Extrahypothalamic oxytocin neurons drive stress-induced social vigilance and avoidance

Oxytocin increases the salience of both positive and negative social contexts and it is thought that these diverse actions on behavior are mediated in part through circuit-specific action. This hypothesis is based primarily on manipulations of oxytocin receptor function, leaving open the question of whether different populations of oxytocin neurons mediate different effects on behavior. Here we inhibited oxytocin synthesis in a stress-sensitive population of oxytocin neurons specifically within the medioventral bed nucleus of the stria terminalis (BNSTmv). Oxytocin knockdown prevented social stress-induced increases in social vigilance and decreases in social approach. Viral tracing of BNSTmv oxytocin neurons revealed fibers in regions controlling defensive behaviors, including lateral hypothalamus, anterior hypothalamus, and anteromedial BNST (BNSTam). Oxytocin infusion into BNSTam in stress naïve mice increased social vigilance and reduced social approach. These results show that a population of extrahypothalamic oxytocin neurons plays a key role in controlling stress-induced social anxiety behaviors

Complementary Neural Circuits for Divergent Effects of Oxytocin: Social Approach Versus Social Anxiety

Oxytocin (OT) is widely known for promoting social interactions, but there is growing appreciation that it can sometimes induce avoidance of social contexts. The social salience hypothesis posed an innovative solution to these apparently opposing actions by proposing that OT enhances the salience of both positive and negative social interactions. The mesolimbic dopamine system was put forth as a likely system to evaluate social salience owing to its well-described role in motivation. Evidence from several sources supports the premise that OT acting within the nucleus accumbens and ventral tegmental area facilitates social reward and approach behavior. However, in aversive social contexts, additional pathways play critical roles in mediating the effects of OT. Recent data indicate that OT acts in the bed nucleus of the stria terminalis to induce avoidance of potentially dangerous social contexts. Here, we review evidence for neural circuits mediating the effects of OT in appetitive and aversive social contexts. Specifically, we propose that distinct but potentially overlapping circuits mediate OT-dependent social approach or social avoidance. We conclude that a broader and more inclusive consideration of neural circuits of social approach and avoidance is needed as the field continues to evaluate the potential of OT-based therapeutics

Convergent neuroendocrine mechanisms of social buffering and stress contagion

Social interactions play a key role in modulating the impact of stressful experiences. In some cases, social interactions can result in social buffering, the process in which the presence of one individual reduces the physiological and behavioral impact of stress in another individual. On the other hand, there is growing evidence that a key initiating factor of social buffering behaviors is the initiation of an anxiogenic state in the individual that was not directly exposed to the stress. This is referred to as stress contagion (a form of emotion contagion). Both processes involve the transmission of social information, suggesting that contagion and buffering could share similar neural mechanisms. In general, mechanistic studies of contagion and buffering are considered separately, even though behavioral studies show that a degree of contagion is usually necessary for social buffering behaviors to occur. Here we consider the extent to which the neuropeptides corticotropin releasing hormone and oxytocin are involved in contagion and stress buffering. We also assess the importance that frontal cortical areas such as the anterior cingulate cortex and infralimbic cortex play in these behavioral processes

Histone deacetylase inhibitor treatment promotes spontaneous caregiving behaviour in non‐aggressive virgin male mice

The majority of mammalian species are uniparental, with the mother solely providing care for young conspecifics, although fathering behaviours can emerge under certain circumstances. For example, a great deal of individual variation in response to young pups has been reported in multiple inbred strains of laboratory male mice. Furthermore, sexual experience and subsequent cohabitation with a female conspecific can induce caregiving responses in otherwise indifferent, fearful or aggressive males. Thus, a highly conserved parental neural circuit is likely present in both sexes; however, the extent to which infants are capable of activating this circuit may vary. In support of this idea, fearful or indifferent responses toward pups in female mice are linked to greater immediate early gene (IEG) expression in a fear/defensive circuit involving the anterior hypothalamus compared to that in an approach/attraction circuit involving the ventral tegmental area. However, experience with infants, particularly in combination with histone deacetylase inhibitor (HDACi) treatment, can reverse this pattern of pup-induced activation of fear/defence circuitry and promote approach behaviour. Thus, HDACi treatment may increase the transcription of primed/poised genes that play a role in the activation and selection of a maternal approach circuit in response to pup stimuli. In the present study, we investigated whether HDACi treatment would impact behavioural response selection and associated IEG expression changes in virgin male mice that are capable of ignoring, attacking or caring for pups. The results obtained indicate that systemic HDACi treatment induces spontaneous caregiving behaviour in non-aggressive male mice and alters the pattern of pup-induced IEG expression across a fear/defensive neural circuit

Histone deacetylase inhibitor treatment promotes spontaneous caregiving behaviour in non‐aggressive virgin male mice

The majority of mammalian species are uniparental, with the mother solely providing care for young conspecifics, although fathering behaviours can emerge under certain circumstances. For example, a great deal of individual variation in response to young pups has been reported in multiple inbred strains of laboratory male mice. Furthermore, sexual experience and subsequent cohabitation with a female conspecific can induce caregiving responses in otherwise indifferent, fearful or aggressive males. Thus, a highly conserved parental neural circuit is likely present in both sexes; however, the extent to which infants are capable of activating this circuit may vary. In support of this idea, fearful or indifferent responses toward pups in female mice are linked to greater immediate early gene (IEG) expression in a fear/defensive circuit involving the anterior hypothalamus compared to that in an approach/attraction circuit involving the ventral tegmental area. However, experience with infants, particularly in combination with histone deacetylase inhibitor (HDACi) treatment, can reverse this pattern of pup-induced activation of fear/defence circuitry and promote approach behaviour. Thus, HDACi treatment may increase the transcription of primed/poised genes that play a role in the activation and selection of a maternal approach circuit in response to pup stimuli. In the present study, we investigated whether HDACi treatment would impact behavioural response selection and associated IEG expression changes in virgin male mice that are capable of ignoring, attacking or caring for pups. The results obtained indicate that systemic HDACi treatment induces spontaneous caregiving behaviour in non-aggressive male mice and alters the pattern of pup-induced IEG expression across a fear/defensive neural circuit

Enriched laboratory housing increases sensitivity to social stress in female California mice (Peromyscus californicus)

Domesticated mice and rats have shown to be powerful model systems for biomedical research, but there are cases in which the biology of species is a poor match for the hypotheses under study. The California mouse (Peromyscus californicus) has unique traits that make it an ideal model for studying biological mechanisms underlying human-relevant behaviors such as intra-female aggression, biparental care, and monogamy. Indeed, peer-reviewed scientific publications using California mouse as a model for behavioral research have more than doubled in the past decade. Critically, behavioral outcomes in captive animals can be profoundly affected by housing conditions, but there is very limited knowledge regarding species-specific housing needs in California mice. Currently, California mouse investigators have to rely on guidelines aimed for more common laboratory species that show vastly different physiology, behavior, and/or ecological niche. This not only could be suboptimal for animals' welfare, but also result in lack of standardization that could potentially compromise experimental reproducibility and replicability across laboratories. With the aim of assessing how different housing systems can affect California mouse behavior both in the home cage as well as the open field and social interaction tests before and after social defeat stress, here we tested three different caging systems: 1. Standard mouse cage, 2. Large cage, and 3. Large cage + environmental enrichment (EE), which focused on increasing vertical complexity based on observations that California mice are semiarboreal in the wild. We found that the effects of housing were largely sex specific: compared to standard cages, in females large + EE reduced home cage stereotypic-like backflipping and rearing behaviors, while large cage increased social interactions. In males, the large+EE cage reduced rearing and digging but did not significantly affect backflipping behavior. Interestingly, while there were no significant differences in the open field and social interaction pre-stress behaviors, large and large+EE housing increased the sensitivity of these tests to detect stress induced phenotypes in females. Together, these results suggest that increasing social and environmental complexity affects home cage behaviors in male and female California mice without interfering with, but rather increasing the magnitude of, the effects of defeat stress on the open field and social interaction tests

Inhibition of vasopressin V1a receptors in the medioventral bed nucleus of the stria terminalis has sex- and context-specific anxiogenic effects.

Vasopressin V1a receptors (V1aR) are thought to contribute to the pathophysiology of psychiatric disorders such as anxiety and depression, sparking interest in V1aR as a therapeutic target. Although the global effects of V1aR have been documented, less is known about the specific neural circuits mediating these effects. Moreover, few studies have examined context-specific V1aR function in both males and females. By using the California mouse, we first studied the effects of sex and social defeat stress on V1aR binding in the forebrain. In females but not males, V1aR binding in the bed nucleus of the stria terminalis (BNST) was negatively correlated to social interaction behavior. In females stress also increased V1aR binding in the nucleus accumbens (NAc). Infusions of V1aR antagonist in to the medioventral BNST (BNSTmv) had anxiogenic effects only in animals naïve to defeat. For males, inhibition of V1aR in BNSTmv had anxiogenic effects in social and nonsocial contexts, but for females, anxiogenic effects were limited to social contexts. In stressed females, inhibition of V1aR in the NAc shell had no effect on social interaction behavior, but had an anxiogenic effect in an open field test. These data suggest that V1aR in BNSTmv have anxiolytic and prosocial effects in males, and that in females, prosocial and anxiolytic effects of V1aR appear to be mediated independently by receptors in the BNSTmv and NAc shell, respectively. These findings suggest that males have more overlap in neural circuits modulating anxiety in social and nonsocial contexts than females