Microglia-dependent mechanisms governing neural circuit plasticity

控制神经回路可塑性的小胶质细胞依赖性机制

• 批准号: 9365846
• 负责人: Dorothy Patricia Schafer
• 金额: $ 40.53万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-15 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9365846
• 关键词: Address; Adult; Alzheimer' s Disease; Architecture; Autistic Disorder; Biological Assay; Birth; Body part; Brain; CSF1 gene; CSF1R gene; CX3CL1 gene; CX3CR1 gene; Cellular Assay; Complement Receptor; Data; Defect; Development; Disease; Etiology; Excision; Fractalkine; Functional Imaging; Goals; Knockout Mice; Learning; Life; Ligands; Light; Location; Macrophage Colony-Stimulating Factor Receptor; Macrophage-1 Antigen; Maintenance; Maps; Measures; Mediating; Memory; Microglia; Molecular; Molecular Biology; Mus; Neonatal; Nervous System Physiology; Patients; Positioning Attribute; Research; Resolution; Rodent; Role; Schizophrenia; Sensory; Sensory Deprivation; Shapes; Signal Transduction; Symptoms; Synapses; System; Testing; Thinking; Time; Touch sensation; Vibrissae; Vision; Work; barrel cortex; cell motility; chemokine; chemokine receptor; cortex mapping; density; deprivation; experience; experimental study; fractalkine receptor; high resolution imaging; insight; macrophage; neonate; nervous system disorder; neural circuit; neuropsychiatric disorder; novel; presynaptic; receptor; relating to nervous system; response; retinogeniculate; synaptogenesis; temporal measurement

The goal of this proposal is to determine how microglia and sensory experience integrate to remodel synapses into precise, functional brain maps. Trillions of synapses form highly precise topographic maps in the brain representing each part of the body. These maps are shaped and maintained by sensory experience (vision, touch, etc.), including elimination of less active synapses and formation and maintenance of other synapses. Despite over 50 years of research, the underlying mechanisms by which experience dictates removal or maintenance of specific synapses still remains an open question. We made the initial exciting and unexpected observation that microglia, the resident CNS macrophages, engulfed and eliminated a subset of less active synapses in the developing retinogeniculate system. Further, reducing microglia-mediated engulfment of synapses by 50% (complement receptor 3 KO) resulted in sustained increases in retinogeniculate synapse number. This work established a new way of thinking about synaptic remodeling and inspired several important new questions: Is microglia-mediated synaptic remodeling necessary for achieving functional circuits? Do microglia remodel synapses in the adult brain? How does neural activity regulate microglia-mediated synaptic remodeling? The retinogeniculate system was limiting for addressing these questions. We required a robust system for studying synaptic remodeling that involved plasticity of synapses throughout life, tractable assays for measuring function, and a topographic arrangment with high spatial and temporal resolution. The mouse barrel cortex fit all these critera and will enable us to test the hypothesis that experience regulates microglia to shape developing and mature syanpses into functional brain circuits. Our new preliminary data show for the first time that microglia engulf excitatory thalamocortical (TC) synapses in the developing barrel cortex and following sensory deprivation (whisker removal) in the neonate. Further, mice deficient in microglia (colony stimulating factor 1 receptor KO; CSF1R KO) have defects in the development of approriate barrel architecture and TC input elimination following whisker deprivation is completely blocked in mice deficient in a microglia-specific chemokine receptor (fractalkine receptor KO, CX3CR1 KO). We will now use a combination of high resolution static and functional imaging and molecular biology in the mouse barrel cortex to: 1) Determine whether microglia sculpt developing cortical circuits into functional brain maps (Aim 1). 2) Determine whether microglia regulate experience-dependent plasticity of cortical maps in the neonate and adult (Aim 2). 3) Identify how microglia remodel synapses in response to changes in neural activity (Aim 3). Answers will uncover new mechanisms regulating how sensory experience regulates the development of structural and functional brain maps, will identify new ways to achieve plasticity in the adult brain, and will provide new mechanistic insight into how synapses remodel in multiple contexts (development, learning and memory, disease, etc.).

该提案的目的是确定小胶质细胞和感官体验如何融入 重塑突触成精确的功能性脑图。数万亿个突触形成高度精确的 大脑中的地形图代表身体的每个部分。这些地图由 感官体验（视觉，触摸等），包括消除较不活跃的突触和形成和形成和 维护其他突触。尽管进行了50多年的研究，但其基本机制 经验决定了特定突触的去除或维护仍然是一个悬而未决的问题。我们做了 最初令人兴奋和意外的观察，即小胶质细胞，常驻CNS巨噬细胞，被吞噬并 消除了发育中的视网膜生成系统中活性突触较低的子集。此外，还原 小胶质细胞介导的突触吞噬50％（补体受体3 KO）导致持续 视网膜生成的突触数增加。这项工作建立了一种关于突触的新思维方式 重塑并启发了几个重要的新问题：是小胶质细胞介导的突触重塑 实现功能电路所必需的？成人大脑中的小胶质细胞重塑是否会突触？怎么样 神经活动调节小胶质细胞介导的突触重塑？视网膜生成系统是限制的 解决这些问题。我们需要一个可靠的系统来研究涉及的突触重塑 一生的突触的可塑性，可用于测量功能的可疗法测定法和地形布置 具有高空间和时间分辨率。鼠标桶皮质适合所有这些核心，并将使我们能够测试 经验的假设调节小胶质细胞将发育和成熟的syanpes塑造成功能 脑电路。我们的新初步数据首次显示小胶质细胞刺激性丘脑皮层 （TC）发育中的枪管皮层中的突触，并在感觉剥夺后（晶须去除） 新生儿。此外，缺乏小胶质细胞（菌落刺激因子1受体KO； CSF1R KO）的小鼠具有缺陷 在开发适当的桶形体系结构和TC输入消除时，须渗透是 在小鼠特异性趋化因子受体（Fractalkine受体KO， CX3CR1 KO）。现在，我们将使用高分辨率静态成像和分子的组合 小鼠桶皮层中的生物学：1）确定小胶质细胞是否雕刻了皮质回路 功能性大脑图（AIM 1）。 2）确定小胶质细胞是否调节经验依赖性可塑性 新生儿和成人的皮质图（AIM 2）。 3）确定如何响应小胶质细胞重塑突触 神经活动的变化（AIM 3）。答案将发现新的机制，以调节感官体验的方式 调节结构和功能性大脑图的发展，将确定实现可塑性的新方法 在成人大脑中，将提供有关在多种情况下突触重塑如何重塑的新机械洞察力 （发展，学习和记忆，疾病等）。