OSBPL6 protects against demyelination and behavioral disorder via promoting cholesterol transport in oligodendrocyte

• Demyelination is associated with behavioral disorders in chronic stress-induced depression mouse model. • Cholesterol transport disorder in oligodendrocyte contribute to the damage of myelin sheaths. • Down-regulation of OSBPL6 induced cholesterol transport disorder and demyelination in depression mouse model. • Up-regulating OSBPL6 signaling promote cholesterol transport, improved myelin sheaths, and reversed behavioral disorders. Demyelination is associated with behavioral disorder and cognitive impairment in neuropsychiatric diseases, including major depressive disorder (MDD). However, the mechanism underlying myelin damage remains unclear, despite stress maybe a major risk factor. Here, we demonstrate that hippocampal neurons in the chronic stress-induced depressive mice are prone to demyelination due to disrupted cholesterol transport to myelin sheaths in oligodendrocyte. Single-nucleus RNA sequencing of lipid metabolism-related signaling pathway revealed significant reduced levels of oxysterol binding protein-like 6 (OSBPL6) in hippocampal oligodendrocytes of depression mouse model. Consistently, specific knockdown of OSBPL6 in oligodendrocytes induced loss of myelin structure, while upregulating OSBPL6 or enhancing OSBPL6 transcription improved these impairments in depressive mice. Furthermore, restoring cholesterol transport with β-cyclodextrin decreased cholesterol accumulation, improved damaged myelin structure, and rescued depression-related behaviors in depressive mice. These findings suggest that OSBPL6-mediated cholesterol homeostasis in oligodendrocytes can promote myelin production against chronic stress-induced cerebral demyelination and depression with behavioral disorders.