Abstract
Early life adversity can have a significant long-term impact with implications for the emergence of psychopathology. Disruption to mother-infant interactions is a form of early life adversity that may, in particular, have profound programing effects on the developing brain. However, despite converging evidence from human and animal studies, the precise mechanistic pathways underlying adversity-associated neurobehavioral changes have yet to be elucidated. One approach to the study of mechanism is exploration of epigenetic changes associated with early life experience. In the current study, we examined the effects of postnatal maternal separation (MS) in mice and assessed the behavioral, brain gene expression, and epigenetic effects of this manipulation in offspring. Importantly, we included two different mouse strains (C57BL/6J and Balb/cJ) and both male and female offspring to determine strain- and/or sex-associated differential response to MS. We found both strain-specific and sex-dependent effects of MS in early adolescent offspring on measures of open-field exploration, sucrose preference, and social behavior. Analyses of cortical and hippocampal mRNA levels of the glucocorticoid receptor (Nr3c1) and brain-derived neurotrophic factor (Bdnf) genes revealed decreased hippocampal Bdnf expression in maternally separated C57BL/6J females and increased cortical Bdnf expression in maternally separated male and female Balb/cJ offspring. Analyses of Nr3c1and Bdnf (IV and IX) CpG methylation indicated increased hippocampal Nr3c1 methylation in maternally separated C57BL/6J males and increased hippocampal Bdnf IX methylation in male and female maternally separated Balb/c mice. Overall, though effect sizes were modest, these findings suggest a complex interaction between early life adversity, genetic background, and sex in the determination of neurobehavioral and epigenetic outcomes that may account for differential vulnerability to later-life disorder.
Highlights
The experience of adversity in the early stages of development can have a profound impact on psychological and physical health
The maternal separation (MS) protocol, involving prolonged, daily separation between dams and litters from postnatal days (PND) 1–14, was implemented in B6 and Balb/c mice and compared to a control rearing condition
In Balb/c mice, we found a significant sex-specific rearing condition effect on this measure, with MSreared females exhibiting shorter latencies to enter the inner area compared to control-reared females [χ2(1, 19) = 8.13, p < 0.01; maternal separation PND 1-14 behavioral phenotyping brain mRNA & DNA methylation analyses
Summary
The experience of adversity in the early stages of development can have a profound impact on psychological and physical health In humans, this phenomenon is illustrated in studies of prenatal exposure to stress and nutritional deprivation [1,2,3,4] as well as studies of postnatal neglect and abuse [5,6,7]. Maternal exposure to famine during pregnancy has been found to predict increased risk of schizophrenia and antisocial personality disorder [8, 9] and a history of childhood neglect is associated with an increased risk of depressive disorders, drug abuse, and suicidality [6, 10] These adverse experiences may not be deterministic in predicting later-life disorder, but instead generate a vulnerability to later-life stress or trauma. Understanding the factors that promote both risk and resilience to the effects of early life adversity is essential to further exploration of psychiatric dysfunction
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