The role of oligodendrocyte precursor cells in circuit remodeling in the mature brain

少突胶质细胞前体细胞在成熟脑回路重塑中的作用

基本信息

批准号：
10750508
负责人：
Anya Kim
金额：
$ 5.27万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10750508
关键词：
Ablation Address Adopted Adult Affect Aging Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Antigen Presentation Area Atrophic Automobile Driving Axon Behavior Brain Brain Diseases CSPG4 gene Cell Separation Cells Central Nervous System Central Nervous System Diseases Cicatrix Complex Coupled Deposition Development Disease Disease Progression Elderly Environment Exercise Exhibits Extracellular Matrix Gene Expression Profile Genetic Transcription Goals Hippocampus Image Impairment Individual Inflammation Injury Knowledge Label Learning Life Maintenance Major Histocompatibility Complex Membrane Memory Memory Loss Metabolic Microglia Molecular Analysis Molecular Profiling Morphology Motivation Mus Nerve Degeneration Neurodegenerative Disorders Neuroglia Neuronal Plasticity Neurons Newborn Infant Oligodendroglia Pathogenesis Pathologic Persons Phenotype Play Population Process Production Regulation Reporter Role Shapes Site Stratum Lucidum Stream Synapses Testing Viral Visualization aged aging population cell type density dentate gyrus experience fluorophore genetic manipulation granule cell hippocampal atrophy human old age (65+)in vivo in vivo imaging insight mouse model neural circuit neurogenesis neuron component neuron loss neuronal circuitry neuronal survival newborn neuron novel olfactory bulb oligodendrocyte precursor precursor cell repaired restoration single-cell RNA sequencing stem cells synaptic pruning

项目摘要

Alzheimer’s disease (AD) is a debilitating neurodegenerative condition affecting approximately 6.7 million people in the US aged 65 and older. Individuals with AD experience progressive memory loss and profound atrophy of the hippocampus, the seat of learning and memory in the central nervous system (CNS). Currently there is no cure for AD, and the percentage of affected US citizens is predicted to grow given our steadily aging population. Although neuronal death is prominent in AD, non-neuronal glial cells have been shown to be key players in AD pathogenesis, as they influence the microenvironment, provide metabolic support, and control inflammation. Nevertheless, the precise roles of different glial cell types in hippocampal aging and AD disease progression remain to be defined. Recent evidence indicates that a ubiquitous population of glial progenitor cells, termed oligodendrocyte precursor cells (OPCs) or NG2+ glia, control the extracellular matrix, engulf neuronal processes and present antigen through major histocompatibility complex I and II, and exhibit reactive behavior in disease, suggesting that they may modify the integration and survival of neurons in the brain. Although OPCs give rise to oligodendrocytes in the developing and adult CNS, they persist throughout life and may play important non-progenitor roles. Importantly, transcriptional analysis of OPCs indicate that they take on a unique molecular signature in AD; however, we have only a limited understanding of the impact of OPCs on neural circuit remodeling. An understanding of the mechanisms governing their role in promoting the integration and survival of neurons could reveal their unique role in neurodegeneration. To study the role of OPCs in circuit remodeling in the healthy and diseased brain, I plan to define the role of OPCs in two regions of neuronal integration that persist into adulthood: the stratum lucidum (SL) of the hippocampus (a key site of AD pathogenesis) and the olfactory bulb (OB). My preliminary analyses reveal that OPCs are denser and exhibit a unique morphology and transcriptional profile within the SL, where newly born dentate gyrus granule cells project their axons to area CA3, and within the OB, where neurons arriving from the rostral migratory stream integrate. These findings provide the motivation to explore the distinct features of OPCs in these regions and their involvement in circuit reorganization. I will test the central hypothesis that OPCs facilitate the integration of newly born neurons in the adult CNS and alter neuronal survival in AD. I will define the phenotype of OPCs in areas of active neuronal remodeling through in vivo imaging and scRNA-Seq; I will quantify the role of OPCs in circuit remodeling across aging, exercise, and neurodegeneration (specifically an AD mouse model); and I will genetically manipulate OPCs and determine the effect these manipulations have on neuronal integration. Through these studies, I hope to define the role of OPC-neuron interactions in structural remodeling of neurons in the mature CNS. Understanding the role of OPCs in the development and maintenance of neuronal connectivity could have important implications for brain development, repair, and survival of hippocampal neurons in AD.

阿尔茨海默氏病（AD）是一种令人衰弱的神经退行性疾病，影响了65岁及65岁以上的美国约670万人。患有广告的人会经历渐进的记忆力丧失和海马的深刻萎缩，这是中枢神经系统（CNS）中学习和记忆的所在地。目前尚无广告的治愈方法，鉴于我们人口稳定老龄化，受影响的美国公民的百分比将增长。尽管神经元死亡在AD中很突出，但非神经胶质神经胶质细胞已被证明是AD发病机理的关键参与者，因为它们会影响微环境，提供代谢支持和控制注射。然而，不同神经胶质细胞类型在海马衰老和AD疾病进展中的确切作用仍有待定义。最近的证据表明，称为少突胶质细胞前体细胞（OPC）或NG2+胶质的无处不在的藻类祖细胞群体控制细胞外基质，吞噬神经元过程，并通过主要的组织复杂性I和II，并在疾病中脱颖而出，并在脑子内进行了反应性，并在脑子内进行了反应性，并在脑子内进行了反应性，并在脑子内进行了抗原，并在脑子内进行了反应性。尽管OPC在发展中国家和成人中枢神经系统中产生了少突胶质细胞，但它们一生都持续存在，并可能扮演重要的非企业家角色。重要的是，对OPC的转录分析表明它们在AD中采用了独特的分子签名。但是，我们对OPC对神经循环重塑的影响只有有限的理解。了解其在促进神经元的整合和生存中作用的机制可以揭示其在神经变性中的独特作用。为了研究OPC在健康和解散大脑中电路重塑中的作用，我计划定义OPC在两个持续到成年的神经整合区域中的作用：海马的露西多姆（SL）（SL）（AD AD病原体的关键部位）和橄榄球灯泡（OB）（OB）。我的初步分析表明，OPC在SL内表现出独特的形态和转录曲线，在该SL中，新生出生的齿状回颗粒颗粒细胞将其轴突投射到CA3区域，并在OB中，在OB中，神经元从Rostral迁移流到达的神经元集成了整合。这些发现提供了探索这些区域中OPC的不同特征及其参与电路重组的动力。我将测试中心假设，即OPC支持新生的神经元在成年中枢神经系统中的整合并改变AD中的神经元存活。我将通过体内成像和SCRNA-Seq进行活性神经元重塑的区域定义OPC的表型；我将量化OPC在跨衰老，运动和神经变性（特别是AD小鼠模型）中的电路重塑中的作用；我将一般操纵OPC，并确定这些操纵对神经元整合的影响。通过这些研究，我希望定义OPC神经元相互作用在成熟中枢神经系统中神经元结构重塑中的作用。了解OPC在神经元连通性的发展和维持中的作用可能对AD中海马神经元的脑发育，修复和存活具有重要意义。