The central control and ontogeny of circadian rhythmicity

The field of Chronobiology, the study of the rhythms in plants and animals, was restricted to botanists for centuries. Only recently during the last decades research could be broadened to include animals and later even human beings. Rhythms have been documented and related to the alternation of day and night and to the succession of the seasons. Nowadays chronobiology has developed into a multidisciplinary field in which scientists are involved in basic research as well as in applied topics. This paper gives an introduction to the field, especially dealing with the aspect of rhythm development and the way in which the different 24 hour rhythms in children become apparent.     

Chronobiology in mental retardation research: progress and prospects.

The premise of this review is that chronobiology, the science of biologic time structure and rhythms, is important in investigations concerning the etiology, mechanisms and effects of deficient mental adaptive development. Chronobiology is also shown to have potential importance in therapeutics and rehabilitation. Most of the information available now and supporting this wide-spread relevance of chronobiology relates to circadian rhythms, but physiological and behavioral rhythms having other cycle lengths also contribute. Recent findings in seven topic areas of chronobiology are reviewed with emphasis on facts and relationships actually or potentially important for consideration in mental retardation research. These are: 1) development of sleep and EEG patterns; 2) rhythmic susceptibility to seizures; 3) adrenocortical and dependent rhythms; 4) circadian rhythms in amino acids and biogenic amines; 5) rhythmic behaviors; 6) circadian rhythms in susceptibility and responses to drugs; and 7) circadian rhythms in human perception and performance.     

时间生物学—2017年诺贝尔生理或医学奖解读

时间生物学主要研究生物节律的产生及生物钟的运行机制,2017年诺贝尔生理或医学奖的颁布再次引发人们对该领域诸多科学问题的高度关注。生物钟与日月运行引起的环境信号周期性保持同步,有利于生物节律的相位和组织稳态的精确维持。本文介绍了生物节律现象的早期研究及随后生物钟理论体系建立的发展简史,并结合2017年诺贝尔生理或医学奖的解读阐述了果蝇生物钟基因的发现与分子调控机理,进而简单归纳当前时间生物学领域的前沿科学问题,阐明生物钟研究的意义。     

International Society of Chronobiology: Membership Information

The International Society for Chronobiology has as its aims, furthering the study of temporal changes in living matter, including biological rhythms in development and ageing in individuals and populations; studying and defining the mechanisms of temporal changes; fostering practical applications for chronobiological findings to mankind in basic and applied biology, physiology, work hygiene and the medical sciences; promoting education in and wide understanding of chronobiology; and furthering contact between scientists in the field and providing a forum for practitioners of chronobiology.     

International Society of Chronobiology: Membership Information

The International Society for Chronobiology has as its aims, furthering the study of temporal changes in living matter, including biological rhythms in development and ageing in individuals and populations; studying and defining the mechanisms of temporal changes; fostering practical applications for chronobiological findings to mankind in basic and applied biology, physiology, work hygiene and the medical sciences; promoting education in and wide understanding of chronobiology; and furthering contact between scientists in the field and providing a forum for practitioners of chronobiology.     

褪黑素及其在昆虫学研究中的展望

褪黑素是一种与光周期相关的内源激素。它在生物界分布广泛,并在复杂而漫长的生物进化过程中作为一种多功能分子保留至今。褪黑素在生物体内起着调节时间节律、免疫和抗氧化等作用,从而可使生物机体保持内环境稳定,更好地适应环境。开展昆虫褪黑素与昆虫行为发育关系的研究,尤其是分子生物学方面的研究,对进一步揭示褪黑素的生理功能具有重要的意义。作者根据近年来的相关研究及进展进行了综述。     

Aquaporins and biological rhythm

Aquaporins are membrane-intrinsic proteins that facilitate membrane transport of water and small solutes or even gases. Aquaporin genes are found in almost all living organisms. In plants the proteins account for water uptake and transport as well as CO₂ availability for photosynthesis. These processes are subjected to diurnal or circadian regimes. Expression and even function of aquaporins also follows day - night rhythms. Significance of aquaporin function in chronobiology has been provided by recent publications, which are summarised here. Examples of the significance of aquaporins in processes related to chronobiology are given for root water transport and leaf movement in several plant species.     

Circadian patterns of basic emotional reactivity and stress related events revisited in mice treated with lithium: behavioral rhythmometric analyses

This research dealt with rhythmometric methods for estimating and comparing the main temporal parameters characterizing the circadian structure of behavioral events in mice with and without lithium treatment. Such comparative chronobiologic studies would tend to demonstrate in psychophysiology that this drug does not displace the circadian patterns of basic emotionality, but does displace some behavioral circadian rhythms associated with more corticalized integrations. The present behavioral observations would tend to support the hypothesis that lithium salts modify the circadian structure of emotionality by cortical modulation rather than only by physiological subcortical integrations. Such circadian studies show also that behavioral chronobiology raises some working hypotheses in comparative ethology and permits the development of new heuristic concepts in the field of biological psychiatry.     

Chronobiology of the mammalian response to ionizing radiation. Potential applications in oncology

Ionizing radiation from all sources under appropriate conditions leads to cell death and tissue damage. It is used in cancer treatment under the assumption of a higher radiosensitivity of the fast dividing tumor cells as compared with adjacent host tissues. The radiosensitivities of proliferating host tissues like bone marrow and gastrointestinal lining epithelium are dose limiting. Since these host tissues and many tumors show circadian and other periodicities in their cell proliferation, the timing of radiation treatment according to host and/or tumor rhythms is expected to improve the toxic/therapeutic ratio of the treatment. The experimental data on the chronobiology of radiation exposure show circadian rhythmicity in radiation response after whole body irradiation in mice and rats with highest toxicity in light-dark 12h:12h synchronized animals during their daily activity span. Bone marrow toxicity as well as gastrointestinal epithelial damage show circadian rhythms in part due to radiation damage to the stem cells involved and especially in the intestine also due to damage to the microvasculature. Chronoradiotherapy of malignant tumors seems promising, alone or in combination with response modifiers, provided the host and potential tumor rhythms can be monitored.     

Relationship Between Orcadian Changes in Renal Hemodynamics and Circadian Changes in Urinary Glycosaminoglycan Excretion in Normal Rats

Circadian changes in renal hemodynamics and urinary glycosaminogly-can (GAG) excretion were studied in normal Sprague-Dawley rats to further investigate rhythms in kidney function. Urinary water, protein, and GAG excretion, as well as glomerular filtration rate (GFR) and renal plasma flow (RPF), were determined every 4h over the 24h cycle in an attempt to characterize any temporal changes. Urinary flow rate and proteinuria peaked during the dark activity period of the animals, consistently at the same hour, whereas the lowest values were detected during the resting phase. GAG are mucopolysaccharides entering the constitution of the glomerular basement membrane (GBM), which is the key component in the process of glomerular filtration. Similarly, the urinary excretion rate of GAG showed a circadian rhythmicity in phase with urinary water and protein excretion, with markedly increased values observed during the nocturnal phase of the animals. Moreover, GFR and RPF were demonstrated to exhibit large circadian variations in phase with renal excretory rhythmicity, showing nighttime values significantly greater compared to daytime ones. Strong correlations were found between GFR and RPF rhythms, as well as between GAG and GFR, and GAG and RPF rhythms, although the latter were not statistically significant. This pattern suggests that the circadian rhythmicity in urinary excretion rate of GAG in physiological conditions could presumably be secondary to the temporal changes in renal hemodynamics. In this respect, knowledge of renal chronobiology helpfully contributes to increase our understanding of renal physiology.     

Clinical Chronobiology and Chronotherapeutics with Applications to Asthma

The concept of homeostasis (i.e., constancy of the milieu interne) has long dominated the teaching and practice of medicine. Concepts and findings from chronobiology, the scientific study of biological rhythms, challenge this construct. Biological processes and functions are not at all constant; rather, they are organized in time as rhythms with period lengths that range in duration from as short as a second or less to as long as a year. It is the body's circadian (24h) rhythms that have been researched most intensely. The peak and trough of these rhythms are ordered rather precisely in time to support the biological requirements of activity during the day and sleep at night. The timing of the peak and trough plus the magnitude of variation (amplitude) of physiological and biochemical functions during the 24h give rise to predictable-in-time, day-night patterns in the manifestation and exacerbation of many common medical conditions. Circadian rhythms also can influence the response of patients to diagnostic tests and therapeutic interventions according to their timing with reference to body rhythms. Rhythms in the pathophysiology of medical conditions and patient tolerance to medications constitute the basis for chronotherapeutics, the timing of treatment in relation to biological rhythm determinants as a means of optimizing beneficial effects and safety. The article discusses recent advances in medical chronobiology and chronotherapeutics and their relevance to clinical medicine in general and the management of asthma in particular. Indeed, since asthma is a disease that exhibits rather profound circadian rhythmicity, investigation of its pathophysiology and therapy necessitates a chronobiologic approach.     

Clinical Chronobiology and Chronotherapeutics with Applications to Asthma

The concept of homeostasis (i.e., constancy of the milieu interne) has long dominated the teaching and practice of medicine. Concepts and findings from chronobiology, the scientific study of biological rhythms, challenge this construct. Biological processes and functions are not at all constant; rather, they are organized in time as rhythms with period lengths that range in duration from as short as a second or less to as long as a year. It is the body's circadian (24h) rhythms that have been researched most intensely. The peak and trough of these rhythms are ordered rather precisely in time to support the biological requirements of activity during the day and sleep at night. The timing of the peak and trough plus the magnitude of variation (amplitude) of physiological and biochemical functions during the 24h give rise to predictable-in-time, day-night patterns in the manifestation and exacerbation of many common medical conditions. Circadian rhythms also can influence the response of patients to diagnostic tests and therapeutic interventions according to their timing with reference to body rhythms. Rhythms in the pathophysiology of medical conditions and patient tolerance to medications constitute the basis for chronotherapeutics, the timing of treatment in relation to biological rhythm determinants as a means of optimizing beneficial effects and safety. The article discusses recent advances in medical chronobiology and chronotherapeutics and their relevance to clinical medicine in general and the management of asthma in particular. Indeed, since asthma is a disease that exhibits rather profound circadian rhythmicity, investigation of its pathophysiology and therapy necessitates a chronobiologic approach.     

Biologic rhythms derived from Siberian mammoths' hairs

Hair is preserved for millennia in permafrost; it enshrines a record of biologic rhythms and offers a glimpse at chronobiology as it was in extinct animals. Here we compare biologic rhythms gleaned from mammoth's hairs with those of modern human hair. Four mammoths' hairs came from varying locations in Siberia 4600 km, four time zones, apart ranging in age between 18,000 and 20,000 years before present. We used two contemporaneous human hairs for comparison. Power spectra derived from hydrogen isotope ratios along the length of the hairs gave insight into biologic rhythms, which were different in the mammoths depending on location and differed from humans. Hair growth for mammoths was ～31 cms/year and ～16 cms/year for humans. Recurrent annual rhythms of slow and fast growth varying from 3.4 weeks/cycles to 8.7 weeks/cycles for slow periods and 1.2 weeks/cycles to 2.2 weeks/cycles for fast periods were identified in mammoth's hairs. The mineral content of mammoth's hairs was measured by electron microprobe analysis (k-ratios), which showed no differences in sulfur amongst the mammoth hairs but significantly more iron then in human hair. The fractal nature of the data derived from the hairs became evident in Mandelbrot sets derived from hydrogen isotope ratios, mineral content and geographic location. Confocal microscopy and scanning electron microscopy showed varied degrees of preservation of the cuticle largely independent of age but not location of the specimens. X-ray fluorescence microprobe and fluorescence computed micro-tomography analyses allowed evaluation of metal distribution and visualization of hollow tubes in the mammoth's hairs. Seasonal variations in iron and copper content combined with spectral analyses gave insights into variation in food intake of the animals. Biologic rhythms gleaned from power spectral plots obtained by modern methods revealed life style and behavior of extinct mega-fauna.     

The birth of chronobiology: Julien Joseph Virey 1814

Julien-Joseph Virey (1775-1846) held the position of pharmacist-in-chief at the Val-de-Grace, a military hospital. He was an innovative pharmacist, naturalist, anthropologist, and philosopher and a prolific author. His writings encompassed a wide range of topics, although many of his ideas were sometimes harshly questioned. Interest in Virey's work today stems from renewed appreciation of his doctoral thesis in medicine, which was completed in 1814 in Paris and was the first devoted to biological rhythms. Virey envisioned biological rhythms to be innate in origin and controlled by living clocks entrained by periodic environmental changes, such as the day-night alternation in light and darkness. He also reported that the effects of drugs vary according to their administration time. But, above all, he collected and published quantified time series that demonstrated human circadian and annual mortality rhythms. Statistical analysis of Virey's data using modern time series methods confirms his deduction that human mortality exhibits rhythmicity. Comparison of his findings with those derived from analyses of more recent human mortality time series shows the characteristics of these rhythms have changed little since 1807 despite differences in environmental conditions. Virey deserves credit for establishing the field of chronobiology based on his insights and writings.     

Chlamydomonas reinhardtii as a unicellular model for circadian rhythm analysis

Chlamydomonas reinhardtii has been used as an experimental model organism for circadian rhythm research for more than 30 yr. Some of the physiological rhythms of this alga are well established, and several clock mutants have been isolated. The cloning of clock genes from these mutant strains by positional cloning is under way and should give new insights into the mechanism of the circadian clock. In a spectacular space experiment, the question of the existence of an endogenous clock vs. an exogenous mechanism has been studied in this organism. With the emergence of molecular analysis of circadian rhythms in plants in 1985, a circadian gene expression pattern of several nuclear and chloroplast genes was detected. Evidence is now accumulating that shows circadian control at the translational level. In addition, the gating of the cell cycle by the circadian clock has been analyzed. This review focuses on the different aspects of circadian rhythm research in C. reinhardtii over the past 30 yr. The suitability of Chlamydomonas as a model system in chronobiology research and the adaptive significance of the observed rhythms will be discussed.     

Chlamydomonas reinhardtii as a unicellular model for circadian rhythm analysis

Chlamydomonas reinhardtii has been used as an experimental model organism for circadian rhythm research for more than 30 yr. Some of the physiological rhythms of this alga are well established, and several clock mutants have been isolated. The cloning of clock genes from these mutant strains by positional cloning is under way and should give new insights into the mechanism of the circadian clock. In a spectacular space experiment, the question of the existence of an endogenous clock vs. an exogenous mechanism has been studied in this organism. With the emergence of molecular analysis of circadian rhythms in plants in 1985, a circadian gene expression pattern of several nuclear and chloroplast genes was detected. Evidence is now accumulating that shows circadian control at the translational level. In addition, the gating of the cell cycle by the circadian clock has been analyzed. This review focuses on the different aspects of circadian rhythm research in C. reinhardtii over the past 30 yr. The suitability of Chlamydomonas as a model system in chronobiology research and the adaptive significance of the observed rhythms will be discussed.     

A new ImageJ plug-in "ActogramJ" for chronobiological analyses

While the rapid development of personal computers and high-throughput recording systems for circadian rhythms allow chronobiologists to produce huge amounts of data, the software to analyze them often lags behind. Here, we announce newly developed chronobiology software that is easy to use, compatible with many different systems, and freely available. Our system can perform the most frequently used analyses: actogram drawing, periodogram analysis, and waveform analysis. The software is distributed as a pure Java plug-in for ImageJ and so works on the 3 main operating systems: Linux, Macintosh, and Windows. We believe that this free software raises the speed of data analyses and makes studying chronobiology accessible to newcomers.     

Circadian Pattern of Wheel‐Running Activity of a South American Subterranean Rodent (Ctenomys cf knightii)

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°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.     

EFFECTS OF LIGHT AND MELATONIN TREATMENT ON BODY TEMPERATURE AND MELATONIN SECRETION DAILY RHYTHMS IN A DIURNAL RODENT,THE FAT SAND RAT

Many mammals display predictable daily rhythmicity in both neuroendocrine function and behavior. The basic rest-activity cycles are usually consistent for a given species and vary from night-active (nocturnal), those mostly active at dawn and dusk (i.e., crepuscular), and to day-active (diurnal) species. A number of daily rhythms are oppositely phased with respect to the light/dark (LD) cycle in diurnal compared with nocturnal mammals, whereas others are equally phased with respect to the LD cycle, regardless of diurnality/nocturnality. Pineal produced melatonin (MLT) perfectly matches this phase-locked feature in that its production and secretion always occurs during the night in both diurnal and nocturnal mammals. As most rodents studied to date in the field of chronobiology are nocturnal, the aim in this study was to evaluate the effect of light manipulations and different photoperiods on a diurnal rodent, the fat sand rat, Psammomys obesus. The authors studied its daily rhythms of body temperature (T_b) and 6-sulphatoxymelatonin (6-SMT) under various photoperiodic regimes and light manipulations (acute and chronic exposures) while maintaining a constant ambient temperature of 30°C?±?1°C. The following protocols were used: (A) Control (CON) conditions 12L:12D; (A1) exposure to one light interference (LI) of CON-acclimated individuals for 30?min, 5?h after lights-off; (A2) short photoperiod (SP) acclimation (8L:16D) for 3 wks; (A3) 3 wks of SP acclimation with chronic LI of 15?min, three times a night at 4-h intervals; (A4) chronic exposure to constant dim blue light (470nm, 30 lux) for 24?h for 3 wks (LL). (B) The response to exogenous MLT administration, provided in drinking water, was measured under the following protocols: (B1) After chronic exposure to SP with LI, MLT was provided once, starting 1?h before the end of photophase; (B2) after a continuous exposure to dim blue light, MLT was provided at 15:00?h for 2?h for 2 wks; (B3) to CON animals, MLT was given intraperitoneally (i.p.) at 14:00?h. The results demonstrate that under CON acclimation, Psammomys obesus has robust T_b and 6-SMT daily rhythms in which the acrophase (peak time) of T_b is during the photophase, whereas that of 6-SMT is during scotophase. LI resulted in an elevation of T_b and a reduction of 6-SMT levels. A significant difference in the response was noted between acute and chronic exposure to LI, particularly in 6-SMT levels, which were lower than CON after LI and higher after chronic LI, implying an acclimation process. Constant exposure to blue light abolished T_b and 6-SMT rhythms in all the animals. MLT administration resumed the T_b daily rhythm in these animals, and had a recovery effect on the chronic LI-exposed animals, resulting in a T_b decrease. Altogether, the authors show in this study the different modifications of T_b rhythms and MLT levels in response to environmental light manipulations. These series of experiments may serve as a basis for establishing P. obesus as an animal model for further studies in chronobiology. (Author correspondence: hagitsc@research.haifa.ac.il)     

The social role of Chronobiology

Biological rhythms are currently subject of an increasing interest in the society, especially for its incidence on the health and nowadays they are present in many communication media. The popularization of these topics makes necessary a general training in chronobiology that could take place at all levels of education. Moreover, the timetables in today’s societies are also a matter of debate for its repercussion in the human circadian clock, since they may alter people’s life and health. Here we analyse the need for training on Chronobiology in the society and the different levels in which it could be achieved. Moreover, we analyse several circumstances of time management in the society, which may influence individual’s circadian rhythms. Apart from researching, chronobiologists are also responsible for spreading the scientific basis of the circadian rhythms in the society.