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In almost all living organisms, there is a sequence of biochemical, physiological, and behavioral processes that repeat roughly every 24 h. The timing of such processes is governed by an internal clock that ensures that these processes occur in a manner that optimizes the utilization of external resources such as the sunlight. In humans, peak cognitive and physical performance occurs during the daytime and is coupled with metabolic functions associated with catabolism, while the nighttime is associated with anabolic functions that take place during sleep. The daily rhythms of mental, physiological, and metabolic changes are collectively referred to as circadian cycles, and the internal clock that governs the timing of these processes lies in the suprachiasmatic nuclei (SCN).

Summary Circadian rhythms persist in almost all organisms and are crucial for maintaining appropriate timing in physiology and behaviour. Here, we describe a mouse mutant where the central mammalian pacemaker, the suprachiasmatic nucleus (SCN), has been genetically ablated by conditional deletion of the transcription factor Zfhx3 in the developing hypothalamus. Mutants were arrhythmic over the light-dark cycle and in constant darkness. Moreover, rhythms of metabolic parameters were ablated in vivo although molecular oscillations in the liver maintained some rhythmicity. Despite disruptions to SCN cell identity and circuitry, mutants could still anticipate food availability, yet other zeitgebers - including social cues from cage-mates - were ineffective in restoring rhythmicity although activity levels in mutants were altered. This work highlights a critical role for Zfhx3 in the development of a functional SCN, while its genetic ablation further defines the contribution of SCN circuitry in orchestrating physiological and behavioral responses to environmental signals., Graphical abstract, Highlights • Deletion of Zfhx3 in developing hypothalamus leads to behavioral arrhythmicity • SCN cell identity is absent while other retinal targets and visual functions remain • Rhythms in metabolic functions are lost while some molecular rhythms in liver persist • Conditional mutants can respond to food availability and other environmental cues, Biological sciences; Physiology; Molecular biology; Neuroscience

Chrononutrition is the science that investigates the correlations between mealtimes, metabolism, physiology, and endogenous circadian rhythms, but it also outlines a diet in harmony with biological biorhythms, one of the main processes that is involved in healthiness, causing, if altered, many diseases and syndromes associated with the aging process. These rhythms originate in the hypothalamic suprachiasmatic nucleus (SCN), located in the anterior hypothalamus, and it is mainly controlled by the oscillations, an important type of cellular signaling characterized by the periodic change of the system over time. The oscillation originating in the suprachiasmatic nucleus (SCN) is known as the central oscillator, and all other similar signals are named peripheral oscillations. These rhythms are not only regulated by these endogenous signals, but it may be entrained by external signals named zeitgebers, such as light, exercise, and meal times. The worst outcome of the deregulation of the physiological circadian rhythms is chronodisruption, which consists of desynchronization of peripheral oscillators from the central one. Some causes of this phenomenon are night work and jet lag, including social jet lag, for example, the discrepancy in a person's sleep pattern between the weekday and the weekend which, if continued chronically, have been associated with an increased risk of metabolic syndrome, obesity, and cardiovascular disease, all pathological conditions associated with aging. Both a low-calorie diet and the regular use of functional and mimetic compounds could be the nutritional basis for promoting health in aging, obviously only together with all the other measures that characterize a correct lifestyle. The optimal diet model for that is the one inspired by the food choices typical of the Mediterranean model with oriental influences and adopt a calorie intake that, depending on the proposed diet, provides a quantity of calories that is between a range of 15%–20% around the basal metabolic rate in subjects with a low level of physical activity. Furthermore, an optimal diet should provide a protein content of around 0.95–1 g/kg body weight and follow all other recommendations published by international nutrition companies. This chapter discusses what is currently known about genetics and physiology of the circadian rhythms and zeitgebers, as well as the main evidence regarding the chronodisruption correlations with obesity, metabolic syndrome, and cardiovascular diseases. Furthermore, here we try to gather chrononutrition main aspects with the best dietary regime for ensuring a successful aging.

The response to a zeitgeber, particularly the light/dark cycle, may vary phenotypically. Phenotypic plasticity can be defined as the ability of one genome to express different phenotypes in response to environmental variation. In this opinion paper, we present some evidence that one of the most prominent effects of the introduction of electric light to the everyday life of humans is a significant increase in phenotypic plasticity and differences in interindividual phases of entrainment. We propose that the healthy limits of phenotypic plasticity have been surpassed in contemporary society., Highlights • Electric light increased phenotypic plasticity in humans and differences in interindividual phases of entrainment. • Healthy limits of phenotypic plasticity have been surpassed in contemporary society. • The correlation between biological time (DLMO) and behavioral time (MSFsc) is reduced in the population without access to electrical light.

Background Interleukin-33 (IL-33) is an alarmin cytokine that binds to the interleukin 1 receptor-like 1 protein ST2. Clock is a key circadian gene that is essential for endogenous clockworks in mammals. This study investigated whether Clock temporally regulated IL-33-mediated responses in mast cells. Methods The kinetics of IL-33-mediated IL-6, IL-13, and TNF-α productions were compared between bone marrow-derived mast cells (BMMCs) from wild-type and Clock -mutated mice ( Clock Δ19/Δ19 mice). The kinetics of the neutrophil influx into the peritoneal cavity or expression of IL-13 and Gob-5 in the lung in response to IL-33 were compared between wild-type and Clock Δ19/Δ19 mice. We also examined the kinetics of ST2 expression in mast cells and its association with Clock expression. Results There was a time-of-day-dependent variation in IL-33-mediated IL-6, IL-13, and TNF-α production in wild-type BMMCs, which was absent in Clock -mutated BMMCs. IL-33-induced neutrophil infiltration into the peritoneal cavity also showed a time-of-day-dependent variation in wild-type mice, which was absent in Clock Δ19/Δ19 mice. Furthermore, IL-33-induced IL-13 and Gob-5 expression in the lung exhibited a time-of-day-dependent variation in wild-type mice. These temporal variations in IL-33-mediated mast cell responses were associated with temporal variations of ST2 expression in mast cells. In addition, CLOCK bound to the promoter region of ST2 and Clock deletion resulted in down-regulation of ST2 expression in mast cells. Conclusions CLOCK temporally gates mast cell responses to IL-33 via regulation of ST2 expression. Our findings provide novel insights into IL-33/mast cell-associated physiology and pathologies.

Objective Upregulation of uncoupling protein 2 (UCP2) is associated with impaired glucose-stimulated insulin secretion (GSIS), which is thought to be an important contributor to pathological β cell failure in obesity and type 2 diabetes (T2D); however, the physiological function of UCP2 in the β cell remains undefined. It has been suggested, but not yet tested, that UCP2 plays a physiological role in β cells by coordinating insulin secretion capacity with anticipated fluctuating nutrient supply, such that upregulation of UCP2 in the inactive/fasted state inhibits GSIS as a mechanism to prevent hypoglycemia. Therefore, we hypothesized that daily cycles of GSIS capacity are dependent on rhythmic and predictable patterns of Ucp2 gene expression such that low Ucp2 in the active/fed phase promotes maximal GSIS capacity, whereas elevated Ucp2 expression in the inactive/fasted phase supresses GSIS capacity. We further hypothesized that rhythmic Ucp2 expression is required for the maintenance of glucose tolerance over the 24 h cycle. Methods We used synchronized MIN6 clonal β cells and isolated mouse islets from wild type (C57BL6) and mice with β cell knockout of Ucp2 (Ucp2-βKO; and respective Ins2-cre controls) to determine the endogenous expression pattern of Ucp2 over 24 h and its impact on GSIS capacity and glucose tolerance over 24 h. Results A dynamic pattern of Ucp2 mRNA expression was observed in synchronized MIN6 cells, which showed a reciprocal relationship with GSIS capacity in a time-of-day-specific manner. GSIS capacity was suppressed in islets isolated from wild type and control mice during the light/inactive phase of the daily cycle; a suppression that was dependent on Ucp2 in the β cell and was lost in islets isolated from Ucp2-βKO mice or wild type islets treated with a UCP2 inhibitor. Finally, suppression of GSIS capacity by UCP2 in the light phase was required for the maintenance of normal patterns of glucose tolerance. Conclusions Our study suggests that Ucp2/UCP2 in the β cell is part of an important, endogenous, metabolic regulator that controls the temporal capacity of GSIS over the course of the day/night cycle, which, in turn, regulates time-of-day glucose tolerance. Targeting Ucp2/UCP2 as a therapeutic in type 2 diabetes or any other metabolic condition must take into account the rhythmic nature of its expression and its impact on glucose tolerance over 24 h, specifically during the inactive/fasted phase., Highlights • Ucp2 mRNA expression in MIN6 β cells and isolated islets is dynamic and rhythmic over 24 h. • Daily cycles of glucose-stimulated insulin secretion capacity are dependent on rhythmic Ucp2 expression and UCP2 activity. • Loss of rhythmic Ucp2 mRNA expression triggers glucose intolerance only in the light/inactive phase of the daily cycle. • UCP2 is part of an endogenous diurnal metabolic regulator that coordinates islet function with the daily cycle of fasting and feeding.

Muscle mass is controlled by the balance between muscle synthesis and degradation. Although nutrition is important for the maintenance of muscle mass and growth, the effects of feeding time have remained unclear. In the present study, we aimed to evaluate the effects of day- or night-time-restricted feeding on the muscle volume using muscle atrophy and hypertrophy mouse models. The day- and night-time-restricted feeding was conducted from zeitgeber time 2 (ZT2) to ZT10 and ZT14 to ZT22, respectively. In the unilateral immobilization-induced atrophy model, the decrease in immobilized muscle weight did not significantly change with the feeding time. However, the contralateral non-immobilized muscle weight was lower in the mice fed at day time (inactive phase) than in those fed at night time (active phase). In the overloading-induced hypertrophy model, muscle hypertrophy and protein synthesis were attenuated by day-time feeding. These results suggest that day-time feeding attenuated muscle growth via the inhibition of muscle synthesis. Feeding at an irregular time such as a late-night meal could be detrimental for muscle growth. Keywords: Feeding time, Muscle hypertrophy, Protein synthesis, Time-restricted feeding

Light is the most powerful "zeitgeber" signal to synchronize circadian sleep-wake cycles. In dementia, these rhythms are often fragmented - probably due to loss of neuronal function of the suprachiasmatic nuclei (the biological "master clock" in the brain) and/or weakness of external zeitgebers. We investigated the effects of a prototype dawn-dusk simulator (DDS) on circadian rest-activity cycles, sleep, mood and well-being in a balanced crossover design during fall and winter in 20 institutionalized patients with dementia (86 ± 6 y, 17 f). All participants had one baseline week followed by exposure to individually timed DDS over their beds for 7-8 weeks. They spent 8 weeks without DDS as a control. Mood, self-reliant daily activity, social behavior, agitation, and quality of life were assessed by standardized questionnaires and visual analogue scales, regularly rated by trained caregivers. Circadian and sleep characteristics of their rest-activity cycles were analyzed by actimetry over 17 weeks. DDS exposure led to significantly better mood in the morning hours after waking. The effects were most pronounced in the second 4 weeks with DDS, indicating that positive effects emerged gradually. Differences in circadian rest-activity cycles and sleep were mainly age-dependent. We found statistically significant correlations between measures of higher quality of life and better mood, greater alertness and circadian rhythm stability. We conclude that continuous, long-term application of dawn-dusk simulation at the sleep-wake transitions appears to increase external zeitgeber strength in institutionalized patients with dementia. The DDS may provide an effective, non-invasive tool to improve mood and ameliorate patients' quality of life.

6 pages, 5 figures, 1 table.-- This is an open access article under the CC BY-NC-ND license, We describe the valve-opening behavior of raft-cultivated mussels (Mytilus galloprovincialis) in the Ría de Arousa (Arousa estuary), Spain. Eight rope-grown mussels [mean ± standard error (SEM), shell length 61.6 ± 2.1 mm] were connected to a non-invasive valvometry apparatus that monitored (one measurement min−1) the magnitude of valve openness systematically over a 10 day period. It was found that valves were open 97.5 ± 1.3% percent of the time. Valve closures were not synchronized among the eight monitored mussels, suggesting that feeding cessation was physiologically-regulated rather than environmentally-mediated. The opening amplitudes that were most frequently observed were in the range of 60–90%, indicating that, when open, valves are usually opened relatively close to their maximum possible extent. The majority (7/8) of mussels displayed a circadian rhythm (τ = 24.0 h) in valve opening amplitude. They tended to exhibit maximum valve opening during nighttime and minimum opening during daytime. It is possible that the light:dark cycle represents an environmental zeitgeber entraining an endogenous gaping rhythm in this bivalve, This study was funded by the Spanish government through the Ministerio de Economía y Competitividad (project Mytiga AGL2013- 45945-R)

Circadian clocks have evolved to synchronize physiology, metabolism and behaviour to the 24-h geophysical cycles of the Earth. Understanding the circadian clock mechanism could play an important role in forensic entomology because it temporally gates behaviour such as locomotor activities, feeding, mating, egg laying and adult emergence which could provide useful information for crime reconstruction. The scuttle fly Megaselia scalaris colonises both exposed and buried bodies, whether indoors or outdoors. Locomotor activity, oviposition and adult emergence of this species have been investigated using technologies employed in many previous Drosophila circadian studies. The results reported here clearly highlight the underlying role of the circadian clock in regulating the behaviour of males and females of M. scalaris, and show the role of light as a "zeitgeber" for clock resetting. In contrast to Calliphoridae, M. scalaris can reach the oviposition site and lay eggs in darkness both during the day and the night, although the number of ovipositing females is lower under subjective darkness. The number of eggs laid shows a clear circadian rhythm with much higher numbers laid during the day than during night or subjective night. In conclusion, locomotor activity and oviposition rate of M. scalaris is under circadian clock control with significant forensic implications.

Many aspects of human physiology, metabolism, and behavior are dominated by 24-h circadian rhythms including the sleep-wake cycle, alertness and performance patterns, and some hormones. These rhythms are spontaneously generated by an internal circadian clock in the brain and daily light exposure to the eyes synchronizes the clock with the external environment. Most blind people with no perception of light, however, experience continual circadian desynchrony through a failure of light information to reach the circadian pacemaker, resulting in non-24-h sleep-wake disorder. Daily melatonin administration, which provides a replacement synchronizing daily �time cue,� is a promising therapeutic strategy to treat this disorder. © 2017 Elsevier Inc. All rights reserved.

Internal timekeepers in organisms synchronize internal functions and keep the timing of those functions correct with respect to the daily cycle of light and dark.

External cues, or zeitgebers, keep biological clocks in synchrony with the day–night cycle. Without zeitgebers, biological clocks run slightly off an exact 24-h cycle, so over the span of a few days the internal rhythms of an animal lose their synchrony with the external world. Correct time keeping can be re-established by restoring the zeitgebers.

Irregular sleep-wake rhythm disorder is a disorder characterized by no clearly defined circadian rhythm. In severe cases, sleep and wakefulness can be randomly distributed throughout the day and night. The main symptoms are chronic complaints of insomnia and excessive sleepiness. The disorder is commonly associated with neurological impairment (dementia), but it is also seen in children with mental retardation, and following traumatic brain injuries. The causes may be a damage of the suprachiasmatic nucleus and/or reduced exposure to zeitgebers. Recommended treatment options are bright light exposure and exogenous melatonin administration. The aim is to structure and reinforce the circadian rhythm.

A human’s internal biology is timed to the 24 h light and dark cycles. This synchronizes processes, such as metabolic, digestive, and learning processes with the time of day that they might occur. This way, the internal molecular activities can be carried out efficiently. Many circumstances involving both work and social relationships may conflict with the body’s internal schedule. One example is that our cognitive performance is not stable over the day and the output of circadian rhythms governs this performance. In addition, the sleep pressure interacts with the circadian rhythms to determine the final performance level of the individual. Numerous health and psychological problems have been associated when a long-term mismatch between internal circadian rhythms and external daily activities occurs. In addition with shift work and travel across time zones, our internal biological clock can adapt to match the external inputs. Therefore, circadian rhythms are a critical part of life’s biology.

Chronobiology is the study of biological rhythms. In animals the master biological clock is located in the hypothalamus. Peripheral clocks have also been found in various cells, tissues, and organs. Disruptions of biological rhythms are implicated in general performance decrements and certain medical and psychiatric conditions. Chronotherapeutic modalities include light therapy, wake therapy, shifting of sleep-wake schedules, dark therapy, melatonin, and its synthetic receptor agonists. An improved alignment of biological rhythms with the environmental light-dark exposure and societal demands can have important and broad implications for performance (academic, occupational, and athletic), health, and well-being.

Three properties are most often attributed to the circadian clock: a ca. 24-h free-running rhythm, temperature compensation of the circadian rhythm, and its entrainment to zeitgeber cycles. Relatively few experiments, however, are performed under entrainment conditions. Rather, most chronobiology protocols concern constant conditions. We have turned this paradigm around and used entrainment to study the circadian clock in organisms where a free-running rhythm is weak or lacking. We describe two examples therein: Caenorhabditis elegans and Saccharomyces cerevisiae. By probing the system with zeitgeber cycles that have various structures and amplitudes, we can demonstrate the establishment of systematic entrained phase angles in these organisms. We conclude that entrainment can be utilized to discover hitherto unknown circadian clocks and we discuss the implications of using entrainment more broadly, even in model systems that show robust free-running rhythms.

Nearly all living organisms demonstrate circadian rhythms. Although the properties of circadian oscillators have been known for decades, the role of circadian rhythms in weight regulation and metabolism has only recently begun to be studied. Experimental studies have demonstrated that disruption of circadian rhythms through misalignment of the sleep–wake cycle, inappropriately timed light, activity, or feeding have been linked to changes in sleep, dietary behavior, and weight. This chapter will review the experimental literature in animal models and the experimental and observational human literature linking circadian rhythms of sleep and eating to weight regulation. We will begin with a description of circadian rhythms in humans, including the rhythm of the sleep–wake cycle, hunger, and appetite. The second section will review links between circadian disruption (e.g., CLOCK gene mutations in animals, light exposure, chronotype, and social jet lag) and obesity risk. The third section will review the evidence linking the timing of eating to circadian disruption and weight regulation. Overall, the literature suggests that circadian rhythms are important to weight regulation and metabolism. Suggested mechanisms include dietary behavior, appetite stimulating hormones, and glucose metabolism.

Light is the most important Zeitgeber to entrain the circadian clock of the fruit fly Drosophila melanogaster to the 24-h cycle on earth. The fruit fly's circadian clock is very light sensitive, mainly because about half of the 150 clock neurons in the fly's brain express the blue-light photopigment, Cryptochrome, which provokes an immediate degradation of the clock protein Timeless upon activation by light. Consequently, Drosophila's molecular clock can reset very fast to measure the changes in environmental-lighting conditions. However, usually the responses of the molecular clock to light are not directly measured, but conclusions about entrainment of the circadian clock are drawn from recording the flies' locomotor activity rhythms. Here, we review how the flies' locomotor activity can be recorded under different light regimes and how entrainment can be analyzed and properly judged. We also summarize the influence of different recording and lighting methods on the flies' activity pattern, highlight their advantages and disadvantages, and stress general pitfalls.

Biological rhythms evolved to adapt to and to anticipate the 24-h cycle of light and darkness. The physiological framework that underpins these circadian (about 24-h) rhythms comprises oscillations in the expression of clock genes and their protein products. The molecular machinery of the circadian system plays a pivotal role in a wide range of functional systems, ranging from the control of cell cycle, to the regulation of cardiac and metabolic function, and of the human sleep–wake cycle. However, disruptions of the fine-tuned regulation of clock gene expression can result in numerous symptoms and disorders, including circadian rhythm sleep disorders (CRSD), metabolic syndrome, and cardiovascular diseases. This article focuses on the implication of the molecular mechanisms driving circadian rhythms in CRSD. A general portrait of the complex interplay of genetic and environmental factors on the human sleep–wake cycle is also presented.

Publisher Summary This chapter discusses the molecular and neural control of insect circadian rhythms. There are four fundamental properties that define circadian rhythms. Perhaps their most striking property is their “free running” nature, which means that they persist under constant conditions, without any environmental cues. A second canonical property is that these circadian rhythms have a period of approximately, but not exactly, 24 hours. The third property is that they can be synchronized by various environmental inputs, called Zeitgebers. The fourth fundamental property of circadian rhythms is called temperature compensation. The period of circadian rhythms stays very stable under a wide range of ambient temperatures, although the kinetics of most biochemical reactions increases with higher temperature. These four canonical properties define endogenous circadian rhythms. Insects are the most widely distributed and diverse group of animals on the planet. They can be found in nearly all environments, including those exposed to extremely cold and warm temperatures. Insects are thus powerful models to study circadian rhythms at the cellular, physiological, behavioral, ecological, and evolutionary levels.

Although circannual rhythms controlling different physiological processes and various aspects of behavior have been reported in numerous organisms, our understanding of the underlying biological mechanisms is still quite limited. We examined the mechanisms controlling the circannual pupation rhythm of the varied carpet beetle, Anthrenus verbasci. This rhythm is self-sustainable, exhibits temperature compensation of the periodicity, and is entrainable to environmental changes. In addition, the circannual phase response curves to a photoperiod pulse display Type 0 or Type 1 resetting, depending on the duration of the pulse. Thus, we infer that this rhythm is derived from a self-sustaining biological oscillator with a period of about a year, that is, a circannual clock, analogous to the circadian clock. Further, a circadian clock appears to mediate photoperiodic time measurement for phase resetting of the circannual clock. Based on these results and previous research performed in other organisms, we discuss the general characteristics of the physiological mechanisms underpinning circannual rhythmicity.

The phase of the mammalian circadian system can be entrained to a range of environmental stimuli, or zeitgebers, including food availability and light. Further, locomotor activity can act as an entraining signal and represents a mechanism for an endogenous behavior to feedback and influence subsequent circadian function. This process involves a number of nuclei distributed across the brain stem, thalamus, and hypothalamus and ultimately alters SCN electrical and molecular function to induce phase shifts in the master circadian pacemaker. Locomotor activity feedback to the circadian system is effective across both nocturnal and diurnal species, including humans, and has recently been shown to improve circadian function in a mouse model with a weakened circadian system. This raises the possibility that exercise may be useful as a noninvasive treatment in cases of human circadian dysfunction including aging, shift work, transmeridian travel, and the blind.

Daily rhythms that ebb and flow in amplitude over the course of the day can be seen in almost any behavioral or physiological response that one cares to measure. Intuitively, it seems that these rhythmic responses are caused by the changing light–dark cycle or by responses to the alarm clock signaling that it is time to go to work or school. In fact, daily cycles are orchestrated by an internal timing system in the body, and these endogenously driven responses are termed circadian rhythms. This timing system consists of oscillators or ‘clock cells’ located in many tissues, whose timing ( period and phase) is synchronized by a master clock located in the suprachiasmatic nucleus (SCN) of the hypothalamic area of the brain. The SCN is set to local time by signals from the light–dark cycle, and the output of this nucleus determines the timing of activity in various bodily functions. Impressively, a diffusible signal is sufficient to determine activity cycles, while a neural output signal controls endocrine rhythms. In this article, we consider the evolution, adaptive significance, development, and mechanisms of the circadian timing system. We also consider the fascinating story of how this system determines annual rhythms in anticipation of changing seasons.

Publisher Summary This chapter discusses the circadian disruption of hormone release and immune-related mechanisms in the rat adjuvant arthritis model. The experimental manipulation used perturbed the temporal organization by affecting the shape and amplitude of the rhythm. Although circadian rhythms are anchored genetically, they are synchronized by and maintain certain phase relationships to external factors. In mammals, the circadian system is composed of many individual, tissue-specific cellular clocks. To generate coherent physiological and behavioral responses, a master circadian pacemaker orchestrates the phases of a multitude of cellular clocks. This circadian pacemaker resides in the suprachiasmatic nuclei (SCN) of the hypothalamus. At a molecular level, circadian clocks are based on clock genes, some of which encode proteins able to feed back and inhibit their own transcription. The daily variation of biological variables arises from an internal time-keeping system, and the major action of the environment is to synchronize this internal clock to a period of exactly 24 hours. The light–dark cycle, food, ambient temperature, scents, and social cues have been identified as environmental synchronizers or “Zeitgebers” in rats. Further experiments are needed to assess whether the changes in amplitude, as well in the timing of 24-hour rhythms discussed herein, can be attributed to an effect on the SCN or to a masking effect on some output(s) of the clock.

What is it that keeps us awake? Our assumption is that we consciously control our daily activities including sleep-wake behavior, as indicated by our need to make use of an alarm clock to wake up in the morning in order to be at work on time. However, when we travel across multiple time zones or do shift work, we realize that our intentionally planned timings to rest and to remain active can interfere with an intrinsic regulation of sleep/wake cycles. This regulation is driven by a small region in the anterior hypothalamus of the brain, termed as the "circadian clock". This clock spontaneously synchronizes with the environmental light-dark cycle, thus enabling all organisms to adapt to and anticipate environmental changes. As a result, the circadian clock actively gates sleep and wakefulness to occur in synchrony with the light-dark cycles. Indeed, our internal clock is our best morning alarm clock, since it shuts off melatonin production and boosts cortisol secretion and heart rate 2-3h prior awakening from Morpheus arms. The main reason most of us still use artificial alarm clocks is that we habitually carry on a sleep depth and/or the sleep-wake timing is not ideally matched with our social/work schedule. This in turn can lead hourglass processes, as indexed by accumulated homeostatic sleep need over time, to strongly oppose the clock. To add to the complexity of our sleep and wakefulness behavior, light levels as well as exogenous melatonin can impinge on the clock, by means of their so-called zeitgeber (synchronizer) role or by acutely promoting sleep or wakefulness. Here we attempt to bring a holistic view on how light, melatonin, and the brain circuitry underlying circadian and homeostatic processes can modulate sleep and in particular alertness, by actively promoting awakening/arousal and sleep at certain times during the 24-h day.

Circadian rhythms, common to most organisms, from bacteria to human, are driven by circadian clocks. These intrinsic timekeeping systems regulate various biochemical, physiological, and behavioral processes with a periodicity of about 24 h, enhancing the efficiency and survival of organisms by allowing them to anticipate and adapt to changing environmental conditions. Mammalian circadian rhythms are generated in pacemaker cells within the suprachiasmatic nuclei (SCN) of the hypothalamus. Pacemakers are composed of molecular oscillators responsible for the control of overt circadian rhythms in the animal’s physiology and behavior. Circadian oscillators are endogenous, cell-autonomous systems that maintain their rhythm even in the absence of external time cues. Importantly, entrainment of the endogenous clock is achieved by specific cues, such as light. It is now well established that peripheral tissues also contain independent oscillators, functionally orchestrated by the central clock within the SCN. The circadian clock is constituted by three conceptual components, the intrinsic pacemaker, the input, and the output pathways. Here we summarize the important molecular and cellular features of the mammalian circadian clock which are critical for the establishment and maintenance of circadian rhythms.

A major factor in the evolution of circadian rhythms is the control of phase relationships – both among various rhythms and with respect to daily cycles of the immediate external environment. The daily light cycle is the environmental factor that most influences the circadian system. Therefore the photic environment of the organism, largely determined by behavioral strategies, is a major selective force in the evolution of circadian systems and provides a framework for interpretation of phylogenetic differences in the physiological and anatomical organization of circadian systems in the metazoa.

Many aspects of human physiology and behavior are dominated by 24 h rhythms that have a major impact on our health and well-being. The daily light-dark cycle plays the primary role in synchronizing these rhythms with the 24 h day. The properties of light that determine the efficacy of its circadian phase-resetting effects include the timing, intensity, duration, pattern, wavelength, and history of exposure. Major advances have been made in understanding how light is detected by the eye to reset circadian rhythms. A novel photoreceptor system has been discovered that mediates circadian photic responses that is anatomically and functionally distinct from the visual system. © 2009 Elsevier Ltd All rights reserved.

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 behavioral 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 nonhuman primates furthermore suggest that the SCN is the locus of the brain’s endogenous calendar, enabling organisms to anticipate seasonal environmental changes. This article 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. The functional activity of the biological clock is entrained to the seasonal photic cycle and photoperiod (day length) may act as an effective zeitgeber. Furthermore, electrophysiological and molecular studies suggest 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.

Neuroscience Institute, Morehouse School of Medicine, Atlanta, GA, USAIntroductionDaily rhythmicity is a ubiquitous feature of living systems. Generally, theserhythms are not just passive consequences of cyclic fluctuations in the environ-ment, but, rather they originate within the organisms. They are generatedand controlled by endogenous physiological oscillators. The fundamentaladaptive function of an endogenously programmed rhythmicity is to providean optimal and anticipatory temporal organization of physiological processesand behavior in relation to the environment. Endogenously controlled dailyrhythms are called circadian rhythms, referring to the fact that they have aperiod of about a day. Under conditions of temporal isolation this period,in most cases, slightly deviates from exactly 24 h. Synchronization of endo-genous circadian rhythms to the environment occurs through daily adjustmentof the clock by external time cues or zeitgebers. The most important and reliablecue for synchronization is the daily light–dark cycle (Pittendrigh and Daan,1976).Properties of circadian rhythmsSince some of the terminology used in this review is specific to the circadianspecialty, we will begin this chapter with an explanation of the most commonterms used to describe circadian rhythms. A circadian clock is a part of anorganism which is capable of generating a self-sustained rhythm with a periodclose to 24 h. A rhythm is characterized by three features: period, amplitudeand phase (Fig. 1). The period is the length of time necessary to completeone full cycle, the amplitude is, roughly, the difference between the maximumand the minimum levels observed during a full cycle, and the phase refers to thetemporal relationship between a specific identifiable point on the cycle and apoint on a reference cycle.When an organism is maintained under constant conditions its circadianrhythms persist with a period close to, but different from 24 h. The fact thatrhythmicity persists under constant condition demonstrates that the rhythmis endogenous. The period of a rhythm under constant conditions is called its

The circadian timing system (CTS) allows organisms on earth to synchronize internal rhythms to the environmental 24-hour light-dark cycle and anticipate the body on the forthcoming period of either activity or rest. The central pacemaker of the CTS is the hypothalamic suprachiasmatic nucleus (SCN) regulating most, if not all, circadian rhythms in the body. The plasticity of this system at old age is the subject of this review, with special regard to its major internal stimulus, the pineal hormone melatonin. The circadian rhythm in melatonin production is regulated by the SCN and results in low daytime circulating levels of melatonin and an increase of circulating melatonin after darkness onset. This rhythm, like other circadian rhythms, is attenuated in elderly subjects. The relation between the age-related change in melatonin levels and sleep is discussed in this paper. Based on the hypothesis that there is a relationship between the increased prevalence of sleepdisturbances and decreased melatonin levels in elderly, several studies have been performed to investigate the effect of exogenous melatonin supplementation on sleep in elderly and demented subjects. An overview of these findings is presented and the various results are discussed.

Publisher Summary Studies of immediate-early genes (IEG) expression in the circadian regulatory system and in structures involved in sleep-wake control have been useful in identifying anatomical sites that play a role in these mechanisms. They help to identify candidate molecular mechanisms that mediate environmental and endogenous regulation of sleep-wake and circadian rhythmicity at the cellular level. Studies of IEGs have taken advantage of their rapid, brief expression changes in response to signals to better understand processes involved in responding to photic input and to sleep deprivation. Studies of patterns of activation using IEG expression have provided interesting hints about the way different brain regions respond to different timed periods of sleep deprivation. These results may provide an indication of the differential roles of these structures in evaluating and responding to sleep loss and in integrating the influences of homeostatic and circadian regulators of sleep onset and maintenance.

Publisher Summary This chapter discusses factors influencing long-term time estimation in humans. The chapter describes in detail the limited data addressing what is known about human long-term time estimation. It speculates on possible mechanisms involved in the perception of the passage of long intervals. However, a brief background in the area of human circadian rhythms is provided, since the very nature of studies into long-term time estimation frequently necessitates the use of experimental settings and methodologies unique to the study of human circadian rhythmicity. The chapter suggests that the human time sense, particularly as it applies to the estimation of longer intervals, is intimately tied to the functioning of the circadian timing system. Human circadian rhythms, like those of all other organisms studied, are strongly influenced by the natural, 24-hour alternation of light and darkness, and to a lesser extent by the social and behavioral cues that structure human's daily lives. Thus, to rule out the potential entraining influences of these external time cues, it is necessary to study putative endogenous rhythms under conditions in which such zeitgebers are eliminated or strictly controlled.

The early development of circadian rhythms in primates, including man, was reviewed. Continuous 24-h recordings were carried out for maternal and fetal circadian rhythms during gestation as well as in preterm infants. Several propositions were made based on these new findings: 1. The fetal biological clock is an endogenous clock capable of generating circadian rhythms and responding to maternal entraining signals long before the moment of birth. 2. Through the fetal biological clock, maternal circadian rhythms influence the fetal overt rhythms. 3. Maternal rhythms influence the fetus, and fetal rhythms feed back to the mother (via the placenta). Disruption of this fetal-maternal interaction during gestation leads to: a. disturbances of maternal and fetal circadian rhythms; b. disappearance of circadian rhythms at the time of birth; c. a gestational period which is either too short or too long (see also Honnebier and Swaab, 1973); d. delayed or impaired maturation of the circadian rhythms of the infant.

Publisher Summary Mammalian circadian rhythms are controlled by a pacemaker that is located in the suprachiasmatic nucleus (SCN) of the hypothalamus. The SCN produces rhythms of roughly 24 hours. In the external world, circadian rhythms are entrained to the environmental light/dark cycle and adopt the external period of 24 hours. As a consequence, animals time their behaviour properly in view of the light/dark cycle that enhances their chance of survival. In this chapter, the current knowledge on photo entrainment is reviewed. The photic entrainment of the biological pacemaker is based on adjustments to the light/dark cycle made possible by a phase-dependent responsiveness of the pacemaker to light. Additional mechanisms increase the animal's ability to entrain. The magnitude of a phase shift that can be obtained at a given phase of the circadian cycle depends on (a) light intensity, (b) duration of a light pulse, and (c) wavelength of light. The role of any of these three parameters is investigated by manipulating only one of them while keeping the other two constant.

Publisher Summary This chapter focuses on some evidence for signal integration within the circadian system at anatomical, cellular, and chemical levels of organization. It also examines the idea that a primary function of the temporal organization of photic and non-photic responsiveness is to precisely define the transitions among organisms' physiological day and night. The influence of non-photic events may be critically important for the day-to-day regulation of physiological and behavioral timing. Phase angle of entrainment is a primary phenotypic expression of the circadian system that is subject to natural selection, and numerous mechanisms may have evolved to adjust species-specific entrainment or to allow individuals to briefly adjust for the daily exigencies of their environment. The fact that circadian systems are designed to allow the interaction of photic and non-photic responses at many levels of organization attests to the need for integration in the regulation of entrainment. The accuracy and stability of entrainment, and the precision of some overt circadian rhythms, rely not only on the ability to respond to a Zeitgeber but also on the ability to integrate the variety of signals that may directly alter the phase or affect the responsiveness of the clock to other Zeitgeber and regulatory input.

Publisher Summary This chapter focuses on the genes and proteins controlling circadian rhythms in drosophila . Thus far, two genes, timeless ( tim ) and period ( per) have been identified that are essential for production of all known behavioral and molecular circadian rhythms. Therefore, the molecular changes associated with the arrhythmic and certain long-period and short-period mutations are known. For per , mutations changing period length thus far have been associated with single amino acid substitutions in the encoded protein. As might be expected from these effects of gene dosage on period length, transient increases in the titer of per RNA can shift the phase of the circadian rhythm. As comparable shifts in phase can be induced by Zeitgeber, such as entraining light pulses, the results suggest that the changes in the abundance or activities of PER proteins may be a part of the normal mechanism by which circadian behavioral rhythms are endogenously generated and reset by environmental stimuli. In the absence of such a delay, constitutive application of feedback regulation will specify an equilibrium state associated with constant levels of per and tim RNA and proteins. In contrast, by separating the phases of RNA and protein accumulation through a requirement for PER–TIM interaction, feedback control is applied at only some times of day. Sustained cycling of RNA and protein levels is expected if nuclear PER inhibits per and tim RNA synthesis.

Publisher Summary This chapter discusses the relationship between the pineal gland and cancer. The rhythm parameters can differ, but the occurrence of seasonality may still be a result of the same biological factors. The pineal gland is affected by growth of malignant tumors, particularly of breast and prostate, and the pineal hormone melatonin and also other yet unidentified pineal substances are capable of inhibiting a number of experimental tumors in vivo and in vitro. Human patients suffering from breast and prostate cancer show a tumor-stage-dependent depression of circadian serum melatonin rhythms when compared to age-matched patients with benign tumors. To prove the involvement of olfactory or geomagnetic factors as zeitgebers for seasonal rhythms, experiments will have to be performed under complete shielding of such influences that require highly sophisticated experimental setups. Irrespective of the factors acting as zeitgebers for the synchronization of endogenous rhythms under controlled laboratory conditions, the fact remains that such rhythms cannot be easily extinguished, neither in humans nor in experimental animals.

Publisher Summary This chapter describes daily melatonin infusion entrains free-running activity Syrian and Siberian hamsters. One aspect of melatonin secretion that has not to be forgotten is that its rhythm is a circadian one that, like many other circadian rhythms, is directly generated in the suprachiasmatic nuclei of the hypothalamus. Considerable speculation has surrounded this possible role of melatonin as a circadian zeitgeber, especially in humans for the treatment of pathologically or socially induced disturbances of biological rhythms. During an experiment described in the chapter, animals were housed individually in infusion cages, each of these cages being placed inside a light-tight and sound isolated ventilated wooden box. For Syrian hamster, to test a possible effect of Ringer infusion, the animals were prepared and placed in the system a few weeks before starting the Ringer infusion. Syrian hamsters, contrary to rats, are not entrained by daily injections of melatonin. The data confirm the hypothesis that in mammals, like in nonmammalian vertebrates, melatonin is involved in the control or the expression of circadian rhythms.

Circadian rhythms are already present in the fetus. At a certain stage of pre-natal hypothalamic development (around 30 weeks of gestation) the fetus becomes responsive to maternal circadian signals. Moreover, recent studies showed that the fetal biological clock is able to generate circadian rhythms, as exemplified by the rhythms of body temperature and heart rate of pre-term babies in the absence of maternal or environmental entrainment factors. Pre-term babies that are deprived of maternal entrainment and kept under constant environmental conditions (e.g., continuous light) in the neonatal intensive care unit run the risk of developing a biological clock dysfunctioning. However, the fact should be acknowledged that at least in mice the development of the circadian pacemaker (i.e., SCN) does not depend on environmental influences (Davis and Menaker, 1981), although other data suggest that severe disruption of the maternal circadian rhythm indeed abolishes the circadian rhythm of the fetal SCN (Shibata and Moore, 1988). During aging and in particular in AD circadian rhythms are disturbed. These disturbances include phase advance and reduced period and amplitude, as well as an increased intradaily variability and a decreased interdaily stability of the rhythm. Among the factors underlying these changes the loss of SCN neurons seems to play a central role. Other contributory factors may be reduced amount of light, degenerative changes in the visual system and the level of activity and decreased melatonin.

The concept of the hypothalamus as a distinct neurological entity concerned with a variety of regulatory processes dates back to the end of the 19th century. Before 1900 there were only vague intimations of the function of the brain surrounding the third ventricle and these were based primarily on various pathological and assorted clinical observations. Since then a large body of evidence has been derived implicating that the hypothalamus contains the control systems which are critically involved in many physiological, endocrine and behavioral processes. Among these are feeding and drinking, reproduction and the regulation of the sleep-wake cycle and temperature. Although the human hypothalamus accounts for only 4 cm3, or 0.3% of the adult brain volume, it contains the integrative systems critical for all these processes. A comparative morphometric analysis of the hypothalamus among mammals revealed that the volume of this part of the brain is highly correlated with brain size, irrespective of the ecological strategy or evolutionary history of the species considered. It appears that the human hypothalamus has just the size we may expect of such a large-brained mammal, but it is considerably larger than would be predicted from its body size. In mammals the preoptic region of the hypothalamus is implicated in the neural control of endocrine functions and in the temporal organization of a wide spectrum of biological rhythms. In recent years, the pivotal role of two hypothalamic cell groups have been considered in this context: the sexually dimorphic nucleus (SDN-POA) as part of the neural circuitry underlying masculine sexual behavior and reproductive functions and the suprachiasmatic nucleus (SCN) as the principal component of the central clock mechanism. Consistent with its role in the temporal organization of circadian processes, investigations in rodents and non-human primates suggest that the SCN is also involved in the seasonal control of reproductive and metabolic phenomena. Since the environmental light-dark cycle is the main Zeitgeber for circadian and seasonal rhythms in most species, including man, photic information could have substantial effects, not only on the neural activity of the biological clock, but also on its underlying structure. Our observations on the human SCN in relation to photoperiod indeed revealed a marked seasonal variation in the morphology of the human SCN. The volume of the SCN was, on average, twice as large in the autumn as in the summer and contained more than twice as many vasopressin immunoreactive neurons.(ABSTRACT TRUNCATED AT 400 WORDS)

The circadian eciosion rhythm of Ch. thummi is synchronized with the photoperiod. The pattern, however, is modified by the temperature level. The midges emerge from cold water near noon, from warmer water in the evening. Temperature cycles can synchronize eclosion in constant light. Under light-dark conditions, however, they hardly affect the pattern as long as their amplitude is below 4° C. With much higher amplitudes the phase as well as the level of the temperature cycle can modify the eclosion time, but the influence of the photoperiod is never completely overruled.

Publisher Summary This chapter focuses on the circadian rhythm mechanisms. It describes those by which oscillator activity might originate. The role of zeitgeber or synchronizers is to entrain or adjust the free-running circadian rhythm to the external environment. As the importance of entrainment is to ensure that the peaks of the rhythms are appropriately phased with respect to the environment, interest has centered on the relationship that exists between the phase of the zeitgeber and that of the circadian rhythms. The chapter discusses the relationship between entrainment and zeitgeber , the means of identifying zeitgeber , and the means by which zeitgeber might affect rhythms. Studies on zeitgeber in humans have rarely distinguished the process of entrainment from that of masking, and experiments in which a single zeitgeber has been introduced into an environment that was otherwise constant have not been performed. In practice, the experimental protocol has generally consisted of a comparison of circadian rhythms after a putative zeitgeber has been shifted or removed. The chapter highlights the second approach. The concept of social factors is the most important zeitgeber in humans. It is not possible to assess the relative importance of the different putative zeitgeber to humans because of discrepancies in the data and difficulties in interpretation. Nevertheless, some comment can be made relating to the manner in which zeitgeber as a group acts on the process of synchronization.

Publisher Summary This chapter describes the 48-hour cycles of depression and their biological concomitants with and without zeitgebers. A general feature of 48-hour cycles in the mental state is that mainly, though not exclusively, general activity and mood are involved with a dramatic change from either one abnormal extreme to the opposite extreme or from one of them to a normal state. Commonly, one state lasts for 24 h so that in the latter case, bad days and good days run in alternation. In most cases, the change takes place during the night while the patients are sleeping so that they awake in the morning with quite a different mental condition compared to the day before. The time of change may vary between patients, but for each individual, this time may be remarkably stable. Very often, the change occurs very rapidly, in some instances even within a few seconds. The transition involves a whole spectrum of symptoms in the areas of activity, mood, thought content, and others. The resulting syndromes cannot be differentiated from those seen in other organic or functional mental disorders, either general paralysis with excitement and/or affective symptomatology or episodic psychoses of a schizophrenic, schizoaffective, or purely affective type.

Publisher Summary This chapter discusses several basic properties of the circadian system. Circadian rhythms are characterized by their capability to free-run in constant conditions like self-sustaining oscillations and by the way in which they are synchronized—entrained—by periodic factors in the environment, the Zeitgebers. Circadian rhythms are only entrainable by Zeitgebers within a limited range of periods. Within this range of entrainment, the rhythm changes its phase-relationship to the Zeitgeber: the rhythm phase leads a Zeitgeber having a relatively long period, and phase lags a Zeitgeber with a short period. Moreover, when exposed to an appropriate Zeitgeber, for example, a light-dark cycle complemented by regular gong signals, human circadian rhythms can be entrained—within limits—to periods other than 24 h.

Publisher Summary This chapter provides an overview of steroid effects on the cells, tissues, and organs of the various species. Glucocorticoids are secreted on demand from the adrenal cortex under immediate control of pituitary adrenocorticotropic hormone (ACTH) and other products of pro-opiomelanocortin in the longer term. ACTH has two patterns of secretion: (1) circadian, with a major peak around waking, minor meal-related peaks, and troughs of very low levels, and (2) episodic, in response to stress. High-affinity receptors, occupied or empty during the diurnal variations in glucocorticoid levels, are ideally placed to mediate, for example, glucocorticoid effects on mood, appetite and sleep/wake patterns, or permissive effects on the production of milk proteins. Classical glucocorticoid receptors have much lower affinity for natural glucocorticoids; these sites are substantially occupied only by levels of glucocorticoid, which are a response to supranormal levels of ACTH following stress. Glucocorticoids may play two physiological roles: (1) the first is a in a time dimension, serving as a diurnal Zeitgeber for various neural and secretory processes via type I receptors and (2) the other is via type II receptors, as the endocrine equivalent of the sympathetic nervous system, serving to integrate cellular and organ adaptations to stress, primordially in response to changes in energy balance.