The Genetics of Mammalian Circadian Order and Disorder: Implications for Physiology and Disease
TL;DR: Together, these studies set the scene for applying the knowledge of circadian biology to the understanding and treatment of a range of human diseases, including cancer and metabolic and behavioural disorders.
Abstract: Circadian cycles affect a variety of physiological processes, and disruptions of normal circadian biology therefore have the potential to influence a range of disease-related pathways. The genetic basis of circadian rhythms is well studied in model organisms and, more recently, studies of the genetic basis of circadian disorders has confirmed the conservation of key players in circadian biology from invertebrates to humans. In addition, important advances have been made in understanding how these molecules influence physiological functions in tissues throughout the body. Together, these studies set the scene for applying our knowledge of circadian biology to the understanding and treatment of a range of human diseases, including cancer and metabolic and behavioural disorders.
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TL;DR: An emerging view for the adaptive significance of circadian clocks is their fundamental role in orchestrating metabolism.
Abstract: The circadian system of mammals is composed of a hierarchy of oscillators that function at the cellular, tissue, and systems levels. A common molecular mechanism underlies the cell-autonomous circadian oscillator throughout the body, yet this clock system is adapted to different functional contexts. In the central suprachiasmatic nucleus (SCN) of the hypothalamus, a coupled population of neuronal circadian oscillators acts as a master pacemaker for the organism to drive rhythms in activity and rest, feeding, body temperature, and hormones. Coupling within the SCN network confers robustness to the SCN pacemaker, which in turn provides stability to the overall temporal architecture of the organism. Throughout the majority of the cells in the body, cell-autonomous circadian clocks are intimately enmeshed within metabolic pathways. Thus, an emerging view for the adaptive significance of circadian clocks is their fundamental role in orchestrating metabolism.
1,674 citations
Cites background from "The Genetics of Mammalian Circadian..."
...All rights reserved 0147-006X/12/0721-0445$20.00 The circadian system of mammals is composed of a hierarchy of oscillators that function at the cellular, tissue, and systems levels....
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...In mammals, the mechanism of the circadian clock is cell autonomous and arises from an autoregulatory negative-feedback transcriptional network (Lowrey & Takahashi 2004, Takahashi et al. 2008) (Figure 1)....
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...Living systems possess an exquisitely accurate internal biological clock that times daily events ranging from sleep and wakefulness in humans to photosynthesis in plants (Takahashi et al. 2008)....
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...Other feedback loops involve the PAR-bZip family members, DBP, HLF, and TEF; the bZip protein, E4BP4 (Nfil3); and the bHLH proteins, DEC1 and DEC2 (Bhlhb2, Bhlhb3), all of which are transcriptional targets of CLOCK-BMAL1 (Gachon 2007, Lowrey & Takahashi 2004, Takahashi et al. 2008)....
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TL;DR: Advances in understanding the interrelationship among circadian disruption, sleep deprivation, obesity, and diabetes are reviewed and implications for rational therapeutics for these conditions are reviewed.
Abstract: Circadian clocks align behavioral and biochemical processes with the day/night cycle. Nearly all vertebrate cells possess self-sustained clocks that couple endogenous rhythms with changes in cellular environment. Genetic disruption of clock genes in mice perturbs metabolic functions of specific tissues at distinct phases of the sleep/wake cycle. Circadian desynchrony, a characteristic of shift work and sleep disruption in humans, also leads to metabolic pathologies. Here, we review advances in understanding the interrelationship among circadian disruption, sleep deprivation, obesity, and diabetes and implications for rational therapeutics for these conditions.
1,538 citations
TL;DR: Genome-wide analyses of the clock transcriptional feedback loop have revealed a global circadian regulation of processes such as transcription factor occupancy, RNA polymerase II recruitment and initiation, nascent transcription, and chromatin remodelling.
Abstract: Circadian clocks are endogenous oscillators that control 24-hour physiological and behavioural processes in organisms. These cell-autonomous clocks are composed of a transcription-translation-based autoregulatory feedback loop. With the development of next-generation sequencing approaches, biochemical and genomic insights into circadian function have recently come into focus. Genome-wide analyses of the clock transcriptional feedback loop have revealed a global circadian regulation of processes such as transcription factor occupancy, RNA polymerase II recruitment and initiation, nascent transcription, and chromatin remodelling. The genomic targets of circadian clocks are pervasive and are intimately linked to the regulation of metabolism, cell growth and physiology.
1,538 citations
TL;DR: Genetic studies suggest that brain mechanisms controlling waking and NREM sleep are strongly conserved throughout evolution, underscoring their enormous importance for brain function.
Abstract: This review summarizes the brain mechanisms controlling sleep and wakefulness. Wakefulness promoting systems cause low-voltage, fast activity in the electroencephalogram (EEG). Multiple interacting neurotransmitter systems in the brain stem, hypothalamus, and basal forebrain converge onto common effector systems in the thalamus and cortex. Sleep results from the inhibition of wake-promoting systems by homeostatic sleep factors such as adenosine and nitric oxide and GABAergic neurons in the preoptic area of the hypothalamus, resulting in large-amplitude, slow EEG oscillations. Local, activity-dependent factors modulate the amplitude and frequency of cortical slow oscillations. Non-rapid-eye-movement (NREM) sleep results in conservation of brain energy and facilitates memory consolidation through the modulation of synaptic weights. Rapid-eye-movement (REM) sleep results from the interaction of brain stem cholinergic, aminergic, and GABAergic neurons which control the activity of glutamatergic reticular formation neurons leading to REM sleep phenomena such as muscle atonia, REMs, dreaming, and cortical activation. Strong activation of limbic regions during REM sleep suggests a role in regulation of emotion. Genetic studies suggest that brain mechanisms controlling waking and NREM sleep are strongly conserved throughout evolution, underscoring their enormous importance for brain function. Sleep disruption interferes with the normal restorative functions of NREM and REM sleep, resulting in disruptions of breathing and cardiovascular function, changes in emotional reactivity, and cognitive impairments in attention, memory, and decision making.
1,101 citations
TL;DR: The SCN network synchronizes its component cellular oscillators, reinforces their oscillations, responds to light input by altering their phase distribution, increases their robustness to genetic perturbations, and enhances their precision.
Abstract: The suprachiasmatic nucleus (SCN) is the primary circadian pacemaker in mammals. Individual SCN neurons in dispersed culture can generate independent circadian oscillations of clock gene expression and neuronal firing. However, SCN rhythmicity depends on sufficient membrane depolarization and levels of intracellular calcium and cAMP. In the intact SCN, cellular oscillations are synchronized and reinforced by rhythmic synaptic input from other cells, resulting in a reproducible topographic pattern of distinct phases and amplitudes specified by SCN circuit organization. The SCN network synchronizes its component cellular oscillators, reinforces their oscillations, responds to light input by altering their phase distribution, increases their robustness to genetic perturbations, and enhances their precision. Thus, even though individual SCN neurons can be cell-autonomous circadian oscillators, neuronal network properties are integral to normal function of the SCN.
1,045 citations
Cites background from "The Genetics of Mammalian Circadian..."
...In recent years, there has been a growing recognition of the importance of clock genes and circadian regulation for health; circadian clock genes have been directly implicated not only in sleep disorders but also in diabetes, cancer, and bipolar disorder (4)....
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...The circadian clock that operates in mammalian cells is based on delayed negative feedback (18) in a core transcriptional feedback loop (4, 19)....
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Journal Article•
TL;DR: Although the questionnaire appears to be valid, further evaluation using a wider subject population is required, as sleep habits are an important déterminant of peak time there are other contibutory factors, and these appear to be partly covered by the questionnaire.
Abstract: An English language self-assessment Morningness-Eveningness questionnaire is presented and evaluated against individual differences in the circadian vatiation of oral temperature 48 subjects falling into Morning, Evening and Intermediate type categories regularly took their temperature Circadian peak time were identified from the smoothed temperature curves of each subject Results showed that Morning types and a significantly earlier peak time than Evening types and tended to have a higher daytime temperature and lower post peak temperature The Intermediate type had temperatures between those of the other groups Although no significant differences in sleep lengths were found between the three types, Morning types retired and arose significantly earlier than Evening types Whilst these time significatly correlated with peak time, the questionnaire showed a higher peak time correlation Although sleep habits are an important determinant of peak time there are other contibutory factors, and these appear to be partly covered by the questionnaire Although the questionnaire appears to be valid, further evaluation using a wider subject population is required
4,758 citations
TL;DR: It is suggested that in the clinical setting, actigraphy is reliable for evaluating sleep patterns in patients with insomnia, for studying the effect of treatments designed to improve sleep, in the diagnosis of circadian rhythm disorders (including shift work), and in evaluating sleep in individuals who are less likely to tolerate PSG, such as infants and demented elderly.
Abstract: In summary, although actigraphy is not as accurate as PSG for determining some sleep measurements, studies are in general agreement that actigraphy, with its ability to record continuously for long time periods, is more reliable than sleep logs which rely on the patients' recall of how many times they woke up or how long they slept during the night and is more reliable than observations which only capture short time periods Actigraphy can provide information obtainable in no other practical way It can also have a role in the medical care of patients with sleep disorders However, it should not be held to the same expectations as polysomnography Actigraphy is one-dimensional, whereas polysomnography comprises at least 3 distinct types of data (EEG, EOG, EMG), which jointly determine whether a person is asleep or awake It is therefore doubtful whether actigraphic data will ever be informationally equivalent to the PSG, although progress on hardware and data processing software is continuously being made Although the 1995 practice parameters paper determined that actigraphy was not appropriate for the diagnosis of sleep disorders, more recent studies suggest that for some disorders, actigraphy may be more practical than PSG While actigraphy is still not appropriate for the diagnosis of sleep disordered breathing or of periodic limb movements in sleep, it is highly appropriate for examining the sleep variability (ie, night-to-night variability) in patients with insomnia Actigraphy is also appropriate for the assessment of and stability of treatment effects of anything from hypnotic drugs to light treatment to CPAP, particularly if assessments are done before and after the start of treatment A recent independent review of the actigraphy literature by Sadeh and Acebo reached many of these same conclusions Some of the research studies failed to find relationships between sleep measures and health-related symptoms The interpretation of these data is also not clear-cut Is it that the actigraph is not reliable enough to the access the relationship between sleep changes and quality of life measures, or, is it that, in fact, there is no relationship between sleep in that population and quality of life measures? Other studies of sleep disordered breathing, where actigraphy was not used and was not an outcome measure also failed to find any relationship with quality of life Is it then the actigraph that is not reliable or that the associations just do not exist? The one area where actigraphy can be used for clinical diagnosis is in the evaluation of circadian rhythm disorders Actigraphy has been shown to be very good for identifying rhythms Results of actigraphic recordings correlate well with measurements of melatonin and of core body temperature rhythms Activity records also show sleep disturbance when sleep is attempted at an unfavorable phase of the circadian cycle Actigraphy therefore would be particularly good for aiding in the diagnosis of delayed or advanced sleep phase syndrome, non-24-hour-sleep syndrome and in the evaluation of sleep disturbances in shift workers It must be remembered, however, that overt rest-activity rhythms are susceptible to various masking effects, so they may not always show the underlying rhythm of the endogenous circadian pacemaker In conclusion, the latest set of research articles suggest that in the clinical setting, actigraphy is reliable for evaluating sleep patterns in patients with insomnia, for studying the effect of treatments designed to improve sleep, in the diagnosis of circadian rhythm disorders (including shift work), and in evaluating sleep in individuals who are less likely to tolerate PSG, such as infants and demented elderly While actigraphy has been used in research studies for many years, up to now, methodological issues had not been systematically addressed in clinical research and practice Those issues have now been addressed and actigraphy may now be reaching the maturity needed for application in the clinical arena
2,321 citations
TL;DR: These findings explain how various drugs affect sleep and wakefulness, and provide the basis for a wide range of environmental influences to shape wake–sleep cycles into the optimal pattern for survival.
Abstract: A series of findings over the past decade has begun to identify the brain circuitry and neurotransmitters that regulate our daily cycles of sleep and wakefulness. The latter depends on a network of cell groups that activate the thalamus and the cerebral cortex. A key switch in the hypothalamus shuts off this arousal system during sleep. Other hypothalamic neurons stabilize the switch, and their absence results in inappropriate switching of behavioural states, such as occurs in narcolepsy. These findings explain how various drugs affect sleep and wakefulness, and provide the basis for a wide range of environmental influences to shape wake-sleep cycles into the optimal pattern for survival.
2,295 citations
"The Genetics of Mammalian Circadian..." refers background in this paper
...1 ), and these output pathways are responsible for proper timing of hormone release, feeding behaviour and body-temperature fluctuation...
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TL;DR: Estimation of transcripts encoding selected hypothalamic peptides associated with energy balance was attenuated in the Clock mutant mice, suggesting that the circadian clock gene network plays an important role in mammalian energy balance.
Abstract: The CLOCK transcription factor is a key component of the molecular circadian clock within pacemaker neurons of the hypothalamic suprachiasmatic nucleus. We found that homozygous Clock mutant mice have a greatly attenuated diurnal feeding rhythm, are hyperphagic and obese, and develop a metabolic syndrome of hyperleptinemia, hyperlipidemia, hepatic steatosis, hyperglycemia, and hypoinsulinemia. Expression of transcripts encoding selected hypothalamic peptides associated with energy balance was attenuated in the Clock mutant mice. These results suggest that the circadian clock gene network plays an important role in mammalian energy balance.
2,241 citations
"The Genetics of Mammalian Circadian..." refers background in this paper
...mutant mice are hyperphagic and obese, and not only lose rhythms of core clock genes, but also have lower levels of hypocretin (orexin) and ghrelin neuropeptide gene expression in the arcuate nucleus...
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TL;DR: Genetic and genomic analysis suggests that a relatively small number of output genes are directly regulated by core oscillator components, and major processes regulated by the SCN and liver were found to be under circadian regulation.
2,227 citations
"The Genetics of Mammalian Circadian..." refers background in this paper
...Peripheral clocks and tissue-specific control Following the initial discovery of circadian clock genes in mammals, it became clear that the expression of these genes was ubiquitous and that the majority of tissues throughout the body expressed circadian oscillations in gene expressio...
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