Stress exposure at different ages and Distinct epigenetic signatures: effect on behaviour, physical outcomes, and inflammatory pathways

Abstract

Early life stress represents increases the vulnerability for several psychiatric disorders and metabolic illnesses via activation of inflammation, however the ultimate outcome depends on several factors, including timing and duration of these negative life experiences, but also on the possible interaction with epigenetic and biological mechanisms. Here we used the Prenatal Stress Model (PNS) and we found that PNS affects behaviour at adolescence and adulthood in a social interaction test, both in male and females animals (n=34 Females and 33 males; p<0.05 for both sexes at both ages). By running omics and metabolic analyses we found alterations in several inflammatory pathways, including FoxO1 signaling both in the brain and also in peripheral organs (e.g. liver) in PNS adolescent and adult offspring.Interestingly FoxO1 alterations were observed also in blood samples of individuals exposed to childhood trauma (n=86; 40 M/36 F, p<0.05) and with depressive symptoms or metabolic dysfunctions. A downregulation of specific miRNAs (miR29a and miR29a) was observed in the brain of PNS exposed animals as well as in blood samples of subjects exposed to childhood trauma and in MDD patients. Interestingly, a different set of miRNAs has been found associated with a pro-inflammatory status in animals exposed to a stress paradigm at adulthood, with a sex specific effect, indicating that different mechanisms leading to inflammation can be activated according to the timing of the exposure. Overall, our data indicate that specific inflammatory mediators could be used as biomarkers of risk to identify vulnerable individuals and as novel targets for prevention.