Populations of biochemical oscillators as circadian clocks

Various types of populations of interacting oscillators were analyzed and their synchronization states were determined. One of the systems involving biochemical oscillators was simulated on the computer and the occurence of rhythm splitting was observed. A comparison of its attributes with experimental results on circadian ryhythms showed good agreement. This allows us to distinguish between types of mechanisms held responsible for the splitting phenomenon in the past. The present model also offers a new explanation about the differences of light action on diurnal and nocturnal organisms.     

Hierarchically coupled ultradian oscillators generating robust circadian rhythms

Ensembles of mutually coupled ultradian cellular oscillators have been proposed by a number of authors to explain the generation of circadian rhythms in mammals. Most mathematical models using many coupled oscillators predict that the output period should vary as the square root of the number of participating units, thus being inconsistent with the well-established experimental result that ablation of substantial parts of the suprachiasmatic nuclei (SCN), the main circadian pacemaker in mammals, does not eliminate the overt circadian functions, which show no changes in the phases or periods of the rhythms. From these observations, we have developed a theoretical model that exhibits the robustness of the circadian clock to changes in the number of cells in the SCN, and that is readily adaptable to include the successful features of other known models of circadian regulation, such as the phase response curves and light resetting of the phase.     

Qualitative similarities between the behavior of coupled oscillators and circadian rhythms

This paper summarizes in a nonmathematical way the major properties of coupled oscillators which relate to circadian rhythms. For certain values of the coupling strength it is far easier to maintain synchrony than to achieve it among the various interacting units. This property not only simulates the free run period lability but also the effects of critical pulses.     

A case for multiple oscillators controlling different circadian rhythms in Drosophila melanogaster

A population of the fruit fly Drosophila melanogaster was raised in periodic light/dark (LD) cycles of 12:12 h for about 35 generations. Eclosion, locomotor activity, and oviposition were found to be rhythmic in these flies, when assayed in constant laboratory conditions where the light intensity, temperature, humidity and other factors which could possibly act as time cue for these flies, were kept constant. These rhythms also entrained to a LD cycle of 12:12 h in the laboratory with each of them adopting a different temporal niche. The free-running periods (tau) of the eclosion, locomotor activity and oviposition rhythms were significantly different from each other. The peak of eclosion and the onset of locomotor activity occurred during the light phase of the LD cycle, whereas the peak of oviposition was found to occur during the dark phase of the LD cycle. Based on these results, we conclude that different circadian oscillators control the eclosion, locomotor activity and oviposition rhythms in the fruit fly D. melanogaster.     

Two coupled oscillators: simulations of the circadian pacemaker in mammalian activity rhythms

In the activity rhythms of captive small mammals a variety of features, most notably “splitting”, suggest that two coupled oscillators may constitute the pacemaker system which underlies the rhythms. A phenomenological model proposed by Pittendrigh is developed and expanded here using an explicit quantitative structure. It is found that such a system can simulate several qualitative features in the experimental data: the inter-dependence of free-running period (gt) and activity time (α) with changing light intensity described in Aschoff's rule, after-effects on τ and α of prior conditions, and the occasional existence of two stable phase relationships, with different τ values for a given light intensity, as observed in “splitting”. It is hoped that the model will suggest experiments aimed at the elucidation of the physiological basis of these phenomena.     

Human sleep and circadian rhythms: a simple model based on two coupled oscillators

We propose a model of the human circadian system. The sleep-wake and body temperature rhythms are assumed to be driven by a pair of coupled nonlinear oscillators described by phase variables alone. The novel aspect of the model is that its equations may be solved analytically. Computer simulations are used to test the model against sleep-wake data pooled from 15 studies of subjects living for weeks in unscheduled, time-free environments. On these tests the model performs about as well as the existing models, although its mathematical structure is far simpler.Supported by NIGMS Grant No. 5-R01-GM-30719-03     

Socially synchronized circadian oscillators

Daily rhythms of physiology and behaviour are governed by an endogenous timekeeping mechanism (a circadian ‘clock’). The alternation of environmental light and darkness synchronizes (entrains) these rhythms to the natural day–night cycle, and underlying mechanisms have been investigated using singly housed animals in the laboratory. But, most species ordinarily would not live out their lives in such seclusion; in their natural habitats, they interact with other individuals, and some live in colonies with highly developed social structures requiring temporal synchronization. Social cues may thus be critical to the adaptive function of the circadian system, but elucidating their role and the responsible mechanisms has proven elusive. Here, we highlight three model systems that are now being applied to understanding the biology of socially synchronized circadian oscillators: the fruitfly, with its powerful array of molecular genetic tools; the honeybee, with its complex natural society and clear division of labour; and, at a different level of biological organization, the rodent suprachiasmatic nucleus, site of the brain''s circadian clock, with its network of mutually coupled single-cell oscillators. Analyses at the ‘group’ level of circadian organization will likely generate a more complex, but ultimately more comprehensive, view of clocks and rhythms and their contribution to fitness in nature.     

Insect circadian rhythms and photoperiodism

Two clock-controlled processes, overt circadian rhythmicity and the photoperiodic induction of diapause, are described in the blow fly,Calliphora vicina and the fruit fly,Drosophila melanogaster. Circadian locomotor rhythms of the adult flies reflect endogenous, self-sustained oscillations with a temperature compensated period. The free-running rhythms become synchronised (entrained) to daily light:dark cycles, but become arrhythmic in constant light above a certain intensity. Some flies show fragmented rhythms (internal desynchronisation) suggesting that overt rhythmicity is the product of a multioscillator (multicellular) system. Photoperiodic induction of larval diapause inC. vicina and of ovarian diapause inD. melanogaster is also based on the circadian system but seems, to involve a separate mechanism at both the molecular and neuronal levels. For both processes in both species, the compound eyes and ocelli are neither essential nor necessary for photic entrainment, and the circadian clock mechanism is not within the optic lobes. The central brain is the most likely site for both rhythm generation and extra-optic photoreception. InD. melanogaster, a group of lateral brain neurons has been identified as important circadian pacemaker cells, which are possibly also photo-sensitive. Similar lateral brain neurons, staining for arrestin, a protein in the phototransduction ‘cascade’ and a selective marker for photoreceptors in both vertebrates and invertebrates, have been identified inC. vicina. Much less is known about the cellular substrate of the photoperiodic mechanism, but this may involve thepars intercerebralis region of the mid-brain.     

The circadian locomotor rhythm of Hemideina thoracica (Orthoptera; Stenopelmatidae): the circadian clock as a population of interacting oscillators

ABSTRACT. The behaviour of the circadian locomotor rhythm of the New Zealand weta, Hemideina thoracica (White), supports the model that the underlying pacemaker consists of a population of weakly coupled oscillators. Certain patterns of locomotor activity, previously demonstrated almost exclusively in vertebrates, are presented here as evidence for the above hypothesis. They include after-effects of various pre-treatments, rhythm-splitting and spontaneous changes in the rhythm. After-effects, which describe the unstable behaviour of free-running circadian rhythms following particular experimental perturbations, have been observed in Hemideina following single light pulses, constant dim light, and laboratory and natural entrainment. Period changes occurred in the activity rhythm after single light pulses of 8-h and 12-h duration (25 lx). Constant dim light (0.1 lx) increased the free-running period (τ) of the activity rhythm, but the after-effect of constant dim light was either an increase or a decrease in τ. After-effects upon both τ and the active phase length of the activity rhythm were found following non-24-h light entrainment cycles with 8-h and 12-h light phases of 25 lx. Qualitative measurements of these after-effects upon τ are presented which reveal a relationship between both the direction and amount of change in τ, and the difference between entrainment cycle length (T) and pre-entrainment free-running period. The after-effect of natural entrainment was an initial short-period free-run (τ < 24h) lasting 5–10 days, generally followed by a rapid period lengthening to τ= 25–26 h. Support for the population model was provided by spontaneous dampening, recovery, and period changes of the rhythm, together with the disruption of the active phase following critical light perturbations, and rhythm-splitting. These Hemideina results are compared with the simulations of the Coupled Stochastic System of Enright (1980).     

Spontaneous synchronization of coupled circadian oscillators

In mammals, the circadian pacemaker, which controls daily rhythms, is located in the suprachiasmatic nucleus (SCN). Circadian oscillations are generated in individual SCN neurons by a molecular regulatory network. Cells oscillate with periods ranging from 20 to 28 h, but at the tissue level, SCN neurons display significant synchrony, suggesting a robust intercellular coupling in which neurotransmitters are assumed to play a crucial role. We present a dynamical model for the coupling of a population of circadian oscillators in the SCN. The cellular oscillator, a three-variable model, describes the core negative feedback loop of the circadian clock. The coupling mechanism is incorporated through the global level of neurotransmitter concentration. Global coupling is efficient to synchronize a population of 10,000 cells. Synchronized cells can be entrained by a 24-h light-dark cycle. Simulations of the interaction between two populations representing two regions of the SCN show that the driven population can be phase-leading. Experimentally testable predictions are: 1), phases of individual cells are governed by their intrinsic periods; and 2), efficient synchronization is achieved when the average neurotransmitter concentration would dampen individual oscillators. However, due to the global neurotransmitter oscillation, cells are effectively synchronized.     

哺乳动物生物钟的遗传和表观遗传研究进展

生物钟对生物机体的生存与环境适应具有着重要意义,其相关研究近年来受到人们的广泛关注。生物钟的重要性质之一是内源节律的周期性,当前的研究认为这种周期性是由生物钟相关基因转录翻译的多反馈环路构成核心机制调控着近似24 h的节律振荡。哺乳动物的生物钟系统存在一个多层次的结构,包括位于视交叉上核的主时钟和外周器官和组织的子时钟。虽然主时钟和子时钟存在的组织不同,但是参与调节生物钟的分子机制是一致的。近年来,通过正向、反向遗传学方法和表观遗传学的研究方法,对生物钟的分子机制的解析和认知愈发深入。本文在简单回顾生物钟基因发现历史的基础上,重点从遗传学和表观遗传学两个方面,从振荡周期的角度,对哺乳动物生物钟分子机制的研究进展进行了综述性介绍,以期为靶向调节生物钟来改善机体的稳态系统的研究提供参考,同时希望能促进时间生物学领域与更多其他领域形成交叉研究。