Investigating role of maternal gut microbiome in microglia-neuron dynamics and development of somatosensory circuits

研究母体肠道微生物组在小胶质细胞神经元动力学和体感回路发育中的作用

• 批准号: 10614065
• 负责人: Helen Vuong
• 金额: $ 22.5万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10614065
• 关键词: Adult Children; Affect; Animals; Antibiotics; Axon; Back; Behavior; Behavioral; Biological; Biology; Brain; CSF1R gene; Calcium; Central Nervous System; Child; Coculture Techniques; Cognitive; Communication; Development; Diet; Elderly; Embryo; Environment; Environmental Risk Factor; Etiology; Experimental Designs; Feedback; Fetal Reduction; Foundations; Fragile X Syndrome; Functional disorder; Gene Expression; Genetic; Germ-Free; Goals; Grant; Growth; Hypersensitivity; Image; Infection; Intellectual functioning disability; K-Series Research Career Programs; Laboratory Research; Lead; Mediating; Mentors; Methodology; Microbe; Microglia; Molecular; Molecular Target; Morphology; Mus; Muscle fasciculation; Neocortex; Neurodevelopmental Disorder; Neuroimmune; Neurons; Pathway interactions; Patients; Phagocytes; Pharmaceutical Preparations; Phase; Phenotype; Poly I-C; Pregnancy; Prosencephalon; RNA analysis; Research; Ribosomal DNA; Risk Factors; Role; Schizophrenia; Sensory; Shapes; Signal Transduction; Somatosensory Cortex; Sorting; Stimulus; Stress; Tactile; Techniques; Testing; Thalamic structure; Therapeutic Intervention; Training; Transplantation; Work; Writing; autism spectrum disorder; autistic children; awake; career; experimental study; fetal; genetic risk factor; germ free condition; glial activation; glial cell development; gut microbes; gut microbiome; gut microbiota; immune activation; improved; in utero; in vivo; in vivo imaging; inhibitor; insight; maternal microbiome; maternal microbiota; maternal stress; meetings; microbiome; microbiome alteration; microbiota; migration; myelination; neocortical; nerve supply; neural circuit; neurodevelopment; neurophysiology; neuropsychiatric disorder; neuroregulation; new therapeutic target; novel; offspring; postnatal; prenatal; response; sensory cortex; sensory processing disorder; sensory stimulus; single-cell RNA sequencing; skills; social; somatosensory; symposium; targeted treatment; transcriptome; white matter

Project Summary Sensory processing disorder is associated with neurodevelopmental disorders such as autism spectrum disorder and intellectual disability, affecting 1 in 20 children. Increasing evidence reveal that the maternal environment strongly impacts the etiopathogenesis of neurodevelopmental disorders, suggesting in utero factors such as the maternal gut microbiota holds profound influence on fetal brain development. Therefore, understanding the role of maternal gut microbes in the development of neural circuits and abnormal behaviors can provide insights to the underlying mechanisms of neurodevelopmental disorders. Recent work has illuminated mechanisms that occur during gestation whereby the absence of the maternal gut microbiota yields offspring with altered fetal brain gene expression, reduced fetal thalamocortical axon development, and abnormal tactile sensory behavior in later life. This proposal aims to explore how maternal gut microbiota alters fetal brain development. In Aim 1 (K99), the role of the maternal gut microbiome in the development of prenatal microglia will be determined by single-cell RNA sequencing of microglia gene expression, CLARITY imaging of microglia morphology and in vivo imaging of awake animals during somatosensory behaviors for microglia function. Aim 2 of this proposal (K99) will employ a depletion and novel “add-back” approach of embryonic microglia from specific pathogen-free (SPF) brains, which have a normal gut microbiota, into embryonic brains of offspring from dams that are germ-free (GF) or antibiotic-treated (ABX), which are depleted of the maternal gut microbiome. This set of experiments will address the causal role of microglia and test whether prenatal microglia mediate maternal gut microbiome effects on brain development. Since microglial activation is implicated in behavioral deficits seen in autism spectrum disorder and schizophrenia, R00 will leverage techniques developed in the K99 phase to ask whether maternal gut microbiota contributes to the effects of microglial activation on fetal brain development and later life behaviors. The successful completion of these aims could lead to new biological targets for therapeutic intervention, while also expanding our understanding of microbes during development of the central nervous system. These proposed experiments will provide me with new training in methodologies (single cell RNA sequencing and analysis, and in vivo imaging of awake behaving animals) and concepts (microglial biology) to serve as the foundation of an independent research laboratory that will study maternal gut microbes and neuroimmune development, and elucidate the cellular and molecular mechanisms governing neurodevelopmental disorders. This work will be completed at UCLA, where the opportunities for technical and intellectual growth are innumerable. I will attend regular meetings with mentors and collaborators to receive feedback on experimental design and career advice. I will attend grant writing and research seminars at UCLA, while also improving my communication skills by presenting at scientific conferences. Together, this career development award will help me establish and lead a successful neurodevelopmental biology research group.

项目概要 感觉处理障碍与自闭症谱系障碍等神经发育障碍有关 和智力障碍，影响每 20 名儿童中就有 1 名。越来越多的证据表明，母亲的环境 强烈影响神经发育障碍的发病机制，表明子宫内因素，例如 母体肠道微生物群对胎儿大脑发育有着深远的影响。因此，了解角色 母体肠道微生物在神经回路和异常行为发育中的作用可以提供见解 神经发育障碍的潜在机制。最近的工作阐明了以下机制： 发生在妊娠期间，母体肠道微生物群的缺失导致后代胎儿发生改变 大脑基因表达、胎儿丘脑皮质轴突发育减少和触觉感觉行为异常 在以后的生活中。该提案旨在探索母体肠道微生物群如何改变胎儿大脑发育。目标 1 (K99)，母体肠道微生物组在产前小胶质细胞发育中的作用将由以下因素决定 小胶质细胞基因表达的单细胞 RNA 测序、小胶质细胞形态和体内的 CLARITY 成像 清醒动物体感行为期间小胶质细胞功能的成像。本提案的目标 2 (K99) 将采用一种去除特定病原体（SPF）的胚胎小胶质细胞的新型“回加”方法 将具有正常肠道微生物群的大脑移植到无菌水坝后代的胚胎大脑中 (GF) 或抗生素治疗 (ABX)，这些药物会耗尽母体肠道微生物群。这组实验将 解决小胶质细胞的因果作用并测试产前小胶质细胞是否介导母体肠道微生物组的影响 关于大脑发育。由于小胶质细胞的激活与自闭症谱系中的行为缺陷有关 R00 将利用 K99 阶段开发的技术来询问母亲是否患有精神障碍和精神分裂症 肠道微生物群有助于小胶质细胞激活对胎儿大脑发育和以后的生活的影响 行为。这些目标的成功完成可能会带来新的生物治疗靶点 干预，同时也扩大了我们对中枢神经发育过程中微生物的了解 系统。这些拟议的实验将为我提供新的方法学培训（单细胞 RNA 测序和分析，以及清醒行为动物的体内成像）和概念（小胶质细胞生物学） 作为独立研究实验室的基础，该实验室将研究母体肠道微生物和 神经免疫发育，并阐明控制的细胞和分子机制 神经发育障碍。这项工作将在加州大学洛杉矶分校完成，在那里提供技术和 智力的增长是无数的。我将参加与导师和合作者的定期会议，以获得 对实验设计和职业建议的反馈。我将参加加州大学洛杉矶分校的资助写作和研究研讨会， 同时还通过在科学会议上发言来提高我的沟通技巧。一起，这个职业 发展奖将帮助我建立并领导一个成功的神经发育生物学研究小组。