Location, location, location: important for jet-lagged circadian loops

Harrington, Mary E.

doi:10.1172/jci43632

Cited by 30 publications

(21 citation statements)

References 21 publications

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“…Indeed, the synchronization of internal clocks with environmental cues is thought to be essential for health and fitness [5]. As an example, Clock-mutant mice display abnormal rhythmicity of several physiological functions (for example, sleep/wake cycles, food intake and basal metabolism), show behavioral disturbances, are susceptible to diet-induced obesity, and present frequent pregnancy failures [3].…”

Section: Discussionmentioning

confidence: 99%

Genetic adaptation of the human circadian clock to day-length latitudinal variations and relevance for affective disorders

et al. 2014

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Background: The temporal coordination of biological processes into daily cycles is a common feature of most living organisms. In humans, disruption of circadian rhythms is commonly observed in psychiatric diseases, including schizophrenia, bipolar disorder, depression and autism. Light therapy is the most effective treatment for seasonal affective disorder and circadian-related treatments sustain antidepressant response in bipolar disorder patients. Day/night cycles represent a major circadian synchronizing signal and vary widely with latitude. Results: We apply a geographically explicit model to show that out-of-Africa migration, which led humans to occupy a wide latitudinal area, affected the evolutionary history of circadian regulatory genes. The SNPs we identify using this model display consistent signals of natural selection using tests based on population genetic differentiation and haplotype homozygosity. Signals of natural selection driven by annual photoperiod variation are detected for schizophrenia, bipolar disorder, and restless leg syndrome risk variants, in line with the circadian component of these conditions. Conclusions: Our results suggest that human populations adapted to life at different latitudes by tuning their circadian clock systems. This process also involves risk variants for neuropsychiatric conditions, suggesting possible genetic modulators for chronotherapies and candidates for interaction analysis with photoperiod-related environmental variables, such as season of birth, country of residence, shift-work or lifestyle habits.

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Section: Discussionmentioning

confidence: 99%

Genetic adaptation of the human circadian clock to day-length latitudinal variations and relevance for affective disorders

et al. 2014

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“…It is not known what caused this increase in mortality, although jet-lag paradigms in rodents have been linked with cardiomyopathy [20], accelerated tumor growth [21] and dysregulation of immune responses [22]. The relevance of these to humans is not clear although shift work, which is analogous to chronic jet-lag, is known to have detrimental effects on health and survival (for review, see [23]). …”

Section: Discussionmentioning

confidence: 99%

Adaptation to Experimental Jet-Lag in R6/2 Mice despite Circadian Dysrhythmia

et al. 2013

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The R6/2 transgenic mouse model of Huntington’s disease (HD) shows a disintegration of circadian rhythms that can be delayed by pharmacological and non-pharmacological means. Since the molecular machinery underlying the circadian clocks is intact, albeit progressively dysfunctional, we wondered if light phase shifts could modulate the deterioration in daily rhythms in R6/2 mice. Mice were subjected to four x 4 hour advances in light onset. R6/2 mice adapted to phase advances, although angles of entrainment increased with age. A second cohort was subjected to a jet-lag paradigm (6 hour delay or advance in light onset, then reversal after 2 weeks). R6/2 mice adapted to the original shift, but could not adjust accurately to the reversal. Interestingly, phase shifts ameliorated the circadian rhythm breakdown seen in R6/2 mice under normal LD conditions. Our previous finding that the circadian period (tau) of 16 week old R6/2 mice shortens to approximately 23 hours may explain how they adapt to phase advances and maintain regular circadian rhythms. We tested this using a 23 hour period light/dark cycle. R6/2 mice entrained to this cycle, but onsets of activity continued to advance, and circadian rhythms still disintegrated. Therefore, the beneficial effects of phase-shifting are not due solely to the light cycle being closer to the tau of the mice. Our data show that R6/2 mice can adapt to changes in the LD schedule, even beyond the age when their circadian rhythms would normally disintegrate. Nevertheless, they show abnormal responses to changes in light cycles. These might be caused by a shortened tau, impaired photic re-synchronization, impaired light detection and/or reduced masking by evening light. If similar abnormalities are present in HD patients, they may suffer exaggerated jet-lag. Since the underlying molecular clock mechanism remains intact, light may be a useful treatment for circadian dysfunction in HD.

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“…The molecular clockwork is highly conserved in man and animals, and orchestrates the daily patterning of diverse physiological processes such as sleep/wake cycles, feeding, and metabolism. Many diseases exhibit circadian rhythmicity in their pathology, and lifestyles that disrupt inherent timing systems, such as chronic shift work, are associated with an increased risk of cancer, metabolic disorders, and cardiovascular and cerebrovascular disease (1). Inflammatory diseases in particular exhibit strong time-of-day symptoms.…”

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confidence: 99%

The nuclear receptor REV-ERBα mediates circadian regulation of innate immunity through selective regulation of inflammatory cytokines

Gibbs

Blaikley

Beesley

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

563

583

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Diurnal variation in inflammatory and immune function is evident in the physiology and pathology of humans and animals, but molecular mechanisms and mediating cell types that provide this gating remain unknown. By screening cytokine responses in mice to endotoxin challenge at different times of day, we reveal that the magnitude of response exhibited pronounced temporal dependence, yet only within a subset of proinflammatory cytokines. Disruption of the circadian clockwork in macrophages (primary effector cells of the innate immune system) by conditional targeting of a key clock gene (bmal1) removed all temporal gating of endotoxin-induced cytokine response in cultured cells and in vivo. Loss of circadian gating was coincident with suppressed rev-erbα expression, implicating this nuclear receptor as a potential link between the clock and inflammatory pathways. This finding was confirmed in vivo and in vitro through genetic and pharmacological modulation of REV-ERBα activity. Circadian gating of endotoxin response was lost in rev-erbα −/− mice and in cultured macrophages from these animals, despite maintenance of circadian rhythmicity within these cells. Using human macrophages, which show circadian clock gene oscillations and rhythmic endotoxin responses, we demonstrate that administration of a synthetic REV-ERB ligand, or genetic knockdown of rev-erbα expression, is effective at modulating the production and release of the proinflammatory cytokine IL-6. This work demonstrates that the macrophage clockwork provides temporal gating of systemic responses to endotoxin, and identifies REV-ERBα as the key link between the clock and immune function. REV-ERBα may therefore represent a unique therapeutic target in human inflammatory disease.C ircadian clocks provide organisms with an internal mechanism to maintain temporal order in a rhythmic environment. The molecular clockwork is highly conserved in man and animals, and orchestrates the daily patterning of diverse physiological processes such as sleep/wake cycles, feeding, and metabolism. Many diseases exhibit circadian rhythmicity in their pathology, and lifestyles that disrupt inherent timing systems, such as chronic shift work, are associated with an increased risk of cancer, metabolic disorders, and cardiovascular and cerebrovascular disease (1). Inflammatory diseases in particular exhibit strong time-of-day symptoms. For example, rheumatoid arthritis (RA) has a strong diurnal variation in disease expression, which is accompanied by fluctuations in circulating IL-6 concentration (2). In mice, significant temporal dependence of LPS-induced endotoxic shock has been reported (3), and circadian disruption mimicking jet lag can greatly magnify LPS response (4). Many facets of immune function show diurnal variation, and recent studies have revealed that macrophages, important regulators of innate immune responses, exhibit robust circadian oscillations in gene expression, including genes responsible for pathogen recognition and cytokine secretion (5, 6). However, the mole...

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Location, location, location: important for jet-lagged circadian loops

Cited by 30 publications

References 21 publications

Genetic adaptation of the human circadian clock to day-length latitudinal variations and relevance for affective disorders

Genetic adaptation of the human circadian clock to day-length latitudinal variations and relevance for affective disorders

Adaptation to Experimental Jet-Lag in R6/2 Mice despite Circadian Dysrhythmia

The nuclear receptor REV-ERBα mediates circadian regulation of innate immunity through selective regulation of inflammatory cytokines

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