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.

产前压力 (PNS) 与后代的神经精神疾病有关，包括焦虑、抑郁和自闭症谱系障碍。越来越多的证据表明这些行为表型起源于子宫。母体微生物、炎症和血清素功能障碍被认为是 PNS 行为后果的潜在介质。这些系统是否以及如何相互作用尚不清楚。在这里，我们使用野生型 (WT)、无菌 (GF) 和 CCL2 ^{- / -中的妊娠晚期母体约束压力检查 PNS}在子宫内的影响基因敲除（KO）小鼠。在 WT 小鼠中，PNS 导致胎盘和胎儿脑部炎症，包括趋化因子 CCL2 升高。这种炎症在 GF 小鼠中基本不存在，表明母体微生物在介导子宫内免疫过程中的关键作用。此外，在没有 CCL2 的情况下，PNS 未能增加胎儿大脑中的促炎细胞因子 IL-6。^{PNS 后代也表现出 CCL2 - /-} PNS 后代不存在的社交能力和焦虑样行为缺陷。WT PNS 胎盘中的色氨酸和血清素 (5-HT) 升高，但在 CCL2 中不升高^{- /-}和 GF 动物。总之，这些发现表明母体微生物、炎症和血清素代谢之间的复杂相互作用调节了 PNS 后行为异常的出现。