Maternal separation is associated with strain‐specific responses to stress and epigenetic alterations to <i>Nr3c1</i>,<i> Avp</i>, and <i>Nr4a1</i> in mouse

<jats:title>Abstract</jats:title><jats:p>Stressful events early in life have been widely linked to behavioral phenotypes and have been implicated in the development of psychiatric disorders. Using a maternal separation paradigm, we investigated phenotypic and epigenetic changes following early life stress in two inbred strains of mice, <jats:styled-content style="fixed-case">C</jats:styled-content>57<jats:styled-content style="fixed-case">BL</jats:styled-content>/6<jats:styled-content style="fixed-case">J</jats:styled-content> and <jats:styled-content style="fixed-case">DBA</jats:styled-content>/2<jats:styled-content style="fixed-case">J</jats:styled-content>. We found an increase in the corticosterone response to stress in male, <jats:styled-content style="fixed-case">C</jats:styled-content>57<jats:styled-content style="fixed-case">BL</jats:styled-content>/6<jats:styled-content style="fixed-case">J</jats:styled-content> mice that had undergone maternal separation compared to controls. In addition, early life stress induced a number of mild but significant behavioral changes, many of which were sex and strain dependent. Following maternal separation anxiety was decreased in males but increased in <jats:styled-content style="fixed-case">DBA</jats:styled-content>/2<jats:styled-content style="fixed-case">J</jats:styled-content> females, <jats:styled-content style="fixed-case">DBA</jats:styled-content>/2<jats:styled-content style="fixed-case">J</jats:styled-content> males displayed reduced exploration of a novel object, and baseline activity was altered in males of both strains. Finally, we examined <jats:styled-content style="fixed-case">DNA</jats:styled-content> methylation levels in the hippocampus across promoter regions of <jats:italic>Nr3c1, Avp</jats:italic>, and <jats:italic>Nr4a1</jats:italic>, and found altered levels at several CpG sites in maternally separated male mice compared to controls. This study contributes to a growing body of recent literature suggesting that epigenetic changes may mediate the impact of early life stress on behavior. In particular, we establish that the phenotypic and epigenetic responses to an adverse environment differ as a function of genetic background.</jats:p>