Altered sleep and behavioral activity phenotypes in PER3-deficient mice.

Sleep homeostasis and circadian rhythmicity interact to determine the timing of behavioral activity. Circadian clock genes contribute to circadian rhythmicity centrally and in the periphery, but some also have roles within sleep regulation. The clock gene Period3 (Per3) has a redundant function within the circadian system and is associated with sleep homeostasis in humans. This study investigated the role of PER3 in sleep/wake activity and sleep homeostasis in mice by recording wheel-running activity under baseline conditions in wild-type (WT; n = 54) and in PER3-deficient (Per3(-/-); n = 53) mice, as well as EEG-assessed sleep before and after 6 h of sleep deprivation in WT (n = 7) and Per3(-/-) (n = 8) mice. Whereas total activity and vigilance states did not differ between the genotypes, the temporal distribution of wheel-running activity, vigilance states, and EEG delta activity was affected by genotype. In Per3(-/-) mice, running wheel activity was increased, and REM sleep and NREM sleep were reduced in the middle of the dark phase, and delta activity was enhanced at the end of the dark phase. At the beginning of the baseline light period, there was less wakefulness and more REM and NREM sleep in Per3(-/-) mice. Per3(-/-) mice spent less time in wakefulness and more time in NREM sleep in the light period immediately after sleep deprivation, and REM sleep accumulated more slowly during the recovery dark phase. These data confirm a role for PER3 in sleep-wake timing and sleep homeostasis.

[1]  E. Mignot,et al.  PER3 Polymorphism Predicts Cumulative Sleep Homeostatic but Not Neurobehavioral Changes to Chronic Partial Sleep Deprivation , 2009, PloS one.

[2]  R. Wever.  Characteristics of circadian rhythms in human functions. , 1986, Journal of neural transmission. Supplementum.

[3]  G. Vandewalle,et al.  Functional Magnetic Resonance Imaging-Assessed Brain Responses during an Executive Task Depend on Interaction of Sleep Homeostasis, Circadian Phase, and PER3 Genotype , 2009, The Journal of Neuroscience.

[4]  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.

[5]  R. Moore,et al.  Loss of a circadian adrenal corticosterone rhythm following suprachiasmatic lesions in the rat. , 1972, Brain research.

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

[7]  D. Skene,et al.  A single‐nucleotide polymorphism in the 5′‐untranslated region of the hPER2 gene is associated with diurnal preference , 2005, Journal of sleep research.

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

[9]  R. Feil,et al.  cGMP-Dependent Protein Kinase Type I Is Implicated in the Regulation of the Timing and Quality of Sleep and Wakefulness , 2009, PloS one.

[10]  T. Deboer,et al.  Sleep and Sleep Regulation in Normal and Prion Protein-Deficient Mice , 1997, The Journal of Neuroscience.

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

[12]  Josephine Arendt,et al.  A length polymorphism in the circadian clock gene Per3 is linked to delayed sleep phase syndrome and extreme diurnal preference. , 2003, Sleep.

[13]  M. Hastings,et al.  Circadian clocks: genes, sleep, and cognition , 2010, Trends in Cognitive Sciences.

[14]  L. Lopez-Molina,et al.  The Transcription Factor DBP Affects Circadian Sleep Consolidation and Rhythmic EEG Activity , 2000, The Journal of Neuroscience.

[15]  Erik D Herzog,et al.  Clock Genes, Oscillators, and Cellular Networks in the Suprachiasmatic Nuclei , 2004, Journal of biological rhythms.

[16]  D. Dijk,et al.  Inter-individual differences in habitual sleep timing and entrained phase of endogenous circadian rhythms of BMAL1, PER2 and PER3 mRNA in human leukocytes. , 2008, Sleep.

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

[18]  Steven M. Reppert,et al.  Differential Functions of mPer1, mPer2, and mPer3 in the SCN Circadian Clock , 2001, Neuron.

[19]  Wever Ra.  Characteristics of circadian rhythms in human functions. , 1986 .

[20]  S. Kay,et al.  Molecular bases of circadian rhythms. , 2001, Annual review of cell and developmental biology.

[21]  A. Borbély.  A two process model of sleep regulation. , 1982, Human neurobiology.

[22]  Christopher R. Jones,et al.  An hPer2 Phosphorylation Site Mutation in Familial Advanced Sleep Phase Syndrome , 2001, Science.

[23]  Derk-Jan Dijk,et al.  Timing and Consolidation of Human Sleep, Wakefulness, and Performance by a Symphony of Oscillators , 2005, Journal of biological rhythms.

[24]  M. W. Young,et al.  A light‐independent oscillatory gene mPer3 in mouse SCN and OVLT , 1998, The EMBO journal.

[25]  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.

[26]  S. Reppert,et al.  Targeted Disruption of the mPer3 Gene: Subtle Effects on Circadian Clock Function , 2000, Molecular and Cellular Biology.

[27]  C A Czeisler,et al.  Variation of electroencephalographic activity during non‐rapid eye movement and rapid eye movement sleep with phase of circadian melatonin rhythm in humans , 1997, The Journal of physiology.

[28]  John A Groeger,et al.  Early morning executive functioning during sleep deprivation is compromised by a PERIOD3 polymorphism. , 2008, Sleep.

[29]  D. Skene,et al.  PER 3 , DIURNAL PHASE AND DELAY SLEEP PHASE SYNDROME Polymorphism in the PER 3 Promoter Associates with Diurnal Preference and Delayed Sleep Phase Disorder , 2010 .

[30]  B. Zheng,et al.  Homeostatic sleep regulation is preserved in mPer1 and mPer2 mutant mice , 2002, The European journal of neuroscience.

[31]  S. Yamazaki,et al.  Distinct Functions of Period2 and Period3 in the Mouse Circadian System Revealed by In Vitro Analysis , 2010, PloS one.

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

[33]  D. Dijk,et al.  PERIOD3, circadian phenotypes, and sleep homeostasis. , 2010, Sleep medicine reviews.

[34]  D. Skene,et al.  Polymorphism in the PER3 promoter associates with diurnal preference and delayed sleep phase disorder. , 2010, Sleep.

[35]  D. Weaver,et al.  Sleep rhythmicity and homeostasis in mice with targeted disruption of mPeriod genes. , 2004, American journal of physiology. Regulatory, integrative and comparative physiology.

[36]  D. P. King,et al.  A CLOCK polymorphism associated with human diurnal preference. , 1998, Sleep.

[37]  T. Meitinger,et al.  CLOCK Gene Variants Associate with Sleep Duration in Two Independent Populations , 2010, Biological Psychiatry.

[38]  I. Zucker,et al.  Circadian rhythms in drinking behavior and locomotor activity of rats are eliminated by hypothalamic lesions. , 1972, Proceedings of the National Academy of Sciences of the United States of America.

[39]  D. Dijk,et al.  PER3 Polymorphism Predicts Sleep Structure and Waking Performance , 2007, Current Biology.

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

[41]  S. Archer,et al.  Light-Dependent Behavioral Phenotypes in PER3-Deficient Mice , 2010, Journal of biological rhythms.

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

[43]  C A Czeisler,et al.  Timing of REM sleep is coupled to the circadian rhythm of body temperature in man. , 1980, Sleep.

[44]  J. Takahashi,et al.  Effects of aging on the circadian rhythm of wheel-running activity in C57BL/6 mice. , 1997, American journal of physiology. Regulatory, integrative and comparative physiology.