Vasoactive intestinal peptide is critical for circadian regulation of glucocorticoids - PubMed (original) (raw)

Vasoactive intestinal peptide is critical for circadian regulation of glucocorticoids

Dawn H Loh et al. Neuroendocrinology. 2008.

Abstract

Background/aims: Circadian control of behavior and physiology is a central characteristic of all living organisms. The master clock in mammals resides in the hypothalamus, where the suprachiasmatic nucleus (SCN) synchronizes daily rhythms. A variety of recent evidence indicates that the neuropeptide vasoactive intestinal peptide (VIP) is critical for normal functioning of the SCN. The aim of our study was to examine the possible role of VIP in driving circadian rhythms in the hypothalamic-pituitary-adrenal axis.

Methods: Circulating ACTH and corticosterone concentrations were determined by round-the-clock sampling under diurnal and circadian conditions. The responsive aspects of the hypothalamic-pituitary-adrenal axis were tested by application of acute stress by footshock and light.

Results: We demonstrate that the circadian rhythms in ACTH and corticosterone are lost in VIP-deficient mice. The ability of light to induce a corticosterone response was also compromised in the mutant mice, as was photic induction of Per1 in the adrenal glands. In contrast, the acute stress response was apparently unaltered by the loss of VIP.

Conclusion: Thus, our data demonstrate that VIP is essential for the circadian regulation of an otherwise intact hypothalamic-pituitary-adrenal axis.

Copyright 2008 S. Karger AG, Basel.

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Figures

Figure 1

Figure 1

Concentration of corticosterone in serum over a 24 hour period in wild-type (WT) and _Vip_−/− (VIP KO) mice. Serum was sampled every 3 hours (_n_=3 per time point) under light-dark conditions (LD) and every 4 hours under constant darkness (DD). Circulating corticosterone concentration (ng/ml) was determined by ELISA. A. Serum corticosterone concentration under 12:12 LD conditions plotted against zeitgeber time (ZT). The WT peak in corticosterone at ZT8 was 30-fold higher than the trough at ZT2 and cycling conditions for WT concentrations were determined to be significant (P<0.001) by ANOVA. In contrast, VIP KO mice displayed no such rhythmicity in basal concentration of corticosterone. B. Corticosterone measurements plotted against circadian time (CT) in DD. Again, WT concentrations were determined to be significantly different by ANOVA (P<0.05) with a fourfold difference between peak and trough values at CT10 and CT2 respectively.

Figure 2

Figure 2

ACTH measurements from WT and VIP KO mice in LD plotted against ZT (A) and DD plotted against CT (B). Concentration of ACTH in the serum was determined by ELISA in 3 hour intervals in LD and 4 hour intervals in DD (_n_=2 or 3 for every time point). Circulating ACTH concentrations were found to be significantly rhythmic by ANOVA (P<0.01) for WT mice in LD and DD. The peak concentration of diurnal (LD) ACTH was determined to be at ZT11, and was 3-fold higher than at ZT2. Under DD, ACTH concentration peaked at CT12, where it was found to be 2-fold higher than CT4. In contrast, VIP KO mice did not display rhythmicity under either LD or DD, with circulating corticosterone concentrations remaining high throughout the 24-hour period.

Figure 3

Figure 3

Corticosterone response to acute stress by footshock in early night (ZT15). WT mice displayed a significant induction of corticosterone in response to acute stress (baseline: 33.63±16.07 ng/ml, _n_=5; vs. stress: 201.30±17.16 ng/ml, _n_=5; P<0.01). A similar corticosterone response to acute stress was also observed in VIP KO mice (baseline: 13.14±6.49 ng/ml, _n_=3; vs. stress 243.00±35.39 ng/ml, _n_=6; P<0.05). Statistical significances were determined by non-parametric Mann-Whitney t-tests.

Figure 4

Figure 4

Corticosterone induction by exposure to light in early night (ZT16). Serum corticosterone from untreated mice (_n_=4) and mice subjected to a light treatment (15μW/cm2, 30 minute duration, _n_=4) were determined by ELISA. WT mice respond to the light with a significance increase in circulating corticosterone concentration (283.60±28.84 ng/ml; P<0.05), but VIP KO mice failed to show a significant corticosterone response (33.42±17.79 ng/ml).

Figure 5

Figure 5

Photic induction of Per1 in the adrenal glands. 60 min after the start of the light treatment in early night (CT16; 15μW/cm2, 30 minute duration), adrenal glands were removed for RNA analysis by quantitative RT-PCR. Expression levels of Per1 were normalised to Hprt using the 2_−ΔΔCt_ method. WT mice showed a significant increase in relative Per1 expression (baseline: 3.29±0.43, _n_=4; vs. light pulse 14.37±1.27, _n_=4; P<0.001). VIP KO mice did not show a significant increase in Per1 expression (baseline: 5.76±0.59, _n_=4; vs. light pulse 5.93±1.01, _n_=4).

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