Tract-specific regulation of oligodendrocyte precursor cell activation and extracellular matrix remodeling shapes myelin repair

Oligodendrocytes produce myelin, a multilamellar membrane that ensheathes axons and enables rapid, saltatory conduction. Disruption of myelin integrity is a hallmark of several neurological disorders, including multiple sclerosis, yet therapies aimed at promoting remyelination have shown limited efficacy in clinical trials. A key challenge is that demyelination and repair processes are not uniform across the central nervous system, with different white matter tracts exhibiting distinct vulnerabilities and regenerative capacities. However, the extent to which regional microenvironmental factors and cellular dynamics shape these differences remains incompletely understood. Here, we used focal lysophosphatidylcholine (LPC)-induced demyelination to compare the spatial and temporal progression of myelin loss and repair in two anatomically and functionally distinct white matter tracts: the hippocampal fimbria and lateral olfactory tract (LOT). Stereotaxic LPC injections were performed in mice, with contralateral saline-injected tracts serving as within-subject controls. Animals were euthanized at multiple times (3, 7, 14, 21 and 28 days post-injection, dpi). Histological and immunohistochemical approaches were employed to quantify lesion evolution, oligodendrocyte lineage dynamics, myelin integrity, glial activation, extracellular matrix remodeling, apoptosis, and neuronal density. We showed that while both tracts eventually showed complete lesion resolution by 28 dpi, the course of demyelination and repair is highly region dependent. The fimbria displays larger lesion diameter and a more rapid recruitment of oligodendrocyte precursor cells, whereas the LOT exhibits an earlier loss of myelin basic protein expression. Despite these differences, both regions follow a coordinated but temporally altered sequence of microglial activation, OPC migration, astroglial response, and extracellular matrix remodeling. Notably, microglial response is consistently lower in the LOT, and the fimbria shows a more prominent expression of the chondroitin sulfate proteoglycan, versican. Apoptosis is transient and neuronal density is preserved in both regions, suggesting that minimal neurodegeneration accompanies LPC-induced demyelination. Together, these findings demonstrate that LPC-induced demyelination elicits a spatially heterogeneous repair progression shaped by local microenvironmental context. This study highlights regional anatomical variations as contributors to remyelination dynamics and underscores the need for region-tailored approaches to enhance myelin repair.