Examining the Acute and Chronic Effects of Sepsis on the Circadian Clock in the Mouse

Circadian rhythms are recurring patterns (~24hrs) in behaviour and physiology that are driven primarily by an endogenous biological timekeeping system, with the master pacemaker located in the suprachiasmatic nucleus. Studies have indicated bidirectional relationships between the circadian and the immune systems, however while there is much evidence regarding the regulation of immune function by the circadian system, information regarding the impact of immune processes on the timekeeping system is more limited, including that regarding the long-term modulation of the circadian system following immune challenge. The current set of studies address this gap in the literature by examining the long-term impact of sepsis, a substantial immune challenge, on circadian timekeeping processes, following sepsis induction by peripheral treatment with lipopolysaccharide (5mg/kg). Following recovery, post-septic circadian behaviour, SCN molecular oscillations and SCN responsiveness were assessed. SCN neurochemistry was also assessed both in the acute phase and in the long-term post LPS treatment. LPS induced sepsis did not affect core circadian locomotor rhythmicity parameters, but did result in long-term attenuations in post-septic resetting in response to phase advancing photic stimulation, and alterations in re-entrainment to advances of the photoperiod. Perturbations were observed in SCN neurochemistry in the acute phase following septic LPS treatment, and chronic attenuations were also found in post-septic SCN clock gene protein product expression. LPS induced sepsis caused attenuations in SCN functional activation in response to both photic and immune stimulation, as well as alterations in circadian resetting in response to phase resetting immune stimuli. Overall, these data provide further insight into immune circadian communication, and the long-term impact of immune challenge on timekeeping processes, and describe a previously unknown impact of the chronic effects of experimental sepsis on the circadian timekeeping system