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Cited by 33Genetics and Neurodevelopmental DisordersAutism Spectrum Disorder ResearchNeuroscience and Neuropharmacology Research

Reduced sociability and social agency encoding in adult Shank3-mutant mice are restored through gene re-expression in real time

Open access
Lee, Daniel K., Li, S. William, Bounni, Firas, Friedman, Gabriel, Jamali, Mohsen, Strahs, Leah, Zeliger, Omer, Gabrieli, Pauline +3 more·2021·Nature Neuroscience
DOI 10.1038/s41593-021-00888-4PMC PMC8410666
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Abstract

Despite a growing understanding of the molecular and developmental basis of autism spectrum disorder (ASD), how the neuronal encoding of social information is disrupted in ASD and whether it contributes to abnormal social behavior remains unclear. Here, we disrupted and then restored expression of the ASD-associated gene Shank3 in adult male mice while tracking the encoding dynamics of neurons in the medial prefrontal cortex (mPFC) over weeks. We find that Shank3 disruption led to a reduction of neurons encoding the experience of other mice and an increase in neurons encoding the animal’s own experience. This shift was associated with a loss of ability by neurons to distinguish other from self and, therefore, the inability to encode social agency. Restoration of Shank3 expression in the mPFC reversed this encoding imbalance and increased sociability over 5–8 weeks. These findings reveal a neuronal-encoding process that is necessary for social behavior and that may be disrupted in ASD. Lee et al. show that in male Shank3-mutant mice, mPFC neurons are impaired in encoding of social agency. Shank3 reexpression in mPFC restored this ability in real time, and this was accompanied by rescue of normal social behavior.

AI snapshot

Written from the paper’s full text.

TL;DR

Disrupting Shank3 in adult male mice reduced mPFC neurons encoding another mouse’s experience and increased self-encoding, collapsing self–other distinction; restoring Shank3 reversed this imbalance and increased sociability. Changes in social-agency encoding and sociability were temporally related, and local mPFC restoration or inhibition indicated mPFC involvement.

Key findings

  • In WT mice, 30.0% (33/112) of task-modulated mPFC neurons encoded the other’s experience and 25.9% (29/112) encoded self; only 9 overlapped. In HET mice before TMX, other encoding fell to 9.2% (12/131), self encoding rose to 38.2% (50/131), and the other:self ratio fell from 1.1:1 in WT to 1:4 in HET; all 12 other-encoding HET neurons also encoded self, versus 9/33 in WT.
  • After TMX, HET other encoding increased from 9.2% to 35.5% (49/138 at ≥5 weeks) and self encoding decreased from 38.2% to 19.5% (27/138); no such changes occurred in CreER−/− controls.
  • HET mice showed no baseline preference for a non-familiar mouse over an object (p = 0.85), while WT mice did (p = 1.0 × 10−4); after TMX, HET mice showed significant preference (p = 7.0 × 10−4). Cross-correlation between social-agency encoding and sociability was r = 0.88, p = 0.0041, with peak lag 5–6 days.
  • Local endoxifen restoration in mPFC increased sociability (p = 0.0087) and other encoding (χ2(1) = 4.11, p = 0.043), with lag 0 days (r = 0.82, p = 0.0073); muscimol in WT mPFC abolished preference (p = 0.52) versus saline (p = 4.19 × 10−3).

Methods

  • Adult male mice: 77 total (28 WT, 49 heterozygous Shank3); Cre-dependent FLEx switch in Shank3fx/+:CreER+/− and controls; TMX or endoxifen restored Shank3 globally or locally in mPFC.
  • mPFC microelectrode arrays recorded single units during a paired social interaction task varying social agency (self/other), experience valence (appetitive/aversive), and identity (familiar/non-familiar), with inanimate-totem and visual-block controls; behavior was tracked genotype-blinded.
  • Sociability was assessed with a modified three-chamber task; additional assays included place preference, respiratory rate, corticosterone, and elevated zero maze. Analyses included three-way ANOVA, chi-square tests, decoding/SVM, cross-correlation, and permutation tests.

Limitations

  • Paper states: the study focused on mPFC, while ASD involves other cortical–subcortical circuits; findings do not reveal how mPFC Shank3 relates to excitability or synaptic structure; mouse models do not fully recapitulate human social complexity or the ASD spectrum.
  • Evident from text: main experiments used only adult male mice, so sex/generalization limits are not addressed; heterozygous Shank3 constructs were used, not homozygous or other mutations.
  • Evident from text: data distribution was assumed normal but not formally tested, and no statistical method was used to predetermine sample size.

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

Integrity signals

Registry

Crossref · 10.1038/s41593-021-00888-4

Cites

67 of 67 references verified0 citation errors · 0 not checkable

Statistics

13 tests recomputed · 0 with the reported and recomputed p on opposite sides of .05

Claims the paper makes

0 of 76 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    The shift in neuronal encoding after Shank3 disruption was associated with loss of ability by neurons to distinguish other-from-self and therefore the inability to encode social agency.

    “This shift was associated with loss of ability by neurons to distinguish other-from-self and, therefore, the inability to encode social agency.”
    Quote in the paperSubstantial claim
  • Findingown data

    In WT mice, 112 of 188 recorded mPFC neurons displayed task-related modulation (three-way ANOVA, p < 0.0125).

    “using a three-way analysis of variance that considered social agency, experience valence and identity for the main effects across the 188 WT neurons recorded, we found 112 neurons that displayed task-related modulation (three-way ANOVA, p < 0.0125 with post-hoc comparisons).”
    Quote in the paperSubstantial claim
  • Findingown data

    Neurons that encoded the other animal's experience were largely distinct from those that encoded the animal's own experience.

    “Neurons that encoded the other animal’s experience were largely distinct from those that encoded the animal’s own experience.”
    Quote in the paperNot a substantial claim
  • Findingown data

    Of task-modulated WT neurons, 30.0% (33 of 112) responded to variations in the other social agent's experience.

    “Of these neurons, 30.0% (n = 33 of 112) responded to variations in the other social agent’s experience”
    Quote in the paperSubstantial claim
  • Findingown data

    Of task-modulated WT neurons, 25.9% (29 of 112) encoded the animal's own experiences.

    “Of neurons that were modulated by the task, 25.9% (n = 29 of 112) encoded the animal’s own experiences”
    Quote in the paperSubstantial claim
  • May combine two claims. 45
  • Classified as probably not a substantial claim. 53
  • The quote only partly states this claim. 1

  • May combine two claims.

    Findingown data

    Shank3 disruption in adult male mice led to a reduction of neurons encoding the experience of other mice and an increase in neurons encoding the animal's own experience.

    “We find that Shank3 disruption led to reduction of neurons encoding the experience of other mice and increase in neurons encoding the animal’s own.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Restoration of Shank3 expression in the mPFC reversed the encoding imbalance and increased sociability over 5-8 weeks.

    “Restoration of Shank3 expression in the mPFC reversed this encoding imbalance and increased sociability over 5-8 weeks.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Under the inanimate totem condition, only 3.6% (4 of 112) of WT neurons responded to appetitive and aversive stimuli, of which 3 were among neurons encoding the other's experience (Chi-square χ2(1)=10.9, p=9.6e-4).

    “Under this setting, only 3.6% of neurons (n = 4 of 112 cells) responded to the appetitive and aversive stimuli, of which 3 were among the neurons found to encode the other’s experience (Chi-square test, χ2(1) = 10.9, p = 9.6 x 10−4).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    With visual access blocked by an odor- and sound-permeable barrier, only 7.1% (8 of 112) of WT neurons responded to aversive and appetitive conditions, of which only one overlapped with other-encoding neurons (Chi-square χ2(1)=62.1, p<1.0e-7).

    “Now, though, only 7.1% (n = 8 of 112) of neurons responded to the aversive and appetitive conditions, of which only one neuron overlapped with those encoding the other’s experience (Chi-square test, χ2(1) = 62.1, p < 1.0 × 10−7”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Of WT neurons that encoded the animal's own experience, only 9 also encoded the other animal's experience, a proportion significantly lower than expected from chance (bootstrap p < 0.01).

    “Of the neurons that encoded the animal’s own experience, however, only 9 also encoded the other animal’s experience; a proportion that was significantly lower than expected from chance (bootstrap analysis, p < 0.01)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Similar results were found by decoding analysis and within- vs. between-group comparisons, indicating these differences in neuronal encoding were robust.

    “Similar results were found by decoding analysis (Extended Data Table 3) as well as when performing within- vs. between-group comparisons, indicating that these differences in neuronal encoding were robust (Extended Data Fig. 4).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Although the increase in corticosterone was smaller in HET than WT, genotype had no independent effect on this change (two-way ANOVA, p = 0.23).

    “Although this increase in corticosterone levels was smaller in HET mice than in WT mice, the genotype of the animals had no independent effect on this change (two-way ANOVA, p = 0.23; Extended Data Fig. 6c).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    HET mice displayed a difference in respiratory rate (ANOVA, p = 0.0031), suggesting they were able to discriminate between aversive and appetitive conditions.

    “they did display a difference in respiratory rate (ANOVA, p = 0.0031; Extended Data Fig. 6b) to suggest that they were able to discriminate between these conditions.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Of task-modulated HET neurons, only 9.2% (12 of 131) encoded the other agent's experience, a proportion significantly smaller than in WT (Chi-square χ2(1)=10.5, p=1.2e-3).

    “Of task-modulated neurons, only 9.2% (n = 12 of 131; Fig. 1d) encoded the other agent’s experience, a proportion that was significantly smaller than that observed in WT (Chi-square test, χ2(1) = 10.5, p = 1.2 × 10−3”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Time spent in the open area did not differ between WT and HET mice (n=27; t-test, p=0.73), nor did the number of visits (p=0.77) or head-dipping events (p=0.92).

    “The time spend in the open area, however, did not differ from that of the HET mice (n = 27; t-test, p = 0.73), nor did the number of visits (t-test, p = 0.77) or head-dipping events (t-test, p = 0.92; Extended Data Fig. 7).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    WT and HET mice did not differ in movement velocities (t(217)=0.48, p=0.63) or distribution of distances traveled (t(217)=0.32, p=0.75).

    “WT and HET mice did not differ otherwise in movement velocities (two-sample t-test, ts(217) = 0.48, p = 0.63) or distribution of distances traveled (two-sample t-test, ts(217) = 0.32, p = 0.75; Fig. 4d).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    TMX globally increased Shank3 expression in haploinsufficient animals; increase in α, β and γ SHANK3 isoforms was confirmed using brain synaptosome preparation and Western blot.

    “TMX was used here to globally increase Shank3 expression in the haploinsufficent animals. Increase in α, β and γ SHANK3 isoforms in the Shank3fx/+:CreER+/− mice was confirmed using brain synaptosome preparation and Western blot”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    No change in sociability was observed in Shank3fx/+:CreER−/− mice that received endoxifen injection in the mPFC but lacked the CreER recombinase gene and did not demonstrate increased Shank3 expression in the mPFC (two-sample t-test, t(15)=-0.41, p=0.69).

    “and in Shank3fx/+:CreER−/− mice, which received endoxifen injection in the mPFC but which lacked the CreER recombinase gene and therefore did not demonstrate increased Shank3 expression in the mPFC (two-sample t-test, ts(15) = −0.41, p = 0.69; Fig. 7a, right).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    No change was found in HET mice after TMX in the proportion of neurons that were simply task-modulated (χ2(1)=0.25, p=0.61) or in the proportion that responded to familiarity (χ2(1)=0.34, p=0.56).

    “We also found no change in HET mice after TMX in the proportion of neurons that were simply task-modulated (Chi-square test, χ2(1) = 0.25, p = 0.61) or in the proportion of neurons that responded to familiarity (Chi-square test, χ2(1) = 0.34, p = 0.56).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    HET mice that underwent local endoxifen-driven Cre-lox recombination and restoration of Shank3 expression in the mPFC displayed a marked increase in sociability, showing a significant increase in preference for non-familiar animals over inanimate objects over the 8 week course of testing (two sample t-test, t(15)=-4.14, p=0.0087; >5 weeks).

    “HET mice that underwent local endoxifen-driven Cre-lox recombination and restoration of Shank3 expression in the mPFC also displayed a marked increase in sociability. As seen in Figure 7a, they showed a significant increase in preference for the non-familiar animals compared to inanimate objects over the 8 week course of testing (two sample t-test, t(15) −4.14, p = 0.0087; >5 weeks).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    WT mice did not display a change in sociability (permutation test, p > 0.2) or neuronal encoding (permutation test, p > 0.2) when tracked over time.

    “Similarly, the WT mice did not display a change in sociability (permutation test, p > 0.2) or neuronal encoding (permutation test, p > 0.2) when tracked over time (Extended Data Fig. 8d)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Shank3fx/+:CreER−/− animals did not show a change in agency encoding and no relation between social behavior and neuronal encoding (cross-correlation, p > 0.25).

    “These mice did not show a change in agency encoding and no relation between social behavior and neuronal encoding (cross-correlation, p > 0.25; Fig. 5b, right and Fig. 6).”
    Quote in the paperSubstantial claim

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

    Findingown data

    Mean spiking activity in WT mice was slightly but non-significantly lower than for HET mice (3.37 ± 0.37 vs. 3.54 ± 0.31 spikes/sec, two-sample t-test, ts = −0.52, p = 0.61) during neutral trials.

    “Mean spiking activity in WT mice was slightly but non-significantly lower than for that of HET mice (3.37 ± 0.37 vs. 3.54 ± 0.31 spikes/sec, two-sample t-test, ts = −0.52, p = 0.61) during neutral trials.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    For pyramidal neurons in WT mice, 46% (n=25) responded to self-experience and 54% (n=29) to other-experience.

    “For the pyramidal neurons in the WT mice, 46% (n=25) responded to self-experience and 54% (n=29) to other-experience”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    For interneurons in WT mice, 50% (n=4) responded to self-experience and 50% (n=4) to other-experience.

    “For interneurons in the WT mice, 50% (n=4) responded to self-experience and 50% (n=4) to other-experience”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    For interneurons in HET mice, 73% (n=11) responded to self-experience and only 27% (n=4) to other-experience.

    “whereas, for interneurons in the HET mice 73% (n=11) responded to self-experience and only 27% (n=4) to other-experience.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Across conditions, the other-to-self ratio was relatively stable, with HET results ranging from 1:2.3 to 1:4.6 and WT results ranging from 1.1:1 to 1:1.7.

    “Across conditions, other-to-self ratio was relatively stable, with HET and WT results ranging from 1:2.3 to 1:4.6, and 1.1:1 to 1:1.7, respectively.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    There was no significant difference in the degree of modulation at the very end of the trial (p > 0.2).

    “While there was a slightly lower degree of modulation at the very end of the trial, this difference was not significant (repeated measures ANVOA, p > 0.2).”
    Quote in the paperNot a substantial claim
    • The authors state this as an assumption: The data distribution was assumed to be normal, but this was not formally tested.

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

    Findingown data

    In total, 112 neurons in WT mice and 131 neurons in Shank3 mice displayed task-related modulation.

    “In total, 112 neurons and 131 neurons displayed task-related modulation in the WT and Shank3 mice, respectively.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    There was no difference in the total number of neurons that displayed significant modulation over the course of the trial (p > 0.5).

    “Similarly, we find no difference in the total number of neurons that displayed significant modulation over the course of the trial (Chi-square, p > 0.5).”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Prior investigations in rodents and primates have provided evidence for neurons that encode information about other individuals, demonstrating changes in activity when animals observe another's appetitive or aversive experiences.

    “Prior investigations in rodents and primates, for example, have provided evidence for the presence of neurons that encode information about other individuals, demonstrating changes in activity when the animals observe another’s appetitive or aversive experiences 1–11.”
    Quote in the paperNot a substantial claim0 of 10 sources checked
    • cites [1] Rudebeck, P. H., Buckley, M. J., Walton, M. E. & Rushworth, M. F. A role for the macaque anterior cingulate gyrus in social valuation. Science 313, 1310–1312 (2006). source

      Not checked in the free run.

    • cites [2] Chang, S. W., Gariepy, J. F. & Platt, M. L. Neuronal reference frames for social decisions in primate frontal cortex. Nat. Neurosci. 16, 243–250 (2013). source

      Not checked in the free run.

    • cites [3] Dolen, G., Darvishzadeh, A., Huang, K. W. & Malenka, R. C. Social reward requires coordinated activity of nucleus accumbens oxytocin and serotonin. Nature 501, 179–184 (2013). source

      Not checked in the free run.

    • cites [4] Li, Y. et al. Neuronal representation of social information in the medial amygdala of awake behaving mice. Cell 171, 1176–1190 (2017). source

      Not checked in the free run.

    • cites [5] Caggiano, V., Fogassi, L., Rizzolatti, G., Thier, P. & Casile, A. Mirror neurons differentially encode the peripersonal and extrapersonal space of monkeys. Science 324, 403–406 (2009). source

      Not checked in the free run.

    • cites [6] Omer, D. B., Maimon, S. R., Las, L. & Ulanovsky, N. Social place-cells in the bat hippocampus. Science 359, 218–224 (2018). source

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    • cites [7] Haroush, K. & Williams, Z. M. Neuronal prediction of opponent’s behavior during cooperative social interchange in primates. Cell 160, 1233–1245 (2015). source

      Not checked in the free run.

    • cites [8] Allsop, S. A. et al. Corticoamygdala transfer of socially derived information gates observational learning. Cell 173, 1329–1342 (2018). source

      Not checked in the free run.

    • cites [9] Yoshida, K., Saito, N., Iriki, A. & Isoda, M. Social error monitoring in macaque frontal cortex. Nat. Neurosci. 15, 1307–1312 (2012). source

      Not checked in the free run.

    • cites [10] Murugan, M. et al. Combined social and spatial coding in a descending projection from the prefrontal cortex. Cell 171, 1663–1677 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    These findings reveal a neuronal encoding process that is necessary for social behavior and that may be disrupted in ASD.

    “These findings reveal a neuronal encoding process that is necessary for social behavior and that may be disrupted in ASD.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Prior investigations have provided evidence for neurons that encode another animal's familiarity or dominance.

    “They have also provided evidence for neurons that encode another animals’ familiarity or dominance 12,13”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [12] Burkett, J. P. et al. Oxytocin-dependent consolation behavior in rodents. Science 351, 375–378 (2016). source

      Not checked in the free run.

    • cites [13] Chang, L. & Tsao, D. Y. The code for facial identity in the primate brain. Cell 169, 1013–1028 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In mice, both congenital knockout and haploinsufficiency of Shank3 lead to diminished social interest in others and are associated with disruption of cortical and subcortical circuits thought to be involved in ASD and its ontogenesis.

    “In mice, both congenital knockout and haploinsufficiency of Shank3 leads to diminished social interest in others and is associated with the disruption of cortical and subcortical circuits thought to be involved in ASD 22–26 and its ontogenesis 22,25,27,28.”
    Quote in the paperSubstantial claim0 of 7 sources checked
    • cites [22] Yi, F. et al. Autism-associated SHANK3 haploinsufficiency causes Ih channelopathy in human neurons. Science 352, aaf2669 (2016). source

      Not checked in the free run.

    • cites [23] Bariselli, S. et al. SHANK3 controls maturation of social reward circuits in the VTA. Nat. Neurosci. 19, 926–934 (2016). source

      Not checked in the free run.

    • cites [24] Duffney, L. J. et al. Shank3 deficiency induces NMDA receptor hypofunction via an actin-dependent mechanism. J. Neurosci. 33, 15767–15778 (2013). source

      Not checked in the free run.

    • cites [25] Peca, J. et al. Shank3 mutant mice display autistic-like behaviours and striatal dysfunction. Nature 472, 437–442 (2011). source

      Not checked in the free run.

    • cites [26] Yizhar, O. et al. Neocortical excitation/inhibition balance in information processing and social dysfunction. Nature 477, 171–178 (2011). source

      Not checked in the free run.

    • cites [27] Stoodley, C. J. et al. Altered cerebellar connectivity in autism and cerebellar-mediated rescue of autism-related behaviors in mice. Nat. Neurosci. 20, 1744–1751 (2017). source

      Not checked in the free run.

    • cites [28] Twining, R. C., Vantrease, J. E., Love, S., Padival, M. & Rosenkranz, J. A. An intra-amygdala circuit specifically regulates social fear learning. Nat. Neurosci. 20, 459–469 (2017). source

      Not checked in the free run.

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

    Premisecitation

    Heterozygous mutations of the Shank3 gene are associated with up to one percent of ASD cases and are a major contributor in Phelan-McDermid syndrome.

    “Heterozygous mutations of the Shank3 gene are associated with up to one percent of ASD cases 20,21 and are a major contributor in Phelan-McDermid syndrome.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [20] Uchino, S. & Waga, C. SHANK3 as an autism spectrum disorder-associated gene. Brain Dev. 35, 106–110 (2013). source

      Not checked in the free run.

    • cites [21] Guilmatre, A., Huguet, G., Delorme, R. & Bourgeron, T. The emerging role of SHANK genes in neuropsychiatric disorders. Dev. Neurobiol. 74, 113–122 (2014). source

      Not checked in the free run.

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

    Premisecitation

    Individuals with ASD often show difficulty in evaluating social cues and in appropriately interpreting another person's experiences or emotions, and may display a preoccupation with self or limited interest in others.

    “Individuals with ASD often show difficulty in evaluating social cues and in appropriately interpreting another person’s experiences or emotions, and may display a preoccupation with self or limited interest in others 14–19.”
    Quote in the paperNot a substantial claim0 of 6 sources checked
    • cites [14] Amaral, D., Dawson, G. & Geschwind, D. H. Autism Spectrum Disorders (Oxford University Press, 2011). source

      Not checked in the free run.

    • cites [15] Lord, C. & Bishop, S. L. Recent advances in autism research as reflected in DSM-5 criteria for autism spectrum disorder. Annu. Rev. Clin. Psychol. 11, 53–70 (2015). source

      Not checked in the free run.

    • cites [16] Lamm, C., Bukowski, H. & Silani, G. From shared to distinct self–other representations in empathy: evidence from neurotypical function and socio-cognitive disorders. Philos. Trans. R. Soc. Lond. B Biol. Sci. 371, 20150083 (2016). source

      Not checked in the free run.

    • cites [17] Steinbeis, N. The role of self–other distinction in understanding others’ mental and emotional states: neurocognitive mechanisms in children and adults. Philos. Trans. R. Soc. Lond. B Biol. Sci. 371, 20150074 (2016). source

      Not checked in the free run.

    • cites [18] Uddin, L. Q. et al. Neural basis of self and other representation in autism: an fMRI study of self-face recognition. PLoS ONE 3, e3526 (2008). source

      Not checked in the free run.

    • cites [19] Senju, A. Spontaneous theory of mind and its absence in autism spectrum disorders. Neuroscientist 18, 108–113 (2012). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisenone given

    Whether and how Shank3 mutations or haploinsufficiency disrupt the processes by which social information is precisely encoded by individual neurons in behaving animals remains largely unknown.

    “Yet, whether and how Shank3 mutations or haploinsufficiency disrupt the processes by which social information is precisely encoded by individual neurons in behaving animals remains largely unknown.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Cells in HET mice responded similarly irrespective of whether the experience was given to the other animal or self, suggesting reduced Shank3 expression was associated with a diminished ability of neurons to represent social agency.

    “Cells in the HET mice therefore responded similarly irrespective of whether the experience was given to the other animal or self, together suggesting that reduced expression of Shank3 the was associated with a diminished ability of neurons to represent social agency (i.e., the ability to distinguish other from self).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductown data

    These differences in encoding between WT and HET mice were largely independent of the statistical thresholding used (p < 0.05 to 0.0025) and were consistent across animals.

    “These differences in encoding between the WT and HET mice was also largely independent of the statistical thresholding used (p < 0.05 to 0.0025; Extended Data Fig. 5a) and was consistent across animals (Extended Data Fig. 5b)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Taken together, neuronal responses to the other's experience reflected the social context of their interaction rather than simply information about the sensory stimuli or enclosures themselves.

    “Taken together, neuronal responses to the other’s experience reflected the social context of their interaction rather than simply information about the sensory stimuli or enclosures themselves.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Local activation of Shank3 expression in the mPFC was associated with a near simultaneous change in neuronal encoding and social behavior, unlike the 5-6 day lag in HET mice after global restoration of Shank3 expression.

    “Thus, local activation of Shank3 expression in the mPFC was associated with a near simultaneous change in neuronal encoding and social behavior (i.e., unlike the 5-6 day lag in HET mice after global restoration of Shank3 expression).”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductnone given

    All task conditions were counterbalanced so that an equal number of self- and other- trials and an equal number of appetitive- and aversive- conditions were performed.

    “All task conditions were counterbalanced so that an equal number of self- and other- trials as well as an equal number of appetitive- and aversive- conditions were performed.”
    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

    The animals' behaviors were tracked using a ceiling mounted digital camera, with task condition and animal position determined in an automated, genotype-blinded manner.

    “The animals’ behaviors were tracked using a ceiling mounted digital camera; with the task condition and animal position being determined in an automated, genotype-blinded manner (Methods).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Heterozygous constructs were used to mimic the physiological expression of Shank3 and because, unlike animals with homozygous mutations, they generally do not exhibit motoric dysfunction, anxiety or self-injurious behavior that could potentially confound social testing.

    “In our study, we used heterozygous constructs to mimic the physiological expression of Shank3 and because, unlike animals with homozygous mutations, they generally do not exhibit motoric dysfunction, anxiety or self-injurious behavior that could potentially confound social testing 22,33.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [22] Yi, F. et al. Autism-associated SHANK3 haploinsufficiency causes Ih channelopathy in human neurons. Science 352, aaf2669 (2016). source

      Not checked in the free run.

    • cites [33] Jaramillo, T. C. et al. Novel Shank3 mutant exhibits behaviors with face validity for autism and altered striatal and hippocampal function. Autism Res. 10, 42–65 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductcitation

    All enclosures were well-habituated and did not require conditioning, allowing consistent study of neuronal response across multiple interleaved trials.

    “All enclosures were well-habituated and did not require conditioning (e.g. tone-shock pairing) 28, therefore, allowing us to consistently study neuronal response across multiple interleaved trials.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [28] Twining, R. C., Vantrease, J. E., Love, S., Padival, M. & Rosenkranz, J. A. An intra-amygdala circuit specifically regulates social fear learning. Nat. Neurosci. 20, 459–469 (2017). source

      Not checked in the free run.

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

    Premisecitation

    The mPFC is an area suggested to be involved in social behavior and disorders such as ASD.

    “Here, we used microelectrode arrays that were implanted in the animal’s mPFC (Extended Data Fig. 1b), an area suggested to be involved in social behavior 1,7,12,26,34 and disorders such as ASD 14,21,35,36.”
    Quote in the paperNot a substantial claim0 of 9 sources checked
    • cites [1] Rudebeck, P. H., Buckley, M. J., Walton, M. E. & Rushworth, M. F. A role for the macaque anterior cingulate gyrus in social valuation. Science 313, 1310–1312 (2006). source

      Not checked in the free run.

    • cites [7] Haroush, K. & Williams, Z. M. Neuronal prediction of opponent’s behavior during cooperative social interchange in primates. Cell 160, 1233–1245 (2015). source

      Not checked in the free run.

    • cites [12] Burkett, J. P. et al. Oxytocin-dependent consolation behavior in rodents. Science 351, 375–378 (2016). source

      Not checked in the free run.

    • cites [26] Yizhar, O. et al. Neocortical excitation/inhibition balance in information processing and social dysfunction. Nature 477, 171–178 (2011). source

      Not checked in the free run.

    • cites [34] Singer, T. et al. Empathy for pain involves the affective but not sensory components of pain. Science 303, 1157–1162 (2004). source

      Not checked in the free run.

    • cites [14] Amaral, D., Dawson, G. & Geschwind, D. H. Autism Spectrum Disorders (Oxford University Press, 2011). source

      Not checked in the free run.

    • cites [21] Guilmatre, A., Huguet, G., Delorme, R. & Bourgeron, T. The emerging role of SHANK genes in neuropsychiatric disorders. Dev. Neurobiol. 74, 113–122 (2014). source

      Not checked in the free run.

    • cites [35] Zielinski, B. A. et al. Longitudinal changes in cortical thickness in autism and typical development. Brain 137, 1799–1812 (2014). source

      Not checked in the free run.

    • cites [36] Stone, V. E., Baron-Cohen, S. & Knight, R. T. Frontal lobe contributions to theory of mind. J. Cogn. Neurosci. 10, 640–656 (1998). source

      Not checked in the free run.

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

    Premisecitation

    Previous investigations have provided insight into how discrete aspects of another animal's experience, such as receipt of reward, may be encoded by cells.

    “Previous investigations have provided insight into how discrete aspects of another animal’s experience, such as receipt of reward, may be encoded by cells 1–7,9.”
    Quote in the paperNot a substantial claim0 of 8 sources checked
    • cites [1] Rudebeck, P. H., Buckley, M. J., Walton, M. E. & Rushworth, M. F. A role for the macaque anterior cingulate gyrus in social valuation. Science 313, 1310–1312 (2006). source

      Not checked in the free run.

    • cites [2] Chang, S. W., Gariepy, J. F. & Platt, M. L. Neuronal reference frames for social decisions in primate frontal cortex. Nat. Neurosci. 16, 243–250 (2013). source

      Not checked in the free run.

    • cites [3] Dolen, G., Darvishzadeh, A., Huang, K. W. & Malenka, R. C. Social reward requires coordinated activity of nucleus accumbens oxytocin and serotonin. Nature 501, 179–184 (2013). source

      Not checked in the free run.

    • cites [4] Li, Y. et al. Neuronal representation of social information in the medial amygdala of awake behaving mice. Cell 171, 1176–1190 (2017). source

      Not checked in the free run.

    • cites [5] Caggiano, V., Fogassi, L., Rizzolatti, G., Thier, P. & Casile, A. Mirror neurons differentially encode the peripersonal and extrapersonal space of monkeys. Science 324, 403–406 (2009). source

      Not checked in the free run.

    • cites [6] Omer, D. B., Maimon, S. R., Las, L. & Ulanovsky, N. Social place-cells in the bat hippocampus. Science 359, 218–224 (2018). source

      Not checked in the free run.

    • cites [7] Haroush, K. & Williams, Z. M. Neuronal prediction of opponent’s behavior during cooperative social interchange in primates. Cell 160, 1233–1245 (2015). source

      Not checked in the free run.

    • cites [9] Yoshida, K., Saito, N., Iriki, A. & Isoda, M. Social error monitoring in macaque frontal cortex. Nat. Neurosci. 15, 1307–1312 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    mPFC neurons represent another animal's specific experience and differentiate the other's specific experience from the animal's own.

    “Together, our findings suggest a functional division of labor within the mPFC by which neurons not only represent another animal’s specific experience but also differentiate the other’s specific experience from the animal’s own.”
    • Also stated in: § Discussion · hedged
      “In particular, these findings suggest a coding mechanism by which neurons in the mPFC represent information about a conspecific’s specific experience (i.e., whether it is aversive or appetitive) as well as to differentiate the conspecific’s experience from one’s own.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Individuals with ASD are often described as having inability to organize social information or appropriately interpret the state and experience of others.

    “Individuals with ASD are often described as having inability to organize social information or appropriately interpret the state and experience of others 14–19.”
    Quote in the paperNot a substantial claim0 of 6 sources checked
    • cites [14] Amaral, D., Dawson, G. & Geschwind, D. H. Autism Spectrum Disorders (Oxford University Press, 2011). source

      Not checked in the free run.

    • cites [15] Lord, C. & Bishop, S. L. Recent advances in autism research as reflected in DSM-5 criteria for autism spectrum disorder. Annu. Rev. Clin. Psychol. 11, 53–70 (2015). source

      Not checked in the free run.

    • cites [16] Lamm, C., Bukowski, H. & Silani, G. From shared to distinct self–other representations in empathy: evidence from neurotypical function and socio-cognitive disorders. Philos. Trans. R. Soc. Lond. B Biol. Sci. 371, 20150083 (2016). source

      Not checked in the free run.

    • cites [17] Steinbeis, N. The role of self–other distinction in understanding others’ mental and emotional states: neurocognitive mechanisms in children and adults. Philos. Trans. R. Soc. Lond. B Biol. Sci. 371, 20150074 (2016). source

      Not checked in the free run.

    • cites [18] Uddin, L. Q. et al. Neural basis of self and other representation in autism: an fMRI study of self-face recognition. PLoS ONE 3, e3526 (2008). source

      Not checked in the free run.

    • cites [19] Senju, A. Spontaneous theory of mind and its absence in autism spectrum disorders. Neuroscientist 18, 108–113 (2012). source

      Not checked in the free run.

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

    Premisecitation

    Individuals with ASD may have heightened sensitivity and preoccupation with self.

    “They may also have heightened sensitivity and preoccupation with self 45,46.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [45] Orefice, L. L. et al. Peripheral mechanosensory neuron dysfunction underlies tactile and behavioral deficits in mouse models of ASDs. Cell 166, 299–313 (2016). source

      Not checked in the free run.

    • cites [46] Duerden, E. G. et al. Self-injurious behaviours are associated with alterations in the somatosensory system in children with autism spectrum disorder. Brain Struct. Funct. 219, 1251–1261 (2014). source

      Not checked in the free run.

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

    Premisecitation

    ASD is known to involve other cortical-subcortical circuits.

    “ASD is known to involve other cortical-subcortical circuits 27,36”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [27] Stoodley, C. J. et al. Altered cerebellar connectivity in autism and cerebellar-mediated rescue of autism-related behaviors in mice. Nat. Neurosci. 20, 1744–1751 (2017). source

      Not checked in the free run.

    • cites [36] Stone, V. E., Baron-Cohen, S. & Knight, R. T. Frontal lobe contributions to theory of mind. J. Cogn. Neurosci. 10, 640–656 (1998). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    The current study's findings in a mouse model of ASD provide a prospective cellular substrate for the observations that individuals with ASD have difficulty organizing social information or interpreting others' states and may have heightened self-sensitivity.

    “The current study’s findings in a mouse model of ASD provide a prospective cellular substrate for these observations.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The Shank3-mutant mice used here constitute a mouse model of ASD.

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

    Premisecitation

    Various neurophysiological features such as cortical volume and connectivity are also altered in ASD.

    “various neurophysiological features such as cortical volume 35,47 and connectivity 27 are also altered in ASD.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [35] Zielinski, B. A. et al. Longitudinal changes in cortical thickness in autism and typical development. Brain 137, 1799–1812 (2014). source

      Not checked in the free run.

    • cites [47] Libero, L. E., DeRamus, T. P., Deshpande, H. D. & Kana, R. K. Surface-based morphometry of the cortical architecture of autism spectrum disorders: volume, thickness, area, and gyrification. Neuropsychologia 62, 1–10 (2014). source

      Not checked in the free run.

    • cites [27] Stoodley, C. J. et al. Altered cerebellar connectivity in autism and cerebellar-mediated rescue of autism-related behaviors in mice. Nat. Neurosci. 20, 1744–1751 (2017). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    The mice were age- and sex-matched for control.

    “They were also age- and sex-matched for control.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    Animals were randomly assigned to the various experiments.

    “Animals were randomly assigned to the various experiments”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    The locations of implantations were confirmed by histology.

    “The locations of implantations were confirmed by histology as described previously 52.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [52] Shapiro, R. M., Badalamenti, J. I. & Glick, S. D. A simple and rapid technique for preparing histological sections of brain. Pharmacol. Biochem. Behav. 19, 1049–1050 (1983). source

      Not checked in the free run.

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

    Study design and conductnone given

    Electrolytic lesions were used to confirm localization of the areas recorded from.

    “Electrolytic lesions were used to confirm localization of the areas recorded from”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    For control comparison, TMX was given to both the Shank3fx/+:CreER+/− and Shank3fx/+:CreER−/− mice.

    “For control comparison, TMX was given to both the Shank3fx/+:CreER+/− and Shank3fx/+:CreER−/− mice.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Animal models of social behavior, including the mice used here, do not fully recapitulate the complexity and natural process in which humans interact, or capture the wide spectrum of behavioral phenotypes that are affected by ASD.

    “animal models of social behavior, including the mice used here, do not fully recapitulate the complexity and natural process in which humans interact, or capture the wide spectrum of behavioral phenotypes that are affected by ASD 14,48,49.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [14] Amaral, D., Dawson, G. & Geschwind, D. H. Autism Spectrum Disorders (Oxford University Press, 2011). source

      Not checked in the free run.

    • cites [48] Sukhodolsky, D. G., Bloch, M. H., Panza, K. E. & Reichow, B. Cognitive-behavioral therapy for anxiety in children with high-functioning autism: a meta-analysis. Pediatrics 132, e1341–e1350 (2013). source

      Not checked in the free run.

    • cites [49] Harrington, J. W. & Allen, K. The clinician’s guide to autism. Pediatr. Rev. 35, 62–78 (2014). source

      Not checked in the free run.

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

    Study design and conductnone given

    To further confirm antibody selectivity, in a separate control, the rabbit anti-Shank3 primary antibody was combined with SH3 protein prior to incubation.

    “To further confirm antibody selectivity, in a separate control, we combined the rabbit anti-Shank3 primary antibody with SH3 protein prior to incubation.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    Fluorescent dye injection was used to confirm cannula localization.

    “whereas fluorescent dye injection was used to confirm cannula localization.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    All of the main comparisons in our study were made between littermates.

    “All of the main comparisons in our study were made between littermates.”
    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

    All procedures were approved by the Massachusetts General Hospital IACUC and kept in strict accordance with the Harvard Medical School Institutional Animal Care and Use Committee guidelines.

    “All procedures were approved by the Massachusetts General Hospital IACUC and kept in strict accordance with the Harvard Medical School Institutional Animal Care and Use Committee guidelines.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    For the main tasks, no subjects were excluded from the analyses.

    “for the main tasks, no subjects were excluded from the analyses.”
    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 conductnone given

    Females were only used for breeding purposes and were not used for behavioral testing or recordings.

    “females were only used in our study for breeding purposes and were not used for behavioral testing or recordings.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductnone given

    The task conditions were counterbalanced so that an equal number of self- and other- trials as well as an equal number of appetitive- and aversive- conditions were performed and the conditions were given in pseudo-random fashion.

    “The task conditions were therefore counterbalanced so that an equal number of self- and other- trials as well as an equal number of appetitive- and aversive- conditions were performed and the conditions were given in pseudo-random fashion.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    No multiunit activity was used.

    “No multiunit activity was used.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    For additional cross-validation, a blinded tester visually inspected each trial and corrected any discrepancies in the automated parameters.

    “For additional cross-validation, a blinded tester visually inspected each trial (as recorded by the digital camera), and corrected any discrepancies in the above automated parameters using custom-written scripts in MATLAB (Mathworks).”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    This operation was repeated 1000 times using a random sampling of the total trials.

    “This operation was repeated 1000 times using a random sampling of the total trials.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    RR data were excluded for trials where animals failed to investigate one of the two enclosures more than 10s.

    “We excluded RR data for trials where animals failed to investigate one of the two enclosures more than 10s.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    A bootstrapping procedure was used to determine whether the neuron could discriminate between conditions at an accuracy that was greater than chance.

    “A bootstrapping procedure was then used to determine whether the neuron could discriminate between conditions at an accuracy that was greater than chance.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    To determine whether the animals perceived the other's experience rather than simply the appetitive or aversive stimuli themselves, control trials were included in which the two conspecifics were replaced with inanimate totems that were "experiencing" the same appetitive or aversive conditions.

    “To determine whether the animals perceived the other’s experience rather than simply the appetitive or aversive stimuli themselves, we also included control trials in which the two conspecifics were replaced with inanimate totems that were “experiencing” the same appetitive (food-bated) or aversive (confined tube) conditions.”
    Quote in the paperSubstantial claim

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

    Study design and conductreasoning

    In order to control for possible location bias by the test subjects, the location of the animals undergoing the appetitive or aversive experiences were counter-balanced across the opposite areas.

    “In order to control for possible location bias by the test subjects, the location of the animals undergoing the appetitive or aversive experiences were counter-balanced across the opposite areas.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    Contaminated samples were excluded.

    “Contaminated samples were excluded.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    For validation, the neuronal data were divided into a training set consisting of 80% of the trials and tested the accuracy of the prediction on the remaining 20% of trials for validation.

    “For validation, we divided the neuronal data into a training set consisting of 80% of the trials and tested the accuracy of the prediction on the remaining 20% of trials for validation.”
    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

    Trials in which tracked mice did not leave the starting, central chamber or trials in which tracked mice were immobile in any particular chamber for greater than 50% of the recorded time were excluded.

    “Trials in which tracked mice did not leave the starting, central chamber or trials in which tracked mice were immobile in any particular chamber for greater than 50% of the recorded time were excluded.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Significance was set at p < 0.0125 for the primary reported findings.

    “Significance was set at p < 0.0125 for the primary reported findings.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    We evaluated for motoric differences in the recorded animals that could potentially contribute to neuronal response.

    “We evaluated for motoric differences in the recorded animals that could potentially contribute to neuronal response.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductnone given

    Putative neurons were required to separate clearly from channel noise, demonstrate waveform morphology consistent with a cortical neuron, and have at least 99% of spikes separated by a minimum refractory inter-spike interval of 1 ms.

    “Putative neurons were required to separate clearly from any channel noise, to demonstrate waveform morphology consistent with that of a cortical neuron, and to have at least 99% of spikes separated by a minimum refractory inter-spike interval of 1 ms.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Each animal's position within their enclosure, movement velocity and head-direction were determined in an automated, genotype-blinded manner using Ethovision XT.

    “Each animal’s position within their enclosure, movement velocity and head-direction were determined in an automated, genotype-blinded manner using Ethovision XT (Noldus).”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    Several controls were performed to evaluate for other sensory-related aspects of the task.

    “Several controls were performed to evaluate for other sensory-related aspects of the task.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    All injections were verified histologically by injecting 100nL DiI through 9mm 30 gauge internal cannulae.

    “All injections were verified histologically by injecting 100nL DiI through 9mm 30 gauge internal cannulae.”
    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 conductnone given

    Only littermates were used for comparisons and all were male mice.

    “Only littermates were used for comparisons and all were male mice.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Support vector machines with nonlinear kernels are well-suited for identifying neuronal subspaces in relation to specific task features and account for potential nonlinearities in the response properties of the neurons.

    “As described previously 62–64, these approaches are well-suited for identifying neuronal ‘subspaces’ in relation to specific task features and account for potential nonlinearities in the response properties of the neurons.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [62] Wasserman, L. All of Statistics: A Concise Course in Statistical Inference (Springer Texts, 2005). source

      Not checked in the free run.

    • cites [63] Shanechi, M. M. et al. Neural population partitioning and a concurrent brain–machine interface for sequential motor function. Nat. Neurosci. 15, 1715–1722 (2012). source

      Not checked in the free run.

    • cites [64] McCullagh, P., Nelder, J. A. Generalized Linear Models (Chapman & Hall, 1989). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductown data

    Microelectrode recording locations were in the medial prefrontal cortex (mPFC).

    “Displayed left is a histological section with bilateral electrolytic lesions indicating the microelectrode recording locations from the medial prefrontal cortex (mPFC).”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    An FDA correction was used to account for repeated comparison across conditions (experience valence, social agency and identity; p < 0.0125).

    “As before, we used an FDA correction to account for repeated comparison across conditions (i.e, experience valence, social agency and identity; p < 0.0125).”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    Both statistical approaches (ANOVA and linear decoding) were associated with a similar proportion of neurons that responded to self- and other-experience.

    “Overall, both statistical approaches were associated with a similar proportion of neurons that responded to self- and other-experience.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    All data collection and analyses were performed blind to animal genotype (WT vs HET), gavage (TMX vs corn oil), and injection (saline vs endoxifen; saline vs muscimol).

    “All data collection and analyses were performed blind to animal genotype (WT vs HET), gavage (TMX vs corn oil); injection (saline vs endoxifen; saline vs muscimol).”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    No statistical method was used to predetermine sample size.

    “No statistical method was used to predetermine sample size.”
    Quote in the paperNot a substantial claim
84 of 84

  • The paper relies on this without support.

    The Shank3-mutant mice used here constitute a mouse model of ASD.

    “The current study’s findings in a mouse model of ASD provide a prospective cellular substrate for these observations.”

  • The paper relies on this without support.

    The appetitive and aversive stimuli used (food reward and narrow tube enclosure) are clearly apparent and salient to the recorded mouse.

    “Here, we selected these stimuli because the other’s experiences needed to be clearly apparent and salient to the recorded mouse.”

  • The authors state this as an assumption.

    The data distribution was assumed to be normal, but this was not formally tested.

    “The data distribution was assumed to be normal, but this was not formally tested.”
3 of 3

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?

  • Restoration of Shank3 expression in the mPFC rescued sociability deficits in Shank3 deletion mice.

    “restoration of Shank3 expression in the mPFC rescued sociability deficits in Shank3 deletion mice [128].”

    From Neural circuits regulating prosocial behaviors (2023) · cites this paper as [128]

Statistics that don’t add up

Each reported p-value recomputed from its test statistic and degrees of freedom.

  • Inconsistent p-value: χ2(1) = 0.29, p = .86

    Minor

    The paper reports p = .86 here; recomputing from the test statistic and its degrees of freedom gives p = .590. The check cannot tell whether the statistic or the p-value is the misprint.

    Reported p = .86 · recomputed p = .590

1 of 1

Statistics recomputed

Every reported test result, recomputed from its test statistic and degrees of freedom. A result shows as not adding up only once an independent check has confirmed it.

  • Doesn’t add upχ²(1) = 0.29reported p = .86 · recomputed p = .590

    “χ2(1) = 0.29, p = .86”

  • Consistentχ²(1) = 62.1reported p < 1 · recomputed p < .001

    “χ2(1) = 62.1, p < 1.0”

  • Consistentχ²(1) = 7.1reported p = .0075 · recomputed p = .008

    “χ2(1) = 7.1, p = .0075”

  • Consistentχ²(1) = 6reported p = .014 · recomputed p = .014

    “χ2(1) = 6.0, p = .014”

  • Consistentχ²(1) = 24.9reported p < 1 · recomputed p < .001

    “χ2(1) = 24.9, p < 1.0”

  • Consistentt(15) = 1.1reported p = .29 · recomputed p = .289

    “t(15) = 1.10, p = .29”

  • Consistentχ²(1) = 0.095reported p = .76 · recomputed p = .758

    “χ2 (1) = 0.095, p = .76”

  • Consistentχ²(1) = 0.3reported p = .58 · recomputed p = .584

    “χ2 (1) = 0.30, p = .58”

  • Consistentχ²(1) = 0.25reported p = .61 · recomputed p = .617

    “χ2(1) = 0.25, p = .61”

  • Consistentχ²(1) = 0.34reported p = .56 · recomputed p = .560

    “χ2(1) = 0.34, p = .56”

  • Consistentt(15) = -1.4reported p = .18 · recomputed p = .182

    “t(15) = −1.40, p = .18”

  • Consistentχ²(1) = 4.11reported p = .043 · recomputed p = .043

    “χ2(1) =4.11, p = .043”

  • Consistentχ²(3) = 3.5reported p = .33 · recomputed p = .321

    “χ2(3) = 3.5, p = .33”

13 of 13

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.

  • WT and HET firing-rate errors are swapped

    Minor

    The Results and Methods give the same WT and HET mean firing rates but assign their ± values to opposite groups.

  • Other-experience percentage does not match its count

    Minor

    The reported 33 of 112 neurons is 29.5% to one decimal place, not 30.0%.

    Reported 30 · recomputed 29.464286

2 of 2

Cites

Flagged first, then by citations

Cited by

Sorted by citations

Related

Authors
Lee, D. K., Li, S. W., Bounni, F., Friedman, G., Jamali, M., Strahs, L., Zeliger, O., Gabrieli, P., Stankovich, M. A., Demaree, J., & Williams, Z. M.
Affiliations
  • Harvard University (US)
  • Boston University (US)
  • Northeastern University (US)
Corresponding author
Williams, Ziv M.
ORCID
Venue
Nature Neuroscience
Publisher
Springer Science and Business Media LLC
Published
2021-07-12
Volume
24
Issue
9
Pages
1243-1255
ISSN
  • 1097-6256 (ISSN-L)
  • 1546-1726
DOI
10.1038/s41593-021-00888-4
PMC
PMC8410666
OpenAlex
W3179442887
Semantic Scholar
4103afb529b8c615f34d58f42e2080b69e629be8
Cited by
33
References
67
Citations by year
2026: 4 · 2025: 7 · 2024: 1 · 2023: 7 · 2022: 10 · 2021: 4
FWCI
3.11
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Neuroscience (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Howard Hughes Medical Institute
  • National Institute of Mental Health (R01MH112846)
  • National Institute of Neurological Disorders and Stroke (R01NS091390, UE5NS065743)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD059852)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
SHANK3, autism spectrum disorder, social agency, medial prefrontal cortex, sociability, self-other distinction, gene re-expression, adult neurogenesis, social behavior
MeSH terms
Autism Spectrum Disorder, Animals, Male, Mice, Inbred C57BL, Microfilament Proteins, Nerve Tissue Proteins, Neurons, Social Behavior, Prefrontal Cortex, Mice

About these checks

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

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

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

Statistics and arithmetic are recomputed, not judged.

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

What counts as a claim ›How we measure confidence ›How we check this ›

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