Prenatal inflammation disrupts blood-brain barrier development and long-term function.

摘要 胎儿发育期间母体免疫激活(MIA)增加神经发育障碍的风险 (NDDS)在后代生活的后期。孕期MIA暴露下成年子代的慢性小胶质细胞激活 会导致一系列行为的改变。然而，MIA导致这种情况的发育机制持续存在 在整个生命周期中，后代大脑小胶质细胞的激活还不清楚。全身炎症引发 在成年期被证明扰乱血脑屏障(BBB)功能，诱导小胶质细胞激活， 神经炎症，并导致神经病理学的进行性出现。即使具有可比性 在经历过妊娠MIA的成年后代中观察结果，无论是否有类似的BBB 在子宫中导致这些表型的破坏和机制尚不清楚。这是一个重要的 知识差距，因为MIA是NNDS的危险因素，而且越来越多的证据表明血管功能障碍 对这些疾病的分子病理学有贡献。 研究人员获得的初步数据显示，在怀孕期间，由病毒模拟聚(I：C)引发的MIA 小鼠破坏胎儿血脑屏障的形成，导致新生的血脑屏障通透性增加，这是用实时胎儿核磁共振测量的。 他们的数据进一步表明，胎儿大脑小胶质细胞中环氧合酶-2(COX2；Ptgs2)途径的激活 是MIA效应的因果关系。重要的是，纵向核磁共振分析表明，胎儿血脑屏障形成的中断 导致持续性血脑屏障高通透性和终生脑小胶质细胞激活，脑血管炎症， 以及后代的行为变化。 通过四个不同研究小组的综合专业知识，研究人员开发出了 活体(MRI)和体外(全胎儿)测量胎儿脑血脑屏障通透性的新方法 与条件基因敲除小鼠品系一起，将用于测试：1)MIA是否激活以及如何激活 胎儿小胶质细胞中COX2通路的缺失在发育的关键时期扰乱了胎儿血脑屏障的形成，导致 不成熟，以及2)是否以及如何导致COX2途径在居民中的持久激活 小胶质细胞在后代的寿命中延长了血脑屏障结构的破坏和神经炎症。这个自我- 脑部炎症和血脑屏障紊乱的持续循环最终会增加患脑部疾病的风险 子代的神经病理学。从病因学的角度来看，这项临床前的提案将定义新的细胞 以及涉及产前侮辱的终身影响的分子途径，通过以下方式揭示这些机制 早期炎症与神经发育障碍中的血管中断有因果关系。

SUMMARY Maternal immune activation (MIA) during fetal development increases risk for neurodevelopmental disorders (NDDs) later in the offspring life. Chronic microglial activation in the adult offspring exposed to gestational MIA leads to a range of altered behaviors. Yet, the developmental mechanisms whereby MIA induces this sustained activation of offspring brain microglia across the lifespan are not understood. Systemic inflammation triggered during adulthood was shown to disrupt blood-brain barrier (BBB) function, inducing microglial activation, neuroinflammation and leading to the progressive emergence of neuropathologies. Even though comparable outcomes are observed in adult offspring who experienced gestational MIA, whether there is similar BBB disruption and the mechanisms leading to these phenotypes in utero are not known. This is an important knowledge gap because MIA is a risk factor for NNDs and there is growing evidence of vascular dysfunction contributing to the molecular pathology of these disorders. The investigators obtained preliminary data showing that MIA triggered by the viral mimetic poly(I:C) in pregnant mice disrupts fetal BBB formation leading to increased nascent BBB permeability measured using live fetal MRI. Their data further suggest that activation of the cyclooxygenase-2 (COX2; Ptgs2) pathway in fetal brain microglia is causal to MIA effects. Importantly, longitudinal MRI analyses suggest that disruption of fetal BBB formation induces persistent BBB hyperpermeability and life-long brain microglial activation, cerebrovascular inflammation, and behavioral alterations in the offspring. Through the combined expertises of four different research groups, the investigators developed and validated new methods for measuring fetal brain BBB permeability in vivo (MRI) and ex vivo (whole fetus perfusion) which, together with conditional knockout mouse lines, will be used to test: 1) if and how MIA activation of the COX2 pathway in fetal microglia perturbs fetal BBB formation at a critical time of development, leading to incomplete maturation, and 2) if and how the resulting protracted activation of COX2 pathway in resident microglia prolongs BBB structural disruption and neuroinflammation over the offspring lifespan. This self- perpetuating cycle of brain inflammation and BBB disruption would ultimately promote increased risk for neuropathology in the offspring. From an etiological standpoint, this pre-clinical proposal will define novel cellular and molecular pathways involved in life-long effects of prenatal insults, shedding light on the mechanisms by which early inflammation is causally linked to vascular disruptions in neurodevelopmental disorders.