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.

项目摘要 感觉处理障碍与神经发育障碍（例如自闭症谱系障碍）有关 和智力残疾，影响20个儿童中有1个。越来越多的证据表明母亲环境 强烈影响神经发育障碍的病毒作用，这表明子宫因素（例如 母体肠道微生物群对胎儿脑发育有深远的影响。因此，了解角色 在神经回路和异常行为的发展中，母体肠道微生物可以为您提供见解 神经发育障碍的基本机制。最近的工作具有照明机制 在妊娠期间发生，因此不存在遗产肠道菌群会随着胎儿改变而产生后代 脑基因表达，胎儿丘脑皮质轴突发育减少和异常触觉行为 在以后的生活中。该建议旨在探讨产妇肠道微生物群如何改变胎儿脑发育。在目标1中 （K99），母体肠道微生物组在产前小胶质细胞发展中的作用将由 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清晰度成像 小胶质细胞功能的体感行为中清醒动物的成像。该提案的目标2（K99） 将采用特定无病原体（SPF）的胚胎小胶质细胞的部署和新颖的“添加”方法 大脑具有正常的肠道菌群，进入胚胎的胚胎大脑，从无菌的大坝中 （GF）或抗生素处理的（ABX），其耗尽了母体肠道微生物组。这套实验将 解决小胶质细胞的因果作用，并测试产前小胶质细胞培养基肠道肠道微生物组效应 关于大脑发育。由于在自闭症谱系中所见的行为定义中暗示了小胶质激活 疾病和精神分裂症，R00将利用在K99阶段开发的技术来询问母体是否存在 肠道微生物群有助于小胶质细胞激活对胎儿脑发育的影响 行为。这些目标的成功完成可能会导致新的生物学靶标 干预措施，同时还扩大了我们在中枢神经发展过程中对微生​​物的理解 系统。这些提出的实验将为我提供方法（单细胞RNA）的新培训 测序和分析，以及对醒着的行为动物的体内成像）和概念（小胶质生物学） 作为一个独立研究实验室的基础，该实验室将研究产妇肠道微生物和 神经免疫性发育，并阐明了控制的细胞和分子机制 神经发育障碍。这项工作将在UCLA完成，在这里，技术和 智力增长是无数的。我将与导师和合作者定期会议以接收 有关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赠款写作和研究中心 同时还通过在科学会议上展示我的沟通技巧。在一起，这个职业 发展奖将帮助我建立并领导成功的神经发育生物学研究小组。