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Oxytocin Receptors in the Anteromedial Bed Nucleus of the Stria Terminalis Promote Stress-Induced Social Avoidance in Female California Mice
Open accessAbstract
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.
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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.
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74 Own result · 29 Not checked yet · 17 Own interpretation · 5 Own method · 1 No basis given
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Oxytocin Receptors in the Anteromedial Bed Nucleus of the Stria Terminalis Promote Stress-Induced Social Avoidance in Female California Mice > Abstract > Results
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“did not activate G-proteins in the absence of OT”
§ Oxytocin Receptors in the Anteromedial Bed Nucleus of the Stria Terminalis Promote Stress-Induced Social Avoidance in Female California Mice > Abstract > Results
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ Oxytocin Receptors in the Anteromedial Bed Nucleus of the Stria Terminalis Promote Stress-Induced Social Avoidance in Female California Mice > Abstract > Results
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“A single dose of systemic L-368,899 increased social approach in stressed females”
§ Oxytocin Receptors in the Anteromedial Bed Nucleus of the Stria Terminalis Promote Stress-Induced Social Avoidance in Female California Mice > Abstract > Results
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ Oxytocin Receptors in the Anteromedial Bed Nucleus of the Stria Terminalis Promote Stress-Induced Social Avoidance in Female California Mice > Abstract > Results
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ Oxytocin Receptors in the Anteromedial Bed Nucleus of the Stria Terminalis Promote Stress-Induced Social Avoidance in Female California Mice > Abstract > Results
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“decreased social approach in males naïve to defeat”
§ Oxytocin Receptors in the Anteromedial Bed Nucleus of the Stria Terminalis Promote Stress-Induced Social Avoidance in Female California Mice > Abstract > Results
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“L-368,899 prevented OT activation of G proteins”
§ Oxytocin Receptors in the Anteromedial Bed Nucleus of the Stria Terminalis Promote Stress-Induced Social Avoidance in Female California Mice > Abstract > Results
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ Oxytocin Receptors in the Anteromedial Bed Nucleus of the Stria Terminalis Promote Stress-Induced Social Avoidance in Female California Mice > Abstract > Results
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“In the BNSTam there was evidence for sex-specific effects of intranasal OT on EGR1 immunoreactivity (Figure 4B; sex*drug interaction, p=0.08).”
§ Oxytocin Receptors in the Anteromedial Bed Nucleus of the Stria Terminalis Promote Stress-Induced Social Avoidance in Female California Mice > RESULTS > Effects of intranasal administration of OT and systemic administration of OTA on EGR1 immunoreactivity
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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- Probably not a substantial claim. 28
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In the paper
“There were no main effects of estrous cycle or interaction with stress or treatment (Supplementary Table S2).”
§ Oxytocin Receptors in the Anteromedial Bed Nucleus of the Stria Terminalis Promote Stress-Induced Social Avoidance in Female California Mice > MATERIALS AND METHODS > Statistical analysis
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In the paper
“In the NAc shell, females had more EGR1 positive cells than males (Supplementary Figure S4, main effect of sex, p=0.03).”
§ Oxytocin Receptors in the Anteromedial Bed Nucleus of the Stria Terminalis Promote Stress-Induced Social Avoidance in Female California Mice > RESULTS > Effects of intranasal administration of OT and systemic administration of OTA on EGR1 immunoreactivity
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“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).”
§ Oxytocin Receptors in the Anteromedial Bed Nucleus of the Stria Terminalis Promote Stress-Induced Social Avoidance in Female California Mice > RESULTS > Effects of systemic administration of OTA on social interaction behavior
plaindirect- Asserted: passes — The authors put it forward as true.
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“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).”
§ Oxytocin Receptors in the Anteromedial Bed Nucleus of the Stria Terminalis Promote Stress-Induced Social Avoidance in Female California Mice > RESULTS > Effects of intranasal administration of OT and systemic administration of OTA on EGR1 immunoreactivity
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
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In the paper
“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).”
§ Oxytocin Receptors in the Anteromedial Bed Nucleus of the Stria Terminalis Promote Stress-Induced Social Avoidance in Female California Mice > RESULTS > Effects of systemic administration of OTA on social interaction behavior
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“There were no significant differences in time spent in active investigation (Figure 1C) or in corner zones (Figure 1D).”
§ Oxytocin Receptors in the Anteromedial Bed Nucleus of the Stria Terminalis Promote Stress-Induced Social Avoidance in Female California Mice > RESULTS > Effects of systemic administration of OTA on social interaction behavior
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In the paper
“Surprisingly, neither control nor stressed males showed a preference for any odor, and this was not affected by OTA treatment.”
§ Oxytocin Receptors in the Anteromedial Bed Nucleus of the Stria Terminalis Promote Stress-Induced Social Avoidance in Female California Mice > RESULTS > Effects of systemic administration of OTA on odor preference behavior
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In the paper
“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).”
§ Oxytocin Receptors in the Anteromedial Bed Nucleus of the Stria Terminalis Promote Stress-Induced Social Avoidance in Female California Mice > RESULTS > Effects of OTA infusion into BNSTam or NAcdl in stressed females on SI
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In the paper
“stressed females spent more time oriented towards the target mouse, but not an empty cage, when outside of the interaction zone.”
§ Oxytocin Receptors in the Anteromedial Bed Nucleus of the Stria Terminalis Promote Stress-Induced Social Avoidance in Female California Mice > DISCUSSION > Stress induces vigilance and avoidance of unfamiliar social contexts
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In the paper
“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).”
§ Oxytocin Receptors in the Anteromedial Bed Nucleus of the Stria Terminalis Promote Stress-Induced Social Avoidance in Female California Mice > RESULTS > Effects of OTA on risk assessment behavior
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In the paper
“A single injection of OTA in to BNSTam but not the NAcdl, increased social approach in stressed females.”
§ Oxytocin Receptors in the Anteromedial Bed Nucleus of the Stria Terminalis Promote Stress-Induced Social Avoidance in Female California Mice > DISCUSSION > Specific-site effects of OTR on social avoidance
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In the paper
“Intranasal OT reduces amygdala reactivity in men (5, 7)”
§ Oxytocin Receptors in the Anteromedial Bed Nucleus of the Stria Terminalis Promote Stress-Induced Social Avoidance in Female California Mice > INTRODUCTION
What the sources say
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In the paper
“but increases it in women (11, 12).”
§ Oxytocin Receptors in the Anteromedial Bed Nucleus of the Stria Terminalis Promote Stress-Induced Social Avoidance in Female California Mice > INTRODUCTION
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“post-mortem analyses showed that humans suffering from depression had more OT immunoreactive neurons in the hypothalamus (10).”
§ Oxytocin Receptors in the Anteromedial Bed Nucleus of the Stria Terminalis Promote Stress-Induced Social Avoidance in Female California Mice > INTRODUCTION
What the sources say
- Not checked yetcites [10] Purba, 1996, Increased number of vasopressin- and oxytocin-expressing neurons in the paraventricular nucleus of the hypothalamus in depression, Arch Gen Psychiatry source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Nonetheless, it is clear in some cases that OT is anxiogenic (9).”
§ Oxytocin Receptors in the Anteromedial Bed Nucleus of the Stria Terminalis Promote Stress-Induced Social Avoidance in Female California Mice > INTRODUCTION
What the sources say
- Not checked yetcites [9] Eckstein, 2014, Oxytocin facilitates the sensation of social stress, Hum Brain Mapp source
boosteddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Oxytocin (OT) is an evolutionary conserved neuropeptide that is a key regulator of social and emotional behaviors (1–4).”
§ Oxytocin Receptors in the Anteromedial Bed Nucleus of the Stria Terminalis Promote Stress-Induced Social Avoidance in Female California Mice > INTRODUCTION
What the sources say
- Not checked yetcites [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 yetcites [2] Heinrichs, 2007, Neuroendocrine mechanisms of stress and social interaction: Implications for mental disorders, Curr Opin Psychiatry source
- Not checked yetcites [3] Johnson, 2017, Oxytocin and vasopressin neural networks: Implications for social behavioral diversity and translational neuroscience, Neurosci Biobehav Rev source
- Not checked yetcites [4] Neumann, 2016, Oxytocin in general anxiety and social fear: A translational approach, Biol Psychiatry source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“some OTR antagonists, such as atosiban, can activate selective Gi pathways (36, 38).”
§ Oxytocin Receptors in the Anteromedial Bed Nucleus of the Stria Terminalis Promote Stress-Induced Social Avoidance in Female California Mice > MATERIALS AND METHODS > Effects of OTA on OT activation of G-proteins and β-arrestins recruitment
What the sources say
- Not checked yetcites [36] Busnelli, 2013, Selective and potent agonists and antagonists for investigating the role of mouse oxytocin receptors, J Pharmacol Exp Ther source
- Not checked yetcites [38] Reversi, 2005, The oxytocin receptor antagonist atosiban inhibits cell growth via a “biased agonist” mechanism, J Biol Chem source
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In the paper
“EGR1 has been shown to be useful as an indirect marker of neuronal activation in a variety of species and contexts (28–30).”
§ Oxytocin Receptors in the Anteromedial Bed Nucleus of the Stria Terminalis Promote Stress-Induced Social Avoidance in Female California Mice > MATERIALS AND METHODS > Effects of intranasal OT and systemic OTA on EGR1 immunoreactivity
What the sources say
- Not checked yetcites [28] Perkeybile, 2015, Intergenerational transmission of alloparental behavior and oxytocin and vasopressin receptor distribution in the prairie vole, Front Behav Neurosci source
- Not checked yetcites [29] Hasen, 2006, Maternal aggression: New insights from Egr-1, Brain Res source
- Not checked yetcites [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
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ Oxytocin Receptors in the Anteromedial Bed Nucleus of the Stria Terminalis Promote Stress-Induced Social Avoidance in Female California Mice > INTRODUCTION
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In the paper
“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”
§ Oxytocin Receptors in the Anteromedial Bed Nucleus of the Stria Terminalis Promote Stress-Induced Social Avoidance in Female California Mice > MATERIALS AND METHODS > Site-specific injection of OTA
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In the paper
“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”
§ Oxytocin Receptors in the Anteromedial Bed Nucleus of the Stria Terminalis Promote Stress-Induced Social Avoidance in Female California Mice > MATERIALS AND METHODS > Social interaction test (SI)
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In the paper
“Male and female mice were randomly assigned to control handling or social defeat for 3 consecutive days as described (16).”
§ Oxytocin Receptors in the Anteromedial Bed Nucleus of the Stria Terminalis Promote Stress-Induced Social Avoidance in Female California Mice > MATERIALS AND METHODS > Social defeat
What the sources say
- Not checked yetcites [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
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In the paper
“Histology was used to determine injection sites (see Supplementary methods).”
§ Oxytocin Receptors in the Anteromedial Bed Nucleus of the Stria Terminalis Promote Stress-Induced Social Avoidance in Female California Mice > MATERIALS AND METHODS > Site-specific injection of OTA
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ Oxytocin Receptors in the Anteromedial Bed Nucleus of the Stria Terminalis Promote Stress-Induced Social Avoidance in Female California Mice > MATERIALS AND METHODS > Effects of OTA on OT activation of G-proteins and β-arrestins recruitment
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Estrous cycle was assessed post mortem to avoid disrupting behavior (40).”
§ Oxytocin Receptors in the Anteromedial Bed Nucleus of the Stria Terminalis Promote Stress-Induced Social Avoidance in Female California Mice > MATERIALS AND METHODS > Statistical analysis
What the sources say
- Not checked yetcites [40] Silva, 2010, Effects of photoperiod and experience on aggressive behavior in female California mice, Behav Brain Res source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Results from the odor preference test suggest that defeat induces a preference for familiar social contexts and that OTR facilitates this preference.”
§ Oxytocin Receptors in the Anteromedial Bed Nucleus of the Stria Terminalis Promote Stress-Induced Social Avoidance in Female California Mice > DISCUSSION
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“intranasal OT has been reported to increase perceived social stress (9) and mistrust (77) in humans.”
§ Oxytocin Receptors in the Anteromedial Bed Nucleus of the Stria Terminalis Promote Stress-Induced Social Avoidance in Female California Mice > DISCUSSION > Conclusions
What the sources say
- Not checked yetcites [9] Eckstein, 2014, Oxytocin facilitates the sensation of social stress, Hum Brain Mapp source
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“The BNST is thought to be a key center for integrating information from social and physical environments to generate avoidance/approach responses (61).”
§ Oxytocin Receptors in the Anteromedial Bed Nucleus of the Stria Terminalis Promote Stress-Induced Social Avoidance in Female California Mice > DISCUSSION > Specific-site effects of OTR on social avoidance
What the sources say
- Not checked yetcites [61] Lebow, 2016, Overshadowed by the amygdala: The bed nucleus of the stria terminalis emerges as key to psychiatric disorders, Mol Psychiatry source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“Anteromedial portions of BNST receive inputs from the medial amygdala and posterior BNST, and send direct projections to PVN and CeA (70, 71).”
§ Oxytocin Receptors in the Anteromedial Bed Nucleus of the Stria Terminalis Promote Stress-Induced Social Avoidance in Female California Mice > DISCUSSION > Specific-site effects of OTR on social avoidance
What the sources say
- Not checked yetcites [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 yetcites [71] Gomez, 1992, Differential projections of the anterior and posterior regions of the medial amygdaloid nucleus in the Syrian hamster, J Comp Neurol source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Head orientation was recorded by an observer blind to treatment groups.”
§ Oxytocin Receptors in the Anteromedial Bed Nucleus of the Stria Terminalis Promote Stress-Induced Social Avoidance in Female California Mice > RESULTS > Effects of OTA on risk assessment behavior
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Intranasal OT reduced social interaction behavior in female but not male California mice (15)”
§ Oxytocin Receptors in the Anteromedial Bed Nucleus of the Stria Terminalis Promote Stress-Induced Social Avoidance in Female California Mice > DISCUSSION > Specific-site effects of OTR on social avoidance
What the sources say
- Not checked yetcites [15] Steinman, 2016, Sex-specific effects of stress on oxytocin neurons correspond with responses to intranasal oxytocin, Biol Psychiatry source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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.”
§ Oxytocin Receptors in the Anteromedial Bed Nucleus of the Stria Terminalis Promote Stress-Induced Social Avoidance in Female California Mice > DISCUSSION > Conclusions
What the sources say
- Not checked yetcites [15] Steinman, 2016, Sex-specific effects of stress on oxytocin neurons correspond with responses to intranasal oxytocin, Biol Psychiatry source
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Similarly, the social salience hypothesis posits that OT enhances the salience of both positive and negative social experiences (75).”
§ Oxytocin Receptors in the Anteromedial Bed Nucleus of the Stria Terminalis Promote Stress-Induced Social Avoidance in Female California Mice > DISCUSSION > Stress induces vigilance and avoidance of unfamiliar social contexts
What the sources say
- Not checked yetcites [75] Shamay-Tsoory, 2016, The social salience hypothesis of oxytocin, Biol Psychiatry source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
In the paper
“intranasal OT has been reported to increase perceived social stress (9) and mistrust (77) in humans.”
§ Oxytocin Receptors in the Anteromedial Bed Nucleus of the Stria Terminalis Promote Stress-Induced Social Avoidance in Female California Mice > DISCUSSION > Conclusions
What the sources say
- Not checked yetcites [77] Bartz, 2011, Oxytocin can hinder trust and cooperation in borderline personality disorder, Soc Cogn Affect Neurosci source
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Local infusion of OTA in to the BNSTam, but not NAcdl, mimics the effects of systemic administration”
§ Oxytocin Receptors in the Anteromedial Bed Nucleus of the Stria Terminalis Promote Stress-Induced Social Avoidance in Female California Mice > DISCUSSION
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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).”
§ Oxytocin Receptors in the Anteromedial Bed Nucleus of the Stria Terminalis Promote Stress-Induced Social Avoidance in Female California Mice > DISCUSSION > Stress induces vigilance and avoidance of unfamiliar social contexts
What the sources say
- Not checked yetcites [61] Lebow, 2016, Overshadowed by the amygdala: The bed nucleus of the stria terminalis emerges as key to psychiatric disorders, Mol Psychiatry source
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“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.”
§ Oxytocin Receptors in the Anteromedial Bed Nucleus of the Stria Terminalis Promote Stress-Induced Social Avoidance in Female California Mice > DISCUSSION > Specific-site effects of OTR on social avoidance
What the sources say
- Not checked yetcites [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 yetcites [73] Bakos, 2013, Oxytocin receptor ligands induce changes in cytoskeleton in neuroblastoma cells, J Mol Neurosci source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ Oxytocin Receptors in the Anteromedial Bed Nucleus of the Stria Terminalis Promote Stress-Induced Social Avoidance in Female California Mice > DISCUSSION > Stress induces vigilance and avoidance of unfamiliar social contexts
What the sources say
- Not checked yetcites [74] Blanchard, 1989, Antipredator defensive behaviors in a visible burrow system, J Comp Psychol source
- Not checked yetcites [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
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“When effects of stress were observed, OTR expression was decreased, possibly as a negative feedback response to elevated OT release (55).”
§ Oxytocin Receptors in the Anteromedial Bed Nucleus of the Stria Terminalis Promote Stress-Induced Social Avoidance in Female California Mice > DISCUSSION > Sex-specific effects of systemic inhibition of OTR
What the sources say
- Not checked yetcites [55] Phaneuf, 2000, Loss of myometrial oxytocin receptors during oxytocin-induced and oxytocin-augmented labour, J Reprod Fertil source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Interestingly, the OTR ligand atosiban, considered to be an OTR antagonist, actually activates Gi-mediated pathways in vitro (36, 38) and in vivo (57).”
§ Oxytocin Receptors in the Anteromedial Bed Nucleus of the Stria Terminalis Promote Stress-Induced Social Avoidance in Female California Mice > DISCUSSION > Sex-specific effects of systemic inhibition of OTR
What the sources say
- Not checked yetcites [36] Busnelli, 2013, Selective and potent agonists and antagonists for investigating the role of mouse oxytocin receptors, J Pharmacol Exp Ther source
- Not checked yetcites [38] Reversi, 2005, The oxytocin receptor antagonist atosiban inhibits cell growth via a “biased agonist” mechanism, J Biol Chem source
- Not checked yetcites [57] Eliava, 2016, A new population of parvocellular oxytocin neurons controlling magnocellular neuron activity and inflammatory pain processing, Neuron source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“It has been previously reported that OTR play a critical role in learning during aversive social contexts (76).”
§ Oxytocin Receptors in the Anteromedial Bed Nucleus of the Stria Terminalis Promote Stress-Induced Social Avoidance in Female California Mice > DISCUSSION > Stress induces vigilance and avoidance of unfamiliar social contexts
What the sources say
- Not checked yetcites [76] Choe, 2015, Oxytocin mediates entrainment of sensory stimuli to social cues of opposing valence, Neuron source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“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).”
§ Oxytocin Receptors in the Anteromedial Bed Nucleus of the Stria Terminalis Promote Stress-Induced Social Avoidance in Female California Mice > DISCUSSION > Sex-specific effects of systemic inhibition of OTR
What the sources say
- Not checked yetcites [57] Eliava, 2016, A new population of parvocellular oxytocin neurons controlling magnocellular neuron activity and inflammatory pain processing, Neuron source
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
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.”
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?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“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]
The cited source says what the claim attributes to it.
In the citing paper
“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 the citing paper
“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]
In the citing paper
“Additionally, more recent studies have demonstrated some antisocial effects of OT in both humans (De Dreu et al., 2010, De Dreu et al., 2011, Eckstein et al., 2014, Shamay-Tsoory et al., 2009) and other animals (Duque-Wilckens et al., 2018, Guzmán et al., 2013, Huang et al., 2014).”
From Wireless Optogenetic Stimulation of Oxytocin Neurons in a Semi-natural Setup Dynamically Elevates Both Pro-social and Agonistic Behaviors (2020) · cites this paper as Duque-Wilckens et al., 2018
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.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Oxytocin Receptors in the Anteromedial Bed Nucleus of the Stria Terminalis Promote Stress-Induced Social Avoidance in Female California Mice > DISCUSSION > Sex-specific effects of systemic inhibition of OTR
“There were no sex differences in OTR expression, consistent with previous reports in other species (53, 54).”
§ Oxytocin Receptors in the Anteromedial Bed Nucleus of the Stria Terminalis Promote Stress-Induced Social Avoidance in Female California Mice > RESULTS > Effects of stress on OTR expression in males and females
“In the PVN, females had significantly less OTR binding than males (Figure 3F; main effect of sex; p<0.001) and there was no effect of stress.”
Citations
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Metadata
- 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)
- 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
- green
- www.ncbi.nlm.nih.gov
- 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
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › 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
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