Synchronization Of Circadian Oscillators Research Articles

Jet Lag Recovery: Synchronization of Circadian Oscillators as a Mean Field Game

A mean field game is proposed for the synchronization of oscillators facing conflicting objectives. Our motivation is to offer an alternative to recent attempts to use dynamical systems to illustrate some of the idiosyncrasies of jet lag recovery. Our analysis is driven by two goals: (1) to understand the long time behavior of the oscillators when an individual remains in the same time zone, and (2) to quantify the costs from jet lag recovery when the individual has traveled across time zones. Finite difference schemes are used to find numerical approximations to the mean field game solutions. They are benchmarked against explicit solutions derived for a special case. Numerical results are presented and conjectures are formulated. The numerics suggest that the cost the oscillators accrue while recovering is larger for eastward travel which is consistent with the widely admitted wisdom that jet lag is worse after traveling east than west.

Abstract B34: Investigating disruptions in the circadian clock in cancer cells

Abstract The circadian clock is man's internal time-keeping mechanism; it synchronizes human physiology with the external cycle of day and night. At the molecular level, all cells display a circadian clock driven by core clock proteins that constitute transcription-translation feedback loops, generating oscillating patterns of circadian clock gene expression over time. It is becoming increasingly apparent that disruptions in the circadian clock may contribute to cancer development. This study aimed to investigate the molecular components of the circadian clock in two cancer types prevalent in South Africa: cervical and oesophageal cancer. To our knowledge the circadian clock has not previously been investigated in these cancer types. Microarray and real-time RT-PCR analyses revealed significantly decreased expression of Period 2 (Per2) mRNA in cervical and oesophageal cancer patient tissue compared to normal tissue. Cervical and oesophageal cancer cell lines similarly displayed significantly reduced mRNA and protein levels of certain circadian clock genes, including positive and negative regulators of the circadian clock. Nuclear transport of circadian clock proteins was investigated, since cancer cells display increased nuclear transport rates and circadian clock proteins rely on nucleocytoplasmic shuttling to maintain the correct pace of the circadian clock. Fluorescence recovery after photobleaching (FRAP) analysis was performed and revealed increased nuclear import rates of Bmal1 in cancer compared to normal cells. Altered expression and nuclear import rates of circadian clock proteins in cancer cells suggest these cells might harbor an impaired circadian clock. Luminescence assays are thus currently being employed to determine whether cancer cells display rhythmic expression of core clock genes, as an indication of a functioning circadian clock. A real-time bioluminescence imager is being used to measure Bmal1 and Per2 promoter-luciferase activities in cancer cells over time, after synchronization of circadian oscillators with the glucocorticoid analogue, Dexamethasone. This type of study is relevant to the field of chronotherapy, where elucidating differences in circadian clock functioning in normal and cancer cells could yield better insights into the timing of administration of chemotherapy, ultimately ensuring a better patient response. Citation Format: Waldo Lexow, Sian-Ailin Da Silva, Virna D. Leaner, Pauline J. van der Watt. Investigating disruptions in the circadian clock in cancer cells [abstract]. In: Proceedings of the AACR International Conference: New Frontiers in Cancer Research; 2017 Jan 18-22; Cape Town, South Africa. Philadelphia (PA): AACR; Cancer Res 2017;77(22 Suppl):Abstract nr B34.

SYNCHRONIZATION OF CLOCKS COUPLED BY NEUROTRANSMITTER IN THE SCN

In mammals, the suprachiasmatic nucleus (SCN) of the hypothalamus is considered as the master circadian pacemaker. Each cell in the SCN contains an autonomous molecular clock, and the SCN is composed of multiple single-cell circadian oscillators. The fundamental question is how the individual cellular oscillators, expressing a wide range of periods, interact and assemble to achieve phase synchronization. In natural conditions, the interaction between the SCN neurons is non-negligible and coupling between cells in the SCN is achieved partly by neurotransmitters. Though there have been a lot of works about the synchronization of circadian oscillators coupled by neurotransmitter, most of the works are based on numerical simulation with little theoretical analysis. In this paper, from the theoretical analysis, we prove that the clocks can be synchronized by the neurotransmitter with mathematical knowledge. Our results also show that the coupling among neurons can synchronize circadian oscillators but the synchronized oscillators are not with period of 24 h, which indicates that environmental cues are necessary to entrain oscillators with period of 24 h. This work can offer theoretical basis to study circadian synchronization in a numerical or experimental way.

Spatiotemporal dynamics of circadian clock in lettuce

Abstract Plant circadian clock controls many physiological events by synchronization with environmental changes. The clock can be controlled artificially by imposing various light conditions in a closed system for plant cultivation in plant factory. The plant circadian rhythm is formed by enormous self-sustained cellular circadian oscillators, so that the synchronization of circadian oscillators is of great importance to the formation of individual circadian rhythms. Therefore, the study of synchronization phenomena is important for precise control of the circadian rhythm. In this study, we have investigated the spatiotemporal dynamics of circadian oscillators in lettuce (Lactuca sativa L.). Bioluminescence of transgenic lettuce carrying a CCA1::LUC construct as a reporter of a circadian gene expression was measured in the leaf and root. We observed phase wave propagation in the leaf with a phase delay in the region of the primary vein, with the primary vein region showing lower amplitude than the other regions. Wave propagation occurred from the edge of the leaf inward. In addition, a striped wave traveled from the base to the tip along the roots, which were grown under continuous dark or light conditions. The features observed in the lettuce plants could be explained by phase oscillator models established in the study of Arabidopsis thaliana. The results of this study show the possibility of applying circadian clock control in a model plant for plant production.

Light pulses administered during the circadian dark phase alter expression of cell cycle associated transcripts in mouse brain

The circadian mode of cell division has been known for more than a century, but the association between circadian rhythms and mitosis is not yet clear. Synchronization of circadian oscillators with the outside world is achieved because light, or other external temporal cues, have acute effects on the levels of the clock's molecular components. Thus, an important question is whether environmental signals also affect transcription levels of cell machinery genes in a similar manner? In a microarray analysis, we have tested the influence of light pulses on the expression of transcripts in the mouse brain. Light pulses consistently affect transcription levels of genes that are essential and directly control the cell cycle mechanism, as well as levels of genes that are associated with the various cell cycle checkpoints. The changes in the levels and the direction of these changes could possibly lead to cell cycle arrest. We also found consistent changes in transcription levels of genes that are associated with tumorigenesis and are directly implicated with enhanced proliferation and metastasis.

Effects of restricted feeding on circadian activity rhythms of sheep—A brief report

The purpose of the present experiment was to investigate the impact of timed restricted feeding on the behavioural circadian organization of sheep. For this purpose, total activities of sheep subjected both to 12-h light:12-h dark (12:12 LD) cycle and to periodic food-availability during the dark phase were recorded. When food was available ad libitum, sheep activity was entrained to the 12:12 LD cycle. During the restricted feeding treatment, most activity occurred in the dark. Activity in the dark was confined to the food restriction time and a food anticipatory activity was clearly present. Restricted feeding-entrained activity demonstrated the existence of both food entrainable and food anticipatory activities in sheep, a diurnal mammalian species. Our results represent the first study on the feeding entrainment of behaviour in a ruminant farm species. Furthermore, they allow to plan a deeper analysis concerning the synchronization of circadian oscillators by periodic food access in non-rodent mammals.

Light Pulse‐Induced Heme and Iron‐Associated Transcripts in Mouse Brain: A Microarray Analysis

Synchronization of circadian oscillators with the outside world is achieved by the acute effects of light on the levels of one or more clock components. In mammals the PAS transcription factors Clock, NPAS2, and BMAL1 regulate gene expression as a function of the day‐night cycle. Both PAS domains of NPAS2 were found to bind heme as a prosthetic group, form a gas‐regulated sensor, and exert heme‐status control of DNA binding in vitro. In a microarray analysis comparing overall changes in brain transcript levels between mice subjected to light pulses during the dark phase with animals maintained in darkness, we traced consistent changes in more than 200 different transcripts. Of these, 20 are associated with heme and iron biosynthesis and catabolism. A model for the pathway of induction of heme and iron homeostasis‐related transcripts resulting from light pulses suggests that light signals (as stressors) induce transcription of heme oxygenase 2 (Hmox2) and cytochrome P450 oxidoreductase (Por), which may serve as a primary line of cellular defense. HMOX2 degrades heme from proteins such as hemoglobin. This degradation generates CO, a signal molecule, and may also change the redox state of the cell by reducing the NADPH/NADP ratio. This could lead to up‐regulation of globin gene transcription, thereby releasing iron that in turn controls production of ferritins, and further up‐regulating aminolevulinate synthase 2 (Alas2).

Circadian rhythm entrainment in flies and mammals.

Circadian rhythms are a fundamental adaptation of living cells to the daily and seasonal fluctuation in light and temperature. Circadian oscillations persist in constant conditions; however, they are also phase-adjusted (entrained) by day-night cycles. It is this entrainability that provides for the proper phasing of the program, to the sequence of external changes that it has evolved to exploit. Synchronization of circadian oscillators with the outside world is achieved because light, temperature, or other external temporal cues, have acute effects on the levels of one or more of the clock's components. The consequences are ripples through the interconnected molecular loops, leading to a stable phase realignment of the endogenous rhythm generator and the external conditions. This review summarized the evolving knowledge of the different types, modes, and molecular processes of entrainment in flies and mammals.