Circadian Timing: From Genetics to Behavior (original) (raw)
The circadian cycle: daily rhythms from behaviour to genes
Embo Reports, 2005
The daily recurrence of activity and rest are so common as to seem trivial. However, they reflect a ubiquitous temporal programme called the circadian clock. In the absence of either anatomical clock structures or clock genes, the timing of sleep and wakefulness is disrupted. The complex nature of circadian behaviour is evident in the fact that phasing of the cycle
The search for circadian clock components in humans: new perspectives for association studies
Brazilian Journal of Medical and Biological Research, 2008
Individual circadian clocks entrain differently to environmental cycles (zeitgebers, e.g., light and darkness), earlier or later within the day, leading to different chronotypes. In human populations, the distribution of chronotypes forms a bell-shaped curve, with the extreme early and late types -larks and owls, respectively -at its ends. Human chronotype, which can be assessed by the timing of an individual's sleep-wake cycle, is partly influenced by genetic factors -known from animal experimentation. Here, we review population genetic studies which have used a questionnaire probing individual daily timing preference for associations with polymorphisms in clock genes. We discuss their inherent limitations and suggest an alternative approach combining a short questionnaire (Munich ChronoType Questionnaire, MCTQ), which assesses chronotype in a quantitative manner, with a genome-wide analysis (GWA). The advantages of these methods in comparison to assessing time-of-day preferences and single nucleotide polymorphism genotyping are discussed. In the future, global studies of chronotype using the MCTQ and GWA may also contribute to understanding the influence of seasons, latitude (e.g., different photoperiods), and climate on allele frequencies and chronotype distribution in different populations.
Circadian clocks, brain function, and development
Annals of the New York Academy of Sciences, 2013
Circadian clocks are temporal interfaces that organize biological systems and behavior to dynamic external environments. Components of the molecular clock are expressed throughout the brain and are centrally poised to play an important role in brain function. This paper focuses on key issues concerning the relationship among circadian clocks, brain function, and development, and discusses three topic areas: (1) sleep and its relationship to the circadian system; (2) systems development and psychopathology (spanning the prenatal period through late life); and (3) circadian factors and their application to neuropsychiatric disorders. We also explore circadian genetics and psychopathology and the selective pressures on the evolution of clocks. Last, a lively debate is presented on whether circadian factors are central to mood disorders. Emerging from research on circadian rhythms is a model of the interaction among genes, sleep, and the environment that converges on the circadian clock to influence susceptibility to developing psychopathology. This model may lend insight into effective treatments for mood disorders and inform development of new interventions.
A CLOCK Polymorphism Associated with Human Diurnal Preference
Sleep, 1998
A single nucleotide polymorphism located in the 3 flanking region of the human CLOCK gene was investigated as a predictor of diurnal preference in a population-based random sample of 410 normal adults. Morningnesseveningness preferences were determined using the 19-item Horne-Ostberg questionnaire. Subjects carrying one of the two CLOCK alleles, 3111C, had a significantly lower mean Horne-Ostberg score. The distribution of scores was clearly shifted toward eveningness for these subjects. The score difference was independent of age, sex and ethnic heritage, thus making population stratification effects unlikely to explain this difference. These subjects had a substantial 10-to 44minute delay in preferred timing for activity or sleep episodes. We suggest that the identified polymorphism or another tightly linked polymorphism within the CLOCK gene or its regulatory elements may be responsible for the finding.
Searching for Genes Underlying Behavior: Lessons from Circadian Rhythms
Science, 2008
The success of forward genetic (from phenotype to gene) approaches to uncover genes that drive the molecular mechanism of circadian clocks and control circadian behavior has been unprecedented. Links among genes, cells, neural circuits, and circadian behavior have been uncovered in the Drosophila and mammalian systems, demonstrating the feasibility of finding single genes that have major effects on behavior. Why was this approach so successful in the elucidation of circadian rhythms? This article explores the answers to this question and describes how the methods used successfully for identifying the molecular basis of circadian rhythms can be applied to other behaviors such as anxiety, addiction, and learning and memory.
Brain Research Reviews, 1993
Circadian rhythms are a ubiquitous adaptation of eukaryotic organisms to the most reliable and predictable of environmental changes, the daily cycles of light and temperature. Prominent daily rhythms in behavior, physiology, hormone levels and biochemistry &eluding gene expression) are not merely responses to these environmental cycles, however, but embody the organism's ability to keep and tell time. At the core of circadian systems is a mysterious mechanism, located in the brain (actually the suprachiasmatic nucleus of the hypothalamus) of mammals, buf present even in unicellular organisms, that functions as a clock. This clock drives circadian rhythms. It is independent of, but remains responsive to, environmental cycles (especially light). The interest in temporal regulation-its organization, mechanism and consequences-unites investigators in diverse disciplines studying otherwise disparate systems. This diversity is reflected in the brief reviews that summarize the ~~sen~a~jons at a meeting on circadian rhythms held in New York City on October 31,1992. The meeting was sponsored by the Fandation pour I'Etude du Systime Nerveux (FESN) and followed a larger meeting heId 18 manths eartier in Geneva, whose proceedings have been published (M. Katz (Ed,), Report of the Ninth FESN Study Group on 'Circadian Rhythms', Disc~&~~ in Newosc&ceJ Vd KY& Mm.
Life between Clocks: Daily Temporal Patterns of Human Chronotypes
Human behavior shows large interindividual variation in temporal organization. Extreme "larks" wake up when extreme "owls" fall asleep. These chronotypes are attributed to differences in the circadian clock, and in animals, the genetic basis of similar phenotypic differences is well established. To better understand the genetic basis of temporal organization in humans, the authors developed a questionnaire to document individual sleep times, self-reported light exposure, and self-assessed chronotype, considering work and free days separately. This report summarizes the results of 500 questionnaires completed in a pilot study. Individual sleep times show large differences between work and free days, except for extreme early types. During the workweek, late chronotypes accumulate considerable sleep debt, for which they compensate on free days by lengthening their sleep by several hours. For all chronotypes, the amount of time spent outdoors in broad daylight significantly affects the timing of sleep: Increased self-reported light exposure advances sleep. The timing of selfselected sleep is multifactorial, including genetic disposition, sleep debt accumulated on workdays, and light exposure. Thus, accurate assessment of genetic chronotypes has to incorporate all of these parameters. The dependence of human chronotype on light, that is, on the amplitude of the light:dark signal, follows the known characteristics of circadian systems in all other experimental organisms. Our results predict that the timing of sleep has changed during industrialization and that a majority of humans are sleep deprived during the workweek. The implications are far ranging concerning learning, memory, vigilance, performance, and quality of life.
On the Adaptive Significance of Circadian Clocks for Their Owners
Chronobiology International, 2013
Circadian rhythms are believed to be an evolutionary adaptation to daily environmental cycles resulting from Earth's rotation about its axis. A trait evolved through a process of natural selection is considered as adaptation; therefore, rigorous demonstration of adaptation requires evidence suggesting evolution of a trait by natural selection. Like any other adaptive trait, circadian rhythms are believed to be advantageous to living beings through some perceived function. Circadian rhythms are thought to confer advantage to their owners through scheduling of biological functions at appropriate time of daily environmental cycle (extrinsic advantage), coordination of internal physiology (intrinsic advantage), and through their role in responses to seasonal changes. So far, the adaptive value of circadian rhythms has been tested in several studies and evidence indeed suggests that they confer advantage to their owners. In this review, we have discussed the background for development of the framework currently used to test the hypothesis of adaptive significance of circadian rhythms. Critical examination of evidence reveals that there are several lacunae in our understanding of circadian rhythms as adaptation. Although it is well known that demonstrating a given trait as adaptation (or setting the necessary criteria) is not a trivial task, here we recommend some of the basic criteria and suggest the nature of evidence required to comprehensively understand circadian rhythms as adaptation. Thus, we hope to create some awareness that may benefit future studies in this direction.
Sleep, Circadian Rhythms, and Interval Timing: Evolutionary Strategies to Time Information
Frontiers in Integrative Neuroscience, 2012
A crucial property of the brain is to integrate temporal information with accurate physiological responses . Evolution has favored biological clocks that dictate homeostatic processes (e.g., the circadian timing of sleep) and, on a smaller time-scale, timed behavioral responses (e.g., interval timing). The interplay between such time-keeping mechanisms is intriguing but biologically complex. Moreover, in biology, analogous problems can be successfully solved by multiple computations. In this article I will discuss of sleep, circadian rhythms, and interval timing by delineating several aspects that suggest a common evolutionary role in providing neurobiological mechanisms for temporal information processing.
Circadian clocks - from genes to complex behaviour
Reproduction Nutrition Development, 1999
Circadian clocks control temporal structure in practically all organisms and on all levels of biology, from gene expression to complex behaviour and cognition. Over the last decades, research has begun to unravel the physiological and, more recently, molecular mechanisms that underlie this endogenous temporal programme. The generation of circadian rhythms can be explained, at the molecular level, by a model based upon a set of genes and their products which form an autoregulating negative feedback loop. The elements contributing to this transcriptional feedback appear to be conserved from insects to mammals. Here, we summarize the process of the genetic and molecular research that led to 'closing the molecular loop'. Now that the reductionist approach has led to the description of a detailed clock model at the molecular level, further insights into the circadian system can be provided by combining the extensive knowledge gained from decades of physiological research with molecular tools, thereby reconstructing the clock within the organism and its environment. We describe experiments combining old and new tools and show that they constitute a powerful approach to understanding the mechanisms that lead to temporal structure in complex behaviour. © Inra/Elsevier, Paris
Frontiers in physiology, 2024
Urban environments, in which ambient light has become a less-reliable entrainer, are challenging for the biological clock to maintain performance. As a consequence, human circadian rhythms are less robust and more variable among individuals. Assessing the individual phase of entrainment, as well as its plastic shifts in response to disturbances of the physical and social environment, is a way to measure circadian disruption. However, this is still difficult to address in real-life scenarios in which several factors modulate the circadian phase not always in a concerted manner. In this perspective, we present the contribution of two real-life situations, in which the circadian system is challenged by important alterations in entraining signals: 1) a trip to the Antarctic summer (socioenvironmental challenge), and 2) dancers trained in morning/night shifts (socio-behavioral challenge). Both natural chronobiological experiments are helpful in exploring the functioning and plasticity of the circadian clock and allow for considering individual characteristics and history.
Journal of Circadian Rhythms, 2015
Background: Circadian rhythms play an integral role in human behavior, physiology and health. Individual differences in daily rhythms (chronotypes) can affect individual sleep-wake cycles, activity patterns and behavioral choices. Diurnal preference, the tendency towards morningness or eveningness among individuals, has been associated with interpersonal variation in circadian clock-related output measures, including body temperature, melatonin levels and clock gene mRNA in blood, oral mucosa, and dermal fibroblast cell cultures. Methods: Here we report gene expression data from two principal clock genes sampled from hair follicle cells, a peripheral circadian clock. Hair follicle cells from fourteen individuals of extreme morning or evening chronotype were sampled at three time points. RNA was extracted and quantitative PCR assays were used to measure mRNA expression patterns of two clock genes, Per3 and Nr1d2. Results: We found significant differences in clock gene expression over time between chronotype groups, independent of gender or age of participants. Extreme evening chronotypes have a delay in phase of circadian clock gene oscillation relative to extreme morning types. Variation in the molecular clockwork of chronotype groups represents nearly three-hour phase differences (Per3: 2.61 hours; Nr1d2: 3.08 hours, both: 2.86) in circadian oscillations of these clock genes. Conclusions: The measurement of gene expression from hair follicles at three time points allows for a direct, efficient method of estimating phase shifts of a peripheral circadian clock in real-life conditions. The robust phase differences in temporal expression of clock genes associated with diurnal preferences provide the framework for further studies of the molecular mechanisms and gene-by-environment interactions underlying chronotype-specific behavioral phenomena, including social jetlag.
Genetics and Molecular Biology, 2010
Several studies have shown that mutations and polymorphisms in clock genes are associated with abnormal circadian parameters in humans and also with more subtle non-pathological phenotypes like chronotypes. However, there have been conflicting results, and none of these studies analyzed the combined effects of more than one clock gene. Up to date, association studies in humans have focused on the analysis of only one clock gene per study. Since these genes encode proteins that physically interact with each other, combinations of polymorphisms in different clock genes could have a synergistic or an inhibitory effect upon circadian phenotypes. In the present study, we analyzed the combined effects of four polymorphisms in four clock genes (Per2, Per3, Clock and Bmal1) in people with extreme diurnal preferences (morning or evening). We found that a specific combination of polymorphisms in these genes is more frequent in people who have a morning preference for activity and there is a different combination in individuals with an evening preference for activity. Taken together, these results show that it is possible to detect clock gene interactions associated with human circadian phenotypes and bring an innovative idea of building a clock gene variation map that may be applied to human circadian biology.
The circadian cycle: is the whole greater than the sum of its parts?
Trends in Genetics, 2001
The term 'circadian rhythm' describes an oscillatory behavior in the absence of exogenous environmental cues, with a period of about a day. As yet, we don't fully understand which biological mechanisms join together to supply a stable and selfsustained oscillation with such a long period. By chipping away at the molecular mechanism with genetic approaches, some common features are emerging. In combining molecular analyses and physiological experiments, those features that are crucial for structuring a circadian day could be uncovered.
Epidemiology of the human circadian clock
Sleep Medicine Reviews, 2007
Humans show large inter-individual differences in organising their behaviour within the 24-h day-this is most obvious in their preferred timing of sleep and wakefulness. Sleep and wake times show a near-Gaussian distribution in a given population, with extreme early types waking up when extreme late types fall asleep. This distribution is predominantly based on differences in an individuals' circadian clock. The relationship between the circadian system and different ''chronotypes'' is formally and genetically well established in experimental studies in organisms ranging from unicells to mammals. To investigate the epidemiology of the human circadian clock, we developed a simple questionnaire (Munich ChronoType Questionnaire, MCTQ) to assess chronotype. So far, more than 55,000 people have completed the MCTQ, which has been validated with respect to the Horne-Østberg morningness-eveningness questionnaire (MEQ), objective measures of activity and rest (sleep-logs and actimetry), and physiological parameters. As a result of this large survey, we established an algorithm which optimises chronotype assessment by incorporating the information on timing of sleep and wakefulness for both work and free days. The timing and duration of sleep are generally independent. However, when the two are analysed separately for work and free days, sleep duration strongly depends on chronotype. In addition, chronotype is both age-and sex-dependent.