Development and validation of computational models for mammalian circadian oscillators

Circadian rhythms are endogenous rhythms with a cycle length of approximately 24 h. Rhythmic production of specific proteins within pacemaker structures is the basis for these physiological and behavioral rhythms. Prior work on mathematical modeling of molecular circadian oscillators has focused on the fruit fly, Drosophila melanogaster. Recently, great advances have been made in our understanding of the molecular basis of circadian rhythms in mammals. Mathematical models of the mammalian circadian oscillator are needed to piece together diverse data, predict experimental results, and help us understand the clock as a whole. Our objectives are to develop mathematical models of the mammalian circadian oscillator, generate and test predictions from these models, gather information on the parameters needed for model development, integrate the molecular model with an existing model of the influence of light and rhythmicity on human performance, and make models available in BioSpice so that they can be easily used by the general community. Two new mammalian models have been developed, and experimental data are summarized. These studies have the potential to lead to new strategies for resetting the circadian clock. Manipulations of the circadian clock can be used to optimize performance by promoting alertness and physiological synchronization.     

A blend of two circadian clocks, seasoned to perfection

The daily activity of the fruit fly Drosophila is controlled by both a "morning" and an "evening" circadian clock. In this issue Stoleru et al. (2007) demonstrate that day length determines which clock dominates the neural circuitry governing circadian behavior. Thus, these findings suggest a mechanism by which the system for circadian timing adapts to changes in the seasons to impose appropriate rhythms of daily activity.     

Circadian control of eclosion: interaction between a central and peripheral clock in Drosophila melanogaster

Drosophila melanogaster display overt circadian rhythms in rest:activity behavior and eclosion. These rhythms have an endogenous period of approximately 24 hr and can adjust or "entrain" to environmental inputs such as light. Circadian rhythms depend upon a functioning molecular clock that includes the core clock genes period and timeless (reviewed in and ). Although we know that a clock in the lateral neurons (LNs) of the brain controls rest:activity rhythms, the cellular basis of eclosion rhythms is less well understood. We show that the LN clock is insufficient to drive eclosion rhythms. We establish that the prothoracic gland (PG), a tissue required for fly development, contains a functional clock at the time of eclosion. This clock is required for normal eclosion rhythms. However, both the PG clock function and eclosion rhythms require the presence of LNs. In addition, we demonstrate that pigment-dispersing factor (PDF), a neuropeptide secreted from LNs, is necessary for the PG clock and eclosion rhythms. Unlike other clocks in the fly periphery, the PG is similar to mammalian peripheral oscillators because it depends upon input, including PDF, from central pacemaker cells. This is the first report of a peripheral clock necessary for a circadian event.     

The circadian conidiation rhythm inNeurospora crassa

The filamentous fungusNeurospora crassais one of the best organisms for analysing the molecular basis of the circadian rhythm observed in asexual spore formation, conidiation. Many clock mutants in which the circadian conidiation rhythm has different characteristics compared to those in the wild-type strain have been isolated since the early 1970s. With the cloning of one of these clock genes,frq, the molecular basis of the circadian clock inNeurosporahas become gradually clearer. Physiological and pharmacological studies have also contributed to our understanding of the physiological basis of the circadian clock inNeurospora. These studies strongly indicate that the circadian clock is based on or is closely related to a network of metabolic processes for cellular activities. Based on these studies, it may be possible to isolate new types of clock mutants which should contribute to a better understanding of the molecular basis of the circadian clock inNeurospora.     

生物钟基因研究新进展

生物钟基因普遍存在于生物界,其作用在于产生和控制昼夜节律的运转。生物钟基因及其编码的蛋白质组成反馈回路,维持振荡系统持续进行并与环境周期保持同步。各级进化水平物种生物钟的基因组成和控制途径有同有异。此文主要介绍蓝细菌、脉孢菌、果蝇、鼠和人昼夜钟的分子运作机制以及研究钟基因的意义和展望。 Abstract:The circadian clock genes,which generate and control the running of the circadian rhythms,exist in organisms ranging from prokaryotes to mammals.The oscillator genes and its coding proteins compose the feedback loops of circadian system.The kind,number and regulating route of clock genes are characterized by living things at different evolution levels.The molecular mechanism of the run of circadian clock genes in cyanobacteria,neurospore,fruit fly,mouse and human being is introduced in this article.     

Sleep and circadian rhythms: key components in the regulation of energy metabolism

In this review, we present evidence from human and animal studies to evaluate the hypothesis that sleep and circadian rhythms have direct impacts on energy metabolism, and represent important mechanisms underlying the major health epidemics of obesity and diabetes. The first part of this review will focus on studies that support the idea that sleep loss and obesity are "interacting epidemics." The second part will discuss recent evidence that the circadian clock system plays a fundamental role in energy metabolism at both the behavioral and molecular levels. These lines of research must be seen as in their infancy, but nevertheless, have provided a conceptual and experimental framework that potentially has great importance for understanding metabolic health and disease.     

Insect photoperiodism and circadian clocks: models and mechanisms

Photoperiodic clocks allow organisms to predict the coming season. In insects, the seasonal adaptive response mainly takes the form of diapause. The extensively studied photoperiodic clock in insects was primarily characterized by a "black-box" approach, resulting in numerous cybernetic models. This is in contrast with the circadian clock, which has been dissected pragmatically at the molecular level, particularly in Drosophila. Unfortunately, Drosophila melanogaster, the favorite model organism for circadian studies, does not demonstrate a pronounced seasonal response, and consequently molecular analysis has not progressed in this area. In the current article, the authors explore different ways in which identified molecular components of the circadian pacemaker may play a role in photoperiodism. Future progress in understanding the Drosophila circadian pacemaker, particularly as further output components are identified, may provide a direct link between the clock and photoperiodism. In addition, with improved molecular tools, it is now possible to turn to other insects that have a more dramatic photoperiodic response.     

Neurobiology of the fruit fly's circadian clock

Studying the fruit fly Drosophila melanogaster has revealed mechanisms underlying circadian clock function. Rhythmic behavior could be assessed to the function of several clock genes that generate circadian oscillations in certain brain neurons, which finally modulate behavior in a circadian manner. This review outlines how individual circadian pacemaker neurons in the fruit fly's brain control rhythm in locomotor activity and eclosion.     

Chlamydomonas reinhardtii as a new model system for studying the molecular basis of the circadian clock

The genome of the unicellular green alga Chlamydomonas reinhardtii has both plant-like and animal-like genes. It is of interest to know which types of clock genes this alga has. Recent forward and reverse genetic studies have revealed that its clock has both plant-like and algal clock components. In addition, since C. reinhardtii is a useful model organism also called "green yeast", the identification of clock genes will make C. reinhardtii a powerful model for studying the molecular basis of the eukaryotic circadian clock. In this review, we describe our forward genetic approach in C. reinhardtii and discuss some recent findings about its circadian clock.     

Insect circadian clocks: is it all in their heads?

Circadian rhythms are ubiquitous in living organisms, synchronizing life functions at the biochemical, physiological, and behavioral levels. The rhythm-generating mechanisms, collectively known as circadian clocks, are not fully understood in any organism. Research in the fruit fly Drosophila has led to the identification of several clock genes that are involved in the function of the brain-centered clock, which controls behavioral rhythms of adult flies. With the use of clock genes as markers, putative circadian clocks were mapped in the fly peripheral organs and shown to be independent from clocks located in the brain. A homologue of fruit fly period gene has been identified in moths and other insects, allowing investigations of this gene's role in known insect rhythms. This approach may increase our understanding of how circadian clocks are organized into the circadian system that orchestrates temporal integration of life processess in insects.     

Casein kinase 2, circadian clocks, and the flight from mutagenic light

Circadian clocks play a fundamental role in biology and disease. Much has been learned about the molecular underpinnings of these biological clocks from genetic studies in model organisms, such as the fruit fly, Drosophila melanogaster. Here we review the literature from our lab and others that establish a role for the protein kinase CK2 in Drosophila clock timing. Among the clock genes described thus far, CK2 is unique in its involvement in plant, fungal, as well as animal circadian clocks. We propose that this reflects an ancient, conserved function for CK2 in circadian clocks. CK2 and other clock genes have been implicated in cellular responses to DNA damage, particularly those induced by ultraviolet (UV) light. The finding of a dual function of CK2 in clocks and in UV responses supports the notion that clocks evolved to assist organisms in avoiding the mutagenic effects of daily sunlight.     

Analysis of locomotor activity rhythms in Drosophila

The genetic, molecular and anatomical dissection of the circadian clock in Drosophila and other higher organisms relies on the quantification of rhythmic phenotypes. Here, we introduce the methods currently in use in our laboratories for the analysis of fly locomotor activity rhythms. This phenotype provides a relatively simple, automated, efficient, reliable and robust output for the circadian clock. Thus it is not surprising that it is the preferred readout for measuring rhythmicity under a variety of conditions for most fly clock laboratories. The procedure requires at least 10 days of data collection and several days for analysis. In this protocol we advise on fly maintenance and on experimental design when studying the genetics of behavioral traits. We describe the setup for studying locomotor activity rhythms in the fruit fly and we introduce the statistical methods in use in our laboratories for the analysis of periodic data.     

Circadian molecular clocks tick along ontogenesis

The circadian system controls the timing of behavioral and physiological functions in most organisms studied. The review addresses the question of when and how the molecular clockwork underlying circadian oscillations within the central circadian clock in the suprachiasmatic nuclei of the hypothalamus (SCN) and the peripheral circadian clocks develops during ontogenesis. The current model of the molecular clockwork is summarized. The central SCN clock is viewed as a complex structure composed of a web of mutually synchronized individual oscillators. The importance of development of both the intracellular molecular clockwork as well as intercellular coupling for development of the formal properties of the circadian SCN clock is also highlighted. Recently, data has accumulated to demonstrate that synchronized molecular oscillations in the central and peripheral clocks develop gradually during ontogenesis and development extends into postnatal period. Synchronized molecular oscillations develop earlier in the SCN than in the peripheral clocks. A hypothesis is suggested that the immature clocks might be first driven by external entraining cues, and therefore, serve as "slave" oscillators. During ontogenesis, the clocks may gradually develop a complete set of molecular interlocked oscillations, i.e., the molecular clockwork, and become self-sustained clocks.