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Cited by 142Neuroendocrine regulation and behaviorOlfactory and Sensory Function StudiesNeuropeptides and Animal Physiology

Social stimuli induce activation of oxytocin neurons within the paraventricular nucleus of the hypothalamus to promote social behavior in male mice

Open access
Resendez, Shanna L., Namboodiri, Vijay Mohan K., Otis, James M., Eckman, Louisa E.H., Rodriguez-Romaguera, Jose, Ung, Randall L., Basiri, Marcus L., Kosyk, Oksana +3 more·2020·The Journal of Neuroscience
DOI 10.1523/jneurosci.1515-18.2020PMC PMC7083279
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Abstract

Oxytocin (OT) is critical for the expression of social behavior across a wide array of species; however, the role of this system in the encoding of socially relevant information is not well understood. In the present study, we show that chemogenetic activation of OT neurons within the paraventricular nucleus of the hypothalamus (PVH) of male mice (OT-Ires-Cre) enhanced social investigation during a social choice test, while chemogenetic inhibition of these neurons abolished typical social preferences. These data suggest that activation of the OT system is necessary to direct behavior preferentially toward social stimuli. To determine whether the presence of a social stimulus is sufficient to induce activation of PVH-OT neurons, we performed the first definitive recording of OT neurons in awake mice using two-photon calcium imaging. These recordings demonstrate that social stimuli activate PVH-OT neurons and that these neurons differentially encode social and nonsocial stimuli, suggesting that PVH-OT neurons may act to convey social salience of environmental stimuli. Finally, an attenuation of social salience is associated with social disorders, such as autism. We therefore also examined possible OT system dysfunction in a mouse model of autism, Shank3b knock-out (KO) mice. Male Shank3b KO mice showed a marked reduction in PVH-OT neuron number and administration of an OT receptor agonist improved social deficits. Overall, these data suggest that the presence of a social stimulus induces activation of the PVH-OT neurons to promote adaptive social behavior responses. SIGNIFICANCE STATEMENT Although the oxytocin (OT) system is well known to regulate a diverse array of social behaviors, the mechanism in which OT acts to promote the appropriate social response is poorly understood. One hypothesis is that the presence of social conspecifics activates the OT system to generate an adaptive social response. Here, we selectively recorded from OT neurons in the paraventricular hypothalamic nucleus (PVH) to show that social stimulus exposure indeed induces activation of the OT system. We also show that activation of the OT system is necessary to promote social behavior and that mice with abnormal social behavior have reduced numbers of PVH-OT neurons. Finally, aberrant social behavior in these mice was rescued by administration of an OT receptor agonist.

AI snapshot

Written from the paper’s full text.

TL;DR

Chemogenetic activation of PVH oxytocin neurons enhanced social investigation, while inhibition abolished social preference in male mice. Awake two-photon calcium imaging showed social stimuli activate PVH-OT neurons more than nonsocial stimuli, and Shank3b KO mice had fewer medial PVH OT neurons with social deficits rescued by an OT receptor agonist.

Key findings

  • Chemogenetic Gq activation of PVH-OT neurons increased time investigating the social zone versus saline (Tukey’s post hoc, p = 0.04, n = 6); Gi-mediated inhibition abolished social preference (CNO vs nonsocial, p = 0.63, n = 7), whereas saline produced robust social preference (p < 0.0001, n = 7).
  • In awake head-fixed mice, social stimulus presentation increased PVH-OT neuron activity compared with nonsocial stimulus (Wilcoxon signed-rank, W(102) = 1556, p = 0.0004); 52% of recorded neurons increased activity to social versus 32% to nonsocial, and nonsocial stimulus produced more decreases (52%) than social (35%) (102 neurons, n = 8 mice). Social exposure increased event rate (two-way ANOVA, p = 0.0003; Stim vs Pre p < 0.0001) but not event amplitude or duration.
  • Sucrose consumption did not increase PVH-OT activity: day 1, 89% of neurons were unresponsive and 11% decreased; day 2, 96% no response, 3% negative, 1% positive (105 neurons, n = 3 mice).
  • Shank3b KO mice showed reduced OT neurons in the medial PVH (two-way ANOVA, F(2,85) = 53.87, p < 0.0001; vs WT p = 0.0004; vs heterozygous p = 0.005), and the OT receptor agonist Way267464 at 10 mg/kg (p = 0.01) or 30 mg/kg (p = 0.03) restored social preference in KO mice (n = 7/group).

Methods

  • Adult male OT-Ires-Cre mice received bilateral PVH injections of Cre-inducible hM3Dq or hM4Di DREADDs; social behavior was tested in a 3-chamber social choice task with CNO (1 mg/kg i.p.) or saline 45 min before testing, with Cre-negative littermate controls.
  • For in vivo imaging, GCaMP6s was expressed in PVH-OT neurons, a GRIN lens was implanted above the PVH, and two-photon calcium imaging was performed in awake, head-fixed mice during 5 min social (anesthetized juvenile) or nonsocial (plastic bottle) stimulus exposure flanked by 5 min baselines; sucrose was delivered randomly (100 trials/session). Patch-clamp recordings validated GCaMP6s fluorescence against action potential firing.
  • Shank3b KO, heterozygous, and WT littermates were used for OT immunofluorescence cell counts in rostral, medial, and caudal PVH and for behavioral pharmacology with Way267464 (10 or 30 mg/kg i.p.) 30 min before the 3-chamber social choice test. Statistical significance used t tests or two-way ANOVA with α = 0.05.

Limitations

  • Stated: the head-fixed imaging setup prevents the test subject from following and engaging with a freely moving social conspecific, so an anesthetized social stimulus was used; the paper notes this stimulus is sufficient to provoke social engagement but may not be the most potent.
  • Evident from the text: all test subjects were male, so findings may not generalize to females.
  • Evident from the text: some experiments rely on small samples, including imaging (n = 8 mice, 102 neurons), sucrose (n = 3 mice, 105 neurons), and Shank3b OT cell counts (4–5 mice/group and 1–3 sections per subject).

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

Integrity signals

Registry

Crossref · 10.1523/jneurosci.1515-18.2020

Cites

80 of 80 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 54 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Male Shank3b KO mice showed a marked reduction in PVH-OT neuron number.

    “Male Shank3b KO mice showed a marked reduction in PVH-OT neuron number”
    • Also stated in: § Significance Statement · plain
      “we identified that a mouse model of ASD (Shank3b KO mice) has reduced numbers of PVH-OT neurons.”
    Quote in the paperSubstantial claim
  • Findingown data

    Saline administration before the social choice test resulted in robust preferences for social stimulus investigation in mice with Gi-DREADD in PVH-OT neurons.

    “In contrast, saline administration before the social choice test resulted in robust preferences for social stimulus investigation (Tukey's post hoc test, p Ͻ 0.0001, n ϭ 7).”
    Quote in the paperSubstantial claim
  • Findingown data

    Adult male mice prefer to investigate an anesthetized juvenile stimulus compared with a nonsocial stimulus.

    “Behavioral studies confirmed that, similar to an awake juvenile stimulus, adult male mice prefer to investigate an anesthetized juvenile stimulus compared with a nonsocial stimulus (t test, t (7) ϭ 6.78, p ϭ 0.0003, n ϭ 8 mice) (Fig. 3 D, E).”
    Quote in the paperSubstantial claim
  • Findingown data

    Social stimuli activate PVH-OT neurons.

    “These recordings demonstrate that social stimuli activate PVH-OT neurons”
    • Also stated in: § Significance Statement · boosted
      “Here, we selectively recorded from OT neurons in the paraventricular hypothalamic nucleus (PVH) to show that social stimulus exposure indeed induces activation of the OT system.”
    Quote in the paperSubstantial claim
  • Findingown data

    PVH-OT neurons differentially encode social and nonsocial stimuli.

    “and that these neurons differentially encode social and nonsocial stimuli”
    • Also stated in: § Significance Statement · plain
      “These data reveal that conspecific animal presentation increases the activity of OT neurons and that OT neurons were more robustly activated in response to socially rewarding stimuli compared with a nonsocial, appetitive stimulus.”
    Quote in the paperSubstantial claim
  • May combine two claims. 47
  • Classified as probably not a substantial claim. 26

  • May combine two claims.

    Findingown data

    52% of recorded PVH-OT neurons showed an increase in activity in response to the social stimulus, while only 32% showed an increase in response to the nonsocial stimulus.

    “with 52% of recorded neurons showing an increase in activity in response to the social stimulus and only 32% of neurons showing an increase in activity in response to the nonsocial stimulus (Fig. 3I )”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Administration of CNO did not alter the total distance traveled or velocity.

    “Finally, administration of CNO did not alter the total distance traveled (Gq-DREADD: t test, t (5) ϭ 0.87, p ϭ 0.42; Gi-DREADD, t test, t (6) ϭ 0.18, p ϭ 0.99) (Fig. 1C,D) or velocity (Gq-DREADD, t test, t (5) ϭ 0.67, p ϭ 0.45, Gi-DREADD, t test, t (6) ϭ 0.10, p ϭ 0.93)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Among high-power PVH-OT neurons that exhibited a positive response to the social stimulus, 72% also responded positively to the nonsocial stimulus, 17% exhibited a decrease in activity, and 11% did not show a change in activity to the nonsocial stimulus.

    “For high-power neurons that exhibited a positive response to the social stimulus, 72% of these neurons also responded positively to the nonsocial stimulus, 17% of neurons exhibited a decrease in activity, and 11% of neurons did not show a change in activity to the nonsocial stimulus (Fig. 6B).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Classification of PVH-OT neurons by mean power during the 5 min baseline period resulted in 67 of 102 neurons (66%) classified as low powered and 35 (34%) as high powered.

    “This resulted in 67 of 102 neurons to be classified as low powered (66%) and 35 to be classified as high powered (34%).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    For PVH-OT neurons that responded negatively to the social stimulus, 22% exhibited a positive response to the nonsocial stimulus, 61% exhibited a negative response, and 17% exhibited no response.

    “For neurons that responded negatively the social stimulus, 22% of these neurons exhibited a positive response the nonsocial stimulus, 61% exhibited a negative response, and 17% exhibited no response.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Shank3b KO mice have fewer OT neurons within the PVH and treatment with OT rescues social deficits in these mice.

    “Importantly, deficits in social attention are thought to contribute to the etiology of autism (Ozonoff et al., 2010) and we show that Shank3b KO mice have fewer OT neurons within the PVH and that treatment with OT rescues social deficits in these mice.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    For PVH-OT neurons that did not respond to the social stimulus, 69% exhibited a negative response to the nonsocial stimulus and 31% showed no response to the nonsocial stimulus.

    “Finally, for neurons that did not respond to the social stimulus, 69% of these neurons exhibited a negative response to the nonsocial stimulus and 31% showed no response to the nonsocial stimulus.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    For low-power PVH-OT neurons that exhibited a decrease in activity to the social stimulus, 21% increased activity in response to the nonsocial stimulus, 67% decreased activity in response to the nonsocial stimulus, and 12% did not respond to the nonsocial stimulus.

    “For low-power PVH-OT neurons that exhibited a decrease in activity to the social stimulus, 21% of these neurons increased activity in response to the nonsocial stimulus, 67% decreased activity in response to the nonsocial stimulus, and 12% of neurons did not respond to the nonsocial stimulus (Fig. 6C).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Low-power PVH-OT neurons responded primarily with increases in activity to the social stimulus and decreases in activity to the nonsocial stimulus.

    “In general, low-power PVH-OT neurons responded primarily with increases in activity to the social stimulus and decreases in activity to the nonsocial stimulus (Wilcoxon signed-rank t test, t (67) ϭ 490, p ϭ 0.00005) (Fig. 5C,D)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Among low-power PVH-OT neurons that exhibited a positive response to the social stimulus, 34% also exhibited a positive response to the nonsocial stimulus, 54% exhibited a negative response, and 12% did not show a change in activity.

    “Among OT-PVH neurons classified as low power and that exhibited a positive response to the social stimulus, 34% of these neurons also exhibited a positive response to the nonsocial stimulus, while 54% of these neurons exhibited a negative response and 12% did not show a change in activity (Fig. 6A).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Acute administration of an OT receptor agonist did not impact locomotor behavior or the duration of time spent in any compartment of the chamber that did not directly include interaction zones.

    “In addition, acute administration of an OT receptor agonist did not impact locomotor behavior (Fig. 9G-L) or the duration of time spent in any compartment of the chamber that did not directly include interaction zones (WT: two-way ANOVA, F (2,21) ϭ 1.51, p ϭ 0.25; heterozygous: two-way ANOVA, F (2,24) ϭ 0.65, p ϭ 0.53; homozygous: two-way ANOVA, F (2,18) ϭ 0.93, p ϭ 0.41.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Of PVH-OT neurons that showed a positive response to the social stimulus, 47% also responded positively to the nonsocial stimulus, 42% showed a negative response to the nonsocial stimulus, and 11% did not respond to the nonsocial stimulus.

    “Of the neurons that showed a positive response to the social stimulus, 47% of these neurons also responded positively to the nonsocial stimulus, 42% showed a negative response to the nonsocial stimulus, and 11% did not respond to the nonsocial stimulus (Fig. 4A).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Consumption of randomly administered sucrose did not result in increases in PVH-OT neuron activity; 89% of neurons were unresponsive and 11% showed decreases in their activity.

    “Unlike exposure to a social stimulus, consumption of randomly administered sucrose (100 trials/session) did not result in increases in PVH-OT neuron activity as 89% of neurons were unresponsive and 11% of neurons showed decreases in their activity (data from 105 neurons recorded from n ϭ 3 mice) (Fig. 7 A, C).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The reduction in OT neurons in Shank3b-/- mice was specific to the medial PVH; reductions were not identified within the rostral or caudal PVH.

    “This reduction was specific to the medial PVH, where the density of OT neurons is the highest.Reductions were not identified within the rostral (WT vs Shank3b Ϫ / Ϫ : p ϭ 0.96, Shank3b Ϫ / Ϫ vs Shank3b ϩ/ Ϫ : p ϭ 0.46) or caudal PVH (WT vs Shank3b Ϫ / Ϫ : p ϭ 0.72, Shank3b Ϫ / Ϫ vs Shank3b ϩ/ Ϫ : p ϭ 0.32) (Fig. 8D).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    When given the choice between an anesthetized juvenile stimulus or an empty behavioral chamber, test subjects preferred interacting with the anesthetized social stimulus over the empty chamber, similar to behavioral results with an awake stimulus.

    “Our behavioral studies indicated that when given the choice between an anesthetized juvenile stimulus or an empty behavioral chamber, test subjects preferred interacting with the anesthetized social stimulus over the empty chamber, similar to behavioral results with an awake stimulus.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingreasoning

    The increase in PVH-OT neuron activity to social stimulus was moderate, yet significant, and was sustained over the duration of the trial, which is consistent with the activity of OT neurons under conditions that do not induce burst firing.

    “This increase in activity was moderate, yet significant, and was sustained over the duration of the trial, which is consistent with the activity of OT neurons under conditions that do not induce burst firing.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Among high-power PVH-OT neurons that showed a positive response to the social stimulus, 72% also showed a positive response to the nonsocial stimulus, 17% decreased their activity to the nonsocial stimulus, and 11% showed no response.

    “In contrast, 72% of high-power neurons that showed a positive response to the social stimulus also showed a positive response to the nonsocial stimulus.Seventeen percent of these neurons decreased their activity to the nonsocial stimulus and 11% showed no response.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Among PVH-OT neurons that showed a negative response to the social stimulus, 22% showed an increase in activity to the nonsocial stimulus, 61% exhibited a decrease in activity to the nonsocial stimulus, and 17% did not change their activity.

    “For neurons that showed a negative response to the social stimulus, 22% of these neurons showed an increase an activity to the nonsocial stimulus, 61% exhibited a decrease in activity to the nonsocial stimulus, and 17% of these neurons did not change their activity.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Among high-power PVH-OT neurons that decreased their activity to the social stimulus, 25% showed an increase in activity to the nonsocial stimulus, 50% decreased their activity, and 25% showed no change in activity.

    “For high-powered neurons that decreased their activity to the social stimulus, 25% of these neurons showed an increase in activity to the nonsocial stimulus, 50% decreased their activity, and 25% showed no change in activity.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Among low-power PVH-OT neurons that decreased activity to the nonsocial stimulus, 21% also decreased activity to the nonsocial stimulus, 67% increased their activity, and 12% exhibited no response.

    “For low-powered neurons that decreased activity to the nonsocial stimulus, 21% also decreased activity to the nonsocial stimulus, while 67% increased their activity and 12% exhibited no response.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Activation of PVH-OT neurons facilitates social behavior and promotes social orienting.

    “Activation of PVH-OT neurons facilitates social behavior and promotes social orienting.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Among high-power PVH-OT neurons that did not exhibit a change in activity to the social stimulus, 80% decreased activity to the nonsocial stimulus and 20% did not show a change in activity; none increased their activity.

    “that did not exhibit a change in activity to the social stimulus, 80% decreased activity to the nonsocial stimulus and 20% did not show a change in activity.None of these neurons increased their activity.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Among low-power PVH-OT neurons that responded with an increase in activity to the social stimulus, 34% also responded with an increase in activity to the nonsocial stimulus, 54% decreased their activity, and 12% exhibited no change in activity.

    “For low-powered power neurons that responded with an increase in activity to the social stimulus, 34% of these neurons also responded with an increase in activity to the nonsocial stimulus, while 54% decreased their activity and 12% exhibited no change in activity.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Among PVH-OT neurons that did not change their activity upon presentation of the social stimulus, 69% decreased their activity to the nonsocial stimulus and 31% did not have a change in activity; none responded with an increase in activity to the nonsocial stimulus.

    “For neurons that did not change their activity upon presentation of the social stimulus, 69% of these neurons decreased their activity to the nonsocial stimulus and 31% did not have a change inactivity.None of these neurons responded with an increase in activity to the nonsocial stimulus.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Among low-power PVH-OT neurons that did not respond to the social stimulus, 63% decreased their activity to the nonsocial stimulus; none responded with an increase in activity.

    “For low-powered neurons that did not respond to the social stimulus, 63% decreased their activity to the nonsocial stimulus.None of these neurons responded with an increase in activity.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Among PVH-OT neurons that responded with an increase in activity to the social stimulus, 47% also showed an increase in activity to the nonsocial stimulus, 42% showed a decrease in activity, and 11% showed no change in activity.

    “For neurons that responded with an increase in activity to the social stimulus, 47% of these neurons also showed an increase in activity to the nonsocial stimulus, 42% showed a decrease in inactivity, and 11% showed no change in activity.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    The pervasive influence of the OT system extends to social contexts of both positive and negative valence and may play a critical role in the regulation of processes fundamental to the expression of all social behaviors.

    “The pervasive influence of the OT system extends to social contexts of both positive and negative valence and may play a critical role in the regulation of processes that are fundamental to the expression of all social behaviors (Choe et al., 2015;Nardou et al., 2019).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Choe et al., 2015

      Not checked in the free run.

    • cites Nardou et al., 2019

      Not checked in the free run.

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

    Premisecitation

    Doses and time points for Way267464 were chosen based on previous studies demonstrating behavioral effects in mice.

    “These doses and time points were chosen based on previous studies demonstrating behavioral effects in mice (Ring et al., 2010;Olszewski et al., 2014).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Ring et al., 2010

      Not checked in the free run.

    • cites Olszewski et al., 2014

      Not checked in the free run.

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

    Study design and conductnone given

    The p values were corrected for multiple comparisons across neurons using the Benjamini-Hochberg false discovery rate correction.

    “The p values were corrected for multiple comparisons across neurons using the Benjamini-Hochberg false discovery rate correction.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    The effect of CNO was specific to social function and not a result of alterations in locomotor activity.

    “indicating that the effect of CNO was specific to social function and not a result of alterations in locomotor activity.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    OT is a neuropeptide that plays a broad role in modulating the social repertoire of species across the animal kingdom.

    “Oxytocin (OT) is a neuropeptide that plays a broad role in modulating the social repertoire of species across the animal kingdom (Insel, 1992;Donaldson and Young, 2008;Neumann, 2008;Bales and Perkeybile, 2012;Carter, 2014;Tabbaa et al., 2016).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Insel, 1992

      Not checked in the free run.

    • cites Donaldson and Young, 2008

      Not checked in the free run.

    • cites Neumann, 2008

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Impairments in social attention have been considered one of the core deficits in autism spectrum disorders (ASD).

    “Finally, impairments in social attention have been considered to be one of the core deficits in autism spectrum disorders (ASD) (Chevallier et al., 2012)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Chevallier et al., 2012

      Not checked in the free run.

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

    Premisecitation

    The capacity to detect and interpret social cues is fundamental to the expression of adaptive social behaviors that are critical for species survival.

    “The capacity to detect and interpret social cues is fundamental to the expression of adaptive social behaviors that are critical for species survival (Bachner-Melman and Ebstein, 2014).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Bachner-Melman and Ebstein, 2014

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

    Study design and conductcitation

    All behavioral sessions were counterbalanced.

    “All behavioral sessions were counterbalanced (Crawley, 2008;Silverman et al., 2010).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Crawley, 2008

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    • cites Silverman et al., 2010

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

    Premisecitation

    The OT system has been associated with social recognition, social learning and memory, social reward, and attachment formation.

    “To date, the OT system has been associated with social recognition (Oettl et al., 2016), social learning and memory (Ferguson et al., 2001;Choe et al., 2015), social reward (Do ¨len et al., 2013;Young et al., 2014), attachment formation (Insel, 1992;Wang and Aragona, 2004;Young and Wang, 2004)”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Oettl et al., 2016

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    • cites Ferguson et al., 2001

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    • cites Do ¨len et al., 2013

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

    Premisecitation

    Previous in vivo recordings from putative PVH-OT neurons have indicated that these neurons display a heterogeneous pattern of firing activity.

    “In addition, previous in vivo recordings from putative PVH-OT neurons have indicated that these neurons display a heterogeneous pattern of firing activity (Poulain and Wakerley, 1982).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Poulain and Wakerley, 1982

      Not checked in the free run.

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

    Study design and conductnone given

    All procedures were conducted in accordance with the guides for animal care and use as outlined in the Guide for the Care and Use of Laboratory Animals (NIH) and Institutional Care and Use Committee at the University of North Carolina (UNC) at Chapel Hill.

    “All procedures were conducted in accordance with the guides for animal care and use as outlined in the Guide for the Care and Use of Laboratory Animals (NIH) and Institutional Care and Use Committee at the University of North Carolina (UNC) at Chapel Hill.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    A greater proportion of low-power PVH-OT neurons responded with an increase in activity selectively to the social stimulus, while high-power neurons tended to respond nonselectively with increases in activity to both types of stimuli.

    “Thus, a greater proportion of low power PVH-OT neurons responded with an increase in activity selectively to the social stimulus, while high-power neurons tended to respond nonselectively with increases in activity to both types of stimuli.”
    Quote in the paperNot a substantial claim

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

    Interpretationcitation

    The low-power group of PVH-OT neurons is likely similar to OT neurons characterized in previous studies as silent or firing in a slow irregular pattern.

    “This group of neurons is likely similar to OT neurons characterized in previous studies as silent or firing in a slow irregular pattern (Poulain and Wakerley, 1982).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Poulain and Wakerley, 1982

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    There are subsets of PVH-OT neurons that exhibit opposing responses to social and nonsocial stimuli (socially specific), while a subset of neurons respond with an increase in activity to either stimulus (nonspecific).

    “Thus, there are subsets of PVH-OT neurons that exhibit opposing responses to social and nonsocial stimuli (socially specific), while a subset of neurons respond with an increase in activity to either stimulus (nonspecific).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    OT neurons play a critical role in the encoding of socially specific stimuli and in guiding behavior toward such stimuli.

    “Together, these data suggest that OT neurons play a critical role in the encoding of socially specific stimuli and in guiding behavior toward such stimuli.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Many previous identification methods required the use of stimuli that robustly activate OT neurons, such as suckling of a lactating female, which induces burst-like firing patterns that may not be representative of OT neuron activity under other social contexts.

    “Moreover, many of these previous identification methods required the use of stimuli that robustly activate OT neurons (Brimble et al., 1978;Moos et al., 2004), such as suckling of a lactating female, which induces burst-like firing patterns (Summerlee and Lincoln, 1981;Belin et al., 1984) that may not be representative of OT neuron activity under other social contexts.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Brimble et al., 1978

      Not checked in the free run.

    • cites Moos et al., 2004

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    • cites Summerlee and Lincoln, 1981

      Not checked in the free run.

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

    Premisecitation

    Under most physiological conditions, putative OT neurons have typically been classified as either firing at a very slow rate or in a fast continuous pattern.

    “Thus, under most physiological conditions, putative OT neurons have typically been classified as either firing at a very slow rate or in a fast continuous pattern (Brimble et al., 1978;Moos et al., 2004;Sabatier and Leng, 2006).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Brimble et al., 1978

      Not checked in the free run.

    • cites Moos et al., 2004

      Not checked in the free run.

    • cites Sabatier and Leng, 2006

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Many previous studies attempting to record from OT neurons have been limited by the ability to definitively identify these neurons.

    “Given the large diversity of cell types within this region, many previous studies attempting to record from OT neurons have been limited by the ability to definitively identify these neurons (Poulain and Wakerley, 1982).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Poulain and Wakerley, 1982

      Not checked in the free run.

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

    Premisecitation

    In mammals, OT neurons are found in several nuclei throughout the hypothalamus, such as the PVH.

    “In mammals, OT neurons are found in several nuclei throughout the hypothalamus, such as the PVH-a heterogeneous brain structure containing a wide array of cell types including OT, vasopressin, corticotropin releasing hormone, thyrotropin releasing hormone, somatostatin, and kisspeptinexpressing neurons (Zhu et al., 2007;Della Torre et al., 2014).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Zhu et al., 2007

      Not checked in the free run.

    • cites Della Torre et al., 2014

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    A failure to attend to socially salient stimuli in the environment is a core symptom of ASD.

    “A failure to attend to socially salient stimuli in the environment is a core symptom of ASD (Ozonoff et al., 2010;Chevallier et al., 2012).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Ozonoff et al., 2010

      Not checked in the free run.

    • cites Chevallier et al., 2012

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    PVH-OT neurons are composed of a heterogeneous population of neurons in which low-power neurons show more robust encoding of social stimuli.

    “Thus, PVH-OT neurons are composed of a heterogeneous population of neurons in which low-power neurons show more robust encoding of social stimuli.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    OT is critical for the expression of a wide array of social behaviors.

    “OT is critical for the expression of a wide array of social behaviors (Gimpl and Fahrenholz, 2001;Kelly and Goodson, 2014); however, the specific function of this neuromodulator in social interactions is not well understood.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Gimpl and Fahrenholz, 2001

      Not checked in the free run.

    • cites Kelly and Goodson, 2014

      Not checked in the free run.

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

    Premisecitation

    Previous in vivo recordings from putative OT neurons in the PVH of awake rodents have indicated that these neurons display a heterogeneous pattern of firing activity that can be assigned to one of three categories: silent to slow irregular, fast continuous, or phasic firing cells.

    “Previous in vivo recordings from putative OT neurons located in the PVH of awake rodents have indicated that these neurons display a heterogeneous pattern of firing activity that can be assigned to one of three categories: silent to slow irregular, fast continuous, or phasic firing cells (Poulain and Wakerley, 1982).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Poulain and Wakerley, 1982

      Not checked in the free run.

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

    Premisecitation

    In the adult brain, oxytocin acts in sensory processing regions of the brain to enhance signal-to-noise processing in a socially specific manner.

    “In the adult brain, it is known that OT acts in sensory processing regions of the brain to enhance signal-to-noise processing in a socially specific manner (Marlin et al., 2015;Oettl et al., 2016)”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Marlin et al., 2015

      Not checked in the free run.

    • cites Oettl et al., 2016

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Moderate and sustained increases in putative OT neuron activity are associated with the central release of OT, while burst firing of OT neurons is associated with bolus release of OT into the bloodstream.

    “Importantly, moderate and sustained increases in putative OT neuron activity are associated with the central release of OT (Sabatier et Figure 7. PVH-OT neurons do not respond to sucrose consumption.A, B, Activity heatmaps for all PVH-OT neurons following the consumption of randomly delivered sucrose on (A) the first and (B) the second day of exposure.Each session consisted of 100 trials and the”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Sabatier et al., 2003

      Not checked in the free run.

    • cites Summerlee and Lincoln, 1981

      Not checked in the free run.

    • cites Israel et al., 2003

      Not checked in the free run.

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

    Premisecitation

    In Shank3 mouse models with deletions of the exons encoding the PDZ binding domain (Shank3B-/-), a reduction in corticostriatal connectivity has been identified, which is thought to partially underlie the high levels of repetitive behaviors displayed by these animals.

    “In Shank3 mouse models with deletions of the exons encoding the PDZ binding domain (Shank3B Ϫ / Ϫ ), a reduction in corticostriatal connectivity has been identified, which is thought to partially underlie the high levels of repetitive behaviors displayed by these animals (Pec ¸a et al., 2011;Peixoto et al., 2016).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Pec ¸a et al., 2011

      Not checked in the free run.

    • cites Peixoto et al., 2016

      Not checked in the free run.

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

    Premisecitation

    Central and peripheral release of OT can be regulated independently and by different mechanisms.

    “Thus, central and peripheral release of OT can be regulated independently and by different mechanisms (Moos et al., 2004).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Moos et al., 2004

      Not checked in the free run.

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

    Premisecitation

    Early in development, Shank3 expression occurs widely throughout the rodent brain, but 2 weeks following birth, Shank3 expression becomes restricted, with the highest densities occurring in the cortex, striatum, and hippocampus.

    “Early in development, expression of this protein occurs widely throughout the rodent brain, but 2 weeks following birth, Shank3 expression becomes restricted, with the highest densities occurring in the cortex, striatum, and hippocampus (Bo ¨ckers et al., 2001;Pec ¸a et al., 2011).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Bo ¨ckers et al., 2001

      Not checked in the free run.

    • cites Pec ¸a et al., 2011

      Not checked in the free run.

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

    Interpretationreasoning

    It is possible that graded continuous release of OT into the brain is important for priming and maintaining social behavior, while pulsatile release of OT into the bloodstream may be more critical for regulating muscle contraction during lactation and birth.

    “Thus, it is possible that graded continuous release of OT into the brain is important for priming and maintaining social behavior, while pulsatile release of OT into the bloodstream may be more critical for regulating muscle contraction during lactation and birth.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    In the Cntnap2 model, early treatment with OT was sufficient to rescue reduced OT immunoreactivity as well as social functioning, suggesting that there may be a critical developmental time window for optimal treatment.

    “In the Cntnap2 model, early treatment with OT was sufficient to rescue reduced OT immunoreactivity as well as social functioning, suggesting that there may be a critical developmental time window for optimal treatment (Pen ˜agarikano et al., 2015).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Pen ˜agarikano et al., 2015

      Not checked in the free run.

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

    Premisecitation

    Shank3 protein is found postsynaptically at glutamatergic synapses where it plays a critical role in excitatory synapse formation and plasticity.

    “Shank3 protein is found postsynaptically at glutamatergic synapses where it plays a critical role in excitatory synapse formation and plasticity (Jiang and Ehlers, 2013).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Jiang and Ehlers, 2013

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    While an anesthetized social stimulus is sufficient to provoke social engagement among test subjects, it may not be the most potent stimulus.

    “Together, these results indicate that while an anesthetized social stimulus is sufficient to provoke social engagement among test subjects, it may not be the most potent stimulus.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The neural and behavioral manifestation of Shank3 mutations is likely dependent on the specific type of mutation as well as the location of this mutation within the gene.

    “Thus, the neural and behavioral manifestation of Shank3 mutations is likely depen-dent on the specific type of mutation as well as the location of this mutation within the gene.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Deficits in both the OT system and social behavior have been reported in two other models of autism, the hyperserotonemia model of autism and the Cntnap2 mouse model.

    “Moreover, deficits in both the OT system and social behavior have been reported in two other models of autism, the hyperserotonemia model of autism (McNamara et al., 2008;Martin et al., 2012) and the Cntnap2 mouse model (Pen ˜agarikano et al., 2015).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites McNamara et al., 2008

      Not checked in the free run.

    • cites Martin et al., 2012

      Not checked in the free run.

    • cites Pen ˜agarikano et al., 2015

      Not checked in the free run.

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

    Premisecitation

    Rat mothers will approach anesthetized pups; however, they were shown to engage with them for shorter durations than awake vocalizing pups.

    “and that rat mothers will approach anesthetized pups; however, they were shown to engage with them for shorter durations than awake vocalizing pups (Okabe et al., 2013).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Okabe et al., 2013

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    It is possible that the deficits in Shank3b-/- mice are at least mediated by abnormal functioning of the OT system and that the development of therapeutics that directly target the OT system may provide novel treatments for social impairments in ASDs.

    “Thus, it is possible, that these deficits are at least mediated by abnormal functioning of the OT system and that the development of therapeutics that directly target the OT system may provide novel treatments for social impairments in ASDs.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    In mouse models containing mutations in other regions of the Shank3 gene, impairments in hippocampal transmission and plasticity have been reported as well as deficits in performance in a Morris water maze task.

    “In addition, in mouse models containing mutations in other regions of the Shank3 gene, such as those with insertion of a transcriptional stop cassette upstream of the PDZ domain coding exons, impairments in hippocampal transmission and plasticity have been reported as well as deficits in performance in a Morris water maze task (Jaramillo et al., 2017).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Jaramillo et al., 2017

      Not checked in the free run.

63 of 63

  • The paper relies on this without support.

    The neural mechanisms that enable the conveyance of social salience are not well understood.

    “Importantly, although the encoding of social information is critical for species survival, the neural mechanisms that enable the conveyance of social salience are not well understood.”

  • The paper relies on this without support.

    It has yet to be determined how the presence of a social conspecific modulates the activity of OT neurons within the PVH.

    “However, it has yet to be determined how the presence of a social conspecific modulates the activity of OT neurons within the PVH.”

  • The paper relies on this without support.

    Socially induced activation of OT neurons has not been directly demonstrated.

    “Although it has been hypothesized that social stimulus exposure activates the OT system to promote appropriate social-behavioral responses (Shamay-Tsoory and Abu-Akel, 2016), socially induced activation of OT neurons has not been directly demonstrated.”

  • The paper relies on this without support.

    The lack of evidence for socially induced activation of OT neurons is primarily related to the inability to record from these neurons in an awake behaving animal.

    “A lack of evidence for such responses is primarily related to the inability to record from these neurons in an awake behaving animal.”

  • The paper relies on this without support.

    The mechanism in which OT acts to promote the appropriate social response is poorly understood.

    “Although the oxytocin (OT) system is well known to regulate a diverse array of social behaviors, the mechanism in which OT acts to promote the appropriate social response is poorly understood.”

  • The paper relies on this without support.

    The first step to the successful expression of social behavior is the encoding of stimuli as social.

    “Thus, the first step to the successful expression of social behavior is the encoding of stimuli as social.”

  • The paper relies on this without support.

    Without the encoding of stimuli as social, more complex social behavioral processes necessary for species survival, such as mating and defensive behavior, cannot occur.

    “Without this fundamental first step, more complex social behavioral processes that are necessary for species survival, such as mating and defensive behavior, cannot occur.”

  • The paper relies on this without support.

    The OT receptor agonist Way267464 specifically activates OT receptors to produce the observed rescue of social deficits.

    “However, Shank3b KO mice receiving i.p injections of either 10 mg/kg ( p ϭ 0.01) or 30 mg/kg ( p ϭ 0.03) of an OT receptor agonist (Way267464) showed a significant preference for the social zone (Fig. 9 A, B).”

  • The paper relies on this without support.

    The reduction in immunopositive OT neurons in the medial PVH of Shank3b-/- mice reflects a loss of OT neurons rather than reduced OT expression or detection.

    “Indeed, Shank3b Ϫ / Ϫ mice showed a marked reduction in the number of immunopositive OT neurons within the medial region of the PVH (two-way ANOVA, F (2,85) ϭ 53.87, p Ͻ 0.0001, n ϭ 3-4 mice/ group) compared with both wild-type (WT) (Tukey's post hoc test, p ϭ 0.0004) and heterozygous littermates (Tukey's post hoc test, p ϭ 0.005) (Fig. 8A-D).”

  • The paper relies on this without support.

    The classification of PVH-OT neurons into low-power and high-power groups based on mean power during baseline reflects meaningful physiological subpopulations.

    “This resulted in 67 of 102 neurons to be classified as low powered (66%) and 35 to be classified as high powered (34%).”
10 of 10

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?

  • Resendez et al. (2020) observed heterogeneous Ca2+ signals in PVN oxytocin neurons when mice were presented with anesthetized juveniles.

    “Using two-photon imaging in head-fixed adult males, Resendez et al. (2020) observed heterogeneous Ca2+ signals in PVN oxytocin neurons when the mice were presented with anesthetized juveniles.”

    From Oxytocin, Neural Plasticity, and Social Behavior (2021) · cites this paper as Resendez et al. 2020

  • Sucrose, a nonsocial appetitive stimulus, did not activate PVN oxytocin neurons.

    “In contrast, sucrose (a nonsocial appetitive stimulus) did not activate PVN oxytocin neurons.”

    From Oxytocin, Neural Plasticity, and Social Behavior (2021) · cites this paper as Resendez et al. 2020

  • Paraventricular oxytocin cells in adults are active during interactions with juveniles, and stimulation of paraventricular oxytocin terminals in the ventral tegmental area increased social investigation through actions on OXTR.

    “PVN OXT cells in adults are also active during interactions with juveniles (85), and stimulation of PVN OXT terminals in the VTA increased social investigation through actions on OXTR specifically.”

    From Oxytocin, Vasopressin, and Social Behavior: From Neural Circuits to Clinical Opportunities (2022) · cites this paper as [85]

  • The presence of a conspecific activates the oxytocin system, increases oxytocin release, activates dopamine neurons of the VTA, and promotes the initiation and maintenance of social interaction.

    “Indeed, the presence of a conspecific activates the oxytocin system, which increases oxytocin release, activates DA neurons of the VTA, and promotes the initiation and maintenance of social interaction (Resendez et al., 2020; Oettl et al., 2016).”

    From Oxytocin neurons mediate the effect of social isolation via the VTA circuits (2022) · cites this paper as Resendez et al., 2020

  • PVN oxytocin cells receive projections from many areas of the brain.

    “PVN oxytocin cells receive projections from many areas of the brain”

    From Neural circuitry for maternal oxytocin release induced by infant cries (2023) · cites this paper as [12]

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.

  • Gq DREADD is identified as two different constructs

    Minor

    The Results identify the Gq construct as hM4D(Gq), whereas the Methods identify the injected Gq construct as hM3D(Gq).

  • Conflicting mouse counts for OT-neuron staining

    Minor

    The Results report 3-4 mice per group for the OT-neuron comparison, while the corresponding Figure 8 legend reports 4-5 mice per group.

  • Figure 3L is labeled as two different measurements

    Minor

    The Results identify Figure 3L as event duration, but its legend identifies it as event amplitude, which the same legend already assigns to Figure 3K.

  • Figure 6C reverses the reported response proportions

    Minor

    The Results say that, among low-power neurons with a negative social response, 21% increased and 67% decreased their activity in response to the nonsocial stimulus. The Figure 6C legend assigns those percentages to the opposite responses and describes the initial group differently.

4 of 4

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Related

Authors
Resendez, S. L., Namboodiri, V. M. K., Otis, J. M., Eckman, L. E. H., Rodriguez-Romaguera, J., Ung, R. L., Basiri, M. L., Kosyk, O., Rossi, M. A., Dichter, G. S., & Stuber, G. D.
Affiliations
University of North Carolina at Chapel Hill (US)
ORCID
Venue
The Journal of Neuroscience
Publisher
Society for Neuroscience
Published
2020-02-05
Volume
40
Issue
11
Pages
2282-2295
ISSN
  • 0270-6474 (ISSN-L)
  • 1529-2401
DOI
10.1523/jneurosci.1515-18.2020
PMC
PMC7083279
OpenAlex
W3005528311
Semantic Scholar
812d067e75979cfd78ff90c1b1b91ccaa13baf6a
Cited by
142
References
80
Citations by year
2026: 12 · 2025: 24 · 2024: 27 · 2023: 17 · 2022: 29 · 2021: 22 · 2020: 10 · 2018: 1
FWCI
21.31
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
  • UNC Libraries
Funders
  • National Institute on Drug Abuse (R01DA032750, DA038168, DA032750, R01DA038168, R37DA032750)
  • National Institute of Neurological Disorders and Stroke (P30NS045892)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (U54HD079124, T32HD040127)
Topics
  • Social Sciences › Psychology › Social Psychology › Neuroendocrine regulation and behavior
  • Life Sciences › Neuroscience › Sensory Systems › Olfactory and Sensory Function Studies
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
Keywords
oxytocin, paraventricular nucleus, social behavior, social salience, social investigation, social choice, chemogenetic activation, two-photon calcium imaging, autism spectrum disorder, oxytocin receptor agonists, social preferences, male mice
MeSH terms
Action Potentials, Animals, Appetitive Behavior, Autistic Disorder, Benzodiazepines, Clozapine, Disease Models, Animal, Exploratory Behavior, Male, Microfilament Proteins, Nerve Tissue Proteins, Neurons, Oxytocin, Paraventricular Hypothalamic Nucleus, Pyrazoles, Social Behavior, Wakefulness, Genes, Reporter, Receptors, Oxytocin, Mice, Knockout, Patch-Clamp Techniques, Calcium Signaling, Mice

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

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

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

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