The mouse
            <i>Clock</i>
            mutation reduces circadian pacemaker amplitude and enhances efficacy of resetting stimuli and phase–response curve amplitude

Vitaterna, Martha Hotz; Ko, Caroline H.; Chang, Anne Marie; Buhr, Ethan D.; Fruechte, Ethan M.; Schook, Andrew C.; Antoch, Marina P.; Turek, Fred W.; Takahashi, Joseph S.

doi:10.1073/pnas.0603601103

Cited by 208 publications

(226 citation statements)

References 38 publications

(41 reference statements)

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“…These findings build upon previous studies that have revealed other deficits in peripheral rhythms in aged rats including lower circadian amplitude or arrhythmicity, altered phase relationships and shortened period [37]. Although one could speculate that an increased rate of shifting for arcuate nucleus and pineal gland correlates with decreased circadian amplitude in vivo [33], indirect measurements of rhythm robustness for pineal gland did not reveal any age-related differences in amplitude [37]. It must be noted that culture preparation can affect the circadian phase of some cultured tissues [38].…”

Section: Discussionsupporting

confidence: 87%

Resetting of central and peripheral circadian oscillators in aged rats

Davidson

Yamazaki

Arble

et al. 2008

Neurobiology of Aging

115

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The mammalian circadian timing system is affected by aging. Analysis of the suprachiasmatic nucleus (SCN) and of other circadian oscillators reveals age-related changes which are most profound in extra-SCN tissues. Some extra-SCN oscillators appear to stop oscillating in vivo or display altered phase relationships. To determine whether the dynamic behavior of circadian oscillators is also affected by aging we studied the resetting behavior of the Period1 transcriptional rhythm of peripheral and central oscillators in response to a 6 hr advance or delay in the light schedule. We employed a transgenic rat with a luciferase reporter to allow for real-time measurements of transcriptional rhythmicity. While phase-resetting in the SCN following an advance or a delay of the light cycle appears nearly normal in 2-year old rats, resynchronization of the liver was seriously disrupted. In addition, the arcuate nucleus and pineal gland exhibited faster resetting in aged rats relative to 4-8 month-old controls. The consequences of these deficits are unknown, but may contribute to organ and brain diseases in the aged as well as the health problems that are common in older shift-workers.

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Section: Discussionsupporting

confidence: 87%

Resetting of central and peripheral circadian oscillators in aged rats

Davidson

Yamazaki

Arble

et al. 2008

Neurobiology of Aging

115

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“…Specifically, Vitaterna et al. (2006) experimentally showed that mutations in the CLOCK gene PolyQ cTNR reduced the amplitude of the circadian pacemaker in mice, thereby effectively increasing the efficiency with which mice can synchronize to external light cues. The PER1 gene is a light‐sensitive core component of the circadian clock (Hunt & Sassone‐Corsi, 2007), with variability in expression allowing for entrainment of circadian rhythms in synchrony with the external environment (Yamamoto et al., 2004).…”

Section: Methodsmentioning

confidence: 99%

Signatures of selection in mammalian clock genes with coding trinucleotide repeats: Implications for studying the genomics of high‐pace adaptation

Prentice

Bowman

Lalor

et al. 2017

Ecology and Evolution

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Climate change is predicted to affect the reproductive ecology of wildlife; however, we have yet to understand if and how species can adapt to the rapid pace of change. Clock genes are functional genes likely critical for adaptation to shifting seasonal conditions through shifts in timing cues. Many of these genes contain coding trinucleotide repeats, which offer the potential for higher rates of change than single nucleotide polymorphisms (SNPs) at coding sites, and, thus, may translate to faster rates of adaptation in changing environments. We characterized repeats in 22 clock genes across all annotated mammal species and evaluated the potential for selection on repeat motifs in three clock genes (NR1D1,CLOCK, and PER1) in three congeneric species pairs with different latitudinal range limits: Canada lynx and bobcat (Lynx canadensis and L. rufus), northern and southern flying squirrels (Glaucomys sabrinus and G. volans), and white‐footed and deer mouse (Peromyscus leucopus and P. maniculatus). Signatures of positive selection were found in both the interspecific comparison of Canada lynx and bobcat, and intraspecific analyses in Canada lynx. Northern and southern flying squirrels showed differing frequencies at common CLOCK alleles and a signature of balancing selection. Regional excess homozygosity was found in the deer mouse at PER1 suggesting disruptive selection, and further analyses suggested balancing selection in the white‐footed mouse. These preliminary signatures of selection and the presence of trinucleotide repeats within many clock genes warrant further consideration of the importance of candidate gene motifs for adaptation to climate change.

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“…90 It has been reported that reduced amplitude of circadian oscillators can increase the efficacy of perturbing agents such as light and other stimuli in causing phase shifts in various organisms. 89,[91][92][93] Although the observed reduction in the amplitude of circadian gene expression in BPI was subtle and only showed a trend for significance after correction for multiple comparisons, it is possible that the core clocks in bipolar patients are more vulnerable to external stimulation, which may contribute to unstable or more variable circadian rhythms as have been observed in bipolar patients. 13,94,95 Alterations in the overall expression level of core clock genes and clock-controlled genes can lead to anomalies in the circadian rhythmicity.…”

Section: Discussionmentioning

confidence: 97%

“…Consistence with our hypothesis, attenuated expression of mBmal1 in SCN was reported to accompany disrupted rest-activity patterns in mouse models. 88 Furthermore, the CLOCK mutant mice, which have reduced pacemaker amplitude, 89 showed mania-like behavior. 90 It has been reported that reduced amplitude of circadian oscillators can increase the efficacy of perturbing agents such as light and other stimuli in causing phase shifts in various organisms.…”

Section: Discussionmentioning

confidence: 99%

Assessment of circadian function in fibroblasts of patients with bipolar disorder

et al. 2008

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Previous studies have implicated the circadian system in the pathophysiology of bipolar disorder, but conclusive evidence for altered circadian clocks is lacking. Cultured fibroblasts harbor circadian clocks representative of those in the master clock resident in the suprachiasmatic nuclei, providing a new avenue to investigate the core clock machinery in patients with bipolar illness. We examined the rhythmic expression patterns of core clock genes (BMAL1, PER1, PER2, REV-ERBa, DEC2, DBP) in fibroblasts from 12 bipolar patients and 12 healthy controls. Although we did not detect differences in the circadian period between bipolar patients and controls, the amplitude of rhythmic expression for BMAL1, REVERBa and DBP, as well as the overall mRNA expression level for DEC2 and DBP was reduced in fibroblasts from bipolar patients. Bonferroni's correction for multiple comparisons still resulted in significantly reduced DBP expression level, and trends toward reduced overall expression level of DEC2 and circadian amplitude of BMAL1, in fibroblasts from bipolar patients. We next examined an expanded cohort of 18 bipolar patients and 35 healthy controls for mRNA expression levels of four kinases (CKId, CKIe, GSK3a and GSK3b) and the protein and phosphorylation levels of two of them (GSK3a and GSK3b). We did not detect differences in steady-state mRNA levels or protein levels of these kinases between bipolar patients and controls, but the level of GSK3b phosphorylation was significantly reduced in bipolar patients within an Old Order Amish bipolar kindred. Our results suggest that the reduced amplitudes and overall expression levels of circadian genes, and the decreased phosphorylation level of GSK3b may lead to dysregulation of downstream genes, which could explain some pathological features of bipolar disorder.

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The mouse Clock mutation reduces circadian pacemaker amplitude and enhances efficacy of resetting stimuli and phase–response curve amplitude

Cited by 208 publications

References 38 publications

Resetting of central and peripheral circadian oscillators in aged rats

Resetting of central and peripheral circadian oscillators in aged rats

Signatures of selection in mammalian clock genes with coding trinucleotide repeats: Implications for studying the genomics of high‐pace adaptation

Assessment of circadian function in fibroblasts of patients with bipolar disorder

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