Characterization of oxytocin and vasopressin receptors in the Southern giant pouched rat and comparison to other rodents.

Vasopressin and oxytocin are well known and evolutionarily ancient modulators of social behavior. The distribution and relative densities of vasopressin and oxytocin receptors are known to modulate the sensitivity to these signaling molecules. Comparative work is needed to determine which neural networks have been conserved and modified over evolutionary time, and which social behaviors are commonly modulated by nonapeptide signaling. To this end, we used receptor autoradiography to determine the distribution of vasopressin 1a and oxytocin receptors in the Southern giant pouched rat (Cricetomys ansorgei) brain, and to assess the relative densities of these receptors in specific brain regions. We then compared the relative receptor pattern to 23 other species of rodents using a multivariate ANOVA. Pouched rat receptor patterns were strikingly similar to hamsters and voles overall, despite the variation in social organization among species. Uniquely, the pouched rat had dense vasopressin 1a receptor binding in the caudate-putamen (i.e., striatum), an area that might impact affiliative behavior in this species. In contrast, the pouched rat had relatively little oxytocin receptor binding in much of the anterior forebrain. Notably, however, oxytocin receptor binding demonstrated extremely dense binding in the bed nucleus of the stria terminalis, which is associated with the modulation of several social behaviors and a central hub of the social decision-making network. Examination of the nonapeptide system has the potential to reveal insights into species-specific behaviors and general themes in the modulation of social behavior.

Leveraging the unique social organization of California mice to study circuit-specific effects of oxytocin on behavior.

Oxytocin is a versatile neuropeptide that modulates many different forms of social behavior. Recent hypotheses pose that oxytocin enhances the salience of rewarding and aversive social experiences, and the field has been working to identify mechanisms that allow oxytocin to have diverse effects on behavior. Here we review studies conducted on the California mouse (Peromyscus californicus) that shed light on how oxytocin modulates social behavior following stressful experiences. In this species, both males and females exhibit high levels of aggression, which has facilitated the study of how social stress impacts both sexes. We review findings of short- and long-term effects of social stress on the reactivity of oxytocin neurons. We also consider the results of pharmacological studies which show that oxytocin receptors in the bed nucleus of the stria terminalis and nucleus accumbens have distinct but overlapping effects on social approach behaviors. These findings help explain how social stress can have different behavioral effects in males and females, and how oxytocin can have such divergent effects on behavior. Finally, we consider how new technological developments and innovative research programs take advantage of the unique social organization of California mice to address questions that can be difficult to study in conventional rodent model species. These new methods and questions have opened new avenues for studying the neurobiology of social behavior.

Assessment of Tissue Expression of the Oxytocin-Vasopressin Pathway in the Placenta of Women with a First-Episode Psychosis during Pregnancy.

Psychosis refers to a mental health condition characterized by a loss of touch with reality, comprising delusions, hallucinations, disorganized thought, disorganized behavior, catatonia, and negative symptoms. A first-episode psychosis (FEP) is a rare condition that can trigger adverse outcomes both for the mother and newborn. Previously, we demonstrated the existence of histopathological changes in the placenta of pregnant women who suffer an FEP in pregnancy. Altered levels of oxytocin (OXT) and vasopressin (AVP) have been detected in patients who manifested an FEP, whereas abnormal placental expression of these hormones and their receptors (OXTR and AVPR1A) has been proven in different obstetric complications. However, the precise role and expression of these components in the placenta of women after an FEP have not been studied yet. Thus, the purpose of the present study was to analyze the gene and protein expression, using RT-qPCR and immunohistochemistry (IHC), of OXT, OXTR, AVP, and AVPR1a in the placental tissue of pregnant women after an FEP in comparison to pregnant women without any health complication (HC-PW). Our results showed increased gene and protein expression of OXT, AVP, OXTR, and AVPR1A in the placental tissue of pregnant women who suffer an FEP. Therefore, our study suggests that an FEP during pregnancy may be associated with an abnormal paracrine/endocrine activity of the placenta, which can negatively affect the maternofetal wellbeing. Nevertheless, additional research is required to validate our findings and ascertain any potential implications of the observed alterations.

Male-selective effects of oxytocin agonism on alcohol intake: behavioral assessment in socially housed prairie voles and involvement of RAGE.

Targeting the oxytocin (OXT) peptide system has emerged as a promising new approach for the treatment of alcohol use disorder (AUD). However, further advancements in this development depend on properly modeling various complex social aspects of AUD and its treatment. Here we examined behavioral and molecular underpinnings of OXT receptor (OXTR) agonism in prairie voles, a rodent species with demonstrated translational validity for neurobiological mechanisms regulating social affiliations. To further improve translational validity of these studies, we examined effects of intranasal (IN) OXT administration in male and female prairie voles socially housed in the presence of untreated cagemates. IN OXT selectively inhibited alcohol drinking in male, but not female, animals. Further, we confirmed that exogenously administered OXT penetrates the prairie vole brain and showed that Receptor for Advanced Glycation End-products assists this penetration after IN, but not intraperitoneal (IP), OXT administration. Finally, we demonstrated that IP administration of LIT-001, a small-molecule OXTR agonist, inhibits alcohol intake in male, but not female, prairie voles socially housed in the presence of untreated cagemates. Taken together, results of this study support the promise of selectively targeting OXTR for individualized treatment of AUD.

A Primer on DNA Methylation and Its Potential to Impact Maternal Depression Risk and Assessment During Pregnancy and the Postpartum.

Depression onset during and after pregnancy is prevalent and associated with significant implications for maternal, child, and family health. Although environmental risk factors important to the expression of pregnancy-related depression are well known, knowledge of the genetic underpinning is limited. Given the joint contribution of environmental and genetic factors to depression risk liability, DNA methylation presents itself as an ideal biomarker to investigate basic mechanisms and opportunities for translational research to care for pregnancy-related depression health outcomes. This article is an introduction to DNA methylation and its potential to serve as a marker of depression risk during pregnancy and the postpartum. This commentary discusses current clinical uses of DNA methylation-based testing and how it may be applied to perinatal depression clinical care and management.

Strategies for Sharing Limited Resources among Children and Adolescents in Three Traditional Societies of East Africa: Sociocultural and Genetic Factors.

Egalitarianism, pursuit for equality, and altruism are the most important evolutionarily stable strategies in the human society. This study presents data on the results of economic games for sharing with a potential friend or unfamiliar peer in three ethnic groups of East Africa (Hadza, Iraqw, and Meru). The total sample was 583 children and adolescents; mean age, 13.5 ± 3.1 years. In addition, DNA analysis was carried out and the OXTR gene rs53576 single nucleotide polymorphism was genotyped for 162 Meru individuals. The pronounced individual variability in making decisions on sharing with a potential partner was established. Children and adolescents behaved altruistically towards friends significantly more frequently as compared with strangers. Carriers of the OXTR rs53576 GG variant displayed altruism significantly more frequently both to friends (U = 3376.500, p = 0.047; OR = 3.075, p = 0.032) and to strangers (U = 3478.000, p = 0.025; OR = 3.133, p = 0.007). Significant intergroup differences in egalitarianism, egoism, and altruism were also demonstrated. Data obtained suggest a positive group selection towards altruists.

Targeted bisulfite sequencing: A novel tool for the assessment of DNA methylation with high sensitivity and increased coverage.

DNA methylation analysis is increasingly used in stress research. Available methods are expensive, laborious and often limited by either the analysis of short CpG stretches or low assay sensitivity. Here, we present a cost-efficient next generation sequencing-based strategy for the simultaneous investigation of multiple candidate genes in large cohorts. To illustrate the method, we present analysis of four candidate genes commonly assessed in psychoneuroendocrine research: Glucocorticoid receptor (NR3C1), Serotonin transporter (SLC6A4), FKBP Prolyl isomerase 5 (FKBP5), and the Oxytocin receptor (OXTR). DNA methylation standards (100 %; 75 %; 50 %; 25 % and 0 %) and DNA of a female and male donor were bisulfite treated in three independent trials and were used to generate sequencing libraries for 42 CpGs from the NR3C1 1 F promoter region, 84 CpGs of the SLC6A4 5' regulatory region, 5 CpGs located in FKBP5 intron 7, and additional 12 CpGs located in a potential enhancer element in intron 3 of the OXTR. In addition, DNA of 45 patients with borderline personality disorder (BPD) and 45 healthy controls was assayed. Multiplex libraries of all samples were sequenced on a MiSeq system and analyzed for mean methylation values of all CpG sites using amplikyzer2 software. Results indicated excellent accuracy of the assays when investigating replicates generated from the same bisulfite converted DNA, and very high linearity (R2 > 0.9) of the assays shown by the analysis of differentially methylated DNA standards. Comparing DNA methylation between BPD and healthy controls revealed no biologically relevant differences. The technical approach as described here facilitates targeted DNA methylation analysis and represents a highly sensitive, cost-efficient and high throughput tool to close the gap between coverage and precision in epigenetic research of stress-associated phenotypes.

A genetic profile of oxytocin receptor improves moral acceptability of outcome-maximizing harm in male insurance brokers.

In recent years, conflicting findings have been reported in the scientific literature about the influence of dopaminergic, serotonergic and oxytocinergic gene variants on moral behavior. Here, we utilized a moral judgment paradigm to test the potential effects on moral choices of three polymorphisms of the Oxytocin receptor (OXTR): rs53576, rs2268498 and rs1042770. We analyzed the influence of each single polymorphism and of genetic profiles obtained by different combinations of their genotypes in a sample of male insurance brokers (n = 129), as compared to control males (n = 109). Insurance brokers resulted significantly more oriented to maximize outcomes than control males, thus they expressed more than controls the utilitarian attitude phenotype. When analyzed individually, none of the selected variants influenced the responses to moral dilemmas. In contrast, a composite genetic profile that potentially increases OXTR activity was associated with higher moral acceptability in brokers. We hypothesize that this genetic profile promotes outcome-maximizing behavior in brokers by focusing their attention on what represents a greater good, that is, saving the highest number of people, even though at the cost of sacrificing one individual. Our data suggest that investigations in a sample that most expresses the phenotype of interest, combined with the analysis of composite genetic profiles rather than individual variants, represent a promising strategy to find out weak genetic influences on complex phenotypes, such as moral behavior.

Childhood Adversity, Socioeconomic Instability, Oxytocin-Receptor-Gene Methylation, and Romantic-Relationship Support Among Young African American Men.

Men's emerging adult romantic relationships forecast downstream relationship behavior, including commitment and quality. Accumulating evidence implicates methylation of the oxytocin-receptor-gene (OXTR) system in regulating relationship behavior. We tested hypotheses regarding the links between (a) childhood adversity and (b) socioeconomic instability in emerging adulthood on supportive romantic relationships via their associations with OXTR methylation. Hypotheses were tested using path analysis with data from 309 participants in the African American Men's Project. Consistent with our hypotheses, results showed that OXTR methylation proximally predicted changes in relationship support during a 1.5-year period. Childhood adversity was not directly associated with OXTR methylation but, rather, with contemporaneous socioeconomic instability, which in turn predicted elevated OXTR methylation. Findings suggest that early adversity is indirectly associated with OXTR methylation by links with downstream socioeconomic instability. Findings must be considered provisional, however, because preregistered replications are needed to establish more firmly the relations among these variables.

Oxytocin receptor genotype and low economic privilege reverses ventral striatum-social anxiety association.

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.

Epigenetic modification of the oxytocin and glucocorticoid receptor genes is linked to attachment avoidance in young adults.

Attachment in the context of intimate pair bonds is most frequently studied in terms of the universal strategy to draw near, or away, from significant others at moments of personal distress. However, important interindividual differences in the quality of attachment exist, usually captured through secure versus insecure - anxious and/or avoidant - attachment orientations. Since Bowlby's pioneering writings on the theory of attachment, it has been assumed that attachment orientations are influenced by both genetic and social factors - what we would today describe and measure as gene by environment interaction mediated by epigenetic DNA modification - but research in humans on this topic remains extremely limited. We for the first time examined relations between intra-individual differences in attachment and epigenetic modification of the oxytocin receptor (OXTR) and glucocorticoid receptor (NR3C1) gene promoter in 109 young adult human participants. Our results revealed that attachment avoidance was significantly and specifically associated with increased OXTR and NR3C1 promoter methylation. These findings offer first tentative clues on the possible etiology of attachment avoidance in humans by showing epigenetic modification in genes related to both social stress regulation and HPA axis functioning.

Socioeconomic Disparities in Childhood Obesity Risk: Association With an Oxytocin Receptor Polymorphism.

Importance: Pediatricians are paying increased attention to the effects of socioeconomic status (SES) on children's health. Low SES is a robust predictor of obesity across the life course and may interact with genes affecting metabolism to influence obesity risk. Recent animal literature and burgeoning human research suggest that the hormone oxytocin (OT) may be important for metabolic regulation. To date, this association has not been examined in children. Objectives: To examine whether an OT receptor polymorphism (rs53576) interacts with SES, potentially exacerbating and buffering the effects of stress, to predict anthropometry during childhood, and based on differential neurobiological susceptibility theory, to test whether carriers of the A allele of the OXTR gene, compared with GG genotyped individuals, would be most sensitive to the effects of SES on anthropometry for better or for worse. Design, Setting, and Participants: In this observational study, families were recruited from public school classrooms and enrolled in the Peers and Wellness Study (PAWS), which examined the effects of social status on health. Families were assessed during children's kindergarten year (fall semester of 2003, 2004, and 2005) and again during middle childhood (2009-2011) for a follow-up assessment that included anthropometric measures and DNA collection. The dates of the analysis were January 2015 to June 2016. Exposures: Socioeconomic disparities. Main Outcomes and Measures: Child body mass index z score (BMIz) and triceps skinfold thickness. Family SES was collected through questionnaires mailed to homes. Body measurements and DNA were collected in homes by trained research assistants. Results: From the original community sample of 338 typically developing children, participants were 186 socioeconomically and racially/ethnically diverse children (mean age, 10.3 years; age range, 9.4-11.3 years; 93 females [50%]) who had sufficient data at the follow-up assessment for inclusion in this study. Among 97 A allele carriers, a 1-SD increase in SES was associated with a decrease in BMIz of 0.28 (95% CI, -0.47 to -0.09) and a decrease in skinfold thickness of 0.95 (95% CI, -1.77 to -0.12) mm, such that they exhibited the highest BMIz and skinfold thickness in contexts of low SES but exhibited the lowest BMIz and skinfold thickness in contexts of high SES. Socioeconomic status was unrelated to BMIz (95% CI, -0.21 to 0.26) or skinfold thickness (95% CI, -0.42 to 1.45) for 89 GG genotyped children. Conclusions and Relevance: These findings advance etiologic understanding of childhood obesity, highlighting complex effects of SES on child health and adding to growing evidence that OT relates to human obesity risk. The results also support differential neurobiological susceptibility theory, suggesting that the A allele renders individuals more sensitive to both positive and negative health effects of socioecological context.

Neuroanatomical distribution of oxytocin receptor binding in the female rabbit forebrain: Variations across the reproductive cycle.

Oxytocin receptors (OTR) have been characterized in the brains of several mammals, including rodents, carnivores, and primates. Their species-specific distribution in the brain has been associated with species differences in social organization, including mating strategy and parenting behavior. In several species, the density of OTR binding in specific brain regions varies according to reproductive condition, including ovarian cycle, pregnancy and lactation. Rabbits are induced ovulators, polygamous, and monoparental but their distribution and regulation of brain OTR has not been described. Here we used receptor autoradiography to quantitatively characterize OTR binding in the brains of estrous, ovariectomized, late pregnant, and lactating does. Intense binding occurred in the prefrontal cortex (PFC), preoptic area (POA), lateral septum (LS; dorsal and ventral), hippocampus, and medial amygdala. Variations among the experimental groups were seen only in PFC, POA, LS. Ovariectomy increased OTR density in PFC but had the opposite effect in POA. Lactating does had significantly reduced OTR density, relative to late pregnancy, in PFC and POA. Our results are consistent with a possible role of OT in modulating social and maternal behavior in rabbits since the brain regions sensitive to OT have been implicated in social interaction, learning and memory, olfactory processing and maternal behavior.

Oxytocin receptor gene polymorphism, perceived social support, and psychological symptoms in maltreated adolescents.

Despite the detrimental consequences of child maltreatment on developmental processes, some individuals show remarkable resilience, with few signs of psychopathology, while others succumb to dysfunction. Given that oxytocin has been shown to be involved in social affiliation, attachment, social support, trust, empathy, and other social or reproductive behaviors, we chose to examine the possible moderation of maltreatment effects on perceived social support and on psychological symptoms by a common single nucleotide polymorphism (rs53576) in the oxytocin receptor gene. We studied adolescents (N = 425) aged approximately 13-15, including participants with objectively documented maltreatment histories (N = 263) and a nonmaltreated comparison group from a comparable low socioeconomic status background (N = 162). There was a significant genotype by maltreatment interaction, such that maltreated adolescents with the G/G genotype perceived significantly lower social support compared to maltreated A-carriers, with no effect of genotype in the comparison group. Maltreated G/Gs also reported higher levels of internalizing symptoms than did A-carriers, even though they did not differ from them on objective measures of maltreatment (type, duration, or severity). G/G homozygotes may be more attuned to negative social experiences, such as family maltreatment, while maltreated A-carriers were indistinguishable from nonmaltreated adolescents in levels of mental health symptoms.

Peripheral administration of oxytocin increases social affiliation in the naked mole-rat (Heterocephalus glaber).

The neuropeptide oxytocin regulates a wide variety of social behaviors across diverse species. However, the types of behaviors that are influenced by this hormone are constrained by the species in question and the social organization that a particular species exhibits. Therefore, the present experiments investigated behaviors regulated by oxytocin in a eusocial mammalian species by using the naked mole-rat (Heterocephalus glaber). In Experiment 1, adult non-breeding mole-rats were given intraperitoneal injections of either oxytocin (1mg/kg or 10mg/kg) or saline on alternate days. Animals were then returned to their colony and behavior was recorded for minutes 15-30 post-injection. Both doses of oxytocin increased huddling behavior during this time period. In Experiment 2, animals received intraperitoneal injections of either oxytocin (1mg/kg), an oxytocin-receptor antagonist (0.1mg/kg), a cocktail of oxytocin and the antagonist, or saline across 4 testing days in a counterbalanced design. Animals were placed in either a 2-chamber arena with a familiar conspecific or in a small chamber with 1week old pups from their home colony and behaviors were recorded for minutes 15-30 post-injection. Oxytocin increased investigation of, and time spent in close proximity to, a familiar conspecific; these effects were blocked by the oxytocin antagonist. No effects were seen on pup-directed behavior. These data suggest that oxytocin is capable of modulating affiliative-like behavior in this eusocial species.

Plasticity and constraints on social evolution in African mole-rats: ultimate and proximate factors.

Here, we review comparative studies of African mole-rats (family Bathyergidae) to explain how constraints acting at the ultimate (environmental) and proximate (organismal) levels have led to convergent gains and losses of sociality within this extensive adaptive radiation of subterranean rodents endemic to sub-Saharan Africa. At the ultimate level, living in environments that range from mesic through to arid has led to both variation and flexibility in social organization among species, culminating in the pinnacle of social evolution in the eusocial naked and Damaraland mole-rats (Heterocephalus glaber and Fukomys damarensis). The common mole-rat (Cryptomys hottentotus) provides a model example of how plasticity in social traits exists within a single species inhabiting areas with different ecological constraint. At the proximate level, reproductive strategies and cooperative breeding may be constrained by the correlated evolution of a suite of traits including physiological suppression of reproduction, the development of physiological and morphological castes, and the mode of ovulatory control and seasonality in breeding. Furthermore, recent neurobiological advances indicate that differential patterns of neurotransmitter expression within the forebrain may underpin (and limit) either a solitary or group living/cooperative lifestyle not only in mole-rats, but also more widely among disparate mammalian taxa.

Environmental stress, oxytocin receptor gene (OXTR) polymorphism, and mental health following collective stress.

We examined whether the oxytocin receptor gene (OXTR) single nucleotide polymorphism (SNP) rs53576 genotype buffers the combined impact of negative social environments (e.g., interpersonal conflict/constraint) and economic stress on post-traumatic stress (PTS) symptoms and impaired daily functioning following collective stress (September 11th terrorist attacks). Saliva was collected by mail and used to genotype 704 respondents. Participants completed Web-based assessments of pre-9/11 mental health, acute stress 9-23 days after 9/11, the quality of social environments 1 year post-9/11, economic stress 18 months post-9/11, and PTS symptoms and impaired functioning 2 and 3 years post-9/11. Interactions between negative social environments and economic stress were examined separately based on OXTR rs53576 genotype (GG vs. any A allele). For individuals with an A allele, a negative social environment significantly increased PTS symptoms without regard to the level of economic stress experienced. However, for respondents with a GG genotype, negative social environments predicted elevated PTS symptoms only for those also experiencing high economic stress. Gender moderated associations between negative social environments, economic stress, and impaired functioning. The functioning of females was most affected by negative social environments regardless of genotype and economic stress, whereas the functioning of males was differentially susceptible to economic stress depending on OXTR genotype and negative social environments. These findings suggest that it is important to consider the combined impact of gender and ongoing stress in different domains as moderators of genetic vulnerability following collective stress.

No association between oxytocin receptor (OXTR) gene polymorphisms and experimentally elicited social preferences.

BACKGROUND: Oxytocin (OXT) has been implicated in a suite of complex social behaviors including observed choices in economic laboratory experiments. However, actual studies of associations between oxytocin receptor (OXTR) gene variants and experimentally elicited social preferences are rare. METHODOLOGY/PRINCIPAL FINDINGS: We test hypotheses of associations between social preferences, as measured by behavior in two economic games, and 9 single nucleotide polymorphisms (SNPs) of the OXTR gene in a sample of Swedish twins (n = 684). Two standard economic games, the dictator game and the trust game, both involving real monetary consequences, were used to elicit such preferences. After correction for multiple hypothesis testing, we found no significant associations between any of the 9 single nucleotide polymorphisms (SNPs) and behavior in either of the games. CONCLUSION: We were unable to replicate the most significant association reported in previous research between the amount donated in a dictator game and an OXTR genetic variant.

Telencephalic binding sites for oxytocin and social organization: a comparative study of eusocial naked mole-rats and solitary cape mole-rats.

African mole-rats provide a unique taxonomic group for investigating the evolution and neurobiology of sociality. The two species investigated here display extreme differences in social organization and reproductive strategy. Naked mole-rats (NMRs) live in colonies, dominated by a queen and her consorts; most members remain nonreproductive throughout life but cooperate in burrowing, foraging, and caring for pups, for which they are not biological parents (alloparenting). In contrast, Cape mole-rats (CMRs) are solitary and intolerant of conspecifics, except during fleeting seasonal copulation or minimal maternal behavior. Research on other mammals suggests that oxytocin receptors at various telencephalic sites regulate social recognition, monogamous pair bonding, and maternal/allomaternal behavior. Current paradigms in this field derive from monogamous and polygamous species of New World voles, which are evolutionarily remote from Old World mole-rats. The present findings indicate that NMRs exhibit a considerably greater level of oxytocin receptor (OTR) binding than CMRs in the: nucleus accumbens; indusium griseum; central, medial, and cortical amygdaloid nuclei; bed nucleus of the stria terminalis; and CA1 hippocampal subfield. In contrast, OTR binding in the piriform cortex is intense in CMRs but undetectable in NMRs. We speculate that the abundance of OTR binding and oxytocin-neurophysin-immunoreactive processes in the nucleus accumbens of NMRs reflects their sociality, alloparenting behavior, and potential for reproductive attachments. In contrast, the paucity of oxytocin and its receptors at this site in CMRs may reflect a paucity of prosocial behaviors. Whether similarities in OTR expression between eusocial mole-rats and monogamous voles are due to gene conservation or convergent evolution remains to be determined.

The oxytocin receptor (OXTR) contributes to prosocial fund allocations in the dictator game and the social value orientations task.

BACKGROUND: Economic games observe social decision making in the laboratory that involves real money payoffs. Previously we have shown that allocation of funds in the Dictator Game (DG), a paradigm that illustrates costly altruistic behavior, is partially determined by promoter-region repeat region variants in the arginine vasopressin 1a receptor gene (AVPR1a). In the current investigation, the gene encoding the related oxytocin receptor (OXTR) was tested for association with the DG and a related paradigm, the Social Values Orientation (SVO) task. METHODOLOGY/PRINCIPAL FINDINGS: Association (101 male and 102 female students) using a robust-family based test between 15 single tagging SNPs (htSNPs) across the OXTR was demonstrated with both the DG and SVO. Three htSNPs across the gene region showed significant association with both of the two games. The most significant association was observed with rs1042778 (p = 0.001). Haplotype analysis also showed significant associations for both DG and SVO. Following permutation test adjustment, significance was observed for 2-5 locus haplotypes (p<0.05). A second sample of 98 female subjects was subsequently and independently recruited to play the dictator game and was genotyped for the three significant SNPs found in the first sample. The rs1042778 SNP was shown to be significant for the second sample as well (p = 0.004, Fisher's exact test). CONCLUSIONS: The demonstration that genetic polymorphisms for the OXTR are associated with human prosocial decision making converges with a large body of animal research showing that oxytocin is an important social hormone across vertebrates including Homo sapiens. Individual differences in prosocial behavior have been shown by twin studies to have a substantial genetic basis and the current investigation demonstrates that common variants in the oxytocin receptor gene, an important element of mammalian social circuitry, underlie such individual differences.