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

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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.