Oxytocin Receptors and Neurobehavior

Abstract

Research across species has shown that the neuropeptide oxytocin plays a key role in the regulation of social cognition and behavior. It is important for attachment, social exploration, and social recognition, as well as anxiety and stress-related behaviors. Based on oxytocin administration studies and measurements of peripheral oxytocin levels, it has been suggested that signaling of oxytocin is impaired in mental disorders associated with social defi cits, including autism, bor-derline personality disorder, and social anxiety disorder. There are several factors infl uencing interindividual differences in social-cognitive abilities and differences in the susceptibility to psychiatric disorders, including variability in genes involved in oxytocin signaling. In addition to sequence variation, interindividual differences might in part be explained by variation in epigenetic processes infl uencing gene expression. Here, we provide an overview of the functional organization and epi-genetic regulation of the murine and human oxytocin receptor gene. Studies in mice have shown that the oxytocin receptor gene (Oxtr) is epigeneti-cally regulated by DNA methylation with experience-and tissue-specifi c expression patterns. In humans, functional studies on epigenetic mechanisms have focused on oxytocin receptor gene (OXTR) DNA methylation and have provided evidence for the infl uence of OXTR promoter methylation on OXTR mRNA expression. A small number of studies have investigated the role of OXTR methylation in behavioral phenotypes and mental illness. There is fi rst evidence that OXTR methylation is associated with different aspects of social cognition as well as with psychiatric dis-orders characterized by defi cits in social cognition, including autism, high callous-unemotional traits in youth, social anxiety, and anorexia nervosa. Given evidence that epigenetic states of genes can be modifi ed by experiences, especially those occurring in sensitive periods early in development, we conclude with a discussion on the effects of traumatic experience on the developing oxytocin system. Epigenetic modifi cation of genes involved in oxytocin signaling might play a part in the mechanisms mediating the long-term infl uence of early adverse experiences on socio-behavioral outcomes. 10.1.1 The Murine Oxytocin Receptor Gene (Oxtr) Several rodent species, including voles, rats, and mice, have been used as model organisms to characterize the role of the oxytocin in social behaviors. However, in terms of epigenetic regulation, only the murine Oxtr has been investigated system-atically so far. The murine Oxtr gene sequence was fi rst published by Kubota and colleagues (1996) who mapped it to chromosome 6 (D86599; chr6: 112.425.884-112.440.884; July 2007 – NCBI37/mm9). It covers a region of about 20 kilobases (kb) and is comprised of four exons and three introns. The start codon of the 2914 nucleotide mRNA transcript is located within exon III, with a coding sequence extending into exon IV as matrix for a 388 amino acid (aa) seven transmembrane domain receptor. At the DNA sequence level, the murine Oxtr displays 87 % simi-larity to the coding sequence of its human orthologue; on protein level, 92 % simi-larity between murine and human oxytocin receptor is found. In its 5′ regulatory region, the Oxtr promoter lacks typical elements of eukaryotic promotors like a TATA or CAAT box but contains an 859 basepair (bp) CpG island 1