Biological Rhythms (original) (raw)
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J Biol Rhythms-2012-Casiraghi-59-69 PDF
We studied locomotor activity rhythms of C57/Bl6 mice under a chronic jet lag (CJL) protocol (ChrA 6/2 ), which consisted of 6-hour phase advances of the light-dark schedule (LD) every 2 days. Through periodogram analysis, we found 2 components of the activity rhythm: a short-period component (21.01 ± 0.04 h) that was entrained by the LD schedule and a long-period component (24.68 ± 0.26 h). We developed a mathematical model comprising 2 coupled circadian oscillators that was tested experimentally with different CJL schedules. Our simulations suggested that under CJL, the system behaves as if it were under a zeitgeber with a period determined by (24 -[phase shift size/days between shifts]). Desynchronization within the system arises according to whether this effective zeitgeber is inside or outside the range of entrainment of the oscillators. In this sense, ChrA 6/2 is interpreted as a (24 -6/2 = 21 h) zeitgeber, and simulations predicted the behavior of mice under other CJL schedules with an effective 21-hour zeitgeber. Animals studied under an asymmetric T = 21 h zeitgeber (carried out by a 3-hour shortening of every dark phase) showed 2 activity components as observed under ChrA 6/2 : an entrained short-period (21.01 ± 0.03 h) and a long-period component (23.93 ± 0.31 h). Internal desynchronization was lost when mice were subjected to 9-hour advances every 3 days, a possibility also contemplated by the simulations. Simulations also predicted that desynchronization should be less prevalent under delaying than under advancing CJL. Indeed, most mice subjected to 6-hour delay shifts every 2 days (an effective 27-hour zeitgeber) displayed a single entrained activity component (26.92 ± 0.11 h). Our results demonstrate that the disruption provoked by CJL schedules is not dependent on the phase-shift magnitude or the frequency of the shifts separately but on the combination of both, through its ratio and additionally on their absolute values. In this study, we present a novel model of forced desynchronization in mice under a specific CJL schedule; in addition, our model provides theoretical tools for the evaluation of circadian disruption under CJL conditions that are currently used in circadian research.
Proceedings of the National Academy of Sciences, 2005
Oscillations are found throughout the physical and biological worlds. Their interactions can result in a systematic process of synchronization called entrainment, which is distinct from a simple stimulus-response pattern. Oscillators respond to stimuli at some times in their cycle and may not respond at others. Oscillators can also be driven if the stimulus is strong (or if the oscillator is weak); i.e., they restart their cycle every time they receive a stimulus. Stimuli can also directly affect rhythms without entraining the underlying oscillator (masking): Drivenness and masking are often difficult to distinguish. Here we use the circadian biological clock to explore properties of entrainment. We confirm previous results showing that the residual circadian system in Neurospora can be entrained in a mutant of the clock gene frequency (frq 9 , a strain deficient in producing a functional FRQ protein). This finding has implications for understanding the evolution of circadian programs. By comparing data sets from independent studies, we develop a template for analyzing, modeling, and dissecting the interactions of entrained and masked components. These insights can be applied to oscillators of all periodicities.
From biological clock to biological rhythms
Genome biology, 2000
The genetic and molecular analysis of circadian timekeeping mechanisms has accelerated as a result of the increasing volume of genomic markers and nucleotide sequence information. Completion of whole genome sequences and the use of differential gene expression technology will hasten the discovery of the clock output pathways that control diverse rhythmic phenomena.
1999
The biological clock Under natural conditions, all eukaryotic and some prokaryotic organisms express daily rhythms in behavior, physiology and biochemistry-parallel in their length to the solar day. These circadian rhythms are generated by an endogenous clock that exhibit free-running behavior under constant environmental conditions, with a period close to, but rarely exactly, 24 hours. Circadian rhythms are a fundamental organizing feature of organisms with properties that are unique and widely conserved: they are self-sustaining, cell autonomous and involve oscillating gene expression (1-3). Clock mechanism models: the unsolved problem Transcriptional models, based on molecular and genetic analysis, that focus on autoregulatory gene expression oscillation, are the dominant theories for clock mechanism in the circadian rhythm field today (4-9). Enormous progress has been achieved, mainly in the study of circadian gene expression and protein levels of per and tim in Drosophila melanogaster; and in the study of frq, wc-1 and wc-2 genes in Neurospora (7,10-14). The clock's initial requirement to sustain a 'core-oscillator' is fulfilled by the genes' demonstrated oscillative expression (e.g. per and frq). Biochemical feedback-loop models and membrane models were also suggested to function as core oscillators (15-17). However, no single model accounts for all circadian properties: cell autonomy, environmental responsiveness and self-sustaining. Clock entrainment by time-cues is an inherent trait Time-cue sensing is a critical property of the biological clock; in fact, this ability is the foundation of clock existence. 'Knowing' what time it is in the external world provides the means for harmonic relations between the organism and its surroundings. Indeed, the ability to sense geophysical stimuli is a leading trait of the clock. Organisms are capable of responding to environmental time-cues-light-dark and temperature changes-that are
Annual Review of Physiology, 2010
Most physiology and behavior of mammalian organisms follow daily oscillations. These rhythmic processes are governed by environmental cues (e.g., fluctuations in light intensity and temperature), an internal circadian timing system, and the interaction between this timekeeping system and environmental signals. In mammals, the circadian timekeeping system has a complex architecture, composed of a central pacemaker in the brain's suprachiasmatic nuclei (SCN) and subsidiary clocks in nearly every body cell. The central clock is synchronized to geophysical time mainly via photic cues perceived by the retina and transmitted by electrical signals to SCN neurons. In turn, the SCN influences circadian physiology and behavior via neuronal and humoral cues and via the synchronization of local oscillators that are operative in the cells of most organs and tissues. Thus, some of the SCN output pathways serve as input pathways for peripheral tissues. Here we discuss knowledge acquired during the past few years on the complex structure and function of the mammalian circadian timing system. 517 Annu. Rev. Physiol. 2010.72:517-549. Downloaded from arjournals.annualreviews.org by Kanton-und Universitatsbib. -Unversity of Fribourg on 02/14/10. For personal use only. Click here for quick links to Annual Reviews content online, including: • Other articles in this volume • Top cited articles • Top downloaded articles • Our comprehensive search Further ANNUAL REVIEWS SCN: suprachiasmatic nucleus Suprachiasmatic Nuclei: Master Clock or Master Synchronizer? Initially, circadian rhythms were seen as a diffuse time-measuring capacity of the organism as a whole, until Pittendrigh (2) developed the 518 Dibner · Schibler · Albrecht Annu. Rev. Physiol. 2010.72:517-549. Downloaded from arjournals.annualreviews.org by Kanton-und Universitatsbib. -Unversity of Fribourg on 02/14/10. For personal use only. www.annualreviews.org • Central and Peripheral Clocks 519 Annu. Rev. Physiol. 2010.72:517-549. Downloaded from arjournals.annualreviews.org by Kanton-und Universitatsbib. -Unversity of Fribourg on 02/14/10. For personal use only. 520 Dibner · Schibler · Albrecht Annu. Rev. Physiol. 2010.72:517-549. Downloaded from arjournals.annualreviews.org by Kanton-und Universitatsbib. -Unversity of Fribourg on 02/14/10. For personal use only. www.annualreviews.org • Central and Peripheral Clocks 521 Annu. Rev. Physiol. 2010.72:517-549. Downloaded from arjournals.annualreviews.org by Kanton-und Universitatsbib. -Unversity of Fribourg on 02/14/10. For personal use only. 522 Dibner · Schibler · Albrecht Annu. Rev. Physiol. 2010.72:517-549. Downloaded from arjournals.annualreviews.org by Kanton-und Universitatsbib. -Unversity of Fribourg on 02/14/10. For personal use only. 534 Dibner · Schibler · Albrecht Annu. Rev. Physiol. 2010.72:517-549. Downloaded from arjournals.annualreviews.org by Kanton-und Universitatsbib. -Unversity of Fribourg on 02/14/10. For personal use only.
Current Biology, 2008
With our growing awareness of the complexity underlying biological phenomena, our need for computational models becomes increasingly apparent. Due to their properties, biological clocks have always lent themselves to computational modelling. Their capacity to oscillate without dampening -even when deprived of all rhythmic environmental information -required the hypothesis of an endogenous oscillator. The notion of a 'clock' provided a conceptual model of this system well before the dynamics of circadian oscillators were probed by computational modelling. With growing insight into the molecular basis of circadian rhythmicity, computational models became more concrete and quantitative. Here, we review the history of modelling circadian oscillators and establish a taxonomy of the modelling world to put the large body of circadian modelling literature into context. Finally, we assess the predictive power of circadian modelling and its success in creating new hypotheses.
Circadian rhythms from multiple oscillators: lessons from diverse organisms
Nature Reviews Genetics, 2005
| The organization of biological activities into daily cycles is universal in organisms as diverse as cyanobacteria, fungi, algae, plants, flies, birds and man. Comparisons of circadian clocks in unicellular and multicellular organisms using molecular genetics and genomics have provided new insights into the mechanisms and complexity of clock systems. Whereas unicellular organisms require stand-alone clocks that can generate 24-hour rhythms for diverse processes, organisms with differentiated tissues can partition clock function to generate and coordinate different rhythms. In both cases, the temporal coordination of a multi-oscillator system is essential for producing robust circadian rhythms of gene expression and biological activity.
Synchronize Your Biological Rhythm
Current Trends in diagnosis & Treatment
Synchronize Your Biological Rhythm "Rhythm is sound in motion. It is related to the pulse, the heartbeat, the way we breathe. It rises and falls. It takes us into ourselves; it takes us out of ourselves." Edward Hirsch We all have an internal biological clock that coordinates our circadian rhythm. It operates on a roughly 24 hrs cycle and is calibrated by the appearance and disappearance of natural light. Sunlight teaches the master clock in the brain to keep on track. The rotation of our planet around its central axis creates daily rhythm in environment factors, light intensity, temperature and availability of food. Organisms adapt to the changes present in their environment to enhance their survival. Most of the living organisms, including humans have evolved a biological clock that can anticipate and adapt these 24 hrs changes in the environment. This internal clock in humans resides in the suprachiasmatic nucleus (SCN) in the ventral hypothalamus. 1 Besides light, exercise, hormones and medications affect the SCN and setting of circadian rhythm. The SCN has around 20,000 neurons responsible for generating the rhythm. The neurons receive signals from the eye using light information projected via retinohypothalmic tract (RHT), which is then passed on to other areas of the brain. 2, 3 The nobel assembly at Karolinska Institute has awarded 2017 Nobel Prize in Physiology and Medicine jointly to Jeffrey C Hall, Michael Rosbach and Michael W Young for their discoveries of molecular mechanisms controlling the circadian rhythm. Hall and Rosbach both worked at Brandeis University in USA when they began their Nobelwinning work. Hall is presently associated with University of Maine. Michael Young is a faculty at Rockfeller University in USA. Their work explains how plants, animals and humans adapt their biological clock to synchronize with the Earth's revolutions. The Nobel laureates isolated a gene which controls the biological rhythm, using fruit flies (Drosophila) as their experimental organism. In 1984 Jeffrey C Hall and Michael Rosbach together and also Michael Young almost at the same time succeeded in isolating the period gene, they later discovered that PER-the protein coded by this gene accumulates at night and disintegrates during the day. 4, 5 The PER protein oscillate over a 24 hrs cycle in synchrony with the circadian rhythm. There is also an inhibitory feedback loop by which PER can regulate its own level throughout the day, therefore whenever PER levels increased in the cells its production decreased. 6 But the question remained as to how PER protein formed in the cytoplasm reaches the nucleus. In 1994 Michael Young discovered a second gene timeless, encoding the TIM protein required for circadian rhythm (Fig. 1). When TIM was bound to PER, the two proteins were able to enter the nucleus where they blocked period gene activity to close the inhibitory feedback loop. 7 These two proteins accumulate in the cytoplasm, but move into the nucleus of the cells if co-expressed. Regulation of cytoplasmic localization domains activity by assembly of PER/ TIM complex is seen to be a key determinant of period length. 8
Elucidating the Ticking of an In Vitro Circadian Clockwork
PLOS Biology, 2007
A biochemical oscillator can be reconstituted in vitro with three purified proteins, that displays the salient properties of circadian (daily) rhythms, including self-sustained 24-h periodicity that is temperature compensated. We analyze the biochemical basis of this oscillator by quantifying the time-dependent interactions of the three proteins (KaiA, KaiB, and KaiC) by electron microscopy and native gel electrophoresis to elucidate the timing of the formation of complexes among the Kai proteins. The data are used to derive a dynamic model for the in vitro oscillator that accurately reproduces the rhythms of KaiABC complexes and of KaiC phosphorylation, and is consistent with biophysical observations of individual Kai protein interactions. We use fluorescence resonance energy transfer (FRET) to confirm that monomer exchange among KaiC hexamers occurs. The model demonstrates that the function of this monomer exchange may be to maintain synchrony among the KaiC hexamers in the reaction, thereby sustaining a highamplitude oscillation. Finally, we apply the first perturbation analyses of an in vitro oscillator by using temperature pulses to reset the phase of the KaiABC oscillator, thereby testing the resetting characteristics of this unique circadian oscillator. This study analyzes a circadian clockwork to an unprecedented level of molecular detail.