Dynamic regulation of murine cortical transcriptome by early-life stress: Impairment of myelination and cognitive functions. Mus musculus strain:C57Bl/6

Stressful events in early postnatal period have critical consequences for the individuals life and can increase later risk for the development of psychiatric disorders. The maturation of brain structures continues in the postnatal period in both humans and animals. Early-life stress negatively affects the formation of the brain regions taking part in the implementation of emotion, memory and cognition. The aim of our study was the investigation of the transcriptome profile in the prefrontal cortex both immediately after prolonged maternal separation and through a long period of comfortable life. Comparison of immediate and delayed effects on transcription should contribute significantly to our knowledge of a link between early life exposures and neurobiological and behavioral outcomes in adulthood. Given the fact that the prefrontal cortex is responsible for complex cognitive functions, regulation of emotion, and adaptation to stress, we expected to reveal some alterations in gene expression in this brain region reflecting the long-lasting consequences of stress early in life.We used two types of early life stress: prolonged repeated separation of pups from their mothers for 3h per day during the first 2 weeks of life (maternal separation, MS), or 24h single maternal separation on 9th day of life (maternal deprivation, MD). We analyzed the effects of stress on transcriptome of the prefrontal cortex of 15-days pups (at 24h after the last stress exposure) and 3 months old adult mice. To validate the RNA-seq results, the expression of selected up- or down-regulated genes were confirmed by real-time PCR.We revealed the weak effect of stress on the expression patterns of genes in 15-days pups: only 6 genes were differentially expressed in MS group to compare with controls. Stress early in life resulted in changes in expression of genes whose proteins connected with myelin sheath development (Mag, Mobp, Mog, Mal, Plp1 and Ugt8a, all down-regulated). Despite weak changes in pups, transcriptome analysis of the prefrontal cortex in adult mice showed a number of differentially expressed genes in MS and MD groups compared to controls (648 genes in MS group and 192 genes in MD group). In MS group the changes mainly occur in systems associated with the development of the myelin sheath, regulation of trans-synaptic signaling and regulation of membrane potential. All the genes that were changed in prefrontal cortex of 15-days pups also remained altered in adults, but in the opposite direction. Genes, which were differentially expressed in MD group to compare with controls, relate to different systems, without significant overrepresentation of any one.The obtained results suggest the existence of delayed long-term expression changes in the prefrontal cortex triggered by early postnatal stress. We can suggest that disturbances in myelination can underlie enhanced susceptibility to mental illness.