Diminished circadian rhythms in microglia may contribute to age-related neuroinflammatory sensitization

Abstract

Circadian rhythms change dramatically across the lifespan, with aged animals exhibiting diminished molecular and behavioral circadian rhythms. Both aging and circadian disruption are associated with sensitized neuroinflammatory processes. We previously demonstrated that microglia – the primary innate immune cell of the central nervous system – possess endogenous circadian timekeeping mechanisms that regulate immune responses. Here, we explored whether age-associated neuroinflammatory sensitization is associated with disrupted diurnal rhythms in microglia. Hippocampal microglia were isolated from aged (24 mos.) and young FBN rats at 6 h intervals. As expected, microglia from young rats rhythmically expressed core circadian clock genes. Microglia from aged rats displayed comparable rhythms in several clock genes including BMAL1 and Rev-erb; however, rhythmic expression of Per1 and Per2 were completely ablated. Unstimulated microglia from young rats also exhibited robust rhythms of TNFalpha and IL1beta mRNA, with peak cytokine expression during the middle of the light phase. In contrast, aged microglia had tonically elevated inflammatory cytokines that were not regulated by time-of-day. Similarly, diurnal differences in responsivity to ex vivo stimulation with lipopolysaccharide were not apparent in aged microglia. Corticosterone treatment induced Per1 expression in aged and young microglia; however, glucocorticoid rhythms were suppressed in the aged hippocampus. This suggests that changes in entrainment signals may be disrupted with aging. Overall, here we show intrinsic microglial rhythms in clock and inflammatory genes are dysregulated with aging.