Abstract # 3111 Chronic adolescent stress differentially sensitizes neuro-immune reactivity in male and female rats

Abstract

Adversity early in life is a reliable predictor of mood disorders which involve excessive innate immune signaling. However, the mechanisms by which early life adversity promotes inflammation are not yet fully understood. Using a chronic adolescent stress (CAS) model in rats, we hypothesized that a history of CAS exaggerates induction of the pro-inflammatory NF-kappa-B pathway in adult rat hippocampus without impacting the peripheral immune response. We assessed potential sex differences to determine whether females, who suffer from mood disorders twice as often as males, are disproportionally affected by stress-primed inflammation. Male and female adolescent rats underwent the CAS paradigm or received no stress. Six weeks following the last stressor, all rats received a single systemic injection of either lipopolysaccharide (LPS) or vehicle to unmask possible immune-priming effects of CAS. RNA-Seq revealed that upon LPS stimulation, both male and female CAS rats displayed enhanced enrichment of the NF-kappa-B pathway in the hippocampus compared to non-stressed, same-sex controls. Peripheral inflammatory indices including splenic NF-kappa-B activity, serum cytokine and corticosterone concentrations were not altered by CAS in females, suggesting brain-specific CAS impact. Conversely, CAS males displayed lower serum corticosterone and exaggerated serum IL-1beta responses following LPS, suggesting glucocorticoid resistance. We conclude that while CAS enhances neuro-immune reactivity in both males and females months removed from the stressor exposure, the mechanism and manifestation of such alterations are sex-specific.