Stress-induced neuroinflammatory priming is time of day dependent

Abstract

Circadian rhythms are endogenous cycles of physiology and behavior that align with the daily rotation of the planet and resulting light-dark cycle. The circadian system ensures homeostatic balance and regulates many aspects of physiology, including the stress response and susceptibility to and/or severity of stress-related sequelae. Both acute and chronic stressors amplify neuroinflammatory responses to a subsequent immune challenge, however it is not known whether circadian timing of the stressor regulates the priming response. Here, we test whether stress-induced neuroinflammatory priming is regulated by the circadian system. As has been previously shown, exposure to 100 inescapable tails shocks (IS) increased hippocampal cytokines following a subsequent inflammatory challenge. However, this effect was limited to animals that experienced the stressor during the light phase. Rats exposed to stress during the dark phase did not alter inflammatory potential following lipopolysaccharide (LPS) challenge. To determine whether microglia might be involved in diurnal differences in neuroinflammatory priming, microglia were isolated 24 h after stress that occurred either during the middle of the light or dark phase. Only microglia isolated from animals stressed during the light phase demonstrated an exaggerated inflammatory response when treated ex vivo with LPS. To determine possible circadian dependency of microglia responsiveness to glucocorticoids – the likely proximal mediator for stress associated neuroinflammatory priming – microglia were isolated during the middle of the light or dark phase and treated ex vivo with corticosterone. Glucocorticoids treatment downregulated CX3CR1 and CD200R, two genes involved in microglial inflammatory “off” signaling; however, there was no effect of time of day on expression of either gene. Importantly, while absolute concentrations of corticosterone were comparable following IS during the light and dark phase, the magnitude of change in corticosterone was greater during the light phase. This work highlights the importance of studying circadian rhythms to elucidate biological mechanisms of stress.

The protective effects of resveratrol on social stress-induced cytokine release and depressive-like behavior

“…Although resting cytokine levels were normalized 5 days post stress in our study, there is a vast body of literature indicating that inflammatory priming can also occur following stress exposure (Fonken et al, 2016; Frank et al, 2012; Frank et al, 2011; Weber et al, 2013; Wohleb et al, 2014a). Priming can result in a sensitized inflammatory response both in the periphery and the brain to a future stress exposure or endotoxin challenge (Wohleb et al, 2014a).…”

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

“…The LPS concentrations and incubation time were based on previously published time courses and LPS concentrations curves (Frank et al, 2006b, Frank et al, 2010). In a separate experiment, microglia were treated with corticosterone (Sigma-C2505) at concentrations of 1, 10, or 100 nM for 2 h (Fonken et al, 2016). Corticosterone was first diluted to a concentration of 10 mM in EtOH followed by serial dilution in media (0 nM control contains EtOH equivalent to 1000 nM EtOH concentration).…”

Chronic unpredictable stress exacerbates surgery-induced sickness behavior and neuroinflammatory responses via glucocorticoids secretion in adult rats

“…Acute and chronic stress sensitized or primed neuroinflammatory responses to both peripheral and central immunologic challenges [ 5 , 6 ]. For example, chronic unpredictable stress (CUS) potentiated LPS-induced pro-inflammatory mediators (e.g., IL-1β, inducible nitric oxide synthase, and TNF-α) in frontal cortex and hippocampus of rats [ 7 ].…”