal lifestyle of our ancestors to a more nocturnal one. This voluntarily decision to stay awake long into the evening hours leads to circadian disruption at the system, tissue, and cellular levels. These derangements are in turn associated with clinical impairments in metabolic processes and physiology. The use of animal models for circadian disruption provides an important opportunity to determine mechanisms by which disorganization in the circadian system can lead to metabolic dysfunction in response to genetic, environmental, and behavioral perturbations. Here we review recent key animal studies involving circadian disruption and discuss the possible translational implications of these studies for human health and particularly for the development of metabolic disease.
Lee, J; Liu, R; de Jesus, D; Kim, B S; Ma, K; Moulik, M; Yechoor, V
Circadian disruption is the bane of modern existence and its deleterious effects on health; in particular, diabetes and metabolic syndrome have been well recognized in shift workers. Recent human studies strongly implicate a 'dose-dependent' relationship between circadian disruption and diabetes. Genetic and environmental disruption of the circadian clock in rodents leads to diabetes secondary to β-cell failure. Deletion of Bmal1, a non-redundant core clock gene, leads to defects in β-cell stimulus-secretion coupling, decreased glucose-stimulated ATP production, uncoupling of OXPHOS and impaired glucose-stimulated insulin secretion. Both genetic and environmental circadian disruptions are sufficient to induce oxidative stress and this is mediated by a disruption of the direct transcriptional control of the core molecular clock and Bmal1 on Nrf2, the master antioxidant transcription factor in the β-cell. In addition, circadian disruption also leads to a dysregulation of the unfolded protein response and leads to endoplasmic reticulum stress in β-cells. Both the oxidative and endoplasmic reticulum (ER) stress contribute to an impairment of mitochondrial function and β-cell failure. Understanding the basis of the circadian control of these adaptive stress responses offers hope to target them for pharmacological modulation to prevent and mitigate the deleterious metabolic consequences of circadian disruption.
Sahar, Saurabh; Nin, Veronica; Barbosa, Maria Thereza; Chini, Eduardo Nunes; Sassone-Corsi, Paolo
The Intracellular levels of nicotinamide adenine dinucleotide (NAD+) are rhythmic and controlled by the circadian clock. However, whether NAD+ oscillation in turn contributes to circadian physiology is not fully understood. To address this question we analyzed mice mutated for the NAD+ hydrolase CD38. We found that rhythmicity of NAD+ was altered in the CD38-deficient mice. The high, chronic levels of NAD+ results in several anomalies in circadian behavior and metabolism. CD38-null mice display a shortened period length of locomotor activity and alteration in the rest-activity rhythm. Several clock genes and, interestingly, genes involved in amino acid metabolism were deregulated in CD38-null livers. Metabolomic analysis identified alterations in the circadian levels of several amino acids, specifically tryptophan levels were reduced in the CD38-null mice at a circadian time paralleling with elevated NAD+ levels. Thus, CD38 contributes to behavioral and metabolic circadian rhythms and altered NAD+ levels influence the circadian clock. PMID:21937766
Martynhak, Bruno Jacson; Pereira, Marcela; de Souza, Camila Pasquini; Andreatini, Roberto
Disturbances in the circadian rhythms have long been associated with depression and mania. Animal models of mania and depression exhibit differential effects upon the intrinsic circadian period and the same occurs with antidepressants and mood stabilizers treatment. The intrinsic circadian period is expressed when there are no time clues or when the light/dark cycle length is beyond the capacity of synchronization. In summary, while there is no clear association between the circadian period and mania, depressive-like behaviour is generally associated either with lengthening of the circadian period or with arrythmicity, and the improvement of depressive-like behaviour is associated with shortening of the circadian period. Thus, this review is an attempt to summarize data regarding these correlations and find a putative role of the circadian intrinsic period in mood regulation, particularly concerning the switch from depression to mania.
Robertson, Laura; Jones, M. Gail
The study of biological clocks and circadian rhythms is an excellent way to address the inquiry strand in the National Science Education Standards (NSES) (NRC 1996). Students can study these everyday phenomena by designing experiments, gathering and analyzing data, and generating new experiments. As students explore biological clocks and circadian…
Tranel, Hannah R.; Schroder, Elizabeth A.; England, Jonathan; Black, W. Scott; Bush, Heather; Hughes, Michael E.; Esser, Karyn A.; Clasey, Jody L.
Circadian rhythms are ≈ 24 h oscillations in physiology and behavior, and disruptions have been shown to have negative effects on health. Wrist skin temperature has been used by several groups as a valid method of assessing circadian rhythms in humans. We tested the hypothesis that circadian temperature amplitude (TempAmp) and stability (TempStab) would significantly differ among groups of healthy young men of varying adiposities, and that we could identify physiological and behavioral measures that were significantly associated with these temperature parameters. Wrist skin temperatures taken at 10 min intervals for 7 consecutive days were determined in 18 optimal (OGroup), 20 fair (FGroup) and 21 poor (PGroup) %Fat grouped young men and subsequently analyzed using available validated software. Body composition, cardiorespiratory fitness, actigraphy, daily nutritional and sleep data, and fasting lipid, insulin and glucose concentration measures were also determined. Significant changes in TempAmp and TempStab parameters in subjects with a single metabolic syndrome (MetS) risk factor compared to those with no MetS factors was observed. In addition, stepwise multivariate regression analyses showed that 50% of the variance in TempAmp was explained by actigraphy (mean steps taken per day; MSTPD), cardiorespiratory fitness, and late night eating per week (#LNE); and 57% in TempStab by MSTPD, time spent in moderate-to-vigorous activity per day, fat mass, and #LNE. Overwhelmingly, physical activity was the most important measure associated with the differences in circadian rhythm parameters. Further research is warranted to determine the effects of increasing the amount and timing of physical activity on the status of the circadian system in a variety of populations. PMID:26101893
Tranel, Hannah R; Schroder, Elizabeth A; England, Jonathan; Black, W Scott; Bush, Heather; Hughes, Michael E; Esser, Karyn A; Clasey, Jody L
Circadian rhythms are ≈24 h oscillations in physiology and behavior, and disruptions have been shown to have negative effects on health. Wrist skin temperature has been used by several groups as a valid method of assessing circadian rhythms in humans. We tested the hypothesis that circadian temperature amplitude (TempAmp) and stability (TempStab) would significantly differ among groups of healthy young men of varying adiposities, and that we could identify physiological and behavioral measures that were significantly associated with these temperature parameters. Wrist skin temperatures taken at 10 min intervals for 7 consecutive days were determined in 18 optimal (OGroup), 20 fair (FGroup) and 21 poor (PGroup) %Fat grouped young men and subsequently analyzed using available validated software. Body composition, cardiorespiratory fitness, actigraphy, daily nutritional and sleep data, and fasting lipid, insulin and glucose concentration measures were also determined. Significant changes in TempAmp and TempStab parameters in subjects with a single metabolic syndrome (MetS) risk factor compared to those with no MetS factors was observed. In addition, stepwise multivariate regression analyses showed that 50% of the variance in TempAmp was explained by actigraphy (mean steps taken per day; MSTPD), cardiorespiratory fitness, and late night eating per week (#LNE); and 57% in TempStab by MSTPD, time spent in moderate-to-vigorous activity per day, fat mass, and #LNE. Overwhelmingly, physical activity was the most important measure associated with the differences in circadian rhythm parameters. Further research is warranted to determine the effects of increasing the amount and timing of physical activity on the status of the circadian system in a variety of populations.
Gander, P. H.; Kronauer, R. E.; Graeber, R. C.
Two Van der Pol oscillators with reciprocal linear velocity coupling are utilized to model the response of the human circadian timing system to abrupt displacements of the environmental time cues (zeitgebers). The core temperature rhythm and sleep-wake cycle simulated by the model are examined. The relationship between the masking of circadian rhythms by environmental variables and behavioral and physiological events and the rates of resynchronization is studied. The effects of zeitgeber phase shifts and zeitgeber strength on the resynchronization rates are analyzed. The influence of intrinsic pacemakers periods and coupling strength on resynchronization are investigated. The simulated data reveal that: resynchronization after a time zone shift depends on the magnitude of the shift; the time of day of the shift has little influence on resynchronization; the strength of zeitgebers affects the rate and direction of the resynchronization; the intrinsic pacemaker periods have a significant effect on resynchronization; and increasing the coupling between the oscillators results in an increase in the rate of resynchronization. The model data are compared to transmeridian flight studies data and similar resynchronization patterns are observed.
Curtis, Anne M; Bellet, Marina M; Sassone-Corsi, Paolo; O'Neill, Luke A J
Immune parameters change with time of day and disruption of circadian rhythms has been linked to inflammatory pathologies. A circadian-clock-controlled immune system might allow an organism to anticipate daily changes in activity and feeding and the associated risk of infection or tissue damage to the host. Responses to bacteria have been shown to vary depending on time of infection, with mice being more at risk of sepsis when challenged ahead of their activity phase. Studies highlight the extent to which the molecular clock, most notably the core clock proteins BMAL1, CLOCK, and REV-ERBα, control fundamental aspects of the immune response. Examples include the BMAL1:CLOCK heterodimer regulating toll-like receptor 9 (TLR9) expression and repressing expression of the inflammatory monocyte chemokine ligand (CCL2) as well as REV-ERBα suppressing the induction of interleukin-6. Understanding the daily rhythm of the immune system could have implications for vaccinations and how we manage infectious and inflammatory diseases.
Zambotti, G.; Guan, W.; Gest, J.
Human migration has been an important activity in human societies since antiquity. Since 1890, approximately three percent of the world's population has lived outside of their country of origin. As globalization intensifies in the modern era, human migration persists even as governments seek to more stringently regulate flows. Understanding this phenomenon, its causes, processes and impacts often starts from measuring and visualizing its spatiotemporal patterns. This study builds a generic online platform for users to interactively visualize human migration through space and time. This entails quickly ingesting human migration data in plain text or tabular format; matching the records with pre-established geographic features such as administrative polygons; symbolizing the