Neuronal diversity of the amygdala and the bed nucleus of the stria terminalis

The amygdala complex is a diverse group of more than 13 nuclei, segregated in five major groups: the basolateral (BLA), central (CeA), medial (MeA), cortical (CoA), and basomedial (BMA) amygdala nuclei. These nuclei can be distinguished depending on their cytoarchitectonic properties, connectivity, genetic, and molecular identity, and most importantly, on their functional role in animal behavior. The extended amygdala includes the CeA and the bed nucleus of the stria terminalis (BNST). Both CeA and the BNST share similar cellular organization, including common neuron types, reciprocal connectivity, and many overlapping downstream targets. In this section, we describe the advances of our knowledge on neuronal diversity in the amygdala complex and the BNST, based on recent functional studies, performed at genetic, molecular, physiological, and anatomical levels in rodent models, especially rats and mice. Molecular and connection property can be used separately, or in combinations, to define neuronal populations, leading to a multiplexed neuronal diversity-supporting different functional roles. © 2020 Elsevier B.V

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

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

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

Social approach and social vigilance are differentially regulated by oxytocin receptors in the nucleus accumbens.

Oxytocin is currently being considered as a novel therapeutic for anxiety disorders due to its ability to promote affiliative behaviors. In the nucleus accumbens (NAc) activation of oxytocin receptors (OTR) promotes social approach (time spent near an unfamiliar individual). Here, we show that stressful social experiences reduce the expression of NAc OTR mRNA, coinciding with decreases in social approach. Social stressors also increase social vigilance, characterized as orienting to an unfamiliar individual without approaching. Vigilance is a key component of behavioral inhibition, a personality trait that is a risk factor for anxiety disorders. To understand whether NAc OTR can modulate both social approach and vigilance, we use pharmacological approaches to assess the impact of activation or inhibition of NAc OTR downstream pathways on these behaviors. First, we show that in unstressed male and female California mice, inhibition of OTR by an unbiased antagonist (L-368,899) reduces social approach but does not induce social vigilance. Next, we show that infusion of Atosiban, an OTR-Gq antagonist/OTR-Gi agonist, has the same effect in unstressed females. Finally, we show that Carbetocin, a biased OTR-Gq agonist, increases social approach in stressed females while simultaneously inhibiting social vigilance. Taken together these data suggest that OTR in the NAc differentially modulate social approach and social vigilance, primarily through an OTR-Gq mechanism. Importantly, pharmacological inhibition of OTR alone is insufficient to induce vigilance in unstressed mice, suggesting that mechanisms modulating social approach may be distinct from mechanisms modulating social vigilance