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Cited by 212Neuroendocrine regulation and behaviorNeuropeptides and Animal PhysiologyOlfactory and Sensory Function Studies

Oxytocin Signaling in the Central Amygdala Modulates Emotion Discrimination in Mice

Open access
Ferretti, Valentina, Maltese, Federica, Contarini, Gabriella, Nigro, Marco, Bonavia, Alessandra, Huang, Huiping, Gigliucci, Valentina, Morelli, Giovanni +8 more·2019·Current Biology
DOI 10.1016/j.cub.2019.04.070
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Abstract

Recognition of other's emotions influences the way social animals interact and adapt to the environment. The neuropeptide oxytocin (OXT) has been implicated in different aspects of emotion processing. However, the role of endogenous OXT brain pathways in the social response to different emotional states in conspecifics remains elusive. Here, using a combination of anatomical, genetic, and chemogenetic approaches, we investigated the contribution of endogenous OXT signaling in the ability of mice to discriminate unfamiliar conspecifics based on their emotional states. We found that OXTergic projections from the paraventricular nucleus of the hypothalamus (PVN) to the central amygdala (CeA) are crucial for the discrimination of both positively and negatively valenced emotional states. In contrast, blocking PVN OXT release into the nucleus accumbens, prefrontal cortex, and hippocampal CA2 did not alter this emotion discrimination. Furthermore, silencing each of these PVN OXT pathways did not influence basic social interaction. These findings were further supported by the demonstration that virally mediated enhancement of OXT signaling within the CeA was sufficient to rescue emotion discrimination deficits in a genetic mouse model of cognitive liability. Our results indicate that CeA OXT signaling plays a key role in emotion discrimination both in physiological and pathological conditions.

AI snapshot

Written from the paper’s full text.

TL;DR

Using a two-choice social task, this study shows that mice discriminate unfamiliar conspecifics based on both negatively and positively valenced emotional states, and that endogenous oxytocin signaling from the paraventricular nucleus of the hypothalamus to the central amygdala is necessary for this ability. Enhancing oxytocin receptor levels in the central amygdala rescues emotion discrimination deficits in dysbindin-1 heterozygous mice.

Key findings

  • Observer mice increased sniffing toward fear-conditioned demonstrators in the last 2-min epoch (males: F₁,₁₅ = 6.51, p = 0.022; females: F₁,₁₁ = 10.98, p = 0.006) and toward relief demonstrators in the first 2-min epoch (males: F₁,₁₄ = 15.07, p = 0.001; females: F₁,₁₄ = 14.60, p = 0.001).
  • Inhibiting PVN OXT neurons abolished discrimination of fear and relief states; selective inhibition of PVN→CeA OXT projections recapitulated this deficit (fear vehicle: F₁,₈ = 5.76, p = 0.043; CNO: F₁,₈ = 1.57, p = 0.25; relief vehicle: F₁,₇ = 12.66, p = 0.009; CNO: F₁,₇ = 0.13, p = 0.73), whereas inhibiting PVN→NAcc, PVN→mPFC, or PVN→CA2 projections did not.
  • Dysbindin-1 heterozygous (Dys+/−) mice had reduced OXTR binding in the CeA (F₁,₆ = 12.5035, p = 0.01) but not BLA or MeA, and showed emotion discrimination deficits; viral OXTR overexpression in the CeA rescued these deficits (fear OXTR virus: F₁,₈ = 13.63, p = 0.006; relief OXTR virus: F₁,₇ = 6.11, p = 0.043).
  • Discrimination persisted in complete darkness; ultrasonic vocalizations were detected in very few mice (3/12) with no differences among conditions; odor-only presentation produced avoidance of fear odor and increased sniffing of relief odor.

Methods

  • Two-choice emotion discrimination task: an observer mouse was placed with two age- and sex-matched unfamiliar demonstrators in wire cups; one demonstrator was fear conditioned to a tone (4 kHz, 80 dB, 30 s; three scrambled shocks 0.7 mA, 2 s, 90 s intershock interval) or made “relief” by 23-h water deprivation followed by 1-h ad libitum water. The 6-min test was divided into three 2-min epochs, and sniffing was scored.
  • Circuit manipulations: rAAV OXTp-hM4D(Gi) DREADD in PVN with CNO (3 mg/kg i.p., 30 min before test); projection-specific CAV2-Cre into CeA, NAcc, mPFC, or CA2 plus DIO-hM4D(Gi)-mCherry in PVN; ex vivo patch-clamp validation; OXTR autoradiography; and AAV-EF1a-OXTR-IRES-EYFP into CeA of Dys+/− mice.
  • Subjects and analysis: male and female C57BL/6J, Dys+/− and wild-type littermates, and Oxtr−/− mice, 3–6 months old; repeated-measures ANOVAs, two-way ANOVAs, t tests, and Newman-Keul’s post hoc tests, with significance at p < 0.05.

Limitations

  • Stated: the authors define “emotions” as subjective internal states inferred from behavioral output, acknowledging that this is not a direct measure of subjective emotion; they also state they cannot exclude unidentified auditory cues or later emotion contagion.
  • Stated: no statistical methods were used to predetermine sample sizes, and no explicit randomization method was used to allocate animals to groups, although samples came from same litters and testing/analysis were blinded.
  • Evident from the text: some experiments used small group sizes (e.g., n = 4/5 per group for autoradiography; n = 4/9 observers in some Dys+/− comparisons), and demonstrators were occasionally reused up to two/three times with at least one week between tests, though the paper reports no differences based on prior demonstrator experience.

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

Integrity signals

Registry

Crossref · 10.1016/j.cub.2019.04.070

Cites

128 of 128 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 73 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Silencing each of the PVN OXT pathways (CeA, NAcc, mPFC, CA2) does not influence basic social interaction.

    “Finally, none of the OXT pathways manipulations altered the ability to interact with an unfamiliar conspecific in a one-on-one free-interaction setting (Figures S4K-S4O), further supporting the distinction between emotion discrimination and sociability measures.”
    • Also stated in: § Abstract · plain
      “Furthermore, silencing each of these PVN OXT pathways did not influence basic social interaction.”
    Quote in the paperSubstantial claim
  • Findingown data

    Virally mediated enhancement of OXT signaling within the CeA is sufficient to rescue emotion discrimination deficits in a genetic mouse model of cognitive liability.

    “Increasing OXTR levels in CeA of Dys+/À mice was sufficient to rescue their emotion discrimination deficits (Figures 6F and 6G).”
    • Also stated in: § Abstract · boosted
      “These findings were further supported by the demonstration that virally mediated enhancement of OXT signaling within the CeA was sufficient to rescue emotion discrimination deficits in a genetic mouse model of cognitive liability.”
    Quote in the paperSubstantial claim
  • Findingown data

    The impact of Dys mutation is selective for emotion discrimination, as Dys+/À sociability and social novelty in the classic 3-chamber test are similar to Dys+/+ controls.

    “In particular, we found that the impact of Dys mutation was selective for emotion discrimination, as Dys+/À sociability and social novelty in the classic 3-chamber test were similar to Dys+/+ controls (Figures S6A and S6B).”
    Quote in the paperSubstantial claim
  • Findingown data

    Olfactory cues convey information related to mouse emotional states.

    “These results confirm that olfactory cues convey information related to mouse emotional states”
    Quote in the paperSubstantial claim
  • Findingown data

    Mice can discriminate between a neutral and an emotionally altered conspecific even in complete darkness.

    “However, when we performed the test in complete darkness (Figure 3A), mice were still able to discriminate between a neutral and an emotionally altered conspecific (Figures 3B and 3C), similarly to that observed in standard lighting conditions (Figures 1 and 2).”
    Quote in the paperSubstantial claim
  • May combine two claims. 9
  • Classified as probably not a substantial claim. 37
  • The quote only partly states this claim. 3

  • May combine two claims.

    Findingown data

    Dys+/À mice have reduced expression levels of OXTR in the CeA, but not in the BLA or MeA, compared to wild-type littermates.

    “we identified reduced expression levels of OXT receptors (OXTR) in the CeA, but not in the BLA or MeA compared to wild-type littermates (Dys+/+; Figures 6A and 6B).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Dys+/À mice show deficits in emotion discrimination in both fear and relief conditions.

    “We then assessed Dys+/À mouse emotion discrimination abilities and observed deficits in both the fear and relief conditions (Figures 6C and 6D).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing). The quote only partly states this claim.

    Findingown data

    There was no significant correlation between the time the fear-conditioned demonstrator spent freezing and the time the observer spent sniffing the fear-conditioned demonstrator in the 4-6 min epoch.

    “Correlation analyses between the time the fear-conditioned demonstrator spent freezing (in y axis) and the time the observer spent sniffing the fearconditioned demonstrator (in x axis; E) in the 2-to 4-min epoch or (F) in the 4-to 6-min epoch of the test (r = À0.4310 for 2-4 min; r = À0.11 for 4-6 min).”
    Quote in the paperNot a substantial claim
    • The authors state this as an assumption: The behavioral output (sniffing) of observer mice reflects the subjective internal emotional states of the demonstrators.

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

    Findingown data

    There were no significant differences in rearing or grooming in proximity of demonstrators between neutral and fear states.

    “Time (in seconds) spent (G) rearing and (H) grooming in proximity of the demonstrators in neutral (gray bars) or fear states (red bars) displayed by the same observer mice during the test (RM ANOVAs showed no significant differences).”
    Quote in the paperNot a substantial claim
    • The authors state this as an assumption: The behavioral output (sniffing) of observer mice reflects the subjective internal emotional states of the demonstrators.

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

    Findingown data

    Locomotor activity of observer mice changed significantly over the test, with a significant difference versus minute 0-2.

    “Locomotor activity displayed by the same observer mice during the test (RM ANOVA F 2,18 = 4.35; p = 0.04).*p < 0.05 versus minute 0-2.n = 10 observers.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    There were no significant differences in rearing or grooming in proximity of demonstrators between neutral and relief states.

    “Time (in seconds) spent in (H) rearing and (I) grooming in proximity of demonstrators in neutral (gray bars) or relief (yellow bars) state displayed by observer mice during the test (RM ANOVAs showed no significant differences).”
    Quote in the paperNot a substantial claim
    • The authors state this as an assumption: The behavioral output (sniffing) of observer mice reflects the subjective internal emotional states of the demonstrators.

  • The quote only partly states this claim.

    Findingown data

    Dys+/- observer mice did not show a significant difference in sniffing relief demonstrators versus neutral in the first 2-min epoch.

    “Time (in seconds) dysbindin-1 wild-type (Dys+/+) or heterozygous (Dys+/À) observer mice spent sniffing wild-type demonstrators in the two versions of the emotion discrimination test.Time spent sniffing neutral demonstrators is represented by gray bars.Time spent sniffing (C) fear demonstrators (only the last 2 min are displayed) or (D) water-induced relief state (only the first 2 min are displayed”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: The behavioral output (sniffing) of observer mice reflects the subjective internal emotional states of the demonstrators.

  • The quote only partly states this claim.

    Interpretationown data

    OXTergic projections from the PVN to the CeA are crucial for discrimination of both positively and negatively valenced emotional states.

    “selective inhibition of OXT neurons projecting from the PVN to the CeA (Figures 5A, S4B, and S4G) was sufficient to recapitulate the deficits in emotion discrimination found by silencing all PVN projections (Figures 4B, 4C, and S3B).”
    • Also stated in: § (legend continued on next page) · boosted
      “Overall, these findings demonstrate a pre-eminent contribution of the CeA in emotion discrimination abilities in mice and indicate that PVN OXTergic projections to the CeA are an essential neural substrate of this social cognitive function.”
    • Also stated in: § DISCUSSION · boosted
      “this study reveals that the CeA, and in particular the OXTergic projections from the PVN to the CeA, is an essential neuronal substrate for the ability to socially respond to emotional states evoked in unfamiliar conspecifics.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Interpretationcitation

    The close proximity of highly enriched PVN-OXT fibers to GABAergic CeA neurons expressing OXTR suggests that a similar modulation might occur during emotion discrimination in the CeA.

    “The close proximity of highly enriched PVN-OXT fibers to GABAergic CeA neurons expressing OXTR [22] suggests that a similar modulation might occur during emotion discrimination in the CeA.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [22] Knobloch, 2012, Evoked axonal oxytocin release in the central amygdala attenuates fear response, Neuron source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    The ensemble of results indicates the potential of this experimental setting to investigate a range of behavioral responses induced by emotional stimuli of different intensity and with potentially different ethological significance.

    “Moreover, the ensemble of the presented results indicates the potential of this experimental setting to investigate a range of behavioral responses induced by emotional stimuli of different intensity and with potentially different ethological significance.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    The attraction exerted by the relief condition is supported by approach toward the relief mouse, its odor, place preference conditioning, and reduced corticosterone levels, all pointing to an attractive signal of this positively valenced state.

    “The attraction exerted by the relief condition is instead consistently supported by several complementary findings: the approach toward the relief mouse, its odor, the induced place preference conditioning, and the reduced corticosterone levels, all point to an attractive signal of this positively valenced state.”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: Relief from the distressing water deprivation results in a positively valenced emotional state.

  • May combine two claims.

    Premisecitation

    OXT increases neuronal firing rates mainly through inhibition of interneuron activity, resulting in an increase in signal-to-noise ratio and enhanced information transfer.

    “Mechanistically, OXT has been documented to increase neuronal firing rates, mainly through inhibition of interneuron activity, which results in an increase in signal-noise ratio and subsequently enhanced information transfer [13,22,[109][110][111].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [13,22,[109][110][111]

      Not checked in the free run.

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

    Premisecitation

    OXT has been shown to modulate emotion processing in rodents through an action in the anterior cingulate cortex, insula, and lateral septum.

    “OXT has been shown to modulate emotion processing in rodents through an action in the anterior cingulate cortex, insula and lateral septum [16,23,24].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [16] Rogers-Carter, 2018, Insular cortex mediates approach and avoidance responses to social affective stimuli, Nat. Neurosci. source

      Not checked in the free run.

    • cites [23] Pisansky, 2017, Oxytocin enhances observational fear in mice, Nat. Commun. source

      Not checked in the free run.

    • cites [24] Menon, 2018, Oxytocin signaling in the lateral septum prevents social fear during lactation, Curr. Biol. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    In rodents, neurons in the PVN are the main source of OXT projections to the brain.

    “In rodents, neurons in the PVN are the main source of OXT projections to the brain [22,69].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [22] Knobloch, 2012, Evoked axonal oxytocin release in the central amygdala attenuates fear response, Neuron source

      Not checked in the free run.

    • cites [69] 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.

  • May combine two claims.

    Interpretationown data

    The two-choice emotion discrimination setting measures aspects of rodent social cognition that have been scarcely explored and can complement currently available tools.

    “Altogether, our findings suggest that the two-choice emotion discrimination setting measures aspects of rodent social cognition that have been scarcely explored and that can complement currently available tools.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    The OXT system plays a pivotal role in social perception and cognition.

    “The OXT system plays a pivotal role in social perception and cognition [8][9][10].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [8][9][10]

      Not checked in the free run.

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

    Premisecitation

    The amygdala is a critical hub in the processing of both positive and negative states.

    “These findings are in line with strong evidence across species, which implicate the amygdala as a critical hub in the processing of both positive and negative states [88][89][90][91][92].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [88][89][90][91][92]

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    OXT signaling within the CeA and OXTR levels within this brain region constitute a crucial target to modulate emotion discrimination abilities.

    “strengthen the evidence that OXT signaling within the CeA and, specifically, OXTR levels within this brain region constitute a crucial target to modulate emotion discrimination abilities.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Genetic variants in dysbindin-1 are strongly associated with human intelligence.

    “Genetic variants in dysbindin-1 are strongly associated with human intelligence [51].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [51] Savage, 2018, Genome-wide association meta-analysis in 269,867 individuals identifies new genetic and functional links to intelligence, Nat. Genet. source

      Not checked in the free run.

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

    Premisecitation

    Altered levels of OXT and OXTR in specific brain regions have been reported in animal models of psychiatric and neurodevelopmental disorders.

    “Altered levels of OXT and OXTR in specific regions of the brain have been reported in a number of animal models of psychiatric and neurodevelopmental disorders [116-119].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [116] Schaller, 2010, A single postnatal injection of oxytocin rescues the lethal feeding behaviour in mouse newborns deficient for the imprinted Magel2 gene, Hum. Mol. Genet. source

      Not checked in the free run.

    • cites [117] Gigliucci, 2014, Region specific up-regulation of oxytocin receptors in the opioid oprm1 (-/-) mouse model of autism, Front Pediatr. source

      Not checked in the free run.

    • cites [118] Peñagarikano, 2015, Exogenous and evoked oxytocin restores social behavior in the Cntnap2 mouse model of autism, Sci. Transl. Med. source

      Not checked in the free run.

    • cites [119] Francis, 2014, Oxytocin and vasopressin systems in genetic syndromes and neurodevelopmental disorders, Brain Res. source

      Not checked in the free run.

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

    Study design and conductnone given

    Mice were divided in the two experimental groups with similar preconditioning time values in the two sides of place conditioning apparatus.

    “Mice were then divided in the two experimental groups with similar preconditioning time values in the two sides of place conditioning apparatus.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Mice that had been injected with AAVs and/or CAV2 were allowed 1 month to recover and for the viral transgenes to adequately express before undergoing behavioral experiments.

    “Mice that had been injected with AAVs and/or CAV2 were allowed 1 month to recover and for the viral transgenes to adequately express before undergoing behavioral experiments.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Premisecitation

    The OXT system is regarded as a promising target for the treatment of social cognitive dysfunctions.

    “The OXT system is regarded as a promising target for the treatment of social cognitive dysfunctions [31].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [31] Young, 2015, Neuroscience. Can oxytocin treat autism?, Science source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    The novel behavioral paradigm extends the opportunity to investigate previously unexplored aspects of social cognitive processes in mice.

    “These mechanisms were revealed by a novel behavioral paradigm, which extends the opportunity to investigate previously unexplored aspects of social cognitive processes in mice.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    Test order was counterbalanced.

    “Test order was counterbalanced.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Distinct neuronal populations in sub-regions of the amygdala control specific behavioral responses to fear.

    “Distinct neuronal populations in sub-regions of the amygdala have indeed been shown to control specific behavioral responses to fear [104, 108]”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [104] Viviani, 2011, Oxytocin selectively gates fear responses through distinct outputs from the central amygdala, Science source

      Not checked in the free run.

    • cites [108] Huber, 2005, Vasopressin and oxytocin excite distinct neuronal populations in the central amygdala, Science source

      Not checked in the free run.

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

    Study design and conductnone given

    No differences were observed in the performance of the observer mice depending on the demonstrators' previous experience.

    “No differences were observed in the performance of the observer mice depending on the demonstrators' previous experience.”
    Quote in the paperNot a substantial claim

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    Study design and conductown data

    An experienced user checked the accuracy of call detection and obtained a 100% concordance between automated and observational detection.

    “An experienced user checked the accuracy of call detection and obtained a 100% concordance between automated and observational detection.”
    Quote in the paperNot a substantial claim

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    Study design and conductnone given

    The two camera settings gave the same experimental results.

    “The two camera settings gave the same experimental results.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    The order of insertion of the neutral or emotionally-altered demonstrator was randomly assigned.

    “The order of insertion of the neutral or emotionally-altered demonstrator was randomly assigned.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    In humans, alterations in amygdala responses to positive and negative emotions have been reported in neuropsychiatric conditions such as autism and schizophrenia, in association with OXTR genetic variants or following intranasal OXT.

    “In humans, alterations in amygdala responses to positive and negative emotions have been reported in neuropsychiatric conditions, such as autism and schizophrenia [72,73], in association with OXTR genetic variants [41,102] or following intranasal OXT [33,36,38,103].”
    Quote in the paperNot a substantial claim0 of 8 sources checked
    • cites [72] Tottenham, 2014, Elevated amygdala response to faces and gaze aversion in autism spectrum disorder, Soc. Cogn. Affect. Neurosci. source

      Not checked in the free run.

    • cites [73] Goghari, 2017, Task-related functional connectivity analysis of emotion discrimination in a family study of schizophrenia, Schizophr. Bull. source

      Not checked in the free run.

    • cites [41] Tost, 2010, A common allele in the oxytocin receptor gene (OXTR) impacts prosocial temperament and human hypothalamic-limbic structure and function, Proc. Natl. Acad. Sci. USA source

      Not checked in the free run.

    • cites [102] Haram, 2016, Contribution of oxytocin receptor polymorphisms to amygdala activation in schizophrenia spectrum disorders, BJPsych Open source

      Not checked in the free run.

    • cites [33] Domes, 2007, Oxytocin attenuates amygdala responses to emotional faces regardless of valence, Biol. Psychiatry source

      Not checked in the free run.

    • cites [36] Leppanen, 2017, Meta-analysis of the effects of intranasal oxytocin on interpretation and expression of emotions, Neurosci. Biobehav. Rev. source

      Not checked in the free run.

    • cites [38] Shahrestani, 2013, The impact of a single administration of intranasal oxytocin on the recognition of basic emotions in humans: a meta-analysis, Neuropsychopharmacology source

      Not checked in the free run.

    • cites [103] Gamer, 2010, Different amygdala subregions mediate valence-related and attentional effects of oxytocin in humans, Proc. Natl. Acad. Sci. USA source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Only mice with appropriate placements were included in the reported data.

    “Only mice with appropriate placements were included in the reported data (Figures S5H-S5L and S6F).”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Exploratory behaviors initiated by the test subject were timed by two independent experimenters blind to the manipulations.

    “exploratory behaviors initiated by the test subject were timed by two independent experimenters blind to the manipulations.”
    Quote in the paperSubstantial claim

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    Study design and conductnone given

    Samples always derived from mice of the same litter.

    “but samples always derived from mice of the same litter.”
    Quote in the paperNot a substantial claim

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    Study design and conductnone given

    Behavioral scoring was performed a posteriori from videos by trained experimenters blind to the manipulations of both the observers and demonstrators.

    “Behavioral scoring was performed a posteriori from videos by trained experimenters, blind to the manipulations of both the observers and demonstrators.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Emotion recognition tasks rely on the ability to discriminate basic expression of emotions in others and are the most extensively used paradigms to assess human social cognition, with direct relevance for a number of pathologies, including autism and schizophrenia.

    “Emotion recognition tasks rely on the ability to discriminate basic expression of emotions in others and are the most extensively used paradigms to assess human social cognition [3,43], with direct relevance for a number of pathologies, including autism and schizophrenia [5,6].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [3] Henry, 2016, Clinical assessment of social cognitive function in neurological disorders, Nat. Rev. Neurol. source

      Not checked in the free run.

    • cites [43] Green, 2015, Social cognition in schizophrenia, Nat. Rev. Neurosci. source

      Not checked in the free run.

    • cites [5] Fletcher-Watson, 2014, Interventions based on the theory of mind cognitive model for autism spectrum disorder (ASD), Cochrane Database Syst. Rev.

      Not checked in the free run.

    • cites [6] Kurtz, 2012, Social cognitive training for schizophrenia: a meta-analytic investigation of controlled research, Schizophr. Bull. source

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    Study design and conductnone given

    No explicit randomization method was used to allocate animals to different experimental groups.

    “No explicit randomization method was used to allocate animals to different experimental groups”
    Quote in the paperNot a substantial claim

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    Study design and conductnone given

    All datasets were tested to fit a normal distribution using the Kolmogorov-Smirnov and Pearson's chi-square tests.

    “All datasets were tested to fit a normal distribution using the Kolmogorov-Smirnov and Pearson's chi-square tests.”
    Quote in the paperNot a substantial claim

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    Study design and conductnone given

    Investigators were blinded to the treatment and genotype of the animals during testing and data processing.

    “Experimenters were blind to the mouse treatments and genotype during testing.”
    • Also stated in: § Additional information · plain
      “Mice were tested and data were processed by investigators blinded to the treatment and genotype of the animals.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    No statistical methods were used to predetermine sample sizes.

    “No statistical methods were used to predetermine sample sizes”
    Quote in the paperNot a substantial claim

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    Study design and conductown data

    No correlation was found between estrus status and performance in the test.

    “no correlation was found between estrus status and performance in the test.”
    Quote in the paperNot a substantial claim

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    Study design and conductnone given

    The emotion discrimination experiments were independently replicated by nine different researchers in three different laboratories.

    “The emotion discrimination experiments reported in this work were independently replicated by nine different researchers in three different laboratories.”
    Quote in the paperNot a substantial claim

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    Study design and conductown data

    Three independent persons scored the same data with an inter-rater reliability r score of 0.954.

    “Three independent persons scored the same data with an inter-rater reliability r score of 0.954.”
    Quote in the paperNot a substantial claim

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    Study design and conductcitation

    Sample sizes were consistent with those of previous studies.

    “although sample sizes were consistent with those of previous studies [19,23,80].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [19] Burkett, 2016, Oxytocin-dependent consolation behavior in rodents, Science source

      Not checked in the free run.

    • cites [23] Pisansky, 2017, Oxytocin enhances observational fear in mice, Nat. Commun. source

      Not checked in the free run.

    • cites [80] Sterley, 2018, Social transmission and buffering of synaptic changes after stress, Nat. Neurosci. source

      Not checked in the free run.

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

    Premisecitation

    Human emotion recognition paradigms include the presentation of positively and negatively valenced emotions.

    “Human emotion recognition paradigms include the presentation of positively and negatively valenced emotions [3].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [3] Henry, 2016, Clinical assessment of social cognitive function in neurological disorders, Nat. Rev. Neurol. source

      Not checked in the free run.

45 of 45

  • The authors state this as an assumption.

    Relief from the distressing water deprivation results in a positively valenced emotional state.

    “We assumed that the relief from the distressing water deprivation would result in a positively valenced emotional state (''relief'').”

  • The authors state this as an assumption.

    The behavioral output (sniffing) of observer mice reflects the subjective internal emotional states of the demonstrators.

    “Throughout the paper, we referred to ''emotions'' as subjective internal states of mice evoked by behavioral manipulations, aware that our definition is based on the assessment of behavioral output more than on the intangible and unmeasurable nature of emotions.”
2 of 2

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?

  • Mice can discriminate positive and negative emotional states of other mice, and chemogenetic inhibition of PVN oxytocin projections to central amygdala abolishes this ability.

    “Mice can discriminate positive and negative emotional states of other mice (Ferretti et al. 2019), and chemogenetic inhibition of PVN oxytocin projections to central amygdala abolishes this ability.”

    From Oxytocin, Neural Plasticity, and Social Behavior (2021) · cites this paper as Ferretti et al. 2019

  • Inhibition of central amygdala projecting paraventricular nucleus oxytocin neurons, but not projections to the nucleus accumbens, medial prefrontal cortex, or CA2, impairs the discrimination of fear in a novel conspecific.

    “Furthermore, inhibition of central amygdala projecting PVN OXT neurons, but not projections to the NAc, mPFC, or CA2, impairs the discrimination of fear in a novel conspecific [110].”

    From Neural circuits regulating prosocial behaviors (2023) · cites this paper as [110]

  • Paraventricular oxytocin input to the central amygdala mediates the ability of mice to discriminate between negative and positive emotional states of conspecifics.

    “For example, PVN OXT input to the central amygdala mediates the ability of mice to discriminate between negative and positive emotional states of conspecifics (104).”

    From Oxytocin, Vasopressin, and Social Behavior: From Neural Circuits to Clinical Opportunities (2022) · cites this paper as [104]

  • Oxytocin signaling in insular cortex, central amygdala, and anterior cingulate cortex modulates emotion detection and responses to social affect of conspecifics.

    “Additionally, oxytocin signaling in insular cortex, central amygdala, and anterior cingulate cortex modulates emotion detection and responses to social affect of conspecifics [26–28].”

    From Translational opportunities for circuit-based social neuroscience: advancing 21st century psychiatry (2021) · cites this paper as [28]

  • A mouse study demonstrated a crucial role for OT in discriminating emotion of both positive and negative valence in a conspecific.

    “Support for this idea was recently shown in a mouse study demonstrating a crucial role for OT in discriminating emotion of both positive and negative valence in a conspecific”

    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 Ferretti et al., 2019

Self-check

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

  • Relief-odor test degrees of freedom exceed the stated sample size

    Minor

    The relief-odor comparison reports F(1,11), which requires 12 observers for a within-observer comparison. The stated range is only 7-11 observers per group.

    Reported 11 · recomputed 10

1 of 1

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Authors
Ferretti, V., Maltese, F., Contarini, G., Nigro, M., Bonavia, A., Huang, H., Gigliucci, V., Morelli, G., Scheggia, D., Managò, F., Castellani, G., Lefevre, A., Cancedda, L., Chini, B., Grinevich, V., & Papaleo, F.
Affiliations
  • Italian Institute of Technology (IT)
  • Heidelberg University (DE)
Corresponding author
Papaleo, Francesco
ORCID
Venue
Current Biology
Publisher
Elsevier BV
Published
2019-06
Volume
29
Issue
12
Pages
1938-1953.e6
ISSN
0960-9822 (ISSN-L)
DOI
10.1016/j.cub.2019.04.070
OpenAlex
W2948406230
Semantic Scholar
f6a73e4427f54833b1e3d83842b19117d175a093
Cited by
212
References
128
Citations by year
2026: 22 · 2025: 36 · 2024: 34 · 2023: 24 · 2022: 31 · 2021: 43 · 2020: 16 · 2019: 4
FWCI
29.53
Type
journal article
Language
en
Open access
Licence
Locations
  • Current Biology (publishedVersion)
  • PubMed (publishedVersion)
  • IRIS Research product catalog (Sapienza University of Rome) (submittedVersion, other-oa)
  • Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
Funders
  • Istituto Italiano di Tecnologia (intramural funding)
  • Brain and Behavior Research Foundation (23234)
  • Compagnia di San Paolo (2015-0321)
  • Chica and Heinz Schaller Research Foundation
  • SFB (1134, 1158)
  • DFG-ANR (GR 3619/7-1)
  • DFG-Swiss (3619/8-1)
  • Human Frontiers Science Program (RGP0019/2015)
  • Fyssen Foundation
Topics
  • Social Sciences › Psychology › Social Psychology › Neuroendocrine regulation and behavior
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
  • Life Sciences › Neuroscience › Sensory Systems › Olfactory and Sensory Function Studies
Keywords
oxytocin, central amygdala, emotion discrimination, paraventricular nucleus, social recognition, emotion recognition, chemogenetic silencing, social interaction, nucleus accumbens, prefrontal cortex, hippocampal CA2
MeSH terms
Animals, Emotions, Female, Male, Mice, Inbred C57BL, Oxytocin, Paraventricular Hypothalamic Nucleus, Signal Transduction, Mice, Knockout, Recognition, Psychology, Mice, Central Amygdaloid Nucleus

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.

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