Oxytocin Gene Research Articles

Acute, chronic and conditioned effects of intranasal oxytocin in the mu-opioid receptor knockout mouse model of autism: Social context matters

Autism Spectrum Disorders (ASD) are neurodevelopmental disorders whose diagnosis relies on deficient social interaction and communication together with repetitive behaviours. Multiple studies have highlighted the potential of oxytocin (OT) to ameliorate behavioural abnormalities in animal models and subjects with ASD. Clinical trials, however, yielded disappointing results. Our study aimed at assessing the behavioural effects of different regimens of OT administration in the Oprm1 null mouse model of ASD. We assessed the effects of intranasal OT injected once at different doses (0.15, 0.3, and 0.6 IU) and time points (5, 15, and 30 min) following administration, or chronically, on ASD-related behaviours (social interaction and preference, stereotypies, anxiety, nociception) in Oprm1+/+and Oprm1-/- mice. We then tested whether pairing intranasal OT injection with social experience would influence its outcome on ASD-like symptoms, and measured gene expression in the reward/social circuit. Acute intranasal OT at 0.3 IU improved social behaviour in Oprm1-/- mice 5 min after administration, with limited effects on non-social behaviours. Chronic (8–17 days) OT maintained rescuing effects in Oprm1 null mice but was deleterious in wild-type mice. Finally, improvements in the social behaviour of Oprm1-/- mice were greater and longer lasting when OT was administered in a social context. Under these conditions, the expression of OT and vasopressin receptor genes, as well as marker genes of striatal projection neurons, was suppressed. We detected no sex difference in OT effects. Our results highlight the importance of considering dosage and social context when evaluating the effects of OT treatment in ASD.

From molecular variations to behavioral adaptations: Unveiling adaptive epistasis in primate oxytocin system.

Our primary objective was to investigate the variability of oxytocin (OT) and the GAMEN binding motif within the LNPEP oxytocinase in primates. We sequenced the LNPEP segment encompassing the GAMEN motif in 34 Platyrrhini species, with 21 of them also sequenced for the OT gene. Our dataset was supplemented with primate sequences of LNPEP, OT, and the oxytocin receptor (OTR) sourced from public databases. Evolutionary analysis and coevolution predictions were made followed by the macroevolution analysis of relevant amino acids associated with phenotypic traits, such as mating systems, parental care, and litter size. To account for phylogenetic structure, we utilized two distinct statistical tests. Additionally, we calculated binding energies focusing on the interaction between Callithtrix jacchus VAMEN and Pro8OT. We identified two novel motifs (AAMEN and VAMEN), challenging the current knowledge of motif conservation in placental mammals. Coevolution analysis demonstrated a correlation between GAMEN, AAMEN, and VAMEN and their corresponding OTs and OTRs. Callithrix jacchus exhibited a higher binding energy between VAMEN and Pro8OT than orthologous molecules found in humans (GAMEN and Leu8OT). The coevolution of AAMEN and VAMEN with their corresponding OTs and OTRs suggests a functional relationship that could have contributed to specific reproductive and adaptive behaviors, including paternal care, social monogamy, and twin births, prominent traits in Cebidae species, such as marmosets and tamarins. Our findings underscore the coevolution of taxon-specific amino acids among the three studied molecules, shedding light on the oxytocinergic system as an adaptive epistatic repertoire in primates.

Genetic Markers Associated with Postpartum Depression: A Review.

Postpartum depression (PPD) is a common illness in mothers after childbirth. PPD negatively affect the mother's quality of life and the bond with the infant, which can interfere with the infant's emotional, social, and cognitive development. PPD is caused by various biological and psychosocial factors. The aim of this review is to summarize the latest evidence of the associations between genetic polymorphisms and PPD. PubMed and Scopus were used as the literature search databases for this review. The keywords used were postpartum depression, postnatal depression, genetic, and polymorphism. Twenty-seven articles were reviewed after screening and applying the inclusion criteria. As results, the serotonin gene (5-HTTLPR) and oxytocin genes (OXTR) have the most significant associations with PPD among other genes. Further research on PPD biomarkers should be conducted to diagnose and treat PPD patients.

Methylation of the Oxytocin, Oxytocin Receptor, and Vasopressin Gene Promoters in Tobacco Use Disorder during Cessation

Introduction: Vasopressin (AVP) and oxytocin (OT) exert sex-specific effects on social pair bonding and stress reactions while also influencing craving in substance use disorders. In this regard, intranasal oxytocin (OT) and AVP antagonists present potential treatments for tobacco use disorder (TUD). Since transcription of both hormones is also regulated by gene methylation, we hypothesized sex-specific changes in methylation levels of the AVP, OT, and OT receptor (OXTR) gene during nicotine withdrawal. Methods: The study population consisted of 49 smokers (29 males, 20 females) and 51 healthy non-smokers (25 males, 26 females). Blood was drawn at day 1, day 7, and day 14 of smoking cessation. Craving was assessed with the questionnaire on smoking urges (QSU). Results: Throughout cessation, mean methylation of the OT promoter gene increased in males and decreased in females. OXTR receptor methylation decreased in females, while in males it was significantly lower at day 7. Regarding the AVP promoter, mean methylation increased in males while there were no changes in females. Using mixed linear modeling, CpG position, time point, sex, and the interaction of time point and sex as well as time point, sex, and QSU had a significant fixed effect on OT and AVP gene methylation. The interaction effect suggests that sex, time point, and QSU are interrelated, meaning that, depending on the sex, methylation could be different at different time points and vice versa. There was no significant effect of QSU on mean OXTR methylation. Discussion: We identified differences at specific CpGs between controls and smokers in OT and AVP and in overall methylation of the AVP gene. Furthermore, we found sex-specific changes in mean methylation levels of the mentioned genes throughout smoking cessation, underlining the relevance of sex in the OT and vasopressin system. This is the first study on epigenetic regulation of the OT promoter in TUD. Our results have implications for research on the utility of the AVP and OT system for treating substance craving. Future studies on both targets need to analyze their effect in the context of sex, social factors, and gene regulation.

Standardized mixture of Pluchea indica and Sauropus androgynus extract stimulates the gene expression associated with lactogenesis in rats

Pluchea indica (P. indica) and Sauropus androgynus (S. androgynus) are medicinal plants empirically used as an herbal galactogogue, but their mechanism of action has not been elucidated at the molecular level in the form of a mixed extract. This research aimed to standardize and investigate the combined effects of P. indica leaf extract (EPI) and S. androgynus leaf extract (ESA) on the expressions of prolactin (PRL), PRL receptor (PRLR), oxytocin (OXT), and OXT receptor (OXTR) genes in pituitary and mammary glands of lactating rats. The extracts were prepared by maceration in 70% ethanol. Standardization was done by examining non-specific parameters and determining total flavonoids using spectrophotometric analysis. Twenty-four lactating rats were divided into six groups. Group I: CMC 0.5% as control, II: EPI 500 mg/kgBW, III: ESA 125 mg/kgBW, and IV–VI were given combination formula EPI-ESA 1: 125+31.25, EPI-ESA 2: 250+62.5, and EPI-ESA 3: 500+125 mg/kgBW (orally, once a day) from the 2nd–15th day after parturition. On the 16th day, experimental animals were euthanized for tissue sampling, and gene expression was measured using real-time reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The study of the non-specific parameters revealed water content, total ash, and acid-insoluble ash met criteria based on the Indonesian Herbal Pharmacopoeia. Evaluation of total flavonoids yielded 7.33% ± 0.00% and 3.84% ± 0.01% w/w for EPI and ESA, respectively. Test results showed balanced induction of all target genes was achieved when subjects received EPI-ESA 2. We concluded that EPI-ESA can potentially support lactogenesis by stimulating the expressions of PRL, PRLR, OXT, and OXTR genes.

A diet enriched with Pistacia atlantica fruits improves the female rats' reproductive system

Background and aimBaneh (Pistacia atlantica) is a plant species that is commonly consumed as food and has a long-standing traditional use as a sexual enhancer. Despite its widespread use, a limited amount of academic and scientific literature is available regarding its potential impact on the reproductive system. The present research aimed to study the effect of a diet enriched with Baneh on the female rats’ reproductive system. Experimental procedureThree groups of rats (n = 8) were subjected to the intended diet for six weeks. Subsequently, their histomorphometric parameters, sex hormone levels, as well as the expression of oxytocin (OXT) and oxytocin receptor (OXTR) genes were measured. The rats’ serum vitamin D, zinc, and lipid profiles were also evaluated. Results and conclusionResults revealed that compared to the normal food, the diet containing 20 % Baneh significantly increased the progesterone and estradiol levels three and two times, respectively. It decreased the total body weight while increasing the ratio of ovary weight to the body weight. Furthermore, the Baneh-enriched diet raised HDL, zinc, and vitamin D levels, though it reduced the LDL and TG levels by 15 μg/dl and 24 μg/dl, respectively, and the concentration of ovary malondialdehyde decreased by 50 % in the treated group. Also, the diet increased the follicle graph, corpus luteum, the thickness of the epithelium, the number of endometrial glands, and the expression of both OXT and OXTR genes. Our findings suggested that P. atlantica could considerably improve the female sex hormone levels and their reproductive system.

The relationship between OXT gene polymorphisms and reproductive hormones in pregnant and lactating Awassi Ewes.

Numerous genetic loci interact intricately to control reproduction in mammals. The oxytocin gene (OXT) is a promising candidate for reproductive traits in mammals. Previously, sheep and goats have been studied for the presence of the OXT polymorphism. As of yet, no polymorphisms have been identified in the OXT gene of Awassi sheep. Thus, this study was conducted to determine the effects of OXT polymorphism and litter size on reproductive hormones in pregnant and lactating Awassi ewes. This study evaluated 232 ewes aged 3 and 4 years (123 single-progeny ewes and 109 twin-producing ewes). Serum was collected to measure reproductive hormones using ELISA kits manufactured by ELK Biotechnology. DNA was extracted from sheep blood for genotyping and sequencing to identify variations in OXT gene (exon 2, 266bp). Genotyping analysis revealed three genotypes within 266bp: CC, CA, and AA. Sequence analysis revealed a novel mutation in exon 2: 188C > A. Statistical analysis showed significant associations between the 188C > A SNP and phenotypic traits. Twin-pregnant ewes carrying CC genotypes had higher estrogen, progesterone, and follicle-stimulating hormone/luteinizing hormone levels (65.86 ± 3.87) (pg/mL), (6.51 ± 0.39) (ng/mL), and (20.22 ± 1.27) (ng/mL)/( 23.37 ± 2.14) (ng/mL) respectively, compared to CA and AA genotypes in the fourth month of twin-pregnant ewes compared to single-pregnant ewes. This study found that the 188C > A SNP negatively affected reproductive hormone levels in Awassi sheep. These findings provide breeders with a new insight into the sheep OXT gene, useful for future breeding.

Oxytocinergic neurons, but not oxytocin, are crucial for male penile erection

The cumulative evidence suggests that oxytocin is involved in the male sexual behaviors. However, no significant sexual impairments were observed in oxytocin gene knock-out (KO) mice, suggesting that oxytocin is not necessary for sexual behavior in male mice. To better understand the role of oxytocin in male erection, two types of oxytocin gene KO mice were created. In the first type, the oxytocin gene was deleted in the zygote, while in the second type, the oxytocin gene was mutated in adulthood by injecting the CRISPR/Cas9 AAVs. The results showed that disrupting the oxytocin gene at either the embryonic or adult stage did not affect erection, indicating that oxytocin is not necessary for penile erection. Pharmacologically, injecting oxytocin receptor agonist Carbetocin into the VTA of the oxytocin gene KO mice still evoked penile erection. By employing the Oxt-Ires-Cre mice, we found that specifically activating oxytocinergic neurons through chemogenetics strongly induced penile erection, while inhibiting these neurons blocked the erection responses. Furthermore, ablating PVN oxytocinergic neurons abolished the male erection response. In conclusion, although the neuropeptide oxytocin is not essential for male erection, the activity of oxytocinergic neurons is required. Our results might reflect the redundancy in the central nerve system in the sense that many signals contribute to the activation of oxytocinergic neurons to evoke penile erection during sexual behaviors.

The importance of oxytocin neurons in the supraoptic nucleus for breastfeeding in mice.

The hormone oxytocin, secreted from oxytocin neurons in the paraventricular (PVH) and supraoptic (SO) hypothalamic nuclei, promotes parturition, milk ejection, and maternal caregiving behaviors. Previous experiments with whole-body oxytocin knockout mice showed that milk ejection was the unequivocal function of oxytocin, whereas parturition and maternal behaviors were less dependent on oxytocin. Whole-body knockout, however, could induce the enhancement of expression of related gene(s), a phenomenon called genetic compensation, which may hide the actual functions of oxytocin. In addition, the relative contributions of oxytocin neurons in the PVH and SO have not been well documented. Here, we show that females with conditional knockout of oxytocin gene in both the PVH and SO undergo grossly normal parturition and maternal caregiving behaviors, while dams with a smaller number of remaining oxytocin-expressing neurons exhibit severe impairments in breastfeeding, leading to the death of their pups within 24 hours after birth. We also found that the growth of pups is normal even under oxytocin conditional knockout in PVH and SO as long as pups survive the next day of delivery, suggesting that the reduced oxytocin release affects the onset of lactation most severely. These phenotypes are largely recapitulated by SO-specific oxytocin conditional knockout, indicating the unequivocal role of oxytocin neurons in the SO in successful breastfeeding. Given that oxytocin neurons not only secrete oxytocin but also non-oxytocin neurotransmitters or neuropeptides, we further performed cell ablation of oxytocin neurons in the PVH and SO. We found that cell ablation of oxytocin neurons leads to no additional abnormalities over the oxytocin conditional knockout, suggesting that non-oxytocin ligands expressed by oxytocin neurons have negligible functions on the responses measured in this study. Collectively, our findings confirm the dispensability of oxytocin for parturition or maternal behaviors, as well as the importance of SO-derived oxytocin for breastfeeding.

The role of single nucleotide polymorphisms within genes for oxytocin and vasopressin receptors in the presentation and severity of autistic traits

IntroductionAutism spectrum disorder is a heterogeneous group of disorders that affects virtually every population, regardless of their ethnic or socioeconomic origin. The pathogenesis of ASD is probably multifactorial, based on interactions between genetic and environmental factors. Their key elements are disorders in the field of social communication, establishing and maintaining relationships and the so-called stereotypical and repetitive patterns of interests and activities. However, of the above- mentioned symptoms, the most important are communication disorders, which are the basis for many of the functional difficulties observed in these patients.ObjectivesThe aim of the presented study was to analyze the clinical picture of social cognition deficits in males with autism spectrum disorders, and to link its elements with the frequency of alleles of selected polymorphisms within the OXTR and AVPR1A genes.MethodsThe study included 132 people, 77.5% of whom were male (n = 100). 113 participants (85.6%) were diagnosed with autism spectrum disorders confirmed by the ADOS-2 test conducted by a certified diagnostician. In this group, men constituted 76.1% of the population (n = 77). The remaining 28 people did not have a diagnosis of autism spectrum disorders, and in the ADOS-2 study they obtained the result below the cut-off level. The mean age in the whole group was 14.4 years (95% CI: 13.92-14.93).ResultsA higher frequency of the rs53576 A allele and the rs10877969 C allele could be observed than expected on the basis of the European / world population. In the case of the rs7294536 and rs2254298 polymorphisms, no differences in the distribution of alleles in relation to the expected values were observed. In the network analysis reference allele (T) of SNPs rs10877969 was linked to the higher outcome of the “social affect” domain of ADOS-2 and through it influenced ADOS-2 outcome. All other SNPs did not significantly affect neither domain of ADOS-2. Reference allele (A) of rs53576 was linked with higher odds ratio of clinical diagnosis of ASD in logistic regression. Similarly the rs10877969 polymorphism within the AVPR1a gene significantly shaped the risk of autism spectrum disorders, while in the combined analysis with rs7294536 within the haplotype, the observed effect was significantly stronger.ConclusionsThe studied polymorphisms may constitute an element of larger haplotypes which, depending on the number of mutated alleles, may determine the severity of autism spectrum traits, from the neurotypical population, through people with a broad autism phenotype, to people diagnosed with ASD. Further research is required on the potential clinical application of genotype analysis of the studied polymorphisms and on the exact mechanism of their impact on the risk of ASD and the development of social cognition disorders.Disclosure of InterestNone Declared

Vasopressin, and not oxytocin, receptor gene methylation is associated with individual differences in receptive joint attention in chimpanzees (Pan troglodytes).

Joint attention (JA) is an important milestone in human infant development and is predictive of the onset of language later in life. Clinically, it has been reported that children at risk for or with a diagnosis of autism spectrum disorder (ASD) perform more poorly on measures of JA compared to neurotypical controls. JA is not unique to humans but has also been reported in great apes and to a lesser extent in more distantly related monkeys. Further, individual differences in JA among chimpanzees are associated with polymorphisms in the vasopressin and oxytocin genes, AVPR1A and OXTR. Here, we tested whether individual variation in DNA methylation of OXTR and AVPR1A were associated with performance on JA tasks in chimpanzees. We found that individual differences in JA performance was associated with AVPR1A methylation, but not OXTR methylation in the chimpanzees. The collective results provide further evidence of the role of AVPR1A in JA abilities in chimpanzees. The results further suggest that methylation values for AVPR1A may be useful biomarkers for identifying individuals at risk for ASD or related neurodevelopmental disorders associated with impairments in JA abilities.

Vasopressin receptor 1a, oxytocin receptor, and oxytocin knockout male and female mice display normal perceptual abilities towards non-social odorants

Genetic knockouts of the vasopressin receptor 1a (Avpr1a), oxytocin receptor (Oxtr), or oxytocin (Oxt) gene in mice have helped cement the causal relationship between these neuropeptide systems and various social behaviors (e.g., social investigation, recognition, and communication, as well as territoriality and aggression). In mice, these social behaviors depend upon the olfactory system. Thus, it is critical to assess the olfactory capabilities of these knockout models to accurately interpret the observed differences in social behavior. Prior studies utilizing these transgenic mice have sought to test for baseline deficits in olfactory processing; predominantly through use of odor habituation/dishabituation tasks, buried food tests, or investigation assays using non-social odorants. While informative, these assays rely on the animal's intrinsic motivation and locomotor behavior to measure olfactory capabilities and thus, often yield mixed results. Instead, psychophysical analyses using operant conditioning procedures and flow-dilution olfactometry are ideally suited to precisely quantify olfactory perception. In the present study, we used these methods to assess the main olfactory capabilities of adult male and female Avpr1a, Oxtr, and Oxt transgenic mice to volatile non-social odorants. Our results indicate that homozygous and heterozygous knockout mice of all three strains have the same sensitivity and discrimination ability as their wild-type littermates. These data strongly support the hypothesis that the observed social deficits of these global knockout mice are not due to baseline deficits of their main olfactory system.

A novel deleterious oxytocin variant is associated with the lower twinning ratio in Awassi ewes

This study aimed to assess the possible association of oxytocin (OXT) gene with reproductive traits in two groups of Awassi ewes that differ in their reproductive potentials. Sheep were genotyped using PCR—single-stranded conformation polymorphism approach. Three genotypes were detected in exon 2, CC, CA, and AA, and a novel SNP was identified with a missense effect on oxytocin (c.188C > A → p.Arg55Leu). A significant (p < 0.01) association of p.Arg55Leu with the twinning rate was found as ewes with AA and CA genotypes exhibited, respectively a lower twinning ratio than those with the wild-type CC genotype. The deleterious impact of p.Arg55Leu was demonstrated by all in silico tools that were utilized to assess the effect of this variant on the structure, function, and stability of oxytocin. Molecular docking showed that p.Arg55Leu caused a dramatic alteration in the binding of oxytocin with its receptor and reduced the number of interacted amino acids between them. Our study suggests that ewes with AA and CA genotypes showed a lower reproductive performance due to the presence of p.Arg55Leu, which caused damaging impacts on oxytocin and is binding with the OXT receptor. The utilization of the p.Arg55Leu could be useful for improving Awassi reproductive potential.

Leptin enhances social motivation and reverses chronic unpredictable stress-induced social anhedonia during adolescence

Social anhedonia, a loss of interest and pleasure in social interactions, is a common symptom of major depression as well as other psychiatric disorders. Depression can occur at any age, but typically emerges in adolescence or early adulthood, which represents a sensitive period for social interaction that is vulnerable to stress. In this study, we evaluated social interaction reward using a conditioned place preference (CPP) paradigm in adolescent male and female mice. Adolescent mice of both sexes exhibited a preference for the social interaction-associated context. Chronic unpredictable stress (CUS) impaired the development of CPP for social interaction, mimicking social anhedonia in depressed adolescents. Conversely, administration of leptin, an adipocyte-derived hormone, enhanced social interaction-induced CPP in non-stressed control mice and reversed social anhedonia in CUS mice. By dissecting the motivational processes of social CPP into social approach and isolation avoidance components, we demonstrated that leptin treatment increased isolation aversion without overt social reward effect. Further mechanistic exploration revealed that leptin stimulated oxytocin gene transcription in the paraventricular nucleus of the hypothalamus, while oxytocin receptor blockade abolished the leptin-induced enhancement of socially-induced CPP. These results establish that chronic unpredictable stress can be used to study social anhedonia in adolescent mice and provide evidence that leptin modulates social motivation possibly via increasing oxytocin synthesis and oxytocin receptor activation.

Oestrogen-dependent hypothalamic oxytocin expression with changes in feeding and body weight in female rats

Oxytocin (OXT) is produced in the hypothalamic nuclei and secreted into systemic circulation from the posterior pituitary gland. In the central nervous system, OXT regulates behaviours including maternal and feeding behaviours. Our aim is to evaluate whether oestrogen regulates hypothalamic OXT dynamics. Herein, we provide the first evidence that OXT dynamics in the hypothalamus vary with sex and that oestrogen may modulate dynamic changes in OXT levels, using OXT-mRFP1 transgenic rats. The fluorescence intensity of OXT-mRFP1 and expression of the OXT and mRFP1 genes in the hypothalamic nuclei is highest during the oestrus stage in female rats and decreased significantly in ovariectomised rats. Oestrogen replacement caused significant increases in fluorescence intensity and gene expression in a dose-related manner. This is also demonstrated in the rats’ feeding behaviour and hypothalamic Fos neurons using cholecystokinin-8 and immunohistochemistry. Hypothalamic OXT expression is oestrogen-dependent and can be enhanced centrally by the administration of oestrogen.

Recording and manipulation of the maternal oxytocin neural activities in mice

Pulsatile release of the hormone oxytocin (OT) mediates uterine contraction during parturition and milk ejection during lactation.1-3 These pulses are generated by the unique activity patterns of the central neuroendocrine OT neurons located in the paraventricular and supraoptic hypothalamus. Classical studies have characterized putative OT neurons by invivo extracellular recording techniques in rats and rabbits.1,4-10 Due to technical limitations, however, the identity of OT neurons in these previous studies was speculative based on their electrophysiological characteristics and axonal projection to the posterior pituitary, not on OT gene expression. To pinpoint OT neural activities among other hypothalamic neurons that project to the pituitary11,12 and make better use of cell-type-specific neuroscience toolkits,13 a mouse model needs to be developed for the studies of parturition and lactation. We herein introduce viral genetic approaches in mice to characterize the maternal activities of OT neurons by fiber photometry. A sharp photometric peak of OT neurons appeared at approximately 520s following simultaneous suckling stimuli from three pups. The amplitude of the peaks increased as the mother mice experienced lactation, irrespective of the age of the pups, suggesting the intrinsic plasticity of maternal OT neurons. Based on a mono-synaptic input map to OT neurons, we pharmacogenetically activated the inhibitory neurons in the bed nucleus of the stria terminalis and found the suppression of the activities of OT neurons. Collectively, our study illuminates temporal dynamics in the maternal neural activities of OT neurons and identifies one of its modulatory inputs.

Identifying Risk and Resilience Factors in the Intergenerational Cycle of Maltreatment: Results From the TRANS-GEN Study Investigating the Effects of Maternal Attachment and Social Support on Child Attachment and Cardiovascular Stress Physiology.

IntroductionChildhood maltreatment (CM) is a developmental risk factor and can negatively influence later psychological functioning, health, and development in the next generation. A comprehensive understanding of the biopsychosocial underpinnings of CM transmission would allow to identify protective factors that could disrupt the intergenerational CM risk cycle. This study examined the consequences of maternal CM and the effects of psychosocial and biological resilience factors on child attachment and stress-regulatory development using a prospective trans-disciplinary approach.MethodsMother-child dyads (N = 158) participated shortly after parturition (t0), after 3 months (t1), and 12 months later (t2). Mothers’ CM experiences were assessed at t0, attachment representation at t1 and psychosocial risk and social support were assessed at t1 and t2. At t2, dyads participated in the Strange Situation Procedure (SSP). Children’s attachmen status were classified as organized vs. disorganized, including their level of disorganized behavior, and heart rate (HR) and respiratory sinus arrhythmia (RSA) were recorded as stress response measures of the autonomic nervous system. Maternal caregiving during SSP was assessed using the AMBIANCE scale. Child’s single nucleotide polymorphisms rs2254298 within the oxytocin receptor (OXTR) and rs2740210 of the oxytocin gene (OXT) were genotyped using DNA isolated from cord blood.ResultsMaternal CM experiences (CM+) were significantly associated with an unresolved attachment status, higher perceived stress and more psychological symptoms. These negative effects of CM were attenuated by social support. As expected, maternal unresolved attachment and child disorganized attachment were significantly associated. Maternal caregiving did not mediate the relationship between maternal and child attachment but influenced children’s HR and RSA response and disorganized behavior. Moreover, the rs2254298 genotype of the OXTR gene moderated the stress response of children from mothers with CM. Children carrying the rs2740210 risk allele of the OXT gene showed more disorganized behavior independent from maternal CM experiences.ConclusionWe replicated and extended existing CM and attachment models by co-examining maternal attachment, social support, and child genetic susceptibility on child attachment and cardiovascular stress regulation. The findings contribute to an extended understanding of risk and resilience factors and enable professionals to target adequate services to parents and children at risk.

An epigenomic shift in amygdala marks the transition to maternal behaviors in alloparenting virgin female mice.

Adults of many species will care for young offspring that are not their own, a phenomenon called alloparenting. However, in many cases, nonparental adults must be sensitized by repeated or extended exposures to newborns before they will robustly display parental-like behaviors. To capture neurogenomic events underlying the transition to active parental caring behaviors, we analyzed brain gene expression and chromatin profiles of virgin female mice co-housed with pregnant dams during pregnancy and after birth. After an initial display of antagonistic behaviors and a surge of defense-related gene expression, we observed a dramatic shift in the chromatin landscape specifically in amygdala of the pup-exposed virgin females compared to females co-housed with mother before birth, accompanied by a dampening of anxiety-related gene expression. This epigenetic shift coincided with hypothalamic expression of the oxytocin gene and the emergence of behaviors and gene expression patterns classically associated with maternal care. The results outline a neurogenomic program associated with dramatic behavioral changes and suggest molecular networks relevant to human postpartum mental health.

Paternal stress in rats increased oxytocin, oxytocin receptor, and arginine vasopressin gene expression in the male offspring amygdala with no effect on their social interaction behaviors

Environmental and hereditary factors play roles in shaping the personality of offspring which are often associated with gene expression alterations. The long-term effects of the environment that are modulated by the epigenetic mechanisms can be even transmitted to the next generations. This study aimed to investigate the effects of paternal stress, such as paternal aggression and food deprivation, on the social interaction behaviors of offspring in adulthood and the expression of genes that are associated with these behaviors. The intruder-resident method, followed by an electric shock, was used to induce aggression in male Wistar rats before mating. To induce food deprivation, father rats were given 10 g pellets every day without restriction on water consumption for 2 weeks before mating. Social interactions of the male offspring were evaluated at the age of 8 weeks using a three-chamber social interaction test. Real-time PCR was applied to quantify the expression levels of oxytocin (OXT), oxytocin receptor (OXTR), and arginine vasopressin (AVP) genes in the amygdala of offspring. One-way analysis of variance was used to compare the means of experimental groups. The results did not show significant changes in the social interaction behaviors for the offspring of aggressive and food-deprived fathers compared to the control group. However, molecular investigations indicated increased levels of OXT, OXTR, and AVP gene expression in the offspring amygdala of aggressive and food-deprived fathers. The results showed that paternal stress, such as aggression and food deprivation, induced gene expression alterations in the offspring, although they did not affect their social interaction behaviors.

Oxytocin system gene methylation is associated with empathic responses towards children

Empathy is an essential component of sensitive caregiving behavior, which in turn is an important predictor of children’s healthy social-emotional development. The oxytocin (OXT) system plays a key role in promoting sensitive parenting and empathy. In this study, we investigated how OXT system gene methylation was associated with empathic processes in nulliparous women (M age = 23.60, SD =0.44)—measuring both physiological facial muscle responses and ratings of compassion and positive affect to affective images depicting children. Linear mixed effects analyses demonstrated that lower methylation levels in the OXT and OXTR genes were related to enhanced empathic responses. The effect of OXT system gene methylation on empathic processes was partly qualified by an interaction with individual variations in women’s care motivation. Our findings provide experimental evidence for an association between the methylation of OXT system genes and empathy.