Abstract
The characteristics of the cycles of activity and rest stand out among the most intensively investigated aspects of circadian rhythmicity in humans and experimental animals. Alterations in the circadian patterns of activity and rest are strongly linked to cognitive and emotional dysfunctions in severe mental illnesses such as Alzheimer’s disease (AD) and major depression (MDD). The proinflammatory cytokine interleukin 6 (IL-6) has been prominently associated with the pathogenesis of AD and MDD. However, the potential involvement of IL-6 in the modulation of the diurnal rhythms of activity and rest has not been investigated. Here, we set out to study the role of IL-6 in circadian rhythmicity through the characterization of patterns of behavioral locomotor activity in IL-6 knockout (IL-6 KO) mice and wild-type littermate controls. Deletion of IL-6 did not alter the length of the circadian period or the amount of locomotor activity under either light-entrained or free-running conditions. IL-6 KO mice also presented a normal phase shift in response to light exposure at night. However, the temporal architecture of the behavioral rhythmicity throughout the day, as characterized by the quantity of ultradian activity bouts, was significantly impaired under light-entrained and free-running conditions in IL-6 KO. Moreover, the assessment of clock gene expression in the hippocampus, a brain region involved in AD and depression, revealed altered levels of cry1, dec2, and rev-erb-beta in IL-6 KO mice. These data propose that IL-6 participates in the regulation of ultradian activity/rest rhythmicity and clock gene expression in the mammalian brain. Furthermore, we propose IL-6-dependent circadian misalignment as a common pathogenetic principle in some neurodegenerative and neuropsychiatric disorders.
Highlights
Changes in the diurnal oscillations of the periods of activity and rest are in the spotlight of basic and applied biomedical research on circadian rhythms in humans and other animals (1)
The interest in analyzing these changes in active wakefulness and quiescent rest rhythmicity relates to the fact that alterations of these rhythmic fluctuations are associated with a wide spectrum of pathologies, Circadian Rhythms in interleukin 6 (IL-6) Knockout Mice ranging from metabolic and cardiovascular dysfunctions to tumorigenesis and cancer
To characterize the effects of genetic IL-6 deficiency on behavioral rhythms of rest and activity, wheel-running activity was monitored in IL-6 knockout (IL-6 KO) and WT littermate control mice
Summary
Changes in the diurnal oscillations of the periods of activity and rest are in the spotlight of basic and applied biomedical research on circadian rhythms in humans and other animals (1). Strong clinical and experimental evidence supports a link between disturbances of the sleep–wake cycle and other physiological functions regulated by the circadian system in the pathophysiology of Alzheimer’s disease (AD) and major depression (MDD). These dysfunctions include interruptions of the wakefulness during the day and bursts of activity during the night in individuals suffering from AD (2–6). The specific relationship between IL-6 and the diurnal rhythms of activity and rest remain poorly understood as varying observations regarding IL-6 levels under physiological and pathology conditions emerge from literature These apparent discrepancies may be a consequence of species-specific effects and/or depend on the sample type or methodological approaches employed (31, 44–46, 49). To determine the impact of IL-6 deletion on the orchestration of circadian rhythmicity at the molecular level, the expression of 19 clock and clock-controlled genes was analyzed in the hippocampus, a brain region importantly implicated in the pathophysiology of MDD and AD
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