Adolescent stress leads to enduring enrichment of inflammatory pathways in the hippocampus without peripheral immune consequences

Abstract

Chronic adolescent stress (CAS) has previously been shown to prime the hippocampal inflammatory response in adult male rats; however, the underlying mechanism and origin are undefined. Here we tested the hypothesis that CAS exaggerates induction of the pro-inflammatory NF-kappa-B pathway in adult rat hippocampus without compromising the peripheral immune response. Male and female adolescent rats underwent a mixed-modality CAS paradigm or received no stress. Five weeks following the last stressor all rats received a single, systemic injection of either a low dose of lipopolysaccharide (LPS) or vehicle to unmask possible priming effects of CAS. Total RNA from the hippocampus was used to perform RNA-Seq and enriched transcriptional pathways were identified using gene set enrichment analysis. NF-kappa-B emerged as the most enriched pathway in CAS males and females compared to non-stressed controls following LPS. Targeted qPCR experiments further confirmed that CAS exaggerated the expression of I- kappa-B (F(1,105) = 4.209, p = 0.043), p65 (F(1,105) = 5.262, p = 0.024), and p52 (F(1,105) = 8.186, p = 0.005). CAS impacted neither LPS-induced NF-kappa-B activity in the spleen (F(1,57) = 0.256, p > 0.05) nor plasma IL-6 (F(1,58) = 1.083, p > 0.05) and TNF-alpha (F(1,43) = 0.60, p > 0.05), suggesting that the central effects of CAS on the NF-kappa-B pathway are independent of changes to the peripheral immune response. Collectively, our results indicate that chronic stress experienced during adolescence leads to long-lasting changes to the hippocampal genomic profile, and that the inflammatory consequences of CAS are specific to the brain.