Noise Induces Oscillation and Synchronization of the Circadian Neurons

The principle clock of mammals, named suprachiasmatic nucleus (SCN), coordinates the circadian rhythms of behavioral and physiological activity to the external 24 h light-dark cycle. In the absence of the daily cycle, the SCN acts as an endogenous clock that regulates the ~24h rhythm of activity. Experimental and theoretical studies usually take the light-dark cycle as a main external influence, and often ignore light pollution as an external influence. However, in modern society, the light pollution such as induced by electrical lighting influences the circadian clock. In the present study, we examined the effect of external noise (light pollution) on the collective behavior of coupled circadian oscillators under constant darkness using a Goodwin model. We found that the external noise plays distinct roles in the network behavior of neurons for weak or strong coupling between the neurons. In the case of strong coupling, the noise reduces the synchronization and the period of the SCN network. Interestingly, in the case of weak coupling, the noise induces a circadian rhythm in the SCN network which is absent in noise-free condition. In addition, the noise increases the synchronization and decreases the period of the SCN network. Our findings may shed new light on the impact of the external noise on the collective behavior of SCN neurons.     

Influence of the quantity and quality of light on photosynthetic periodicity in coral endosymbiotic algae

Symbiotic corals, which are benthic organisms intimately linked with their environment, have evolved many ways to deal with fluctuations in the local marine environment. One possible coping mechanism is the endogenous circadian clock, which is characterized as free running, maintaining a ～24 h periodicity of circuits under constant stimuli or in the absence of external cues. The quantity and quality of light were found to be the most influential factors governing the endogenous clock for plants and algae. Unicellular dinoflagellate algae are among the best examples of organisms that exhibit circadian clocks using light as the dominant signal. This study is the first to examine the effects of light intensity and quality on the rhythmicity of photosynthesis in the symbiotic dinoflagellate Symbiodinium sp., both as a free-living organism and in symbiosis with the coral Stylophora pistillata. Oxygen production measurements in Symbiodinium cultures exhibited rhythmicity with a periodicity of approximately 24 h under constant high light (LL), whereas under medium and low light, the cycle time increased. Exposing Symbiodinium cultures and corals to spectral light revealed different effects of blue and red light on the photosynthetic rhythm, specifically shortening or increasing the cycle time respectively. These findings suggest that the photosynthetic rhythm is entrained by different light cues, which are wired to an endogenous circadian clock. Furthermore, we provide evidence that mRNA expression was higher under blue light for two potential cryptochrome genes and higher under red light for a phytochrome gene isolated from Symbiodinium. These results offer the first evidence of the impact of the intensity and quality of light on the photosynthetic rhythm in algal cells living freely or as part of a symbiotic association. Our results indicate the presence of a circadian oscillator in Symbiodinium governing the photosynthetic apparatus through a light-induced signaling pathway that has yet to be described.     

Intercellular coupling mechanism for synchronized and noise-resistant circadian oscillators

The circadian clock in multicellular organisms consists of multiple autonomous single-cell oscillators. These individual oscillator cells produce coherent oscillations even in the presence of internal noise associated with rhythm-generating reaction rates and in the absence of external time cues such as light and temperature. Thus, an intercellular coupling mechanism must synchronize the cells to induce coherent circadian oscillations. We propose the roles of a synchronizing factor that is secreted from individual cells during subjective day to induce light-pulse-type phase shifts in the neighboring cells or, alternatively, a factor that is secreted during subjective night to induce dark-pulse-type phase shifts. Here, we present our multicellular stochastic model of Drosophila circadian rhythms that emulates the intercellular coupling mechanism and suggest that the mechanism facilitates the constancy of the circadian rhythm with possible functional redundancy among different synchronizing factors.     

Simulation of circadian rhythm generation in the suprachiasmatic nucleus with locally coupled self-sustained oscillators

In mammals, circadian rhythms are driven by a pacemaker located in the suprachiasmatic nuclei (SCN) of the anterior hypothalamus. The firing rate of neurons within the SCN exhibits a circadian rhythm. There is evidence that individual neurons within the SCN act as circadian oscillators. Rhythm generation in the SCN was therefore modeled by a system of self-sustained oscillators. The model is composed of up to 10000 oscillatory elements arranged in a square array. Each oscillator has its own (randomly determined) intrinsic period reflecting the widely dispersed periods observed in the SCN. The model behavior was investigated mainly in the absence of synchronizing zeitgebers. Due to local coupling the oscillators synchronized and an overall rhythm emerged. This indicates that a locally coupled system is capable of integrating the output of individual clock cells with widely dispersed periods. The period of the global output (average of all oscillators) corresponded to the average of the intrinsic periods and was stable even for small amplitudes and during transients. Noise, reflecting biological fluctuations at the cellular level, distorted the global rhythm in small arrays. The period of the rhythm could be stabilized by increasing the array size, which thus increased the robustness against noise. Since different regions of the SCN have separate output pathways, the array of oscillators was subdivided into four quadrants. Sudden deviations of periodicity sometimes appeared in one quadrant, while the periods of the other quadrants were largely unaffected. This result could represent a model for splitting, which has been observed in animal experiments. In summary, the multi-oscillator model of the SCN showed a broad repertoire of dynamic patterns, revealed a stable period (even during transients) with robustness against noise, and was able to account for such a complex physiological behavior as splitting.     

Robust entrainment of circadian oscillators requires specific phase response curves

The circadian clocks keeping time in many living organisms rely on self-sustained biochemical oscillations entrained by external cues, such as light, to the 24-h cycle induced by Earth's rotation. However, environmental cues are unreliable due to the variability of habitats, weather conditions, or cue-sensing mechanisms among individuals. A tempting hypothesis is that circadian clocks have evolved so as to be robust to fluctuations in the signal that entrains them. To support this hypothesis, we analyze the synchronization behavior of weakly and periodically forced oscillators in terms of their phase response curve (PRC), which measures phase changes induced by a perturbation applied at different times of the cycle. We establish a general relationship between the robustness of key entrainment properties, such as stability and oscillator phase, on the one hand, and the shape of the PRC as characterized by a specific curvature or the existence of a dead zone, on the other hand. The criteria obtained are applied to computational models of circadian clocks and account for the disparate robustness properties of various forcing schemes. Finally, the analysis of PRCs measured experimentally in several organisms strongly suggests a case of convergent evolution toward an optimal strategy for maintaining a clock that is accurate and robust to environmental fluctuations.     

Circadian modulation of light-induced locomotion responses in Drosophila melanogaster

The relationship between light and the circadian system has long been a matter of discussion. Many studies have focused on entrainment of light with the internal biological clock. Light also functions as an environmental stimulus that affects the physiology and behaviour of animals directly. In this study, we used light as an unexpected stimulus for flies at different circadian times. We found that wildtype flies showed circadian changes in light-induced locomotion responses. Elevation of locomotor activity by light occurred during the subjective night, and performance in response to light pulses declined to trough during the subjective day. Moreover, arrhythmic mutants lost the rhythm of locomotion responses to light, with promotion of activity by light in timeless(01)mutants and inhibition of activity by light in Clock(ar)mutants. However, neither ablation of central oscillators nor disturbance of the functional clock inside compound eyes was sufficient to disrupt the rhythm of light responses. We show that, compound eyes, which have been identified as the control point for normal masking (promotion of activity by light), are sufficient but not necessary for paradoxical masking (suppression of activity by light) under high light intensity. This, taken together with the clear difference of light responses in wildtype flies, suggests that two different masking mechanisms may underlie the circadian modulation of light-induced locomotion responses.     

The comparison between circadian oscillators in mouse liver and pituitary gland reveals different integration of feeding and light schedules

The mammalian circadian system is composed of multiple peripheral clocks that are synchronized by a central pacemaker in the suprachiasmatic nuclei of the hypothalamus. This system keeps track of the external world rhythms through entrainment by various time cues, such as the light-dark cycle and the feeding schedule. Alterations of photoperiod and meal time modulate the phase coupling between central and peripheral oscillators. In this study, we used real-time quantitative PCR to assess circadian clock gene expression in the liver and pituitary gland from mice raised under various photoperiods, or under a temporal restricted feeding protocol. Our results revealed unexpected differences between both organs. Whereas the liver oscillator always tracked meal time, the pituitary circadian clockwork showed an intermediate response, in between entrainment by the light regimen and the feeding-fasting rhythm. The same composite response was also observed in the pituitary gland from adrenalectomized mice under daytime restricted feeding, suggesting that circulating glucocorticoids do not inhibit full entrainment of the pituitary clockwork by meal time. Altogether our results reveal further aspects in the complexity of phase entrainment in the circadian system, and suggest that the pituitary may host oscillators able to integrate multiple time cues.     

Coupling-induced synchronization in multicellular circadian oscillators of mammals

In mammals, circadian rhythms are controlled by the neurons located in the suprachiasmatic nucleus (SCN) of the hypothalamus. Each neuron in the SCN contains an autonomous molecular clock. The fundamental question is how the individual cellular oscillators, expressing a wide range of periods, interact and assemble to achieve phase synchronization. Most of the studies carried out so far emphasize the crucial role of the periodicity imposed by the light-dark cycle in neuronal synchronization. However, in natural conditions, the interaction between the SCN neurons is non-negligible and coupling between cells in the SCN is achieved partly by neurotransmitters. In this paper, we use a model of nonidentical, globally coupled cellular clocks considered as Goodwin oscillators. We mainly study the synchronization induced by coupling from an analytical way. Our results show that the role of the coupling is to enhance the synchronization to the external forcing. The conclusion of this paper can help us better understand the mechanism of circadian rhythm.     

Light regulates the cell cycle in zebrafish

The timing of cell proliferation is a key factor contributing to the regulation of normal growth. Daily rhythms of cell cycle progression have been documented in a wide range of organisms. However, little is known about how environmental, humoral, and cell-autonomous factors contribute to these rhythms. Here, we demonstrate that light plays a key role in cell cycle regulation in the zebrafish. Exposure of larvae to light-dark (LD) cycles causes a range of different cell types to enter S phase predominantly at the end of the day. When larvae are raised in constant darkness (DD), a low level of arrhythmic S phase is observed. In addition, light-entrained cell cycle rhythms persist for several days after transfer to DD, both observations pointing to the involvement of the circadian clock. We show that the number of LD cycles experienced is essential for establishing this rhythm during larval development. Furthermore, we reveal that the same phenomenon exists in a zebrafish cell line. This represents the first example of a vertebrate cell culture system where circadian rhythms of the cell cycle are observed. Thus, we implicate the cell-autonomous circadian clock in the regulation of the vertebrate cell cycle by light.     

The brain's calendar: neural mechanisms of seasonal timing

The suprachiasmatic nucleus (SCN) of the hypothalamus is the principal component of the mammalian biological clock, the neural timing system that generates and coordinates a broad spectrum of physiological, endocrine and behavioural circadian rhythms. The pacemaker of the SCN oscillates with a near 24 h period and is entrained to the diurnal light-dark cycle. Consistent with its role in circadian timing, investigations in rodents and non-human primates furthermore suggest that the SCN is the locus of the brain's endogenous calendar, enabling organisms to anticipate seasonal environmental changes. The present review focuses on the neuronal organization and dynamic properties of the biological clock and the means by which it is synchronized with the environmental lighting conditions. It is shown that the functional activity of the biological clock is entrained to the seasonal photic cycle and that photoperiod (day length) may act as an effective zeitgeber. Furthermore, new insights are presented, based on electrophysiological and molecular studies, that the mammalian circadian timing system consists of coupled oscillators and that the clock genes of these oscillators may also function as calendar genes. In summary, there are now strong indications that the neuronal changes and adaptations in mammals that occur in response to a seasonally changing environment are driven by an endogenous circadian clock located in the SCN, and that this neural calendar is reset by the seasonal fluctuations in photoperiod.     

Effects of restricted feeding on daily fluctuations of hepatic functions including p450 monooxygenase activities in rats

Hepatic P450 monooxygenase activities, assessed by measurement of 7-alkoxycoumarin O-dealkylase (ACD) activities, show obvious daily fluctuations in male rats with high values during the dark period and low values during the light period. We have already confirmed that the ACD activities are controlled by the suprachiasmatic nucleus (SCN), which is well known as the oscillator of circadian rhythm. Recently, it is reported that circadian oscillators exist not only in the SCN but also in peripheral organs. To date, it is unclear which circadian oscillators predominantly drive the daily fluctuations of hepatic ACD activities. To address this question, we examined the effects of restricted feeding, which uncouples the circadian oscillators in the liver from the central pacemaker in the SCN, on the daily fluctuations in hepatic ACD activities in male rats. Here we show that restricted feeding inverts the oscillation phase of the daily fluctuations in hepatic ACD activities. Regarding the hepatic P450 content, there were no fluctuations between the light and dark periods under ad libitum and restricted feeding conditions. Therefore, it is considered that the daily fluctuations in hepatic ACD activities are predominantly driven by the circadian factors in peripheral organs rather than by the oscillator in the SCN directly.     

Systems biology of cellular rhythms

Rhythms abound in biological systems, particularly at the cellular level where they originate from the feedback loops present in regulatory networks. Cellular rhythms can be investigated both by experimental and modeling approaches, and thus represent a prototypic field of research for systems biology. They have also become a major topic in synthetic biology. We review advances in the study of cellular rhythms of biochemical rather than electrical origin by considering a variety of oscillatory processes such as Ca++ oscillations, circadian rhythms, the segmentation clock, oscillations in p53 and NF-κB, synthetic oscillators, and the oscillatory dynamics of cyclin-dependent kinases driving the cell cycle. Finally we discuss the coupling between cellular rhythms and their robustness with respect to molecular noise.     

The photoperiod, circadian regulation and chronodisruption: the requisite interplay between the suprachiasmatic nuclei and the pineal and gut melatonin

The current scientific literature is replete with investigations providing information on the molecular mechanisms governing the regulation of circadian rhythms by neurons in the suprachiasmatic nucleus (SCN), the master circadian generator. Virtually every function in an organism changes in a highly regular manner during every 24-hour period. These rhythms are believed to be a consequence of the SCN, via neural and humoral means, regulating the intrinsic clocks that perhaps all cells in organisms possess. These rhythms optimize the functions of cells and thereby prevent or lower the incidence of pathologies. Since these cyclic events are essential for improved cellular physiology, it is imperative that the SCN provide the peripheral cellular oscillators with the appropriate time cues. Inasmuch as the 24-hour light:dark cycle is a primary input to the central circadian clock, it is obvious that disturbances in the photoperiodic environment, e.g., light exposure at night, would cause disruption in the function of the SCN which would then pass this inappropriate information to cells in the periphery. One circadian rhythm that transfers time of day information to the organism is the melatonin cycle which is always at low levels in the blood during the day and at high levels during darkness. With light exposure at night the amount of melatonin produced is compromised and this important rhythm is disturbed. Another important source of melatonin is the gastrointestinal tract (GIT) that also influences the circulating melatonin is the generation of this hormone by the entero-endocrine (EE) cells in the gut following ingestion of tryptophan-containing meal. The consequences of the altered melatonin cycle with the chronodisruption as well as the alterations of GIT melatonin that have been linked to a variety of pathologies, including those of the gastrointestinal tract.     

Potent Circadian Effects of Dim Illumination at Night in Hamsters

Conventional wisdom holds that the circadian pacemaker of rodents and humans is minimally responsive to light of the intensity provided by dim moonlight and starlight. However, dim illumination (<0.005 lux) provided during the daily dark periods markedly alters entrainment in hamsters. Under dimly lit scotophases, compared to completely dark ones phases, the upper range of entrainment is increased by ～4 h, and re‐entrainment is accelerated following transfer from long to short day lengths. Moreover, the incidence of bimodal entrainment to 24 h light:dark:light:dark cycles is increased fourfold. Notably, the nocturnal illumination inducing these pronounced effects is equivalent in photic energy to that of a 2 sec, 100 lux light pulse. These effects may be parsimoniously interpreted as an action of dim light on the phase relations between multiple oscillators comprising the circadian pacemaker. An action of dim light distinct from that underlying bright‐light phase‐resetting may promote more effective entrainment. Together, the present results refute the view that scotopic illumination is environmental “noise” and indicate that clock function is conspicuously altered by nighttime illumination like that experienced under dim moonlight and starlight. We interpret our results as evidence for a novel action of dim light on the coupling of multiple circadian oscillators.