Microglia function in synaptic plasticity

小胶质细胞在突触可塑性中的功能

基本信息

批准号：
8316644
负责人：
Christopher Neal Parkhurst
金额：
$ 4.16万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-05-14 至 2015-08-13
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8316644
关键词：
Address Alleles Autistic Disorder Behavior Behavioral Paradigm Biological Assay Brain CNS processing CX3CL1 gene Candidate Disease Gene Cells Dendritic Spines Development Diphtheria Toxin Disease Gene Targeting Goals Immune Impairment Kinetics Learning Life Maintenance Memory Microglia Microscopy Molecular Monitor Mus Nervous System Physiology Neuraxis Neurodevelopmental Disorder Pathologic Processes Performance Peripheral Phagocytosis Physiological Physiological Processes Process Proteins RNA Role Sampling Schizophrenia Series Signal Pathway Signal Transduction Structure Synapses Synaptic plasticity Tamoxifen Testing Time Tissues Transgenic Mice Vertebral column Western Blotting diphtheria toxin receptor in vivo insight macrophage motor learning nervous system development nervous system disorder neural circuit neuropsychiatry promoter recombinase research study tool two-photon

项目摘要

DESCRIPTION (provided by applicant): The goal of this proposal is to determine the role of microglia in regulating the structure and function of the brain. Microglia are the resident immune cells of the central nervous system and display highly motile processes occupying a non-overlapping territory. Under physiological conditions, microglia may monitor the brain's microenvironment for damage signals and participate in the development and plasticity of neural circuits. Under pathological conditions, microglia undergo a series of morphological and functional changes, and may engage in containing tissue damage, phagocytosis and clearance of cellular debris, and/or the secretion of proinflammatory factors. Although microglia have been implicated in a multitude of physiological and pathological processes in the central nervous system, direct evidence of their functions remains elusive. Hampering efforts to delineate the role of microglia is the lack of tools to specifically perturb microglial function in vivo. I have recently generated mice with a targeted gene insertion allowing for the expression of tamoxifen- inducible Cre recombinase in CX3CR1 expressing microglial cells. This transgenic mouse line provides a molecular handle for the in vivo manipulation of microglia including deletion. By specifically ablating microglial cells in living mice, I will elucidate the role of microglia in anmal behavior and learning-dependent synaptic plasticity. As activated microglia are involved in almost every pathological condition in the brain, the proposed studies to identify the functions of microglia will provide important insights for the understanding and treatment of many neurological diseases. PUBLIC HEALTH RELEVANCE: Using the CX3CR1-CreER mouse that I have developed I will examine the role of microglia in synaptic structural plasticity as well as in learning and memory. The experiments proposed here will allow me to reveal important functions of microglia in the maintenance and remodeling of synapses. As activated microglia are involved in almost every pathological condition in the brain, including neuropsychiatric and neurodevelopmental disorders, the proposed studies will provide important insights for the understanding and treatment of many neurological diseases.

描述（由申请人提供）：该提案的目标是确定小胶质细胞在调节大脑结构和功能中的作用。小胶质细胞是中枢神经系统的常驻免疫细胞，并表现出占据非重叠区域的高度活动的过程。在生理条件下，小胶质细胞可以监测大脑微环境中的损伤信号，并参与神经回路的发育和可塑性。在病理条件下，小胶质细胞发生一系列形态和功能变化，并可能参与抑制组织损伤、吞噬和清除细胞碎片和/或分泌促炎因子。尽管小胶质细胞与中枢神经系统的多种生理和病理过程有关，但其功能的直接证据仍然难以捉摸。缺乏专门干扰体内小胶质细胞功能的工具阻碍了描述小胶质细胞作用的努力。我最近培育了带有靶向基因插入的小鼠，允许在表达 CX3CR1 的小胶质细胞中表达他莫昔芬诱导型 Cre 重组酶。该转基因小鼠系为小胶质细胞的体内操作（包括删除）提供了分子手柄。通过专门消融活体小鼠的小胶质细胞，我将阐明小胶质细胞在动物行为和学习依赖性突触可塑性中的作用。由于激活的小胶质细胞几乎与大脑的所有病理状况有关，因此拟议的研究旨在确定小胶质细胞的功能小胶质细胞将为理解和治疗许多神经系统疾病提供重要的见解。公共健康相关性：使用我开发的 CX3CR1-CreER 小鼠，我将研究小胶质细胞在突触结构可塑性以及学习和记忆中的作用。这里提出的实验将使我能够揭示小胶质细胞在突触维护和重塑中的重要功能。由于激活的小胶质细胞几乎涉及大脑的所有病理状况，包括神经精神和神经发育障碍，因此拟议的研究将为理解和治疗许多神经系统疾病提供重要的见解。