Age and axon-specific forms of cortical remyelination by divergent populations of NG2-glia

Abstract

Myelin is critical for neural circuit function and its destruction is widespread in neurodegenerative disease and aging. In these conditions, homeostatic repair mechanisms initiate oligodendrocyte replacement by resident progenitor cells called NG2-glia. To investigate the cellular dynamics of this repair we developed a novel demyelination model by combining intravital myelin imaging with a targeted single-cell ablation technique called 2Phatal. Oligodendrocyte 2Phatal activated a stereotyped degeneration cascade which triggered remyelination by local NG2-glia. Remyelination efficiency was dependent on initial myelin patterning and dynamic imaging revealed rapid repair mechanisms resulting in near-seamless transitions between myelin loss and repair. A subset of morphologically complex NG2-glia executed this remyelination, pointing towards unrecognized functional diversity within this population. Age-related demyelination mirrored the degenerative cascade observed with 2Phatal, while remyelination in aging was defective due to failed oligodendrogenesis. Thus, oligodendrocyte 2Phatal revealed cellular diversity within the oligodendrocyte lineage and uncovered novel forms of rapid remyelination.

Remyelination protects neurons from DLK-mediated neurodegeneration

“…The remyelination process begins rapidly in the optic nerves of Myrf ΔiPlp1 mice, even before all myelin destined to be lost has degenerated. This is in accordance with a recent live-imaging study demonstrating that remyelination can be near synchronous with demyelination replacing individual internodes as they are lost 71 . In the present study, we found the delay of conduction within the visual system correlates temporally with demyelination, whereas restoration is associated with remyelination in Myrf ΔiPlp1 mice.…”

Aging differentially alters the transcriptome and landscape of chromatin accessibility in the male and female mouse hippocampus

“…Produced by oligodendrocytes, myelin is important for axon integrity and action potential conductance (Nave and Werner, 2014) and has been found to be critical for memory retention (Xin and Chan, 2020). During aging, impaired myelin debris clearance and diminished OPC differentiation reduce the efficiency of remyelination (Sim et al, 2002;Franklin and Goldman, 2015;Franklin and Simons, 2022;Chapman et al, 2023). A previous study showed that enhancing OPC proliferation and myelination in the aged hippocampus increased memory retention in mice (Iram et al, 2022).…”