Homeostatic and Circadian Regulation of the Sleep-Wake Cycle

Transcription

1 Homeostatic and Circadian Regulation of the Sleep-Wake Cycle Derk-Jan Dijk, PhD, FRSB Professor of Sleep and Physiology Presentation for International Sleep Medicine Course Cardiff 6-9 June 216 Monday, 16 May 216 1

2 Regulation of sleep/wake cycle Outline Sleep and sleep stages Sleep homeostasis Global aspects of sleep regulation Local aspects of sleep regulation Circadian aspects of sleep regulation Many apes sleep in nests in the trees (Credit: Kathelijne Koops) Monday, 16 May 216 2

3 Conceptual frame-work for sleep-wake regulation Light-Dark Cycle Waking Performance Social/Behavioural Factors Individual Circadian Photoreception Sleep-Wake Cycle Circadian Homeostat Genetic variation Biological time Sleep-wake history Dijk and Lockley, 22; Archer et al. 213

4 Timing of sleep and time course of sleep stages LD cycle 16 h Wakefulness 8 h Sleep 16 h Wakefulness Sleep Stage Plasma Melatonin (pmol/liter) W REM 2 1 Sleep onset Melatonin onset Time of Day (h) Subject y.o M Dijk; Unpublished

5 Time course of slow waves and sleep spindles Sigma Activity Slow Wave Activity Sleep Stage (uv 2 /Hz) (uv 2 /Hz) W REM Spindle Activity Slow Wave Activity Sleep Stage Plasma Melatonin (pmol/liter) Time of Day (h) SP#3 Subject y.o. M Dijk, Duffy, Czeisler; Unpublished

6 Borbely: A two-process model of sleep-regulation; Human Neurobiol 1982 Global regulation of sleep Sleep Homeostasis Build-up of sleep pressure during wakefulness Dissipation of sleep pressure during sleep Further build-up of sleep pressure during sleep deprivation More intense and longer recovery sleep Note: Circadian rhythm not affected

7 SWA (%) Examples of Sleep Homeostasis (I): Regulation of SWS Decline and fall of SWA. During nocturnal sleep SWA declines and SWA in daytime naps increases progressively with the duration of wakefulness preceding the nap. Please note that naps were not taken on the same day Nocturnal sleep Daytime naps Time of day (h) Sleep (h) Wakefulness (h) Data from 7 female healthy volunteers Dijk D-J. Behav Brain Res 1995;69:19 116

8 SWA (μv 2 ) Sleep Homeostasis (II): Regulation of SWS More SWA and longer sleep after total sleep deprivation in humans and rats Time course of SWA during baseline sleep and recovery sleep following sleep deprivation in human and rat Baseline Recovery from sleep deprivation Human a W NR Rat b W NR Time since sleep onset (h) a 36-h sleep deprivation (data from a single male subject) b 24-h sleep deprivation Dijk D-J, et al. Am J Physiol 199;258:R65 661Franken P, et al. Am J Physiol 1995;269:R691 71

9 Sleep Homeostasis III: Partial sleep deprivation Partial sleep deprivation: primary effect on REM sleep; preservation of SWA; Rebound of REM sleep Brunner et al. Electroencephalogr Clin Neurophysiol. 199 Jun;75(6):492-9

10 Sleep Homeostasis IV: Selective SWS deprivation Through acoustic stimuli; leads to rebound in subsequent night n=1 Dijk D-J et al. J Sleep Res 15 (Suppl. 1): (Abstr. No. P536)

11 Homeostatic sleep pressure Sleep Homeostasis V: effects of too much sleep [Nap] Theoretical influence of nap on subsequent sleep NAP A nap in the afternoon will lead to a dissipation of sleep pressure The increase in sleep pressure during wakefulness after the nap is insufficient to restore sleep pressure at habitual bed time to normal levels Dijk, Unpublished figure

12 Sleep latency (min) SWA (%) Reduced sleep propensity and SWA after a nap in the early evening 5 1 B N+P N P B=Baseline N=Nap P=Post-nap N+P=Sum of Nap plus Post-nap Baseline Post-nap Sleep a Wakefulness NonREM REM Study in 9 healthy male volunteers Time of day (h) a Time course of SWA and vigilance states from a single volunteer Werth E, et al. Am J Physiol Regulatory Integrative Comp Physiol 1996;271:51 51

13 SWA (μv 2 /.25 Hz) Sleep Homeostasis: Local aspects of sleep regulation Frontal predominance during baseline and after sleep deprivation 5 * Frontal Central Parietal Occipital 4 * * * * * Recovery a Baseline Quarters of sleep episode *p<.5 baseline vs recovery (n=6 healthy volunteers) a First sleep episode following 4-h sleep deprivation Cajochen C, et al. Sleep Res Online 1999;2:65 69

14 Sleep Homeostasis: Local aspects Specific sensory stimulation leads to a use-dependent increase of SWA in non REM sleep humans animals EEG asymmetry ( Hz) (deviation from baseline) 3 RIGHT LEFT -3 RIGHT HAND VIBRATION * EEG POWER DENSITY IN NREMS (% OF IPSILATERAL 2-h INTERVAL) * * * h INTERVALS BARREL CORTEX NREMS episode Kattler et al., J Sleep Res,1994 Vyazovskiy et al., J Sleep Res. 9: , 2

15 Consequences of insufficient sleep for waking functioning Light-Dark Cycle Waking Performance Social/Behavioural Factors Individual Circadian Photoreception Sleep-Wake Cycle Circadian Homeostat Genetic variation Biological time Sleep-wake history Dijk and Lockley, 22; Archer et al. 213

16 Effect of total sleep deprivation on sleepiness, sustained attention and working memory during the day N=36; age=27.6 (4.) years Implied effect size Large effect on sleepiness and sustained attention Lo et al. PLoS One, 212

17 Effect of total sleep deprivation on sleepiness, sustained attention and working memory during the night N=36; age=27.6 (4.) years Sleep restriction B D1 D2 D3 D4 D5 D6 TD1 TN1 TD2 Effect size (f 2 ) of (CRD1 vs CRN1) Implied effect size Control f 2 Largest effect on sleepiness and sustained attention B D1 D2 D3 D4 D5 D6 TD1 TN1 TD2 Subjective Sustained alertness attention KSS PVT speed SART A' Task V1-bk A' Working memory V2-bk A' V3-bk A' Large Lo et al. PLoS One, 212

18 Lo et al. PLoS One, 212 Effect of repeated partial sleep deprivation on sleepiness, sustained attention and working memory N=36; age=27.6 (4.) years 1 h vs. 6 h TIB 8.6 vs. 5.8 h TST Sleep restriction Control B D1 D2 D3 D4 D5 D6 TD1 TN1 TD2 Effect size (f 2 ) of chronic (condition effect on D5 and D6 combined) B D1 D2 D3 D4 D5 D6 TD1 TN1 TD2 Implied effect size f Subjective Sustained alertness attention Working memory Large Medium.1 Small Largest effect on sleepiness and sustained attention. KSS PVT speed SART A' Task V1-bk A' V2-bk A' V3-bk A'

19 Sleep-wake regulation: homeostasis Conclusion (I) Sleep homeostasis: Sleep homeostasis: Total sleep deprivation Partial sleep deprivation Selective sleep deprivation Extra sleep All these manipulations activate sleep homeostatic mechanisms and lead to changes in subsequent sleep Slow Wave Activity is one sensitive marker of sleep homeostasis There are both local and global aspects to sleep and sleep regulation There is a use dependent aspect to sleep regulation Neuronal networks that have been activated extensively during wakefulness appear to show more slow waves during subsequent sleep Insufficient sleep: Impaired waking function Increased Sleepiness Reduced Sustained Attention

20 Circadian aspects of sleep regulation Light-Dark Cycle Waking Performance Social/Behavioural Factors Individual Circadian Photoreception Sleep-Wake Cycle Circadian Homeostat Genetic variation Biological time Sleep-wake history Dijk and Lockley, 22; Archer et al. 213

21 Main points of circadian aspect of sleep-regulation The master circadian clock is located in the suprachiasmatic nucleus (SCN) of the hypothalamus Light is the major synchronizer of the SCN The SCN drives rhythms in many variables Sleep-wake consolidation is achieved by an opponent process organisation The duration and structure of sleep are modulated by the phase of the circadian cycle at which sleep occurs Clock genes and individual differences Mistimed sleep disrupts circadian rhythmicity in the periphery Monday, 16 May

22 Days Circadian sleep wake rhythms Natural situations Free running in an isolated situation Sleep wake cycles: Persist in the absence of external 24-hour light dark and social cycles Are generated by an internal circadian clock 4 45 Entrained to a 24-hour day Sleep episode Wake episode Core body temperature nadir Midnight Noon Midnight Time of day Noon Midnight Aschoff J. Science 1965; 148:

23 Physiology of circadian rhythms The master circadian clock is located in the suprachiasmatic nucleus (SCN) of the hypothalamus Light is the major synchronizer of the SCN The SCN drives rhythms in many variables WAKE Abbott A. Nature 23;425:

24 Suprachiasmatic Nucleus Melatonin rhythm The SCN drives the melatonin rhythm through a: A polysynaptic pathway including the paraventricular nucleus of the hypothalamus the intermediolateral cell column the superior cervical ganglion pineal Monday, 16 May

25 Kalsbeek et al. Effects of SCN lesion on melatonin, cortisol, activity Melatonin Cortisol

26 Circadian aspects of sleep regulation Artificial light and why we sleep so late Light-Dark Cycle Waking Performance Social/Behavioural Factors Individual Circadian Photoreception Sleep-Wake Cycle Circadian Homeostat Genetic variation Biological time Sleep-wake history Dijk and Lockley, 22; Archer et al. 213

27 Based on data published in Lo et al Front Neurol. 5:81:214 Why do we sleep so late? [Relative to the natural L-D cycle] Photoperiod and sleep timing in Surrey Dawn Dusk January Wake Time Bedtime Weekend December Weekdays N= Local Time (h)

28 Renewed interest in effects of light on brain function Melanopsin and intrinsically photosensitive retinal ganglion cells For a review of Mammalian inner retinal photoreception.see Lucas RJ Curr Biol. 213;23:R

29 Light: Phase shifting effects Slowing down and speeding up the clock Light in the morning: Advances Suprachiasmatic nucleus Hypothalamus Retina Light Optic nerve Signals to the body Pineal gland Light in the evening: Delays Abbott A. Nature 23; 425 (6961): Zeitzer et al J Physiol 2 526:

30 Before the advent of artificial light, the rotation of the Earth dictated light and darkness, and the timing of our biological clocks 3

31 Does this artificial light influence our sleep and biological clocks? 31

32 Light exposure at home Dawn Wake time Dusk Bedtime 1 SLEEP WAKE SLEEP WAKE Irradiance ( w/cm 2 ) : 12: : 12: : Clock Time N=22 (male=15) aged ± 4.67 Blue Green Red Dawn Dusk Monday, 16 May 216 Santhi et al, 212;J Pineal Research 32

33 Investigating the effects of artificial light Artificial light of an intensity we are exposed to at home suppresses melatonin More biologically effective light 4 hours of light exposure in the evening Relative Clock Time Irradiance ( w/cm 2 ) Home Near-Darkness Blue-Depleted Blue-Intermediate Blue-Enhanced Bright Blue-Enhanced Melatonin Concentration (pg/ml) Bed 19:3 2:3 21:3 22:3 23:3 Time Time Relative to Bed Time (minutes) Monday, 16 May 216 Santhi et al, 212;J Pineal Research

34 The rhythm of melatonin and the biological night Melatonin heralds the biological night and facilitates sleep onset CORRESPONDING TIME OF DAY WAKEFULNESS IN Drive SLEEP for EPISODES wakefulness (% OF RT) 2 PLASMA MELATONIN (Z-SCORES) Melatonin 2 1 Sleep opening of sleep gate CIRCADIAN PHASE (degrees) degrees = melatonin maximum Monday, 16 May 216 Modified from Dijk et al. J Physiol 1997

35 Light in the evening reduces sleepiness & delays sleep onset Even light from laptops and other gadgets can have effects Reduced Evening Sleepiness Delayed Sleep Onset 25 Sleep Latency (minutes) Light Condition Col 1 More Biologically Effective Light Monday, 16 May 216 Santhi et al, 212;J Pineal Research

36 Light, circadian rhythms and sleep Summary Light of an intensity and spectral composition comparable to the light we are exposed to at home: Reduces sleepiness Disrupts sleep Suppresses melatonin Effects are: Melanopsin mediated (at least in part)

37 Circadian regulation of sleep And its interaction with sleep homeostasis Light-Dark Cycle Daytime functioning Social/Behavioural Factors Individual Circadian Photoreception Sleep-Wake Cycle Circadian Homeostat Genetic variation Biological time Sleep-wake history

38 A closer look at the circadian regulation of human sleep Estimating the contribution of circadian rhythmicity and time asleep to sleep propensity and sleep structure The problem During a normal nocturnal sleep period we travel through 1/3 of a circadian cycle and at the same time dissipate sleep pressure How to estimate the relative contribution of circadian rhythmicity and time asleep to sleep propensity/structure? Desynchronise sleep from circadian rhythms Assess sleep Estimate the main effects of sleep-wake and circadian rhythmicity and their interaction WAKE Monday, 16 May

39 Separating the circadian and homeostatic component of sleep through forced desynchrony of sleep and SCN driven rhythms In dim light! Clock time (h) Day 1 28 h S-W Cycle Day 6 Sleep episode Day 11 Melatonin Day 16 Day 21 Modified from Dijk DJ, Duffy JF. Ann Med 1999; 31 (2): 13 14

40 Timing of sleep at baseline and during forced desynchrony Relative to melatonin time Lazar et al. Neuroimage, 215

41 Plasma melatonin (z-scores) Wakefulness in scheduled sleep episodes (%) Plasma melatonin (z-scores) Sleep latency (min) Dijk D-J, et al. J Physiol 1999; 516 (Pt 2): Maximum circadian drive for wakefulness: Just before the nocturnal increase in melatonin secretion Maximum circadian drive for sleep: in the early morning hours 4 Corresponding time of day during entrainment Corresponding time of day during entrainment Young men (n=11) Young men (n=11) Circadian phase ( degrees = melatonin maximum) Circadian phase ( degrees = melatonin maximum)

42 Dijk and Czeisler; Neurosci Lett 1994 The propensity to awaken depends on circadian phase and elapsed time asleep CIRCADIAN SLEEP-DEPENDENT 3 A B Wakefulness (%) Circadian Phase Time in Sleep Episode (Degrees) (Hours)

43 CIRCADIAN TIME OF DAY DURING ENTRAINMENT SLEEP-DEPENDENT 3 WAKEFULNESS (% of recording time) REM SLEEP ( % of TST) A B Circadian and sleep-wake dependent regulation of sleep propensity and sleep structure 15 NonREM SLEEP ( % of TST) 8 65 C Strong circadian regulation of REM sleep SIGMA ACTIVITY in NonREM sleep (deviation from mean; %) D Strong homeostatic regulation of Slow Wave Sleep and Slow Wave Activity SLOW-WAVE ACTIVITY in NonREM sleep (deviation from mean; %) 8-8 E Sigma-activity/sleep spindles under both circadian and homeostatic control BODY TEMPERATURE (degrees Celsius) 37. F CIRCADIAN PHASE TIME IN SLEEP EPISODE (degrees) (minutes) Dijk and Czeisler J Neurosci 1995

44 Circadian and Homeostatic Interaction Opponent processes Homeostatic 9 AM 3 PM 9 PM 3 AM 9 AM Sleep load Wake Wake propensity Circadian Alerting Signal 9 AM 3 PM 9 PM 3 AM 9 AM Sleep Day - Awake Night - Asleep After Edgar et al. J Neurosci. 1993;13:165

45 Circadian phase and time asleep interact in the regulation of the propensity to wake-up Dijk and Czeisler Neurosci Lett 1994

46 Performance: Addition 16 Time of Day Commute home 14 Hours Awake Poor Good Biological Time of Day Modified from Dijk, Duffy, Czeisler; 1992

47 Individual differences in sleep-wake timing Physiological correlates Light-Dark Cycle Daytime functioning Social/Behavioural Factors Individual Circadian Photoreception Sleep-Wake Cycle Circadian Homeostat Genetic variation Biological time Sleep-wake history

48 Surrey Sleep Research Centre Sleep Survey; Groeger,, Dijk; J Sleep Res; 24 Individual differences in sleep timing Morning and evening types? Percentage of total number of observations Percentage of total number of observations Week Days Weekend Get-up times (hours)

49 The core molecular circadian clock Per 1,2, 3 I. Robinson, A.B. Reddy; FEBS Letters; 214

50 PER3 Variable Number Tandem Repeat predicts diurnal preference in healthy men and women aged 2-35 Lazar,...,Dijk; Chronobiology International; 212

51 Genotypes PER3 VNTR predicts self-reported sleep timing in ~675 healthy men and women aged 2-35 * * * * * * * * * * * Bedtime Midpoint of sleep Wakeup time 23:15 23:3 23:45 : 3:45 4: 4:15 8: 8:15 8:3 Clock time (hours:minutes) PER3 4/4 PER3 4/5 PER3 5/5 Lazar,...,Dijk; Chronobiology International; 212

52 Groeger et al. J Sleep Res, 24 Variation in sleep timing Morning and Evening types Percentage of total number of observations Percentage of total number of observations Week Days Weekend Get-up times (hours)

53 Association: habitual sleep-timing and phase of melatonin Assessed in the absence of sleep-wake cycle Archer et al. Sleep, 28; Dijk and Archer. Sleep Medicine Reviews, 21

54 Association between sleep-wake timing and Period of melatonin rhythm? Forced desynchrony protocol to assess intrinsic period of melatonin rhythm Hasan et al. FASEB, 212

55 Period of melatonin rhythm correlates with diurnal preference Owls: Slow clock; Larks: Fast clock Number of individuals Circadian Period (h) Fast Slow Morningness-Eveningness score 86 'morning Lark type' Circadian period (h) Fast n = 31 rs = p =.41 Owl 'evening type' Slow Modified from Hasan et al. FASEB, 212

56 Period of melatonin rhythm correlates with melatonin phase Fast clock-> melatonin rises well before bedtime 16 Number of individuals Circadian Period (h) Fast Slow Modified from Hasan et al. FASEB, 212

57 Melatonin phase predicts latency to sleep onset when sleeping at habitual time Early melatonin phase easy to fall asleep Latency to persistent sleep (min) n=34 r s =.48 P= Timing of melatonin onset relative to bedtime (h) Lazar et al. J Sleep Res, 213

58 and especially so in women Men n = 16, r s =.1, p =.723 Women n=18, r s =.76, P<.1) Latency to persistent sleep (min) Latency to persistent sleep (min) Timing of melatonin onset relative to bedtime (h) Timing of melatonin onset relative to bedtime (h) Lazar et al. J Sleep Res, 213

59 Period of melatonin rhythm and extra sleep during the weekend Those with a slow clock sleep longer during the weekend (and less during the week) 16 Number of individuals Extra time in bed (h) n=31 r s =.5 p= Circadian Period (h) -3 Fast Circadian Period (h) Slow Fast Slow Lazar et al. J Sleep Res, 213

60 Phase and Period of melatonin rhythm and sleep-wake timing Phase of melatonin rhythm correlates with Sleep timing Sleep latency Period of melatonin rhythm correlates with Diurnal preference Melatonin phase Extra time in bed during the weekend

61 Feedback of sleep-wake cycle on circadian rhythmcity in periphery Physiological correlates Light-Dark Cycle Daytime functioning Social/Behavioural Factors Individual Circadian Photoreception Sleep-Wake Cycle Circadian Homeostat Genetic variation Biological time Sleep-wake history

62 Effects of mistimed sleep on the blood transcriptome A model for circadian disruption? 22 participants (11 male) 2 Conditions (sequential design) Control (sleeping in phase with melatonin) Mistimed sleep (sleep out of phase with melatonin) RNA Sampling during 28-h sleep-wake cycle (7 samples per condition) Polymerase (RNA) II (DNA Directed) Polypeptide H Archer et al. PNAS 214;111(6):E682-91

63 Archer et al. PNAS 214;111(6):E Circadian rhythmicity in the periphery [The blood transcriptome] 6 Fold reduction in rhythmic genes when sleep is mistimed In phase: 1,396 rhythmic genes ; 6.4% Out of phase: 228 rhythmic genes ; 1.% Night

64 Main effect of sleeping out of phase 31,95 transcripts analysed: 913 down regulated 26 up regulated Associated processes: Macromolecular metabolism Gene expression Nucleic acid metabolism RNA metabolic process DNA & RNA binding Hemoglobin metabolic process Oxygen transporter activity Peroxiredoxin activity others Archer et al. PNAS 214;111(6):E Laing et al. BioEssays 215; 37:

65 Effects of Desynchrony/Mistimed sleep Relation to health effects? Mistiming of sleep-wake cycles affects molecular processes that are at the core of the regulation of the temporal organisation of the transcriptome and circadian rhythmicity This is observed while melatonin is not supressed Genes and processes affected are involved in many of the negative health outcomes associated with shift work Transcriptomics of whole blood holds promise for biomarker discovery 65

66 Circadian regulation of sleep-wake cycle Summary SCN is a master circadian pacemaker Light as a very relevant environmental factor for sleep timing Circadian rhythmicity and sleep homeostasis: opponent processes Melatonin phase and period as a correlates of individual differences in sleep timing Polymorphisms in clock genes as correlates of individual differences in sleep timing and diurnal preference Mistimed sleep affect the temporal organisation of the blood transcriptome A better understanding of these effects and the underlying mechanisms may help to prevent the adverse health consequences of insufficient and mistimed sleep 66

67 Acknowledgements Surrey Sleep Research Centre Simon Archer John A Groeger Malcolm von Schantz Nayantara Santhi Alpar Lazar Sibah Hasan June Lo Raphaelle Winsky-Sommerer Daan van der Veen Antoine Viola Lynette James Ana Slak Ciro Della Monica Emma Arbon Mathieu Nolllet Giuseppe Atzori Faculty of Health & Medical Sciences Colin Smith Giselda Bucca Carla Moller-Levet Emma Laing Jonathan Johnston Renata Kabiljo Faculty of Electronic and Physical Sciences - Anne Skeldon - Gianne Derks Surrey Clinical Research Centre Dr Julia Boyle Statisticians: Dr Sigurd Johnsen & Mr Patrick McCabe Clinical, research, and recruitment teams Participants This research is supported by grants from the AFOSR (FA ) and the BBSRC (BB/F22883/1, BSS/B/8523, BB/E3672/1),the Wellcome Trust (74293/Z/4/Z) and the Royal Society

68 Thank you Monday, 16 May