Involvement of Oxytocin Receptor/Erk/MAPK Signaling in the mPFC in Early Life Stress-Induced Autistic-Like Behaviors

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.

Protein expression profiling of rat uteruses with primary dysmenorrhea syndrome

“…It is demonstrated that oxytocin signaling and the in ammatory response play critical roles in the occurrence of PD [22][23][24]. MAP kinases, including p38MAP kinase, c-Jun N-terminal kinase (JNK/SAPK), and extracellular signal-related kinase (ERK) were shown to mediate oxytocin signaling and regulate the production of in ammatory cytokines [25][26][27][28]. In the present study, the phosphorylation levels of p38, ERK, and JNK, were all signi cantly up-regulated in the uterus of PD rats, while the total expression of these MAP kinases remained unchanged.…”

The oxytocin system and early‐life experience‐dependent plastic changes

“…79,80 Reduction of oxytocin content has also been reported in the amygdala of adult male rats. 81 Maternal separation for a longer duration (e.g., 3 h day -1 ) has also been reported to induce a long-lasting decrease in oxytocin mRNA or oxytocin content in the hypothalamus and/or in other brain regions in mice, 82,83 rats 84,85 and Degus 86 (but see also Tsuda et al 87 ). Maternal separation has also been shown to reduce oxytocin receptor binding in the lateral septum and the caudate putamen, whereas maternal separation increases oxytocin receptor binding in the ventromedial hypothalamus in rats in adulthood.…”

Effects of early intermittent maternal separation on cognitive development of the prefrontal cortex in piglets

“…Studies in mice have shown that the early life stress from NMS caused some impairment in brain development, which exhibit fear and anxiety-like behaviors in behavioral tests, and had a signi cant impact on cognitive abilities (Wei et al, 2020). Siegford et al(2008) demonstrated that piglets weaned on PND12 while MS for a long period time were limited in their ability to reach the hidden-platform task (spatial task) in the Morris water maze, suggesting that the piglets' cognitive abilities were limited.…”