Prenatal stress causes intrauterine inflammation and serotonergic dysfunction, and long-term behavioral deficits through microbe- and CCL2-dependent mechanisms

Abstract

Prenatal stress (PNS) is associated with neuropsychiatric disorders in offspring, including anxiety, depression, and autism spectrum disorders. There is mounting evidence that these behavioral phenotypes have origins in utero. Maternal microbes, inflammation, and serotonergic dysfunction have been implicated as potential mediators of the behavioral consequences of PNS; whether and how these systems interact is unclear. Here, we examine the effects of PNS in utero using late-gestation maternal restraint stress in wild-type (WT), germ-free (GF), and CCL2−/− genetic knock-out (KO) mice. In WT mice, PNS leads to placental and fetal brain inflammation, including an elevation in the chemokine CCL2. This inflammation is largely absent in GF mice, indicating the critical role of maternal microbes in mediating immune processes in utero. Furthermore, PNS in the absence of CCL2 failed to increase pro-inflammatory cytokine IL-6 in the fetal brain. PNS offspring also exhibited deficits in sociability and anxiety-like behavior that were absent in CCL2−/− PNS offspring. Tryptophan and serotonin (5-HT) were elevated in the WT PNS placenta, but not in CCL2−/− and GF animals. Altogether, these findings suggest that a complex interaction between maternal microbes, inflammation, and serotonin metabolism regulates the emergence of behavioral abnormalities following PNS.

Unique maternal immune and functional microbial profiles during prenatal stress

“…Furthermore, unlike other models 70 , 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 25,44 , which are largely CCL2-dependent 45 . 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 45 .…”

“…Even still, our previous observations demonstrate significant impacts of gestational restraint stress on offspring inflammation and behavior 25,44 , which are largely CCL2-dependent 45 . 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 45 . Therefore, it is possible that more nuanced inflammatory signaling patterns (involving CCL2-CCR2 chemokine signaling) are occurring systemically and at the maternal-fetal interface that are not reflected in CD11b + CD45 + cell proportions here.…”

“…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 25,44 . 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 45 . While our data indicate that CCL2-signaling and endogenous microbes play integral roles in mediating prenatal stress outcomes 45 , it is not yet known whether these factors may also coincide with an infiltration of immune cells to the maternal-fetal interface.…”

“…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 45 . While our data indicate that CCL2-signaling and endogenous microbes play integral roles in mediating prenatal stress outcomes 45 , it is not yet known whether these factors may also coincide with an infiltration of immune cells to the maternal-fetal interface. Here, we examined maternal endocrine and immune outcomes in order to establish a comprehensive gestational stress phenotype and to determine whether leukocyte trafficking to the maternal-fetal interface augments detrimental intrauterine inflammation.…”

Characterization of Gut Microbiota in Prenatal Cold Stress Offspring Rats by 16S rRNA Sequencing

“…The offspring that experience prenatal psychosocial stress were at elevated risk of anxiety disorders [8]. Prenatal restraint stress caused long-term behavioral deficits in offspring through microbe and C-C motif chemokine ligand 2-dependent mechanisms [9].…”