Physiological reviewPERIOD3, circadian phenotypes, and sleep homeostasis
Introduction
Sleep is a rich phenotype and individual differences in sleep encompass aspects such as its timing, duration and sleep structure. These differences are observed in the population of healthy individuals and extend into the realm of sleep disorders. For example, inter-individual variation in sleep timing and diurnal preference is considerable within the healthy non-complaining population,1, 2 but in its extremes may lead to a clinically significant complaint, such as advanced or delayed sleep phase disorder (ADSP, DSPD). The mechanisms underlying these individual differences are of great interest, not only because they may provide insight into their functional significance, but also because this may lead to new treatments of the disorders of sleep, including insomnia.3, 4, 5
The two-process model of sleep regulation has provided a widely accepted conceptual approach to the study of differences in sleep regulation.6, 7 In essence, it states that sleep is regulated though the interaction of two oscillatory processes: the sleep homeostat and the circadian pacemaker. The sleep homeostat is an hourglass oscillator tracking the history of sleep and wakefulness, and thereby tracks sleep debt. Established markers of the sleep homeostat are slow wave activity (SWA) in the EEG during NREM sleep8 and theta EEG activity during wakefulness.9 It has been suggested that changes in these markers are related to some of the biochemical consequences of sleep and wakefulness such as variation in extracellular adenosine concentration and other sleep regulatory substances, or related to variation in connectivity, i.e., synaptic strength, in neuronal networks.10, 11, 12 The circadian oscillator, located in the suprachiasmatic nuclei (SCN) of the hypothalamus, is a self-sustained oscillator that determines the preferred timing of sleep and wakefulness.13 Established markers of the circadian process include plasma melatonin, cortisol and core body temperature.14
There is now a wealth of data supporting the essential features of this model.14, 15, 16 Furthermore, the neuroanatomical basis of the circadian regulation of sleep in particular has been elucidated in some detail.17 In fact, new mathematical models based on this functional neuroanatomy have been developed.18, 19
We will summarize some of the data in support of the circadian and homeostatic regulation of sleep and waking performance, and discuss how detailed analyses of the interaction of these two processes has provided evidence that, contrary to the predictions of the two-process model, the sleep homeostat feeds back onto the circadian process.20 We also describe how individual differences in sleep or circadian phenotypes may, theoretically, be related to either of these two processes or their interaction.
Genetic factors have been shown to contribute considerably to individual differences in sleep traits such as diurnal preference,21 or EEG characteristics,22 but few of the genes that mediate this heritability have been identified. However, the core set of genes that are involved in the generation of circadian rhythmicity have been recognized. The molecular oscillator consists of the positive transcription factors CLOCK and BMAL1, which as a dimer bind to promoter elements of PERIOD (PER) and CRYPTOCHROME (CRY) genes and induce their expression. PER and CRY proteins are translated in the cytoplasm, where they can be phosphorylated by Casein Kinase 1, a process that can either target the proteins for F-box-mediated proteosomal degradation, or enhance nuclear translocation, depending upon the site of phosphorylation. PER and CRY proteins form dimers that can translocate to the nucleus, where they provide negative feedback on promotion of their own genes by inhibiting CLOCK/BMAL1-mediated expression. This molecular feedback loop sets the period of the oscillator, which can be governed by post-translational modification, such as phosphorylation.*23, 24 Variations in these genes have been related to some individual differences in sleep and circadian phenotypes. Please note that some of the genes involved in the homeostatic regulation of sleep have also been identified. These include genes coding for the adenosine receptors, as well as adenosine deaminase.25 We will not discuss the contribution of these genes to the homeostatic and circadian regulation of sleep. Here, we will only discuss the impact of variation in one of the clock genes, PER3, on sleep and circadian phenomenology, and discuss these effects within the context of the homeostatic and circadian regulation of sleep. One main conclusion derived from these observations and related findings on the effects of other clock genes on sleep homeostasis in animals, is that at the molecular level, circadian rhythmicity and sleep homeostasis are closely interrelated.26
Section snippets
Determinants of individual differences in sleep and circadian phenotypes: theoretical considerations
Differences in sleep timing may be related to social factors, such as work schedules, variation in light input as well as variation in the circadian and homeostatic processes (Fig. 1).
It has been established that variation in the timing of sleep is associated with variation in the timing of rhythms driven by the SCN. The core body temperature, cortisol and melatonin rhythm of healthy early sleepers is set to an earlier phase compared to late sleepers. The differences in the timing of these
PER3: association with diurnal preference
In an association study, the frequency of people homozygous for the 5-repeat was found to be higher in the morning types than in evening types, whereas in DSPD the prevalence of the 5-repeat allele was very low.52 The association between diurnal preference and the VNTR polymorphism persisted in an extended sample, and there was some evidence that the association was age-dependent 56 The association between PER3 genotypes and diurnal preference was confirmed in an independent Brazilian study,
PER3: sleep timing and mRNA rhythms in leukocytes
In a first approach, we investigated the association between circadian parameters and habitual sleep timing in a group of individuals selected only on the basis of homozygosity for each allele. In both genotypes, we observed robust associations between habitual sleep timing and the rhythms of melatonin, as well as cortisol, as assessed under constant routine conditions. We also investigated associations between habitual sleep timing and the phase of the rhythm of mRNA of BMAL1, PER2 and PER3 in
PER3: sleep and waking EEG
We next characterised aspects of sleep homeostasis by recording sleep and waking performance under baseline conditions and in response to sleep deprivation in a prospective study in which subjects were recruited on the basis of their PER3 genotype.58 At baseline, PER35/5 individuals displayed many of the sleep characteristics previously observed in morning types. Thus, compared to evening types, they had shorter sleep latency, more SWS, and more SWA, in particular in the first part of the
PER3: autonomic regulation of the heart
The autonomic regulation of the heart is modulated by vigilance state and circadian phase. In particular, in the course of a NREM/REM sleep cycle, the sympathovagal balance changes dramatically, such that sympathetic dominance is lowest during NREM sleep and highest during REM sleep. Comparing the time course of the sympathovagal balance during baseline sleep and during recovery sleep after sleep deprivation revealed differences between PER35/5 and PER34/4 individuals, such that the amplitude
PER3: effects on cognitive performance
We next quantified the time course of waking performance during sleep deprivation in the two genotypes. Because it was initially our desire to characterise overall waking performance, we computed a composite score based on verbal and spatial 1-, 2-, and 3-back tests; a sustained-attention-to-response task; a paced-visual-serial-addition task; a self-paced digit-symbol-substitution test; simple-reaction-time and serial-reaction-time tests; and a motor-tracking task, thereby covering a wide-range
PER3: fMRI-assessed brain responses
All of the above findings, which were based on data collected in one group of subjects, are consistent with the notion that the PER3 VNTR affects the homeostatic regulation of sleep and that this difference in the homeostatic regulation of sleep, in interaction with the circadian rhythmicity, underlies the differential susceptibility to the negative effects of sleep deprivation on performance.
To further substantiate this hypothesis, we proceeded in two ways. We first investigated whether the
PER3: modelling the genotype-specific interaction between the circadian and homeostatic processes
To further strengthen the conceptual framework in which to interpret these findings, we analysed and interpreted our data within the context of our knowledge about the interaction of circadian and homeostatic processes. We first established that the observed differences in SWS and SWA reflect a difference in parameters of the homeostatic process, and are not secondary to the small and statistically not significant differences in sleep duration between the two genotypes. In our original study,
Acknowledgements
The authors’ research on sleep, circadian rhythms and PER3 genotype is funded by BBSRC, AFOSR, Wellcome Trust and Philips Lighting. The opinions presented in this review are those of the authors. We thank Dr Viola for preparing Fig. 2.
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