Early Life Mild Adversity Affects in a Sexually Dimorphic Way the Oxytocinergic System Reducing Close Social...

The oxytocinergic system is highly responsive to early-life experiences, playing a crucial role in regulating social behaviors. In this study, we examined the effects of a neonatal experience modeling maternal neglect on the oxytocinergic system in the adult rat brain. To investigate this, rat pups were exposed to a T-maze during Postnatal Days 10-13, where prohibition of contact with the mother-which served as the expected reward-constituted a mildly aversive experience (Denial of Expected Reward, DER). Our findings revealed that adult males subjected to the DER experience exhibited reduced levels of close social interaction, which could be ameliorated by acute intranasal oxytocin administration. Moreover, adult DER males had decreased expression of oxytocin receptors (OTR) in the medial nucleus of the amygdala (MeA) accompanied by alterations in the methylation profile of the OTR gene proximal promoter in MeA, specifically increased methylation levels of cytosines at positions -65, -19 and -11. No such effects were detected in the hippocampus or the medial-orbital prefrontal cortex (MO PFC). Notably, in adult females the DER experience did not affect OTR expression in the brain areas examined (MeA, hippocampus and MO PFC) or their social interaction. These results suggest that the aversive early-life experience of DER has affected the epigenetic regulation of OTR expression in a sexually dimorphic, brain region-specific manner, leading to a reduction in oxytocinergic activity within the adult male amygdala, accompanied by impaired social interactions.