Epigenetic regulation of the oxytocin receptor is associated with neural response during selective social attention

Abstract

Aberrant attentional biases to social stimuli have been implicated in a number of disorders including autism and social anxiety disorder. Oxytocin, a naturally-occurring mammalian hormone and neuromodulator involved in regulating social behavior, has been proposed to impact basic biological systems that facilitate the detection of and orientation to social information. Here, we investigate a role for naturally-occurring variability in the endogenous oxytocinergic system in regulating neural response during attention to social information. Participants performed a selective social attention task while undergoing fMRI, provided a blood sample for epigenetic analysis, and completed self-report measures of social functioning. We find that a functional epigenetic modification to the oxytocin receptor, OXTR methylation, is associated with increased neural response within and decreased functional coupling between regions of the salience and attentional control networks during selective social attention. We also show that subclinical variability in autistic and social anxiety traits moderates this epigenetic regulation of neural response. These data offer a mechanistic explanation to a growing literature associating social behavior and disorder with epigenetic modification to OXTR by suggesting that OXTR methylation reflects a decrease in the extent to which social information automatically captures attention. We highlight the importance that treatment efficacy be considered in relation to individual differences in molecular makeup, and that future studies aimed at uncovering biomarkers of disorder carefully consider measurement at both the biological and phenotypic level.

Endogenous oxytocin inhibits hypothalamic corticotrophin‐releasing hormone neurones following acute hypernatraemia

“…Indeed, functional expression of Oxtr(s) is likely to be subject to robust and dynamic regulatory control. [31][32][33] Overall, we consider that these results reinforce the conclusion that a substantial subset of PVN Nevertheless, it should also be noted that there was no significant difference between group means for CRH-Oxtr KO mice and littermates when compared directly to one another using a two-sample t test (P = .12).…”

“…Although it is plausible that protocol differences increase bias towards false positives in protocol 1 and false negatives in protocol 2, it is also plausible that actual cohort variability contributed significantly to these results. Indeed, functional expression of Oxtr(s) is likely to be subject to robust and dynamic regulatory control . Overall, we consider that these results reinforce the conclusion that a substantial subset of PVN CRH neurones contain detectable levels of Oxtr mRNA.…”

Epigenetic dysregulation of Oxtr in Tet1-deficient mice has implications for neuropsychiatric disorders

“…OXTR has been the focus of extensive genetic and epigenetic studies for its role in psychiatric diseases or morbid behaviors in humans. There are more than 20 studies focusing on analysis of 5mC in the different CpG sites within the CpG island in humans (Supplemental Figure 10) (14,17,(54)(55)(56)(82)(83)(84)(85)(86)(87)(88)(89)(90)(91)(92). The regions equivalent to the hypermethylated BS1 and BS2 in Tet1 mutant mice have been the focus in these studies.…”

Epigenetic tuning of brain signal entropy in emergent human social behavior

“…(2) highly variable in the general population and associated with neural response during social perceptual tasks in neurotypical adults [47][48][49], suggesting it is a viable marker of individual differences in (endo) phenotypes; and (3) elevated in the brain and blood of both individuals with autism [46] and vole pups who experienced lower parental care early in life [50], suggesting this marker is indicative of individual developmental differences that are reflected in both causative (brain) and peripheral (blood) tissue.…”