Empathy reflects the natural ability to perceive and be sensitive to the emotional states of others, coupled with a motivation to care for their well-being. It has evolved in the context of parental care for offspring, as well as within kinship bonds, to help facilitate group living. In this paper, we integrate the perspectives of evolution, animal behaviour, developmental psychology, and social and clinical neuroscience to elucidate our understanding of the proximate mechanisms underlying empathy. We focus, in particular, on processing of signals of distress and need, and their relation to prosocial behaviour. The ability to empathize, both in animals and humans, mediates prosocial behaviour when sensitivity to others' distress is paired with a drive towards their welfare. Disruption or atypical development of the neural circuits that process distress cues and integrate them with decision value leads to callous disregard for others, as is the case in psychopathy. The realization that basic forms of empathy exist in non-human animals is crucial for gaining new insights into the underlying neurobiological and genetic mechanisms of empathy, enabling translation towards therapeutic and pharmacological interventions.

Human altruism is a widespread phenomenon that puzzled evolutionary biologists since Darwin. Economic games illustrate human altruism by showing that behavior deviates from economic predictions of profit maximization. A game that most plainly shows this altruistic tendency is the Dictator Game. We hypothesized that human altruistic behavior is to some extent hardwired and that a likely candidate that may contribute to individual differences in altruistic behavior is the arginine vasopressin 1a (AVPR1a) receptor that in some mammals such as the vole has a profound impact on affiliative behaviors. In the current investigation, 203 male and female university students played an online version of the Dictator Game, for real money payoffs. All subjects and their parents were genotyped for AVPR1a RS1 and RS3 promoter-region repeat polymorphisms. Parents did not participate in online game playing. As variation in the length of a repetitive element in the vole AVPR1a promoter region is associated with differences in social behavior, we examined the relationship between RS1 and RS3 repeat length (base pairs) and allocation sums. Participants with short versions (308-325 bp) of the AVPR1a RS3 repeat allocated significantly (likelihood ratio 5 14.75, P 5 0.001, df 5 2) fewer shekels to the 'other' than participants with long versions (327-343 bp). We also implemented a family-based association test, UNPHASED, to confirm and validate the correlation between the AVPR1a RS3 repeat and monetary allocations in the dictator game. Dictator game allocations were significantly associated with the RS3 repeat (global P value: likelihood ratio x 2 5 11.73, df 5 4, P 5 0.019). The association between the AVPR1a RS3 repeat and altruism was also confirmed using two selfreport scales (the Bardi-Schwartz Universalism and Benevolence Value-expressive Behavior scales). RS3 long alleles were associated with higher scores on both measures. Finally, long AVPR1a RS3 repeats were associated with higher AVPR1a human post-mortem hippocampal messenger RNA levels than short RS3 repeats (one-way analysis of variance (ANOVA): F 5 15.04, P 5 0.001, df 5 14) suggesting a functional molecular genetic basis for the observation that participants with the long RS3 repeats allocate more money than participants with the short repeats. This is the first investigation showing that a common human polymorphism, with antecedents in lower mammals, contributes to decision making in an economic game. The finding that the same gene contributing to social bonding in lower animals also appears to operate similarly in human behavior suggests a common evolutionary mechanism.

BackgroundEconomic 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 FindingsAssociation (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).ConclusionsThe 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.

Increasing evidence suggests that two nonapeptides, arginine vasopressin and oxytocin, shape human social behavior in both nonclinical and clinical subjects. Evidence is discussed that in autism spectrum disorders genetic polymorphisms in the vasopressin-oxytocin pathway, notably the arginine vasopressin receptor 1a (AVPR1a), the oxytocin receptor (OXTR), neurophysin I and II, and CD38 (recently shown to be critical for social behavior by mediating oxytocin secretion) contribute to deficits in socialization skills in this group of patients. We also present first evidence that CD38 expression in lymphoblastoid cells derived from subjects diagnosed with autism is correlated with social skill phenotype inventoried by the Vineland Adaptive Behavioral Scales. Additionally, we discuss molecular genetic evidence that in nonclinical subjects both AVPR1a and OXTR genes contribute to prosocial or altruistic behavior inventoried by two experimental paradigms, the dictator game and social values orientation. The role of the AVPR1a is also analyzed in prepulse inhibition. Prepulse inhibition of the startle response to auditory stimuli is a largely autonomic response that resonates with social cognition in both animal models and humans. First results are presented showing that intranasal administration of arginine vasopressin increases salivary cortisol levels in the Trier Social Stress test. To summarize, accumulating studies employing a broad array of cutting-edge tools in psychology, neuroeconomics, molecular genetics, pharmacology, electrophysiology, and brain imaging are beginning to elaborate the intriguing role of oxytocin and arginine vasopressin in human social behavior. We expect that future studies will continue this advance and deepen our understanding of these complex events.

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