Prenatal stress disrupts social behavior, cortical neurobiology and commensal microbes in adult male offspring

Abstract

In utero and early neonatal exposure to maternal stress is linked with psychiatric disorders, and the underlying mechanisms are currently being elucidated. We used a prenatal stressor in pregnant mice to examine novel relationships between prenatal stress exposure, changes in the gut microbiome, and social behavior. Here, we show that males exposed to prenatal stress had a significant reduction in social behavior in adulthood, with increased corticosterone release following social interaction. Male offspring exposed to prenatal stress also had neuroinflammation, decreased oxytocin receptor, and decreased serotonin metabolism in their cortex in adulthood, which are linked to decreased social behavior. Finally, we found a significant difference in commensal microbes, including decreases in Bacteroides and Parabacteroides, in adult male offspring exposed to prenatal stress when compared to non-stressed controls. Our findings indicate that gestation is a critical window where maternal stress contributes to the development of aberrant social behaviors and alterations in cortical neurobiology, and that prenatal stress is sufficient to disrupt the male gut-brain axis into adulthood.

Unique maternal immune and functional microbial profiles during prenatal stress

“…Furthermore, unlike other models 68 , mRNA transcripts of inflammatory signaling molecules within uterine tissue were not altered in our model. Even still, our previous observations demonstrate significant impacts of gestational restraint stress on offspring inflammation and behavior 25,42 , which are largely CCL2dependent 43 . Altered production and expression of CCL2 and CCR2 in both the fetal brain and placenta coincide with pro-inflammatory signatures within these tissues and appear to drive offspring sociability 43 .…”

“…In animal models, systemic administration of particular cytokines in circulation, such as IL-6 and IL-1β, is sufficient to recapitulate specific offspring neuroimmune abnormalities seen with prenatal stress 59,60 . Interestingly, while psychological stress is thought to induce cytokine production in animal models (and is frequently described in placental and offspring brain tissue, including by our group 25,42 ), few, if any, studies have reported maternal circulating cytokine levels. Here, we found a decrease in IL-5 and a trending decrease in CCL2 in maternal circulation, and none of the suspected increases in IL-6 and IL-1β.…”

“…Thus, a reduction in microbial inflammatory genes, including those associated with succinate, may be detrimental both for appropriate microbial transfer from mother to infant 29,93 and for necessary infant immune education 94 . Long-term effects of maternal stress upon offspring notably include microbiome shifts 25,26,42 , but also spread into basic immune function, including elevated inflammatory output and a dysregulated adaptive immune response 95,96 . There is the strong potential that Parasutterella may mediate proper metabolic function in late pregnancy and even early immune development in the offspring; future studies by our group will delve deeper into how Parasutterella and its production of metabolites (i.e.…”

“…Using a murine model of psychological restraint stress during gestation, we tested the hypothesis that stress activates the HPA-axis and disrupts the endogenous GI microbial community, augmenting leukocytosis and subsequent leukocyte trafficking to uterine and placental tissues. Previously, we have shown that our model of prenatal stress leads to increased inflammation in the placenta and fetal brain, and results in aberrant behaviors and neuroinflammation in adult offspring 25,42 . We recently demonstrated that stressor-induced fetal brain and placental inflammation is largely absent in CCL2 knock-out (KO) and germ-free animals, and that CCL2 KO adult offspring are protected from deficits in sociability 43 .…”

“…Females were bred over two nights and pregnancy was verified by the presence of a vaginal plug (designated as GD1). Pregnant females were randomly assigned to the experimental stress group or the non-stress control group, with the stress group undergoing repeated restraint stress from GD10 to GD16, as previously described 25,42 . Briefly, pregnant dams were placed in a perforated 50 mL conical for two hours each day between the hours of 09:00 to 12:00 for seven consecutive days; non-stressed control dams were left undisturbed.…”