Estrogen receptor (ER)β-mediated repression of prenatal inflammation in fetal microglia and its impact on autism

摘要 在美国，每68名儿童中就有一名被诊断出患有自闭症谱系障碍(ASD)，但有 目前还没有基础疗法可用。此外，流行病学研究表明，近五年来 受自闭症影响的男孩是女孩的两倍，但这种性别二型性背后的机制并不好 明白了。ASD的发病机制既有遗传因素，也有环境因素。中的 环境因素，流行病学表明，母体感染引起的产前炎症 与ASD风险增加相关，但这种联系背后的机制仍需阐明。 我们的实验室一直致力于了解环境因素如何影响正常大脑 通过重点研究小胶质细胞，中枢神经系统中的常驻免疫细胞， 控制大脑中的先天免疫反应。更具体地说，我们感兴趣的是性激素 及其相应的核受体(雌激素受体和雄激素受体)可能能够 诱导小胶质细胞基因表达改变和表观遗传调控以恢复正常中枢神经系统 功能和改善神经炎性疾病，如ASD。我们对这一提议的中心假设是 先天性免疫信号，如Toll样受体(TLR)介导的胎儿小胶质细胞炎症，是 参与诱导特定的、类似ASD的行为变化。此外，我们预测，基因的表达水平 胎儿小胶质细胞中抗炎ERβ配体决定其对产前炎症和 导致在ASD中观察到的男性偏见。我们将使用产前的小鼠模型来检验这些假设。 炎症性ASD。 这项建议的主要目标是了解对TLR介导的产前的差异反应 炎症可以影响胎儿长期的小胶质细胞转录和表观遗传调节，导致ASD样 行为。此外，我们将确定ERβ介导的转录和表观遗传学的调控 调节可以恢复受产前炎症影响的正常小胶质细胞功能，从而改善ASD- 就像后代的行为一样。预计这项提议的总体影响是，它将扩大 通过阐明不同的母体和胎儿TLR介导的信号通路来理解它们 与ASD中观察到的特定行为变化相关。我们还将充分阐明急诊室及其 配体有助于在ASD中观察到的男性偏见，以及这些配体如何在ASD中恢复体内平衡 小胶质细胞以改善小鼠模型中ASD样行为。

Abstract One in 68 children are diagnosed with autism spectrum disorders (ASD) in the US, yet there are currently no fundamental therapies available. Furthermore, epidemiological research suggests that nearly five times more boys than girls are affected by ASD, but the mechanisms behind this sex dimorphism are not well understood. It is known that both genetic and environmental factors are involved in ASD pathogenesis. Of the environmental factors, epidemiology suggests that prenatal inflammation induced by maternal infection is associated with an increased risk of ASD, yet the mechanisms behind this link still need to be elucidated. Our lab has been working on understanding how environmental factors affect normal brain development and functions by focusing on how microglia, resident immune cells in the central nervous system, control innate immune responses in the brain. More specifically, we are interested in whether sex hormones and their corresponding nuclear receptors (Estrogen Receptors and Androgen Receptor) may be able to induce changes in gene expression and epigenetic regulation in microglia that can restore normal CNS functions and improve neuroinflammatory diseases such as ASD. Our central hypothesis for this proposal is that innate immune signaling, such as toll-like receptor (TLR)-mediated inflammation in fetal microglia, is involved in inducing specific, ASD-like behavior changes. Furthermore, we predict that the expression levels of anti-inflammatory ERβ ligands in fetal microglia determine their sensitivity to prenatal inflammation and contribute to the male bias observed in ASD. We will test these hypotheses using mouse models of prenatal inflammation-induced ASD. The primary goal of this proposal is to understand how differential responses to TLR-mediated prenatal inflammation can affect long-term fetal microglial transcription and epigenetic regulation, resulting in ASD-like behaviors. Moreover, we will determine whether modulation of ERβ-mediated transcription and epigenetic regulation can restore normal microglial functions affected by prenatal inflammation, thus ameliorating ASD- like behaviors in offspring. The expected overall impact of this proposal is that it will expand the mechanistic understanding of distinct maternal and fetal TLR-mediated signaling pathways by clarifying how they are associated to specific behavior changes observed in ASD. We will also fully elucidate how ERs and their ligands contribute to the male bias observed in ASD and how these ligands can restore homeostasis in microglia to improve ASD-like behaviors in a mouse model.