Clock Gene Modulates Roles of OXTR and AVPR1b Genes in Prosociality

Background

The arginine vasopressin receptor (AVPR) and oxytocin receptor (OXTR) genes have been demonstrated to contribute to prosocial behavior. Recent research has focused on the manner by which these simple receptor genes influence prosociality, particularly with regard to the AVP system, which is modulated by the clock gene. The clock gene is responsible for regulating the human biological clock, affecting sleep, emotion and behavior. The current study examined in detail whether the influences of the OXTR and AVPR1b genes on prosociality are dependent on the clock gene.

Methodology/Principal Findings

This study assessed interactions between the clock gene (rs1801260, rs6832769) and the OXTR (rs1042778, rs237887) and AVPR1b (rs28373064) genes in association with individual differences in prosociality in healthy male Chinese subjects (n = 436). The Prosocial Tendencies Measure (PTM-R) was used to assess prosociality. Participants carrying both the GG/GA variant of AVPR1b rs28373064 and the AA variant of clock rs6832769 showed the highest scores on the Emotional PTM. Carriers of both the T allele of OXTR rs1042778 and the C allele of clock rs1801260 showed the lowest total PTM scores compared with the other groups.

Conclusions

The observed interaction effects provide converging evidence that the clock gene and OXT/AVP systems are intertwined and contribute to human prosociality.     

Chimpanzee sociability is associated with vasopressin (Avpr1a) but not oxytocin receptor gene (OXTR) variation

The importance of genes in regulating phenotypic variation of personality traits in humans and animals is becoming increasingly apparent in recent studies. Here we focus on variation in the vasopressin receptor gene 1a (Avpr1a) and oxytocin receptor gene (OXTR) and their effects on social personality traits in chimpanzees. We combine newly available genetic data on Avpr1a and OXTR allelic variation of 62 captive chimpanzees with individual variation in personality, based on behavioral assessments. Our study provides support for the positive association of the Avpr1a promoter region, in particular the presence of DupB, and sociability in chimpanzees. This complements findings of previous studies on adolescent chimpanzees and studies that assessed personality using questionnaire data. In contrast, no significant associations were found for the single nucleotide polymorphism (SNP) ss1388116472 of the OXTR and any of the personality components. Most importantly, our study provides additional evidence for the regulatory function of the 5′ promoter region of Avpr1a on social behavior and its evolutionary stable effect across species, including rodents, chimpanzees and humans. Although it is generally accepted that complex social behavior is regulated by a combination of genes, the environment and their interaction, our findings highlight the importance of candidate genes with large effects on behavioral variation.     

Molecular Variation in AVP and AVPR1a in New World Monkeys (Primates,Platyrrhini): Evolution and Implications for Social Monogamy

The neurohypophysial hormone arginine vasopressin (AVP) plays important roles in fluid regulation and vascular resistance. Differences in AVP receptor expression, particularly mediated through variation in the noncoding promoter region of the primary receptor for AVP (AVPR1a), may play a role in social phenotypes, particularly social monogamy, in rodents and humans. Among primates, social monogamy is rare, but is common among New World monkeys (NWM). AVP is a nonapeptide and generally conserved among eutherian mammals, although a recent paper demonstrated that some NWM species possess a novel form of the related neuropeptide hormone, oxytocin. We therefore characterized variation in the AVP and AVPR1a genes in 22 species representing every genus in the three major platyrrhine families (Cebidae, Atelidae and Pitheciidae). For AVP, a total of 16 synonymous substitutions were detected in 15 NWM species. No non-synonymous substitutions were noted, hence, AVP is conserved in NWM. By contrast, relative to the human AVPR1a, 66 predicted amino acids (AA) substitutions were identified in NWM. The AVPR1a N-terminus (ligand binding domain), third intracellular (G-protein binding domain), and C-terminus were variable among species. Complex evolution of AVPR1a is also apparent in NWM. A molecular phylogenetic tree inferred from AVPR1a coding sequences revealed some consensus taxonomic separation by families, but also a mixed group composed of genera from all three families. The overall dN/dS ratio of AVPR1a was 0.11, but signals of positive selection in distinct AVPR1a regions were observed, including the N-terminus, in which we identified six potential positive selection sites. AA substitutions at positions 241, 319, 399 and 409 occurred uniquely in marmosets and tamarins. Our results enhance the appreciation of genetic diversity in the mammalian AVP/AVPR1a system, and set the stage for molecular modeling of the neurohypophyseal hormones and social behavior in primates.     

Association between the oxytocin receptor (OXTR) gene and children's social cognition at 18 months

At 18 months, children engage in a variety of social behaviors that reflect their nascent ability to understand the intentions of other people (e.g. joint attention, empathy, cooperation and self‐recognition). Although numerous contextual factors have been shown to predict social cognition in young children, the genetic underpinnings of social‐cognitive traits has been understudied in this age group. Owing to the known effects of oxytocin on adult social cognition and psychopathology, this study hypothesized that variability in the oxytocin receptor gene (OXTR) would be associated with social cognition in children at 18 months. Participants consisted of 350 children (182 males; 168 females) who were part of an ongoing longitudinal study that aimed to assess environmental and genetic contributions to children's cognitive and socio‐emotional functioning. At 18 months, social cognition was measured using previously validated and developmentally sensitive tasks assessing children's joint attention, empathy, cooperation and self‐recognition. Five potentially functional OXTR variants were genotyped: rs1042778, rs2254298, rs11131149, rs237897 and rs237899. A family‐based association design was used to control for population admixture and stratification, and additional non‐genomic covariates were controlled. Results showed that variability in rs11131149 was significantly associated with social cognition (P = 0.009), with more copies of the major allele related to higher social cognition, and more copies of the minor (risk) allele associated with lower social cognition. A haplotype consisting of rs11131149–rs2254298 was also associated with social cognition (P = 0.020). Implications for normative and pathological development are discussed, and key areas for future research are proposed.     

Genetic variants in oxytocin receptor and arginine-vasopressin receptor 1A are associated with the neural correlates of maternal and paternal affection towards their child

There is extensive evidence in animal studies, particularly in vole species (Microtus), that oxytocin (OT) receptor and arginine-vasopressin (AVP) receptor 1a is critical for the regulation of maternal and paternal behavior, respectively. Human studies have gained insight into the relationship between both hormone receptor gene variants and behavior, but not between the variants and the underlying brain activity. To study this, we investigated the association between neural activation of the anterior prefrontal cortex (APFC) in mothers and fathers in response to their child smiling video stimuli to induce the positive affect related to attachment with their child, and genetic variants of OT receptor (OXTR) and AVP receptor 1A (AVPR1A). Overall, 43 mothers and 41 fathers participated, and each parent's child smiling was video recorded. Participants were then genotyped and underwent near-infrared spectroscopy to measure neural activation of the APFC while observing their own child smiling compared with an unfamiliar child. We found that the right inferior APFC was activated in response to child video stimuli in mothers and differential hemispheric activation of the inferior APFC in OXTR rs2254298-G/G mothers compared with -A carrier mothers, but not in fathers. Furthermore, we found a difference in the left inferior APFC activation between AVPR1A RS3-non-334 and -334 carrier fathers, but not mothers. Our results indicate a sex-dependent association between the genetic variants and the inferior APFC activations of maternal and paternal positive affect, analogous to the results reported in voles.     

BDNF Val66Met Polymorphism Is Associated with Self-Reported Empathy

Empathy is an important driver of human social behaviors and presents genetic roots that have been studied in neuroimaging using the intermediate phenotype approach. Notably, the Val66Met polymorphism of the Brain-derived neurotrophic factor (BDNF) gene has been identified as a potential target in neuroimaging studies based on its influence on emotion perception and social cognition, but its impact on self-reported empathy has never been documented. Using a neurogenetic approach, we investigated the association between the BDNF Val66Met polymorphism and self-reported empathy (Davis’ Interpersonal Reactivity Index; IRI) in a sample of 110 young adults. Our results indicate that the BDNF genotype is significantly associated with the linear combination of the four facets of the IRI, one of the most widely used self-reported empathy questionnaire. Crucially, the effect of BDNF Val66Met goes beyond the variance explained by two polymorphisms of the oxytocin transporter gene previously associated with empathy and its neural underpinnings (OXTR rs53576 and rs2254298). These results represent the first evidence suggesting a link between the BDNF gene and self-reported empathy and warrant further studies of this polymorphism due to its potential clinical significance.     

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.     

Oxytocin and Vasopressin Receptor Gene Variation as a Proximate Base for Inter- and Intraspecific Behavioral Differences in Bonobos and Chimpanzees

Recent literature has revealed the importance of variation in neuropeptide receptor gene sequences in the regulation of behavioral phenotypic variation. Here we focus on polymorphisms in the oxytocin receptor gene (OXTR) and vasopressin receptor gene 1a (Avpr1a) in chimpanzees and bonobos. In humans, a single nucleotide polymorphism (SNP) in the third intron of OXTR (rs53576 SNP (A/G)) is linked with social behavior, with the risk allele (A) carriers showing reduced levels of empathy and prosociality. Bonobos and chimpanzees differ in these same traits, therefore we hypothesized that these differences might be reflected in variation at the rs53576 position. We sequenced a 320 bp region surrounding rs53576 but found no indications of this SNP in the genus Pan. However, we identified previously unreported SNP variation in the chimpanzee OXTR sequence that differs from both humans and bonobos. Humans and bonobos have previously been shown to have a more similar 5′ promoter region of Avpr1a when compared to chimpanzees, who are polymorphic for the deletion of ∼360 bp in this region (+/− DupB) which includes a microsatellite (RS3). RS3 has been linked with variation in levels of social bonding, potentially explaining part of the interspecies behavioral differences found in bonobos, chimpanzees and humans. To date, results for bonobos have been based on small sample sizes. Our results confirmed that there is no DupB deletion in bonobos with a sample size comprising approximately 90% of the captive founder population, whereas in chimpanzees the deletion of DupB had the highest frequency. Because of the higher frequency of DupB alleles in our bonobo population, we suggest that the presence of this microsatellite may partly reflect documented differences in levels of sociability found in bonobos and chimpanzees.     

Introduction of the human AVPR1A gene substantially alters brain receptor expression patterns and enhances aspects of social behavior in transgenic mice

Central arginine vasopressin receptor 1A (AVPR1A) modulates a wide range of behaviors, including stress management and territorial aggression, as well as social bonding and recognition. Inter- and intra-species variations in the expression pattern of AVPR1A in the brain and downstream differential behavioral phenotypes have been attributed to differences in the non-coding regions of the AVPR1A gene, including polymorphic elements within upstream regulatory areas. Gene association studies have suggested a link between AVPR1A polymorphisms and autism, and AVPR1A has emerged as a potential pharmacological target for treatment of social cognitive impairments and mood and anxiety disorders. To further investigate the genetic mechanism giving rise to species differences in AVPR1A expression patterns and associated social behaviors, and to create a preclinical mouse model useful for screening drugs targeting AVPR1A, we engineered and extensively characterized bacterial artificial chromosome (BAC) transgenic mice harboring the entire human AVPR1A locus with the surrounding regulatory elements. Compared with wild-type animals, the humanized mice displayed a more widely distributed ligand-AVPR1A binding pattern, which overlapped with that of primates. Furthermore, humanized AVPR1A mice displayed increased reciprocal social interactions compared with wild-type animals, but no differences in social approach and preference for social novelty were observed. Aspects of learning and memory, specifically novel object recognition and spatial relocation recognition, were unaffected. The biological alterations in humanized AVPR1A mice resulted in the rescue of the prepulse inhibition impairments that were observed in knockout mice, indicating conserved functionality. Although further behavioral paradigms and additional cohorts need to be examined in humanized AVPR1A mice, the results demonstrate that species-specific variations in the genomic content of regulatory regions surrounding the AVPR1A locus are responsible for differential receptor protein expression patterns across species and that they are likely to contribute to species-specific behavioral variation. The humanized AVPR1A mouse is a potential preclinical model for further understanding the regulation of receptor gene expression and the impact of variation in receptor expression on behaviors, and should be useful for screening drugs targeting human AVPR1A, taking advantage of the expression of human AVPR1A in human-relevant brain regions.KEY WORDS: AVPR1A, Humanized mouse, Social behavior, Species-specific, Microsatellite, Autism     

Intranasal oxytocin and a polymorphism in the oxytocin receptor gene are associated with human-directed social behavior in golden retriever dogs

The oxytocin system may play an important role in dog domestication from the wolf. Dogs have evolved unique human analogue social skills enabling them to communicate and cooperate efficiently with people. Genomic differences in the region surrounding the oxytocin receptor (OXTR) gene have previously been associated with variation in dogs' communicative skills. Here we have utilized the unsolvable problem paradigm to investigate the effects of oxytocin and OXTR polymorphisms on human-directed contact seeking behavior in 60 golden retriever dogs. Human-oriented behavior was quantified employing a previously defined unsolvable problem paradigm. Behaviors were tested twice in a repeated, counterbalanced design, where dogs received a nasal dose of either oxytocin or saline 45 min before each test occasion. Buccal DNA was analysed for genotype on three previously identified SNP-markers associated with OXTR. The same polymorphisms were also genotyped in 21 wolf blood samples to explore potential genomic differences between the species. Results showed that oxytocin treatment decreased physical contact seeking with the experimenter and one of the three polymorphisms was associated with degree of physical contact seeking with the owner. Dogs with the AA-genotype at this locus increased owner physical contact seeking in response to oxytocin while the opposite effect was found in GG-genotype individuals. Hence, intranasal oxytocin treatment, an OXTR polymorphism and their interaction are associated with dogs' human-directed social skills, which can explain previously described breed differences in oxytocin response. Genotypic variation at the studied locus was also found in wolves indicating that it was present even at the start of dog domestication.     

The contributions of oxytocin and vasopressin pathway genes to human behavior

Arginine vasopressin (AVP) and oxytocin (OXT) are social hormones and mediate affiliative behaviors in mammals and as recently demonstrated, also in humans. There is intense interest in how these simple nonapeptides mediate normal and abnormal behavior, especially regarding disorders of the social brain such as autism that are characterized by deficits in social communication and social skills. The current review examines in detail the behavioral genetics of the first level of human AVP-OXT pathway genes including arginine vasopressin 1a receptor (AVPR1a), oxytocin receptor (OXTR), AVP (AVP-neurophysin II [NPII]) and OXT (OXT neurophysin I [NPI]), oxytocinase/vasopressinase (LNPEP), ADP-ribosyl cyclase (CD38) and arginine vasopressin 1b receptor (AVPR1b). Wherever possible we discuss evidence from a variety of research tracks including molecular genetics, imaging genomics, pharmacology and endocrinology that support the conclusions drawn from association studies of social phenotypes and detail how common polymorphisms in AVP-OXT pathway genes contribute to the behavioral hard wiring that enables individual Homo sapiens to interact successfully with conspecifics. This article is part of a Special Issue entitled Oxytocin, Vasopressin, and Social Behavior.     

Variation in mothers' arginine vasopressin receptor 1a and dopamine receptor D4 genes predicts maternal sensitivity via social cognition

We examined the extent to which the arginine vasopressin receptor 1a (AVPR1a) and dopamine receptor D4 (DRD4) were related to sensitive maternal behavior directly or indirectly via maternal social cognition. Participants were 207 (105 European‐American and 102 African‐American) mothers and their children (52% females). Sensitive maternal behavior was rated and aggregated across a series of tasks when infants were 6 months, 1 year and 2 years old. At 6 months, mothers were interviewed about their empathy, attributions about infant behavior and beliefs about crying to assess their parenting‐related social cognition. Mothers with long alleles for AVPR1a and DRD4 engaged in more mother‐oriented social cognition (i.e. negative attributions and beliefs about their infants' crying, β = 0.13, P < 0.05 and β = 0.16, P < 0.05, respectively), which in turn predicted less sensitive maternal behavior (β = ?0.23, P < 0.01). Both indirect effects were statistically significant independent of one another and covariates [95% confidence interval (CI): ?0.22, ?0.03 and β = ?0.03 for AVPR; 95% CI: ?0.20, ?0.03 and β = ?0.04 for DRD4]. There were no significant direct effects of AVPR1a or DRD4 on maternal sensitivity (β = 0.02, P = .73 and β = ?0.10, P = .57, respectively). The results did not vary for African‐American and European‐American mothers (Δχ² = 18.76, Δdf = 16, P = 0.28). Results support the view that one mechanism by which maternal genes are associated with parental behavior is via social cognition.     

Pharmacological chaperones for the oxytocin receptor increase oxytocin responsiveness in myometrial cells

Oxytocin is a potent uterotonic agent administered to nearly all patients during childbirth in the United States. Inadequate oxytocin response can necessitate Cesarean delivery or lead to uterine atony and postpartum hemorrhage. Thus, it may be clinically useful to identify patients at risk for poor oxytocin response and develop strategies to sensitize the uterus to oxytocin. Previously, we showed that the V281M variant in the oxytocin receptor (OXTR) gene impairs OXTR trafficking to the cell surface, leading to a decreased oxytocin response in cells. Here, we sought to identify pharmacological chaperones that increased oxytocin response in cells expressing WT or V281M OXTR. We screened nine small-molecule agonists and antagonists of the oxytocin/vasopressin receptor family and identified two, SR49059 and L371,257, that restored both OXTR trafficking and oxytocin response in HEK293T cells transfected with V281M OXTR. In hTERT-immortalized human myometrial cells, which endogenously express WT OXTR, treatment with SR49059 and L371,257 increased the amount of OXTR on the cell surface by two- to fourfold. Furthermore, SR49059 and L371,257 increased the endogenous oxytocin response in hTERT-immortalized human myometrial cells by 35% and induced robust oxytocin responses in primary myometrial cells obtained from patients at the time of Cesarean section. If future studies demonstrate that these pharmacological chaperones or related compounds function similarly in vivo, we propose that they could potentially be used to enhance clinical response to oxytocin.     

Interaction between Oxytocin Genotypes and Early Experience Predicts Quality of Mothering and Postpartum Mood

Individual differences in maternal behavior are affected by both early life experiences and oxytocin, but little is known about genetic variation in oxytocin genes and its effects on mothering. We examined two polymorphisms in the oxytocin peptide gene OXT (rs2740210 and rs4813627) and one polymorphism in the oxytocin receptor gene OXTR (rs237885) in 187 Caucasian mothers at six months postpartum. For OXT, both rs2740210 and rs4813627 significantly associated with maternal vocalizing to the infant. These polymorphisms also interacted with the quality of care mothers experienced in early life, to predict variation in maternal instrumental care and postpartum depression. However, postpartum depression did not mediate the gene-environment effects of the OXT SNPs on instrumental care. In contrast, the OXTR SNP rs237885 did not associate with maternal behavior, but it did associate with pre-natal (but not post-natal) depression score. The findings illustrate the importance of variation in oxytocin genes, both alone and in interaction with early environment, as predictors of individual differences in human mothering. Furthermore, depression does not appear to have a causal role on the variation we report in instrumental care. This suggests that variation in instrumental care varies in association with a gene-early environment effect regardless of current depressive symptomatology. Finally, our findings highlight the importance of examining multiple dimensions of human maternal behavior in studies of genetic associations.     

Polymorphisms in Genes of Relevance for Oestrogen and Oxytocin Pathways and Risk of Barrett’s Oesophagus and Oesophageal Adenocarcinoma: A Pooled Analysis from the BEACON Consortium

Background

The strong male predominance in oesophageal adenocarcinoma (OAC) and Barrett’s oesophagus (BO) continues to puzzle. Hormonal influence, e.g. oestrogen or oxytocin, might contribute.

Methods

This genetic-epidemiological study pooled 14 studies from three continents, Australia, Europe, and North America. Polymorphisms in 3 key genes coding for the oestrogen pathway (receptor alpha (ESR1), receptor beta (ESR2), and aromatase (CYP19A1)), and 3 key genes of the oxytocin pathway (the oxytocin receptor (OXTR), oxytocin protein (OXT), and cyclic ADP ribose hydrolase glycoprotein (CD38)), were analysed using a gene-based approach, versatile gene-based test association study (VEGAS).

Results

Among 1508 OAC patients, 2383 BO patients, and 2170 controls, genetic variants within ESR1 were associated with BO in males (p = 0.0058) and an increased risk of OAC and BO combined in males (p = 0.0023). Genetic variants within OXTR were associated with an increased risk of BO in both sexes combined (p = 0.0035) and in males (p = 0.0012). We followed up these suggestive findings in a further smaller data set, but found no replication. There were no significant associations between the other 4 genes studied and risk of OAC, BO, separately on in combination, in males and females combined or in males only.

Conclusion

Genetic variants in the oestrogen receptor alpha and the oxytocin receptor may be associated with an increased risk of BO or OAC, but replication in other large samples are needed.     

Impact of Childhood Adversity and Vasopressin receptor 1a Variation on Social Interaction in Adulthood: A Cross-Sectional Study

Background

Arginine vasopressin (AVP) plays a role in social behavior, through receptor AVPR1A. The promoter polymorphism AVPR1A RS3 has been associated with human social behaviors, and with acute response to stress. Here, the relationships between AVPR1A RS3, early-life stressors, and social interaction in adulthood were explored.

Methods

Adult individuals from a Swedish population-based cohort (n = 1871) were assessed for self-reported availability of social integration and social attachment and for experience of childhood adversities. Their DNA samples were genotyped for the microsatellite AVPR1A RS3.

Results

Among males, particularly those homozygous for the long alleles of AVPR1A RS3 were vulnerable to childhood adversity for their social attachment in adulthood. A similar vulnerability to childhood adversity among long allele carriers was found on adulthood social integration, but here both males and females were influenced.

Limitation

Data were self-reported and childhood adversity data were retrospective.

Conclusions

Early-life stress influenced the relationship between AVPR1A genetic variants and social interaction. For social attachment, AVPR1A was of importance in males only. The findings add to previous reports on higher acute vulnerability to stress in persons with long AVPR1A RS3 alleles and increased AVP levels.     

Sexually dimorphic effects of oxytocin receptor gene (OXTR ) variants on Harm Avoidance

Background

Recent research has suggested that oxytocin receptor gene (OXTR) variants may account for individual differences in social behavior, the effects of stress and parenting styles. Little is known, however, on a putative role of the gene in heritable temperamental traits.

Methods

We addressed effects of two common OXTR variants, rs237900 and rs237902, on personality dimensions in 99 healthy subjects using the Temperament and Character Inventory.

Results

When sex was controlled for and an OXTR genotype*sex interaction term was included in the regression model, 11% of the variance in Harm Avoidance could be explained (uncorrected p????0.01). Female carriers of the minor alleles scored highest, and a novel A217T mutation emerged in the most harm avoidant male participant.

Conclusions

Findings lend support to a modulatory effect of common OXTR variants on Harm Avoidance in healthy caucasian women and invite resequencing of the gene in anxiety phenotypes to identify more explanatory functional variation.     

Neuroelectric Correlates of Pragmatic Emotional Incongruence Processing: Empathy Matters

The emotions people feel can be simulated internally based on emotional situational contexts. In the present study, we assessed the behavioral and neuroelectric effects of seeing an unexpected emotional facial expression. We investigated the correct answer rate, response times and Event-Related Potential (ERP) effects during an incongruence paradigm between emotional faces and sentential contexts allowing emotional inferences. Most of the 36 healthy participants were recruited from a larger population (1 463 subjects), based on their scores on the Empathy Questionnaire (EQ). Regression analyses were conducted on these ratings using EQ factors as predictors (cognitive empathy, emotional reactivity and social skills). Recognition of pragmatic emotional incongruence was less accurate (P < .05) and slower (P < .05) than recognition of congruence. The incongruence effect on response times was inversely predicted by social skills. A significant N400 incongruence effect was found at the centro-parietal (P < .001) and centro-posterior midline (P < .01) electrodes. Cognitive empathy predicted the incongruence effect in the left occipital region, in the N400 time window. Finally, incongruence effects were also found on the LPP wave, in frontal midline and dorso-frontal regions, (P < .05), with no modulation by empathy. Processing pragmatic emotional incongruence is more cognitively demanding than congruence (as reflected by both behavioral and ERP data). This processing shows modulation by personality factors at the behavioral (through self-reported social skills) and neuroelectric levels (through self-reported cognitive empathy).     

AVPR1A Sequence Variation in Monogamous Owl Monkeys (Aotus azarai) and Its Implications for the Evolution of Platyrrhine Social Behavior

The arginine vasopressin V1a receptor gene (AVPR1A) has been implicated in increased partner preference and pair bonding behavior in mammalian lineages. This observation is of considerable importance for studies of social monogamy, which only appears in a small subset of primate taxa, including the Argentinean owl monkey (Aotus azarai). Thus, to investigate the possible influence of AVPR1A on the evolution of social behavior in owl monkeys, we sequenced this locus in a wild population from the Gran Chaco. We also assessed the interspecific variation of AVPR1A in platyrrhine species that represent a set of phylogenetically and behaviorally disparate taxa. The resulting data revealed A. azarai to have a unique genic structure for AVPR1A that varies in coding sequence and microsatellite repeat content relative to other primate and mammalian species. Specifically, one repetitive region that has been the focus in studies of human AVPR1A diversity, “RS3,” is completely absent in A. azarai and all other platyrrhines examined. This finding suggests that, if AVPR1A modulates behavior in owl monkeys and other neotropical primates, it does so independent of this region. These observations have also provided clues about the process by which the range of social behavior in the Order Primates evolved through lineage-specific neurogenetic variation.     

AVPR1A variation is linked to gray matter covariation in the social brain network of chimpanzees

The vasopressin system has been implicated in the regulation of social behavior and cognition in humans, nonhuman primates and other social mammals. In chimpanzees, polymorphisms in the vasopressin V1a receptor gene (AVPR1A) have been associated with social dimensions of personality, as well as to responses to sociocommunicative cues and mirror self‐recognition. Despite evidence of this association with social cognition and behavior, there is little research on the neuroanatomical correlates of AVPR1A variation. In the current study, we tested the association between AVPR1A polymorphisms in the RS3 promotor region and gray matter covariation in chimpanzees using magnetic resonance imaging and source‐based morphometry. The analysis identified 13 independent brain components, three of which differed significantly in covariation between the two AVPR1A genotypes (DupB?/? and DupB+/?; P < .05). DupB+/? chimpanzees showed greater covariation in gray matter in the premotor and prefrontal cortex, basal forebrain, lunate and cingulate cortex, and lesser gray matter covariation in the superior temporal sulcus and postcentral sulcus. Some of these regions were previously found to differ in vasopressin and oxytocin neural fibers between nonhuman primates, and in AVPR1A gene expression in humans with different RS3 alleles. This is the first report of an association between AVPR1A and gray matter covariation in nonhuman primates, and specifically links an AVPR1A polymorphism to structural variation in the social brain network. These results further affirm the value of chimpanzees as a model species for investigating the relationship between genetic variation, brain structure and social cognition with relevance to psychiatric disorders, including autism.