Physiological review
PERIOD3, circadian phenotypes, and sleep homeostasis

https://doi.org/10.1016/j.smrv.2009.07.002Get rights and content

Summary

Circadian rhythmicity and sleep homeostasis contribute to sleep phenotypes and sleep–wake disorders, some of the genetic determinants of which are emerging. Approximately 10% of the population are homozygous for the 5-repeat allele (PER35/5) of a variable number tandem repeat polymorphism in the clock gene PERIOD3 (PER3). We review recent data on the effects of this polymorphism on sleep–wake regulation. PER35/5 are more likely to show morning preference, whereas homozygosity for the four-repeat allele (PER34/4) associates with evening preferences. The association between sleep timing and the circadian rhythms of melatonin and PER3 RNA in leukocytes is stronger in PER35/5 than in PER34/4. EEG alpha activity in REM sleep, theta/alpha activity during wakefulness and slow wave activity in NREM sleep are elevated in PER35/5. PER35/5 show a greater cognitive decline, and a greater reduction in fMRI-assessed brain responses to an executive task, in response to total sleep deprivation. These effects are most pronounced during the late circadian night/early morning hours, i.e., approximately 0–4 h after the crest of the melatonin rhythm. We interpret the effects of the PER3 polymorphism within the context of a conceptual model in which higher homeostatic sleep pressure in PER35/5 through feedback onto the circadian pacemaker modulates the amplitude of diurnal variation in performance. These findings highlight the interrelatedness of circadian rhythmicity 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.

References* (80)

  • T. Yoshimura et al.

    Molecular analysis of avian circadian clock genes

    Brain Res Mol Brain Res

    (2000)
  • C.J. Winrow et al.

    Refined anatomical isolation of functional sleep circuits exhibits distinctive regional and circadian gene transcriptional profiles

    Brain Res

    (2009)
  • K. Bae et al.

    Differential functions of mPer1, mPer2, and mPer3 in the SCN circadian clock

    Neuron

    (2001)
  • A.U. Viola et al.

    PER3 polymorphism predicts sleep structure and waking performance

    Curr Biol

    (2007)
  • C. Roth et al.

    Alpha activity in the human REM sleep EEG: topography and effect of REM sleep deprivation

    Clin Neurophysiol

    (1999)
  • R.E. Mistlberger

    Circadian regulation of sleep in mammals: role of the suprachiasmatic nucleus

    Brain Res Brain Res Rev

    (2005)
  • P. Artioli et al.

    How do genes exert their role? Period 3 gene variants and possible influences on mood disorder phenotypes

    Eur Neuropsychopharmacol

    (2007)
  • D.J. Dijk et al.

    Circadian and Homeostatic Regulation of Human Sleep and Cognitive Performance and its Modulation by PERIOD3

    Sleep Med Clin

    (2009)
  • V. Natale et al.

    Season of birth, gender, and social-cultural effects on sleep timing preferences in humans

    Sleep

    (2009)
  • T.I. Morgenthaler et al.

    Practice parameters for the clinical evaluation and treatment of circadian rhythm sleep disorders. An American Academy of Sleep Medicine report

    Sleep

    (2007)
  • R.L. Sack et al.

    Circadian rhythm sleep disorders: part II, advanced sleep phase disorder, delayed sleep phase disorder, free-running disorder, and irregular sleep–wake rhythm. An American Academy of Sleep Medicine review

    Sleep

    (2007)
  • J.C. Ong et al.

    Characteristics of insomniacs with self-reported morning and evening chronotypes

    J Clin Sleep Med

    (2007)
  • A.A. Borbély

    A two process model of sleep regulation

    Hum Neurobiol

    (1982)
  • S. Daan et al.

    Timing of human sleep: recovery process gated by a circadian pacemaker

    Am J Physiol

    (1984)
  • D.J. Dijk et al.

    EEG power density during nap sleep: reflection of an hourglass measuring the duration of prior wakefulness

    J Biol Rhythms

    (1987)
  • J.M. Krueger et al.

    Sleep as a fundamental property of neuronal assemblies

    Nat Rev Neurosci

    (2008)
  • C.A. Czeisler et al.

    Human circadian physiology and sleep–wake regulation

  • P. Acherman et al.

    Mathmatical models of sleep regulation

    Front Biosci

    (2003)
  • D.J. Dijk et al.

    Timing and consolidation of human sleep, wakefulness, and performance by a symphony of oscillators

    J Biol Rhythms

    (2005)
  • C.B. Saper et al.

    Hypothalamic regulation of sleep and circadian rhythms

    Nature

    (2005)
  • A.J. Phillips et al.

    A quantitative model of sleep–wake dynamics based on the physiology of the brainstem ascending arousal system

    J Biol Rhythms

    (2007)
  • M.J. Rempe et al.

    A mathematical model of the sleep/wake cycle

    J Math Biol

    (2009 Jun 26)
  • M. Koskenvuo et al.

    Heritability of diurnal type: a nationwide study of 8753 adult twin pairs

    J Sleep Res

    (2007)
  • L. De Gennaro et al.

    The electroencephalographic fingerprint of sleep is genetically determined: a twin study

    Ann Neurol

    (2008)
  • J.S. Takahashi et al.

    The genetics of mammalian circadian order and disorder: implications for physiology and disease

    Nat Rev Genet

    (2008)
  • J.V. Retey et al.

    A functional genetic variation of adenosine deaminase affects the duration and intensity of deep sleep in humans

    Proc Natl Acad Sci U S A

    (2005)
  • P. Franken et al.

    Circadian clock genes and sleep homeostasis

    Eur J Neurosci

    (2009)
  • J.F. Duffy et al.

    Association of intrinsic circadian period with morningness–eveningness, usual wake time, and circadian phase

    Behav Neurosci

    (2001)
  • S.N. Archer et al.

    von SM, Dijk DJ. Inter-individual differences in habitual sleep timing and entrained phase of endogenous circadian rhythms of BMAL1, PER2 and PER3 mRNA in human leukocytes

    Sleep

    (2008)
  • J.K. Wyatt et al.

    Circadian phase in delayed sleep phase syndrome: predictors and temporal stability across multiple assessments

    Sleep

    (2006)
  • Cited by (208)

    • Attention and memory changes

      2023, Encyclopedia of Sleep and Circadian Rhythms: Volume 1-6, Second Edition
    • Sleepiness

      2023, Encyclopedia of Sleep and Circadian Rhythms: Volume 1-6, Second Edition
    • Genetic effects

      2023, Encyclopedia of Sleep and Circadian Rhythms: Volume 1-6, Second Edition
    • Sleep homeostasis

      2023, Encyclopedia of Sleep and Circadian Rhythms: Volume 1-6, Second Edition
    View all citing articles on Scopus
    *

    The most important references are denoted by an asterisk.

    View full text