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Cited by 268Neuroendocrine regulation and behaviorNeurogenesis and neuroplasticity mechanismsInfant Health and Development

Oxytocin neurons enable social transmission of maternal behaviour

Open access
Carcea, Ioana, Caraballo, Naomi López, Marlin, Bianca J., Ooyama, Rumi, Riceberg, Justin S., Mendoza Navarro, Joyce M., Opendak, Maya, Diaz, Veronica E. +18 more·2021·Nature
DOI 10.1038/s41586-021-03814-7PMC PMC8387235
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Abstract

Maternal care, including by non-biological parents, is important for offspring survival 1–8 . Oxytocin 1,2,9–15 , which is released by the hypothalamic paraventricular nucleus (PVN), is a critical maternal hormone. In mice, oxytocin enables neuroplasticity in the auditory cortex for maternal recognition of pup distress 15 . However, it is unclear how initial parental experience promotes hypothalamic signalling and cortical plasticity for reliable maternal care. Here we continuously monitored the behaviour of female virgin mice co-housed with an experienced mother and litter. This documentary approach was synchronized with neural recordings from the virgin PVN, including oxytocin neurons. These cells were activated as virgins were enlisted in maternal care by experienced mothers, who shepherded virgins into the nest and demonstrated pup retrieval. Virgins visually observed maternal retrieval, which activated PVN oxytocin neurons and promoted alloparenting. Thus rodents can acquire maternal behaviour by social transmission, providing a mechanism for adapting the brains of adult caregivers to infant needs via endogenous oxytocin.

AI snapshot

Written from the paper’s full text.

TL;DR

Co-housed virgin female mice acquire maternal pup retrieval by observing and being shepherded by experienced dams, and this social transmission requires PVN oxytocin neurons and visual input. Oxytocin-dependent PVN→left auditory cortex signaling pairs maternal experiences with pup cues, promoting cortical plasticity and alloparenting.

Key findings

  • Virgin females co-housed with dams and litters (D+ virgins, n = 14) began reliable retrieval on day two, earlier than virgins co-housed with pups but no dam (D− virgins, n = 10; P < 0.0001). Dams shepherded virgins back to the nest, and shepherding frequency correlated with virgin retrieval on day 1 (r = 0.75, P = 0.001); virgin nest entry also correlated with day-1 retrieval (r = 0.66, P = 0.009).
  • PVN and OT-PVN neurons were activated by shepherding and initial nest entry; chemogenetic silencing of OT-PVN cells delayed retrieval onset in naive co-housed virgins. Recordings included n = 17 virgins, 541 PVN units, and 21 OT-PVN units.
  • Non-co-housed virgins observing dam retrieval learned to retrieve: no barrier, 11 out of 15 virgins (P = 0.0002); transparent barrier, 12 out of 19 (P < 0.0001); opaque barrier, 2 out of 18 (P = 0.2); OXTR-KO virgins behind a transparent barrier, 3 out of 10 (P = 0.1). Optogenetic sSC→PVN stimulation during opaque-barrier observation increased retrieval (ChR2-Venus: 4 out of 5; control: 1 out of 6; P = 0.03).
  • PVN→auditory cortex oxytocin signaling supported learning: cortical OTA infusion reduced retrieval (saline, 7 out of 9; OTA, 2 out of 10; P = 0.03), and optogenetic OT-PVN→auditory cortex stimulation during opaque-barrier observation enhanced retrieval (ChETA-EYFP, 4 out of 4; EYFP, 2 out of 4; P = 0.008). Single-trial PVN activity correlated with pup call-evoked cortical responses (r = 0.5, P = 0.00001, n = 4), and auditory cortex photometry increased before retrieval onset (P = 0.003, n = 3).

Methods

  • Design: continuous days-long synchronized video, ultrasonic audio, and neural recordings in home cages containing a dam, litter, and co-housed virgin; behavioral ethograms and daily pup retrieval tests; separate observational-learning tests with no barrier, transparent barrier, or opaque barrier.
  • Sample/data: pup-naive C57Bl/6 virgin females around eight weeks old; dams pre-screened for maternal behavior; co-housing for 4–6 consecutive days; retrieval testing with 10 trials per session; neural recordings, DREADD silencing, optogenetics, fiber photometry, rabies tracing, and μCT/MRI electrode localization.
  • Analysis: two-way ANOVA with Sidak corrections, Student’s t-tests, Fisher’s exact tests, chi-square tests, Kaplan–Meier/Mantel–Cox tests, permutation tests with false-discovery-rate correction for spike modulation, and cross-correlations of simultaneously recorded units.

Limitations

  • The paper states that no statistical methods were used to predetermine sample size, the experiments were not randomized, and behavioral raters were blinded to allocation during co-housing and outcome assessment.
  • Evident from the text: several neural, photometry, and optogenetic subgroups were small (for example, n = 3 learners and 5 non-learners; photometry n = 3; optogenetic groups of 4–6 animals), limiting statistical power and generalizability.
  • Evident from the text: findings are in mice, and the observational-learning rate was slower than in co-housed virgins, which the authors suggest may reflect heterogeneity of PVN and OT-PVN responses to maternal interactions.

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

Integrity signals

Registry

Crossref · 10.1038/s41586-021-03814-7

Cites

42 of 42 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 40 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Silencing PVN oxytocin neurons with DREADDi delayed retrieval onset in naive co-housed virgins.

    “We used designer receptors exclusively activated by designer drugs coupled to inhibitory G-protein receptors (DREADDi) to silence PVN oxytocin neurons (OT-PVN cells; Extended Data Fig. 4a), and found that retrieval onset in naive co-housed virgins was delayed (Fig. 2a).”
    Quote in the paperSubstantial claim
  • Findingown data

    Silencing of OT-PVN cells had little effect after virgins began retrieving.

    “However, silencing of OT-PVN cells had little effect after virgins began retrieving (Extended Data Fig. 4b), similar to primiparous dams17.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [17] Rich, M. E. et al. Impairments in the initiation of maternal behavior in oxytocin receptor knockout mice. Plos ONE 9, 0098839 (2014). source

      Not checked in the free run.

  • Findingown data

    Retrieval by dams evoked responses in virgin PVN, although the virgin was not directly involved.

    “Remarkably, retrieval by dams evoked responses in virgin PVN (Fig. 3b, c), although the virgin was not directly involved.”
    Quote in the paperSubstantial claim
  • Findingown data

    PVN oxytocin neurons in virgin mice are activated when virgins are enlisted in maternal care by experienced mothers.

    “These cells were activated as virgins were enlisted in maternal care by experienced mothers, who shepherded virgins into the nest and demonstrated pup retrieval.”
    Quote in the paperSubstantial claim
  • Findingown data

    Pairs containing OT-PVN cells were more correlated during shepherding, nest entry and dam retrieval.

    “We analysed cross-correlations across simultaneously recorded units, and found that pairs containing OT-PVN cells were more correlated during shepherding, nest entry and dam retrieval (Extended Data Fig. 7d, e).”
    Quote in the paperSubstantial claim
  • May combine two claims. 30
  • Classified as probably not a substantial claim. 33
  • The quote only partly states this claim. 2

  • May combine two claims.

    Findingown data

    Pup retrieval was not initially performed by virgins but was reliably performed by dams regardless of litter size.

    “Pup retrieval was not initially performed by virgins but was reliably performed by dams regardless of litter size (Extended Data Fig. 2c).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Virgins visually observe maternal retrieval, which activates PVN oxytocin neurons and promotes alloparenting.

    “Virgins visually observed maternal retrieval, which activated PVN oxytocin neurons and promoted alloparenting.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Virgin alloparenting and PVN activity increased after spontaneous pup retrieval by dams.

    “We also found that virgin alloparenting and PVN activity increased after spontaneous pup retrieval by dams.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Some PVN and OT-PVN units responded to both shepherding and dam retrieval, but population responses were heterogeneous.

    “Some PVN and OT-PVN units responded to both shepherding and dam retrieval, but population responses were heterogeneous (Fig. 3d).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Shepherding occurred hundreds of times during co-housing, and its frequency correlated with virgin retrieval at day 1 (r = 0.75, P = 0.001).

    “Shepherding occurred hundreds of times during co-housing (Fig. 1j, Extended Data Fig. 1a), and its frequency correlated with virgin retrieval at day 1 (Fig. 1k; r = 0.75, P = 0.001).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Virgins co-housed with dams and litters (D+ virgins, n = 14) began reliably retrieving on day two of co-housing, earlier than virgins co-housed with pups but without dams (D− virgins, n = 10) (P < 0.0001).

    “Virgins co-housed with dams and litters (D+ virgins, n = 14) began reliably retrieving (in more than 1 out of 10 trials) on day two of co-housing, earlier than virgins co-housed with pups but without dams (D− virgins, n = 10) (Fig. 1c, d, Extended Data Fig. 2a, b, Supplementary Videos 3,4; P < 0.0001).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Virgins began to spend time in the nest with pups, and the more virgins entered the nest, the more likely retrieval occurred on day 1 (r = 0.66, P = 0.009).

    “Virgins also began to spend time in the nest with pups (Fig. 1b, e; P < 0.0001), and the more virgins entered the nest, the more likely it was that retrieval occurred on day 1 (Fig. 1f; r = 0.66, P = 0.009).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    About once every two hours, dams dropped and then retrieved pups, sometimes bringing pups to the virgin.

    “About once every two hours, dams dropped and then retrieved pups, sometimes bringing pups to the virgin (Fig. 3a, Extended Data Figs. 1, 8a, b, Supplementary Videos 1, 8–10).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Virgin PVN and OT-PVN units were activated by shepherding or initial nest entry, with less activation from chasing dams, entry into an empty nest or pup calls.

    “Virgin PVN and OT-PVN units were activated by shepherding or initial nest entry, with less activation from chasing dams, entry into an empty nest or pup calls (Fig. 2c–j, Extended Data Figs. 6c–e, 7a–c).”
    Quote in the paperSubstantial claim

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

    Findingown data

    Data from restrained and unrestrained mice showed similar trends and were pooled together.

    “Data from restrained or unrestrained mice showed similar trends, and were thus pooled together.”
    Quote in the paperNot a substantial claim

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

    Findingnone given

    Three out of seven mice in the mCherry+ CNO cohort had DREADDi virus expressed outside of the PVN due to mis-targeting.

    “Three out of seven mice in the mCherry+ CNO cohort had DREADDi virus expressed outside of the PVN due to mis-targeting.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Increased PVN activity was higher on first day versus last day of observation, and was elevated only in those non-co-housed virgins that eventually began retrieving (n = 3 learners, 5 non-learners; P = 0.0001).

    “Increased PVN activity was higher on first day versus the last day of observation (Fig. 3j, left), and was elevated only in those non-co-housed virgins that eventually began retrieving (Fig. 3j, right; n = 3 learners, 5 non-learners; P = 0.0001).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Although virgin PVN did not respond directly to pup calls, virgin PVN and OT-PVN neurons were recruited by specific experiences during co-housing when abandoned pups would emit distress calls.

    “Our results show that although virgin PVN did not respond directly to pup calls, virgin PVN and OT-PVN neurons were recruited by specific experiences during co-housing when abandoned pups would emit distress calls (Extended Data Fig. 6a, b).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Onset of retrieval in non-co-housed virgins increased after observed dam retrievals (No barrier: 11 out of 15 virgins retrieving after 40 maternal demonstrations; P = 0.0002), but independently of pup behaviours.

    “Onset of retrieval in virgins increased after observed dam retrievals (Fig. 3e–g, No barrier: 11 out of 15 virgins retrieving after 40 maternal demonstrations; P = 0.0002, Fisher’s exact test), but independently of pup behaviours (Extended Data Fig. 8c).”
    Quote in the paperSubstantial claim

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

    Findingown data

    Pup group size did not affect retrieval behaviour.

    “The entire litter (ranging from 3 to 7 P1–4 pups) were grouped in a corner of the arena and covered with nesting material, and the adult female given an additional 2 min of acclimatization (pup group size did not affect retrieval behaviour; Extended Data Fig. 2c).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Oxytocin, released by the hypothalamic paraventricular nucleus (PVN), is a critical maternal hormone.

    “Oxytocin1,2,9–15, which is released by the hypothalamic paraventricular nucleus (PVN), is a critical maternal hormone.”
    Quote in the paperSubstantial claim0 of 9 sources checked
    • cites [1] Insel, T. R. & Young, L. J. The neurobiology of attachment. Nat. Rev. Neurosci. 2, 129–136 (2001). source

      Not checked in the free run.

    • cites [2] Dulac, C., O’Connell, L. A. & Wu, Z. Neural control of maternal and paternal behaviors. Science 345, 765–770 (2014). source

      Not checked in the free run.

    • cites [9] Insel, T. R. & Shapiro, L. E. Oxytocin receptor distribution reflects social organization in monogamous and polygamous voles. Proc. Natl Acad. Sci. USA 89, 5981–5985 (1992). source

      Not checked in the free run.

    • cites [10] Nishimori, K. et al. Oxytocin is required for nursing but is not essential for parturition or reproductive behavior. Proc. Natl Acad. Sci. USA 93, 11699–11704 (1996). source

      Not checked in the free run.

    • cites [11] Johnson, Z. V. et al. Oxytocin receptors modulate a social salience neural network in male prairie voles. Horm. Behav. 87, 16–24 (2017). source

      Not checked in the free run.

    • cites [12] Burkett, J. P. et al. Oxytocin-dependent consolation behavior in rodents. Science 22, 375–378 (2016). source

      Not checked in the free run.

    • cites [13] Kendrick, K. M. et al. Neural control of maternal behavior and olfactory recognition of offspring. Brain Res. Bull. 44, 383–395 (1997). source

      Not checked in the free run.

    • cites [14] Okabe, S. et al. Pup exposure facilitates retrieving behavior via the oxytocin neural system in female mice. Psychoneuroendocrinology 79, 20–30 (2017). source

      Not checked in the free run.

    • cites [15] Marlin, B. J. et al. Oxytocin enables maternal behavior by balancing cortical inhibition. Nature 520, 499–504 (2015). source

      Not checked in the free run.

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

    Premisecitation

    In primates, including humans, non-biological parents can learn to care for children after instruction or observation of experienced caretakers and infants.

    “In primates, including humans, non-biological parents can learn to care for children after instruction or observation of experienced caretakers and infants1–8.”
    Quote in the paperNot a substantial claim0 of 8 sources checked
    • cites [1] Insel, T. R. & Young, L. J. The neurobiology of attachment. Nat. Rev. Neurosci. 2, 129–136 (2001). source

      Not checked in the free run.

    • cites [2] Dulac, C., O’Connell, L. A. & Wu, Z. Neural control of maternal and paternal behaviors. Science 345, 765–770 (2014). source

      Not checked in the free run.

    • cites [3] Feldman, R. The neurobiology of human attachments. Trends Cogn. Sci. 21, 80–99 (2017). source

      Not checked in the free run.

    • cites [4] Opendak, M., Gould, E. & Sullivan, R. Early life adversity during the infant sensitive period for attachment: programming of behavioral neurobiology of threat processing and social behavior. Dev. Cogn. Neurosci. 25, 145–159 (2017). source

      Not checked in the free run.

    • cites [5] Wilson, E. O. Sociobiology: The New Synthesis (Harvard Univ. Press, 1975).

      Not checked in the free run.

    • cites [6] Moehlman, P. D. Jackal helpers and pup survival. Nature 277, 382–383 (1979). source

      Not checked in the free run.

    • cites [7] Lee, P. C. Allomothering among African elephants. Animal Behavior 35, 278–291 (1987). source

      Not checked in the free run.

    • cites [8] Hotelling, B. A. Newborn capabilities: parent teaching is a necessity. J. Perinat. Educ. 13, 43–49 (2004). source

      Not checked in the free run.

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

    Premisecitation

    Oxytocin acts in the brain to increase the salience of social information and enable alloparenting in mice.

    “Oxytocin also acts in the brain to increase the salience of social information and enable alloparenting in mice1,9,12–14.”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [1] Insel, T. R. & Young, L. J. The neurobiology of attachment. Nat. Rev. Neurosci. 2, 129–136 (2001). source

      Not checked in the free run.

    • cites [9] Insel, T. R. & Shapiro, L. E. Oxytocin receptor distribution reflects social organization in monogamous and polygamous voles. Proc. Natl Acad. Sci. USA 89, 5981–5985 (1992). source

      Not checked in the free run.

    • cites [12] Burkett, J. P. et al. Oxytocin-dependent consolation behavior in rodents. Science 22, 375–378 (2016). source

      Not checked in the free run.

    • cites [13] Kendrick, K. M. et al. Neural control of maternal behavior and olfactory recognition of offspring. Brain Res. Bull. 44, 383–395 (1997). source

      Not checked in the free run.

    • cites [14] Okabe, S. et al. Pup exposure facilitates retrieving behavior via the oxytocin neural system in female mice. Psychoneuroendocrinology 79, 20–30 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Rodents can acquire maternal behaviour by social transmission, providing a mechanism for adapting the brains of adult caregivers to infant needs via endogenous oxytocin.

    “Thus rodents can acquire maternal behaviour by social transmission, providing a mechanism for adapting the brains of adult caregivers to infant needs via endogenous oxytocin.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Shepherding behaviour emerged over hours to days and seemed different from maternal aggression; rather than preventing contact with pups, dams encouraged virgins to enter and remain in the nest.

    “Shepherding behaviour emerged over hours to days (Extended Data Fig. 3a) and seemed different from maternal aggression; rather than preventing contact with pups, dams encouraged virgins to enter and remain in the nest.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    Three separate teams of independent scorers scored videos blind to conditions, and results from each lab were cross-validated.

    “Three separate teams of independent scorers (two scorers from the Sullivan laboratory, three scorers from the Carcea laboratory and four scorers from the Froemke laboratory) were trained in a similar way on how to identify relevant individual and social behaviours during co-housing, and then scored the videos blind to the conditions.”
    • Also stated in: § Behaviour · plain
      “The results from each raster were compared and compiled, and results from each lab were cross-validated.”
    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

    Dams were pre-screened to ensure they behaved maternally; about 1% did not retrieve pups and were not used for co-housing.

    “Dams were initially pre-screened to ensure they behaved maternally, meaning that they retrieved pups and built nests; about 1% of dams did not retrieve pups and these animals were not used for co-housing.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    Neurons that reliably fired (≥70% of trials) at short latency (≤4 ms) after the onset of blue light were selected as being oxytocin neurons.

    “For identifying oxytocin neurons in optically tagged recordings, we aligned neuronal activity to the onset of the blue light pulse30. Neurons that reliably fired (≥70% of trials) at short latency (≤4 ms) after the onset of blue light were selected as being oxytocin neurons.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [30] Hangya, B., Ranade, S. P., Lorenc, M. & Kepecs, A. Central cholinergic neurons are rapidly recruited by reinforcement feedback. Cell 162, 1155–1168 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Alloparenting experiences acquired during co-housing are likely to improve the quality of early maternal care when the virgins themselves have litters, and could occur throughout early life in animals living communally in the wild.

    “These valuable alloparenting experiences acquired during co-housing are likely to improve the quality of early maternal care when the virgins themselves have litters, and could occur throughout early life in animals living communally in the wild.”
    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

    Naive virgins were pre-screened for retrieval or pup mauling; around 5% retrieved at least one pup or mauled pups and were excluded from subsequent behavioural studies.

    “Naive virgins were initially pre-screened for retrieval or pup mauling before co-housing; around 5% of the naive virgins retrieved at least one pup or mauled pups during pre-screening and these mice were excluded from subsequent behavioural studies.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    Behavioural raters were blinded to allocation during co-housing and outcome assessment.

    “The behavioural raters were blinded to allocation during co-housing and outcome assessment.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Social learning of pup retrieval by virgins depended on visual input, and direct projections from visual layers of superior colliculus onto PVN oxytocin neurons were identified.

    “This social learning depended on visual input, and we identified direct projections from visual layers of superior colliculus onto PVN oxytocin neurons.”
    Quote in the paperSubstantial claim

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

    Study design and conductreasoning

    To minimize potential adaptation or synaptic depression, optogenetic stimulation was performed for ≤5 min, enough time for dams to complete 10 retrievals.

    “To minimize potential adaptation or synaptic depression, stimulation was performed for ≤5 min, enough time for dams to complete 10 retrievals.”
    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

    Spikes that violated a refractory period of 2-3 ms and spikes simultaneously recorded in 10 or more channels were eliminated as potential artifacts.

    “We eliminated spikes that violated a refractory period of 2–3 ms, and spikes that were simultaneously recorded in 10 or more channels (as potential artifacts).”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    The localization of the implanted electrodes was assessed in vivo using μCT scans followed by co-registration with an online digital MRI mouse brain atlas.

    “The localization of the implanted electrodes was assessed in vivo using μCT scans in post-implanted mice, followed by co-registration with an online digital MRI mouse brain atlas.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    Our approach combined registration of post-implant μCT with an existing online MRI brain atlas for adult C57Bl/6 mice from the Mouse Imaging Centre.

    “Our approach combined registration of post-implant µCT with an existing online MRI brain atlas for adult C57Bl/6 mice from the Mouse Imaging Centre”
    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 optical identification procedure was <5 min each day, and lower frequency (2 Hz) stimulation was used to minimize the likelihood of functional changes induced by optogenetic stimulation.

    “The optical identification procedure was <5 min each day, and we used lower frequency (2 Hz) stimulation to minimize the likelihood of functional changes induced by optogenetic stimulation.”
    Quote in the paperNot a substantial claim

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

    Study design and conductreasoning

    Head positioning helped reduce the risks of image artifacts that could be induced by the implant along the path of the X-ray beam.

    “To this effect, the head positioning helped reduce the risks of image artifacts that could be induced by the implant along the path of the X-ray beam.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    The experiments were not randomized.

    “The experiments were not randomized.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    The three-dimensional MRI mouse brain atlas was established by acquiring 40 individual ex vivo mice using T2-weighted sequence on a 7-Tesla scanner.

    “The three-dimensional MRI mouse brain atlas was established by acquiring 40 individual ex vivo mice using T2-weighted sequence on a 7-Tesla scanner.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Dorr et al. (ref. 41)

      Not checked in the free run.

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

    Study design and conductreasoning

    To avoid possible changes in the magnitude of calcium transients with changes in the position of the mouse relative to the speaker, in some recordings the mouse was restrained in a mash cup at the same distance from the speaker.

    “To avoid possible changes in the magnitude of calcium transients with changes in the position of the mouse relative to the speaker, in some recordings we restrained the mouse in a mash cup, at the same distance from the speaker.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Experienced mothers shepherd virgins towards pups in the nest but not an empty nest, ensuring that pups are protected by at least one co-caregiver.

    “We found that experienced mothers shepherd virgins towards pups in the nest but not an empty nest, ensuring that pups are protected by at least one co-caregiver.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    No statistical methods were used to predetermine sample size.

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

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

    Premisecitation

    All data from the MRI mouse brain atlas were averaged into a 40 μm isotropic resolution dataset.

    “All the data were averaged and resulted into a 40 µm isotropic resolution dataset detailed in Dorr et al. (ref. 41).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Dorr et al. (ref. 41)

      Not checked in the free run.

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

    Interpretationreasoning

    Socially transmitted parental behaviour would be useful for helping to ensure the survival and success of offspring in consociating species such as rodents and humans.

    “Socially transmitted parental behaviour would then be useful for helping to ensure the survival and success of offspring in consociating species such as rodents and humans.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Sensory inputs from social experience converge to activate oxytocin neurons and possibly other hypothalamic cell types to enable parental care.

    “These results suggest a circuit model by which sensory inputs from social experience converge to activate oxytocin neurons and possibly other hypothalamic cell types to enable parental care (Extended Data Fig. 9e).”
    Quote in the paperSubstantial claim

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

    Premisecitation

    The large extracranial metal components and dental cement of the implant can cause beam hardening that can appear as cupping, streaks, dark bands or flare in the μCT.

    “the large extracranial metal components and dental cement of the implant can cause beam hardening that can appear as cupping, streaks, dark bands or flare in the µCT38–40.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [38] Barrett, J. F. & Keat, N. Artifacts in CT: recognition and avoidance. Radiographics 24, 1679–1691 (2004). source

      Not checked in the free run.

    • cites [39] Duerinckx, A. J. & Macovski, A. Polychromatic streak artifacts in computed tomography images. J. Comput. Assist. Tomogr. 2, 481–487 (1978). source

      Not checked in the free run.

    • cites [40] Joseph, P. M. & Spital, R. D. A method for correcting bone induced artifacts in computed tomography scanners. J. Comput. Assist. Tomogr. 2, 100–108 (1978). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    Cells for which the modulation of activity in the unshifted data was greater than modulation in 950 shuffles were considered to be potentially significantly activated.

    “All cells for which the modulation of activity in the unshifted data was greater than modulation in 950 shuffles were considered to be potentially significantly activated31.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [31] Driscoll, L. N., Pettit, N. L., Minderer, M., Chettih, S. N. & Harvey, C. D. Dynamic reorganization of neuronal activity patterns in parietal cortex. Cell 170, 986–999 (2017). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    To determine if the fraction of activated neurons is meaningful, a one-sided Fisher's exact test was applied with the null hypothesis of zero neurons being activated and the threshold for alpha set at 0.05.

    “To determine if the fraction of activated neurons is meaningful, we then applied a one-sided Fisher’s exact test (with the null hypothesis of zero neurons being activated) with the threshold for alpha set at 0.05 (ref. 32).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [32] Benjamini, Y. & Hochberg, Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J. R. Stat. Soc. B 57, 289–300 (1995). source

      Not checked in the free run.

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

    Study design and conductnone given

    The intensity of blue light excitation was adjusted to produce similar baseline fluorescence levels across sessions in the same mouse.

    “The intensity of blue light excitation was adjusted to produce similar baseline fluorescence levels across sessions in the same mouse.”
    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 conductown data

    Viral expression was verified at the end of the experiments using immunohistochemistry.

    “To verify viral expression at the end of the experiments, animals were fixed with transcardiac perfusions of 4% paraformaldehyde.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    In the case of 'nest entry', a 40-s cut-off was used to minimize the impact from other behaviours that occur in the nest over longer time periods, and this cut-off was chosen as most nest dwell times were ≤40 s.

    “In the case of ‘nest entry’, we used a 40-s cut-off, in order to minimize the impact from other behaviours that occur in the nest over longer time periods (for example, grooming, sleeping and nest building); this cut-off was chosen as most nest dwell times were ≤40 s (Extended Data Fig. 7b).”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    A rigid co-registration between μCT and the modified MRI atlas images was systematically performed using Amira, and both datasets were overlaid for visual analysis to determine the sub-millimetric localization of the electrode tip.

    “A rigid co-registration between µCT and the modified MRI atlas images was systematically performed using a commercial software Amira (Thermo Fisher Scientific). Both datasets were then overlaid for visual analysis and to determine the sub-millimetric localization of the electrode tip.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    The sound processor used for delivering the pup calls was synchronized with the fibre photometry system.

    “The sound processor used for delivering the pup calls (RZ6, TDT) was synchronized with the fibre photometry system.”
    Quote in the paperNot a substantial claim

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

    Study design and conductcitation

    The hypothalamic PVN was manually segmented and color-coded with the guidance of the P56 coronal Allen mouse histology brain atlas, and this region was set as the target of reference.

    “The hypothalamic PVN was manually segmented and color-coded, with the guidance of the P56 coronal Allen mouse histology brain atlas42. This region was set as the target of reference.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [42] Dong, H. W. The Allen Reference Atlas: A Digital Color Brain Atlas of the C57Bl/6J Male Mouse (Wiley, 2008).

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    Cells for which the change in firing rate was smaller than the change in 950 shuffles were considered to be potentially significantly suppressed.

    “Cells for which the change in firing rate was smaller than the change in 950 shuffles were considered to be potentially significantly suppressed.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [31] Driscoll, L. N., Pettit, N. L., Minderer, M., Chettih, S. N. & Harvey, C. D. Dynamic reorganization of neuronal activity patterns in parietal cortex. Cell 170, 986–999 (2017). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductown data

    A false-discovery rate correction was applied for the multiple comparisons performed on each data subset to identify neurons with significant changes in firing rate, with the threshold for q-value set at 0.05.

    “For each unit, we computed the P-value from the permutation analysis and then applied a false-discovery rate correction for the multiple comparisons performed on each data subset (all OT-PVN or all PVN neurons recorded in a day), to identify neurons with significant changes in firing rate. The threshold for q-value was set 0.05, that is, 5% accepted false-discovery rate.”
    Quote in the paperSubstantial claim
52 of 52

  • The paper relies on this without support.

    It is unclear whether alloparenting can be learned from experience in species other than primates, and what neural mechanisms might underlie maternal learning.

    “However, it is unclear whether alloparenting can be learned from experience in other species, and what neural mechanisms might underlie maternal learning.”

  • The paper relies on this without support.

    Little is known about when PVN neurons in nulliparous, non-lactating adults are activated to promote alloparenting behaviour.

    “However, little is known about when PVN neurons in nulliparous, non-lactating adults are activated to promote alloparenting behaviour.”

  • The paper relies on this without support.

    It is unclear how initial parental experience promotes hypothalamic signalling and cortical plasticity for reliable maternal care.

    “However, it is unclear how initial parental experience promotes hypothalamic signalling and cortical plasticity for reliable maternal care.”
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?

  • Paraventricular oxytocin neurons are activated when virgin mice observe pup retrievals by another mother and optogenetic stimulation of paraventricular oxytocin efferents to auditory cortex enhances pup retrieval learning in virgin mice.

    “Further, PVN OXT neurons are activated when virgin mice observe pup retrievals by another mother and optogenetic stimulation of PVN OXT efferents to auditory cortex enhances pup retrieval learning in virgin mice (124, 125).”

    From Oxytocin, Vasopressin, and Social Behavior: From Neural Circuits to Clinical Opportunities (2022) · cites this paper as [125]

  • 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 [14]

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Authors
Carcea, I., Caraballo, N. L., Marlin, B. J., Ooyama, R., Riceberg, J. S., Mendoza Navarro, J. M., Opendak, M., Diaz, V. E., Schuster, L., Alvarado Torres, M. I., Lethin, H., Ramos, D., Minder, J., Mendoza, S. L., Bair-Marshall, C. J., Samadjopoulos, G. H., Hidema, S., Falkner, A., Lin, D., Mar, A., Wadghiri, Y. Z., Nishimori, K., Kikusui, T., Mogi, K., Sullivan, R. M., & Froemke, R. C.
Affiliations
  • Rutgers, The State University of New Jersey (US)
  • NYU Langone Health (US)
  • Icahn School of Medicine at Mount Sinai (US)
  • Nathan Kline Institute for Psychiatric Research (US)
  • Fukushima Medical University (JP)
  • Princeton University (US)
  • New York University (US)
  • Azabu University (JP)
Corresponding author
  • Carcea, Ioana
  • Froemke, Robert C.
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2021-08-11
Volume
596
Issue
7873
Pages
553-557
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/s41586-021-03814-7
PMC
PMC8387235
OpenAlex
W3190811994
Semantic Scholar
573766f7f950e32eca4c2e8db392fb4491f86c2b
Cited by
268
References
42
Citations by year
2026: 57 · 2025: 57 · 2024: 47 · 2023: 39 · 2022: 57 · 2021: 11
FWCI
37.73
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
Funders
  • School of Medicine, New York University
  • Japan Society for the Promotion of Science (21H04981, 19H00972, 18H02356)
  • National Institute of Mental Health (K99MH106744, F32MH112232, R00MH106744, T32MH019524)
  • National Cancer Institute (P30CA016087)
  • National Institute on Deafness and Other Communication Disorders (R01DC012557)
  • National Institute of Neurological Disorders and Stroke (U19NS107616)
  • National Institute of Biomedical Imaging and Bioengineering (P41EB017183)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD088411)
Topics
  • Social Sciences › Psychology › Social Psychology › Neuroendocrine regulation and behavior
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
  • Health Sciences › Health Professions › Pharmacy › Infant Health and Development
Keywords
oxytocin neurons, maternal behavior, social transmission, alloparenting, paraventricular nucleus, hypothalamus, pup retrieval, maternal care, virgin mice, social learning
MeSH terms
Animals, Female, Housing, Animal, Learning, Litter Size, Maternal Behavior, Mothers, Nesting Behavior, Neuronal Plasticity, Neurons, Oxytocin, Paraventricular Hypothalamic Nucleus, Sexual Abstinence, Teaching, 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.

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