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Sample records for endogenous circadian period

  1. Racial Differences in the Human Endogenous Circadian Period

    PubMed Central

    Smith, Mark R.; Burgess, Helen J.; Fogg, Louis F.; Eastman, Charmane I.

    2009-01-01

    The length of the endogenous period of the human circadian clock (tau) is slightly greater than 24 hours. There are individual differences in tau, which influence the phase angle of entrainment to the light/dark (LD) cycle, and in doing so contribute to morningness-eveningness. We have recently reported that tau measured in subjects living on an ultradian LD cycle averaged 24.2 hours, and is similar to tau measured using different experimental methods. Here we report racial differences in tau. Subjects lived on an ultradian LD cycle (1.5 hours sleep, 2.5 hours wake) for 3 days. Circadian phase assessments were conducted before and after the ultradian days to determine the change in circadian phase, which was attributed to tau. African American subjects had a significantly shorter tau than subjects of other races. We also tested for racial differences in our previous circadian phase advancing and phase delaying studies. In the phase advancing study, subjects underwent 4 days of a gradually advancing sleep schedule combined with a bright light pulse upon awakening each morning. In the phase delaying study, subjects underwent 4 days of a gradually delaying sleep schedule combined with evening light pulses before bedtime. African American subjects had larger phase advances and smaller phase delays, relative to Caucasian subjects. The racial differences in tau and circadian phase shifting have important implications for understanding normal phase differences between individuals, for developing solutions to the problems of jet lag and shift work, and for the diagnosis and treatment of circadian rhythm based sleep disorders such as advanced and delayed sleep phase disorder. PMID:19564915

  2. Circadian rhythm phase shifts and endogenous free-running circadian period differ between African-Americans and European-Americans

    PubMed Central

    Eastman, Charmane I.; Suh, Christina; Tomaka, Victoria A.; Crowley, Stephanie J.

    2015-01-01

    Successful adaptation to modern civilization requires the internal circadian clock to make large phase shifts in response to circumstances (e.g., jet travel and shift work) that were not encountered during most of our evolution. We found that the magnitude and direction of the circadian clock's phase shift after the light/dark and sleep/wake/meal schedule was phase-advanced (made earlier) by 9 hours differed in European-Americans compared to African-Americans. European-Americans had larger phase shifts, but were more likely to phase-delay after the 9-hour advance (to phase shift in the wrong direction). The magnitude and direction of the phase shift was related to the free-running circadian period, and European-Americans had a longer circadian period than African-Americans. Circadian period was related to the percent Sub-Saharan African and European ancestry from DNA samples. We speculate that a short circadian period was advantageous during our evolution in Africa and lengthened with northern migrations out of Africa. The differences in circadian rhythms remaining today are relevant for understanding and treating the modern circadian-rhythm-based disorders which are due to a misalignment between the internal circadian rhythms and the times for sleep, work, school and meals. PMID:25670162

  3. Age-associated circadian period changes in Arabidopsis leaves

    PubMed Central

    Kim, Hyunmin; Kim, Yumi; Yeom, Miji; Lim, Junhyun; Nam, Hong Gil

    2016-01-01

    As most organisms age, their appearance, physiology, and behaviour alters as part of a life history strategy that maximizes their fitness over their lifetime. The passage of time is measured by organisms and is used to modulate these age-related changes. Organisms have an endogenous time measurement system called the circadian clock. This endogenous clock regulates many physiological responses throughout the life history of organisms to enhance their fitness. However, little is known about the relation between ageing and the circadian clock in plants. Here, we investigate the association of leaf ageing with circadian rhythm changes to better understand the regulation of life-history strategy in Arabidopsis. The circadian periods of clock output genes were approximately 1h shorter in older leaves than younger leaves. The periods of the core clock genes were also consistently shorter in older leaves, indicating an effect of ageing on regulation of the circadian period. Shortening of the circadian period with leaf age occurred faster in plants grown under a long photoperiod compared with a short photoperiod. We screened for a regulatory gene that links ageing and the circadian clock among multiple clock gene mutants. Only mutants for the clock oscillator TOC1 did not show a shortened circadian period during leaf ageing, suggesting that TOC1 may link age to changes in the circadian clock period. Our findings suggest that age-related information is incorporated into the regulation of the circadian period and that TOC1 is necessary for this integrative process. PMID:27012281

  4. Ethanol consumption in mice: relationships with circadian period and entrainment

    PubMed Central

    Trujillo, Jennifer L.; Do, David T.; Grahame, Nicholas J.; Roberts, Amanda J.; Gorman, Michael R.

    2011-01-01

    A functional connection between the circadian timing system and alcohol consumption is suggested by multiple lines of converging evidence. Ethanol consumption perturbs physiological rhythms in hormone secretion, sleep and body temperature, and conversely, genetic and environmental perturbations of the circadian system can alter alcohol intake. A fundamental property of the circadian pacemaker, the endogenous period of its cycle under free-running conditions, was previously shown to differ between selectively bred High- (HAP) and Low- (LAP) Alcohol Preferring replicate 1 mice. To test whether there is a causal relationship between circadian period and ethanol intake, we induced experimental, rather than genetic, variations in free-running period. Male inbred C57Bl/6J mice and replicate 2 male and female HAP2 and LAP2 mice were entrained to light:dark cycles of 26 h or 22 h or remained in a standard 24 h cycle. Upon discontinuation of the light:dark cycle, experimental animals exhibited longer and shorter free-running periods, respectively. Despite robust effects on circadian period and clear circadian rhythms in drinking, these manipulations failed to alter the daily ethanol intake of the inbred strain or selected lines. Likewise, driving the circadian system at long and short periods produced no change in alcohol intake. In contrast with replicate 1 HAP and LAP lines, there was no difference in free-running period between ethanol naïve HAP2 and LAP2 mice. HAP2 mice, however, were significantly more active than LAP2 mice as measured by general home-cage movement and wheel running, a motivated behavior implicating a selection effect on reward systems. Despite a marked circadian regulation of drinking behavior, the free-running and entrained period of the circadian clock does not determine daily ethanol intake. PMID:20880659

  5. Ethanol consumption in mice: relationships with circadian period and entrainment.

    PubMed

    Trujillo, Jennifer L; Do, David T; Grahame, Nicholas J; Roberts, Amanda J; Gorman, Michael R

    2011-03-01

    A functional connection between the circadian timing system and alcohol consumption is suggested by multiple lines of converging evidence. Ethanol consumption perturbs physiological rhythms in hormone secretion, sleep, and body temperature; and conversely, genetic and environmental perturbations of the circadian system can alter alcohol intake. A fundamental property of the circadian pacemaker, the endogenous period of its cycle under free-running conditions, was previously shown to differ between selectively bred high- (HAP) and low- (LAP) alcohol preferring replicate 1 mice. To test whether there is a causal relationship between circadian period and ethanol intake, we induced experimental, rather than genetic, variations in free-running period. Male inbred C57Bl/6J mice and replicate 2 male and female HAP2 and LAP2 mice were entrained to light:dark cycles of 26 or 22 h or remained in a standard 24 h cycle. On discontinuation of the light:dark cycle, experimental animals exhibited longer and shorter free-running periods, respectively. Despite robust effects on circadian period and clear circadian rhythms in drinking, these manipulations failed to alter the daily ethanol intake of the inbred strain or selected lines. Likewise, driving the circadian system at long and short periods produced no change in alcohol intake. In contrast with replicate 1 HAP and LAP lines, there was no difference in free-running period between ethanol naïve HAP2 and LAP2 mice. HAP2 mice, however, were significantly more active than LAP2 mice as measured by general home-cage movement and wheel running, a motivated behavior implicating a selection effect on reward systems. Despite a marked circadian regulation of drinking behavior, the free-running and entrained period of the circadian clock does not determine daily ethanol intake. PMID:20880659

  6. Light-induced suppression of endogenous circadian amplitude in humans

    NASA Technical Reports Server (NTRS)

    Jewett, Megan; Czeisler, Charles A.; Kronauer, Richard E.

    1991-01-01

    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.

  7. Circadian periodicity of tryptophan metabolism

    PubMed Central

    Rapoport, Morton I.; Beisel, William R.

    1968-01-01

    Rhythmicity of tryptophan metabolism via the kynurenine pathway has been demonstrated in man. Normal subjects given 3 g of tryptophan at 0900 hours excreted almost three times the quantity of kynurenine, kynurenic acid, and xanthurenic acid than did subjects given the same dose at 2100 hours. Other metabolites of the kynurenine pathway varied in the same fashion but with lesser magnitude. In contrast, indican, a tryptophan metabolite not in the kynurenine pathway, varied inversely with the other metabolites measured. The data suggest that the liver enzyme tryptophan pyrrolase has a circadian rhythm in man similar to that already described in mice in a previous study. Tryptophan tolerance tests in the future should be controlled relative to time of amino acid administration. PMID:5641628

  8. Simulations of light effects on the human circadian pacemaker: implications for assessment of intrinsic period

    NASA Technical Reports Server (NTRS)

    Klerman, E. B.; Dijk, D. J.; Kronauer, R. E.; Czeisler, C. A.

    1996-01-01

    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.

  9. Stability, precision, and near-24-hour period of the human circadian pacemaker

    NASA Technical Reports Server (NTRS)

    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.

    1999-01-01

    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.

  10. Circadian rhythms and period expression in the Hawaiian cricket genus Laupala

    PubMed Central

    Fergus, Daniel J.; Shaw, Kerry L.

    2013-01-01

    Daily activity times and circadian rhythms of crickets have been a subject of behavioral and physiological study for decades. However, recent studies suggest that the underlying molecular mechanism of cricket endogenous clocks differ from the model of circadian rhythm generation in Drosophila. Here we examine the circadian free-running periods of walking and singing in two Hawaiian swordtail cricket species, Laupala cerasina and Laupala paranigra, that differ in the daily timing of mating related activities. Additionally, we examine variation in sequence and daily cycling of the period (per) gene transcript between these species. The species differed significantly in free-running period of singing, but did not differ significantly in the free-running period of locomotion. Like in Drosophila, per transcript abundance showed cycling consistent with a role in circadian rhythm generation. The amino acid differences identified between these species suggest a potential of the per gene in interspecific behavioral variation in Laupala. PMID:23436058

  11. Circadian rhythms and period expression in the Hawaiian cricket genus Laupala.

    PubMed

    Fergus, Daniel J; Shaw, Kerry L

    2013-05-01

    Daily activity times and circadian rhythms of crickets have been a subject of behavioral and physiological study for decades. However, recent studies suggest that the underlying molecular mechanism of cricket endogenous clocks differ from the model of circadian rhythm generation in Drosophila. Here we examine the circadian free-running periods of walking and singing in two Hawaiian swordtail cricket species, Laupala cerasina and Laupala paranigra, that differ in the daily timing of mating related activities. Additionally, we examine variation in sequence and daily cycling of the period (per) gene transcript between these species. The species differed significantly in free-running period of singing, but did not differ significantly in the free-running period of locomotion. Like in Drosophila, per transcript abundance showed cycling consistent with a role in circadian rhythm generation. The amino acid differences identified between these species suggest a potential of the per gene in interspecific behavioral variation in Laupala. PMID:23436058

  12. A circadian clock in Antarctic krill: an endogenous timing system governs metabolic output rhythms in the euphausid species Euphausia superba.

    PubMed

    Teschke, Mathias; Wendt, Sabrina; Kawaguchi, So; Kramer, Achim; Meyer, Bettina

    2011-01-01

    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

  13. Alterations in endogenous circadian rhythm of core temperature in senescent Fischer 344 rats

    NASA Technical Reports Server (NTRS)

    McDonald, R. B.; Hoban-Higgins, T. M.; Ruhe, R. C.; Fuller, C. A.; Horwitz, B. A.

    1999-01-01

    We assessed whether alterations in endogenous circadian rhythm of core temperature (CRT) in aging rats are associated with chronological time or with a biological marker of senescence, i.e., spontaneous rapid body weight loss. CRT was measured in male Fischer 344 (F344) rats beginning at age 689 days and then continuously until death. Young rats were also monitored. The rats were housed under constant dim red light at 24-26 degrees C, and core temperature was recorded every 10 min via biotelemetry. The CRT amplitude of the body weight-stable (presenescent) old rats was significantly less than that of young rats at all analysis periods. At the onset of spontaneous rapid weight loss (senescence), all measures of endogenous CRT differed significantly from those in the presenescent period. The suprachiasmatic nucleus (a circadian pacemaker) of the senescent rats maintained its light responsiveness as determined by an increase in c-fos expression after a brief light exposure. These data demonstrate that some characteristics of the CRT are altered slowly with chronological aging, whereas others occur rapidly with the onset of senescence.

  14. A novel circadianly expressed Drosophila melanogaster gene dependent on the period gene for its rhythmic expression.

    PubMed Central

    Van Gelder, R N; Krasnow, M A

    1996-01-01

    The Drosophila melanogaster period (per) gene is required for expression of endogenous circadian rhythms of locomotion and eclosion. per mRNA is expressed with a circadian rhythm that is dependent on Per protein; this feedback loop has been proposed to be essential to the central circadian pacemaker. This model would suggest the Per protein also controls the circadian expression of other genetic loci to generate circadian behavior and physiology. In this paper we describe Dreg-5, a gene whose mRNA is expressed in fly heads with a circadian rhythm nearly identical to that of the per gene. Dreg-5 mRNA continues to cycle in phase with that of per mRNA in conditions of total darkness and also when the daily feeding time is altered. Like per mRNA, Dreg-5 mRNA is not expressed rhythmically in per null mutant flies. Dreg-5 encodes a novel 298 residue protein and Dreg-5 protein isoforms also oscillate in abundance with a circadian rhythm. The phase of Dreg-5 protein oscillation, however, is different from that of Per protein expression, suggesting that Dreg-5 and per have common translational but different post-translational control mechanisms. These results demonstrate that the per gene is capable of modulating the rhythmic expression of other genes; this activity may form the basis of the output of circadian rhythmicity in Drosophila. Images PMID:8612586

  15. Association of intrinsic circadian period with morningness-eveningness, usual wake time, and circadian phase

    NASA Technical Reports Server (NTRS)

    Duffy, J. F.; Rimmer, D. W.; Czeisler, C. A.

    2001-01-01

    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.

  16. Visualizing and Quantifying Intracellular Behavior and Abundance of the Core Circadian Clock Protein PERIOD2.

    PubMed

    Smyllie, Nicola J; Pilorz, Violetta; Boyd, James; Meng, Qing-Jun; Saer, Ben; Chesham, Johanna E; Maywood, Elizabeth S; Krogager, Toke P; Spiller, David G; Boot-Handford, Raymond; White, Michael R H; Hastings, Michael H; Loudon, Andrew S I

    2016-07-25

    Transcriptional-translational feedback loops (TTFLs) are a conserved molecular motif of circadian clocks. The principal clock in mammals is the suprachiasmatic nucleus (SCN) of the hypothalamus. In SCN neurons, auto-regulatory feedback on core clock genes Period (Per) and Cryptochrome (Cry) following nuclear entry of their protein products is the basis of circadian oscillation [1, 2]. In Drosophila clock neurons, the movement of dPer into the nucleus is subject to a circadian gate that generates a delay in the TTFL, and this delay is thought to be critical for oscillation [3, 4]. Analysis of the Drosophila clock has strongly influenced models of the mammalian clock, and such models typically infer complex spatiotemporal, intracellular behaviors of mammalian clock proteins. There are, however, no direct measures of the intracellular behavior of endogenous circadian proteins to support this: dynamic analyses have been limited and often have no circadian dimension [5-7]. We therefore generated a knockin mouse expressing a fluorescent fusion of native PER2 protein (PER2::VENUS) for live imaging. PER2::VENUS recapitulates the circadian functions of wild-type PER2 and, importantly, the behavior of PER2::VENUS runs counter to the Drosophila model: it does not exhibit circadian gating of nuclear entry. Using fluorescent imaging of PER2::VENUS, we acquired the first measures of mobility, molecular concentration, and localization of an endogenous circadian protein in individual mammalian cells, and we showed how the mobility and nuclear translocation of PER2 are regulated by casein kinase. These results provide new qualitative and quantitative insights into the cellular mechanism of the mammalian circadian clock. PMID:27374340

  17. Later endogenous circadian temperature nadir relative to an earlier wake time in older people

    NASA Technical Reports Server (NTRS)

    Duffy, J. F.; Dijk, D. J.; Klerman, E. B.; Czeisler, C. A.

    1998-01-01

    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.

  18. Endogenous circadian system and circadian misalignment impact glucose tolerance via separate mechanisms in humans.

    PubMed

    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

    2015-04-28

    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

  19. No endogenous circadian rhythm in resting plasma Hsp72 concentration in humans

    PubMed Central

    Fortes, Matthew B.

    2008-01-01

    Extra-cellular (e) heat shock protein (Hsp)72 has been shown to be elevated in a number of clinical conditions and has been proposed as a potential diagnostic marker. From a methodological and diagnostic perspective, it is important to investigate if concentrations of eHsp72 fluctuate throughout the day; hence, the purpose of the study was to measure resting concentrations of plasma eHsp72 throughout a 24-h period. Blood samples were taken every hour from 1200–2100 hours and from 0700–1200 hours the following day from seven healthy recreationally active males. Participants remained in the laboratory throughout the trial, performed light sedentary activities and were provided with standardised meals and fluids. Physical activity was quantified throughout by the use of an accelerometer. Ethylenediaminetetraacetic acid blood samples were analysed for eHsp72 concentration using a commercially available high-sensitivity enzyme-linked immunosorbent assay (intra-assay coefficient of variation = 1.4%). One-way repeated measures analysis of variance revealed that measures of physiological stress such as heart rate, systolic and diastolic blood pressure remained stable throughout the trial and subjects remained sedentary throughout (mean activity energy expenditure above resting metabolic rate—35.7 ± 10.0 kcal∙h−1). Plasma Hsp72 concentration did not fluctuate significantly throughout the day and showed no apparent endogenous circadian rhythm in absolute (P = 0.367) or plasma volume change corrected data (P = 0.380). Individual coefficients of variation ranged from 3.8–7.7% (mean 5.4%). Mean Hsp72 concentration across all subjects and time points was 1.49 ± 0.08 ng∙ml−1. These data show that in a rested state, plasma eHsp72 concentration shows no apparent endogenous circadian rhythm. PMID:18839337

  20. Neurospora circadian rhythms in space: a reexamination of the endogenous-exogenous question.

    PubMed

    Sulzman, F M; Ellman, D; Fuller, C A; Moore-Ede, M C; Wassmer, G

    1984-07-13

    To test the functioning of circadian rhythms removed from periodicities of the earth's 24-hour rotation, the conidiation rhythm of the fungus Neurospora crassa was monitored in constant darkness during spaceflight. The free-running period of the rhythm was the same in space as on the earth, but there was a marked reduction in the clarity of the rhythm, and apparent arrhythmicity in some tubes. At the current stage of analysis of our results there is insufficient evidence to determine whether the effect seen in space was related to removal from 24-hour periodicities and whether the circadian timekeeping mechanism, or merely its expression, was affected. PMID:11540800

  1. Neurospora circadian rhythms in space - A reexamination of the endogenous-exogenous question

    NASA Technical Reports Server (NTRS)

    Sulzman, F. M.; Ellman, D.; Wassmer, G.; Fuller, C. A.; Moore-Ede, M.

    1984-01-01

    To test the functioning of circadian rhythms removed from periodicities of the earth's 24-hour rotation, the conidiation rhythm of the fungus Neurospora crassa was monitored in constant darkness during spaceflight. The free-running period of the rhythm was the same in space as on the earth, but there was a marked reduction in the clarity of the rhythm, and apparent arrhythmicity in some tubes. At the current stage of analysis of the results there is insufficient evidence to determine whether the effect seen in space was related to removal from 24-hour periodicities and whether the circadian timekeeping mechanism, or merely its expression, was affected.

  2. Intrinsic near-24-h pacemaker period determines limits of circadian entrainment to a weak synchronizer in humans.

    PubMed

    Wright, K P; Hughes, R J; Kronauer, R E; Dijk, D J; Czeisler, C A

    2001-11-20

    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. PMID:11717461

  3. Intrinsic near-24-h pacemaker period determines limits of circadian entrainment to a weak synchronizer in humans

    NASA Technical Reports Server (NTRS)

    Wright, K. P. Jr; Hughes, R. J.; Kronauer, R. E.; Dijk, D. J.; Czeisler, C. A.

    2001-01-01

    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.

  4. A novel E4BP4 element drives circadian expression of mPeriod2.

    PubMed

    Ohno, Tomoya; Onishi, Yoshiaki; Ishida, Norio

    2007-01-01

    Period2 (Per2) is an essential component of the mammalian clock mechanism and robust circadian expression of Per2 is essential for the maintenance of circadian rhythms. Although recent studies have shown that the circadian E2 enhancer (a non-canonical E-box) accounts for most of the circadian transcriptional drive of mPer2, little is known about the other cis-elements of mPer2 oscillatory transcription. Here, we examined the contribution of E4BP4 to Per2 mRNA oscillation in the cell-autonomous clock. Knockdown experiments of E4BP4 in both Northern blots and real-time luciferase assays suggested that endogenous E4BP4 negatively regulates Per2 mRNA oscillation. Sequence analysis revealed two putative E4BP4-binding sites (termed A-site and B-site) on mammalian Per2 promoter regions. Luciferase assays with mutant constructs showed that a novel E4BP4-binding site (B-site) is responsible for E4BP4-mediated transcriptional repression of Per2. Furthermore, chromatin immunoprecipitation assays in vivo showed that the peak of E4BP4 binding to the B-site on the Per2 promoter almost matched the trough of Per2 mRNA expression. Importantly, real-time luciferase assays showed that the B-site in addition to the E2 enhancer is required for robust circadian expression of Per2 in the cell-autonomous clock. These findings indicated that E4BP4 is required for the negative regulation of mammalian circadian clocks. PMID:17182630

  5. Circadian Transcription Contributes to Core Period Determination in Drosophila

    PubMed Central

    Kadener, Sebastian; Menet, Jerome S; Schoer, Rebecca; Rosbash, Michael

    2008-01-01

    The Clock–Cycle (CLK–CYC) heterodimer constitutes a key circadian transcription complex in Drosophila. CYC has a DNA-binding domain but lacks an activation domain. Previous experiments also indicate that most of the transcriptional activity of CLK–CYC derives from the glutamine-rich region of its partner CLK. To address the role of transcription in core circadian timekeeping, we have analyzed the effects of a CYC–viral protein 16 (VP16) fusion protein in the Drosophila system. The addition of this potent and well-studied viral transcriptional activator (VP16) to CYC imparts to the CLK–CYC-VP16 complex strongly enhanced transcriptional activity relative to that of CLK–CYC. This increase is manifested in flies expressing CYC-VP16 as well as in S2 cells. These flies also have increased levels of CLK–CYC direct target gene mRNAs as well as a short period, implicating circadian transcription in period determination. A more detailed examination of reporter gene expression in CYC-VP16–expressing flies suggests that the short period is due at least in part to a more rapid transcriptional phase. Importantly, the behavioral effects require a period (per) promoter and are therefore unlikely to be merely a consequence of generally higher PER levels. This indicates that the CLK–CYC-VP16 behavioral effects are a consequence of increased per transcription. All of this also suggests that the timing of transcriptional activation and not the activation itself is the key event responsible for the behavioral effects observed in CYC-VP16-expressing flies. The results taken together indicate that circadian transcription contributes to core circadian function in Drosophila. PMID:18494558

  6. Impact of dispersed coupling strength on the free running periods of circadian rhythms.

    PubMed

    Gu, Changgui; Rohling, Jos H T; Liang, Xiaoming; Yang, Huijie

    2016-03-01

    The dominant endogenous clock, named the suprachiasmatic nucleus (SCN), regulates circadian rhythms of behavioral and physiological activity in mammals. One of the main characteristics of the SCN is that the animal maintains a circadian rhythm with a period close to 24 h in the absence of a daily light-dark cycle (called the free running period). The free running period varies among species due to heterogeneity of the SCN network. Previous studies have shown that the heterogeneity in cellular coupling as well as in intrinsic neuronal periods shortens the free running period. Furthermore, as derived from experiments, one neuron's coupling strength is negatively associated with its period. It is unknown what the effects of this association between coupling strength and period are on the free running period and how the heterogeneity in coupling strength influences this free running period. In the present study we found that in the presence of a negative relationship between one neuron's coupling strength and its period, surprisingly, the dispersion of coupling strengths increases the free running period. Our present finding may shed new light on the understanding of the heterogeneous SCN network and provides an alternative explanation for the diversity of free running periods between species. PMID:27078397

  7. Impact of dispersed coupling strength on the free running periods of circadian rhythms

    NASA Astrophysics Data System (ADS)

    Gu, Changgui; Rohling, Jos H. T.; Liang, Xiaoming; Yang, Huijie

    2016-03-01

    The dominant endogenous clock, named the suprachiasmatic nucleus (SCN), regulates circadian rhythms of behavioral and physiological activity in mammals. One of the main characteristics of the SCN is that the animal maintains a circadian rhythm with a period close to 24 h in the absence of a daily light-dark cycle (called the free running period). The free running period varies among species due to heterogeneity of the SCN network. Previous studies have shown that the heterogeneity in cellular coupling as well as in intrinsic neuronal periods shortens the free running period. Furthermore, as derived from experiments, one neuron's coupling strength is negatively associated with its period. It is unknown what the effects of this association between coupling strength and period are on the free running period and how the heterogeneity in coupling strength influences this free running period. In the present study we found that in the presence of a negative relationship between one neuron's coupling strength and its period, surprisingly, the dispersion of coupling strengths increases the free running period. Our present finding may shed new light on the understanding of the heterogeneous SCN network and provides an alternative explanation for the diversity of free running periods between species.

  8. Alterations of estrous activity in the ewe by circadian-based manipulation of the endogenous pacemaker.

    PubMed

    Guerin, M V; Matthews, C D

    1998-02-01

    The timing of reproductive activity in the seasonal breeding Romney Marsh ewe depends on the measurement of photoperiodic time. In this experiment, artificial light and dark signals are provided in a measured sequence at an inappropriate time of year to induce breeding out of phase with environmental photoperiod. The endogenous circadian responses and reproductive effects are documented. One group (Group A, control) of 6 Romney Marsh ewes was held in natural photoperiod throughout the experiment. For 8 weeks centered about the winter solstice (Stage 1), an additional 18 animals (Groups B, C, and D) were exposed to an artificial earlier dawn. Measurements of endogenous melatonin performed under acutely extended darkness confirmed a phase advance of the endogenous circadian pacemaker of the suprachiasmatic nucleus compared to control animals. In Stage 2, to the summer solstice (21 December), Group B animals were returned to natural photoperiod, Group C animals were subjected to an earlier artificial dusk, and Group D animals were subjected to an artificial delayed dawn. Melatonin measurements during Stage 2 confirmed that onset and offset times for Group C were earlier and that onset and offset times for Group D were delayed compared to corresponding times for Group B animals. Ovarian activity was monitored throughout. During Stage 2, Groups C and D commenced reproductive activity in mid-spring, and this continued until the experimental conditions changed. Groups A and B commenced reproductive activity at the normal timing in the subsequent autumn. Although not exclusive, these results are consistent with a coincidence model to explain the timing of seasonal breeding in this species with a dusk-located phase of the endogenous pacemaker sensitive to both light and melatonin. The temporal relationship between circadian alterations and the environmental photoperiod warrants further investigation as an explanation for seasonal breeding. PMID:9486844

  9. p53 Regulates Period2 Expression and the Circadian Clock

    PubMed Central

    Miki, Takao; Matsumoto, Tomoko; Zhao, Zhaoyang; Lee, Cheng Chi

    2013-01-01

    The mechanistic interconnectivity between circadian regulation and the genotoxic stress response remains poorly understood. Here we show that the expression of Period 2 (Per2), a circadian regulator, is directly regulated by p53 binding to a response element in the Per2 promoter. This p53 response element is evolutionarily conserved and overlaps with the E-Box element critical for BMAL1/CLOCK binding and its transcriptional activation of Per2 expression. Our studies reveal that p53 blocks BMAL1/CLOCK binding to the Per2 promoter leading to repression of Per2 expression. In the suprachiasmatic nucleus (SCN), p53 expression and its binding to the Per2 promoter are under circadian control. Per2 expression in the SCN is altered by p53 deficiency or stabilization of p53 by Nutlin-3. Behaviorally, p53−/− mice have a shorter period length that lacks stability and they exhibit impaired photo-entrainment to a light pulse under a free-running state. Our studies demonstrate that p53 modulates mouse circadian behavior. PMID:24051492

  10. Alpha-amylase circadian rhythm of young rat parotid gland: an endogenous rhythm with maternal coordination.

    PubMed

    Bellavía, S L; Sanz, E G; Sereno, R; Vermouth, N T

    1992-01-01

    The circadian rhythm of alpha-amylase, E.C. 3.2.1.1. alpha-1,4-glucan-4-glucanohydrolase) in the parotid glands of 25-day-old rats were studied under different experimental designs (fasting, reversed photoperiod, constant lighting conditions and treatment with reserpine and alpha-methyl-p-tyrosine). The rhythm of fasted rats did not change. There were modifications in the rhythm of rats submitted to a reversed photoperiod or treated with reserpine or alpha-methyl-p-tyrosine. The rhythm was present, with changes in the acrophase, in parotids of rats kept during their gestation and postnatal life in constant light or dark. Results suggest that the circadian rhythm of alpha-amylase in parotid gland of young rats is endogenous, synchronized by the photoperiod, and with maternal coordination. PMID:1610312

  11. Effects of gravity on the circadian period in rats

    NASA Technical Reports Server (NTRS)

    Murakami, Dean M.; Demaria, Victor H.; Fuller, Charles A.

    1991-01-01

    The effect of increased gravity force on the circadian period of body temperature and activity of rats was investigated using rats implanted with a small radio telemetry device and, after a 2-week recovery and a 3-week control period at 1G, rotated at for 4 weeks at a constant 2G field in a 18-ft-diam centrifuge. Measurements of the mean freerunning period of the temperature and activity rhythms after 10 days showed that the exposure to 2G led to a functional separation of the pacemakers that regulate the activity and the temperature in the animals. Each pacemaker reacted differently: the activity period increased and the temperature period decreased. By the third or the fourth week, the activity and the temperature periods have returned to 1G control levels.

  12. microRNA modulation of circadian clock period and entrainment

    PubMed Central

    Cheng, Hai-Ying M.; Papp, Joseph W.; Varlamova, Olga; Dziema, Heather; Russell, Brandon; Curfman, John P.; Nakazawa, Takanobu; Shimizu, Kimiko; Okamura, Hitoshi; Impey, Soren; Obrietan, Karl

    2007-01-01

    microRNAs (miRNAs) are a class of small, non-coding, RNAs that regulate the stability or translation of mRNA transcripts. Although recent work has implicated miRNAs in development and in disease, the expression and function of miRNAs in the adult mammalian nervous system has not been extensively characterized. Here, we examine the role of two brain-specific miRNAs, miR-219 and miR-132, in modulating the circadian clock located in the suprachiasmatic nucleus. miR-219 is a target of the CLOCK/BMAL1 complex, exhibits robust circadian rhythms of expression and the in vivo knockdown of miR-219 lengthens the circadian period. miR-132 is induced by photic entrainment cues via a MAPK/CREB-dependent mechanism, modulates clock gene expression, and attenuates the entraining effects of light. Collectively, these data reveal miRNAs as clock- and light-regulated genes and provide a mechanistic examination of their roles as effectors of pacemaker activity and entrainment. PMID:17553428

  13. Sex difference in the near-24-hour intrinsic period of the human circadian timing system

    PubMed Central

    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.

    2011-01-01

    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

  14. Phosphorylation of the D1 Photosystem II Reaction Center Protein Is Controlled by an Endogenous Circadian Rhythm1

    PubMed Central

    Booij-James, Isabelle S.; Swegle, W. Mark; Edelman, Marvin; Mattoo, Autar K.

    2002-01-01

    The light dependence of D1 phosphorylation is unique to higher plants, being constitutive in cyanobacteria and algae. In a photoautotrophic higher plant, Spirodela oligorrhiza, grown in greenhouse conditions under natural diurnal cycles of solar irradiation, the ratio of phosphorylated versus total D1 protein (D1-P index: [D1-P]/[D1] + [D1-P]) of photosystem II is shown to undergo reproducible diurnal oscillation. These oscillations were clearly out of phase with the period of maximum in light intensity. The timing of the D1-P index maximum was not affected by changes in temperature, the amount of D1 kinase activity present in the thylakoid membranes, the rate of D1 protein synthesis, or photoinhibition. However, when the dark period in a normal diurnal cycle was cut short artificially by transferring plants to continuous light conditions, the D1-P index timing shifted and reached a maximum within 4 to 5 h of light illumination. The resultant diurnal oscillation persisted for at least two cycles in continuous light, suggesting that the rhythm is endogenous (circadian) and is entrained by an external signal. PMID:12481090

  15. Rhythmic control of mRNA stability modulates circadian amplitude of mouse Period3 mRNA.

    PubMed

    Kim, Sung-Hoon; Lee, Kyung-Ha; Kim, Do-Yeon; Kwak, Eunyee; Kim, Seunghwan; Kim, Kyong-Tai

    2015-03-01

    The daily oscillations observed in most living organisms are endogenously generated with a period of 24 h, and the underlying structure of periodic oscillation is an autoregulatory transcription-translation feedback loop. The mechanisms of untranslated region (UTR)-mediated post-transcriptional regulation (e.g., mRNA degradation and internal ribosomal entry site (IRES)-mediated translation) have been suggested to fine-tune the expression of clock genes. Mouse Period3 (mPer3) is one of the paralogs of Period gene and its function is important in peripheral clocks and sleep physiology. mPer3 mRNA displays a circadian oscillation as well as a circadian phase-dependent stability, while the stability regulators still remain unknown. In this study, we identify three proteins - heterogeneous nuclear ribonucleoprotein (hnRNP) K, polypyrimidine tract-binding protein (PTB), and hnRNP D - that bind to mPer3 mRNA 3'-UTR. We show that hnRNP K is a stabilizer that increases the amplitude of circadian mPer3 mRNA oscillation and hnRNP D is a destabilizer that decreases it, while PTB exhibits no effect on mPer3 mRNA expression. Our experiments describe their cytoplasmic roles for the mRNA stability regulation and the circadian amplitude formation. Moreover, our mathematical model suggests a mechanism through which post-transcriptional mRNA stability modulation provides not only the flexibility of oscillation amplitude, but also the robustness of the period and the phase for circadian mPer3 expression. Mouse Period3 (mPer3) is one of well-known clock genes. We identified three 3'-UTR-binding proteins that modulate the mRNA stability, and they influenced to the amplitude of circadian mPer3 mRNA oscillation. Our mathematical model not only showed the relationship between mRNA stability and its oscillation profile but provided the molecular mechanism for the robustness of the period and the phase in circadian oscillation. hnK, heterogeneous nuclear ribonucleoprotein (hnRNP) K; hnD, hn

  16. Lithium lengthens circadian period of cultured brain slices in area specific manner.

    PubMed

    Yoshikawa, Tomoko; Honma, Sato

    2016-11-01

    Lithium has been used for the treatment of bipolar disorder (BD). However, the mechanisms how lithium exerts its mood stabilizing effects remain to be studied. The disorder in circadian pacemaking has been suggested as an underlying mechanism of the characteristic mood instability of the BD. Lithium is also known to lengthen the circadian periods. We recently proposed that chronic methamphetamine treatment induced circadian oscillation as a complex oscillator including multiple dopaminergic brain areas, and the complex oscillator regulates behavior rhythm independent from the central circadian oscillator in the suprachiasmatic nucleus (SCN). Sleep-wake pattern of rapid cycling BD exhibits similar rhythm disorganization to methamphetamine treated animals. Therefore, we hypothesized that the dysregulated circadian rhythm in BD patients is caused by desynchronization of sleep-wake rhythms from the central clock in the SCN, and that mood stabilizing effect of lithium is achieved through their resynchronization. In the present experiment, we examined how lithium affects the circadian rhythms of brain areas involved in the complex oscillator as well as the SCN. Here we report that lithium lengthens the circadian periods in the SCN, olfactory bulb, median eminence and substantia nigra with dose and area specific manner. The effective lithium dose was much higher than the plasma levels that are required for lengthening the circadian behavior rhythms as well for therapeutic use. Low dose of lithium did not lengthen the period but enhanced the amplitude of circadian rhythms, which may exert therapeutic effects on BD. PMID:27478137

  17. Plasticity of the Intrinsic Period of the Human Circadian Timing System

    PubMed Central

    Scheer, Frank A.J.L.; Wright, Kenneth P.; Kronauer, Richard E.; Czeisler, Charles A.

    2007-01-01

    Human expeditions to Mars will require adaptation to the 24.65-h Martian solar day-night cycle (sol), which is outside the range of entrainment of the human circadian pacemaker under lighting intensities to which astronauts are typically exposed. Failure to entrain the circadian time-keeping system to the desired rest-activity cycle disturbs sleep and impairs cognitive function. Furthermore, differences between the intrinsic circadian period and Earth's 24-h light-dark cycle underlie human circadian rhythm sleep disorders, such as advanced sleep phase disorder and non-24-hour sleep-wake disorders. Therefore, first, we tested whether exposure to a model-based lighting regimen would entrain the human circadian pacemaker at a normal phase angle to the 24.65-h Martian sol and to the 23.5-h day length often required of astronauts during short duration space exploration. Second, we tested here whether such prior entrainment to non-24-h light-dark cycles would lead to subsequent modification of the intrinsic period of the human circadian timing system. Here we show that exposure to moderately bright light (∼450 lux; ∼1.2 W/m2) for the second or first half of the scheduled wake episode is effective for entraining individuals to the 24.65-h Martian sol and a 23.5-h day length, respectively. Estimations of the circadian periods of plasma melatonin, plasma cortisol, and core body temperature rhythms collected under forced desynchrony protocols revealed that the intrinsic circadian period of the human circadian pacemaker was significantly longer following entrainment to the Martian sol as compared to following entrainment to the 23.5-h day. The latter finding of after-effects of entrainment reveals for the first time plasticity of the period of the human circadian timing system. Both findings have important implications for the treatment of circadian rhythm sleep disorders and human space exploration. PMID:17684566

  18. Skylab SO71/SO72 circadian periodicity experiment. [experimental design and checkout of hardware

    NASA Technical Reports Server (NTRS)

    Fairchild, M. K.; Hartmann, R. A.

    1973-01-01

    The circadian rhythm hardware activities from 1965 through 1973 are considered. A brief history of the programs leading to the development of the combined Skylab SO71/SO72 Circadian Periodicity Experiment (CPE) is given. SO71 is the Skylab experiment number designating the pocket mouse circadian experiment, and SO72 designates the vinegar gnat circadian experiment. Final design modifications and checkout of the CPE, integration testing with the Apollo service module CSM 117 and the launch preparation and support tasks at Kennedy Space Center are reported.

  19. Endogenous Circadian Regulation of Pro-inflammatory Cytokines and Chemokines in the Presence of Bacterial Lipopolysaccharide in Humans

    PubMed Central

    Rahman, Shadab A.; Castanon-Cervantes, Oscar; Scheer, Frank A.J.L.; Shea, Steven A.; Czeisler, Charles A.; Davidson, Alec J.; Lockley, Steven W.

    2015-01-01

    Various aspects of immune response exhibit 24-hour variations suggesting that infection susceptibility and treatment efficacy may vary by time of day. Whether these 24-hour variations are endogenous or evoked by changes in environmental or behavioral conditions is not known. We assessed the endogenous circadian control and environmental and behavioral influences on ex-vivo lipopolysaccharide stimulation of whole blood in thirteen healthy participants under 48 hours of baseline conditions with standard sleep-wake schedules and 40–50 hours of constant environmental and behavioral (constant routine; CR) conditions. Significant 24-hour rhythms were observed under baseline conditions in Monocyte Chemotactic Protein, Granulocyte-Macrophage Colony-Stimulating Factor and Interleukin 8 but not Tumor Necrosis Factor alpha whereas significant 24-hour rhythms were observed in all four immune factors under CR conditions. The rhythm amplitudes, expressed as a percentage of mean, were comparable between immune factors and across conditions. In contrast, the acrophase time (time of the fitted peak) was different between immune factors, and included daytime and nighttime peaks and changes across behavioral conditions. These results suggest that the endogenous circadian system underpins the temporal organization of immune responses in humans with additional effects of external environmental and behavioral cycles. These findings have implications for understanding the adverse effects of recurrent circadian disruption and sleep curtailment on immune function. PMID:25452149

  20. Periodic dip of lipidperoxidation in humans: a redox signal to synchronize peripheral circadian clocks?

    PubMed

    Cardona, F

    2004-01-01

    The output generated by the endogenous circadian clock to control circadian functions and temporal organization in metazoans is unknown. Redox state perturbations generated by reactive oxygen species (ROS) and antioxidants are known to influence the expression of a number of genes and signal transduction pathways. Evidence has been recently provided that the reduced redox cofactors NAD and NADP both regulate clock gene activity in the suprachiasmatic nucleus (SCN) and are induced by it. Significant periodic variations of lipidperoxidation in human blood with a dip at 04.00 h have been previously reported. Such variations could be expected to alter the cellular redox state, thus possibly functioning as periodic redox signals from the master clock. To verify the existence of the mentioned variations the serum levels of malondialdehyde (MDA), a marker of lipidperoxidation, were monitored by High-Performance Liquid Chromatography in 39 healthy subjects at 3-h intervals over a 24-h period. Throughout the test period, only biological noise could be detected in all test persons. However, the normalized MDA levels at 03.00 h were significantly lower (p < 0.05 to < 0.00005) in 38 (97%) of the cases and showed a significantly lower standard deviation (p < 0.004) than at any of the other 3-h intervals, indicating a periodic dip of lipidperoxidation (PDL) in diurnal active subjects. We hypothesize that the PDL, on the basis of its time of appearance, its frequency and its potential influence on cellular redox state, represents a periodic systemic redox output of the SCN, in terms of a relatively short and sudden interruption of the daily oxidative noise. According to recent research, it could be the result of redox alterations induced by the SCN activity and at the same time the pathway by which the master clock resets and synchronizes peripheral oscillators to the light/dark cycle. Additionally, the antioxidative function of the pineal gland activity postulated elsewhere

  1. The parathyroid hormone circadian rhythm is truly endogenous--a general clinical research center study

    NASA Technical Reports Server (NTRS)

    el-Hajj Fuleihan, G.; Klerman, E. B.; Brown, E. N.; Choe, Y.; Brown, E. M.; Czeisler, C. A.

    1997-01-01

    While circulating levels of PTH follow a diurnal pattern, it has been unclear whether these changes are truly endogenous or are dictated by external factors that themselves follow a diurnal pattern, such as sleep-wake cycles, light-dark cycles, meals, or posture. We evaluated the diurnal rhythm of PTH in 11 normal healthy male volunteers in our Intensive Physiologic Monitoring Unit. The first 36 h spent under baseline conditions were followed by 28-40 h of constant routine conditions (CR; enforced wakefulness in the strict semirecumbent position, with the consumption of hourly snacks). During baseline conditions, PTH levels followed a bimodal diurnal rhythm with an average amplitude of 4.2 pg/mL. A primary peak (t1max) occurred at 0314 h, and the secondary peak (t2max) occurred at 1726 h, whereas the primary and secondary nadirs (t1min and t2min) took place, on the average, at 1041 and 2103 h, respectively. This rhythm was preserved under CR conditions, albeit with different characteristics, thus confirming its endogenous nature. The serum ionized calcium (Cai) demonstrated a rhythm in 3 of the 5 subjects studied that varied widely between individuals and did not have any apparent relation to PTH. Urinary calcium/creatinine (UCa/Cr), phosphate/Cr (UPO4/Cr), and sodium/Cr (UNa/Cr) ratios all followed a diurnal rhythm during the baseline day. These rhythms persisted during the CR, although with different characteristics for the first two parameters, whereas that of UNa/Cr was unchanged. In general, the temporal pattern for the UCa/Cr curve was a mirror image of the PTH curve, whereas the UPO4/Cr pattern moved in parallel with the PTH curve. In conclusion, PTH levels exhibit a diurnal rhythm that persists during a CR, thereby confirming that a large component of this rhythm is an endogenous circadian rhythm. The clinical relevance of this rhythm is reflected in the associated rhythms of biological markers of PTH effect at the kidney, namely UCa/Cr and UPO4/Cr.

  2. Circadian rhythms in Macaca mulatta monkeys during Bion 11 flight

    NASA Technical Reports Server (NTRS)

    Alpatov, A. M.; Hoban-Higgins, T. M.; Klimovitsky, V. Y.; Tumurova, E. G.; Fuller, C. A.

    2000-01-01

    Circadian rhythms of primate brain temperature, head and ankle skin temperature, motor activity, and heart rate were studied during spaceflight and on the ground. In space, the circadian rhythms of all the parameters were synchronized with diurnal Zeitgebers. However, in space the brain temperature rhythm showed a significantly more delayed phase angle, which may be ascribed to an increase of the endogenous circadian period.

  3. Circadian and Circalunar Clock Interactions in a Marine Annelid

    PubMed Central

    Zantke, Juliane; Ishikawa-Fujiwara, Tomoko; Arboleda, Enrique; Lohs, Claudia; Schipany, Katharina; Hallay, Natalia; Straw, Andrew D.; Todo, Takeshi; Tessmar-Raible, Kristin

    2013-01-01

    Summary Life is controlled by multiple rhythms. Although the interaction of the daily (circadian) clock with environmental stimuli, such as light, is well documented, its relationship to endogenous clocks with other periods is little understood. We establish that the marine worm Platynereis dumerilii possesses endogenous circadian and circalunar (monthly) clocks and characterize their interactions. The RNAs of likely core circadian oscillator genes localize to a distinct nucleus of the worm’s forebrain. The worm’s forebrain also harbors a circalunar clock entrained by nocturnal light. This monthly clock regulates maturation and persists even when circadian clock oscillations are disrupted by the inhibition of casein kinase 1δ/ε. Both circadian and circalunar clocks converge on the regulation of transcript levels. Furthermore, the circalunar clock changes the period and power of circadian behavior, although the period length of the daily transcriptional oscillations remains unaltered. We conclude that a second endogenous noncircadian clock can influence circadian clock function. PMID:24075994

  4. The Arabidopsis Circadian System

    PubMed Central

    McClung, C. Robertson; Salomé, Patrice A.; Michael, Todd P.

    2002-01-01

    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

  5. Human Gut Bacteria Are Sensitive to Melatonin and Express Endogenous Circadian Rhythmicity

    PubMed Central

    Paulose, Jiffin K.; Wright, John M.; Patel, Akruti G; Cassone, Vincent M.

    2016-01-01

    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

  6. Period-independent novel circadian oscillators revealed by timed exercise and palatable meals

    PubMed Central

    Flôres, Danilo E. F. L.; Bettilyon, Crystal N.; Yamazaki, Shin

    2016-01-01

    The mammalian circadian system is a hierarchical network of oscillators organized to optimally coordinate behavior and physiology with daily environmental cycles. The suprachiasmatic nucleus (SCN) of the hypothalamus is at the top of this hierarchy, synchronizing to the environmental light-dark cycle, and coordinates the phases of peripheral clocks. The Period genes are critical components of the molecular timekeeping mechanism of these clocks. Circadian clocks are disabled in Period1/2/3 triple mutant mice, resulting in arrhythmic behavior in constant conditions. We uncovered rhythmic behavior in this mutant by simply exposing the mice to timed access to a palatable meal or running wheel. The emergent circadian behavior rhythms free-ran for many cycles under constant conditions without cyclic environmental cues. Together, these data demonstrate that the palatable meal-inducible circadian oscillator (PICO) and wheel-inducible circadian oscillator (WICO) are generated by non-canonical circadian clocks. Entrainment of these novel oscillators by palatable snacks and timed exercise could become novel therapeutics for human conditions caused by disruptions of the circadian clocks. PMID:26904978

  7. Period-independent novel circadian oscillators revealed by timed exercise and palatable meals.

    PubMed

    Flôres, Danilo E F L; Bettilyon, Crystal N; Yamazaki, Shin

    2016-01-01

    The mammalian circadian system is a hierarchical network of oscillators organized to optimally coordinate behavior and physiology with daily environmental cycles. The suprachiasmatic nucleus (SCN) of the hypothalamus is at the top of this hierarchy, synchronizing to the environmental light-dark cycle, and coordinates the phases of peripheral clocks. The Period genes are critical components of the molecular timekeeping mechanism of these clocks. Circadian clocks are disabled in Period1/2/3 triple mutant mice, resulting in arrhythmic behavior in constant conditions. We uncovered rhythmic behavior in this mutant by simply exposing the mice to timed access to a palatable meal or running wheel. The emergent circadian behavior rhythms free-ran for many cycles under constant conditions without cyclic environmental cues. Together, these data demonstrate that the palatable meal-inducible circadian oscillator (PICO) and wheel-inducible circadian oscillator (WICO) are generated by non-canonical circadian clocks. Entrainment of these novel oscillators by palatable snacks and timed exercise could become novel therapeutics for human conditions caused by disruptions of the circadian clocks. PMID:26904978

  8. Deviation of innate circadian period from 24 hours reduces longevity in mice

    PubMed Central

    Libert, Sergiy; Bonkowski, Michael S.; Pointer, Kelli; Pletcher, Scott D.; Guarente, Leonard

    2012-01-01

    Summary The variation of individual lifespans, even in highly inbred cohorts of animals and under strictly controlled environmental conditions, is substantial and not well understood. This variation in part could be due to epigenetic variation, which later affects the animal’s physiology and ultimately longevity. Identification of the physiological properties that impact health and lifespan is crucial for longevity research and the development of anti-aging therapies. Here we measured individual circadian and metabolic characteristics in a cohort of inbred F1 hybrid mice and correlated these parameters to their lifespans. We found that mice with innate circadian periods close to 24 hours (revealed during 30 days of housing in total darkness) enjoyed nearly 20% longer lifespans than their littermates, which had shorter or longer innate circadian periods. These findings show that maintenance of a 24 hour intrinsic circadian period is a positive predictor of longevity. Our data suggest that circadian period may be used to predict individual longevity and that processes that control innate circadian period affect aging. PMID:22702406

  9. A Role for the PERIOD:PERIOD Homodimer in the Drosophila Circadian Clock

    PubMed Central

    Wolf, Eva; Stanewsky, Ralf

    2009-01-01

    Circadian clocks in eukaryotes rely on transcriptional feedback loops, in which clock genes repress their own transcription resulting in molecular oscillations with a period of ∼24 h. In Drosophila, the clock proteins Period (PER) and Timeless (TIM) operate in such a feedback loop, whereby they first accumulate in the cytoplasm of clock cells as a heterodimer. Nuclear translocation of the complex or the individual PER and TIM proteins is followed by repression of per and tim transcription, whereby PER seems to act as the prime repressor. We found that in addition to PER:TIM complexes, functional PER:PER homodimers exist in flies. Specific disruption of PER homodimers results in drastically impaired behavioral and molecular rhythmicity, pointing the biological importance of this clock protein complex. Analysis of PER subcellular distribution and repressor competence in the PER dimer mutant revealed defects in PER nuclear translocation and a disruption of rhythmic period transcription. The striking similarity of these phenotypes with that of reduced CKII activity suggests that the formation or function of the PER dimer is closely linked to this kinase. Our results confirm a previous structural model for PER and provide strong evidence that PER homodimers are important for circadian clock function. PMID:19402744

  10. Circadian genes Period 1 and Period 2 in the nucleus accumbens regulate anxiety-related behavior

    PubMed Central

    Spencer, Sade; Falcon, Edgardo; Kumar, Jaswinder; Krishnan, Vaishnav; Mukherjee, Shibani; Birnbaum, Shari G.; McClung, Colleen A.

    2013-01-01

    It has been suggested for some time that circadian rhythm abnormalities underlie the development of multiple psychiatric disorders. However, it is unclear how disruptions in individual circadian genes might regulate mood and anxiety. Here we found that mice lacking functional mPeriod 1 (mPer1) or mPeriod 2 (mPer2) individually did not have consistent behavioral abnormalities in measures of anxiety-related behavior. However, mice deficient in both mPer1 and mPer2 had an increase in levels of anxiety-like behavior in multiple measures. Moreover, we found that mPer1 and mPer2 expression was reduced in the nucleus accumbens (NAc) after exposure to chronic social defeat stress, a paradigm that led to increased anxiety-related behavior. Following social defeat, chronic treatment with fluoxetine normalized Per gene expression towards wild-type levels. Knockdown of both mPer1 and mPer2 expression via RNA interference specifically in the NAc led to a similar increase in anxiety-like behavior as seen in the mutant animals. Taken together, these results implicate the Per genes in the NAc in response to stress and the development of anxiety. PMID:23039899

  11. Circadian oscillations in period gene mRNA levels are transcriptionally regulated.

    PubMed Central

    Hardin, P E; Hall, J C; Rosbash, M

    1992-01-01

    The period (per) gene is involved in regulating circadian rhythms in Drosophila melanogaster. The per gene is expressed in a circadian manner, where fluctuations in per mRNA abundance are influenced by its own translation product, which also cycles in abundance. Since per gene expression is necessary for circadian rhythmicity, we sought to determine how certain features of this feedback loop operate. The results of this study reveal that fluctuations in per mRNA are primarily controlled by fluctuations in per gene transcription, that per mRNA has a relatively short half-life, and that sequences sufficient to drive per mRNA cycling are present in 1.3 kilobases of 5' flanking sequences. These and other results indicate that the per feedback loop has all of the basic properties necessary to be a component of a circadian oscillator. Images PMID:1465387

  12. Glucocorticoid-mediated Period2 induction delays the phase of circadian rhythm

    PubMed Central

    Cheon, Solmi; Park, Noheon; Cho, Sehyung; Kim, Kyungjin

    2013-01-01

    Glucocorticoid (GC) signaling synchronizes the circadian rhythm of individual peripheral cells and induces the expression of circadian genes, including Period1 (Per1) and Period2 (Per2). However, no GC response element (GRE) has been reported in the Per2 promoter region. Here we report the molecular mechanisms of Per2 induction by GC signaling and its relevance to the regulation of circadian timing. We found that GC prominently induced Per2 expression and delayed the circadian phase. The overlapping GRE and E-box (GE2) region in the proximal Per2 promoter was responsible for GC-mediated Per2 induction. The GRE in the Per2 promoter was unique in that brain and muscle ARNT-like protein-1 (BMAL1) was essential for GC-induced Per2 expression, whereas other GRE-containing promoters, such as Per1 and mouse mammary tumor virus, responded to dexamethasone in the absence of BMAL1. This specialized regulatory mechanism was mediated by BMAL1-dependent binding of the GC receptor to GRE in Per2 promoter. When Per2 induction was abrogated by the mutation of the GRE or E-box, the circadian oscillation phase failed to be delayed compared with that of the wild-type. Therefore, the current study demonstrates that the rapid Per2 induction mediated by GC is crucial for delaying the circadian rhythm. PMID:23620290

  13. Mutations in the circadian gene period alter behavioral and biochemical responses to ethanol in Drosophila.

    PubMed

    Liao, Jennifer; Seggio, Joseph A; Ahmad, S Tariq

    2016-04-01

    Clock genes, such as period, which maintain an organism's circadian rhythm, can have profound effects on metabolic activity, including ethanol metabolism. In turn, ethanol exposure has been shown in Drosophila and mammals to cause disruptions of the circadian rhythm. Previous studies from our labs have shown that larval ethanol exposure disrupted the free-running period and period expression of Drosophila. In addition, a recent study has shown that arrhythmic flies show no tolerance to ethanol exposure. As such, Drosophila period mutants, which have either a shorter than wild-type free-running period (perS) or a longer one (perL), may also exhibit altered responses to ethanol due to their intrinsic circadian differences. In this study, we tested the initial sensitivity and tolerance of ethanol exposure on Canton-S, perS, and perL, and then measured their Alcohol Dehydrogenase (ADH) and body ethanol levels. We showed that perL flies had slower sedation rate, longer recovery from ethanol sedation, and generated higher tolerance for sedation upon repeated ethanol exposure compared to Canton-S wild-type flies. Furthermore, perL flies had lower ADH activity and had a slower ethanol clearance compared to wild-type flies. The findings of this study suggest that period mutations influence ethanol induced behavior and ethanol metabolism in Drosophila and that flies with longer circadian periods are more sensitive to ethanol exposure. PMID:26802726

  14. The Physiological Period Length of the Human Circadian Clock In Vivo Is Directly Proportional to Period in Human Fibroblasts

    PubMed Central

    Moriggi, Ermanno; Revell, Victoria L.; Hack, Lisa M.; Lockley, Steven W.; Arendt, Josephine; Skene, Debra J.; Meier, Fides; Izakovic, Jan; Wirz-Justice, Anna; Cajochen, Christian; Sergeeva, Oksana J.; Cheresiz, Sergei V.; Danilenko, Konstantin V.; Eckert, Anne; Brown, Steven A.

    2010-01-01

    Background Diurnal behavior in humans is governed by the period length of a circadian clock in the suprachiasmatic nuclei of the brain hypothalamus. Nevertheless, the cell-intrinsic mechanism of this clock is present in most cells of the body. We have shown previously that for individuals of extreme chronotype (“larks” and “owls”), clock properties measured in human fibroblasts correlated with extreme diurnal behavior. Methodology/Principal Findings In this study, we have measured circadian period in human primary fibroblasts taken from normal individuals and, for the first time, compared it directly with physiological period measured in vivo in the same subjects. Human physiological period length was estimated via the secretion pattern of the hormone melatonin in two different groups of sighted subjects and one group of totally blind subjects, each using different methods. Fibroblast period length was measured via cyclical expression of a lentivirally delivered circadian reporter. Within each group, a positive linear correlation was observed between circadian period length in physiology and in fibroblast gene expression. Interestingly, although blind individuals showed on average the same fibroblast clock properties as sighted ones, their physiological periods were significantly longer. Conclusions/Significance We conclude that the period of human circadian behaviour is mostly driven by cellular clock properties in normal individuals and can be approximated by measurement in peripheral cells such as fibroblasts. Based upon differences among sighted and blind subjects, we also speculate that period can be modified by prolonged unusual conditions such as the total light deprivation of blindness. PMID:21042402

  15. Competing E3 ubiquitin ligases govern circadian periodicity by degradation of CRY in nucleus and cytoplasm.

    PubMed

    Yoo, Seung-Hee; Mohawk, Jennifer A; Siepka, Sandra M; Shan, Yongli; Huh, Seong Kwon; Hong, Hee-Kyung; Kornblum, Izabela; Kumar, Vivek; Koike, Nobuya; Xu, Ming; Nussbaum, Justin; Liu, Xinran; Chen, Zheng; Chen, Zhijian J; Green, Carla B; Takahashi, Joseph S

    2013-02-28

    Period determination in the mammalian circadian clock involves the turnover rate of the repressors CRY and PER. We show that CRY ubiquitination engages two competing E3 ligase complexes that either lengthen or shorten circadian period in mice. Cloning of a short-period circadian mutant, Past-time, revealed a glycine to glutamate missense mutation in Fbxl21, an F-box protein gene that is a paralog of Fbxl3 that targets the CRY proteins for degradation. While loss of function of FBXL3 leads to period lengthening, mutation of Fbxl21 causes period shortening. FBXL21 forms an SCF E3 ligase complex that slowly degrades CRY in the cytoplasm but antagonizes the stronger E3 ligase activity of FBXL3 in the nucleus. FBXL21 plays a dual role: protecting CRY from FBXL3 degradation in the nucleus and promoting CRY degradation within the cytoplasm. Thus, the balance and cellular compartmentalization of competing E3 ligases for CRY determine circadian period of the clock in mammals. PMID:23452855

  16. Temporally chimeric mice reveal flexibility of circadian period-setting in the suprachiasmatic nucleus

    PubMed Central

    Smyllie, Nicola J.; Chesham, Johanna E.; Hamnett, Ryan; Maywood, Elizabeth S.; Hastings, Michael H.

    2016-01-01

    The suprachiasmatic nucleus (SCN) is the master circadian clock controlling daily behavior in mammals. It consists of a heterogeneous network of neurons, in which cell-autonomous molecular feedback loops determine the period and amplitude of circadian oscillations of individual cells. In contrast, circuit-level properties of coherence, synchrony, and ensemble period are determined by intercellular signals and are embodied in a circadian wave of gene expression that progresses daily across the SCN. How cell-autonomous and circuit-level mechanisms interact in timekeeping is poorly understood. To explore this interaction, we used intersectional genetics to create temporally chimeric mice with SCN containing dopamine 1a receptor (Drd1a) cells with an intrinsic period of 24 h alongside non-Drd1a cells with 20-h clocks. Recording of circadian behavior in vivo alongside cellular molecular pacemaking in SCN slices in vitro demonstrated that such chimeric circuits form robust and resilient circadian clocks. It also showed that the computation of ensemble period is nonlinear. Moreover, the chimeric circuit sustained a wave of gene expression comparable to that of nonchimeric SCN, demonstrating that this circuit-level property is independent of differences in cell-intrinsic periods. The relative dominance of 24-h Drd1a and 20-h non-Drd1a neurons in setting ensemble period could be switched by exposure to resonant or nonresonant 24-h or 20-h lighting cycles. The chimeric circuit therefore reveals unanticipated principles of circuit-level operation underlying the emergent plasticity, resilience, and robustness of the SCN clock. The spontaneous and light-driven flexibility of period observed in chimeric mice provides a new perspective on the concept of SCN pacemaker cells. PMID:26966234

  17. Temporally chimeric mice reveal flexibility of circadian period-setting in the suprachiasmatic nucleus.

    PubMed

    Smyllie, Nicola J; Chesham, Johanna E; Hamnett, Ryan; Maywood, Elizabeth S; Hastings, Michael H

    2016-03-29

    The suprachiasmatic nucleus (SCN) is the master circadian clock controlling daily behavior in mammals. It consists of a heterogeneous network of neurons, in which cell-autonomous molecular feedback loops determine the period and amplitude of circadian oscillations of individual cells. In contrast, circuit-level properties of coherence, synchrony, and ensemble period are determined by intercellular signals and are embodied in a circadian wave of gene expression that progresses daily across the SCN. How cell-autonomous and circuit-level mechanisms interact in timekeeping is poorly understood. To explore this interaction, we used intersectional genetics to create temporally chimeric mice with SCN containing dopamine 1a receptor (Drd1a) cells with an intrinsic period of 24 h alongside non-Drd1a cells with 20-h clocks. Recording of circadian behavior in vivo alongside cellular molecular pacemaking in SCN slices in vitro demonstrated that such chimeric circuits form robust and resilient circadian clocks. It also showed that the computation of ensemble period is nonlinear. Moreover, the chimeric circuit sustained a wave of gene expression comparable to that of nonchimeric SCN, demonstrating that this circuit-level property is independent of differences in cell-intrinsic periods. The relative dominance of 24-h Drd1a and 20-h non-Drd1a neurons in setting ensemble period could be switched by exposure to resonant or nonresonant 24-h or 20-h lighting cycles. The chimeric circuit therefore reveals unanticipated principles of circuit-level operation underlying the emergent plasticity, resilience, and robustness of the SCN clock. The spontaneous and light-driven flexibility of period observed in chimeric mice provides a new perspective on the concept of SCN pacemaker cells. PMID:26966234

  18. Codon usage affects the structure and function of the Drosophila circadian clock protein PERIOD.

    PubMed

    Fu, Jingjing; Murphy, Katherine A; Zhou, Mian; Li, Ying H; Lam, Vu H; Tabuloc, Christine A; Chiu, Joanna C; Liu, Yi

    2016-08-01

    Codon usage bias is a universal feature of all genomes, but its in vivo biological functions in animal systems are not clear. To investigate the in vivo role of codon usage in animals, we took advantage of the sensitivity and robustness of the Drosophila circadian system. By codon-optimizing parts of Drosophila period (dper), a core clock gene that encodes a critical component of the circadian oscillator, we showed that dper codon usage is important for circadian clock function. Codon optimization of dper resulted in conformational changes of the dPER protein, altered dPER phosphorylation profile and stability, and impaired dPER function in the circadian negative feedback loop, which manifests into changes in molecular rhythmicity and abnormal circadian behavioral output. This study provides an in vivo example that demonstrates the role of codon usage in determining protein structure and function in an animal system. These results suggest a universal mechanism in eukaryotes that uses a codon usage "code" within genetic codons to regulate cotranslational protein folding. PMID:27542830

  19. The circadian clock gene period extends healthspan in aging Drosophila melanogaster

    PubMed Central

    Krishnan, Natraj; Kretzschmar, Doris; Rakshit, Kuntol; Chow, Eileen; Giebultowicz, Jadwiga M.

    2009-01-01

    There is increasing evidence that aging is affected by biological (circadian) clocks - the internal mechanisms that coordinate daily changes in gene expression, physiological functions and behavior with external day/night cycles. Recent data suggest that disruption of the mammalian circadian clock results in accelerated aging and increased age-related pathologies such as cancer; however, the links between loss of daily rhythms and aging are not understood. We sought to determine whether disruption of the circadian clock affects lifespan and healthspan in the model organism Drosophila melanogaster. We examined effects of a null mutation in the circadian clock gene period (per01) on the fly healthspan by challenging aging flies with short-term oxidative stress (24h hyperoxia) and investigating their response in terms of mortality hazard, levels of oxidative damage, and functional senescence. Exposure to 24h hyperoxia during middle age significantly shortened the life expectancy in per01 but not in control flies. This homeostatic challenge also led to significantly higher accumulation of oxidative damage in per01 flies compared to controls. In addition, aging per01 flies showed accelerated functional decline, such as lower climbing ability and increased neuronal degeneration compared to age-matched controls. Together, these data suggest that impaired stress defense pathways may contribute to accelerated aging in the per mutant. In addition, we show that the expression of per gene declines in old wild type flies, suggesting that the circadian regulatory network becomes impaired with age. PMID:20157575

  20. Melanopsin resets circadian rhythms in cells by inducing clock gene Period1

    NASA Astrophysics Data System (ADS)

    Yamashita, Shuhei; Uehara, Tomoe; Matsuo, Minako; Kikuchi, Yo; Numano, Rika

    2014-02-01

    The biochemical, physiological and behavioral processes are under the control of internal clocks with the period of approximately 24 hr, circadian rhythms. The expression of clock gene Period1 (Per1) oscillates autonomously in cells and is induced immediately after a light pulse. Per1 is an indispensable member of the central clock system to maintain the autonomous oscillator and synchronize environmental light cycle. Per1 expression could be detected by Per1∷luc and Per1∷GFP plasmid DNA in which firefly luciferase and Green Fluorescence Protein were rhythmically expressed under the control of the mouse Per1 promoter in order to monitor mammalian circadian rhythms. Membrane protein, MELANOPSIN is activated by blue light in the morning on the retina and lead to signals transduction to induce Per1 expression and to reset the phase of circadian rhythms. In this report Per1 induction was measured by reporter signal assay in Per1∷luc and Per1∷GFP fibroblast cell at the input process of circadian rhythms. To the result all process to reset the rhythms by Melanopsin is completed in single cell like in the retina projected to the central clock in the brain. Moreover, the phase of circadian rhythm in Per1∷luc cells is synchronized by photo-activated Melanopsin, because the definite peak of luciferase activity in one dish was found one day after light illumination. That is an available means that physiological circadian rhythms could be real-time monitor as calculable reporter (bioluminescent and fluorescent) chronological signal in both single and groups of cells.

  1. Chronic ethanol intake alters circadian phase shifting and free-running period in mice.

    PubMed

    Seggio, Joseph A; Fixaris, Michael C; Reed, Jeffrey D; Logan, Ryan W; Rosenwasser, Alan M

    2009-08-01

    Chronic alcohol intake is associated with widespread disruptions in sleep and circadian rhythms in both human alcoholics and in experimental animals. Recent studies have demonstrated that chronic and acute ethanol treatments alter fundamental properties of the circadian pacemaker--including free-running period and responsiveness to photic and nonphotic phase-shifting stimuli--in rats and hamsters. In the present work, the authors extend these observations to the C57BL/6J mouse, an inbred strain characterized by very high levels of voluntary ethanol intake and by reliable and stable free-running circadian activity rhythms. Mice were housed individually in running-wheel cages under conditions of either voluntary or forced ethanol intake, whereas controls were maintained on plain water. Forced ethanol intake significantly attenuated photic phase delays (but not phase advances) and shortened free-running period in constant darkness, but voluntary ethanol intake failed to affect either of these parameters. Thus, high levels of chronic ethanol intake, beyond those normally achieved under voluntary drinking conditions, are required to alter fundamental circadian pacemaker properties in C57BL/6J mice. These observations may be related to the relative ethanol insensitivity displayed by this strain in several other phenotypic domains, including ethanol-induced sedation, ataxia, and withdrawal. Additional experiments will investigate chronobiological sensitivity to ethanol in a range of inbred strains showing diverse ethanol-related phenotypes. PMID:19625732

  2. Chronic Ethanol Intake Alters Circadian Phase Shifting and Free-Running Period in Mice

    PubMed Central

    Seggio, Joseph A.; Fixaris, Michael C.; Reed, Jeffrey D.; Logan, Ryan W.; Rosenwasser, Alan M.

    2011-01-01

    Chronic alcohol intake is associated with widespread disruptions in sleep and circadian rhythms in both human alcoholics and in experimental animals. Recent studies have demonstrated that chronic and acute ethanol treatments alter fundamental properties of the circadian pacemaker—including free-running period and responsiveness to photic and nonphotic phase-shifting stimuli—in rats and hamsters. In the present work, the authors extend these observations to the C57BL/6J mouse, an inbred strain characterized by very high levels of voluntary ethanol intake and by reliable and stable free-running circadian activity rhythms. Mice were housed individually in running-wheel cages under conditions of either voluntary or forced ethanol intake, whereas controls were maintained on plain water. Forced ethanol intake significantly attenuated photic phase delays (but not phase advances) and shortened free-running period in constant darkness, but voluntary ethanol intake failed to affect either of these parameters. Thus, high levels of chronic ethanol intake, beyond those normally achieved under voluntary drinking conditions, are required to alter fundamental circadian pacemaker properties in C57BL/6J mice. These observations may be related to the relative ethanol insensitivity displayed by this strain in several other phenotypic domains, including ethanol-induced sedation, ataxia, and withdrawal. Additional experiments will investigate chronobiological sensitivity to ethanol in a range of inbred strains showing diverse ethanol-related phenotypes. PMID:19625732

  3. Dynamics of the circadian clock protein PERIOD2 in living cells.

    PubMed

    Öllinger, Rupert; Korge, Sandra; Korte, Thomas; Koller, Barbara; Herrmann, Andreas; Kramer, Achim

    2014-10-01

    In mammals, circadian rhythms are generated by delayed negative feedback, in which period (PER1-PER3) and cryptochrome (CRY1, CRY2) proteins gradually accumulate in the nucleus to suppress the transcription of their own genes. Although the importance of nuclear import and export signals for the subcellular localization of clock proteins is well established, little is known about the dynamics of these processes as well as their importance for the generation of circadian rhythms. We show by pharmacological perturbations of oscillating cells that nuclear import and export are of crucial importance for the circadian period. Live-cell fluorescence microscopy revealed that nuclear import of the key circadian protein PER2 is fast and further accelerated by CRY1. Moreover, PER2 nuclear import is crucially dependent on a specific nuclear-receptor-binding motif in PER2 that also mediates nuclear immobility. Nuclear export, however, is relatively slow, supporting a model of PER2 nuclear accumulation by rapid import, slow export and substantial nuclear degradation. PMID:25074809

  4. The negative transcription factor E4BP4 is associated with circadian clock protein PERIOD2.

    PubMed

    Ohno, Tomoya; Onishi, Yoshiaki; Ishida, Norio

    2007-03-23

    The bZIP transcription factor E4BP4, is a mammalian homologue of vrille that functions as a key negative component of the circadian clock. We have shown that the E4BP4-binding site (B-site) is required in addition to a non-canonical E-box (E2 enhancer) for robust circadian Period2 (Per2) expression in the cell-autonomous clock. While the E2 enhancer and the B-site are closely situated, correlations between each component bound to the E2 enhancer and the B-site remain obscure. Here, we show that E4BP4 interacts with PER2, which represses transcriptional activity via the E-box enhancer. Interaction with PER2 required the carboxyl-terminal region that contains the repression domain of E4BP4. We also found that E4BP4 interacts with CRYPTOCHROME2 (CRY2), a key negative regulator in the mammalian circadian clock. These results suggest that E4BP4 is a component of the negative regulator complex of mammalian circadian clocks. PMID:17274955

  5. An approximation to the temporal order in endogenous circadian rhythms of genes implicated in human adipose tissue metabolism

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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...

  6. Bidirectional Interactions between Circadian Entrainment and Cognitive Performance

    ERIC Educational Resources Information Center

    Gritton, Howard J.; Kantorowski, Ana; Sarter, Martin; Lee, Theresa M.

    2012-01-01

    Circadian rhythms influence a variety of physiological and behavioral processes; however, little is known about how circadian rhythms interact with the organisms' ability to acquire and retain information about their environment. These experiments tested whether rats trained outside their endogenous active period demonstrate the same rate of…

  7. A PERIOD3 variant causes a circadian phenotype and is associated with a seasonal mood trait.

    PubMed

    Zhang, Luoying; Hirano, Arisa; Hsu, Pei-Ken; Jones, Christopher R; Sakai, Noriaki; Okuro, Masashi; McMahon, Thomas; Yamazaki, Maya; Xu, Ying; Saigoh, Noriko; Saigoh, Kazumasa; Lin, Shu-Ting; Kaasik, Krista; Nishino, Seiji; Ptáček, Louis J; Fu, Ying-Hui

    2016-03-15

    In humans, the connection between sleep and mood has long been recognized, although direct molecular evidence is lacking. We identified two rare variants in the circadian clock gene PERIOD3 (PER3-P415A/H417R) in humans with familial advanced sleep phase accompanied by higher Beck Depression Inventory and seasonality scores. hPER3-P415A/H417R transgenic mice showed an altered circadian period under constant light and exhibited phase shifts of the sleep-wake cycle in a short light period (photoperiod) paradigm. Molecular characterization revealed that the rare variants destabilized PER3 and failed to stabilize PERIOD1/2 proteins, which play critical roles in circadian timing. Although hPER3-P415A/H417R-Tg mice showed a mild depression-like phenotype, Per3 knockout mice demonstrated consistent depression-like behavior, particularly when studied under a short photoperiod, supporting a possible role for PER3 in mood regulation. These findings suggest that PER3 may be a nexus for sleep and mood regulation while fine-tuning these processes to adapt to seasonal changes. PMID:26903630

  8. A PERIOD3 variant causes a circadian phenotype and is associated with a seasonal mood trait

    PubMed Central

    Zhang, Luoying; Hirano, Arisa; Hsu, Pei-Ken; Jones, Christopher R.; Sakai, Noriaki; Okuro, Masashi; McMahon, Thomas; Yamazaki, Maya; Xu, Ying; Saigoh, Noriko; Saigoh, Kazumasa; Lin, Shu-Ting; Kaasik, Krista; Nishino, Seiji; Ptáček, Louis J.; Fu, Ying-Hui

    2016-01-01

    In humans, the connection between sleep and mood has long been recognized, although direct molecular evidence is lacking. We identified two rare variants in the circadian clock gene PERIOD3 (PER3-P415A/H417R) in humans with familial advanced sleep phase accompanied by higher Beck Depression Inventory and seasonality scores. hPER3-P415A/H417R transgenic mice showed an altered circadian period under constant light and exhibited phase shifts of the sleep-wake cycle in a short light period (photoperiod) paradigm. Molecular characterization revealed that the rare variants destabilized PER3 and failed to stabilize PERIOD1/2 proteins, which play critical roles in circadian timing. Although hPER3-P415A/H417R-Tg mice showed a mild depression-like phenotype, Per3 knockout mice demonstrated consistent depression-like behavior, particularly when studied under a short photoperiod, supporting a possible role for PER3 in mood regulation. These findings suggest that PER3 may be a nexus for sleep and mood regulation while fine-tuning these processes to adapt to seasonal changes. PMID:26903630

  9. Physiology of circadian entrainment.

    PubMed

    Golombek, Diego A; Rosenstein, Ruth E

    2010-07-01

    Mammalian circadian rhythms are controlled by endogenous biological oscillators, including a master clock located in the hypothalamic suprachiasmatic nuclei (SCN). Since the period of this oscillation is of approximately 24 h, to keep synchrony with the environment, circadian rhythms need to be entrained daily by means of Zeitgeber ("time giver") signals, such as the light-dark cycle. Recent advances in the neurophysiology and molecular biology of circadian rhythmicity allow a better understanding of synchronization. In this review we cover several aspects of the mechanisms for photic entrainment of mammalian circadian rhythms, including retinal sensitivity to light by means of novel photopigments as well as circadian variations in the retina that contribute to the regulation of retinal physiology. Downstream from the retina, we examine retinohypothalamic communication through neurotransmitter (glutamate, aspartate, pituitary adenylate cyclase-activating polypeptide) interaction with SCN receptors and the resulting signal transduction pathways in suprachiasmatic neurons, as well as putative neuron-glia interactions. Finally, we describe and analyze clock gene expression and its importance in entrainment mechanisms, as well as circadian disorders or retinal diseases related to entrainment deficits, including experimental and clinical treatments. PMID:20664079

  10. Relationship of endogenous circadian melatonin and temperature rhythms to self-reported preference for morning or evening activity in young and older people

    NASA Technical Reports Server (NTRS)

    Duffy, J. F.; Dijk, D. J.; Hall, E. F.; Czeisler, C. A.

    1999-01-01

    BACKGROUND: Morningness-eveningness refers to interindividual differences in preferred timing of behavior (i.e., bed and wake times). Older people have earlier wake times and rate themselves as more morning-like than young adults. It has been reported that the phase of circadian rhythms is earlier in morning-types than in evening types, and that older people have earlier phases than young adults. These changes in phase have been considered to be the chronobiological basis of differences in preferred bed and wake times and age-related changes therein. Whether such differences in phase are associated with changes in the phase relationship between endogenous circadian rhythms and the sleep-wake cycle has not been investigated previously. METHODS: We investigated the association between circadian phase, the phase relationship between the sleep-wake cycle and circadian rhythms, and morningness-eveningness, and their interaction with aging. In this circadian rhythm study, 68 young and 40 older subjects participated. RESULTS: Among the young subjects, the phase of the melatonin and core temperature rhythms occurred earlier in morning than in evening types and the interval between circadian phase and usual wake time was longer in morning types. Thus, while evening types woke at a later clock hour than morning types, morning types actually woke at a later circadian phase. Comparing young and older morning types we found that older morning types had an earlier circadian phase and a shorter phase-wake time interval. The shorter phase-waketime interval in older "morning types" is opposite to the change associated with morningness in young people, and is more similar to young evening types. CONCLUSIONS: These findings demonstrate an association between circadian phase, the relationship between the sleep-wake cycle and circadian phase, and morningness-eveningness in young adults. Furthermore, they demonstrate that age-related changes in phase angle cannot be attributed fully to

  11. IA Channels Encoded by Kv1.4 and Kv4.2 Regulate Circadian Period of PER2 Expression in the Suprachiasmatic Nucleus

    PubMed Central

    Granados-Fuentes, Daniel; Hermanstyne, Tracey O.; Carrasquillo, Yarimar; Nerbonne, Jeanne M.; Herzog, Erik D.

    2016-01-01

    Neurons in the suprachiasmatic nucleus (SCN), the master circadian pacemaker in mammals, display daily rhythms in electrical activity with more depolarized resting potentials and higher firing rates during the day than at night. Although these daily variations in the electrical properties of SCN neurons are required for circadian rhythms in physiology and behavior, the mechanisms linking changes in neuronal excitability to the molecular clock are not known. Recently, we reported that mice deficient for either Kcna4 (Kv1.4−/−) or Kcnd2 (Kv4.2−/−; but not Kcnd3, Kv4.3−/−), voltage-gated K+ (Kv) channel poreforming subunits that encode subthreshold, rapidly activating, and inactivating K+ currents (IA), have shortened (0.5 h) circadian periods in SCN firing and in locomotor activity compared with wild-type (WT) mice. In the experiments here, we used a mouse (Per2Luc) line engineered with a bioluminescent reporter construct, PERIOD2::LUCIFERASE (PER2::LUC), replacing the endogenous Per2 locus, to test the hypothesis that the loss of Kv1.4- or Kv4.2-encoded IA channels also modifies circadian rhythms in the expression of the clock protein PERIOD2 (PER2). We found that SCN explants from Kv1.4−/−Per2Luc and Kv4.2−/−Per2Luc, but not Kv4.3−/−Per2Luc, mice have significantly shorter (by approximately 0.5 h) circadian periods in PER2 rhythms, compared with explants from Per2Luc mice, revealing that the membrane properties of SCN neurons feedback to regulate clock (PER2) expression. The combined loss of both Kv1.4- and Kv4.2-encoded IA channels in Kv1.4−/−/Kv4.2−/−Per2Luc SCN explants did not result in any further alterations in PER2 rhythms. Interestingly, however, mice lacking both Kv1.4 and Kv4.2 show a striking (approximately 1.8 h) advance in their daily activity onset in a light cycle compared with WT mice, suggesting additional roles for Kv1.4- and Kv4.2-encoded IA channels in controlling the light-dependent responses of neurons within

  12. Explaining the sawtooth: latitudinal periodicity in a circadian gene correlates with shifts in generation number.

    PubMed

    Levy, R C; Kozak, G M; Wadsworth, C B; Coates, B S; Dopman, E B

    2015-01-01

    Many temperate insects take advantage of longer growing seasons at lower latitudes by increasing their generation number or voltinism. In some insects, development time abruptly decreases when additional generations are fit into the season. Consequently, latitudinal 'sawtooth' clines associated with shifts in voltinism are seen for phenotypes correlated with development time, like body size. However, latitudinal variation in voltinism has not been linked to genetic variation at specific loci. Here, we show a pattern in allele frequency among voltinism ecotypes of the European corn borer moth (Ostrinia nubilalis) that is reminiscent of a sawtooth cline. We characterized 145 autosomal and sex-linked SNPs and found that period, a circadian gene that is genetically linked to a major QTL determining variation in post-diapause development time, shows cyclical variation between voltinism ecotypes. Allele frequencies at an unlinked circadian clock gene cryptochrome1 were correlated with period. These results suggest that selection on development time to 'fit' complete life cycles into a latitudinally varying growing season produces oscillations in alleles associated with voltinism, primarily through changes at loci underlying the duration of transitions between diapause and other life history phases. Correlations among clock loci suggest possible coupling between the circadian clock and the circannual rhythms for synchronizing seasonal life history. We anticipate that latitudinal oscillations in allele frequency will represent signatures of adaptation to seasonal environments in other insects and may be critical to understanding the ecological and evolutionary consequences of variable environments, including response to global climate change. PMID:25430782

  13. ATAXIN-2 activates PERIOD translation to sustain circadian rhythms in Drosophila.

    PubMed

    Lim, Chunghun; Allada, Ravi

    2013-05-17

    Evidence for transcriptional feedback in circadian timekeeping is abundant, yet little is known about the mechanisms underlying translational control. We found that ATAXIN-2 (ATX2), an RNA-associated protein involved in neurodegenerative disease, is a translational activator of the rate-limiting clock component PERIOD (PER) in Drosophila. ATX2 specifically interacted with TWENTY-FOUR (TYF), an activator of PER translation. RNA interference-mediated depletion of Atx2 or the expression of a mutant ATX2 protein that does not associate with polyadenylate-binding protein (PABP) suppressed behavioral rhythms and decreased abundance of PER. Although ATX2 can repress translation, depletion of Atx2 from Drosophila S2 cells inhibited translational activation by RNA-tethered TYF and disrupted the association between TYF and PABP. Thus, ATX2 coordinates an active translation complex important for PER expression and circadian rhythms. PMID:23687047

  14. period-1 encodes an ATP-dependent RNA helicase that influences nutritional compensation of the Neurospora circadian clock

    SciTech Connect

    Emerson, Jillian M.; Bartholomai, Bradley M.; Ringelberg, Carol; Baker, Scott E.; Loros, Jennifer J.; Dunlap, Jay C.

    2015-12-22

    Mutants in the period-1 (prd-1) gene, characterized by a recessive allele, display a reduced growth rate and period lengthening of the developmental cycle controlled by the circadian clock. We refined the genetic location of prd-1 and used whole genome sequencing to find the mutation defining it, confirming the identity of prd-1 by rescuing the mutant circadian phenotype via transformation. PRD-1 is an RNA helicase whose orthologs, DDX5 and DDX17 in humans and Dbp2p in yeast, are implicated in various processes including transcriptional regulation, elongation, and termination, 23 ribosome biogenesis, and RNA decay. Although prdi-1smutantssiois an ATP-dependent RNA helicase, member of a sub-family display a long period (~25 hrs) circadian developmental cycle, they interestingly display a wild type period when the core circadian oscillator is tracked using a frq-luciferase transcriptional fusion under conditions of limiting nutritional carbon; the core oscillator runs with a long period under glucose-sufficient conditions. Thus PRD-1 clearly impacts the circadian oscillator and is not only part of a metabolic oscillator ancillary to the core clock. PRD-1 is an essential protein and its expression is neither light-regulated nor clock-regulated. However, it is transiently induced by glucose; in the presence of sufficient glucose PRD-1 is in the nucleus until glucose runs out which elicits its disappearance from the nucleus. Because circadian period length is carbon concentration-dependent, prd­-1 may be formally viewed as clock mutant with defective nutritional compensation of circadian period length.

  15. period-1 encodes an ATP-dependent RNA helicase that influences nutritional compensation of the Neurospora circadian clock

    PubMed Central

    Emerson, Jillian M.; Bartholomai, Bradley M.; Ringelberg, Carol S.; Baker, Scott E.; Loros, Jennifer J.; Dunlap, Jay C.

    2015-01-01

    Mutants in the period-1 (prd-1) gene, characterized by a recessive allele, display a reduced growth rate and period lengthening of the developmental cycle controlled by the circadian clock. We refined the genetic location of prd-1 and used whole genome sequencing to find the mutation defining it, confirming the identity of prd-1 by rescuing the mutant circadian phenotype via transformation. PRD-1 is an RNA helicase whose orthologs, DDX5 [DEAD (Asp-Glu-Ala-Asp) Box Helicase 5] and DDX17 in humans and DBP2 (Dead Box Protein 2) in yeast, are implicated in various processes, including transcriptional regulation, elongation, and termination, ribosome biogenesis, and mRNA decay. Although prd-1 mutants display a long period (∼25 h) circadian developmental cycle, they interestingly display a WT period when the core circadian oscillator is tracked using a frq-luciferase transcriptional fusion under conditions of limiting nutritional carbon; the core oscillator in the prd-1 mutant strain runs with a long period under glucose-sufficient conditions. Thus, PRD-1 clearly impacts the circadian oscillator and is not only part of a metabolic oscillator ancillary to the core clock. PRD-1 is an essential protein, and its expression is neither light-regulated nor clock-regulated. However, it is transiently induced by glucose; in the presence of sufficient glucose, PRD-1 is in the nucleus until glucose runs out, which elicits its disappearance from the nucleus. Because circadian period length is carbon concentration-dependent, prd-1 may be formally viewed as a clock mutant with defective nutritional compensation of circadian period length. PMID:26647184

  16. Molecular Mechanisms that Regulate the Coupled Period of the Mammalian Circadian Clock

    NASA Astrophysics Data System (ADS)

    Kim, Jae Kyoung; Kilpatrick, Zachary P.; Bennett, Matthew R.; Josić, Krešimir

    2014-05-01

    In mammals, most cells in the brain and peripheral tissues generate circadian (~24hr) rhythms autonomously. These self-sustained rhythms are coordinated and entrained by a master circadian clock in the suprachiasmatic nucleus (SCN). Within the SCN, the individual rhythms of each neuron are synchronized through intercellular signaling. One important feature of SCN is that the synchronized period is close to the cell population mean of intrinsic periods. In this way, the synchronized period of the SCN stays close to the periods of cells in peripheral tissues. This is important for SCN to entrain cells throughout the body. However, the mechanism that drives the period of the coupled SCN cells to the population mean is not known. We use mathematical modeling and analysis to show that the mechanism of transcription repression plays a pivotal role in regulating the coupled period. Specifically, we use phase response curve analysis to show that the coupled period within the SCN stays near the population mean if transcriptional repression occurs via protein sequestration. In contrast, the coupled period is far from the mean if repression occurs through highly nonlinear Hill-type regulation (e.g. oligomer- or phosphorylation-based repression). Furthermore, we find that the timescale of intercellular coupling needs to be fast compared to that of intracellular feedback to maintain the mean period. These findings reveal the important relationship between the intracellular transcriptional feedback loop and intercellular coupling. This relationship explains why transcriptional repression appears to occur via protein sequestration in multicellular organisms, mammals and Drosophila, in contrast with the phosphorylation-based repression in unicellular organisms. That is, transition to protein sequestration is essential for synchronizing multiple cells with a period close to the population mean (~24hr).

  17. Extrinsic light:dark cycles, rather than endogenous circadian cycles, affect the photoperiodic counter in the pitcher-plant mosquito, Wyeomyia smithii.

    PubMed

    Emerson, Kevin J; Letaw, Alathea D; Bradshaw, William E; Holzapfel, Christina M

    2008-07-01

    A wide diversity of organisms use photoperiod (daylength) as an environmental cue to anticipate the changing seasons and to time various life-history events such as dormancy and migration. Photoperiodic time measurement consists of two main components, (1) the photoperiodic timer that discriminates between long and short days, and (2) the photoperiodic counter that accumulates and stores information from the timer and then induces the phenotypic output. Herein, we use extended night treatments to show that light is necessary to accumulate photoperiodic information across the geographic range of the mosquito, Wyeomyia smithii and that the photoperiodic counter counts extrinsic (external) light:dark cycles and not endogenous (internal) circadian cycles. PMID:18427810

  18. Extrinsic light:dark cycles, rather than endogenous circadian cycles, affect the photoperiodic counter in the pitcher-plant mosquito, Wyeomyia smithii

    PubMed Central

    Emerson, Kevin J.; Letaw, Alathea D.; Bradshaw, William E.; Holzapfel, Christina M.

    2014-01-01

    A wide diversity of organisms use photoperiod (daylength) as an environmental cue to anticipate the changing seasons and to time various life-history events such as dormancy and migration. Photoperiodic time measurement consists of two main components, (1) the photoperiodic timer that discriminates between long and short days, and (2) the photoperiodic counter that accumulates and stores information from the timer and then induces the phenotypic output. Herein, we use extended night treatments to show that light is necessary to accumulate photoperiodic information across the geographic range of the mosquito, Wyeomyia smithii and that the photoperiodic counter counts extrinsic (external) light:dark cycles and not endogenous (internal) circadian cycles. PMID:18427810

  19. Selective serotonin reuptake inhibitors and raft inhibitors shorten the period of Period1-driven circadian bioluminescence rhythms in rat-1 fibroblasts.

    PubMed

    Nomura, Kazumi; Castanon-Cervantes, Oscar; Davidson, Alec; Fukuhara, Chiaki

    2008-06-01

    Alterations in circadian rhythm generation may be related to the development of mood disorders. Although it has been reported that the most popular antidepressant, selective serotonin reuptake inhibitors (SSRIs) affect circadian phase, no data are available that describe the effects of SSRIs on other circadian parameters (period, amplitude and damping rate) in dissociated cells. In the present study we used real-time monitoring of bioluminescence in rat-1 fibroblasts expressing the Period1-luciferase transgene, and that in Period1-luciferase transgenic mouse suprachiasmatic nucleus (SCN) explants, in order to characterize the effects of SSRI on circadian oscillator function in vitro. We found that mRNA of the serotonin transporter (SERT), a target of SSRIs, was expressed in rat-1 fibroblasts. Sertraline, fluoxetine, fluvoxamine, citalopram and paroxetine all significantly shortened the period of Period1-bioluminescence rhythms in rat-1 fibroblasts. The amplitude was reduced by sertraline, and the damping rate was decreased by sertraline, fluoxetine, flvoxamine and paroxetine. The effect of sertraline was dose-dependent, and it also shortened the circadian period in the SCN. SERT is associated with lipid microdomains, which are required for efficient SERT activity. Indeed, cholesterol chelating reagent methyl-beta-cyclodextrin significantly reduced the period and the amplitude in rat-1 fibroblasts. Furthermore, lipid binding reagent xylazine significantly reduced the period. In summary our data present evidence that SSRIs affect circadian rhythmicity. The action of SSRIs is likely mediated by suppression of SERT activity. A better understanding of the relationship between mental illness and biological timing may yield new insight into disease etiology and avenues for treatment. PMID:18482738

  20. Postoperative circadian disturbances.

    PubMed

    Gögenur, Ismail

    2010-12-01

    An increasing number of studies have shown that circadian variation in the excretion of hormones, the sleep wake circle, the core body temperature rhythm, the tone of the autonomic nervous system and the activity rhythm are important both in health and in disease processes. An increasing attention has also been directed towards the circadian variation in endogenous rhythms in relation to surgery. The attention has been directed to the question whether the circadian variation in endogenous rhythms can affect postoperative recovery, morbidity and mortality. Based on the lack of studies where these endogenous rhythms have been investigated in relation to surgery we performed a series of studies exploring different endogenous rhythms and factors affecting these rhythms. We also wanted to examine whether the disturbances in the postoperative circadian rhythms could be correlated to postoperative recovery parameters, and if pharmacological administration of chronobiotics could improve postoperative recovery. Circadian rhythm disturbances were found in all the examined endogenous rhythms. A delay was found in the endogenous rhythm of plasma melatonin and excretion of the metabolite of melatonin (AMT6s) in urine the first night after both minor and major surgery. This delay after major surgery was correlated to the duration of surgery. The amplitude in the melatonin rhythm was unchanged the first night but increased in the second night after major surgery. The amplitude in AMT6s was reduced the first night after minimally invasive surgery. The core body temperature rhythm was disturbed after both major and minor surgery. There was a change in the sleep wake cycle with a significantly increased duration of REM-sleep in the day and evening time after major surgery compared with preoperatively. There was also a shift in the autonomic nervous balance after major surgery with a significantly increased number of myocardial ischaemic episodes during the nighttime period. The

  1. The frequency of hippocampal theta rhythm is modulated on a circadian period and is entrained by food availability

    PubMed Central

    Munn, Robert G. K.; Tyree, Susan M.; McNaughton, Neil; Bilkey, David K.

    2015-01-01

    The hippocampal formation plays a critical role in the generation of episodic memory. While the encoding of the spatial and contextual components of memory have been extensively studied, how the hippocampus encodes temporal information, especially at long time intervals, is less well understood. The activity of place cells in hippocampus has previously been shown to be modulated at a circadian time-scale, entrained by a behavioral stimulus, but not entrained by light. The experimental procedures used in the previous study of this phenomenon, however, necessarily conflated two alternative entraining stimuli, the exposure to the recording environment and the availability of food, making it impossible to distinguish between these possibilities. Here we demonstrate that the frequency of theta-band hippocampal EEG varies with a circadian period in freely moving animals and that this periodicity mirrors changes in the firing rate of hippocampal neurons. Theta activity serves, therefore, as a proxy of circadian-modulated hippocampal neuronal activity. We then demonstrate that the frequency of hippocampal theta driven by stimulation of the reticular formation also varies with a circadian period. Because this effect can be observed without having to feed the animal to encourage movement we were able to identify what stimulus entrains the circadian oscillation. We show that with reticular-activated recordings started at various times of the day the frequency of theta varies quasi-sinusoidally with a 25 h period and phase-aligned when referenced to the animal’s regular feeding time, but not the recording start time. Furthermore, we show that theta frequency consistently varied with a circadian period when the data obtained from repeated recordings started at various times of the day were referenced to the start of food availability in the recording chamber. This pattern did not occur when data were referenced to the start of the recording session or to the actual time of

  2. CUL1 Regulates TOC1 Protein Stability in the Arabidopsis Circadian Clock

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The circadian clock is the endogenous timer that coordinates physiological processes with daily and seasonal environmental changes. In Arabidopsis thaliana, establishment of the circadian period relies on targeted degradation of TIMING OF CAB EXPRESSION 1 (TOC1) by the 26S proteasome. ZEITLUPE (ZTL)...

  3. The circadian system in Alzheimer's disease: disturbances, mechanisms, and opportunities.

    PubMed

    Coogan, Andrew N; Schutová, Barbora; Husung, Susanne; Furczyk, Karolina; Baune, Bernhard T; Kropp, Peter; Häßler, Frank; Thome, Johannes

    2013-09-01

    Alzheimer's disease (AD) is a devastating neurodegenerative condition associated with severe cognitive and behavioral impairments. Circadian rhythms are recurring cycles that display periods of approximately 24 hours and are driven by an endogenous circadian timekeeping system centered on the suprachiasmatic nucleus of the hypothalamus. We review the compelling evidence that circadian rhythms are significantly disturbed in AD and that such disturbance is of significant clinical importance in terms of behavioral symptoms. We also detail findings from neuropathological studies of brain areas associated with the circadian system in postmortem studies, the use of animal models of AD in the investigation of circadian processes, and the evidence that chronotherapeutic approaches aimed at bolstering weakened circadian rhythms in AD produce beneficial outcomes. We argue that further investigation in such areas is warranted and highlight areas for future research that might prove fruitful in ultimately providing new treatment options for this most serious and intractable of conditions. PMID:23273723

  4. Length polymorphism in the Period 3 gene is associated with sleepiness and maladaptive circadian phase in night-shift workers.

    PubMed

    Drake, Christopher L; Belcher, Ren; Howard, Ryan; Roth, Thomas; Levin, Albert M; Gumenyuk, Valentina

    2015-06-01

    The objective of the current study was to determine if night-shift workers carrying the five-repeat variant of the Period 3 gene show elevated levels of nocturnal sleepiness and earlier circadian phase compared with homozygotes for the four-repeat allele. Twenty-four permanent night-shift workers were randomly selected from a larger study. Participants took part in an observational laboratory protocol including an overnight multiple sleep latency test and half-hourly saliva collection for calculation of dim-light melatonin onset. Period 3(-/5) shift workers had significantly lower multiple sleep latency test during overnight work hours compared with Period 3(4/4) workers (3.52 ± 23.44 min versus 10.39 ± 6.41 min, P = 0.003). We observed no significant difference in sleepiness during early morning hours following acute sleep deprivation. Long-allele carriers indicated significantly higher sleepiness on the Epworth Sleepiness Scale administered at 17:00 hours (12.08 ± 2.55 versus 8.00 ± 1.94, P < 0.001). We observed a significantly earlier melatonin onset in Period 3(-/5) individuals compared with Period 3(4/4) shift workers (20:44 ± 6:37 versus 02:46 ± 4:58, P = 0.021). Regression analysis suggests that Period 3 genotype independently predicts sleepiness even after controlling for variations in circadian phase, but we were unable to link Period 3 to circadian phase when controlling for sleepiness. Period 3(-/5) shift workers showed both subjective and objective sleepiness in the pathological range, while their Period 3(4/4) counterparts showed sleepiness within normal limits. Period 3(-/5) night workers also show a mean circadian phase 6 h earlier (i.e. less adapted) than Period 3(4/4) workers. Because Period 3(-/5) workers have maladaptive circadian phase as well as pathological levels of sleepiness, they may be at greater risk for occupational and automotive accidents. We interpret these findings as a call for future research on the role of Period 3 in

  5. Early doors (Edo) mutant mouse reveals the importance of period 2 (PER2) PAS domain structure for circadian pacemaking

    PubMed Central

    Militi, Stefania; Maywood, Elizabeth S.; Sandate, Colby R.; Chesham, Johanna E.; Parsons, Michael J.; Vibert, Jennifer L.; Joynson, Greg M.; Partch, Carrie L.; Hastings, Michael H.; Nolan, Patrick M.

    2016-01-01

    The suprachiasmatic nucleus (SCN) defines 24 h of time via a transcriptional/posttranslational feedback loop in which transactivation of Per (period) and Cry (cryptochrome) genes by BMAL1–CLOCK complexes is suppressed by PER–CRY complexes. The molecular/structural basis of how circadian protein complexes function is poorly understood. We describe a novel N-ethyl-N-nitrosourea (ENU)-induced mutation, early doors (Edo), in the PER-ARNT-SIM (PAS) domain dimerization region of period 2 (PER2) (I324N) that accelerates the circadian clock of Per2Edo/Edo mice by 1.5 h. Structural and biophysical analyses revealed that Edo alters the packing of the highly conserved interdomain linker of the PER2 PAS core such that, although PER2Edo complexes with clock proteins, its vulnerability to degradation mediated by casein kinase 1ε (CSNK1E) is increased. The functional relevance of this mutation is revealed by the ultrashort (<19 h) but robust circadian rhythms in Per2Edo/Edo; Csnk1eTau/Tau mice and the SCN. These periods are unprecedented in mice. Thus, Per2Edo reveals a direct causal link between the molecular structure of the PER2 PAS core and the pace of SCN circadian timekeeping. PMID:26903623

  6. In vitro and in vivo Phase Changes of the Mouse Circadian Clock by Oxidative Stress

    PubMed Central

    Tahara, Yu; Yokota, Aya; Shiraishi, Takuya; Yamada, Shunya; Haraguchi, Atsushi; Shinozaki, Ayako

    2016-01-01

    Mammalian circadian rhythms are governed by an endogenous circadian clock system, including the molecular clock works in each cell and tissue. Adaptation of the circadian clock to different environmental stimuli such as light, food, and stress is essential for homeostasis maintenance. However, the influence of oxidative stress on the circadian clock phase is not fully understood in vitro and in vivo. Here, we examined the effects of hydrogen peroxide (H2O2)-induced oxidative stress on the PERIOD2::LUCIFERASE bioluminescence rhythm in mouse embryonic fibroblasts in vitro and in mouse peripheral tissues in vivo. The circadian clock phase changed with the dose of H2O2 and time of day in vitro; similar phase changes were observed in vivo in the circadian clocks of the peripheral tissues. In addition, mice treated with hemin-induced oxidative stress also showed phase changes of peripheral clocks, similarly as H2O2 treatment. Thus, oxidative stress can entrain circadian clock systems.

  7. Molecular assembly of the period-cryptochrome circadian transcriptional repressor complex

    PubMed Central

    Nangle, Shannon N; Rosensweig, Clark; Koike, Nobuya; Tei, Hajime; Takahashi, Joseph S; Green, Carla B; Zheng, Ning

    2014-01-01

    The mammalian circadian clock is driven by a transcriptional–translational feedback loop, which produces robust 24-hr rhythms. Proper oscillation of the clock depends on the complex formation and periodic turnover of the Period and Cryptochrome proteins, which together inhibit their own transcriptional activator complex, CLOCK-BMAL1. We determined the crystal structure of the CRY-binding domain (CBD) of PER2 in complex with CRY2 at 2.8 Å resolution. PER2-CBD adopts a highly extended conformation, embracing CRY2 with a sinuous binding mode. Its N-terminal end tucks into CRY adjacent to a large pocket critical for CLOCK-BMAL1 binding, while its C-terminal half flanks the CRY2 C-terminal helix and sterically hinders the recognition of CRY2 by the FBXL3 ubiquitin ligase. Unexpectedly, a strictly conserved intermolecular zinc finger, whose integrity is important for clock rhythmicity, further stabilizes the complex. Our structure-guided analyses show that these interspersed CRY-interacting regions represent multiple functional modules of PERs at the CRY-binding interface. DOI: http://dx.doi.org/10.7554/eLife.03674.001 PMID:25127877

  8. Effects of training periodization on cardiac autonomic modulation and endogenous stress markers in volleyball players.

    PubMed

    Mazon, J; Gastaldi, A; Di Sacco, T; Cozza, I; Dutra, S; Souza, H

    2013-02-01

    We investigated the effects of selective loads of periodization model (SLPM) on autonomic modulation of heart rate variability (HRV) and endogenous stress markers before and after a competition period in volleyball players (N=32). The experimental protocol for the evaluation of HRV consisted of using spectral analysis of time series composed of the R-R intervals derived from electrocardiogram obtained in the supine position and during the tilt test. Stress marker levels were determined by quantifying the plasma concentration of endogenous catecholamines, cortisol and free testosterone. The results showed no changes between the levels of HRV before and after a competition period. In contrast, the quantification of the plasma concentration of endogenous stress markers revealed reductions in the levels of total catecholamines, noradrenaline and cortisol. These changes were accompanied by increases in the concentration of free testosterone and in the testosterone/cortisol ratio. In conclusion, our results demonstrate that the SLPM did not change the cardiac autonomic modulation of HRV, but promoted beneficial adaptations in athletes, including positive changes in the plasma concentration of the endogenous stress markers. The absence of changes in HRV indicates that there is no direct relationship between cardiac autonomic modulation and endogenous stress markers in the present study. PMID:21812826

  9. Circadian pacemaker in the suprachiasmatic nuclei of teleost fish revealed by rhythmic period2 expression.

    PubMed

    Watanabe, Nanako; Itoh, Kae; Mogi, Makoto; Fujinami, Yuichiro; Shimizu, Daisuke; Hashimoto, Hiroshi; Uji, Susumu; Yokoi, Hayato; Suzuki, Tohru

    2012-09-01

    In mammals, the role of the suprachiasmatic nucleus (SCN) as the primary circadian clock that coordinates the biological rhythms of peripheral oscillators is well known. However, in teleosts, it remains unclear whether the SCN also functions as a circadian pacemaker. We used in situ hybridization (ISH) techniques to demonstrate that the molecular clock gene, per2, is expressed in the SCN of flounder (Paralichthys olivaceus) larvae during the day and down-regulated at night, demonstrating that a circadian pacemaker exists in the SCN of this teleost. The finding that per2 expression in the SCN was also observed in the amberjack (Seriola dumerili), but not in medaka (Oryzias latipes), implies that interspecific variation exists in the extent to which the SCN controls the circadian rhythms of fish species, presumably reflecting their lifestyle. Rhythmic per2 expression was also detected in the pineal gland and pituitary, and aperiodic per2 expression was observed in the habenula, which is known to exhibit circadian rhythms in rodents. Since the ontogeny of per2 expression in the brain of early flounder larvae can be monitored by whole mount ISH, it is possible to investigate the effects of drugs and environmental conditions on the functional development of circadian clocks in the brain of fish larvae. In addition, flounder would be a good model for understanding the rhythmicity of marine fish. Our findings open a new frontier for investigating the role of the SCN in teleost circadian rhythms. PMID:22732079

  10. Timing Matters: Circadian Rhythm in Sepsis, Obstructive Lung Disease, Obstructive Sleep Apnea, and Cancer.

    PubMed

    Truong, Kimberly K; Lam, Michael T; Grandner, Michael A; Sassoon, Catherine S; Malhotra, Atul

    2016-07-01

    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. PMID:27104378

  11. Expression of the circadian clock gene Period2 in the hippocampus: possible implications for synaptic plasticity and learned behaviour

    PubMed Central

    Wang, Louisa M-C; Dragich, Joanna M; Kudo, Takashi; Odom, Irene H; Welsh, David K; O'Dell, Thomas J; Colwell, Christopher S

    2009-01-01

    Genes responsible for generating circadian oscillations are expressed in a variety of brain regions not typically associated with circadian timing. The functions of this clock gene expression are largely unknown, and in the present study we sought to explore the role of the Per2 (Period 2) gene in hippocampal physiology and learned behaviour. We found that PER2 protein is highly expressed in hippocampal pyramidal cell layers and that the expression of both protein and mRNA varies with a circadian rhythm. The peaks of these rhythms occur in the late night or early morning and are almost 180° out-of-phase with the expression rhythms measured from the suprachiasmatic nucleus of the same animals. The rhythms in Per2 expression are autonomous as they are present in isolated hippocampal slices maintained in culture. Physiologically, Per2-mutant mice exhibit abnormal long-term potentiation. The underlying mechanism is suggested by the finding that levels of phosphorylated cAMP-response-element-binding protein, but not phosphorylated extracellular-signal-regulated kinase, are reduced in hippocampal tissue from mutant mice. Finally, Per2-mutant mice exhibit deficits in the recall of trace, but not cued, fear conditioning. Taken together, these results provide evidence that hippocampal cells contain an autonomous circadian clock. Furthermore, the clock gene Per2 may play a role in the regulation of long-term potentiation and in the recall of some forms of learned behaviour. PMID:19570032

  12. Period1 gates the circadian modulation of memory-relevant signaling in mouse hippocampus by regulating the nuclear shuttling of the CREB kinase pP90RSK.

    PubMed

    Rawashdeh, Oliver; Jilg, Antje; Maronde, Erik; Fahrenkrug, Jan; Stehle, Jörg H

    2016-09-01

    Memory performance varies over a 24-h day/night cycle. While the detailed underlying mechanisms are yet unknown, recent evidence suggests that in the mouse hippocampus, rhythmic phosphorylation of mitogen-activated protein kinase (MAPK) and cyclic adenosine monophosphate response element-binding protein (CREB) are central to the circadian (~ 24 h) regulation of learning and memory. We recently identified the clock protein PERIOD1 (PER1) as a vehicle that translates information encoding time of day to hippocampal plasticity. We here elaborate how PER1 may gate the sensitivity of memory-relevant hippocampal signaling pathways. We found that in wild-type mice (WT), spatial learning triggers CREB phosphorylation only during the daytime, and that this effect depends on the presence of PER1. The time-of-day-dependent induction of CREB phosphorylation can be reproduced pharmacologically in acute hippocampal slices prepared from WT mice, but is absent in preparations made from Per1-knockout (Per1(-/-) ) mice. We showed that the PER1-dependent CREB phosphorylation is regulated downstream of MAPK. Stimulation of WT hippocampal neurons triggered the co-translocation of PER1 and the CREB kinase pP90RSK (pMAPK-activated ribosomal S6 kinase) into the nucleus. In hippocampal neurons from Per1(-/-) mice, however, pP90RSK remained perinuclear. A co-immunoprecipitation assay confirmed a high-affinity interaction between PER1 and pP90RSK. Knocking down endogenous PER1 in hippocampal cells inhibited adenylyl cyclase-dependent CREB activation. Taken together, the PER1-dependent modulation of cytoplasmic-to-nuclear signaling in the murine hippocampus provides a molecular explanation for how the circadian system potentially shapes a temporal framework for daytime-dependent memory performance, and adds a novel facet to the versatility of the clock gene protein PER1. We provide evidence that the circadian clock gene Period1 (Per1) regulates CREB phosphorylation in the mouse hippocampus

  13. Circadian gene variants in cancer

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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...

  14. Genetic determinism of parasitic circadian periodicity and subperiodicity in human lymphatic filariasis.

    PubMed

    Pichon, Gaston; Treuil, Jean-Pierre

    2004-12-01

    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. PMID:15656351

  15. The Circadian Clock Gene Period1 Connects the Molecular Clock to Neural Activity in the Suprachiasmatic Nucleus

    PubMed Central

    Block, Gene D.; Colwell, Christopher S.

    2015-01-01

    The neural activity patterns of suprachiasmatic nucleus (SCN) neurons are dynamically regulated throughout the circadian cycle with highest levels of spontaneous action potentials during the day. These rhythms in electrical activity are critical for the function of the circadian timing system and yet the mechanisms by which the molecular clockwork drives changes in the membrane are not well understood. In this study, we sought to examine how the clock gene Period1 (Per1) regulates the electrical activity in the mouse SCN by transiently and selectively decreasing levels of PER1 through use of an antisense oligodeoxynucleotide. We found that this treatment effectively reduced SCN neural activity. Direct current injection to restore the normal membrane potential partially, but not completely, returned firing rate to normal levels. The antisense treatment also reduced baseline [Ca2+]i levels as measured by Fura2 imaging technique. Whole cell patch clamp recording techniques were used to examine which specific potassium currents were altered by the treatment. These recordings revealed that the large conductance [Ca2+]i-activated potassium currents were reduced in antisense-treated neurons and that blocking this current mimicked the effects of the anti-sense on SCN firing rate. These results indicate that the circadian clock gene Per1 alters firing rate in SCN neurons and raise the possibility that the large conductance [Ca2+]i-activated channel is one of the targets. PMID:26553726

  16. Circadian clock and cardiac vulnerability: A time stamp on multi-scale neuroautonomic regulation

    NASA Astrophysics Data System (ADS)

    Ivanov, Plamen Ch.

    2005-03-01

    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.

  17. Getting through to circadian oscillators: why use constant routines?

    NASA Technical Reports Server (NTRS)

    Duffy, Jeanne F.; Dijk, Derk-Jan

    2002-01-01

    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.

  18. Circadian influences on myocardial infarction.

    PubMed

    Virag, Jitka A I; Lust, Robert M

    2014-01-01

    Components of circadian rhythm maintenance, or "clock genes," are endogenous entrainable oscillations of about 24 h that regulate biological processes and are found in the suprachaismatic nucleus (SCN) and many peripheral tissues, including the heart. They are influenced by external cues, or Zeitgebers, such as light and heat, and can influence such diverse phenomena as cytokine expression immune cells, metabolic activity of cardiac myocytes, and vasodilator regulation by vascular endothelial cells. While it is known that the central master clock in the SCN synchronizes peripheral physiologic rhythms, the mechanisms by which the information is transmitted are complex and may include hormonal, metabolic, and neuronal inputs. Whether circadian patterns are causally related to the observed periodicity of events, or whether they are simply epi-phenomena is not well established, but a few studies suggest that the circadian effects likely are real in their impact on myocardial infarct incidence. Cycle disturbances may be harbingers of predisposition and subsequent response to acute and chronic cardiac injury, and identifying the complex interactions of circadian rhythms and myocardial infarction may provide insights into possible preventative and therapeutic strategies for susceptible populations. PMID:25400588

  19. Circadian influences on myocardial infarction

    PubMed Central

    Virag, Jitka A. I.; Lust, Robert M.

    2014-01-01

    Components of circadian rhythm maintenance, or “clock genes,” are endogenous entrainable oscillations of about 24 h that regulate biological processes and are found in the suprachaismatic nucleus (SCN) and many peripheral tissues, including the heart. They are influenced by external cues, or Zeitgebers, such as light and heat, and can influence such diverse phenomena as cytokine expression immune cells, metabolic activity of cardiac myocytes, and vasodilator regulation by vascular endothelial cells. While it is known that the central master clock in the SCN synchronizes peripheral physiologic rhythms, the mechanisms by which the information is transmitted are complex and may include hormonal, metabolic, and neuronal inputs. Whether circadian patterns are causally related to the observed periodicity of events, or whether they are simply epi-phenomena is not well established, but a few studies suggest that the circadian effects likely are real in their impact on myocardial infarct incidence. Cycle disturbances may be harbingers of predisposition and subsequent response to acute and chronic cardiac injury, and identifying the complex interactions of circadian rhythms and myocardial infarction may provide insights into possible preventative and therapeutic strategies for susceptible populations. PMID:25400588

  20. C-H activation generates period-shortening molecules that target cryptochrome in the mammalian circadian clock.

    PubMed

    Oshima, Tsuyoshi; Yamanaka, Iori; Kumar, Anupriya; Yamaguchi, Junichiro; Nishiwaki-Ohkawa, Taeko; Muto, Kei; Kawamura, Rika; Hirota, Tsuyoshi; Yagita, Kazuhiro; Irle, Stephan; Kay, Steve A; Yoshimura, Takashi; Itami, Kenichiro

    2015-06-01

    The synthesis and functional analysis of KL001 derivatives, which are modulators of the mammalian circadian clock, are described. By using cutting-edge C-H activation chemistry, a focused library of KL001 derivatives was rapidly constructed, which enabled the identification of the critical sites on KL001 derivatives that induce a rhythm-changing activity along with the components that trigger opposite modes of action. The first period-shortening molecules that target the cryptochrome (CRY) were thus discovered. Detailed studies on the effects of these compounds on CRY stability implicate the existence of an as yet undiscovered regulatory mechanism. PMID:25960183

  1. Cellular DBP and E4BP4 proteins are critical for determining the period length of the circadian oscillator.

    PubMed

    Yamajuku, Daisuke; Shibata, Yasutaka; Kitazawa, Masashi; Katakura, Toshie; Urata, Hiromi; Kojima, Tomoko; Takayasu, Satoko; Nakata, Osamu; Hashimoto, Seiichi

    2011-07-21

    The phenotypes of mice carrying clock gene mutations have been critical to understanding the mammalian clock function. However, behavior does not necessarily reflect cell-autonomous clock phenotypes, because of the hierarchical dominance of the central clock. We performed cell-based siRNA knockdown and cDNA overexpression and monitored rhythm using bioluminescent reporters of clock genes. We found that knockdown of DBP, D-box positive regulator, in our model led to a short-period phenotype, whereas overexpressing of DBP produced a long-period rhythm when compared to controls. Furthermore, knockdown and overexpressing of E4BP4, D-box negative regulator, led to an opposite effect of DBP. Our experiments demonstrated that D-box regulators play a crucial role in determining the period length of Per1 and Per2 promoter-driven circadian rhythms in Rat-1 fibroblasts. PMID:21635892

  2. Effect of Mefloquine, a Gap Junction Blocker, on Circadian Period2 Gene Oscillation in the Mouse Suprachiasmatic Nucleus Ex Vivo

    PubMed Central

    Koo, Jinmi; Choe, Han Kyoung; Kim, Hee-Dae; Chun, Sung Kook; Son, Gi Hoon

    2015-01-01

    Background In mammals, the master circadian pacemaker is localized in an area of the ventral hypothalamus known as the suprachiasmatic nucleus (SCN). Previous studies have shown that pacemaker neurons in the SCN are highly coupled to one another, and this coupling is crucial for intrinsic self-sustainability of the SCN central clock, which is distinguished from peripheral oscillators. One plausible mechanism underlying the intercellular communication may involve direct electrical connections mediated by gap junctions. Methods We examined the effect of mefloquine, a neuronal gap junction blocker, on circadian Period 2 (Per2) gene oscillation in SCN slice cultures prepared from Per2::luciferase (PER2::LUC) knock-in mice using a real-time bioluminescence measurement system. Results Administration of mefloquine causes instability in the pulse period and a slight reduction of amplitude in cyclic PER2::LUC expression. Blockade of gap junctions uncouples PER2::LUC-expressing cells, in terms of phase transition, which weakens synchrony among individual cellular rhythms. Conclusion These findings suggest that neuronal gap junctions play an important role in synchronizing the central pacemaker neurons and contribute to the distinct self-sustainability of the SCN master clock. PMID:25491783

  3. Identification of Light-Sensitive Phosphorylation Sites on PERIOD That Regulate the Pace of Circadian Rhythms in Drosophila.

    PubMed

    Yildirim, Evrim; Chiu, Joanna C; Edery, Isaac

    2016-03-01

    The main components regulating the pace of circadian (≅24 h) clocks in animals are PERIOD (PER) proteins, transcriptional regulators that undergo daily changes in levels and nuclear accumulation by means of complex multisite phosphorylation programs. In the present study, we investigated the function of two phosphorylation sites, at Ser826 and Ser828, located in a putative nuclear localization signal (NLS) on the Drosophila melanogaster PER protein. These sites are phosphorylated by DOUBLETIME (DBT; Drosophila homolog of CK1δ/ε), the key circadian kinase regulating the daily changes in PER stability and phosphorylation. Mutant flies in which phosphorylation at Ser826/Ser828 is blocked manifest behavioral rhythms with periods slightly longer than 1 h and with altered temperature compensation properties. Intriguingly, although phosphorylation at these sites does not influence PER stability, timing of nuclear entry, or transcriptional autoinhibition, the phospho-occupancy at Ser826/Ser828 is rapidly stimulated by light and blocked by TIMELESS (TIM), the major photosensitive clock component in Drosophila and a crucial binding partner of PER. Our findings identify the first phosphorylation sites on core clock proteins that are acutely regulated by photic cues and suggest that some phosphosites on PER proteins can modulate the pace of downstream behavioral rhythms without altering central aspects of the clock mechanism. PMID:26711257

  4. The Zebrafish Period2 Protein Positively Regulates the Circadian Clock through Mediation of Retinoic Acid Receptor (RAR)-related Orphan Receptor α (Rorα)*

    PubMed Central

    Wang, Mingyong; Zhong, Zhaomin; Zhong, Yingbin; Zhang, Wei; Wang, Han

    2015-01-01

    We report the characterization of a null mutant for zebrafish circadian clock gene period2 (per2) generated by transcription activator-like effector nuclease and a positive role of PER2 in vertebrate circadian regulation. Locomotor experiments showed that per2 mutant zebrafish display reduced activities under light-dark and 2-h phase delay under constant darkness, and quantitative real time PCR analyses showed up-regulation of cry1aa, cry1ba, cry1bb, and aanat2 but down-regulation of per1b, per3, and bmal1b in per2 mutant zebrafish, suggesting that Per2 is essential for the zebrafish circadian clock. Luciferase reporter assays demonstrated that Per2 represses aanat2 expression through E-box and enhances bmal1b expression through the Ror/Rev-erb response element, implicating that Per2 plays dual roles in the zebrafish circadian clock. Cell transfection and co-immunoprecipitation assays revealed that Per2 enhances bmal1b expression through binding to orphan nuclear receptor Rorα. The enhancing effect of mouse PER2 on Bmal1 transcription is also mediated by RORα even though it binds to REV-ERBα. Moreover, zebrafish Per2 also appears to have tissue-specific regulatory roles in numerous peripheral organs. These findings help define the essential functions of Per2 in the zebrafish circadian clock and in particular provide strong evidence for a positive role of PER2 in the vertebrate circadian system. PMID:25544291

  5. The Circadian Clock in Cancer Development and Therapy

    PubMed Central

    Fu, Loning; Kettner, Nicole M.

    2014-01-01

    Most aspects of mammalian function display circadian rhythms driven by an endogenous clock. The circadian clock is operated by genes and comprises a central clock in the brain that responds to environmental cues and controls subordinate clocks in peripheral tissues via circadian output pathways. The central and peripheral clocks coordinately generate rhythmic gene expression in a tissue-specific manner in vivo to couple diverse physiological and behavioral processes to periodic changes in the environment. However, as the world industrialized, activities that disrupt endogenous homeostasis with external circadian cues have increased. This change in lifestyle has been linked to increased risk of diseases in all aspects of human health, including cancer. Studies in humans and animal models have revealed that cancer development in vivo is closely associated with the loss of circadian homeostasis in energy balance, immune function and aging that are supported by cellular functions important for tumor suppression including cell proliferation, senescence, metabolism and DNA damage response. The clock controls these cellular functions both locally in cells of peripheral tissues and at the organismal level via extracellular signaling. Thus, the hierarchical mammalian circadian clock provides a unique system to study carcinogenesis as a deregulated physiological process in vivo. The asynchrony between host and malignant tissues in cell proliferation and metabolism also provides new and exciting options for novel anti-cancer therapies. PMID:23899600

  6. The mood stabilizer valproic acid opposes the effects of dopamine on circadian rhythms.

    PubMed

    Landgraf, Dominic; Joiner, William J; McCarthy, Michael J; Kiessling, Silke; Barandas, Rita; Young, Jared W; Cermakian, Nicolas; Welsh, David K

    2016-08-01

    Endogenous circadian (∼24 h) clocks regulate key physiological and cognitive processes via rhythmic expression of clock genes. The main circadian pacemaker is the hypothalamic suprachiasmatic nucleus (SCN). Mood disorders, including bipolar disorder (BD), are commonly associated with disturbed circadian rhythms. Dopamine (DA) contributes to mania in BD and has direct impact on clock gene expression. Therefore, we hypothesized that high levels of DA during episodes of mania contribute to disturbed circadian rhythms in BD. The mood stabilizer valproic acid (VPA) also affects circadian rhythms. Thus, we further hypothesized that VPA normalizes circadian disturbances caused by elevated levels of DA. To test these hypotheses, we examined locomotor rhythms and circadian gene cycling in mice with reduced expression of the dopamine transporter (DAT-KD mice), which results in elevated DA levels and mania-like behavior. We found that elevated DA signaling lengthened the circadian period of behavioral rhythms in DAT-KD mice and clock gene expression rhythms in SCN explants. In contrast, we found that VPA shortened circadian period of behavioral rhythms in DAT-KD mice and clock gene expression rhythms in SCN explants, hippocampal cell lines, and human fibroblasts from BD patients. Thus, DA and VPA have opposing effects on circadian period. To test whether the impact of VPA on circadian rhythms contributes to its behavioral effects, we fed VPA to DAT-deficient Drosophila with and without functioning circadian clocks. Consistent with our hypothesis, we found that VPA had potent activity-suppressing effects in hyperactive DAT-deficient flies with intact circadian clocks. However, these effects were attenuated in DAT-deficient flies in which circadian clocks were disrupted, suggesting that VPA functions partly through the circadian clock to suppress activity. Here, we provide in vivo and in vitro evidence across species that elevated DA signaling lengthens the circadian

  7. Association of the circadian factor Period 2 to p53 influences p53's function in DNA-damage signaling

    PubMed Central

    Gotoh, Tetsuya; Vila-Caballer, Marian; Liu, Jingjing; Schiffhauer, Samuel; Finkielstein, Carla V.

    2015-01-01

    Circadian period proteins influence cell division and death by associating with checkpoint components, although their mode of regulation has not been firmly established. hPer2 forms a trimeric complex with hp53 and its negative regulator Mdm2. In unstressed cells, this association leads to increased hp53 stability by blocking Mdm2-dependent ubiquitination and transcription of hp53 target genes. Because of the relevance of hp53 in checkpoint signaling, we hypothesize that hPer2 association with hp53 acts as a regulatory module that influences hp53's downstream response to genotoxic stress. Unlike the trimeric complex, whose distribution was confined to the nuclear compartment, hPer2/hp53 was identified in both cytosol and nucleus. At the transcriptional level, a reporter containing the hp21WAF1/CIP1 promoter, a target of hp53, remained inactive in cells expressing a stable form of the hPer2/hp53 complex even when treated with γ-radiation. Finally, we established that hPer2 directly acts on the hp53 node, as checkpoint components upstream of hp53 remained active in response to DNA damage. Quantitative transcriptional analyses of hp53 target genes demonstrated that unbound hp53 was absolutely required for activation of the DNA-damage response. Our results provide evidence of the mode by which the circadian tumor suppressor hPer2 modulates hp53 signaling in response to genotoxic stress. PMID:25411341

  8. Circadian Rhythms

    MedlinePlus

    ... 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 ...

  9. Influence of the autonomic nervous system on circadian patterns of myocardial ischaemia: comparison of stable angina with the early postinfarction period.

    PubMed Central

    Marchant, B.; Stevenson, R.; Vaishnav, S.; Wilkinson, P.; Ranjadayalan, K.; Timmis, A. D.

    1994-01-01

    OBJECTIVE--To compare the circadian rhythm of myocardial ischaemia in patients with stable angina with that in patients in the early postinfarction period with particular emphasis on the role of the autonomic nervous system. PATIENTS--44 patients with stable angina and ischaemia on treadmill testing (group A) were compared with 131 patients in the early postinfarction period (group B). All had 48 hour ambulatory Holter monitoring. SETTING--Coronary care unit and cardiology department of a district general hospital. DESIGN--Prospective, between group, comparative study. RESULTS--337 ischaemic episodes occurred in 35 patients in group A and 370 ischaemic episodes occurred in 65 patients in group B. 34% of patients in group A had only silent episodes of ischaemia compared with 97% in group B (p < 0.0001). In group A ischaemic episodes showed a circadian rhythm that peaked during the daytime hours (p < 0.0001), but this was not seen in group B. Both the high (0.15-0.40 Hz) and low (0.04-0.15 Hz) frequency spectral components of heart rate variability showed a clear circadian rhythm (p < 0.0001); peak values occurred during the sleeping hours, although this pattern was less pronounced in group B. The ratio of low to high frequency variability (a measure of sympathovagal balance) showed a peak in daytime hours in group A (p < 0.002), but this was not seen in group B. CONCLUSION--In stable angina, myocardial ischaemia peaks during the day and is associated with a similar circadian rhythm of sympathovagal balance. In the early postinfarction period both the ischaemic and sympathovagal rhythms are severely diminished or lost altogether. Circadian changes in sympathovagal tone may explain, at least in part, the circadian rhythm of ambulatory myocardial ischaemia in patients with stable angina. PMID:8198882

  10. Circadian Clocks and Metabolism

    PubMed Central

    Marcheva, Biliana; Ramsey, Kathryn M.; Peek, Clara B.; Affinati, Alison; Maury, Eleonore; Bass, Joseph

    2014-01-01

    Circadian clocks maintain periodicity in internal cycles of behavior, physiology, and metabolism, enabling organisms to anticipate the 24-h rotation of the Earth. In mammals, circadian integration of metabolic systems optimizes energy harvesting and utilization across the light/dark cycle. Disruption of clock genes has recently been linked to sleep disorders and to the development of cardiometabolic disease. Conversely, aberrant nutrient signaling affects circadian rhythms of behavior. This chapter reviews the emerging relationship between the molecular clock and metabolic systems and examines evidence that circadian disruption exerts deleterious consequences on human health. PMID:23604478

  11. Temperature compensation and entrainment in circadian rhythms

    NASA Astrophysics Data System (ADS)

    Bodenstein, C.; Heiland, I.; Schuster, S.

    2012-06-01

    To anticipate daily variations in the environment and coordinate biological activities into a daily cycle many organisms possess a circadian clock. In the absence of external time cues the circadian rhythm persists with a period of approximately 24 h. The clock phase can be shifted by single pulses of light, darkness, chemicals, or temperature and this allows entrainment of the clock to exactly 24 h by cycles of these zeitgebers. On the other hand, the period of the circadian rhythm is kept relatively constant within a physiological range of constant temperatures, which means that the oscillator is temperature compensated. The mechanisms behind temperature compensation and temperature entrainment are not fully understood, neither biochemically nor mathematically. Here, we theoretically investigate the interplay of temperature compensation and entrainment in general oscillatory systems. We first give an analytical treatment for small temperature shifts and derive that every temperature-compensated oscillator is entrainable to external small-amplitude temperature cycles. Temperature compensation ensures that this entrainment region is always centered at the endogenous period regardless of possible seasonal temperature differences. Moreover, for small temperature cycles the entrainment region of the oscillator is potentially larger for rectangular pulses. For large temperature shifts we numerically analyze different circadian clock models proposed in the literature with respect to these properties. We observe that for such large temperature shifts sinusoidal or gradual temperature cycles allow a larger entrainment region than rectangular cycles.

  12. Natural selection against a circadian clock gene mutation in mice

    PubMed Central

    Spoelstra, Kamiel; Wikelski, Martin; Daan, Serge; Loudon, Andrew S. I.; Hau, Michaela

    2016-01-01

    Circadian rhythms with an endogenous period close to or equal to the natural light–dark cycle are considered evolutionarily adaptive (“circadian resonance hypothesis”). Despite remarkable insight into the molecular mechanisms driving circadian cycles, this hypothesis has not been tested under natural conditions for any eukaryotic organism. We tested this hypothesis in mice bearing a short-period mutation in the enzyme casein kinase 1ε (tau mutation), which accelerates free-running circadian cycles. We compared daily activity (feeding) rhythms, survivorship, and reproduction in six replicate populations in outdoor experimental enclosures, established with wild-type, heterozygous, and homozygous mice in a Mendelian ratio. In the release cohort, survival was reduced in the homozygote mutant mice, revealing strong selection against short-period genotypes. Over the course of 14 mo, the relative frequency of the tau allele dropped from initial parity to 20%. Adult survival and recruitment of juveniles into the population contributed approximately equally to the selection for wild-type alleles. The expression of activity during daytime varied throughout the experiment and was significantly increased by the tau mutation. The strong selection against the short-period tau allele observed here contrasts with earlier studies showing absence of selection against a Period 2 (Per2) mutation, which disrupts internal clock function, but does not change period length. These findings are consistent with, and predicted by the theory that resonance of the circadian system plays an important role in individual fitness. PMID:26715747

  13. Natural selection against a circadian clock gene mutation in mice.

    PubMed

    Spoelstra, Kamiel; Wikelski, Martin; Daan, Serge; Loudon, Andrew S I; Hau, Michaela

    2016-01-19

    Circadian rhythms with an endogenous period close to or equal to the natural light-dark cycle are considered evolutionarily adaptive ("circadian resonance hypothesis"). Despite remarkable insight into the molecular mechanisms driving circadian cycles, this hypothesis has not been tested under natural conditions for any eukaryotic organism. We tested this hypothesis in mice bearing a short-period mutation in the enzyme casein kinase 1ε (tau mutation), which accelerates free-running circadian cycles. We compared daily activity (feeding) rhythms, survivorship, and reproduction in six replicate populations in outdoor experimental enclosures, established with wild-type, heterozygous, and homozygous mice in a Mendelian ratio. In the release cohort, survival was reduced in the homozygote mutant mice, revealing strong selection against short-period genotypes. Over the course of 14 mo, the relative frequency of the tau allele dropped from initial parity to 20%. Adult survival and recruitment of juveniles into the population contributed approximately equally to the selection for wild-type alleles. The expression of activity during daytime varied throughout the experiment and was significantly increased by the tau mutation. The strong selection against the short-period tau allele observed here contrasts with earlier studies showing absence of selection against a Period 2 (Per2) mutation, which disrupts internal clock function, but does not change period length. These findings are consistent with, and predicted by the theory that resonance of the circadian system plays an important role in individual fitness. PMID:26715747

  14. A meeting of two chronobiological systems: circadian proteins Period1 and BMAL1 modulate the human hair cycle clock.

    PubMed

    Al-Nuaimi, Yusur; Hardman, Jonathan A; Bíró, Tamás; Haslam, Iain S; Philpott, Michael P; Tóth, Balázs I; Farjo, Nilofer; Farjo, Bessam; Baier, Gerold; Watson, Rachel E B; Grimaldi, Benedetto; Kloepper, Jennifer E; Paus, Ralf

    2014-03-01

    The hair follicle (HF) is a continuously remodeled mini organ that cycles between growth (anagen), regression (catagen), and relative quiescence (telogen). As the anagen-to-catagen transformation of microdissected human scalp HFs can be observed in organ culture, it permits the study of the unknown controls of autonomous, rhythmic tissue remodeling of the HF, which intersects developmental, chronobiological, and growth-regulatory mechanisms. The hypothesis that the peripheral clock system is involved in hair cycle control, i.e., the anagen-to-catagen transformation, was tested. Here we show that in the absence of central clock influences, isolated, organ-cultured human HFs show circadian changes in the gene and protein expression of core clock genes (CLOCK, BMAL1, and Period1) and clock-controlled genes (c-Myc, NR1D1, and CDKN1A), with Period1 expression being hair cycle dependent. Knockdown of either BMAL1 or Period1 in human anagen HFs significantly prolonged anagen. This provides evidence that peripheral core clock genes modulate human HF cycling and are an integral component of the human hair cycle clock. Specifically, our study identifies BMAL1 and Period1 as potential therapeutic targets for modulating human hair growth. PMID:24005054

  15. Metabolic circadian rhythms in embryonic turtles.

    PubMed

    Loudon, Fiona Kay; Spencer, Ricky-John; Strassmeyer, Alana; Harland, Karen

    2013-07-01

    Oviparous species are model organisms for investigating embryonic development of endogenous physiological circadian rhythms without the influence of maternal biorhythms. Recent studies have demonstrated that heart rates and metabolic rates of embryonic turtles are not constant or always maximal and can be altered in response to the presence of embryos at a more advanced stage of development within the nest. A first step in understanding the physiological mechanisms underpinning these responses in embryonic ectothermic organisms is to develop metabolic profiles (e.g., heart rate) at different temperatures throughout incubation. Heart beat and rhythmic patterns or changes in development may represent important signals or cues within a nest and may be vital to coordinate synchronous hatching well in advance of the final stages of incubation. We developed baseline embryonic heart-rate profiles of embryos of the short-necked Murray River turtle (Emydura macquarii) to determine the stage of embryogenesis that metabolic circadian rhythms become established, if at all. Eggs were incubated at constant temperatures (26°C and 30°C) and heart rates were monitored at 6-h intervals over 24 h every 7-11 days until hatching. Circadian heart rate rhythms were detected at the mid-gestation period and were maintained until hatching. Heart rates throughout the day varied by up to 20% over 24 h and were not related to time of day. This study demonstrated that endogenous metabolic circadian rhythms in developing embryos in turtle eggs establish earlier in embryogenesis than those documented in other vertebrate taxa during embryogenesis. Early establishment of circadian rhythms in heart rates may be critical for communication among embryos and synchrony in hatching and emergence from the nest. PMID:23652198

  16. Temperature compensation and temperature sensation in the circadian clock

    PubMed Central

    Kidd, Philip B.; Young, Michael W.; Siggia, Eric D.

    2015-01-01

    All known circadian clocks have an endogenous period that is remarkably insensitive to temperature, a property known as temperature compensation, while at the same time being readily entrained by a diurnal temperature oscillation. Although temperature compensation and entrainment are defining features of circadian clocks, their mechanisms remain poorly understood. Most models presume that multiple steps in the circadian cycle are temperature-dependent, thus facilitating temperature entrainment, but then insist that the effect of changes around the cycle sums to zero to enforce temperature compensation. An alternative theory proposes that the circadian oscillator evolved from an adaptive temperature sensor: a gene circuit that responds only to temperature changes. This theory implies that temperature changes should linearly rescale the amplitudes of clock component oscillations but leave phase relationships and shapes unchanged. We show using timeless luciferase reporter measurements and Western blots against TIMELESS protein that this prediction is satisfied by the Drosophila circadian clock. We also review evidence for pathways that couple temperature to the circadian clock, and show previously unidentified evidence for coupling between the Drosophila clock and the heat-shock pathway. PMID:26578788

  17. Optimal Schedules of Light Exposure for Rapidly Correcting Circadian Misalignment

    PubMed Central

    Serkh, Kirill; Forger, Daniel B.

    2014-01-01

    Jet lag arises from a misalignment of circadian biological timing with the timing of human activity, and is caused by rapid transmeridian travel. Jet lag's symptoms, such as depressed cognitive alertness, also arise from work and social schedules misaligned with the timing of the circadian clock. Using experimentally validated mathematical models, we develop a new methodology to find mathematically optimal schedules of light exposure and avoidance for rapidly re-entraining the human circadian system. In simulations, our schedules are found to significantly outperform other recently proposed schedules. Moreover, our schedules appear to be significantly more robust to both noise in light and to inter-individual variations in endogenous circadian period than other proposed schedules. By comparing the optimal schedules for thousands of different situations, and by using general mathematical arguments, we are also able to translate our findings into general principles of optimal circadian re-entrainment. These principles include: 1) a class of schedules where circadian amplitude is only slightly perturbed, optimal for dim light and for small shifts 2) another class of schedules where shifting occurs along the shortest path in phase-space, optimal for bright light and for large shifts 3) the determination that short light pulses are less effective than sustained light if the goal is to re-entrain quickly, and 4) the determination that length of daytime should be significantly shorter when delaying the clock than when advancing it. PMID:24722195

  18. Circadian rhythms have broad implications for understanding brain and behavior

    PubMed Central

    Silver, Rae; Kriegsfeld, Lance J.

    2015-01-01

    Circadian rhythms are generated by an endogenously organized timing system that drives daily rhythms in behavior, physiology and metabolism. In mammals, the suprachiasmatic nucleus (SCN) of the hypothalamus is the locus of a master circadian clock. The SCN is synchronized to environmental changes in the light:dark cycle by direct, monosynaptic innervation via the retino-hypothalamic tract. In turn, the SCN coordinates the rhythmic activities of innumerable subordinate clocks in virtually all bodily tissues and organs. The core molecular clockwork is composed of a transcriptional/post-translational feedback loop in which clock genes and their protein products periodically suppress their own transcription. This primary loop connects to downstream output genes by additional, interlocked transcriptional feedback loops to create tissue-specific ‘circadian transcriptomes’. Signals from peripheral tissues inform the SCN of the internal state of the organism and the brain’s master clock is modified accordingly. A consequence of this hierarchical, multilevel feedback system is that there are ubiquitous effects of circadian timing on genetic and metabolic responses throughout the body. This overview examines landmark studies in the history of the study of circadian timing system, and highlights our current understanding of the operation of circadian clocks with a focus on topics of interest to the neuroscience community. PMID:24799154

  19. HIGH EXPRESSION OF OSMOTICALLY RESPONSIVE GENES1 Is Required for Circadian Periodicity through the Promotion of Nucleo-Cytoplasmic mRNA Export in Arabidopsis[W][OPEN

    PubMed Central

    MacGregor, Dana R.; Gould, Peter; Foreman, Julia; Griffiths, Jayne; Bird, Susannah; Page, Rhiannon; Stewart, Kelly; Steel, Gavin; Young, Jack; Paszkiewicz, Konrad; Millar, Andrew J.; Halliday, Karen J.; Hall, Anthony J.; Penfield, Steven

    2013-01-01

    Cold acclimation has been shown to be attenuated by the degradation of the INDUCER OF CBF EXPRESSION1 protein by the E3 ubiquitin ligase HIGH EXPRESSION OF OSMOTICALLY RESPONSIVE GENES1 (HOS1). However, recent work has suggested that HOS1 may have a wider range of roles in plants than previously appreciated. Here, we show that hos1 mutants are affected in circadian clock function, exhibiting a long-period phenotype in a wide range of temperature and light environments. We demonstrate that hos1 mutants accumulate polyadenylated mRNA in the nucleus and that the circadian defect in hos1 is shared by multiple mutants with aberrant mRNA export, but not in a mutant attenuated in nucleo-cytoplasmic transport of microRNAs. As revealed by RNA sequencing, hos1 exhibits gross changes to the transcriptome with genes in multiple functional categories being affected. In addition, we show that hos1 and other previously described mutants with altered mRNA export affect cold signaling in a similar manner. Our data support a model in which altered mRNA export is important for the manifestation of hos1 circadian clock defects and suggest that HOS1 may indirectly affect cold signaling through disruption of the circadian clock. PMID:24254125

  20. Effects of exercise on circadian rhythms and mobility in aging Drosophila melanogaster.

    PubMed

    Rakshit, Kuntol; Wambua, Rebecca; Giebultowicz, Tomasz M; Giebultowicz, Jadwiga M

    2013-11-01

    Daily life functions such as sleep and feeding oscillate with circa 24 h period due to endogenous circadian rhythms generated by circadian clocks. Genetic or environmental disruption of circadian rhythms is associated with various aging-related phenotypes. Circadian rhythms decay during normal aging, and there is a need to explore strategies that could avert age-related changes in the circadian system. Exercise was reported to delay aging in mammals. Here, we investigated whether daily exercise via stimulation of upward climbing movement could improve circadian rest/activity rhythms in aging Drosophila melanogaster. We found that repeated exercise regimen did not strengthen circadian locomotor activity rhythms in aging flies and had no effect on their lifespan. We also tested the effects of exercise on mobility and determined that regular exercise lowered age-specific climbing ability in both wild type and clock mutant flies. Interestingly, the climbing ability was most significantly reduced in flies carrying a null mutation in the core clock gene period, while rescue of this gene significantly improved climbing to wild type levels. Our work highlights the importance of period in sustaining endurance in aging flies exposed to physical challenge. PMID:23916842

  1. Circadian Clock-Regulated Expression of Phytochrome and Cryptochrome Genes in Arabidopsis1

    PubMed Central

    Tóth, Réka; Kevei, Éva; Hall, Anthony; Millar, Andrew J.; Nagy, Ferenc; Kozma-Bognár, László

    2001-01-01

    Many physiological and biochemical processes in plants exhibit endogenous rhythms with a period of about 24 h. Endogenous oscillators called circadian clocks regulate these rhythms. The circadian clocks are synchronized to the periodic environmental changes (e.g. day/night cycles) by specific stimuli; among these, the most important is the light. Photoreceptors, phytochromes, and cryptochromes are involved in setting the clock by transducing the light signal to the central oscillator. In this work, we analyzed the spatial, temporal, and long-term light-regulated expression patterns of the Arabidopsis phytochrome (PHYA to PHYE) and cryptochrome (CRY1 and CRY2) promoters fused to the luciferase (LUC+) reporter gene. The results revealed new details of the tissue-specific expression and light regulation of the PHYC and CRY1 and 2 promoters. More importantly, the data obtained demonstrate that the activities of the promoter::LUC+ constructs, with the exception of PHYC::LUC+, display circadian oscillations under constant conditions. In addition, it is shown by measuring the mRNA abundance of PHY and CRY genes under constant light conditions that the circadian control is also maintained at the level of mRNA accumulation. These observations indicate that the plant circadian clock controls the expression of these photoreceptors, revealing the formation of a new regulatory loop that could modulate gating and resetting of the circadian clock. PMID:11743105

  2. Circadian secretion of cortisol and melatonin in cluster headache during active cluster periods and remission.

    PubMed Central

    Waldenlind, E; Gustafsson, S A; Ekbom, K; Wetterberg, L

    1987-01-01

    The cyclic nature of cluster headache warranted a study of the 24-hour rhythms of serum cortisol and melatonin. They were both altered during cluster periods as compared with periods of remission and healthy controls. The 24-hour mean and maximal cortisol levels were higher and the timing of the cortisol minimum was delayed as compared to the same patients in remission. Although there was no relation between the cortisol and melatonin levels and headaches, the rise of cortisol following many attacks might in part represent an adaptive response to pain. The nocturnal melatonin maximum was lower during cluster periods than in remission. This finding, and the dysautonomic signs during attacks, may reflect a change of the vegetative tone in a hyposympathetic direction. Images PMID:3572435

  3. Temperature cycle amplitude alters the adult eclosion time and expression pattern of the circadian clock gene period in the onion fly.

    PubMed

    Miyazaki, Yosuke; Watari, Yasuhiko; Tanaka, Kazuhiro; Goto, Shin G

    2016-03-01

    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. PMID:26776097

  4. Endocrine regulation of circadian physiology.

    PubMed

    Tsang, Anthony H; Astiz, Mariana; Friedrichs, Maureen; Oster, Henrik

    2016-07-01

    Endogenous circadian clocks regulate 24-h rhythms of behavior and physiology to align with external time. The endocrine system serves as a major clock output to regulate various biological processes. Recent findings suggest that some of the rhythmic hormones can also provide feedback to the circadian system at various levels, thus contributing to maintaining the robustness of endogenous rhythmicity. This delicate balance of clock-hormone interaction is vulnerable to modern lifestyle factors such as shiftwork or high-calorie diets, altering physiological set points. In this review, we summarize the current knowledge on the communication between the circadian timing and endocrine systems, with a focus on adrenal glucocorticoids and metabolic peptide hormones. We explore the potential role of hormones as systemic feedback signals to adjust clock function and their relevance for the maintenance of physiological and metabolic circadian homeostasis. PMID:27106109

  5. Tuning the phase of circadian entrainment

    PubMed Central

    Bordyugov, Grigory; Abraham, Ute; Granada, Adrian; Rose, Pia; Imkeller, Katharina; Kramer, Achim; Herzel, Hanspeter

    2015-01-01

    The circadian clock coordinates daily physiological, metabolic and behavioural rhythms. These endogenous oscillations are synchronized with external cues (‘zeitgebers’), such as daily light and temperature cycles. When the circadian clock is entrained by a zeitgeber, the phase difference ψ between the phase of a clock-controlled rhythm and the phase of the zeitgeber is of fundamental importance for the fitness of the organism. The phase of entrainment ψ depends on the mismatch between the intrinsic period τ and the zeitgeber period T and on the ratio of the zeitgeber strength to oscillator amplitude. Motivated by the intriguing complexity of empirical data and by our own experiments on temperature entrainment of mouse suprachiasmatic nucleus (SCN) slices, we present a theory on how clock and zeitgeber properties determine the phase of entrainment. The wide applicability of the theory is demonstrated using mathematical models of different complexity as well as by experimental data. Predictions of the theory are confirmed by published data on Neurospora crassa strains for different period mismatches τ − T and varying photoperiods. We apply a novel regression technique to analyse entrainment of SCN slices by temperature cycles. We find that mathematical models can explain not only the stable asymptotic phase of entrainment, but also transient phase dynamics. Our theory provides the potential to explore seasonal variations of circadian rhythms, jet lag and shift work in forthcoming studies. PMID:26136227

  6. Tuning the phase of circadian entrainment.

    PubMed

    Bordyugov, Grigory; Abraham, Ute; Granada, Adrian; Rose, Pia; Imkeller, Katharina; Kramer, Achim; Herzel, Hanspeter

    2015-07-01

    The circadian clock coordinates daily physiological, metabolic and behavioural rhythms. These endogenous oscillations are synchronized with external cues ('zeitgebers'), such as daily light and temperature cycles. When the circadian clock is entrained by a zeitgeber, the phase difference ψ between the phase of a clock-controlled rhythm and the phase of the zeitgeber is of fundamental importance for the fitness of the organism. The phase of entrainment ψ depends on the mismatch between the intrinsic period τ and the zeitgeber period T and on the ratio of the zeitgeber strength to oscillator amplitude. Motivated by the intriguing complexity of empirical data and by our own experiments on temperature entrainment of mouse suprachiasmatic nucleus (SCN) slices, we present a theory on how clock and zeitgeber properties determine the phase of entrainment. The wide applicability of the theory is demonstrated using mathematical models of different complexity as well as by experimental data. Predictions of the theory are confirmed by published data on Neurospora crassa strains for different period mismatches τ - T and varying photoperiods. We apply a novel regression technique to analyse entrainment of SCN slices by temperature cycles. We find that mathematical models can explain not only the stable asymptotic phase of entrainment, but also transient phase dynamics. Our theory provides the potential to explore seasonal variations of circadian rhythms, jet lag and shift work in forthcoming studies. PMID:26136227

  7. Circadian gene variants in cancer

    PubMed Central

    Kettner, Nicole M.; Katchy, Chinenye A.; Fu, Loning

    2014-01-01

    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

  8. Circadian rhythms of female mating activity governed by clock genes in Drosophila

    PubMed Central

    Sakai, Takaomi; Ishida, Norio

    2001-01-01

    The physiological and behavioral activities of many animals are restricted to specific times of the day. The daily fluctuation in the mating activity of some insects is controlled by an endogenous clock, but the genetic mechanism that controls it remains unknown. Here we demonstrate that wild-type Drosophila melanogaster display a robust circadian rhythm in the mating activity, and that these rhythms are abolished in period- or timeless-null mutant flies (per01 and tim01). Circadian rhythms were lost when rhythm mutant females were paired with wild-type males, demonstrating that female mating activity is governed by clock genes. Furthermore, we detected an antiphasic relationship in the circadian rhythms of mating activity between D. melanogaster and its sibling species Drosophila simulans. Female- and species-specific circadian rhythms in the mating activity of Drosophila seem to cause reproductive isolation. PMID:11470898

  9. Mop3 Is an Essential Component of the Master Circadian Pacemaker in Mammals

    PubMed Central

    Bunger, Maureen K.; Wilsbacher, Lisa D.; Moran, Susan M.; Clendenin, Cynthia; Radcliffe, Laurel A.; Hogenesch, John B.; Simon, M. Celeste; Takahashi, Joseph S.; Bradfield, Christopher A.

    2013-01-01

    Summary Circadian oscillations in mammalian physiology and behavior are regulated by an endogenous biological clock. Here we show that loss of the PAS protein MOP3 (also known as BMAL1) in mice results in immediate and complete loss of circadian rhythmicity in constant darkness. Additionally, locomotor activity in light–dark (LD) cycles is impaired and activity levels are reduced in Mop3−/− mice. Analysis of Period gene expression in the suprachiasmatic nucleus (SCN) indicates that these behavioral phenotypes arise from loss of circadian function at the molecular level. These results provide genetic evidence that MOP3 is the bona fide heterodimeric partner of mCLOCK. Furthermore, these data demonstrate that MOP3 is a non-redundant and essential component of the circadian pacemaker in mammals. PMID:11163178

  10. Circadian control of oscillations in mitochondrial rate-limiting enzymes and nutrient utilization by PERIOD proteins.

    PubMed

    Neufeld-Cohen, Adi; Robles, Maria S; Aviram, Rona; Manella, Gal; Adamovich, Yaarit; Ladeuix, Benjamin; Nir, Dana; Rousso-Noori, Liat; Kuperman, Yael; Golik, Marina; Mann, Matthias; Asher, Gad

    2016-03-22

    Mitochondria are major suppliers of cellular energy through nutrients oxidation. Little is known about the mechanisms that enable mitochondria to cope with changes in nutrient supply and energy demand that naturally occur throughout the day. To address this question, we applied MS-based quantitative proteomics on isolated mitochondria from mice killed throughout the day and identified extensive oscillations in the mitochondrial proteome. Remarkably, the majority of cycling mitochondrial proteins peaked during the early light phase. We found that rate-limiting mitochondrial enzymes that process lipids and carbohydrates accumulate in a diurnal manner and are dependent on the clock proteins PER1/2. In this conjuncture, we uncovered daily oscillations in mitochondrial respiration that peak during different times of the day in response to different nutrients. Notably, the diurnal regulation of mitochondrial respiration was blunted in mice lacking PER1/2 or on a high-fat diet. We propose that PERIOD proteins optimize mitochondrial metabolism to daily changes in energy supply/demand and thereby, serve as a rheostat for mitochondrial nutrient utilization. PMID:26862173

  11. The circadian clock in cancer development and therapy

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Most aspects of mammalian function display circadian rhythms driven by an endogenous clock. The circadian clock is operated by genes and comprises a central clock in the brain that responds to environmental cues and controls subordinate clocks in peripheral tissues via circadian output pathways. The...

  12. Diurnal oscillations of soybean circadian clock and drought responsive genes

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Rhythms produced by the endogenous circadian clock play a critical role in allowing plants to respond and adapt to the environment. While there is a well-established regulatory link between the circadian clock and responses to abiotic stress in model plants, little is known of the circadian system i...

  13. Entrainment of the circadian rhythm in the rat pineal N-acetyltransferase activity by prolonged periods of light.

    PubMed

    Illnerová, H; Vanĕcek, J

    1987-08-01

    Entertainment of the circadian rhythm in the pineal N-acetyltranferase activity by prolonged periods of light was studied in rats synchronized with a light:dark regime of 12:12 h by observing phase-shifts in rhythm after delays in switching off the light in the evening or after bringing forward of the morning onset of light. When rats were subjected to delays in switching off the light of up to 10 h and then were released into darkness, phase-delays of the evening N-acetyltransferase rise during the same night corresponded roughly to delays in the light switch off. However, phase-delays of the morning decline were much smaller. After a delay in the evening switch off of 11 h, no N-acetyltransferase rhythm was found in the subsequent darkness. The evening N-acetyltransferase rise was phase-delayed by 6.2 h at most 1 day after delays. Phase-delays of the morning N-acetyltransferase decline were shorter than phase-delays of the N-acetyltransferase rise by only 0.7 h to 0.9 h at most. Hence, 1 day after delays in the evening switch off, the period of the high night N-acetyltransferase activity may be shortened only slightly. The N-acetyltransferase rhythm was abolished only after a 12 h delay in switching off the light. Rats were subjected to a bringing forward of the morning light onset and then were released into darkness 4 h before the usual switch off of light. In the following night, the morning N-acetyltransferase decline, but not the evening rise, was phase advanced considerably. Moreover, when the onset of light was brought forward to before midnight, the N-acetyltransferase rise was even phase-delayed. Hence, 1 day after bringing forward the morning onset of light, the period of the high night N-acetyltransferase activity may be drastically reduced. When rats were subjected to a 4 h light pulse around midnight and then released into darkness, the N-acetyltransferase rhythm in the next night was abolished. The data are discussed in terms of a two

  14. Socially synchronized circadian oscillators

    PubMed Central

    Bloch, Guy; Herzog, Erik D.; Levine, Joel D.; Schwartz, William J.

    2013-01-01

    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. PMID:23825203

  15. Circadian changes in endogenous concentrations of indole-3-acetic acid, melatonin, serotonin, abscisic acid and jasmonic acid in Characeae (Chara australis Brown)

    PubMed Central

    Beilby, Mary J; Turi, Christina E; Baker, Teesha C; Tymm, Fiona JM; Murch, Susan J

    2015-01-01

    Giant-celled Characeae (Chara australis Brown), grown for 4 months on 12/12 hr day/night cycle and summer/autumn temperatures, exhibited distinct concentration maxima in auxin (indole-3-acetic acid; IAA), melatonin and serotonin about 4 hr after subjective daybreak. These concentration peaks persisted after 3 day pretreatment in continuous darkness: confirming a circadian rhythm, rather than a response to “light on.” The plants pretreated for 3 d in continuous light exhibited several large IAA concentration maxima throughout the 24 hr. The melatonin and serotonin concentrations decreased and were less synchronized with IAA. Chara plants grown on 9/15 hr day/night cycle for 4 months and winter/spring temperatures contained much smaller concentrations of IAA, melatonin and serotonin. The IAA concentration maxima were observed in subjective dark phase. Serotonin concentration peaks were weakly correlated with those of IAA. Melatonin concentration was low and mostly independent of circadian cycle. The “dark” IAA concentration peaks persisted in plants treated for 3 d in the dark. The plants pretreated for 3 d in the light again developed more IAA concentration peaks. In this case the concentration maxima in melatonin and serotonin became more synchronous with those in IAA. The abscisic acid (ABA) and jasmonic acid (JA) concentrations were also measured in plants on winter regime. The ABA concentration did not exhibit circadian pattern, while JA concentration peaks were out of phase with those of IAA. The data are discussed in terms of crosstalk between metabolic pathways. PMID:26382914

  16. Cardiac Atrial Circadian Rhythms in PERIOD2::LUCIFERASE and per1:luc Mice: Amplitude and Phase Responses to Glucocorticoid Signaling and Medium Treatment

    PubMed Central

    Xi, Yang; Li, Lei; Duffield, Giles E.

    2012-01-01

    Circadian rhythms in cardiac function are apparent in e.g., blood pressure, heart rate, and acute adverse cardiac events. A circadian clock in heart tissue has been identified, but entrainment pathways of this clock are still unclear. We cultured tissues of mice carrying bioluminescence reporters of the core clock genes, period 1 or 2 (per1luc or PER2LUC) and compared in vitro responses of atrium to treatment with medium and a synthetic glucocorticoid (dexamethasone [DEX]) to that of the suprachiasmatic nucleus (SCN) and liver. We observed that PER2LUC, but not per1luc is rhythmic in atrial tissue, while both per1luc and PER2LUC exhibit rhythmicity in other cultured tissues. In contrast to the SCN and liver, both per1luc and PER2LUC bioluminescence amplitudes were increased in response to DEX treatment, and the PER2LUC amplitude response was dependent on the time of treatment. Large phase-shift responses to both medium and DEX treatments were observed in the atrium, and phase responses to medium treatment were not attributed to serum content but the treatment procedure itself. The phase-response curves of atrium to both DEX and medium treatments were found to be different to the liver. Moreover, the time of day of the culturing procedure itself influenced the phase of the circadian clock in each of the cultured tissues, but the magnitude of this response was uniquely large in atrial tissue. The current data describe novel entrainment signals for the atrial circadian clock and specifically highlight entrainment by mechanical treatment, an intriguing observation considering the mechanical nature of cardiac tissue. PMID:23110090

  17. Circadian Behaviour in Neuroglobin Deficient Mice

    PubMed Central

    Hundahl, Christian A.; Fahrenkrug, Jan; Hay-Schmidt, Anders; Georg, Birgitte; Faltoft, Birgitte; Hannibal, Jens

    2012-01-01

    Neuroglobin (Ngb), a neuron-specific oxygen-binding globin with an unknown function, has been proposed to play a key role in neuronal survival. We have previously shown Ngb to be highly expressed in the rat suprachiasmatic nucleus (SCN). The present study addresses the effect of Ngb deficiency on circadian behavior. Ngb-deficient and wild-type (wt) mice were placed in running wheels and their activity rhythms, endogenous period and response to light stimuli were investigated. The effect of Ngb deficiency on the expression of Period1 (Per1) and the immediate early gene Fos was determined after light stimulation at night and the neurochemical phenotype of Ngb expressing neurons in wt mice was characterized. Loss of Ngb function had no effect on overall circadian entrainment, but resulted in a significantly larger phase delay of circadian rhythm upon light stimulation at early night. A light-induced increase in Per1, but not Fos, gene expression was observed in Ngb-deficient mice. Ngb expressing neurons which co-stored Gastrin Releasing Peptide (GRP) and were innervated from the eye and the geniculo-hypothalamic tract expressed FOS after light stimulation. No PER1 expression was observed in Ngb-positive neurons. The present study demonstrates for the first time that the genetic elimination of Ngb does not affect core clock function but evokes an increased behavioural response to light concomitant with increased Per1 gene expression in the SCN at early night. PMID:22496809

  18. Kernel Architecture of the Genetic Circuitry of the Arabidopsis Circadian System

    PubMed Central

    Foo, Mathias; Somers, David E.; Kim, Pan-Jun

    2016-01-01

    A wide range of organisms features molecular machines, circadian clocks, which generate endogenous oscillations with ~24 h periodicity and thereby synchronize biological processes to diurnal environmental fluctuations. Recently, it has become clear that plants harbor more complex gene regulatory circuits within the core circadian clocks than other organisms, inspiring a fundamental question: are all these regulatory interactions between clock genes equally crucial for the establishment and maintenance of circadian rhythms? Our mechanistic simulation for Arabidopsis thaliana demonstrates that at least half of the total regulatory interactions must be present to express the circadian molecular profiles observed in wild-type plants. A set of those essential interactions is called herein a kernel of the circadian system. The kernel structure unbiasedly reveals four interlocked negative feedback loops contributing to circadian rhythms, and three feedback loops among them drive the autonomous oscillation itself. Strikingly, the kernel structure, as well as the whole clock circuitry, is overwhelmingly composed of inhibitory, rather than activating, interactions between genes. We found that this tendency underlies plant circadian molecular profiles which often exhibit sharply-shaped, cuspidate waveforms. Through the generation of these cuspidate profiles, inhibitory interactions may facilitate the global coordination of temporally-distant clock events that are markedly peaked at very specific times of day. Our systematic approach resulting in experimentally-testable predictions provides insights into a design principle of biological clockwork, with implications for synthetic biology. PMID:26828650

  19. A PTH-responsive circadian clock operates in ex vivo mouse femur fracture healing site.

    PubMed

    Kunimoto, Tatsuya; Okubo, Naoki; Minami, Yoichi; Fujiwara, Hiroyoshi; Hosokawa, Toshihiro; Asada, Maki; Oda, Ryo; Kubo, Toshikazu; Yagita, Kazuhiro

    2016-01-01

    The circadian clock contains clock genes including Bmal1 and Period2, and it maintains an interval rhythm of approximately 24 hours (the circadian rhythm) in various organs including growth plate and articular cartilage. As endochondral ossification is involved not only in growth plate but also in fracture healing, we investigated the circadian clock functions in fracture sites undergoing healing. Our fracture models using external fixation involved femurs of Period2::Luciferase knock-in mice which enables the monitoring of endogenous circadian clock state via bioluminescence. Organ culture was performed by collecting femurs, and fracture sites were observed using bioluminescence imaging systems. Clear bioluminescence rhythms of 24-hour intervals were revealed in fracture healing sites. When parathyroid hormone (PTH) was administered to fractured femurs in organ culture, peak time of Period2::Luciferase activity in fracture sites and growth plates changed, indicating that PTH-responsive circadian clock functions in the mouse femur fracture healing site. While PTH is widely used in treating osteoporosis, many studies have reported that it contributes to improvement of fracture healing. Future studies of the role of this local clock in wound healing may reveal a novel function of the circadian timing mechanism in skeletal cells. PMID:26926165

  20. A PTH-responsive circadian clock operates in ex vivo mouse femur fracture healing site

    PubMed Central

    Kunimoto, Tatsuya; Okubo, Naoki; Minami, Yoichi; Fujiwara, Hiroyoshi; Hosokawa, Toshihiro; Asada, Maki; Oda, Ryo; Kubo, Toshikazu; Yagita, Kazuhiro

    2016-01-01

    The circadian clock contains clock genes including Bmal1 and Period2, and it maintains an interval rhythm of approximately 24 hours (the circadian rhythm) in various organs including growth plate and articular cartilage. As endochondral ossification is involved not only in growth plate but also in fracture healing, we investigated the circadian clock functions in fracture sites undergoing healing. Our fracture models using external fixation involved femurs of Period2::Luciferase knock-in mice which enables the monitoring of endogenous circadian clock state via bioluminescence. Organ culture was performed by collecting femurs, and fracture sites were observed using bioluminescence imaging systems. Clear bioluminescence rhythms of 24-hour intervals were revealed in fracture healing sites. When parathyroid hormone (PTH) was administered to fractured femurs in organ culture, peak time of Period2::Luciferase activity in fracture sites and growth plates changed, indicating that PTH-responsive circadian clock functions in the mouse femur fracture healing site. While PTH is widely used in treating osteoporosis, many studies have reported that it contributes to improvement of fracture healing. Future studies of the role of this local clock in wound healing may reveal a novel function of the circadian timing mechanism in skeletal cells. PMID:26926165

  1. Circadian misalignment increases cardiovascular disease risk factors in humans

    PubMed Central

    Morris, Christopher J.; Purvis, Taylor E.; Hu, Kun; Scheer, Frank A. J. L.

    2016-01-01

    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

  2. Circadian Regulation of Synaptic Plasticity.

    PubMed

    Frank, Marcos G

    2016-01-01

    Circadian rhythms refer to oscillations in biological processes with a period of approximately 24 h. In addition to the sleep/wake cycle, there are circadian rhythms in metabolism, body temperature, hormone output, organ function and gene expression. There is also evidence of circadian rhythms in synaptic plasticity, in some cases driven by a master central clock and in other cases by peripheral clocks. In this article, I review the evidence for circadian influences on synaptic plasticity. I also discuss ways to disentangle the effects of brain state and rhythms on synaptic plasticity. PMID:27420105

  3. Circadian rhythm and its role in malignancy

    PubMed Central

    2010-01-01

    Circadian rhythms are daily oscillations of multiple biological processes directed by endogenous clocks. The circadian timing system comprises peripheral oscillators located in most tissues of the body and a central pacemaker located in the suprachiasmatic nucleus (SCN) of the hypothalamus. Circadian genes and the proteins produced by these genes constitute the molecular components of the circadian oscillator which form positive/negative feedback loops and generate circadian rhythms. The circadian regulation extends beyond clock genes to involve various clock-controlled genes (CCGs) including various cell cycle genes. Aberrant expression of circadian clock genes could have important consequences on the transactivation of downstream targets that control the cell cycle and on the ability of cells to undergo apoptosis. This may lead to genomic instability and accelerated cellular proliferation potentially promoting carcinogenesis. Different lines of evidence in mice and humans suggest that cancer may be a circadian-related disorder. The genetic or functional disruption of the molecular circadian clock has been found in various cancers including breast, ovarian, endometrial, prostate and hematological cancers. The acquisition of current data in circadian clock mechanism may help chronotherapy, which takes into consideration the biological time to improve treatments by devising new therapeutic approaches for treating circadian-related disorders, especially cancer. PMID:20353609

  4. Extent of mismatch between the period of circadian clocks and light/dark cycles determines time-to-emergence in fruit flies.

    PubMed

    Yadav, Pankaj; Choudhury, Deepak; Sadanandappa, Madhumala K; Sharma, Vijay Kumar

    2015-08-01

    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. PMID:24668961

  5. Circadian Control of Global Transcription

    PubMed Central

    Li, Shujing; Zhang, Luoying

    2015-01-01

    Circadian rhythms exist in most if not all organisms on the Earth and manifest in various aspects of physiology and behavior. These rhythmic processes are believed to be driven by endogenous molecular clocks that regulate rhythmic expression of clock-controlled genes (CCGs). CCGs consist of a significant portion of the genome and are involved in diverse biological pathways. The transcription of CCGs is tuned by rhythmic actions of transcription factors and circadian alterations in chromatin. Here, we review the circadian control of CCG transcription in five model organisms that are widely used, including cyanobacterium, fungus, plant, fruit fly, and mouse. Comparing the similarity and differences in the five organisms could help us better understand the function of the circadian clock, as well as its output mechanisms adapted to meet the demands of diverse environmental conditions. PMID:26682214

  6. CUL1 regulates TOC1 protein stability in the Arabidopsis circadian clock

    PubMed Central

    Harmon, Frank; Imaizumi, Takato; Gray, William M.

    2010-01-01

    Summary The circadian clock is the endogenous timer that coordinates physiological processes with daily and seasonal environmental changes. In Arabidopsis thaliana, establishment of the circadian period relies on targeted degradation of TIMING OF CAB EXPRESSION 1 (TOC1) by the 26S proteasome. ZEITLUPE (ZTL) is the F-box protein that associates with the SCF (Skp/Cullin/F-box) E3 ubiquitin ligase that is responsible for marking TOC1 for turnover. CULLIN1 (CUL1) is a core component of SCF complexes and is involved in multiple signaling pathways. To assess the contribution of CUL1-containing SCF complexes to signaling within the plant oscillator, circadian rhythms were examined in the recessive, temperature-sensitive CUL1 allele axr6-3. The activity of CUL1 in this mutant declines progressively with increasing ambient temperature, resulting in more severe defects in CUL1-dependent activities at elevated temperature. Examination of circadian rhythms in axr6-3 revealed circadian phenotypes comparable to those observed in ztl null mutants; namely, lengthened circadian period, altered expression of core oscillator genes, and limited degradation of TOC1. In addition, treatment of seedlings with exogenous auxin did not alter TOC1 stability. These results demonstrate that CUL1 is required for TOC1 degradation and further suggest that this protein is the functional cullin for the SCFZTL complex. PMID:18433436

  7. Phenotyping Circadian Rhythms in Mice.

    PubMed

    Eckel-Mahan, Kristin; Sassone-Corsi, Paolo

    2015-01-01

    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. PMID:26331760

  8. Role of Circadian Rhythms in Potassium Homeostasis

    PubMed Central

    Gumz, Michelle L.; Rabinowitz, Lawrence

    2013-01-01

    It has been known for decades that urinary potassium excretion varies with a circadian pattern. In this review, we consider the historical evidence for this phenomenon and present an overview of recent developments in the field. Extensive evidence from the latter part of the last century clearly demonstrates that circadian potassium excretion does not depend on endogenous aldosterone. Of note is the recent discovery that the expression of several renal potassium transporters varies with a circadian pattern that appears to be consistent with substantial clinical data regarding daily fluctuations in urinary potassium levels. We propose the circadian clock mechanism as a key regulator of renal potassium transporters, and consequently renal potassium excretion. Further investigation into the mechanism of regulation of renal potassium transport by the circadian clock is warranted in order to increase our understanding of the clinical relevance of circadian rhythms to potassium homeostasis. PMID:23953800

  9. Circadian regulation of locomotor activity and skeletal muscle gene expression in the horse.

    PubMed

    Martin, Ann-Marie; Elliott, Jeffrey A; Duffy, Pat; Blake, Catriona M; Ben Attia, Sarra; Katz, Lisa M; Browne, John A; Gath, Vivian; McGivney, Beatrice A; Hill, Emmeline W; Murphy, Barbara A

    2010-11-01

    Circadian rhythms are innate 24-h cycles in behavioral and biochemical processes that permit physiological anticipation of daily environmental changes. Elucidating the relationship between activity rhythms and circadian patterns of gene expression may contribute to improved human and equine athletic performance. Six healthy, untrained mares were studied to determine whether locomotor activity behavior and skeletal muscle gene expression reflect endogenous circadian regulation. Activity was recorded for three consecutive 48-h periods: as a group at pasture (P), and individually stabled under a light-dark (LD) cycle and in constant darkness (DD). Halter-mounted Actiwatch-L data-loggers recorded light exposure and motor activity. Analysis of mean activity (average counts/min, activity bouts/day, average bout length) and cosinor parameters (acrophase, amplitude, mesor, goodness of fit) revealed a predominantly ultradian (8.9 ± 0.7 bouts/24 h) and weakly circadian pattern of activity in all three conditions (P, LD, DD). A more robust circadian pattern was observed during LD and DD. Muscle biopsies were obtained from the middle gluteal muscles every 4 h for 24 h under DD. One-way qRT-PCR results confirmed the circadian expression (P < 0.05) of six core clock genes (Arntl, Per1, Per2, Nr1d1, Nr1d2, Dbp) and the muscle-specific transcript, Myf6. Additional genes, Ucp3, Nrip1, and Vegfa, demonstrated P values approaching significance. These findings demonstrate circadian regulation of muscle function and imply that human management regimes may strengthen, or unmask, equine circadian behavioral outputs. As exercise synchronizes circadian rhythms, our findings provide a basis for future work determining peak times for training and competing horses, to reduce injury and to achieve optimal performance. PMID:20847133

  10. Noise Induces Oscillation and Synchronization of the Circadian Neurons.

    PubMed

    Gu, Changgui; Xu, Jinshan; Rohling, Jos; Yang, Huijie; Liu, Zonghua

    2015-01-01

    The principle clock of mammals, named suprachiasmatic nucleus (SCN), coordinates the circadian rhythms of behavioral and physiological activity to the external 24 h light-dark cycle. In the absence of the daily cycle, the SCN acts as an endogenous clock that regulates the ~24 h rhythm of activity. Experimental and theoretical studies usually take the light-dark cycle as a main external influence, and often ignore light pollution as an external influence. However, in modern society, the light pollution such as induced by electrical lighting influences the circadian clock. In the present study, we examined the effect of external noise (light pollution) on the collective behavior of coupled circadian oscillators under constant darkness using a Goodwin model. We found that the external noise plays distinct roles in the network behavior of neurons for weak or strong coupling between the neurons. In the case of strong coupling, the noise reduces the synchronization and the period of the SCN network. Interestingly, in the case of weak coupling, the noise induces a circadian rhythm in the SCN network which is absent in noise-free condition. In addition, the noise increases the synchronization and decreases the period of the SCN network. Our findings may shed new light on the impact of the external noise on the collective behavior of SCN neurons. PMID:26691765

  11. Sleep and circadian rhythms

    NASA Technical Reports Server (NTRS)

    Monk, Timothy H.

    1991-01-01

    Three interacting processes are involved in the preservation of circadian rhythms: (1) endogenous rhythm generation mechanisms, (2) entrainment mechanisms to keep these rhythms 'on track', and (3) exogenous masking processes stemming from changes in environment and bahavior. These processes, particularly the latter two, can be dramatically affected in individuals of advanced age and in space travelers, with a consequent disruption in sleep and daytime functioning. This paper presents results of a phase-shift experiment investigating the age-related effects of the exogeneous component of circadian rhythms in various physiological and psychological functions by comparing these functions in middle aged and old subjects. Dramatic differences were found between the two age groups in measures of sleep, mood, activation, and performance efficiency.

  12. Parathyroid hormone resets the cartilage circadian clock of the organ-cultured murine femur

    PubMed Central

    Okubo, Naoki; Fujiwara, Hiroyoshi; Minami, Yoichi; Kunimoto, Tatsuya; Hosokawa, Toshihiro; Umemura, Yasuhiro; Inokawa, Hitoshi; Asada, Maki; Oda, Ryo; Kubo, Toshikazu

    2015-01-01

    Background and purpose The circadian clock governs endogenous day-night variations. In bone, the metabolism and growth show diurnal rhythms. The circadian clock is based on a transcription-translation feedback loop composed of clock genes including Period2 (Per2), which encodes the protein period circadian protein homolog 2. Because plasma parathyroid hormone (PTH) levels show diurnal variation, we hypothesized that PTH could carry the time information to bone and cartilage. In this study, we analyzed the effect of PTH on the circadian clock of the femur. Patients and methods Per2::Luciferase (Per2::Luc) knock-in mice were used and their femurs were organ-cultured. The bioluminescence was measured using photomultiplier tube-based real-time bioluminescence monitoring equipment or real-time bioluminescence microscopic imaging devices. PTH or its vehicle was administered and the phase shifts were calculated. Immunohistochemistry was performed to detect PTH type 1 receptor (PTH1R) expression. Results Real-time bioluminescence monitoring revealed that PTH reset the circadian rhythm of the Per2::Luc activity in the femurs in an administration time-dependent and dose-dependent manner. Microscopic bioluminescence imaging revealed that Per2::Luc activity in the growth plate and the articular cartilage showed that the circadian rhythms and their phase shifts were induced by PTH. PTH1R was expressed in the growth plate cartilage. Interpretation In clinical practice, teriparatide (PTH (1-34)) treatment is widely used for osteoporosis. We found that PTH administration regulated the femoral circadian clock oscillation, particularly in the cartilage. Regulation of the local circadian clock by PTH may lead to a more effective treatment for not only osteoporosis but also endochondral ossification in bone growth and fracture repair. PMID:25765847

  13. PPAR{alpha} is a potential therapeutic target of drugs to treat circadian rhythm sleep disorders

    SciTech Connect

    Shirai, Hidenori; Oishi, Katsutaka; Kudo, Takashi; Shibata, Shigenobu; Ishida, Norio . E-mail: n.ishida@aist.go.jp

    2007-06-08

    Recent progress at the molecular level has revealed that nuclear receptors play an important role in the generation of mammalian circadian rhythms. To examine whether peroxisome proliferator-activated receptor alpha (PPAR{alpha}) is involved in the regulation of circadian behavioral rhythms in mammals, we evaluated the locomotor activity of mice administered with the hypolipidemic PPAR{alpha} ligand, bezafibrate. Circadian locomotor activity was phase-advanced about 3 h in mice given bezafibrate under light-dark (LD) conditions. Transfer from LD to constant darkness did not change the onset of activity in these mice, suggesting that bezafibrate advanced the phase of the endogenous clock. Surprisingly, bezafibrate also advanced the phase in mice with lesions of the suprachiasmatic nucleus (SCN; the central clock in mammals). The circadian expression of clock genes such as period2, BMAL1, and Rev-erb{alpha} was also phase-advanced in various tissues (cortex, liver, and fat) without affecting the SCN. Bezafibrate also phase-advanced the activity phase that is delayed in model mice with delayed sleep phase syndrome (DSPS) due to a Clock gene mutation. Our results indicated that PPAR{alpha} is involved in circadian clock control independently of the SCN and that PPAR{alpha} could be a potent target of drugs to treat circadian rhythm sleep disorders including DSPS.

  14. Circadian Control of Neuroendocrine Circuits Regulating Female Reproductive Function

    PubMed Central

    Williams, Wilbur P.; Kriegsfeld, Lance J.

    2012-01-01

    Female reproduction requires the precise temporal organization of interacting, estradiol-sensitive neural circuits that converge to optimally drive hypothalamo-pituitary–gonadal (HPG) axis functioning. In mammals, the master circadian pacemaker in the suprachiasmatic nucleus (SCN) of the anterior hypothalamus coordinates reproductively relevant neuroendocrine events necessary to maximize reproductive success. Likewise, in species where periods of fertility are brief, circadian oversight of reproductive function ensures that estradiol-dependent increases in sexual motivation coincide with ovulation. Across species, including humans, disruptions to circadian timing (e.g., through rotating shift work, night shift work, poor sleep hygiene) lead to pronounced deficits in ovulation and fecundity. Despite the well-established roles for the circadian system in female reproductive functioning, the specific neural circuits and neurochemical mediators underlying these interactions are not fully understood. Most work to date has focused on the direct and indirect communication from the SCN to the gonadotropin-releasing hormone (GnRH) system in control of the preovulatory luteinizing hormone (LH) surge. However, the same clock genes underlying circadian rhythms at the cellular level in SCN cells are also common to target cell populations of the SCN, including the GnRH neuronal network. Exploring the means by which the master clock synergizes with subordinate clocks in GnRH cells and its upstream modulatory systems represents an exciting opportunity to further understand the role of endogenous timing systems in female reproduction. Herein we provide an overview of the state of knowledge regarding interactions between the circadian timing system and estradiol-sensitive neural circuits driving GnRH secretion and the preovulatory LH surge. PMID:22661968

  15. Preliminary characterization of persisting circadian rhythms during space flight: Neurospora as a model system

    NASA Technical Reports Server (NTRS)

    Sulzman, F. W.

    1981-01-01

    The effects of the Spacelab environment on the circadian rhythms in microorganisms are investigated. Neurospora is chosen because of its well characterized circadian rhythm of growth. Growth rate, banding patterns, and circadian period and phase information are studied.

  16. Biomedical effects associated with energy-transmission systems: effects of 60-Hz electric fields on circadian and ultradian physiological and behavioral functions in small rodents. Period covered: January 1, 1980-December 31, 1980

    SciTech Connect

    Ehret, C.F.; Rosenberg, R.S.; Sacher, G.A.; Duffy, P.H.; Groh, K.R.; Russell, J.J.

    1980-01-01

    The effects of extremely low frequency (ELF) electric fields on transient patterns of circadian rhythms of physiological and behavioral end points are being investigated. This project is developing a data base to determine the exposure conditions that disturb the highly characteristic waveforms of ultradian, circadian, and infradian rhythms. The project has taken the following approach: (1) small rodents are exposed to well-defined ELF horizontal or vertical electric fields at nominal field strengths as high as 100 kV/m in individual residential facilities; (2) exposures follow a variety of schedules ranging from brief (one minute) to continuous, and including variations of circadian periodicities; (3) end points such as metabolism, activity, core body temperature, operant performance, and weight gain are continuously recorded for long intervals by microprocessor-controlled data acquisition systems; (4) the characteristic waveforms are analyzed by several statistical procedures for deviations from their unperturbed ultradian and circadian patterns; and (5) when and if exposures induce distrubances of the patterns, a search for concomitant neurochemical changes will begin. The following conclusions were reached: under a variety of exposure conditions the circadian regulatory system of the rat remained intact; brief ELF exposures at field strengths above 35 kV/m, presented during the inactive phase of the circadian cycle, produced a transient arousal in mice, characterized by increases in motor activity, carbon dioxide production, and oxygen consumption; the transient arousal habituated rapidly; no significant effects were seen in the second, third, or fourth exposure of mice using a one hour on, one hour off protocol; and there were no circadian aftereffects of the intermittent ELF stimulus in mice, based on measuresof rhythms of activity and gas metabolism.

  17. Disruption of circadian clocks has ramifications for metabolism, brain, and behavior

    PubMed Central

    Karatsoreos, Ilia N.; Bhagat, Sarah; Bloss, Erik B.; Morrison, John H.; McEwen, Bruce S.

    2011-01-01

    Circadian (daily) rhythms are present in almost all plants and animals. In mammals, a brain clock located in the hypothalamic suprachiasmatic nucleus maintains synchrony between environmental light/dark cycles and physiology and behavior. Over the past 100 y, especially with the advent of electric lighting, modern society has resulted in a round-the-clock lifestyle, in which natural connections between rest/activity cycles and environmental light/dark cycles have been degraded or even broken. Instances in which rapid changes to sleep patterns are necessary, such as transmeridian air travel, demonstrate negative effects of acute circadian disruption on physiology and behavior. However, the ramifications of chronic disruption of the circadian clock for mental and physical health are not yet fully understood. By housing mice in 20-h light/dark cycles, incongruous with their endogenous ∼24-h circadian period, we were able to model the effects of chronic circadian disruption noninvasively. Housing in these conditions results in accelerated weight gain and obesity, as well as changes in metabolic hormones. In the brain, circadian-disrupted mice exhibit a loss of dendritic length and decreased complexity of neurons in the prelimbic prefrontal cortex, a brain region important in executive function and emotional control. Disrupted animals show decreases in cognitive flexibility and changes in emotionality consistent with the changes seen in neural architecture. How our findings translate to humans living and working in chronic circadian disruption is unknown, but we believe that this model can provide a foundation to understand how environmental disruption of circadian rhythms impacts the brain, behavior, and physiology. PMID:21220317

  18. Dynamic Evolution of Endogenous Retrovirus-Derived Genes Expressed in Bovine Conceptuses during the Period of Placentation

    PubMed Central

    Nakagawa, So; Bai, Hanako; Sakurai, Toshihiro; Nakaya, Yuki; Konno, Toshihiro; Miyazawa, Takayuki; Gojobori, Takashi; Imakawa, Kazuhiko

    2013-01-01

    In evolution of mammals, some of essential genes for placental development are known to be of retroviral origin, as syncytin-1 derived from an envelope (env) gene of an endogenous retrovirus (ERV) aids in the cell fusion of placenta in humans. Although the placenta serves the same function in all placental mammals, env-derived genes responsible for trophoblast cell fusion and maternal immune tolerance differ among species and remain largely unidentified in the bovine species. To examine env-derived genes playing a role in the bovine placental development comprehensively, we determined the transcriptomic profiles of bovine conceptuses during three crucial windows of implantation periods using a high-throughput sequencer. The sequence reads were mapped into the bovine genome, in which ERV candidates were annotated using RetroTector© (7,624 and 1,542 for ERV-derived and env-derived genes, respectively). The mapped reads showed that approximately 18% (284 genes) of env-derived genes in the genome were expressed during placenta formation, and approximately 4% (63 genes) were detected for all days examined. We verified three env-derived genes that are expressed in trophoblast cells by polymerase chain reaction. Out of these three, the sequence of env-derived gene with the longest open reading frame (named BERV-P env) was found to show high expression levels in trophoblast cell lines and to be similar to those of syncytin-Car1 genes found in dogs and cats, despite their disparate origins. These results suggest that placentation depends on various retrovirus-derived genes that could have replaced endogenous predecessors during evolution. PMID:23335121

  19. Lung Adenocarcinoma Distally Rewires Hepatic Circadian Homeostasis.

    PubMed

    Masri, Selma; Papagiannakopoulos, Thales; Kinouchi, Kenichiro; Liu, Yu; Cervantes, Marlene; Baldi, Pierre; Jacks, Tyler; Sassone-Corsi, Paolo

    2016-05-01

    The circadian clock controls metabolic and physiological processes through finely tuned molecular mechanisms. The clock is remarkably plastic and adapts to exogenous "zeitgebers," such as light and nutrition. How a pathological condition in a given tissue influences systemic circadian homeostasis in other tissues remains an unanswered question of conceptual and biomedical importance. Here, we show that lung adenocarcinoma operates as an endogenous reorganizer of circadian metabolism. High-throughput transcriptomics and metabolomics revealed unique signatures of transcripts and metabolites cycling exclusively in livers of tumor-bearing mice. Remarkably, lung cancer has no effect on the core clock but rather reprograms hepatic metabolism through altered pro-inflammatory response via the STAT3-Socs3 pathway. This results in disruption of AKT, AMPK, and SREBP signaling, leading to altered insulin, glucose, and lipid metabolism. Thus, lung adenocarcinoma functions as a potent endogenous circadian organizer (ECO), which rewires the pathophysiological dimension of a distal tissue such as the liver. PAPERCLIP. PMID:27153497

  20. A circadian rhythm of conidiation in Neurospora crassa (L-12)

    NASA Technical Reports Server (NTRS)

    Miyoshi, Yashuhiro

    1993-01-01

    Two fungi growth chambers containing six growth tubes each are used in this experiment. One chamber is for the space experiment; the other is for the simultaneous ground control experiment. The hyphae of Neurospora crassa band A mutant are inoculated at one end of each tube. Both the chambers are kept at 3 C plus or minus 1.5 C to stop hyphae growth until the Spacelab is activated. After the activation, each chamber is transferred simultaneously to the Spacelab and a phytotron in KSC and kept in continuous light at the same temperature. After about 24 hours of light exposure, each chamber is inserted into a growth chamber bag to keep it in constant darkness. The circadian rhythm of conidiation is initiated by this light to dark transition. After the dark incubation for 5 days at room temperature, both the growth chambers are kept at 3 C plus or minus 1.5 C to stop growth of the hyphae. After the space shuttle lands, both conidiation patterns are compared and analyzed. It has been known that numerous physiological phenomena show circadian rhythms. They are characterized by the fact that the oscillation can persist under constant conditions of light and temperature. Therefore, it has been accepted by most investigators that the generation mechanism of the circadian rhythm is endogeneous. However, one cannot reject the possibility that these rhythms are caused by some geophysical exogeneous factor having a 24-hour period, such as atmospheric pressure, gravity, or electromagnetic radiation. We use Neurospora crassa band A mutual which shows an obvious circadian rhythm in its spore-forming (conidiation) on the ground, and we intend to attempt the conidation of this mutant in the Spacelab where 24-hour periodicity is severely attenuated and to elucidate the effect of the geophysical exogeneous factor in the generation mechanism of the circadian rhythm.

  1. Light-regulated translational control of circadian behavior by eIF4E phosphorylation.

    PubMed

    Cao, Ruifeng; Gkogkas, Christos G; de Zavalia, Nuria; Blum, Ian D; Yanagiya, Akiko; Tsukumo, Yoshinori; Xu, Haiyan; Lee, Choogon; Storch, Kai-Florian; Liu, Andrew C; Amir, Shimon; Sonenberg, Nahum

    2015-06-01

    The circadian (∼24 h) clock is continuously entrained (reset) by ambient light so that endogenous rhythms are synchronized with daily changes in the environment. Light-induced gene expression is thought to be the molecular mechanism underlying clock entrainment. mRNA translation is a key step of gene expression, but the manner in which clock entrainment is controlled at the level of mRNA translation is not well understood. We found that a light- and circadian clock-regulated MAPK/MNK pathway led to phosphorylation of the cap-binding protein eIF4E in the mouse suprachiasmatic nucleus of the hypothalamus, the locus of the master circadian clock in mammals. Phosphorylation of eIF4E specifically promoted translation of Period 1 (Per1) and Period 2 (Per2) mRNAs and increased the abundance of basal and inducible PER proteins, which facilitated circadian clock resetting and precise timekeeping. Together, these results highlight a critical role for light-regulated translational control in the physiology of the circadian clock. PMID:25915475

  2. Aggressive and sexual social stimuli do not phase shift the circadian temperature rhythm in rats.

    PubMed

    Meerlo, P; Daan, S

    1998-05-01

    The objective of the present study was to determine whether the rat circadian system is sensitive to social stimuli. Male rats were subjected to a sociosexual interaction with an estrous female or to an aggressive interaction with a dominant male conspecific. The interactions lasted for 1 h and took place in the middle of the circadian resting phase. Control animals were picked up and handled for a few minutes, but were otherwise left undisturbed. Animals were housed under constant dim red light during the whole period of the experiment. To assess the effects of the interactions on free-running circadian rhythmicity, body temperature was measured by means of radio telemetry. neither the sociosexual interaction with a female nor the aggressive interaction with another male induced phase shifts or changes in the free-running period. The rat circadian system does not seem to be sensitive to social stimuli directly. Moreover, the finding that aggressive interactions do not phase shift circadian rhythms indicates that the endogenous pacemaker in rats is not sensitive to stressors. PMID:9653577

  3. Nonphotic entrainment of the human circadian pacemaker

    NASA Technical Reports Server (NTRS)

    Klerman, E. B.; Rimmer, D. W.; Dijk, D. J.; Kronauer, R. E.; Rizzo, J. F. 3rd; Czeisler, C. A.

    1998-01-01

    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.

  4. A Novel Quantitative Trait Locus on Mouse Chromosome 18, “era1,” Modifies the Entrainment of Circadian Rhythms

    PubMed Central

    Wisor, Jonathan P.; Striz, Martin; DeVoss, Jason; Murphy, Greer M.; Edgar, Dale M.; O'Hara, Bruce F.

    2007-01-01

    Study Objectives: The mammalian circadian clock in the suprachiasmatic nuclei (SCN) of the hypothalamus conveys 24-h rhythmicity to sleep-wake cycles, locomotor activity, and other behavioral and physiological processes. The timing of rhythms relative to the light/dark (LD12:12) cycle is influenced in part by the endogenous circadian period and the time of day specific sensitivity of the clock to light. We now describe a novel circadian rhythm phenotype, and a locus influencing that phenotype, in a segregating population of mice. Methods: By crossbreeding 2 genetically distinct nocturnal strains of mice (Cast/Ei and C57BL/6J) and backcrossing the resulting progeny to Cast/Ei, we have produced a novel circadian phenotype, called early runner mice. Results: Early runner mice entrain to a light/dark cycle at an advanced phase, up to 9 hours before dark onset. This phenotype is not significantly correlated with circadian period in constant darkness and is not associated with disruption of molecular circadian rhythms in the SCN, as assessed by analysis of period gene expression. We have identified a genomic region that regulates this phenotype—a major quantitative trait locus on chromosome 18 (near D18Mit184) that we have named era1 for Early Runner Activity locus one. Phase delays caused by light exposure early in the subjective night were of smaller magnitude in backcross offspring that were homozygous Cast/Ei at D18Mit184 than in those that were heterozygous at this locus. Conclusion: Genetic variability in the circadian response to light may, in part, explain the variance in phase angle of entrainment in this segregating mouse population. Citation: Wisor JP; Striz M; DeVoss J; Murphy GM; Edgar DM; O'Hara BF. A novel quantitative trait locus on mouse chromosome 18, “era1,” modifies the entrainment of circadian rhythms. SLEEP 2007;30(10):1255-1263. PMID:17969459

  5. Analysis of Circadian Leaf Movements.

    PubMed

    Müller, Niels A; Jiménez-Gómez, José M

    2016-01-01

    The circadian clock is a molecular timekeeper that controls a wide variety of biological processes. In plants, clock outputs range from the molecular level, with rhythmic gene expression and metabolite content, to physiological processes such as stomatal conductance or leaf movements. Any of these outputs can be used as markers to monitor the state of the circadian clock. In the model plant Arabidopsis thaliana, much of the current knowledge about the clock has been gained from time course experiments profiling expression of endogenous genes or reporter constructs regulated by the circadian clock. Since these methods require labor-intensive sample preparation or transformation, monitoring leaf movements is an interesting alternative, especially in non-model species and for natural variation studies. Technological improvements both in digital photography and image analysis allow cheap and easy monitoring of circadian leaf movements. In this chapter we present a protocol that uses an autonomous point and shoot camera and free software to monitor circadian leaf movements in tomato. PMID:26867616

  6. Phenotyping Circadian Rhythms in Mice

    PubMed Central

    Eckel-Mahan, Kristin; Sassone-Corsi, Paolo

    2015-01-01

    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

  7. Circadian clock genes universally control key agricultural traits

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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...

  8. Circadian Modulation of Short-Term Memory in "Drosophila"

    ERIC Educational Resources Information Center

    Lyons, Lisa C.; Roman, Gregg

    2009-01-01

    Endogenous biological clocks are widespread regulators of behavior and physiology, allowing for a more efficient allocation of efforts and resources over the course of a day. The extent that different processes are regulated by circadian oscillators, however, is not fully understood. We investigated the role of the circadian clock on short-term…

  9. Exercise influences circadian gene expression in equine skeletal muscle.

    PubMed

    Murphy, B A; Wagner, A L; McGlynn, O F; Kharazyan, F; Browne, J A; Elliott, J A

    2014-07-01

    Circadian rhythms are endogenously generated 24-h oscillations that coordinate numerous aspects of mammalian physiology, metabolism and behaviour. The existence of a molecular circadian clock in equine skeletal muscle has previously been demonstrated. This study investigates how the circadian 24-h expression of exercise-relevant genes in skeletal muscle is influenced by a regular exercise regime. Mid-gluteal, percutaneous muscle biopsies were obtained over a 24-h period from six Thoroughbred mares before and after an 8-week exercise programme. Real-time qPCR assays were used to assess the expression patterns of core clock genes ARNTL, PER2, NR1D1, clock-controlled gene DBP, and muscle genes MYF6, UCP3, VEGFA, FOXO1, MYOD1, PPARGC1A, PPARGC1B, FBXO32 and PDK4. Two-way repeated measures ANOVA revealed a significant interaction between circadian time and exercise for muscle genes MYF6, UCP3, MYOD1 and PDK4. A significant effect of time was observed for all genes with the exception of VEGFA, where a main effect of exercise was observed. By cosinor analysis, the core clock genes, ARNTL (P <0.01) and NR1D1 (P <0.05), showed 24-h rhythmicity both pre- and post-exercise, while PER2 expression was rhythmic post-exercise (P <0.05) but not pre-exercise. The expression profiles of muscle genes MYOD1 and MYF6 showed significant fits to a 24-h cosine waveform indicative of circadian rhythmicity post-exercise only (P <0.01). This study suggests that the metabolic capacity of muscle is influenced by scheduled exercise and that optimal athletic performance may be achieved when exercise times and competition times coincide. PMID:24888677

  10. Molecular Mechanisms of Circadian Regulation During Spaceflight

    NASA Technical Reports Server (NTRS)

    Zanello, S. B.; Boyle, R.

    2012-01-01

    The physiology of both vertebrates and invertebrates follows internal rhythms coordinated in phase with the 24-hour daily light cycle. This circadian clock is governed by a central pacemaker, the suprachiasmatic nucleus (SCN) in the brain. However, peripheral circadian clocks or oscillators have been identified in most tissues. How the central and peripheral oscillators are synchronized is still being elucidated. Light is the main environmental cue that entrains the circadian clock. Under the absence of a light stimulus, the clock continues its oscillation in a free-running condition. In general, three functional compartments of the circadian clock are defined. The vertebrate retina contains endogenous clocks that control many aspects of retinal physiology, including retinal sensitivity to light, neurohormone synthesis (melatonin and dopamine), rod disk shedding, signalling pathways and gene expression. Neurons with putative local circadian rhythm generation are found among all the major neuron populations in the mammalian retina. In the mouse, clock genes and function are more localized to the inner retinal and ganglion cell layers. The photoreceptor, however, secrete melatonin which may still serve a an important circadian signal. The reception and transmission of the non-visual photic stimulus resides in a small subpopulation (1-3%) or retinal ganglion cells (RGC) that express the pigment melanopsin (Opn4) and are called intrisically photoreceptive RGC (ipRGC). Melanopsin peak absorption is at 420 nm and all the axons of the ipRGC reach the SCN. A common countermeasure for circadian re-entrainment utilizes blue-green light to entrain the circadian clock and mitigate the risk of fatigue and health and performance decrement due to circadian rhythm disruption. However, an effective countermeasure targeting the photoreceptor system requires that the basic circadian molecular machinery remains intact during spaceflight. We hypothesize that spaceflight may affect ip

  11. The neurochemical basis of photic entrainment of the circadian pacemaker

    NASA Technical Reports Server (NTRS)

    Rea, Michael A.; Buckley, Becky; Lutton, Lewis M.

    1992-01-01

    Circadian rhythmicity in mammals is controlled by the action of a light-entrainable hypothalamus, in association with two cell clusters known as the supra chiasmatic nuclei (SCN). In the absence of temporal environmental clues, this pacemaker continues to measure time by an endogenous mechanism (clock), driving biochemical, physiological, and behavioral rhythms that reflect the natural period of the pacemaker oscillation. This endogenous period usually differs slightly from 24 hours (i.e., circadian). When mammals are maintained under a 24 hour light-dark (LD) cycle, the pacemaker becomes entrained such that the period of the pacemaker oscillation matches that of the LD cycle. Potentially entraining photic information is conveyed to the SCN via a direct retinal projection, the retinohypothalamic tract (RHT). RHT neurotransmission is thought to be mediated by the release of excitatory amino acids (EAA) in the SCN. In support of this hypothesis, recent experiments using nocturnal rodents have shown that EAA antagonists block the effects of light on pacemaker-driven behavioral rhythms, and attenuate light induced gene expression in SCN cells. An understanding of the neurochemical basis of the photic entrainment process would facilitate the development of pharmacological strategies for maintaining synchrony among shift workers in environments, such as the Space Station, which provide unreliable or conflicting temporal photic clues.

  12. SKIP Is a Component of the Spliceosome Linking Alternative Splicing and the Circadian Clock in Arabidopsis[W

    PubMed Central

    Wang, Xiaoxue; Wu, Fangming; Xie, Qiguang; Wang, Huamei; Wang, Ying; Yue, Yanling; Gahura, Ondrej; Ma, Shuangshuang; Liu, Lei; Cao, Ying; Jiao, Yuling; Puta, Frantisek; McClung, C. Robertson; Xu, Xiaodong; Ma, Ligeng

    2012-01-01

    Circadian clocks generate endogenous rhythms in most organisms from cyanobacteria to humans and facilitate entrainment to environmental diurnal cycles, thus conferring a fitness advantage. Both transcriptional and posttranslational mechanisms are prominent in the basic network architecture of circadian systems. Posttranscriptional regulation, including mRNA processing, is emerging as a critical step for clock function. However, little is known about the molecular mechanisms linking RNA metabolism to the circadian clock network. Here, we report that a conserved SNW/Ski-interacting protein (SKIP) domain protein, SKIP, a splicing factor and component of the spliceosome, is involved in posttranscriptional regulation of circadian clock genes in Arabidopsis thaliana. Mutation in SKIP lengthens the circadian period in a temperature-sensitive manner and affects light input and the sensitivity of the clock to light resetting. SKIP physically interacts with the spliceosomal splicing factor Ser/Arg-rich protein45 and associates with the pre-mRNA of clock genes, such as PSEUDORESPONSE REGULATOR7 (PRR7) and PRR9, and is necessary for the regulation of their alternative splicing and mRNA maturation. Genome-wide investigations reveal that SKIP functions in regulating alternative splicing of many genes, presumably through modulating recognition or cleavage of 5′ and 3′ splice donor and acceptor sites. Our study addresses a fundamental question on how the mRNA splicing machinery contributes to circadian clock function at a posttranscriptional level. PMID:22942380

  13. Clocks for the city: circadian differences between forest and city songbirds

    PubMed Central

    Dominoni, D. M.; Helm, B.; Lehmann, M.; Dowse, H. B.; Partecke, J.

    2013-01-01

    To keep pace with progressing urbanization organisms must cope with extensive habitat change. Anthropogenic light and noise have modified differences between day and night, and may thereby interfere with circadian clocks. Urbanized species, such as birds, are known to advance their activity to early morning and night hours. We hypothesized that such modified activity patterns are reflected by properties of the endogenous circadian clock. Using automatic radio-telemetry, we tested this idea by comparing activity patterns of free-living forest and city European blackbirds (Turdus merula). We then recaptured the same individuals and recorded their activity under constant conditions. City birds started their activity earlier and had faster but less robust circadian oscillation of locomotor activity than forest conspecifics. Circadian period length predicted start of activity in the field, and this relationship was mainly explained by fast-paced and early-rising city birds. Although based on only two populations, our findings point to links between city life, chronotype and circadian phenotype in songbirds, and potentially in other organisms that colonize urban habitats, and highlight that urban environments can significantly modify biologically important rhythms in wild organisms. PMID:23740778

  14. CRTC Potentiates Light-independent timeless Transcription to Sustain Circadian Rhythms in Drosophila.

    PubMed

    Kim, Minkyung; Lee, Hoyeon; Hur, Jin-Hoe; Choe, Joonho; Lim, Chunghun

    2016-01-01

    Light is one of the strongest environmental time cues for entraining endogenous circadian rhythms. Emerging evidence indicates that CREB-regulated transcription co-activator 1 (CRTC1) is a key player in this pathway, stimulating light-induced Period1 (Per1) transcription in mammalian clocks. Here, we demonstrate a light-independent role of Drosophila CRTC in sustaining circadian behaviors. Genomic deletion of the crtc locus causes long but poor locomotor rhythms in constant darkness. Overexpression or RNA interference-mediated depletion of CRTC in circadian pacemaker neurons similarly impairs the free-running behavioral rhythms, implying that Drosophila clocks are sensitive to the dosage of CRTC. The crtc null mutation delays the overall phase of circadian gene expression yet it remarkably dampens light-independent oscillations of TIMELESS (TIM) proteins in the clock neurons. In fact, CRTC overexpression enhances CLOCK/CYCLE (CLK/CYC)-activated transcription from tim but not per promoter in clock-less S2 cells whereas CRTC depletion suppresses it. Consistently, TIM overexpression partially but significantly rescues the behavioral rhythms in crtc mutants. Taken together, our data suggest that CRTC is a novel co-activator for the CLK/CYC-activated tim transcription to coordinate molecular rhythms with circadian behaviors over a 24-hour time-scale. We thus propose that CRTC-dependent clock mechanisms have co-evolved with selective clock genes among different species. PMID:27577611

  15. Protein sequestration versus Hill-type repression in circadian clock models.

    PubMed

    Kim, Jae Kyoung

    2016-08-01

    Circadian (∼24 h) clocks are self-sustained endogenous oscillators with which organisms keep track of daily and seasonal time. Circadian clocks frequently rely on interlocked transcriptional-translational feedback loops to generate rhythms that are robust against intrinsic and extrinsic perturbations. To investigate the dynamics and mechanisms of the intracellular feedback loops in circadian clocks, a number of mathematical models have been developed. The majority of the models use Hill functions to describe transcriptional repression in a way that is similar to the Goodwin model. Recently, a new class of models with protein sequestration-based repression has been introduced. Here, the author discusses how this new class of models differs dramatically from those based on Hill-type repression in several fundamental aspects: conditions for rhythm generation, robust network designs and the periods of coupled oscillators. Consistently, these fundamental properties of circadian clocks also differ among Neurospora, Drosophila, and mammals depending on their key transcriptional repression mechanisms (Hill-type repression or protein sequestration). Based on both theoretical and experimental studies, this review highlights the importance of careful modelling of transcriptional repression mechanisms in molecular circadian clocks. PMID:27444022

  16. CRTC Potentiates Light-independent timeless Transcription to Sustain Circadian Rhythms in Drosophila

    PubMed Central

    Kim, Minkyung; Lee, Hoyeon; Hur, Jin-Hoe; Choe, Joonho; Lim, Chunghun

    2016-01-01

    Light is one of the strongest environmental time cues for entraining endogenous circadian rhythms. Emerging evidence indicates that CREB-regulated transcription co-activator 1 (CRTC1) is a key player in this pathway, stimulating light-induced Period1 (Per1) transcription in mammalian clocks. Here, we demonstrate a light-independent role of Drosophila CRTC in sustaining circadian behaviors. Genomic deletion of the crtc locus causes long but poor locomotor rhythms in constant darkness. Overexpression or RNA interference-mediated depletion of CRTC in circadian pacemaker neurons similarly impairs the free-running behavioral rhythms, implying that Drosophila clocks are sensitive to the dosage of CRTC. The crtc null mutation delays the overall phase of circadian gene expression yet it remarkably dampens light-independent oscillations of TIMELESS (TIM) proteins in the clock neurons. In fact, CRTC overexpression enhances CLOCK/CYCLE (CLK/CYC)-activated transcription from tim but not per promoter in clock-less S2 cells whereas CRTC depletion suppresses it. Consistently, TIM overexpression partially but significantly rescues the behavioral rhythms in crtc mutants. Taken together, our data suggest that CRTC is a novel co-activator for the CLK/CYC-activated tim transcription to coordinate molecular rhythms with circadian behaviors over a 24-hour time-scale. We thus propose that CRTC-dependent clock mechanisms have co-evolved with selective clock genes among different species. PMID:27577611

  17. Clocks for the city: circadian differences between forest and city songbirds.

    PubMed

    Dominoni, D M; Helm, B; Lehmann, M; Dowse, H B; Partecke, J

    2013-07-22

    To keep pace with progressing urbanization organisms must cope with extensive habitat change. Anthropogenic light and noise have modified differences between day and night, and may thereby interfere with circadian clocks. Urbanized species, such as birds, are known to advance their activity to early morning and night hours. We hypothesized that such modified activity patterns are reflected by properties of the endogenous circadian clock. Using automatic radio-telemetry, we tested this idea by comparing activity patterns of free-living forest and city European blackbirds (Turdus merula). We then recaptured the same individuals and recorded their activity under constant conditions. City birds started their activity earlier and had faster but less robust circadian oscillation of locomotor activity than forest conspecifics. Circadian period length predicted start of activity in the field, and this relationship was mainly explained by fast-paced and early-rising city birds. Although based on only two populations, our findings point to links between city life, chronotype and circadian phenotype in songbirds, and potentially in other organisms that colonize urban habitats, and highlight that urban environments can significantly modify biologically important rhythms in wild organisms. PMID:23740778

  18. Ubiquitin ligase Siah2 regulates RevErbα degradation and the mammalian circadian clock

    PubMed Central

    DeBruyne, Jason P.; Baggs, Julie E.; Sato, Trey K.; Hogenesch, John B.

    2015-01-01

    Regulated degradation of proteins by the proteasome is often critical to their function in dynamic cellular pathways. The molecular clock underlying mammalian circadian rhythms relies on the rhythmic expression and degradation of its core components. However, because the tools available for identifying the mechanisms underlying the degradation of a specific protein are limited, the mechanisms regulating clock protein degradation are only beginning to be elucidated. Here we describe a cell-based functional screening approach designed to quickly identify the ubiquitin E3 ligases that induce the degradation of potentially any protein of interest. We screened the nuclear hormone receptor RevErbα (Nr1d1), a key constituent of the mammalian circadian clock, for E3 ligases that regulate its stability and found Seven in absentia2 (Siah2) to be a key regulator of RevErbα stability. Previously implicated in hypoxia signaling, Siah2 overexpression destabilizes RevErbα/β, and siRNA depletion of Siah2 stabilizes endogenous RevErbα. Moreover, Siah2 depletion delays circadian degradation of RevErbα and lengthens period length. These results demonstrate the utility of functional screening approaches for identifying regulators of protein stability and reveal Siah2 as a previously unidentified circadian clockwork regulator that mediates circadian RevErbα turnover. PMID:26392558

  19. Post-transcriptional control of the mammalian circadian clock: implications for health and disease.

    PubMed

    Preußner, Marco; Heyd, Florian

    2016-06-01

    Many aspects of human physiology and behavior display rhythmicity with a period of approximately 24 h. Rhythmic changes are controlled by an endogenous time keeper, the circadian clock, and include sleep-wake cycles, physical and mental performance capability, blood pressure, and body temperature. Consequently, many diseases, such as metabolic, sleep, autoimmune and mental disorders and cancer, are connected to the circadian rhythm. The development of therapies that take circadian biology into account is thus a promising strategy to improve treatments of diverse disorders, ranging from allergic syndromes to cancer. Circadian alteration of body functions and behavior are, at the molecular level, controlled and mediated by widespread changes in gene expression that happen in anticipation of predictably changing requirements during the day. At the core of the molecular clockwork is a well-studied transcription-translation negative feedback loop. However, evidence is emerging that additional post-transcriptional, RNA-based mechanisms are required to maintain proper clock function. Here, we will discuss recent work implicating regulated mRNA stability, translation and alternative splicing in the control of the mammalian circadian clock, and its role in health and disease. PMID:27108448

  20. Circadian clock in Ciona intestinalis revealed by microarray analysis and oxygen consumption.

    PubMed

    Minamoto, Toshifumi; Hanai, Shuji; Kadota, Koji; Oishi, Katsutaka; Matsumae, Hiromi; Fujie, Manabu; Azumi, Kaoru; Satoh, Noriyuki; Satake, Masanobu; Ishida, Norio

    2010-02-01

    The molecular mechanisms of the endogenous circadian clocks that allow most animals to adapt to environmental cycles have recently been uncovered. The draft genome of the ascidian, Ciona intestinalis, a model animal that is close to vertebrates, has been described. However, the C. intestinalis genome lacks the canonical clock genes such as Per, Bmal and Clock that are shared by vertebrates and insects. Here, we found the circadian rhythms at the physiological and molecular levels. The oxygen consumption rate was lower during the light phase and higher during the dark phase during a day, and the rhythm highly damped and continued under constant darkness. From the microarray analysis, the 396 spots (1.8% of the total; corresponding to 388 clones) were extracted as candidates for circadian expression. We confirmed the circadian expression of several candidate genes by northern blotting. Furthermore, three of four rhythmic expressed genes showed phase-shifts to prolonged light period. However, most of known clock genes did not oscillate. These data suggest that C. intestinalis have a unique molecular circadian clock and the daily environmental change is not such a strong effect for sea squirt in its evolution when compared to vertebrates and insects. PMID:19855119

  1. CIRCADIAN RHYTHM REPROGRAMMING DURING LUNG INFLAMMATION

    PubMed Central

    Haspel, Jeffrey A.; Chettimada, Sukrutha; Shaik, Rahamthulla S.; Chu, Jen-Hwa; Raby, Benjamin A.; Cernadas, Manuela; Carey, Vincent; Process, Vanessa; Hunninghake, G. Matthew; Ifedigbo, Emeka; Lederer, James A.; Englert, Joshua; Pelton, Ashley; Coronata, Anna; Fredenburgh, Laura E.; Choi, Augustine M. K.

    2014-01-01

    Circadian rhythms are known to regulate immune responses in healthy animals, but it is unclear whether they persist during acute illnesses where clock gene expression is disrupted by systemic inflammation. Here, we use a genome-wide approach to investigate circadian gene and metabolite expression in the lungs of endotoxemic mice and find that novel cellular and molecular circadian rhythms are elicited in this setting. The endotoxin-specific circadian program exhibits unique features, including a divergent group of rhythmic genes and metabolites compared to the basal state and a distinct periodicity and phase distribution. At the cellular level endotoxin treatment also alters circadian rhythms of leukocyte counts within the lung in a bmal1-dependent manner, such that granulocytes rather than lymphocytes become the dominant oscillating cell type. Our results show that inflammation produces a complex reorganization of cellular and molecular circadian rhythms that are relevant to early events in lung injury. PMID:25208554

  2. Effects of Gravity on Insect Circadian Rhythmicity

    NASA Technical Reports Server (NTRS)

    Hoban-Higgins, Tana M.

    2000-01-01

    Circadian rhythms - endogenous daily rhythmic fluctuations in virtually all characteristics of life - are generated and coordinated by the circadian timing system (CTS). The CTS is synchronized to the external 24-hour day by time cues such as the light/dark cycle. In an environment without time cues, the length of an animal's day is determined by the period of its internal pacemaker (tau) and the animal is said to be free-running. All life on earth evolved under the solar day; the CTS exists as an adaptation that allows organisms to anticipate and to prepare for rhythmic environmental fluctuations. All life on earth also evolved under the force of earth's gravitational environment. While it is therefore not surprising that changes in the lighting environment affect the CTS, it is surprising that changes in the gravitational environment would do so. However, recent data from one of our laboratories using the brn-3.1 knockout mouse revealed that this model, which lacks the sensory receptor hair cells within the neurovestibular system, does not respond to exposure to a hyperdynamic environment in the same fashion as normal mice. The brn-3.1 mice did not show the expected suppression of circadian rhythmicity shown by control mice exposed to 2G. Exposure to altered ambient force environments affects the amplitude, mean and timing of circadian rhythms in species from unicellular organisms to man. In addition, there is a circadian influence on the homeostatic response to acute 2G acceleration and pulses of 2G can act as a time cue, synchronizing the CTS. This is of significance because maintenance of internal and external temporal coordination is critical for normal physiological and psychological function. Typically, during adaptation to an increased gravitational environment (+G), an initial acute reaction is followed by adaptation and, eventually, a new steady state (14-16), which can take weeks to months to establish. Until the development of space stations, exposure

  3. Identification of rhythmic subsystems in the circadian cycle of crassulacean acid metabolism under thermoperiodic perturbations.

    PubMed

    Bohn, Andreas; Hinderlich, Sven; Hütt, Marc-Thorsten; Kaiser, Friedemann; Lüttge, Ulrich

    2003-05-01

    Leaves of the Crassulacean acid metabolism (CAM) plant Kalanchoë daigremontiana Hamet et Perrier de la Bâthie show overt circadian rhythms in net CO2 uptake, leaf conductance to water and intercellular CO2 concentration, which are entrained by periodic temperature cycles. To probe their sensitivity to thermoperiodic perturbations, intact leaves were exposed to continuous light intensity and temperature cycles with a period of 16 h, applying a set of different baseline temperatures and thermodriver amplitudes. All three overt rhythms were analyzed with respect to their frequency spectra and their phase relations with the thermodriver. For most stimulation protocols, stomatal conductance and net CO2 change were fully or partially entrained by the temperature pulses, while the internal CO2 concentration remained dominated by oscillations in the circadian range. Prolonged time series recorded for up to 22 d in continuous light underline the robustness of these circadian oscillations. This suggests that the overt circadian rhythm of net CO2 uptake in CAM results from the interaction of two coupled original systems: (i) an endogenous cycle of CO2 fixation in the mesophyll, showing very robust periodic activity, and (ii) stomatal movements that respond to environmental stimuli independently of rhythmic processes in the mesophyll, and thus modulate the gas exchange amplitude. PMID:12817468

  4. Comparison of arbitrary definitions of circadian time periods with those determined by wrist actigraphy in analysis of ABPM data.

    PubMed

    Eissa, M A; Yetman, R J; Poffenbarger, T; Portman, R J

    1999-07-01

    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. PMID:10449208

  5. Comparison of arbitrary definitions of circadian time periods with those determined by wrist actigraphy in analysis of ABPM data.

    PubMed

    Eissa, M A; Yetman, R J; Poffenbarger, T; Portman, R J

    1999-11-01

    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. PMID:10578220

  6. INTRINSIC CIRCADIAN RHYTHMS IN THE CARDIOMYOCYTE

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The cardiomyocyte possesses a fully functional circadian clock. Circadian clocks are a set of proteins that generate self-sustained transcriptional positive and negative feedback loops with a free-running period of 24 hours. These intracellular molecular mechanisms confer the selective advantage of ...

  7. Klf15 orchestrates circadian nitrogen homeostasis

    PubMed Central

    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.

    2012-01-01

    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

  8. Circadian Rhythms, Sleep Deprivation, and Human Performance

    PubMed Central

    Goel, Namni; Basner, Mathias; Rao, Hengyi; Dinges, David F.

    2014-01-01

    Much of the current science on, and mathematical modeling of, dynamic changes in human performance within and between days is dominated by the two-process model of sleep–wake regulation, which posits a neurobiological drive for sleep that varies homeostatically (increasing as a saturating exponential during wakefulness and decreasing in a like manner during sleep), and a circadian process that neurobiologically modulates both the homeostatic drive for sleep and waking alertness and performance. Endogenous circadian rhythms in neurobehavioral functions, including physiological alertness and cognitive performance, have been demonstrated using special laboratory protocols that reveal the interaction of the biological clock with the sleep homeostatic drive. Individual differences in circadian rhythms and genetic and other components underlying such differences also influence waking neurobehavioral functions. Both acute total sleep deprivation and chronic sleep restriction increase homeostatic sleep drive and degrade waking neurobehavioral functions as reflected in sleepiness, attention, cognitive speed, and memory. Recent evidence indicating a high degree of stability in neurobehavioral responses to sleep loss suggests that these trait-like individual differences are phenotypic and likely involve genetic components, including circadian genes. Recent experiments have revealed both sleep homeostatic and circadian effects on brain metabolism and neural activation. Investigation of the neural and genetic mechanisms underlying the dynamically complex interaction between sleep homeostasis and circadian systems is beginning. A key goal of this work is to identify biomarkers that accurately predict human performance in situations in which the circadian and sleep homeostatic systems are perturbed. PMID:23899598

  9. Circadian regulation of renal function.

    PubMed

    Firsov, Dmitri; Bonny, Olivier

    2010-10-01

    Urinary excretion of water and all major electrolytes exhibit robust circadian oscillations. The 24-h periodicity has been well documented for several important determinants of urine formation, including renal blood flow, glomerular filtration, tubular reabsorption, and tubular secretion. 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 that are entrained by rest/activity and feeding/fasting cycles. However, numerous studies have shown that 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 made of a system of autoregulatory transcriptional/translational feedback loops, which have been found in all tissues studied, including the kidney. Here, we present a review of the growing evidence showing the involvement of the molecular clock in the generation of renal excretory rhythms. PMID:20664559

  10. Circadian pattern of wheel-running activity of a South American subterranean rodent (Ctenomys cf knightii).

    PubMed

    Valentinuzzi, Veronica Sandra; Oda, Gisele Akemi; Araujo, John Fontenele; Ralph, Martin Roland

    2009-01-01

    Circadian rhythms are regarded as essentially ubiquitous features of animal behavior and are thought to confer important adaptive advantages. However, although circadian systems of rodents have been among the most extensively studied, most comparative biology is restricted to a few related species. In this study, the circadian organization of locomotor activity was studied in the subterranean, solitary north Argentinean rodent, Ctenomys knightii. The genus, Ctenomys, commonly known as Tuco-tucos, comprises more than 50 known species over a range that extends from 12 degrees S latitude into Patagonia, and includes at least one social species. The genus, therefore, is ideal for comparative and ecological studies of circadian rhythms. Ctenomys knightii is the first of these to be studied for its circadian behavior. All animals were wild caught but adapted quickly to laboratory conditions, with clear and precise activity-rest rhythms in a light-dark (LD) cycle and strongly nocturnal wheel running behavior. In constant dark (DD), the rhythm expression persisted with free-running periods always longer than 24 h. Upon reinstatement of the LD cycle, rhythms resynchronized rapidly with large phase advances in 7/8 animals. In constant light (LL), six animals had free-running periods shorter than in DD, and 4/8 showed evidence of "splitting." We conclude that under laboratory conditions, in wheel-running cages, this species shows a clear nocturnal rhythmic organization controlled by an endogenous circadian oscillator that is entrained to 24 h LD cycles, predominantly by light-induced advances, and shows the same interindividual variable responses to constant light as reported in other non-subterranean species. These data are the first step toward understanding the chronobiology of the largest genus of subterranean rodents. PMID:19142755

  11. The role of circadian rhythm in breast cancer

    PubMed Central

    Li, Shujing; Ao, Xiang

    2013-01-01

    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. PMID:23997531

  12. Circadian disc shedding in Xenopus retina in vitro

    SciTech Connect

    Flannery, J.G.; Fisher, S.K.

    1984-02-01

    To further examine the endogenous rhythm of disc shedding and phagocytosis observed in several species, adult Xenopus were entrained to a 12 hr light/12 hr dark cycle and then placed in constant darkness. At various times during a 3-day period of constant darkness, eyes were explanted and placed into culture medium, then processed for light and electron microscopy. A clear rhythmicity of disc shedding was observed, with pronounced peaks at the times light onset occurred in the original entrainment cycle. Modification of the HCO/sub 3/- ion concentration in the medium was found to raise the amplitude of the peak of endogenous disc shedding. Explants maintained in culture medium containing deuterium oxide (a compound known to perturb circadian oscillators) were found to shed with a longer interval between peaks. The addition of the protein synthesis inhibitor, anisomycin, to this preparation suppressed the shedding rhythm. The action of anisomycin was investigated by autoradiographic examination of the pattern of /sup 3/H-leucine uptake and protein synthesis by the explant. The findings suggest the presence of a circadian oscillator for rhythmic disc shedding within the amphibian eye.

  13. Low-Salt Diet and Circadian Dysfunction Synergize to Induce Angiotensin II-Dependent Hypertension in Mice.

    PubMed

    Pati, Paramita; Fulton, David J R; Bagi, Zsolt; Chen, Feng; Wang, Yusi; Kitchens, Julia; Cassis, Lisa A; Stepp, David W; Rudic, R Daniel

    2016-03-01

    Blood pressure exhibits a robust circadian rhythm in health. In hypertension, sleep apnea, and even shift work, this balanced rhythm is perturbed via elevations in night-time blood pressure, inflicting silent damage to the vasculature and body organs. Herein, we examined the influence of circadian dysfunction during experimental hypertension in mice. Using radiotelemetry to measure ambulatory blood pressure and activity, the effects of angiotensin II administration were studied in wild-type (WT) and period isoform knockout (KO) mice (Per2-KO, Per2, 3-KO, and Per1, 2, 3-KO/Per triple KO [TKO] mice). On a normal diet, administration of angiotensin II caused nondipping blood pressure and exacerbated vascular hypertrophy in the Period isoform KO mice relative to WT mice. To study the endogenous effects of angiotensin II stimulation, we then administered a low-salt diet to the mice, which does stimulate endogenous angiotensin II in addition to lowering blood pressure. A low-salt diet decreased blood pressure in wild-type mice. In contrast, Period isoform KO mice lost their circadian rhythm in blood pressure on a low-salt diet, because of an increase in resting blood pressure, which was restorable to rhythmicity by the angiotensin receptor blocker losartan. Chronic administration of low salt caused vascular hypertrophy in Period isoform KO mice, which also exhibited increased renin levels and altered angiotensin 1 receptor expression. These data suggest that circadian clock genes may act to inhibit or control renin/angiotensin signaling. Moreover, circadian disorders such as sleep apnea and shift work may alter the homeostatic responses to sodium restriction to potentially influence nocturnal hypertension. PMID:26781276

  14. Two mechanisms of rephasal of circadian rhythms in response to a 180 deg phase shift /simulated 12-hr time zone change/

    NASA Technical Reports Server (NTRS)

    Deroshia, C. W.; Winget, C. M.; Bond, G. H.

    1976-01-01

    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.

  15. Dipper and non-dipper blood pressure 24-hour patterns: circadian rhythm-dependent physiologic and pathophysiologic mechanisms.

    PubMed

    Fabbian, Fabio; Smolensky, Michael H; Tiseo, Ruana; Pala, Marco; Manfredini, Roberto; Portaluppi, Francesco

    2013-03-01

    Neuroendocrine mechanisms are major determinants of the normal 24-h blood pressure (BP) pattern. At the central level, integration of the major driving factors of this temporal variability is mediated by circadian rhythms of monoaminergic systems in conjunction with those of the hypothalamic-pituitary-adrenal, hypothalamic-pituitary-thyroid, opioid, renin-angiotensin-aldosterone, plus endothelial systems and specific vasoactive peptides. Humoral secretions are typically episodic, coupled either to sleep and/or the circadian endogenous (suprachiasmatic nucleus) central pacemaker clock, but exhibiting also weekly, monthly, seasonal, and annual periodicities. Sleep induction and arousal are influenced also by many hormones and chemical substances that exhibit 24-h variation, e.g., arginine vasopressin, vasoactive intestinal peptide, melatonin, somatotropin, insulin, steroids, serotonin, corticotropin-releasing factor, adrenocorticotropic hormone, thyrotropin-releasing hormone, endogenous opioids, and prostaglandin E2, all with established effects on the cardiovascular system. As a consequence, physical, mental, and pathologic stimuli that activate or inhibit neuroendocrine effectors of biological rhythmicity may also interfere with, or modify, the temporal BP structure. Moreover, immediate adjustment to exogenous components/environment demands by BP rhythms is modulated by the circadian-time-dependent responsiveness of biological oscillators and their neuroendocrine effectors. This knowledge contributes to a better understanding of the pathophysiology of abnormalities of the 24-h BP pattern and level and their correction through circadian rhythm-based chronotherapeutic strategies. PMID:23002916

  16. Light and Gravity Effects on Circadian Rhythms of Rhesus Macaques

    NASA Technical Reports Server (NTRS)

    Fuller, Charles

    1997-01-01

    Temporal integration of a biological organism's physiological, behavioral and biochemical systems depends upon its circadian timing system. The endogenous period of this timing system is typically synchronized to the 24- hour day by environmental cues. The daily alternation of light and dark has long been known as one of the most potent environmental synchronizers influencing the circadian timing system. Alterations in the lighting environment (length or intensity of light exposure) can also affect the homeostatic state of the organism. A series of experiments was performed using rhesus monkeys with the objective of defining the fundamental properties of the circadian rhythm of body temperature. Three major experiments were performed in addition to several preliminary studies. These experiments explored 1.) the response of the rhesus body temperature rhythm to varying day length and light intensity; 2.) the response of the body temperature rhythm to light exposure as a function of time of day; and 3.) the characteristics of the metabolic heat production rhythm which is responsible for the daily cycle in body temperature. Results of these three completed experiments will be reported here. In addition, preliminary experiments were also performed in social entrainment of rhesus circadian rhythms and the properties of rhesus body temperature rhythms in constant conditions, where no external time cues were provided. Four adult male rhesus monkeys served as subjects in all experiments. All experiments were performed at the California Regional Primate Research Center. Each animal was implanted with a biotelemetry unit that measured deep body temperature. All surgeries were performed by a board certified veterinary surgeon under sterile conditions. The biotelemetry implants also provided an index of activity level in each animal. For metabolic heat production measurements, oxygen consumption and carbon dioxide production were measured and the caloric equivalent of these

  17. Circadian Cycles of Gene Expression in the Coral, Acropora millepora

    PubMed Central

    Brady, Aisling K.; Snyder, Kevin A.; Vize, Peter D.

    2011-01-01

    Background Circadian rhythms regulate many physiological, behavioral and reproductive processes. These rhythms are often controlled by light, and daily cycles of solar illumination entrain many clock regulated processes. In scleractinian corals a number of different processes and behaviors are associated with specific periods of solar illumination or non-illumination—for example, skeletal deposition, feeding and both brooding and broadcast spawning. Methodology/Principal Findings We have undertaken an analysis of diurnal expression of the whole transcriptome and more focused studies on a number of candidate circadian genes in the coral Acropora millepora using deep RNA sequencing and quantitative PCR. Many examples of diurnal cycles of RNA abundance were identified, some of which are light responsive and damped quickly under constant darkness, for example, cryptochrome 1 and timeless, but others that continue to cycle in a robust manner when kept in constant darkness, for example, clock, cryptochrome 2, cycle and eyes absent, indicating that their transcription is regulated by an endogenous clock entrained to the light-dark cycle. Many other biological processes that varied between day and night were also identified by a clustering analysis of gene ontology annotations. Conclusions/Significance Corals exhibit diurnal patterns of gene expression that may participate in the regulation of circadian biological processes. Rhythmic cycles of gene expression occur under constant darkness in both populations of coral larvae that lack zooxanthellae and in individual adult tissue containing zooxanthellae, indicating that transcription is under the control of a biological clock. In addition to genes potentially involved in regulating circadian processes, many other pathways were found to display diel cycles of transcription. PMID:21949855

  18. Circadian rhythms: glucocorticoids and arthritis.

    PubMed

    Cutolo, Maurizio; Sulli, Alberto; Pizzorni, Carmen; Secchi, Maria Elena; Soldano, Stefano; Seriolo, Bruno; Straub, Rainer H; Otsa, Kati; Maestroni, Georges J

    2006-06-01

    Circadian rhythms are driven by biological clocks and are endogenous in origin. Therefore, circadian changes in the metabolism or secretion of endogenous glucocorticoids are certainly responsible in part for the time-dependent changes observed in the inflammatory response and arthritis. More recently, melatonin (MLT), another circadian hormone that is the secretory product of the pineal gland, has been found implicated in the time-dependent inflammatory reaction with effects opposite those of cortisol. Interestingly, cortisol and MLT show an opposite response to the light. The light conditions in the early morning have a strong impact on the morning cortisol peak, whereas MLT is synthesized in a strictly nocturnal pattern. Recently, a diurnal rhythmicity in healthy humans between cellular (Th1 type) or humoral (Th2 type) immune responses has been found and related to immunomodulatory actions of cortisol and MLT. The interferon (IFN)-gamma/interleukin (IL)-10 ratio peaked during the early morning and correlated negatively with plasma cortisol and positively with plasma MLT. Accordingly, the intensity of the arthritic pain varies consistently as a function of the hour of the day: pain is greater after waking up in the morning than in the afternoon or evening. The reduced cortisol and adrenal androgen secretion, observed during testing in rheumatoid arthritis (RA) patients not treated with glucocoticoids, should be clearly considered as a "relative adrenal insufficiency" in the presence of a sustained inflammatory process, and allows Th1 type cytokines to be produced in higher amounts during the late night. In conclusion, the right timing (early morning) for the glucocorticoid therapy in arthritis is fundamental and well justified by the circadian rhythms of the inflammatory mechanisms. PMID:16855156

  19. α1B-Adrenergic receptor signaling controls circadian expression of Tnfrsf11b by regulating clock genes in osteoblasts

    PubMed Central

    Hirai, Takao; Tanaka, Kenjiro; Togari, Akifumi

    2015-01-01

    ABSTRACT Circadian clocks are endogenous and biological oscillations that occur with a period of <24 h. In mammals, the central circadian pacemaker is localized in the suprachiasmatic nucleus (SCN) and is linked to peripheral tissues through neural and hormonal signals. In the present study, we investigated the physiological function of the molecular clock on bone remodeling. The results of loss-of-function and gain-of-function experiments both indicated that the rhythmic expression of Tnfrsf11b, which encodes osteoprotegerin (OPG), was regulated by Bmal1 in MC3T3-E1 cells. We also showed that REV-ERBα negatively regulated Tnfrsf11b as well as Bmal1 in MC3T3-E1 cells. We systematically investigated the relationship between the sympathetic nervous system and the circadian clock in osteoblasts. The administration of phenylephrine, a nonspecific α1-adrenergic receptor (AR) agonist, stimulated the expression of Tnfrsf11b, whereas the genetic ablation of α1B-AR signaling led to the alteration of Tnfrsf11b expression concomitant with Bmal1 and Per2 in bone. Thus, this study demonstrated that the circadian regulation of Tnfrsf11b was regulated by the clock genes encoding REV-ERBα (Nr1d1) and Bmal1 (Bmal1, also known as Arntl), which are components of the core loop of the circadian clock in osteoblasts. PMID:26453621

  20. Nutrition and the Circadian System

    PubMed Central

    Potter, Gregory D M; Cade, Janet E; Grant, Peter J; Hardie, Laura J

    2016-01-01

    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

  1. Nutrition and the circadian system.

    PubMed

    Potter, Gregory D M; Cade, Janet E; Grant, Peter J; Hardie, Laura J

    2016-08-01

    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. PMID:27221157

  2. Circadian and wakefulness-sleep modulation of cognition in humans.

    PubMed

    Wright, Kenneth P; Lowry, Christopher A; Lebourgeois, Monique K

    2012-01-01

    Cognitive and affective processes vary over the course of the 24 h day. Time of day dependent changes in human cognition are modulated by an internal circadian timekeeping system with a near-24 h period. The human circadian timekeeping system interacts with sleep-wakefulness regulatory processes to modulate brain arousal, neurocognitive and affective function. Brain arousal is regulated by ascending brain stem, basal forebrain (BF) and hypothalamic arousal systems and inhibition or disruption of these systems reduces brain arousal, impairs cognition, and promotes sleep. The internal circadian timekeeping system modulates cognition and affective function by projections from the master circadian clock, located in the hypothalamic suprachiasmatic nuclei (SCN), to arousal and sleep systems and via clock gene oscillations in brain tissues. Understanding the basic principles of circadian and wakefulness-sleep physiology can help to recognize how the circadian system modulates human cognition and influences learning, memory and emotion. Developmental changes in sleep and circadian processes and circadian misalignment in circadian rhythm sleep disorders have important implications for learning, memory and emotion. Overall, when wakefulness occurs at appropriate internal biological times, circadian clockwork benefits human cognitive and emotion function throughout the lifespan. Yet, when wakefulness occurs at inappropriate biological times because of environmental pressures (e.g., early school start times, long work hours that include work at night, shift work, jet lag) or because of circadian rhythm sleep disorders, the resulting misalignment between circadian and wakefulness-sleep physiology leads to impaired cognitive performance, learning, emotion, and safety. PMID:22529774

  3. Circadian and wakefulness-sleep modulation of cognition in humans

    PubMed Central

    Wright, Kenneth P.; Lowry, Christopher A.; LeBourgeois, Monique K.

    2012-01-01

    Cognitive and affective processes vary over the course of the 24 h day. Time of day dependent changes in human cognition are modulated by an internal circadian timekeeping system with a near-24 h period. The human circadian timekeeping system interacts with sleep-wakefulness regulatory processes to modulate brain arousal, neurocognitive and affective function. Brain arousal is regulated by ascending brain stem, basal forebrain (BF) and hypothalamic arousal systems and inhibition or disruption of these systems reduces brain arousal, impairs cognition, and promotes sleep. The internal circadian timekeeping system modulates cognition and affective function by projections from the master circadian clock, located in the hypothalamic suprachiasmatic nuclei (SCN), to arousal and sleep systems and via clock gene oscillations in brain tissues. Understanding the basic principles of circadian and wakefulness-sleep physiology can help to recognize how the circadian system modulates human cognition and influences learning, memory and emotion. Developmental changes in sleep and circadian processes and circadian misalignment in circadian rhythm sleep disorders have important implications for learning, memory and emotion. Overall, when wakefulness occurs at appropriate internal biological times, circadian clockwork benefits human cognitive and emotion function throughout the lifespan. Yet, when wakefulness occurs at inappropriate biological times because of environmental pressures (e.g., early school start times, long work hours that include work at night, shift work, jet lag) or because of circadian rhythm sleep disorders, the resulting misalignment between circadian and wakefulness-sleep physiology leads to impaired cognitive performance, learning, emotion, and safety. PMID:22529774

  4. A circadian rhythm in the expression of PERIOD2 protein reveals a novel SCN-controlled oscillator in the oval nucleus of the bed nucleus of the stria terminalis.

    PubMed

    Amir, Shimon; Lamont, Elaine Waddington; Robinson, Barry; Stewart, Jane

    2004-01-28

    Circadian rhythms in mammals are regulated not only globally by the master clock in the suprachiasmatic nucleus (SCN), but also locally by widely distributed populations of clock cells in the brain and periphery that control tissue-specific rhythmic outputs. Here we show that the oval nucleus of the bed nucleus of the stria terminalis (BNST-OV) exhibits a robust circadian rhythm in expression of the Period2 (PER2) clock protein. PER2 expression is rhythmic in the BNST-OV in rats housed under a light/dark cycle or in constant darkness, in blind rats, and in mice, and is in perfect synchrony with the PER2 rhythm of the SCN. Constant light or bilateral SCN lesions abolish the rhythm of PER2 in the BNST-OV. Large abrupt shifts in the light schedule transiently uncouple the BNST-OV rhythm from that of the SCN. Re-entrainment of the PER2 rhythm is faster in the SCN than in the BNST-OV, and it is faster after a delay than an advance shift. Bilateral adrenalectomy blunts the PER2 rhythm in the BNST-OV. Thus, the BNST-OV contains circadian clock cells that normally oscillate in synchrony with the SCN, but these cells appear to require both input from the SCN and circulating glucocorticoids to maintain their circadian oscillation. Taken together with what is known about the functional organization of the connections of the BNST-OV with systems of the brain involved in stress and motivational processes, these findings place BNST-OV oscillators in a position to influence specific physiological and behavioral rhythms downstream from the SCN clock. PMID:14749422

  5. Circadian Clock Control of Liver Metabolic Functions.

    PubMed

    Reinke, Hans; Asher, Gad

    2016-03-01

    The circadian clock is an endogenous biological timekeeping system that synchronizes physiology and behavior to day/night cycles. A wide variety of processes throughout the entire gastrointestinal tract and notably the liver appear to be under circadian control. These include various metabolic functions such as nutrient uptake, processing, and detoxification, which align organ function to cycle with nutrient supply and demand. Remarkably, genetic or environmental disruption of the circadian clock can cause metabolic diseases or exacerbate pathological states. In addition, modern lifestyles force more and more people worldwide into asynchrony between the external time and their circadian clock, resulting in a constant state of social jetlag. Recent evidence indicates that interactions between altered energy metabolism and disruptions in the circadian clock create a downward spiral that can lead to diabetes and other metabolic diseases. In this review, we provide an overview of rhythmic processes in the liver and highlight the functions of circadian clock genes under physiological and pathological conditions; we focus on their roles in regulation of hepatic glucose as well as lipid and bile acid metabolism and detoxification and their potential effects on the development of fatty liver and nonalcoholic steatohepatitis. PMID:26657326

  6. Caffeine does not entrain the circadian clock but improves daytime alertness in blind patients with non-24-hour rhythms

    PubMed Central

    St. Hilaire, Melissa A.; Lockley, Steven W.

    2015-01-01

    Objective/Background Totally blind individuals are highly likely to suffer from Non-24-Hour Sleep-Wake Disorder due to a failure of light to reset the circadian pacemaker in the suprachiasmatic nuclei. In this outpatient case series, we investigated whether daily caffeine administration could entrain the circadian pacemaker in non-entrained blind patients to alleviate symptoms of non-24-hour sleep–wake disorder. Patients/Methods Three totally blind males (63.0 ± 7.5 years old) were studied at home over ~4 months. Urinary 6-sulphatoxymelatonin (aMT6s) rhythms were measured for 48 h every 1–2 weeks. Participants completed daily sleep–wake logs, and rated their alertness and mood using nine-point scales every ~2–4 h while awake on urine sampling days. Caffeine capsules (150 mg per os) were self-administered daily at 10 a.m. for approximately one circadian beat cycle based on each participant's endogenous circadian period τ and compared to placebo (n = 2) or no treatment (n = 1) in a single-masked manner. Results Non-24-h aMT6s rhythms were confirmed in all three participants (τ range = 24.32–24.57 h). Daily administration of 150 mg caffeine did not entrain the circadian clock. Caffeine treatment significantly improved daytime alertness at adverse circadian phases (p < 0.0001) but did not decrease the occurrence of daytime naps compared with placebo. Conclusions Although caffeine was able to improve daytime alertness acutely and may therefore provide temporary symptomatic relief, the inability of caffeine to correct the underlying circadian disorder means that an entraining agent is required to treat Non-24-Hour Sleep–Wake Disorder in the blind appropriately. PMID:25891543

  7. Daily Rhythms of Hunger and Satiety in Healthy Men during One Week of Sleep Restriction and Circadian Misalignment

    PubMed Central

    Sargent, Charli; Zhou, Xuan; Matthews, Raymond W.; Darwent, David; Roach, Gregory D.

    2016-01-01

    The impact of sleep restriction on the endogenous circadian rhythms of hunger and satiety were examined in 28 healthy young men. Participants were scheduled to 2 × 24-h days of baseline followed by 8 × 28-h days of forced desynchrony during which sleep was either moderately restricted (equivalent to 6 h in bed/24 h; n = 14) or severely restricted (equivalent to 4 h in bed/24 h; n = 14). Self-reported hunger and satisfaction were assessed every 2.5 h during wake periods using visual analogue scales. Participants were served standardised meals and snacks at regular intervals and were not permitted to eat ad libitum. Core body temperature was continuously recorded with rectal thermistors to determine circadian phase. Both hunger and satiety exhibited a marked endogenous circadian rhythm. Hunger was highest, and satiety was lowest, in the biological evening (i.e., ~17:00–21:00 h) whereas hunger was lowest, and satiety was highest in the biological night (i.e., 01:00–05:00 h). The results are consistent with expectations based on previous reports and may explain in some part the decrease in appetite that is commonly reported by individuals who are required to work at night. Interestingly, the endogenous rhythms of hunger and satiety do not appear to be altered by severe—as compared to moderate—sleep restriction. PMID:26840322

  8. Sex Differences in Circadian Timing Systems: Implications for Disease

    PubMed Central

    Bailey, Matthew; Silver, Rae

    2014-01-01

    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

  9. Clock Genes Show Circadian Rhythms in Salivary Glands

    PubMed Central

    Zheng, L.; Seon, Y.J.; McHugh, J.; Papagerakis, S.; Papagerakis, P.

    2012-01-01

    Circadian rhythms are endogenous self-sustained oscillations with 24-hour periods that regulate diverse physiological and metabolic processes through complex gene regulation by “clock” transcription factors. The oral cavity is bathed by saliva, and its amount and content are modified within regular daily intervals. The clock mechanisms that control salivary production remain unclear. Our objective was to evaluate the expression and periodicity of clock genes in salivary glands. Real-time quantitative RT-PCR, in situ hybridization, and immunohistochemistry were performed to show circadian mRNA and protein expression and localization of key clock genes (Bmal1, Clock, Per1, and Per2), ion and aqua channel genes (Ae2a, Car2, and Aqp5), and salivary gland markers. Clock gene mRNAs and clock proteins were found differentially expressed in the serous acini and duct cells of all major salivary glands. The expression levels of clock genes and Aqp5 showed regular oscillatory patterns under both light/dark and complete-dark conditions. Bmla1 overexpression resulted in increased Aqp5 expression levels. Analysis of our data suggests that salivary glands have a peripheral clock mechanism that functions both in normal light/dark conditions and in the absence of light. This finding may increase our understanding of the control mechanisms of salivary content and flow. PMID:22699207

  10. Cloning of circadian rhythmic pathway genes and perturbation of oscillation patterns in endocrine disrupting chemicals (EDCs)-exposed mangrove killifish Kryptolebias marmoratus.

    PubMed

    Rhee, Jae-Sung; Kim, Bo-Mi; Lee, Bo-Young; Hwang, Un-Ki; Lee, Yong Sung; Lee, Jae-Seong

    2014-08-01

    -associated genes showed a regular oscillation pattern over a period of approximately 24h during a 12L:12D cycle. However, the circadian rhythm of BPA-exposed juvenile K. marmoratus liver tissue was perturbed over a 12L:12D period. This study will aid in our understanding of how EDCs perturb endogenous circadian rhythms, particularly in BPA-exposed fish liver tissue. PMID:24726801

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

    PubMed Central

    O'Callaghan, Emma K.; Anderson, Sean T.; Moynagh, Paul N.; Coogan, Andrew N.

    2012-01-01

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

  12. The Neuroendocrine Control of the Circadian System: Adolescent Chronotype

    PubMed Central

    Hagenauer, Megan Hastings; Lee, Theresa M.

    2012-01-01

    Scientists, public health and school officials are paying growing attention to the mechanism underlying the delayed sleep patterns common in human adolescents. Data suggest that a propensity towards evening chronotype develops during puberty, and may be caused by developmental alterations in internal daily timekeeping. New support for this theory has emerged from recent studies which show that pubertal changes in chronotype occur in many laboratory species similar to human adolescents. Using these species as models, we find that pubertal changes in chronotype differ by sex, are internally generated, and driven by reproductive hormones. These chronotype changes are accompanied by alterations in the fundamental properties of the circadian timekeeping system, including endogenous rhythm period and sensitivity to environmental time cues. After comparing the developmental progression of chronotype in different species, we propose a theory regarding the ecological relevance of adolescent chronotype, and provide suggestions for improving the sleep of human adolescents. PMID:22634481

  13. The Nonlinear Phase Response Curve of the Human Circadian Pacemaker and How Complex Behaviors Might Arise in Nature

    NASA Astrophysics Data System (ADS)

    Leder, Ron S.

    2002-08-01

    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.

  14. Impact of nutrients on circadian rhythmicity

    PubMed Central

    Oosterman, Johanneke E.; Kalsbeek, Andries; la Fleur, Susanne E.

    2014-01-01

    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

  15. Circadian systems biology: When time matters

    PubMed Central

    Fuhr, Luise; Abreu, Mónica; Pett, Patrick; Relógio, Angela

    2015-01-01

    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

  16. Circadian Variation in Suicide Attempts in Tokyo from 1978 to 1985.

    ERIC Educational Resources Information Center

    Motohashi, Yutaka

    1990-01-01

    Analyzed circadian variations in suicide attempts in Tokyo from 1978 to 1985 from records of Ambulance Service of Tokyo. Findings showed significant circadian variation in suicide attempts which seemed to be associated with endogenous rhythms, such as mood, and daily variation in social activities. Established peak time for suicide attempts as…

  17. Circadian phenotyping of obese and diabetic db/db mice.

    PubMed

    Grosbellet, Edith; Dumont, Stephanie; Schuster-Klein, Carole; Guardiola-Lemaitre, Beatrice; Pevet, Paul; Criscuolo, François; Challet, Etienne

    2016-05-01

    Growing evidence links metabolic disorders to circadian alterations. Genetically obese db/db mice, lacking the long isoform of leptin receptor, are a recognized model of type 2 diabetes. In this study, we aimed at characterizing the potential circadian alterations of db/db mice in comparison to db/+ control mice. By using telemetry devices, we first reported arrhythmicity in general activity of most db/db mice under both light-dark cycle and constant darkness, while their rhythm of body temperature is less dramatically disrupted. Water access restricted to nighttime restores significant rhythmicity in behaviorally arrhythmic db/db mice, indicating a masking effect of polydipsia when water is available ad libitum. Endogenous period of temperature rhythm under constant dark conditions is significantly increased (+30 min) in db/db compared with db/+ mice. Next, we studied the oscillations of clock proteins (PER1, PER2 and BMAL1) in the suprachiasmatic nuclei (SCN), the site of the master clock, and detected no difference according to the genotype. Furthermore, c-FOS and P-ERK1/2 expression in response to a light pulse in late night was significantly increased (+80 and +55%, respectively) in the SCN of these diabetic mice. We previously showed that, in addition to altered activity rhythms, db/db mice exhibit altered feeding rhythm. Therefore, we investigated daily patterns of clock protein expression in medial hypothalamic oscillators involved in feeding behavior (arcuate nucleus, ventro- and dorso-medial hypothalamic nuclei). Compared with db/+ mice, very subtle or no difference in oscillations of PER1 and BMAL1 is found in the medial hypothalamus. Although we did not find a clear link between altered hypothalamic clockwork and behavioral rhythms in db/db mice, our results highlight a lengthened endogenous period and altered photic integration in these genetically obese and diabetic mice. PMID:26144489

  18. Circadian rhythms and fractal fluctuations in forearm motion

    NASA Astrophysics Data System (ADS)

    Hu, Kun; Hilton, Michael F.

    2005-03-01

    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.

  19. Characterisation of circadian rhythms of various duckweeds.

    PubMed

    Muranaka, T; Okada, M; Yomo, J; Kubota, S; Oyama, T

    2015-01-01

    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. PMID:24942699

  20. Circadian rhythms, alcohol and gut interactions

    PubMed Central

    Forsyth, Christopher B.; Voigt, Rbin M.; Burgess, Helen J.; Swanson, Garth R.; Keshavarzian, Ali

    2015-01-01

    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

  1. Circadian Misalignment, Reward-Related Brain Function, and Adolescent Alcohol Involvement

    PubMed Central

    Hasler, Brant P.; Clark, Duncan B.

    2013-01-01

    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

  2. A Circadian Clock Gene, Cry, Affects Heart Morphogenesis and Function in Drosophila as Revealed by Optical Coherence Microscopy

    PubMed Central

    Zeng, Xianxu; Tate, Rebecca E.; McKee, Mary L.; Capen, Diane E.; Zhang, Zhan; Tanzi, Rudolph E.; Zhou, Chao

    2015-01-01

    Circadian rhythms are endogenous, entrainable oscillations of physical, mental and behavioural processes in response to local environmental cues such as daylight, which are present in the living beings, including humans. Circadian rhythms have been related to cardiovascular function and pathology. However, the role that circadian clock genes play in heart development and function in a whole animal in vivo are poorly understood. The Drosophila cryptochrome (dCry) is a circadian clock gene that encodes a major component of the circadian clock negative feedback loop. Compared to the embryonic stage, the relative expression levels of dCry showed a significant increase (>100-fold) in Drosophila during the pupa and adult stages. In this study, we utilized an ultrahigh resolution optical coherence microscopy (OCM) system to perform non-invasive and longitudinal analysis of functional and morphological changes in the Drosophila heart throughout its post-embryonic lifecycle for the first time. The Drosophila heart exhibited major morphological and functional alterations during its development. Notably, heart rate (HR) and cardiac activity period (CAP) of Drosophila showed significant variations during the pupa stage, when heart remodeling took place. From the M-mode (2D + time) OCM images, cardiac structural and functional parameters of Drosophila at different developmental stages were quantitatively determined. In order to study the functional role of dCry on Drosophila heart development, we silenced dCry by RNAi in the Drosophila heart and mesoderm, and quantitatively measured heart morphology and function in those flies throughout its development. Silencing of dCry resulted in slower HR, reduced CAP, smaller heart chamber size, pupal lethality and disrupted posterior segmentation that was related to increased expression of a posterior compartment protein, wingless. Collectively, our studies provided novel evidence that the circadian clock gene, dCry, plays an essential

  3. A Circadian Clock Gene, Cry, Affects Heart Morphogenesis and Function in Drosophila as Revealed by Optical Coherence Microscopy.

    PubMed

    Alex, Aneesh; Li, Airong; Zeng, Xianxu; Tate, Rebecca E; McKee, Mary L; Capen, Diane E; Zhang, Zhan; Tanzi, Rudolph E; Zhou, Chao

    2015-01-01

    Circadian rhythms are endogenous, entrainable oscillations of physical, mental and behavioural processes in response to local environmental cues such as daylight, which are present in the living beings, including humans. Circadian rhythms have been related to cardiovascular function and pathology. However, the role that circadian clock genes play in heart development and function in a whole animal in vivo are poorly understood. The Drosophila cryptochrome (dCry) is a circadian clock gene that encodes a major component of the circadian clock negative feedback loop. Compared to the embryonic stage, the relative expression levels of dCry showed a significant increase (>100-fold) in Drosophila during the pupa and adult stages. In this study, we utilized an ultrahigh resolution optical coherence microscopy (OCM) system to perform non-invasive and longitudinal analysis of functional and morphological changes in the Drosophila heart throughout its post-embryonic lifecycle for the first time. The Drosophila heart exhibited major morphological and functional alterations during its development. Notably, heart rate (HR) and cardiac activity period (CAP) of Drosophila showed significant variations during the pupa stage, when heart remodeling took place. From the M-mode (2D + time) OCM images, cardiac structural and functional parameters of Drosophila at different developmental stages were quantitatively determined. In order to study the functional role of dCry on Drosophila heart development, we silenced dCry by RNAi in the Drosophila heart and mesoderm, and quantitatively measured heart morphology and function in those flies throughout its development. Silencing of dCry resulted in slower HR, reduced CAP, smaller heart chamber size, pupal lethality and disrupted posterior segmentation that was related to increased expression of a posterior compartment protein, wingless. Collectively, our studies provided novel evidence that the circadian clock gene, dCry, plays an essential

  4. Opening the Debate: How to Fulfill the Need for Physicians’ Training in Circadian-Related Topics in a Full Medical School Curriculum

    PubMed Central

    Selfridge, Julia M; Moyer, Kurtis; Capelluto, Daniel G S

    2015-01-01

    Background: Circadian rhythms are daily changes in our physiology and behavior that are manifested as patterns of brain wave activity, periodic hormone production, recurring cell regeneration, and other oscillatory biological activities. Their importance to human health is becoming apparent; they are deranged by shift work and jet-lag and in disparate conditions such as insomnia, sleep syndromes, coronary heart attacks, and depression, and are endogenous factors that contribute to cancer development and progression. Discussion: As evidence of the circadian connection to human health has grown, so has the number of Americans experiencing disruption of circadian rhythms due to the demands of an industrialized society. Today, there is a growing work force that experiences night shift work and time-zone shifts shaping the demands on physicians to best meet the needs of patients exposed to chronic circadian disruptions. The diverse range of illness associated with altered rhythms suggests that physicians in various fields will see its impact in their patients. However, medical education, with an already full curriculum, struggles to address this issue. Summary: Here, we emphasize the need for incorporating the topic of circadian rhythms in the medical curriculum and propose strategies to accomplish this goal. PMID:27103933

  5. Characterization of neurospora circadian rhythms in space

    NASA Technical Reports Server (NTRS)

    Ferraro, James S.

    1987-01-01

    To determine whether the circadian rhythm of conidiation in neurospora crassa is endogenously derived or is driven by some geophysical time cue, an experiment was conducted on space shuttle flight STS-9, where inoculated race tubes were exposed to the microgravity environment of space. The results demonstated that the rhythm can persist in space. However, there were several minor alterations noted; an increase in the period of the oscillation and the variability of the growth rate and a diminished rhythm amplitude, which eventually damped out in 25% of the flight tubes. On day seven of the flight, the tubes were exposed to light while their growth fronts were marked. It appears that some aspects of this marking process reinstated a robust rhythm in all the tubes which continued throughout the remainder of the flight. It was hypothesized that the damping found prior to the marking procedure on STS-9 may have been a result of the hypergravity pulse of launch and not due to the microgravity of the orbital lab; furthermore, that the marking procedure, by exposing the samples to light, had reinstated rhythmicity. To test this, an investigation was conducted into the effects of acute and chronic exposure to hypergravity.

  6. Increased neuropeptide Y concentrations in the lateral hypothalamic area of the rat after the onset of darkness: Possible relevance to the circadian periodicity of feeding behavior

    SciTech Connect

    McKibbin, P.E.; Robers, P.; Williams, G. )

    1991-01-01

    Neuropeptide Y (NPY) is a major hypothalamic peptide which powerfully stimulates feeding when injected into the hypothalamus and is implicated in circadian rhythmicity. To investigate whether NPY is involved in the increased feeding that follows the onset of darkness in rats, NPY levels were measured in discrete hypothalamic areas before and after darkness. Four groups of eight adult female Wistar rats were habituated to a 12:12 hour light:dark cycle, with food presented at the onset of darkness (19.00 hours). Seven hypothalamic regions were microdissected from slices of fresh brain and acid-extracted for radioimmunoassay of NPY. NPY levels ((fmol/{mu}g) protein) were significantly higher in the lateral hypothalamic area (LHA) of the dark-phase group in both studies. In the other six regions, NPY levels did not differ between light and dark phases. The LHA regulates the circadian rhythmicity of feeding and NPY injection here stimulates feeding. Alterations in NPY in the LHA around the onset of darkness may be related to the initiation of dark-phase feeding.

  7. A tunable artificial circadian clock in clock-defective mice

    PubMed Central

    D'Alessandro, Matthew; Beesley, Stephen; Kim, Jae Kyoung; Chen, Rongmin; Abich, Estela; Cheng, Wayne; Yi, Paul; Takahashi, Joseph S.; Lee, Choogon

    2015-01-01

    Self-sustaining oscillations are essential for diverse physiological functions such as the cell cycle, insulin secretion and circadian rhythms. Synthetic oscillators using biochemical feedback circuits have been generated in cell culture. These synthetic systems provide important insight into design principles for biological oscillators, but have limited similarity to physiological pathways. Here we report the generation of an artificial, mammalian circadian clock in vivo, capable of generating robust, tunable circadian rhythms. In mice deficient in Per1 and Per2 genes (thus lacking circadian rhythms), we artificially generate PER2 rhythms and restore circadian sleep/wake cycles with an inducible Per2 transgene. Our artificial clock is tunable as the period and phase of the rhythms can be modulated predictably. This feature, and other design principles of our work, might enhance the study and treatment of circadian dysfunction and broader aspects of physiology involving biological oscillators. PMID:26617050

  8. Effects of Withdrawal from Chronic Intermittent Ethanol Vapor on the Level and Circadian Periodicity of Running-Wheel Activity in C57BL/6J and C3H/HeJ Mice

    PubMed Central

    Logan, Ryan W.; McCulley, Walter D.; Seggio, Joseph A.; Rosenwasser, Alan M.

    2011-01-01

    Background Alcohol withdrawal is associated with behavioral and chronobiological disturbances that may persist during protracted abstinence. We previously reported that C57BL/6J (B6) mice show marked but temporary reductions in running-wheel activity, and normal free-running circadian rhythms, following a 4-day chronic intermittent ethanol vapor (CIE) exposure (16 hours of ethanol vapor exposure alternating with 8 hours of withdrawal). In the present experiments, we extend these observations in two ways: (1) by examining post-CIE locomotor activity in C3H/HeJ (C3H) mice, an inbred strain characterized by high sensitivity to ethanol withdrawal, and (2) by directly comparing the responses of B6 and C3H mice to a longer-duration CIE protocol. Methods In Experiment 1, C3H mice were exposed to the same 4-day CIE protocol used in our previous study with B6 mice (referred to here as the 1-cycle CIE protocol). In Experiment 2, C3H and B6 mice were exposed to three successive 4-day CIE cycles, each separated by 2 days of withdrawal (the 3-cycle CIE protocol). Running-wheel activity was monitored prior to and following CIE, and post-CIE activity was recorded in constant darkness to allow assessment of free-running circadian period and phase. Results C3H mice displayed pronounced reductions in running-wheel activity that persisted for the duration of the recording period (up to 30 days) following both 1-cycle (Experiment 1) and 3-cycle (Experiment 2) CIE protocols. In contrast, B6 mice showed reductions in locomotor activity that persisted for about one week following the 3-cycle CIE protocol, similar to the results of our previous study using a 1-cycle protocol in this strain. Additionally, C3H mice showed significant shortening of free-running period following the 3-cycle, but not the 1-cycle, CIE protocol, while B6 mice showed normal free-running rhythms. Conclusions These results reveal genetic differences in the persistence of ethanol withdrawal-induced hypo

  9. Circadian gating of neuronal functionality: a basis for iterative metaplasticity.

    PubMed

    Iyer, Rajashekar; Wang, Tongfei A; Gillette, Martha U

    2014-01-01

    Brain plasticity, the ability of the nervous system to encode experience, is a modulatory process leading to long-lasting structural and functional changes. Salient experiences induce plastic changes in neurons of the hippocampus, the basis of memory formation and recall. In the suprachiasmatic nucleus (SCN), the central circadian (~24-h) clock, experience with light at night induces changes in neuronal state, leading to circadian plasticity. The SCN's endogenous ~24-h time-generator comprises a dynamic series of functional states, which gate plastic responses. This restricts light-induced alteration in SCN state-dynamics and outputs to the nighttime. Endogenously generated circadian oscillators coordinate the cyclic states of excitability and intracellular signaling molecules that prime SCN receptivity to plasticity signals, generating nightly windows of susceptibility. We propose that this constitutes a paradigm of ~24-h iterative metaplasticity, the repeated, patterned occurrence of susceptibility to induction of neuronal plasticity. We detail effectors permissive for the cyclic susceptibility to plasticity. We consider similarities of intracellular and membrane mechanisms underlying plasticity in SCN circadian plasticity and in hippocampal long-term potentiation (LTP). The emerging prominence of the hippocampal circadian clock points to iterative metaplasticity in that tissue as well. Exploring these links holds great promise for understanding circadian shaping of synaptic plasticity, learning, and memory. PMID:25285070

  10. [The kidney and circadian rhythms: a whole new world?].

    PubMed

    Manfredini, Roberto; Sasso, Ferdinando Carlo; Pala, Marco; De Giorgi, Alfredo; Fabbian, Fabio

    2013-01-01

    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. PMID:24403200

  11. Neuroimaging, cognition, light and circadian rhythms.

    PubMed

    Gaggioni, Giulia; Maquet, Pierre; Schmidt, Christina; Dijk, Derk-Jan; Vandewalle, Gilles

    2014-01-01

    In humans, sleep and wakefulness and the associated cognitive processes are regulated through interactions between sleep homeostasis and the circadian system. Chronic disruption of sleep and circadian rhythmicity is common in our society and there is a need for a better understanding of the brain mechanisms regulating sleep, wakefulness and associated cognitive processes. This review summarizes recent investigations which provide first neural correlates of the combined influence of sleep homeostasis and circadian rhythmicity on cognitive brain activity. Markers of interindividual variations in sleep-wake regulation, such as chronotype and polymorphisms in sleep and clock genes, are associated with changes in cognitive brain responses in subcortical and cortical areas in response to manipulations of the sleep-wake cycle. This review also includes recent data showing that cognitive brain activity is regulated by light, which is a powerful modulator of cognition and alertness and also directly impacts sleep and circadian rhythmicity. The effect of light varied with age, psychiatric status, PERIOD3 genotype and changes in sleep homeostasis and circadian phase. These data provide new insights into the contribution of demographic characteristics, the sleep-wake cycle, circadian rhythmicity and light to brain functioning. PMID:25071478

  12. Circadian rhythmometry of mammalian radiosensitivity

    NASA Technical Reports Server (NTRS)

    Haus, E.; Halberg, F.; Loken, M. K.; Kim, Y. S.

    1974-01-01

    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.

  13. Circadian desynchrony and metabolic dysfunction; did light pollution make us fat?

    PubMed

    Wyse, C A; Selman, C; Page, M M; Coogan, A N; Hazlerigg, D G

    2011-12-01

    Circadian rhythms are daily oscillations in physiology and behaviour that recur with a period of 24h, and that are entrained by the daily photoperiod. The cycle of sunrise and sunset provided a reliable time cue for many thousands of years, until the advent of artificial lighting disrupted the entrainment of human circadian rhythms to the solar photoperiod. Circadian desynchrony (CD) occurs when endogenous rhythms become misaligned with daily photoperiodic cycles, and this condition is facilitated by artificial lighting. This review examines the hypothesis that chronic CD that has accompanied the availability of electric lighting in the developed world induces a metabolic and behavioural phenotype that is predisposed to the development of obesity. The evidence to support this hypothesis is based on epidemiological data showing coincidence between the appearance of obesity and the availability of artificial light, both geographically, and historically. This association links CD to obesity in humans, and is corroborated by experimental studies that demonstrate that CD can induce obesity and metabolic dysfunction in humans and in rodents. This association between CD and obesity has far reaching implications for human health, lifestyle and work practices. Attention to the rhythmicity of daily sleep, exercise, work and feeding schedules could be beneficial in targeting or reversing the modern human predisposition to obesity. PMID:21983352

  14. Seasonality in circadian locomotor activity and serum testosterone level in the subtropical tree sparrow (Passer montanus).

    PubMed

    Dixit, Anand S; Singh, Namram S

    2016-05-01

    Seasonality in daily locomotor activity pattern was investigated in the subtropical tree sparrow by exposing a group of birds to natural day lengths (NDL) for 30days and another group to 12L/12D for 14days followed by transfer to constant dim light (LLdim) for another 15days in four different seasons of the year. Serum testosterone levels were also measured during different seasons. Sparrows, under NDL, exhibited distinct circadian rhythmicity in their locomotor activity with almost similar general pattern in different seasons that restricted mainly to the light hours. However, they showed season-dependent differences in the characteristics of circadian locomotor activity rhythm. Birds, when exposed to 12L/12D, showed entrainment of their locomotor activity rhythm with the activity confined mainly during the light phase. Though, tau (τ) under free run conditions did not show any significant difference, the activity period varied significantly in different seasons. The highest level of testosterone was recorded in the spring season that corresponded with the maximum locomotor activity in spring months. The seasonality in daily locomotor activity correlates with the seasonal changes in testosterone levels suggesting the influence of gonadal steroids on endogenous circadian system which is indicative of adaptation of tree sparrow to local photoperiodic conditions. PMID:26945648

  15. Influence of the Circadian System on Disease Severity

    PubMed Central

    Litinski, Mikhail; Scheer, Frank AJL; Shea, Steven A

    2009-01-01

    Synopsis The severity of many diseases varies across the day and night. For example, adverse cardiovascular incidents peak in the morning, asthma is often worse at night and temporal lobe epileptic seizures are most prevalent in the afternoon. These patterns may be due to the day/night rhythm in environment and behavior, and/or endogenous circadian rhythms in physiology. Furthermore, chronic misalignment between the endogenous circadian timing system and the behavioral cycles could be a cause of increased risk of diabetes, obesity, cardiovascular disease and certain cancers in shift workers. Here we describe the magnitude, relevance and potential biological basis of such daily changes in disease severity and of circadian/behavioral misalignment, and present how these insights may help in the development of appropriate chronotherapy. PMID:20161149

  16. Circadian Entrainment, Sleep-Wake Regulation and Neurobehavioral Performance During Extended Duration Space Flight

    NASA Technical Reports Server (NTRS)

    Czeisler, Charles A.

    1999-01-01

    Long-duration manned space flight requires crew members to maintain a high level of cognitive performance and vigilance while operating and monitoring sophisticated instrumentation. However, the reduction in the strength of environmental synchronizers in the space environment leads to misalignment of circadian phase among crew members, coupled with restricted time available to sleep, results in sleep deprivation and consequent deterioration of neurobehavioral function. Crew members are provided, and presently use, long-acting benzodiazepine hypnotics on board the current, relatively brief space shuttle missions to counteract such sleep disruption, a situation that is only likely to worsen during extended duration missions. Given the known carry-over effects of such compounds on daytime performance, together with the reduction in emergency readiness associated with their use at night, NASA has recognized the need to develop effective but safe countermeasures to allow crew members to obtain an adequate amount of sleep. Over the past eight years, we have successfully implemented a new technology for shuttle crew members involving bright light exposure during the pre-launch period to facilitate adaptation of the circadian timing system to the inversions of the sleep-wake schedule often required during dual shift missions. However for long duration space station missions it will be necessary to develop effective and attainable countermeasures that can be used chronically to optimize circadian entrainment. Our current research effort is to study the effects of light-dark cycles with reduced zeitgeber strength, such as are anticipated during long-duration space flight, on the entrainment of the endogenous circadian timing system and to study the effects of a countermeasure that consists of scheduled brief exposures to bright light on the human circadian timing system. The proposed studies are designed to address the following Specific Aims: (1) test the hypothesis that

  17. Endotoxin Disrupts Circadian Rhythms in Macrophages via Reactive Oxygen Species

    PubMed Central

    Wang, Yusi; Pati, Paramita; Xu, Yiming; Chen, Feng; Stepp, David W.; Huo, Yuqing; Rudic, R. Daniel; Fulton, David J. R.

    2016-01-01

    The circadian clock is a transcriptional network that functions to regulate the expression of genes important in the anticipation of changes in cellular and organ function. Recent studies have revealed that the recognition of pathogens and subsequent initiation of inflammatory responses are strongly regulated by a macrophage-intrinsic circadian clock. We hypothesized that the circadian pattern of gene expression might be influenced by inflammatory stimuli and that loss of circadian function in immune cells can promote pro-inflammatory behavior. To investigate circadian rhythms in inflammatory cells, peritoneal macrophages were isolated from mPer2luciferase transgenic mice and circadian oscillations were studied in response to stimuli. Using Cosinor analysis, we found that LPS significantly altered the circadian period in peritoneal macrophages from mPer2luciferase mice while qPCR data suggested that the pattern of expression of the core circadian gene (Bmal1) was disrupted. Inhibition of TLR4 offered protection from the LPS-induced impairment in rhythm, suggesting a role for toll-like receptor signaling. To explore the mechanisms involved, we inhibited LPS-stimulated NO and superoxide. Inhibition of NO synthesis with L-NAME had no effect on circadian rhythms. In contrast, inhibition of superoxide with Tempol or PEG-SOD ameliorated the LPS-induced changes in circadian periodicity. In gain of function experiments, we found that overexpression of NOX5, a source of ROS, could significantly disrupt circadian function in a circadian reporter cell line (U2OS) whereas iNOS overexpression, a source of NO, was ineffective. To assess whether alteration of circadian rhythms influences macrophage function, peritoneal macrophages were isolated from Bmal1-KO and Per-TKO mice. Compared to WT macrophages, macrophages from circadian knockout mice exhibited altered balance between NO and ROS release, increased uptake of oxLDL and increased adhesion and migration. These results

  18. Neuroendocrine underpinnings of sex differences in circadian timing systems.

    PubMed

    Yan, Lily; Silver, Rae

    2016-06-01

    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

  19. Traumatic Brain Injury-Induced Dysregulation of the Circadian Clock

    PubMed Central

    Boone, Deborah R.; Sell, Stacy L.; Micci, Maria-Adelaide; Crookshanks, Jeanna M.; Parsley, Margaret; Uchida, Tatsuo; Prough, Donald S.; DeWitt, Douglas S.; Hellmich, Helen L.

    2012-01-01

    Circadian rhythm disturbances are frequently reported in patients recovering from traumatic brain injury (TBI). Since circadian clock output is mediated by some of the same molecular signaling cascades that regulate memory formation (cAMP/MAPK/CREB), cognitive problems reported by TBI survivors may be related to injury-induced dysregulation of the circadian clock. In laboratory animals, aberrant circadian rhythms in the hippocampus have been linked to cognitive and memory dysfunction. Here, we addressed the hypothesis that circadian rhythm disruption after TBI is mediated by changes in expression of clock genes in the suprachiasmatic nuclei (SCN) and hippocampus. After fluid-percussion TBI or sham surgery, male Sprague-Dawley rats were euthanized at 4 h intervals, over a 48 h period for tissue collection. Expression of circadian clock genes was measured using quantitative real-time PCR in the SCN and hippocampus obtained by laser capture and manual microdissection respectively. Immunofluorescence and Western blot analysis were used to correlate TBI-induced changes in circadian gene expression with changes in protein expression. In separate groups of rats, locomotor activity was monitored for 48 h. TBI altered circadian gene expression patterns in both the SCN and the hippocampus. Dysregulated expression of key circadian clock genes, such as Bmal1 and Cry1, was detected, suggesting perturbation of transcriptional-translational feedback loops that are central to circadian timing. In fact, disruption of circadian locomotor activity rhythms in injured animals occurred concurrently. These results provide an explanation for how TBI causes disruption of circadian rhythms as well as a rationale for the consideration of drugs with chronobiotic properties as part of a treatment strategy for TBI. PMID:23056261

  20. NONO couples the circadian clock to the cell cycle

    PubMed Central

    Kowalska, Elzbieta; Ripperger, Juergen A.; Hoegger, Dominik C.; Bruegger, Pascal; Buch, Thorsten; Birchler, Thomas; Mueller, Anke; Albrecht, Urs; Contaldo, Claudio; Brown, Steven A.

    2013-01-01

    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

  1. Revealing a circadian clock in captive arctic-breeding songbirds, lapland longspurs (Calcarius lapponicus), under constant illumination.

    PubMed

    Ashley, Noah T; Ubuka, Takayoshi; Schwabl, Ingrid; Goymann, Wolfgang; Salli, Brady M; Bentley, George E; Buck, C Loren

    2014-12-01

    Most organisms in temperate or tropic regions employ the light-dark (LD) cycle as the primary Zeitgeber to synchronize circadian rhythms. At higher latitudes (>66°33'), continuous illumination during the summer presents a significant time-keeping dilemma for polar-adapted species. Lapland longspurs (Calcarius lapponicus), arctic-breeding migratory songbirds, are one of the few recorded species maintaining an intact diel rhythm in activity and plasma melatonin titers during polar summer. However, it is unknown whether rhythms are endogenous and entrain to low-amplitude polar Zeitgeber signals, such as daily variations in light intensity and the spectral composition of the sun (as measured by color temperature). Wild-caught male and female longspurs were brought into captivity, and locomotor activity was assessed using infrared detection. To examine if rhythms were endogenous, birds were exposed to constant bright light (LL; 1300 lux) or constant darkness (DD; 0.1 lux). All birds exhibited free-running activity rhythms in LL and DD, suggesting the presence of a functional circadian clock. Mean periods in LL (22.86 h) were significantly shorter than those in DD (23.5 h), in accordance with Aschoff's rule. No birds entrained to diel changes in light intensity, color temperature, or both. To examine endogenous molecular clock function, the Per2 gene was partially cloned in longspurs (llPer2) and transcripts were measured in hypothalamic tissue punches, eye, and liver using competitive polymerase chain reaction. Ocular llPer2 gene expression was periodic in LL and elevated at ZT24 (CT24) for LD or constant conditions (LL and DD), but llPer2 rhythmicity was not detected in hypothalamus or liver. Plasma melatonin was significantly lower in LL compared with LD or DD. In conclusion, rhythmic ocular Per2 expression and melatonin secretion may maintain the circadian activity rhythm across the polar day. PMID:25326246

  2. Developmental alcohol and circadian clock function.

    PubMed

    Earnest, D J; Chen, W J; West, J R

    2001-01-01

    Studies in rats found that alcohol exposure during the early postnatal period, particularly during the brain-growth-spurt period, can result in cell loss in various brain regions and persistent behavioral impairments. Some investigators have speculated that the body's internal clock, which is located in the suprachiasmatic nuclei (SCN) in the brain, may also be affected by developmental alcohol exposure. For example, alcohol-induced damage to the SCN cells and their function could result in disturbances of the circadian timekeeping function, and these disturbances might contribute to the behavioral impairments and affective disorders observed in people prenatally exposed to alcohol. Preliminary findings of studies conducted in rats suggest that developmental alcohol exposure may indeed interfere with circadian clock function as evidenced by a shortened circadian sleep-wake cycle and changes in the release of certain brain chemicals (i.e., neuropeptides) by SCN cells. PMID:11584552

  3. Nutrient Sensing and the Circadian Clock

    PubMed Central

    Peek, Clara B.; Ramsey, Kathryn M.; Marcheva, Biliana; Bass, Joseph

    2012-01-01

    The circadian system synchronizes behavioral and physiologic processes with daily changes in the external light-dark cycle, optimizing energetic cycles with the rising and setting of the sun. Molecular clocks are organized hierarchically, with neural clocks orchestrating the daily switch between periods of feeding and fasting, and peripheral clocks generating 24hr oscillations of energy storage and utilization. Recent studies indicate that clocks respond to nutrient signals, and that high-fat diet influences the period of locomotor activity under free-running conditions, a core property of the clock. A major goal is to identify the molecular basis for the reciprocal relationship between metabolic and circadian pathways. Here, we highlight the role of peptidergic hormones and macromolecules as nutrient signals integrating circadian and metabolic systems. PMID:22424658

  4. Circadian Role in Daily Pattern of Cardiovascular Risk

    NASA Astrophysics Data System (ADS)

    Ivanov, Plamen Ch.; Hu, Kun; Chen, Zhi; Hilton, Michael F.; Stanley, H. Eugene; Shea, Steven A.

    2004-03-01

    Numerous epidemiological studies demonstrate that sudden cardiac death, pulmonary embolism, myocardial infarction, and stroke have a 24-hour daily pattern with a broad peak between 9-11am. Such a daily pattern in cardiovascular risk could be attributable to external factors, such as the daily behavior patterns, including sleep-wake cycles and activity levels, or internal factors, such as the endogenous circadian pacemaker. Findings of significant alternations in the temporal organization and nonlinear properties of heartbeat fluctuations with disease and with sleep-wake transitions raise the intriguing possibility that changes in the mechanism of control associated with behavioral sleep-wake transition may be responsible for the increased cardiac instability observed in particular circadian phases. Alternatively, we hypothesize that there is a circadian clock, independent of the sleep-wake cycle, which affects the cardiac dynamics leading to increased cardiovascular risk. We analyzed continuous recordings from healthy subjects during 7 cycles of forced desynchrony routine wherein subjects' sleep-wake cycles are adjusted to 28 hours so that their behaviors occur across all circadian phases. Heartbeat data were divided into one-hour segments. For each segment, we estimated the correlations and the nonlinear properties of the heartbeat fluctuations at the corresponding circadian phase. Since the sleep and wake contributions are equally weighted in our experiment, a change of the properties of the heartbeat dynamics with circadian phase suggest a circadian rhythm. We show significant circadian-mediated alterations in the correlation and nonlinear properties of the heartbeat resembling those observed in patients with heart failure. Remarkably, these dynamical alterations are centered at 60 degrees circadian phase, coinciding with the 9-11am window of cardiac risk.

  5. Intrinsic, nondeterministic circadian rhythm generation in identified mammalian neurons

    PubMed Central

    Webb, Alexis B.; Angelo, Nikhil; Huettner, James E.; Herzog, Erik D.

    2009-01-01

    Circadian rhythms are modeled as reliable and self-sustained oscillations generated by single cells. The mammalian suprachiasmatic nucleus (SCN) keeps near 24-h time in vivo and in vitro, but the identity of the individual cellular pacemakers is unknown. We tested the hypothesis that circadian cycling is intrinsic to a unique class of SCN neurons by measuring firing rate or Period2 gene expression in single neurons. We found that fully isolated SCN neurons can sustain circadian cycling for at least 1 week. Plating SCN neurons at <100 cells/mm2 eliminated synaptic inputs and revealed circadian neurons that contained arginine vasopressin (AVP) or vasoactive intestinal polypeptide (VIP) or neither. Surprisingly, arrhythmic neurons (nearly 80% of recorded neurons) also expressed these neuropeptides. Furthermore, neurons were observed to lose or gain circadian rhythmicity in these dispersed cell cultures, both spontaneously and in response to forskolin stimulation. In SCN explants treated with tetrodotoxin to block spike-dependent signaling, neurons gained or lost circadian cycling over many days. The rate of PERIOD2 protein accumulation on the previous cycle reliably predicted the spontaneous onset of arrhythmicity. We conclude that individual SCN neurons can generate circadian oscillations; however, there is no evidence for a specialized or anatomically localized class of cell-autonomous pacemakers. Instead, these results indicate that AVP, VIP, and other SCN neurons are intrinsic but unstable circadian oscillators that rely on network interactions to stabilize their otherwise noisy cycling. PMID:19805326

  6. Intrinsic, nondeterministic circadian rhythm generation in identified mammalian neurons.

    PubMed

    Webb, Alexis B; Angelo, Nikhil; Huettner, James E; Herzog, Erik D

    2009-09-22

    Circadian rhythms are modeled as reliable and self-sustained oscillations generated by single cells. The mammalian suprachiasmatic nucleus (SCN) keeps near 24-h time in vivo and in vitro, but the identity of the individual cellular pacemakers is unknown. We tested the hypothesis that circadian cycling is intrinsic to a unique class of SCN neurons by measuring firing rate or Period2 gene expression in single neurons. We found that fully isolated SCN neurons can sustain circadian cycling for at least 1 week. Plating SCN neurons at <100 cells/mm(2) eliminated synaptic inputs and revealed circadian neurons that contained arginine vasopressin (AVP) or vasoactive intestinal polypeptide (VIP) or neither. Surprisingly, arrhythmic neurons (nearly 80% of recorded neurons) also expressed these neuropeptides. Furthermore, neurons were observed to lose or gain circadian rhythmicity in these dispersed cell cultures, both spontaneously and in response to forskolin stimulation. In SCN explants treated with tetrodotoxin to block spike-dependent signaling, neurons gained or lost circadian cycling over many days. The rate of PERIOD2 protein accumulation on the previous cycle reliably predicted the spontaneous onset of arrhythmicity. We conclude that individual SCN neurons can generate circadian oscillations; however, there is no evidence for a specialized or anatomically localized class of cell-autonomous pacemakers. Instead, these results indicate that AVP, VIP, and other SCN neurons are intrinsic but unstable circadian oscillators that rely on network interactions to stabilize their otherwise noisy cycling. PMID:19805326

  7. Regulation of circadian rhythms in mammals by behavioral arousal.

    PubMed

    Webb, Ian C; Antle, Michael C; Mistlberger, Ralph E

    2014-06-01

    Circadian rhythms in most mammals are synchronized to local time by phase and period resetting actions of daily light-dark cycles on a retino-recipient, light-entrainable circadian pacemaker, the suprachiasmatic nucleus (SCN). The SCN receives input from other brain regions, some of which mediate the phase and period resetting actions of behavioral arousal on circadian rhythms. We review historical milestones in the discovery of so-called "nonphotic" circadian clock resetting induced by environmentally stimulated arousal, or by feedback from clock-controlled rest-activity cycles. Topics include species generality, interactions between concurrent or successive photic and nonphotic inputs to the circadian clock, neural pathways, neurotransmitters, and clock cell responses that mediate resetting by behavioral arousal. The role of behavioral inputs to the circadian clock in determining the phase of entrainment to local time in natural environments is not well understood. Nonetheless, nonphotic effects are of sufficient magnitude to raise issues for the design of experiments in behavioral neuroscience (any procedure that is sufficiently arousing may alter the timing of circadian clocks that regulate dependent variables of primary interest). Nonphotic inputs to the clock may be exploited in strategies to reset or strengthen circadian rhythms in humans. PMID:24773430

  8. A novel role of microRNA 17-5p in the modulation of circadian rhythm.

    PubMed

    Gao, Qian; Zhou, Lan; Yang, Su-Yu; Cao, Ji-Min

    2016-01-01

    The circadian clock helps living organisms to adjust their physiology and behaviour to adapt environmental day-night cycles. The period length of circadian rhythm reflects the endogenous cycle transition rate and is modulated by environmental cues or internal molecules, and the latter are of substantial importance but remain poorly revealed. Here, we demonstrated that microRNA 17-5p (miR-17-5p), which has been associated with tumours, was an important factor in controlling the circadian period. MiR-17-5p was rhythmically expressed in synchronised fibroblasts and mouse master clock suprachiasmatic nuclei (SCN). MiR-17-5p and the gene Clock exhibited a reciprocal regulation: miR-17-5p inhibited the translation of Clock by targeting the 3'UTR (untranslated region) of Clock mRNA, whereas the CLOCK protein directly bound to the promoter of miR-17 and enhanced its transcription and production of miR-17-5p. In addition, miR-17-5p suppressed the expression of Npas2. At the cellular level, bidirectional changes in miR-17-5p or CLOCK resulted in CRY1 elevation. Accordingly, in vivo, both increase and decrease of miR-17-5p in the mouse SCN led to an increase in CRY1 level and shortening of the free-running period. We conclude that miR-17-5p has an important role in the inspection and stabilisation of the circadian-clock period by interacting with Clock and Npas2 and potentially via the output of CRY1. PMID:27440219

  9. A novel role of microRNA 17-5p in the modulation of circadian rhythm

    PubMed Central

    Gao, Qian; Zhou, Lan; Yang, Su-Yu; Cao, Ji-Min

    2016-01-01

    The circadian clock helps living organisms to adjust their physiology and behaviour to adapt environmental day-night cycles. The period length of circadian rhythm reflects the endogenous cycle transition rate and is modulated by environmental cues or internal molecules, and the latter are of substantial importance but remain poorly revealed. Here, we demonstrated that microRNA 17-5p (miR-17-5p), which has been associated with tumours, was an important factor in controlling the circadian period. MiR-17-5p was rhythmically expressed in synchronised fibroblasts and mouse master clock suprachiasmatic nuclei (SCN). MiR-17-5p and the gene Clock exhibited a reciprocal regulation: miR-17-5p inhibited the translation of Clock by targeting the 3′UTR (untranslated region) of Clock mRNA, whereas the CLOCK protein directly bound to the promoter of miR-17 and enhanced its transcription and production of miR-17-5p. In addition, miR-17-5p suppressed the expression of Npas2. At the cellular level, bidirectional changes in miR-17-5p or CLOCK resulted in CRY1 elevation. Accordingly, in vivo, both increase and decrease of miR-17-5p in the mouse SCN led to an increase in CRY1 level and shortening of the free-running period. We conclude that miR-17-5p has an important role in the inspection and stabilisation of the circadian-clock period by interacting with Clock and Npas2 and potentially via the output of CRY1. PMID:27440219

  10. Effect of circadian rhythm disturbance on morphine preference and addiction in male rats: Involvement of period genes and dopamine D1 receptor.

    PubMed

    Garmabi, B; Vousooghi, N; Vosough, M; Yoonessi, A; Bakhtazad, A; Zarrindast, M R

    2016-05-13

    It is claimed that a correlation exists between disturbance of circadian rhythms by factors such as alteration of normal light-dark cycle and the development of addiction. However, the exact mechanisms involved in this relationship are not much understood. Here we have studied the effect of constant light on morphine voluntary consumption and withdrawal symptoms and also investigated the involvement of Per1, Per2 and dopamine D1 receptor in these processes. Male wistar rats were kept under standard (LD) or constant light (LL) conditions for one month. The plasma concentration of melatonin was evaluated by enzyme-linked immunosorbent assay (ELISA). Real-time PCR was used to determine the mRNA expression of Per1, Per2 and dopamine D1 receptor in the striatum and prefrontal cortex. Morphine preference (50mg/L) was evaluated in a two-bottle-choice paradigm for 10 weeks and withdrawal symptoms were recorded after administration of naloxone (3mg/kg). One month exposure to constant light resulted in a significant decrease of melatonin concentration in the LL group. In addition, mRNA levels of Per2 and dopamine D1 receptor were up-regulated in both the striatum and prefrontal cortex of the LL group. However, expression of Per1 gene was only up-regulated in the striatum of LL rats in comparison to LD animals. Furthermore, after one month exposure to constant light, morphine consumption and preference ratio and also severity of naloxone-induced withdrawal syndrome were significantly greater in LL animals. It is concluded that exposure to constant light by up-regulation of Per2 and dopamine D1 receptor in the striatum and prefrontal cortex and up-regulation of Per1 in the striatum and the possible involvement of melatonin makes animals vulnerable to morphine preference and addiction. PMID:26892296

  11. Decreased human circadian pacemaker influence after 100 days in space: a case study

    NASA Technical Reports Server (NTRS)

    Monk, T. H.; Kennedy, K. S.; Rose, L. R.; Linenger, J. M.

    2001-01-01

    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.

  12. Biophotonics: Circadian photonics

    NASA Astrophysics Data System (ADS)

    Rea, Mark S.

    2011-05-01

    A growing body of medical evidence suggests that disrupting the body's biological clock can have adverse effects on health. Researchers are now creating the photonic tools to monitor, predict and influence the circadian rhythm.

  13. A matter of time: study of circadian clocks and their role in inflammation.

    PubMed

    Carter, Stuart J; Durrington, Hannah J; Gibbs, Julie E; Blaikley, John; Loudon, Andrew S; Ray, David W; Sabroe, Ian

    2016-04-01

    Circadian rhythms regulate changes in physiology, allowing organisms to respond to predictable environmental demands varying over a 24 h period. A growing body of evidence supports a key role for the circadian clock in the regulation of immune functions and inflammatory responses, which influence the understanding of infections and inflammatory diseases and their treatment. A variety of experimental methods have been used to assess the complex bidirectional crosstalk between the circadian clock and inflammation. In this review, we summarize the organization of the molecular clock, experimental methods used to study circadian rhythms, and both the inflammatory and immune consequences of circadian disturbance. PMID:26856993

  14. Molecular components of the circadian clock in mammals.

    PubMed

    Takahashi, J S

    2015-09-01

    The circadian clock mechanism in animals involves a transcriptional feedback loop in which the bHLH-PAS proteins CLOCK and BMAL1 form a transcriptional activator complex to activate the transcription of the Period and Cryptochrome genes, which in turn feed back to repress their own transcription. In the mouse liver, CLOCK and BMAL1 interact with the regulatory regions of thousands of genes, which are both cyclically and constitutively expressed. The circadian transcription in the liver is clustered in phase and this is accompanied by circadian occupancy of RNA polymerase II recruitment and initiation. These changes also lead to circadian fluctuations in histone H3 lysine4 trimethylation (H3K4me3) as well as H3 lysine9 acetylation (H3K9ac) and H3 lysine27 acetylation (H3K27ac). Thus, the circadian clock regulates global transcriptional poise and chromatin state by regulation of RNA polymerase II. PMID:26332962

  15. An antennal circadian clock and circadian rhythms in peripheral pheromone reception in the moth Spodoptera littoralis.

    PubMed

    Merlin, Christine; Lucas, Philippe; Rochat, Didier; François, Marie-Christine; Maïbèche-Coisne, Martine; Jacquin-Joly, Emmanuelle

    2007-12-01

    Circadian rhythms are observed in mating behaviors in moths: females emit sex pheromones and males are attracted by these pheromones in rhythmic fashions. In the moth Spodoptera littoralis, we demonstrated the occurrence of a circadian oscillator in the antenna, the peripheral olfactory organ. We identified different clock genes, period (per), cryptochrome1 (cry1) and cryptochrome2 (cry2), in this organ. Using quantitative real-time PCR (qPCR), we found that their corresponding transcripts cycled circadianly in the antenna as well as in the brain. Electroantennogram (EAG) recordings over 24 h demonstrated for the first time a circadian rhythm in antennal responses of a moth to sex pheromone. qPCR showed that out of one pheromone-binding protein (PBP), one olfactory receptor (OR), and one odorant-degrading enzyme (ODE), all putatively involved in the pheromone reception, only the ODE transcript presented a circadian rhythm that may be related to rhythms in olfactory signal resolution. Peripheral or central circadian clock control of olfaction is then discussed in light of recent data. PMID:18057325

  16. Sleep and circadian contributions to adolescent alcohol use disorder.

    PubMed

    Hasler, Brant P; Soehner, Adriane M; Clark, Duncan B

    2015-06-01

    Adolescence is a time of marked changes across sleep, circadian rhythms, brain function, and alcohol use. Starting at puberty, adolescents' endogenous circadian rhythms and preferred sleep times shift later, often leading to a mismatch with the schedules imposed by secondary education. This mismatch induces circadian misalignment and sleep loss, which have been associated with affect dysregulation, increased drug and alcohol use, and other risk-taking behaviors in adolescents and adults. In parallel to developmental changes in sleep, adolescent brains are undergoing structural and functional changes in the circuits subserving the pursuit and processing of rewards. These developmental changes in reward processing likely contribute to the initiation of alcohol use during adolescence. Abundant evidence indicates that sleep and circadian rhythms modulate reward function, suggesting that adolescent sleep and circadian disturbance may contribute to altered reward function, and in turn, alcohol involvement. In this review, we summarize the relevant evidence and propose that these parallel developmental changes in sleep, circadian rhythms, and neural processing of reward interact to increase risk for alcohol use disorder (AUD). PMID:25442171

  17. Sleep and Circadian Contributions to Adolescent Alcohol Use Disorder

    PubMed Central

    Hasler, Brant P.; Soehner, Adriane M.; Clark, Duncan B.

    2014-01-01

    Adolescence is a time of marked changes across sleep, circadian rhythms, brain function, and alcohol use. Starting at puberty, adolescents’ endogenous circadian rhythms and preferred sleep times shift later, often leading to a mismatch with the schedules imposed by secondary education. This mismatch induces circadian misalignment and sleep loss, which have been associated with affect dysregulation, increased drug and alcohol use, and other risk-taking behaviors in adolescents and adults. In parallel to developmental changes in sleep, adolescent brains are undergoing structural and functional changes in the circuits subserving the pursuit and processing of rewards. These developmental changes in reward processing likely contribute to the initiation of alcohol use during adolescence. Abundant evidence indicates that sleep and circadian rhythms modulate reward function, suggesting that adolescent sleep and circadian disturbance may contribute to altered reward function, and in turn, alcohol involvement. In this review, we summarize the relevant evidence and propose that these parallel developmental changes in sleep, circadian rhythms, and neural processing of reward interact to increase risk for alcohol use disorder (AUD). PMID:25442171

  18. Quantification of Circadian Rhythms in Single Cells

    PubMed Central

    Westermark, Pål O.; Welsh, David K.; Okamura, Hitoshi; Herzel, Hanspeter

    2009-01-01

    Bioluminescence techniques allow accurate monitoring of the circadian clock in single cells. We have analyzed bioluminescence data of Per gene expression in mouse SCN neurons and fibroblasts. From these data, we extracted parameters such as damping rate and noise intensity using two simple mathematical models, one describing a damped oscillator driven by noise, and one describing a self-sustained noisy oscillator. Both models describe the data well and enabled us to quantitatively characterize both wild-type cells and several mutants. It has been suggested that the circadian clock is self-sustained at the single cell level, but we conclude that present data are not sufficient to determine whether the circadian clock of single SCN neurons and fibroblasts is a damped or a self-sustained oscillator. We show how to settle this question, however, by testing the models' predictions of different phases and amplitudes in response to a periodic entrainment signal (zeitgeber). PMID:19956762

  19. Optimal Implementations for Reliable Circadian Clocks

    NASA Astrophysics Data System (ADS)

    Hasegawa, Yoshihiko; Arita, Masanori

    2014-09-01

    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.

  20. Circadian clocks and breast cancer.

    PubMed

    Blakeman, Victoria; Williams, Jack L; Meng, Qing-Jun; Streuli, Charles H

    2016-01-01

    Circadian clocks respond to environmental time cues to coordinate 24-hour oscillations in almost every tissue of the body. In the breast, circadian clocks regulate the rhythmic expression of numerous genes. Disrupted expression of circadian genes can alter breast biology and may promote cancer. Here we overview circadian mechanisms, and the connection between the molecular clock and breast biology. We describe how disruption of circadian genes contributes to cancer via multiple mechanisms, and link this to increased tumour risk in women who work irregular shift patterns. Understanding the influence of circadian rhythms on breast cancer could lead to more efficacious therapies, reformed public health policy and improved patient outcome. PMID:27590298

  1. Circadian rhythms, oxidative stress, and antioxidative defense mechanisms.

    PubMed

    Hardeland, Rüdiger; Coto-Montes, Ana; Poeggeler, Burkhard

    2003-11-01

    Endogenous circadian and exogenously driven daily rhythms of antioxidative enzyme activities and of low molecular weight antioxidants (LMWAs) are described in various phylogenetically distant organisms. Substantial amplitudes are detected in several cases, suggesting the significance of rhythmicity in avoiding excessive oxidative stress. Mammalian and/or avian glutathione peroxidase and, as a consequence, glutathione reductase activities follow the rhythm of melatonin. Another hint for an involvement of melatonin in the control of redox processes is seen in its high-affinity binding to cytosolic quinone reductase 2, previously believed to be a melatonin receptor. Although antioxidative protection by pharmacological doses of melatonin is repeatedly reported, explanations of these findings are still insufficient and their physiological and chronobiological relevance is not yet settled. Recent data indicate a role of melatonin in the avoidance of mitochondrial radical formation, a function which may prevail over direct scavenging. Rhythmic changes in oxidative damage of protein and lipid molecules are also reported. Enhanced oxidative protein modification accompanied by a marked increase in the circadian amplitude of this parameter is detected in the Drosophila mutant rosy, which is deficient in the LMWA urate. Preliminary evidence for the significance of circadian rhythmicity in diminishing oxidative stress comes from clock mutants. In Drosophila, moderately enhanced protein damage is described for the arrhythmic and melatonin null mutant per0, but even more elevated, periodic damage is found in the short-period mutant per(s), synchronized to LD 12:12. Remarkably large increases in oxidative protein damage, along with impairment of tissue integrity and--obviously insufficient--compensatory elevations in protective enzymes are observed in a particularly vulnerable organ, the Harderian gland, of another short-period mutant tau, in the Syrian hamster. Mice deficient in

  2. Physiological effects of light on the human circadian pacemaker

    NASA Technical Reports Server (NTRS)

    Shanahan, T. L.; Czeisler, C. A.

    2000-01-01

    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.

  3. Integration of human sleep-wake regulation and circadian rhythmicity

    NASA Technical Reports Server (NTRS)

    Dijk, Derk-Jan; Lockley, Steven W.

    2002-01-01

    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.

  4. Circadian Rhythmicity of Active GSK3 Isoforms Modulates Molecular Clock Gene Rhythms in the Suprachiasmatic Nucleus

    PubMed Central

    Besing, R.C.; Paul, J.R.; Hablitz, L.M.; Rogers, C.O.; Johnson, R.L.; Young, M.E.; Gamble, K.L.

    2015-01-01

    The suprachiasmatic nucleus (SCN) drives and synchronizes daily rhythms at the cellular level via transcriptional-translational feedback loops comprised of clock genes such as Bmal1 and Period (Per). Glycogen synthase kinase 3 (GSK3), a serine/threonine kinase, phosphorylates at least five core clock proteins and shows diurnal variation in phosphorylation state (inactivation) of the GSK3β isoform. Whether phosphorylation of the other primary isoform (GSK3α) varies across the subjective day-night cycle is unknown. The purpose of this study was to determine if the endogenous rhythm of GSK3 (α and β) phosphorylation is critical for rhythmic BMAL1 expression and normal amplitude and periodicity of the molecular clock in the SCN. Significant circadian rhythmicity of phosphorylated GSK3 (α and β) was observed in the SCN from wild-type mice housed in constant darkness for two weeks. Importantly, chronic activation of both GSK3 isoforms impaired rhythmicity of the GSK3 target BMAL1. Furthermore, chronic pharmacological inhibition of GSK3 with 20 μM CHIR-99021 enhanced the amplitude and shortened the period of PER2::luciferase rhythms in organotypic SCN slice cultures. These results support the model that GSK3 activity status is regulated by the circadian clock and that GSK3 feeds back to regulate the molecular clock amplitude in the SCN. PMID:25724980

  5. p38 MAP kinase regulates circadian rhythms in Drosophila.

    PubMed

    Vrailas-Mortimer, Alysia D; Ryan, Sarah M; Avey, Matthew J; Mortimer, Nathan T; Dowse, Harold; Sanyal, Subhabrata

    2014-12-01

    The large repertoire of circadian rhythms in diverse organisms depends on oscillating central clock genes, input pathways for entrainment, and output pathways for controlling rhythmic behaviors. Stress-activated p38 MAP Kinases (p38K), although sparsely investigated in this context, show circadian rhythmicity in mammalian brains and are considered part of the circadian output machinery in Neurospora. We find that Drosophila p38Kb is expressed in clock neurons, and mutants in p38Kb either are arrhythmic or have a longer free-running periodicity, especially as they age. Paradoxically, similar phenotypes are observed through either transgenic inhibition or activation of p38Kb in clock neurons, suggesting a requirement for optimal p38Kb function for normal free-running circadian rhythms. We also find that p38Kb genetically interacts with multiple downstream targets to regulate circadian locomotor rhythms. More specifically, p38Kb interacts with the period gene to regulate period length and the strength of rhythmicity. In addition, we show that p38Kb suppresses the arrhythmic behavior associated with inhibition of a second p38Kb target, the transcription factor Mef2. Finally, we find that manipulating p38K signaling in free-running conditions alters the expression of another downstream target, MNK/Lk6, which has been shown to cycle with the clock and to play a role in regulating circadian rhythms. These data suggest that p38Kb may affect circadian locomotor rhythms through the regulation of multiple downstream pathways. PMID:25403440

  6. System identification of the Arabidopsis plant circadian system

    NASA Astrophysics Data System (ADS)

    Foo, Mathias; Somers, David E.; Kim, Pan-Jun

    2015-02-01

    The circadian system generates an endogenous oscillatory rhythm that governs the daily activities of organisms in nature. It offers adaptive advantages to organisms through a coordination of their biological functions with the optimal time of day. In this paper, a model of the circadian system in the plant Arabidopsis (species thaliana) is built by using system identification techniques. Prior knowledge about the physical interactions of the genes and the proteins in the plant circadian system is incorporated in the model building exercise. The model is built by using primarily experimentally-verified direct interactions between the genes and the proteins with the available data on mRNA and protein abundances from the circadian system. Our analysis reveals a great performance of the model in predicting the dynamics of the plant circadian system through the effect of diverse internal and external perturbations (gene knockouts and day-length changes). Furthermore, we found that the circadian oscillatory rhythm is robust and does not vary much with the biochemical parameters except those of a light-sensitive protein P and a transcription factor TOC1. In other words, the circadian rhythmic profile is largely a consequence of the network's architecture rather than its particular parameters. Our work suggests that the current experimental knowledge of the gene-to-protein interactions in the plant Arabidopsis, without considering any additional hypothetical interactions, seems to suffice for system-level modeling of the circadian system of this plant and to present an exemplary platform for the control of network dynamics in complex living organisms.

  7. ‘The clocks that time us’—circadian rhythms in neurodegenerative disorders

    PubMed Central

    Videnovic, Aleksandar; Lazar, Alpar S.; Barker, Roger A.; Overeem, Sebastiaan

    2015-01-01

    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

  8. The statistical analysis of circadian phase and amplitude in constant-routine core-temperature data

    NASA Technical Reports Server (NTRS)

    Brown, E. N.; Czeisler, C. A.

    1992-01-01

    Accurate estimation of the phases and amplitude of the endogenous circadian pacemaker from constant-routine core-temperature series is crucial for making inferences about the properties of the human biological clock from data collected under this protocol. This paper presents a set of statistical methods based on a harmonic-regression-plus-correlated-noise model for estimating the phases and the amplitude of the endogenous circadian pacemaker from constant-routine core-temperature data. The methods include a Bayesian Monte Carlo procedure for computing the uncertainty in these circadian functions. We illustrate the techniques with a detailed study of a single subject's core-temperature series and describe their relationship to other statistical methods for circadian data analysis. In our laboratory, these methods have been successfully used to analyze more than 300 constant routines and provide a highly reliable means of extracting phase and amplitude information from core-temperature data.

  9. The effect of hatching time on the bioenergetics of northern pike (Esox lucius) larvae from a single egg batch during the endogenous feeding period.

    PubMed

    Trabelsi, Awatef; Jaworski, Andrzej; Kamler, Ewa; Gardeur, Jean-Noël; Teletchea, Fabrice; Ayadi, Habib; Fontaine, Pascal

    2016-04-01

    Size, caloric value and chemical composition were measured separately in the progeny of two northern pike (Esox lucius) females at 3-day intervals during the endogenous feeding period from hatching to final yolk resorption. Tissue, yolk and entire larvae were analysed separately in three groups of larvae that hatched at different times (between 88 and 106 degree-days post-fertilization). An integrated approach with the Gompertz model was used to compute the yolk conversion efficiency and time to maximum tissue size in early, mid and late hatched larvae. At hatching, unresorbed yolk of early hatched larvae contained more energy (39.20 J) and more protein (0.99 mg) compared to the yolk of larvae that hatched later (38.13 J and 0.92 mg protein for late hatched larvae, p < 0.05). In contrast, a significant reduction in tissue weight (-0.7 mg DW) and protein content (-0.5 mg) was found in early hatched larvae compared to those which hatched later (p < 0.05). Between days 9 and 12 post-hatching (108 and 144 degree-days post-hatching), close to the final yolk resorption, late hatched larvae stopped growing and their tissue began to be resorbed. This tissue resorption time was delayed in early hatched larvae which presented at the end of the experiment a greater tissue weight than late hatched ones. Yolk conversion efficiency in term of energy from hatching to complete yolk resorption stage was significantly higher for early and mid hatched larvae (51%) compared to late hatched ones (44%) (p = 0.004). Furthermore, the time to maximum tissue size was found to be negatively related to hatching time which implies that early hatched larvae take longer time to switch from one developmental stage to the next. The maximum tissue dry weight and energy content were found to be reached at approximately the same age post-fertilization for both early hatched and late hatched larvae, suggesting that the principal steps in a fish's lifespan are better correlated with time of

  10. Central Control of Circadian Phase in Arousal-Promoting Neurons

    PubMed Central

    Mahoney, Carrie E.; McKinley Brewer, Judy; Bittman, Eric L.

    2013-01-01

    Cells of the dorsomedial/lateral hypothalamus (DMH/LH) that produce hypocretin (HCRT) promote arousal in part by activation of cells of the locus coeruleus (LC) which express tyrosine hydroxylase (TH). The suprachiasmatic nucleus (SCN) drives endogenous daily rhythms, including those of sleep and wakefulness. These circadian oscillations are generated by a transcriptional-translational feedback loop in which the Period (Per) genes constitute critical components. This cell-autonomous molecular clock operates not only within the SCN but also in neurons of other brain regions. However, the phenotype of such neurons and the nature of the phase controlling signal from the pacemaker are largely unknown. We used dual fluorescent in situ hybridization to assess clock function in vasopressin, HCRT and TH cells of the SCN, DMH/LH and LC, respectively, of male Syrian hamsters. In the first experiment, we found that Per1 expression in HCRT and TH oscillated in animals held in constant darkness with a peak phase that lagged that in AVP cells of the SCN by several hours. In the second experiment, hamsters induced to split their locomotor rhythms by exposure to constant light had asymmetric Per1 expression within cells of the middle SCN at 6 h before activity onset (AO) and in HCRT cells 9 h before and at AO. We did not observe evidence of lateralization of Per1 expression in the LC. We conclude that the SCN communicates circadian phase to HCRT cells via lateralized neural projections, and suggests that Per1 expression in the LC may be regulated by signals of a global or bilateral nature. PMID:23826226

  11. Altered behavioral and metabolic circadian rhythms in mice with disrupted NAD+ oscillation

    PubMed Central

    Sahar, Saurabh; Nin, Veronica; Barbosa, Maria Thereza; Chini, Eduardo Nunes; Sassone-Corsi, Paolo

    2011-01-01

    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

  12. Establishment of human cell lines showing circadian rhythms of bioluminescence.

    PubMed

    Yoshikawa, Aki; Shimada, Hiroko; Numazawa, Kahori; Sasaki, Tsukasa; Ikeda, Masaaki; Kawashima, Minae; Kato, Nobumasa; Tokunaga, Katsushi; Ebisawa, Takashi

    2008-11-28

    We have established human retinal pigment epithelial cell lines stably expressing the luciferase gene, driven by the human Bmal1 promoter, to obtain human-derived cells that show circadian rhythms of bioluminescence after dexamethasone treatment. The average circadian period of bioluminescence for the obtained clones was 24.07+/-0.48 h. Lithium (10 mM) in the medium significantly lengthened the circadian period of bioluminescence, which is consistent with previous reports, while 2 mM or 5 mM lithium had no effect. This is the first report on the establishment of human-derived cell lines that proliferate infinitely and show circadian rhythms of bioluminescence, and also the first to investigate the effects of low-dose lithium on the circadian rhythms of human-derived cells in vitro. The established cells will be useful for various in vitro studies of human circadian rhythms and for the development of new therapies for human disorders related to circadian rhythm disturbances. PMID:18809466

  13. Coupling governs entrainment range of circadian clocks

    PubMed Central

    Abraham, Ute; Granada, Adrián E; Westermark, Pål O; Heine, Markus; Kramer, Achim; Herzel, Hanspeter

    2010-01-01

    Circadian clocks are endogenous oscillators driving daily rhythms in physiology and behavior. Synchronization of these timers to environmental light–dark cycles (‘entrainment') is crucial for an organism's fitness. Little is known about which oscillator qualities determine entrainment, i.e., entrainment range, phase and amplitude. In a systematic theoretical and experimental study, we uncovered these qualities for circadian oscillators in the suprachiasmatic nucleus (SCN—the master clock in mammals) and the lung (a peripheral clock): (i) the ratio between stimulus (zeitgeber) strength and oscillator amplitude and (ii) the rigidity of the oscillatory system (relaxation rate upon perturbation) determine entrainment properties. Coupling among oscillators affects both qualities resulting in increased amplitude and rigidity. These principles explain our experimental findings that lung clocks entrain to extreme zeitgeber cycles, whereas SCN clocks do not. We confirmed our theoretical predictions by showing that pharmacological inhibition of coupling in the SCN leads to larger ranges of entrainment. These differences between master and the peripheral clocks suggest that coupling-induced rigidity in the SCN filters environmental noise to create a robust circadian system. PMID:21119632

  14. Mutation at the circadian clock gene EARLY MATURITY 8 adapts domesticated barley (Hordeum vulgare) to short growing seasons

    PubMed Central

    Faure, Sebastien; Turner, Adrian S.; Gruszka, Damian; Christodoulou, Vangelis; Davis, Seth J.; von Korff, Maria; Laurie, David A.

    2012-01-01

    The circadian clock is an autonomous oscillator that produces endogenous biological rhythms with a period of about 24 h. This clock allows organisms to coordinate their metabolism and development with predicted daily and seasonal changes of the environment. In plants, circadian rhythms contribute to both evolutionary fitness and agricultural productivity. Nevertheless, we show that commercial barley varieties bred for short growing seasons by use of early maturity 8 (eam8) mutations, also termed mat-a, are severely compromised in clock gene expression and clock outputs. We identified EAM8 as a barley ortholog of the Arabidopsis thaliana circadian clock regulator EARLY FLOWERING3 (ELF3) and demonstrate that eam8 accelerates the transition from vegetative to reproductive growth and inflorescence development. We propose that eam8 was selected as barley cultivation moved to high-latitude short-season environments in Europe because it allowed rapid flowering in genetic backgrounds that contained a previously selected late-flowering mutation of the photoperiod response gene Ppd-H1. We show that eam8 mutants have increased expression of the floral activator HvFT1, which is independent of allelic variation at Ppd-H1. The selection of independent eam8 mutations shows that this strategy facilitates short growth-season adaptation and expansion of the geographic range of barley, despite the pronounced clock defect. PMID:22566625

  15. Circadian control of bile acid synthesis by a KLF15-Fgf15 axis

    PubMed Central

    Han, Sean (Shuxin); Zhang, Rongli; Jain, Rajan; Shi, Hong; Zhang, Lilei; Zhou, Guangjin; Sangwung, Panjamaporn; Tugal, Derin; Atkins, G. Brandon; Prosdocimo, Domenick A.; Lu, Yuan; Han, Xiaonan; Tso, Patrick; Liao, Xudong; Epstein, Jonathan A.; Jain, Mukesh K.

    2015-01-01

    Circadian control of nutrient availability is critical to efficiently meet the energetic demands of an organism. Production of bile acids (BAs), which facilitate digestion and absorption of nutrients, is a major regulator of this process. Here we identify a KLF15-Fgf15 signalling axis that regulates circadian BA production. Systemic Klf15 deficiency disrupted circadian expression of key BA synthetic enzymes, tissue BA levels and triglyceride/cholesterol absorption. Studies in liver-specific Klf15-knockout mice suggested a non-hepatic basis for regulation of BA production. Ileal Fgf15 is a potent inhibitor of BA synthesis. Using a combination of biochemical, molecular and functional assays (including ileectomy and bile duct catheterization), we identify KLF15 as the first endogenous negative regulator of circadian Fgf15 expression. Elucidation of this novel pathway controlling circadian BA production has important implications for physiologic control of nutrient availability and metabolic homeostasis. PMID:26040986

  16. The circadian clock rephases during lateral root organ initiation in Arabidopsis thaliana.

    PubMed

    Voß, Ute; Wilson, Michael H; Kenobi, Kim; Gould, Peter D; Robertson, Fiona C; Peer, Wendy A; Lucas, Mikaël; Swarup, Kamal; Casimiro, Ilda; Holman, Tara J; Wells, Darren M; Péret, Benjamin; Goh, Tatsuaki; Fukaki, Hidehiro; Hodgman, T Charlie; Laplaze, Laurent; Halliday, Karen J; Ljung, Karin; Murphy, Angus S; Hall, Anthony J; Webb, Alex A R; Bennett, Malcolm J

    2015-01-01

    The endogenous circadian clock enables organisms to adapt their growth and development to environmental changes. Here we describe how the circadian clock is employed to coordinate responses to the key signal auxin during lateral root (LR) emergence. In the model plant, Arabidopsis thaliana, LRs originate from a group of stem cells deep within the root, necessitating that new organs emerge through overlying root tissues. We report that the circadian clock is rephased during LR development. Metabolite and transcript profiling revealed that the circadian clock controls the levels of auxin and auxin-related genes including the auxin response repressor IAA14 and auxin oxidase AtDAO2. Plants lacking or overexpressing core clock components exhibit LR emergence defects. We conclude that the circadian clock acts to gate auxin signalling during LR development to facilitate organ emergence. PMID:26144255

  17. The circadian clock rephases during lateral root organ initiation in Arabidopsis thaliana

    PubMed Central

    Voß, Ute; Wilson, Michael H.; Kenobi, Kim; Gould, Peter D.; Robertson, Fiona C.; Peer, Wendy A.; Lucas, Mikaël; Swarup, Kamal; Casimiro, Ilda; Holman, Tara J.; Wells, Darren M.; Péret, Benjamin; Goh, Tatsuaki; Fukaki, Hidehiro; Hodgman, T. Charlie; Laplaze, Laurent; Halliday, Karen J.; Ljung, Karin; Murphy, Angus S.; Hall, Anthony J.; Webb, Alex A. R.; Bennett, Malcolm J.

    2015-01-01

    The endogenous circadian clock enables organisms to adapt their growth and development to environmental changes. Here we describe how the circadian clock is employed to coordinate responses to the key signal auxin during lateral root (LR) emergence. In the model plant, Arabidopsis thaliana, LRs originate from a group of stem cells deep within the root, necessitating that new organs emerge through overlying root tissues. We report that the circadian clock is rephased during LR development. Metabolite and transcript profiling revealed that the circadian clock controls the levels of auxin and auxin-related genes including the auxin response repressor IAA14 and auxin oxidase AtDAO2. Plants lacking or overexpressing core clock components exhibit LR emergence defects. We conclude that the circadian clock acts to gate auxin signalling during LR development to facilitate organ emergence. PMID:26144255

  18. Circadian Rhythms in Cyanobacteria.

    PubMed

    Cohen, Susan E; Golden, Susan S

    2015-12-01

    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

  19. Circadian regulation of hormone signaling and plant physiology.

    PubMed

    Atamian, Hagop S; Harmer, Stacey L

    2016-08-01

    The survival and reproduction of plants depend on their ability to cope with a wide range of daily and seasonal environmental fluctuations during their life cycle. Phytohormones are plant growth regulators that are involved in almost every aspect of growth and development as well as plant adaptation to myriad abiotic and biotic conditions. The circadian clock, an endogenous and cell-autonomous biological timekeeper that produces rhythmic outputs with close to 24-h rhythms, provides an adaptive advantage by synchronizing plant physiological and metabolic processes to the external environment. The circadian clock regulates phytohormone biosynthesis and signaling pathways to generate daily rhythms in hormone activity that fine-tune a range of plant processes, enhancing adaptation to local conditions. This review explores our current understanding of the interplay between the circadian clock and hormone signaling pathways. PMID:27061301

  20. Circadian Dysrhythmias, Physiological Aberrations, and the Link to Skin Cancer

    PubMed Central

    Gutierrez, Daniel; Arbesman, Joshua

    2016-01-01

    Circadian rhythms are core regulators of a variety of mammalian physiologic processes and oscillate in a 24-h pattern. Many peripheral organs possess endogenous rhythmicity that is then modulated by a master clock; the skin is one of these peripheral organs. The dysregulation of rhythms is associated with decreased ability to ameliorate cellular stressors at a local and global level, which then increases the propensity for the development of neoplastic growths. In this article, we review the implications of altered circadian rhythms on DNA repair as well as modified gene expression of core clock proteins with particular focus on skin models. These findings are then correlated with epidemiologic data regarding skin cancer to showcase the effects of circadian disruption on this phenomenon. PMID:27128901

  1. Circadian Rhythms, Metabolism, and Chrononutrition in Rodents and Humans.

    PubMed

    Johnston, Jonathan D; Ordovás, José M; Scheer, Frank A; Turek, Fred W

    2016-03-01

    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

  2. Relationship between Oxidative Stress, Circadian Rhythms, and AMD

    PubMed Central

    Fanjul-Moles, María Luisa; López-Riquelme, Germán Octavio

    2016-01-01

    This work reviews concepts regarding oxidative stress and the mechanisms by which endogenous and exogenous factors produce reactive oxygen species (ROS). It also surveys the relationships between oxidative stress, circadian rhythms, and retinal damage in humans, particularly those related to light and photodamage. In the first section, the production of ROS by different cell organelles and biomolecules and the antioxidant mechanisms that antagonize this damage are reviewed. The second section includes a brief review of circadian clocks and their relationship with the cellular redox state. In the third part of this work, the relationship between retinal damage and ROS is described. The last part of this work focuses on retinal degenerative pathology, age-related macular degeneration, and the relationships between this pathology, ROS, and light. Finally, the possible interactions between the retinal pigment epithelium (RPE), circadian rhythms, and this pathology are discussed. PMID:26885250

  3. Circadian rhythm of gravitaxis in Euglena gracilis.

    PubMed

    Lebert, M; Porst, M; Hader, D P

    1999-09-01

    Euglena gracilis, a unicellular, photosynthetic flagellate is a model system for environmentally controlled behavioral reactions. One pronounced reaction is the orientation with respect to gravity. In synchronized cultures with no cell growth a distinct circadian rhythm of negative gravitactic orientation could be observed. The main maximum of sensitivity was detected 5 h after the beginning of the subjective day, the main minimum 5 h before the beginning of the subjective day. Transferring synchronized cultures to continuous light resulted in an almost instantaneous loss of rhythmicity. In contrast, after transfer to permanent darkness cells exhibited a circadian rhythm with a progressive shortening of the period for more than 5 days. These findings are in contrast to the circadian rhythm of phototaxis in Euglena, where a free-running period of 24 h was observed. Parallel measurements of negative gravitactic orientation, velocity, cell shape as well as cAMP concentration in synchronized cultures revealed a circadian rhythm of all reactions. The results are discussed with regard to the possible role of cell shape and cAMP in gravitactic orientation. PMID:11542916

  4. Regulation of behavioral circadian rhythms and clock protein PER1 by the deubiquitinating enzyme USP2

    PubMed Central

    Yang, Yaoming; Duguay, David; Bédard, Nathalie; Rachalski, Adeline; Baquiran, Gerardo; Na, Chan Hyun; Fahrenkrug, Jan; Storch, Kai-Florian; Peng, Junmin; Wing, Simon S.; Cermakian, Nicolas

    2012-01-01

    Summary Endogenous 24-hour rhythms are generated by circadian clocks located in most tissues. The molecular clock mechanism is based on feedback loops involving clock genes and their protein products. Post-translational modifications, including ubiquitination, are important for regulating the clock feedback mechanism. Previous work has focused on the role of ubiquitin ligases in the clock mechanism. Here we show a role for the rhythmically-expressed deubiquitinating enzyme ubiquitin specific peptidase 2 (USP2) in clock function. Mice with a deletion of the Usp2 gene (Usp2 KO) display a longer free-running period of locomotor activity rhythms and altered responses of the clock to light. This was associated with altered expression of clock genes in synchronized Usp2 KO mouse embryonic fibroblasts and increased levels of clock protein PERIOD1 (PER1). USP2 can be coimmunoprecipitated with several clock proteins but directly interacts specifically with PER1 and deubiquitinates it. Interestingly, this deubiquitination does not alter PER1 stability. Taken together, our results identify USP2 as a new core component of the clock machinery and demonstrate a role for deubiquitination in the regulation of the circadian clock, both at the level of the core pacemaker and its response to external cues. PMID:23213472

  5. Pup circadian rhythm entrainment--effect of maternal ganglionectomy or pinealectomy.

    PubMed

    Bellavía, S L; Carpentieri, A R; Vaqué, A M; Macchione, A F; Vermouth, N T

    2006-10-30

    In rodents, during late embryonic and early neonatal development, circadian rhythms develop in synchrony with those of their mothers, which in turn are synchronized with the environmental photoperiod. This paper examines the effect of maternal ganglionectomy (pineal gland sympathetic denervation) or extirpation of the pineal gland on pups' drinking rhythms, a behavior that is continuously monitored in individual animals starting after weaning and studied up to 3 weeks later. Maternal ganglionectomy or pinealectomy performed on the 7th day of gestation significantly disrupts rat pups' drinking behavior, within and among litters. In both treatments, circadian rhythm characteristics of the free-running period (tau), phase, amplitude and alpha were significantly altered compared to those of the control pups born from sham-operated mothers. With the exception of the alpha component, both maternal treatments have similar effects. When melatonin was given to the mothers instead of the endogenous pineal secretory activity for 5 days during the late period of gestation, this treatment reversed the effects of maternal ganglionectomy and pinealectomy. These observations, together with previous studies of our group, indicate that the maternal superior cervical ganglia and pineal gland are necessary components of the mechanism for maternal synchronization, and that maternal melatonin may, directly or indirectly, affect the performance of the pups' central oscillator during early pup rat development. PMID:16899263

  6. Time-Specific Fear Acts as a Non-Photic Entraining Stimulus of Circadian Rhythms in Rats.

    PubMed

    Pellman, Blake A; Kim, Earnest; Reilly, Melissa; Kashima, James; Motch, Oleksiy; de la Iglesia, Horacio O; Kim, Jeansok J

    2015-01-01

    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

  7. Circadian Rhythm Sleep Disorders

    PubMed Central

    Kim, Min Ju; Lee, Jung Hie; Duffy, Jeanne F.

    2014-01-01

    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

  8. Glaucoma Alters the Circadian Timing System

    PubMed Central

    Drouyer, Elise; Dkhissi-Benyahya, Ouria; Chiquet, Christophe; WoldeMussie, Elizabeth; Ruiz, Guadalupe; Wheeler, Larry A.; Denis, Philippe; Cooper, Howard M.

    2008-01-01

    Glaucoma is a widespread ocular disease and major cause of blindness characterized by progressive, irreversible damage of the optic nerve. Although the degenerative loss of retinal ganglion cells (RGC) and visual deficits associated with glaucoma have been extensively studied, we hypothesize that glaucoma will also lead to alteration of the circadian timing system. Circadian and non-visual responses to light are mediated by a specialized subset of melanopsin expressing RGCs that provide photic input to mammalian endogenous clock in the suprachiasmatic nucleus (SCN). In order to explore the molecular, anatomical and functional consequences of glaucoma we used a rodent model of chronic ocular hypertension, a primary causal factor of the pathology. Quantitative analysis of retinal projections using sensitive anterograde tracing demonstrates a significant reduction (∼50–70%) of RGC axon terminals in all visual and non-visual structures and notably in the SCN. The capacity of glaucomatous rats to entrain to light was challenged by exposure to successive shifts of the light dark (LD) cycle associated with step-wise decreases in light intensity. Although glaucomatous rats are able to entrain their locomotor activity to the LD cycle at all light levels, they require more time to re-adjust to a shifted LD cycle and show significantly greater variability in activity onsets in comparison with normal rats. Quantitative PCR reveals the novel finding that melanopsin as well as rod and cone opsin mRNAs are significantly reduced in glaucomatous retinas. Our findings demonstrate that glaucoma impacts on all these aspects of the circadian timing system. In light of these results, the classical view of glaucoma as pathology unique to the visual system should be extended to include anatomical and functional alterations of the circadian timing system. PMID:19079596

  9. Resetting of circadian melatonin and cortisol rhythms in humans by ordinary room light

    NASA Technical Reports Server (NTRS)

    Boivin, D. B.; Czeisler, C. A.

    1998-01-01

    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.

  10. Circadian Disruption in Psychiatric Disorders.

    PubMed

    Jones, Stephanie G; Benca, Ruth M

    2015-12-01

    Evidence suggests that abnormalities in circadian rhythms might prove causally or pathophysiologically significant in psychiatric illness. The circadian regulation of hormonal and behavioral timekeeping processes is often altered in patients with major depression, bipolar disorder, and schizophrenia, and a susceptibility to rhythm instability may contribute to the functional impairment. For some patients, interventions that stabilize or resynchronize circadian rhythms prove therapeutically effective. Circadian disruption in the clinical profiles of most psychiatric illnesses and the treatment efficacy of chronobiological interventions suggest that attention to circadian phenotypes in a range of psychiatric disorders may help to uncover shared pathophysiologic mechanisms. PMID:26568124

  11. Circadian Clocks, Stress, and Immunity

    PubMed Central

    Dumbell, Rebecca; Matveeva, Olga; Oster, Henrik

    2016-01-01

    In mammals, molecular circadian clocks are present in most cells of the body, and this circadian network plays an important role in synchronizing physiological processes and behaviors to the appropriate time of day. The hypothalamic–pituitary–adrenal endocrine axis regulates the response to acute and chronic stress, acting through its final effectors – glucocorticoids – released from the adrenal cortex. Glucocorticoid secretion, characterized by its circadian rhythm, has an important role in synchronizing peripheral clocks and rhythms downstream of the master circadian pacemaker in the suprachiasmatic nucleus. Finally, glucocorticoids are powerfully anti-inflammatory, and recent work has implicated the circadian clock in various aspects and cells of the immune system, suggesting a tight interplay of stress and circadian systems in the regulation of immunity. This mini-review summarizes our current understanding of the role of the circadian clock network in both the HPA axis and the immune system, and discusses their interactions. PMID:27199894

  12. Redox rhythm reinforces the circadian clock to gate immune response

    PubMed Central

    Zhou, Mian; Wang, Wei; Karapetyan, Sargis; Mwimba, Musoki; Marqués, Jorge; Buchler, Nicolas E.; Dong, Xinnian

    2015-01-01

    Recent studies have shown that in addition to the transcriptional circadian clock, many organisms, including Arabidopsis, have a circadian redox rhythm driven by the organism’s metabolic activities1–3. It has been hypothesized that the redox rhythm is linked to the circadian clock, but the mechanism and the biological significance of this link have only begun to be investigated4–7. Here we report that the master immune regulator NPR1 (non-expressor of pathogenesis-related gene 1) of Arabidopsis is a sensor of the plant’s redox state and regulates transcription of core circadian clock genes even in the absence of pathogen challenge. Surprisingly, acute perturbation in the redox status triggered by the immune signal salicylic acid (SA) does not compromise the circadian clock but rather leads to its reinforcement. Mathematical modelling and subsequent experiments show that NPR1 reinforces the circadian clock without changing the period by regulating both the morning and the evening clock genes. This balanced network architecture helps plants gate their immune responses towards the morning and minimize costs on growth at night. Our study demonstrates how a sensitive redox rhythm interacts with a robust circadian clock to ensure proper responsiveness to environmental stimuli without compromising fitness of the organism. PMID:26098366

  13. The Circadian Clock in Oral Health and Diseases

    PubMed Central

    Papagerakis, S.; Zheng, L.; Schnell, S.; Sartor, M.A.; Somers, E.; Marder, W.; McAlpin, B.; Kim, D.; McHugh, J.; Papagerakis, P.

    2014-01-01

    Most physiological processes in mammals display circadian rhythms that are driven by the endogenous circadian clock. This clock is comprised of a central component located in the hypothalamic suprachiasmatic nucleus and subordinate clocks in peripheral tissues. Circadian rhythms sustain 24-hour oscillations of a large number of master genes controlling the correct timing and synchronization of diverse physiological and metabolic processes within our bodies. This complex regulatory network provides an important communication link between our brain and several peripheral organs and tissues. At the molecular level, circadian oscillations of gene expression are regulated by a family of transcription factors called “clock genes”. Dysregulation of clock gene expression results in diverse human pathological conditions, including autoimmune diseases and cancer. There is increasing evidence that the circadian clock affects tooth development, salivary gland and oral epithelium homeostasis, and saliva production. This review summarizes current knowledge of the roles of clock genes in the formation and maintenance of oral tissues, and discusses potential links between “oral clocks” and diseases such as head and neck cancer and Sjögren’s syndrome. PMID:24065634

  14. The circadian clock in oral health and diseases.

    PubMed

    Papagerakis, S; Zheng, L; Schnell, S; Sartor, M A; Somers, E; Marder, W; McAlpin, B; Kim, D; McHugh, J; Papagerakis, P

    2014-01-01

    Most physiological processes in mammals display circadian rhythms that are driven by the endogenous circadian clock. This clock is comprised of a central component located in the hypothalamic suprachiasmatic nucleus and subordinate clocks in peripheral tissues. Circadian rhythms sustain 24-hour oscillations of a large number of master genes controlling the correct timing and synchronization of diverse physiological and metabolic processes within our bodies. This complex regulatory network provides an important communication link between our brain and several peripheral organs and tissues. At the molecular level, circadian oscillations of gene expression are regulated by a family of transcription factors called "clock genes". Dysregulation of clock gene expression results in diverse human pathological conditions, including autoimmune diseases and cancer. There is increasing evidence that the circadian clock affects tooth development, salivary gland and oral epithelium homeostasis, and saliva production. This review summarizes current knowledge of the roles of clock genes in the formation and maintenance of oral tissues, and discusses potential links between "oral clocks" and diseases such as head and neck cancer and Sjögren's syndrome. PMID:24065634

  15. A role for Drosophila ATX2 in activation of PER translation and circadian behavior.

    PubMed

    Zhang, Yong; Ling, Jinli; Yuan, Chunyan; Dubruille, Raphaëlle; Emery, Patrick

    2013-05-17

    A negative transcriptional feedback loop generates circadian rhythms in Drosophila. PERIOD (PER) is a critical state-variable in this mechanism, and its abundance is tightly regulated. We found that the Drosophila homolog of ATAXIN-2 (ATX2)--an RNA-binding protein implicated in human neurodegenerative diseases--was required for circadian locomotor behavior. ATX2 was necessary for PER accumulation in circadian pacemaker neurons and thus determined period length of circadian behavior. ATX2 was required for the function of TWENTY-FOUR (TYF), a crucial activator of PER translation. ATX2 formed a complex with TYF and promoted its interaction with polyadenylate-binding protein (PABP). Our work uncovers a role for ATX2 in circadian timing and reveals that this protein functions as an activator of PER translation in circadian neurons. PMID:23687048

  16. Neuroanatomy of the Extended Circadian Rhythm System

    PubMed Central

    Morin, Lawrence P

    2012-01-01

    The suprachiasmatic nucleus (SCN), site of the primary clock in the circadian rhythm system, has three major afferent connections. The most important consists of a retinohypothalamic projection through which photic information, received by classical rod/cone photoreceptors and intrinsically photoreceptive retinal ganglion cells, gains access to the clock. This information influences phase and period of circadian rhythms. The two other robust afferent projections are the median raphe serotonergic pathway and the geniculohypothalamic (GHT), NPY-containing pathway from the thalamic intergeniculate leaflet (IGL). Beyond this simple framework, the number of anatomical routes that could theoretically be involved in rhythm regulation is enormous, with the SCN projecting to 15 regions and being directly innervated by about 35. If multisynaptic afferents to the SCN are included, the number expands to approximately brain 85 areas providing input to the SCN. The IGL, a known contributor to circadian rhythm regulation, has a still greater level of complexity. This nucleus connects abundantly throughout the brain (to approximately 100 regions) by pathways that are largely bilateral and reciprocal. Few of these sites have been evaluated for their contributions to circadian rhythm regulation, although most have a theoretical possibility of doing so via the GHT. The anatomy of IGL connections suggests that one of its functions may be regulation of eye movements during sleep. Together, neural circuits of the SCN and IGL are complex and interconnected. As yet, few have been tested with respect to their involvement in rhythm regulation. PMID:22766204

  17. Peripheral circadian clocks--a conserved phenotype?

    PubMed

    Weigl, Yuval; Harbour, Valerie L; Robinson, Barry; Dufresne, Line; Amir, Shimon

    2013-05-01

    The circadian system of mammals regulates the timing of occurrence of behavioral and physiological events, thereby optimizing adaptation to their surroundings. This system is composed of a single master pacemaker located in the suprachiasmatic nucleus (SCN) and a population of peripheral clocks. The SCN integrates time information from exogenous sources and, in turn, synchronizes the downstream peripheral clocks. It is assumed that under normal conditions, the circadian phenotype of different peripheral clocks would be conserved with respect to its period and robustness. To study this idea, we measured the daily wheel-running activity (WRA; a marker of the SCN output) in 84 male inbred LEW/Crl rats housed under a 12 h:12 h light-dark cycle. In addition, we assessed the mRNA expression of two clock genes, rPer2 and rBmal1, and one clock-controlled gene, rDbp, in four tissues that have the access to time cues other than those emanating from the SCN: olfactory bulbs (OBs), liver, tail skin, and white blood cells (WBCs). In contrast with the assumption stated above, we found that circadian clocks in peripheral tissues differ in the temporal pattern of the expression of circadian clock genes, in the robustness of the rhythms, and possibly in the number of functional ~24-h-clock cells. Based on the tissue diversity in the robustness of the clock output, the hepatic clock is likely to house the highest number of functional ~24-h-clock cells, and the OBs, the fewest number. Thus, the phenotype of the circadian clock in the periphery is tissue specific and may depend not only on the SCN but also on the sensitivity of the tissue to non-SCN-derived time cues. In the OBs and liver, the circadian clock phenotypes seem to be dominantly shaped by the SCN output. However, in the tail skin and WBC, other time cues participate in the phenotype design. Finally, our study suggests that the basic phenotype of the circadian clock is constructed at the transcript level of the core clock

  18. Biological Clocks & Circadian Rhythms

    ERIC Educational Resources Information Center

    Robertson, Laura; Jones, M. Gail

    2009-01-01

    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…

  19. Facilitated physiological adaptation to prolonged circadian disruption through dietary supplementation with essence of chicken.

    PubMed

    Wu, Tao; Yao, Cencen; Tsang, Fai; Huang, Liangfeng; Zhang, Wanjing; Jiang, Jianguo; Mao, Youxiang; Shao, Yujian; Kong, Boda; Singh, Paramjeet; Fu, Zhengwei

    2015-01-01

    Synchrony between circadian and metabolic processes is critical to the maintenance of energy homeostasis. Studies on essence of chicken (EC), a chicken meat extract rich in proteins, amino acids and peptides, showed its effectiveness in alleviating fatigue and promoting metabolism. A recent study revealed that it facilitated the re-entrainment of clock genes (Bmal1, Cry1, Dec1, Per1 and Per2) in the pineal gland and liver in a rat model of circadian disruption. Here, we investigated the role of EC-facilitated circadian synchrony in the maintenance of the energy homeostasis using a mouse model of prolonged circadian disruption. Prolonged circadian disruption (12 weeks) resulted in hepatic maladaptation, manifested by a mild but significant (p < 0.05) hepatomegaly, accompanied by disturbed hepatic lipid metabolism and liver injury (indicated by increased circulating hepatic enzymes). Evidently, there was marked elevations of hepatic inflammatory mediators (interleukin-1beta and interleukin-6), suggesting an underlying inflammation leading to the hepatic injury and functional impairment. Importantly, the disruption paradigm caused the decoupling between key metabolic regulators (e.g. mTOR and AMPK) and hepatic clock genes (Per1, Cry1, Dec1, Bmal1). Further, we showed that the loss of circadian synchrony between the master and hepatic clock genes (Per1, Cry1, Dec1, Bmal1) could be the underlying cause of the maladaptation. When supplemented with EC, the functional impairment and inflammation were abolished. The protective effects could be linked to its effectiveness in maintaining the synchrony between the master and hepatic clocks, and the resultant improved coupling of the circadian oscillators (Per1, Cry1, Dec1, Bmal1) and metabolic regulators (mTOR, AMPK). Overall, EC supplementation promoted the physiological adaptation to the prolonged circadian disruption through facilitation of endogenous circadian synchrony and the coupling of circadian oscillators and

  20. miR-124 Regulates the Phase of Drosophila Circadian Locomotor Behavior

    PubMed Central

    Lamba, Pallavi; Guo, Peiyi

    2016-01-01

    Animals use circadian rhythms to anticipate daily environmental changes. Circadian clocks have a profound effect on behavior. In Drosophila, for example, brain pacemaker neurons dictate that flies are mostly active at dawn and dusk. miRNAs are small, regulatory RNAs (≈22 nt) that play important roles in posttranscriptional regulation. Here, we identify miR-124 as an important regulator of Drosophila circadian locomotor rhythms. Under constant darkness, flies lacking miR-124 (miR-124KO) have a dramatically advanced circadian behavior phase. However, whereas a phase defect is usually caused by a change in the period of the circadian pacemaker, this is not the case in miR-124KO flies. Moreover, the phase of the circadian pacemaker in the clock neurons that control rhythmic locomotion is not altered either. Therefore, miR-124 modulates the output of circadian clock neurons rather than controlling their molecular pacemaker. Circadian phase is also advanced under temperature cycles, but a light/dark cycle partially corrects the defects in miR-124KO flies. Indeed, miR-124KO shows a normal evening phase under the latter conditions, but morning behavioral activity is suppressed. In summary, miR-124 controls diurnal activity and determines the phase of circadian locomotor behavior without affecting circadian pacemaker function. It thus provides a potent entry point to elucidate the mechanisms by which the phase of circadian behavior is determined. SIGNIFICANCE STATEMENT In animals, molecular circadian clocks control the timing of behavioral activities to optimize them with the day/night cycle. This is critical for their fitness and survival. The mechanisms by which the phase of circadian behaviors is determined downstream of the molecular pacemakers are not yet well understood. Recent studies indicate that miRNAs are important regulators of circadian outputs. We found that miR-124 shapes diurnal behavioral activity and has a striking impact on the phase of circadian

  1. Circadian rhythms in circulating T lymphocyte subtypes and plasma testosterone, total and free cortisol in five healthy men

    PubMed Central

    Lévi, F. A.; Canon, Chantal; Touitou, Y.; Sulon, J.; Mechkouri, M.; Ponsart, Emilie Demey; Touboul, J. P.; Vannetzel, J. M.; Mowzowicz, Irène; Reinberg, A.; Mathe, G.

    1988-01-01

    Circadian variations of circulating T lymphocyte subtypes and their possible relations with those of endogenous cortisol or testosterone were investigated in five healthy young men. Venous blood (40 ml) was obtained every 4 h for 24 h from each subject in January, March, June, August and November. Leucocyte and differential counts were measured. Mononuclear cells were isolated on Ficoll-Paque gradient, and samples were incubated with OKT3, OKT4 or OKT8 monoclonal antibodies for characterizing all T, T helper and T suppressor-cytotoxic lymphocytes respectively. The proportion of labelled lymphocytes was determined under an epifluorescence microscope and the counts of circulating lymphocyte subsets (cells/mm3) computed. Total and free cortisol and testosterone were also determined in the corresponding plasma samples. Results from analysis of variance and cosinor indicated statistically significant differences (P<0·001) as a function of both individual subject and circadian sampling time for all variables. Circadian rhythms (with a period, τ≡24 h) were validated for total, T and T helper lymphocytes and for the T helper: T suppressor-cytotoxic ratio (P<0·001), with double amplitudes (2A, total extent of variation accounted for by the fitted cosine function) ranging from 25% up to 50% of the 24 h mean (M), and acrophases (Φ, time of maximum) localized near 0100 h. A rhythm with τ≡12 h characterized circulating T suppressor-cytotoxic lymphocytes (P<0·001; 2A=36% of M; Φ=0830 and 2030 h). Circadian rhythms were also found for plasma cortisol (either total or free) and testosterone (P<0·001). No correlation was found however between time-qualified data of these hormones and the immunological variables herein investigated (162 pairs of data) whether or not a 4 h or an 8 h lag time was considered to allow for hormonal actions to operate. This suggests that neither the circadian organization of the adrenal cortex nor that of the testis play a prominent role in

  2. Influence of the Quantity and Quality of Light on Photosynthetic Periodicity in Coral Endosymbiotic Algae

    PubMed Central

    Sorek, Michal; Levy, Oren

    2012-01-01

    Symbiotic corals, which are benthic organisms intimately linked with their environment, have evolved many ways to deal with fluctuations in the local marine environment. One possible coping mechanism is the endogenous circadian clock, which is characterized as free running, maintaining a ∼24 h periodicity of circuits under constant stimuli or in the absence of external cues. The quantity and quality of light were found to be the most influential factors governing the endogenous clock for plants and algae. Unicellular dinoflagellate algae are among the best examples of organisms that exhibit circadian clocks using light as the dominant signal. This study is the first to examine the effects of light intensity and quality on the rhythmicity of photosynthesis in the symbiotic dinoflagellate Symbiodinium sp., both as a free-living organism and in symbiosis with the coral Stylophora pistillata. Oxygen production measurements in Symbiodinium cultures exhibited rhythmicity with a periodicity of approximately 24 h under constant high light (LL), whereas under medium and low light, the cycle time increased. Exposing Symbiodinium cultures and corals to spectral light revealed different effects of blue and red light on the photosynthetic rhythm, specifically shortening or increasing the cycle time respectively. These findings suggest that the photosynthetic rhythm is entrained by different light cues, which are wired to an endogenous circadian clock. Furthermore, we provide evidence that mRNA expression was higher under blue light for two potential cryptochrome genes and higher under red light for a phytochrome gene isolated from Symbiodinium. These results offer the first evidence of the impact of the intensity and quality of light on the photosynthetic rhythm in algal cells living freely or as part of a symbiotic association. Our results indicate the presence of a circadian oscillator in Symbiodinium governing the photosynthetic apparatus through a light-induced signaling

  3. The circadian clock and cell cycle: Interconnected biological circuits

    PubMed Central

    Masri, Selma; Cervantes, Marlene; Sassone-Corsi, Paolo

    2014-01-01

    The circadian clock governs biological timekeeping on a systemic level, helping to regulate and maintain physiological processes, including endocrine and metabolic pathways with a periodicity of 24-hours. Disruption within the circadian clock machinery has been linked to numerous pathological conditions, including cancer, suggesting that clock-dependent regulation of the cell cycle is an essential control mechanism. This review will highlight recent advances on the ‘gating’ controls of the circadian clock at various checkpoints of the cell cycle and also how the cell cycle can influence biological rhythms. The reciprocal influence that the circadian clock and cell cycle exert on each other suggests that these intertwined biological circuits are essential and multiple regulatory/control steps have been instated to ensure proper timekeeping. PMID:23969329

  4. Circadian Phase Resetting via Single and Multiple Control Targets

    PubMed Central

    Bagheri, Neda; Stelling, Jörg; Doyle, Francis J.

    2008-01-01

    Circadian entrainment is necessary for rhythmic physiological functions to be appropriately timed over the 24-hour day. Disruption of circadian rhythms has been associated with sleep and neuro-behavioral impairments as well as cancer. To date, light is widely accepted to be the most powerful circadian synchronizer, motivating its use as a key control input for phase resetting. Through sensitivity analysis, we identify additional control targets whose individual and simultaneous manipulation (via a model predictive control algorithm) out-perform the open-loop light-based phase recovery dynamics by nearly 3-fold. We further demonstrate the robustness of phase resetting by synchronizing short- and long-period mutant phenotypes to the 24-hour environment; the control algorithm is robust in the presence of model mismatch. These studies prove the efficacy and immediate application of model predictive control in experimental studies and medicine. In particular, maintaining proper circadian regulation may significantly decrease the chance of acquiring chronic illness. PMID:18795146

  5. Thermoregulation is impaired in an environment without circadian time cues

    NASA Technical Reports Server (NTRS)

    Fuller, C. A.; Sulzman, F. M.; Moore-Ede, M. C.

    1978-01-01

    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.

  6. A Compact Model for the Complex Plant Circadian Clock

    PubMed Central

    De Caluwé, Joëlle; Xiao, Qiying; Hermans, Christian; Verbruggen, Nathalie; Leloup, Jean-Christophe; Gonze, Didier

    2016-01-01

    The circadian clock is an endogenous timekeeper that allows organisms to anticipate and adapt to the daily variations of their environment. The plant clock is an intricate network of interlocked feedback loops, in which transcription factors regulate each other to generate oscillations with expression peaks at specific times of the day. Over the last decade, mathematical modeling approaches have been used to understand the inner workings of the clock in the model plant Arabidopsis thaliana. Those efforts have produced a number of models of ever increasing complexity. Here, we present an alternative model that combines a low number of equations and parameters, similar to the very earliest models, with the complex network structure found in more recent ones. This simple model describes the temporal evolution of the abundance of eight clock gene mRNA/protein and captures key features of the clock on a qualitative level, namely the entrained and free-running behaviors of the wild type clock, as well as the defects found in knockout mutants (such as altered free-running periods, lack of entrainment, or changes in the expression of other clock genes). Additionally, our model produces complex responses to various light cues, such as extreme photoperiods and non-24 h environmental cycles, and can describe the control of hypocotyl growth by the clock. Our model constitutes a useful tool to probe dynamical properties of the core clock as well as clock-dependent processes. PMID:26904049

  7. Endogenous ochronosis.

    PubMed

    Turgay, E; Canat, D; Gurel, M S; Yuksel, T; Baran, M F; Demirkesen, C

    2009-12-01

    Endogenous ochronosis or alkaptonuria is a rare, autosomal recessive disease of tyrosine metabolism that is caused by a deficiency of the enzyme homogentisic acid oxidase. The disease results in the accumulation and deposition of homogentisic acid in the cartilage, eyelids, forehead, cheeks, axillae, genital region, buccal mucosa, larynx, tympanic membranes, and tendons. The disease generally presents in adults with arthritis and skin abnormalities; occasionally, involvement of other organs may be seen. A 49-year-old man was referred to our clinic with verrucous lesions on his hands. On physical examination, caviar-like ochronotic papules were found around his eyes and the helix cartilage of his ears, and on the dorsa of both hands. There were brown macules on the sclera (Osler's sign). The patient had arthritis and nephrolithiasis, and a sample of his urine darkened upon standing. Histopathological examination showed deposition of ochronotic pigment. High-dose ascorbic acid was given, and the patient showed improvement on follow-up examination 6 months later. PMID:20055850

  8. Endogenous circadian regulation of carbon dioxide exchange in terrestrial ecosystems

    Technology Transfer Automated Retrieval System (TEKTRAN)

    We tested the hypothesis that diurnal changes in terrestrial CO2 exchange are driven exclusively by the direct effect of the physical environment on plant physiology. We failed to corroborate this assumption, finding instead large diurnal fluctuations in whole ecosystem carbon assimilation across a ...

  9. Circadian regulation of slow waves in human sleep: Topographical aspects

    PubMed Central

    Lazar, Alpar S.; Lazar, Zsolt I.; Dijk, Derk-Jan

    2015-01-01

    Slow waves (SWs, 0.5–4 Hz) in field potentials during sleep reflect synchronized alternations between bursts of action potentials and periods of membrane hyperpolarization of cortical neurons. SWs decline during sleep and this is thought to be related to a reduction of synaptic strength in cortical networks and to be central to sleep's role in maintaining brain function. A central assumption in current concepts of sleep function is that SWs during sleep, and associated recovery processes, are independent of circadian rhythmicity. We tested this hypothesis by quantifying all SWs from 12 EEG derivations in 34 participants in whom 231 sleep periods were scheduled across the circadian cycle in a 10-day forced-desynchrony protocol which allowed estimation of the separate circadian and sleep-dependent modulation of SWs. Circadian rhythmicity significantly modulated the incidence, amplitude, frequency and the slope of the SWs such that the peaks of the circadian rhythms in these slow-wave parameters were located during the biological day. Topographical analyses demonstrated that the sleep-dependent modulation of SW characteristics was most prominent in frontal brain areas whereas the circadian effect was similar to or greater than the sleep-dependent modulation over the central and posterior brain regions. The data demonstrate that circadian rhythmicity directly modulates characteristics of SWs thought to be related to synaptic plasticity and that this modulation depends on topography. These findings have implications for the understanding of local sleep regulation and conditions such as ageing, depression, and neurodegeneration which are associated with changes in SWs, neural plasticity and circadian rhythmicity. PMID:25979664

  10. Circadian regulation of slow waves in human sleep: Topographical aspects.

    PubMed

    Lazar, Alpar S; Lazar, Zsolt I; Dijk, Derk-Jan

    2015-08-01

    Slow waves (SWs, 0.5-4Hz) in field potentials during sleep reflect synchronized alternations between bursts of action potentials and periods of membrane hyperpolarization of cortical neurons. SWs decline during sleep and this is thought to be related to a reduction of synaptic strength in cortical networks and to be central to sleep's role in maintaining brain function. A central assumption in current concepts of sleep function is that SWs during sleep, and associated recovery processes, are independent of circadian rhythmicity. We tested this hypothesis by quantifying all SWs from 12 EEG derivations in 34 participants in whom 231 sleep periods were scheduled across the circadian cycle in a 10-day forced-desynchrony protocol which allowed estimation of the separate circadian and sleep-dependent modulation of SWs. Circadian rhythmicity significantly modulated the incidence, amplitude, frequency and the slope of the SWs such that the peaks of the circadian rhythms in these slow-wave parameters were located during the biological day. Topographical analyses demonstrated that the sleep-dependent modulation of SW characteristics was most prominent in frontal brain areas whereas the circadian effect was similar to or greater than the sleep-dependent modulation over the central and posterior brain regions. The data demonstrate that circadian rhythmicity directly modulates characteristics of SWs thought to be related to synaptic plasticity and that this modulation depends on topography. These findings have implications for the understanding of local sleep regulation and conditions such as ageing, depression, and neurodegeneration which are associated with changes in SWs, neural plasticity and circadian rhythmicity. PMID:25979664

  11. Circadian clocks and cell division

    PubMed Central

    2010-01-01

    Evolution has selected a system of two intertwined cell cycles: the cell division cycle (CDC) and the daily (circadian) biological clock. The circadian clock keeps track of solar time and programs biological processes to occur at environmentally appropriate times. One of these processes is the CDC, which is often gated by the circadian clock. The intermeshing of these two cell cycles is probably responsible for the observation that disruption of the circadian system enhances susceptibility to some kinds of cancer. The core mechanism underlying the circadian clockwork has been thought to be a transcription and translation feedback loop (TTFL), but recent evidence from studies with cyanobacteria, synthetic oscillators and immortalized cell lines suggests that the core circadian pacemaking mechanism that gates cell division in mammalian cells could be a post-translational oscillator (PTO). PMID:20890114

  12. Adaptive temperature compensation in circadian oscillations.

    PubMed

    François, Paul; Despierre, Nicolas; Siggia, Eric D

    2012-01-01

    A temperature independent period and temperature entrainment are two defining features of circadian oscillators. A default model of distributed temperature compensation satisfies these basic facts yet is not easily reconciled with other properties of circadian clocks, such as many mutants with altered but temperature compensated periods. The default model also suggests that the shape of the circadian limit cycle and the associated phase response curves (PRC) will vary since the average concentrations of clock proteins change with temperature. We propose an alternative class of models where the twin properties of a fixed period and entrainment are structural and arise from an underlying adaptive system that buffers temperature changes. These models are distinguished by a PRC whose shape is temperature independent and orbits whose extrema are temperature independent. They are readily evolved by local, hill climbing, optimization of gene networks for a common quality measure of biological clocks, phase anticipation. Interestingly a standard realization of the Goodwin model for temperature compensation displays properties of adaptive rather than distributed temperature compensation. PMID:22807663

  13. Adaptive Temperature Compensation in Circadian Oscillations

    PubMed Central

    François, Paul; Despierre, Nicolas; Siggia, Eric D.

    2012-01-01

    A temperature independent period and temperature entrainment are two defining features of circadian oscillators. A default model of distributed temperature compensation satisfies these basic facts yet is not easily reconciled with other properties of circadian clocks, such as many mutants with altered but temperature compensated periods. The default model also suggests that the shape of the circadian limit cycle and the associated phase response curves (PRC) will vary since the average concentrations of clock proteins change with temperature. We propose an alternative class of models where the twin properties of a fixed period and entrainment are structural and arise from an underlying adaptive system that buffers temperature changes. These models are distinguished by a PRC whose shape is temperature independent and orbits whose extrema are temperature independent. They are readily evolved by local, hill climbing, optimization of gene networks for a common quality measure of biological clocks, phase anticipation. Interestingly a standard realization of the Goodwin model for temperature compensation displays properties of adaptive rather than distributed temperature compensation. PMID:22807663

  14. Environmental synchronizers of squirrel monkey circadian rhythms

    NASA Technical Reports Server (NTRS)

    Sulzman, F. M.; Fuller, C. A.; Moore-Ede, M. C.

    1977-01-01

    Various temporal signals in the environment were tested to determine if they could synchronize the circadian timing system of the squirrel monkey (Saimiri sciureus). The influence of cycles of light and dark, eating and fasting, water availability and deprivation, warm and cool temperature, sound and quiet, and social interaction and isolation on the drinking and activity rhythms of unrestrained monkeys was examined. In the absence of other time cues, 24-hr cycles of each of these potential synchronizers were applied for up to 3 wk, and the periods of the monkey's circadian rhythms were examined. Only light-dark cycles and cycles of food availability were shown to be entraining agents, since they were effective in determining the period and phase of the rhythmic variables. In the presence of each of the other environmental cycles, the monkey's circadian rhythms exhibited free-running periods which were significantly different from 24 hr with all possible phase relationships between the rhythms and the environmental cycles being examined.

  15. Circadian regulation gene polymorphisms are associated with sleep disruption and duration, and circadian phase and rhythm in adults with HIV.

    PubMed

    Lee, Kathryn A; Gay, Caryl; Byun, Eeeseung; Lerdal, Anners; Pullinger, Clive R; Aouizerat, Bradley E

    2015-01-01

    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

  16. Ontogenetic expression of metabolic genes and microRNAs in rainbow trout alevins during the transition from the endogenous to the exogenous feeding period.

    PubMed

    Mennigen, Jan A; Skiba-Cassy, Sandrine; Panserat, Stéphane

    2013-05-01

    As oviparous fish, rainbow trout change their nutritional strategy during ontogenesis. This change is divided into the exclusive utilization of yolk-sac reserves (endogenous feeding), the concurrent utilization of yolk reserves and exogenous feeds (mixed feeding) and the complete dependence on external feeds (exogenous feeding). The change in food source is accompanied by well-characterized morphological changes, including the development of adipose tissue as an energy storage site, and continuous muscle development to improve foraging. The aim of this study was to investigate underlying molecular mechanisms that contribute to these ontogenetic changes between the nutritional phenotypes in rainbow trout alevins. We therefore analyzed the expression of marker genes of metabolic pathways and microRNAs (miRNAs) important in the differentiation and/or maintenance of metabolic tissues. In exogenously feeding alevins, the last enzyme involved in glucose production (g6pca and g6pcb) and lipolytic gene expression (cpt1a and cpt1b) decreased, while that of gk, involved in hepatic glucose use, was induced. This pattern is consistent with a progressive switch from the utilization of stored (gluconeogenic) amino acids and lipids in endogenously feeding alevins to a utilization of exogenous feeds via the glycolytic pathway. A shift towards the utilization of external feeds is further evidenced by the increased expression of omy-miRNA-143, a homologue of the mammalian marker of adipogenesis. The expression of its predicted target gene abhd5, a factor in triglyceride hydrolysis, decreased concurrently, suggesting a potential mechanism in the onset of lipid deposition. Muscle-specific omy-miRNA-1/133 and myod1 expression decreased in exogenously feeding alevins, a molecular signature consistent with muscle hypertrophy, which may be linked to nutritional cues or increased foraging. PMID:23348939

  17. CIRCADIAN REGULATION OF METABOLISM

    PubMed Central

    Bailey, Shannon M.; Udoh, Uduak S.; Young, Martin E.

    2014-01-01

    In association with sleep/wake and fasting/feeding cycles, organisms experience dramatic oscillations in energetic demands and nutrient supply. It is therefore not surprising that various metabolic parameters, ranging from the activity status of molecular energy sensors to circulating nutrient levels, oscillate in time-of-day-dependent manners. It has become increasingly clear that rhythms in metabolic processes are not simply in response to daily environmental/behavioral influences, but are driven in part by cell autonomous circadian clocks. By synchronizing the cell with its environment, clocks modulate a host of metabolic processes in a temporally appropriate manner. The purpose of this article is to review current understanding of the interplay between circadian clocks and metabolism, in addition to the pathophysiologic consequences of disruption of this molecular mechanism, in terms of cardiometabolic disease development. PMID:24928941

  18. Electric light, particularly at night, disrupts human circadian rhythmicity: is that a problem?

    PubMed Central

    Stevens, Richard G.; Zhu, Yong

    2015-01-01

    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

  19. Electric light, particularly at night, disrupts human circadian rhythmicity: is that a problem?

    PubMed

    Stevens, Richard G; Zhu, Yong

    2015-05-01

    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

  20. Dynamical Analysis of bantam-Regulated Drosophila Circadian Rhythm Model

    NASA Astrophysics Data System (ADS)

    Li, Ying; Liu, Zengrong

    MicroRNAs (miRNAs) interact with 3‧untranslated region (UTR) elements of target genes to regulate mRNA stability or translation, and play a crucial role in regulating many different biological processes. bantam, a conserved miRNA, is involved in several functions, such as regulating Drosophila growth and circadian rhythm. Recently, it has been discovered that bantam plays a crucial role in the core circadian pacemaker. In this paper, based on experimental observations, a detailed dynamical model of bantam-regulated circadian clock system is developed to show the post-transcriptional behaviors in the modulation of Drosophila circadian rhythm, in which the regulation of bantam is incorporated into a classical model. The dynamical behaviors of the model are consistent with the experimental observations, which shows that bantam is an important regulator of Drosophila circadian rhythm. The sensitivity analysis of parameters demonstrates that with the regulation of bantam the system is more sensitive to perturbations, indicating that bantam regulation makes it easier for the organism to modulate its period against the environmental perturbations. The effectiveness in rescuing locomotor activity rhythms of mutated flies shows that bantam is necessary for strong and sustained rhythms. In addition, the biological mechanisms of bantam regulation are analyzed, which may help us more clearly understand Drosophila circadian rhythm regulated by other miRNAs.

  1. Caenorhabditis elegans opens up new insights into circadian clock mechanisms.

    PubMed

    Hasegawa, Kenji; Saigusa, Tetsu; Tamai, Yoichi

    2005-01-01

    The roundworm, Caenorhabditis elegans, is known to carry homologues of clock genes such as per (=period) and tim (=timeless), which constitute the core of the circadian clock in Drosophila and mammals: lin-42 and tim-1. Analyses using WormBase (C. elegans gene database) have identified with relatively high identity analogous of the clock genes recognized in Drosophila and mammals, with the notable exception of cry (=cryptochrome), which is lacking in C. elegans. All of these C. elegans cognates of the clock genes appear to belong to members of the PAS-superfamily and to participate in development or responsiveness to the environment but apparently are not involved in the C. elegans circadian clock. Nevertheless, C. elegans exhibits convincing circadian rhythms in locomotor behavior in the adult stage and in resistance to hyperosmotic stress in starved larvae (L1) after hatching, indicating that it has a circadian clock with a core design entirely different from that of Drosophila and mammals. Here two possibilities are considered. First, the core of the C. elegans circadian clock includes transcriptional/translational feedback loops between genes and their protein products that are entirely different from those of Drosophila and mammals. Second, a more basic principle such as homeostasis governs the circadian cellular physiology, and was established primarily to minimize the accumulation of DNA damage in response to an environment cycling at 24 h intervals. PMID:15865318

  2. Sensitivity Measures for Oscillating Systems: Application to Mammalian Circadian Gene Network

    PubMed Central

    Taylor, Stephanie R.; Gunawan, Rudiyanto; Petzold, Linda R.; Doyle, Francis J.

    2009-01-01

    Vital physiological behaviors exhibited daily by bacteria, plants, and animals are governed by endogenous oscillators called circadian clocks. The most salient feature of the circadian clock is its ability to change its internal time (phase) to match that of the external environment. The circadian clock, like many oscillators in nature, is regulated at the cellular level by a complex network of interacting components. As a complementary approach to traditional biological investigation, we utilize mathematical models and systems theoretic tools to elucidate these mechanisms. The models are systems of ordinary differential equations exhibiting stable limit cycle behavior. To study the robustness of circadian phase behavior, we use sensitivity analysis. As the standard set of sensitivity tools are not suitable for the study of phase behavior, we introduce a novel tool, the parametric impulse phase response curve (pIPRC). PMID:19593456

  3. Melatonin shifts human circadian rhythms according to a phase-response curve.

    PubMed

    Lewy, A J; Ahmed, S; Jackson, J M; Sack, R L

    1992-10-01

    A physiological dose of orally administered melatonin shifts circadian rhythms in humans according to a phase-response curve (PRC) that is nearly opposite in phase with the PRCs for light exposure: melatonin delays circadian rhythms when administered in the morning and advances them when administered in the afternoon or early evening. The human melatonin PRC provides critical information for using melatonin to treat circadian phase sleep and mood disorders, as well as maladaptation to shift work and transmeridional air travel. The human melatonin PRC also provides the strongest evidence to date for a function of endogenous melatonin and its suppression by light in augmenting entrainment of circadian rhythms by the light-dark cycle. PMID:1394610

  4. The Impact of Sleep and Circadian Disturbance on Hormones and Metabolism

    PubMed Central

    Kim, Tae Won; Jeong, Jong-Hyun; Hong, Seung-Chul

    2015-01-01

    The levels of several hormones fluctuate according to the light and dark cycle and are also affected by sleep, feeding, and general behavior. The regulation and metabolism of several hormones are influenced by interactions between the effects of sleep and the intrinsic circadian system; growth hormone, melatonin, cortisol, leptin, and ghrelin levels are highly correlated with sleep and circadian rhythmicity. There are also endogenous circadian mechanisms that serve to regulate glucose metabolism and similar rhythms pertaining to lipid metabolism, regulated through the actions of various clock genes. Sleep disturbance, which negatively impacts hormonal rhythms and metabolism, is also associated with obesity, insulin insensitivity, diabetes, hormonal imbalance, and appetite dysregulation. Circadian disruption, typically induced by shift work, may negatively impact health due to impaired glucose and lipid homeostasis, reversed melatonin and cortisol rhythms, and loss of clock gene rhythmicity. PMID:25861266

  5. Dynamic resetting of the human circadian pacemaker by intermittent bright light

    NASA Technical Reports Server (NTRS)

    Rimmer, D. W.; Boivin, D. B.; Shanahan, T. L.; Kronauer, R. E.; Duffy, J. F.; Czeisler, C. A.

    2000-01-01

    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.

  6. Suppressing the Neurospora crassa circadian clock while maintaining light responsiveness in continuous stirred tank reactors

    PubMed Central

    Cockrell, Allison L.; Pirlo, Russell K.; Babson, David M.; Cusick, Kathleen D.; Soto, Carissa M.; Petersen, Emily R.; Davis, Miah J.; Hong, Christian I.; Lee, Kwangwon; Fitzgerald, Lisa A.; Biffinger, Justin C.

    2015-01-01

    Neurospora crassa has been utilized as a model organism for studying biological, regulatory, and circadian rhythms for over 50 years. These circadian cycles are driven at the molecular level by gene transcription events to prepare for environmental changes. N. crassa is typically found on woody biomass and is commonly studied on agar-containing medium which mimics its natural environment. We report a novel method for disrupting circadian gene transcription while maintaining light responsiveness in N. crassa when held in a steady metabolic state using bioreactors. The arrhythmic transcription of core circadian genes and downstream clock-controlled genes was observed in constant darkness (DD) as determined by reverse transcription-quantitative PCR (RT-qPCR). Nearly all core circadian clock genes were up-regulated upon exposure to light during 11hr light/dark cycle experiments under identical conditions. Our results demonstrate that the natural timing of the robust circadian clock in N. crassa can be disrupted in the dark when maintained in a consistent metabolic state. Thus, these data lead to a path for the production of industrial scale enzymes in the model system, N. crassa, by removing the endogenous negative feedback regulation by the circadian oscillator. PMID:26031221

  7. Human skeletal myotubes display a cell-autonomous circadian clock implicated in basal myokine secretion

    PubMed Central

    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

    2015-01-01

    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

  8. Manipulations of amyloid precursor protein cleavage disrupt the circadian clock in aging Drosophila.

    PubMed

    Blake, Matthew R; Holbrook, Scott D; Kotwica-Rolinska, Joanna; Chow, Eileen S; Kretzschmar, Doris; Giebultowicz, Jadwiga M

    2015-05-01

    Alzheimer's disease (AD) is a neurodegenerative disease characterized by severe cognitive deterioration. While causes of AD pathology are debated, a large body of evidence suggests that increased cleavage of Amyloid Precursor Protein (APP) producing the neurotoxic Amyloid-β (Aβ) peptide plays a fundamental role in AD pathogenesis. One of the detrimental behavioral symptoms commonly associated with AD is the fragmentation of sleep-activity cycles with increased nighttime activity and daytime naps in humans. Sleep-activity cycles, as well as physiological and cellular rhythms, which may be important for neuronal homeostasis, are generated by a molecular system known as the circadian clock. Links between AD and the circadian system are increasingly evident but not well understood. Here we examined whether genetic manipulations of APP-like (APPL) protein cleavage in Drosophila melanogaster affect rest-activity rhythms and core circadian clock function in this model organism. We show that the increased β-cleavage of endogenous APPL by the β-secretase (dBACE) severely disrupts circadian behavior and leads to reduced expression of clock protein PER in central clock neurons of aging flies. Our data suggest that behavioral rhythm disruption is not a product of APPL-derived Aβ production but rather may be caused by a mechanism common to both α and β-cleavage pathways. Specifically, we show that increased production of the endogenous Drosophila Amyloid Intracellular Domain (dAICD) caused disruption of circadian rest-activity rhythms, while flies overexpressing endogenous APPL maintained stronger circadian rhythms during aging. In summary, our study offers a novel entry point toward understanding the mechanism of circadian rhythm disruption in Alzheimer's disease. PMID:25766673

  9. Circadian Disorganization Alters Intestinal Microbiota

    PubMed Central

    Voigt, Robin M.; Forsyth, Christopher B.; Green, Stefan J.; Mutlu, Ece; Engen, Phillip; Vitaterna, Martha H.; Turek, Fred W.; Keshavarzian, Ali

    2014-01-01

    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

  10. Calculating activation energies for temperature compensation in circadian rhythms

    NASA Astrophysics Data System (ADS)

    Bodenstein, C.; Heiland, I.; Schuster, S.

    2011-10-01

    Many biological species possess a circadian clock, which helps them anticipate daily variations in the environment. In the absence of external stimuli, the rhythm persists autonomously with a period of approximately 24 h. However, single pulses of light, nutrients, chemicals or temperature can shift the clock phase. In the case of light- and temperature-cycles, this allows entrainment of the clock to cycles of exactly 24 h. Circadian clocks have the remarkable property of temperature compensation, that is, the period of the circadian rhythm remains relatively constant within a physiological range of temperatures. For several organisms, temperature-regulated processes within the circadian clock have been identified in recent years. However, how these processes contribute to temperature compensation is not fully understood. Here, we theoretically investigate temperature compensation in general oscillatory systems. It is known that every oscillator can be locally temperature compensated around a reference temperature, if reactions are appropriately balanced. A balancing is always possible if the control coefficient with respect to the oscillation period of at least one reaction in the oscillator network is positive. However, for global temperature compensation, the whole physiological temperature range is relevant. Here, we use an approach which leads to an optimization problem subject to the local balancing principle. We use this approach to analyse different circadian clock models proposed in the literature and calculate activation energies that lead to temperature compensation.

  11. Lack of evidence for a marked endogenous component determining food intake in humans during forced desynchrony.

    PubMed

    Waterhouse, Jim; Jones, Kay; Edwards, Ben; Harrison, Yvonne; Nevill, Alan; Reilly, Thomas

    2004-05-01

    In an attempt to investigate the relative importance of endogenous and exogenous factors in determining food intake, 14 healthy subjects were studied while living in an Isolation Unit (where external time cues were absent) for eighteen 28 h "days" (equal to 21 solar days). The subjects were free to spend their waking time as they chose, and they had a free choice of what they ate and when they ate it. The only restrictions were that no naps were allowed in the "daytime," that some time was required to perform a variety of tests at regular intervals throughout the 18.67 h waking periods, and that any food preparation had to be performed by the subjects themselves. Core (rectal) temperature and activity were monitored throughout, and the subjects answered a questionnaire on their eating habits at 3 h intervals during the waking periods. The questionnaire investigated reasons for eating or not eating a meal during the previous 3 h and, if a meal had been eaten, its type, the factors influencing that choice, and the subjects' subjective responses (hunger before, enjoyment during, and satiety after) to it. The results were analyzed (two-way ANOVA) in terms of both the imposed day length (the exogenous component) and the free-running period of the temperature rhythm (the endogenous component). Results indicated that by far the main reason for eating/not eating was hunger/lack of hunger rather than factors such as food availability and time-pressure. There were statistically significant effects of time within the imposed waking periods upon the type of meal eaten--"breakfast" tending to be a snack, "lunch" a small hot meal, and the "evening meal" a large hot meal. Hot meals (whether small or large) were associated with more hunger before the meal, more enjoyment of the meal, and a greater degree of satiety afterward than were cold meals. These effects suggest that the individuals adjusted their eating habits to fit in with the imposed wake times. By contrast, the effect

  12. Absence of Circadian Rhythms of Preterm Premature Rupture of Membranes and Preterm Placental Abruption

    PubMed Central

    Luque-Fernandez, Miguel Angel; Ananth, Cande V.; Sanchez, Sixto E.; Qiu, Chun-fang; Hernandez-Diaz, Sonia; Valdimarsdottir, Unnur; Gelaye, Bizu; Williams, Michelle A.

    2014-01-01

    Purpose Data regarding circadian rhythm in the onset of spontaneous preterm premature rupture of membranes (PROM) and placental abruption (PA) cases are conflicting. We modeled the time of onset of preterm PROM and PA cases and examined if the circadian profiles varied based on the gestational age at delivery. Methods We used parametric and nonparametric methods, including trigonometric regression in the framework of generalized linear models, to test the presence of circadian rhythms in the time of onset of preterm PROM and PA cases, among 395 women who delivered a singleton between 2009 and 2010 in Lima, Peru. Results We found a diurnal circadian pattern, with a morning peak at 07h:32’ (95%CI:05h:46’ – 09h:18’) among moderate preterm PROM cases (P-value<0.001), and some evidence of a diurnal circadian periodicity among PA cases in term infants (P-value=0.067). However, we did not find evidence of circadian rhythms in the time of onset of extremely or very preterm PROM (P-value=0.259) and preterm PA (P-value=0.224). Conclusions The circadian rhythms of the time of onset of preterm PROM and PA cases varied based on gestational weeks at delivery. While circadian rhythms were presented among moderate preterm PROM and term PA cases, there was no evidence of circadian rhythms among preterm PA and very or extremely preterm PROM cases, underlying other mechanisms associated with the time of onset. PMID:25453346

  13. Circadian rhythm asynchrony in man during hypokinesis.

    NASA Technical Reports Server (NTRS)

    Winget, C. M.; Vernikos-Danellis, J.; Cronin, S. E.; Leach, C. S.; Rambaut, P. C.; Mack, P. B.

    1972-01-01

    Posture and exercise were investigated as synchronizers of certain physiologic rhythms in eight healthy male subjects in a defined environment. Four subjects exercised during bed rest. Body temperature (BT), heart rate, plasma thyroid hormone, and plasma steroid data were obtained from the subjects for a 6-day ambulatory equilibration period before bed rest, 56 days of bed rest, and a 10-day recovery period after bed rest. The results indicate that the mechanism regulating the circadian rhythmicity of the cardiovascular system is rigorously controlled and independent of the endocrine system, while the BT rhythm is more closely aligned to the endocrine system.

  14. ATPase activity of KaiC determines the basic timing for circadian clock of cyanobacteria.

    PubMed

    Terauchi, Kazuki; Kitayama, Yohko; Nishiwaki, Taeko; Miwa, Kumiko; Murayama, Yoriko; Oyama, Tokitaka; Kondo, Takao

    2007-10-01

    Self-sustainable oscillation of KaiC phosphorylation has been reconstituted in vitro, demonstrating that this cycle is the basic time generator of the circadian clock of cyanobacteria. Here we show that the ATPase activity of KaiC satisfies the characteristics of the circadian oscillation, the period length, and the temperature compensation. KaiC possesses extremely weak but stable ATPase activity (15 molecules of ATP per day), and the addition of KaiA and KaiB makes the activity oscillate with a circadian period in vitro. The ATPase activity of KaiC is inherently temperature-invariant, suggesting that temperature compensation of the circadian period could be driven by this simple biochemical reaction. Moreover, the activities of wild-type KaiC and five period-mutant proteins are directly proportional to their in vivo circadian frequencies, indicating that the ATPase activity defines the circadian period. Thus, we propose that KaiC ATPase activity constitutes the most fundamental reaction underlying circadian periodicity in cyanobacteria. PMID:17901204

  15. Ras-Mediated Deregulation of the Circadian Clock in Cancer

    PubMed Central

    Relógio, Angela; Thomas, Philippe; Medina-Pérez, Paula; Reischl, Silke; Bervoets, Sander; Gloc, Ewa; Riemer, Pamela; Mang-Fatehi, Shila; Maier, Bert; Schäfer, Reinhold; Leser, Ulf; Herzel, Hanspeter; Kramer, Achim; Sers, Christine

    2014-01-01

    Circadian rhythms are essential to the temporal regulation of molecular processes in living systems and as such to life itself. Deregulation of these rhythms leads to failures in biological processes and eventually to the manifestation of pathological phenotypes including cancer. To address the questions as to what are the elicitors of a disrupted clock in cancer, we applied a systems biology approach to correlate experimental, bioinformatics and modelling data from several cell line models for colorectal and skin cancer. We found strong and weak circadian oscillators within the same type of cancer and identified a set of genes, which allows the discrimination between the two oscillator-types. Among those genes are IFNGR2, PITX2, RFWD2, PPARγ, LOXL2, Rab6 and SPARC, all involved in cancer-related pathways. Using a bioinformatics approach, we extended the core-clock network and present its interconnection to the discriminative set of genes. Interestingly, such gene signatures link the clock to oncogenic pathways like the RAS/MAPK pathway. To investigate the potential impact of the RAS/MAPK pathway - a major driver of colorectal carcinogenesis - on the circadian clock, we used a computational model which predicted that perturbation of BMAL1-mediated transcription can generate the circadian phenotypes similar to those observed in metastatic cell lines. Using an inducible RAS expression system, we show that overexpression of RAS disrupts the circadian clock and leads to an increase of the circadian period while RAS inhibition causes a shortening of period length, as predicted by our mathematical simulations. Together, our data demonstrate that perturbations induced by a single oncogene are sufficient to deregulate the mammalian circadian clock. PMID:24875049

  16. Ras-mediated deregulation of the circadian clock in cancer.

    PubMed

    Relógio, Angela; Thomas, Philippe; Medina-Pérez, Paula; Reischl, Silke; Bervoets, Sander; Gloc, Ewa; Riemer, Pamela; Mang-Fatehi, Shila; Maier, Bert; Schäfer, Reinhold; Leser, Ulf; Herzel, Hanspeter; Kramer, Achim; Sers, Christine

    2014-01-01

    Circadian rhythms are essential to the temporal regulation of molecular processes in living systems and as such to life itself. Deregulation of these rhythms leads to failures in biological processes and eventually to the manifestation of pathological phenotypes including cancer. To address the questions as to what are the elicitors of a disrupted clock in cancer, we applied a systems biology approach to correlate experimental, bioinformatics and modelling data from several cell line models for colorectal and skin cancer. We found strong and weak circadian oscillators within the same type of cancer and identified a set of genes, which allows the discrimination between the two oscillator-types. Among those genes are IFNGR2, PITX2, RFWD2, PPARγ, LOXL2, Rab6 and SPARC, all involved in cancer-related pathways. Using a bioinformatics approach, we extended the core-clock network and present its interconnection to the discriminative set of genes. Interestingly, such gene signatures link the clock to oncogenic pathways like the RAS/MAPK pathway. To investigate the potential impact of the RAS/MAPK pathway - a major driver of colorectal carcinogenesis - on the circadian clock, we used a computational model which predicted that perturbation of BMAL1-mediated transcription can generate the circadian phenotypes similar to those observed in metastatic cell lines. Using an inducible RAS expression system, we show that overexpression of RAS disrupts the circadian clock and leads to an increase of the circadian period while RAS inhibition causes a shortening of period length, as predicted by our mathematical simulations. Together, our data demonstrate that perturbations induced by a single oncogene are sufficient to deregulate the mammalian circadian clock. PMID:24875049

  17. Circadian oscillatory transcriptional programs in grapevine ripening fruits

    PubMed Central

    2014-01-01

    Background Temperature and solar radiation influence Vitis vinifera L. berry ripening. Both environmental conditions fluctuate cyclically on a daily period basis and the strength of this fluctuation affects grape ripening too. Additionally, a molecular circadian clock regulates daily cyclic expression in a large proportion of the plant transcriptome modulating multiple developmental processes in diverse plant organs and developmental phases. Circadian cycling of fruit transcriptomes has not been characterized in detail despite their putative relevance in the final composition of the fruit. Thus, in this study, gene expression throughout 24 h periods in pre-ripe berries of Tempranillo and Verdejo grapevine cultivars was followed to determine whether different ripening transcriptional programs are activated during certain times of day in different grape tissues and genotypes. Results Microarray analyses identified oscillatory transcriptional profiles following circadian variations in the photocycle and the thermocycle. A higher number of expression oscillating transcripts were detected in samples carrying exocarp tissue including biotic stress-responsive transcripts activated around dawn. Thermotolerance-like responses and regulation of circadian clock-related genes were observed in all studied samples. Indeed, homologs of core clock genes were identified in the grapevine genome and, among them, VvREVEILLE1 (VvRVE1), showed a consistent circadian expression rhythm in every grape berry tissue analysed. Light signalling components and terpenoid biosynthetic transcripts were specifically induced during the daytime in Verdejo, a cultivar bearing white-skinned and aromatic berries, whereas transcripts involved in phenylpropanoid biosynthesis were more prominently regulated in Tempranillo, a cultivar bearing black-skinned berries. Conclusions The transcriptome of ripening fruits varies in response to daily environmental changes, which might partially be under the control

  18. Protein phosphatase PHLPP1 controls the light-induced resetting of the circadian clock

    PubMed Central

    Masubuchi, Satoru; Gao, Tianyan; O'Neill, Audrey; Eckel-Mahan, Kristin; Newton, Alexandra C.; Sassone-Corsi, Paolo

    2010-01-01

    The pleckstrin homology domain leucine-rich repeat protein phosphatase 1 (PHLPP1) differentially attenuates Akt, PKC, and ERK1/2 signaling, thereby controlling the duration and amplitude of responses evoked by these kinases. PHLPP1 is expressed in the mammalian central clock, the suprachiasmatic nucleus, where it oscillates in a circadian fashion. To explore the role of PHLPP1 in vivo, we have generated mice with a targeted deletion of the PHLPP1 gene. Here we show that PHLPP1-null mice, although displaying normal circadian rhythmicity, have a drastically impaired capacity to stabilize the circadian period after light-induced resetting, producing a large phase shift after light resetting. Our findings reveal that PHLPP1 exerts a previously unappreciated role in circadian control, governing the consolidation of circadian periodicity after resetting. PMID:20080691

  19. Circadian Clock Control of Endocrine Factors

    PubMed Central

    Gamble, Karen L.; Berry, Ryan; Frank, Stuart J.; Young, Martin E.

    2015-01-01

    Organisms experience dramatic fluctuations in demands/stresses over the course of the day. In order to maintain biological processes within physiologic boundaries, it is imperative that mechanisms have evolved for anticipation of, and adaptation to, these daily fluctuations. Endocrine factors undoubtedly play an integral role in homeostasis. Not only do circulating levels of various endocrine factors oscillate over the 24 period, but so too does responsiveness of target tissues to these signals/stimuli. Emerging evidence suggests that these daily oscillations do not occur solely in response to behavioral fluctuations associated with sleep/wake and feeding/fasting cycles, but are orchestrated in part by an intrinsic timekeeping mechanism known as the circadian clock. Disruption of circadian clocks, through genetic and/or environmental means, appears to precipitate numerous common disorders, including cardiometabolic diseases and cancer. Collectively, these observations, which are reviewed within the current article, have led to suggestion that strategies designed to realign normal circadian rhythmicities hold a therapeutic potential for the treatment of various endocrine-related disorders. PMID:24863387

  20. Inositols affect the mating circadian rhythm of Drosophila melanogaster

    PubMed Central

    Sakata, Kazuki; Kawasaki, Haruhisa; Suzuki, Takahiro; Ito, Kumpei; Negishi, Osamu; Tsuno, Takuo; Tsuno, Hiromi; Yamazaki, Youta; Ishida, Norio

    2015-01-01

    Accumulating evidence indicates that the molecular circadian clock underlies the mating behavior of Drosophila melanogaster. However, information about which food components affect circadian mating behavior is scant. The ice plant, Mesembryanthemum crystallinum has recently become a popular functional food. Here, we showed that the close-proximity (CP) rhythm of D. melanogaster courtship behavior was damped under low-nutrient conditions, but significantly enhanced by feeding the flies with powdered ice plant. Among various components of ice plants, we found that myo-inositol increased the amplitude and slightly shortened the period of the CP rhythm. Real-time reporter assays showed that myo-inositol and D-pinitol shortened the period of the circadian reporter gene Per2-luc in NIH 3T3 cells. These data suggest that the ice plant is a useful functional food and that the ability of inositols to shorten rhythms is a general phenomenon in insects as well as mammals. PMID:26097456

  1. Molecular bases of circadian rhythmicity in renal physiology and pathology.

    PubMed

    Bonny, Olivier; Vinciguerra, Manlio; Gumz, Michelle L; Mazzoccoli, Gianluigi

    2013-10-01

    The physiological processes that maintain body homeostasis oscillate during the day. Diurnal changes characterize kidney functions, comprising regulation of hydro-electrolytic and acid-base balance, reabsorption of small solutes and hormone production. Renal physiology is characterized by 24-h periodicity and contributes to circadian variability of blood pressure levels, related as well to nychthemeral changes of sodium sensitivity, physical activity, vascular tone, autonomic function and neurotransmitter release from sympathetic innervations. The circadian rhythmicity of body physiology is driven by central and peripheral biological clockworks and entrained by the geophysical light/dark cycle. Chronodisruption, defined as the mismatch between environmental-social cues and physiological-behavioral patterns, causes internal desynchronization of periodic functions, leading to pathophysiological mechanisms underlying degenerative, immune related, metabolic and neoplastic diseases. In this review we will address the genetic, molecular and anatomical elements that hardwire circadian rhythmicity in renal physiology and subtend disarray of time-dependent changes in renal pathology. PMID:23901050

  2. Molecular bases of circadian rhythmicity in renal physiology and pathology

    PubMed Central

    Bonny, Olivier; Vinciguerra, Manlio; Gumz, Michelle L.; Mazzoccoli, Gianluigi

    2013-01-01

    The physiological processes that maintain body homeostasis oscillate during the day. Diurnal changes characterize kidney functions, comprising regulation of hydro-electrolytic and acid-base balance, reabsorption of small solutes and hormone production. Renal physiology is characterized by 24-h periodicity and contributes to circadian variability of blood pressure levels, related as well to nychthemeral changes of sodium sensitivity, physical activity, vascular tone, autonomic function and neurotransmitter release from sympathetic innervations. The circadian rhythmicity of body physiology is driven by central and peripheral biological clockworks and entrained by the geophysical light/dark cycle. Chronodisruption, defined as the mismatch between environmental–social cues and physiological–behavioral patterns, causes internal desynchronization of periodic functions, leading to pathophysiological mechanisms underlying degenerative, immune related, metabolic and neoplastic diseases. In this review we will address the genetic, molecular and anatomical elements that hardwire circadian rhythmicity in renal physiology and subtend disarray of time–dependent changes in renal pathology. PMID:23901050

  3. Emerging Models for the Molecular Basis of Mammalian Circadian Timing

    PubMed Central

    2015-01-01

    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

  4. Environmental Perturbation of the Circadian Clock Disrupts Pregnancy in the Mouse

    PubMed Central

    Summa, Keith C.; Vitaterna, Martha Hotz; Turek, Fred W.

    2012-01-01

    Background The circadian clock has been linked to reproduction at many levels in mammals. Epidemiological studies of female shift workers have reported increased rates of reproductive abnormalities and adverse pregnancy outcomes, although whether the cause is circadian disruption or another factor associated with shift work is unknown. Here we test whether environmental disruption of circadian rhythms, using repeated shifts of the light:dark (LD) cycle, adversely affects reproductive success in mice. Methodology/Principal Findings Young adult female C57BL/6J (B6) mice were paired with B6 males until copulation was verified by visual identification of vaginal plug formation. Females were then randomly assigned to one of three groups: control, phase-delay or phase-advance. Controls remained on a constant 12-hr light:12-hr dark cycle, whereas phase-delayed and phase-advanced mice were subjected to 6-hr delays or advances in the LD cycle every 5–6 days, respectively. The number of copulations resulting in term pregnancies was determined. Control females had a full-term pregnancy success rate of 90% (11/12), which fell to 50% (9/18; p<0.1) in the phase-delay group and 22% (4/18; p<0.01) in the phase-advance group. Conclusions/Significance Repeated shifting of the LD cycle, which disrupts endogenous circadian timekeeping, dramatically reduces pregnancy success in mice. Advances of the LD cycle have a greater negative impact on pregnancy outcomes and, in non-pregnant female mice, require longer for circadian re-entrainment, suggesting that the magnitude or duration of circadian misalignment may be related to the severity of the adverse impact on pregnancy. These results explicitly link disruptions of circadian entrainment to adverse pregnancy outcomes in mammals, which may have important implications for the reproductive health of female shift workers, women with circadian rhythm sleep disorders and/or women with disturbed circadian rhythms for other reasons. PMID

  5. Glucocorticosteroid injection is a circadian zeitgeber in the laboratory rat

    SciTech Connect

    Horseman, N.D.; Ehret, C.F.

    1982-09-01

    Intraperitoneal temperatures were monitored by radiotelemetry to observe the thermoregulatory rhythm of male laboratory rats (Rattus norvegicus albinus). Rats received single injections of dexamethasone (as dexamethasone sodium phosphate) during constant darkness (0.1 lx) with food freely available or no food available. No phase shifts occurred following saline injection or dexamethasone at 1 mg/kg body wt. Depending on the phase of injection relative to the circadian cycle, dexamethasone at 10 mg/kg caused thermoregulatory peaks to be either delayed or advanced on the 4th and 5th days after injection. There was an insensitive interval which corresponded to subjective day. Phase shifts induced by dexamethasone during ad libitum feeding were of less magnitude than those induced during starvation. The determination of phase-shifting parameters (i.e., a phase-response curve) for hormonal substances represents a rigorous and broadly applicable technique for determining endogenous mechanisms for circadian phase control and entrainment.

  6. Circadian clock functioning is linked to acute stress reactivity in rats.

    PubMed

    Weibel, L; Maccari, S; Van Reeth, O

    2002-10-01

    At least two major physiological systems are involved in the adaptation of the organism to environmental challenges: the circadian system and the stress reaction. This study addressed the possibility that interindividual differences in stress sensitivity and in the functioning of the circadian system are related. At 2 months of age, corticosterone secretion in response to a 20-min restraint stress was assessed in 9 Sprague-Dawley rats for which running wheel activity was recorded as a rhythmic behavioral marker of the circadian clock. Two weeks later, the adaptive response of the circadian system to an abrupt shift in the light:dark (LD) cycle was assessed in those rats using a jet-lag paradigm. Finally, after resynchronization to the new LD cycle, rats were transferred to constant darkness to assess the free-running period of their circadian rhythm of running-wheel activity. Results indicate that stress-induced corticosterone secretion was (1) positively correlated with the number of days to resynchronize the circadian activity rhythm to the new LD cycle, and with the value of its free-running period, and (2) negatively correlated with the intensity of daily locomotor activity. Those data, emphasizing the interactions between the stress response of an organism and the functioning of its circadian system, could explain interindividual differences in humans' susceptibility to shift work or other circadian-related disorders. PMID:12375620

  7. Genome-wide expression analysis reveals 100 adrenal gland-dependent circadian genes in the mouse liver.

    PubMed

    Oishi, Katsutaka; Amagai, Noriko; Shirai, Hidenori; Kadota, Koji; Ohkura, Naoki; Ishida, Norio

    2005-01-01

    Recent progress in genome-wide expression analysis has identified hundreds of circadian genes not only in the suprachiasmatic nucleus (the mammalian master clock) but also in peripheral tissues, such as heart, liver and kidney of mammals. Glucocorticoid is thought to be a circadian time cue for mammalian peripheral clocks. To identify the genes of which the circadian expression is regulated by endogenous glucocorticoids, we performed DNA microarray analysis using hepatic RNA from adrenalectomized (ADX) and sham-operated mice. We identified 169 genes that fluctuated between day and night in the livers of the sham-operated mice. Among these, 100 lost circadian rhythmicity in ADX mice. These included the genes for key enzymes of liver metabolic functions, such as glucokinase, HMG-CoA reductase and glucose-6-phosphatase. The circadian expression of Lpin1, FKBP51 and S-adenosyl methionine decarboxylase was also abolished in the ADX mice. On the other hand, although the circadian expression of clock or clock-related genes, such as mPer2, DBP, E4BP4, mDec1, Usp2 and Wee1 remained almost totally intact in the liver of ADX mice, it was extremely damped in homozygous Clock mutant mice. The present findings suggested that one type of hepatic circadian genes in mice is transcriptionally regulated by core components of the circadian clock, such as CLOCK and BMAL1, and that the other depends on the adrenal gland. PMID:16303750

  8. Endocrine Effects of Circadian Disruption.

    PubMed

    Bedrosian, Tracy A; Fonken, Laura K; Nelson, Randy J

    2016-01-01

    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. PMID:26208951

  9. Nocturia: The circadian voiding disorder

    PubMed Central

    Moon, Young Tae; Kim, Kyung Do

    2016-01-01

    Nocturia is a prevalent condition of waking to void during the night. The concept of nocturia has evolved from being a symptomatic aspect of disease associated with the prostate or bladder to a form of lower urinary tract disorder. However, recent advances in circadian biology and sleep science suggest that it might be important to consider nocturia as a form of circadian dysfunction. In the current review, nocturia is reexamined with an introduction to sleep disorders and recent findings in circadian biology in an attempt to highlight the importance of rediscovering nocturia as a problem of chronobiology. PMID:27195315

  10. Nocturia: The circadian voiding disorder.

    PubMed

    Kim, Jin Wook; Moon, Young Tae; Kim, Kyung Do

    2016-05-01

    Nocturia is a prevalent condition of waking to void during the night. The concept of nocturia has evolved from being a symptomatic aspect of disease associated with the prostate or bladder to a form of lower urinary tract disorder. However, recent advances in circadian biology and sleep science suggest that it might be important to consider nocturia as a form of circadian dysfunction. In the current review, nocturia is reexamined with an introduction to sleep disorders and recent findings in circadian biology in an attempt to highlight the importance of rediscovering nocturia as a problem of chronobiology. PMID:27195315

  11. Neurobiology of Circadian Rhythm Regulation.

    PubMed

    Rosenwasser, Alan M; Turek, Fred W

    2015-12-01

    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. PMID:26568118

  12. Circadian variation of heart rate variability among welders

    PubMed Central

    Cavallari, Jennifer M; Fang, Shona C; Mittleman, Murray A; Christiani, David C

    2011-01-01

    Objective To compare the circadian variation of hourly heart rate variability (HRV) on work and non-workdays among boilermaker construction workers. Method A panel study of 18 males monitored by 24-h ambulatory ECG over 44 observation-days on paired work and non-workdays was conducted. ECGs were analysed and the SD of normal-to-normal beats index (SDNNi) was calculated from 5-min data and summarised hourly. SDNNis over work and non-workdays were compared using linear mixed-effects models to account for repeated measures and harmonic regression to account for circadian variation. Results Both work and non-work hourly HRV exhibited circadian variation with an increase in the evening and a decrease in the afternoon. SDNNi was lower on workdays as compared with non-workdays with the largest, statistically significant differences observed between 10:00 and 16:00, during active working. Lower SDNNi, albeit smaller yet statistically significant differences, was also observed in the evening hours following work (17:00–21:00) and early morning (4:00). In regression models using all time periods, an average workday SDNNi was 8.1 ms (95% CI –9.8 to –6.3) lower than non-workday SDNNi. The circadian pattern of HRV exhibited two peaks which differed on work and non-workdays. Conclusion While workday and non-workday HRV followed a circadian pattern, decreased HRV and variation of the circadian pattern were observed on workdays. Declines and changes in the circadian pattern of HRV is a concern among this exposed population. PMID:20798005

  13. A Long Noncoding RNA Perturbs the Circadian Rhythm of Hepatoma Cells to Facilitate Hepatocarcinogenesis12

    PubMed Central

    Cui, Ming; Zheng, Minying; Sun, Baodi; Wang, Yue; Ye, Lihong; Zhang, Xiaodong

    2015-01-01

    Clock circadian regulator (CLOCK)/brain and muscle arnt-like protein-1 (BMAL1) complex governs the regulation of circadian rhythm through triggering periodic alterations of gene expression. However, the underlying mechanism of circadian clock disruption in hepatocellular carcinoma (HCC) remains unclear. Here, we report that a long noncoding RNA (lncRNA), highly upregulated in liver cancer (HULC), contributes to the perturbations in circadian rhythm of hepatoma cells. Our observations showed that HULC was able to heighten the expression levels of CLOCK and its downstream circadian oscillators, such as period circadian clock 1 and cryptochrome circadian clock 1, in hepatoma cells. Strikingly, HULC altered the expression pattern and prolonged the periodic expression of CLOCK in hepatoma cells. Mechanistically, the complementary base pairing between HULC and the 5' untranslated region of CLOCK mRNA underlay the HULC-modulated expression of CLOCK, and the mutants in the complementary region failed to achieve the event. Moreover, immunohistochemistry staining and quantitative real-time polymerase chain reaction validated that the levels of CLOCK were elevated in HCC tissues, and the expression levels of HULC were positively associated with those of CLOCK in clinical HCC samples. In functional experiments, our data exhibited that CLOCK was implicated in the HULC-accelerated proliferation of hepatoma cells in vitro and in vivo. Taken together, our data show that an lncRNA, HULC, is responsible for the perturbations in circadian rhythm through upregulating circadian oscillator CLOCK in hepatoma cells, resulting in the promotion of hepatocarcinogenesis. Thus, our finding provides new insights into the mechanism by which lncRNA accelerates hepatocarcinogenesis through disturbing circadian rhythm of HCC. PMID:25622901

  14. A long noncoding RNA perturbs the circadian rhythm of hepatoma cells to facilitate hepatocarcinogenesis.

    PubMed

    Cui, Ming; Zheng, Minying; Sun, Baodi; Wang, Yue; Ye, Lihong; Zhang, Xiaodong

    2015-01-01

    Clock circadian regulator (CLOCK)/brain and muscle arnt-like protein-1 (BMAL1) complex governs the regulation of circadian rhythm through triggering periodic alterations of gene expression. However, the underlying mechanism of circadian clock disruption in hepatocellular carcinoma (HCC) remains unclear. Here, we report that a long noncoding RNA (lncRNA), highly upregulated in liver cancer (HULC), contributes to the perturbations in circadian rhythm of hepatoma cells. Our observations showed that HULC was able to heighten the expression levels of CLOCK and its downstream circadian oscillators, such as period circadian clock 1 and cryptochrome circadian clock 1, in hepatoma cells. Strikingly, HULC altered the expression pattern and prolonged the periodic expression of CLOCK in hepatoma cells. Mechanistically, the complementary base pairing between HULC and the 5' untranslated region of CLOCK mRNA underlay the HULC-modulated expression of CLOCK, and the mutants in the complementary region failed to achieve the event. Moreover, immunohistochemistry staining and quantitative real-time polymerase chain reaction validated that the levels of CLOCK were elevated in HCC tissues, and the expression levels of HULC were positively associated with those of CLOCK in clinical HCC samples. In functional experiments, our data exhibited that CLOCK was implicated in the HULC-accelerated proliferation of hepatoma cells in vitro and in vivo. Taken together, our data show that an lncRNA, HULC, is responsible for the perturbations in circadian rhythm through upregulating circadian oscillator CLOCK in hepatoma cells, resulting in the promotion of hepatocarcinogenesis. Thus, our finding provides new insights into the mechanism by which lncRNA accelerates hepatocarcinogenesis through disturbing circadian rhythm of HCC. PMID:25622901

  15. Role of cardiomyocyte circadian clock in myocardial metabolic adaptation

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Marked circadian rhythmicities in cardiovascular physiology and pathophysiology exist. The cardiomyocyte circadian clock has recently been linked to circadian rhythms in myocardial gene expression, metabolism, and contractile function. For instance, the cardiomyocyte circadian clock is essential f...

  16. Dysregulation of circadian rhythms following prolactin-secreting pituitary microadenoma.

    PubMed

    Borodkin, Katy; Ayalon, Liat; Kanety, Hanna; Dagan, Yaron

    2005-01-01

    A patient who developed an irregular sleep-wake pattern following prolactin-secreting pituitary microadenoma is described. The patient reported difficulties in sleep onset and awakening at the desired time, which caused major dysfunction in his daily life activities. Despite these difficulties, the sleep-related complaints of the patient remained unrecognized for as long as three yrs. Statistical analyses of the patient's rest-activity patterns revealed that the disruption of the sleep-wake circadian rhythm originated from a disharmony between ultradian (semicircadian) and circadian components. The circadian component displayed shorter than 24 h periodicity most of the time, but the semicircadian component fluctuated between longer and shorter than 12 h periods. Additionally, desynchrony in terms of period length was found in the tentative analyses of the rest-activity pattern, salivary melatonin, and oral temperature. While the salivary melatonin time series data could be characterized by a best-fit cosine curve of 24 h, the time series data of oral temperature was more compatible with 28 h best-fit curve. The rest-activity cycle during the simultaneous measurements, however, was best approximated by a best-fit curve of 21 h. The dysregulation of circadian rhythms occurred concomitantly, but not beforehand, with the onset of pituitary disease, thus suggesting an association between the two phenomena. This association may have interesting implications to the modeling of the circadian time-keeping system. This case also highlights the need to raise the awareness to circadian rhythm sleep disorders and to consider disruptions of sleep-wake cycle in patients with pituitary adenoma. PMID:15865328

  17. The Circadian Clock in Murine Chondrocytes Regulates Genes Controlling Key Aspects of Cartilage Homeostasis

    PubMed Central

    Gossan, Nicole; Zeef, Leo; Hensman, James; Hughes, Alun; Bateman, John F; Rowley, Lynn; Little, Christopher B; Piggins, Hugh D; Rattray, Magnus; Boot-Handford, Raymond P; Meng, Qing-Jun

    2013-01-01

    ObjectiveTo characterize the circadian clock in murine cartilage tissue and identify tissue-specific clock target genes, and to investigate whether the circadian clock changes during aging or during cartilage degeneration using an experimental mouse model of osteoarthritis (OA). MethodsCartilage explants were obtained from aged and young adult mice after transduction with the circadian clock fusion protein reporter PER2::luc, and real-time bioluminescence recordings were used to characterize the properties of the clock. Time-series microarrays were performed on mouse cartilage tissue to identify genes expressed in a circadian manner. Rhythmic genes were confirmed by quantitative reverse transcription–polymerase chain reaction using mouse tissue, primary chondrocytes, and a human chondrocyte cell line. Experimental OA was induced in mice by destabilization of the medial meniscus (DMM), and articular cartilage samples were microdissected and subjected to microarray analysis. ResultsMouse cartilage tissue and a human chondrocyte cell line were found to contain intrinsic molecular circadian clocks. The cartilage clock could be reset by temperature signals, while the circadian period was temperature compensated. PER2::luc bioluminescence demonstrated that circadian oscillations were significantly lower in amplitude in cartilage from aged mice. Time-series microarray analyses of the mouse tissue identified the first circadian transcriptome in cartilage, revealing that 615 genes (∼3.9% of the expressed genes) displayed a circadian pattern of expression. This included genes involved in cartilage homeostasis and survival, as well as genes with potential importance in the pathogenesis of OA. Several clock genes were disrupted in the early stages of cartilage degeneration in the DMM mouse model of OA. ConclusionThese results reveal an autonomous circadian clock in chondrocytes that can be implicated in key aspects of cartilage biology and pathology. Consequently

  18. Circadian Modulation of Alcohol-Induced Sedation and Recovery in Male and Female Drosophila.

    PubMed

    De Nobrega, Aliza K; Lyons, Lisa C

    2016-04-01

    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

  19. Assaying Locomotor Activity to Study Circadian Rhythms and Sleep Parameters in Drosophila

    PubMed Central

    Chiu, Joanna C.; Low, Kwang Huei; Pike, Douglas H.; Yildirim, Evrim; Edery, Isaac

    2010-01-01

    Most life forms exhibit daily rhythms in cellular, physiological and behavioral phenomena that are driven by endogenous circadian (≡24 hr) pacemakers or clocks. Malfunctions in the human circadian system are associated with numerous diseases or disorders. Much progress towards our understanding of the mechanisms underlying circadian rhythms has emerged from genetic screens whereby an easily measured behavioral rhythm is used as a read-out of clock function. Studies using Drosophila have made seminal contributions to our understanding of the cellular and biochemical bases underlying circadian rhythms. The standard circadian behavioral read-out measured in Drosophila is locomotor activity. In general, the monitoring system involves specially designed devices that can measure the locomotor movement of Drosophila. These devices are housed in environmentally controlled incubators located in a darkroom and are based on using the interruption of a beam of infrared light to record the locomotor activity of individual flies contained inside small tubes. When measured over many days, Drosophila exhibit daily cycles of activity and inactivity, a behavioral rhythm that is governed by the animal's endogenous circadian system. The overall procedure has been simplified with the advent of commercially available locomotor activity monitoring devices and the development of software programs for data analysis. We use the system from Trikinetics Inc., which is the procedure described here and is currently the most popular system used worldwide. More recently, the same monitoring devices have been used to study sleep behavior in Drosophila. Because the daily wake-sleep cycles of many flies can be measured simultaneously and only 1 to 2 weeks worth of continuous locomotor activity data is usually sufficient, this system is ideal for large-scale screens to identify Drosophila manifesting altered circadian or sleep properties. PMID:20972399

  20. Circadian regulation of human sleep and age-related changes in its timing, consolidation and EEG characteristics

    NASA Technical Reports Server (NTRS)

    Dijk, D. J.; Duffy, J. F.

    1999-01-01

    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.

  1. Circadian regulation of human sleep and age-related changes in its timing, consolidation and EEG characteristics.

    PubMed

    Dijk, D J; Duffy, J F

    1999-04-01

    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. PMID:10344586

  2. Entrainment of the mouse circadian clock by sub-acute physical and psychological stress.

    PubMed

    Tahara, Yu; Shiraishi, Takuya; Kikuchi, Yosuke; Haraguchi, Atsushi; Kuriki, Daisuke; Sasaki, Hiroyuki; Motohashi, Hiroaki; Sakai, Tomoko; Shibata, Shigenobu

    2015-01-01

    The effects of acute stress on the peripheral circadian system are not well understood in vivo. Here, we show that sub-acute stress caused by restraint or social defeat potently altered clock gene expression in the peripheral tissues of mice. In these peripheral tissues, as well as the hippocampus and cortex, stressful stimuli induced time-of-day-dependent phase-advances or -delays in rhythmic clock gene expression patterns; however, such changes were not observed in the suprachiasmatic nucleus, i.e. the central circadian clock. Moreover, several days of stress exposure at the beginning of the light period abolished circadian oscillations and caused internal desynchronisation of peripheral clocks. Stress-induced changes in circadian rhythmicity showed habituation and disappeared with long-term exposure to repeated stress. These findings suggest that sub-acute physical/psychological stress potently entrains peripheral clocks and causes transient dysregulation of circadian clocks in vivo. PMID:26073568

  3. Aging human circadian rhythms: conventional wisdom may not always be right

    NASA Technical Reports Server (NTRS)

    Monk, Timothy H.

    2005-01-01

    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.

  4. Treatment of a Circadian Rhythm Disturbance in a 2-Year-Old Blind Child.

    ERIC Educational Resources Information Center

    Mindell, J. A.; And Others

    1996-01-01

    The use of sleep scheduling and a daytime routine for the treatment of circadian rhythm disorder was found helpful in decreasing a blind 2-year old's nighttime wake periods and daytime sleepiness. (DB)

  5. Sleep and Circadian Rhythms in Four Orbiting Astronauts

    NASA Technical Reports Server (NTRS)

    Monk, Timothy H.; Buysse, Daniel J.; Billy, Bart D.; Kennedy, Kathy S.; Willrich, Linda M.

    1999-01-01

    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.

  6. Dynamical mechanism of circadian singularity behavior in Neurospora

    NASA Astrophysics Data System (ADS)

    Sun, Maorong; Wang, Yi; Xu, Xin; Yang, Ling

    2016-09-01

    Many organisms have oscillators with a period of about 24 hours, called "circadian clocks". They employ negative biochemical feedback loops that are self-contained within a single cell (requiring no cell-to-cell interaction). Circadian singularity behavior is a phenomenon of the abolishment of circadian rhythmicities by a critical stimulus. These behaviors have been found experimentally in Neurospora, human and hamster, by temperature step-up or light pulse. Two alternative models have been proposed to explain this phenomenon: desynchronization of cell populations, and loss of oscillations in all cells by resetting each cell close to a steady state. In this work, we use a mathematical model to investigate the dynamical mechanism of circadian singularity behavior in Neurospora. Our findings suggest that the arrhythmic behavior after the critical stimulus is caused by the collaboration of the desynchronization and the loss of oscillation amplitude. More importantly, we found that the stable manifold of the unstable equilibrium point, instead of the steady state itself, plays a crucial role in circadian singularity behavior.

  7. Circadian rhythms in a long-term duration space flight

    NASA Astrophysics Data System (ADS)

    Alpatov, Alexey M.

    In order to maintain cosmonaut health and performance, it is important for the work-rest schedule to follow human circadian rhythms (CR). What happens with CR in space flight? Investigations of CR in mammals revealed, that the circadian phase in flight is less stable, probably due to a displacement of the range of entrainment, resulting from internal period change (the latter was confirmed on insects). The circadian period may be a gravity-dependent parameter. If so, the basic biological requirement for the day length might be different in weightlessness. On this basis, a higher risk of desynchronosis is expected in a long-duration space flight. As a countermeasure, a non-24-hr day length could be suggested, being close to the internal circadian period (in humans about 25 hr). Taking into account a possible displacement of period in weightlessness, it seems reasonable to establish a flexible work-rest schedule, capable to follow the body temperature CR by means of biofeedback.

  8. The circadian modulation of leptin-controlled bone formation

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Mice with circadian gene Period and Cryptochrome mutations develop high bone mass early in life. Such a phenotype is accompanied by an increase in osteoblast numbers in mutant bone and cannot be corrected by leptin intracerebroventricular infusion. Thus, the molecular clock plays a key role in lepti...

  9. Heterogeneity induces rhythms of weakly coupled circadian neurons.

    PubMed

    Gu, Changgui; Liang, Xiaoming; Yang, Huijie; Rohling, Jos H T

    2016-01-01

    The main clock located in the suprachiasmatic nucleus (SCN) regulates circadian rhythms in mammals. The SCN is composed of approximately twenty thousand heterogeneous self-oscillating neurons, that have intrinsic periods varying from 22 h to 28 h. They are coupled through neurotransmitters and neuropeptides to form a network and output a uniform periodic rhythm. Previous studies found that the heterogeneity of the neurons leads to attenuation of the circadian rhythm with strong cellular coupling. In the present study, we investigate the heterogeneity of the neurons and of the network in the condition of constant darkness. Interestingly, we found that the heterogeneity of weakly coupled neurons enables them to oscillate and strengthen the circadian rhythm. In addition, we found that the period of the SCN network increases with the increase of the degree of heterogeneity. As the network heterogeneity does not change the dynamics of the rhythm, our study shows that the heterogeneity of the neurons is vitally important for rhythm generation in weakly coupled systems, such as the SCN, and it provides a new method to strengthen the circadian rhythm, as well as an alternative explanation for differences in free running periods between species in the absence of the daily cycle. PMID:26898574

  10. Heterogeneity induces rhythms of weakly coupled circadian neurons

    PubMed Central

    Gu, Changgui; Liang, Xiaoming; Yang, Huijie; Rohling, Jos H. T.

    2016-01-01

    The main clock located in the suprachiasmatic nucleus (SCN) regulates circadian rhythms in mammals. The SCN is composed of approximately twenty thousand heterogeneous self-oscillating neurons, that have intrinsic periods varying from 22 h to 28 h. They are coupled through neurotransmitters and neuropeptides to form a network and output a uniform periodic rhythm. Previous studies found that the heterogeneity of the neurons leads to attenuation of the circadian rhythm with strong cellular coupling. In the present study, we investigate the heterogeneity of the neurons and of the network in the condition of constant darkness. Interestingly, we found that the heterogeneity of weakly coupled neurons enables them to oscillate and strengthen the circadian rhythm. In addition, we found that the period of the SCN network increases with the increase of the degree of heterogeneity. As the network heterogeneity does not change the dynamics of the rhythm, our study shows that the heterogeneity of the neurons is vitally important for rhythm generation in weakly coupled systems, such as the SCN, and it provides a new method to strengthen the circadian rhythm, as well as an alternative explanation for differences in free running periods between species in the absence of the daily cycle. PMID:26898574

  11. Mass spectrometry-based absolute quantification reveals rhythmic variation of mouse circadian clock proteins.

    PubMed

    Narumi, Ryohei; Shimizu, Yoshihiro; Ukai-Tadenuma, Maki; Ode, Koji L; Kanda, Genki N; Shinohara, Yuta; Sato, Aya; Matsumoto, Katsuhiko; Ueda, Hiroki R

    2016-06-14

    Absolute values of protein expression levels in cells are crucial information for understanding cellular biological systems. Precise quantification of proteins can be achieved by liquid chromatography (LC)-mass spectrometry (MS) analysis of enzymatic digests of proteins in the presence of isotope-labeled internal standards. Thus, development of a simple and easy way for the preparation of internal standards is advantageous for the analyses of multiple target proteins, which will allow systems-level studies. Here we describe a method, termed MS-based Quantification By isotope-labeled Cell-free products (MS-QBiC), which provides the simple and high-throughput preparation of internal standards by using a reconstituted cell-free protein synthesis system, and thereby facilitates both multiplexed and sensitive quantification of absolute amounts of target proteins. This method was applied to a systems-level dynamic analysis of mammalian circadian clock proteins, which consist of transcription factors and protein kinases that govern central and peripheral circadian clocks in mammals. Sixteen proteins from 20 selected circadian clock proteins were successfully quantified from mouse liver over a 24-h time series, and 14 proteins had circadian variations. Quantified values were applied to detect internal body time using a previously developed molecular timetable method. The analyses showed that single time-point data from wild-type mice can predict the endogenous state of the circadian clock, whereas data from clock mutant mice are not applicable because of the disappearance of circadian variation. PMID:27247408

  12. Profiling molecular and behavioral circadian rhythms in the non-symbiotic sea anemone Nematostella vectensis

    PubMed Central

    Oren, Matan; Tarrant, Ann M.; Alon, Shahar; Simon-Blecher, Noa; Elbaz, Idan; Appelbaum, Lior; Levy, Oren

    2015-01-01

    Endogenous circadian clocks are poorly understood within early-diverging animal lineages. We have characterized circadian behavioral patterns and identified potential components of the circadian clock in the starlet sea anemone, Nematostella vectensis: a model cnidarian which lacks algal symbionts. Using automatic video tracking we showed that Nematostella exhibits rhythmic circadian locomotor activity, which is persistent in constant dark, shifted or disrupted by external dark/light cues and maintained the same rate at two different temperatures. This activity was inhibited by a casein kinase 1δ/ε inhibitor, suggesting a role for CK1 homologue(s) in Nematostella clock. Using high-throughput sequencing we profiled Nematostella transcriptomes over 48 hours under a light-dark cycle. We identified 180 Nematostella diurnally-oscillated transcripts and compared them with previously established databases of adult and larvae of the symbiotic coral Acropora millepora, revealing both shared homologues and unique rhythmic genes. Taken together, this study further establishes Nematostella as a non-symbiotic model organism to study circadian rhythms and increases our understanding about the fundamental elements of circadian regulation and their evolution within the Metazoa PMID:26081482

  13. Profiling molecular and behavioral circadian rhythms in the non-symbiotic sea anemone Nematostella vectensis.

    PubMed

    Oren, Matan; Tarrant, Ann M; Alon, Shahar; Simon-Blecher, Noa; Elbaz, Idan; Appelbaum, Lior; Levy, Oren

    2015-01-01

    Endogenous circadian clocks are poorly understood within early-diverging animal lineages. We have characterized circadian behavioral patterns and identified potential components of the circadian clock in the starlet sea anemone, Nematostella vectensis: a model cnidarian which lacks algal symbionts. Using automatic video tracking we showed that Nematostella exhibits rhythmic circadian locomotor activity, which is persistent in constant dark, shifted or disrupted by external dark/light cues and maintained the same rate at two different temperatures. This activity was inhibited by a casein kinase 1δ/ε inhibitor, suggesting a role for CK1 homologue(s) in Nematostella clock. Using high-throughput sequencing we profiled Nematostella transcriptomes over 48 hours under a light-dark cycle. We identified 180 Nematostella diurnally-oscillated transcripts and compared them with previously established databases of adult and larvae of the symbiotic coral Acropora millepora, revealing both shared homologues and unique rhythmic genes. Taken together, this study further establishes Nematostella as a non-symbiotic model organism to study circadian rhythms and increases our understanding about the fundamental elements of circadian regulation and their evolution within the Metazoa. PMID:26081482

  14. Vasoactive intestinal polypeptide mediates circadian rhythms in mammalian olfactory bulb and olfaction.

    PubMed

    Miller, Jae-Eun Kang; Granados-Fuentes, Daniel; Wang, Thomas; Marpegan, Luciano; Holy, Timothy E; Herzog, Erik D

    2014-04-23

    Accumulating evidence suggests that the olfactory bulbs (OBs) function as an independent circadian system regulating daily rhythms in olfactory performance. However, the cells and signals in the olfactory system that generate and coordinate these circadian rhythms are unknown. Using real-time imaging of gene expression, we found that the isolated olfactory epithelium and OB, but not the piriform cortex, express similar, sustained circadian rhythms in PERIOD2 (PER2). In vivo, PER2 expression in the OB of mice is circadian, approximately doubling with a peak around subjective dusk. Furthermore, mice exhibit circadian rhythms in odor detection performance with a peak at approximately subjective dusk. We also found that circadian rhythms in gene expression and odor detection performance require vasoactive intestinal polypeptide (VIP) or its receptor VPAC2R. VIP is expressed, in a circadian manner, in interneurons in the external plexiform and periglomerular layers, whereas VPAC2R is expressed in mitral and external tufted cells in the OB. Together, these results indicate that VIP signaling modulates the output from the OB to maintain circadian rhythms in the mammalian olfactory system. PMID:24760863

  15. Vasoactive Intestinal Polypeptide Mediates Circadian Rhythms in Mammalian Olfactory Bulb and Olfaction

    PubMed Central

    Miller, Jae-eun Kang; Granados-Fuentes, Daniel; Wang, Thomas; Marpegan, Luciano; Holy, Timothy E.

    2014-01-01

    Accumulating evidence suggests that the olfactory bulbs (OBs) function as an independent circadian system regulating daily rhythms in olfactory performance. However, the cells and signals in the olfactory system that generate and coordinate these circadian rhythms are unknown. Using real-time imaging of gene expression, we found that the isolated olfactory epithelium and OB, but not the piriform cortex, express similar, sustained circadian rhythms in PERIOD2 (PER2). In vivo, PER2 expression in the OB of mice is circadian, approximately doubling with a peak around subjective dusk. Furthermore, mice exhibit circadian rhythms in odor detection performance with a peak at approximately subjective dusk. We also found that circadian rhythms in gene expression and odor detection performance require vasoactive intestinal polypeptide (VIP) or its receptor VPAC2R. VIP is expressed, in a circadian manner, in interneurons in the external plexiform and periglomerular layers, whereas VPAC2R is expressed in mitral and external tufted cells in the OB. Together, these results indicate that VIP signaling modulates the output from the OB to maintain circadian rhythms in the mammalian olfactory system. PMID:24760863

  16. Circadian rhythms of temperature and activity in obese and lean Zucker rats

    NASA Technical Reports Server (NTRS)

    Murakami, D. M.; Horwitz, B. A.; Fuller, C. A.

    1995-01-01

    The circadian timing system is important in the regulation of feeding and metabolism, both of which are aberrant in the obese Zucker rat. This study tested the hypothesis that these abnormalities involve a deficit in circadian regulation by examining the circadian rhythms of body temperature and activity in lean and obese Zucker rats exposed to normal light-dark cycles, constant light, and constant dark. Significant deficits in both daily mean and circadian amplitude of temperature and activity were found in obese Zucker female rats relative to lean controls in all lighting conditions. However, the circadian period of obese Zucker rats did not exhibit differences relative to lean controls in either of the constant lighting conditions. These results indicate that although the circadian regulation of temperature and activity in obese Zucker female rats is in fact depressed, obese rats do exhibit normal entrainment and pacemaker functions in the circadian timing system. The results suggest a deficit in the process that generates the amplitude of the circadian rhythm.

  17. Dual KaiC-based oscillations constitute the circadian system of cyanobacteria

    PubMed Central

    Kitayama, Yohko; Nishiwaki, Taeko; Terauchi, Kazuki; Kondo, Takao

    2008-01-01

    In the cyanobacterium Synechococcus elongatus PCC 7942, the KaiA, KaiB, and KaiC proteins are essential for the generation of circadian rhythms. Both in vivo and in vitro, phosphorylation of KaiC is regulated positively by KaiA and negatively by KaiB and shows circadian rhythmicity. The autonomous circadian cycling of KaiC phosphorylation is thought to be the basic pacemaker of the circadian clock and to control genome-wide gene expression in cyanobacteria. In this study, we found that temperature-compensated circadian oscillations of gene expression persisted even when KaiC was arrested in the phosphorylated state due to kaiA overexpression. Moreover, two phosphorylation mutants showed transcriptional oscillation with a long period. In kaiA-overexpressing and phosphorylation-deficient strains, KaiC oscillated and transient overexpression of phosphorylation-deficient kaiC reset the phase of the rhythm. These results suggest that transcription- and translation-based oscillations in KaiC abundance are also important for circadian rhythm generation in cyanobacteria. Furthermore, at low temperature, cyanobacteria can show circadian rhythms only when both the KaiC phosphorylation cycle and the transcription and translation cycle are intact. Our findings indicate that multiple coupled oscillatory systems based on the biochemical properties of KaiC are important to maintain robust and precise circadian rhythms in cyanobacteria. PMID:18477603

  18. Interaction of MAGED1 with nuclear receptors affects circadian clock function.

    PubMed

    Wang, Xiaohan; Tang, Jing; Xing, Lijuan; Shi, Guangsen; Ruan, Haibin; Gu, Xiwen; Liu, Zhiwei; Wu, Xi; Gao, Xiang; Xu, Ying

    2010-04-21

    The circadian clock has a central role in physiological adaption and anticipation of day/night changes. In a genetic screen for novel regulators of circadian rhythms, we found that mice lacking MAGED1 (Melanoma Antigen Family D1) exhibit a shortened period and altered rest-activity bouts. These circadian phenotypes are proposed to be caused by a direct effect on the core molecular clock network that reduces the robustness of the circadian clock. We provide in vitro and in vivo evidence indicating that MAGED1 binds to RORalpha to bring about positive and negative effects on core clock genes of Bmal1, Rev-erbalpha and E4bp4 expression through the Rev-Erbalpha/ROR responsive elements (RORE). Maged1 is a non-rhythmic gene that, by binding RORalpha in non-circadian way, enhances rhythmic input and buffers the circadian system from irrelevant, perturbing stimuli or noise. We have thus identified and defined a novel circadian regulator, Maged1, which is indispensable for the robustness of the circadian clock to better serve the organism. PMID:20300063

  19. Interaction of MAGED1 with nuclear receptors affects circadian clock function

    PubMed Central

    Wang, Xiaohan; Tang, Jing; Xing, Lijuan; Shi, Guangsen; Ruan, Haibin; Gu, Xiwen; Liu, Zhiwei; Wu, Xi; Gao, Xiang; Xu, Ying

    2010-01-01

    The circadian clock has a central role in physiological adaption and anticipation of day/night changes. In a genetic screen for novel regulators of circadian rhythms, we found that mice lacking MAGED1 (Melanoma Antigen Family D1) exhibit a shortened period and altered rest–activity bouts. These circadian phenotypes are proposed to be caused by a direct effect on the core molecular clock network that reduces the robustness of the circadian clock. We provide in vitro and in vivo evidence indicating that MAGED1 binds to RORα to bring about positive and negative effects on core clock genes of Bmal1, Rev-erbα and E4bp4 expression through the Rev-Erbα/ROR responsive elements (RORE). Maged1 is a non-rhythmic gene that, by binding RORα in non-circadian way, enhances rhythmic input and buffers the circadian system from irrelevant, perturbing stimuli or noise. We have thus identified and defined a novel circadian regulator, Maged1, which is indispensable for the robustness of the circadian clock to better serve the organism. PMID:20300063

  20. Maternal-fetal communication of circadian phase in a precocious rodent, the spiny mouse

    SciTech Connect

    Weaver, D.R.; Reppert, S.M. )

    1987-10-01

    The development of circadian rhythms was examined in a precocious rodent species, the spiny mouse. Spiny mouse pups born and reared in constant darkness expressed robust circadian rhythms in locomotor activity as early as day 5 of live. Free-running activity rhythms of pups born and reared in constant darkness were coordinated with the dam on the day of birth. Postnatal maternal influences on pup rhythmicity are minimal in this species, as pups fostered on the day of birth to dams whose circadian phases were opposite to the pups' original dams were coordinated with their original dams on the day of birth. Studies using 2-deoxy-D-(1-{sup 14}C)-glucose authoradiography showed that there were synchronous (coordinated) rhythms in metabolic activity in the maternal and fetal suprachiasmatic nuclei, directly demonstrating prenatal coordination of maternal and fetal rhythmicity. Maternal-fetal coordination of circadian phase was not the result of direct entrainment of the fetuses to the environmental light-dark cycle. These results demonstrate that there is prenatal communication of circadian phase in this precocious species, without demonstrable postnatal maternal influences on pup circadian rhythmicity. Spiny mice therefore represent an important animal model in which circadian rhythms in the postnatal period can be used to precisely assess prenatal influences on circadian phase.

  1. Endogenous rhythms influence interpersonal synchrony.

    PubMed

    Zamm, Anna; Wellman, Chelsea; Palmer, Caroline

    2016-05-01

    Interpersonal synchrony, the temporal coordination of actions between individuals, is fundamental to social behaviors from conversational speech to dance and music-making. Animal models indicate constraints on synchrony that arise from endogenous rhythms: Intrinsic periodic behaviors or processes that continue in the absence of change in external stimulus conditions. We report evidence for a direct causal link between endogenous rhythms and interpersonal synchrony in a music performance task, which places high demands on temporal coordination. We first establish that endogenous rhythms, measured by spontaneous rates of individual performance, are stable within individuals across stimulus materials, limb movements, and time points. We then test a causal link between endogenous rhythms and interpersonal synchrony by pairing each musician with a partner who is either matched or mismatched in spontaneous rate and by measuring their joint behavior up to 1 year later. Partners performed melodies together, using either the same or different hands. Partners who were matched for spontaneous rate showed greater interpersonal synchrony in joint performance than mismatched partners, regardless of hand used. Endogenous rhythms offer potential to predict optimal group membership in joint behaviors that require temporal coordination. (PsycINFO Database Record PMID:26820249

  2. Entrainment of mouse peripheral circadian clocks to <24 h feeding/fasting cycles under 24 h light/dark conditions

    PubMed Central

    Hamaguchi, Yutaro; Tahara, Yu; Kuroda, Hiroaki; Haraguchi, Atsushi; Shibata, Shigenobu

    2015-01-01

    The circadian clock system in peripheral tissues can endogenously oscillate and is entrained by the light-dark and fasting-feeding cycles in mammals. Although the system’s range of entrainment to light-dark cycles with a non-24 h (<24 h) interval has been studied, the range of entrainment to fasting-feeding cycles with shorter periods (<24 h) has not been investigated in peripheral molecular clocks. In the present study, we measured this range by monitoring the mouse peripheral PER2::LUCIFERASE rhythm in vivo at different periods under each feeding cycle (Tau (T) = 15–24 h) under normal light-dark conditions. Peripheral clocks could be entrained to the feeding cycle with T = 22–24 h, but not to that with T = 15–21 h. Under the feeding cycle with T = 15–18 h, the peripheral clocks oscillated at near the 24-h period, suggesting that they were entrained to the light-dark cycle. Thus, for the first time, we demonstrated the range of entrainment to the non-24 h feeding cycle, and that the circadian range (T = 22–24 h) of feeding stimulus is necessary for peripheral molecular clock entrainment under light-dark cycles. PMID:26395309

  3. Metabolic Cycles in Yeast Share Features Conserved among Circadian Rhythms

    PubMed Central

    Causton, Helen C.; Feeney, Kevin A.; Ziegler, Christine A.; O’Neill, John S.

    2015-01-01

    Summary Cell-autonomous circadian rhythms allow organisms to temporally orchestrate their internal state to anticipate and/or resonate with the external environment [1, 2]. Although ∼24-hr periodicity is observed across aerobic eukaryotes, the central mechanism has been hard to dissect because few simple models exist, and known clock proteins are not conserved across phylogenetic kingdoms [1, 3, 4]. In contrast, contributions to circadian rhythmicity made by a handful of post-translational mechanisms, such as phosphorylation of clock proteins by casein kinase 1 (CK1) and glycogen synthase kinase 3 (GSK3), appear conserved among phyla [3, 5]. These kinases have many other essential cellular functions and are better conserved in their contribution to timekeeping than any of the clock proteins they phosphorylate [6]. Rhythmic oscillations in cellular redox state are another universal feature of circadian timekeeping, e.g., over-oxidation cycles of abundant peroxiredoxin proteins [7–9]. Here, we use comparative chronobiology to distinguish fundamental clock mechanisms from species and/or tissue-specific adaptations and thereby identify features shared between circadian rhythms in mammalian cells and non-circadian temperature-compensated respiratory oscillations in budding yeast [10]. We find that both types of oscillations are coupled with the cell division cycle, exhibit period determination by CK1 and GSK3, and have peroxiredoxin over-oxidation cycles. We also explore how peroxiredoxins contribute to YROs. Our data point to common mechanisms underlying both YROs and circadian rhythms and suggest two interpretations: either certain biochemical systems are simply permissive for cellular oscillations (with frequencies from hours to days) or this commonality arose via divergence from an ancestral cellular clock. PMID:25866393

  4. Metabolic Cycles in Yeast Share Features Conserved among Circadian Rhythms.

    PubMed

    Causton, Helen C; Feeney, Kevin A; Ziegler, Christine A; O'Neill, John S

    2015-04-20

    Cell-autonomous circadian rhythms allow organisms to temporally orchestrate their internal state to anticipate and/or resonate with the external environment. Although ∼24-hr periodicity is observed across aerobic eukaryotes, the central mechanism has been hard to dissect because few simple models exist, and known clock proteins are not conserved across phylogenetic kingdoms. In contrast, contributions to circadian rhythmicity made by a handful of post-translational mechanisms, such as phosphorylation of clock proteins by casein kinase 1 (CK1) and glycogen synthase kinase 3 (GSK3), appear conserved among phyla. These kinases have many other essential cellular functions and are better conserved in their contribution to timekeeping than any of the clock proteins they phosphorylate. Rhythmic oscillations in cellular redox state are another universal feature of circadian timekeeping, e.g., over-oxidation cycles of abundant peroxiredoxin proteins. Here, we use comparative chronobiology to distinguish fundamental clock mechanisms from species and/or tissue-specific adaptations and thereby identify features shared between circadian rhythms in mammalian cells and non-circadian temperature-compensated respiratory oscillations in budding yeast. We find that both types of oscillations are coupled with the cell division cycle, exhibit period determination by CK1 and GSK3, and have peroxiredoxin over-oxidation cycles. We also explore how peroxiredoxins contribute to YROs. Our data point to common mechanisms underlying both YROs and circadian rhythms and suggest two interpretations: either certain biochemical systems are simply permissive for cellular oscillations (with frequencies from hours to days) or this commonality arose via divergence from an ancestral cellular clock. PMID:25866393

  5. Human Diurnal Preference and Circadian Rhythmicity are Not Associated with the CLOCK 3111C/T Gene Polymorphism

    PubMed Central

    Chang, Anne-Marie; Buch, Alison M.; Bradstreet, Dayna S.; Klements, David J.; Duffy, Jeanne F.

    2013-01-01

    Genetic association studies of the CLOCK 3111C/T polymorphism and diurnal preference have yielded conflicting results since the first report that the 3111C allele was associated with eveningness. The goal of the present study was to investigate the association of this polymorphism with diurnal preference and circadian physiology in a group of 179 individuals, by comparing the frequency of the 3111C allele to diurnal preference, habitual sleep timing, circadian phase markers, and circadian period. We did not find a significant association between this allele and morningness/eveningness or any circadian marker. PMID:21628555

  6. Ontogenetic development of the mammalian circadian system.

    PubMed

    Weinert, Dietmar

    2005-01-01

    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

  7. Circadian Stress Regimes Affect the Circadian Clock and Cause Jasmonic Acid-Dependent Cell Death in Cytokinin-Deficient Arabidopsis Plants.

    PubMed

    Nitschke, Silvia; Cortleven, Anne; Iven, Tim; Feussner, Ivo; Havaux, Michel; Riefler, Michael; Schmülling, Thomas

    2016-07-01

    The circadian clock helps plants measure daylength and adapt to changes in the day-night rhythm. We found that changes in the light-dark regime triggered stress responses, eventually leading to cell death, in leaves of Arabidopsis thaliana plants with reduced cytokinin levels or defective cytokinin signaling. Prolonged light treatment followed by a dark period induced stress and cell death marker genes while reducing photosynthetic efficiency. This response, called circadian stress, is also characterized by altered expression of clock and clock output genes. In particular, this treatment strongly reduced the expression of CIRCADIAN CLOCK ASSOCIATED1 (CCA1) and LATE ELONGATED HYPOCOTYL (LHY). Intriguingly, similar changes in gene expression and cell death were observed in clock mutants lacking proper CCA1 and LHY function. Circadian stress caused strong changes in reactive oxygen species- and jasmonic acid (JA)-related gene expression. The activation of the JA pathway, involving the accumulation of JA metabolites, was crucial for the induction of cell death, since the cell death phenotype was strongly reduced in the jasmonate resistant1 mutant background. We propose that adaptation to circadian stress regimes requires a normal cytokinin status which, acting primarily through the AHK3 receptor, supports circadian clock function to guard against the detrimental effects of circadian stress. PMID:27354555

  8. Circadian Stress Regimes Affect the Circadian Clock and Cause Jasmonic Acid-Dependent Cell Death in Cytokinin-Deficient Arabidopsis Plants[OPEN

    PubMed Central

    Nitschke, Silvia; Cortleven, Anne; Iven, Tim; Havaux, Michel; Schmülling, Thomas

    2016-01-01

    The circadian clock helps plants measure daylength and adapt to changes in the day-night rhythm. We found that changes in the light-dark regime triggered stress responses, eventually leading to cell death, in leaves of Arabidopsis thaliana plants with reduced cytokinin levels or defective cytokinin signaling. Prolonged light treatment followed by a dark period induced stress and cell death marker genes while reducing photosynthetic efficiency. This response, called circadian stress, is also characterized by altered expression of clock and clock output genes. In particular, this treatment strongly reduced the expression of CIRCADIAN CLOCK ASSOCIATED1 (CCA1) and LATE ELONGATED HYPOCOTYL (LHY). Intriguingly, similar changes in gene expression and cell death were observed in clock mutants lacking proper CCA1 and LHY function. Circadian stress caused strong changes in reactive oxygen species- and jasmonic acid (JA)-related gene expression. The activation of the JA pathway, involving the accumulation of JA metabolites, was crucial for the induction of cell death, since the cell death phenotype was strongly reduced in the jasmonate resistant1 mutant background. We propose that adaptation to circadian stress regimes requires a normal cytokinin status which, acting primarily through the AHK3 receptor, supports circadian clock function to guard against the detrimental effects of circadian stress. PMID:27354555

  9. Picrotoxin dramatically speeds the mammalian circadian clock independent of Cys-loop receptors

    PubMed Central

    Freeman, G. Mark; Nakajima, Masato; Ueda, Hiroki R.

    2013-01-01

    Picrotoxin is extensively and specifically used to inhibit GABAA receptors and other members of the Cys-loop receptor superfamily. We find that picrotoxin acts independently of known Cys-loop receptors to shorten the period of the circadian clock markedly by specifically advancing the accumulation of PERIOD2 protein. We show that this mechanism is surprisingly tetrodotoxin-insensitive, and the effect is larger than any known chemical or genetic manipulation. Notably, our results indicate that the circadian target of picrotoxin is common to a variety of human and rodent cell types but not Drosophila, thereby ruling out all conserved Cys-loop receptors and known regulators of mammalian PERIOD protein stability. Given that the circadian clock modulates significant aspects of cell physiology including synaptic plasticity, these results have immediate and broad experimental implications. Furthermore, our data point to the existence of an important and novel target within the mammalian circadian timing system. PMID:23576702

  10. [Effects of surgical treatment on circadian variations of arterial pressure in patients with primary aldosteronism and renovascular hypertension].

    PubMed

    Kosmacheva, E D; Minkin, S E; Chikhladze, N M; Arabidze, G G; At'kov, O Iu

    1990-05-01

    Noninvasive recording of blood pressure (BP) with a portable Del Mar Avionics monitor (USA) revealed its abnormal circadian rhythm in patients with renovascular hypertension or arterial hypertension caused by adrenal aldosteroma. Surgical treatment was shown to result in a significant decrease in blood pressures and normalization of its circadian rhythm in the early postoperative period. PMID:2391803

  11. Cryptochromes define a novel circadian clock mechanism in monarch butterflies that may underlie sun compass navigation.

    PubMed

    Zhu, Haisun; Sauman, Ivo; Yuan, Quan; Casselman, Amy; Emery-Le, Myai; Emery, Patrick; Reppert, Steven M

    2008-01-01

    The circadian clock plays a vital role in monarch butterfly (Danaus plexippus) migration by providing the timing component of time-compensated sun compass orientation, a process that is important for successful navigation. We therefore evaluated the monarch clockwork by focusing on the functions of a Drosophila-like cryptochrome (cry), designated cry1, and a vertebrate-like cry, designated cry2, that are both expressed in the butterfly and by placing these genes in the context of other relevant clock genes in vivo. We found that similar temporal patterns of clock gene expression and protein levels occur in the heads, as occur in DpN1 cells, of a monarch cell line that contains a light-driven clock. CRY1 mediates TIMELESS degradation by light in DpN1 cells, and a light-induced TIMELESS decrease occurs in putative clock cells in the pars lateralis (PL) in the brain. Moreover, monarch cry1 transgenes partially rescue both biochemical and behavioral light-input defects in cry(b) mutant Drosophila. CRY2 is the major transcriptional repressor of CLOCK:CYCLE-mediated transcription in DpN1 cells, and endogenous CRY2 potently inhibits transcription without involvement of PERIOD. CRY2 is co-localized with clock proteins in the PL, and there it translocates to the nucleus at the appropriate time for transcriptional repression. We also discovered CRY2-positive neural projections that oscillate in the central complex. The results define a novel, CRY-centric clock mechanism in the monarch in which CRY1 likely functions as a blue-light photoreceptor for entrainment, whereas CRY2 functions within the clockwork as the transcriptional repressor of a negative transcriptional feedback loop. Our data further suggest that CRY2 may have a dual role in the monarch butterfly's brain-as a core clock element and as an output that regulates circadian activity in the central complex, the likely site of the sun compass. PMID:18184036

  12. Lactation Biology Symposium: circadian clocks as mediators of the homeorhetic response to lactation.

    PubMed

    Casey, T M; Plaut, K

    2012-03-01

    The transition from pregnancy to lactation is the most stressful period in the life of a cow. During this transition, homeorhetic adaptations are coordinated across almost every organ and are marked by changes in hormones and metabolism to accommodate the increased energetic demands of lactation. Recent data from our laboratory showed that changes in circadian clocks occur in multiple tissues during the transition period in rats and indicate that the circadian system coordinates changes in the physiology of the dam needed to support lactation. Circadian rhythms coordinate the timing of physiological processes and synchronize these processes with the environment of the animal. Circadian rhythms are generated by molecular circadian clocks located in the hypothalamus (the master clock) and peripherally in every organ of the body. The master clock receives environmental and physiological cues and, in turn, synchronizes internal physiology by coordinating endocrine rhythms and metabolism through peripheral clocks. The effect of the circadian clock on lactation may be inferred by the photoperiod effect on milk production, which is accompanied by coordinated changes in the endocrine system and metabolic capacity of the dam to respond to changes in day length. We have shown that bovine mammary epithelial cells possess a functional clock that can be synchronized by external stimuli, and the expression of the aryl hydrocarbon receptor nuclear translocator-like gene, a positive limb of the core clock, is responsive to prolactin in bovine mammary explants. Others showed that 7% of genes expressed in breasts of lactating women had circadian patterns of expression, and we report that the diurnal variation of composition of bovine milk is associated with changes in expression of mammary core clock genes. Together these studies indicate that the circadian system coordinates the metabolic and hormonal changes needed to initiate and sustain lactation, and we believe that the

  13. Bifurcations in a mathematical model for circadian oscillations of clock genes.

    PubMed

    Tsumoto, Kunichika; Yoshinaga, Tetsuya; Iida, Hitoshi; Kawakami, Hiroshi; Aihara, Kazuyuki

    2006-03-01

    Circadian oscillations with a period of about 24h are observed in nearly all living organisms as conspicuous biological rhythms. In this paper, we investigate various kinds of bifurcation phenomena produced in a circadian oscillator model of Drosophila. In Drosophila, it is known that circadian oscillations in the levels of two proteins, PER and TIM, result from the negative feedback exerted by a PER-TIM complex on the expression of the per and tim genes that code for the two proteins. For studying circadian oscillations of proteins in Drosophila, a mathematical model has been proposed. The model cannot only account for regular circadian oscillations in environmental conditions such as constant darkness, but also give rise to more complex oscillatory phenomena including chaos and birhythmicity. By calculating bifurcations using Kawakami's method, we obtain detailed bifurcation diagrams related to stable and unstable invariant sets, and identify parameter regions in which the model generates complex oscillations as well as regular circadian oscillations. Moreover, we study bifurcations observed in the model incorporating the effect on a light-dark (LD) cycle and show that the waveform of the periodic variation in the light-induced parameter has a marked influence on the global bifurcation structure or the type of dynamic behavior resulting from the forcing term of the circadian oscillator by the LD cycles. PMID:16143345

  14. Evolution of photoperiodic time measurement is independent of the circadian clock in the pitcher-plant mosquito, Wyeomyia smithii

    PubMed Central

    Emerson, Kevin J.; Dake, Sabrina J.; Bradshaw, William E.; Holzapfel, Christina M.

    2014-01-01

    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. PMID:19190920

  15. Evolution of photoperiodic time measurement is independent of the circadian clock in the pitcher-plant mosquito, Wyeomyia smithii.

    PubMed

    Emerson, Kevin J; Dake, Sabrina J; Bradshaw, William E; Holzapfel, Christina M

    2009-04-01

    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. PMID:19190920

  16. Architecture of retinal projections to the central circadian pacemaker.

    PubMed

    Fernandez, Diego Carlos; Chang, Yi-Ting; Hattar, Samer; Chen, Shih-Kuo

    2016-05-24

    The suprachiasmatic nucleus (SCN) receives direct retinal input from the intrinsically photosensitive retinal ganglion cells (ipRGCs) for circadian photoentrainment. Interestingly, the SCN is the only brain region that receives equal inputs from the left and right eyes. Despite morphological assessments showing that axonal fibers originating from ipRGCs cover the entire SCN, physiological evidence suggests that only vasoactive intestinal polypeptide (VIP)/gastrin-releasing peptide (GRP) cells located ventrally in the SCN receive retinal input. It is still unclear, therefore, which subpopulation of SCN neurons receives synaptic input from the retina and how the SCN receives equal inputs from both eyes. Here, using single ipRGC axonal tracing and a confocal microscopic analysis in mice, we show that ipRGCs have elaborate innervation patterns throughout the entire SCN. Unlike conventional retinal ganglion cells (RGCs) that innervate visual targets either ipsilaterally or contralaterally, a single ipRGC can bilaterally innervate the SCN. ipRGCs form synaptic contacts with major peptidergic cells of the SCN, including VIP, GRP, and arginine vasopressin (AVP) neurons, with each ipRGC innervating specific subdomains of the SCN. Furthermore, a single SCN-projecting ipRGC can send collateral inputs to many other brain regions. However, the size and complexity of the axonal arborizations in non-SCN regions are less elaborate than those in the SCN. Our results provide a better understanding of how retinal neurons connect to the central circadian pacemaker to synchronize endogenous circadian clocks with the solar day. PMID:27162356

  17. Circadian rhythm of alpha-amylase in rat parotid gland.

    PubMed

    Bellavía, S L; Sanz, E G; Chiarenza, A P; Sereno, R; Vermouth, N T

    1990-01-01

    The circadian rhythm of alpha-amylase, E.C. 3.2.1.1. (alpha-1,4-glucan-4-glucanohydrolase) in parotid gland of 25 day old rats was studied under different experimental conditions (fast, reversed photoperiod, constant light or darkness and treatment with reserpine and alpha-methyl-p-tyrosine). The rhythm of rats fasted or exposed for 7 days to constant darkness did not change. There were modifications in the rhythm of rats submitted to a reversed photoperiod and it disappeared in animals submitted to constant light or darkness for 15 days or treated with reserpine or alpha-methyl-p-tyrosine. The rhythm persisted, with minor changes in the acrophase, in parotids of rats kept during their gestation and post-natal life in constant light or darkness. Results suggest that the circadian rhythm of alpha-amylase in parotid gland of young rats is endogenous, synchronized by the photoperiod, under autonomous nervous system control and maternal coordination. This model appears to be useful in the study of sympathetic nervous system control of target organs and circadian rhythms in general. PMID:2076161

  18. A Novel Bmal1 Mutant Mouse Reveals Essential Roles of the C-Terminal Domain on Circadian Rhythms

    PubMed Central

    Cheon, Solmi; Row, Hansang; Lee, Jiyeon; Han, Dong-Hee; Cho, Sehyung; Kim, Kyungjin

    2015-01-01

    The mammalian circadian clock is an endogenous biological timer comprised of transcriptional/translational feedback loops of clock genes. Bmal1 encodes an indispensable transcription factor for the generation of circadian rhythms. Here, we report a new circadian mutant mouse from gene-trapped embryonic stem cells harboring a C-terminus truncated Bmal1 (Bmal1GTΔC) allele. The homozygous mutant (Bmal1GTΔC/GTΔC) mice immediately lost circadian behavioral rhythms under constant darkness. The heterozygous (Bmal1+/GTΔC) mice displayed a gradual loss of rhythms, in contrast to Bmal1+/- mice where rhythms were sustained. Bmal1GTΔC/GTΔC mice also showed arrhythmic mRNA and protein expression in the SCN and liver. Lack of circadian reporter oscillation was also observed in cultured fibroblast cells, indicating that the arrhythmicity of Bmal1GTΔC/GTΔC mice resulted from impaired molecular clock machinery. Expression of clock genes exhibited distinct responses to the mutant allele in Bmal1+/GTΔC and Bmal1GTΔC/GTΔC mice. Despite normal cellular localization and heterodimerization with CLOCK, overexpressed BMAL1GTΔC was unable to activate transcription of Per1 promoter and BMAL1-dependent CLOCK degradation. These results indicate that the C-terminal region of Bmal1 has pivotal roles in the regulation of circadian rhythms and the Bmal1GTΔC mice constitute a novel model system to evaluate circadian functional mechanism of BMAL1. PMID:26394143

  19. Circadian Clock Genes Are Essential for Normal Adult Neurogenesis, Differentiation, and Fate Determination.

    PubMed

    Malik, Astha; Kondratov, Roman V; Jamasbi, Roudabeh J; Geusz, Michael E

    2015-01-01

    Adult neurogenesis creates new neurons and glia from stem cells in the human brain throughout life. It is best understood in the dentate gyrus (DG) of the hippocampus and the subventricular zone (SVZ). Circadian rhythms have been identified in the hippocampus, but the role of any endogenous circadian oscillator cells in hippocampal neurogenesis and their importance in learning or memory remains unclear. Any study of stem cell regulation by intrinsic circadian timing within the DG is complicated by modulation from circadian clocks elsewhere in the brain. To examine circadian oscillators in greater isolation, neurosphere cultures were prepared from the DG of two knockout mouse lines that lack a functional circadian clock and from mPer1::luc mice to identify circadian oscillations in gene expression. Circadian mPer1 gene activity rhythms were recorded in neurospheres maintained in a culture medium that induces neurogenesis but not in one that maintains the stem cell state. Although the differentiating neural stem progenitor cells of spheres were rhythmic, evidence of any mature neurons was extremely sparse. The circadian timing signal originated in undifferentiated cells within the neurosphere. This conclusion was supported by immunocytochemistry for mPER1 protein that was localized to the inner, more stem cell-like neurosphere core. To test for effects of the circadian clock on neurogenesis, media conditions were altered to induce neurospheres from BMAL1 knockout mice to differentiate. These cultures displayed unusually high differentiation into glia rather than neurons according to GFAP and NeuN expression, respectively, and very few BetaIII tubulin-positive, immature neurons were observed. The knockout neurospheres also displayed areas visibly devoid of cells and had overall higher cell death. Neurospheres from arrhythmic mice lacking two other core clock genes, Cry1 and Cry2, showed significantly reduced growth and increased astrocyte proliferation during

  20. Circadian Clock Genes Are Essential for Normal Adult Neurogenesis, Differentiation, and Fate Determination

    PubMed Central

    Kondratov, Roman V.; Jamasbi, Roudabeh J.

    2015-01-01

    Adult neurogenesis creates new neurons and glia from stem cells in the human brain throughout life. It is best understood in the dentate gyrus (DG) of the hippocampus and the subventricular zone (SVZ). Circadian rhythms have been identified in the hippocampus, but the role of any endogenous circadian oscillator cells in hippocampal neurogenesis and their importance in learning or memory remains unclear. Any study of stem cell regulation by intrinsic circadian timing within the DG is complicated by modulation from circadian clocks elsewhere in the brain. To examine circadian oscillators in greater isolation, neurosphere cultures were prepared from the DG of two knockout mouse lines that lack a functional circadian clock and from mPer1::luc mice to identify circadian oscillations in gene expression. Circadian mPer1 gene activity rhythms were recorded in neurospheres maintained in a culture medium that induces neurogenesis but not in one that maintains the stem cell state. Although the differentiating neural stem progenitor cells of spheres were rhythmic, evidence of any mature neurons was extremely sparse. The circadian timing signal originated in undifferentiated cells within the neurosphere. This conclusion was supported by immunocytochemistry for mPER1 protein that was localized to the inner, more stem cell-like neurosphere core. To test for effects of the circadian clock on neurogenesis, media conditions were altered to induce neurospheres from BMAL1 knockout mice to differentiate. These cultures displayed unusually high differentiation into glia rather than neurons according to GFAP and NeuN expression, respectively, and very few BetaIII tubulin-positive, immature neurons were observed. The knockout neurospheres also displayed areas visibly devoid of cells and had overall higher cell death. Neurospheres from arrhythmic mice lacking two other core clock genes, Cry1 and Cry2, showed significantly reduced growth and increased astrocyte proliferation during

  1. Presence of endogenous prednisolone in human urine.

    PubMed

    Fidani, Marco; Gamberini, Maria C; Pompa, Giuseppe; Mungiguerra, Francesca; Casati, Alessio; Arioli, Francesco

    2013-02-01

    The possibility of an endogenous presence of the glucocorticoid prednisolone has already been demonstrated in bovine and horse urine, with the aim of clarifying its origin in this matrix, which is used by official agencies for the control of illicit treatments. From this point of view, the endogenous nature of prednisolone could be a major topic in doping control of both amateur and professional human athletes. A study was therefore made on 34 human volunteers (13 males and 21 females; aged 22-62) to detect the presence of prednisolone in their urine by HPLC-MS(3). One of the volunteers underwent vernal allergy treatment with betamethasone for two subsequent years. An investigation was carried out with the aim of verifying if the suppression, and the circadian rhythm, of cortisol urinary levels could also apply to prednisolone. The results of the study show that prednisolone was present in the urine of all 34 volunteers, with a concentration very close to 100-times lower that of cortisol, with no dependence on gender. The same ratio (1/100) was observed in the prednisolone and cortisol levels detected during the 24h together with the suppression of prednisolone by betamethasone treatment. These data demonstrate the endogenous nature of low concentrations of prednisolone in human urine, and motivate further studies about the biosynthetic pathways of this corticosteroid and its relationship with stress in humans, as already described in cows. PMID:23182764

  2. Circadian molecular clock in lung pathophysiology.

    PubMed

    Sundar, Isaac K; Yao, Hongwei; Sellix, Michael T; Rahman, Irfan

    2015-11-15

    Disrupted daily or circadian rhythms of lung function and inflammatory responses are common features of chronic airway diseases. At the molecular level these circadian rhythms depend on the activity of an autoregulatory feedback loop oscillator of clock gene transcription factors, including the BMAL1:CLOCK activator complex and the repressors PERIOD and CRYPTOCHROME. The key nuclear receptors and transcription factors REV-ERBα and RORα regulate Bmal1 expression and provide stability to the oscillator. Circadian clock dysfunction is implicated in both immune and inflammatory responses to environmental, inflammatory, and infectious agents. Molecular clock function is altered by exposomes, tobacco smoke, lipopolysaccharide, hyperoxia, allergens, bleomycin, as well as bacterial and viral infections. The deacetylase Sirtuin 1 (SIRT1) regulates the timing of the clock through acetylation of BMAL1 and PER2 and controls the clock-dependent functions, which can also be affected by environmental stressors. Environmental agents and redox modulation may alter the levels of REV-ERBα and RORα in lung tissue in association with a heightened DNA damage response, cellular senescence, and inflammation. A reciprocal relationship exists between the molecular clock and immune/inflammatory responses in the lungs. Molecular clock function in lung cells may be used as a biomarker of disease severity and exacerbations or for assessing the efficacy of chronotherapy for disease management. Here, we provide a comprehensive overview of clock-controlled cellular and molecular functions in the lungs and highlight the repercussions of clock disruption on the pathophysiology of chronic airway diseases and their exacerbations. Furthermore, we highlight the potential for the molecular clock as a novel chronopharmacological target for the management of lung pathophysiology. PMID:26361874

  3. Circadian photoentrainment: parameters of phase delaying.

    PubMed

    DeCoursey, P J

    1986-01-01

    Experiments were carried out using simulated den cages to delineate specific characteristics of phase delaying in circadian photoentrainment of a nocturnal rodent, the flying squirrel. The principal experiments entailed presentation of one to five consecutive 15-min white-light pulses per activity cycle at activity onset to animals free-running in darkness, in order to determine the immediate and final phase-shifting effect. Auxiliary experiments recorded entrainment patterns on light-dark (LD) schedules in the den cages. Phase response curves (PRCs) based on 15-min white-light pulses in standard wheel cages were also constructed for these animals as background information for interpreting the phase-delaying experiments. Exposure of a den animal to light by light sampling at the time of initial arousal from the rest state at circadian time (CT) 12, either by an LD schedule or by a 15-min light pulse, resulted in a return to the nest box for a short rest period. The phase delay occurring after a single light exposure at activity onset was equal to the induced rest, thus suggesting an immediate phase shift. The maximum delay was about 1 1/2 hr/cycle, with the amount of delay related to the number of light exposures. During the photoentrained state on an LD schedule, the activity rhythm of a den-housed animal was essentially free-running on the days following a phase delay. The data are used to expand current models for photoentrainment of circadian activity rhythms in nocturnal rodents. PMID:2979583

  4. Effect of Circadian Rhythm on Clinical and Pathophysiological Conditions and Inflammation.

    PubMed

    Kizaki, Takako; Sato, Shogo; Shirato, Ken; Sakurai, Takuya; Ogasawara, Junetsu; Izawa, Tetsuya; Ohira, Yoshinobu; Suzuki, Kenji; Ohno, Hideki

    2015-01-01

    Circadian rhythms have long been known to regulate numerous physiological processes that vary across the diurnal cycle. The circadian clock system also controls various parameters of the immune system and its biological defense functions, allowing an organism to anticipate daily changes in activity and feeding and the associated risk of infection. Inflammation is an immune response triggered in living organisms in response to external stimuli. The risk of sepsis, an excessive inflammatory response, has been shown to have a diurnal variation. On the other hand, inflammatory responses are emerging to be induced by endogenous factors. Recent studies have suggested that chronic inflammation causes chronic diseases including rheumatoid arthritis, allergies, and aging-related diseases and that proteins encoded by clock genes affect the development of such chronic inflammatory diseases or increase the severity of their symptoms. Therefore, detailed understanding of circadian rhythm effects on inflammatory responses is expected to lead to new strategies for prevention or treatment of inflammatory diseases. PMID:26757391

  5. Small Heterodimer Partner (NR0B2) Coordinates Nutrient Signaling and the Circadian Clock in Mice.

    PubMed

    Wu, Nan; Kim, Kang Ho; Zhou, Ying; Lee, Jae Man; Kettner, Nicole M; Mamrosh, Jennifer L; Choi, Sungwoo; Fu, Loning; Moore, David D

    2016-09-01

    Circadian rhythm regulates multiple metabolic processes and in turn is readily entrained by feeding-fasting cycles. However, the molecular mechanisms by which the peripheral clock senses nutrition availability remain largely unknown. Bile acids are under circadian control and also increase postprandially, serving as regulators of the fed state in the liver. Here, we show that nuclear receptor Small Heterodimer Partner (SHP), a regulator of bile acid metabolism, impacts the endogenous peripheral clock by directly regulating Bmal1. Bmal1-dependent gene expression is altered in Shp knockout mice, and liver clock adaptation is delayed in Shp knockout mice upon restricted feeding. These results identify SHP as a potential mediator connecting nutrient signaling with the circadian clock. PMID:27427832

  6. Measuring seasonal time within the circadian system: regulation of the suprachiasmatic nuclei by photoperiod.

    PubMed

    Johnston, J D

    2005-07-01

    Day-length (photoperiod) is the primary environmental signal used to synchronise endogenous rhythms of physiology and behaviour. In mammals, the suprachiasmatic nuclei (SCN) of the hypothalamus house the master circadian clock. The SCN incorporate photoperiodic information and therefore measure both daily and seasonal time. Over the past decade, there have been significant advances in the understanding of the molecular basis of circadian clocks. It is now becoming apparent that the core molecular clock mechanism is itself regulated by photoperiod, although there is currently debate as to how this occurs. One recent model proposes that distinct groups of core 'clock genes' are associated with either morning or evening phases of the daily light/dark cycle. However, the validity of associating particular genes to morning and evening has been questioned. This article reviews the evidence for photoperiodic regulation of circadian clock function and then discusses alternative models that may explain the available data. PMID:15946164

  7. Circadian glucocorticoid oscillations promote learning-dependent synapse formation and maintenance

    PubMed Central

    Liston, Conor; Cichon, Joseph M; Jeanneteau, Freddy; Jia, Zhengping; Chao, Moses V; Gan, Wen-Biao

    2013-01-01

    Excessive glucocorticoid exposure during chronic stress causes synapse loss and learning impairment. Under normal physiological conditions, glucocorticoid activity oscillates in synchrony with the circadian rhythm. Whether and how endogenous glucocorticoid oscillations modulate synaptic plasticity and learning is unknown. Here we show that circadian glucocorticoid peaks promote postsynaptic dendritic spine formation in the mouse cortex after motor skill learning, whereas troughs are required for stabilizing newly formed spines that are important for long-term memory retention. Conversely, chronic and excessive exposure to glucocorticoids eliminates learning-associated new spines and disrupts previously acquired memories. Furthermore, we show that glucocorticoids promote rapid spine formation through a non-transcriptional mechanism by means of the LIM kinase–cofilin pathway and increase spine elimination through transcriptional mechanisms involving mineralocorticoid receptor activation. Together, these findings indicate that tightly regulated circadian glucocorticoid oscillations are important for learning-dependent synaptic formation and maintenance. They also delineate a new signaling mechanism underlying these effects. PMID:23624512

  8. Casein kinase 1 promotes synchrony of the circadian clock network.

    PubMed

    Zheng, Xiangzhong; Sowcik, Mallory; Chen, Dechun; Sehgal, Amita

    2014-07-01

    Casein kinase 1, known as DOUBLETIME (DBT) in Drosophila melanogaster, is a critical component of the circadian clock that phosphorylates and promotes degradation of the PERIOD (PER) protein. However, other functions of DBT in circadian regulation are not clear, in part because severe reduction of dbt causes preadult lethality. Here we report the molecular and behavioral phenotype of a viable dbt(EY02910) loss-of-function mutant. We found that DBT protein levels are dramatically reduced in adult dbt(EY02910) flies, and the majority of mutant flies display arrhythmic behavior, with a few showing weak, long-period (∼32 h) rhythms. Peak phosphorylation of PER is delayed, and both hyper- and hypophosphorylated forms of the PER and CLOCK proteins are present throughout the day. In addition, molecular oscillations of the circadian clock are dampened. In the central brain, PER and TIM expression is heterogeneous and decoupled in the canonical clock neurons of the dbt(EY02910) mutants. We also report an interaction between dbt and the signaling pathway involving pigment dispersing factor (PDF), a synchronizing peptide in the clock network. These data thus demonstrate that overall reduction of DBT causes long and arrhythmic behavior, and they reveal an unexpected role of DBT in promoting synchrony of the circadian clock network. PMID:24820422

  9. Casein Kinase 1 Promotes Synchrony of the Circadian Clock Network

    PubMed Central

    Zheng, Xiangzhong; Sowcik, Mallory; Chen, Dechun

    2014-01-01

    Casein kinase 1, known as DOUBLETIME (DBT) in Drosophila melanogaster, is a critical component of the circadian clock that phosphorylates and promotes degradation of the PERIOD (PER) protein. However, other functions of DBT in circadian regulation are not clear, in part because severe reduction of dbt causes preadult lethality. Here we report the molecular and behavioral phenotype of a viable dbtEY02910 loss-of-function mutant. We found that DBT protein levels are dramatically reduced in adult dbtEY02910 flies, and the majority of mutant flies display arrhythmic behavior, with a few showing weak, long-period (∼32 h) rhythms. Peak phosphorylation of PER is delayed, and both hyper- and hypophosphorylated forms of the PER and CLOCK proteins are present throughout the day. In addition, molecular oscillations of the circadian clock are dampened. In the central brain, PER and TIM expression is heterogeneous and decoupled in the canonical clock neurons of the dbtEY02910 mutants. We also report an interaction between dbt and the signaling pathway involving pigment dispersing factor (PDF), a synchronizing peptide in the clock network. These data thus demonstrate that overall reduction of DBT causes long and arrhythmic behavior, and they reveal an unexpected role of DBT in promoting synchrony of the circadian clock network. PMID:24820422

  10. Dissonance between Parent-Selected Bedtimes and Young Children's Circadian Physiology Influences Nighttime Settling Difficulties

    ERIC Educational Resources Information Center

    LeBourgeois, Monique K.; Wright, Kenneth P., Jr.; LeBourgeois, Hannah B.; Jenni, Oskar G.

    2013-01-01

    Nighttime settling difficulties (i.e., bedtime resistance, sleep-onset delay) occur in about 25% of young children and are associated with attentional, behavioral, and emotional problems. We examined whether the timing of internal (endogenous) circadian melatonin phase (i.e., dim light melatonin onset; DLMO) and its relationship with…

  11. Contribution of C3 carboxylation to the circadian rhythm of carbon dioxide uptake in a Crassulacean acid metabolism plant Kalanchoë daigremontiana.

    PubMed

    Wyka, Tomasz P; Lüttge, Ulrich E

    2003-05-01

    During the endogenous circadian rhythm of carbon dioxide uptake in continuous light by a Crassula cean acid metabolism plant, Kalanchoë daigremontiana, the two carboxylating enzymes, phosphoenolpyruvate carboxylase (PEPC) and ribulose 1,5 bisphosphate carboxylase/oxygenase (Rubisco), are active simultaneously, although, until now, only the role of PEPC in generating the rhythm has been acknowledged. According to the established model, the rhythm is primarily regulated at the PEPC activity level, modulated by periodic compartmentation of its inhibitor, malate, in the vacuole and controlled by tension/relaxation of the tonoplast. However, the circadian accumulation of malic acid (the main indicator of PEPC activity) dampened significantly within the first few periods without affecting the rhythm's amplitude. Moreover, the amount of malate accumulated during a free-running oscillation was several-fold lower than the amount expected if PEPC were the key carboxylating enzyme, based on a 1:1 stoichiometry of CO(2) and malate. Together with the observation that rates of CO(2) uptake under continuous light were higher than in darkness, the evidence shows that C(3) carboxylation greatly contributes to the generation of rhythmic CO(2) uptake in continuous light in this 'obligate' CAM plant. Because the shift from predominantly CAM to predominantly C(3) carboxylation is smooth and does not distort the trajectory of the rhythm, its control probably arises from a robust network of oscillators, perhaps also involving stomata. PMID:12709493

  12. Acute allograft rejection and immunosuppression: influence on endogenous melatonin secretion.

    PubMed

    Cardell, Markus; Jung, Florian Johannes; Zhai, Wei; Hillinger, Sven; Welp, Andre; Manz, Bernhard; Weder, Walter; Korom, Stephan

    2008-04-01

    Melatonin displays a dose-dependent immunoregulatory effect in vitro and in vivo. Exogenous high-dose melatonin therapy exerted an immunosuppressive effect, abrogating acute rejection (AR), significantly prolonging transplant survival. Endogenous melatonin secretion, in response to heterotopic rat cardiac allograft transplantation (Tx), was investigated during the AR response and under standardized immunosuppressive maintenance therapy with cyclosporin A (CsA) and rapamycin (RPM). Recipients of syngeneic transplants, and recipients of allogeneic grafts, either untreated or receiving immunosuppressive therapy constituted the experimental groups. Endogenous circadian melatonin levels were measured at 07:00, 19:00, and 24:00 hr, using a novel radioimmunoassay (RIA) procedure, under standardized 12-hr-light/dark-conditions (light off: 19:00 hr; light on: 07:00 hr), before and after Tx. Neither the operative trauma, nor the challenge with a perfused allograft or the AR response influenced endogenous melatonin peak secretion. Immunosuppressive therapy with CsA led to a significant increase in peak secretion, measured for days 7 (212 +/- 40.7 pg/mL; P < 0.05), 14 (255 +/- 13.9 pg/mL; P < 0.001), and 21 (219 +/- 34 pg/mL; P < 0.01) after Tx, as compared with naïve animals (155 +/- 25.8 pg/mL). In contrast, treatment with RPM significantly decreased the melatonin peak post-Tx up to day 7 (87 +/- 25.2 pg/mL; P < 0.001), compared with naïve animals (155 +/- 25.8 pg/mL). These findings imply a robust nature of the endogenous circadian melatonin secretion kinetics, even against the background of profound allogeneic stimuli. Immunosuppressive maintenance therapy with CsA and RPM modulated early melatonin secretion, indicating a specific secondary action of these drugs. Further studies are necessary to disclose the long-term effect of immunosuppressive therapy on circadian melatonin secretion in transplant recipients. PMID:18339121

  13. Circadian Rhythms in Stomatal Responsiveness to Red and Blue Light.

    PubMed Central

    Gorton, H. L.; Williams, W. E.; Assmann, S. M.

    1993-01-01

    Stomata of many plants have circadian rhythms in responsiveness to environmental cues as well as circadian rhythms in aperture. Stomatal responses to red light and blue light are mediated by photosynthetic photoreceptors; responses to blue light are additionally controlled by a specific blue-light photoreceptor. This paper describes circadian rhythmic aspects of stomatal responsiveness to red and blue light in Vicia faba. Plants were exposed to a repeated light:dark regime of 1.5:2.5 h for a total of 48 h, and because the plants could not entrain to this short light:dark cycle, circadian rhythms were able to "free run" as if in continuous light. The rhythm in the stomatal conductance established during the 1.5-h light periods was caused both by a rhythm in sensitivity to light and by a rhythm in the stomatal conductance established during the preceding 2.5-h dark periods. Both rhythms peaked during the middle of the subjective day. Although the stomatal response to blue light is greater than the response to red light at all times of day, there was no discernible difference in period, phase, or amplitude of the rhythm in sensitivity to the two light qualities. We observed no circadian rhythmicity in net carbon assimilation with the 1.5:2.5 h light regime for either red or blue light. In continuous white light, small rhythmic changes in photosynthetic assimilation were observed, but at relatively high light levels, and these appeared to be attributable largely to changes in internal CO2 availability governed by stomatal conductance. PMID:12231947

  14. Circadian Clock, Cancer, and Chemotherapy

    PubMed Central

    2015-01-01

    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

  15. Protein Phosphatase 1 (PP1) Is a Post-Translational Regulator of the Mammalian Circadian Clock

    PubMed Central

    Schmutz, Isabelle; Wendt, Sabrina; Schnell, Anna; Kramer, Achim; Mansuy, Isabelle M.; Albrecht, Urs

    2011-01-01

    Circadian clocks coordinate the timing of important biological processes. Interconnected transcriptional and post-translational feedback loops based on a set of clock genes generate and maintain these rhythms with a period of about 24 hours. Many clock proteins undergo circadian cycles of post-translational modifications. Among these modifications, protein phosphorylation plays an important role in regulating activity, stability and intracellular localization of clock components. Several protein kinases were characterized as regulators of the circadian clock. However, the function of protein phosphatases, which balance phosphorylation events, in the mammalian clock mechanism is less well understood. Here, we identify protein phosphatase 1 (PP1) as regulator of period and light-induced resetting of the mammalian circadian clock. Down-regulation of PP1 activity in cells by RNA interference and in vivo by expression of a specific inhibitor in the brain of mice tended to lengthen circadian period. Moreover, reduction of PP1 activity in the brain altered light-mediated clock resetting behavior in mice, enhancing the phase shifts in either direction. At the molecular level, diminished PP1 activity increased nuclear accumulation of the clock component PER2 in neurons. Hence, PP1, may reduce PER2 phosphorylation thereby influencing nuclear localization of this protein. This may at least partially influence period and phase shifting properties of the mammalian circadian clock. PMID:21712997

  16. A Mathematical Model of the Circadian Phase-Shifting Effects of Exogenous Melatonin

    PubMed Central

    Breslow, Emily R.; Phillips, Andrew J.K.; Huang, Jean M.; St. Hilaire, Melissa A.; Klerman, Elizabeth B.

    2013-01-01

    Melatonin is endogenously produced and released in humans during nighttime darkness and is suppressed by ocular light exposure. Exogenous melatonin is used to induce circadian phase shifts and sleep. The circadian phase-shifting ability of a stimulus (e.g., melatonin or light) relative to its timing may be displayed as a phase response curve (PRC). Published PRCs to exogenous melatonin show a transition from phase advances to delays approximately 1 h after dim light melatonin onset. A previously developed mathematical model simulates endogenous production and clearance of melatonin as a function of circadian phase, light-induced suppression, and resetting of circadian phase by light. We extend this model to include the pharmacokinetics of oral exogenous melatonin and phase-shifting effects via melatonin receptors in the suprachiasmatic nucleus of the mammalian hypothalamus. Model parameters are fit using 2 data sets: (1) blood melatonin concentration following a 0.3- or 5.0-mg dose, and (2) a PRC to a 3.0-mg dose of melatonin. After fitting to the 3.0-mg PRC, the model correctly predicts that, by comparison, the 0.5-mg PRC is slightly decreased in amplitude and shifted to a later circadian phase. This model also reproduces blood concentration profiles of various melatonin preparations that differ only in absorption rate and percentage degradation by first-pass hepatic metabolism. This model can simulate experimental protocols using oral melatonin, with potential application to guide dose size and timing to optimally shift and entrain circadian rhythms. PMID:23382594

  17. Circadian Insights into Motivated Behavior.

    PubMed

    Antle, Michael C; Silver, Rae

    2016-01-01

    For an organism to be successful in an evolutionary sense, it and its offspring must survive. Such survival depends on satisfying a number of needs that are driven by motivated behaviors, such as eating, sleeping, and mating. An individual can usually only pursue one motivated behavior at a time. The circadian system provides temporal structure to the organism's 24 hour day, partitioning specific behaviors to particular times of the day. The circadian system also allows anticipation of opportunities to engage in motivated behaviors that occur at predictable times of the day. Such anticipation enhances fitness by ensuring that the organism is physiologically ready to make use of a time-limited resource as soon as it becomes available. This could include activation of the sympathetic nervous system to transition from sleep to wake, or to engage in mating, or to activate of the parasympathetic nervous system to facilitate transitions to sleep, or to prepare the body to digest a meal. In addition to enabling temporal partitioning of motivated behaviors, the circadian system may also regulate the amplitude of the drive state motivating the behavior. For example, the circadian clock modulates not only when it is time to eat, but also how hungry we are. In this chapter we explore the physiology of our circadian clock and its involvement in a number of motivated behaviors such as sleeping, eating, exercise, sexual behavior, and maternal behavior. We also examine ways in which dysfunction of circadian timing can contribute to disease states, particularly in psychiatric conditions that include adherent motivational states. PMID:26419240

  18. Cryptochrome 1 regulates the circadian clock through dynamic interactions with the BMAL1 C terminus.

    PubMed

    Xu, Haiyan; Gustafson, Chelsea L; Sammons, Patrick J; Khan, Sanjoy K; Parsley, Nicole C; Ramanathan, Chidambaram; Lee, Hsiau-Wei; Liu, Andrew C; Partch, Carrie L

    2015-06-01

    The molecular circadian clock in mammals is generated from transcriptional activation by the bHLH-PAS transcription factor CLOCK-BMAL1 and subsequent repression by PERIOD and CRYPTOCHROME (CRY). The mechanism by which CRYs repress CLOCK-BMAL1 to close the negative feedback loop and generate 24-h timing is not known. Here we show that, in mouse fibroblasts, CRY1 competes for binding with coactivators to the intrinsically unstructured C-terminal transactivation domain (TAD) of BMAL1 to establish a functional switch between activation and repression of CLOCK-BMAL1. TAD mutations that alter affinities for co-regulators affect the balance of repression and activation to consequently change the intrinsic circadian period or eliminate cycling altogether. Our results suggest that CRY1 fulfills its role as an essential circadian repressor by sequestering the TAD from coactivators, and they highlight regulation of the BMAL1 TAD as a critical mechanism for establishing circadian timing. PMID:25961797

  19. Peripheral circadian clocks are diversely affected by adrenalectomy.

    PubMed

    Soták, M; Bryndová, J; Ergang, P; Vagnerová, K; Kvapilová, P; Vodička, M; Pácha, J; Sumová, A

    2016-01-01

    Glucocorticoids are considered to synchronize the rhythmicity of clock genes in peripheral tissues; however, the role of circadian variations of endogenous glucocorticoids is not well defined. In the present study, we examined whether peripheral circadian clocks were impaired by adrenalectomy. To achieve this, we tested the circadian rhythmicity of core clock genes (Bmal1, Per1-3, Cry1, RevErbα, Rora), clock-output genes (Dbp, E4bp4) and a glucocorticoid- and clock-controlled gene (Gilz) in liver, jejunum, kidney cortex, splenocytes and visceral adipose tissue (VAT). Adrenalectomy did not affect the phase of clock gene rhythms but distinctly modulated clock gene mRNA levels, and this effect was partially tissue-dependent. Adrenalectomy had a significant inhibitory effect on the level of Per1 mRNA in VAT, liver and jejunum, but not in kidney and splenocytes. Similarly, adrenalectomy down-regulated mRNA levels of Per2 in splenocytes and VAT, Per3 in jejunum, RevErbα in VAT and Dbp in VAT, kidney and splenocytes, whereas the mRNA amounts of Per1 and Per2 in kidney and Per3 in VAT and splenocytes were up-regulated. On the other hand, adrenalectomy had minimal effects on Rora and E4bp4 mRNAs. Adrenalectomy also resulted in decreased level of Gilz mRNA but did not alter the phase of its diurnal rhythm. Collectively, these findings suggest that adrenalectomy alters the mRNA levels of core clock genes and clock-output genes in peripheral organs and may cause tissue-specific modulations of their circadian profiles, which are reflected in changes of the amplitudes but not phases. Thus, the circulating corticosteroids are necessary for maintaining the high-amplitude rhythmicity of the peripheral clocks in a tissue-specific manner. PMID:27031999

  20. Morning Circadian Misalignment during Short Sleep Duration Impacts Insulin Sensitivity.

    PubMed

    Eckel, Robert H; Depner, Christopher M; Perreault, Leigh; Markwald, Rachel R; Smith, Mark R; McHill, Andrew W; Higgins, Janine; Melanson, Edward L; Wright, Kenneth P

    2015-11-16

    Short sleep duration and circadian misalignment are hypothesized to causally contribute to health problems including obesity, diabetes, metabolic syndrome, heart disease, mood disorders, cognitive impairment, and accidents. Here, we investigated the influence of morning circadian misalignment induced by an imposed short nighttime sleep schedule on impaired insulin sensitivity, a precursor to diabetes. Imposed short sleep duration resulted in morning wakefulness occurring during the biological night (i.e., circadian misalignment)-a time when endogenous melatonin levels were still high indicating the internal circadian clock was still promoting sleep and related functions. We show the longer melatonin levels remained high after wake time, insulin sensitivity worsened. Overall, we find a simulated 5-day work week of 5-hr-per-night sleep opportunities and ad libitum food intake resulted in ∼20% reduced oral and intravenous insulin sensitivity in otherwise healthy men and women. Reduced insulin sensitivity was compensated by an increased insulin response to glucose, which may reflect an initial physiological adaptation to maintain normal blood sugar levels during sleep loss. Furthermore, we find that transitioning from the imposed short sleep schedule to 9-hr sleep opportunities for 3 days restored oral insulin sensitivity to baseline, but 5 days with 9-hr sleep opportunities was insufficient to restore intravenous insulin sensitivity to baseline. These findings indicate morning wakefulness and eating during the biological night is a novel mechanism by which short sleep duration contributes to metabolic dysregulation and suggests food intake during the biological night may contribute to other health problems associated with short sleep duration. PMID:26549253

  1. In vitro circadian rhythms: imaging and electrophysiology.

    PubMed

    Beaulé, Christian; Granados-Fuentes, Daniel; Marpegan, Luciano; Herzog, Erik D

    2011-06-30

    In vitro assays have localized circadian pacemakers to individual cells, revealed genetic determinants of rhythm generation, identified molecular players in cell-cell synchronization and determined physiological events regulated by circadian clocks. Although they allow strict control of experimental conditions and reduce the number of variables compared with in vivo studies, they also lack many of the conditions in which cellular circadian oscillators normally function. The present review highlights methods to study circadian timing in cultured mammalian cells and how they have shaped the hypothesis that all cells are capable of circadian rhythmicity. PMID:21819387

  2. In vitro circadian rhythms: imaging and electrophysiology

    PubMed Central

    Beaulé, Christian; Granados-Fuentes, Daniel; Marpegan, Luciano; Herzog, Erik D.

    2013-01-01

    In vitro assays have localized circadian pacemakers to individual cells, revealed genetic determinants of rhythm generation, identified molecular players in cell-cell synchronization and determined physiological events regulated by circadian clocks. Although they allow strict control of experimental conditions and reduce the number of variables compared with in vivo studies, they also lack many of the conditions in which cellular circadian oscillators normally function. The present review highlights methods to study circadian timing in cultured mammalian cells and how they have shaped the hypothesis that all cells are capable of circadian rhythmicity. PMID:21819387

  3. Circadian synchronization determines critical day length for seasonal responses.

    PubMed

    Majumdar, Gaurav; Trivedi, Amit Kumar; Gupta, Neelu Jain; Kumar, Vinod

    2015-08-01

    A photoperiodic species initiates fat deposition (in migrants) and gonadal recrudescence in response to a specific duration of natural daylight, called critical day length (CD), when light extends in the inductive phase of the endogenous circadian rhythm of photoinducibility (CRP). The molecular basis of species-specificCD, determined by the entrainment of the CRP, has been poorly understood. To investigate this, we measured expression levels of genes implicated in the photoperiod-induced changes in reproduction (EYA3, TSH beta, DIO2, DIO3, GNRH and GNIH) and metabolism (SIRT1, HMGCR, FASN and PPAR alpha) in photosensitive redheaded buntings subjected to light-dark cycles of varying period lengths (T-photocycles). Buntings were exposed to six T22, T24 or T26 photocycles, with 1h additional light at night falling at different phases of the entrained CRP (T2211L=6L:4D:1L:11D; T2411L=6L:4D:1L:13D,T2412L=6L:5D:1L:12D, T2413L=6L:6D:1L:11D; T2612L=6L:5D:1L:14D). Photoinduction at genetic and phenotypic levels in T2412L and T2413L, not T2411L, groups confirmed CD being close to 12h in buntings under T24. Compared to T24, exposure to T22 advanced CD by 1h, as evidenced by photoinduction in the T2211L, not T226L, group. Similarly, CD appeared to be delayed under T26, with no photoinduction in the T2612L group. Further, to show that induction of response under a T-photocycle was because of the interaction of inductive phase of the CRP with 1h during the dark period in each cycle, not with the 6h main light periods falling 2h earlier each successive 24hday in a T22 paradigm, a group of buntings was exposed to 6L:16D (T226L), to which they did not respond. The mRNA expression of genes, particularly TSH beta, DIO2, DIO3 and PPAR alpha, was significantly correlated with changes in reproductive and metabolic phenotypes. These results suggest CRP-entrainment based genetic regulation of the CD, and extend the idea that synchronization with environment is a critical measure in a

  4. Circadian clocks optimally adapt to sunlight for reliable synchronization

    PubMed Central

    Hasegawa, Yoshihiko; Arita, Masanori

    2014-01-01

    Circadian oscillation provides selection advantages through synchronization to the daylight cycle. However, a reliable clock must be designed through two conflicting properties: entrainability to synchronize internal time with periodic stimuli such as sunlight, and regularity to oscillate with a precise period. These two aspects do not easily coexist, because better entrainability favours higher sensitivity which may sacrifice regularity. To investigate conditions for satisfying the two properties, we analytically calculated the optimal phase–response curve with a variational method. Our results indicate an existence of a dead zone, i.e. a time period during which input stimuli neither advance nor delay the clock. A dead zone appears only when input stimuli obey the time course of actual solar radiation, but a simple sine curve cannot yield a dead zone. Our calculation demonstrates that every circadian clock with a dead zone is optimally adapted to the daylight cycle. PMID:24352677

  5. Circadian rhythms in the short-tailed shrew, Blarina brevicauda.

    PubMed

    Antipas, A J; Madison, D M; Ferraro, J S

    1990-08-01

    Circadian rhythms of wheel running and feeding were measured in the short-tailed shrew. Shrews were strongly nocturnal, and their activity rhythms entrained to both long-day (LD 16:8) and short-day (LD 6:18) photocycles. Under conditions of continuous light (LL) or darkness (DD), the activity rhythms free-ran with average periodicities of 25.1 hours and 24.1 hours, respectively. In LL the level of activity was depressed, and in some cases wheel running was completely inhibited. No significant sex differences were observed in the period or amplitude of the monitored circadian rhythms. All shrews fed throughout the day and night; however, unlike in previous reports, ultradian periods of feeding behavior were not found. The results are related to Aschoff's four observations for the effect of light on activity rhythms in nocturnal rodents. PMID:2255728

  6. Rhythmic expression of cryptochrome induces the circadian clock of arrhythmic suprachiasmatic nuclei through arginine vasopressin signaling.

    PubMed

    Edwards, Mathew D; Brancaccio, Marco; Chesham, Johanna E; Maywood, Elizabeth S; Hastings, Michael H

    2016-03-01

    Circadian rhythms in mammals are coordinated by the suprachiasmatic nucleus (SCN). SCN neurons define circadian time using transcriptional/posttranslational feedback loops (TTFL) in which expression of Cryptochrome (Cry) and Period (Per) genes is inhibited by their protein products. Loss of Cry1 and Cry2 stops the SCN clock, whereas individual deletions accelerate and decelerate it, respectively. At the circuit level, neuronal interactions synchronize cellular TTFLs, creating a spatiotemporal wave of gene expression across the SCN that is lost in Cry1/2-deficient SCN. To interrogate the properties of CRY proteins required for circadian function, we expressed CRY in SCN of Cry-deficient mice using adeno-associated virus (AAV). Expression of CRY1::EGFP or CRY2::EGFP under a minimal Cry1 promoter was circadian and rapidly induced PER2-dependent bioluminescence rhythms in previously arrhythmic Cry1/2-deficient SCN, with periods appropriate to each isoform. CRY1::EGFP appropriately lengthened the behavioral period in Cry1-deficient mice. Thus, determination of specific circadian periods reflects properties of the respective proteins, independently of their phase of expression. Phase of CRY1::EGFP expression was critical, however, because constitutive or phase-delayed promoters failed to sustain coherent rhythms. At the circuit level, CRY1::EGFP induced the spatiotemporal wave of PER2 expression in Cry1/2-deficient SCN. This was dependent on the neuropeptide arginine vasopressin (AVP) because it was prevented by pharmacological blockade of AVP receptors. Thus, our genetic complementation assay reveals acute, protein-specific induction of cell-autonomous and network-level circadian rhythmicity in SCN never previously exposed to CRY. Specifically, Cry expression must be circadian and appropriately phased to support rhythms, and AVP receptor signaling is required to impose circuit-level circadian function. PMID:26903624

  7. Ube3a Imprinting Impairs Circadian Robustness in Angelman Syndrome Models

    PubMed Central

    Shi, Shu-qun; Bichell, Terry Jo; Ihrie, Rebecca A.; Johnson, Carl Hirschie

    2015-01-01

    Summary Background The paternal allele of Ube3a is silenced by imprinting in neurons, and Angelman Syndrome (AS) is a disorder arising from a deletion or mutation of the maternal Ube3a allele, which thereby eliminates Ube3a neuronal expression. Sleep disorders such as short sleep duration and increased sleep onset latency are very common in AS. Results We found an unique link between neuronal imprinting of Ube3a and circadian rhythms in two mouse models of AS, including enfeebled circadian activity behavior and slowed molecular rhythms in ex vivo brain tissues. As a consequence of compromised circadian behavior, metabolic homeostasis is also disrupted in AS mice. Unsilencing the paternal Ube3a allele restores functional circadian periodicity in neurons deficient in maternal Ube3a, but does not affect periodicity in peripheral tissues that are not imprinted for uniparental Ube3a expression. The ubiquitin ligase encoded by Ube3a interacts with the central clock components BMAL1 and BMAL2. Moreover, inactivation of Ube3a expression elevates BMAL1 levels in brain regions that control circadian behavior of AS model mice, indicating an important role for Ube3a in modulating BMAL1 turnover. Conclusions Ube3a expression constitutes a direct mechanistic connection between symptoms of a human neurological disorder and the central circadian clock mechanism. The lengthened circadian period leads to delayed phase, which could explain the short sleep duration and increased sleep onset latency of AS subjects. Moreover, we report the pharmacological rescue of an AS phenotype, in this case, altered circadian period. These findings reveal potential treatments for sleep disorders in AS patients. PMID:25660546

  8. Circadian rhythms: basic neurobiology and clinical applications.

    PubMed

    Moore, R Y

    1997-01-01

    Circadian rhythms are major features of adaptation to our environment. In mammals, circadian rhythms are generated and regulated by a circadian timing system. This system consists of entertainment pathways, pacemakers, and pace-maker output to effector systems that are under circadian control. The primary entertainment pathway is the retinohypothalamic tract, which terminates in the circadian pacemakers, the suprachiasmatic nuclei of the hypothalamus. The output of the suprachiasmatic nuclei is principally to the hypothalamus, the midline thalamus, and the basal forebrain. This provides a temporal organization to the sleep-wake cycle, to many physiological and endocrine functions, and to psychomotor performance functions. Disorders of circadian timing primarily affect entertainment and pacemaker functions. The pineal hormone, melatonin, appears to be promising agent for therapy of some circadian timing disorders. PMID:9046960

  9. Circadian Rhythm Disruption Promotes Lung Tumorigenesis.

    PubMed

    Papagiannakopoulos, Thales; Bauer, Matthew R; Davidson, Shawn M; Heimann, Megan; Subbaraj, Lakshmipriya; Bhutkar, Arjun; Bartlebaugh, Jordan; Vander Heiden, Matthew G; Jacks, Tyler

    2016-08-01

    Circadian rhythms are 24-hr oscillations that control a variety of biological processes in living systems, including two hallmarks of cancer, cell division and metabolism. Circadian rhythm disruption by shift work is associated with greater risk for cancer development and poor prognosis, suggesting a putative tumor-suppressive role for circadian rhythm homeostasis. Using a genetically engineered mouse model of lung adenocarcinoma, we have characterized the effects of circadian rhythm disruption on lung tumorigenesis. We demonstrate that both physiologic perturbation (jet lag) and genetic mutation of the central circadian clock components decreased survival and promoted lung tumor growth and progression. The core circadian genes Per2 and Bmal1 were shown to have cell-autonomous tumor-suppressive roles in transformation and lung tumor progression. Loss of the central clock components led to increased c-Myc expression, enhanced proliferation, and metabolic dysregulation. Our findings demonstrate that both systemic and somatic disruption of circadian rhythms contribute to cancer progression. PMID:27476975

  10. Metabolism and the Circadian Clock Converge

    PubMed Central

    Eckel-Mahan, Kristin

    2013-01-01

    Circadian rhythms occur in almost all species and control vital aspects of our physiology, from sleeping and waking to neurotransmitter secretion and cellular metabolism. Epidemiological studies from recent decades have supported a unique role for circadian rhythm in metabolism. As evidenced by individuals working night or rotating shifts, but also by rodent models of circadian arrhythmia, disruption of the circadian cycle is strongly associated with metabolic imbalance. Some genetically engineered mouse models of circadian rhythmicity are obese and show hallmark signs of the metabolic syndrome. Whether these phenotypes are due to the loss of distinct circadian clock genes within a specific tissue versus the disruption of rhythmic physiological activities (such as eating and sleeping) remains a cynosure within the fields of chronobiology and metabolism. Becoming more apparent is that from metabolites to transcription factors, the circadian clock interfaces with metabolism in numerous ways that are essential for maintaining metabolic homeostasis. PMID:23303907

  11. Prokineticin 2 and circadian clock output

    PubMed Central

    Zhou, Qun-Yong; Cheng, Michelle Y.

    2009-01-01

    Circadian timing from the suprachiasmatic nucleus (SCN) is a critical component of sleep regulation. Animal lesion and genetic studies have indicated an essential interaction between the circadian signals and the homeostatic processes that regulate sleep. Here we summarize the biological functions of prokineticins, a pair of newly discovered regulatory proteins, with focus on the circadian function of prokineticin 2 (PK2) and its potential role in sleep-wake regulation. PK2 has been shown as a candidate SCN output molecule that regulates circadian locomotor behavior. The PK2 molecular rhythm in the SCN is predominantly controlled by the circadian transcriptional/translational loops, but also regulated directly by light. The receptor for PK2 is expressed in the primary SCN output targets that regulate circadian behavior including sleep-wake. The depolarizing effect of PK2 on neurons that express PK2 receptor may represent a possible mechanism for the regulatory role of PK2 in circadian rhythms. PMID:16279936

  12. Circadian Gene Clock Regulates Psoriasis-Like Skin Inflammation in Mice

    PubMed Central

    Ando, Noriko; Nakamura, Yuki; Aoki, Rui; Ishimaru, Kayoko; Ogawa, Hideoki; Okumura, Ko; Shibata, Shigenobu; Shimada, Shinji; Nakao, Atsuhito

    2015-01-01

    There are several reports suggesting that the pathophysiology of psoriasis may be associated with aberrant circadian rhythms. However, the mechanistic link between psoriasis and the circadian time-keeping system, “the circadian clock,” remains unclear. This study determined whether the core circadian gene, Clock, had a regulatory role in the development of psoriasis. For this purpose, we compared the development of psoriasis-like skin inflammation induced by the Toll-like receptor 7 ligand imiquimod (IMQ) between wild-type mice and mice with a loss-of-function mutation of Clock. We also compared the development of IMQ-induced dermatitis between wild-type mice and mice with a loss-of-function mutation of Period2 (Per2), another key circadian gene that inhibits CLOCK activity. We found that Clock mutation ameliorated IMQ-induced dermatitis, whereas the Per2 mutation exaggerated IMQ-induced dermatitis, when compared with wild-type mice associated with decreased or increased IL-23 receptor (IL-23R) expression in γ/δ+ T cells, respectively. In addition, CLOCK directly bound to the promoter of IL-23R in γ/δ+ T cells, and IL-23R expression in the mouse skin was under circadian control. These findings suggest that Clock is a novel regulator of psoriasis-like skin inflammation in mice via direct modulation of IL-23R expression in γ/δ+ T cells, establishing a mechanistic link between psoriasis and the circadian clock. PMID:26291684

  13. Punctual transcriptional regulation by the rice circadian clock under fluctuating field conditions.

    PubMed

    Matsuzaki, Jun; Kawahara, Yoshihiro; Izawa, Takeshi

    2015-03-01

    Plant circadian clocks that oscillate autonomously with a roughly 24-h period are entrained by fluctuating light and temperature and globally regulate downstream genes in the field. However, it remains unknown how punctual internal time produced by the circadian clock in the field is and how it is affected by environmental fluctuations due to weather or daylength. Using hundreds of samples of field-grown rice (Oryza sativa) leaves, we developed a statistical model for the expression of circadian clock-related genes integrating diurnally entrained circadian clock with phase setting by light, both responses to light and temperature gated by the circadian clock. We show that expression of individual genes was strongly affected by temperature. However, internal time estimated from expression of multiple genes, which may reflect transcriptional regulation of downstream genes, is punctual to 22 min and not affected by weather, daylength, or plant developmental age in the field. We also revealed perturbed progression of internal time under controlled environment or in a mutant of the circadian clock gene GIGANTEA. Thus, we demonstrated that the circadian clock is a regulatory network of multiple genes that retains accurate physical time of day by integrating the perturbations on individual genes under fluctuating environments in the field. PMID:25757473

  14. Chronic hyperammonemia alters the circadian rhythms of corticosteroid hormone levels and of motor activity in rats.

    PubMed

    Ahabrach, Hanan; Piedrafita, Blanca; Ayad, Abdelmalik; El Mlili, Nisrin; Errami, Mohammed; Felipo, Vicente; Llansola, Marta

    2010-05-15

    Patients with liver cirrhosis may present hepatic encephalopathy with a wide range of neurological disturbances and alterations in sleep quality and in the sleep-wake circadian rhythm. Hyperammonemia is a main contributor to the neurological alterations in hepatic encephalopathy. We have assessed, in an animal model of chronic hyperammonemia without liver failure, the effects of hyperammonemia per se on the circadian rhythms of motor activity, temperature, and plasma levels of adrenal corticosteroid hormones. Chronic hyperammonemia alters the circadian rhythms of locomotor activity and of cortisol and corticosterone levels in blood. Different types of motor activity are affected differentially. Hyperammonemia significantly alters the rhythm of spontaneous ambulatory activity, reducing strongly ambulatory counts and slightly average velocity during the night (the active phase) but not during the day, resulting in altered circadian rhythms. In contrast, hyperammonemia did not affect wheel running at all, indicating that it affects spontaneous but not voluntary activity. Vertical activity was affected only very slightly, indicating that hyperammonemia does not induce anxiety. Hyperammonemia abolished completely the circadian rhythm of corticosteroid hormones in plasma, completely eliminating the peaks of cortisol and corticosterone present in control rats at the start of the dark period. The data reported show that chronic hyperammonemia, similar to that present in patients with liver cirrhosis, alters the circadian rhythms of corticosteroid hormones and of motor activity. This suggests that hyperammonemia would be a relevant contributor to the alterations in corticosteroid hormones and in circadian rhythms in patients with liver cirrhosis. PMID:19998493

  15. Circadian rhythms of gastrointestinal function are regulated by both central and peripheral oscillators

    PubMed Central

    Malloy, Jaclyn N.; Paulose, Jiffin K.; Li, Ye

    2012-01-01

    Circadian clocks are responsible for daily rhythms in a wide array of processes, including gastrointestinal (GI) function. These are vital for normal digestive rhythms and overall health. Previous studies demonstrated circadian clocks within the cells of GI tissue. The present study examines the roles played by the suprachiasmatic nuclei (SCN), master circadian pacemaker for overt circadian rhythms, and the sympathetic nervous system in regulation of circadian GI rhythms in the mouse Mus musculus. Surgical ablation of the SCN abolishes circadian locomotor, feeding, and stool output rhythms when animals are presented with food ad libitum, while restricted feeding reestablishes these rhythms temporarily. In intact mice, chemical sympathectomy with 6-hydroxydopamine has no effect on feeding and locomotor rhythmicity in light-dark cycles or constant darkness but attenuates stool weight and stool number rhythms. Again, however, restricted feeding reestablishes rhythms in locomotor activity, feeding, and stool output rhythms. Ex vivo, intestinal tissue from PER2::LUC transgenic mice expresses circadian rhythms of luciferase bioluminescence. Chemical sympathectomy has little effect on these rhythms, but timed administration of the β-adrenergic agonist isoproterenol causes a phase-dependent shift in PERIOD2 expression rhythms. Collectively, the data suggest that the SCN are required to maintain feeding, locomotor, and stool output rhythms during ad libitum conditions, acting at least in part through daily activation of sympathetic activity. Even so, this input is not necessary for entrainment to timed feeding, which may be the province of oscillators within the intestines themselves or other components of the GI system. PMID:22723262

  16. Research on sleep, circadian rhythms and aging - Applications to manned spaceflight

    NASA Technical Reports Server (NTRS)

    Czeisler, Charles A.; Chiasera, August J.; Duffy, Jeanne F.

    1991-01-01

    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.

  17. Punctual Transcriptional Regulation by the Rice Circadian Clock under Fluctuating Field Conditions[OPEN

    PubMed Central

    Matsuzaki, Jun; Kawahara, Yoshihiro; Izawa, Takeshi

    2015-01-01

    Plant circadian clocks that oscillate autonomously with a roughly 24-h period are entrained by fluctuating light and temperature and globally regulate downstream genes in the field. However, it remains unknown how punctual internal time produced by the circadian clock in the field is and how it is affected by environmental fluctuations due to weather or daylength. Using hundreds of samples of field-grown rice (Oryza sativa) leaves, we developed a statistical model for the expression of circadian clock-related genes integrating diurnally entrained circadian clock with phase setting by light, both responses to light and temperature gated by the circadian clock. We show that expression of individual genes was strongly affected by temperature. However, internal time estimated from expression of multiple genes, which may reflect transcriptional regulation of downstream genes, is punctual to 22 min and not affected by weather, daylength, or plant developmental age in the field. We also revealed perturbed progression of internal time under controlled environment or in a mutant of the circadian clock gene GIGANTEA. Thus, we demonstrated that the circadian clock is a regulatory network of multiple genes that retains accurate physical time of day by integrating the perturbations on individual genes under fluctuating environments in the field. PMID:25757473

  18. Circadian rhythms and the suprachiasmatic nucleus in perinatal development, aging and Alzheimer's disease.

    PubMed

    Mirmiran, M; Swaab, D F; Kok, J H; Hofman, M A; Witting, W; Van Gool, W A

    1992-01-01

    Circadian rhythms are already present in the fetus. At a certain stage of pre-natal hypothalamic development (around 30 weeks of gestation) the fetus becomes responsive to maternal circadian signals. Moreover, recent studies showed that the fetal biological clock is able to generate circadian rhythms, as exemplified by the rhythms of body temperature and heart rate of pre-term babies in the absence of maternal or environmental entrainment factors. Pre-term babies that are deprived of maternal entrainment and kept under constant environmental conditions (e.g., continuous light) in the neonatal intensive care unit run the risk of developing a biological clock dysfunctioning. However, the fact should be acknowledged that at least in mice the development of the circadian pacemaker (i.e., SCN) does not depend on environmental influences (Davis and Menaker, 1981), although other data suggest that severe disruption of the maternal circadian rhythm indeed abolishes the circadian rhythm of the fetal SCN (Shibata and Moore, 1988). During aging and in particular in AD circadian rhythms are disturbed. These disturbances include phase advance and reduced period and amplitude, as well as an increased intradaily variability and a decreased interdaily stability of the rhythm. Among the factors underlying these changes the loss of SCN neurons seems to play a central role. Other contributory factors may be reduced amount of light, degenerative changes in the visual system and the level of activity and decreased melatonin. PMID:1480747

  19. The ancestral circadian clock of monarch butterflies: role in time-compensated sun compass orientation.

    PubMed

    Reppert, S M

    2007-01-01

    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. PMID:18419268

  20. Circadian Rhythms: Hijacking the Cyanobacterial Clock

    PubMed Central

    Hoyle, Nathaniel P.; O’Neill, John S

    2016-01-01

    The production of limitless carbon-free energy is a long-sought dream of scientists and politicians alike. One strategy for achieving this aim is the production of hydrogen by photosynthetic microorganisms – harnessing the effectively limitless power of the sun to power our cars, toasters and PCR machines. It may be tempting to think of host expression systems as miniature factories given over entirely to the production our molecule of interest. However, the biological nature of the host must be taken into account if we are to maximize productivity. The circadian rhythm, an organism’s entrainable oscillation of biological processes with a period of around 24 hours, is one such aspect that has received scant attention but is likely to be of particular importance to photosynthetic host systems. In this issue of current biology Xu et al. describe how our knowledge of the Synechococcus elongatus circadian clock can be leveraged to improve the production of exogeneous proteins, including those involved in the production of hydrogen [1]. PMID:24309283

  1. Unraveling the complexities of circadian and sleep interactions with memory formation through invertebrate research

    PubMed Central

    Michel, Maximilian; Lyons, Lisa C.

    2014-01-01

    Across phylogeny, the endogenous biological clock has been recognized as providing adaptive advantages to organisms through coordination of physiological and behavioral processes. Recent research has emphasized the role of circadian modulation of memory in generating peaks and troughs in cognitive performance. The circadian clock along with homeostatic processes also regulates sleep, which itself impacts the formation and consolidation of memory. Thus, the circadian clock, sleep and memory form a triad with ongoing dynamic interactions. With technological advances and the development of a global 24/7 society, understanding the mechanisms underlying these connections becomes pivotal for development of therapeutic treatments for memory disorders and to address issues in cognitive performance arising from non-traditional work schedules. Invertebrate models, such as Drosophila melanogaster and the mollusks Aplysia and Lymnaea, have proven invaluable tools for identification of highly conserved molecular processes in memory. Recent research from invertebrate systems has outlined the influence of sleep and the circadian clock upon synaptic plasticity. In this review, we discuss the effects of the circadian clock and sleep on memory formation in invertebrates drawing attention to the potential of in vivo and in vitro approaches that harness the power of simple invertebrate systems to correlate individual cellular processes with complex behaviors. In conclusion, this review highlights how studies in invertebrates with relatively simple nervous systems can provide mechanistic insights into corresponding behaviors in higher organisms and can be used to outline possible therapeutic options to guide further targeted inquiry. PMID:25136297

  2. Assessment of Circadian and Light-Entrainable Parameters in Mice Using Wheel-Running Activity.

    PubMed

    Banks, Gareth T; Nolan, Patrick M

    2011-01-01

    In most organisms, physiological variables are regulated by an internal clock. This endogenous circadian (∼24-hr) clock enables organisms to anticipate daily environmental changes and modify behavioral and physiological functions appropriately. Processes regulated by the circadian clock include sleep-wake and locomotor activity, core body temperature, metabolism, water/food intake, and available hormone levels. At the core of the mammalian circadian system are molecular oscillations within the hypothalamic suprachiasmatic nucleus. These oscillations are modifiable by signals from the environment (so called zeitgebers or time-givers) and, once integrated within the suprachiasmatic nucleus, are conveyed to remote neural circuits where output rhythms are regulated. Disrupting any of a number of neural processes can affect how rhythms are generated and relayed to the periphery and disturbances in circadian/entrainment parameters are associated with numerous human conditions. These non-invasive protocols can be used to determine whether circadian/entrainment parameters are affected in mouse mutants or treatment groups. Curr. Protoc. Mouse Biol. 1:369-381 © 2011 by John Wiley & Sons, Inc. PMID:26068996

  3. Circadian time-place learning in mice depends on Cry genes.

    PubMed

    Van der Zee, Eddy A; Havekes, Robbert; Barf, R Paulien; Hut, Roelof A; Nijholt, Ingrid M; Jacobs, Edwin H; Gerkema, Menno P

    2008-06-01

    Endogenous biological clocks allow organisms to anticipate daily environmental cycles. The ability to achieve time-place associations is key to the survival and reproductive success of animals. The ability to link the location of a stimulus (usually food) with time of day has been coined time-place learning, but its circadian nature was only shown in honeybees and birds. So far, an unambiguous circadian time-place-learning paradigm for mammals is lacking. We studied whether expression of the clock gene Cryptochrome (Cry), crucial for circadian timing, is a prerequisite for time-place learning. Time-place learning in mice was achieved by developing a novel paradigm in which food reward at specific times of day was counterbalanced by the penalty of receiving a mild footshock. Mice lacking the core clock genes Cry1 and Cry2 (Cry double knockout mice; Cry1(-/-)Cry2(-/-)) learned to avoid unpleasant sensory experiences (mild footshock) and could locate a food reward in a spatial learning task (place preference). These mice failed, however, to learn time-place associations. This specific learning and memory deficit shows that a Cry-gene dependent circadian timing system underlies the utilization of time of day information. These results reveal a new functional role of the mammalian circadian timing system. PMID:18514517

  4. Interplay between Dioxin-Mediated Signaling and Circadian Clock: A Possible Determinant in Metabolic Homeostasis

    PubMed Central

    Wang, Chun; Zhang, Zhi-Ming; Xu, Can-Xin; Tischkau, Shelley A.

    2014-01-01

    The rotation of the earth on its axis creates the environment of a 24 h solar day, which organisms on earth have used to their evolutionary advantage by integrating this timing information into their genetic make-up in the form of a circadian clock. This intrinsic molecular clock is pivotal for maintenance of synchronized homeostasis between the individual organism and the external environment to allow coordinated rhythmic physiological and behavioral function. Aryl hydrocarbon receptor (AhR) is a master regulator of dioxin-mediated toxic effects, and is, therefore, critical in maintaining adaptive responses through regulating the expression of phase I/II drug metabolism enzymes. AhR expression is robustly rhythmic, and physiological cross-talk between AhR signaling and circadian rhythms has been established. Increasing evidence raises a compelling argument that disruption of endogenous circadian rhythms contributes to the development of disease, including sleep disorders, metabolic disorders and cancers. Similarly, exposure to environmental pollutants through air, water and food, is increasingly cited as contributory to these same problems. Thus, a better understanding of interactions between AhR signaling and the circadian clock regulatory network can provide critical new insights into environmentally regulated disease processes. This review highlights recent advances in the understanding of the reciprocal interactions between dioxin-mediated AhR signaling and the circadian clock including how these pathways relate to health and disease, with emphasis on the control of metabolic function. PMID:24987953

  5. Dose-response relationships for resetting of human circadian clock by light

    NASA Technical Reports Server (NTRS)

    Boivin, D. B.; Duffy, J. F.; Kronauer, R. E.; Czeisler, C. A.

    1996-01-01

    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.

  6. CIRCADIAN CLOCK-ASSOCIATED 1 regulates ROS homeostasis and oxidative stress responses

    PubMed Central

    Lai, Alvina Grace; Doherty, Colleen J.; Mueller-Roeber, Bernd; Kay, Steve A.; Schippers, Jos H. M.; Dijkwel, Paul P.

    2012-01-01

    Organisms have evolved endogenous biological clocks as internal timekeepers to coordinate metabolic processes with the external environment. Here, we seek to understand the mechanism of synchrony between the oscillator and products of metabolism known as Reactive Oxygen Species (ROS) in Arabidopsis thaliana. ROS-responsive genes exhibit a time-of-day–specific phase of expression under diurnal and circadian conditions, implying a role of the circadian clock in transcriptional regulation of these genes. Hydrogen peroxide production and scavenging also display time-of-day phases. Mutations in the core-clock regulator, CIRCADIAN CLOCK ASSOCIATED 1 (CCA1), affect the transcriptional regulation of ROS-responsive genes, ROS homeostasis, and tolerance to oxidative stress. Mis-expression of EARLY FLOWERING 3, LUX ARRHYTHMO, and TIMING OF CAB EXPRESSION 1 affect ROS production and transcription, indicating a global effect of the clock on the ROS network. We propose CCA1 as a master regulator of ROS homeostasis through association with the Evening Element in promoters of ROS genes in vivo to coordinate time-dependent responses to oxidative stress. We also find that ROS functions as an input signal that affects the transcriptional output of the clock, revealing an important link between ROS signaling and circadian output. Temporal coordination of ROS signaling by CCA1 and the reciprocal control of circadian output by ROS reveal a mechanistic link that allows plants to master oxidative stress responses. PMID:23027948

  7. Circadian Rhythms, the Molecular Clock, and Skeletal Muscle

    PubMed Central

    Lefta, Mellani; Wolff, Gretchen; Esser, Karyn A.

    2015-01-01

    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

  8. Kinetics of circadian band development in Neurospora crassa.

    PubMed

    Castro-Longoria, E; Brody, S; Bartnicki-García, S

    2007-07-01

    The circadian rhythm of Neurospora crassa can be seen as a conidiation rhythm that produces concentric rings of bands (conidiating regions) alternating with interbands (non-conidiating regions) on the surface of an agar medium. To follow quantitatively this rhythm, densitometric analysis, gravimetric procedures, and video microscopy were employed. The circadian behavior of N. crassa is commonly monitored by cultivation in race tubes; in this work we report different growth kinetics during cultivation in conventional Petri dish cultures. Two different growth parameters were measured: total colony mass (true growth rate) and distance (colony radial expansion or hyphal elongation). Determinations of cellular mass revealed a dramatic circadian oscillation with a marked drop in growth rate during new interband formation followed by a sharp increase during the development of a new conidiation band. On the other hand, we found that the radial expansion of the colony previously reported to decrease periodically seemed unaffected by the circadian clock. Densitometric analysis showed no initial difference in the expanding margin of the colony, independent of whether that area was destined to be a band or an interband. The band areas increased rapidly in density for about 15 h whereas the interband areas maintained an equally rapid rate of increase for only 6h. The density of band areas kept increasing slowly for almost 40 h, along with an increase in the amount of conidia. Video microscopy showed the importance of cytoplasmic flow in colony development with continuous forward flow to support hyphal morphogenesis and reverse flow to support an extended period of conidiogenesis. Our results indicate that the circadian system of Neurospora can be expressed at the level of cellular mass formation, not just as the developmental conidiation rhythm. PMID:17329132

  9. Circadian malfunctions in depression - neurobiological and psychosocial approaches.

    PubMed

    Nechita, Florina; Pîrlog, Mihail Cristian; ChiriŢă, Anca Livia

    2015-01-01

    Depression leads to disturbances in physiological rhythms, which result in disturbances in circadian sleep-wake cycles, hormonal secretion patterns and fluctuations in mood, all of which can be objectively measured. These disturbances, which are associated with depression, can be also used to define depression. Beyond these "transversal" time-related symptoms, there are the "longitudinal" time-related symptoms, since depression evolves over a long period of time, with a profound impact on a person's life and is often associated with long-term psychosocial consequences (Mendlewicz, 2010). The circadian rhythm reflects an approximate 24-hour cycle in the biochemical, physiological and behavioral processes of living entities, which crucially influences human well-being and health. Increasing evidence from clinical and neurobiological research suggests that disrupted temporal organization impairs behavior, cognition, mood, sleep and social activity and may be implicated in mental disorders. It has been proposed that circadian malfunction is a major core feature of mood disorders, depression in particular. In depressed patients, circadian rhythms and homeostatic processes are disrupted, thereby affecting mood, sleep, activity and a variety of biological functions such as hormone secretion and body temperature (Hajak & Landgrebe, 2010). Sleep difficulties are among the most current symptoms in depressed patients. Insomnia is often the reason why depressed patients seek help and relief of sleep disturbance may encourage compliance with antidepressant treatment. Apart from the discomfort that sleep problems produce, they may lead to exhaustion, poor functioning and they are associated with an increase in suicide risk (Wilson et al., 2013). PMID:26662127

  10. Single-cell analysis of circadian dynamics in tissue explants

    PubMed Central

    Lande-Diner, Laura; Stewart-Ornstein, Jacob; Weitz, Charles J.; Lahav, Galit

    2015-01-01

    Tracking molecular dynamics in single cells in vivo is instrumental to understanding how cells act and interact in tissues. Current tissue imaging approaches focus on short-term observation and typically nonendogenous or implanted samples. Here we develop an experimental and computational setup that allows for single-cell tracking of a transcriptional reporter over a period of >1 wk in the context of an intact tissue. We focus on the peripheral circadian clock as a model system and measure the circadian signaling of hundreds of cells from two tissues. The circadian clock is an autonomous oscillator whose behavior is well described in isolated cells, but in situ analysis of circadian signaling in single cells of peripheral tissues is as-yet uncharacterized. Our approach allowed us to investigate the oscillatory properties of individual clocks, determine how these properties are maintained among different cells, and assess how they compare to the population rhythm. These experiments, using a wide-field microscope, a previously generated reporter mouse, and custom software to track cells over days, suggest how many signaling pathways might be quantitatively characterized in explant models. PMID:26269583

  11. Circadian rhythms in cardiac arrhythmias and opportunities for their chronotherapy.

    PubMed

    Portaluppi, Francesco; Hermida, Ramón C

    2007-08-31

    It is now well established that nearly all functions of the body, including those that influence the pharmacokinetics and pharmacodynamics of medications, exhibit significant 24-hour variation. The electrical properties of the heart as well as cardiac arrhythmias also vary as circadian rhythms, even though the suboptimal methods initially used for their investigation slowed their identification and thorough characterization. The application of continuous Holter monitoring of the electrical properties of the heart has revealed 24-hour variation in the occurrence of ventricular premature beats with the peak in events, in diurnally active persons, between 6 a.m. and noon. After the introduction of implantable cardioverter-defibrillators, ventricular tachycardia or fibrillation were also found to peak in the same period of the day. Even defibrillator energy requirements show circadian variation, thus supporting the need for a temporal awareness in the therapeutic approach to arrhythmias. Imbalanced autonomic tone, circulating levels of catecholamines, increased heart rate and blood pressure, all established determinants of cardiac arrhythmias, show circadian variations and underlie the genesis of the circadian pattern of cardiac arrhythmias. Arrhythmogenesis appears to be suppressed during nighttime sleep, and this can influence the evaluation of the efficacy of antiarrhythmic medications in relation to their administration time. Unfortunately, very few studies have been undertaken to assess the proper timing (chronotherapy) of antiarrhythmic medications as means to maximize efficacy and possibly reduce side effects. Further research in this field is warranted and could bring new insight and clinical advantage. PMID:17659808

  12. Circadian melatonin rhythm and excessive daytime sleepiness in Parkinson’s disease

    PubMed Central

    Videnovic, Aleksandar; Noble, Charleston; Reid, Kathryn J.; Peng, Jie; Turek, Fred W.; Marconi, Angelica; Rademaker, Alfred W.; Simuni, Tanya; Zadikoff, Cindy; Zee, Phyllis C.

    2014-01-01

    Importance Diurnal fluctuations of motor and non-motor symptoms and high prevalence of sleep/wake disturbances in Parkinson’s disease (PD) suggest a role of the circadian system in the modulation of these symptoms. Yet, surprisingly little is known regarding circadian function in PD, and whether circadian dysfunction is involved in the development of sleep/wake disturbances in PD. Objective The objective of this study was to determine the relationship between the timing and amplitude of the 24-hour melatonin rhythm, a marker of endogenous circadian rhythmicity, with self-reported sleep quality, the severity of daytime sleepiness and disease metrics. Design A cross-sectional study, (2009–2012). Setting PD and Movement Disorders Center, Northwestern University, Chicago. Participants Twenty PD patients on stable dopaminergic therapy and 15 age-matched controls underwent blood sampling for the measurement of serum melatonin levels at 30-minute intervals for 24 hours under modified constant routine conditions. Main Outcome Measure(s) Clinical and demographic data, self-reported measures of sleep quality (Pittsburgh Sleep Quality Index (PSQI)) and daytime sleepiness (Epworth Sleepiness Scale (ESS)), circadian markers of the melatonin rhythm, including the amplitude, area-under-the-curve (AUC), and phase of the 24-hour rhythm. Results Participants with PD had a blunted circadian rhythms of melatonin secretion compared to controls; both the amplitude of the melatonin rhythm and the 24-hour AUC for circulating melatonin levels were significantly lower in PD participants compared with controls (p<0.001). Markers of circadian phase were not significantly different between the two groups. Among PD participants, those with excessive daytime sleepiness (ESS score ≥10) had a significantly lower amplitude of the melatonin rhythm and the 24-hour melatonin AUC compared with PD participants without excessive sleepiness (p=0.001). Disease duration, UPDRS scores, levodopa

  13. Synchronization to light and mealtime of the circadian rhythms of self-feeding behavior and locomotor activity of white shrimps (Litopenaeus vannamei).

    PubMed

    Santos, Aline Dos Anjos; López-Olmeda, José Fernando; Sánchez-Vázquez, Francisco Javier; Fortes-Silva, Rodrigo

    2016-09-01

    The role of light and feeding cycles in synchronizing self-feeding and locomotor activity rhythms was studied in white shrimps using a new self-feeding system activated by photocell trigger. In experiment 1, shrimps maintained under a 12:12h light/dark (LD) photoperiod were allowed to self-feed using feeders connected to a photoelectric cell, while locomotor activity was recorded with a second photocell. On day 30, animals were subjected to constant darkness (DD) for 12days to check the existence of endogenous circadian rhythms. In the experiment 2, shrimps were exposed to both a 12:12h LD photoperiod and a fixed meal schedule in the middle of the dark period (MD, 01:00h). On day 20, shrimps were exposed to DD conditions and the same fixed feeding. On day 30, they were maintained under DD and fasted for 7days. The results revealed that under LD, shrimps showed a clear nocturnal feeding pattern and locomotor activity (81.9% and 67.7% of total daily food-demands and locomotor activity, respectively, at nighttime). Both feeding and locomotor rhythms were endogenously driven and persisted under DD with an average period length (τ) close to 24h (circadian) (τ=24.18±0.13 and 23.87±0.14h for locomotor and feeding, respectively). Moreover, Shrimp showed a daily food intake under LD condition (1.1±0.2gday(-1) in the night phase vs. 0.2±0.1gday(-1) in the light phase). Our findings might be relevant for some important shrimp aquaculture aspects, such as developing suitable feeding management on shrimp farms. PMID:27155052

  14. Does the Precision of a Biological Clock Depend upon Its Period? Effects of the Duper and tau Mutations in Syrian Hamsters

    PubMed Central

    Bittman, Eric L.

    2012-01-01

    Mutations which alter the feedback loops that generate circadian rhythms may provide insight into their insensitivity to perturbation robustness) and their consistency of period (precision). I examined relationships between endogenous period, activity and rest (τDD, α and ρ) in Syrian hamsters using two different mutations, duper and tau, both of which speed up the circadian clock. I generated 8 strains of hamsters that are homozygous or heterozygous for the tau, duper, and wild type alleles in all combinations. The endogenous period of activity onsets among these strains ranged from 17.94+0.04 to 24.13±0.04 h. Contrary to predictions, the variability of period was unrelated to its absolute value: all strains showed similar variability of τDD when activity onsets and acrophase were used as phase markers. The τDD of activity offsets was more variable than onsets but also differed little between genotypes. Cycle variation and precision were not correlated with τDD within any strain, and only weakly correlated when all strains are considered together. Only in animals homozygous for both mutations (super duper hamsters) were cycle variation and precision reduced. Rhythm amplitude differed between strains and was positively correlated with τDD and precision. All genotypes showed negative correlations between α and ρ. This confirms the expectation that deviations in the duration of subjective day and night should offset one another in order to conserve circadian period, even though homeostatic maintenance of energy reserves predicts that longer intervals of activity or rest would be followed by longer durations of rest or activity. Females consistently showed greater variability of the period of activity onset and acrophase, and of α, but variability of the period of offset differed between sexes only in super duper hamsters. Despite the differences between genotypes in τDD, ρ was consistently more strongly correlated with the preceding than the succeeding

  15. Effects of chronic administration and withdrawal of antidepressant agents on circadian activity rhythms in rats.

    PubMed

    Wollnik, F

    1992-10-01

    Experimental and clinical studies indicate that clinical depression may be associated with disturbances of circadian rhythms. To explore the interaction between circadian rhythmicity, behavioral state, and monoaminergic systems, the present study investigated the effects of chronic administration and withdrawal of the following antidepressant agents on circadian wheel-running rhythms of laboratory rats: a) moclobemide, a reversible and selective monoamine oxidase (MAO) type A inhibitor; b) Ro 19-6327, a selective MAO type B inhibitor; c) desipramine, a preferential norepinephrine reuptake inhibitor; d) clomipramine and e) fluoxetine, both serotonin reuptake inhibitors; and f) levoprotiline, an atypical antidepressant whose biochemical mechanism is still unknown. Wheel-running activity rhythms were studied in three inbred strains of laboratory rats (ACI, BH, LEW) under constant darkness (DD). Two of these inbred strains (BH and LEW) show profound abnormalities in their circadian activity rhythms, namely, a reduced overall level of activity and bimodal or multimodal activity patterns. Chronic treatment with moclobemide and desipramine consistently increased the overall level, as well as the circadian amplitude, of the activity rhythm. Furthermore, the abnormal activity pattern of the LEW strain was changed into a unimodal activity pattern like that of other laboratory rats. The free-running period tau was slightly shortened by moclobemide and dramatically shortened by desipramine. Effects of moclobemide and desipramine treatment on overall activity level and duration were reversed shortly after termination of treatment, whereas long aftereffects were observed for the free-running period. All other substances tested had no systematic effects on the activity rhythms of any of the strains. The fact that moclobemide and desipramine altered the period, amplitude, and pattern of circadian activity rhythms is consistent with the hypothesis that monoaminergic transmitters

  16. Predicted Role of NAD Utilization in the Control of Circadian Rhythms during DNA Damage Response.

    PubMed

    Luna, Augustin; McFadden, Geoffrey B; Aladjem, Mirit I; Kohn, Kurt W

    2015-05-01

    The circadian clock is a set of regulatory steps that oscillate with a period of approximately 24 hours influencing many biological processes. These oscillations are robust to external stresses, and in the case of genotoxic stress (i.e. DNA damage), the circadian clock responds through phase shifting with primarily phase advancements. The effect of DNA damage on the circadian clock and the mechanism through which this effect operates remains to be thoroughly investigated. Here we build an in silico model to examine damage-induced circadian phase shifts by investigating a possible mechanism linking circadian rhythms to metabolism. The proposed model involves two DNA damage response proteins, SIRT1 and PARP1, that are each consumers of nicotinamide adenine dinucleotide (NAD), a metabolite involved in oxidation-reduction reactions and in ATP synthesis. This model builds on two key findings: 1) that SIRT1 (a protein deacetylase) is involved in both the positive (i.e. transcriptional activation) and negative (i.e. transcriptional repression) arms of the circadian regulation and 2) that PARP1 is a major consumer of NAD during the DNA damage response. In our simulations, we observe that increased PARP1 activity may be able to trigger SIRT1-induced circadian phase advancements by decreasing SIRT1 activity through competition for NAD supplies. We show how this competitive inhibition may operate through protein acetylation in conjunction with phosphorylation, consistent with reported observations. These findings suggest a possible mechanism through which multiple perturbations, each dominant during different points of the circadian cycle, may result in the phase advancement of the circadian clock seen during DNA damage. PMID:26020938

  17. Epigenetic and Posttranslational Modifications in Light Signal Transduction and the Circadian Clock in Neurospora crassa

    PubMed Central

    Proietto, Marco; Bianchi, Michele Maria; Ballario, Paola; Brenna, Andrea

    2015-01-01

    Blue light, a key abiotic signal, regulates a wide variety of physiological processes in many organisms. One of these phenomena is the circadian rhythm presents in organisms sensitive to the phase-setting effects of blue light and under control of the daily alternation of light and dark. Circadian clocks consist of autoregulatory alternating negative and positive feedback loops intimately connected with the cellular metabolism and biochemical processes. Neurospora crassa provides an excellent model for studying the molecular mechanisms involved in these phenomena. The White Collar Complex (WCC), a blue-light receptor and transcription factor of the circadian oscillator, and Frequency (FRQ), the circadian clock pacemaker, are at the core of the Neurospora circadian system. The eukaryotic circadian clock relies on transcriptional/translational feedback loops: some proteins rhythmically repress their own synthesis by inhibiting the activity of their transcriptional factors, generating self-sustained oscillations over a period of about 24 h. One of the basic mechanisms that perpetuate self-sustained oscillations is post translation modification (PTM). The acronym PTM generically indicates the addition of acetyl, methyl, sumoyl, or phosphoric groups to various types of proteins. The protein can be regulatory or enzymatic or a component of the chromatin. PTMs influence protein stability, interaction, localization, activity, and chromatin packaging. Chromatin modification and PTMs have been implicated in regulating circadian clock function in Neurospora. Research into the epigenetic control of transcription factors such as WCC has yielded new insights into the temporal modulation of light-dependent gene transcription. Here we report on epigenetic and protein PTMs in the regulation of the Neurospora crassa circadian clock. We also present a model that illustrates the molecular mechanisms at the basis of the blue light control of the circadian clock. PMID:26198228

  18. Predicted Role of NAD Utilization in the Control of Circadian Rhythms during DNA Damage Response

    PubMed Central

    Luna, Augustin; McFadden, Geoffrey B.; Aladjem, Mirit I.; Kohn, Kurt W.

    2015-01-01

    The circadian clock is a set of regulatory steps that oscillate with a period of approximately 24 hours influencing many biological processes. These oscillations are robust to external stresses, and in the case of genotoxic stress (i.e. DNA damage), the circadian clock responds through phase shifting with primarily phase advancements. The effect of DNA damage on the circadian clock and the mechanism through which this effect operates remains to be thoroughly investigated. Here we build an in silico model to examine damage-induced circadian phase shifts by investigating a possible mechanism linking circadian rhythms to metabolism. The proposed model involves two DNA damage response proteins, SIRT1 and PARP1, that are each consumers of nicotinamide adenine dinucleotide (NAD), a metabolite involved in oxidation-reduction reactions and in ATP synthesis. This model builds on two key findings: 1) that SIRT1 (a protein deacetylase) is involved in both the positive (i.e. transcriptional activation) and negative (i.e. transcriptional repression) arms of the circadian regulation and 2) that PARP1 is a major consumer of NAD during the DNA damage response. In our simulations, we observe that increased PARP1 activity may be able to trigger SIRT1-induced circadian phase advancements by decreasing SIRT1 activity through competition for NAD supplies. We show how this competitive inhibition may operate through protein acetylation in conjunction with phosphorylation, consistent with reported observations. These findings suggest a possible mechanism through which multiple perturbations, each dominant during different points of the circadian cycle, may result in the phase advancement of the circadian clock seen during DNA damage. PMID:26020938

  19. Drosophila spaghetti and doubletime link the circadian clock and light to caspases, apoptosis and tauopathy.

    PubMed

    Means, John C; Venkatesan, Anandakrishnan; Gerdes, Bryan; Fan, Jin-Yuan; Bjes, Edward S; Price, Jeffrey L

    2015-05-01

    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