A common allele in the oxytocin receptor gene (OXTR) impacts prosocial temperament and human hypothalamic-limbic structure and function

Abstract

The evolutionarily highly conserved neuropeptide oxytocin is a key mediator of social and emotional behavior in mammals, including humans. A common variant (rs53576) in the oxytocin receptor gene (OXTR) has been implicated in social-behavioral phenotypes, such as maternal sensitivity and empathy, and with neuropsychiatric disorders associated with social impairment, but the intermediate neural mechanisms are unknown. Here, we used multimodal neuroimaging in a large sample of healthy human subjects to identify structural and functional alterations in OXTR risk allele carriers and their link to temperament. Activation and interregional coupling of the amygdala during the processing of emotionally salient social cues was significantly affected by genotype. In addition, evidence for structural alterations in key oxytocinergic regions emerged, particularly in the hypothalamus. These neural characteristics predicted lower levels of reward dependence, specifically in male risk allele carriers. Our findings identify sex-dependent mechanisms impacting the structure and function of hypothalamic-limbic circuits that are of potential clinical and translational significance.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.

Allelic variation in OXTR predicts differences in hypothalamus volume. The minor allele carriers of OXTR rs53576 show a significant decrease in hypothalamus gray matter (P = 0.012, FWE corrected). Bar plots depict the mean value for the parameter estimates of the peak voxels, stratified by genotype. Error bars illustrate the variance of parameter estimates (±SEM).

Fig. 2.

Allelic variation in OXTR predicts differences in prosocial temperament. Distribution of TPQ reward dependence (RD) scores between rs53576 genotype groups. The comparison of the two homozygote groups (G/G vs. A/A) confirmed the presence of significantly lower RD values in OXTR risk allele carriers.

Fig. 3.

Allelic variation in OXTR predicts differences in amygdala activation and connectivity during the perceptual processing of facial emotion. (A) Significant activation decrease of the amygdala in the minor allele carriers for rs53576 (P = 0.036, FWE corrected). (B) Significant increase in the functional correlation of the hypothalamus and amygdala in minor allele carriers for rs53576 (P = 0.036, FWE corrected). Bar plots depict the mean value for the parameter estimates of the peak voxels stratified by genotype. Error bars illustrate the variance of parameter estimates (±SEM). The blue region illustrates the hypothalamus seed region of the analysis.