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 自闭症谱系障碍（ASD）目前影响美国59名儿童中有1个。产前暴露 激活免疫系统的空气污染等环境因素与 增加ASD风险。但是，怀孕期间不利环境暴露的机制 导致胎儿脑的成熟改变仍然未知。小胶质细胞，大脑的常驻免疫细胞， 是对免疫激活的神经反应和发展组织的关键调节者 神经回路，使它们独特地准备将这种不利环境暴露转化为神经 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），导致异常的神经回路形成。我们最近开发了小胶质的 发展指数（MDI）基于 转录组测序。在小鼠中，我们表明MDI是通过急性免疫挑战加速的 只有男性。使用人数据集，我们发现ASD患者的MDI高于对照组。一起， 这些发现表明，小胶质成熟的变化代表了一种潜在的机制 免疫侮辱会增加性别特定方式的ASD风险。我们的实验室开发了一种新颖的鼠标模型 产前免疫激活将暴露于柴油排气颗粒（DEP）与母体相结合 压力源（资源剥夺； MS）。我的初步数据表明，DEP/MS暴露会损害社交 男性后代的行为。因此，在AIM 1中，我将在孤立的 小胶质细胞检验以下假设：DEP/MS暴露只会加速男性MDI。我的初步 数据还表明，DEP/MS暴露降低了核中多巴胺D1受体（D1R）mRNA a尊（NAC）。此外，我们最近发现，小胶质细胞介导的突触修剪对 NAC中D1R的自然发展和社会行为。因此，在AIM 2中，我将检验以下假设。 DEP/MS暴露仅增加男性NAC-D1R的小胶质细胞修剪。最后，在AIM 3中，我将测试 DEP/MS诱导的NAC-D1R变化是DEP/MS诱导的社会缺陷的假设 行为。具体而言，我预测a）局部抑制NAC中的小胶质细胞修剪将防止社会 行为缺陷以下dep/ms和b），如果这些效果特别依赖于D1R信号，则 这种恢复将通过并发的NAC-D1R拮抗作用减弱。在一起，这项工作将有一个 对我们对小胶质细胞发育生物学的基本理解的重要积极影响以及 神经免疫信号对ASD病因的特定贡献。