Sex-Specific Effects of Gestational Environmental Enrichment and Postnatal Stress on Social Behavior and Lateral Septum Gene Expression in Adolescent Rats

Gestational environmental enrichment (EE) has beneficial effects on neurodevelopment, whereas postnatal stress (PS) is a key factor in epigenetic programming that can shape later behavior. Both experiences can alter the expression of genes involved in the stress response and neuronal plasticity through changes in DNA methylation and other epigenetic marks. This study evaluated whether gestational EE buffers the effects of PS (maternal separation or male intruder exposure [MI]) on social behavior and spatial memory, and on the expression of Bdnf, Nr3c1, Dnmt3a, Tet1, and Tet2 in the lateral septum and hippocampus of adolescent male and female rats. At postnatal day 45, the three-chamber test showed an EE × PS interaction on sociability, with EE attenuating the effect of MI. EE and PS also had main effects on social novelty, with MI reducing and EE increasing the social novelty index. All groups improved spatial memory across trials, with no treatment differences. In the lateral septum, PS and EE × sex affected Bdnf expression, with higher levels in EE males exposed to MI. Nr3c1 and Dnmt3a showed an EE × PS × sex interaction, whereas Tet1 and Tet2 were unaffected. No significant effects were detected in the hippocampus. These results indicate that gestational EE and early-life stress interact to shape adolescent social behavior, with sex- and region-specific effects on gene expression.