Circadian rhythms from flies to human

In this era of jet travel, our body 'remembers' the previous time zone, such that when we travel, our sleep wake pattern, mental alertness, eating habits and many other physiological processes temporarily suffer the consequences of time displacement until we adjust to the new time zone. Although the existence of a circadian clock in humans had been postulated for decades, an understanding of the molecular mechanisms has required the full complement of research tools. To gain the initial insights into circadian mechanisms, researchers turned to genetically tractable model organisms such as Drosophila.     

南极人体生理学和心理学研究进展

对国我近年来有关南极人本生理学和心理学的部分研究资料作了简述，研究者们普遍认为，南极特殊的自然和社会环境可引起人体血压，心率，体温，免疫功能，睡眠，生物节律和心理活动等方面的变化，人体对这种环境有一定的适应能力，南极环境对考察队员的心理产生不同程度的应激刺激，在考察人员的选拔工作中，特别是需要注重效度（尤其是预测效度）的检验，以上资料为进一步开展南极人体医学考察提供了依据。     

A benzodiazepine used in the treatment of insomnia phase-shifts the mammalian circadian clock

Between 5 and 20% of the adult population in Western countries suffer from insufficient and/or unsatisfying sleep, often associated with certain psychiatric disorders or with certain types of professional activities (for example, shift workers) and travel schedules (for example, jet lag). The benzodiazepines are at present the drug treatment of choice for the management of anxiety and stress-related conditions as well as insomnia. Benzodiazepines are thought to act by potentiating the action of the neurotransmitter gamma-aminobutyric acid (GABA), a widely distributed transmitter in the central nervous system. The circadian system has a key role in the regulation of the sleep-wake cycle, and at least some forms of insomnia may be the result of a disorder of the circadian sleep-wake rhythm. Similarly, at least some forms of depression may also involve disruption of normal circadian rhythmicity. A central pacemaker for the generation of many circadian rhythms in mammals, including the sleep-wake cycle, appears to be located in the suprachiasmatic nucleus, and recent research indicates that both cell bodies and axons containing GABA are present within the bilaterally paired suprachiasmatic nuclei. These findings raise the possibility that the benzodiazepines, commonly prescribed for sleep and mental disorders, may have an effect on the central circadian pacemaker. Here we report that the acute administration of triazolam, a short-acting benzodiazepine commonly prescribed for the treatment of insomnia, induces a phase-shift in the circadian rhythm of locomotor activity in golden hamsters. This suggests a role for GABA-containing neurones in the mammalian circadian system.     

中长跑训练与昼夜节律

时间生物学认为人体内存在着体力节律、情绪节律、智力节律、星期节律、昼夜节律等人体生物节律，教练员了解掌握人体生物节律，并用于训练和比赛，使自己的运动员能够提高训练效率，在比赛中发挥最佳成绩。本文讨论人体生物节律中昼夜节律对成绩的影响，以及如何把它运用于组织中长跑训练。     

Functional consequences of a CKIdelta mutation causing familial advanced sleep phase syndrome

Familial advanced sleep phase syndrome (FASPS) is a human behavioural phenotype characterized by early sleep times and early-morning awakening. It was the first human, mendelian circadian rhythm variant to be well-characterized, and was shown to result from a mutation in a phosphorylation site within the casein kinase I (CKI)-binding domain of the human PER2 gene. To gain a deeper understanding of the mechanisms of circadian rhythm regulation in humans, we set out to identify mutations in human subjects leading to FASPS. We report here the identification of a missense mutation (T44A) in the human CKIdelta gene, which results in FASPS. This mutant kinase has decreased enzymatic activity in vitro. Transgenic Drosophila carrying the human CKIdelta-T44A gene showed a phenotype with lengthened circadian period. In contrast, transgenic mice carrying the same mutation have a shorter circadian period, a phenotype mimicking human FASPS. These results show that CKIdelta is a central component in the mammalian clock, and suggest that mammalian and fly clocks might have different regulatory mechanisms despite the highly conserved nature of their individual components.     

蜜蜂生物节律研究进展

 生物节律主要指有机体生命活动的内在节律性。蜜蜂生物节律受到其社会性的影响,从而参与许多复杂行为的调控。与果蝇相比,蜜蜂的生物节律与哺乳动物更相似。工蜂和蜂王的生物节律表现出高度的可塑性。例如,工蜂的昼夜节律受其劳动分工形式的调控,并通过与幼蜂的直接接触来调节,哺育蜂昼夜照料幼虫,在行为或时钟基因表达方面没有昼夜节律变化。从蜜蜂的社会性、蜜蜂生物节律产生的分子机制、神经基础、研究方法、可塑性、蜜蜂的睡眠等方面综述了蜜蜂生物节律的研究进展。     

Stimulated activity mediates phase shifts in the hamster circadian clock induced by dark pulses or benzodiazepines

A number of environmental and pharmacological stimuli capable of inducing phase shifts and/or period changes in the circadian clock of mammals have now been identified. Agents that can alter circadian clocks provide a means for investigating the cellular and neural mechanisms responsible for their generation, regulation and entrainment. Two stimuli that have been used to probe the basis of circadian rhythmicity are pulses of darkness on a background of constant light and injections of short-acting benzodiazepines, such as triazolam. Surprisingly, these two very different stimuli have remarkably similar phase-shifting effects on the circadian clock of hamsters. The observation that a short-term increase in locomotor activity occurs when the circadian activity rhythm of hamsters is shifted by dark pulses or triazolam injections, coupled with the finding that activity bouts themselves are capable of shifting this rhythm, raises the possibility that dark pulses or triazolam alter the circadian clock by inducing acute hyperactivity. Here we demonstrate that the phase-advancing and phase-delaying effects of dark pulses or triazolam on the circadian activity rhythm can be totally suppressed by immobilization of the animals during treatment. These results indicate that behavioural events mediate the phase-shifting effects of both dark pulses and triazolam on the circadian activity rhythm and question present hypotheses regarding the pathways by which light-dark information and pharmacological agents influence circadian pacemakers.     

机组疲劳评估系统模型对中国航司国际航班飞行员疲劳预测的适用性

研究旨在对经典生物数学模型在中国航空公司运营环境下的适用性进行研究。首先在我国航空公司的运营环境下,使用持续绩效测试(CPT)、卡罗林斯卡嗜睡量表(KSS)和机组人员状态检查表(SP)观测飞行员飞行过程中的警觉度绩效和主观疲劳自评。其次使用机组疲劳评估系统(SAFE)模拟并量化了相应的飞行员疲劳。最后比较了SAFE模型预测的机组警觉度值与其疲劳主观自评、客观绩效之间的差异,使用方差分析来探究疲劳影响因子对模型预测和主客观疲劳的影响差异。结果表明：SAFE模型预测机组人员疲劳与其主观疲劳有较强的相关性,整体上模型对机组人员疲劳预测体现了与执勤时长及昼夜节律相关因素的变化趋势,但是连续执勤18h后预测值会偏高。可见随着对该模型验证数据量的增加及调整模型相关参数以适应我国飞行运行环境,该模型将能够作为我国航空公司疲劳风险管理体系(FRMS)预测式危险源识别的客观工具,同时也可为我国本土化生物数学模型的理论研究与工程应用提供借鉴。     

Research Progress on the Relationship among Circadian Rhythm,Melatonin and Aging

It is generally believed that aging is a gradual decline in the efficiency of our biological metabolism, which eventually leads to the deterioration of individual physiological function and the development of a series of age-related degenerative diseases.The circadian clock machinery orchestrates the normal metabolism of the organism in order to assure that individual growth,development and reproduction are adapted to the changes of diurnal environmental variations. The circadian rhythm in the elderly is attenuated with age and is accompanied by the onset of metabolic syndrome, the accumulation of genomic or epigenomic instability, the decline of metabolic tissue homeostasis and the change of natural feeding behavior. Existing results corroborate that light at night(LAN) and melatonin inhibition affect genomic integrity and normal metabolic function. In several animal models,LAN accelerated aging by inhibiting melatonin production in the pineal gland and promoting age-related carcinogenesis. This paper reviews the effects of the circadian rhythm on aging and discusses the complex relationship among circadian rhythms, melatonin and aging in different models of organisms, which may provide clues for prolonging human life and maintaining health.     

An inducible promoter fused to the period gene in Drosophila conditionally rescues adult per-mutant arrhythmicity

The period (per) gene of Drosophila melanogaster is involved in the expression of circadian rhythms of locomotor activity in adult flies. Molecular studies of per (reviewed in ref. 2) have shown that the transcribed and translated products of this gene are present primarily at the embryonic, pupal and adult stages. Here we describe experiments with arrhythmic per mutants bearing an inducible form of this gene which indicate that strongly rhythmic adult behaviour can be obtained only if per expression is induced in the adult, independent of its history of expression earlier in development. Thus per-mutant locomotor-activity phenotypes seem not to result from abnormalities in the development of neural structures or in physiological processes that may be required at pre-adult stages for the expression of this circadian rhythm. Moreover, the action of per after light:dark cycle entrainment seems to be sufficient for activity rhythms to be exhibited in constant darkness; this suggests further that the per product is required only during the time that the rhythmic behaviour is being manifested. Our strategy used a heat-shock gene promotor fused to per coding sequences to obtain conditional gene expression. Heat-shock promoter-driven genes have previously been used to study the mode of action and tissue specificity of a variety of Drosophila genes; our experiments on circadian rhythms demonstrate the use of such gene constructions for the temporal manipulation of genes whose phenotypes, behavioural and otherwise, affect whole organisms.     

粗糙脉孢菌中几丁质合酶1缺失突变体的构建及表型分析

在丝状真菌中,几丁质是真菌细胞壁的主要成分之一,对维持细胞形态和结构起到了重要的作用.几丁质是由几丁质合酶(chitin synthase,CHS)催化合成的,几丁质合酶参与生物钟调节的生理活动.本文以丝状真菌粗糙脉孢菌几丁质合酶1(CHS-1)为研究对象,通过同源重组基因敲除技术、电转化、分生孢子过膜以及PCR鉴定的方法,获得了chs-1缺失突变菌株CHS-1KO.通过竞争性生长管(racetube)培养分析发现:对照Ku70RIP和突变菌株CHS-1KO(Ku70RIP背景)均具有明显的分生孢子带,但分生孢子带昼夜节律周期缩短,直线生长速率显著减慢,ku70RIP菌丝生长长度是3.4±0.31 cm/24 h,而突变菌株CHS-1KO(Ku70RIP背景)菌丝生长长度是2.07±0.19 cm/24 h.并进一步结合细胞壁染色对细胞形态分析发现:变菌株CHS-1KO菌丝沿生长方向膨胀、分支变短.这些结果表明:几丁质合酶1在粗糙脉孢菌分生孢子带昼夜节律形成和菌丝生长中发挥重要的作用.     

Cycles of presence and absence of mother mouse entrain the circadian clock of pups

Recent findings on neural and endocrine rhythms in infant mice and rats show that maternal coordination has an important role in setting the phase of the developing circadian clock both in the fetus and soon after birth. However, less information is available about the influence of the mother on activity/rest cycles of infants. Separation of the mother from infants in guinea pigs, monkeys and rats results in an increase in sleep disturbance (enhanced activity?). In this context it may be a common feature that during the postnatal period there is enhanced activity of pups during the hours when the mother is not nearby. Conversely, the social influences exerted by the mother while present with her young possibly leads to a relative rest stage. We have now tested this assumption in the night-active mouse Mus booduga. Our study addressed the postulate that the circadian activity/rest cycles of the pups are controlled by cyclic(?) presence and absence of the mother. The results reported here clearly indicate that the circadian locomotor activity of pups kept under continuous illumination or continuous darkness do entrain them to a regime of imposed 12:12-h cyclic presence and absence of the mother. The characteristics of this entrainment confer on the mother mouse the role of zeitgeber.     

Regulation of circadian behaviour and metabolism by synthetic REV-ERB agonists

Synchronizing rhythms of behaviour and metabolic processes is important for cardiovascular health and preventing metabolic diseases. The nuclear receptors REV-ERB-α and REV-ERB-β have an integral role in regulating the expression of core clock proteins driving rhythms in activity and metabolism. Here we describe the identification of potent synthetic REV-ERB agonists with in vivo activity. Administration of synthetic REV-ERB ligands alters circadian behaviour and the circadian pattern of core clock gene expression in the hypothalami of mice. The circadian pattern of expression of an array of metabolic genes in the liver, skeletal muscle and adipose tissue was also altered, resulting in increased energy expenditure. Treatment of diet-induced obese mice with a REV-ERB agonist decreased obesity by reducing fat mass and markedly improving dyslipidaemia and hyperglycaemia. These results indicate that synthetic REV-ERB ligands that pharmacologically target the circadian rhythm may be beneficial in the treatment of sleep disorders as well as metabolic diseases.     

连续记录动物冬眠体温数据分析系统的研究

动物冬眠研究是生物学科专家研究动物对环境适应能力的一个重要领域,生物学科专家在动物冬眠的实验研究过程中会采集到大量冬眠数据,这些冬眠数据的分析需要计算机领域的相关技术做支撑。通过在达乌尔黄鼠体内植入半导体温度记录元件记录其冬眠期间体温的变化,由MATLAB与Excel结合对实验数据进行分析研究,开发出了一个基于MATLAB的连续记录动物冬眠体温数据分析的系统。系统主要实现对达乌尔黄鼠冬眠数据的分析,通过设定黄鼠的入眠温度、出眠温度来计算冬眠历时,并由GUI图形用户界面形象的显示出结果。系统程序便于修改、直观易操作,便于生物学科专家通过获取理想分析结果,简化生物学科研究人员对初始的繁琐数据操作过程,为后期生物领域研究做基础。     

A circadian oscillator in cultured cells of chicken pineal gland

The activity of serotonin N-acetyltransferase, the key enzyme of melatonin synthesis, shows a marked circadian rhythm in the pineal glands of various animal species. The regulation mechanism of the N-acetyltransferse rhythm in birds is different from that in mammals. N-Acetyltransferase activity in rat pineal gland is controlled by the central nervous system through the sympathetic nerves from the superior cervical ganglion, while in chicken the endogenous oscillator for N-acetyltransferase rhythm is presumably located in the pineal gland. Recently it has been shown that N-acetyltransferase activity oscillates in a circadian manner in the organ culture of chicken pineal glands. When chicken pineal glands were organ-cultured under continuous illumination, the nocturnal increase of enzyme activity was suppressed. These observations suggested that chicken pineal gland contains a circadian oscillator, a photoreceptor and melatonin-synthesising machinery. A central question arises whether the circadian oscillation of N-acetyltransferase activity and its response to environmental lighting are generated within the cell or are emergent properties of interaction between different types of pineal cells. I report here that in the dispersed cell culture of chicken pineal gland, N-acetyltransferase activity exhibits a circadian rhythm and responds to environmental lighting in the same manner as in the organ culture.     

The ELF3 zeitnehmer regulates light signalling to the circadian clock

The circadian system regulates 24-hour biological rhythms and seasonal rhythms, such as flowering. Long-day flowering plants like Arabidopsis thaliana, measure day length with a rhythm that is not reset at lights-off, whereas short-day plants measure night length on the basis of circadian rhythm of light sensitivity that is set from dusk, early flowering 3 (elf3) mutants of Arabidopsis are aphotoperiodic and exhibit light-conditional arrhythmias. Here we show that the elf3-7 mutant retains oscillator function in the light but blunts circadian gating of CAB gene activation, indicating that deregulated phototransduction may mask rhythmicity. Furthermore, elf3 mutations confer the resetting pattern of short-day photoperiodism, indicating that gating of phototransduction may control resetting. Temperature entrainment can bypass the requirement for normal ELF3 function for the oscillator and partially restore rhythmic CAB expression. Therefore, ELF3 specifically affects light input to the oscillator, similar to its function in gating CAB activation, allowing oscillator progression past a light-sensitive phase in the subjective evening. ELF3 provides experimental demonstration of the zeitnehmer ('time-taker') concept.     

Keeping time with the human genome

The cloning and characterization of 'clock gene' families has advanced our understanding of the molecular control of the mammalian circadian clock. We have analysed the human genome for additional relatives, and identified new candidate genes that may expand our knowledge of the molecular workings of the circadian clock. This knowledge could lead to the development of therapies for treating jet lag and sleep disorders, and add to our understanding of the genetic contribution of clock gene alterations to sleep and neuropsychiatric disorders. The human genome will also aid in the identification of output genes that ultimately control circadian behaviours.     

生物钟的研究、功能和机理——2017年度诺贝尔生理学或医学奖成果简析

 生物日节律（circadian rhythm）也叫昼夜节律,是以约昼夜24 h为周期的、在生命体中普遍存在的节律性生理生化和行为活动,是众多生物节律或生物钟的一种。美国的3位科学家杰弗理·霍尔（Jeffrey C.Hall）、迈克尔·罗斯巴什（Michael Ros-bash）和迈克尔·杨（Michael W.Young）因发现调节生物日节律行为的基因并阐明其作用原理获得了2017年的诺贝尔生理学或医学奖。这项工作揭示了一个普遍存在的基本生命现象的分子机理,对了解生命的运行原理以及生命在演化过程中与环境之间的相互作用有着重要的意义,同时也为治疗由于生物钟失常而导致的人类疾病和开发调控生物钟元件的药物奠定了基础。本文介绍生物节律的研究历史,解读生物节律的分子机理,展望生物节律研究的方向,并探讨其对人类健康和农业的意义。     

Diurnal modulation of pacemaker potentials and calcium current in the mammalian circadian clock

The central biological clock of the mammalian brain is located in the suprachiasmatic nucleus. This hypothalamic region contains neurons that generate a circadian rhythm on a single-cell basis. Clock cells transmit their circadian timing signals to other brain areas by diurnal modulation of their spontaneous firing rate. The intracellular mechanism underlying rhythm generation is thought to consist of one or more self-regulating molecular loops, but it is unknown how these loops interact with the plasma membrane to modulate the ionic conductances that regulate firing behaviour. Here we demonstrate a diurnal modulation of Ca2+ current in suprachiasmatic neurons. This current strongly contributes to the generation of spontaneous oscillations in membrane potential, which occur selectively during daytime and are tightly coupled to spike generation. Thus, day-night modulation of Ca2+ current is a central step in transducing the intracellular cycling of molecular clocks to the rhythm in spontaneous firing rate.