Objective: To investigate histological and genetic changes in TNF-α, IL-10, and Sox2 expression following spinal cord injury in zebrafish, and to determine their roles in oligodendrocyte activation and subsequent spinal cord regeneration. Methods: Adult zebrafish (Danio rerio) underwent complete spinal cord transection at the level of the fifth vertebra. Spinal cord tissues were harvested at multiple post-injury time points (1, 3, 7, 14, and 28 days post-injury, dpi). Histological evaluation included H&E staining, Luxol fast blue for myelin, and immunofluorescence for oligodendrocyte markers (Olig2, APC/CC1). Gene expression of TNF-α, IL-10, and Sox2 was quantified by qRT-PCR. Oligodendrocyte lineage dynamics and Sox2 co-localization were assessed by confocal microscopy. Functional recovery was evaluated using swim behavior assays. Pharmacological modulation (TNF-α neutralization, IL-10 inhibition, or Sox2 knockdown via morpholinos) was performed in separate cohorts. Results: Histological analysis revealed progressive tissue bridging and remyelination beginning at 7 dpi, with near-complete structural restoration by 28 dpi. TNF-α expression peaked rapidly at 1–3 dpi (12-fold increase, p<0.001), coinciding with acute inflammatory infiltrates and early oligodendrocyte progenitor proliferation. IL-10 expression rose later (7–14 dpi, 8-fold increase, p<0.01), correlating with the transition to regenerative inflammation and oligodendrocyte maturation. Sox2 expression showed a biphasic pattern: an early increase (3 dpi) in ependymal cells, followed by a second peak (14 dpi) in Olig2+ oligodendrocyte lineage cells. Immunofluorescence confirmed Sox2 nuclear localization in proliferating oligodendrocyte precursors at the lesion bridge. TNF-α neutralization delayed oligodendrocyte activation and reduced Sox2 expression in glial cells (p<0.05), while IL-10 inhibition prolonged inflammation and impaired remyelination. Sox2 knockdown significantly reduced oligodendrocyte precursor proliferation and migration, leading to persistent demyelination and poor functional recovery (swim deficits through 28 dpi). Conclusion: Spinal cord injury in zebrafish induces distinct temporal genetic signatures: an early pro-inflammatory TNF-α peak that primes oligodendrocyte activation, followed by an IL-10-dependent anti-inflammatory phase supporting remyelination. Sox2 acts downstream of these inflammatory cues as an essential regulator of oligodendrocyte precursor plasticity. These findings establish zebrafish as a powerful model for dissecting immune–glial interactions and identify TNF-α/IL-10/Sox2 axis as a potential therapeutic target for promoting remyelination and regeneration after mammalian spinal cord injur
