Early life stress impairs postnatal oligodendrogenesis and adult behavior through activity-dependent mechanisms

Exposure to stress during early life (infancy/childhood) has long-term effects on the structure and function of the prefrontal cortex (PFC) and increases the risk for depression and anxiety disorders. However, little is known about the molecular and cellular mechanisms of these effects. Here we focused on changes in a mouse model of early stress induced by chronic maternal separation (MS). Unbiased mRNA expression profiles in the medial PFC (mPFC) of MS pups (P15) identified an increased expression of myelin-related genes and a decreased expression of immediate early genes. We further analyzed oligodendrocyte lineage markers and performed birthdating experiments to show a precocious oligodendrocyte differentiation in the mPFC of MS pups that led to a depletion of the oligodendrocyte progenitor pool in adults. Pharmacogenetic inhibition of neuronal activity in the developing mPFC of control animals induced a similar premature differentiation of the oligodendrocyte lineage, while the transient increase of mPFC activity in MS pups prevented this change. Moreover, the developmental diminution of mPFC activity mimicked the emotional and cognitive phenotypes observed in MS, while activating the mPFC during MS prevented the emergence of depression and cognitive disorders in adulthood. Altogether, our results identify an activity-dependent maturation process in the developing mPFC that is influenced by early life stress and has critical functions on postnatal oligodendrogenesis as well as adult emotional and cognitive behaviors.