Abstract
Daily patterns of activity and physiology are termed circadian rhythms and are driven primarily by an endogenous biological timekeeping system, with the master clock located in the suprachiasmatic nucleus. Previous studies have indicated reciprocal relationships between the circadian and the immune systems, although to date there have been only limited explorations of the long-term modulation of the circadian system by immune challenge, and it is to this question that we addressed ourselves in the current study. Sepsis was induced by peripheral treatment with lipopolysaccharide (5 mg/kg) and circadian rhythms were monitored following recovery. The basic parameters of circadian rhythmicity (free-running period and rhythm amplitude, entrainment to a light/dark cycle) were unaltered in post-septic animals compared to controls. Animals previously treated with LPS showed accelerated re-entrainment to a 6 hour advance of the light/dark cycle, and showed larger phase advances induced by photic stimulation in the late night phase. Photic induction of the immediate early genes c-FOS, EGR-1 and ARC was not altered, and neither was phase-shifting in response to treatment with the 5-HT-1a/7 agonist 8-OH-DPAT. Circadian expression of the clock gene product PER2 was altered in the suprachiasmatic nucleus of post-septic animals, and PER1 and PER2 expression patterns were altered also in the hippocampus. Examination of the suprachiasmatic nucleus 3 months after treatment with LPS showed persistent upregulation of the microglial markers CD-11b and F4/80, but no changes in the expression of various neuropeptides, cytokines, and intracellular signallers. The effects of sepsis on circadian rhythms does not seem to be driven by cell death, as 24 hours after LPS treatment there was no evidence for apoptosis in the suprachiasmatic nucleus as judged by TUNEL and cleaved-caspase 3 staining. Overall these data provide novel insight into how septic shock exerts chronic effects on the mammalian circadian system.
Highlights
Circadian rhythms are recurring patterns in behaviour and physiology and many other parameters that repeat with periods of near 24 hrs under constant environmental conditions and are driven by an endogenous pacemaker [1]
The suprachiasmatic nucleus (SCN) of the anterior ventral hypothalamus is the location of the master circadian oscillator which serves to coordinate the phase of other brain and peripheral circadian clocks [2,3]
Long-term effects of sepsis on clock gene protein expression As behavioural circadian rhythms are known to be driven by molecular oscillations in the SCN and other clock sites, we examined the rhythmic expression of three clock gene protein products (PER1, PER2, CLOCK) and c-FOS in the SCN and the hippocampus across the circadian cycle
Summary
Circadian rhythms are recurring patterns in behaviour and physiology and many other parameters that repeat with periods of near 24 hrs under constant environmental conditions and are driven by an endogenous pacemaker [1]. The molecular basis of circadian rhythm generation is reasonably well defined and involves a number of interlocking transcriptional loops of clock genes and post-translational regulation of their protein products [4]. This distributed circadian systems serves to impose a daily temporal regulation on numerous physiological and psychological processes, such as metabolism, immune function and cognition, and circadian rhythm disruption is associated with a number of pathological states [3,5,6]. Direct administration of immune signals such as LPS [15] and cytokines [13,16] has been shown to phase shift circadian rhythms. Immune stimulation with peripheral LPS induces SCN expression of the immediate early gene c-Fos and the p65 subunit of NF-kB, showing that cellular activity in the SCN is modulated by immune status [11]
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