Stress-induced Social Avoidance Research Articles

Hypocretin in the nucleus accumbens shell modulates social approach in female but not male California mice.

The hypocretin (Hcrt) system modulates arousal and anxiety-related behaviors and has been considered as a novel treatment target for stress-related affective disorders. We examined the effects of Hcrt acting in the nucleus accumbens shell (NAcSh) and anterodorsal bed nucleus of the stria terminalis (adBNST) on social behavior in male and female California mice (Peromyscus californicus). In female but not male California mice, infusion of Hcrt1 into NAcSh decreased social approach. Weak effects of Hcrt1 on social vigilance were observed in both females and males. No behavioral effects of Hcrt1 infused into the adBNST were observed. Analyses of sequencing data from California mice and Mus musculus NAc showed that Hcrtr2 was more abundant than Hcrtr1, so we infused the selective Hcrt receptor 2 antagonist into the NAcSh, which increased social approach in females previously exposed to social defeat. A calcium imaging study in the NAcSh of females before and after stress exposure showed that neural activity increased immediately following the expression of social avoidance but not during freezing behavior. This observation is consistent with previous studies that identified populations of neurons in the NAc that drive avoidance. Intriguingly, calcium transients were not affected by stress. These data suggest that hypocretin acting in the NAcSh plays a key role in modulating stress-induced social avoidance.

Limbic oxytocin receptor expression alters molecular signaling and social avoidance behavior in female prairie voles (Microtus ochrogaster).

The social defeat paradigm is the most representative animal model to study social anxiety disorder (SAD) and its underlying neuronal mechanisms. We have previously reported that defeat progressively reduces oxytocin receptors (OXTR) in limbic regions of the brain over an eight-week period in female prairie voles (Microtus ochrogaster). Oxytocin receptors activate the mitogen-activated protein kinase (MAPK) pathway, which has been previously associated with the anxiolytic effects of oxytocin. Here, we assessed the functional significance of OXTR in stress-induced social avoidance and the response of the MAPK signaling pathway in the nucleus accumbens (NAc), anterior cingulate cortex (ACC), and basolateral amygdala (BLA) of female prairie voles. In experiment 1, Sexually naïve adult female prairie voles were defeated for three consecutive days and tested a week after for social preference/avoidance (SPA) test. Control subjects were similarly handled without defeat conditioning. In experiment 2, sexually and stress naïve adult female prairie voles were bilaterally injected into the NAc, ACC, or the BLA with a CRISPR/Cas9 virus targeting the Oxtr coding sequence to induce OXTR knockdown. Two weeks post-surgery, subjects were tested for SPA behavior. Viral control groups were similarly handled but injected with a control virus. A subgroup of animals from each condition in both experiments were similarly treated and euthanized without being tested for SPA behavior. Brains were harvested for OXTR autoradiography, western blot analysis of MAPK proteins and quantification of local oxytocin content in the NAc, BLA, ACC, and PVN through ELISA. Social defeat reduced OXTR binding in the NAc and affected MAPK pathway activity and oxytocin availability. These results were region-specific and sensitive to exposure to the SPA test. Additionally, OXTR knockdown in the NAc, ACC, and BLA induced social avoidance and decreased basal MAPK activity in the NAc. Finally, we found that OXTR knockdown in these regions was associated with less availability of oxytocin in the PVN. Dysregulation of the oxytocin system and MAPK signaling pathway in the NAc, ACC, and BLA are important in social behavior disruptions in female voles. This dysregulation could, therefore, play an important role in the etiology of SAD in women.

Depression: Monocytes on my mind

Activation of the peripheral immune system contributes to stress-related neuropsychiatric symptoms. Recently in Nature, Cathomas etal. demonstrate that stress-induced social avoidance is mediated by monocyte-derived MMP8 that remodels the extracellular space of the nucleus accumbens.

Circulating myeloid-derived MMP8 in stress susceptibility and depression

Psychosocial stress has profound effects on the body, including the immune system and the brain1,2. Although a large number of pre-clinical and clinical studies have linked peripheral immune system alterations to stress-related disorders such as major depressive disorder (MDD)3, the underlying mechanisms are not well understood. Here we show that expression of a circulating myeloid cell-specific proteinase, matrix metalloproteinase 8 (MMP8), is increased in the serum of humans with MDD as well as in stress-susceptible mice following chronic social defeat stress (CSDS). In mice, we show that this increase leads to alterations in extracellular space and neurophysiological changes in the nucleus accumbens (NAc), as well as altered social behaviour. Using a combination of mass cytometry and single-cell RNA sequencing, we performed high-dimensional phenotyping of immune cells in circulation and in the brain and demonstrate that peripheral monocytes are strongly affected by stress. In stress-susceptible mice, both circulating monocytes and monocytes that traffic to the brain showed increased Mmp8 expression following chronic social defeat stress. We further demonstrate that circulating MMP8 directly infiltrates the NAc parenchyma and controls the ultrastructure of the extracellular space. Depleting MMP8 prevented stress-induced social avoidance behaviour and alterations in NAc neurophysiology and extracellular space. Collectively, these data establish a mechanism by which peripheral immune factors can affect central nervous system function and behaviour in the context of stress. Targeting specific peripheral immune cell-derived matrix metalloproteinases could constitute novel therapeutic targets for stress-related neuropsychiatric disorders.

Prior experience with behavioral control over stress facilitates social dominance

Dominance status has extensive effects on physical and mental health, and an individual's relative position can be shaped by experiential factors. A variety of considerations suggest that the experience of behavioral control over stressors should produce winning in dominance tests and that winning should blunt the impact of later stressors, as does prior control. To investigate the interplay between competitive success and stressor control, we first examined the impact of stressor controllability on subsequent performance in a warm spot competition test modified for rats. Prior experience of controllable, but not physically identical uncontrollable, stress increased later effortful behavior and occupation of the warm spot. Controllable stress subjects consistently ranked higher than did uncontrollable stress subjects. Pharmacological inactivation of the prelimbic (PL) cortex during behavioral control prevented later facilitation of dominance. Next, we explored whether repeated winning experiences produced later resistance against the typical sequelae of uncontrollable stress. To establish dominance status, triads of rats were given five sessions of warm spot competition. The development of stable dominance was prevented by reversible inactivation of the PL or NMDA receptor blockade in the dorsomedial striatum. Stable winning blunted the later stress-induced increase in dorsal raphe nucleus serotonergic activity, as well as prevented uncontrollable stress-induced social avoidance. In contrast, endocrine and neuroimmune responses to uncontrollable stress were unaffected, indicating a selective impact of prior dominance. Together, these data demonstrate that instrumental control over stress promotes later dominance, but also reveal that winning experiences buffer against the neural and behavioral outcomes of future adversity.

Enhancement of peripheral fatty acyl ethanolamide signaling prevents stress-induced social avoidance and anxiety-like behaviors in male rats

Abstract Rationale Exposure to traumatic events can lead to alterations in social and anxiety-related behaviors. Emerging evidence suggests that peripheral host-defense processes are implicated in the expression of stress-induced behavioral responses and may be targeted to mitigate the negative sequalae of stress exposure. Objectives In this study, we used the peripherally restricted FAAH inhibitor URB937 to investigate the effects of the fatty acyl ethanolamide (FAE) family of lipid mediators – which include the endocannabinoid anandamide and the endogenous PPAR-α agonists, oleoylethanolamide and palmitoylethanolamide – on behavioral and peripheral biochemical responses to two ethologically distinct rat models of stress. Methods Male adult rats were exposed to acute social defeat, a model of psychological stress (Experiment 1), or to the predator odor 2,5-dihydro-2,4,5-trimethylthiazoline (TMT), a test of innate predator-evoked fear (Experiment 2), and subsequently treated with URB937 (1 or 3 mg/kg, intraperitoneal) or vehicle. Behavioral analyses were conducted 24 h (Experiment 1) or 7 days (Experiment 2) after exposure. Results URB937 administration prevented the emergence of both social avoidance behavior after social defeat stress and anxiety-related behaviors after TMT exposure. Further, URB937 administration blocked social defeat-induced transient increase in plasma concentrations of pro-inflammatory cytokines and the elevation in plasma corticosterone levels observed 24 h after social defeat Conclusions Enhancement of peripheral FAAH-regulated lipid signaling prevents the emergence of stress-induced social avoidance and anxiety-like behaviors in male rats through mechanisms that may involve an attenuation of peripheral cytokine release induced by stress exposure.

Methylone produces antidepressant-relevant actions and prosocial effects

Methylone (3,4-methylenedioxy-N-methylcathinone) is a rapid-acting entactogen that has been shown to have significant benefits in patients with post-traumatic stress disorder and major depressive disorder and is well tolerated in phase 1 clinical trials. A recent preclinical study reported that methylone produced robust antidepressant-like actions in naïve rats. However, its antidepressant effects on various stress-related psychopathologies and other neuropsychological actions remain unclear. In the present study, we examined the antidepressant-relevant effects of methylone in learned helplessness (LH) and social defeat stress C57BL/6J male mouse models and further explored its sociability-relevant neuropsychological actions. Our results indicate that methylone produces antidepressant-relevant effects on the helpless phenotype, LH-evoked depressive-like behaviors, and psychosocial stress-induced social avoidance, and induced depressive-like behaviors. In addition, methylone was found to enhance social preference and increase various social behaviors, including social contact, sniffing, allogrooming, and following. Moreover, methylone appeared to elevate empathy-like phenotypes and was also found to increase helping-like behavior. Overall, the present results suggest that methylone plays an antidepressant-like role in various stress-relevant psychopathologies and could be an ideal antidepressant candidate. In addition, novel findings on the elevated tendencies of social preference and empathy-like and helping-like phenotypes reveal that methylone may have potential application in patients with social deficits.

Repeated Social Defeat Stress Induces HMGB1 Nuclear Export in Prefrontal Neurons, Leading to Social Avoidance in Mice.

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.

Gains and Losses: Resilience to Social Defeat Stress in Adolescent Female Mice

BackgroundAdolescence is a unique period of psychosocial growth during which social adversity can negatively influence mental health trajectories. Understanding how adolescent social stress impacts males and females and why some individuals are particularly affected is becoming increasingly urgent. Social defeat stress models for adolescent male mice have been effective in reproducing some physical/psychological aspects of bullying. Designing a model suitable for females has proven challenging. MethodsWe report a version of the adolescent male accelerated social defeat stress (AcSD) paradigm adapted for females. Early adolescent C57BL/6J female mice (N = 107) were exposed to our modified AcSD procedure twice a day for 4 days and categorized as resilient or susceptible based on a social interaction test 24 hours later. Mice were then assessed for changes in Netrin-1/DCC guidance cue expression in dopamine systems, for inhibitory control in adulthood using the Go/No-Go task, or for alterations in dopamine connectivity organization in the matured prefrontal cortex. ResultsMost adolescent females showed protection against stress-induced social avoidance, but in adulthood, these resilient females developed inhibitory control deficits and showed diminution of prefrontal cortex presynaptic dopamine sites. Female mice classified as susceptible were protected against cognitive and dopaminergic alterations. AcSD did not alter Netrin-1/DCC in early adolescent females, contrary to previous findings with males. ConclusionsPreserving prosocial behavior in adolescent females may be important for survival advantage but seems to come at the price of developing persistent cognitive and dopamine deficiencies. The female AcSD paradigm produced findings comparable to those found in males, allowing mechanistic investigation in both sexes.

Female rats are more responsive than are males to the protective effects of voluntary physical activity against the behavioral consequences of inescapable stress

Common stress-related mental health disorders affect women more than men. Physical activity can provide protection against the development of future stress-related mental health disorders (i.e. stress resistance) in both sexes, but whether there are sex differences in exercise-induced stress resistance is unknown. We have previously observed that voluntary wheel running (VWR) protects both female and male rats against the anxiety- and exaggerated fear-like behavioral effects of inescapable stress, but the time-course and magnitude of VWR-induced stress resilience has not been compared between sexes. The goal of the current study was to determine whether there are sex differences in the time-course and magnitude of exercise-induced stress resistance. In adult female and male Sprague Dawley rats, 6 weeks of VWR produced robust protection against stress-induced social avoidance and exaggerated fear. The magnitude of stress protection was similar between the sexes and was independent of reactivity to shock, general locomotor activity, and circulating corticosterone. Interestingly, 3 weeks of VWR prevented both stress-induced social avoidance and exaggerated fear in females but only prevented stress-induced social avoidance in males. Ovariectomy altered wheel-running behavior in females such that it resembled that of males, however; 3 weeks of VWR still protected females against behavioral consequences of stress regardless of the absence of ovaries. These data indicate that female Sprague Dawley rats are more responsive to exercise-induced stress resistance than are males.

Inhibition of FKBP51 induces stress resilience and alters hippocampal neurogenesis

Stress-related psychiatric disorders such as depression are among the leading causes of morbidity and mortality. Considering that many individuals fail to respond to currently available antidepressant drugs, there is a need for antidepressants with novel mechanisms. Polymorphisms in the gene encoding FK506-binding protein 51 (FKBP51), a co-chaperone of the glucocorticoid receptor, have been linked to susceptibility to stress-related psychiatric disorders. Whether this protein can be targeted for their treatment remains largely unexplored. The aim of this work was to investigate whether inhibition of FKBP51 with SAFit2, a novel selective inhibitor, promotes hippocampal neuron outgrowth and neurogenesis in vitro and stress resilience in vivo in a mouse model of chronic psychosocial stress. Primary hippocampal neuronal cultures or hippocampal neural progenitor cells (NPCs) were treated with SAFit2 and neuronal differentiation and cell proliferation were analyzed. Male C57BL/6 mice were administered SAFit2 while concurrently undergoing a chronic stress paradigm comprising of intermittent social defeat and overcrowding, and anxiety and depressive -related behaviors were evaluated. SAFit2 increased neurite outgrowth and number of branch points to a greater extent than brain derived neurotrophic factor (BDNF) in primary hippocampal neuronal cultures. SAFit2 increased hippocampal NPC neurogenesis and increased neurite complexity and length of these differentiated neurons. In vivo, chronic SAFit2 administration prevented stress-induced social avoidance, decreased anxiety in the novelty-induced hypophagia test, and prevented stress-induced anxiety in the open field but did not alter adult hippocampal neurogenesis in stressed animals. These data warrant further exploration of inhibition of FKBP51 as a strategy to treat stress-related disorders.

P674. Sex Differences in miR-218 Levels During Prefrontal Cortex Development

MicroRNA miR-218 is a potent expression regulator of genes known to control adolescent prefrontal cortex (PFC) development and is altered in the PFC of adult depressed subjects who died by suicide. miR-218 expression in blood in adolescent and adult male mice positively correlates with miR-218 expression in the PFC and predicts chronic stress-induced social avoidance in adulthood. We find a gradual rise of miR-218 levels in the PFC from early adolescence to adulthood. Here, we assessed (i) miR-218 levels in females over PFC development, (ii) whether miR-218 levels in blood match expression brain.

Deficient Autophagy in Microglia Aggravates Repeated Social Defeat Stress-Induced Social Avoidance.

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.

Daily perceived stress predicts less next day social interaction: Evidence from a naturalistic mobile sensing study.

Although mammals have a strong motivation to engage in social interaction, stress can significantly interfere with this desire. Indeed, research in nonhuman animals has shown that stress reduces social interaction, a phenomenon referred to as "stress-induced social avoidance." While stress and social disconnection are also intertwined in humans, to date, evidence that stress predicts reductions in social interaction is mixed, in part, because existing paradigms fail to capture social interaction naturalistically. To help overcome this barrier, we combined experience sampling and passive mobile sensing methods with time-lagged analyses (i.e., vector autoregressive modeling) to investigate the temporal impact of stress on real-world indices of social interaction. We found that, across a 2-month period, greater perceived stress on a given day predicted significantly decreased social interaction-measured by the amount of face to face conversation-the following day. Critically, the reverse pattern was not observed (i.e., social interaction did not temporally predict stress), and the effect of stress on social interaction was present while accounting for other related variables such as sleep, movement, and time spent at home. These findings are consistent with animal research on stress-induced social avoidance and lay the groundwork for creating naturalistic, mobile-sensing based human models to further elucidate the cycle between stress and real-world social interaction. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Specific sub-regions of the longitudinal axis of the hippocampus mediate behavioural responses to chronic psychosocial stress

Accumulating evidence suggests that the hippocampus is functionally segregated along its longitudinal axis into a dorsal (dHi) sub-region, shown to play roles in learning & memory and a ventral sub-region (vHi), involved in anxiety and antidepressant action. Recent studies also suggest that the intermediate hippocampus (iHi) might be functionally independent, but it has received relatively little attention. We recently found that the iHi is involved in the behavioural effects of chronic treatment with the antidepressant fluoxetine in the forced swim test. However, the roles of specific sub-regions of the longitudinal axis of the hippocampus in the response to chronic stress, a risk factor for depression and anxiety disorders, has not yet been investigated. Therefore, we used excitotoxic lesions of the dHi, iHi or vHi in male C57BL/6 mice to investigate the roles of these sub-regions in the behavioural (anxiety, anhedonia, depression) responses to chronic psychosocial stress. We found that stress-induced increases in anxiety in the novelty-induced hypophagia and marble burying tests were prevented by each of the sub-region lesions, but only vHi lesions attenuated stress-induced anxiety in the open field test. Stress-induced anhedonia was reduced in dHi- and vHi- but not iHi-lesioned mice. In stressed mice, only vHi lesions induced an antidepressant-like effect in the forced swim test and prolonged latency to adopt a defeat posture during social defeat, suggesting an increase in stress resilience. Interestingly, iHi lesions increased stress-induced social avoidance in the social interaction test. In summary, we found that all hippocampal sub-regions are involved in the anxiogenic effects of chronic stress but that the iHi plays a predominant role in stress-induced social avoidance and the vHi has a predominant role in active coping behaviours and antidepressant-like behaviour following chronic stress.

Chronic intranasal oxytocin reverses stress-induced social avoidance in female prairie voles

Social anxiety disorder (SAD) is a prevalent mental illness in both men and women, but current treatment approaches with selective serotonin reuptake inhibitors (SSRI) have limited success. The neuropeptide oxytocin (OXT) has become a therapeutic target due to its prosocial and anxiolytic effects. Nevertheless, no research has focused on the impact of chronic OXT treatment in animal models of SAD. Social defeat stress is an animal model of social conflict that reliably induces a social avoidance phenotype, reflecting symptoms observed in individuals suffering from SAD. Here, we used the socially monogamous prairie vole, which exhibits aggressive behavior in both sexes, to examine the effects of OXT and SSRI treatment following social defeat stress in males and females. Defeated voles became avoidant in unfamiliar social situations as early as one day after defeat experience, and this phenotype persisted for at least eight weeks. OXT receptor (OXTR) binding in mesocorticolimbic and paralimbic regions was reduced in defeated females during the eight-week recovery period. In males, serotonin 1A receptor binding was decreased in the basolateral amygdala and dorsal raphe nucleus starting at one week and four weeks post-defeat, respectively. Chronic intranasal treatment with OXT had a negative effect on sociability and mesolimbic OXTR binding in non-defeated females. However, chronic intranasal OXT promoted social engagement and increased mesolimbic OXTR binding in defeated females but not males. SSRI treatment led to only modest effects. This study identifies a sex-specific and stress-dependent function of intranasal OXT on mesolimbic OXTR and social behaviors.

Molecular laterality encodes stress susceptibility in the medial prefrontal cortex

Functional lateralization of the prefrontal cortex has been implicated in stress and emotional disorders, yet underlying gene expression changes remains unknown. Here, we report molecular signatures lateralized by chronic social defeats between the two medial prefrontal cortices (mPFCs). Stressed mice show 526 asymmetrically expressed genes between the mPFCs. This cortical asymmetry selectively occurs in stressed mice with depressed social activity, but not in resilient mice with normal behavior. We have isolated highly asymmetric genes including connective tissue growth factor (CTGF), a molecule that modulates wound healing at the periphery. Knockdown of CTGF gene in the right mPFC by shRNA led to a stress-resistant behavioral phenotype. Overexpression of CTGF in the right mPFC using viral transduction induces social avoidance while the left mPFC thereof prevent stress-induced social avoidance. Our study provides a molecular window into the mechanism of stress-induced socioemotional disorders, which can pave the way for new interventions by targeting cortical asymmetry.

Unique effects of social defeat stress in adolescent male mice on the Netrin-1/DCC pathway, prefrontal cortex dopamine and cognition (Social stress in adolescent vs. adult male mice).

For some individuals, social stress is a risk factor for psychiatric disorders characterized by adolescent onset, prefrontal cortex (PFC) dysfunction and cognitive impairments. Social stress may be particularly harmful during adolescence when dopamine (DA) axons are still growing to the PFC, rendering them sensitive to environmental influences. The guidance cue Netrin-1 and its receptor, DCC, coordinate to control mesocorticolimbic DA axon targeting and growth during this age. Here, we adapted the accelerated social defeat (AcSD) paradigm to expose male mice to social stress in either adolescence or adulthood and categorized them as “resilient” or “susceptible” based on social avoidance behavior. We examined whether stress would alter the expression of DCC and Netrin-1 in mesolimbic DA regions and would have enduring consequences on PFC DA connectivity and cognition. While in adolescence the majority of mice are resilient but exhibit risk-taking behavior, AcSD in adulthood leads to a majority of susceptible mice without altering anxiety-like traits. In adolescent, but not adult mice, AcSD dysregulates DCC and Netrin-1 expression in mesolimbic DA regions. These molecular changes in adolescent mice are accompanied by changes in PFC DA connectivity. Following AcSD in adulthood, cognitive function remains unaffected, but all mice exposed to AcSD in adolescence show deficits in inhibitory control when they reach adulthood. These findings indicate that exposure to AcSD in adolescence versus adulthood has substantially different effects on brain and behavior and that stress-induced social avoidance in adolescence does not predict vulnerability to deficits in cognitive performance.

A projection from the paraventricular nucleus of the thalamus to the shell of the nucleus accumbens contributes to footshock stress-induced social avoidance

The paraventricular nucleus of the thalamus (PVT) is an area of the dorsal midline thalamus that contributes to footshock induced anxiety. The PVT sends a dense projection to the shell of the nucleus accumbens (NAcSh) and the present study explored if this projection is involved in the behavioral changes produced by a single exposure of rats to inescapable footshocks. The inhibitory Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) hM4Di was transduced in PVT neurons that project to the NAcSh. Rats were exposed to an episode of moderately intense footshock (1.5 mA × 2 s × 5) and assigned to either high-responder (HR) or low-responder groups (LR) according to their level of fear generalization 24 h later. The effect of chemogenetic inhibition of the PVT-NAcSh projection on anxiety- and fear-like behaviors was assessed at approximately 2 weeks post-footshock. HR showed a higher level of social avoidance compared to non-shocked animals and LR. The elevated level of social avoidance was attenuated in the HR treated with the hM4Di agonist clozapine (0.01 mg/kg, i.p.) or clozapine N-oxide (CNO) administrations in the NAcSh while avoidance of open spaces and contextual fear expression were not affected. Analysis of protein product of the early to immediate gene cfos indicated that these effects were mediated by dynorphin neurons in the NAcSh. This study provides evidence for a role of a projection from the PVT to the NAcSh in stress-induced social avoidance independent of anxiety to non-social stimuli and contextual fear mechanisms.

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.