The Microglial Developmental Index: A Novel Framework for Understanding the Role of Microglia in the Etiology of Autism Spectrum Disorder

小胶质细胞发育指数：了解小胶质细胞在自闭症谱系障碍病因学中的作用的新框架

• 批准号: 9761008
• 负责人: Caroline Jackson Smith
• 金额: $ 6.16万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9761008
• 关键词: Acute; Adolescent Development; Adult; Affect; Air; Air Pollution; Attenuated; Biological Assay; Brain; Child; DNA; Data; Data Analyses; Data Set; Development; Developmental Biology; Diesel Exhaust; Disease; Dopamine D1 Receptor; Environmental Exposure; Environmental Risk Factor; Etiology; Exposure to; Female; Fetal Development; Functional disorder; Genetic Risk; Goals; Hippocampus (Brain); Human; Immune; Immune system; Impairment; Inflammatory; Lead; Light; Literature; Measures; Mediating; Messenger RNA; Microglia; Morphology; Mus; Neuroimmune; Nucleus Accumbens; Outcome; Patients; Pattern; Perinatal; Phagocytosis; Pharmacology; Play; Pregnancy; RNA; Receptor Activation; Receptor Signaling; Regulation; Research; Resources; Role; Signal Transduction; Social Behavior; Social support; Stress; Structure; Synapses; System; Techniques; Testing; Training; Translating; United States; Western Blotting; Work; autism spectrum disorder; base; brain cell; deprivation; developmental plasticity; disorder risk; experience; experimental study; fetal; genome sequencing; immune activation; in vivo; indexing; male; molecular targeted therapies; mouse model; neural circuit; next generation; novel; novel strategies; offspring; particle; particle exposure; pollutant; postnatal; pregnant; prenatal; prenatal exposure; prevent; receptor; receptor expression; relating to nervous system; response; restoration; sex; social; social deficits; stressor; synaptic pruning; transcriptome sequencing; transcriptomics; whole genome

Project Summary Autism spectrum disorder (ASD) currently affects 1 in 59 children in the United States. Prenatal exposure to environmental factors like air pollution, which activate the immune system, have been associated with increased ASD risk. However, the mechanisms by which adverse environmental exposures during pregnancy lead to altered maturation of the fetal brain remain unknown. Microglia, the resident immune cells of the brain, are key regulators of both the neural response to immune activation and the developmental organization of neural circuits, making them uniquely poised to translate such adverse environmental exposures into neural outcomes. Interestingly, recent studies suggest that prenatal challenges can alter the trajectory of brain development (maturation), leading to aberrant neural circuit formation. We recently developed the microglial developmental index (MDI) to objectively measure the global maturational state of microglia based on transcriptomic sequencing. In mice, we showed that the MDI is accelerated by an acute immune challenge in males only. Using human datasets, we found that the MDI is higher in ASD patients than in controls. Together, these findings suggest that changes in microglial maturation represent a potential mechanism by which immune insults increase ASD risk in sex-specific ways. Our lab has developed a novel mouse model of prenatal immune activation which combines exposure to diesel exhaust particles (DEP) with a maternal stressor (resource deprivation; MS). My preliminary data demonstrate that DEP/MS exposure impairs social behavior in male offspring only. Therefore, in Aim 1, I will use next-generation RNA sequencing on isolated microglia to test the hypothesis that DEP/MS exposure will accelerate the MDI in males only. My preliminary data also show that DEP/MS exposure decreases dopamine D1 receptor (D1R) mRNA in the nucleus accumbens (NAc). Moreover, we recently found that microglia-mediated synaptic pruning is critical to the natural development of D1R in the NAc, and social behavior. Thus, in Aim 2, I will test the hypothesis that DEP/MS exposure increases microglial pruning of NAc-D1Rs in males only. Finally, in Aim 3 I will test the hypothesis that DEP/MS-induced changes in NAc-D1R are causal to DEP/MS-induced deficits in social behavior. Specifically, I predict that a) local inhibition of microglial pruning in the NAc will prevent social behavior deficits following DEP/MS and b), if these effects are dependent on D1R signaling specifically, then this restoration will be attenuated by concurrent NAc-D1R antagonism. Together, this work will have an important positive impact on both our basic understanding of the developmental biology of microglia, as well as the specific contribution of neuro-immune signaling to the etiology of ASD.

项目摘要 目前，美国每59名儿童中就有1名患有自闭症谱系障碍（ASD）。产前暴露于 环境因素，如空气污染，激活免疫系统，已与 ASD风险增加然而，怀孕期间不良环境暴露的机制 导致胎儿大脑成熟的改变仍然是未知的。小胶质细胞，大脑的常驻免疫细胞， 是免疫激活的神经反应和发育组织的关键调节因子。 神经回路，使它们能够将这种不利的环境暴露转化为神经回路， 结果。有趣的是，最近的研究表明，产前挑战可以改变大脑的轨迹， 发育（成熟），导致异常神经回路形成。我们最近开发了一种 发育指数（MDI），以客观地衡量小胶质细胞的整体成熟状态， 转录组测序。在小鼠中，我们发现MDI被急性免疫攻击加速， 仅限男性。使用人类数据集，我们发现ASD患者的MDI高于对照组。在一起， 这些发现表明小胶质细胞成熟的变化代表了一种潜在的机制， 免疫损伤以性别特异性方式增加ASD风险。我们的实验室开发了一种新的小鼠模型， 产前免疫激活结合暴露于柴油机尾气颗粒（DEP）与母体 应激源（资源剥夺）。我的初步数据表明，DEP/MS暴露损害社会 仅在雄性后代中表现。因此，在目标1中，我将使用下一代RNA测序对分离的 小胶质细胞，以测试DEP/MS暴露将加速MDI仅在男性中的假设。我的初步 数据还表明，DEP/MS暴露降低了细胞核中多巴胺D1受体（D1 R）mRNA （NAc）.此外，我们最近发现，小胶质细胞介导的突触修剪对神经元的生长至关重要。 NAc中D1 R的自然发展和社会行为。因此，在目标2中，我将检验以下假设： DEP/MS暴露仅在雄性中增加NAc-D1 R的小胶质细胞修剪。最后，在目标3中，我将测试 假设DEP/MS诱导的NAc-D1 R的变化是DEP/MS诱导的社交缺陷的原因， 行为具体来说，我预测a）NAc中小胶质细胞修剪的局部抑制将阻止社会性 DEP/MS后的行为缺陷和B），如果这些效应特异性依赖于D1 R信号传导，则 这种恢复将被同时发生的NAc-D1 R拮抗作用减弱。总之，这项工作将有一个 这对我们对小胶质细胞发育生物学的基本理解产生了重要的积极影响， 神经免疫信号对ASD病因学的特殊贡献。