Shift Work Schedules Alter Immune Cell Regulation and Accelerate Cognitive Impairment During Aging

Introduction: Disturbances in the sleep-wake cycle and circadian rhythms typically precede age-related deficits in learning and memory, suggesting that these alterations may contribute to progressive cognitive decline during aging.

Methods: Because both age-related dementia and altered circadian regulation are associated with immune cell activation and inflammation, we used C57Bl/6J mice exposed to shifted light-dark (LD) cycles (12-hr advance/5 days) during early adulthood (4-6 months) to test the long-term effects of circadian rhythm dysregulation on cognitive performance, immune cell regulation, and hippocampal microglia at middle age (13-14 months). Activity rhythm entrainment was stable in mice on a fixed LD 12:12 cycle, but fully compromised during shifted LD cycles. Following exposure to experimental lighting conditions, re-entrainment in shifted LD mice was marked by a delayed phase angle of entrainment and increased day-to-day variability in activity onset times, which persisted into middle age. These changes in light-dark entrainment led to significant impairment in the Barnes maze test for all shifted LD mice at middle age, well before cognitive decline was first observed in aged (18-22 months) animals maintained on fixed LD cycles.

Results: In conjunction with circadian dysregulation effects on cognition, shifted LD mice at middle age exhibited significant expansion of splenic B cells and B cell subtypes expressing activation marker CD69 or inflammatory marker CLIP, along with increases in CLIP+, 41BB-Ligand+, and CD74+ B cells in meningeal lymphatics. There were alterations in T cell phenotypes in the spleen, and increased numbers and morphological changes in dentate gyrus microglia. In mice exposed to shifted LD cycles, the expansion of splenic B cells was negatively correlated with cognitive performance, indicating that higher B cell counts corresponded to lower cognitive index scores and worse performance in the Barnes maze.

Conclusion : Collectively, these results indicate that circadian dysregulation associated with early exposure to shift work-like schedules accelerates cognitive decline during aging, in conjunction with altered immune cell regulation and microglial changes in the brain.