Cited by 79Neuroendocrine regulation and behaviorNeurotransmitter Receptor Influence on BehaviorMemory and Neural Mechanisms

Insular cortex projections to nucleus accumbens core mediate social approach to stressed juvenile rats

Open access
Rogers-Carter, Morgan M., Djerdjaj, Anthony, Gribbons, K. Bates, Varela, Juan A., Christianson, John P.·2019·The Journal of Neuroscience

Published version of a preprint

Abstract

Social interactions are shaped by features of the interactants, including age, emotion, sex, and familiarity. Age-specific responses to social affect are evident when an adult male rat is presented with a pair of unfamiliar male conspecifics, one of which is stressed via two foot shocks and the other naive to treatment. Adult test rats prefer to interact with stressed juvenile (postnatal day 30, PN30) conspecifics but avoid stressed adult (PN50) conspecifics. This pattern depends upon the insular cortex (IC), which is anatomically connected to the nucleus accumbens core (NAc). The goal of this work was to test the necessity of IC projections to NAc during social affective behavior. Here, bilateral pharmacological inhibition of the NAc with tetrodotoxin (1 μ m ; 0.5 μl/side) abolished the preference for stressed PN30, but did not alter interactions with PN50 conspecifics. Using a combination of retrograding tracing and c-Fos immunohistochemistry, we report that social interactions with stressed PN30 conspecifics elicit greater Fos immunoreactivity in IC → NAc neurons than interactions with naive PN30 conspecifics. Chemogenetic stimulation of IC terminals in the NAc increased social exploration with juvenile, but not adult, conspecifics, whereas chemogenetic inhibition of this tract blocked the preference to investigate stressed PN30 conspecifics, which expands upon our previous finding that optogenetic inhibition of IC projection neurons mediated approach and avoidance. These new findings suggest that outputs of IC to the NAc modulate social approach, which provides new insight to the neural circuitry underlying social decision-making. SIGNIFICANCE STATEMENT Social decision-making underlies an animal's behavioral response to others in a range of social contexts. Previous findings indicate the insular cortex (IC) and the nucleus accumbens (NAc) play important roles in social behaviors, and human neuroimaging implicates both IC and NAc in autism and other psychiatric disorders characterized by aberrant social cognition. To test whether IC projections to the NAc are involved in social decision-making, circuit-specific chemogenetic manipulations demonstrated that the IC → NAc pathway mediates social approach toward distressed juvenile, but not adult, conspecifics. This finding is the first to implicate this circuit in rodent socioemotional behaviors and may be a neuroanatomical substrate for integration of emotion with social reward.

AI snapshot

Written from the paper’s full text.

TL;DR

Bilateral pharmacological inhibition of nucleus accumbens core (NAc) abolished adult male rats’ preference for stressed juvenile (PN30) conspecifics but not avoidance of stressed adult (PN50) conspecifics. The insular cortex (IC)→NAc projection was necessary and sufficient for social approach to stressed juveniles, with greater Fos in NAc-projecting posterior IC neurons after interaction with stressed PN30 rats.

Key findings

  • NAc inactivation with TTX (0.5 µl/side) blocked the preference for stressed PN30 conspecifics: vehicle-treated rats preferred stressed over naive PN30 (p = 0.006), while TTX-treated rats did not (p = 0.203). TTX did not alter PN50 avoidance: vehicle- and TTX-treated rats both preferred naive over stressed PN50 (p = 0.031 and p = 0.020, respectively).
  • Social interaction with stressed PN30 conspecifics increased Fos immunoreactivity in IC→NAc neurons: main effect of conspecific stress F(1,16) = 16.89, p = 0.0008, with the only significant post hoc comparison in posterior IC (p = 0.015). Rats also showed more social exploration with stressed PN30 than naive PN30 conspecifics (t(10) = 3.281, p = 0.008).
  • Chemogenetic inhibition of IC terminals in NAc blocked preference for stressed PN30 conspecifics: vehicle-treated rats preferred stressed PN30 (p = 0.023), while CNO-treated rats did not (p = 0.959); preference scores were reduced by CNO (t(9) = 2.089, p = 0.033). This manipulation did not alter PN50 avoidance (main effect of stress p = 0.003; preference score effect of CNO t(9) = 0.57, p = 0.293).
  • Chemogenetic activation of IC terminals in NAc increased social exploration with PN30 conspecifics (CNO vs vehicle p = 0.030) but not PN50 conspecifics (p = 0.998). IC inhibition did not affect social novelty preference (main effect of familiarity p = 0.005; CNO effect p = 0.27).

Methods

  • Male Sprague Dawley rats were used: experimental adults at PN60–PN80, juvenile conspecifics at PN30, and adult conspecifics at PN50. In the social affective preference (SAP) test, experimental rats explored two novel conspecifics for 5 min, one stressed via two foot shocks (5 s, 1 mA, 60 s intershock interval) and one naive; social exploration was scored by blinded observers.
  • Surgeries included bilateral NAc cannula implantation, viral microinjections into posterior IC (hM4Di, hM3Dq, or mCherry), and unilateral NAc injection of retrograde tracer CTb488. Drugs included TTX infused into NAc, CNO given intraperitoneally or infused into NAc, and vehicle controls. Fos/mCherry immunohistochemistry and cell counting were used, with whole-cell electrophysiology to verify hM4Di and hM3Dq efficacy.
  • Analyses used two-way ANOVAs, t tests, mixed-model ANOVAs, preference scores, and Sidak post hoc comparisons in Prism 8.2; effect sizes reported as η² or partial η². Sample sizes were based on a priori power analysis with a minimum of eight subjects per treatment condition.

Limitations

  • The paper states that the retrograde Fos experiment had a small sample size and may have been underpowered to detect smaller effects of conspecific stress on IC→NAc neurons in anterior IC; future studies are needed to directly address whether these projections are involved in social approach behavior.
  • The paper states that it cannot be sure approach to stressed juveniles is a prosocial response.
  • Evident from the text: only male rats were studied, so sex differences are not addressed; some Fos-count groups had n = 3 or 4 observations per group.

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

Integrity signals

Registry

Crossref · 10.1523/jneurosci.0316-19.2019

Cites

82 of 82 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 50 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Chemogenetic inhibition of the IC-to-NAc tract blocked the preference to investigate stressed PN30 conspecifics.

    “chemogenetic inhibition of this tract blocked the preference to investigate stressed PN30 conspecifics”
    Quote in the paperSubstantial claim
  • Findingown data

    Social interactions with stressed PN30 conspecifics elicit greater Fos immunoreactivity in IC-to-NAc neurons than interactions with naive PN30 conspecifics.

    “Using a combination of retrograding tracing and c-Fos immunohistochemistry, we report that social interactions with stressed PN30 conspecifics elicit greater Fos immunoreactivity in IC ¡ NAc neurons than interactions with naive PN30 conspecifics.”
    Quote in the paperSubstantial claim
  • Findingown data

    A two-way ANOVA revealed a main effect of ROI on Fos-positive cells.

    “Proceeding to the Fos analyses, a 2-way ANOVA revealed a main effect of ROI (F (2,10) ϭ 30.53, p Ͻ 0.0001).”
    Quote in the paperNot a substantial claim
  • Findingcitation

    Experimental rats displayed higher levels of social exploration with stressed PN30 conspecifics compared with naive PN30 conspecifics.

    “As previously reported (Rogers-Carter et al., 2018b), experimental rats displayed higher levels of social exploration with stressed PN30 conspecifics compared with naive PN30 conspecifics (t (10) ϭ 3.281, p ϭ 0.008, ␩ 2 ϭ 0.52; Fig. 2D).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Rogers-Carter et al., 2018b

      Not checked in the free run.

  • Findingown data

    Anterior IC had significantly more CTb488-positive cells than medial or posterior IC.

    “Anterior IC had significantly more CTb 488 -positive cells than medial or posterior IC ( p Ͻ 0.001; Fig. 2F ).”
    Quote in the paperNot a substantial claim
  • May combine two claims. 40
  • Classified as probably not a substantial claim. 49
  • May combine two claims.

    Findingown data

    Bilateral pharmacological inhibition of the NAc with tetrodotoxin abolishes the preference for stressed PN30 conspecifics but does not alter interactions with PN50 conspecifics.

    “Bilateral pharmacological inhibition of the NAc with tetrodotoxin (1 M; 0.5 l/side) abolished the preference for stressed PN30, but did not alter interactions with PN50 conspecifics.”
    • Also stated in: § Pharmacological inactivation of NAc abolished preference for stressed PN30, but not PN50, conspecifics · boosted
      “These analyses demonstrate that the NAc is necessary for experimental rats' preference to explore stressed PN30 but did not influence interactions with either stressed or naive PN50, conspecifics.”
    • Also stated in: § Pharmacological inactivation of NAc abolished preference for stressed PN30, but not PN50, conspecifics · plain
      “After vehicle treatment, rats tested with PN30 conspecifics showed a preference to explore the stressed conspecific over the naive ( p ϭ 0.006), which was abolished after bilateral pharmacological inactivation of NAc ( p ϭ 0.203; Fig. 1D).”
    Quote in the paperSubstantial claim
  • May combine two claims.

    Findingown data

    Chemogenetic stimulation of IC terminals in the NAc increased social exploration with juvenile, but not adult, conspecifics.

    “Chemogenetic stimulation of IC terminals in the NAc increased social exploration with juvenile, but not adult, conspecifics”
    Quote in the paperSubstantial claim
  • May combine two claims.

    Findingown data

    In PN50 tests, rats preferred the naive conspecific over the stressed conspecific after vehicle treatment, and this preference was maintained after TTX treatment.

    “For rats tested with PN50 conspecifics, a two-way ANOVA found a main effect of conspecific affect (F (1,6) ϭ 5.45, p ϭ 0.058, ␩ P 2 ϭ 0.30), which confirmed replication our previous findings (Rogers-Carter et al., 2018a,b) that experimental rats prefer to explore the naive conspecific over the stressed after vehicle treatment ( p ϭ 0.031), which was also maintained after TTX treatment ( p ϭ 0.020;”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Rogers-Carter et al., 2018a,b

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    Bath application of 10 M CNO reliably hyperpolarized and reduced excitability of IC neurons visually identified as mCherry-positive at the time of recording.

    “bath application of 10 M CNO reliably hyperpolarized and reduced excitability of IC neurons visually identified as mCherry-positive at the time of recording.”
    Quote in the paperSubstantial claim
  • May combine two claims.

    Findingown data

    Administration of CNO alone, or vehicle or CNO to rats with sham mCherry virus, did not disrupt baseline preference to explore stressed PN30 conspecific.

    “In no instance did administration of CNO alone (F (7,14) ϭ 0.343, p ϭ 0.956, ␩ 2 Ͻ 0.01), or vehicle or CNO administration to rats with the sham mCherry virus (t (8) ϭ 0.010, p ϭ 0.992, h 2 Ͻ 0.01) disrupt the baseline preference to explore the stressed PN30 conspecific.”
    Quote in the paperSubstantial claim
  • May combine two claims.

    Findingown data

    Percentage preference scores reflected more time spent with the stressed conspecific after vehicle injections, which was reduced by CNO.

    “experimental rats showed scores that reflected more time spent with the stressed conspecific after vehicle injections, which was reduced by CNO (t (9) ϭ 2.089, p ϭ 0.033, ␩ P 2 ϭ 0.33).”
    Quote in the paperSubstantial claim
  • May combine two claims.

    Findingown data

    There was a main effect of CNO and significantly fewer spikes under CNO compared with aCSF in slice recordings.

    “A one-way repeatedmeasures ANOVA revealed a main effect of CNO (F (2,6) ϭ 6.038, p ϭ 0.040, ␩ 2 ϭ 0.66) and significantly fewer spikes under CNO compared with aCSF ( p ϭ 0.029).”
    Quote in the paperSubstantial claim
  • May combine two claims.

    Findingown data

    The preference for stressed PN30 conspecifics was abolished after inhibition of IC neurons; CNO-treated rats did not show a preference for naive or stressed PN30 conspecific.

    “This preference was abolished after inhibition of IC neurons as experimental rats tested with CNO did not show a preference for the naive or stressed PN30 conspecific ( p ϭ 0.517; Fig. 3F ).”
    Quote in the paperSubstantial claim
  • May combine two claims.

    Findingreasoning

    Chemogenetic stimulation of IC terminals in NAc increased exploration with PN30, but not PN50, conspecifics.

    “Accordingly, chemogenetic stimulation of IC terminals in NAc increased exploration with PN30, but not PN50, conspecifics.”
    Quote in the paperSubstantial claim
  • May combine two claims.

    Findingown data

    Mean social exploration was greater with PN30 conspecifics after CNO treatment than vehicle, whereas mean social exploration with PN50 conspecifics did not differ between CNO and vehicle treatment.

    “Post hoc comparisons show mean social exploration was greater with PN30 conspecifics after CNO treatment than vehicle ( p ϭ 0.030), whereas mean social exploration with PN50 conspecifics did not differ between CNO and vehicle treatment ( p ϭ 0.998) (Fig. 5H ).”
    Quote in the paperSubstantial claim
  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    There was a small but significant effect of CNO on overall interaction levels in adult SAP tests.

    “As in the CNO only experiment, there was a small but significant effect of CNO on overall interaction levels evinced by a main effect of drug (F (1,8) ϭ 5.45, p ϭ 0.047, ␩ P 2 ϭ 0.12).”
    Quote in the paperNot a substantial claim
  • May combine two claims.

    Findingown data

    In SAP tests, chemogenetic inhibition of this circuit blocked the preference for the stressed PN30 conspecific but had no apparent effect on avoidance of stressed PN50 conspecifics.

    “In SAP tests, chemogenetic inhibition of this circuit blocked the preference for the stressed PN30 conspecific but had no apparent effect on avoidance of stressed PN50 conspecifics.”
    Quote in the paperSubstantial claim
  • May combine two claims.

    Findingown data

    Pharmacological inactivation of NAc prevented the expected preference for test rats to explore stressed PN30 conspecifics, but did not alter avoidance of stressed PN50 conspecifics.

    “First, pharmacological inactivation of the NAc prevented the expected preference for test rats to explore stressed PN30 conspecifics, but did not alter the avoidance of stressed PN50 conspecifics.”
    • Also stated in: § Discussion · plain
      “when NAc was pharmacologically inactivated with TTX, rats did not show a social preference for the stressed PN30 conspecific and thus behaved as if each conspecific was equal in valence.”
    Quote in the paperSubstantial claim
  • May combine two claims.

    Findingown data

    Sham experimental rats without hM4D(Gi) transduction preferred to explore the stressed PN30 conspecifics under vehicle treatment, which was maintained after microinfusion of 1 μM CNO to the NAc 45 min before testing.

    “Under vehicle treatment, rats preferred to explore the stressed PN30 conspecifics ( p ϭ 0.003), which was maintained after microinfusion of 1 M CNO to the NAc 45 min before testing (0.031).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The conspecifics designated as stressed were indeed stressed.
  • May combine two claims.

    Premisecitation

    Adult test rats prefer to interact with stressed juvenile (PN30) conspecifics but avoid stressed adult (PN50) conspecifics.

    “Adult test rats prefer to interact with stressed juvenile (postnatal day 30, PN30) conspecifics but avoid stressed adult (PN50) conspecifics.”
    • Also stated in: § Introduction · plain
      “Specifically, in the SAP test, experimental rats exhibit approach toward stressed juvenile rats, but avoid exploring stressed adult rats.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Rogers-Carter et al., 2018b

      Not checked in the free run.

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

    Study design and conductown data

    The initial sample sizes were determined by a priori power analysis using effect sizes from prior observations.

    “The initial sample sizes for these experiments were determined by a priori power analysis (G*Power ver.3.1) using the effect sizes from our prior observations using repeated-measures designs.”
    Quote in the paperNot a substantial claim
  • Classified as probably not a substantial claim.

    Study design and conductown data

    Four animals, two from each stress group, did not exhibit CTb488 in the NAc and were excluded from all subsequent analysis.

    “Four animals, two from each stress group, did not exhibit CTb 488 in the NAc and so were excluded from all subsequent analysis.”
    Quote in the paperSubstantial claim
  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    Experimental treatments were counterbalanced in order and repeated-measures designs were used except when noted.

    “Experimental treatments were counterbalanced in order and repeated-measures designs were used except when noted.”
    Quote in the paperNot a substantial claim
  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Before analysis, all data were visually inspected for normality and order effects.

    “Before analysis, all data were visually inspected for normality and order effects.”
    Quote in the paperNot a substantial claim
  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Fos-immunoreactive cells were manually counted in ImageJ by an observer blind to treatment.

    “Fos-immunoreactive cells were manually counted in ImageJ by an observer blind to treatment.”
    Quote in the paperSubstantial claim
  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    In all cases, the data were deemed suitable for parametric analysis.

    “In all cases, the data were deemed suitable for parametric analysis and all data are depicted in the figures.”
    Quote in the paperNot a substantial claim
  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Insula projections to the NAc are most dense in the anterior IC compared with the posterior IC.

    “It is established that the insula projections to NAc is most dense in the anterior IC, compared with the posterior IC (Parks et al., 2015) and this trend was evident and supported by a significant main effect of ROI (F (2,16) ϭ 19.3, p Ͻ 0.0001).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Parks et al., 2015

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    All data were included unless cannula implants or virus transduction missed the target site.

    “All data were included unless cannula implants or virus transduction missed the target site.”
    Quote in the paperSubstantial claim
  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    The correlation between observers for the SAP trials was r=0.922, R2=0.849, p<0.0001.

    “The correlation between observers for the SAP trials included in the current experiments was r 35 ϭ 0.922, R 2 ϭ 0.849, p Ͻ 0.0001.”
    Quote in the paperNot a substantial claim
  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Counts were unavailable from one subject from each treatment group at the anterior IC and medial IC regions, resulting in n=3 or 4 observations per group.

    “We were unable to obtain counts from one subject from each treatment group at the anterior IC and medial IC regions resulting in n ϭ 3 or 4 observations per group.”
    Quote in the paperNot a substantial claim
  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    A trained observer blinded to treatment quantified social exploration, and a second observer blind to experimental conditions re-quantified from video to establish interrater reliability.

    “A trained observer blinded to treatment quantified the amount of social exploration initiated by the experimental rat”
    • Also stated in: § Subjects. · plain
      “Social exploration was quantified first during live testing and again from digital video recordings by a second observer who was blind to experimental conditions to establish interraterreliability.”
    Quote in the paperNot a substantial claim
  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    The correlation between observers for the social interaction tests was r=0.997, R2=0.993, p<0.0001.

    “The correlation between observers for the social interaction tests included in the current experiments was r 12 ϭ 0.997, R 2 ϭ 0.993, p Ͻ 0.0001.”
    Quote in the paperNot a substantial claim
  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Pilot studies found no evidence of treatment order effects on SAP behavior when using tetrodotoxin or CNO injections.

    “We tested for order effects in pilot studies and did not find evidence of treatment order effects on SAP behavior when using tetrodotoxin or CNO injections (either intraperitoneal or intracranial administration).”
    Quote in the paperNot a substantial claim
  • May combine two claims.

    Interpretationown data

    The IC-to-NAc tract is necessary and sufficient for approach toward stressed juvenile conspecifics, but not avoidance of stressed adult conspecifics.

    “We report that this tract is necessary and sufficient for approach toward stressed juvenile conspecifics, but not avoidance of stressed adult conspecifics.”
    Quote in the paperSubstantial claim
  • Classified as probably not a substantial claim.

    Study design and conductown data

    CTb488 and Fos-positive colabeled cells were manually counted in ImageJ by a trained observer blinded to treatment.

    “CTb 488 and Fos-positive colabeled cells were manually counted in ImageJ by a trained observer blinded to treatment.”
    Quote in the paperSubstantial claim
  • May combine two claims.

    Premisecitation

    The NAc encodes ultrasonic vocalization calls that convey stress and shows enhanced dopaminergic transmission in subjects that observe a conspecific receiving foot shock.

    “NAc encodes ultrasonic vocalization calls that convey stress (Willuhn et al., 2014) and shows enhanced dopaminergic transmission in subjects that observe a conspecific receiving foot shock (Wu et al., 1999)”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Willuhn et al., 2014

      Not checked in the free run.

    • cites Wu et al., 1999

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    The nucleus accumbens core (NAc) is implicated in reward.

    “The nucleus accumbens core (NAc) is implicated in reward (Wise, 2002)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Wise, 2002

      Not checked in the free run.

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

    Premisecitation

    Rodents demonstrate either prosocial or avoidance behaviors toward distressed others.

    “a number of studies report that rodents demonstrate either prosocial or avoidance behaviors toward distressed others (reviewed by (Meyza et al., 2017).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Meyza et al., 2017

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    The insular cortex (IC) is a site of multisensory integration.

    “The insular cortex (IC) is a site of multisensory integration (Rodgers et al., 2008;Gogolla et al., 2014;Gogolla, 2017)”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Rodgers et al., 2008

      Not checked in the free run.

    • cites Gogolla et al., 2014

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    • cites Gogolla, 2017

      Not checked in the free run.

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

    Premisecitation

    The NAc mediates social recognition and reward with juvenile and adult conspecifics.

    “NAc mediates social recognition (Ploeger et al., 1991) and reward with juvenile (Trezza et al., 2011) and adult conspecifics (Do ¨len et al., 2013).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Ploeger et al., 1991

      Not checked in the free run.

    • cites Trezza et al., 2011

      Not checked in the free run.

    • cites Dölen et al., 2013

      Not checked in the free run.

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

    Premisecitation

    Responses to distressed others are modulated by situational factors, including familiarity, age, social rank, sex and prior experience.

    “These responses are modulated by situational factors, including familiarity, age, social rank, sex and prior experience (Langford et al., 2006;Guzma ´n et al., 2009;Ishii et al., 2012;Kiyokawa et al., 2014;Li et al., 2014;Burkett et al., 2016;Meyza et al., 2017;Rogers-Carter et al., 2018a,b)”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Langford et al., 2006

      Not checked in the free run.

    • cites Guzmán et al., 2009

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    • cites Ishii et al., 2012

      Not checked in the free run.

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

    Study design and conductown data

    Two experimental rats were excluded due to lack of virus expression.

    “Two experimental rats were excluded due to lack of virus expression.”
    Quote in the paperNot a substantial claim
  • May combine two claims.

    Interpretationown data

    Exposure to stressed conspecifics led to greater activity in NAc-projecting IC neurons, with the greatest differential activation observed in the posterior subregion of IC.

    “In sum, exposure to stressed conspecifics led to greater activity in NAc-projecting IC neurons with the greatest differential activation observed in the posterior subregion of IC.”
    Quote in the paperSubstantial claim
  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductown data

    Rats were only included in the final analysis if there was positive evidence of virus expression in IC, bilateral cannula tip placement in NAc, and mCherry immunoreactivity of putative IC axon terminals in NAc.

    “Rats were only included in the final analysis if there was positive evidence of virus expression in IC as in Figure 4A, right; map of virus expression in Figure 4B, bilateral cannula tip placement in NAc (Fig. 4A, right, map in Fig. 4C), and mCherry immunoreactivity of putative IC axon terminals in NAc (Fig. 4A, right inset).”
    Quote in the paperSubstantial claim
  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Only rats meeting criteria for IC hM4D(Gi) expression, bilateral NAc cannula placement, mCherry expression in NAc, and avoidance of the stressed conspecific under vehicle conditions were included in analysis.

    “Only rats meeting the criteria for IC hM4D(Gi) expression, bilateral NAc cannula placement, mCherry expression in NAc, and avoidance of the stressed conspecific under vehicle conditions were included in analysis.”
    Quote in the paperSubstantial claim
  • May combine two claims.

    Interpretationown data

    The IC→NAc track is necessary and sufficient for social approach under conditions with a juvenile conspecific.

    “The foregoing results suggest the IC ¡ NAc track is necessary and sufficient for social approach under conditions with a juvenile conspecific.”
    Quote in the paperSubstantial claim
  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Three rats were excluded due to misplaced cannula or lack of virus expression.

    “Three rats were excluded due to misplaced cannula or lack of virus expression.”
    Quote in the paperNot a substantial claim
  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductown data

    For each experimental rat included in the analysis, virus transduction, cannula tip location in NAc, and presence of terminal fibers expressing mCherry in NAc were confirmed.

    “For each experimental rat included in the analysis, we confirmed the virus transduction via fluorescent imaging of the mCherry reporter (Fig. 5 A, C, right), the location of the cannula tips in NAc (Fig. 5 B, C), and the presence of terminal fibers expressing mCherry in NAc (Fig. 5B, inset).”
    Quote in the paperSubstantial claim
  • May combine two claims.

    Interpretationown data

    Excitation of IC terminals in NAc via CNO was sufficient to increase exploration with PN30, but not PN50, conspecifics.

    “These results indicate that excitation of IC terminals in NAc via CNO was sufficient to increase exploration with PN30, but not PN50 conspecifics.”
    Quote in the paperSubstantial claim
  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The involvement of NAc in social affective behavior is consistent with evidence implicating NAc in myriad social processes.

    “The involvement of NAc in social affective behavior is consistent with evidence implicating NAc in myriad social processes.”
    Quote in the paperNot a substantial claim
  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Three rats were removed from analysis because of undetectable virus expression, or failure to show novelty preference under vehicle conditions.

    “Three rats were removed from analysis because of undetect-able virus expression, or failure to show novelty preference under vehicle conditions; virus expression for the included rats is shown in Figure 6D.”
    Quote in the paperNot a substantial claim
  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    NAc is a common node of the social decision-making network which integrates dopaminergic reward circuitry with neuroendocrine centers known to mediate social behavior.

    “O'Connell and Hofmann (2011) placed the NAc as a common node of the social decision-making network which integrates the dopaminergic reward circuitry with the neuroendocrine centers known to mediate social behavior.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites O'Connell and Hofmann (2011)

      Not checked in the free run.

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

    Premisecitation

    NAc appears to decipher aversive from appetitive stimuli and modulate activity patterns in other social decision-making structures based on the valence of sensory information.

    “Importantly, NAc appears to decipher aversive from appetitive stimuli (Xiu et al., 2014) and modulate activity patterns in other social decision-making structures based on the valence of sensory information (Johnson et al., 2017).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Xiu et al., 2014

      Not checked in the free run.

    • cites Johnson et al., 2017

      Not checked in the free run.

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

    Premisecitation

    Recent reports show excitation of IC projections to central amygdala promote relapse of methamphetamine use and IC projections to bed nucleus of the stria terminalis mediate negative affect during alcohol abstinence.

    “Recent reports in drug administration models show excitation of IC projections to central amygdala promote relapse of methamphetamine use (Venniro et al., 2017) and IC projections to the bed nucleus of the stria terminalis mediate negative affect during alcohol abstinence (Centanni et al., 2019).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Venniro et al., 2017

      Not checked in the free run.

    • cites Centanni et al., 2019

      Not checked in the free run.

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

    Premisecitation

    IC is a site of multisensory integration and is reciprocally connected to the extended amygdala, which may underlie its known role in human emotional recognition.

    “IC is a site of multisensory integration (Rodgers et al., 2008;Gogolla et al., 2014;Gogolla, 2017) and is reciprocally connected to the extended amygdala (Shi and Cassell, 1998), which may underlie its known role in human emotional recognition (Adolphs et al., 2003;Gu et al., 2013;Terasawa et al., 2015).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Rodgers et al., 2008

      Not checked in the free run.

    • cites Gogolla et al., 2014

      Not checked in the free run.

    • cites Gogolla, 2017

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Although we cannot be sure that approach to stressed juveniles is a prosocial response, increased NAc activity is associated with many prosocial behaviors.

    “Although we cannot be sure that approach to stressed juveniles is a prosocial response, increased NAc activity is associated with many prosocial behaviors.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Approach to stressed juveniles is a prosocial response.
  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Rats require parental support to develop and survive, and the same mechanisms that evolved to enable parental care may also underlie more complex social abilities.

    “Rats require parental support to develop and survive (Lamers et al., 1986), and the same mechanisms that evolved to enable parental care may also underlie more complex social abilities (Scheiber et al., 2017;Marsh, 2019).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Lamers et al., 1986

      Not checked in the free run.

    • cites Scheiber et al., 2017

      Not checked in the free run.

    • cites Marsh, 2019

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    There is now substantial evidence that IC encodes and distributes negative affective states to subcortical networks to modulate behavior.

    “There is now substantial evidence that IC encodes and distributes negative affective states to to subcortical networks to modulate behavior (Berret et al., 2019;Gehrlach et al., 2019).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Berret et al., 2019

      Not checked in the free run.

    • cites Gehrlach et al., 2019

      Not checked in the free run.

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

    Premisecitation

    In the SAP test, there are changes to several overt conspecific behaviors and to the pattern of ultrasonic vocalizations, which together could convey important features of conspecific stress and age.

    “in the SAP test, we reported that there are changes to several overt conspecific behaviors (e.g., selfgrooming) and to the pattern of ultrasonic vocalizations, which together could convey important features of conspecific stress and age (Rogers-Carter et al., 2018b).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Rogers-Carter et al., 2018b

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Our findings that chemogenetic manipulation of IC terminals in NAc relates to adult-to-juvenile behaviors adds to these NAc-dependent prosocial behaviors and suggest an anatomical tract for socioemotional information to be integrated in social decision-making.

    “Our findings that chemogenetic manipulation of IC terminals in NAc relates to adult-tojuvenile behaviors adds to these NAc-dependent prosocial behaviors and suggest an anatomical tract for socioemotional information to be integrated in social decision-making.”
    Quote in the paperSubstantial claim
  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Optogenetic excitation of ventral tegmental neurons that project to NAc promoted mating behavior and microinfusion of a dopamine reuptake inhibitor increased social play in rats.

    “Optogenetic excitation of ventral tegmental neurons that project to the nucleus accumbens promoted mating behavior (Beny-Shefer et al., 2017) and microinfusion of a dopamine reuptake inhibitor increased social play in rats (Manduca et al., 2016).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Beny-Shefer et al., 2017

      Not checked in the free run.

    • cites Manduca et al., 2016

      Not checked in the free run.

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

    Interpretationcitation

    Because these social actions are necessary for species survival, they are likely reinforced by the reward system to promote their occurrence.

    “Because these social actions are necessary for species survival, they are likely reinforced by the reward system to promote their occurrence (O'Connell and Hofmann, 2011).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites O'Connell and Hofmann, 2011

      Not checked in the free run.

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

    Premisecitation

    Oxytocin in NAc increases social approach and is important for forming pair bonds.

    “Similarly, oxytocin in NAc increases social approach (Steinman et al., 2019) and is important for forming pair bonds (Insel and Shapiro, 1992;Walum et al., 2012;Walum and Young, 2018).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Steinman et al., 2019

      Not checked in the free run.

    • cites Insel and Shapiro, 1992

      Not checked in the free run.

    • cites Walum et al., 2012

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Using both inhibitory and excitatory tract-specific chemogenetic manipulations of IC→NAc terminals, this tract is both necessary for the preference for the stressed juvenile and sufficient to increase overall social exploration directed toward juvenile conspecifics.

    “Further, using both inhibitory and excitatory tract-specific chemogenetic manipulations of IC ¡ NAc terminals, we find that this tract is both necessary for the preference for the stressed juvenile and sufficient to increase overall social exploration directed toward juvenile conspecifics.”
    Quote in the paperSubstantial claim
  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Silencing of IC projection to NAc decreased alcohol self-administration and increased sensitivity to alcohol, and IC projections to central amygdala drive avoidance of an aversive tastant and fear.

    “Similarly, silencing of the IC projection to NAc decreased alcohol self-administration (Jaramillo et al., 2018b) and increased sensitivity to alcohol (Jaramillo et al., 2018a), and IC projections to the central amygdala drive avoidance of an aversive tastant (Schiff et al., 2018) and fear (Berret et al., 2019;Gehrlach et al., 2019).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Jaramillo et al., 2018b

      Not checked in the free run.

    • cites Jaramillo et al., 2018a

      Not checked in the free run.

    • cites Schiff et al., 2018

      Not checked in the free run.

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

    Interpretationcitation

    An emergent theme is that IC mediates both appetitive and aversive behavioral responses to external stimuli via different projections.

    “Although more work will add clarification, an emergent theme is that IC mediates both appetitive and aversive behavioral responses to external stimuli via different projections.”
    Quote in the paperNot a substantial claim
  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    IC contributes to both social approach and avoidance, the latter of which may be mediated by IC projections to central amygdala, which is necessary for social avoidance of stressed conspecifics.

    “IC contributes to both social approach and avoidance (Rogers-Carter et al., 2018b), the latter of which may be mediated IC projections to the central amygdala, which is necessary for social avoidance of stressed conspecifics (Ferretti et al., 2019).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Rogers-Carter et al., 2018b

      Not checked in the free run.

    • cites Ferretti et al., 2019

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductown data

    Bilateral cannula tip placements in NAc were confirmed for experimental rats tested with PN30 (n=9) and PN50 (n=7) conspecifics.

    “Map of bilateral cannula tip placements in NAc from experimental rats tested with PN30 (green; n ϭ 9) and PN50 (blue; n ϭ 7) conspecifics.”
    Quote in the paperSubstantial claim
  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In an appetitive consummatory task, optogenetic stimulation of IC to NAc projections reduced consumption.

    “Interestingly, in an appetitive consummatory task (sucrose preference) optogenetic stimulation of IC to NAc projections reduced consumption (Gehrlach et al., 2019).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Gehrlach et al., 2019

      Not checked in the free run.

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

    Interpretationcitation

    These results parallel several features of human social behavior, namely that social stress cues modulate rodent social interactions in ways that mirror adult preference to lend help to juveniles while showing less empathy toward other adults.

    “These results parallel several features of human social behavior, namely that social stress cues modulate rodent social interactions in ways that mirror adult preference to lend help to juveniles while showing less empathy toward other adults (Batson and Powell, 2003).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Batson and Powell, 2003

      Not checked in the free run.

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

    Study design and conductnone given

    Treatment order on days 3 and 4 was counterbalanced.

    “treatment order on days 3 and 4 was counterbalanced.”
    Quote in the paperNot a substantial claim
  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Cannula tip placements in NAc were summarized.

    “Summary map of cannula tip placements in NAc.”
    Quote in the paperNot a substantial claim
  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Bilateral IC sham pAAV5-hSyn-mCherry expression was confirmed in control rats (n=8).

    “Map of bilateral IC sham pAAV5-hSyn-mCherry expression, n ϭ 8.”
    Quote in the paperNot a substantial claim
  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    mCherry expression in IC was summarized for n=10.

    “Summary of mCherry expression in IC (n ϭ 10)”
    Quote in the paperNot a substantial claim
  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    hM4D(Gi) expression spread in the IC was summarized.

    “Summary of mCherry expression indicating spread of hM4D(Gi) in the IC.”
    Quote in the paperNot a substantial claim
  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Cannula tip placements in NAc were mapped.

    “Map of cannula tip placements in NAc (left)”
    Quote in the paperNot a substantial claim
71 of 71
  • The paper relies on this without support.

    No prior mechanistic studies have explored the role of IC projection tracts in social behavior.

    “No prior mechanistic studies have explored the role of IC projection tracts in social behavior.”
  • The paper relies on this without support.

    Approach to stressed juveniles is a prosocial response.

    “Although we cannot be sure that approach to stressed juveniles is a prosocial response, increased NAc activity is associated with many prosocial behaviors.”
  • The paper relies on this without support.

    The social novelty preference test measures social reward per se.

    “To establish whether IC is involved in situations of social reward per se, we used the social novelty preference test in which others have shown that an experimental rat will spend more time exploring an unfamiliar conspecific than a familiar animal and is dependent upon the NAc (Smith et al., 2018).”
  • The paper relies on this without support.

    The conspecifics designated as stressed were indeed stressed.

    “Experimental rats presented stressed PN30 conspecifics engaged in more social exploration than rats presented naive PN30 conspecifics ( p ϭ 0.008).”
  • The paper relies on this without support.

    Fos immunoreactivity reflects neuronal activity.

    “Exposure to stressed PN30 conspecifics elicited greater Fos immunoreactivity in IC ¡ NAc neurons than exposure to naive PN30 conspecifics.”
  • The paper relies on this without support.

    CTb488 retrogradely labels NAc-projecting IC neurons.

    “Schematic depicting unilateral 300 nl injections of the retrograde tracer CTb 488 in the right hemisphere NAc”
  • The paper relies on this without support.

    TTX infusion in NAc inactivates NAc neurons without affecting adjacent regions.

    “which was abolished via bilateral infusion ofTTX (100 nM, 0.5 l/side) in NAc 15 min before testing ( p ϭ 0.203).”
7 of 7

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?

  • 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].”

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.

  • TTX concentration differs across the paper

    Major

    The methods give the TTX concentration as 10 M, whereas the Figure 1 legend says 100 nM for the same NAc infusion. The abstract gives a third concentration, 1 M, leaving the administered dose unclear.

  • Terminal-inhibition CNO pretreatment times disagree

    Major

    For the PN30 IC-terminal inhibition experiment, the Results say CNO was administered 15 minutes before testing, while the Figure 4 legend says 45 minutes.

  • A p = 0.053 result is described as a main effect

    Minor

    The electrophysiology Results say the ANOVA revealed a main effect at p = 0.053, although the paper specifies p < 0.05 as its significance threshold.

  • Retrograde tracer injection changes hemispheres

    Minor

    The methods and Figure 2 describe a right-hemisphere NAc injection, but the Results say the injections were in the left hemisphere.

  • Terminal-activation CNO pretreatment times disagree

    Minor

    For the IC-terminal activation experiment, the Results place CNO infusion 30 minutes before testing, but the Figure 5 legend places it 45 minutes before testing.

  • Adult preference-score t test has the wrong degrees of freedom

    Minor

    Figure 4 reports nine rats for the PN50 experiment. A paired t test of their vehicle and CNO preference scores would have eight, not nine, degrees of freedom; the preceding ANOVA also uses an error degree of freedom of eight.

    Reported 9 · recomputed 8

  • PN50 TTX preference-score p values disagree

    Minor

    The Results and the Figure 1 legend give different p values for the effect of TTX on PN50 preference scores.

7 of 7

Cites

1 retracted

Flagged first, then by citations

Cited by

Sorted by citations

Authors
Rogers-Carter, M. M., Djerdjaj, A., Gribbons, K. B., Varela, J. A., & Christianson, J. P.
Affiliations
Boston College (US)
Corresponding author
Rogers-Carter, Morgan M.
Venue
The Journal of Neuroscience
Published
2019-10-07
Volume
39
Issue
44
Pages
8717-8729
ISSN
  • 0270-6474 (ISSN-L)
  • 1529-2401
OpenAlex
W2977766168
Cited by
79
References
82
Citations by year
2026: 15 · 2025: 9 · 2024: 7 · 2023: 14 · 2022: 11 · 2021: 13 · 2020: 7 · 2019: 3
FWCI
10.68
Type
journal article
Language
en
Open access
Locations
  • Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Science Foundation
  • Boston College
  • National Institutes of Health
  • National Institute of Mental Health (R56MH109545, R01MH119422)
Topics
  • Social Sciences › Psychology › Social Psychology › Neuroendocrine regulation and behavior
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
Keywords
insula, nucleus accumbens core, social approach, social decision-making, juvenile stress, tetrodotoxin, Fos-like immunoreactivity, chemogenetic manipulation, social reward, autism spectrum disorder
MeSH terms
Animals, Cerebral Cortex, Choice Behavior, Male, Neural Pathways, Nucleus Accumbens, Social Behavior, Stress, Psychological, Rats, Sprague-Dawley

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.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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