Fetal Brain-Placental Immune Activation in Maternal Obesity

项目总结 在美国，三分之一的育龄妇女患有肥胖症。在大型流行病学研究中，产妇 肥胖与儿童的认知缺陷有关，包括智商降低和低智商(70)，以及阅读能力下降 还有数学成绩。潜在的机制仍不清楚。已知的是，母体肥胖是一种 已有胎儿慢性低水平免疫激活、胎盘和脑部炎症的报道。 以及肥胖女性的后代。小胶质细胞是大脑的常驻免疫细胞，与 许多神经发育疾病的发病机制，在后代中出现的频率增加 肥胖的女人。尽管如此，关于胎盘炎症是否影响胎儿大脑/如何影响胎儿大脑的认识还存在差距。 在母亲肥胖的背景下的发展。我们已经展示了性别特定的胎儿大脑转录 母体肥胖的背景，免疫和炎症信号失调是关键影响因素 母体肥胖对男性和女性胚胎大脑的影响。我们随后展示了一个重要的 母体肥胖对胚胎小胶质细胞抗原(Iba-1)密度的性别二型性影响 肥胖暴露的后代中的海马体和海马体学习缺陷，男性后代更多 受到严重影响。这些数据支持这样一种假设，即胚胎生命中异常的大脑免疫激活 是导致持久认知缺陷的一种机制。 因此，不适当的胎儿小胶质细胞启动可能会产生终生的神经发育后果，但直接 评估活着的人类胎儿或新生儿的小胶质细胞功能是不可能的。幸运的是，胎盘 巨噬细胞(霍夫鲍尔细胞)和小胶质细胞在胎儿卵黄囊中有共同的起源。卵黄囊来源 巨噬细胞构成了一个人一生中大脑小胶质细胞的永久池。因此， 胎盘Hofbauer细胞是一种潜在的新的生物前哨，可能反映小胶质细胞 免疫反应性。在这里，我们试图检验以下假设：(1A)母亲肥胖将使两位霍夫鲍尔 细胞和胎儿大脑小胶质细胞对免疫挑战反应过度(1b)母亲肥胖将导致关键 将在霍夫鲍尔细胞中重述的胎儿小胶质细胞单细胞转录组的变化 转录组(2)选择性消融胎脑和胎盘中促炎症的巨噬细胞信号 使用创新的转基因小鼠将挽救母亲肥胖相关的海马区学习缺陷。 拟议中的实验将通过确定是否增加促炎作用来填补知识空白 胎盘和胎脑中的巨噬细胞信号是子代海马区学习的机制 母体肥胖方面的缺陷。证明胎儿胎盘和脑巨噬细胞介导的因果联系 炎症和神经发育异常具有潜在的治疗应用前景。如果霍夫鲍尔细胞可以 作为一种更容易获得的细胞类型，提供关于胎儿大脑小胶质细胞行为的信息，在那里 这可能对在肥胖以外的母亲暴露的情况下评估后代风险具有更广泛的影响。

PROJECT SUMMARY In the United States, one in three women of reproductive age is obese. In large epidemiologic studies, maternal obesity is associated with cognitive deficits in children, including reduced and low IQ (<70), and lower reading and math scores. Underlying mechanisms remain unclear. What is known is that maternal obesity is a state of chronic low-level immune activation, and both placental and brain inflammation have been reported in fetuses and offspring of obese women. Microglia, the resident immune cells of the brain, have been implicated in the pathogenesis of many of the neurodevelopmental morbidities noted with increased frequency in offspring of obese women. Despite this, there is a gap in knowledge about if/how placental inflammation affects fetal brain development in the setting of maternal obesity. We have demonstrated sex-specific fetal brain transcriptomes in the setting of maternal obesity, with dysregulated immune and inflammatory signaling highlighted as key effects of maternal obesity on both the male and female embryonic brain. We subsequently demonstrated a significant and sexually dimorphic effect of maternal obesity on microglial antigen (Iba-1) density in the embryonic hippocampus, and hippocampal learning deficits in obesity-exposed offspring, with male offspring more significantly affected. These data support the hypothesis that aberrant brain immune activation in embryonic life is one mechanism underlying enduring cognitive deficits. Inappropriate fetal microglial priming may therefore have lifelong neurodevelopmental consequences, but direct evaluation of microglial function in a living human fetus or neonate is impossible. Fortunately, placental macrophages (Hofbauer cells) and microglia have a common origin in the fetal yolk sac. Yolk-sac-derived macrophages comprise the permanent pool of brain microglia throughout an individual’s lifetime. Therefore, placental Hofbauer cells represent a potentially novel biologic sentinel that may mirror microglial immunoreactivity. Here, we seek to test the following hypotheses: (1a) maternal obesity will prime both Hofbauer cells and fetal brain microglia to overrespond to an immune challenge (1b) Maternal obesity will induce key alterations in the fetal microglial single cell transcriptome which will be recapitulated in the Hofbauer cell transcriptome (2) Selective ablation of pro-inflammatory macrophage signaling in the fetal brain and placenta using an innovative transgenic mouse will rescue maternal obesity-associated hippocampal learning deficits. The proposed experiments will fill a knowledge gap by ascertaining whether increased pro-inflammatory macrophage signaling in the placenta and fetal brain is a mechanism underlying offspring hippocampal learning deficits in maternal obesity. Demonstrating a causal link between fetal placental and brain macrophage-mediated inflammation and neurodevelopmental morbidity has potential therapeutic applications. If Hofbauer cells can serve as a more accessible cell type that provides information about the behavior of fetal brain microglia, there may be broader implications for assessing offspring risk in the setting of maternal exposures beyond obesity.