Abstract: Adverse life experience induces permanent phenotypic changes in cognitive functions associated with the prefrontal cortex (PFC). However, the underlying mechanisms remain unclear. In this work, we use neonatal maternal separation (NMS) and chronic social defeat (CSD) rat models to address how adverse life experience affects PFC-dependent cognitive functions. Our results show that normal myelination of the medial PFC (mPFC) is necessary for mPFC-dependent behaviors, as experimental blockade of oligodendrocyte differentiation or lysolecithin-induced demyelination impairs mPFC-dependent behaviors. NMS or CSD produces severe deficits in mPFC myelination, while other brain regions, such as the hippocampusa and basal ganglia, remain intact. In parallel, rats with NMS or CSD exhibit anxiety-like behaviors and demonstrate poor performance on mPFC-dependent tasks. Further experiments demonstrate that, histone deacetylases 1/2 (HDAC1/2) are reduced in the mPFC of NMS and CSD rats. Inhibition of HDAC1/2 promotes activation of Wnt signalling, which negatively regulates oligodendrocyte development. Conversely, selective inhibition of Wnt signaling rescues the myelination arrestment and behavioral deficiency induced by NMS or CSD. These findings indicate that NMS or CSD impairs mPFC cognitive functions via regulation of oligodendrogenesis and myelination.

Key words: Adverse life experience, Myelination, Cognitive functions, Prefrontal Cortex, Rat