The association between stress and mental illness has been well documented, but the molecular consequences of repeated exposure to stress have not been completely identified. The present study sought to elucidate the combinatorial effects of early-life maternal separation stress and adult social defeat stress on alterations in signal transduction and gene expression that have been previously implicated in susceptibility to psychosocial stress. Molecular analyses were performed in the prelimbic/infralimbic cortex, amygdala, and nucleus accumbens, three brain regions that have been suggested to play critical roles in determining stress responses. The current data reveal that both maternal separation and social defeat significantly impact the expression of genes involved in histone methylation and the β-catenin-, endogenous opioid-, neurotrophin-, and glucocorticoid signaling pathways. Although the effects of maternal separation and social defeat were largely non-overlapping, a subset of genes in each brain region were governed by additive, opposing, or other types of interactions between these stress paradigms, thus highlighting potential molecular mechanisms through which these stressors might coordinately regulate brain function and behavior.

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