Early-life stress may have a long-term impact on brain activity


A study carried out in mice suggests that early-life stress may promote premature maturation of certain glial cells in the prefrontal cortex, a process that is associated with short- and long-term modification of local neuronal activity.

Stress in early childhood can have a major impact on adult brain function. Children affected by this are known to be more vulnerable to later risk of depression and anxiety, substance abuse, and schizophrenia. But the precise reason for this is unknown: is it epigenetic, molecular, or cellular in nature? To find out, researchers developed and then studied a mouse model of early-life stress. They wanted to observe the immediate impact of stress during development, using genomic studies and cellular analyses of the prefrontal cortex, as this area of the brain plays an important role in emotional regulation. The researchers then studied how the modifications observed affected the behavior of the animals in adulthood.

Anne Teissier,* who led the bulk of the experiments, explains: "We observed early modification of local production of myelin, a protein that is essential for proper nerve conduction. We identified that this phenomenon was due to premature maturation of the oligodendrocyte progenitor cells (OPC) responsible for its synthesis. And this disruption was associated with altered neuronal activity during development."

Cellular abnormalities associated with behavioural disorders

The second part of the research confirmed the association between abnormal cell maturation, modification of neuronal activity, and the behavioral changes observed following early-life stress. This involved the use of chemogenetics: using compounds able to locally modulate neuronal activity during development, the researchers began by inhibiting neuronal activity in the prefrontal cortex in non-stressed mice pups. This experiment resulted in accelerated maturation of OPC, similar to that observed in the first phase of the study. In adulthood, the exposed animals also presented with behavioral problems similar to those seen in the adult mice exposed to early-life stress. Other chemogenetic tools were used to temporarily increase neuronal excitability: this restricted early maturation of OPC and certain behaviors associated with depression.

"This research demonstrates accelerated maturation of myelin-producing cells, which subsequently translates into the inability of the nervous tissue to respond to stress," explains Patricia Gaspar,* who led the work. It could explain why early-life stress results in greater vulnerability to later stress. By extension, this hypothesis could be transposed to humans, but would require validation through specific experiments. If confirmed, detailed understanding of the mechanisms involved might, in the long-term, lead to proposals for how to manage these problems.

* Unit 1270 Inserm/Sorbonne Université, Mechanisms of Brain Development group, Fer à Moulin Institute, Paris

Source : Teissier A et al. Early-life stress impairs postnatal oligodendrogenesis and adult emotional behaviour through activity-dependent mechanisms. Mol Psychiatry, 2019 Aug 22. doi: 10.1038/s41380-019-0493-2