Stress-Induced Cholesterol Metabolic Dysregulation and Differentiation Trajectory Shift in Oligodendrocytes...

Stress-induced demyelination resulting from oligodendrocyte (OLG) dysfunction is one of the key pathological mechanisms of depression, yet its dynamic regulatory network remains unclear. This study integrates single-cell transcriptomics, lineage tracing, and functional interventions to uncover a temporally disordered OLG cholesterol metabolism in a restraint stress mouse model: After 3 days of stress, upregulation of efflux genes Abca1/Abcg1 triggers a compensatory response; however, by day 14, persistent suppression of transport genes (Apoe, Apod) and homeostatic regulatory genes (Dhcr24, Srebf2, etc.) leads to intracellular accumulation of "ineffective cholesterol", with compensatory activation of the AMPK pathway unable to restore cholesterol conversion into myelin. Pseudotime analysis further reveals that stress alters OLG differentiation trajectories, decreasing the proportion of mature OLGs and causing immature precursors to abnormally stall at the late pre-differentiation stage, resulting in myelin regeneration failure. Moreover, an immune OLG_C10 subpopulation expressing complement component C3 and P2ry12 is identified, indicating that OLGs may contribute to neuroinflammatory cascades through immune reprogramming. In summary, these findings reveal a novel mechanism from the dynamic perspective of OLGs, in which the interplay of "metabolic imbalance, differentiation blockade, and immune activation" collaboratively drives stress-induced demyelination, providing a theoretical foundation for depression treatment targeting OLG functional restoration.