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Cited by 291Neuroendocrine regulation and behaviorMemory and Neural MechanismsNeuroscience and Neuropharmacology Research

Neuronal Representation of Social Information in the Medial Amygdala of Awake Behaving Mice

Open access
Li, Ying, Mathis, Alexander, Grewe, Benjamin F., Osterhout, Jessica A., Ahanonu, Biafra, Schnitzer, Mark J., Murthy, Venkatesh N., Dulac, Catherine·2017·Cell
DOI 10.1016/j.cell.2017.10.015PMC PMC5731476
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Abstract

SUMMARY The medial amygdala (MeA) plays a critical role in processing species- and sex-specific signals that trigger social and defensive behaviors. However, the principles by which this deep brain structure encodes social information is poorly understood. We used a miniature microscope to image the Ca2+ dynamics of large neural ensembles in awake behaving mice and tracked the responses of MeA neurons over several months. These recordings revealed spatially intermingled subsets of MeA neurons with distinct temporal dynamics. The encoding of social information in the MeA differed between males and females and relied on information from both individual cells and neuronal populations. By performing long-term Ca2+ imaging across different social contexts, we found that sexual experience triggers lasting and sex-specific changes in MeA activity, which, in males, involve signaling by oxytocin. These findings reveal basic principles underlying the brain’s representation of social information and its modulation by intrinsic and extrinsic factors.

AI snapshot

Written from the paper’s full text.

TL;DR

Using miniature-microscope Ca2+ imaging in awake mice, this study shows that medial amygdala (MeA) neurons represent social cues through spatially intermingled, sex-dependent, and experience-dependent population codes. Sexual experience produces lasting, sex-specific changes in MeA social representation, with oxytocin receptor signaling contributing to these changes in males.

Key findings

  • In the MeApd, 203 ± 58 putative neurons were monitored simultaneously per animal per session across 10 males and 8 females; 87% ± 3% of monitored cells showed significant response strength to at least one social stimulus, while 13% ± 3% did not track social contact.
  • Response types were similar in males and females except mixed responses were more abundant in females (22% ± 3% in males vs. 31% ± 2% in females, p < 0.0001); neurons with the same response type were spatially intermingled, with nearest-neighbor clustering indistinguishable from shuffled data (p = 0.86).
  • Population coding outperformed single neurons: discrimination between social stimuli increased with ensemble size, and female-male discriminability was 74% higher in sessions with fighting/mating than in sessions without these behaviors.
  • Sexual experience changed MeA representation: in males, neurons responding to female cues rose from 46% ± 6% in virgins to 53% ± 6% in co-housed males and 56% ± 7% in experienced males, with no comparable increase in divider-separated controls; specific female-cue encoding rose from 20% ± 2% to 32% ± 6%.
  • Oxytocin receptor antagonism (OTR-A) in sexually experienced males steeply decreased female-male discrimination and lowered the probability of fighting/mating, but had no such effect in experienced females; 73% ± 3% of OXTR-expressing MeApd neurons were vGAT+ and 16% ± 1% were vGlut2+.

Methods

  • Awake behaving mice were imaged with a head-mounted miniature microscope and chronic GRIN lens after AAV2/5-CaMKIIα-GCaMP6m injection into MeApd; social stimuli were adult female, adult male, pups (P0–P5), male rat soiled bedding, and a non-social object, presented in 5-min trials every 5 days across virgin, co-housed, and experienced phases for about 60 days.
  • Neural data were processed with PCA/ICA cell sorting, cross-session image registration, ΔF/F normalization, and fast nonnegative deconvolution; analyses included ROC-based response strength, k-means clustering, linear discriminant analysis d′, Mahalanobis population vector distance, and logistic regression decoding.
  • Oxytocin involvement was tested with intraperitoneal saline or OTR-A (L-368,899, 5 mg/kg) in sexually experienced mice; RNAscope and histology assessed OXTR, vGAT, and vGlut2 expression and implant locations.

Limitations

  • The paper states that datasets with large field-of-view displacements were ignored (<10% of all datasets) and that sessions without proper day-to-day alignment were excluded; it also notes that a within-trial decrease in female-male response difference “might result from sensory adaptation.”
  • Evident from the text: social contacts were manually scored, oxytocin manipulation was systemic rather than circuit-specific, and the study reports correlational links between population discrimination and behavior rather than direct causal circuit manipulation.
  • Evident from the text: sample sizes were 10 males and 8 females, and several conclusions about sex-specific oxytocin effects rest on OTR-A comparisons in experienced animals.

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

Integrity signals

Registry

Crossref · 10.1016/j.cell.2017.10.015

Cites

Statistics

Nothing to recompute.

Claims the paper makes

0 of 57 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Sexual experience triggers lasting and sex-specific changes in MeA activity.

    “By performing long-term Ca2+ imaging across different social contexts, we found that sexual experience triggers lasting and sex-specific changes in MeA activity, which, in males, involve signaling by oxytocin.”
    Quote in the paperSubstantial claim
  • Findingown data

    Only a minority (2% ± 1%) of GCaMP6m-expressing neurons were vGLUT+.

    “The majority (71% ± 3%) of GCaMP6m-expressing neurons were vGAT+ neurons, whereas only a minority (2% ± 1%) were vGLUT+.”
    Quote in the paperNot a substantial claim
  • Findingown data

    MeApd recordings revealed spatially intermingled subsets of MeA neurons with distinct temporal dynamics.

    “These recordings revealed spatially intermingled subsets of MeA neurons with distinct temporal dynamics.”
    Quote in the paperSubstantial claim
  • Findingown data

    The encoding of social information in the MeA differed between males and females.

    “The encoding of social information in the MeA differed between males and females and relied on information from both individual cells and neuronal populations.”
    Quote in the paperSubstantial claim
  • Findingown data

    By statistical clustering of cells with similar activity patterns, six distinct activity groups were identified, characterized by either transient or persistent excitation or inhibition to specific stimuli.

    “By statistical clustering of cells with similar activity patterns (STAR Methods), we identified six distinct activity groups characterized by either transient or persistent excitation or inhibition to specific stimuli (Figures 1D–1G).”
    Quote in the paperSubstantial claim
  • May combine two claims. 47
  • Classified as probably not a substantial claim. 30

  • May combine two claims.

    Findingown data

    No neuronal subset in males or females displayed significant increase in activity that persisted after the end of the interaction with predator cues or showed decrease associated with the stimulus termination.

    “Interestingly, no neuronal subset in males or females displayed significant increase in activity that persisted after the end of the interaction with predator cues or showed decrease associated with the stimulus termination (Figure 1G).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Subsets of neurons were more active during interactions with particular stimuli, with unequal responses during different interaction epochs.

    “These examples, and summary results from all animals across different days (Figure S3A), show that subsets of neurons were more active during interactions with particular stimuli, with unequal responses during different interaction epochs.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Individual neurons that are selectively responsive to particular social stimuli did not respond equally across different interaction epochs and sometimes failed to respond to certain epochs.

    “However, individual neurons that are selectively responsive to particular social stimuli did not respond equally across different interaction epochs and sometimes failed to respond to certain epochs (Figures 3E and S3E).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Responses were significantly larger for certain cues over others and reliable across multiple epochs.

    “Responses were significantly larger for certain cues over others (Figures 2C and S3A) and reliable across multiple epochs (Figures 2D and S3B; STAR Methods).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In virgin males, similar fractions of neurons were sensitive to female (46% ± 6%), male (48% ± 6%), and pup cues (41% ± 8%), and the number of neurons responding to females was significantly smaller than that in virgin females (58% ± 7%).

    “In virgin males, similar fractions of neurons were sensitive to female (46% ± 6%), male (48% ± 6%), and pup cues (41% ± 8%), and the number of neurons responding to females was significantly smaller than that in virgin females (58% ± 7%) (Figure 5B, residential male, blue bars, mean ± SD).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In mated males, the fraction of cells responding to female cues increased to a number similar to that of mated females (from 46% ± 6% in virgin males to 53% ± 6% in co-housed males), and this increase continued through the subsequent 30 days of social isolation from the female partner (experienced males: 56% ± 7%).

    “However, in mated males, the fraction of cells responding to female cues increased to a number similar to that of mated females (Figure 5B, responses to female cues in residential male changed from 46% ± 6% in virgin males to 53% ± 6% in co-housed males, mean ± SD), and this increase continued through the subsequent 30 days of social isolation from the female partner (Figure 5B, experienced males:”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    87% ± 3% of monitored cells showed significant RS values in response to at least one social stimulus, while the remaining 13% ± 3% showed spontaneous activity that was not temporally correlated with social contact.

    “Altogether, 87% ± 3% of the monitored cells showed significant RS values in response to at least one social stimulus, while the remaining 13% ± 3% showed spontaneous activity that was not temporally correlated with social contact.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    No significant difference was observed in the number of neurons responding to social cues and in the tuning selectivity and responsive strength between the two types of trials.

    “Importantly, no significant difference was observed in the number of neurons responding to social cues and in the tuning selectivity and responsive strength between the two types of trials (Figures S4G–S4I).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In the presence of a receptive female or an intruder male, some resident males only investigated the intruder during a 5 min trial, while others additionally engaged in effective reproductive or defensive behavior according to the intruder's sex.

    “In the presence of a receptive female or an intruder male, some resident males only investigated the intruder during a 5 min trial, while the others additionally engaged in effective reproductive or defensive behavior according to the intruder’s sex.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The fractions of cells displaying each type of response were similar in males and females, except for neurons with mixed responses, which were more abundant in females than in males (p < 0.0001).

    “The fractions of cells displaying each type of response were similar in males and females, except for neurons with mixed (i.e., increased and decreased) responses, which were more abundant in females than in males (Figures 3F and 3G, p < 0.0001, χ2 test).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Calcium signals (DF/F) of responsive neurons were temporally locked to social stimuli, with different stimulus selectivity.

    “Calcium signals (DF/F) of responsive neurons were temporally locked to social stimuli (Figure 3C), with different stimulus selectivity (Figures S3C and S3D).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In sexually experienced females, the fractions of neurons responding to female and male cues was higher than that responding to pups and rat-soiled bedding, which is consistent with data from virgin females.

    “In sexually experienced females, the fractions of neurons responding to female and male cues was higher than that responding to pups and rat-soiled bedding, which is consistent with data from virgin females (Figure 5B, residential female, red bars).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    76% ± 11% of MeApd responsive neurons only respond to conspecific cues, 5% ± 1% only respond to predator cues, and 19% ± 5% respond to both types of stimuli.

    “Our data show that 76% ± 11% of MeApd responsive neurons only respond to conspecific cues, 5% ± 1% only respond to predator cues, and 19% ± 5% respond to both types of stimuli (Figure 4A).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Neuronal responses to pups also rose significantly in males and females after sexual experience, as well as in virgin males co-housed but physically separated from a female partner.

    “Neuronal responses to pups also rose significantly in males and females after sexual experience, as well as in virgin males co-housed but physically separated from a female partner, suggesting that exposure to female cues rather than sexual contact is sufficient for neuronal plasticity in responses to pups.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Although the numbers of neurons responding to male and pup cues were not changed after sexual experience, the discrimination between these cues was increased at the population level.

    “Although our data revealed that the numbers of neurons responding to male and pup cues were not changed after sexual experience (Figure 5C), the discrimination between these cues was increased at the population level, which may relate to the increase of response strength to both stimuli in all individualized neurons (Figure 5B).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In males, the normalized d′ between responses to female/male, female/pups, and male/pups were significantly increased (by 74%, 56%, and 86%, respectively) after co-housing with a female partner, which was not observed in virgin males.

    “In males, the normalized d′ between responses to female/male, female/ pups, and male/pups were significantly increased (by 74%, 56%, and 86%, respectively) after co-housing with female partner (Figure 6B, blue), which was not observed in virgin males (Figure 6B, gray).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    There was a preferential representation of male and predator cues in sexually experienced females compared to males, with more neurons responding to male (experienced males, 43% ± 9%; experienced females, 54% ± 8%) and rat bedding (co-housed males, 20% ± 8%; co-housed females, 30 ± 8%) in mated females than in mated males.

    “Interestingly, we also observed a preferential representation of male and predator cues in sexually experienced females compared to males, with more neurons responding to male (experienced males, 43% ± 9%; experienced females, 54% ± 8%, mean ± SD) and rat bedding (co-housed males, 20% ± 8%; co-housed females, 30 ± 8%, mean ± SD) in mated females than in mated males (Figure 5B).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    No significant difference in response selectivity was observed in control males separated from females by a divider or in females throughout various social phases.

    “No significant difference in response selectivity was observed in control males separated from females by a divider (Figure 5C, middle) or in females throughout various social phases (Figure 5C, right).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In both males and females, the RS to female and male stimuli rose significantly during and after sexual experience, and these changes were maintained for at least 3 weeks after social isolation.

    “In both males and females, the RS to female and male stimuli rose significantly during and after sexual experience, and these changes were maintained for at least 3 weeks after social isolation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Such plasticity was less pronounced in control males separated from females by a divider, except for a transient increase in response to female stimuli during the co-housing phase.

    “Such plasticity was less pronounced in control males separated from females by a divider, except for a transient increase in response to female stimuli during the co-housing phase (Figure 5D).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In sexually experienced females, there was an enhancement of social discrimination between male and the other two conspecific cues including female (45% increase) and pup (40% increase), which was observed only at the population level.

    “Similarly, in sexually experienced females, we observed an enhancement of social discrimination between male and the other two conspecific cues including female (45% increase) and pup (40% increase), which was observed only at population level.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingnone given

    Information about social events is present in some individual neurons but is significantly more robust and reliable at the population level.

    “information about these events is present in some individual neurons but is significantly more robust and reliable at the population level.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    When treated with OTR-A, sexually experienced males showed a steep decrease in discrimination of female and male cues, though it remained higher than that in virgin males.

    “However, when treated with OTR-A, sexually experienced males showed a steep decrease in discrimination of female and male cues, though it remained higher than that in virgin males (Figure 7A).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The MeA representation seen in virgin animals is transformed by mating, as pronounced and long-lasting preferential responsiveness to opposite-sex odors emerges in both males and females following a transient period of sexual experience but not in animals cohabitating without sexual experience.

    “Remarkably, the MeA representation seen in virgin animals is transformed by mating, as we see a pronounced and long-lasting preferential responsiveness to opposite-sex odors emerging in both males and females following a transient period of sexual experience but not in animals cohabitating without sexual experience.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Experience-dependent plasticity preferentially enhances the discrimination of social cues from the opposite sex in both males and females, and this change persists and even further develops in both males and females for at least 1 month after the animal is separated from its mating partner.

    “Intriguingly, such experience-dependent plasticity preferentially enhances the discrimination of social cues from the opposite sex in both males and females, and this change persists and even further develops in both males and females for at least 1 month after the animal is separated from its mating partner.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The RS value correlates strongly with reliabilities and weaker with response amplitude.

    “Moreover, the RS value correlates strongly with the reliabilities (Figure S3G) and weaker with the response amplitude (Figure S3F).”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Vomeronasal receptors detect pheromonal cues emitted during social encounters, leading to activation of distinct neural ensembles in the vomeronasal organ.

    “Vomeronasal receptors (VRs) detect pheromonal cues emitted during social encounters, leading to the activation of distinct neural ensembles in the vomeronasal organ (VNO) (Dulac and Torello, 2003; Holy et al., 2000; Isogai et al., 2011).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Dulac and Torello, 2003

      Not checked in the free run.

    • cites Holy et al., 2000 source

      Not checked in the free run.

    • cites Isogai et al., 2011 source

      Not checked in the free run.

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

    Premisecitation

    In rodents, processing of animal cues by the vomeronasal system is essential for discrimination of sex-specific social signals and identification of predators.

    “In rodents, the processing of animal cues by the vomeronasal system is essential for the discrimination of sex-specific social signals and identification of predators (Dulac and Torello, 2003; Ben-Shaul et al., 2010; Kimchi et al., 2007; Stowers et al., 2002).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Dulac and Torello, 2003

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    • cites Ben-Shaul et al., 2010 source

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    • cites Kimchi et al., 2007 source

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

    Premisecitation

    Axons from VNO neurons expressing a given VR project to multiple glomeruli in the accessory olfactory bulb, where they form synaptic connections with AOB mitral/tufted cells, and AOB mitral cells form synapses within multiple glomeruli.

    “In turn, axons from VNO neurons expressing a given VR project to multiple glomeruli in the accessory olfactory bulb (AOB) (Belluscio et al., 1999; Rodriguez et al., 1999), where they form synaptic connections with AOB mitral/tufted cells, and AOB mitral cells form synapses within multiple glomeruli (Wagner et al., 2006).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Belluscio et al., 1999 source

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    • cites Rodriguez et al., 1999 source

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    • cites Wagner et al., 2006 source

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

    Premisecitation

    Fos induction following social interactions showed widely dispersed response patterns.

    “Electrical recordings in the MeApd of anesthetized mice have revealed sex-dependent differences in the neural responses to social cues (Bergan et al., 2014), while Fos induction following social interactions showed widely dispersed response patterns (Carvalho et al., 2015; Choi et al., 2005).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Carvalho et al., 2015 source

      Not checked in the free run.

    • cites Choi et al., 2005 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The MeApd comprises GABAergic and glutamatergic neurons at an approximate ratio of 2:1, with GABAergic neurons representing the major population of projection neurons driving social responses.

    “The MeApd comprises GABAergic and glutamatergic neurons at an approximate ratio of 2:1, with GABAergic neurons representing the major population of projection neurons driving social responses (Choi et al., 2005; Hong et al., 2014; Keshavarzi et al., 2014).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Choi et al., 2005 source

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    • cites Hong et al., 2014 source

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    • cites Keshavarzi et al., 2014 source

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

    Interpretationreasoning

    Already in the AOB the circuitry may achieve a broad integration of chemical information.

    “These anatomical features indicate that already in the AOB the circuitry may achieve a broad integration of chemical information.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Electrical recordings in the MeApd of anesthetized mice have revealed sex-dependent differences in the neural responses to social cues.

    “Electrical recordings in the MeApd of anesthetized mice have revealed sex-dependent differences in the neural responses to social cues (Bergan et al., 2014), while Fos induction following social interactions showed widely dispersed response patterns (Carvalho et al., 2015; Choi et al., 2005).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Bergan et al., 2014 source

      Not checked in the free run.

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

    Premisenone given

    How large neuronal ensembles represent social information in awake animals, and how this representation depends on sex, physiological status, or previous social experience, is still not understood.

    “How large neuronal ensembles represent social information in awake animals—and how this representation depends on the animal’s sex, physiological status, or previous social experience and hence modulates behavioral responses—is still not understood.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    AOB mitral cells project primarily to the medial amygdala, which in turn connects to hypothalamic regions associated with the control of social behaviors.

    “AOB mitral cells project primarily to the medial amygdala (MeA), which in turn connects to hypothalamic regions associated with the control of social behaviors (Keshavarzi et al., 2014).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Keshavarzi et al., 2014 source

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  • May combine two claims.

    Interpretationreasoning

    Although changes in social interaction patterns with females are detected after sexual experience, it is unlikely that they contribute to the observed increase in female-encoding neurons.

    “Therefore, although changes in social interaction patterns with females are detected after sexual experience (Figures S2C–S2E), it is unlikely that they contribute to the observed increase.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Under conditions where single neurons are noisy and unreliable or when diverse stimulus features need to be integrated, population coding can be more effective.

    “Under conditions where single neurons are noisy and unreliable or when diverse stimulus features need to be integrated, population coding can be more effective (Averbeck et al., 2006).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Averbeck et al., 2006 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    The neural representations of distinct social stimuli appear spatially intermingled in the MeApd, without any obvious anatomical clustering of functionally distinct cell ensembles.

    “Thus, the neural representations of distinct social stimuli appear spatially intermingled in the MeApd, without any obvious anatomical clustering of functionally distinct cell ensembles.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Interpretationown data

    The decrease in response difference after mating/fighting might result from sensory adaptation.

    “It is not significantly different from that observed in males without sex-related behaviors (decrease by 43%) in a given trial (Figures S4A and S4B; STAR Methods), which might result from sensory adaptation.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    The RS-score summarizes measures for both response strength and reliability.

    “We verified that the RS-score summarizes measures for both response strength and reliability (Figures 3D, 3E, and S3E–S3G) and used significant RS values to calculate signal strength for each neuron to a particular stimulus.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    The fraction of cells in males responding specifically to female cues rose significantly after co-housing with a mating partner, and sexual experience was essential for the long-term maintenance of these changes.

    “Therefore, the fraction of cells in males responding specifically to female cues rose significantly after co-housing with a mating partner, and sexual experience was essential for the long-term maintenance of these changes.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductown data

    Randomly selecting the same number of neurons across different experience states does not affect the conclusion because trends in d′ across sessions appear similar irrespective of the size of the neuronal population considered.

    “This selection does not affect the conclusion because trends in d′ across sessions appear similar irrespective of the size of the neuronal population considered (Figure 6A).”
    Quote in the paperSubstantial claim

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

    Premisecitation

    The AOB sends major projections to the MeA.

    “In turn, the AOB sends major projections to the MeA (Mohedano-Moriano et al., 2007)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Mohedano-Moriano et al., 2007 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    The neuropeptide oxytocin (OT) is implicated in the modulation of many social responses.

    “The neuropeptide oxytocin (OT) is implicated in the modulation of many social responses (Ross and Young, 2009; Insel and Hulihan, 1995; Ferguson et al., 2001; Dölen et al., 2013).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Ross and Young, 2009 source

      Not checked in the free run.

    • cites Insel and Hulihan, 1995 source

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    • cites Ferguson et al., 2001 source

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

    Premisecitation

    VNO neurons expressing a given VR project to multiple and spatially distributed glomeruli in the AOB, while AOB output neurons send dendrites to multiple glomeruli.

    “VNO neurons expressing a given VR project to multiple and spatially distributed glomeruli in the AOB, while AOB output neurons send dendrites to multiple glomeruli (Belluscio et al., 1999; Dulac and Torello, 2003; Wagner et al., 2006).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Belluscio et al., 1999 source

      Not checked in the free run.

    • cites Dulac and Torello, 2003

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    • cites Wagner et al., 2006 source

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  • May combine two claims.

    Premisecitation

    Activation of MeA neurons is highly dependent on VNO-mediated detection of pheromones, confirming a primary role in sensory processing of VNO information.

    “and the activation of MeA neurons is highly dependent on VNO-mediated detection of pheromones, confirming a primary role in sensory processing of VNO information (Carvalho et al., 2015).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Carvalho et al., 2015 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    OT may directly affect GABAergic neurons in the MeApd and thus alter the social representation by these neurons.

    “These results indicate that OT may indeed directly affect GABAergic neurons in the MeApd and thus alter the social representation by these neurons.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The majority of the neurons recorded in the study are vGAT+.

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

    Premisecitation

    At the level of the accessory olfactory bulb, mating causes a lasting increase in baseline activity by selective regulation of local inhibition.

    “At the level of the accessory olfactory bulb, mating causes a lasting increase in baseline activity by selective regulation of local inhibition (Binns and Brennan, 2005).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Binns and Brennan, 2005

      Not checked in the free run.

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

    Premisecitation

    Adult neurogenesis in the AOB can be regulated by sex hormones.

    “Furthermore, recent work shows that adult neurogenesis in the AOB can be regulated by sex hormones, suggesting another mechanism by which sexual experience can regulate early sensory processing (Schellino et al., 2016).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Schellino et al., 2016 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Unlike in the olfactory cortex, MeA responses are not imposed by experience but are instead configured by stereotyped combinatorial input received by MeA neurons to sort categorical information of natural stimuli from mixed inputs.

    “Thus, unlike in the olfactory cortex, MeA responses are not imposed by experience but are instead configured by stereotyped combinatorial input received by MeA neurons to sort categorical information of natural stimuli from mixed inputs (Figure S3J).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    The distributed non-topographic representation of each stimulus type mirrors the distributed organization in the AOB and suggests that information sorting may further be accomplished through selective projection to downstream regions.

    “Such distributed non-topographic representation of each stimulus type mirrors the distributed organization in the AOB (Belluscio et al., 1999; Rodriguez et al., 1999; Wagner et al., 2006) and suggests that information sorting may further be accomplished through selective projection to downstream regions.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Belluscio et al., 1999 source

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    • cites Rodriguez et al., 1999 source

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    • cites Wagner et al., 2006 source

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

    Premisecitation

    Similar observation was also recently made in the posterolateral cortical amygdala, which mediates innate olfactory responses.

    “Similar observation was also recently made in the posterolateral cortical amygdala, which mediates innate olfactory responses (Iurilli and Datta, 2017).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Iurilli and Datta, 2017

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  • May combine two claims.

    Premisecitation

    MeA neurons express key hormone and neuromodulatory receptors and sex hormone-dependent genes, suggesting that substantial modulation of MeA activity occurs locally.

    “MeA neurons express key hormone and neuromodulatory receptors (Unger et al., 2015; Wu and Gore, 2009; Zaldivar and Krichmar, 2013) and sex hormone-dependent genes (Xu et al., 2012), suggesting that substantial modulation of MeA activity occurs locally.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Unger et al., 2015 source

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    • cites Wu and Gore, 2009

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    • cites Zaldivar and Krichmar, 2013

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

    Premisecitation

    The display of social behaviors is globally controlled by sex hormones and neuromodulators whose level is modulated by sexual experience.

    “The display of social behaviors is globally controlled by sex hormones and neuromodulators (Lim and Young, 2006; Yang and Shah, 2014) whose level is modulated by sexual experience (Ross and Young, 2009; Wu and Gore, 2009).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Lim and Young, 2006 source

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    • cites Yang and Shah, 2014

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    • cites Ross and Young, 2009 source

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

    Premisecitation

    Responses of VNO sensory neurons can be modulated by hormones, internal status, and sensory experience in a sex-specific manner.

    “Indeed, a number of studies have shown that responses of VNO sensory neurons can be modulated by hormones, internal status, and sensory experience in a sex-specific manner (Dey et al., 2015; Halem et al., 2001; Tachikawa et al., 2013; Xu et al., 2016).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Dey et al., 2015 source

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    • cites Halem et al., 2001 source

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    • cites Tachikawa et al., 2013 source

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    Premisecitation

    Selective inhibition also shapes social discrimination in the AOB.

    “Intriguingly, selective inhibition also shapes social discrimination in the AOB (Luo et al., 2003; Meeks et al., 2010).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Luo et al., 2003 source

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    • cites Meeks et al., 2010 source

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    Interpretationcitation

    One possible mechanism by which sexual experience regulates sensory coding in the MeA is to alter sensory inputs to the MeA, at the levels of the VNO and AOB.

    “One possible mechanism is to alter sensory inputs to the MeA, at the levels of the VNO and AOB.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Each mouse was treated with three replicates of saline and OTR-A in 25 days (6 sessions) in a random order.

    “Each mouse was treated with three replicates of saline and OTR-A in 25 days (6 sessions) in a random order.”
    Quote in the paperSubstantial claim

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

    Study design and conductown data

    The positions of all implanted microendoscopes were systematically assessed through posthoc histological inspection, and were only included for further analysis in mice in which the MeApd was correctly targeted based on reconstructed positions aligned to the Allen Brain Atlas.

    “The positions of all implanted microendoscopes were systematically assessed through posthoc histological inspection, and were only included for further analysis in mice in which the MeApd was correctly targeted based on the reconstructed positions of the microendoscopes aligned to the Allen Brain Atlas (Figure 1B).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S2 (checkable). May combine two claims.

    Interpretationreasoning

    The identification of basic organization principles by which social features are represented in the MeA provides a general scheme to understand how behaviorally relevant information is represented in the brain, which neural strategies are used to shape coding specificity, and how neural codes are regulated by previous experience and internal status in awake behaving animals.

    “The identification of basic organization principles by which social features are represented in the MeA provides a general scheme to understand how behaviorally relevant information is represented in the brain, which neural strategies are used to shape coding specificity, and how neural codes are regulated by previous experience and internal status in awake behaving animals.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    The area under the ROC curve quantifies the discriminability of two signals.

    “The area under this curve quantifies the discriminability of the two signals (Britten et al., 1992).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Britten et al., 1992 source

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    Study design and conductown data

    To validate that the locomotor tracking routine accurately tracked mouse locomotor trajectories, the authors confirmed by eye for a subset of behavioral videos that the computationally determined centroid coordinates accurately followed the mouse's movements.

    “To validate that this routine accurately tracked mouse locomotor trajectories, we confirmed by eye for a subset of the behavioral videos that the computationally determined centroid coordinates of the mouse accurately followed the mouse’s movements.”
    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

    Animal care and experiments were carried out in accordance with NIH guidelines and approved by the Harvard University Institutional Animal Care and Use Committee (IACUC).

    “Animal care and experiments were carried out in accordance with the NIH guidelines and approved by the Harvard University Institutional Animal Care and Use Committee (IACUC).”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    To assess the cell identity of GCaMP6m expressing cells, control experiments co-injected a Cre-dependent reporter virus and the AAV2/5-CamKIIα-GCaMP6m virus into the MeApd of either vGATCre/+ or vGLUT2Cre/+ mice.

    “To assess the cell identity of GCaMP6m expressing cells, we performed control experiments in which we co-injected a Cre-dependent reporter virus (AAV2/5-EF1α-Flex-mCherry) and the AAV2/5-CamKIIα-GCaMP6m virus into the MeApd of either vGATCre/+ or vGLUT2Cre/+ mice.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    OT regulates neuronal activities in multiple neural circuits, such as sensory cortices, nucleus accumbens, and prefrontal cortex.

    “OT regulates neuronal activities in multiple neural circuits, such as sensory cortices (Marlin et al., 2015), nucleus accumbens (Dölen et al., 2013), and prefrontal cortex (Nakajima et al., 2014).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Marlin et al., 2015 source

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    • cites Dölen et al., 2013 source

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    • cites Nakajima et al., 2014 source

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  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Five different intruders were randomly introduced to the cage of the residential mice for 5-min with a 10-min interval between stimuli.

    “Five different intruders including an adult female mouse, an adult male mouse, a pair of pups (p0-p5), male rat soiled bedding and a centrifuge tube were randomly introduced to the cage of the residential mice for 5-min with a 10-min interval between stimuli.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductnone given

    The readout weights are cross-validated and generalize well to the test dataset.

    “These readout weights are cross-validated and generalize well to the test dataset.”
    Quote in the paperSubstantial claim
67 of 67

  • The paper relies on this without support.

    An animal’s social and defensive behaviors are influenced by its past experience and physiological status.

    “Because an animal’s social and defensive behaviors are influenced by its past experience and physiological status, we next explored whether and how MeApd representations are modulated by social experience.”

  • The paper relies on this without support.

    In males, social behaviors such as mating and fighting are more efficiently elicited after sexual experience, indicating an improvement of conspecific recognition.

    “In males, social behaviors such as mating and fighting are more efficiently elicited after sexual experience, indicating an improvement of conspecific recognition.”

  • The paper relies on this without support.

    Female mice become pregnant while co-housed with males.

    “Since female mice become pregnant while co-housed with males”

  • The paper relies on this without support.

    The majority of the neurons recorded in the study are vGAT+.

    “Since the majority of the neurons recorded in our study are vGAT+”
4 of 4

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References 57 · Cited by 291

Authors
Li, Y., Mathis, A., Grewe, B. F., Osterhout, J. A., Ahanonu, B., Schnitzer, M. J., Murthy, V. N., & Dulac, C.
Affiliations
  • Howard Hughes Medical Institute (US)
  • Harvard University (US)
Corresponding author
Dulac, Catherine
ORCID
Venue
Cell
Publisher
Elsevier BV
Published
2017-11
Volume
171
Issue
5
Pages
1176-1190.e17
ISSN
0092-8674 (ISSN-L)
DOI
10.1016/j.cell.2017.10.015
PMC
PMC5731476
OpenAlex
W2765951602
Semantic Scholar
79803f8471bd8e7bbbfee55e017f22f2312077cc
Cited by
291
References
57
Citations by year
2026: 19 · 2025: 47 · 2024: 43 · 2023: 32 · 2022: 33 · 2021: 34 · 2020: 36 · 2019: 24 · 2018: 22
FWCI
32.13
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • Digital Access to Scholarship at Harvard (DASH) (Harvard University) (acceptedVersion)
  • Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion, cc-by-nc-nd)
  • Zurich Open Repository and Archive (University of Zurich) (submittedVersion)
Funders
  • Human Frontier Science Program (LT 000382/2014L)
  • Swiss National Science Foundation (CRSII5 17372)
  • Howard Hughes Medical Institute
  • Marie Curie International Fellowship (622943)
  • Deutsche Forschungsgemeinschaft (MA 6176/1-1)
  • HHMI
  • DARPA
  • NIH/NIDCD (R01DC013087, R01DC011291)
Topics
  • Social Sciences › Psychology › Social Psychology › Neuroendocrine regulation and behavior
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
medial amygdala, neuronal ensembles, calcium imaging, sex differences, oxytocin, sexual experience, social behavior, defensive behavior
MeSH terms
Amygdala, Animals, Behavior, Animal, Cues, Endoscopy, Female, Male, Microscopy, Neurons, Oxytocin, Sexual Behavior, Animal, Sex Characteristics, Social Behavior, Wakefulness, Mice

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