Epigenetic modification of the oxytocin receptor gene influences the perception of anger and fear in the human brain

Abstract

In humans, the neuropeptide oxytocin plays a critical role in social and emotional behavior. The actions of this molecule are dependent on a protein that acts as its receptor, which is encoded by the oxytocin receptor gene (OXTR). DNA methylation of OXTR, an epigenetic modification, directly influences gene transcription and is variable in humans. However, the impact of this variability on specific social behaviors is unknown. We hypothesized that variability in OXTR methylation impacts social perceptual processes often linked with oxytocin, such as perception of facial emotions. Using an imaging epigenetic approach, we established a relationship between OXTR methylation and neural activity in response to emotional face processing. Specifically, high levels of OXTR methylation were associated with greater amounts of activity in regions associated with face and emotion processing including amygdala, fusiform, and insula. Importantly, we found that these higher levels of OXTR methylation were also associated with decreased functional coupling of amygdala with regions involved in affect appraisal and emotion regulation. These data indicate that the human endogenous oxytocin system is involved in attenuation of the fear response, corroborating research implicating intranasal oxytocin in the same processes. Our findings highlight the importance of including epigenetic mechanisms in the description of the endogenous oxytocin system and further support a central role for oxytocin in social cognition. This approach linking epigenetic variability with neural endophenotypes may broadly explain individual differences in phenotype including susceptibility or resilience to disease. oxytocin receptor | OXTR | epigenetics | fMRI | social perception

C-tactile afferents: Cutaneous mediators of oxytocin release during affiliative tactile interactions?

“…Further evidence that individual differences in sensitivity to socially relevant stimuli may be related to oxytocin functions comes from several recent epigenetic studies (Jack et al, 2012;Puglia et al, 2015). The first reported that DNA methylation at the OXTR was predictive of an individual's neural response to biological motion (Jack et al, 2012).…”

Oxytocin pathways in the intergenerational transmission of maternal early life stress

“…In addition to sequence variations in OT pathway genes, epigenetic modifications of the OXTR gene have recently attracted considerable attention in clinical, behavioral, and cognitive neurosciences (Kumsta et al, 2013) and have been associated with different phenotypes including maternal PPD (Bell et al, 2015; Kimmel et al, 2016), amygdala reactivity (Puglia et al, 2015), autism (Gregory et al, 2009), and social anxiety disorder (Ziegler et al, 2015) amongst others. Briefly, epigenetics encompasses a set of biochemical modifications of genome function (e.g., histone modifications, DNA methylation, or the effects of small non-coding RNAs, e.g., micro RNAs) that interfere with transcriptional or translational events and can therefore regulate gene expression.…”

“…Effects of maternal care were small, however, and phenotypic differences (i.e., higher depression risk) that could link these differentially methylated regions to variation in observable behavior were not assessed. It has been recently shown that increased peripheral blood cell OXTR promoter methylation at CpG −934 is correlated with higher amygdala reactivity and also with lower functional connectivity between right amygdala and brain areas involved in emotion regulation (cingulate and orbitofrontal cortex), suggesting an inhibition of top-down regulation of the amygdala (Puglia et al, 2015). This finding provides first evidence of the predictive value of peripheral OXTR methylation in explaining variability of functional alterations in brain areas that are key in modulation of affective states.…”

“…Taken together, it would be premature to draw general conclusions from the reported findings. Nevertheless, based on the exciting initial empirical evidence (Bell et al, 2015; Kimmel et al, 2016; Puglia et al, 2015), epigenetic modifications of the OXTR gene clearly deserve further attention when considering the role of OT-related intergenerational transmission pathways in the future.…”

The ANKK1/DRD2 locus is a genomic substrate for affective priming and recognition of angry faces

“…2002) and is modulated by other relevant genetic and epigenetic biomarkers for social behavior like those related to oxytocin (Puglia et al. 2015). Furthermore, some data suggest that the same neural systems activated during the identification of a particular emotion in others also respond to the personal experience of this emotion (Assogna et al.…”