Perinatal Social Stress Impairs Maternal Behavior:the Regulatory Mechanism Of The Hypothalamic Paraventricular Nucleus Oxytocin System

Perinatal stress is a common risk factor for postpartum psychiatric disorders in humans,which can impair maternal behavior and ultimately lead to negative outcomes for offspring’s cognitive,emotional,and social functioning as well as brain development.Therefore,it is critical to investigate the psychological and neurochemical mechanisms underlying the effects of stress on maternal behavior in order to develop interventions that may alleviate psychiatric disorders such as postnatal depression.Oxytocin(OXT)plays an important role in regulating various social behaviors and stress-related disorders by being synthesized mainly in the paraventricular nucleus(PVN)and supraoptic nucleus(SON)of the hypothalamus.It has been shown to play a crucial role in initiating maternal behavior.However,studies examining how perinatal stress affects OXT-mediated regulation of maternal behavior have not yet been comprehensive enough or uniform with regards to timing or methods of exposure.The present study hypothesized that social stress at different stages of the perinatal period would have different disruptive effects on postnatal maternal behavior;the disruptive effects of social stress on maternal behavior are regulated by the OXT system within the PVN.Thus,the present study aims to investigate the distinct effects of social stress on maternal behavior during various stages of the perinatal period and elucidate its psychological mechanisms.Additionally,we will further explore the regulatory mechanisms of the OXT system within the PVN in response to these stress-induced disruptions in maternal behavior.The objective of Study 1 was to investigate the impact of socially frustrating stress during various stages of the perinatal period on maternal behavior and anxiety or depressive mood states.Female rats were subjected to socially frustrating stress either prenatally(experiment 1),postnatally(experiment 2),or throughout the perinatal period(experiment 3).Maternal behavior was assessed in the feeding cage on postpartum day3(PPD 3)following prenatal stress,while postnatal and perinatal stresses were monitored during and after delivery.All three experiments included pup preference tests,elevated cross maze tests,and forced swim tests to evaluate maternal motivation as well as anxiety and depression levels.The findings from Experiment 1 indicated that females exposed to prenatal social defeat stress exhibited poorer maternal behavior in PPD 3,characterized by shorter time spent licking pups and longer latency in retrieving the first pup.However,no significant changes were observed in pup preference among mothers who underwent prenatal stress despite exhibiting significant anxiety-like behaviors but not depression-like behaviors.In contrast,Experiment 2 showed that mothers experiencing postnatal socially frustrating stress displayed disrupted maternal behavior such as significantly decreased pup licking/nursing activity,nest building disturbance with arching back posture after direct stressful events at PPD3;a decrease in nursing/lactation activities during indirect stressful events at PPD4-8.Although there were no significant differences produced between groups for anxiety or depression-like behaviors following completion of postnatal stress on PPD9 compared with baseline measures before exposure to this type of adversity.Partial results from PPD3 validated those obtained from Experiment 1regarding how prenatal social defeat stress can disrupt maternal care during early lactation.Conversely,perinatally stressed females did not exhibit any significant differences before/after initial exposure to adverse conditions at PPD3 but instead spent less time exploring their environment in the rearing cage.In PPD7,maternal behavior was significantly disrupted among females that had completed perinatal stress,with a significant decrease seen in both licking/nursing and breastfeeding activities while assuming a bowed back posture as well as an increase in time spent away from the nest.However,unlike Experiments 1 and 2,perinatally stressed females displayed a significant increase in pup preference rate during the pup preference test.Perinatal stress did not cause depressive or anxious behavior among postnatal mothers.The aim of Study 2 was to investigate the mechanisms of the oxytocin system behind the maternal behavioral decline and anxiety state caused by antenatal social defeat stress,and to regulate the maternal behavioral decline and anxiety state caused by antenatal social defeat stress through chemical genetic activation of OXT neurons in the PVN.Specifically,Cre-dependent adeno-associated viruses were administered into the PVN of female OXT-Cre transgenic rats expressing Cre recombinase in oxytocinpositive cells.The activating virus AAV-h Syn-DIO-hm3D(Gq)-m Cherry and control virus AAV-h Syn-DIO-m Cherry were used for drug-induced atopic manipulation.The results indicated that after prenatal stress,activation of OXT neurons within the PVN improved disrupted maternal behavior such as increased time spent licking pups and nesting time during a test conducted on postpartum day 3(PPD 3).Furthermore,activation of OXT neurons led to an increase in exploration time with pups among females who underwent stress during a pup preference test on PPD4.In addition,elevated cross maze tests performed on PPD5 showed increased exploration times in open arms indicating alleviation of maternal anxiety following activation of OXT neurons within prenatally stressed females’ PVNs.However,no significant changes were observed regarding depressive-like behaviors during forced swim tests conducted on PPD6 after activating OXT neurons within prenatally stressed females’ PVN.In summary,this study revealed that chemical genetic activation targeting the oxytocinergic system within the PVN can reverse adverse effects such as disrupted maternal behavior and anxiety-like behaviors caused by prenatal social defeat stress.The aforementioned results suggest that(1)socially frustrating stress induces anxiety in mothers and disrupts maternal behavior and pup preference in postnatal rats.(2)The disruption of postnatal maternal behavior may be attributed to the impact of prenatal stress on the oxytocin system within the PVN,whereby enhancing its activity can potentially alleviate negative effects caused by prenatal stress.Thus,this study provides insight into the psychological mechanisms underlying perinatal stress-induced impairment of maternal behavior and modulation of oxytocin systems from a perspective centered on altered emotional function.These findings may provide some valuable data support for addressing postpartum anxiety and depression disorders that could be triggered by stressful events.