Extrahypothalamic oxytocin neurons drive stress-induced social vigilance and avoidance.
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ABSTRACT:
SUBMITTER: Duque-Wilckens N
PROVIDER: S-EPMC7585015 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Exogenous application of the neuromodulatory hormone oxytocin (OT) promotes prosocial behavior and can improve social function. It is unclear, however, whether OT promotes prosocial behavior per se, or whether it facilitates social interaction by reducing a state of vigilance toward potential social threats. To disambiguate these two possibilities, we exogenously delivered OT to male rhesus macaques, which have a characteristic pattern of species-typical social vigilance, and examined their performance in three social attention tasks. We first determined that, in the absence of competing task demands or goals, OT increased attention to faces and eyes, as in humans. By contrast, OT reduced species typical social vigilance for unfamiliar, dominant, and emotional faces in two additional tasks. OT eliminated the emergence of a typical state of vigilance when dominant face images were available during a social image choice task. Moreover, OT improved performance on a reward-guided saccade task, despite salient social distractors: OT reduced the interference of unfamiliar faces, particularly emotional ones, when these faces were task irrelevant. Together, these results demonstrate that OT suppresses vigilance toward potential social threats in the rhesus macaque. We hypothesize that a basic role for OT in regulating social vigilance may have facilitated the evolution of prosocial behaviors in humans.
| S-EPMC3710816 | biostudies-other
Project description:BACKGROUND:The neuropeptide oxytocin (OT) is a key regulator of social and emotional behaviors. The effects of OT are context dependent, and it has been proposed that OT increases the salience of both positive and negative social cues. Here we tested whether the bed nucleus of the stria terminalis (BNST) mediates anxiogenic effects of OT. METHODS:First, we studied the effects of systemic administration of an OT receptor (OTR) antagonist L-368,899 on social behavior in male and female California mice exposed to social defeat. We examined the effect of L-368,899 on G protein activation and used early growth response factor 1 immunohistochemistry to identify potential sites of OTR action. Finally, we examined the effects of L-368,899 infused in the BNST on behavior. RESULTS:A single dose of systemic L-368,899 increased social approach in stressed female mice and decreased social approach in male mice naïve to defeat. L-368,899 prevented OT activation of G proteins and did not activate G proteins in the absence of OT. Intranasal OT, which reduces social approach in female mice but not male mice, increased early growth response factor 1 immunoreactivity in the nucleus accumbens core and anteromedial BNST in female mice but not in male mice. Stressed female mice that received an infusion of L-368,899 into the anteromedial BNST but not the nucleus accumbens core increased social approach and decreased social vigilance responses. CONCLUSIONS:Our results suggest that OTR activation in anteromedial BNST induces a vigilance response in which individuals avoid, yet attend to, unfamiliar social contexts. Our results suggest that OTR antagonists may have unappreciated therapeutic potential for stress-induced psychiatric disorders.
| S-EPMC5743604 | biostudies-literature
Project description:Major depressive disorder (MDD) is associated with repeated exposure to environmental stress. Autophagy is activated under various stress conditions that are associated with several diseases in the brain. This study was aimed at elucidating the autophagy signaling changes in the prefrontal cortex (PFC) under repeated social defeat (RSD) to investigate the involvement of microglial autophagy in RSD-induced behavioral changes. We found that RSD stress, an animal model of MDD, significantly induced initial autophagic signals followed by increased transcription of autophagy-related genes (Atg6, Atg7, and Atg12) in the PFC. Similarly, significantly increased transcripts of ATGs (Atg6, Atg7, Atg12, and Atg5) were confirmed in the postmortem PFC of patients with MDD. The protein levels of the prefrontal cortical LC3B were significantly increased, whereas p62 was significantly decreased in the resilient but not in susceptible mice and patients with MDD. This indicates that enhanced autophagic flux may alleviate stress-induced depression. Furthermore, we identified that FKBP5, an early-stage autophagy regulator, was significantly increased in the PFC of resilient mice at the transcript and protein levels. In addition, the resilient mice exhibited enhanced autophagic flux in the prefrontal cortical microglia, and the autophagic deficiency in microglia aggravated RSD-induced social avoidance, indicating that microglial autophagy involves stress-induced behavioral changes.
| S-EPMC8866015 | biostudies-literature
Project description:Oxytocin modulates mammalian social behavior; however, behavioral responses to intranasal oxytocin can vary across species and contexts. The complexity of social interactions increases with group dynamics, and the impacts of oxytocin on both within- and between-group contexts are unknown. We tested the effects of intranasal administration of oxytocin on social and non-social behaviors within in-group and out-group contexts in African lions. We hypothesized that, post intranasal oxytocin administration, lions would be in closer proximity with fellow group members, whereas out-group stimuli could either produce a heightened vigilance response or an attenuated one. Compared to control trials, post oxytocin administration, lions increased their time spent in close proximity (reducing their distance to the nearest neighbor) and decreased vigilance toward out-group intruders (reducing their vocalizations following a roar-playback). These results not only have important implications for understanding the evolution of social circuitry but may also have practical applications for conservation efforts.
| S-EPMC9042884 | biostudies-literature
Project description: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.
| S-EPMC7360746 | biostudies-literature
Project description:The long-term response to chronic stress is variable, with some individuals developing maladaptive functioning, although other "resilient" individuals do not. Stress reduces neurogenesis in the dentate gyrus subgranular zone (SGZ), but it is unknown if stress-induced changes in neurogenesis contribute to individual vulnerability. Using a chronic social defeat stress model, we explored whether the susceptibility to stress-induced social avoidance was related to changes in SGZ proliferation and neurogenesis. Immediately after social defeat, stress-exposed mice (irrespective of whether they displayed social avoidance) had fewer proliferating SGZ cells labeled with the S-phase marker BrdU. The decrease was transient, because BrdU cell numbers were normalized 24 h later. The survival of BrdU cells labeled before defeat stress was also not altered. However, 4 weeks later, mice that displayed social avoidance had more surviving dentate gyrus neurons. Thus, dentate gyrus neurogenesis is increased after social defeat stress selectively in mice that display persistent social avoidance. Supporting a functional role for adult-generated dentate gyrus neurons, ablation of neurogenesis via cranial ray irradiation robustly inhibited social avoidance. These data show that the time window after cessation of stress is a critical period for the establishment of persistent cellular and behavioral responses to stress and that a compensatory enhancement in neurogenesis is related to the long-term individual differences in maladaptive responses to stress.
| S-EPMC2840117 | biostudies-other
Project description:Social transmission of fear is not restricted to visual or auditory cues, but extends to the phylogenetically more ancient olfactory domain. Anxious individuals exhibit heightened sensitivity towards chemosensory stress signals in sweat; however, it is still unknown whether endogenous neuromodulators such as the peptide hormone oxytocin (OXT) influence the chemosensory communication of stress. Here, we investigated whether OXT selectively diminishes behavioral and neural responses to social chemosensory stress cues utilizing a randomized, double-blind, placebo (PLC)-controlled, within-subject functional MRI study design. Axillary sweat was obtained from 30 healthy male donors undergoing the Trier Social Stress Test (stress) and bicycle ergometer training (sport). Subsequently, 58 healthy participants (30 females) completed a forced-choice emotional face recognition task with stimuli of varying intensities (neutral to fearful) while they were exposed to both sweat stimuli and a non-social control odor following intranasal OXT or PLC administration, respectively. OXT diminished stress-induced recognition accuracy and response time biases towards fear. On the neural level, OXT reduced stress-evoked responses in the amygdala in both sexes, the anterior cingulate cortex (ACC) in females, and the hippocampus in males. Furthermore, OXT reinstated the functional connectivity between the ACC and the fusiform face area that was disrupted by stress odors under PLC. Our findings reveal a new role for OXT signaling in the modulation of chemosensory communication of stress in humans. Mechanistically, this effect appears to be rooted in a downregulation of stress-induced limbic activations and concomitant strengthening of top-down control descending from the ACC to the fusiform face area.
| S-EPMC6300531 | biostudies-literature
Project description:Inflammation has been associated with depression, and innate immune receptors, such as the Toll-like receptor (TLR) 2/4 in the medial prefrontal cortex (mPFC), are crucial for chronic stress-induced depression-related behaviors in mice. HMGB1, a putative ligand for TLR2/4, has been suggested to promote depression-related behaviors under acute stress. However, the roles of endogenous HMGB1 under chronic stress remain to be investigated. Here, we found that the cerebroventricular infusion of HMGB1 proteins blocked stress-induced social avoidance and that HMGB1-neutralizing antibodies augmented repeated social defeat stress-induced social avoidance in mice, suggesting the antidepressive-like effect of HMGB1 in the brain. By contrast, the infusion of HMGB1-neutralizing antibodies to the mPFC and HMGB1 knockout in α-CaMKII-positive forebrain neurons attenuated the social avoidance, suggesting the pro-depressive-like effect of HMGB1 released from prefrontal neurons under chronic stress. In addition, repeated social defeat stress induced HMGB1 nuclear export selectively in mPFC neurons, which was abolished in the mice lacking RAGE, one of HMGB1 receptors, suggesting the positive feedback loop of HMGB1-RAGE signaling under chronic stress. These findings pave the way for identifying multiple roles of HMGB1 in the brain for chronic stress and depression.
| S-EPMC10340449 | biostudies-literature
Project description:Chronic stress is a key risk factor for mood disorders like depression, but the stress-induced changes in brain circuit function and gene expression underlying depression symptoms are not completely understood, hindering development of novel treatments. Because of its projections to brain regions regulating reward and anxiety, the ventral hippocampus is uniquely poised to translate the experience of stress into altered brain function and pathological mood, though the cellular and molecular mechanisms of this process are not fully understood. Here, we use a novel method of circuit-specific gene editing to show that the transcription factor ΔFosB drives projection-specific activity of ventral hippocampus glutamatergic neurons causing behaviorally diverse responses to stress. We establish molecular, cellular, and circuit-level mechanisms for depression- and anxiety-like behavior in response to stress and use circuit-specific gene expression profiling to uncover novel downstream targets as potential sites of therapeutic intervention in depression.
| S-EPMC7479591 | biostudies-literature
Project description:Animals have evolved specialized neural circuits to defend themselves from pain- and injury-causing stimuli. Using a combination of optical, behavioral and genetic approaches in the larval zebrafish, we describe a novel role for hypothalamic oxytocin (OXT) neurons in the processing of noxious stimuli. In vivo imaging revealed that a large and distributed fraction of zebrafish OXT neurons respond strongly to noxious inputs, including the activation of damage-sensing TRPA1 receptors. OXT population activity reflects the sensorimotor transformation of the noxious stimulus, with some neurons encoding sensory information and others correlating more strongly with large-angle swims. Notably, OXT neuron activation is sufficient to generate this defensive behavior via the recruitment of brainstem premotor targets, whereas ablation of OXT neurons or loss of the peptide attenuates behavioral responses to TRPA1 activation. These data highlight a crucial role for OXT neurons in the generation of appropriate defensive responses to noxious input.
| S-EPMC6820349 | biostudies-literature