Abstract
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 adult depression and anxiety disorders. However, little is known about the molecular and cellular mechanisms of these effects. Here, we focused on changes induced by chronic maternal separation during the first 2 weeks of postnatal life. Unbiased mRNA expression profiling in the medial PFC (mPFC) of maternally separated (MS) pups identified an increased expression of myelin-related genes and a decreased expression of immediate early genes. Oligodendrocyte lineage markers and birthdating experiments indicated a precocious oligodendrocyte differentiation in the mPFC at P15, leading to a depletion of the oligodendrocyte progenitor pool in MS adults. We tested the role of neuronal activity in oligodendrogenesis, using designed receptors exclusively activated by designed drugs (DREADDs) techniques. hM4Di or hM3Dq constructs were transfected into mPFC neurons using fast-acting AAV8 viruses. Reduction of mPFC neuron excitability during the first 2 postnatal weeks caused a premature differentiation of oligodendrocytes similar to the MS pups, while chemogenetic activation normalised it in the MS animals. Bidirectional manipulation of neuron excitability in the mPFC during the P2–P14 period had long lasting effects on adult emotional behaviours and on temporal object recognition: hM4Di mimicked MS effects, while hM3Dq prevented the pro-depressive effects and short-term memory impairment of MS. Thus, our results identify neuronal activity as a critical target of early-life stress and demonstrate its function in controlling both postnatal oligodendrogenesis and adult mPFC-related behaviours.
Highlights
The environment a child encounters during early life plays a critical role in normal brain development
As a preclinical model of early-life stress (ELS), we used the common model of chronic maternal separation, where pups are daily separated for 3 h from their dam starting at postnatal day 2 (P2) and until P14 (Fig. 1a) [11, 15]
To identify early molecular candidates potentially involved in the permanent alterations induced by ELS, we focused on the chronic effects of maternal separation by analysing P15 brains, sampled 24 h after the last maternal separation (MS), compared with standard facility raised (SFR) pups
Summary
The environment a child encounters during early life plays a critical role in normal brain development. Maternal separation (MS) during the first postnatal weeks induces a permanent impairment of emotional and cognitive behaviours, together with an altered physiology and myelination of the mPFC [12,13,14,15]. These behavioural and structural defects closely reproduce the phenotypes of humans exposed to childhood trauma [10, 16]. We demonstrate that some of the behavioural symptoms induced by ELS in adulthood are modulated by changes in mPFC neuronal activity during development
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