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:
  • 金额:
    $ 5.27万
  • 依托单位:
  • 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

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.
阿尔茨海默病(AD)是一种使人衰弱的神经退行性疾病,影响美国约670万65岁及以上的人。患有AD的个体经历进行性记忆丧失和海马体的深度萎缩,海马体是中枢神经系统(CNS)中的学习和记忆的所在地。目前还没有治愈AD的方法,鉴于我们人口的稳步老龄化,预计受影响的美国公民的比例将增加。虽然神经元死亡在AD中是突出的,但非神经元胶质细胞已被证明是AD发病机制中的关键参与者,因为它们影响微环境,提供代谢支持并控制炎症。然而,不同类型的胶质细胞在海马衰老和AD疾病进展中的确切作用仍有待确定。最近的证据表明,一个无处不在的群体的胶质祖细胞,称为少突胶质细胞前体细胞(OPCs)或NG 2+胶质细胞,控制细胞外基质,吞噬神经元的过程,并通过主要组织相容性复合物I和II的抗原,并表现出反应性行为的疾病,这表明他们可能会修改的整合和生存的神经元在大脑中。虽然OPCs在发育和成年CNS中产生少突胶质细胞,但它们在整个生命过程中持续存在,并可能发挥重要的非祖细胞作用。重要的是,OPCs的转录分析表明它们在AD中具有独特的分子特征;然而,我们对OPCs对神经回路重塑的影响只有有限的了解。了解它们在促进神经元整合和存活中的作用机制,可以揭示它们在神经退行性变中的独特作用。为了研究OPCs在健康和患病大脑回路重塑中的作用,我计划定义OPCs在两个持续到成年期的神经元整合区域中的作用:海马(AD发病机制的关键部位)的透明层(SL)和嗅球(OB)。我的初步分析表明,OPC是密集的,并表现出独特的形态和转录轮廓内的SL,新生的齿状回颗粒细胞投射其轴突到CA 3区,并在OB内,神经元从喙迁移流到达整合。这些发现提供了动机,以探讨这些地区的OPCs的独特功能,并参与电路重组。我将测试的核心假设,即OPCs促进新生神经元在成人中枢神经系统的整合,并改变AD神经元的存活。我将通过体内成像和scRNA-Seq定义OPCs在活跃神经元重塑领域的表型;我将量化OPCs在衰老,运动和神经退行性变(特别是AD小鼠模型)回路重塑中的作用;我将遗传操纵OPCs并确定这些操纵对神经元整合的影响。通过这些研究,我希望确定OPC-神经元相互作用在成熟CNS神经元结构重塑中的作用。了解OPCs在神经元连接的发育和维持中的作用可能对AD患者海马神经元的发育、修复和存活具有重要意义。

项目成果

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