Adrenal glucocorticoids have a key role in circadian resynchronization in a mouse model of jet lag
Silke Kiessling, Gregor Eichele, Henrik Oster
Silke Kiessling, Gregor Eichele, Henrik Oster
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Research Article

Adrenal glucocorticoids have a key role in circadian resynchronization in a mouse model of jet lag

Abstract

Jet lag encompasses a range of psycho- and physiopathological symptoms that arise from temporal misalignment of the endogenous circadian clock with external time. Repeated jet lag exposure, encountered by business travelers and airline personnel as well as shift workers, has been correlated with immune deficiency, mood disorders, elevated cancer risk, and anatomical anomalies of the forebrain. Here, we have characterized the molecular response of the mouse circadian system in an established experimental paradigm for jet lag whereby mice entrained to a 12-hour light/12-hour dark cycle undergo light phase advancement by 6 hours. Unexpectedly, strong heterogeneity of entrainment kinetics was found not only between different organs, but also within the molecular clockwork of each tissue. Manipulation of the adrenal circadian clock, in particular phase-shifting of adrenal glucocorticoid rhythms, regulated the speed of behavioral reentrainment. Blocking adrenal corticosterone either prolonged or shortened jet lag, depending on the time of administration. This key role of adrenal glucocorticoid phasing for resetting of the circadian system provides what we believe to be a novel mechanism-based approach for possible therapies for jet lag and jet lag–associated diseases.

Authors

Silke Kiessling, Gregor Eichele, Henrik Oster

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Figure 3

Clock gene resetting kinetics in different tissues following 6-hour LD phase advance.

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Clock gene resetting kinetics in different tissues following 6-hour LD p...
Resetting is represented by PS50 values (average ± SEM). *P ≤ 0.05, **P < 0.01, ***P < 0.001 versus Per2. Determination of PS50 values from expression data (Supplemental Figure 1; n = 3 animals per time point) was done as described in Figure 2. See Supplemental Table 2 for statistical analysis. (A) In the somatosensory cortex, similar and rapid adaptation of the Per1 and Per2 was followed by slower adaptation of Dbp, Arntl, and Nr1d1. (B) In the adrenal, Per1 and Per2 both showed comparable and fast adaptation, whereas Dbp and Nr1d1 rhythms shifted at a similar, but slower, rate. Arntl showed the slowest adaptation, with a PS50 value of 3.5 ± 0.2 days. (C) A similar hierarchy was observed for kidney, with fast adaptation for Per, Dbp, and Nr1d1, and a slow one for Arntl. (D) In liver, Per2 expression shifted significantly faster than that of the other clock genes except Nr1d1. Per1 and Dbp followed at comparable speed, while Arntl adapted slowest (4.1 ± 0.2 days). (E) In the pancreas, Per1 and Per2 shifting was slow, with PS50 values of 4.8 ± 0.7 and 4.8 ± 0.7 days, respectively, followed by Dbp and Arntl. Nr1d1 adaptation was fastest in this tissue, with a PS50 value of 3.5 ± 0.4 days.