Abstract
The neonatal or infant period is a critical stage for the development of brain neuroplasticity. Early life stresses in the neonatal period, including neonatal maternal separation (NMS), have adverse effects on an increased risk of psychiatric disorders in juveniles and adults. However, the underlying molecular mechanisms are not largely understood. Here, we found that juvenile rats subjected to 4 h daily NMS during postnatal days 1 to 20 exhibited autistic-like behavioral deficits without impairments in learning and memory functions. Molecular mechanism studies showed that oxytocin receptor (OXTR) in the medial prefrontal cortex of NMS rats was evidently downregulated when compared with control pups, especially in neurons. Erk/MAPK signaling, the downstream coupling signaling of OTXR, was also inhibited in NMS juvenile rats. Treatment with oxytocin could relieve NMS-induced social deficit behaviors and activated phosphorylation of Erk/MAPK signaling. Furthermore, medication with the inhibitor of H3K4 demethylase alleviated the abnormal behaviors in NMS rats and increased the expression of OXTR in the medial prefrontal cortex, which showed an epigenetic mechanism underlying social deficits induced by NMS. Taken together, these findings identified a molecular mechanism by which disruptions of mother–infant interactions influenced later displays of typical social behaviors and suggested the potential for NMS-driven epigenetic tuning of OXTR expression.
Highlights
Life, including early childhood, neonatal, or even infant period, is a time of significant brain development and, a time when early social experiences influence the development of the central nervous system and expression of behaviors in subsequent adolescence and adulthood (Cushing and Kramer, 2005; Anda et al, 2006; Tian et al, 2018)
We found that oxytocin receptor (OXTR) in juvenile neonatal maternal separation (NMS) rats was significantly downregulated than control littermate pups, accompanied by phosphorylation inhibition of its downstream Erk/MAPK signaling in the medial prefrontal cortex, an important brain region that plays an essential role in mediating social cognition (Amodio and Frith, 2006)
Our results showed that OT treatment relieved the social deficit of NMS rats with activation of Erk/MAPK signaling, demonstrating that the OT signaling was involved in social deficit in NMS rats
Summary
Life, including early childhood, neonatal, or even infant period, is a time of significant brain development and, a time when early social experiences influence the development of the central nervous system and expression of behaviors in subsequent adolescence and adulthood (Cushing and Kramer, 2005; Anda et al, 2006; Tian et al, 2018). Our behavioral results indicated that maternally separated rats during adolescence showed impaired social novelty preference for strange rats and increased preference for marbleburying behavior. These impairments were typical performances of autistic-like behavioral deficits that were characterized by the core symptoms of impaired social recognition, language communication failure, and stereotyped behaviors (Ferguson et al, 2001). Life adversity events exert long-lasting influences on the brain via epigenetic regulatory mechanisms, making an individual susceptible to later psychiatric disorders (Unternaehrer et al, 2015; Seo et al, 2016). Life experiences could cause epigenetic variability of OXTR in the brain implicated in social behavior (Kraaijenvanger et al, 2019; Tops et al, 2019)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
