Frances S. Chen

Common oxytocin receptor gene (OXTR) polymorphism and social support interact to reduce stress in humans

The neuropeptide oxytocin has played an essential role in the regulation of social behavior and attachment throughout mammalian evolution. Because recent studies in humans have shown that oxytocin administration reduces stress responses and increases prosocial behavior, we investigated whether a common single nucleotide polymorphism (rs53576) in the oxytocin receptor gene (OXTR) might interact with stress-protective effects of social support. Salivary cortisol samples and subjective stress ratings were obtained from 194 healthy male participants before, during, and after a standardized psychosocial laboratory stress procedure. Participants were randomly assigned either to prepare alone or to receive social support from their female partner or close female friend while preparing for the stressful task. Differential stress responses between the genotype groups were observed depending on the presence or absence of social support. Only individuals with one or two copies of the G allele of rs53576 showed lower cortisol responses to stress after social support, compared with individuals with the same genotype receiving no social support. These results indicate that genetic variation of the oxytocin system modulates the effectiveness of positive social interaction as a protective buffer against a stressful experience.

Epigenetic regulation of the oxytocin receptor gene: implications for behavioral neuroscience

Genetic approaches have improved our understanding of the neurobiological basis of social behavior and cognition. For instance, common polymorphisms of genes involved in oxytocin signaling have been associated with sociobehavioral phenotypes in healthy samples as well as in subjects with mental disorders. More recently, attention has been drawn to epigenetic mechanisms, which regulate genetic function and expression without changes to the underlying DNA sequence. We provide an overview of the functional importance of oxytocin receptor gene (OXTR) promoter methylation and summarize studies that have investigated the role of OXTR methylation in behavioral phenotypes. There is first evidence that OXTR methylation is associated with autism, high callous-unemotional traits, and differential activation of brain regions involved in social perception. Furthermore, psychosocial stress exposure might dynamically regulate OXTR. Given evidence that epigenetic states of genes can be modified by experiences, especially those occurring in sensitive periods early in development, we conclude with a discussion on the effects of traumatic experience on the developing oxytocin system. Epigenetic modification of genes involved in oxytocin signaling might be involved in the mechanisms mediating the long-term influence of early adverse experiences on socio-behavioral outcomes.

Integrative Approaches Utilizing Oxytocin to Enhance Prosocial Behavior: From Animal and Human Social Behavior to Autistic Social Dysfunction

The prevalence of autism spectrum disorder (ASD) is as high as 1 in 100 individuals and is a heavy burden to society. Thus, identifying causes and treatments is imperative. Here, we briefly review the topics covered in our 2012 Society for Neuroscience Mini-Symposium entitled “Integrative Approaches Using Oxytocin to Enhance Prosocial Behavior: From Animal and Human Social Behavior to ASDs Social Dysfunction.” This work is not meant to be a comprehensive review of oxytocin and prosocial behavior. Instead, we wish to share the newest findings on the effects of oxytocin on social behavior, the brain, and the social dysfunction of ASD at the molecular, genetic, systemic, and behavior levels, in varied subjects ranging from animal models to humans suffering from autism for the purpose of promoting further study for developing the clinical use of oxytocin in treating ASD.

Evidence for Infants' Internal Working Models of Attachment

Nearly half a century ago, psychiatrist John Bowlby proposed that the instinctual behavioral system that underpins an infant’s attachment to his or her mother is accompanied by ‘‘internal working models’’ of the social world—models based on the infant’s own experience with his or her caregiver (Bowlby, 1958, 1969/1982). These mental models were thought to mediate, in part, the ability of an infant to use the caregiver as a buffer against the stresses of life, as well as the later development of important self-regulatory and social skills. Hundreds of studies now testify to the impact of caregivers’ behavior on infants’ behavior and development: Infants who most easily seek and accept support from their parents are considered secure in their attachments and are more likely to have received sensitive and responsive caregiving than insecure infants; over time, they display a variety of socioemotional advantages over insecure infants (Cassidy & Shaver, 1999). Research has also shown that, at least in older children and adults, individual differences in the security of attachment are indeed related to the individual’s representations of social relations (Bretherton & Munholland, 1999). Yet no study has ever directly assessed internal working models of attachment in infancy. In the present study, we sought to do so. METHOD

Oxytocin receptor (OXTR) polymorphisms and attachment in human infants

Ordinary variations in human infants’ attachment behaviors – their proclivity to seek and accept comfort from caregivers – are associated with a wide range of individual differences in psychological functioning in adults. The current investigation examined variation in the oxytocin receptor (OXTR) gene as one possible source of these variations in infant attachment. One hundred seventy-six infants (77 Caucasian, 99 non-Caucasian) were classified as securely or insecurely attached based on their behavior in the Strange Situation (Ainsworth et al., 1978). The A allele of OXTR rs2254298 was associated with attachment security in the non-Caucasian infants (p < 0.005). These findings underscore the importance of oxytocin in the development of human social behavior and support its role in social stress-regulation and the development of trust.

An Oxytocin Receptor Gene Variant Predicts Attachment Anxiety in Females and Autism-Spectrum Traits in Males

A molecular genetic approach was used to investigate the relationship between common variants of the oxytocin receptor (OXTR) gene and self-reported social functioning in healthy adults. Females with at least one copy of the A allele at OXTR rs2254298 reported greater attachment anxiety than females with two copies of the G allele. Males with at least one copy of the A allele at OXTR rs2254298 reported more autism-associated traits than males with two copies of the G allele. These results support the growing evidence that naturally occurring differences in the oxytocin system contribute to individual differences in social functioning in healthy adults. The authors discuss potential avenues by which sex may moderate the relationship between oxytocin and human social behavior.

Genetic modulation of oxytocin sensitivity : a pharmacogenetic approach

Intranasal administration of the neuropeptide oxytocin has been shown to influence a range of complex social cognitions and social behaviors, and it holds therapeutic potential for the treatment of mental disorders characterized by social functioning deficits such as autism, social phobia and borderline personality disorder. However, considerable variability exists in individual responses to oxytocin administration. Here, we undertook a study to investigate the role of genetic variation in sensitivity to exogenous oxytocin using a socioemotional task. In a randomized, double-blind, placebo-controlled experiment with a repeated-measures (crossover) design, we assessed the performance of 203 men on an emotion recognition task under oxytocin and placebo. We took a haplotype-based approach to investigate the association between oxytocin receptor gene variation and oxytocin sensitivity. We identified a six-marker haplotype block spanning the promoter region and intron 3 that was significantly associated with our measure of oxytocin sensitivity. Specifically, the TTCGGG haplotype comprising single-nucleotide polymorphisms rs237917–rs2268498–rs4564970–rs237897–rs2268495–rs53576 is associated with increased emotion recognition performance under oxytocin versus placebo, and the CCGAGA haplotype with the opposite pattern. These results on the genetic modulation of sensitivity to oxytocin document a significant source of individual differences with implications for personalized treatment approaches using oxytocin administration.

Neuropeptide S receptor gene is associated with cortisol responses to social stress in humans

The neuropeptide S (NPS) and its receptor NPSR represent a transmitter system critically involved in the modulation of anxiety and arousal in rodents. Initial human studies indicate that the T-allele of the functional NPSR gene (NPSR1) polymorphism (rs324981), which increases NPS potency at NPSR, is associated with anxiety-related phenotypes. Since stress is critically involved in the pathogenesis of anxiety disorders, we tested the association between rs324981 and stress reactivity in 196 healthy males. Participants were exposed to the Trier Social Stress Test for Groups (TSST-G), a standardized laboratory protocol for stress exposure in a group format. Salivary cortisol and subjective stress responses were assessed. A significant genotype by time interaction and a main effect of genotype were shown, with T-allele carriers displaying larger cortisol and subjective stress responses. This is the first report to show involvement of the NPS system in the regulation of the neuroendocrine stress response in humans.

Brief Report: Broader Autism Phenotype Predicts Spontaneous Reciprocity of Direct Gaze.

We report evidence for a relationship in the general population between self-reported autism-associated traits and the spontaneous reciprocation of direct gaze, a behavior that we propose may reflect a tendency to synchronize with social partners. Adults viewed videos of actors whose gaze was either directed towards or averted from them. Individuals with lower scores on four subscales of the Autism-Spectrum Quotient (AQ) scale showed a greater tendency to look at directed relative to averted eyes; individuals with higher scores on the AQ did not. This relationship was specific to autism-associated traits and to gaze towards the eyes; it did not generalize to a social anxiety measure or to gaze towards the mouth. We discuss implications for our understanding of the broader autism phenotype.

Oxytocin and intergroup relations: Goodwill is not a fixed pie

De Dreu et al. (1) presented a set of experiments exploring the effects of the neuropeptide oxytocin on implicit associations and moral reasoning about in-group and out-group members. Although their experiments were cleverly designed, their data did not clearly support their interpretation that oxytocin promotes human “ethnocentrism” (1).