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Cited by 115Neuroendocrine regulation and behaviorInfant Health and DevelopmentNeuropeptides and Animal Physiology

Neural circuitry for maternal oxytocin release induced by infant cries

Open access
Valtcheva, Silvana, Issa, Habon A., Bair-Marshall, Chloe J., Martin, Kathleen A., Jung, Kanghoon, Zhang, Yiyao, Kwon, Hyung-Bae, Froemke, Robert C.·2023·Nature
DOI 10.1038/s41586-023-06540-4PMC PMC10639004

Published version of a preprint

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Abstract

Oxytocin is a neuropeptide that is important for maternal physiology and childcare, including parturition and milk ejection during nursing 1-6. Suckling triggers the release of oxytocin, but other sensory cues-specifically, infant cries-can increase the levels of oxytocin in new human mothers 7, which indicates that cries can activate hypothalamic oxytocin neurons. Here we describe a neural circuit that routes auditory information about infant vocalizations to mouse oxytocin neurons. We performed in vivo electrophysiological recordings and photometry from identified oxytocin neurons in awake maternal mice that were presented with pup calls. We found that oxytocin neurons responded to pup vocalizations, but not to pure tones, through input from the posterior intralaminar thalamus, and that repetitive thalamic stimulation induced lasting disinhibition of oxytocin neurons. This circuit gates central oxytocin release and maternal behaviour in response to calls, providing a mechanism for the integration of sensory cues from the offspring in maternal endocrine networks to ensure modulation of brain state for efficient parenting.

AI snapshot

Written from the paper’s full text.

TL;DR

This study identifies a noncanonical auditory circuit from the posterior intralaminar thalamus (PIL) to hypothalamic oxytocin neurons that relays infant pup calls and gates central oxytocin release and maternal behavior. In maternal mice, pup calls—but not pure tones—produce delayed, persistent activation of PVN oxytocin neurons via NMDAR- and dynamin-dependent long-term depression of inhibition.

Key findings

  • Pup-call presentation increased firing of identified PVN oxytocin neurons (ChR2+, OT+) from Pre 2.9 ± 0.7 Hz to Post 5.0 ± 1.6 Hz (P = 0.001, n = 11 cells from N = 6 dams), but not ChR2− (OT−) neurons (Pre 3.1 ± 0.9 Hz, Post 3.6 ± 1.0 Hz; P = 0.07, n = 11, N = 5). Fibre photometry in dams showed significant responses after calls (Pre versus Calls P = 0.0048; Pre versus Post P = 0.0179, N = 7 dams), significant as early as 25 s from call onset (P = 0.013); responses were specific to pup calls and absent for pure tones, adult calls, or FM down-sweeps, and were not observed in virgins.
  • Rabies tracing showed the PIL contributed 100% of auditory inputs to PVN oxytocin cells versus 0% from the medial geniculate body, auditory cortex, and inferior colliculus. The PIL received synaptic inputs from both the inferior colliculus and auditory cortex, with a greater proportion from the inferior colliculus (P = 0.015, two-tailed Fisher’s test), and PIL-to-PVN oxytocin neuron connections occurred with high probability and preferentially targeted parvocellular oxytocin neurons.
  • Repetitive optogenetic stimulation of PIL terminals in the PVN (30 Hz for 1 s, repeated every 2 s for 3 min) induced lasting disinhibition: IPSC amplitudes decreased and the IPSC/EPSC ratio decreased (P = 0.0018). This iLTD was blocked by AP5, intracellular MK801, and a dynamin inhibitory peptide, but not by MAP4 or the oxytocin receptor antagonist OTA; brief PIL stimulation did not trigger iLTD, and iLTD was occluded in slices from dams exposed to pup-call playback immediately before slice preparation.
  • Saline-injected dams needed 41.6 ± 5.9 played calls to approach the speaker, whereas chemogenetic suppression of PIL-to-PVN input reduced speaker preference (P = 0.002) and decreased retrieval probability at later trials; blocking oxytocin signaling in the VTA also decreased retrieval probability (N = 4 dams, P at least <0.02). OXTR-iTango2 labelling in the VTA showed more tdTomato+EGFP+ cells after blue light + pup calls than after blue light + tones or blue light only, with fewer labelled cells when the PIL-to-PVN pathway was inhibited.

Methods

  • Awake head-fixed maternal mice (dams 0–3 weeks postpartum, first or second birth, housed with pups P0–P21 or just weaned; virgins >6 weeks for some comparisons) underwent in vivo cell-attached/whole-cell recordings and fibre photometry from identified PVN oxytocin neurons during playback of pup distress calls, pure tones, adult calls, or FM sweeps.
  • Circuit mapping used Cre-inducible retrograde rabies tracing, channelrhodopsin 2-assisted circuit mapping, in vitro whole-cell recordings in PVN/PIL slices, optogenetic stimulation of PIL terminals, and pharmacological blockers; behavior used chemogenetic inactivation of PIL-to-PVN neurons, VTA cannula infusion of an oxytocin receptor antagonist, and an OXTR-iTango2 oxytocin sensor in the VTA.
  • Analyses used Wilcoxon matched-pairs signed-rank, Friedman, one-sample t-tests, Mann–Whitney, one-way ANOVA, Fisher’s exact, and binomial tests; sample sizes are reported in figure legends, with no statistical methods used to predetermine sample size and experiments not randomized.

Limitations

  • Stated in the paper: no statistical methods were used to predetermine sample size; experiments were not randomized; blinding was not performed for in vivo cell-attached, whole-cell, and tungsten recordings, in vitro whole-cell recordings, and some real-time analyses, though investigators were blinded during behavioral testing and fibre photometry/oxytocin sensor data analysis.
  • Evident from the text: all experiments are in mice, so the human relevance of infant cries increasing oxytocin is inferential; the paper cites human findings but does not test them directly.
  • Evident from the text: several circuit and synaptic conclusions rely on viral tracing, optogenetic/chemogenetic manipulation, pharmacological blockade, and an engineered oxytocin sensor, and some experiments have small sample sizes (e.g., N = 2–7 dams in several photometry, tracing, and sensor experiments).

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

Integrity signals

Registry

Crossref · 10.1038/s41586-023-06540-4

Cites

76 of 76 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 53 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    The increase in spiking of ChR2+ (OT+) neurons was not observed during call presentation itself.

    “This increase in the spiking of ChR2+ (OT+) neurons was not observed during call presentation itself”
    Quote in the paperSubstantial claim
  • Findingown data

    GCaMP6s signals in oxytocin neurons showed substantial responses after calls.

    “observed substantial responses after calls (Pre versus Calls: P = 0.0048; Pre versus Post: P = 0.0179, N = 7 dams”
    Quote in the paperSubstantial claim
  • Findingown data

    The PIL receives synaptic inputs from both the IC and the AuCx.

    “We found that the PIL receives synaptic inputs from both the IC and the AuCx”
    Quote in the paperSubstantial claim
  • Findingown data

    PIL connections preferentially targeted parvocellular oxytocin neurons.

    “and preferentially targeted parvocellular oxytocin neurons”
    Quote in the paperSubstantial claim
  • Findingown data

    A stimulation pattern emulating PIL responses in vivo during pup-call playback did not elicit suprathreshold spiking in oxytocin cells.

    “This stimulation pattern also did not elicit suprathreshold spiking in oxytocin cells”
    Quote in the paperSubstantial claim
  • May combine two claims. 30
  • The quote only partly states this claim. 1
  • Classified as probably not a substantial claim. 22

  • May combine two claims.

    Findingown data

    No retrograde rabies infection and mCherry staining was detected in the medial geniculate body, auditory cortex or inferior colliculus.

    “We did not detect retrograde rabies infection and mCherry staining in the medial geniculate body of the thalamus (MGB; Fig. 2c), the auditory cortex (AuCx; Fig. 2d) or the inferior colliculus (IC; Fig. 2e).”
    Quote in the paperSubstantial claim

  • May combine two claims. The quote only partly states this claim.

    Findingown data

    PIL inputs to oxytocin neurons occurred with high probability but were too weak to trigger postsynaptic spiking responses.

    “these connections were too weak to trigger postsynaptic spiking responses”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The sustained increase in oxytocin-neuron firing was specific to pup calls; PVN neurons did not respond to pure tones, adult calls or frequency-modulated down-sweeps.

    “The sustained increase in oxytocin-neuron firing was specific to pup calls, as PVN neurons did not respond to pure tones, adult calls or frequency-modulated down-sweeps that retained key spectrotemporal characteristics of pup vocalizations”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Optogenetic stimulation of PIL fibres activated NMDARs on oxytocin neurons, as it elicited outward oEPSCs that were blocked by AP5.

    “Optogenetic stimulation of PIL fibres activated NMDAR receptors on oxytocin neurons as it elicited outward oEPSCs, which were blocked by the NMDAR antagonist AP5 (P = 0.02; Fig. 3g).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    iLTD and the change in the IPSC/EPSC ratio were blocked by postsynaptic dynamin inhibitory peptide, but not by a scrambled control.

    “iLTD and the change in the IPSC/EPSC ratio were blocked by infusing the postsynaptic oxytocin neuron with a membrane-impermeable dynamin inhibitory peptide (i-Dynamin inhibitor) through the recording pipette, but not by a scrambled dynamin inhibitor”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    hM4Di dams had a decreased probability of retrieving at later trials, without changes in the time to retrieval.

    “these dams had a decreased probability of retrieving at later trials, without changes in the time to retrieval”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Both bath application of AP5 and intracellular delivery of MK801 abolished iLTD after PIL opto.

    “both bath application of AP5 and intracellular delivery of the use-dependent NMDAR blocker MK801 (i-MK801) through a recording pipette abolished iLTD after PIL opto”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In dams, PVN oxytocin neurons showed delayed and long-lasting increases in firing after exposure to pup calls but not after exposure to pure tones.

    “In dams, PVN oxytocin neurons showed delayed and long-lasting increases in firing after exposure to pup calls but not after exposure to pure tones”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingreasoning

    Multiple calls over several seconds were required to activate oxytocin cells through disinhibition and to induce dams to approach the speaker.

    “Multiple calls over several seconds were required to activate oxytocin cells through disinhibition and to induce dams to approach the speaker.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    ChR2+ OT+ neurons showed increased firing rate during pup calls while ChR2− OT− neurons did not.

    “Note increased firing rate for ChR2+ (OT+) neuron but not ChR2− (OT−) neuron.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Single pulse of optogenetic stimulation triggered postsynaptic potentials but did not induce spiking in oxytocin cells.

    “Single pulse of optogenetic stimulation triggered postsynaptic potentials but did not induce spiking in oxytocin cells (n = 8 neurons).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Prolonged but not brief optogenetic stimulation of PIL axons triggers iLTD.

    “Prolonged but not brief optogenetic stimulation of PIL axons triggers iLTD.”
    • Also stated in: § Extended Data · plain
      “Repeated but brief optogenetic stimulation of PIL axons (‘PIL opto short’) did not induce iLTD: example cell (d; p = 0.74, Mann–Whitney two-tailed test) and summary (e; n = 6 neurons, p = 0.99, one-sample two-tailed Student’s t-test).”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Suckling triggers the release of oxytocin.

    “Suckling triggers the release of oxytocin, but other sensory cues—specifically, infant cries—can increase the levels of oxytocin in new human mothers7”
    Quote in the paperNot a substantial claim0 of 6 sources checked
    • cites [1] Althammer, F. & Grinevich,. Diversity of oxytocin neurons: beyond magno- and parvocellular cell types?. J. Neuroendocrinol. 30, e12549 (2017). source

      Not checked in the free run.

    • cites [2] Jurek, B. & Neumann, I. D. The oxytocin receptor: from intracellular signaling to behavior. Physiol. Rev. 98, 1805–1908 (2018). source

      Not checked in the free run.

    • cites [3] Valtcheva, S. & Froemke, R. C. Neuromodulation of maternal circuits by oxytocin. Cell Tissue Res. 1, 57–68 (2019). source

      Not checked in the free run.

    • cites [4] Froemke, R. C. & Young, L. J. Oxytocin modulation and neural plasticity. Annu. Rev. Neurosci. 8, 359–381 (2021). source

      Not checked in the free run.

    • cites [5] Dulac, C., O’Connell, L. & Wu, Z. Neural control of maternal and paternal behaviors. Science 345, 1063–1069 (2014). source

      Not checked in the free run.

    • cites [6] Dölen, G. Oxytocin: parallel processing in the social brain? J. Neuroendocrinol. 27, 516–535 (2015). source

      Not checked in the free run.

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

    Premisecitation

    Oxytocin is important for maternal physiology and childcare, including parturition and milk ejection during nursing.

    “Oxytocin is a neuropeptide that is important for maternal physiology and childcare, including parturition and milk ejection during nursing1–6.”
    Quote in the paperNot a substantial claim0 of 6 sources checked
    • cites [1] Althammer, F. & Grinevich,. Diversity of oxytocin neurons: beyond magno- and parvocellular cell types?. J. Neuroendocrinol. 30, e12549 (2017). source

      Not checked in the free run.

    • cites [2] Jurek, B. & Neumann, I. D. The oxytocin receptor: from intracellular signaling to behavior. Physiol. Rev. 98, 1805–1908 (2018). source

      Not checked in the free run.

    • cites [3] Valtcheva, S. & Froemke, R. C. Neuromodulation of maternal circuits by oxytocin. Cell Tissue Res. 1, 57–68 (2019). source

      Not checked in the free run.

    • cites [4] Froemke, R. C. & Young, L. J. Oxytocin modulation and neural plasticity. Annu. Rev. Neurosci. 8, 359–381 (2021). source

      Not checked in the free run.

    • cites [5] Dulac, C., O’Connell, L. & Wu, Z. Neural control of maternal and paternal behaviors. Science 345, 1063–1069 (2014). source

      Not checked in the free run.

    • cites [6] Dölen, G. Oxytocin: parallel processing in the social brain? J. Neuroendocrinol. 27, 516–535 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    This circuit gates central oxytocin release and maternal behaviour in response to calls.

    “This circuit gates central oxytocin release and maternal behaviour in response to calls, providing a mechanism for the integration of sensory cues from the offspring in maternal endocrine networks to ensure modulation of brain state for efficient parenting.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Oxytocin is produced mainly in the paraventricular nucleus and supraoptic nucleus of the hypothalamus.

    “oxytocin, a nine-amino-acid peptide that is produced mainly in the paraventricular nucleus (PVN) and supraoptic nucleus of the hypothalamus1–4”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [1] Althammer, F. & Grinevich,. Diversity of oxytocin neurons: beyond magno- and parvocellular cell types?. J. Neuroendocrinol. 30, e12549 (2017). source

      Not checked in the free run.

    • cites [2] Jurek, B. & Neumann, I. D. The oxytocin receptor: from intracellular signaling to behavior. Physiol. Rev. 98, 1805–1908 (2018). source

      Not checked in the free run.

    • cites [3] Valtcheva, S. & Froemke, R. C. Neuromodulation of maternal circuits by oxytocin. Cell Tissue Res. 1, 57–68 (2019). source

      Not checked in the free run.

    • cites [4] Froemke, R. C. & Young, L. J. Oxytocin modulation and neural plasticity. Annu. Rev. Neurosci. 8, 359–381 (2021). source

      Not checked in the free run.

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

    Premisecitation

    Other neurons in the paralaminar thalamus are more efficiently driven by inputs from the IC than from the AuCx.

    “These findings are similar to those in other neurons in the paralaminar thalamus, which are more efficiently driven by inputs from the IC than those from the AuCx26.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [26] Smith, P. H. et al. Cortical and collicular inputs to cells in the rat paralaminar thalamic nuclei adjacent to the medial geniculate body. J. Neurophysiol. 98, 681–695 (2007). source

      Not checked in the free run.

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

    Premisecitation

    Peripheral oxytocin is important for milk ejection during nursing and uterine contractions during labour.

    “Peripheral oxytocin is important for milk ejection during nursing and uterine contractions during labour”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [5] Dulac, C., O’Connell, L. & Wu, Z. Neural control of maternal and paternal behaviors. Science 345, 1063–1069 (2014). source

      Not checked in the free run.

    • cites [6] Dölen, G. Oxytocin: parallel processing in the social brain? J. Neuroendocrinol. 27, 516–535 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Postpartum conditions might relate to lower oxytocin levels and decreased sensitivity to infant cries.

    “Postpartum conditions might relate to lower levels of oxytocin and decreased sensitivity to infant cries9”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [9] Pawluski, J. L., Lonstein, J. S. & Fleming, A. S. The neurobiology of postpartum anxiety and depression. Trends Neurosci. 40, 106–120 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In humans, most nursing mothers respond to baby cries with increased hypothalamic activity, rises in plasma oxytocin, comforting behaviours and occasional milk ejection.

    “In humans, baby cries are a powerful signal of infant distress, and most nursing mothers respond to cries with increased hypothalamic activity, rises in the levels of plasma oxytocin, comforting behaviours towards the infant and occasional milk ejection7,8.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [7] McNeilly, A. S., Robinson, I. C., Houston, M. J. & Howie, P. W. Release of oxytocin and prolactin in response to suckling. Br. Med. J. 286, 257–259 (1983). source

      Not checked in the free run.

    • cites [8] Bornstein, M. H. et al. Neurobiology of culturally common maternal responses to infant cry. Proc. Natl Acad. Sci. USA 114, E9465–E9473 (2017). source

      Not checked in the free run.

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

    Premisecitation

    The PIL has been implicated in maternal and social behaviours.

    “and has also been implicated in maternal and social behaviours22–24.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [22] Dobolyi, A., Cservenák, M. & Young, L. J. Thalamic integration of social stimuli regulating parental behavior and the oxytocin system. Front. Neuroendocrinol. 51, 102–115 (2018). source

      Not checked in the free run.

    • cites [23] Keller, D. et al. A thalamo-preoptic pathway promotes social grooming in rodents. Curr. Biol. 32, 4593–4606 (2022). source

      Not checked in the free run.

    • cites [24] Leithead, A. B., Godino, A., Barbier, M. & Harony-Nicolas, H. Social interaction elicits activity in glutamatergic neurons in the posterior intralaminar complex of the thalamus. Biol. Psychiatry https://doi.org/10.1016/j.biopsych.2023.05.016 (2023). source

      Not checked in the free run.

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

    Premisecitation

    Central oxytocin release is involved in behaviours including reproduction, parental care and pair bonding.

    “whereas oxytocin release in the central nervous system is involved in a wide range of behaviours including reproduction, parental care and pair bonding5,6.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [5] Dulac, C., O’Connell, L. & Wu, Z. Neural control of maternal and paternal behaviors. Science 345, 1063–1069 (2014). source

      Not checked in the free run.

    • cites [6] Dölen, G. Oxytocin: parallel processing in the social brain? J. Neuroendocrinol. 27, 516–535 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The PIL is part of the nonlemniscal auditory pathway that projects to the PVN.

    “The PIL is part of the nonlemniscal auditory pathway that projects to the PVN13,21,22”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [13] Tang, Y. et al. Social touch promotes interfemale communication via activation of parvocellular oxytocin neurons. Nat. Neurosci. 9, 1125–1137 (2020). source

      Not checked in the free run.

    • cites [21] Cai, D. et al. Distinct anatomical connectivity patterns differentiate subdivisions of the nonlemniscal auditory thalamus in mice. Cereb. Cortex 6, 2437–2454 (2018).

      Not checked in the free run.

    • cites [22] Dobolyi, A., Cservenák, M. & Young, L. J. Thalamic integration of social stimuli regulating parental behavior and the oxytocin system. Front. Neuroendocrinol. 51, 102–115 (2018). source

      Not checked in the free run.

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

    Premisecitation

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

    “PVN oxytocin cells receive projections from many areas of the brain”
    Quote in the paperNot a substantial claim0 of 7 sources checked
    • cites [3] Valtcheva, S. & Froemke, R. C. Neuromodulation of maternal circuits by oxytocin. Cell Tissue Res. 1, 57–68 (2019). source

      Not checked in the free run.

    • cites [10] Grinevich, V. & Stoop, R. Interplay between oxytocin and sensory systems in the orchestration of socio-emotional behaviors. Neuron 99, 887–904 (2018). source

      Not checked in the free run.

    • cites [11] Chini, B., Verhage, M. & Grinevich, V. The action radius of oxytocin release in the mammalian CNS: From single vesicles to behavior. Trends Pharmacol. Sci. 11, 982–991 (2017). source

      Not checked in the free run.

    • cites [12] Resendez, S. L. et al. Social stimuli induce activation of oxytocin neurons within the paraventricular nucleus of the hypothalamus to promote social behavior in male mice. J. Neurosci. 40, 2282–2295 (2020). source

      Not checked in the free run.

    • cites [13] Tang, Y. et al. Social touch promotes interfemale communication via activation of parvocellular oxytocin neurons. Nat. Neurosci. 9, 1125–1137 (2020). source

      Not checked in the free run.

    • cites [14] Carcea, I. et al. Oxytocin neurons enable social transmission of maternal behaviour. Nature 596, 553–557 (2021). source

      Not checked in the free run.

    • cites [15] Yukinaga, H. et al. Recording and manipulation of the maternal oxytocin neural activities in mice. Curr. Biol. 32, 3821–3829 (2022). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Pup vocalizations can activate PVN oxytocin neurons, but not with stimulus-locked responses.

    “These results show that pup vocalizations can activate PVN oxytocin neurons, but not with stimulus-locked responses such as those typically observed in the central auditory system”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Blocking oxytocin signalling in the VTA produces a more marked reduction of pup-retrieval behaviour than selective chemogenetic inhibition of upstream PIL inputs to the PVN.

    “This effect is possibly because blocking oxytocin signalling in the VTA produces a more marked reduction of pup-retrieval behaviour than does selective chemogenetic inhibition of upstream PIL inputs to the PVN.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Hypothalamic inhibition increases during lactation and might prevent activation of oxytocin neurons by sparse synaptic inputs.

    “Hypothalamic inhibition increases during lactation46 and might prevent the activation of oxytocin neurons by sparse synaptic inputs”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [46] Giesl, U. & Theodosis, T. Synaptic plasticity in the rat supraoptic nucleus during lactation involves GABA innervation and oxytocin neurons: a quantitative immunocytochemical analysis. J. Neurosci. 5, 2861–2869 (1994). source

      Not checked in the free run.

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

    Study design and conductnone given

    Sample sizes were chosen to reliably measure experimental effects while minimizing the number of animals used.

    “Sample sizes were chosen to reliably measure experimental effects while minimizing the number of animals used in accordance with ethical guidelines.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Parvocellular neurons can directly activate magnocellular neurons and have been proposed to operate as master cells that control the activity of magnocellular cells and gate oxytocin release.

    “Parvocellular neurons can also directly activate magnocellular neurons and have been proposed to operate as ‘master cells’ that control the activity of magnocellular cells and gate oxytocin release1,13.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [1] Althammer, F. & Grinevich,. Diversity of oxytocin neurons: beyond magno- and parvocellular cell types?. J. Neuroendocrinol. 30, e12549 (2017). source

      Not checked in the free run.

    • cites [13] Tang, Y. et al. Social touch promotes interfemale communication via activation of parvocellular oxytocin neurons. Nat. Neurosci. 9, 1125–1137 (2020). source

      Not checked in the free run.

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

    Study design and conductown data

    Experiments were repeated independently with similar results for: N = 6 mice, Fig. 1b; N = 7, Fig. 1i; N = 4, Fig. 2b-e; N = 27, Fig. 4b; N = 5, Fig. 5e,f; N = 4, Fig. 5g; N = 5, Fig. 5h; N = 4, Fig. 5j; N = 6, Extended Data Fig. 4a.

    “Experiments were repeated independently with similar results for: N = 6 mice, Fig. 1b; N = 7, Fig. 1i; N = 4, Fig. 2b–e; N = 27, Fig. 4b; N = 5, Fig. 5e,f; N = 4, Fig. 5g; N = 5, Fig. 5h; N = 4, Fig. 5j; N = 6, Extended Data Fig. 4a.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    No statistical methods were used to predetermine sample 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).

    Study design and conductreasoning

    Blinding was not performed for in vivo cell-attached, whole-cell and tungsten recordings, fiber photometry experiments, oxytocin sensor experiments and in vitro whole-cell recordings because stimuli were performed in real time by the experimenter.

    “Blinding was not relevant and not performed for in vivo cell-attached, whole-cell and tungsten recordings, fiber photometry experiments, oxytocin sensor experiments and in vitro whole-cell recordings because auditory stimuli/optogenetic stimulation in vivo, and optogenetic/electrical stimulation and/or pharmacological application in vitro were performed in real time by the experimenter.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Enhanced firing of PVN oxytocin neurons after pup calls can lead to central oxytocin release in downstream brain areas controlling pup retrieval such as the VTA, and this effect is mediated by activation of PIL inputs to the PVN.

    “This shows that the enhanced firing of PVN oxytocin neurons after pup calls can lead to central oxytocin release in downstream brain areas controlling pup retrieval such as the VTA, and that this effect is mediated by the activation of PIL inputs to the PVN.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    Animals were randomly assigned to different groups.

    “Animals were randomly assigned to different groups.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Postsynaptic NMDARs regulate excitability and trigger somatodendritic oxytocin release.

    “Postsynaptic NMDARs also regulate excitability48,49 and trigger somatodendritic oxytocin release47.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [47] de Kock, C. P. J., Burnashev, N., Lodder, J. C., Mansvelder, H. D. & Brussaard, A. B. NMDA receptors induce somatodendritic secretion in hypothalamic neurones of lactating female rats. J. Physiol. 561, 53–64 (2004). source

      Not checked in the free run.

    • cites [48] Fleming, T. M. et al. State-dependent changes in astrocyte regulation of extrasynaptic NMDA receptor signalling in neurosecretory neurons. J. Physiol. 16, 3929–3941 (2011). source

      Not checked in the free run.

    • cites [49] Naskar, K. & Stern, J. E. A functional coupling between extrasynaptic NMDA receptors and A-type K+ channels under astrocyte control regulates hypothalamic neurosecretory neuronal activity. J. Physiol. 592, 2813–2827 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    PIL inputs onto parvocellular neurons controlled central oxytocin release and the efficiency of pup retrieval over time.

    “PIL inputs onto parvocellular neurons controlled central oxytocin release and the efficiency of pup retrieval over time.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    PIL opto rapidly triggers iLTD in oxytocin neurons through postsynaptic NMDARs and dynamin signalling, possibly triggering internalization of postsynaptic GABAARs.

    “These findings suggest that PIL opto rapidly triggers iLTD in oxytocin neurons through postsynaptic NMDARs and dynamin signalling, possibly triggering the internalization of postsynaptic GABAARs to decrease inhibitory transmission and increase spiking output.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Persistent activity seems to be a hallmark of hypothalamic neurons, which can be highly interconnected and have long integration periods.

    “Persistent activity seems to be a hallmark of hypothalamic neurons, which can be highly interconnected and have long integration periods42–45.”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [42] Iremonger, K. J. & Bains, J. S. Integration of asynchronously released quanta prolongs the postsynaptic spike window. J. Neurosci. 27, 6684–6691 (2007). source

      Not checked in the free run.

    • cites [43] Branco, T. et al. Near-perfect synaptic integration by Nav1.7 in hypothalamic neurons regulates body weight. Cell 165, 1749–1761 (2016). source

      Not checked in the free run.

    • cites [44] Kennedy, A. et al. Stimulus-specific hypothalamic encoding of a persistent defensive state. Nature 586, 730–734 (2020). source

      Not checked in the free run.

    • cites [45] Daviu, N. et al. Paraventricular nucleus CRH neurons encode stress controllability and regulate defensive behavior selection. Nat. Neurosci. 23, 398–410 (2020). source

      Not checked in the free run.

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

    Study design and conductnone given

    Investigators were blinded to allocation during behavioral testing, fiber photometry data analysis and oxytocin sensor data analysis.

    “The investigators were blinded to allocation during behavioral testing, fiber photometry data analysis and oxytocin sensor data analysis.”
    Quote in the paperNot a substantial claim

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

    Interpretationreasoning

    Parvocellular neurons can regulate or control oxytocin release into different brain areas such as the VTA according to animal state and sensory experience.

    “This would allow parvocellular neurons to regulate or control oxytocin release into different brain areas such as the VTA according to animal state and sensory experience.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Detection of endogenously released oxytocin in the VTA of female and male mice during social interactions has been previously demonstrated using OXTR-iTango2.

    “Detection of endogenously released oxytocin in the VTA of female and male mice during social interactions has been previously demonstrated using OXTR-iTango2 (ref. 40).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [40] Mignocchi, N., Jung, K., Lee, D. & Kwon, H.-B. Development of a genetically-encoded oxytocin sensor. Preprint at bioRxiv https://doi.org/10.1101/2020.07.14.202598 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Oxytocin-neuron NMDARs can be activated without postsynaptic spiking, suggesting that prolonged subthreshold activation of oxytocin cells is sufficient to induce NMDAR-dependent inhibitory LTD.

    “Oxytocin-neuron NMDARs can be activated without the need for postsynaptic spiking47, suggesting that even if PIL inputs are too weak to trigger action potentials, prolonged subthreshold activation of oxytocin cells is sufficient to induce NMDAR-dependent inhibitory LTD.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [47] de Kock, C. P. J., Burnashev, N., Lodder, J. C., Mansvelder, H. D. & Brussaard, A. B. NMDA receptors induce somatodendritic secretion in hypothalamic neurones of lactating female rats. J. Physiol. 561, 53–64 (2004). source

      Not checked in the free run.

  • 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

  • Classified as probably not a substantial claim.

    Premisecitation

    PIL lesions can impair pup-retrieval behaviour.

    “PIL lesions can impair pup-retrieval behaviour34.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [34] Factor, E. M., Mayer, A. D. & Rosenblatt, J. S. Peripeduncular nucleus lesions in the rat: I. Effects on maternal aggression, lactation, and maternal behavior during pre- and postpartum periods. Behav. Neurosci. 107, 166–185 (1993). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    The paper defines a noncanonical auditory circuit from the PIL to hypothalamic oxytocin neurons, which relays infant distress sounds to induce release of oxytocin and affect maternal behaviour.

    “Here we define a noncanonical auditory circuit from the PIL to hypothalamic oxytocin neurons, which relays infant distress sounds to induce the release of oxytocin and affect maternal behaviour.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    Recordings were excluded from analysis if the access resistance (Ra) changed by more than 30% compared to baseline.

    “Recordings were excluded from analysis if the access resistance (Ra) changed by more than 30% compared to baseline.”
    Quote in the paperNot a substantial claim
46 of 46

  • The paper relies on this without support.

    Mouse pup distress vocalizations are a valid model for human infant cries in studying maternal oxytocin release.

    “Here we describe a neural circuit that routes auditory information about infant vocalizations to mouse oxytocin neurons.”
    “In humans, baby cries are a powerful signal of infant distress, and most nursing mothers respond to cries with increased hypothalamic activity, rises in the levels of plasma oxytocin, comforting behaviours towards the infant and occasional milk ejection7,8.”
1 of 1

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Each is checked against this paper’s own text: does it say what the citing paper says it does?

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.

  • Random assignment conflicts with nonrandomized experiments

    Major

    The Methods state both that animals were randomly assigned to groups and that the experiments were not randomized.

  • Dark-cycle start times disagree

    Minor

    The stated light period ends at 18:30, but a later sentence says the dark cycle starts at 18:00.

  • Statistical test is described as both one- and two-tailed

    Minor

    The Extended Data Fig. 3 caption calls its test one-tailed, while the Statistics section specifies a two-tailed test for Extended Data Fig. 3a-h.

3 of 3

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Authors
Valtcheva, S., Issa, H. A., Bair-Marshall, C. J., Martin, K. A., Jung, K., Zhang, Y., Kwon, H.-B., & Froemke, R. C.
Affiliations
  • NYU Langone Health (US)
  • Johns Hopkins University (US)
  • New York University (US)
Corresponding author
  • Valtcheva, Silvana
  • Froemke, Robert C.
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2023-09-20
Volume
621
Issue
7980
Pages
788-795
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/s41586-023-06540-4
PMC
PMC10639004
OpenAlex
W4386886852
Cited by
115
References
74
Citations by year
2026: 24 · 2025: 42 · 2024: 30 · 2023: 10 · 2022: 6 · 2021: 3
FWCI
31.31
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • Research Square (acceptedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
Funders
  • National Science Foundation (HD088411)
  • Leon Levy Foundation
  • National Alliance for Research on Schizophrenia and Depression
  • National Institute of Mental Health (DP1MH119428, T32MH019524)
  • National Institute on Deafness and Other Communication Disorders (DC12557, HD088411, R01DC012557)
  • National Institute of Neurological Disorders and Stroke (P01NS074972, U19NS107616)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD088411)
Topics
  • Social Sciences › Psychology › Social Psychology › Neuroendocrine regulation and behavior
  • Health Sciences › Health Professions › Pharmacy › Infant Health and Development
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
Keywords
oxytocin, maternal behavior, infant crying, pup vocalizations, auditory thalamus, neural circuits, disinhibition, sensory cue integration
MeSH terms
Animals, Cues, Female, Hypothalamus, Maternal Behavior, Neural Pathways, Neurons, Oxytocin, Photometry, Thalamic Nuclei, Vocalization, Animal, Wakefulness, 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 2026-10-10.

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

Statistics and arithmetic are recomputed, not judged.

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