Phase-Dependent Shifting of the Adrenal Clock by Acute Stress-Induced ACTH.

William C Engeland,J Marina Yoder,Carley A Karsten,Paulo Kofuji

doi:10.3389/fendo.2016.00081

Abstract

The adrenal cortex has a molecular clock that generates circadian rhythms in glucocorticoid production, yet it is unclear how the clock responds to acute stress. We hypothesized that stress-induced ACTH provides a signal that phase shifts the adrenal clock. To assess whether acute stress phase shifts the adrenal clock in vivo in a phase-dependent manner, mPER2:LUC mice on a 12:12-h light:dark cycle underwent restraint stress for 15 min or no stress at zeitgeber time (ZT) 2 (early subjective day) or at ZT16 (early subjective night). Adrenal explants from mice stressed at ZT2 showed mPER2:LUC rhythms that were phase-advanced by ~2 h, whereas adrenals from mice stressed at ZT16 showed rhythms that were phase-delayed by ~2 h. The biphasic response was also observed in mice injected subcutaneously either with saline or with ACTH at ZT2 or ZT16. Blockade of the ACTH response with the glucocorticoid, dexamethasone, prevented restraint stress-induced phase shifts in the mPER2:LUC rhythm both at ZT2 and at ZT16. The finding that acute stress results in a phase-dependent shift in the adrenal mPER2:LUC rhythm that can be blocked by dexamethasone indicates that stress-induced effectors, including ACTH, act to phase shift the adrenal clock rhythm.

Highlights

The suprachiasmatic nucleus (SCN) is responsible for generating circadian rhythms in mammals [1]
Adrenals from mice that underwent a 15-min restraint stress at ZT2 showed a phase advance in the mPER2:LUC rhythm compared with adrenals from non-stressed mice (Figure 3A), whereas adrenal rhythms from mice that were stressed at ZT16 showed a phase delay compared with controls (Figure 3B)
Adrenals from mice injected with saline at ZT2 showed a phase advance in the mPER2:LUC rhythm compared with adrenals from Control mice (Figure 4A), whereas rhythms from adrenals from mice injected with saline or ACTH at ZT16 showed a phase delay compared with Control mice (Figure 4B)

Summary

Introduction

The suprachiasmatic nucleus (SCN) is responsible for generating circadian rhythms in mammals [1]. The molecular clock that underlies SCN rhythmicity is found in most mammalian cells [2], providing a peripheral clock mechanism that subserves tissue-specific functional rhythms [3]. A fundamental question is how peripheral clocks are entrained to light and to other environmental signals [4]. Knockdown of the adrenal clock results in a corticosterone rhythm with reduced amplitude under constant dark, yet the rhythm is maintained under light–dark (LD) conditions [5]. These results argue for redundancy in controlling corticosterone rhythms, with both clockdependent and clock-independent mechanisms

Methods

Results

Conclusion