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Oxytocin pathways are hypothesized to play important roles in human-animal interactions and may contribute to some benefits of these interspecific social relationships. We explored the effects of naturalistic interactions between children and dogs on oxytocin release in both species, as well as associations between methylation of the oxytocin receptor gene (OXTRm), social behavior, and oxytocin response in this context. Children (N = 55) participated in a within-subjects design involving a) interaction with their pet dog, b) interaction with an unfamiliar dog, and c) a nonsocial control condition (solitary play). We used immunoassays to measure salivary and urinary oxytocin in both the children and dogs, behavioral coding to characterize dog-child interactions, and bisulfite sequencing to quantify methylation of the oxytocin receptor gene (N = 32 children). Child salivary oxytocin decreased moderately across time in all conditions, but the extent of this effect varied between conditions, with greater oxytocin output during interactions with dogs than the control condition. In the pet dog condition, children's salivary oxytocin response was positively associated with the duration of visual co-orientation between the child and dog. Child urinary oxytocin did not deviate substantially from baseline in any condition. Children with higher levels of OXTRm had greater oxytocin output during interactions with their pet dogs, but lower oxytocin output in the control condition, and engaged in lower levels of affectionate interaction with dogs across conditions. Children's pet dogs exhibited increases in salivary oxytocin, but we observed the opposite pattern in the unfamiliar dog, who exhibited decreases in both urinary and salivary oxytocin on average. Collectively, our results support the hypothesis that oxytocin pathways may shape and respond to social interactions between children and dogs, highlighting an important role for companion animals in child development., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Postpartum hemorrhage, or excessive bleeding after birth, is a leading cause of maternal morbidity. A major cause of postpartum hemorrhage is uterine atony, tiring of the uterus which leads to ineffective contractions. Uterine contractions depend on oxytocin signaling in the myometrium, which in turn depends on expression of the oxytocin receptor (OXTR). Both genetic and epigenetic factors related to the oxytocin receptor are associated with risk of postpartum hemorrhage, but a mechanism relating these factors to oxytocin receptor activity in myometrium remains unclear. We report a genetic by epigenetic interaction whereby the relationship between DNA hydroxymethylation and OXTR gene expression depends on a common OXTR gene variant (rs53576). We also provide evidence that a similar genetic by epigenetic interaction using blood-derived DNA methylation is associated with relevant clinical outcomes: quantity of oxytocin administration and odds for postpartum hemorrhage. These results provide new avenues for predicting how women will respond to pharmacological agents in the prevention and treatment of postpartum hemorrhage., (© 2024. The Author(s).)

The oxytocin system plays a role in social stress adaptation, and this role is likely to be particularly important in adolescence. One method of regulating the oxytocin system is through DNA methylation in the promoter of the oxytocin receptor gene (OXTRm), which reduces the gene's expression. This multi-method, longitudinal study, using a diverse community sample of 184 adolescents followed from age 13-28, examined the links between OXTRm and exposure to over-controlling parenting in adolescence and conflict with romantic partners and internalizing symptoms in adulthood. Female, but not male, adolescents who were exposed to psychologically controlling parenting at age 13 had lower levels of OXTRm at site -924 at age 28. Reduced OXTRm at site -924 was associated with greater romantic partner-reported relationship conflict at age 27, and reduced OXTRm at site -934 was marginally associated with greater participant-reported conflict for males. Reduced OXTRm at site -924 was also associated with fewer internalizing symptoms at ages 24-25. These results in adulthood are consistent with an upregulated oxytocin system reducing the salience of negative socioemotional stimuli. Overall, findings are consistent with oxytocin playing a role in the stress response system, and more specifically, by helping us to adapt to social environments like parenting and romantic relationships, reducing the salience of negativity, and reducing risk for common emotional problems., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Exogenous oxytocin (OT) is widely used to induce or augment labor with little understanding of the impact on offspring development. In rodent models, including the prairie vole ( Microtus ochrogaster ), it has been shown that oxytocin administered to mothers can affect the nervous system of the offspring with long lasting behavioral effects especially on sociality. Here, we examined the hypothesis that perinatal oxytocin exposure could have epigenetic and transcriptomic consequences. Prairie voles were exposed to exogenous oxytocin, through injections given to the mother just prior to birth, and were studied at the time of weaning. The outcome of this study revealed increased epigenetic age in oxytocin-exposed animals compared to the saline-exposed group. Oxytocin exposure led to 900 differentially methylated CpG sites (annotated to 589 genes), and 2 CpG sites (2 genes) remained significantly different after correction for multiple comparisons. Differentially methylated CpG sites were enriched in genes known to be involved in regulation of gene expression and neurodevelopment. Using RNA-sequencing we also found 217 nominally differentially expressed genes (p<0.05) in nucleus accumbens, a brain region involved in reward circuitry and social behavior; after corrections for multiple comparisons 6 genes remained significantly differentially expressed. Finally, we found that maternal oxytocin administration led to widespread alternative splicing in the nucleus accumbens. These results indicate that oxytocin exposure during birth may have long lasting epigenetic consequences. A need for further investigation of how oxytocin administration impacts development and behavior throughout the lifespan is supported by these outcomes., Competing Interests: Conflict of Interest Disclosure The authors declare no conflicts of interest.

Interpersonal neural synchrony (INS) occurs when neural electrical activity temporally aligns between individuals during social interactions. It has been used as a metric for interpersonal closeness, often during naturalistic child-parent interactions. This study evaluated whether other biological correlates of social processing predicted the prevalence of INS during child-parent interactions, and whether their observed cooperativity modulated this association. Child-parent dyads (n = 27) performed a visuospatial tower-building task in cooperative and competitive conditions. Neural activity was recorded using mobile electroencephalogram (EEG) headsets, and experimenters coded video-recordings post-hoc for behavioral attunement. DNA methylation of the oxytocin receptor gene (OXTRm) was measured, an epigenetic modification associated with reduced oxytocin activity and socioemotional functioning. Greater INS during competition was associated with lower child OXTRm, while greater behavioral attunement during competition and cooperation was associated with higher parent OXTRm. These differential relationships suggest that interpersonal dynamics as measured by INS may be similarly reflected by other biological markers of social functioning, irrespective of observed behavior. Children's self-perceived communication skill also showed opposite associations with parent and child OXTRm, suggesting complex relationships between children's and their parents' social functioning. Our findings have implications for ongoing developmental research, supporting the utility of biological metrics in characterizing interpersonal relationships., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Postpartum hemorrhage remains a key contributor to overall maternal morbidity in the United States. Current clinical assessment methods used to predict postpartum hemorrhage are unable to prospectively identify about 40% of hemorrhage cases. Oxytocin is a first-line pharmaceutical for preventing and treating postpartum hemorrhage, which acts through oxytocin receptors on uterine myocytes. Existing research indicates that oxytocin function is subject to variation, influenced in part by differences in the DNA sequence within the oxytocin receptor gene. One variant, rs53576, has been shown to be associated with variable responses to exogenous oxytocin when administered during psychological research studies. How this variant may influence myometrial oxytocin response in the setting of third stage labor has not been studied. We tested for differences in the frequency of the oxytocin receptor genotype at rs53576 in relationship to the severity of blood loss among a sample of individuals who experienced vaginal birth., Methods: A case-control prospective design was used to enroll 119 postpartum participants who underwent vaginal birth who were at least 37 weeks of gestation. Cases were defined by either a 1000 mL or greater blood loss or instances of heavier bleeding where parturients were given additional uterotonic treatment due to uterine atony. Controls were matched to cases on primiparity and labor induction status. Genotype was measured from a maternal blood sample obtained during the 2 nd postpartum month from 95 participants. Statistical analysis included bivariate tests and generalized linear and Poisson regression modeling., Results: The distribution of the genotype across the sample of 95 participants was 40% GG (n = 38), 50.5% AG (n = 48) and 9.5% AA (n = 9). Blood loss of 1000 mL or greater occurred at a rate of 7.9% for GG, 12.5% for AG and 55.6% for AA participants (p = 0.005). Multivariable models demonstrated A-carriers (versus GG) had 275.2 mL higher blood loss (95% CI 96.9-453.4, p < 0.01) controlling for parity, intrapartum oxytocin, self-reported ancestry, active management of third stage or genital tract lacerations. Furthermore, A-carrier individuals had a 79% higher risk for needing at least one second-line treatment (RR = 1.79, 95% CI = 1.08-2.95) controlling for covariates. Interaction models revealed that A-carriers who required no oxytocin for labor stimulation experienced 371.4 mL greater blood loss (95% CI 196.6-546.2 mL)., Conclusions: We provide evidence of a risk allele in the oxytocin receptor gene that may be involved in the development of postpartum hemorrhage among participants undergoing vaginal birth, particularly among those with fewer risk factors. The findings, if reproducible, could be useful in studying pharmacogenomic strategies for predicting, preventing or treating postpartum hemorrhage., (© 2022. The Author(s).)

Background: The neuropeptide oxytocin regulates mammalian social behavior. Disruptions in oxytocin signaling are a feature of many psychopathologies. One commonly studied biomarker for oxytocin involvement in psychiatric diseases is DNA methylation at the oxytocin receptor gene (OXTR). Such studies focus on DNA methylation in two regions of OXTR, exon 3 and a region termed MT2 which overlaps exon 1 and intron 1. However, the relative contribution of exon 3 and MT2 in regulating OXTR gene expression in the brain is currently unknown., Results: Here, we use the prairie vole as a translational animal model to investigate genetic, epigenetic, and environmental factors affecting Oxtr gene expression in a region of the brain that has been shown to drive Oxtr related behavior in the vole, the nucleus accumbens. We show that the genetic structure of Oxtr in prairie voles resembles human OXTR. We then studied the effects of early life experience on DNA methylation in two regions of a CpG island surrounding the Oxtr promoter: MT2 and exon 3. We show that early nurture in the form of parental care results in DNA hypomethylation of Oxtr in both MT2 and exon 3, but only DNA methylation in MT2 is associated with Oxtr gene expression. Network analyses indicate that CpG sites in the 3' portion of MT2 are most highly associated with Oxtr gene expression. We also identify two novel SNPs in exon 3 of Oxtr in prairie voles and a novel alternative transcript originating from the third intron of the gene. Expression of the novel alternative transcript is associated with genotype at SNP KLW2., Conclusions: These results identify putative regulatory features of Oxtr in prairie voles which inform future studies examining OXTR in human social behaviors and disorders. These studies indicate that in prairie voles, DNA methylation in MT2, particularly in the 3' portion, is more predictive of Oxtr gene expression than DNA methylation in exon 3. Similarly, in human temporal cortex, we find that DNA methylation in the 3' portion of MT2 is associated with OXTR expression. Together, these results suggest that among the CpG sites studied, DNA methylation of MT2 may be the most reliable indicator of OXTR gene expression. We also identify novel features of prairie vole Oxtr, including SNPs and an alternative transcript, which further develop the prairie vole as a translational model for studies of OXTR.

The Adaptive Calibration Model of Stress Responsivity (ACM) suggests that developmental experiences predictably tune biological systems to meet the demands of the environment. Particularly important is the calibration of reward systems. Using a longitudinal sample (N = 184) followed since adolescence, this study models the dimensions of early life stress and their effects on epigenetic modification of the oxytocin receptor gene (OXTR) and individual differences in neural response to reward anticipation. We first created a latent variable model of developmental context using measures collected when participants were 13 years old. As adults, two subsets of participants completed a reward anticipation fMRI paradigm (N = 82) and agreed to have their blood assayed for (OXTR) DNA methylation (N = 112) at two CpG sites. Three latent constructs of developmental context emerged: Neighborhood Harshness, Family Harshness, and Abuse and Disorder. Greater OXTR DNA methylation at CpG sites -924 and -934 blunted the association between greater Neighborhood Harshness and increased neural activation in caudate in anticipation of rewards. Interaction effects were also found outside of reward-related areas for all three latent constructs. Results indicate an epigenetically derived differential susceptibility model whereby high methylation coincides with decreased association between developmental environment and neural reward anticipation., (© 2020 Wiley Periodicals LLC.)

The neural capacity to discriminate between emotions emerges early in development, though little is known about specific factors that contribute to variability in this vital skill during infancy. In adults, DNA methylation of the oxytocin receptor gene (OXTRm) is an epigenetic modification that is variable, predictive of gene expression, and has been linked to autism spectrum disorder and the neural response to social cues. It is unknown whether OXTRm is variable in infants, and whether it is predictive of early social function. Implementing a developmental neuroimaging epigenetics approach in a large sample of infants (N = 98), we examined whether OXTRm is associated with neural responses to emotional expressions. OXTRm was assessed at 5 months of age. At 7 months of age, infants viewed happy, angry, and fearful faces while functional near-infrared spectroscopy was recorded. We observed that OXTRm shows considerable variability among infants. Critically, infants with higher OXTRm show enhanced responses to anger and fear and attenuated responses to happiness in right inferior frontal cortex, a region implicated in emotion processing through action-perception coupling. Findings support models emphasizing oxytocin's role in modulating neural response to emotion and identify OXTRm as an epigenetic mark contributing to early brain function., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The neuropeptide oxytocin (OT) has been implicated in a wide range of affiliative processes. OT exerts its functions via OT receptors, which are encoded by the oxytocin receptor gene (OXTR). Epigenetic modification of OXTR through the process of DNA methylation has been associated with individual differences in behavioral phenotypes. Specifically, lower levels of OXTR methylation have been linked to better social and affective functioning. However, research on epigenetic mechanisms of OXTR is scarce in non-clinical populations, and even less is known about epigenetic variability across adulthood. The present study assessed methylation levels at OXTR CpG site -934 and plasma OT levels in 22 young (20-31 years, M = 23.6) and 34 older (63-80 years, M = 71.4) participants. Lower levels of OXTR methylation and higher plasma OT levels were associated with less self-reported attachment anxiety in young but not older participants, with largely independent contributions of OXTR methylation and plasma OT levels. In contrast, in the overall sample, lower levels of OXTR methylation were associated with higher self-reported attachment avoidance. Age analysis suggested that these results were largely driven by young adults. Plasma OT levels were unrelated to attachment avoidance. Taken together, these findings support the emerging notion in the literature that epigenetic properties of OXTR, in addition to endogenous OT levels, are related to adult attachment. Further, the age effects observed in the associations between OXTR methylation, plasma OT, and adult attachment emphasize the importance of adopting a developmental perspective when studying properties of the OT system and their relation to affiliative processes. Findings contribute to growing evidence suggesting that epigenetic modification of genes regulating OT pathways and endogenous OT levels are associated with the way people form and maintain intimate social relationships., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Oxytocin receptor gene (OXTR) polymorphisms, lower ventral striatum (VS) response to social stimuli, and lower economic privilege have been independently associated with depression and anxiety. However, the interactions between these risk factors are unknown. One hundred and fifty-seven healthy adult participants genotyped for OXTR rs237915 completed a common emotion-matching task during functional magnetic resonance imaging. Past economic privilege and depression and anxiety symptoms were concurrently assessed through validated self-report measures. The data revealed an interaction between rs237915 genotype and economic privilege on the neural response to negative faces. C-carriers showed decreased VS activation and increased connectivity between the VS and ventromedial prefrontal cortex with increased economic privilege. TT homozygotes showed the reverse pattern. Low VS response to negative faces predicted increased social anxiety, but only for those with either lower economic privilege or the C allele. For those with both, low VS response was associated with paradoxically lower social anxiety. Findings suggest that economic privilege and OXTR rs237915 genotype may calibrate social motivational neural systems for better or worse. While lower VS response to negative faces may generally constitute a risk factor for social anxiety, lower response to social cues may be a benefit for those with dual risk.

Mammalian sociality is regulated in part by the neuropeptide oxytocin. In prairie voles, subtle variation in early life experience changes oxytocin receptor-mediated social behaviors. We report that low levels of early care in voles leads to de novo DNA methylation at specific regulatory sites in the oxytocin receptor gene (Oxtr), impacting gene expression and protein distribution in the nucleus accumbens. DNA methylation state of the blood predicts expression in the brain indicating the utility of the blood as a biomarker for the transcription state of the brain. These experience-sensitive CpG sites are conserved in humans, are related to gene expression in the brain, and have been associated with psychiatric disorders and individual differences in neural response to social stimuli. These results identify a mechanism by which early care regulates later displays of typical prairie vole social behavior and suggest the potential for nurture driven epigenetic tuning of OXTR in humans., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Oxytocin has anxiolytic properties whose mechanisms of action are still being identified. DNA methylation in the promoter region of the oxytocin receptor gene (OXTR), an epigenetic modification that putatively reflects a downtuning of the oxytocin system, has previously been implicated in the regulation of fear-related responses through the amygdala. In this study, we attempted to characterize the relationship between methylation of OXTR and anxiogenesis using two distinct endophenotypes: autonomic nervous system activity and subcortical brain structure. In 79 participants, we found that increased OXTR methylation is associated with attenuated resting parasympathetic tone, measured using high-frequency heart rate variability. Further, we found that this relationship is mediated by brain morphology, such that OXTR methylation is associated with increased gray matter of the central amygdala which is, in turn, associated with decreased parasympathetic tone. These results further our understanding of epigenetic regulation of the human oxytocin system and its role in anxiogenesis.

Aberrant attentional biases to social stimuli have been implicated in a number of disorders including autism and social anxiety disorder. Oxytocin, a naturally-occurring mammalian hormone and neuromodulator involved in regulating social behavior, has been proposed to impact basic biological systems that facilitate the detection of and orientation to social information. Here, we investigate a role for naturally-occurring variability in the endogenous oxytocinergic system in regulating neural response during attention to social information. Participants performed a selective social attention task while undergoing fMRI, provided a blood sample for epigenetic analysis, and completed self-report measures of social functioning. We find that a functional epigenetic modification to the oxytocin receptor, OXTR methylation, is associated with increased neural response within and decreased functional coupling between regions of the salience and attentional control networks during selective social attention. We also show that subclinical variability in autistic and social anxiety traits moderates this epigenetic regulation of neural response. These data offer a mechanistic explanation to a growing literature associating social behavior and disorder with epigenetic modification to OXTR by suggesting that OXTR methylation reflects a decrease in the extent to which social information automatically captures attention. We highlight the importance that treatment efficacy be considered in relation to individual differences in molecular makeup, and that future studies aimed at uncovering biomarkers of disorder carefully consider measurement at both the biological and phenotypic level.

In humans, the neuropeptide oxytocin plays a critical role in social and emotional behavior. The actions of this molecule are dependent on a protein that acts as its receptor, which is encoded by the oxytocin receptor gene (OXTR). DNA methylation of OXTR, an epigenetic modification, directly influences gene transcription and is variable in humans. However, the impact of this variability on specific social behaviors is unknown. We hypothesized that variability in OXTR methylation impacts social perceptual processes often linked with oxytocin, such as perception of facial emotions. Using an imaging epigenetic approach, we established a relationship between OXTR methylation and neural activity in response to emotional face processing. Specifically, high levels of OXTR methylation were associated with greater amounts of activity in regions associated with face and emotion processing including amygdala, fusiform, and insula. Importantly, we found that these higher levels of OXTR methylation were also associated with decreased functional coupling of amygdala with regions involved in affect appraisal and emotion regulation. These data indicate that the human endogenous oxytocin system is involved in attenuation of the fear response, corroborating research implicating intranasal oxytocin in the same processes. Our findings highlight the importance of including epigenetic mechanisms in the description of the endogenous oxytocin system and further support a central role for oxytocin in social cognition. This approach linking epigenetic variability with neural endophenotypes may broadly explain individual differences in phenotype including susceptibility or resilience to disease.

Background: It is assumed that the oxytocin receptor gene (OXTR) is associated with factors that are related to features of reproduction as well as the currently emerging fields of mood and emotional response., Methods: We analysed data from over 8000 mothers who participated in the Avon Longitudinal Study of Parents and Children (ALSPAC). We determined reproductive, emotional and personality differences related to the two SNPs rs53576 and rs2254298 of the oxytocin receptor gene to determine whether there was evidence in this population for: (i) associations with emotional and personality differences, and (ii) behavioural or environmental links with these SNPs using a hypothesis free approach with over 1000 types of exposure., Results: Our analyses of 7723 women showed that there were no differences in 11 mood, social or relationship characteristics associated with the rs2254298, and just one with rs53576 (with emotional loneliness)--one statistically significant out of 22 tests is no more than would be expected by chance. There were no interactions with childhood abuse. Using a hypothesis-free approach we found few indicators of environmental or behavioural differences associated with rs2254298, but there was an excess of associations with eating habits with rs53576. The findings included an association with dieting to lose weight, and habits typical of bulimia for the women with GG. The nutrition of the women also showed negative associations of the GG genotype with 13 nutrients, including vitamins D, B12 and retinol, and intake of calcium, potassium and iodine., Conclusions: We conclude that this large database of pregnant women was unable to provide confirmation of the types of personality associated with these two OXTR SNPs, but we have shown some evidence of eating differences in those with GG on rs53576. Confirmation of our hypothesis free associations using other data sets is important.

Recent research indicates that the neuropeptide oxytocin and the gene for the oxytocin receptor (OXTR) have been implicated in the modulation of various social behaviors, including those related to empathy and sensitivity to others. In this study, we examine the hypothesis that genetic variation in OXTR is associated with autonomic reactions when perceiving others in distress. We also explore the possibility that individual disposition in empathic concern would differ by OXTR genotype. To address these questions, 51 male participants (18-35 years of age), genotyped for OXTR rs53576, viewed a social interaction containing high levels of individual distress and apparent physical pain. Electrodermal activity, a measure of sympathetic nervous system activity, was collected during the presentation of the stimuli. Participants also completed a self-report dispositional measure of empathy prior to starting the study and provided ratings of arousal while viewing the stimuli. OXTR variant rs53576 GG individuals showed increased levels of sympathetic and subjective arousal in response to the stimuli compared to A allele carriers. GG homozygotes also expressed greater levels of empathic concern. These findings support the importance of the oxytocin receptor variation in emotional and physiological reactions to the affective experiences of other conspecifics.

Background: Autism comprises a spectrum of behavioral and cognitive disturbances of childhood development and is known to be highly heritable. Although numerous approaches have been used to identify genes implicated in the development of autism, less than 10% of autism cases have been attributed to single gene disorders., Methods: We describe the use of high-resolution genome-wide tilepath microarrays and comparative genomic hybridization to identify copy number variants within 119 probands from multiplex autism families. We next carried out DNA methylation analysis by bisulfite sequencing in a proband and his family, expanding this analysis to methylation analysis of peripheral blood and temporal cortex DNA of autism cases and matched controls from independent datasets. We also assessed oxytocin receptor (OXTR) gene expression within the temporal cortex tissue by quantitative real-time polymerase chain reaction (PCR)., Results: Our analysis revealed a genomic deletion containing the oxytocin receptor gene, OXTR (MIM accession no.: 167055), previously implicated in autism, was present in an autism proband and his mother who exhibits symptoms of obsessive-compulsive disorder. The proband's affected sibling did not harbor this deletion but instead may exhibit epigenetic misregulation of this gene through aberrant gene silencing by DNA methylation. Further DNA methylation analysis of the CpG island known to regulate OXTR expression identified several CpG dinucleotides that show independent statistically significant increases in the DNA methylation status in the peripheral blood cells and temporal cortex in independent datasets of individuals with autism as compared to control samples. Associated with the increase in methylation of these CpG dinucleotides is our finding that OXTR mRNA showed decreased expression in the temporal cortex tissue of autism cases matched for age and sex compared to controls., Conclusion: Together, these data provide further evidence for the role of OXTR and the oxytocin signaling pathway in the etiology of autism and, for the first time, implicate the epigenetic regulation of OXTR in the development of the disorder.See the related commentary by Gurrieri and Neri: http://www.biomedcentral.com/1741-7015/7/63.