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Abstract
Following general anaesthesia (GA), patients frequently experience sleep disruption and fatigue, which has been hypothesized to result at least in part by GA affecting the circadian clock. Here, we provide the first comprehensive time-dependent analysis of the effects of the commonly administered inhalational anaesthetic, isoflurane, on the murine circadian clock, by analysing its effects on (a) behavioural locomotor rhythms and (b) PER2::LUC expression in the suprachiasmatic nuclei (SCN) of the mouse brain. Behavioural phase shifts elicited by exposure of mice (n = 80) to six hours of GA (2% isoflurane) were determined by recording wheel-running rhythms in constant conditions (DD). Phase shifts in PER2::LUC expression were determined by recording bioluminescence in organotypic SCN slices (n = 38) prior to and following GA exposure (2% isoflurane). Full phase response curves for the effects of GA on behaviour and PER2::LUC rhythms were constructed, which show that the effects of GA are highly time-dependent. Shifts in SCN PER2 expression were much larger than those of behaviour (c. 0.7 h behaviour vs. 7.5 h PER2::LUC). We discuss the implications of this work for understanding how GA affects the clock, and how it may inform the development of chronotherapeutic strategies to reduce GA-induced phase-shifting in patients.
Highlights
The circadian clock is fundamental to human well-being as it regulates almost all aspects of our daily biochemistry, physiology, and behaviour including sleep, immune function, wound healing, and responses to drugs [1,2]
Taking advantage of a powerful transgenic Period 2 (Per2) clock gene reporter system, and using standard anaesthetic protocols and animals of the same genetic background, these experiments, conducted at all times of the day and night, have enabled us to calculate full “phase response curves” for the effects of general anaesthesia (GA) on behaviour and clock gene expression in mice, and to draw conclusions about how anaesthesia may be affecting the circadian system in this central mammalian model
Persistent and reproducible shifts in the phase of locomotor activity rhythms were observed in response to isoflurane anaesthesia administered in constant darkness (Figure 1A,B, Table 1, Supplementary Table S1, Supplementary Figure S1), with no effect on the underlying period of the clock (average free-running periods changing less than 0.025 h following GA (Mean pre-GA τ = 23.72 h (±0.02 h) and post-GA = 23.75 h (±0.02 h)
Summary
The circadian clock is fundamental to human well-being as it regulates almost all aspects of our daily biochemistry, physiology, and behaviour including sleep, immune function, wound healing, and responses to drugs [1,2]. There are in excess of 25 published studies demonstrating that anaesthetics can disrupt the circadian clock and alter circadian rhythms [7] These include three papers in 2020, which demonstrate an effect of inhalational anaesthetics on behaviour and clock gene expression in the mouse [13], and possible effects of melatonin [14] and 5-HT7 serotonin receptors [15] on inhalational anaesthesia-induced circadian disruption in mice. Results from these studies are, largely contradictory, and effects at the molecular and behavioural levels often cannot be reconciled. Taking advantage of a powerful transgenic Per clock gene reporter system, and using standard anaesthetic protocols and animals of the same genetic background, these experiments, conducted at all times of the day and night, have enabled us to calculate full “phase response curves” for the effects of GA on behaviour and clock gene expression in mice, and to draw conclusions about how anaesthesia may be affecting the circadian system in this central mammalian model
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