Circadian rhythms modulate nearly every mammalian physiological process. Chronic disruption of circadian timing in shift work or during chronic jet lag in animal models leads to a higher risk of several pathologies. Many of these conditions in both shift workers and experimental models share the common risk factor of inflammation. In this study, we show that experimentally induced circadian disruption altered innate immune responses. Endotoxemic shock induced by LPS was magnified, leading to hypothermia and death after four consecutive weekly 6-h phase advances of the light/dark schedule, with 89% mortality compared with 21% in unshifted control mice. This may be due to a heightened release of proinflammatory cytokines in response to LPS treatment in shifted animals. Isolated peritoneal macrophages harvested from shifted mice exhibited a similarly heightened response to LPS in vitro, indicating that these cells are a target for jet lag. Sleep deprivation and stress are known to alter immune function and are potential mediators of the effects we describe. However, polysomnographic recording in mice exposed to the shifting schedule revealed no sleep loss, and stress measures were not altered in shifted mice. In contrast, we observed altered or abolished rhythms in the expression of clock genes in the central clock, liver, thymus, and peritoneal macrophages in mice after chronic jet lag. We conclude that circadian disruption, but not sleep loss or stress, are associated with jet lag-related dysregulation of the innate immune system. Such immune changes might be a common mechanism for the myriad negative health effects of shift work.

Summary Interactions among suprachiasmatic nucleus (SCN) neurons are required for robust circadian rhythms entrained to local time. To investigate these coupling mechanisms, we developed a novel functional coupling assay that uniquely captures the dynamic process by which SCN neurons interact. As a population, SCN neurons typically display synchronized rhythms with similar peak times, but will peak 6–12h apart after in vivo exposure to long days. Once removed from these conditions, SCN neurons resynchronize through a phase-dependent coupling process mediated by both vasoactive intestinal polypeptide (VIP) and GABAA signaling. Notably, GABAA signaling contributes to coupling when the SCN network in an anti-phase configuration, but opposes synchrony under steady-state conditions. Further, VIP acts together with GABAA signaling to couple the network in an anti-phase configuration, but promotes synchrony under steady-state conditions by counteracting the actions of GABAA signaling. Thus, SCN neurons interact through non-redundant coupling mechanisms influenced by the state of the network.

Despite the fact that trans-meridian travel and shift work are commonplace in our 24/7 society, few controlled studies have addressed the health effects of repeated phase shifts of the biological clock. Shift work [1] and chronic jet-lag [2] reduce mental acuity and increase the risk of a number of medical problems including cancer, digestive diseases including peptic ulcers, and sleep disorders. Some of these problems become more severe with the number of years on the job, the result either of cumulative damage or the increased age of the subjects [3]. In general, morbidity associated with many organic disorders is increased in the aged; however, the role played by age-associated alterations in the circadian clock is poorly understood. In particular the effect of repeated schedule changes is largely unaddressed.

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The mammalian pacemaker in the suprachiasmatic nucleus (SCN) contains a population of neural oscillators capable of sustaining cell-autonomous rhythms in gene expression and electrical firing. A critical question for understanding pacemaker function is how SCN oscillators are organized into a coherent tissue capable of coordinating circadian rhythms in behavior and physiology. Here we undertake a comprehensive analysis of oscillatory function across the SCN of the adult PER2::LUC mouse by developing a novel approach involving multi-position bioluminescence imaging and unbiased computational analyses. We demonstrate that there is phase heterogeneity across all three dimensions of the SCN that is intrinsically regulated and extrinsically modulated by light in a region-specific manner. By investigating the mechanistic bases of SCN phase heterogeneity, we show for the first time that phase differences are not systematically related to regional differences in period, waveform, amplitude, or brightness. Furthermore, phase differences are not related to regional differences in the expression of arginine vasopressin and vasoactive intestinal polypeptide, two key neuropeptides characterizing functionally distinct subdivisions of the SCN. The consistency of SCN spatiotemporal organization across individuals and across planes of section suggests that the precise phasing of oscillators is a robust feature of the pacemaker important for its function.