Enhancing Oligodendrogenesis Rescues Chronic Stress-Induced Behavioral Disorders Involving Neuronal and Synaptic...

Chronic stress induces psychiatric disorders, including depression and anxiety, yet effective therapies remain limited. Myelin in adult brains undergoes dynamic remodeling through oligodendrocyte precursor cells (OPCs) differentiation into oligodendrocytes (OLs) and the degeneration of pre-existing myelin. However, how chronic stress alters myelin dynamics and whether this represents a therapeutic target remains unclear. Here, adult mice subjected to 4-h daily restraint for 2 weeks exhibited significant anxiety, depression, and social deficits. Histological examinations revealed reduced OPC and OL density, decreased c-Fos-positive neurons, and loss of synaptic proteins in the brains exposed to chronic stress. To understand the dynamic changes of myelin, cell-lineage labeling and tracing demonstrated that chronic stress exposure remarkably inhibited oligodendrogenesis in the medial prefrontal cortex (mPFC), motor cortex, hippocampus, and amygdala, as revealed by the NG2^CreERT; Tau-mGFP line, but did not significantly change pre-existing myelin as revealed by a newly generated line for mature OLs and myelin. To explore the role of myelinogenesis changes, adult myelin formation was inhibited by Olig2 conditional knockout in OPCs, resulting in decreased neuronal synaptic proteins and activity, accompanied by anxiety and depressive-like behaviors. Conversely, enhancing myelinogenesis through conditional deletion of the M1R in OPCs of stressed mice resulted in higher number of c-Fos-positive neurons, elevated synaptic protein expression, and a partial reversal of the behavioral deficits. Importantly, treating the stressed animal with the pro-myelination drug clemastine phenocopied the effects of M1R deletion on histological and behavioral disorders. Together, our findings demonstrate that enhancing oligodendrogenesis represents a promising strategy to rescue CRS-caused behavioral disorders.