Understanding the health consequences of chronic disruption of circadian rhythms can contribute to improving prevention strategies for shift workers. Chronic circadian disruption in shift work has been linked to a higher risk of stroke. Dysregulated immune responses are also linked to circadian disruption and may be a factor in stroke outcomes in shift workers. In this study, we test the hypotheses that specific schedules of circadian disruption exacerbate inflammatory responses in the brain, causing an increase in infarct size after experimentally induced ischemic stroke. Mice were exposed to 1 of 5 different lighting schedules followed by a 30-min middle cerebral artery occlusion, then reperfusion and 3-day recovery. A history of weekly phase advances resulted in an increased infarct volume versus the control lighting schedule. These effects were shift-direction specific, nonpermanent, and required multiple shifts to occur. In a separate cohort, stereotaxic injections of lipopolysaccharide were given bilaterally after exposure to 1 of 3 different lighting schedules. Ratios of pro- to anti-inflammatory cytokine expression show dysregulated responses after a history of phase advances. We conclude that chronic circadian disruption leads to worsened stroke outcome in a direction- and schedule-specific manner likely because of priming of the inflammatory response in the brain. These pieces of evidence suggest that the health impacts of shift work may be improved by targeting shift work scheduling, inflammatory mediators, or both.
Keywords: cerebral stroke; circadian dysregulation; cytokines; jet lag; middle cerebral artery occlusion; neurogenic inflammation; rotating shift work; shift work schedule.