Induction of internal circadian desynchrony by misaligning zeitgebers

Isabel Heyde,Henrik Oster

doi:10.1038/s41598-022-05624-x

Abstract

24-h rhythms in physiology and behaviour are orchestrated by an endogenous circadian clock system. In mammals, these clocks are hierarchically organized with a master pacemaker residing in the hypothalamic suprachiasmatic nucleus (SCN). External time signals—so-called zeitgebers—align internal with geophysical time. During shift work, zeitgeber input conflicting with internal time induces circadian desynchrony which, in turn, promotes metabolic and psychiatric disorders. However, little is known about how internal desynchrony is expressed at the molecular level under chronodisruptive environmental conditions. We here investigated the effects of zeitgeber misalignment on circadian molecular organisation by combining 28-h light–dark (LD-28) cycles with either 24-h (FF-24) or 28-h feeding-fasting (FF-28) regimes in mice. We found that FF cycles showed strong effects on peripheral clocks, while having little effect on centrally coordinated activity rhythms. Systemic, i.e., across-tissue internal circadian desynchrony was profoundly induced within four days in LD-28/FF-24, while phase coherence between tissue clocks was maintained to a higher degree under LD-28/FF-28 conditions. In contrast, temporal coordination of clock gene activity across tissues was reduced under LD-28/FF-28 conditions compared to LD-28/FF-24. These results indicate that timed food intake may improve internal synchrony under disruptive zeitgeber conditions but may, at the same time, weaken clock function at the tissue level.

Highlights

24-h rhythms in physiology and behaviour are orchestrated by an endogenous circadian clock system
After entrainment to a standard 12-h light: 12-h dark cycle with food ad libitum (LD-24) mice were transferred to a 28-h LD cycle (14 h light (300 or 3 lx): 14 h dark; light–dark cycle to 28 h (LD-28)) combined with either a 24- (12 h feeding: 12 h fasting; FF-24—with food access in the 12 h of darkness during the preceding LD-24 cycle) or a 28-h FF regimen (14 h feeding: 14 h fasting; FF-28—with food access coinciding with the 14-h dark phase; Fig. 1a)
Locomotor activity period was largely insensitive to the feeding regimen (25.86 ± 0.11 h under LD-28/FF-24 vs. 25.69 ± 0.18 h under LD-28/FF-28; Fig. 1c–e)

Summary

Introduction

24-h rhythms in physiology and behaviour are orchestrated by an endogenous circadian clock system. Molecular clocks are present in most cells, forming a network, which must be synchronised to generate coherent rhythms in behaviour and physiology[1,2] This circadian clock network is organised in a hierarchical manner with a central pacemaker residing in the hypothalamic suprachiasmatic nucleus (SCN)[3–5]. Temporal restriction of food access to the rest phase (i.e., night in humans and day in nocturnal rodents) can uncouple peripheral tissue clocks from the SCN within a w eek[8,9] Such internal desynchronization of the clock network by misaligned zeitgeber input is suggested to promote the development of shift work associated diseases, e.g., obesity, type-2 diabetes, cardiovascular disorders, and major depression[12–16], though little is known about the molecular underpinnings of such p henomena[16]. Our results suggest a differential role of feeding rhythms in the regulation of internal (mis-)alignment at systemic and tissue levels

Methods

Results

Conclusion