Effect of sleep deprivation on rhythms of clock gene expression and melatonin in humans

This study investigated the impact of sleep deprivation on the human circadian system. Plasma melatonin and cortisol levels and leukocyte expression levels of 12 genes were examined over 48?h (sleep vs. no-sleep nights) in 12 young males (mean?±?SD: 23?±?5 yrs). During one night of total sleep deprivation, BMAL1 expression was suppressed, the heat shock gene HSPA1B expression was induced, and the amplitude of the melatonin rhythm increased, whereas other high-amplitude clock gene rhythms (e.g., PER1-3, REV-ERBα) remained unaffected. These data suggest that the core clock mechanism in peripheral oscillators is compromised during acute sleep deprivation.     

Life's 24-hour clock: molecular control of circadian rhythms in animal cells

Our sleep–wake cycles and many other 24-hour rhythms of behavior and physiology persist in the absence of environmental cues. Genetic and biochemical studies have shown that such rhythms are controlled by internal molecular clocks. These are assembled from the cycling RNA and protein products of a small group of genes that are conserved throughout the animal kingdom.     

生物钟机制研究进展

由生物体内源性生物钟所产生的昼夜节律是近年来生命科学的研究热点之一。几种模型生物（蓝细菌、脉孢菌、拟南芥、果蝇、小鼠）的生物钟相关基因相继被克隆和鉴定,为理解昼夜节律的分子机制奠定了基础。振荡器蛋白对其编码基因的负反馈调控可能是不同生物的生物运作普遍机制,在此基础上,不同生物有不尽相同的调控方式;隐色素可能是高等生物的共同生物钟光受体。     

The daily rhythms of mitochondrial gene expression and oxidative stress regulation are altered by aging in the mouse liver

The circadian clock regulates many cellular processes, notably including the cell cycle, metabolism and aging. Mitochondria play essential roles in metabolism and are the major sites of reactive oxygen species (ROS) production in the cell. The clock regulates mitochondrial functions by driving daily changes in NAD⁺ levels and Sirt3 activity. In addition to this central route, in the present study, we find that the expression of some mitochondrial genes is also rhythmic in the liver, and that there rhythms are disrupted by the Clock^Δ19 mutation in young mice, suggesting that they are regulated by the core circadian oscillator. Related to this observation, we also find that the regulation of oxidative stress is rhythmic in the liver. Since mitochondria and ROS play important roles in aging, and mitochondrial functions are also disturbed by aging, these related observations prompt the compelling hypothesis that circadian oscillators influence aging by regulating ROS in mitochondria. During aging, the expression rhythms of some mitochondrial genes were altered in the liver and the temporal regulation over the dynamics of mitochondrial oxidative stress was disrupted. However, the expression of clock genes was not affected. Our results suggested that mitochondrial functions are combinatorially regulated by the clock and other age-dependent mechanism(s), and that aging disrupts mitochondrial rhythms through mechanisms downstream of the clock.     

Dexamethasone induces high-amplitude rhythms in preadipocytes,But hinders circadian expression in differentiated adipocytes

Glucocorticoids induce circadian gene expression in cultured cells and change the phase of circadian gene expression in vivo. In addition, glucocorticoids induce differentiation of preadipocyte to adipocytes. We set out to test the effect of dexamethasone, a glucocorticoid receptor agonist, on circadian rhythms in 3T3-L1 differentiated adipocytes. Our results show that differentiated adipocytes exhibit robust circadian rhythms without dexamethasone. Dexamethasone induces phase changes and increases the amplitude of circadian gene expression in nondifferentiated 3T3-L1 preadipocytes. However, dexamethasone had an opposite effect on differentiated adipocytes, leading to low-amplitude circadian expression. In conclusion, although glucocorticoids reset circadian rhythms, once rhythms are reset, glucocorticoid administration hinders circadian expression.     

Sleep,daily activity rhythms and postpartum mood: A longitudinal study across the perinatal period

Women with a diagnosis of bipolar and major depressive disorders are at higher risk to develop postpartum depression. The primary objective of this longitudinal study was to determine whether daily activity rhythms and sleep parameters differ between women with and without a history of a mood disorder across the perinatal period. A secondary objective was to determine whether changes in these parameters were associated with postpartum mood. In total, 33 women were included in this study, 15 of which had a history of a mood disorder (high-risk group) and 18 who did not (low-risk group). Sleep and daily rhythms were assessed subjectively and objectively during the third trimester (≥26 weeks gestation) and again at 6–12 weeks postpartum. Mood was also assessed at both time points. Women in the high-risk group showed greater subjective daily rhythms and sleep disturbances across the perinatal period. Objective sleep efficiency was worse in the high-risk group in the postpartum period. Changes in both subjective daily rhythms and objective sleep efficiency were predictive of changes in depressive symptoms across the perinatal period. These findings encourage the development of preventative therapeutics to ensure circadian rhythm and sleep stability throughout the perinatal period.     

Circadian locomotor rhythms in individual honeybees

ABSTRACT. The circadian locomotor (walking) rhythms of individual forager honeybees ( Apis mellifera ligustica L.) were measured under a variety of conditions. In constant dark the rhythms exhibited endogenous periodicities that were less than 24 h, whereas under constant light the periods tended to be greater than 24 h. Individual honeybees readily entrained to photoperiods, displaying a diurnal pattern of entrainment with most of the activity occurring in late photophase. Evidence is presented which suggests that foraging behaviour and general locomotor behaviour may be governed by two different circadian clock systems.     

哺乳动物昼夜节律生物钟研究进展

昼夜节律生物钟是一种以近似24小时为周期的自主维持的振荡器,在分子水平上,该振荡器是一个由9个基因组成的转录翻译反馈环路系统。它能受外界环境影响重新设置节律,使自身机体活动处于最佳状态。除了进行自我调节外,生物钟基因还能通过调节代谢途径中特定基因表达而影响机体生理生化过程。在过去的几年里,借用遗传学和分子生物学工具,我们对哺乳动物昼夜节律生物钟的分子基础有了新的认识,本文综述了这一进展,并展望了它们在研究人的昼夜节律行为异常领域的前景。     

The choroid plexus harbors a circadian oscillator modulated by estrogens

The suprachiasmatic nucleus (SCN) of the hypothalamus is considered the master circadian oscillator in mammals. However, extra-SCN structures in the brain also display daily rhythms. Recently, we have demonstrated that the choroid plexus (CP) expresses core clock genes that are subjected to circadian regulation in a sex-dependent manner. By using CP explants cultured from female knock-in mice carrying the Period-luciferase transgene, we show that CP exhibits endogenous circadian rhythms of PERIOD2::LUCIFERASE expression. Furthermore, we demonstrate that estrogen declines following ovariectomy modulates the daily rhythm expression of Bmal1, Per1 and Per2 in female rat CP, corroborating data obtained in experiments where rat CP epithelial cell (CPEC) cultures were incubated with 17β-estradiol (E2). The molecular mechanism underlying these effects was also investigated, and we provide evidence that the estrogen receptor (ER) mediates the response of clock genes to E2.

In conclusion, our study proves that the CP harbors a circadian oscillator that is modulated by estrogens and demonstrates that E2 regulation occurs through an estrogen-receptor-dependent mechanism.     

Old flies have a robust central oscillator but weaker behavioral rhythms that can be improved by genetic and environmental manipulations

Sleep-wake cycles break down with age, but the causes of this degeneration are not clear. Using a Drosophila model, we addressed the contribution of circadian mechanisms to this age-induced deterioration. We found that in old flies, free-running circadian rhythms (behavioral rhythms assayed in constant darkness) have a longer period and an unstable phase before they eventually degenerate. Surprisingly, rhythms are weaker in light-dark cycles and the circadian-regulated morning peak of activity is diminished under these conditions. On a molecular level, aging results in reduced amplitude of circadian clock gene expression in peripheral tissues. However, oscillations of the clock protein PERIOD (PER) are robust and synchronized among different clock neurons, even in very old, arrhythmic flies. To improve rhythms in old flies, we manipulated environmental conditions, which can have direct effects on behavior, and also tested a role for molecules that act downstream of the clock. Coupling temperature cycles with a light-dark schedule or reducing expression of protein kinase A (PKA) improved behavioral rhythms and consolidated sleep. Our data demonstrate that a robust molecular timekeeping mechanism persists in the central pacemaker of aged flies, and reducing PKA can strengthen behavioral rhythms.     

Endogenous clock gene expression in the suprachiasmatic nuclei of previsual newborn rabbits is entrained by nursing

The rabbit is particularly suitable for investigating the development of mammalian circadian function. Blind at birth, the pups are only visited by the mother to be nursed once every 24 h for about 3 min and so can be studied largely without maternal interference. They anticipate the mother's visit with increased behavioral arousal and with a rise in body temperature, both of which represent endogenous circadian rhythms. We now report that in newborn pups the suprachiasmatic nuclei of the hypothalamus (SCN; the main circadian pacemaker in mammals) show endogenous 24‐h rhythmicity in the expression of the clock genes Per1, Per2, and Bmal1. Pups nursed from postnatal days 1 to 7 and fasted to day 9 showed the same rhythms of clock gene expression as normally nursed controls. We also report that these rhythms are entrained by nursing. Pups killed on postnatal days 3–4 showed the same rhythms in gene expression as pups in the previous experiment, whereas littermates subsequently nursed from postnatal days 4 to 7 with nursing delayed 6 h showed a corresponding shift in the diurnal pattern of clock gene expression. Consistent with this, two groups of pups implanted with telemetric thermal sensors and nursed 6 h apart had daily patterns in body temperature synchronized with the two different nursing times. We conclude that the expression of clock genes associated with the newborn rabbit's circadian system is entrained by nonphotic cues accompanying nursing, the exact nature of which now needs to be clarified. © 2008 Wiley Periodicals, Inc. Develop Neurobiol, 2009     

Circadian rhythms and glial cells of the central nervous system

Glial cells are the most abundant cells in the central nervous system and play crucial roles in neural development, homeostasis, immunity, and conductivity. Over the past few decades, glial cell activity in mammals has been linked to circadian rhythms, the 24-h chronobiological clocks that regulate many physiological processes. Indeed, glial cells rhythmically express clock genes that cell-autonomously regulate glial function. In addition, recent findings in rodents have revealed that disruption of the glial molecular clock could impact the entire organism. In this review, we discuss the impact of circadian rhythms on the function of the three major glial cell types – astrocytes, microglia, and oligodendrocytes – across different locations within the central nervous system. We also review recent evidence uncovering the impact of glial cells on the body's circadian rhythm. Together, this sheds new light on the involvement of glial clock machinery in various diseases.     

Plasticity of diel and circadian activity rhythms in fishes

In many fish species, some individuals arediurnal while others are nocturnal. Sometimes,the same individual can be diurnal at first andthen switch to nocturnalism, or vice-versa.This review examines the factors that areassociated with such plasticity. It covers thebreakdown of activity rhythms during migration,spawning, and the parental phase; reversals ofactivity patterns during ontogeny or from oneseason to the next; effects of light intensity,temperature, predation risk, shoal size, foodavailability, and intraspecific competition.Case studies featuring goldfish (Carassiusauratus), golden shiner (Notemigonuscrysoleucas), lake chub (Couesiusplumbeus), salmonids, sea bass (Dicentrarchus labrax), and parentalsticklebacks and cichlids illustrate some ofthese influences. It is argued that mostspecies have a circadian system but that havingsuch a system does not necessarily imply strictdiurnalism or nocturnalism. Rigidity ofactivity phase seems more common in species,mostly marine, that display behavioral sleep,and for these animals the circadian clock canhelp maintain the integrity of the sleepperiod and ensure that its occurrence takes place atthat time of day to which the animal's sensoryequipment is not as well adapted. However, inother fishes, mostly from freshwater habitats,the circadian clock seems to be used mainly foranticipation of daily events such as thearrival of day, night, or food, and possiblyfor other abilities such as time-place learningand sun compass orientation, rather than forstrict control of activity phase. In thesespecies, various considerations relating toforaging success and predation risk maydetermine whether the animal is diurnal ornocturnal at any particular time and place.     

Circadian genes and lithium response in bipolar disorders: associations with PPARGC1A (PGC‐1α) and RORA

Preliminary studies suggest that lithium (Li) response might be associated with some circadian gene polymorphisms, we therefore performed a pharmacogenetic study on the core clock genes in two independent samples suffering from bipolar disorder (BD) and thoroughly characterized for their Li response. Two independent Caucasian samples (165 and 58 bipolar patients) treated with Li were selected from samples recruited in a French multicenter study and assessed for their Li response using the Alda scale. The two samples were genotyped using the Human660 (H660) and OmniExpress (OE) BeadChips and gene‐based association analyses of 22 core clock genes were conducted. In the first sample (H660 chip), the RAR‐related orphan receptor‐a gene (RORA) and the Peroxisome Proliferator‐Activated Receptor Gamma, Coactivator 1 Alpha gene (PPARGC1A or PGC‐1α) were significantly associated with the Li response (empirical P‐value = 0.0015 and 0.04, respectively), and remained significant only for RORA after Bonferroni correction. In the second sample (OE chip), PPARGC1A was significantly associated with the Li response (empirical P‐value = 0.04), and did not remain significant after Bonferroni correction. PPARGC1A is a master regulator of mitochondrial function and a key component of the endogenous clock that stimulates the expression of Bmal1 and Rev‐erb‐alpha through coactivation of RORA. Although the observed associations deserve further replication and investigation, our results suggest genetic associations between Li response and these two close biological partners: PPARGC1A and RORA involved in circadian rhythms and bioenergetics processes in Li response.     

Psychophysical measure of visual luminance contrast during a daily rhythm

ABSTRACT

This study evaluated visual sensitivity to luminance contrast during a daily period. Twenty-eight young male adults (M = 24.85; SD = 2.4) with normal color vision and 20/20 visual acuity participated in this study. The circadian pattern was assessed using the Karolinska Sleepiness Scale (KSS), the Pittsburgh Sleep Quality Index (PSQI), and a sleep diary. To measure the luminance contrast, we used version 11.0 of the Metropsis software with sine-element frequency stimuli for spatial frequencies of 0.2, 0.6, 1, 3.1, 6.1, 8.8, 13.2, and 15.6 cycles per degree of visual angle (cpd). The stimuli were presented on a 19-inch color cathode ray tube (CRT) video monitor with a resolution of 1024 × 786 pixels, an update rate of 100 Hz, and a photopic luminance of 39.6 cd/m2. There was a significant difference in KSS on the weekdays [χ2₍₂₎ = 20.27; p = .001] and in the luminance contrast for frequencies of 13.2 cpd [χ2₍₂₎ = 8.27; p = .001] and 15.6 cpd [χ2₍₂₎ = 13.72; p = .041]. The results showed greater stability of the measurement during the afternoon and a reduction in the visual sensitivity in the high spatial frequencies during the night.