Leveraging the unique social organization of California mice to study circuit-specific effects of oxytocin on behavior.

Oxytocin is a versatile neuropeptide that modulates many different forms of social behavior. Recent hypotheses pose that oxytocin enhances the salience of rewarding and aversive social experiences, and the field has been working to identify mechanisms that allow oxytocin to have diverse effects on behavior. Here we review studies conducted on the California mouse (Peromyscus californicus) that shed light on how oxytocin modulates social behavior following stressful experiences. In this species, both males and females exhibit high levels of aggression, which has facilitated the study of how social stress impacts both sexes. We review findings of short- and long-term effects of social stress on the reactivity of oxytocin neurons. We also consider the results of pharmacological studies which show that oxytocin receptors in the bed nucleus of the stria terminalis and nucleus accumbens have distinct but overlapping effects on social approach behaviors. These findings help explain how social stress can have different behavioral effects in males and females, and how oxytocin can have such divergent effects on behavior. Finally, we consider how new technological developments and innovative research programs take advantage of the unique social organization of California mice to address questions that can be difficult to study in conventional rodent model species. These new methods and questions have opened new avenues for studying the neurobiology of social behavior.

Oxytocin & well-being as promoters of affect regulation and homeostasis: a neuroscientific review / Ocitocina & bem-estar como promotores da regulação afetiva e da homeostase: uma revisão neurocientífica / Oxitocina y bienestar como promotores de la regulación del afecto y de la homeostasis: una revisión neurocientífica

Context: The term "Well-being" [WB] has many different meanings in scientific literature. Objectives: To search specific situations and related semantics for feelings of well-being [WB] associated to oxytocin [OT] release. Data sources: A systematic review using PRISMA guidelines in PubMed, BVS Virtual (Medline, Lilacs) and SIBI-USP Portal de Busca Integrada (1970-1999 & 2014-2018). Study selection: Reviews and clinical trials (PICOS) on OT, & WB and similar concepts in humans. Data extraction: Independent selection of articles by two reviewers; selection of articles by one reviewer, using predefined criteria. Data synthesis: 46 articles were selected out of 339, with 26 additional articles. Main data referred to social situations, sensorial stimuli, trust and psychiatric and health studies. Conclusions: The identified variables involved brain-body-mind interactions, and health/disease; translational neuroscience seems to be the best theoretical reference to investigate it.

Contexto: O termo "Bem-estar" [WB] apresenta muitos significados diferentes na literatura. Objetivos: Buscar situações específicas e semânticas relacionadas a sentimentos de bem-estar [WB] ligados à ocitocina [OT]. Fontes de dados: Revisão sistemática a partir das Referências PRISMA nas bases de dados PubMed, BVS Virtual (Medline, Lilacs) and SIBI-USP Portal de Busca Integrada (1970-1999 & 2014-2018). Seleção do estudo: revisões e ensaios clínicos (PICOS) sobre OT, & WB e sinônimos, em humanos. Extração de dados: seleção independente de artigos por dois revisores. Um revisor selecionou os textos utilizando critérios pré-definidos. Síntese dos dados: Dentre 339 artigos, 46 foram selecionados, e mais 26 posteriormente adicionados. Os principais dados obtidos referiam-se a situações sociais, estímulos sensoriais, confiança e estudos psiquiátricos e de saúde. Conclusões: As variáveis identificadas envolveram interações cérebro-corpo-mente e saúde; A neurociência translacional parece ser o melhor referencial teórico para investigá-la.

Contexto: El termo "Bienestar" [WB] abarca muchos significados diferentes en la literatura científica. Objetivos: buscar situaciones y semánticas sobre sentimientos de bienestar [WB] asociados con la produccion de oxitocina [OT]. Fuentes de datos: Revisión sistemática en PubMed, BVS Virtual (Medline, Lilacs) y SIBI-USP Portal de Busca Integrada (1970-1999; 2014-2018). Selección de estudios: revisiones y ensayos clínicos (PICOS) en OT, & WB y sinónimos, en humanos. Extracción de datos: Extracion independiente de artículos por dos revisores; selección de artículos por un revisor, utilizando criterios predefinidos. Síntesis de datos: se seleccionaron 46 artículos dentre 339, y mas 26 adicionales. Los datos principales se referían a situaciones sociales, estímulos sensoriales, confianza y estudios psiquiátricos y de salud. Conclusiones: Las variables identificadas involucraron interacciones cerebro-cuerpo-mente y salud; La neurociencia traslacional parece ser el mejor marco teórico para investigarlo.

The neurobiology of mammalian parenting and the biosocial context of human caregiving.

This article is part of a Special Issue "Parental Care". Research on the neurobiology of attachment, pioneered by scholars in the generation that followed the discovery of social bonding, examined the biological basis of mammalian parenting through systematic experiments in animal models and their application to theories on human attachment. This paper argues for the need to construct a theory on the neurobiology of human attachment that integrates findings in animal models with human neuroscience research to formulate concepts based on experimental, not only extrapolative data. Rosenblatt's (2003) three characteristics of mammalian parenting - rapid formation of attachment, behavioral synchrony, and mother-offspring attachment as basis of social organization - are used to guide discussion on mammalian-general versus human-specific attributes of parental care. These highlight specific components of attachment in rodents, primates, and humans that chart the evolution from promiscuous, nest-bound, olfactory-based bonds to exclusive, multi-sensory, and representation-based attachments. Following, three continua are outlined in parental behavior, hormones, and brain, each detailing the evolution from rodents to humans. Parental behavior is defined as a process of trophallaxis - the reciprocal multisensory exchange that supports approach orientation and enables collaboration in social species - and includes human-specific features that enable behavioral synchrony independent of tactile contact. The oxytocin system incorporates conserved and human-specific components and is marked by pulsatile activity and dendritic release that reorganize neural networks on the basis of species-specific attachment experiences. Finally, the subcortical limbic circuit underpinning mammalian mothering extends in humans to include multiple cortical networks implicated in empathy, mentalizing, and emotion regulation that enable flexible, goal-directed caregiving. I conclude by presenting a philosophical continuum from Hobbes to Lorenz, which illustrates how research on the neurobiology of attachment can put in the forefront the social-collaborative elements in human nature and afford a new perspective on the mind-brain polarity.

Control of food intake and energy expenditure by Nos1 neurons of the paraventricular hypothalamus.

The paraventricular nucleus of the hypothalamus (PVH) contains a heterogeneous cluster of Sim1-expressing cell types that comprise a major autonomic output nucleus and play critical roles in the control of food intake and energy homeostasis. The roles of specific PVH neuronal subtypes in energy balance have yet to be defined, however. The PVH contains nitric oxide synthase-1 (Nos1)-expressing (Nos1(PVH)) neurons of unknown function; these represent a subset of the larger population of Sim1-expressing PVH (Sim1(PVH)) neurons. To determine the role of Nos1(PVH) neurons in energy balance, we used Cre-dependent viral vectors to both map their efferent projections and test their functional output in mice. Here we show that Nos1(PVH) neurons project to hindbrain and spinal cord regions important for food intake and energy expenditure control. Moreover, pharmacogenetic activation of Nos1(PVH) neurons suppresses feeding to a similar extent as Sim1(PVH) neurons, and increases energy expenditure and activity. Furthermore, we found that oxytocin-expressing PVH neurons (OXT(PVH)) are a subset of Nos1(PVH) neurons. OXT(PVH) cells project to preganglionic, sympathetic neurons in the thoracic spinal cord and increase energy expenditure upon activation, though not to the same extent as Nos1(PVH) neurons; their activation fails to alter feeding, however. Thus, Nos1(PVH) neurons promote negative energy balance through changes in feeding and energy expenditure, whereas OXT(PVH) neurons regulate energy expenditure alone, suggesting a crucial role for non-OXT Nos1(PVH) neurons in feeding regulation.

Maternal oxytocin response during mother-infant interaction: associations with adult temperament.

Oxytocin is a neuropeptide associated with social affiliation and maternal caregiving. However, its effects appear to be moderated by various contextual factors and stable individual characteristics. The purpose of this study was to investigate the relationship of self-reported state and trait measures (such as temperament, mood and affect) with peripheral oxytocin response in mothers. Fifty-five first-time mothers participated in a semi-structured procedure, during which time repeated peripheral oxytocin levels were measured before, during and after an episode of mother-infant interaction. The maternal oxytocin response was then calculated, based on the difference in oxytocin concentration between initial baseline and interaction phase. Mothers also completed state measures of positive and negative affect and depression, and trait measures of temperament, personality disturbance and depression across time. Regression analyses determined which factors were independently associated with maternal oxytocin response. The trait measure of adult temperament emerged as a significant predictor of oxytocin response. Two out of four Adult Temperament Questionnaire factor scales were independently associated with oxytocin response: Effortful Control was negatively associated, whereas Orienting Sensitivity was positively associated. No state measure significantly predicted oxytocin response. The results indicate that mothers who show an increased oxytocin response when interacting with their infants are more sensitive of moods, emotions and physical sensations; and less compulsive, schedule driven and task oriented. These findings link differences in individual temperament in new mothers with the peripheral oxytocin response, which may have implications in the pharmacologic treatment of disorders such as maternal neglect, post-partum depression and maternal addiction. This article is part of a Special Issue entitled Oxytocin, Vasopressin, and Social Behavior.

Gene targeting approaches to neuroendocrinology: oxytocin, maternal behavior, and affiliation.

Transgenic technology affords exciting new opportunities in the field of behavioral neuroendocrinology. We have extended our research into the behavioral function of oxytocin in maternal and social behavior using two transgenic approaches: (i) targeted deletion of the oxytocin gene in mice and (ii) augmented oxytocin receptor expression in the brain. Mice genetically deficient in oxytocin can mate, give birth, and display normal maternal behavior; however, milk ejection and certain aspects of social behavior are affected. Comparative studies of oxytocin receptors have led to the observation that species differences in social organization are associated with differences in receptor distribution. Specifically, monogamous prairie voles and nonmonogamous, asocial montane voles exhibit different patterns of OT receptor expression in the brain. Transgenic mice have been created with a reporter gene driven by the prairie vole oxytocin receptor gene promoter. Analysis of the expression pattern suggests that it should be possible to manipulate receptor expression in the vole brain in order to examine the effects of receptor distribution on behavior.

A role for central vasopressin in pair bonding in monogamous prairie voles.

Monogamous social organization is characterized by selective affiliation with a partner, high levels of paternal behaviour and, in many species, intense aggression towards strangers for defence of territory, nest and mate. Although much has been written about the evolutionary causes of monogamy, little is known about the proximate mechanisms for pair bonding in monogamous mammals. The prairie vole, Microtus ochrogaster, is a monogamous, biparental rodent which exhibits long-term pair bonds characterized by selective affiliation (partner preference) and aggression. Here we describe the rapid development of both selective aggression and partner preferences following mating in the male of this species. We hypothesized that either arginine-vasopressin (AVP) or oxytocin (OT), two nine-amino-acid neuropeptides with diverse forebrain projections, could mediate the development of selective aggression and affiliation. This hypothesis was based on the following observations: (1) monogamous and polygamous voles differ specifically in the distribution of forebrain AVP and OT receptors; (2) AVP innervation in the prairie vole brain is sexually dimorphic and important for paternal behaviour; (3) central AVP pathways have been previously implicated in territorial displays and social memory; and (4) central OT pathways have been previously implicated in affiliative behaviours. We now demonstrate that central AVP is both necessary and sufficient for selective aggression and partner preference formation, two critical features of pair bonding in the monogamous prairie vole.

Oxytocin receptor distribution reflects social organization in monogamous and polygamous voles.

The neuropeptide oxytocin has been implicated in the mediation of several forms of affiliative behavior including parental care, grooming, and sex behavior. Here we demonstrate that species from the genus Microtus (voles) selected for differences in social affiliation show contrasting patterns of oxytocin receptor expression in brain. By in vitro receptor autoradiography with an iodinated oxytocin analogue, specific binding to brain oxytocin receptors was observed in both the monogamous prairie vole (Microtus ochrogaster) and the polygamous montane vole (Microtus montanus). In the prairie vole, oxytocin receptor density was highest in the prelimbic cortex, bed nucleus of the stria terminalis, nucleus accumbens, midline nuclei of the thalamus, and the lateral aspects of the amygdala. These brain areas showed little binding in the montane vole, in which oxytocin receptors were localized to the lateral septum, ventromedial nucleus of the hypothalamus, and cortical nucleus of the amygdala. Similar differences in brain oxytocin receptor distribution were observed in two additional species, the monogamous pine vole (Microtus pinetorum) and the polygamous meadow vole (Microtus pennsylvanicus). Receptor distributions for two other neurotransmitter systems implicated in the mediation of social behavior, benzodiazepines, and mu opioids did not show comparable species differences. Furthermore, in the montane vole, which shows little affiliative behavior except during the postpartum period, brain oxytocin receptor distribution changed within 24 hr of parturition, concurrent with the onset of maternal behavior. We suggest that variable expression of the oxytocin receptor in brain may be an important mechanism in evolution of species-typical differences in social bonding and affiliative behavior.

Oxytocin--a neuropeptide for affiliation: evidence from behavioral, receptor autoradiographic, and comparative studies.

Oxytocin (OT) is a nine amino acid peptide synthesized in hypothalamic cells which project either to the neurohypophysis or to sites within the central nervous system. Although neurohypophyseal OT release has long been associated with uterine contraction and milk ejection, the function of intracerebral OT remains unclear. On the basis of behavioral, cellular, and comparative studies, this review suggests that brain OT influences the formation of social bonds. The first part of this review examines evidence linking central OT to several forms of affiliation. Central administration of OT induces maternal and reproductive behaviors in rats primed with gonadal steroids. OT antagonists and hypothalamic lesions block the initiation of maternal and reproductive behaviors but have no effects on these behaviors once established. Our new studies in rat pups demonstrate that central OT selectively decreases the separation response, an effect which mimics social contact. These studies of parental, reproductive, and attachment behaviors suggest that exogenous OT has "prosocial" effects and that endogenous OT may be essential for initiating social interaction. In a second series of experiments, we investigated the cellular mechanisms for OT's effects on social behavior by means of autoradiographic receptor binding. In the rat forebrain, OT receptors are expressed in several limbic regions believed to be involved in the integration of sensory processing. The regulation of these receptors is surprisingly resistant to either ablation of OT cells or repeated central administration of OT. However, receptors in two regions, the bed nucleus of the stria terminalis (BNST) and the ventromedial nucleus of the hypothalamus (VMN), appear selectively induced by exogenous or endogenous increases in gonadal steroids. At parturition, binding to OT receptors increases 84% in the BNST, and at estrus, binding increases 35% in the VMN. These results demonstrate that physiologic changes in gonadal steroids can alter receptor expression in anatomically discrete target fields and thereby direct responsiveness to endogenous neuropeptide release. A model for OT's effects on social behavior is proposed, which relies on the heterologous regulation of the brain OT receptor. A third series of experiments tested the hypothesis that brain OT influences affiliation by comparing prairie and montane voles, two closely related species with dichotomous systems of social organization. Although no differences appear in the presynaptic expression of the neuropeptide, OT receptors are distributed in complementary patterns in the two species. In the highly affiliative prairie vole, receptors are most evident in the BNST and one of its primary afferents, the lateral amygdala, highlighting a circuit previously implicated in maternal behavior.(ABSTRACT TRUNCATED AT 400 WORDS)