Placental effects on maternal brain revealed by disrupted placental gene expression in mouse hybrids

The mammalian placenta is both the physical interface between mother and fetus, and the source of endocrine signals that target the maternal hypothalamus, priming females for parturition, lactation and motherhood. Despite the importance of this connection, the effects of altered placental signaling on the maternal brain are understudied. Here, we show that placental dysfunction alters gene expression in the maternal brain, with the potential to affect maternal behavior. Using a cross between the house mouse and the Algerian mouse in which hybrid placental development is abnormal, we sequenced late gestation placental and maternal medial preoptic area transcriptomes and quantified differential expression and placenta-maternal brain co-expression between normal and hybrid pregnancies. The expression of Fmn1, Drd3, Caln1 and Ctsr was significantly altered in the brains of females exposed to hybrid placentas. Most strikingly, expression patterns of placenta-specific gene families and Drd3 in the brains of house mouse females carrying hybrid litters matched those of female Algerian mice, the paternal species in the cross. Our results indicate that the paternally-derived placental genome can influence the expression of maternal-fetal communication genes, including placental hormones, suggesting an effect of the offspring's father on the mother’s brain. Analysis of 15 RNA samples of the maternal medial preotic area at e17.5 of pregnancy (3 groups, 5 biological replicates each) and 29 samples of placental DNA at e17.5 of the same pregnancies (3 groups, 4-5 biological replicates per sex, per group)

哺乳动物胎盘既是母体与胎儿之间的物理界面，同时也是靶向母体下丘脑的内分泌信号的来源，为雌性个体的分娩、泌乳及母性行为做好准备。尽管这一联系至关重要，但胎盘信号改变对母体大脑的影响仍未得到充分研究。本研究发现，胎盘功能异常会改变母体大脑的基因表达，进而可能影响母性行为。本研究利用小家鼠与阿尔及利亚小鼠的杂交体系（该体系中杂交胎盘发育异常），对妊娠晚期的胎盘以及母体内侧视前区（medial preoptic area）的转录组进行测序，并量化正常妊娠与杂交妊娠之间的差异表达及胎盘-母体大脑共表达情况。暴露于杂交胎盘的雌性个体大脑中，Fmn1、Drd3、Caln1及Ctsr的表达量发生了显著改变。最引人注目的是，携带杂交胎仔的小家鼠雌性大脑中，胎盘特异性基因家族及Drd3的表达模式与本杂交体系中的父本物种——阿尔及利亚小鼠雌性的表达模式一致。本研究结果表明，父本来源的胎盘基因组可影响母胎通信基因（包括胎盘激素相关基因）的表达，这提示子代的父本会对母体大脑产生影响。本研究分析了15份妊娠第17.5天（e17.5）的母体内侧视前区RNA样本（分为3组，每组5个生物学重复），以及同批妊娠中29份妊娠第17.5天的胎盘DNA样本（分为3组，每组按性别各有4-5个生物学重复）。