The mammalian circadian system, which is comprised of multiple cellular clocks located in the organs and tissues, orchestrates their regulation in a hierarchical manner throughout the 24 hr of the ...day. At the top of the hierarchy are the suprachiasmatic nuclei, which synchronize subordinate organ and tissue clocks using electrical, endocrine, and metabolic signaling pathways that impact the molecular mechanisms of cellular clocks. The interplay between the central neural and peripheral tissue clocks is not fully understood and remains a major challenge in determining how neurological and metabolic homeostasis is achieved across the sleep-wake cycle. Disturbances in the communication between the plethora of body clocks can desynchronize the circadian system, which is believed to contribute to the development of diseases such as obesity and neuropsychiatric disorders. This review will highlight the relationship between clocks and metabolism, and describe how cues such as light, food, and reward mediate entrainment of the circadian system.
Here, Albrecht reviews the relationship between central and peripheral circadian clocks and how cues such as light, food, and reward mediate entrainment of the circadian system. The implications of desynchronization of these clocks for human health and disease are also discussed.
The circadian system consists of individual cellular clocks. It organizes and synchronizes biochemical and physiological processes in order to optimally adapt an organism to its environment. This ...requires that the circadian system is responsive to environmental cues, which contain information about geophysical time (e.g., light), and allows an organism to predict daily recurring events. However, the system needs to be responsive to unpredictable cues (e.g., predators, stress) as well, which makes it vulnerable in its task to synchronize body functions on a 24-h time scale. If unpredictable signals occur only occasionally, this will have a minor effect on the clock system. Conversely, stress signals that occur more frequently will desynchronize the various cellular and tissue clocks in the body. This will result in biochemical and physiological disorder and as a consequence will lead to various diseases including neurological and mood disorders.
In this review, I will describe molecular mechanisms that have been associated with the circadian clock and mood-related behaviors.
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•Clock genes regulate transcription of enzymes important for dopamine metabolism.•The HPA axis, the clock, and mood regulation influence each other.•Light affects the HPA axis, the clock, and mood.
The circadian system coordinates activities and functions in cells and tissues in order to optimize body functions in anticipation to daily changes in the environment. Disruption of the circadian ...system, due to irregular lifestyle such as rotating shift work, frequent travel across time-zones, or chronic stress, is correlated with several diseases such as obesity, cancer, and neurological disorders. Molecular mechanisms linking the circadian clock with neurological functions have been uncovered suggesting that disruption of the clock may be critically involved in the development of mood disorders. In this mini-review, I will summarize molecular mechanisms in which clock components play a central role for mood regulation. Such mechanisms have been identified in the monoaminergic system, the HPA axis, and neurogenesis.
Circadian clocks are present in nearly all tissues of an organism, including the brain. The brain is not only the site of the master coordinator of circadian rhythms located in the suprachiasmatic ...nuclei (SCN) but also contains SCN-independent oscillators that regulate various functions such as feeding and mood-related behavior. Understanding how clocks receive and integrate environmental information and in turn control physiology under normal conditions is of importance because chronic disturbance of circadian rhythmicity can lead to serious health problems. Genetic modifications leading to disruption of normal circadian gene functions have been linked to a variety of psychiatric conditions including depression, seasonal affective disorder, eating disorders, alcohol dependence, and addiction. It appears that clock genes play an important role in limbic regions of the brain and influence the development of drug addiction. Furthermore, analyses of clock gene polymorphisms in diseases of the central nervous system (CNS) suggest a direct or indirect influence of circadian clock genes on brain function. In this chapter, I will present evidence for a circadian basis of mood disorders and then discuss the involvement of clock genes in such disorders. The relationship between metabolism and mood disorders is highlighted followed by a discussion of how mood disorders may be treated by changing the circadian cycle.
Most physiology and behavior of mammalian organisms follow daily oscillations. These rhythmic processes are governed by environmental cues (e.g., fluctuations in light intensity and temperature), an ...internal circadian timing system, and the interaction between this timekeeping system and environmental signals. In mammals, the circadian timekeeping system has a complex architecture, composed of a central pacemaker in the brain's suprachiasmatic nuclei (SCN) and subsidiary clocks in nearly every body cell. The central clock is synchronized to geophysical time mainly via photic cues perceived by the retina and transmitted by electrical signals to SCN neurons. In turn, the SCN influences circadian physiology and behavior via neuronal and humoral cues and via the synchronization of local oscillators that are operative in the cells of most organs and tissues. Thus, some of the SCN output pathways serve as input pathways for peripheral tissues. Here we discuss knowledge acquired during the past few years on the complex structure and function of the mammalian circadian timing system.
Endogenous circadian rhythms are biological processes generated by an internal body clock. They are self-sustaining, and they govern biochemical and physiological processes. However, circadian ...rhythms are influenced by many external stimuli to reprogram the phase in response to environmental change. Through their adaptability to environmental changes, they synchronize physiological responses to environmental challenges that occur within a sidereal day. The precision of this circadian system is assured by many post-translational modifications (PTMs) that occur on the protein components of the circadian clock mechanism. The most ancient example of circadian rhythmicity driven by phosphorylation of clock proteins was observed in cyanobacteria. The influence of phosphorylation on the circadian system is observed through different kingdoms, from plants to humans. Here, we discuss how phosphorylation modulates the mammalian circadian clock, and we give a detailed overview of the most critical discoveries in the field.
The rotation of the Earth around its axis causes periodic exposure of half of its surface to sunlight. This daily recurring event has been internalized in most organisms in the form of cellular ...circadian clock mechanisms. These cellular clocks are synchronized with each other in various ways to establish circadian networks that build the circadian program in tissues and organs, coordinating physiology and behavior in the entire organism. In the mammalian brain, the suprachiasmatic nucleus (SCN) receives light information via the retina and synchronizes its own neuronal clocks to the light signal. Subsequently, the SCN transmits this information to the network of clocks in tissues and organs, thereby synchronizing body physiology and behavior. Disruption of cellular clocks and/or destruction of the synchronization between the clocks, as experienced for instance in jet lag and shift-work conditions, affects normal brain function and can lead to metabolic problems, sleep disturbance, and accelerated neurological decline. In this review, we highlight ways through which the circadian system can coordinate normal brain function, with a focus on metabolism and metabolic astrocyte–neuron communications. Recent developments, for example, on how waste clearance in the brain could be modulated by the circadian clock, will also be discussed. This synthesis provides insights into the impact of metabolism not only on the circadian clock, but also on sleep and how this connection may exacerbate neurological diseases.
The physiology and metabolism of organisms are organized in a temporal fashion using cellular circadian clocks for timing. These cellular clocks are synchronized at the tissue level and are in stable phase relationships to other tissues and organs, thereby establishing an organism-wide circadian system.
Temporal organization ensures efficient and highly coordinated metabolism, which is essential for adaptability and robustness of physiological functions under changing environmental conditions. Chronic disturbance of this coordination (e.g., rotating shift work, and chronic jet lag) leads to interference between anabolic and catabolic processes and an increase of metabolic and protein waste products coupled with inefficient clearance. As a consequence, metabolic and neurological diseases may develop.
The glymphatic system has emerged as a waste clearance system for the central nervous system. Its detailed function and temporal coordination for optimal waste clearance is subject of intense research.
Mitochondrial fission-fusion dynamics and mitochondrial bioenergetics, including oxidative phosphorylation and generation of ATP, are strongly clock controlled. Here we show that these circadian ...oscillations depend on circadian modification of dynamin-related protein 1 (DRP1), a key mediator of mitochondrial fission. We used a combination of in vitro and in vivo models, including human skin fibroblasts and DRP1-deficient or clock-deficient mice, to show that these dynamics are clock controlled via circadian regulation of DRP1. Genetic or pharmacological abrogation of DRP1 activity abolished circadian network dynamics and mitochondrial respiratory activity and eliminated circadian ATP production. Pharmacological silencing of pathways regulating circadian metabolism and mitochondrial function (e.g., sirtuins, AMPK) also altered DRP1 phosphorylation, and abrogation of DRP1 activity impaired circadian function. Our findings provide new insight into the crosstalk between the mitochondrial network and circadian cycles.
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•The circadian clock controls rhythmic mitochondrial dynamics and metabolic flux•DRP1 is phosphorylated in circadian fashion•Suppression of DRP1 activity eliminates circadian ATP production•Blocking DRP1 function impairs the core circadian clock
Schmitt et al. demonstrate that the circadian clock globally regulates mitochondrial morphology and energy metabolism. Even in non-dividing tissues, rhythmic control of DRP1 phosphorylation directs circadian mitochondrial morphology. This control is not only essential for circadian ATP production but also feeds back to influence the core circadian clock.
The circadian system coordinates mammalian physiology and behavior with the environmental light–dark cycle. It allocates sleep to the inactivity phase using various mechanisms involving ...neurotransmitters, nuclear receptors, and protein kinases. These pathways are related to metabolism, indicating that the circadian system and sleep are connected via metabolic parameters. This suggests that organs other than the brain may “sleep.” A hypothetic view on this aspect is presented providing a different perspective on sleep regulation.
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