Limited effects of early life manipulations on sex-specific gene expression and behavior in adulthood

Exposure to childhood adversity is associated with increased vulnerability to stress-related disorders in adulthood which has been replicated in rodent stress models, whereas environmental enrichment has been suggested to have beneficial effects. However, the exact neurobiological mechanisms underlying these environment influences on adult brain and behavior are not well understood. Therefore, we investigated the long-term effects of maternal separation (MS) or environmental enrichment (EE) in male and female CD1 mice. We found clear sex specific effects, but limited influence of environmental manipulations, on adult behavior, fecal corticosterone metabolite (FCM) levels and stress- and plasticity related gene expression in discrete brain regions. In detail, adult females displayed higher locomotor activity and FCM levels compared to males and EE resulted in attenuation in both measures, but only in females. There were no sex- or postnatal manipulation-dependent differences in anxiety-related behaviors in either sex. Gene expression analyses revealed that adult males showed higher Fkbp5 mRNA levels in hippocampus, hypothalamus and raphe nuclei, and higher hippocampal Nos1 levels. Interestingly, MS elevated Nos1 levels in hippocampus but reduced Fkbp5 expression in hypothalamus of males. Finally, we also found higher Maoa expression in the hypothalamus of adult females, however no differences were observed in the expression levels of Bdnf, Crhr1, Nr3c1 and Htr1a. Our findings further contribute to sex-dependent differences in behavior, corticosterone and gene expression and reveal that the effects of postnatal manipulations on these parameters in outbred CD1 mice are limited.