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Vasotocin (VT) and its mammalian homologue, vasopressin (VP), modulate many social behaviors in a variety of vertebrate species. In songbirds, the effects of centrally administered VT vary according to species, which may reflect species-specific distributions of VT binding sites. Different radioligands used to map receptors in previous autoradiographical studies have revealed nonoverlapping distributions of VT binding, suggesting a heterogeneous population of more than one type of VT receptor. For two model songbird species, the white-throated sparrow (Zonotrichia albicollis) and zebra finch (Taeniopygia guttata), we labeled putative VT receptors with two radioligands, [(125)I]ornithine vasotocin analog ([(125)I]OVTA) and [(125)I]linear VP antagonist ([(125)I]HO-LVA). Competitive binding assays in the lateral septum showed that both ligands were effectively displaced by both VT and a related nonapeptide, mesotocin (MT), showing that these radioligands, which were developed to label mammalian nonapeptide receptors, label at least one population of related receptors in songbirds. [(125)I]OVTA labeled receptors throughout the telencephalon, diencephalon, midbrain, and brainstem, with a similar distribution in both species. In contrast, the binding of [(125)I]HO-LVA was restricted to the septal area, dorsal arcopallium, and optic tectum in sparrow and was essentially undetectable in zebra finch. Because the avian brain is likely to express multiple types of VT receptors, we hypothesize that the binding patterns of these radioligands represent a heterogeneous receptor population.

There is growing evidence that the neuropeptides oxytocin and vasopressin modulate complex social behavior and social cognition. These ancient neuropeptides display a marked conservation in gene structure and expression, yet diversity in the genetic regulation of their receptors seems to underlie natural variation in social behavior, both between and within species. Human studies are beginning to explore the roles of these neuropeptides in social cognition and behavior and suggest that variation in the genes encoding their receptors may contribute to variation in human social behavior by altering brain function. Understanding the neurobiology and neurogenetics of social cognition and behavior has important implications, both clinically and for society.

Oxytocin mediates social affiliation behaviors and social memory in rodents. It has been suggested that disruptions in oxytocin contribute to the deficits in reciprocal social interactions that characterize autism. The present experiments employed a new social approach task for mice which is designed to detect low levels of sociability, representing the first diagnostic criterion for autism. Two lines of oxytocin knockout mice were tested, the National Institute of Mental Health line in Bethesda, and the Baylor/Emory line at the University of North Carolina in Chapel Hill. Similar methods were used for each line to evaluate tendencies to spend time with a stranger mouse versus with an inanimate novel object with no social valence. Adult C57BL/6J males were tested identically, as controls to confirm the robustness of the methods used in the social task. Comprehensive phenotyping of general health, neurological reflexes, olfactory and other sensory abilities, and motor functions was employed to assess both lines. No genotype differences were detected in any of the control measures for either line. Normal sociability, measured as time spent with a novel stranger mouse as compared to time spent with a novel object, was seen in both the NIMH and the Baylor/Emory lines of oxytocin null mutants, heterozygotes, and wild-type littermate controls. Normal preference for social novelty, measured as time spent with a second novel stranger as compared to time spent with a more familiar mouse, was seen in both the NIMH and the Baylor/Emory lines of oxytocin null mutants, heterozygotes, and wild-type littermate controls, with minor exceptions. Similar behavioral results from two independent targeted gene mutations, generated with different targeting vectors, bred on different genetic backgrounds, and tested in different laboratory environments, corroborates the negative findings on sociability in oxytocin mutant mice. Intact tendencies to spend time with another mouse versus with a novel object, in both lines of oxytocin knockouts, supports an interpretation that oxytocin plays a highly specific role in social memory, but is not essential for general spontaneous social approach in mice.

Centrally released oxytocin regulates maternal behavior, social memory, and social bonding. A recent paper by Jin et al. published in Nature demonstrates that the transmembrane receptor CD38 plays a critical role in regulating social behaviors by regulating the release of OT from hypothalamic neurons.

Comparative studies in voles have suggested that a polymorphic microsatellite upstream of the Avpr1a locus contributes to the evolution of monogamy. A recent study challenged this hypothesis by reporting that there is no relationship between microsatellite structure and monogamy in 21 vole species. Although the study demonstrates that the microsatellite is not a universal genetic switch that determines mating strategy, the findings do not preclude a substantial role for Avpr1a in regulating social behaviors associated with monogamy.

Social relationships are essential for maintaining human mental health, yet little is known about the brain mechanisms involved in the development and maintenance of social bonds. Animal models are powerful tools for investigating the neurobiological mechanisms regulating the cognitive processes leading to the development of social relationships and for potentially extending our understanding of the human condition. In this review, we discuss the roles of the neuropeptides oxytocin and vasopressin in the regulation of social bonding as well as related social behaviors which culminate in the formation of social relationships in animal models. The formation of social bonds is a hierarchical process involving social motivation and approach, the processing of social stimuli and formation of social memories, and the social attachment itself. Oxytocin and vasopressin have been implicated in each of these processes. Specifically, these peptides facilitate social affiliation and parental nurturing behavior, are essential for social recognition in rodents, and are involved in the formation of selective mother-infant bonds in sheep and pair bonds in monogamous voles. The convergence of evidence from these animal studies makes oxytocin and vasopressin attractive candidates for the neural modulation of human social relationships as well as potential therapeutic targets for the treatment of psychiatric disorders associated with disruptions in social behavior, including autism.

Endocrine-disrupting chemicals (EDCs) are synthetic chemicals that arise from sources such as pesticides and have the ability to mimic or inhibit gonadal steroid hormones. The objective of this research was to examine the effects of EDCs on the behaviors associated with monogamy and the expression of related neuropeptide receptors. Pine voles, a novel experimental mammal, were chosen because they display strong monogamous pair bonding. Female pine voles were orally administered estrogenic diethylstilbestrol (DES) and methoxychlor (MXC) or oil control throughout gestation and lactation of pups. Exposed pups were tested as adults. Preference for the mate and maternal behaviors were assessed. While the ability to form partner preferences was intact, DES-exposed females showed increased aggression toward a stranger, while MXC exposed females showed a strong trend toward spending more time alone. Oxytocin (OT) receptor binding in the brain was assessed for possible effects on this behaviorally important neuropeptide signaling system. The cingulate cortex showed a reduction in OT binding in the MXC group. These findings demonstrate that exposure to EDCs during pre- and neonatal development can alter female adult neural phenotype and behavior related to monogamous behavior traits.

Studies in monogamous rodents have begun to elucidate the neural circuitry underlying the formation and maintenance of selective pair bonds between mates. This research suggests that at least three distinct, yet interconnected, neural pathways interact in the establishment of the pair bond. These include circuits involved in conveying somatosensory information from the genitalia to the brain during sexual activity, the mesolimbic dopamine circuits of reward and reinforcement, and neuropeptidergic circuits involved specifically in the processing of socially salient cues. Here we present an integrated description of the interaction of these circuits in a model of pair bond formation in rodents with a discussion of the implications of these findings for evolution, individual variation, and human bonding., ((c) 2005 Wiley-Liss, Inc.)

Previous findings with an AVP V1a receptor knockout mouse (V1aRKO) demonstrate a significant role for this receptor in anxiety-like behavior in males. Here we report the lack of anxiety-like effects of the null mutation in female mice. V1aRKO females performed normally on all tests for anxiety-like behavior. This sex difference may be due to the sexual dimorphism in the extra-hypothalamic vasopressin system, with males having significantly more vasopressin fibers in this system.

Corticotropin-releasing factor (CRF) receptor subtypes 1 and 2 have been implicated in rodent models of anxiety, but much less is known about the CRF system and social behavior. Both corticosterone and central CRF receptors modulate pair bonding in the monogamous prairie vole. Using receptor autoradiography, we mapped CRFR(1) and CRFR(2) in the brains of two monogamous vole species, the prairie vole and pine vole, and two promiscuous vole species, the meadow vole and montane vole. We found markedly different patterns of brain CRFR(1) and CRFR(2) binding among the four species, including species differences in the olfactory bulb, nucleus accumbens, lateral septum, hippocampus, laterodorsal thalamus, cingulate cortex, superior colliculus, and dorsal raphe. Interestingly, we also observed striking sex differences in voles: CRFR(2) binding was higher in the encapsulated bed nucleus of the stria terminalis in males than females for all four vole species. These results suggest possible sites of action for CRF-induced facilitation of pair bond formation in prairie voles, as well as potential sex differences in the CRF modulation of pair bonding. Further examination of CRF receptors in vole species may reveal a novel role for CRF in social behavior. Ultimately, our results identify several brain regions with conserved CRF receptor patterns across rodent and primate species, in contrast to several brain regions with phylogenetically plastic CRF receptor patterns, and have interesting implications for the evolution of CRF receptor patterns and behavior., ((c) 2005 Wiley-Liss, Inc.)

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.

While pheromones may act as social memory signals, oxytocin and vasopressin acting in the brain appear to be critical for the neural processing of olfactory signatures used for social discrimination. Evidence from a variety of laboratories using a range of animal models, as well as an array of molecular and pharmacological techniques, have helped to determine the neuroanatomical and functional roles oxytocin and vasopressin play in social cognition. In this review we discuss the considerable evidence for the roles of oxytocin and vasopressin in social recognition in rats and mice, as well as in offspring recognition in sheep and mate preference in monogamous voles.

Forebrain vasopressin/vasotocin systems regulate a diverse set of complex social behaviors in a species-specific manner. Among mammals, vasopressin gene sequences and peptide distributions in the brain are highly conserved across species. In contrast, vasopressin V1a receptors (V1aR) are conserved at the protein level, but not at the level of gene structure or neuroanatomical distribution of the receptor. Here, we examine the functional role of a microsatellite segment in the 5' region of V1aR that differs significantly between monogamous and nonmonogamous vole species with divergent V1aR expression patterns. Using luciferase reporter assays, we demonstrate that this microsatellite plays a significant role in transcriptional regulation in a cell-type-specific manner. These results suggest that significant evolutionary changes in social behavior can occur through variation in regulatory regions of genes already involved in social behavior.

Oxytocin receptors (OTR) and vasopressin V1a receptors (V1aR) in the ventral forebrain play critical roles in the formation of pair bonds in the monogamous prairie vole. Previous reports have been inconsistent in the identification of the specific brain regions in the ventral forebrain that express these receptors. To delineate more clearly the neuroanatomical boundaries of the OTR and V1aR fields in this species, we compared OTR and V1aR binding in adjacent brain sections and also with markers that delineate neuroanatomical boundaries in the ventral forebrain. OTR binding displayed an overlapping distribution with substance P mRNA and preproenkephalin mRNA, both markers for the shell and core of the nucleus accumbens. V1aR binding was nonoverlapping with each of these markers but colocalized with iron accumulation as shown by Perls' iron stain as well as leucine-enkephalin immunoreactivity, both markers for the ventral pallidum. OTR and V1aR mRNA were also restricted within the nucleus accumbens and ventral pallidum, respectively. Furthermore, destruction of ventral striatal dopaminergic terminals with 6-hydroxydopamine infusions into the nucleus accumbens did not alter OTR binding. Immunocytochemical analysis of oxytocin and vasopressin in the ventral forebrain demonstrated the presence of oxytocin-immunoreactive fibers in the nucleus accumbens and vasopressin-immunoreactive fibers in the ventral pallidum, with males showing a greater density of vasopressin fibers than females, but there was no such sex difference in the oxytocin system. Based on these results, we discuss potential neural mechanisms by which receptors in these brain regions mediate pair bond formation in this monogamous species. J. Comp. Neurol. 468:555-570, 2004., (Copyright 2003 Wiley-Liss, Inc.)

Instability in highly repetitive microsatellite DNA located in the regulatory regions of genes may be a major factor producing diversity in both region-specific gene expression and the resulting phenotypes. Polymorphisms in promoter regions affecting expression of genes involved in regulating behaviour may play a role in generating individual variation in behaviour, including psychopathologies in humans, and probably are also important for the evolution of behaviour. Here we discuss the prairie vole vasopressin V1a receptor gene as a model that may be useful for understanding the evolution of promoter sequences and the relationship between gene sequence, expression and behavioural phenotype.

Isoflavone phytoestrogens are growing increasingly popular because of their reported cardiovascular and anticarcinogenic properties, but the effects of these compounds in the brain are largely unknown. In a previous study, we found that an isoflavone supplement, containing a mixture of soy phytoestrogens, inhibited estrogen-dependent female sexual behavior and was antiestrogenic for both ER alpha- and ER beta-dependent gene expression in the hypothalamus. Here we examined the impact of the soy isoflavone genistein, a major component of the supplement, on estrogen-dependent female sexual behavior and ER alpha- and ER beta-dependent gene expression in the rat brain. Genistein, at a dietary concentration of 100 or 500 ppm had no effect on lordosis behavior in rats. However, at 500 ppm genistein had differential activity through ER alpha and ER beta in the hypothalamus. Genistein had no effect, in either the presence or absence of 17 beta-E2, on oxytocin receptor density in the ventromedial nucleus of the hypothalamus, an estrogen-dependent action thought to be regulated via ER alpha. However, genistein increased ER beta mRNA expression in the paraventricular nucleus of the hypothalamus by 24%, whereas 17 beta-E2 decreased ER beta mRNA expression by 26%, a process likely mediated by ER beta itself. These results suggest that at this dose, genistein has antiestrogenic action through ER beta in the paraventricular nucleus but negligible activity through ER alpha in the brain.

Rodent models of social behavior provide powerful experimental tools for elucidating the molecular, cellular, and neurobiological mechanisms regulating social behavior. Here I discuss several rodent models that have been particularly useful in understanding the neurobiology of the discrimination of social verses nonsocial stimuli, affiliative behavior, and social avoidance. The oxytocin knockout mouse model has been useful for understanding how, in the context of social recognition, the brain may process social stimuli differently from nonsocial stimuli. Vole species that are either highly social and monogamous or solitary and promiscuous have provided a model for investigating the brain mechanisms involved in promoting social interactions. Comparative studies in these species strongly implicate the neuropeptides oxytocin and vasopressin in the regulation of affiliative behavior as well as social attachment. A conditioned defeat model in hamsters may provide a useful model to understand how adverse social experiences may facilitate social avoidance. These models have yielded valuable insights into the regulation of social behaviors, and the findings of these studies may prove useful in understanding the neural mechanisms that underlie individual differences in human personality traits.

Isoflavonoids are plant estrogens that are increasingly advocated as a natural alternative to estrogen replacement therapy (ERT) and are available as dietary supplements. As weak estrogen agonists/antagonists with a range of other enzymatic activities, the isoflavonoids provide a useful model for the actions of endocrine disruptors. This paper reviews the responses of rodents to diets containing coumestrol or an isoflavone supplement in comparison to animals fed the phytoestrogen-free AIN76A diet. Neural mechanisms were investigated by examining isoflavonoid effects on ER(alpha)-dependent (regulation of oxytocin receptor [OTR] binding in the ventromedial nucleus of the hypothalamus [VMN]) and ERbeta-dependent (regulation of ERbeta mRNA in the paraventricular nucleus [PVN]) endpoints. Activational as well as organizational effects on sexual behavior and gonadotropin secretion were observed for coumestrol. Treatment of rat dams with a 100-ppm coumestrol diet from birth to postnatal day (PND) 21 induced premature anovulation in female offspring, and treatment from birth to PND 10 suppressed sexual behavior in male offspring. One-week treatment of ovariectomized (OVX) female rats with the same coumestrol diet increased ERbeta mRNA expression in the PVN, an effect opposite to that of estradiol. Ten days of treatment with a 200-ppm coumestrol diet increased LH secretion in OVX wild-type mice, an effect opposite to the normal negative feedback effects of estradiol. No effects were observed in ER(alpha) knockout (ER(alpha)KO)-OVX females, indicating that coumestrol's action on LH was mediated through ER(alpha). Similar activational effects were observed for the isoflavone diet. The lordotic response to estrogen was significantly reduced by 2 days of treatment of OVX adult females with an isoflavone diet providing 13 ppm genistein and 33 ppm daidzein. One week of treatment with the same isoflavone diet produced an effect opposite to that of estradiol in the PVN, increasing ERbeta mRNA expression above control levels. These investigations show that, in spite of their preferential affinity for ERbeta, isoflavonoids act through both ER(alpha) and ERbeta. Moreover, their neurobehavioral actions were antiestrogenic, either antagonizing or producing an action in opposition to that of estradiol. This work demonstrates that even small, physiologically relevant exposure levels can alter estrogen-dependent gene expression in the brain and complex behavior.