The many facets of the oxytocin (OXT) system of the brain and periphery elicited nearly 25,000 publications since 1930 (see FIGURE 1 , as listed in PubMed), which revealed central roles for OXT and ...its receptor (OXTR) in reproduction, and social and emotional behaviors in animal and human studies focusing on mental and physical health and disease. In this review, we discuss the mechanisms of OXT expression and release, expression and binding of the OXTR in brain and periphery, OXTR-coupled signaling cascades, and their involvement in behavioral outcomes to assemble a comprehensive picture of the central and peripheral OXT system. Traditionally known for its role in milk let-down and uterine contraction during labor, OXT also has implications in physiological, and also behavioral, aspects of reproduction, such as sexual and maternal behaviors and pair bonding, but also anxiety, trust, sociability, food intake, or even drug abuse. The many facets of OXT are, on a molecular basis, brought about by a single receptor. The OXTR, a 7-transmembrane G protein-coupled receptor capable of binding to either Gα
or Gα
proteins, activates a set of signaling cascades, such as the MAPK, PKC, PLC, or CaMK pathways, which converge on transcription factors like CREB or MEF-2. The cellular response to OXT includes regulation of neurite outgrowth, cellular viability, and increased survival. OXTergic projections in the brain represent anxiety and stress-regulating circuits connecting the paraventricular nucleus of the hypothalamus, amygdala, bed nucleus of the stria terminalis, or the medial prefrontal cortex. Which OXT-induced patterns finally alter the behavior of an animal or a human being is still poorly understood, and studying those OXTR-coupled signaling cascades is one initial step toward a better understanding of the molecular background of those behavioral effects.
Oxytocin and vasopressin are regulators of anxiety, stress-coping, and sociality. They are released within hypothalamic and limbic areas from dendrites, axons, and perikarya independently of, or ...coordinated with, secretion from neurohypophysial terminals. Central oxytocin exerts anxiolytic and antidepressive effects, whereas vasopressin tends to show anxiogenic and depressive actions. Evidence from pharmacological and genetic association studies confirms their involvement in individual variation of emotional traits extending to psychopathology. Based on their opposing effects on emotional behaviors, we propose that a balanced activity of both brain neuropeptide systems is important for appropriate emotional behaviors. Shifting the balance between the neuropeptide systems towards oxytocin, by positive social stimuli and/or psychopharmacotherapy, may help to improve emotional behaviors and reinstate mental health.
The neuropeptide oxytocin has attracted great attention of the general public, basic neuroscience researchers, psychologists, and psychiatrists due to its profound pro-social, anxiolytic, and ..."anti-stress" behavioral and physiological effects, and its potential application for treatment of mental diseases associated with altered socio-emotional competence. During the last decade, substantial progress has been achieved in understanding the complex neurobiology of the oxytocin system, including oxytocinergic pathways, local release patterns, and oxytocin receptor distribution in the brain, as well as intraneuronal oxytocin receptor signaling. However, the picture of oxytocin actions remains far from being complete, and the central question remains: "How does a single neuropeptide exert such pleotropic actions?" Although this phenomenon, typical for many of about 100 identified neuropeptides, may emerge from the anatomical divergence of oxytocin neurons, their multiple central projections, distinct oxytocin-sensitive cell types in different brain regions, and multiple intraneuronal signaling pathways determining the specific cellular response, further basic studies are required. In conjunction, numerous reports on positive effects of intranasal application of oxytocin on human brain networks controlling socio-emotional behavior in health and disease require harmonic tandems of basic researchers and clinicians. During the COVID-19 crisis in 2020, oxytocin research seems central as question of social isolation-induced inactivation of the oxytocin system, and buffering effects of either activation of the endogenous system or intranasal application of synthetic oxytocin need to be thoroughly investigated.
Abstract The neuropeptide oxytocin (OXT) has been revealed as a profound anxiolytic and antistress factor of the brain, besides its many prosocial and reproductive effects. Therefore, there is ...substantial scientific and medical interest in its potential therapeutic use for the treatment of psychopathologies associated with anxiety, fear, and social dysfunctions, such as generalized anxiety disorder, posttraumatic stress disorder, and social anxiety disorder, as well as autism and schizophrenia, among others. Focusing on preclinical studies, we review the existing evidence for the regulatory capacity of OXT to fine-tune general and social anxiety-related behaviors, as well as cued and social fear conditioning from a translational perspective. The available evidence from animal and human studies substantiates the hypothesis of an imbalance of the endogenous brain OXT system in the etiology of anxiety disorders, particularly those with a social component such as social anxiety disorder. In addition, such an imbalance of the OXT system is also likely to be the consequence of chronic OXT treatment resulting in a dose-dependent reduction in OXT receptor availability and increased anxiety.
Social fear and avoidance of social situations represent the main behavioral symptoms of social anxiety disorder (SAD), a highly prevalent anxiety disorder that is poorly elucidated and has rather ...unsatisfactory therapeutic options. Therefore, animal models are needed to study the underlying etiology and pathophysiology of SAD and to verify the efficacy of possible novel treatment approaches. In this review, we describe and discuss the most important paradigms that have been shown to induce social avoidance and fear in rodents, including foot shock exposure, restraint stress, social isolation, social instability, social defeat, conditioned defeat, social defeat/overcrowding, chronic subordinate colony housing, chronic mild stress, maternal separation and social fear conditioning. We also describe some of the behavioral paradigms used to assess social avoidance and fear in rodents, including the social interaction test, the social preference-avoidance test, the social approach-avoidance test, the three-chambered social approach test, the partition test and the modified Y-maze test. We focus on the behavioral alterations these paradigms induce, especially on social interaction, general anxiety and depressive-like behavior given that SAD is strongly comorbid with anxiety and affective disorders.
During pandemics, governments take drastic actions to prevent the spreading of the disease, as seen during the present COVID-19 crisis. Sanctions of lockdown, social distancing and quarantine urge ...people to exclusively work and teach at home and to restrict social contacts to a minimum; lonely people get into further isolation, while families` nerves are strained to the extreme. Overall, this results in a dramatic and chronic increase in the level of psychosocial stress over several months mainly caused by i) social isolation and ii) psychosocial stress associated with overcrowding, social tension in families, and domestic violence. Moreover, pandemic-associated social restrictions are accompanied by loss of an essential stress buffer and important parameter for general mental and physical health: social support. Chronic psychosocial stress and, in particular, social isolation and lack of social support affect not only mental health, but also the brain oxytocin system and the immune system. Hence, pandemic-associated social restrictions are expected to increase the risk of developing psychopathologies, such as depression, anxiety-related and posttraumatic stress disorders, on the one hand, but also to induce a general inflammatory state and to impair the course of infectious disorders on the other. Due to its pro-social and stress-buffering effects, resulting in an anti-inflammatory state in case of disease, the role of the neuropeptide oxytocin will be discussed and critically considered as an emerging treatment option in cases of pandemic-induced psychosocial stress, viral infection and during recovery. In this review, we aim to critically focus on possible short- and long-term consequences of social restrictions on mental health and the immune system, while discussion oxytocin as a possible treatment option.
•Pandemic-induced social restrictions cause social isolation on the one side and social tension in families on the other.•This results in increased stress susceptibility, and impaired mental and general health.•Lack of the stress buffering effect of social support further impairs both the immune system and mental health.•Due to its multiple beneficial effects, the neuropeptide oxytocin is critically discussed as an emerging treatment option.
In the mammalian peripartum period, the activity of both the brain oxytocin and vasopressin system is elevated as part of the physiological adaptations occurring in the mother. This is reflected by ...increased expression and intracerebral release of oxytocin and vasopressin, as well as increased neuropeptide receptor expression and binding.
In this review we discuss the functional role of the brain oxytocin and vasopressin system in the context of maternal behavior, specifically maternal care and maternal aggression in rodents. In order to enable the identification of significant and peptide-specific contributions to the display of maternal behavior, various complementary animal models of maternal care and/or maternal aggression were studied, including rats selectively bred for differences in anxiety-related behavior (HAB and LAB dams), monitoring of local neuropeptide release during ongoing maternal behavior, and local pharmacological or genetic manipulations of the neuropeptide systems. The medial preoptic area was identified as a major site for oxytocin- and vasopressin-mediated maternal care. Furthermore, both oxytocin and vasopressin release and receptor activation in the central amygdala and the bed nucleus of the stria terminalis play an important role for maternal aggression.
This article is part of a Special Issue entitled Oxytocin, Vasopressin, and Social Behavior.
► Brain OXT and AVP systems are activated peripartum. ► Review of their functional role in maternal care and aggression. ► Summary of central release patterns of OXT and AVP during mother–infant interaction. ► Behavioral changes following specific manipulations of these systems.
Summary The possibility to improve socio-emotional behaviors in humans by intranasal administration of synthetic oxytocin (OXT) attracts increasing attention, but its uptake into the brain has never ...been demonstrated so far. Here we used simultaneous microdialysis in both the dorsal hippocampus and amygdala of rats and mice in combination with concomitant blood sampling from the jugular vein to study the dynamics of the neuropeptide in brain extracellular fluid and plasma after its nasal administration. OXT was found to be increased in microdialysates from both the hippocampus and amygdala with peak levels occurring 30–60 min after nasal administration. Despite a similar temporal profile of OXT concentrations in plasma, peripheral OXT is unlikely to contribute to dialysate OXT as calculated from in vitro recovery data, indicating a central route of transport. Moreover, intraperitoneal administration of synthetic OXT in identical amounts caused rapid peak levels in brain dialysates and plasma during the first 30 min after treatment and a subsequent return toward baseline. While the precise route(s) of central transport remain to be elucidated, our data provide the first evidence that nasally applied OXT indeed reaches behaviorally relevant brain areas, and this uptake is paralleled by changes in plasma OXT.
Central oxytocin (OXT) has anxiolytic and pro-social properties both in humans and rodents, and has been proposed as a therapeutic option for anxiety and social dysfunctions. Here, we utilized a ...mouse model of social fear conditioning (SFC) to study the effects of OXT on social fear, and to determine whether SFC causes alterations in central OXT receptor (OXTR) binding and local OXT release. Central infusion of OXT, but not arginine vasopressin, prior to social fear extinction training completely abolished social fear expression in an OXTR-mediated fashion without affecting general anxiety or locomotion. SFC caused increased OXTR binding in the dorso-lateral septum (DLS), central amygdala, dentate gyrus, and cornu ammunis 1, which normalized after social fear extinction, suggesting that these areas form part of a brain network involved in the development and neural support of social fear. Microdialysis revealed that the increase in OXT release observed in unconditioned mice within the DLS during social fear extinction training was attenuated in conditioned mice. Consequently, increasing the availability of local OXT by infusion of OXT into the DLS reversed social fear. Thus, alterations in the brain OXT system, including altered OXTR binding and OXT release within the DLS, play an important role in SFC and social fear extinction. Thus, we suggest that the OXT system is adversely affected in disorders associated with social fear, such as social anxiety disorder and reinstalling an appropriate balance of the OXT system may alleviate some of the symptoms.
► Neurobiology of brain oxytocin and vasopressin (neuroanatomy, central release, receptor distribution). ► Oxytocin and vasopressin in rodent social behaviors (affiliative behavior, social cognition, ...social approach). ► Translational aspects of brain oxytocin and vasopressin in social behaviors.
Autism spectrum disorders (ASD) and social anxiety disorder involve various forms of social deficits like impaired affiliative behavior, social cognition and social approach. Although the neurobiological underpinnings of these disorders are largely unknown, rodent and human studies suggest an involvement of the evolutionary highly conserved oxytocin (OXT) and vasopressin (AVP), as these neuropeptides modulate various aspects of mammalian social behaviors.
In this review we summarize the current knowledge regarding the involvement of brain OXT and AVP in rodent social behaviors related to social dysfunctions in ASD.
Starting with an introduction into the neurobiology of the central OXT and AVP systems (neuroanatomy, central release, receptor distribution) we describe the distinct roles OXT and AVP play in basic social behaviors in rodents, i.e. affiliative behavior (pair-bonding and maternal behavior), social cognition (social memory), and social approach (social preference or social avoidance). The regulatory capacity of OXT and AVP to modulate social behaviors in various rodent species implies a high translational potential, in particular that dys-regulations in the brain neuropeptide systems may underlie social dysfunctions in ASD. It also suggests that the brain OXT and AVP systems are promising pharmacotherapeutic targets to improve social behaviors and to reverse social deficits.
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