Repetitive microsatellites mutate at relatively high rates and may contribute to the rapid evolution of species-typical traits. We show that individual alleles of a repetitive polymorphic microsatellite in the 5' region of the prairie vole vasopressin 1a receptor (avpr1a) gene modify gene expression in vitro. In vivo, we observe that this regulatory polymorphism predicts both individual differences in receptor distribution patterns and socio-behavioral traits. These data suggest that individual differences in gene expression patterns may be conferred via polymorphic microsatellites in the cis-regulatory regions of genes and may contribute to normal variation in behavioral traits.

Understanding the neurobiological substrates regulating normal social behaviours may provide valuable insights in human behaviour, including developmental disorders such as autism that are characterized by pervasive deficits in social behaviour. Here, we review the literature which suggests that the neuropeptides oxytocin and vasopressin play critical roles in modulating social behaviours, with a focus on their role in the regulation of social bonding in monogamous rodents. Oxytocin and vasopressin contribute to a wide variety of social behaviours, including social recognition, communication, parental care, territorial aggression and social bonding. The effects of these two neuropeptides are species-specific and depend on species-specific receptor distributions in the brain. Comparative studies in voles with divergent social structures have revealed some of the neural and genetic mechanisms of social-bonding behaviour. Prairie voles are socially monogamous; males and females form long-term pair bonds, establish a nest site and rear their offspring together. In contrast, montane and meadow voles do not form a bond with a mate and only the females take part in rearing the young. Species differences in the density of receptors for oxytocin and vasopressin in ventral forebrain reward circuitry differentially reinforce social-bonding behaviour in the two species. High levels of oxytocin receptor (OTR) in the nucleus accumbens and high levels of vasopressin 1a receptor (V1aR) in the ventral pallidum contribute to monogamous social structure in the prairie vole. While little is known about the genetic factors contributing to species-differences in OTR distribution, the species-specific distribution pattern of the V1aR is determined in part by a speciesspecific repetitive element, or 'microsatellite', in the 5 0 regulatory region of the gene encoding V1aR (avpr1a). This microsatellite is highly expanded in the prairie vole (as well as the monogamous pine vole) compared to a very short version in the promiscuous montane and meadow voles. These species differences in microsatellite sequence are sufficient to change gene expression in cell culture. Within the prairie vole species, intraspecific variation in the microsatellite also modulates gene expression in vitro as well as receptor distribution patterns in vivo and influences the probability of social approach and bonding behaviour. Similar genetic variation in the human AVPR1A may contribute to variations in human social behaviour, including extremes outside the normal range of behaviour and those found in autism spectrum disorders. In sum, comparative studies in pair-bonding rodents have revealed neural and genetic mechanisms contributing to social-bonding behaviour. These studies have generated testable hypotheses regarding the motivational systems and underlying molecular neurobiology involved in social engagement and social bond formation that may have important implications for the core social deficits characterizing autism spectrum disorders.

Autism spectrum disorder (ASD) is characterized by core deficits in social behavior, communication, and behavioral flexibility. Several lines of evidence indicate that oxytocin, signaling through its receptor (OXTR), is important in a wide range of social behaviors. In attempts to determine whether genetic variations in the oxytocin signaling system contribute to ASD susceptibility, seven recent reports indicated association of common genetic polymorphisms in the OXTR gene with ASD. Each involved relatively small sample sizes (57 to 436 families) and, where it was examined, failed to identify association of OXTR polymorphisms with measures of social behavior in individuals with ASD. We report genetic association analysis of 25 markers spanning the OXTR locus in 1,238 pedigrees including 2,333 individuals with ASD. Association of three markers previously implicated in ASD susceptibility, rs2268493 (P = 0.043), rs1042778 (P = 0.037), and rs7632287 (P = 0.016), was observed. Further, these genetic markers were associated with multiple core ASD phenotypes, including social domain dysfunction, measured by standardized instruments used to diagnose and describe ASD. The data suggest association of OXTR genetic polymorphisms with ASD, although the results should be interpreted with caution because none of the significant associations would survive appropriate correction for multiple comparisons. However, the current findings of association in a large independent cohort are consistent with previous results, and the biological plausibility of participation of the oxytocin signaling system in modulating social disruptions characteristic of ASD, suggest that functional polymorphisms of OXTR may contribute to ASD risk in a subset of families.

Oxytocin (OXT) has drawn increasing attention as a developmentally relevant neuropeptide given its role in the brain regulation of social behavior. It has been suggested that OXT plays an important role in the infant brain during caregiver attachment in nurturing familial contexts, but there is incomplete experimental evidence. Mouse models of OXT system genes have been particularly informative for the role of the OXT system in social behavior, however, the developing brain areas that could respond to ligand activation of the OXT receptor (OXTR) have yet to be identified in this species. Here we report new data revealing dynamic ligand-binding distribution of OXTR in the developing mouse brain. Using male and female C57BL/6J mice at postnatal days (P) 0, 7, 14, 21, 35, and 60 we quantified OXTR ligand binding in several brain areas which changed across development. Further, we describe OXTR ligand binding in select tissues of the near-term whole embryo at E18.5. Together, these data aid in the interpretation of findings in mouse models of the OXT system and generate new testable hypotheses for developmental roles for OXT in mammalian systems. We discuss our findings in the context of developmental disorders (including autism), attachment biology, and infant physiological regulation.Summary: Quantitative mapping of selective OXTR ligand binding during postnatal development in the mouse reveals an unexpected, transient expression in layers II/III throughout the mouse neocortex. OXTR are also identified in several tissues in the whole late embryo, including the adrenal glands, brown adipose tissue, and the oronasal cavity.