Chronically stressed male and female mice show a similar peripheral and central pro-inflammatory profile after an immune challenge.

Although acute stressors are known for stimulating the production of glucocorticoids and pro-inflammatory cytokines in rodents, the effects of chronic stressors on cytokine levels and the activation of the hypothalamic-pituitary-adrenal (HPA) axis, especially in response to a subsequent challenge, are less clear. In this study, male and female mice were exposed to 6 weeks of chronic variable stress (CVS) and the peripheral and central levels of IL-1ß, IL-6, and TNF-α, as well as the HPA axis reactivity, were measured after an acute injection of LPS. The findings indicate that the pro-inflammatory profile in the plasma, regardless of stress exposure, was similar between male and female animals, whereas there was a region-, sex-, and stress-dependent pattern in the brain. Exposure to chronic stressors blunted the HPA reactivity to the LPS challenge, indicating a modulatory effect on the stress axis responsiveness.

The Effects of Chronic Variable Stress and Photoperiod Alteration on the Hypothalamic-Pituitary-Adrenal Axis Response and Behavior of Mice.

The hypothalamic-pituitary-adrenal (HPA) axis mediates the physiological response to stressors and also synchronizes different physiological systems to environmental cues. Changes in day length (i.e., photoperiod) as well as chronic exposure to stressors are known to impact the HPA axis activity regulating the levels of glucocorticoid hormones. Over-exposure to inappropriate levels of glucocorticoids has been implicated in increased disease risk. In the present study, we examined the impact of chronic stress, using a chronic variable stress (CVS) paradigm, in combination with changes in photoperiod on physiological and behavioral measures, as well as on the reactivity and regulation of the HPA axis, in male and female mice. Six weeks of CVS, regardless of the photoperiod condition, decreased the body weight and attenuated the HPA axis reactivity to an acute stressor in both sexes. The attenuated HPA axis reactivity observed in stressed animals was related to reduced Pro-opiomelanocortin (POMC) mRNA levels in the pituitary of females. The gene expression analyses of key regulators of the HPA axis also indicated a sex-dependent effect with opposite patterns in the pituitary and adrenal glands. CVS effects on behavior were limited and related to an anxiety-like phenotype in both sexes, regardless of photoperiod condition. Our findings highlight sex-specific differences in the HPA axis and also sex-dependent effects of CVS on physiological parameters.