Sex differences in the effects of adolescent stress on adult brain inflammatory markers in rats

Abstract

Both basic and clinical research indicates that females are more susceptible to stress-related affective disorders than males. One of the mechanisms by which stress induces depression is via inflammatory signaling in the brain. Stress during adolescence, in particular, can also disrupt the activation and continued development of both the hypothalamic-pituitary-adrenal (HPA) and -gonadal (HPG) axes, both of which modulate inflammatory pathways and brain regions involved in affective behavior. Therefore, we tested the hypothesis that adolescent stress differentially alters brain inflammatory mechanisms associated with affective-like behavior into adulthood based on sex. Male and female Wistar rats underwent mixed-modality stress during adolescence (PND 37-48) and were challenged with lipopolysaccharide (LPS; 250μg/kg, i.p.) or saline 4.5weeks later (in adulthood). Hippocampal inflammatory marker gene expression and circulating HPA and HPG axes hormone concentrations were then determined. Despite previous studies indicating that adolescent stress induces affective-like behaviors in female rats only, this study demonstrated that adolescent stress increased hippocampal inflammatory responses to LPS in males only, suggesting that differences in neuroinflammatory signaling do not drive the divergent affective-like behaviors. The sex differences in inflammatory markers were not associated with differences in corticosterone. In females that experienced adolescent stress, LPS increased circulating estradiol. Estradiol positively correlated with hippocampal microglial gene expression in control female rats, whereas adolescent stress negated this relationship. Thus, estradiol in females may potentially protect against stress-induced increases in neuroinflammation.

Fig. 1

Stress during adolescence increased hippocampal inflammatory response to LPS in adulthood in male rats only. Fold differences (relative to a transferrin receptor endogenous control) in hippocampal IL-1β (A), TNFα (B), IκBα (C), CD11b (D), and iNOS (E) gene expression relative to the mean expression of the same-sex, no stress, saline control (−2^ΔΔCT) 4 h after LPS (250 μg/kg, i.p.) or saline treatment in adult male or female rats that previously (4.5 weeks earlier) experienced a mixed modality stress paradigm during adolescence (PND 37–48). n = 7–10/group; *p < 0.05 within the same stress treatment between SALINE vs. LPS; ^#p < 0.05 within LPS treatment between ADOL. STRESS and CONTROL.

Fig. 2

Adolescent stress does not alter corticosterone, progesterone, or testosterone concentrations. Circulating plasma corticosterone (A), progesterone (B), and testosterone (C) concentrations 4 h post-LPS (250 μg/kg, i.p.) or saline treatment in adult rats that experienced prior mixed-modality adolescent stress (or no stress). n = 8–10/group; *p < 0.05 within the same stress treatment between SALINE vs. LPS.

Fig. 3

Stress during adolescence increased circulating estradiol response to LPS in female rats and attenuated the correlation between estradiol and Cd11b gene expression. (A) Circulating plasma 17β-estradiol concentrations 4 h post-LPS (250 μg/kg, i.p.) or saline treatment in adult female rats that experienced prior mixed-modality adolescent stress (or no stress). *p < 0.05 within the same stress treatment between SALINE vs. LPS. (B) Linear regressions between circulating estradiol concentrations and Cd11b (microglial) gene expression in the hippocampus. Regression coefficients only for stress-free rats were significant. n = 8–10/group.