Biological processes that occur regularly on approximately a 24-hour cycle are called

VII. Summary

Circadian rhythms touch upon every aspect of human biology. The future of circadian biology will rest heavily on the use of molecular biology techniques to dissect the biological time-keeping processes. For example, we will be able to ask and answer questions such as are circadian disorders and individual variations in period linked to polymorphisms of the clock genes? In addition, advances in circadian biology will allow physicians to develop more efficacious and rational therapies through a greater understanding of temporal variances in sensitivity. Furthermore, an increase our understanding of the “clocks that time us” will aid in the treatment of circadian-related disorders such as depression, sleep–wake disorders, SAD, aging-related circadian problems, and desynchrony (e.g., jet lag).

Introduction

Circadian rhythms are biological rhythms driven by a daily biological clock that persist even in a constant environment. All of us are quite familiar with this rhythmic aspect of our life, whether it is the regular timing of morning awakening or the adjustment to/from daylight savings time, or to travel across many time zones (jet lag). This biological clock is widespread, found in plants, animals, fungi, and even some bacteria (cyanobacteria). The daily clock probably has a selective advantage in nature, allowing organisms to ‘anticipate’ sunrise (or sunset) rather than just react to these events. It may also have an advantage at the cellular level, that is, by restricting certain processes to the night that may be sensitive to bright sunlight (DNA replication). Experiments have shown that organisms whose clock period matches that of their environment will outgrow or compete better than those organisms not in synchrony with their environment.

42.7.1 Identification, characterization, and localization of molecular clockworks in birds

Circadian rhythms are regulated by a highly conserved set of genes, collectively called “clock genes,” whose products are believed to dynamically interact to elicit rhythmic patterns of transcription, translation, biochemical and physiological processes, and behavior (Reppert and Weaver, 2002; Bell-Pedersen et al., 2005; Rosbash et al., 2007). In animals ranging from Drosophila to humans, the central core of this gene network can be broadly characterized as “positive elements” clock and bmal1 and “negative elements” period 1 (per1), period 2 (per2), period 3 (per3), and the cryptochromes cryptochrome 1 (cry1) and cryptochrome 2 (cry2). In contrast to mammals, birds do not express a per1 and have been shown to only express only per2 and per3 (Figure 42.10; Yoshimura et al., 2000; Yasuo et al., 2002; Bailey et al., 2003, 2004). Clock and bmal1 are transcribed and then translated in the cytoplasm, where they dimerize and reenter the nucleus and activate transcription of the negative elements through the activation of E-box promoter elements (Figure 42.5; Haque et al., 2010). The pers and crys in turn are transcribed and translated in the cytoplasm, where the PER proteins are targeted for proteosomal proteolysis by a series of protein kinases, most notably casein kinase 1ε (CK1ε) and CK1δ. This process slows the accumulation of the cytoplasmic PER and thereby increases the period of the molecular cycle. In the cytoplasm, PER and CRY proteins form oligomers that reenter the nucleus and interfere with the CLOCK/BMAL1-mediated activation. A secondary cycle involving two genes containing E-box promoters, Reverbα, and rorA, amplify the cycle by activating and inhibiting bmal1 transcription, respectively. Disruption or knockout of these genes' action has profound effects on the expression of circadian rhythms in animals in which these technologies are possible (i.e., mice and Drosophila) ranging from changes in period to arrhythmicity.

Publisher Summary

This chapter discusses circadian rhythms in insects. Circadian rhythms are daily oscillations in physiology, metabolism, or behavior that persist (freerun) in organisms that have been isolated from periodic fluctuations in the environment. There are four transcriptional regulators genes which are crtical for generating the basic circadian oscillation, the period (per), timeless (tim), cycle (cyc), and clock (clk). There are 4 essential elements–—a pacemaker or oscillator that generates the primary timing signal, photoreceptors for entrainment, and two coupling pathways, one that mediates the flow of entrainment information from the photoreceptor to the pacemaker, and another that couples the pacemaker to the effector mechanisms that it controls. In insects, the circadian system is responsible for imposing daily rhythmicity on a wide variety of processes including locomotor activity, mating, oviposition, egg hatching, pupation and pupal eclosion, pheromone release, retinal sensitivity to light, olfactory sensitivity, and even learning and memory. Studies on the anatomical and physiological organization of circadian systems in insects have largely focused on behavioral rhythms and their control by the nervous system. The goal of these studies has been to identify tissues and cells that comprise the functional defined components of the circadian system.

4 What Controls Circadian Rhythms?

Almost all known plants and animals exhibit circadian rhythms. For instance, the microscopic single-celled aquatic plant, Gonyaulax polyedra, is phosphorescent, lighting up at night, and dimming in the day. In 1958, Hastings and Sweeney demonstrated that Gonyaulax showed peaks and troughs of luminescence even in constant darkness, but the peak time of luminescence shifted a little later each day. If the plant was exposed to brief pulses of light, the peak of luminescence could be shifted to almost any time of day, depending on when the light pulse was given. Thus, light reset the Gonyaulax clock.

In 1972, Moore and Lenn placed a radioactive label into the eyes of rats and found that there was a direct pathway from the retina to two tiny nuclei in the hypothalamus. These nuclei lie behind the eyes right above the location in the brain where fibers from the left and right retinas cross, the optic chiasm, and therefore the nuclei are named the SCN. In that same year, Stephan and Zucker showed that lesions of the SCN could permanently eliminate or weaken circadian patterns of behavior (for a review, see Rusak and Zucker 1979). In a series of papers beginning in 1987, Lehman and his colleagues demonstrated that locomotor activity rhythmicity can be restored in hamsters with SCN lesions by transplants of fetal SCN tissue. There is now no doubt that, for most rhythms, the SCN is the main clock in the mammalian brain. Each morning, light from the eye sends electrical signals to the SCN and resets it. The SCN, in turn, synchronizes the rest of the brain and sets the pace for all daily activity patterns, just as a conductor synchronizes all the instruments in an orchestra.

The analogy of the SCN to an orchestra conductor is inadequate, however, because the cells of the SCN do not act as a single multioscillator unit. Welsh et al. (1995) demonstrated that SCN cells grown in culture oscillate at different rates: this means that each single SCN neuron functions as an independent circadian clock.

Key Facts on Circadian Rhythms

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Circadian rhythms are recurring cycles displaying periods of approximately 24 h. Circadian rhythms are manifest in a host of physiological, endocrine, biochemical, behavioral, and cognitive processes.

Circadian rhythms are internally generated by an endogenous circadian timekeeping system.

The master circadian clock in mammals is located to the SCN of the hypothalamus.

The molecular basis of circadian rhythm generation involves the interplay of the protein products of clock genes.

Circadian rhythms are normally entrained to relevant environmental time cues, the most important one being light.

However, in the absence of such time cues circadian rhythms will still be expressed.

Changes in circadian rhythms are manifest in many common diseases, and likewise circadian dysfunction is a risk factor for many common chronic conditions.

Introduction

Circadian rhythms are essential for aligning behavior with the environment. Misalignment with environmental cues can be associated with an inability to function adequately. While the understanding of the biological clock, localized in the hypothalamic suprachiasmatic nuclei (SCN), and regulation of circadian rhythms as well as circadian rhythm disorders has grown substantially in the last 50 years, the influence of sex on circadian rhythms and disorders has received less attention. (The term sex is commonly used as a biological category of male or female and the term gender is most often used in reference to social or cultural categories.) This article examines what is currently known about the effects of sex on circadian rhythm regulation in humans. Variation in gonadal hormones, such as occurs across the menstrual cycle, is also discussed as a potential moderator of sex differences in circadian rhythms. In the last part of the article, sex-related differences in the incidence, etiology, and impact of circadian rhythm disorders are discussed.

Abstract

Circadian rhythms are 24-h patterns regulating behavior, organs, and cells in living organisms. These rhythms align biological functions with regular and predictable environmental patterns to optimize function and health. Disruption of these rhythms can be detrimental resulting in metabolic syndrome, cancer, or cardiovascular disease, just to name a few. It is now becoming clear that the intestinal microbiome is also regulated by circadian rhythms via intrinsic circadian clocks as well as via the host organism. Microbiota rhythms are regulated by diet and time of feeding which can alter both microbial community structure and metabolic activity which can significantly impact host immune and metabolic function. In this review, we will cover how host circadian rhythms are generated and maintained, how host circadian rhythms can be disrupted, as well as the consequences of circadian rhythm disruption. We will further highlight the newly emerging literature indicating the importance of circadian rhythms of the intestinal microbiota.

Circadian rhythm sleep-wake disorders

Circadian Rhythm Sleep-Wake Disorders (CRSDs) are disorders “caused by alterations of the circadian time-keeping system, its entrainment mechanism, or a misalignment of the endogenous circadian rhythm and the external environment” (p. 189, ICSD-3, 2014). Sleep logs and actigraphy are recommended tools for the clinical evaluation of most CRSDs (Auger et al., 2015). Rating scales may be used in combination with other assessment tools but are not sufficient for diagnosing CRSDs. Current AASM Practice Parameters address use of one rating scale, the Morningness Eveningness Questionnaire (MEQ; Horne and Ostberg, 1976) in the evaluation of CRSDs, concluding there was insufficient evidence to recommend the routine use of the MEQ in the clinical evaluation of CRSDs. The Munich Chronotype Questionnaire (MCTQ) is frequently used to evaluate chronotype (i.e., the preference for earlier or later sleep hours (Roenneberg et al., 2003)). However, while extreme chronotypes may be associated with various health and functional outcomes, they are not in themselves synonymous with CRSDs.

3.1 Introduction

Circadian rhythm sleep-wake disorders (CRSWDs) include conditions in which the individual's natural circadian rhythm is incongruent with the surrounding environmental light/dark phase, resulting in sleep-wake disturbances such as insomnia and/or EDS, which causes distress or impairment (Sateia, 2014a). Abnormalities in the circadian rhythm include having a delayed, advanced, irregular, or non-24-h pattern. Additionally, externally triggered CRSWDs such as shift work disorder and jet lag disorder result from misalignment of the natural circadian rhythm with the individual's school, work, or social activities, or occur secondary to travel, respectively. An estimated 3% percent of the population has a CRSWD (Kim et al., 2013). Both pharmacological and non-pharmacological treatments exist for these conditions. Non-pharmacological therapies include prescribed timing of sleep-wake cycles, physical activity/exercise, and exposure/avoidance of light (Auger et al., 2015), but these will not be covered in this review. As endogenous melatonin is vital to circadian rhythm control throughout the body, melatonin receptor agonists and exogenous melatonin have a unique role in treating these disorders. Following a brief overview of what is known regarding circadian rhythm control, a description of each condition and available pharmacological options will be discussed.