title: Diminished circadian rhythms in hippocampal microglia may contribute to age-related neuroinflammatory sensitization.
abstract: Aged animals exhibit diminished circadian rhythms, and both aging and circadian disruption sensitize neuroinflammatory responses. Microglia-the innate immune cell of the central nervous system-possess endogenous timekeeping mechanisms that regulate immune responses. Here, we explored whether aging is associated with disrupted diurnal rhythms in microglia and neuroinflammatory processes. First, hippocampal microglia isolated from young rats (4 months F344XBN) rhythmically expressed circadian clock genes, whereas microglia isolated from the hippocampus of aged rats (25 months) had aberrant Per1 and Per2 rhythms. Unstimulated microglia from young rats exhibited robust rhythms of TNFα and IL-1β mRNA expression, whereas those from aged rats had flattened and tonically elevated cytokine expression. Similarly, microglial activation markers were diurnally regulated in the hippocampus of young but not aged rats and diurnal differences in responsiveness to both ex vivo and in vivo inflammatory challenges were abolished in aged rats. Corticosterone is an entraining signal for extra-suprachiasmatic nucleus circadian rhythms. Here, corticosterone stimulation elicited similar Per1 induction in aged and young microglia. Overall, these results indicate that aging dysregulates circadian regulation of neuroinflammatory functions.
authors: Department of Psychology and Neuroscience, University of Colorado, Boulder, CO, USA. Electronic address: laura.fonken@colorado.edu.
authors: Laura K
authors: LK
authors: Fonken
authors: Department of Psychology and Neuroscience, University of Colorado, Boulder, CO, USA.
authors: Meagan M
authors: MM
authors: Kitt
authors: Department of Psychology and Neuroscience, University of Colorado, Boulder, CO, USA.
authors: Andrew D
authors: AD
authors: Gaudet
authors: Department of Psychology and Neuroscience, University of Colorado, Boulder, CO, USA.
authors: Ruth M
authors: RM
authors: Barrientos
authors: Department of Psychology and Neuroscience, University of Colorado, Boulder, CO, USA.
authors: Linda R
authors: LR
authors: Watkins
authors: Department of Psychology and Neuroscience, University of Colorado, Boulder, CO, USA.
authors: Steven F
authors: SF
authors: Maier
mesh_terms: D000375:Aging / Q000235:genetics* / Q000502:physiology*; D000818:Animals; D002478:Cells, Cultured; D002940:Circadian Rhythm / Q000235:genetics* / Q000502:physiology*; D003345:Corticosterone / Q000494:pharmacology / Q000502:physiology; D015870:Gene Expression / Q000187:drug effects; D006624:Hippocampus / Q000166:cytology*; D007249:Inflammation / Q000209:etiology*; D053583:Interleukin-1beta / Q000235:genetics; D008297:Male; D017628:Microglia / Q000276:immunology / Q000378:metabolism* / Q000502:physiology*; D056950:Period Circadian Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D012333:RNA, Messenger; D051381:Rats; D011916:Rats, Inbred F344; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
chemical_list: C000594089:IL1B protein, rat; D053583:Interleukin-1beta; C539024:Per1 protein, rat; C513311:Per2 protein, rat; D056950:Period Circadian Proteins; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D003345:Corticosterone
keywords: Aging; Glia; IL-1β; Neuroinflammation; Priming