AUTHOR=Kundakovic Marija , Lim Sean , Gudsnuk Kathryn , Champagne Frances A.

TITLE=Sex-Specific and Strain-Dependent Effects of Early Life Adversity on Behavioral and Epigenetic Outcomes

JOURNAL=Frontiers in Psychiatry

VOLUME=4

YEAR=2013

URL=https://www.frontiersin.org/journals/psychiatry/articles/10.3389/fpsyt.2013.00078

DOI=10.3389/fpsyt.2013.00078

ISSN=1664-0640

ABSTRACT=<p>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 (<italic>Nr3c1</italic>) and brain-derived neurotrophic factor (<italic>Bdnf</italic>) genes revealed decreased hippocampal <italic>Bdnf</italic> expression in maternally separated C57BL/6J females and increased cortical <italic>Bdnf</italic> expression in maternally separated male and female Balb/cJ offspring. Analyses of <italic>Nr3c1</italic>and <italic>Bdnf</italic> (IV and IX) CpG methylation indicated increased hippocampal <italic>Nr3c1</italic> methylation in maternally separated C57BL/6J males and increased hippocampal <italic>Bdnf</italic> 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.</p>