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Cited by 181Neuroendocrine regulation and behaviorNeuropeptides and Animal PhysiologyNeurotransmitter Receptor Influence on Behavior

Oxytocin receptors in the anteromedial bed nucleus of the stria terminalis promote stress-induced social avoidance in female California mice

Open access
Duque-Wilckens, Natalia, Steinman, Michael Q., Busnelli, Marta, Chini, Bice, Yokoyama, Sae, Pham, Mary, Laredo, Sarah A., Hao, Rebecca +5 more·2018·Biological Psychiatry
DOI 10.1016/j.biopsych.2017.08.024PMC PMC5743604
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Abstract

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 EGR1 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 females and decreased social approach in males 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 females but not males, increased EGR1 immunoreactivity in the nucleus accumbens (NAc) core and anteromedial BNST in females but not males. Stressed females that received an infusion of L-368,899 in to anteromedial BNST but not the NAc 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.

AI snapshot

Written from the paper’s full text.

TL;DR

Systemic or anteromedial BNST infusion of the oxytocin receptor antagonist L-368,899 rapidly reversed stress-induced social avoidance in female California mice, while systemic L-368,899 reduced social approach in defeat-naïve males. The results suggest OTR activation in the anteromedial BNST promotes vigilance toward unfamiliar social contexts and social avoidance in stressed females.

Key findings

  • In stressed females, systemic L-368,899 at 5 mg/kg increased time in the interaction zone versus saline-treated stressed females (p<0.05, d=1.03) and increased active investigation; stressed females given saline or 1 mg/kg showed reduced interaction (p<0.001, d=1.6 and p=0.02, d=1.1, respectively). In control males, 5 mg/kg L-368,899 reduced time in the interaction zone (p=0.02, d=1.25).
  • Infusion of L-368,899 into the anteromedial BNST, but not the dorsolateral NAc core, increased social approach in stressed females (BNSTam p<0.001, d=1.27; NAcdl d=0.07; misses d=0.12).
  • Intranasal oxytocin increased EGR1 immunoreactivity in females but not males in the anteromedial BNST (p=0.03, d=1.09) and dorsolateral NAc core (p=0.03, d=0.93).
  • Systemic 5 mg/kg L-368,899 eliminated the stress-induced increase in orientation toward the target mouse in females (P<0.01), and BNSTam infusion reduced this vigilance response (P<0.05). L-368,899 fully prevented oxytocin activation of G-proteins and β-arrestin recruitment without activating them alone.

Methods

  • Male and female California mice were assigned to control handling or 3 days of social defeat, with behavioral and receptor-binding analyses conducted two weeks later.
  • Systemic L-368,899 (1 or 5 mg/kg, intraperitoneal) was given 30 min before social interaction testing; separate tests included odor preference, OTR autoradiography, EGR1 immunohistochemistry after intranasal oxytocin or systemic L-368,899, and BRET assays for G-protein/β-arrestin coupling.
  • Stressed females received bilateral 200 nl infusions of aCSF or L-368,899 (1 µg per side) into the dorsolateral NAc core or anteromedial BNST before social interaction testing; analyses used two-way ANOVA, planned comparisons with Bonferroni correction, Cohen’s d, Spearman correlations, and 3-way ANOVA for estrous cycle.

Limitations

  • The paper states that further study is needed to identify the downstream effects of OTR activation in the anteromedial BNST.
  • Evident from the text: site-specific infusion experiments were performed only in stressed females, so the circuit-level conclusion is limited to females; several key effects were statistical trends, including the systemic female social interaction stress×drug interaction (p=0.06) and EGR1 sex×drug interactions in BNSTam (p=0.08) and NAcdl (p=0.06).
  • The paper reports no main effects of estrous cycle or interactions with stress or treatment in the social interaction and odor preference tests (Supplementary Table S2), but full procedural details are in supplementary methods not included in the provided text.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/j.biopsych.2017.08.024

Cites

77 of 77 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 47 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Stressed female California mice that received an infusion of L-368,899 into the anteromedial BNST increased social approach.

    “Stressed females that received an infusion of L-368,899 in to anteromedial BNST but not the NAc core increased social approach and decreased social vigilance responses.”
    Quote in the paperSubstantial claim
  • Findingown data

    L-368,899 did not activate G-proteins in the absence of OT.

    “did not activate G-proteins in the absence of OT”
    Quote in the paperNot a substantial claim
  • Findingown data

    Stressed female California mice that received an infusion of L-368,899 into the anteromedial BNST decreased social vigilance responses.

    “Stressed females that received an infusion of L-368,899 in to anteromedial BNST but not the NAc core increased social approach and decreased social vigilance responses.”
    Quote in the paperSubstantial claim
  • Findingown data

    Systemic administration of L-368,899 increased social approach in stressed female California mice.

    “A single dose of systemic L-368,899 increased social approach in stressed females”
    Quote in the paperSubstantial claim
  • Findingown data

    Infusion of L-368,899 into the NAc core did not increase social approach in stressed female California mice.

    “Stressed females that received an infusion of L-368,899 in to anteromedial BNST but not the NAc core increased social approach and decreased social vigilance responses.”
    Quote in the paperSubstantial claim
  • May combine two claims. 20
  • Classified as probably not a substantial claim. 28

  • May combine two claims.

    Findingown data

    There were no main effects of estrous cycle or interaction with stress or treatment in the SI and OP tests.

    “There were no main effects of estrous cycle or interaction with stress or treatment (Supplementary Table S2).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    In the NAc shell, female California mice had more EGR1 positive cells than males.

    “In the NAc shell, females had more EGR1 positive cells than males (Supplementary Figure S4, main effect of sex, p=0.03).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In female California mice, stress significantly increased time spent in corners opposite the interaction zone, but only in females receiving saline or 1 mg/Kg OTA, but not 5 mg/Kg OTA.

    “In females, stress also significantly increased time spent in corners opposite the interaction zone (Figure 1D; main effect of stress, p<0.001), but only in females receiving saline (p=0.01, d=0.8) or 1 mg/Kg of OTA (p= 0.047, d=1.3), but not 5 mg/Kg of OTA (d=0.25).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data

    There were no effects of stress, treatment, or their interaction on EGR1 positive cells detected in NAc core ventromedial, LS or PVN.

    “There were no effects of stress, treatment, or their interaction on EGR1 positive cells detected in NAc core ventromedial, LS or PVN (Supplementary Figure S4).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In male California mice, there were no effects of stress, treatment, or their interaction on time spent in interaction zone or corners during acclimation phase and time spent in the center of the open field during open field phase.

    “There were no effects of stress, treatment, or their interaction on time spent in interaction zone or corners during acclimation phase and time spent in the center of the open field during open field phase (Supplementary Figures S1).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In male California mice, there were no significant differences in time spent in active investigation or in corner zones.

    “There were no significant differences in time spent in active investigation (Figure 1C) or in corner zones (Figure 1D).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Neither control nor stressed male California mice showed a preference for any odor, and this was not affected by OTA treatment.

    “Surprisingly, neither control nor stressed males showed a preference for any odor, and this was not affected by OTA treatment.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    No effects of treatment or injection site were detected in time spent in corners during interaction, time in the interaction zone during acclimation, or distance traveled during open field.

    “No effects of treatment or injection site were detected in time spent in corners during interaction (Figure 5C), time in the interaction zone during acclimation (Figure 5D) or distance traveled during open field (Figure 5E).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Stressed females spent more time oriented towards the target mouse, but not an empty cage, when outside of the interaction zone.

    “stressed females spent more time oriented towards the target mouse, but not an empty cage, when outside of the interaction zone.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Treatment with 5 mg/kg of OTA but not 1 mg/kg OTA eliminated the stress-induced increase in time spent oriented toward the target mouse in female California mice.

    “Treatment with 5 mg/kg of OTA but not 1 mg/kg OTA eliminated the stress-induced increase in time spent oriented toward the target mouse (Figure 6B, P<0.01).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    A single injection of OTA into BNSTam, but not NAcdl, increased social approach in stressed females.

    “A single injection of OTA in to BNSTam but not the NAcdl, increased social approach in stressed females.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Intranasal OT reduces amygdala reactivity in men.

    “Intranasal OT reduces amygdala reactivity in men (5, 7)”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [5] Domes, 2007, Oxytocin attenuates amygdala responses to emotional faces regardless of valence, Biol Psychiatry source

      Not checked in the free run.

    • cites [7] Kirsch, 2005, Oxytocin modulates neural circuitry for social cognition and fear in humans, J Neurosci source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Intranasal OT increases amygdala reactivity in women.

    “but increases it in women (11, 12).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [11] Domes, 2010, Effects of intranasal oxytocin on emotional face processing in women, Psychoneuroendocrinology source

      Not checked in the free run.

    • cites [12] Lischke, 2012, Oxytocin increases amygdala reactivity to threatening scenes in females, Psychoneuroendocrinology source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Humans suffering from depression had more OT immunoreactive neurons in the hypothalamus in post-mortem analyses.

    “post-mortem analyses showed that humans suffering from depression had more OT immunoreactive neurons in the hypothalamus (10).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [10] Purba, 1996, Increased number of vasopressin- and oxytocin-expressing neurons in the paraventricular nucleus of the hypothalamus in depression, Arch Gen Psychiatry source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    In some cases, OT is anxiogenic.

    “Nonetheless, it is clear in some cases that OT is anxiogenic (9).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [9] Eckstein, 2014, Oxytocin facilitates the sensation of social stress, Hum Brain Mapp source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    OT is a key regulator of social and emotional behaviors.

    “Oxytocin (OT) is an evolutionary conserved neuropeptide that is a key regulator of social and emotional behaviors (1–4).”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [1] Dumais, 2016, Vasopressin and oxytocin receptor systems in the brain: Sex differences and sex-specific regulation of social behavior, Front Neuroendocrinol source

      Not checked in the free run.

    • cites [2] Heinrichs, 2007, Neuroendocrine mechanisms of stress and social interaction: Implications for mental disorders, Curr Opin Psychiatry source

      Not checked in the free run.

    • cites [3] Johnson, 2017, Oxytocin and vasopressin neural networks: Implications for social behavioral diversity and translational neuroscience, Neurosci Biobehav Rev source

      Not checked in the free run.

    • cites [4] Neumann, 2016, Oxytocin in general anxiety and social fear: A translational approach, Biol Psychiatry source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Some OTR antagonists, such as atosiban, can activate selective Gi pathways.

    “some OTR antagonists, such as atosiban, can activate selective Gi pathways (36, 38).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [36] Busnelli, 2013, Selective and potent agonists and antagonists for investigating the role of mouse oxytocin receptors, J Pharmacol Exp Ther source

      Not checked in the free run.

    • cites [38] Reversi, 2005, The oxytocin receptor antagonist atosiban inhibits cell growth via a “biased agonist” mechanism, J Biol Chem source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    EGR1 has been shown to be useful as an indirect marker of neuronal activation in a variety of species and contexts.

    “EGR1 has been shown to be useful as an indirect marker of neuronal activation in a variety of species and contexts (28–30).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [28] Perkeybile, 2015, Intergenerational transmission of alloparental behavior and oxytocin and vasopressin receptor distribution in the prairie vole, Front Behav Neurosci source

      Not checked in the free run.

    • cites [29] Hasen, 2006, Maternal aggression: New insights from Egr-1, Brain Res source

      Not checked in the free run.

    • cites [30] Yochiy, 2012, Novelty, but not operant aversive learning, enhances Fos and Egr-1 expression in the medial prefrontal cortex and hippocampal areas of rats, Behav Neurosci source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    A single dose of OTA, either systemically or within the BNSTam, rapidly reverses stress-induced social avoidance in females, without affecting behavior in non-social contexts.

    “Our main finding is that a single dose of OTA, either systemically or within the BNSTam, rapidly reverses stress-induced social avoidance in females, without affecting behavior in non-social contexts.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    Females were randomly assigned to receive bilateral infusions of either aCSF or L-368,899 into NAcdl or BNSTam.

    “After recovery, females were randomly assigned to receive bilateral 200 nl infusions of either aCSF or L-368,899 (1 ug per side) into NAcdl or BNSTam”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Social interaction phase videos were reanalyzed by an observer blind to treatment assignment.

    “The interaction phase videos were later reanalyzed by an observer blind to treatment assignment to manually score active investigation, time spent inactive in interaction zone, auto-grooming, and time spent in sides”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    Male and female California mice were randomly assigned to control handling or social defeat for 3 consecutive days.

    “Male and female mice were randomly assigned to control handling or social defeat for 3 consecutive days as described (16).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [16] Trainor, 2013, Sex differences in stress-induced social withdrawal: Independence from adult gonadal hormones and inhibition of female phenotype by corncob bedding, Horm Behav source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Histology was used to determine injection sites.

    “Histology was used to determine injection sites (see Supplementary methods).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    OT facilitates OTR coupling to several different G-proteins and β-arrestins.

    “OT facilitates OTR coupling to several different G-proteins and β-arrestins, allowing for multiple degrees of freedom for effects on neural activity (36, 37).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [36] Busnelli, 2013, Selective and potent agonists and antagonists for investigating the role of mouse oxytocin receptors, J Pharmacol Exp Ther source

      Not checked in the free run.

    • cites [37] Gimpl, 2001, The oxytocin receptor system: Structure, function, and regulation, Physiol Rev source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation

    Estrous cycle was assessed post mortem to avoid disrupting behavior.

    “Estrous cycle was assessed post mortem to avoid disrupting behavior (40).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [40] Silva, 2010, Effects of photoperiod and experience on aggressive behavior in female California mice, Behav Brain Res source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Defeat induces a preference for familiar social contexts and OTR facilitates this preference.

    “Results from the odor preference test suggest that defeat induces a preference for familiar social contexts and that OTR facilitates this preference.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Intranasal OT increases perceived social stress in humans.

    “intranasal OT has been reported to increase perceived social stress (9) and mistrust (77) in humans.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [9] Eckstein, 2014, Oxytocin facilitates the sensation of social stress, Hum Brain Mapp source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The BNST is a key center for integrating information from social and physical environments to generate avoidance/approach responses.

    “The BNST is thought to be a key center for integrating information from social and physical environments to generate avoidance/approach responses (61).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [61] Lebow, 2016, Overshadowed by the amygdala: The bed nucleus of the stria terminalis emerges as key to psychiatric disorders, Mol Psychiatry source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Anteromedial portions of BNST receive inputs from the medial amygdala and posterior BNST, and send direct projections to PVN and CeA.

    “Anteromedial portions of BNST receive inputs from the medial amygdala and posterior BNST, and send direct projections to PVN and CeA (70, 71).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [70] Dong, 2006, Projections from bed nuclei of the stria terminalis, anteromedial area: Cerebral hemisphere integration of neuroendocrine, autonomic, and behavioral aspects of energy balance, J Comp Neurol source

      Not checked in the free run.

    • cites [71] Gomez, 1992, Differential projections of the anterior and posterior regions of the medial amygdaloid nucleus in the Syrian hamster, J Comp Neurol source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Head orientation was recorded by an observer blind to treatment groups.

    “Head orientation was recorded by an observer blind to treatment groups.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Intranasal OT reduces social interaction behavior in female but not male California mice.

    “Intranasal OT reduced social interaction behavior in female but not male California mice (15)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [15] Steinman, 2016, Sex-specific effects of stress on oxytocin neurons correspond with responses to intranasal oxytocin, Biol Psychiatry source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Social defeat induces hyperactivity of BNSTmv and PVN OT neurons, which in turn increase activation of OTR in BNSTam to induce avoidance of unfamiliar social contexts in females.

    “The current findings combined with our previous work (15) suggest a model that social defeat induces hyperactivity of BNSTmv and PVN OT neurons which in turn increase the activation of OTR in the BNSTam to induce avoidance of unfamiliar social contexts in females.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [15] Steinman, 2016, Sex-specific effects of stress on oxytocin neurons correspond with responses to intranasal oxytocin, Biol Psychiatry source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    The social salience hypothesis posits that OT enhances the salience of both positive and negative social experiences.

    “Similarly, the social salience hypothesis posits that OT enhances the salience of both positive and negative social experiences (75).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [75] Shamay-Tsoory, 2016, The social salience hypothesis of oxytocin, Biol Psychiatry source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Intranasal OT increases mistrust in humans.

    “intranasal OT has been reported to increase perceived social stress (9) and mistrust (77) in humans.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [77] Bartz, 2011, Oxytocin can hinder trust and cooperation in borderline personality disorder, Soc Cogn Affect Neurosci source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Local infusion of OTA into the BNSTam, but not NAcdl, mimics the effects of systemic administration.

    “Local infusion of OTA in to the BNSTam, but not NAcdl, mimics the effects of systemic administration”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The BNST plays a critical role in 'valence surveillance', in which an individual assesses social contexts and assigns a positive or negative valence.

    “It has been proposed that the BNST plays a critical role in ‘valence surveillance’, in which an individual assesses social contexts and assigns a positive or negative valence (61).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [61] Lebow, 2016, Overshadowed by the amygdala: The bed nucleus of the stria terminalis emerges as key to psychiatric disorders, Mol Psychiatry source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    OT can increase BDNF expression in hippocampus and neuroblastoma cells.

    “It has been reported that OT can increase BDNF expression in hippocampus (72) and neuroblastoma cells (73), but otherwise little is known about OT-BDNF interactions.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [72] Dayi, 2015, The effects of oxytocin on cognitive defect caused by chronic restraint stress applied to adolescent rats and on hippocampal VEGF and BDNF levels, Med Sci Monit source

      Not checked in the free run.

    • cites [73] Bakos, 2013, Oxytocin receptor ligands induce changes in cytoskeleton in neuroblastoma cells, J Mol Neurosci source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Male rats confronted with threatening stimuli such as a predator or predator odor exhibit similar orienting responses, described as risk assessment or vigilance behavior.

    “Male rats confronted with threatening stimuli such as a predator or predator odor exhibit similar orienting responses (74), which have been described as risk assessment or vigilance behavior (24).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [74] Blanchard, 1989, Antipredator defensive behaviors in a visible burrow system, J Comp Psychol source

      Not checked in the free run.

    • cites [24] Greenberg, 2013, Sex differences in stress-induced social withdrawal: Role of brain derived neurotrophic factor in the bed nucleus of the stria terminalis, Front Behav Neurosci

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationcitation

    When effects of stress were observed, OTR expression was decreased, possibly as a negative feedback response to elevated OT release.

    “When effects of stress were observed, OTR expression was decreased, possibly as a negative feedback response to elevated OT release (55).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [55] Phaneuf, 2000, Loss of myometrial oxytocin receptors during oxytocin-induced and oxytocin-augmented labour, J Reprod Fertil source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Atosiban activates Gi-mediated pathways in vitro and in vivo.

    “Interestingly, the OTR ligand atosiban, considered to be an OTR antagonist, actually activates Gi-mediated pathways in vitro (36, 38) and in vivo (57).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [36] Busnelli, 2013, Selective and potent agonists and antagonists for investigating the role of mouse oxytocin receptors, J Pharmacol Exp Ther source

      Not checked in the free run.

    • cites [38] Reversi, 2005, The oxytocin receptor antagonist atosiban inhibits cell growth via a “biased agonist” mechanism, J Biol Chem source

      Not checked in the free run.

    • cites [57] Eliava, 2016, A new population of parvocellular oxytocin neurons controlling magnocellular neuron activity and inflammatory pain processing, Neuron source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    OTR play a critical role in learning during aversive social contexts.

    “It has been previously reported that OTR play a critical role in learning during aversive social contexts (76).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [76] Choe, 2015, Oxytocin mediates entrainment of sensory stimuli to social cues of opposing valence, Neuron source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Atosiban mimics the inhibitory effect of OT on sensory neurons of the spinal cord, providing evidence of its unique agonist activity on restricted OTR signaling pathways.

    “Atosiban mimicked the inhibitory effect of OT on sensory neurons of the spinal cord, providing clear evidence of its unique agonist activity on restricted OTR signaling pathways (57).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [57] Eliava, 2016, A new population of parvocellular oxytocin neurons controlling magnocellular neuron activity and inflammatory pain processing, Neuron source

      Not checked in the free run.

42 of 42

  • The paper relies on this without support.

    Intranasal OT reduces social interaction in unstressed female California mice.

    “We also found that intranasal OT reduced social interaction in unstressed females, mirroring the effect of social defeat stress.”

  • The paper relies on this without support.

    No study has considered whether sex differences in G-protein activation by a single receptor contributes to sex differences in behavioral effects.

    “To our knowledge, no study has considered whether sex differences in G-protein activation by a single receptor contributes to sex differences in behavioral effects.”

  • The paper relies on this without support.

    No study has systematically compared these ligands in males and females.

    “no study has systematically compared these ligands in males and females.”

  • The paper relies on this without support.

    Little is known about OT-BDNF interactions.

    “but otherwise little is known about OT-BDNF interactions.”
4 of 4

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • This response has been associated with heightened immediate early gene expression in the anteromedial BNST.

    “Social defeat stress increases c-fos expression in oxytocin neurons in the Paraventricular Nucleus of the Hypothalamus (PVN) (37), a response that has been associated with heightened immediate early gene expression in the anteromedial BNST (40).”

    From Sexual differentiation of neural mechanisms of stress sensitivity during puberty (2023) · cites this paper as [40]

    The Results (page unavailable) report that intranasal oxytocin increased EGR1, an immediate early gene marker, in the anteromedial BNST of female mice. The Discussion proposes a link between social defeat–induced activity in PVN oxytocin neurons and BNST oxytocin-receptor activation, but does not show that the PVN response was associated with increased BNST EGR1; the Results report no stress effect on BNST EGR1 in the test described. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • The BNST plays a key role in modulating stress-induced social avoidance and social vigilance in males and females.

    “The BNST plays a key role in modulating stress-induced social avoidance and social vigilance in males and females (38, 40, 41).”

    From Sexual differentiation of neural mechanisms of stress sensitivity during puberty (2023) · cites this paper as [40]

    The Results (Effects of OTA on risk assessment behavior; page unavailable) show that blocking oxytocin receptors in the BNST reduced social vigilance in stressed female California mice; the Discussion also identifies the BNSTam as a site involved in their social avoidance. The claim extends this role to males, but the Results report no stress-induced difference in male social interaction or orientation responses, and the BNSTam infusion experiments were conducted in females. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

  • These results contrast with adults, where social defeat decreases social approach and increases social vigilance in females but not males.

    “These results contrast with observed sex differences in adults, which show that social defeat decreases social approach (38, 42, 43, 51) and increases social vigilance (40) in females but not males.”

    From Sexual differentiation of neural mechanisms of stress sensitivity during puberty (2023) · cites this paper as [40]

  • Previous work in California mice shows changes in BNST drive stress-induced social avoidance and social vigilance.

    “Previous work in California mice (Peromyscus californicus) shows that social defeat stress has stronger effects on BNST structure and function in adult females than males (37, 38) and that these changes drive stress-induced social avoidance and social vigilance (39–41).”

    From Sexual differentiation of neural mechanisms of stress sensitivity during puberty (2023) · cites this paper as [40]

  • In California mice, knockdown of oxytocin or administration of an OXTR antagonist in the anterior bed nucleus of the stria terminalis increased social approach and decreased social vigilance, an anxiety-like behavior, suggesting that oxytocin may also drive social anxiety-like behavior depending on its source or context.

    “However, in California mice, knockdown of OXT or administration of OXTR antagonist in the anterior BNST increased social approach and decreased social vigilance, an anxiety-like behavior, which suggests that OXT may also drive social anxiety-like behavior depending on its source or context (66, 88).”

    From Oxytocin, Vasopressin, and Social Behavior: From Neural Circuits to Clinical Opportunities (2022) · cites this paper as [88]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Claim of no sex differences in OTR conflicts with PVN result

    Minor

    The discussion states that there were no sex differences in OTR expression, but the results report significantly lower OTR binding in the PVN of females than males.

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Authors
Duque-Wilckens, N., Steinman, M. Q., Busnelli, M., Chini, B., Yokoyama, S., Pham, M., Laredo, S. A., Hao, R., Perkeybile, A. M., Minie, V. A., Tan, P. B., Bales, K. L., & Trainor, B. C.
Affiliations
  • University of California, Davis (US)
  • University of Milan (IT)
Corresponding author
Trainor, Brian C.
ORCID
Venue
Biological Psychiatry
Publisher
Elsevier BV
Published
2018-02
Volume
83
Issue
3
Pages
203-213
ISSN
0006-3223 (ISSN-L)
DOI
10.1016/j.biopsych.2017.08.024
PMC
PMC5743604
OpenAlex
W2755709714
Semantic Scholar
dfb392e2b3221906b0d92d515c8101c0845123f1
Cited by
181
References
78
Citations by year
2026: 13 · 2025: 31 · 2024: 22 · 2023: 21 · 2022: 14 · 2021: 31 · 2020: 17 · 2019: 17 · 2018: 15
FWCI
19.18
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Biological Psychiatry (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • National Institutes of Health (P51OD011107)
  • National Institute of Mental Health (F31MH095253, R01MH103322)
Topics
  • Social Sciences › Psychology › Social Psychology › Neuroendocrine regulation and behavior
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
Keywords
oxytocin receptor, bed nucleus of the stria terminalis, social avoidance, social defeat stress, sex differences, L-368,899, G protein activation, early growth response factor-1, nucleus accumbens core, social vigilance, social approach, anxiety
MeSH terms
Animals, Behavior, Animal, Camphanes, Disease Models, Animal, Female, Male, Nucleus Accumbens, Oxytocin, Piperazines, Septal Nuclei, Sex Characteristics, Social Behavior, Stress, Psychological, Receptors, Oxytocin, Mice

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

Statistics and arithmetic are recomputed, not judged.

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