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患有自闭症谱系障碍（ASD），但 目前还没有基本的治疗方法。此外，流行病学研究表明，近5 自闭症男孩的患病率是女孩的1倍，但这种性别二态性背后的机制尚不清楚。 明白遗传和环境因素均参与ASD的发病机制。的 环境因素，流行病学表明，由母体感染引起的产前炎症是 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 通过关注小胶质细胞，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和表观遗传调节变化，可恢复正常CNS 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 先天免疫信号，如胎儿小胶质细胞中的toll样受体（TLR）介导的炎症， 参与诱导特定的ASD样行为改变。此外，我们预测， 胎儿小胶质细胞中的抗炎ERβ配体决定了它们对产前炎症的敏感性， 导致ASD中观察到的男性偏见。我们将使用产前发育的小鼠模型来检验这些假设。 炎症诱导的ASD。 这项建议的主要目标是了解如何差异反应TLR介导的产前 炎症可以影响长期的胎儿小胶质细胞转录和表观遗传调节，导致ASD样 行为。此外，我们将确定是否调节ERβ介导的转录和表观遗传， 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， 比如后代的行为这项建议的预期总体影响是，它将扩大机械化 了解不同的母亲和胎儿TLR介导的信号通路，通过阐明它们是如何 与ASD中观察到的特定行为变化相关。我们还将充分阐明ER及其 配体有助于在ASD中观察到的男性偏好，以及这些配体如何在ASD中恢复稳态。 小胶质细胞来改善小鼠模型中的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.