Summary: To sustain neural signaling and enable plasticity throughout life, the nervous system relies on homeostatic interactions with a diverse population of glial cells, which create and modify the extracellular matrix, remove ions and neurotransmitters, provide metabolic support and promote functional reorganization of circuits in response to changing patterns of activity. Although most studies of glial cells have focused on the three main classes of glia – astrocytes, oligodendrocytes and microglia – the mammalian brain also contains an abundant, highly dynamic population of glial progenitors termed oligodendrocyte precursor cells (OPCs or NG2 glia). These lineage restricted progenitors play crucial roles in generating oligodendrocytes to enable production of new myelin sheaths during motor learning and replacement of myelin destroyed through disease, such as multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS). OPCs remain widely distributed in gray and white matter throughout life, but exhibit profound changes in behavior with aging, including reduced proliferation and differentiation. Emerging evidence suggests that OPCs do more than serve as progenitors for oligodendrocytes, as they are found in regions where there is no myelin, and like microglia, OPCs migrate to sites of injury and contribute to scar formation, features unrelated to their role in oligodendrogenesis and myelin repair. OPCs share many other features with microglia – they are present at a similar density, maintain a grid-like distribution, possess ramified, radially-oriented processes and are highly dynamic, continuously exploring their surrounding environment with motile filopodia. Moreover, recent evidence indicates that OPCs can transform into inflammatory OPCs (iOPCs) that engulf and present exogenous antigens through MHC class I and II when exposed to inflammatory cytokines, suggesting that they may modulate tissue inflammation. While microglia and astrocytes are known to undergo phenotypic changes in response to inflammation that profoundly influence the aging brain, much less is known about the role of OPCs in this context, despite their persistence in brain circuits. In part, this lack of knowledge stems from the limited molecular and physiological interrogation of OPCs that has been completed in vivo. OPCs are underrepresented in available single cell RNA-seq datasets and there have been no studies specifically designed to define how changes in their properties with aging are influenced by their prior behavior. We will leverage a diverse array of methodologies and our combined expertise in physiology, molecular and computational biology to define the causes and consequences of age-dependent changes in these ubiquitous glial cells. The new insight provided by these studies may lead to a deeper understanding of the homeostatic roles performed by these glial cells, and reveal new approaches for rejuvenating their regenerative potential to sustain brain fun...