University roles and responsibilities
- Member University Ethics Committee (2020-)
- Head Department of Biochemical Sciences (2014-2017)
- Member University Ethical Review Committee (2009-2012)
- Member Faculty Research & Enterprise Committee (2007-2012)
- Sleep, Chronobiology & Neuroscience Theme Leader (2007-2012)
- Biochemistry Admissions Tutor (2006-2016)
- Level 4 Exams Officer (2005-2006)
- Chair Faculty Seminar & Research Festival Committee (2004-2008)
Affiliations and memberships
Scientific Committee Member (2010-2014)
Scientific Committee Chair (2012-2014)
Research Networks Committee Member (2010-2014)
Trainee Research Awards Committee Member (2011-2014)
I graduated with a BSc (Hons) in Biological Sciences from the University of Sussex and then a PhD in Zoology from the University of Bristol, where I studied photoreceptor visual pigment absorbance spectra and colour vision polymorphisms. As an MRC postdoctoral fellow at Bristol, I became interested in the genetics of colour vision and used early-application PCR techniques to clone some of the first visual pigment opsin genes. I then moved to Sardinia on an EU Fellowship to help to set up the International Marine Centre (IMC) at Oristano, where I was Senior Scientist and Group Leader of Molecular Sensory Ecology.
In 1999, I moved to the University of Surrey where I am now Professor of Molecular Biology of Sleep in the Surrey Sleep Research Centre. My research has focussed upon the genetics and molecular biology of human sleep and circadian rhythms, and individual differences therein. My work on polymorphisms within human circadian clock genes has led the field in human targeted sleep and circadian genomics. This has been particularly successful with the discovery within PER3 of a variable number tandem repeat (VNTR) polymorphism that associates with a wide range of healthy and clinical phenotypes including chronotype, delayed sleep phase disorder (DSPD), behavioural activity, sleep homeostasis, cognitive performance, fMRI-assessed brain activity, neuronal structure, light sensitivity, melatonin suppression, mood disorders, anxiety, body mass, addiction, and cancer. I have extended the human work to transgenic animal models where I have investigated the effects of PER3 on sleep and circadian rhythms in transgenic knock out mice, and also humanised knock in mice where I introduced the primate-specific VNTR into the mouse PER3, phenocopying sleep homeostasis characteristics measured in humans.
I have also pioneered methods to measure gene expression in human whole blood samples and Surrey has led the field in the development of protocols to measure genome-wide human time series gene expression in clinical studies. Using these state-of-the-art techniques, we have shown how time series gene expression profiles can be disrupted by chronic and acute sleep restriction, and by mistimed sleep during forced desynchronisation, where disruption to circadian gene expression rhythms is profound. More recently, I have used time series whole-blood gene expression to investigate circadian disruption caused by simulated microgravity during a constant bed rest protocol (with ESA). With the application of machine learning to these datasets, we have also developed and validated human blood transcriptome biomarkers for circadian phase and sleep loss.
Indicators of esteem
Editorial Board Member, Frontiers in Neuroscience - Sleep & Circadian Rhythms
Editorial Board Member, Clocks & Sleep
Member Royal Society Research Grants Panel (2014-2020)
Member Canadian Institutes of Health Research Grant Review Panel (2016/2017)
Member UKRI Future Leader Fellowships Peer Review College (2018-)
Member ERC Expert Review Pool
Study Objectives. Sleep disturbances and genetic variants have been identified as risk factors for Alzheimer’s disease. Our goal was to assess whether genome-wide polygenic risk scores (PRS) for AD associate with sleep phenotypes in young adults, decades before typical AD symptom onset. Methods. We computed whole-genome Polygenic Risk Scores (PRS) for AD and extensively phenotyped sleep under different sleep conditions, including baseline sleep, recovery sleep following sleep deprivation and extended sleep opportunity, in a carefully selected homogenous sample of healthy 363 young men (22.1 y ± 2.7) devoid of sleep and cognitive disorders. Results. AD PRS was associated with more slow wave energy, i.e. the cumulated power in the 0.5-4 Hz EEG band, a marker of sleep need, during habitual sleep and following sleep loss, and potentially with large slow wave sleep rebound following sleep deprivation. Furthermore, higher AD PRS was correlated with higher habitual daytime sleepiness. Conclusions. These results imply that sleep features may be associated with AD liability in young adults, when current AD biomarkers are typically negative, and the notion that quantifying sleep alterations may be useful in assessing the risk for developing AD.
Human performance results from an interaction between circadian rhythmicity and homeostatic sleep pressure. Whether and how this interaction is represented at the regional brain level is not established. We quantified changes in brain responses to a sustained-attention task during 13 functional magnetic resonance imaging (fMRI) sessions scheduled across the circadian cycle during 42h of wakefulness and following recovery sleep, in 33 healthy participants. Cortical responses showed significant circadian rhythmicity, the phase of which varied across brain regions. Cortical responses also significantly decreased with accrued sleep debt. Subcortical areas exhibited primarily a circadian modulation, which closely followed the melatonin profile. These findings expand our understanding of the mechanisms involved in maintaining cognition during the day and its deterioration during sleep deprivation and circadian misalignment.
Sleep complaints and irregular sleep patterns, such as curtailed sleep during workdays and longer and later sleep during weekends, are common. It is often implied that differences in circadian period and in entrained phase contribute to these patterns, but few data are available. We assessed parameters of the circadian rhythm of melatonin at baseline and in a forced desynchrony protocol in 35 participants (18 women) with no sleep disorders. Circadian period varied between 23 h 50 min and 24 h 31 min, and correlated positively (n = 31, rs = 0.43, P = 0.017) with the timing of the melatonin rhythm relative to habitual bedtime. The phase of the melatonin rhythm correlated with the Insomnia Severity Index (n = 35, rs = 0.47, P = 0.004). Self-reported time in bed during free days also correlated with the timing of the melatonin rhythm (n = 35, rs = 0.43, P = 0.01) as well as with the circadian period (n = 31, rs = 0.47, P = 0.007), such that individuals with a more delayed melatonin rhythm or a longer circadian period reported longer sleep during the weekend. The increase in time in bed during the free days correlated positively with circadian period (n = 31, rs = 0.54, P = 0.002). Polysomnographically assessed latency to persistent sleep (n = 34, rs = 0.48, P = 0.004) correlated with the timing of the melatonin rhythm when participants were sleeping at their habitual bedtimes in the laboratory. This correlation was significantly stronger in women than in men (Z = 2.38, P = 0.017). The findings show that individual differences in circadian period and phase of the melatonin rhythm associate with differences in sleep, and suggest that individuals with a long circadian period may be at risk of developing sleep problems.
Circadian rhythms, metabolism and nutrition are intimately linked [1, 2], although effects of meal timing on the human circadian system are poorly understood. We investigated the effect of a 5-hour delay in meals on markers of the human master clock and multiple peripheral circadian rhythms. Ten healthy young men undertook a 13-day laboratory protocol. Three meals (breakfast, lunch, dinner) were given at 5-hour intervals, beginning either 0.5 (early) or 5.5 (late) hours after wake. Participants were acclimated to early meals and then switched to late meals for 6 days. After each meal schedule, participants' circadian rhythms were measured in a 37-hour constant routine that removes sleep and environmental rhythms while replacing meals with hourly isocaloric snacks. Meal timing did not alter actigraphic sleep parameters before circadian rhythm measurement. In constant routines, meal timing did not affect rhythms of subjective hunger and sleepiness, master clock markers (plasma melatonin and cortisol), plasma triglycerides, or clock gene expression in whole blood. Following late meals, however, plasma glucose rhythms were delayed by 5.69 ± 1.29 hours (p < 0.001) and average glucose concentration decreased by 0.27 ± 0.05 mM (p < 0.001). In adipose tissue, PER2 mRNA rhythms were delayed by 0.97 ± 0.29 hours (p < 0.01), indicating that human molecular clocks may be regulated by feeding time and could underpin plasma glucose changes. Timed meals therefore play a role in synchronising peripheral circadian rhythms in humans, and may have particular relevance for patients with circadian rhythm disorders, shift workers, and transmeridian travellers.
Polymorphisms in the human circadian clock gene PERIOD3 (PER3) are associated with a wide variety of phenotypes such as diurnal preference, delayed sleep phase disorder, sleep homeostasis, cognitive performance, bipolar disorder, type 2 diabetes, cardiac regulation, cancer, light sensitivity, hormone and cytokine secretion, and addiction. However, the molecular mechanisms underlying these phenotypic associations remain unknown. Per3 knockout mice (Per3
We examined whether a polymorphism of the PERIOD3 gene (PER3; rs57875989) modulated the sleep promoting effects of melatonin in Delayed Sleep-Wake Phase Disorder (DSWPD). One hundred and four individuals (53 males; 29.4±10.0 years) with DSWPD and a delayed dim light melatonin onset (DLMO) collected buccal swabs for genotyping (PER34/4 n=43; PER3 5 allele [heterozygous and homozygous] n=60). Participants were randomised to placebo or 0.5mg melatonin taken 1 hour before desired bedtime (or ~ 1.45 h before DLMO), with sleep attempted at desired bedtime (4 weeks; 5-7 nights/week). We assessed sleep (diary and actigraphy), Pittsburgh Sleep Quality Index (PSQI), Insomnia Severity Index (ISI), Patient-Reported Outcomes Measurement Information System (PROMIS: Sleep Disturbance, Sleep-Related Impairment), Sheehan Disability Scale (SDS), and Patient- and Clinician-Global Improvement (PGI-C, CGI-C). Melatonin treatment response on actigraphic sleep onset time did not differ between genotypes. For PER34/4 carriers, self-reported sleep onset time was advanced by a larger amount and sleep onset latency (SOL) was shorter in melatonin-treated patients compared to those receiving placebo (P=0.008), while actigraphic sleep efficiency in the first third of the sleep episode (SE T1) did not differ. For PER3 5 carriers, actigraphic SOL and SE T1 showed a larger improvement with melatonin (P
The transition from sleep to wakefulness entails a temporary period of reduced alertness and impaired performance known as sleep inertia. The extent to which its severity varies with task and cognitive processes remains unclear. We examined sleep inertia in alertness, attention, working memory and cognitive throughput with the Karolinska Sleepiness Scale (KSS), the Psychomotor Vigilance Task (PVT), n-back and add tasks, respectively. The tasks were administered 2 hours before bedtime and at regular intervals for four hours, starting immediately after awakening in the morning, in eleven participants, in a four-way cross-over laboratory design. We also investigated whether exposure to Blue-Enhanced or Bright Blue-Enhanced white light would reduce sleep inertia. Alertness and all cognitive processes were impaired immediately upon awakening (p
The power of the application of bioinformatics across multiple publicly available transcriptomic data sets was explored. Using 19 human and mouse circadian transcriptomic data sets, we found that NR1D1 and NR1D2 which encode heme-responsive nuclear receptors are the most rhythmic transcripts across sleep conditions and tissues suggesting that they are at the core of circadian rhythm generation. Analyzes of human transcriptomic data show that a core set of transcripts related to processes including immune function, glucocorticoid signalling, and lipid metabolism is rhythmically expressed independently of the sleep-wake cycle. We also identify key transcripts associated with transcription and translation that are disrupted by sleep manipulations, and through network analysis identify putative mechanisms underlying the adverse health outcomes associated with sleep disruption, such as diabetes and cancer. Comparative bioinformatics applied to existing and future data sets will be a powerful tool for the identification of core circadian- and sleep-dependent molecules.
Individual variability in diurnal preference or chronotype is commonly assessed with selfreport scales such as the widely used Morningness-Eveningness Questionnaire (MEQ). We sought to investigate the MEQ’s internal consistency by applying exploratory factor analysis (EFA) to determine the number of underlying latent factors in four different adult samples, two each from the United Kingdom and Brazil (total N=3,457). We focused on factors that were apparent in all samples, irrespective of particular sociocultural diversity and geographical characteristics, so as to show a common core reproducible structure across samples. Results showed a three-factor solution with acceptable to good model fit indexes in all studied populations. Twelve of the 19 MEQ items in the three-correlated factor solution loaded onto the same factors across the four samples. This shows that the scale measures three distinguishable, yet correlated constructs: 1) items related to how people feel in the morning, which we termed efficiency of dissipation of sleep pressure (recovery process) (items 1, 3, 4, 5, 7, 9, 13, and 19); 2) items related to how people feel before sleep, which we called sensitivity to build-up of sleep pressure (items 2, 10, and 12); and 3) peak time of cognitive arousal (item 11). Although the third factor was not regarded as consistent since only one item was common among all samples, it might represent subjective amplitude. These results suggested that the latent constructs of the MEQ reflect dissociable homeostatic processes in addition to a less consistent propensity for cognitive arousal at different times of the day. By analysing answers to MEQ items that compose these latent factors, it may be possible to extract further knowledge of factors that affect morningness-eveningness.
Acute and chronic insufficient sleep are associated with adverse health outcomes and risk of accidents. There is therefore a need for biomarkers to monitor sleep debt status. None are currently available. We applied Elastic-net and Ridge regression to entire and pre-filtered transcriptome samples collected in healthy young adults during acute total sleep deprivation and following 1 week of either chronic insufficient (< 6 h) or sufficient sleep (~8.6 h) to identify panels of mRNA biomarkers of sleep debt status. The size of identified panels ranged from 9-74 biomarkers. Panel performance, assessed by leave-one-subject-out cross-validation and independent validation, varied between sleep debt conditions. Using between-subject assessments based on one blood sample, the accuracy of classifying ‘Acute sleep loss’ was 92%, but only 57% for classifying ‘Chronic sleep insufficiency’. A reasonable accuracy for classifying ‘chronic sleep insufficiency’ could only be achieved by a within-subject comparison of blood samples. Biomarkers for sleep debt status showed little overlap with previously identified biomarkers for circadian phase. Biomarkers for acute and chronic sleep loss also showed little overlap but were associated with common functions related to the cellular stress response, such as heat shock protein activity, the unfolded protein response, protein ubiquitination and endoplasmic reticulum associated protein degradation, and apoptosis. This characteristic response of whole blood to sleep loss can further aid our understanding of how sleep insufficiencies negatively affect health. Further development of these novel biomarkers for research and clinical practice requires validation in other protocols and age groups.
Sleep and circadian rhythms are intrinsically linked, with several sleep traits, including sleep timing and duration, influenced by both sleep homeostasis and the circadian phase. Genetic variation in several circadian genes has been associated with diurnal preference (preference in timing of sleep), although there has been limited research on whether they are associated with other sleep measurements. We investigated whether these genetic variations were associated with diurnal preference (Morningness-Eveningness Questionnaire) and various sleep measures, including: the global Pittsburgh Sleep Quality index score; sleep duration; and sleep latency and sleep quality. We genotyped 10 polymorphisms in genes with circadian expression in participants from the G1219 sample (n = 966), a British longitudinal population sample of young adults. We conducted linear regressions using dominant, additive and recessive models of inheritance to test for associations between these polymorphisms and the sleep measures. We found a significant association between diurnal preference and a polymorphism in period homologue 3 (PER3) (P < 0.005, recessive model) and a novel nominally significant association between diurnal preference and a polymorphism in aryl hydrocarbon receptor nuclear translocator-like 2 (ARNTL2) (P < 0.05, additive model). We found that a polymorphism in guanine nucleotide binding protein beta 3 (GNβ3) was associated significantly with global sleep quality (P < 0.005, recessive model), and that a rare polymorphism in period homologue 2 (PER2) was associated significantly with both sleep duration and quality (P < 0.0005, recessive model). These findings suggest that genes with circadian expression may play a role in regulating both the circadian clock and sleep homeostasis, and highlight the importance of further studies aimed at dissecting the specific roles that circadian genes play in these two interrelated but unique behaviours. © 2014 The Authors.
We examined whether a polymorphism of the PERIOD3 gene (PER3; rs57875989) modulated the sleep‐promoting effects of melatonin in Delayed Sleep‐Wake Phase Disorder (DSWPD). One hundred and four individuals (53 males; 29.4 ±10.0 years) with DSWPD and a delayed dim light melatonin onset (DLMO) collected buccal swabs for genotyping (PER34/4 n = 43; PER3 5 allele [heterozygous and homozygous] n = 60). Participants were randomised to placebo or 0.5 mg melatonin taken 1 hour before desired bedtime (or ~1.45 hours before DLMO), with sleep attempted at desired bedtime (4 weeks; 5‐7 nights/week). We assessed sleep (diary and actigraphy), Pittsburgh Sleep Quality Index (PSQI), Insomnia Severity Index (ISI), Patient‐Reported Outcomes Measurement Information System (PROMIS: Sleep Disturbance, Sleep‐Related Impairment), Sheehan Disability Scale (SDS) and Patient‐ and Clinician‐Global Improvement (PGI‐C, CGI‐C). Melatonin treatment response on actigraphic sleep onset time did not differ between genotypes. For PER34/4 carriers, self‐reported sleep onset time was advanced by a larger amount and sleep onset latency (SOL) was shorter in melatonin‐treated patients compared to those receiving placebo (P = .008), while actigraphic sleep efficiency in the first third of the sleep episode (SE T1) did not differ. For PER3 5 carriers, actigraphic SOL and SE T1 showed a larger improvement with melatonin (P
Cognitive performance deteriorates during extended wakefulness and circadian phase misalignment, and some individuals are more affected than others. Whether performance is affected similarly across cognitive domains, or whether cognitive processes involving Executive Functions are more sensitive to sleep and circadian misalignment than Alertness and Sustained Attention, is a matter of debate.
Prolonged wakefulness alters cortical excitability, which is essential for proper brain function and cognition. However, besides prior wakefulness, brain function and cognition are also affected by circadian rhythmicity. Whether the regulation of cognition involves a circadian impact on cortical excitability is unknown. Here, we assessed cortical excitability from scalp EEG-responses to transcranial magnetic stimulation in 22 participants during 29-h of wakefulness under constant conditions. Data reveal robust circadian dynamics of cortical excitability that were strongest in those individuals with highest endocrine markers of circadian amplitude. In addition, the time course of cortical excitability correlated with changes in EEG synchronization and cognitive performance. These results demonstrate that the crucial factor for cortical excitability, and basic brain function in general, is the balance between circadian rhythmicity and sleep need, rather than sleep homeostasis alone. These findings have implications for clinical applications such as noninvasive brain stimulation in neurorehabilitation.
© Cambridge University Press 2013.It would be extremely unusual, not to mention highly inconvenient, if everyone woke up and went about their daily routines at the same time. Fortunately this is not the case, and humans display a wide range of sleep–wake timing preferences. Some of us like to wake up and get things done in the morning (so-called larks, or morning types), others prefer to be active later in the day and night (owls, or evening types), and many are in between or a mixture of the two. The range in sleep–wake timing is considerable and differences in preferred bedtime and wake time can be as much as 2–3 The on average between morning and evening types , and in circadian rhythm sleep phase disorders, bedtimes can range from 7–9 p.m. (advanced) to 2–6 a.m. (delayed) . It has often been assumed that diurnal preference (morningness versus eveningness) is not an acquired characteristic but relates to biological factors involved in the circadian timing system that regulates the optimum times for waking performance and sleep–wake timing. However, current understanding of factors influencing variation in sleep–wake timing and optimal timing of waking performance emphasizes the interactive contribution of social factors, such as work schedules and leisure time, and biological factors. Underlying biological factors include the timing (phase of entrainment) of the endogenous circadian rhythmicity relative to clock time, and the light–dark cycle . The phase of entrainment is determined by the intrinsic period of the circadian clock, as well as sensitivity to the effects of light on the circadian clock. In addition, sleep homeostatic mechanisms also play an important role in sleep–wake timing. This implies that diurnal preference could be related to any of these three main factors: circadian period, light sensitivity, and sleep homeostasis.
Sleep complaints and irregular sleep patterns, such as curtailed sleep during workdays and longer and later sleep during weekends are common. It is often implied that differences in circadian period and in entrained phase contribute to these patterns but few data are available. We assessed parameters of the circadian rhythm of melatonin at baseline and in a forced desynchrony protocol in 35 participants (18 women) with no sleep disorders. Intrinsic circadian period varied between 23h50min and 24h31min and correlated positively (n=31, rs=0.43, P=0.017) with the timing of the melatonin rhythm relative to habitual bedtime. This phase of the melatonin rhythm correlated with the insomnia severity score (n=35, rs=0.47, P=0.004). Self-reported time in bed (TIB) during free days also correlated with the timing of the melatonin rhythm (n=35, rs=0.43, P=0.01) as well as with circadian period (n=31, rs=0.47, P=0.007) such that individuals with a more delayed melatonin rhythm or a longer circadian period reported longer sleep during the weekend. The increase in TIB during the free days correlated positively with circadian period (n=31, rs=0.54, P=0.002). Polysomnographically-assessed latency to persistent sleep (n=34, rs=0.48, P=0.004) correlated with the timing of the melatonin rhythm when participants were sleeping at their habitual bedtimes in the laboratory. This correlation was significantly stronger in women than in men (Z=2.38, P=0.017). The findings show that individual differences in period and phase of the circadian melatonin rhythm associate with differences in sleep and imply that individuals with a long circadian period are at risk of developing sleep problems.
Circadian organization of the mammalian transcriptome is achieved by rhythmic recruitment of key modifiers of chromatin structure and transcriptional and translational processes. These rhythmic processes, together with posttranslational modification, constitute circadian oscillators in the brain and peripheral tissues, which drive rhythms in physiology and behavior, including the sleep-wake cycle. In humans, sleep is normally timed to occur during the biological night, when body temperature is low and melatonin is synthesized. Desynchrony of sleep-wake timing and other circadian rhythms, such as occurs in shift work and jet lag, is associated with disruption of rhythmicity in physiology and endocrinology. However, to what extent mistimed sleep affects the molecular regulators of circadian rhythmicity remains to be established. Here, we show that mistimed sleep leads to a reduction of rhythmic transcripts in the human blood transcriptome from 6.4% at baseline to 1.0% during forced desynchrony of sleep and centrally driven circadian rhythms. Transcripts affected are key regulators of gene expression, including those associated with chromatin modification (methylases and acetylases), transcription (RNA polymerase II), translation (ribosomal proteins, initiation, and elongation factors), temperature-regulated transcription (cold inducible RNA-binding proteins), and core clock genes including CLOCK and ARNTL (BMAL1). We also estimated the separate contribution of sleep and circadian rhythmicity and found that the sleep-wake cycle coordinates the timing of transcription and translation in particular. The data show that mistimed sleep affects molecular processes at the core of circadian rhythm generation and imply that appropriate timing of sleep contributes significantly to the overall temporal organization of the human transcriptome.
Studying circadian rhythms in most human tissues is hampered by difficulty in collecting serial samples. Here we reveal circadian rhythms in the transcriptome and metabolic pathways of human white adipose tissue. Subcutaneous adipose tissue was taken from seven healthy males under highly controlled ‘constant routine’ conditions. Five biopsies per participant were taken at six-hourly intervals for microarray analysis and in silico integrative metabolic modelling. We identified 837 transcripts exhibiting circadian expression profiles (2% of 41619 transcript targeting probes on the array), with clear separation of transcripts peaking in the morning (258 probes) and evening (579 probes). There was only partial overlap of our rhythmic transcripts with published animal adipose and human blood transcriptome data. Morning-peaking transcripts associated with regulation of gene expression, nitrogen compound metabolism, and nucleic acid biology; evening-peaking transcripts associated with organic acid metabolism, cofactor metabolism and redox activity. In silico pathway analysis further indicated circadian regulation of lipid and nucleic acid metabolism; it also predicted circadian variation in key metabolic pathways such as the citric acid cycle and branched chain amino acid degradation. In summary, in vivo circadian rhythms exist in multiple adipose metabolic pathways, including those involved in lipid metabolism, and core aspects of cellular biochemistry.
Study Objectives: To screen the PER3 promoter for polymorphisms and investigate the phenotypic associations of these polymorphisms with diurnal preference, delayed sleep phase disorder/syndrome (DSPD/DSPS), and their effects on reporter gene expression. Design: Interspecific comparison was used to define the approximate extent of the PER3 promoter as the region between the transcriptional start site and nucleotide position −874. This region was screened in DNA pools using PCR and direct sequencing, which was also used to screen DNA from individual participants. The different promoter alleles were cloned into a luciferase expression vector and a deletion library created. Promoter activation was measured by chemiluminescence. Setting: N/A Patients or Participants: DNA samples were obtained from volunteers with defined diurnal preference (3 x 80, selected from a pool of 1,590), and DSPD patients (n = 23). Interventions: N/A Measurements and Results: We verified three single nucleotide polymorphisms (G −320T, C −319A, G −294A), and found a novel variable number tandem repeat (VNTR) polymorphism (−318 1/2 VNTR). The −320T and −319A alleles occurred more frequently in DSPD compared to morning (P = 0.042 for each) or evening types (P = 0.006 and 0.033). The allele combination TA2G was more prevalent in DSPD compared to morning (P = 0.033) or evening types (P = 0.002). Luciferase expression driven by the TA2G combination was greater than for the more common GC2A (P < 0.05) and the rarer TA1G (P < 0.001) combinations. Deletion reporter constructs identified two enhancer regions (−703 to −605, and −283 to −80). Conclusions: Polymorphisms in the PER3 promoter could affect its expression, leading to potential differences in the observed functions of PER3.
Using the technique of microspectrophotometry (MSP) we have found that the short wavelength sensitive cones in the retina of the pollack (Pollachius pollachius) shift in spectral absorption from a maximum (λ max) at about 420 nm in the violet to about 460 nm in the blue. This shift is not due to chromophore replacement, which substitutes rhodopsin for a porphyropsin, but is more likely to be due to a change in the opsin. The shift appears to be progressive rather than abrupt and coincides with a change in lifestyle of the fish.
Industrialisation greatly increased human night-time exposure to artificial light, which in animal models is a known cause of depressive phenotypes. Whilst many of these phenotypes are ‘direct’ effects of light on affect, an ‘indirect’ pathway via altered sleep-wake timing has been suggested. We have previously shown that the Period3 gene, which forms part of the biological clock, is associated with altered sleep-wake patterns in response to light. Here, we show that both wild-type and Per3-/- mice showed elevated levels of circulating corticosterone and increased hippocampal Bdnf expression after 3 weeks of exposure to dim light at night, but only mice deficient for the PERIOD3 protein (Per3-/-) exhibited a transient anhedonia-like phenotype, observed as reduced sucrose preference, in weeks 2-3 of dim light at night, whereas WT mice did not. Per3-/- mice also exhibited a significantly smaller delay in behavioural timing than WT mice during weeks 1, 2 and 4 of dim light at night exposure. When treated with imipramine, neither Per3-/- nor WT mice exhibited an anhedonia-like phenotype, and neither genotypes exhibited a delay in behavioural timing in responses to dLAN. While the association between both Per3-/- phenotypes remains unclear, both are alleviated by imipramine treatment during dim night-time light.
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 (PER3(5/5)) 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. PER3(5/5) are more likely to show morning preference, whereas homozygosity for the four-repeat allele (PER3(4/4)) associates with evening preferences. The association between sleep timing and the circadian rhythms of melatonin and PER3 RNA in leukocytes is stronger in PER3(5/5) than in PER3(4/4). EEG alpha activity in REM sleep, theta/alpha activity during wakefulness and slow wave activity in NREM sleep are elevated in PER3(5/5). PER3(5/5) 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 PER3(5/5) 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. (C) 2009 Elsevier Ltd. All rights reserved.
Light is a powerful modulator of cognition through its long-term effects on circadian rhythmicity and direct effects on brain function as identified by neuroimaging. How the direct impact of light on brain function varies with wavelength of light, circadian phase, and sleep homeostasis, and how this differs between individuals, is a largely unexplored area. Using functional MRI, we compared the effects of 1 minute of low-intensity blue (473 nm) and green light (527 nm) exposures on brain responses to an auditory working memory task while varying circadian phase and status of the sleep homeostat. Data were collected in 27 subjects genotyped for the PER3 VNTR (12 PER3(5/5) and 15 PER3(4/4) ) in whom it was previously shown that the brain responses to this task, when conducted in darkness, depend on circadian phase, sleep homeostasis, and genotype. In the morning after sleep, blue light, relative to green light, increased brain responses primarily in the ventrolateral and dorsolateral prefrontal cortex and in the intraparietal sulcus, but only in PER3(4/4) individuals. By contrast, in the morning after sleep loss, blue light increased brain responses in a left thalamofrontoparietal circuit to a larger extent than green light, and only so in PER3(5/5) individuals. In the evening wake maintenance zone following a normal waking day, no differential effect of 1 minute of blue versus green light was observed in either genotype. Comparison of the current results with the findings observed in darkness indicates that light acts as an activating agent particularly under those circumstances in which and in those individuals in whom brain function is jeopardized by an adverse circadian phase and high homeostatic sleep pressure.
Cognition is regulated across the 24 h sleep-wake cycle by circadian rhythmicity and sleep homeostasis through unknown brain mechanisms. We investigated these mechanisms in a functional magnetic resonance imaging study of executive function using a working memory 3-back task during a normal sleep-wake cycle and during sleep loss. The study population was stratified according to homozygosity for a variable-number (4 or 5) tandem-repeat polymorphism in the coding region of the clock gene PERIOD3. This polymorphism confers vulnerability to sleep loss and circadian misalignment through its effects on sleep homeostasis. In the less-vulnerable genotype, no changes were observed in brain responses during the normal-sleep wake cycle. During sleep loss, these individuals recruited supplemental anterior frontal, temporal and subcortical regions, while executive function was maintained. In contrast, in the vulnerable genotype, activation in a posterior prefrontal area was already reduced when comparing the evening to the morning during a normal sleep-wake cycle. Furthermore, in the morning after a night of sleep loss, widespread reductions in activation in prefrontal, temporal, parietal and occipital areas were observed in this genotype. These differences occurred in the absence of genotype-dependent differences in circadian phase. The data show that dynamic changes in brain responses to an executive task evolve across the sleep-wake and circadian cycles in a regionally specific manner that is determined by a polymorphism which affects sleep homeostasis. The findings support a model of individual differences in executive control, in which the allocation of prefrontal resources is constrained by sleep pressure and circadian phase.
In humans, a primate-specific variable-number tandem-repeat (VNTR) polymorphism (4 or 5 repeats 54 nt in length) in the circadian gene PER3 is associated with differences in sleep timing and homeostatic responses to sleep loss. We investigated the effects of this polymorphism on circadian rhythmicity and sleep homeostasis by introducing the polymorphism into mice and assessing circadian and sleep parameters at baseline and during and after 12 h of sleep deprivation (SD). Microarray analysis was used to measure hypothalamic and cortical gene expression. Circadian behavior and sleep were normal at baseline. The response to SD of 2 electrophysiological markers of sleep homeostasis, electroencephalography (EEG) θ power during wakefulness and δ power during sleep, were greater in the Per3(5/5) mice. During recovery, the Per3(5/5) mice fully compensated for the SD-induced deficit in δ power, but the Per3(4/4) and wild-type mice did not. Sleep homeostasis-related transcripts (e.g., Homer1, Ptgs2, and Kcna2) were differentially expressed between the humanized mice, but circadian clock genes were not. These data are in accordance with the hypothesis derived from human data that the PER3 VNTR polymorphism modifies the sleep homeostatic response without significantly influencing circadian parameters.-Hasan, S., van der Veen, D. R., Winsky-Sommerer, R., Hogben, A., Laing, E. E., Koentgen, F., Dijk, D.-J., Archer, S. N. A human sleep homeostasis phenotype in mice expressing a primate-specific PER3 variable-number tandem-repeat coding-region polymorphism.
Differences in daily light exposure profiles have been reported, with younger M-types shown to spend more time in bright light, especially in the morning, compared with E-types. This study aimed to investigate how patterns of daily light exposure in older non-resident M-types and E-types compare. Sleep diaries were kept during actigraphic measurement of activity and light using the Actiwatch-L for 14 days in 12 M-types [eight females, mean ± standard deviation (SD) Horne–Östberg Morning–Eveningness Questionnaire (HÖ MEQ) score 75.2 ± 1.6] and 11 E-types (seven females, HÖ MEQ 41.5 ± 4.8), over 60 years old, living in their own homes. Light data were log-transformed, averaged over each hour, and group × time analysis of covariance (ancova) performed with age as a covariate. M-types had significantly earlier bed and wake time than E-types, but there was no significant difference in sleep duration, sleep efficiency or time spent in bed between groups. Daily exposure to light intensity greater than 1000 lux was compared between the two groups, with no significant difference in the duration of exposure to >1000 lux between M-types and E-types. Twenty-four-hour patterns of light exposure show that M-types were exposed to higher light intensity at 06:00 h than E-types. Conversely, E-types were exposed to higher light intensity between 22:00 and 23:00 h than M-types. These findings show that differences in daily light exposure patterns found previously in younger M-types and E-types are also found in older M-types and E-types, but at an earlier clock-time, confirming the tendency to advance with ageing.
Study Objectives: Individual sleep timing differs and is governed partly by circadian oscillators, which may be assessed by hormonal markers, or by clock gene expression. Clock gene expression oscillates in peripheral tissues, including leukocytes. The study objective was to determine whether the endogenous phase of these rhythms, assessed in the absence of the sleep-wake and light-dark cycle, correlates with habitual sleep-wake timing. Design: Observational, cross-sectional. Setting: Home environment and Clinical Research Center. Participants: 24 healthy subjects aged 25.0 ± 3.5 (SD) years. Measurements: Actigraphy and sleep diaries were used to characterize sleep timing. Circadian rhythm phase and amplitude of plasma melatonin, cortisol, and BMAL1, PER2, and PER3 expression were assessed during a constant routine. Results: Circadian oscillations were more robust for PER3 than for BMAL1 or PER2. Average peak timings were 6:05 for PER3, 8:06 for PER2, 15:06 for BMAL1, 4:20 for melatonin, and 10:49 for cortisol. Individual sleep-wake timing correlated with the phases of melatonin and cortisol. Individual PER3 rhythms correlated significantly with sleep-wake timing and the timing of melatonin and cortisol, but those of PER2 and BMAL1 did not reach significance. The correlation between sleep timing and PER3 expression was stronger in individuals homozygous for the variant of the PER3 polymorphism that is associated with morningness. Conclusions: Individual phase differences in PER3 expression during a constant routine correlate with sleep timing during entrainment. PER3 expression in leukocytes represents a useful molecular marker of the circadian processes governing sleep-wake timing.
Diagnosis and treatment of circadian rhythm sleep-wake disorders requires assessment of circadian phase of the brain’s circadian pacemaker. The gold-standard univariate method is based on collection of a 24 h time series of plasma melatonin, a suprachiasmatic nucleus driven pineal hormone. We developed and validated a multivariate whole-blood mRNA based predictor of melatonin phase which requires few samples. Transcriptome data were collected under normal, sleep-deprivation and abnormal sleep-timing conditions to assess robustness of the predictor. Partial least square regression (PLSR), applied to the transcriptome, identified a set of 100 biomarkers primarily related to glucocorticoid signaling and immune function. Validation showed that PLSR-based predictors outperform published blood-derived circadian phase predictors. When given one sample as input, the R2 of predicted vs observed phase was 0.74, whereas for two samples taken 12 h apart, R2 was 0.90. This blood transcriptome based model enables assessment of circadian phase from a few samples.
Light is considered the most potent synchronizer of the human circadian system and exerts many other non-image-forming effects, including those that affect brain function. These effects are mediated in part by intrinsically photosensitive retinal ganglion cells that express the photopigment melanopsin. The spectral sensitivity of melanopsin is greatest for blue light at approximately 480 nm. At present, there is little information on how the spectral composition of light to which people are exposed varies over the 24 h period and across seasons. Twenty-two subjects, aged 22±4 yrs (mean±SD) participated during the winter months (November–February), and 12 subjects aged 25±3 yrs participated during the summer months (April–August). Subjects wore Actiwatch-RGB monitors, as well as Actiwatch-L monitors, for seven consecutive days while living in England. These monitors measured activity and light exposure in the red, green, and blue spectral regions, in addition to broad-spectrum white light, with a 2 min resolution. Light exposure during the day was analyzed for the interval between 09:00 and 21:00 h. The time course of white-light exposure differed significantly between seasons (p = 0.0022), with light exposure increasing in the morning hours and declining in the afternoon hours, and with a more prominent decline in the winter. Overall light exposure was significantly higher in summer than winter (p = 0.0002). Seasonal differences in the relative contribution of blue-light exposure to overall light exposure were also observed (p = 0.0006), in particular during the evening hours. During the summer evenings (17:00–21:00 h), the relative contribution of blue light was significantly higher (p
© Cambridge University Press 2013.In humans, the sleep–wake cycle is determined by the interaction of the endogenous circadian clock and sleep homeostat, and exogenous factors such as the light/dark cycle, which is important for circadian entrainment, and social influences such as work and recreation (Figure 31.1). These factors interact and it is often difficult to determine the causes and nature of altered sleep–wake timing. Abnormal sleep–wake timing may be a simple consequence of an abnormal phase relationship of the circadian clock and environmental time. This may be caused by aberrant light exposure patterns or extreme intrinsic periods of the circadian clock. The timing of the sleep–wake cycle relative to the circadian sleep propensity rhythm may be altered because of fast or slow build-up of homeostatic sleep pressure. Recent mathematical models of the sleep–wake cycle have indeed demonstrated that one particular phenotype may be related to parameters of very different processes . Here, we focus on some of the genetic factors that are associated with abnormally delayed sleep timing, and explore to what extent the effects of these factors can be attributed to physiological processes such as light sensitivity, sleep homeostasis or circadian period. Circadian rhythm sleep disorders (CRSDs) refer to sleep disturbances that are primarily due to alterations of the circadian time-keeping system or are related to a misalignment of endogenous circadian rhythms and the required sleep–wake time (see ). The latter distinction is important because social factors may necessitate a non-desirable sleep–wake schedule, as occurs in shift work, for example. Shift work disorder and jet lag disorder are CRSDs that are caused by exogenous factors, whereas dysfunction of the endogenous circadian clock is thought to be the primary cause of delayed sleep phase disorder (DSPD). A better understanding of what causes CRSDs and inter-individual vulnerability differences is important because of the large proportion of the population who regularly undertake shift work, the epidemiological evidence linking insufficient sleep with negative health outcomes , and known associations between extreme evening preference and health problems such as mood disorders, metabolic disorders, and cardiovascular risk (see ).
The effect of light on circadian rhythms and sleep is mediated by a multi-component photoreceptive system of rods, cones and melanopsin-expressing intrinsically photosensitive retinal ganglion cells. The intensity and spectral sensitivity characteristics of this system are to be fully determined. Whether the intensity and spectral composition of light exposure at home in the evening is such that it delays circadian rhythms and sleep also remains to be established. We monitored light exposure at home during 6-8 wk and assessed light effects on sleep and circadian rhythms in the laboratory. Twenty-two women and men (23.1 ± 4.7 yr) participated in a six-way, cross-over design using polychromatic light conditions relevant to the light exposure at home, but with reduced, intermediate or enhanced efficacy with respect to the photopic and melanopsin systems. The evening rise of melatonin, sleepiness and EEG-assessed sleep onset varied significantly (P
This book represents a timely and much needed review of the wealth of research that has been carried out in the last twenty years.
Several neuropsychiatric and neurological disorders have recently been characterized as dysfunctions arising from a ‘final common pathway’ of imbalanced excitation to inhibition within cortical networks. How the regulation of a cortical E/I ratio is affected by sleep and the circadian rhythm however, remains to be established. Here we addressed this issue through the analyses of TMS-evoked responses recorded over a 29h sleep deprivation protocol conducted in young and healthy volunteers. Spectral analyses of TMS-evoked responses in frontal cortex revealed non-linear changes in gamma band evoked oscillations, compatible with an influence of circadian timing on inhibitory interneuron activity. In silico inferences of cell-to-cell excitatory and inhibitory connectivity and GABA/Glutamate receptor time constant based on neural mass modeling within the Dynamic causal modeling framework, further suggested excitation/inhibition balance was under a strong circadian influence. These results indicate that circadian changes in EEG spectral properties, in measure of excitatory/inhibitory connectivity and in GABA/glutamate receptor function could support the maintenance of cognitive performance during a normal waking day, but also during overnight wakefulness. More generally, these findings demonstrate a slow daily regulation of cortical excitation/inhibition balance, which depends on circadian-timing and prior sleep-wake history.
This book represents a timely and much needed review of the wealth of research that has been carried out in the last twenty years.