Prenatal stress causes intrauterine inflammation and serotonergic dysfunction, and long-term behavioral deficits through microbe- and CCL2-dependent mechanisms
Prenatal stress causes intrauterine inflammation and serotonergic dysfunction, and long-term behavioral deficits through microbe- and CCL2-dependent mechanisms
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产前应激通过微生物和CCL2依赖性机制引起宫内炎症和孕酮能功能障碍以及长期行为缺陷
DOI：
10.1038/s41398-020-00876-5
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发表时间：
2020-06-16
影响因子：
6.8
通讯作者：
Gur, Tamar L.
中科院分区：
文献类型：
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作者：
Chen, Helen J.;Antonson, Adrienne M.;Gur, Tamar L.
产前应激（PNS）与后代的神经精神障碍有关，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内。母体微生物、炎症和激素能功能障碍被认为是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。在此，我们研究了PNS对野生型（WT）、无菌（GF）和CCL 2（-）（/）（-）基因敲除（KO）小鼠妊娠晚期母体束缚应激的影响。在WT小鼠中，PNS导致胎盘和胎脑炎症，包括趋化因子CCL 2的升高。这种炎症在GF小鼠中基本上不存在，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CCL 2的情况下，PNS未能增加胎儿脑中的促炎细胞因子IL-6。PNS后代也表现出社交能力和焦虑样行为的缺陷，而这些缺陷在CCL 2（-）（/-）PNS后代中不存在。色氨酸和5-羟色胺（5-HT）在WT PNS胎盘中升高，但在CCL 2（-）（/-）和GF动物中不升高。总而言之，这些发现表明母体微生物、炎症和5-羟色胺代谢之间的复杂相互作用调节了PNS后行为异常的出现。
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 originsin 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 PNSin uterousing 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 processesin 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.