Homeostatic and circadian contribution to EEG and molecular state variables of sleep regulation.

STUDY OBJECTIVES Besides their well-established role in circadian rhythms, our findings that the forebrain expression of the clock-genes Per2 and Dbp increases and decreases, respectively, in relation to time spent awake suggest they also play a role in the homeostatic aspect of sleep regulation. Here, we determined whether time of day modulates the effects of elevated sleep pressure on clock-gene expression. Time of day effects were assessed also for recognized electrophysiological (EEG delta power) and molecular (Homer1a) markers of sleep homeostasis. DESIGN EEG and qPCR data were obtained for baseline and recovery from 6-h sleep deprivation starting at ZT0, -6, -12, or -18. SETTING Mouse sleep laboratory. PARTICIPANTS Male mice. INTERVENTIONS Sleep deprivation. RESULTS The sleep-deprivation induced changes in Per2 and Dbp expression importantly varied with time of day, such that Per2 could even decrease during sleep deprivations occurring at the decreasing phase in baseline. Dbp showed similar, albeit opposite dynamics. These unexpected results could be reliably predicted assuming that these transcripts behave according to a driven damped harmonic oscillator. As expected, the sleep-wake distribution accounted for a large degree of the changes in EEG delta power and Homer1a. Nevertheless, the sleep deprivation-induced increase in delta power varied also with time of day with higher than expected levels when recovery sleep started at dark onset. CONCLUSIONS Per2 and delta power are widely used as exclusive state variables of the circadian and homeostatic process, respectively. Our findings demonstrate a considerable cross-talk between these two processes. As Per2 in the brain responds to both sleep loss and time of day, this molecule is well positioned to keep track of and to anticipate homeostatic sleep need. CITATION Curie T; Mongrain V; Dorsaz S; Mang GM; Emmenegger Y; Franken P. Homeostatic and circadian contribution to EEG and molecular state variables of sleep regulation. SLEEP 2013;36(3):311-323.

[1]  P. Franken,et al.  A role for cryptochromes in sleep regulation , 2002, BMC Neuroscience.

[2]  K. Kadota,et al.  Genome-wide expression analysis reveals 100 adrenal gland-dependent circadian genes in the mouse liver. , 2005, DNA research : an international journal for rapid publication of reports on genes and genomes.

[3]  D.G.M. Dijk,et al.  Contribution of the circadian pacemaker and the sleep homeostat to sleep propensity, sleep structure, electroencephalographic slow waves, and sleep spindle activity in humans , 1995, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[4]  P. Sassone-Corsi,et al.  Circadian Control of the NAD+ Salvage Pathway by CLOCK-SIRT1 , 2009, Science.

[5]  M. Lancel,et al.  Effects of circadian phase and duration of sleep deprivation on sleep and EEG power spectra in the cat , 1991, Brain Research.

[6]  A. Pack,et al.  Genetic evidence for a role of CREB in sustained cortical arousal. , 2003, Journal of neurophysiology.

[7]  Reto Huber,et al.  Effects of sleep deprivation on sleep and sleep EEG in three mouse strains: empirical data and simulations , 2000, Brain Research.

[8]  Adriano Fontana,et al.  TNF-α suppresses the expression of clock genes by interfering with E-box-mediated transcription , 2007, Proceedings of the National Academy of Sciences.

[9]  H. Heller,et al.  A non-circadian role for clock-genes in sleep homeostasis:a strain comparison , 2007, BMC Neuroscience.

[10]  A. Wirz-Justice,et al.  Power density in theta/alpha frequencies of the waking EEG progressively increases during sustained wakefulness. , 1995, Sleep.

[11]  Steven L McKnight,et al.  Altered Patterns of Sleep and Behavioral Adaptability in NPAS2-Deficient Mice , 2003, Science.

[12]  D. Dijk,et al.  Circadian clock genes and sleep homeostasis , 2009, The European journal of neuroscience.

[13]  F. Stephan,et al.  The “Other” Circadian System: Food as a Zeitgeber , 2002, Journal of biological rhythms.

[14]  F. Turek,et al.  Deletion of the mammalian circadian clock gene BMAL1/Mop3 alters baseline sleep architecture and the response to sleep deprivation. , 2005, Sleep.

[15]  E. Maywood,et al.  Circadian clocks: regulators of endocrine and metabolic rhythms. , 2007, The Journal of endocrinology.

[16]  A. Pack,et al.  Analysis of the QTL for sleep homeostasis in mice: Homer1a is a likely candidate. , 2008, Physiological genomics.

[17]  Ook Joon Yoo,et al.  PERIOD2::LUCIFERASE real-time reporting of circadian dynamics reveals persistent circadian oscillations in mouse peripheral tissues. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[18]  D Chollet,et al.  The Homeostatic Regulation of Sleep Need Is under Genetic Control , 2001, The Journal of Neuroscience.

[19]  Gad Vatine,et al.  Light Directs Zebrafish period2 Expression via Conserved D and E Boxes , 2009, PLoS biology.

[20]  J. Takahashi,et al.  Circadian Clock Feedback Cycle Through NAMPT-Mediated NAD+ Biosynthesis , 2009, Science.

[21]  Erin L. McDearmon,et al.  The genetics of mammalian circadian order and disorder: implications for physiology and disease , 2008, Nature Reviews Genetics.

[22]  S. Pradervand,et al.  How to Keep the Brain Awake? The Complex Molecular Pharmacogenetics of Wake Promotion , 2009, Neuropsychopharmacology.

[23]  R. van der Spek,et al.  Circadian rhythms in the hypothalamo–pituitary–adrenal (HPA) axis , 2012, Molecular and Cellular Endocrinology.

[24]  S. McKnight,et al.  A Conserved DNA Damage Response Pathway Responsible for Coupling the Cell Division Cycle to the Circadian and Metabolic Cycles , 2007, Cell cycle.

[25]  Gerard A. Kerkhof,et al.  Effects of repeated sleep deprivation in the dark- or light-period on sleep in rats , 1989, Physiology & Behavior.

[26]  Ueli Schibler,et al.  System-Driven and Oscillator-Dependent Circadian Transcription in Mice with a Conditionally Active Liver Clock , 2007, PLoS biology.

[27]  M. Carskadon,et al.  Circadian rhythm sleep disorders: part I, basic principles, shift work and jet lag disorders. An American Academy of Sleep Medicine review. , 2007, Sleep.

[28]  Hanspeter Herzel,et al.  Quantification of Circadian Rhythms in Single Cells , 2009, PLoS Comput. Biol..

[29]  D. Dijk,et al.  Circadian and sleep/wake dependent aspects of subjective alertness and cognitive performance , 1992, Journal of sleep research.

[30]  Peter Meerlo,et al.  The suprachiasmatic nucleus regulates sleep timing and amount in mice. , 2004, Sleep.

[31]  J. Auwerx,et al.  Key Electrophysiological, Molecular, and Metabolic Signatures of Sleep and Wakefulness Revealed in Primary Cortical Cultures , 2012, The Journal of Neuroscience.

[32]  H. Heller,et al.  Homeostatic regulation of sleep in arrhythmic Siberian hamsters. , 2004, American Journal of Physiology. Regulatory Integrative and Comparative Physiology.

[33]  Felix Naef,et al.  Circadian Gene Expression in Individual Fibroblasts Cell-Autonomous and Self-Sustained Oscillators Pass Time to Daughter Cells , 2004, Cell.

[34]  Felix Naef,et al.  Dynamical signatures of cellular fluctuations and oscillator stability in peripheral circadian clocks , 2007, Molecular systems biology.

[35]  M. Tafti,et al.  Genetics of sleep. , 2008, Annual review of genetics.

[36]  Richard E Kronauer,et al.  Comparisons of the Variability of Three Markers of the Human Circadian Pacemaker , 2002, Journal of biological rhythms.

[37]  Fred W. Turek,et al.  The Circadian Clock Mutation Alters Sleep Homeostasis in the Mouse , 2000, The Journal of Neuroscience.

[38]  S. Amir,et al.  Glucocorticoid rhythms control the rhythm of expression of the clock protein, Period2, in oval nucleus of the bed nucleus of the stria terminalis and central nucleus of the amygdala in rats , 2006, Neuroscience.

[39]  Yoshiyuki Sakaki,et al.  Circadian Rhythms in Isolated Brain Regions , 2002, The Journal of Neuroscience.

[40]  P. Franken,et al.  Sleep Loss Reduces the DNA-Binding of BMAL1, CLOCK, and NPAS2 to Specific Clock Genes in the Mouse Cerebral Cortex , 2011, PloS one.

[41]  Steven A. Brown,et al.  Resetting of circadian time in peripheral tissues by glucocorticoid signaling. , 2000, Science.

[42]  S. Yamaguchi,et al.  Antagonistic role of E4BP4 and PAR proteins in the circadian oscillatory mechanism. , 2001, Genes & development.

[43]  S. Hashimoto,et al.  Identification of functional clock-controlled elements involved in differential timing of Per1 and Per2 transcription , 2010, Nucleic acids research.

[44]  S. McKnight,et al.  NPAS2 as a transcriptional regulator of non-rapid eye movement sleep: genotype and sex interactions. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[45]  A. Malafosse,et al.  Genetic determinants of sleep regulation in inbred mice. , 1999, Sleep.

[46]  G. Tsujimoto,et al.  Light activates the adrenal gland: timing of gene expression and glucocorticoid release. , 2005, Cell metabolism.

[47]  T. Deboer.  Sleep and sleep homeostasis in constant darkness in the rat , 2009, Journal of sleep research.

[48]  Tomoko Yoshikawa,et al.  Circadian Organization Is Governed by Extra-SCN Pacemakers , 2010, Journal of biological rhythms.

[49]  Derk-Jan Dijk,et al.  Interaction of sleep homeostasis and circadian rhythmicity : dependent or independent systems? , 2005 .

[50]  F. Speleman,et al.  Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes , 2002, Genome Biology.

[51]  G. Tononi,et al.  Stress response genes protect against lethal effects of sleep deprivation in Drosophila , 2002, Nature.

[52]  H. Heller,et al.  Separating the contribution of glucocorticoids and wakefulness to the molecular and electrophysiological correlates of sleep homeostasis. , 2010, Sleep.

[53]  G. Mortier,et al.  qBase relative quantification framework and software for management and automated analysis of real-time quantitative PCR data , 2007, Genome Biology.

[54]  E. Lein,et al.  Sleep Deprivation Effects on Circadian Clock Gene Expression in the Cerebral Cortex Parallel Electroencephalographic Differences among Mouse Strains , 2008, The Journal of Neuroscience.

[55]  R. Huganir,et al.  Homeostatic Scaling Requires Group I mGluR Activation Mediated by Homer1a , 2010, Neuron.

[56]  D. Boivin,et al.  The regulation of central and peripheral circadian clocks in humans , 2009, Obesity reviews : an official journal of the International Association for the Study of Obesity.

[57]  Joseph S. Takahashi,et al.  Circadian Integration of Metabolism and Energetics , 2010, Science.

[58]  G. Tononi,et al.  Differential Expression of Plasticity-Related Genes in Waking and Sleep and Their Regulation by the Noradrenergic System , 2000, The Journal of Neuroscience.

[59]  J. Panksepp,et al.  Sleep as a fundamental property of neuronal assemblies , 2008, Nature Reviews Neuroscience.

[60]  A. Malafosse,et al.  Genetic variation in EEG activity during sleep in inbred mice. , 1998, American journal of physiology. Regulatory, integrative and comparative physiology.

[61]  S. Pradervand,et al.  Homer1a is a core brain molecular correlate of sleep loss , 2007, Proceedings of the National Academy of Sciences.

[62]  Vladyslav V. Vyazovskiy,et al.  Theta activity in the waking EEG is a marker of sleep propensity in the rat , 2005, Brain Research.

[63]  Debra J. Skene,et al.  Visual impairment and circadian rhythm disorders , 2007 .

[64]  A. Fontana,et al.  Clock Gene Modulation by TNF-α Depends on Calcium and p38 MAP Kinase Signaling , 2009, Journal of biological rhythms.

[65]  A. Borbély,et al.  Room light impairs sleep in the albino rat , 1994, Behavioural Brain Research.

[66]  N. Ishida,et al.  The negative transcription factor E4BP4 is associated with circadian clock protein PERIOD2. , 2007, Biochemical and biophysical research communications.

[67]  S. Shibata,et al.  Restricted‐feeding‐induced anticipatory activity rhythm is associated with a phase‐shift of the expression of mPer1 and mPer2 mRNA in the cerebral cortex and hippocampus but not in the suprachiasmatic nucleus of mice , 2001, The European journal of neuroscience.

[68]  P. Achermann,et al.  Sleep homeostasis in the rat in the light and dark period , 2007, Brain Research Bulletin.

[69]  Charalambos P. Kyriacou,et al.  Single Gene Mutations in Drosophila: What can they tell us about the Evolution of Sexual Behaviour? , 2002, Genetica.

[70]  B. Tu,et al.  Metabolic cycles as an underlying basis of biological oscillations , 2006, Nature Reviews Molecular Cell Biology.

[71]  Florian Kreppel,et al.  SIRT1 Regulates Circadian Clock Gene Expression through PER2 Deacetylation , 2008, Cell.

[72]  Gregor Eichele,et al.  Adrenal glucocorticoids have a key role in circadian resynchronization in a mouse model of jet lag. , 2010, The Journal of clinical investigation.

[73]  Paolo Sassone-Corsi,et al.  Bimodal regulation of mPeriod promoters by CREB-dependent signaling and CLOCK/BMAL1 activity , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[74]  P. Achermann,et al.  Mathematical models of sleep regulation. , 2003, Frontiers in bioscience : a journal and virtual library.

[75]  D. Dijk,et al.  Ageing and the circadian and homeostatic regulation of human sleep during forced desynchrony of rest, melatonin and temperature rhythms , 1999, The Journal of physiology.

[76]  S. Shibata,et al.  Refeeding after Fasting Elicits Insulin-Dependent Regulation of Per2 and Rev-erbα with Shifts in the Liver Clock , 2011, Journal of biological rhythms.

[77]  I Tobler,et al.  Sleep deprivation in rats: effects on EEG power spectra, vigilance states, and cortical temperature. , 1991, The American journal of physiology.

[78]  K. Yamamoto,et al.  Glucocorticoid regulation of the circadian clock modulates glucose homeostasis , 2009, Proceedings of the National Academy of Sciences.

[79]  Alexander A. Borbély,et al.  Sleep homeostasis in the rat: Simulation of the time course of EEG slow-wave activity , 1991, Neuroscience Letters.

[80]  H. Heller,et al.  Sleep homeostasis in suprachiasmatic nuclei-lesioned rats: effects of sleep deprivation and triazolam administration , 1992, Brain Research.

[81]  Paul Franken,et al.  Sleep and EEG Phenotyping in Mice. , 2012, Current protocols in mouse biology.

[82]  Ueli Schibler,et al.  Crosstalk between components of circadian and metabolic cycles in mammals. , 2011, Cell metabolism.

[83]  K. Kadota,et al.  Clock mutation affects circadian regulation of circulating blood cells , 2006, Journal of circadian rhythms.

[84]  Peter Achermann,et al.  A model of human sleep homeostasis based on EEG slow-wave activity: Quantitative comparison of data and simulations , 1993, Brain Research Bulletin.