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Cited by 214Stress Responses and CortisolMemory and Neural MechanismsNeuroendocrine regulation and behavior

Early-life stress disrupts attachment learning: the role of amygdala corticosterone, locus ceruleus corticotropin releasing hormone, and olfactory bulb norepinephrine

Open access
Moriceau, Stephanie, Shionoya, Kiseko, Jakubs, Katherine, Sullivan, Regina M.·2009·The Journal of Neuroscience
DOI 10.1523/jneurosci.4106-09.2009PMC PMC3345266
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Abstract

Infant rats require maternal odor learning to guide pups' proximity-seeking of the mother and nursing. Maternal odor learning occurs using a simple learning circuit including robust olfactory bulb norepinephrine (NE), release from the locus ceruleus (LC), and amygdala suppression by low corticosterone (CORT). Early-life stress increases NE but also CORT, and we questioned whether early-life stress disrupted attachment learning and its neural correlates [2-deoxyglucose (2-DG) autoradiography]. Neonatal rats were normally reared or stressed-reared during the first 6 d of life by providing the mother with insufficient bedding for nest building and were odor–0.5 mA shock conditioned at 7 d old. Normally reared paired pups exhibited typical odor approach learning and associated olfactory bulb enhanced 2-DG uptake. However, stressed-reared pups showed odor avoidance learning and both olfactory bulb and amygdala 2-DG uptake enhancement. Furthermore, stressed-reared pups had elevated CORT levels, and systemic CORT antagonist injection reestablished the age-appropriate odor-preference learning, enhanced olfactory bulb, and attenuated amygdala 2-DG. We also assessed the neural mechanism for stressed-reared pups' abnormal behavior in a more controlled environment by injecting normally reared pups with CORT. This was sufficient to produce odor aversion, as well as dual amygdala and olfactory bulb enhanced 2-DG uptake. Moreover, we assessed a unique cascade of neural events for the aberrant effects of stress rearing: the amygdala–LC–olfactory bulb pathway. Intra-amygdala CORT or intra-LC corticotropin releasing hormone (CRH) infusion supported aversion learning with intra-LC CRH infusion associated with increased olfactory bulb NE (microdialysis). These results suggest that early-life stress disturbs attachment behavior via a unique cascade of events (amygdala–LC–olfactory bulb).

AI snapshot

Written from the paper’s full text.

TL;DR

Early-life stress in rat pups switches odor-shock attachment learning from preference to avoidance, with dual activation of olfactory bulb and amygdala. The effect is mediated by elevated corticosterone and an amygdala–locus coeruleus–olfactory bulb cascade involving CRH and norepinephrine.

Key findings

  • Stressed-reared paired pups learned odor avoidance and showed freezing, whereas normally-reared paired pups learned odor preference; systemic CORT antagonist reinstated preference and blocked freezing. Y-maze ANOVA: rearing effect F(1.46)=24.939, p<0.0005; conditioning effect F(3.46)=36.157, p<0.0001; interaction F(3.46)=24.939, p<0.0001. Freezing ANOVA: rearing F(1.32)=66.016, p<0.0001; conditioning F(3.32)=81.926, p<0.0001; interaction F(3.32)=66.016, p<0.0001.
  • Stressed-reared pups had elevated CORT across paired, unpaired, and odor-only groups compared with normally-reared pups. CORT ANOVA: rearing F(1,22)=54.060, p<0.0005; conditioning F(1,22)=4.298, p<0.05; interaction F(2.22)=6.873, p<0.005.
  • 2-DG autoradiography showed stressed-reared paired pups had enhanced olfactory bulb and lateral, basolateral, and central amygdala uptake; CORT antagonist prevented the amygdala enhancement. Systemic CORT injection in normally-reared pups mimicked the aversion learning and dual amygdala/olfactory bulb 2-DG uptake.
  • Intra-amygdala CORT (50 or 100 ng) or intra-LC CRH (100 or 200 ng) supported odor aversion; 50 ng CRH prevented odor-preference learning. Intra-LC CRH increased olfactory bulb NE (microdialysis ANOVA: drug F(1,42)=96.956, p<0.0001; time F(7,42)=50.938, p<0.0001; interaction F(7,42)=41.414, p<0.0001).

Methods

  • Long Evans rat pups of both sexes were normally reared or stressed-reared from PN1–PN7 using limited nesting/bedding (1000 ml, 0.5″ layer vs. normal 4500 ml, 2″ layer). At PN7, pups underwent odor–0.5 mA shock conditioning, followed by Y-maze and freezing tests, RIA for CORT, 2-DG autoradiography, microdialysis/HPLC-EC for olfactory bulb NE, and cannula infusions into amygdala or LC.
  • Comparisons used ANOVA followed by post hoc Fisher tests, with significance set at p<0.05.

Limitations

  • Stated: drug diffusion was not fully confined; amygdala infusions were mostly limited to the amygdala but some spread occurred approximately 1 mm outside it, and LC infusions diffused less than 1 mm. Two paired pups with misplaced LC cannulas did not show aversive behavior.
  • Stated: the NE pathway between the LC, amygdala, and A1/A2 noradrenergic nuclei is incompletely defined, so other pathways cannot be eliminated, including NE feedback to the basolateral amygdala.
  • Evident: the paper has no formal limitations section; Results report ANOVA degrees of freedom but not per-group sample sizes, and the stressed-rearing procedure is a maternal limited-bedding manipulation with pup CORT increases attributed to maternal rough handling.

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

Integrity signals

Registry

Crossref · 10.1523/jneurosci.4106-09.2009

Cites

122 of 122 references verified0 citation errors · 0 not checkable

Statistics

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

Claims the paper makes

0 of 87 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    CORT antagonist injection in stressed-reared paired pups reinstated the learned odor preference.

    “However, CORT antagonist injection in stressed-reared paired pups reinstated the learned odor preference.”
    Quote in the paperSubstantial claim
  • Findingown data

    Paired, unpaired and odor only pups exposed to stressed rearing had increased levels of CORT compared to normally-reared pups.

    “paired, unpaired and odor only pups exposed to stressed rearing had increased levels of CORT compared to normally-reared pups.”
    Quote in the paperSubstantial claim
  • Findingown data

    CORT antagonist injection prevented the enhanced amygdala 2-DG uptake.

    “CORT antagonist injection prevented the enhance amygdala 2-DG uptake.”
    Quote in the paperSubstantial claim
  • Findingown data

    CORT injection produced odor-shock induced enhancement in basolateral and lateral amygdala nuclei 2-DG uptake.

    “CORT injection, which causes pups to learn an odor aversion rather than the age-typical odor preference, produced odor-shock induced enhancement in basolateral and lateral amygdala nuclei 2-DG uptake.”
    Quote in the paperSubstantial claim
  • Findingown data

    Paired pups that received amygdala CORT infusions (50 or 100ng) during odor-shock conditioning exhibited a subsequent odor aversion.

    “paired pups that received amygdala CORT infusions (50 or 100ng) during odor-shock conditioning exhibited a subsequent odor aversion.”
    Quote in the paperSubstantial claim
  • May combine two claims. 33
  • Classified as probably not a substantial claim. 9
  • The quote only partly states this claim. 1

  • May combine two claims.

    Findingown data

    No significant difference in NE metabolites were found; no difference in basal level of NE were found between groups over the 2 hour baseline.

    “No significant difference in NE metabolites were found; also no difference in basal level of NE were found between groups over the 2 hour baseline.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    CRH infusion alone into the LC increases NE levels in the olfactory bulb while saline infusion alone does not change NE levels.

    “CRH infusion alone into the LC increases NE levels in the olfactory bulb while saline infusion alone does not change NE levels.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    2-DG uptake increased within the glomerular layer of the olfactory bulb of pups learning either an odor aversion (stressed-reared paired pups) or an odor preference (normally-reared paired pups and stressed-reared paired pups receiving a CORT antagonist injection); no changes were observed in control groups.

    “Figure 1D illustrates an increase 2-DG uptake within the glomerular layer of the olfactory bulb of pups learning either an odor aversion (stressed-reared paired pups) or an odor preference (normally-reared paired pups and stressed-reared paired pups receiving a CORT antagonist injection). No changes were observed in control groups.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Limited bedding environment decreased dams' ability to construct a nest, resulting in frequent nest building, transporting/rough handling of pups, less licking and nursing.

    “This limited bedding environment decreased the dams' ability to construct a nest, which results in frequent nest building, transporting/rough handling of pups, less licking and nursing (Table 1).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Paired pups that received 100 or 200ng CRH infused into the LC during odor-shock conditioning exhibited an odor aversion whereas 50ng CRH infusion prevented the odor-preference learning in paired pups.

    “paired pups that received 100 or 200ng CRH infused into the LC during odor-shock conditioning exhibited an odor aversion whereas 50ng CRH infusion prevented the odor-preference learning in paired pups.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    At PN7, normally-reared paired odor-0.5mA shock pups learned an odor preference, while stressed-reared paired pups learned an avoidance.

    “As shown in Figure 1A, at PN7, normally-reared paired odor-0.5mA shock pups learned an odor preference, while, stressed-reared paired pups learned an avoidance.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Pups within the nest do not avoid the mother and show normal weight gain, but spend less time in contact with the mother and nursing.

    “While pups within the nest do not avoid the mother and show normal weight gain, they do spend less time in contact with the mother and nursing (see table 1).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Systemic CORT injection produced increased 2-DG uptake within the glomerular layer of the olfactory bulb of pups learning either an odor aversion (CORT injected pups) or an odor preference (saline injected pups); no changes in control groups.

    “Figure 2B depicted an increase 2-DG uptake within the glomerular layer of the olfactory bulb of pups learning either an odor aversion (CORT injected pups) or an odor preference (saline injected pups). No changes were observed in control groups.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Stressed-reared paired pups showed freezing compared to normally-reared paired pups or stressed-reared paired pups receiving a CORT antagonist injection, which do not show freezing behavior.

    “stressed-reared paired pups showed freezing compared to normally-reared paired pups or stressed-reared paired pups receiving a CORT antagonist injection, which do not show freezing behavior.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    The potential pathway supporting the combined fear/attachment learning circuit involves a cascade beginning with CORT release in response to stress, which activates the amygdala supporting aversion/fear learning, excites the LC via CRH afferents from the amygdala, and increases olfactory bulb NE.

    “The potential pathway to support this combined fear/attachment learning circuit involves a cascade of events beginning with CORT release in response to stress, which will activate the amygdala supporting aversion/fear learning, that will excite the LC via CRH afferents from the amygdala and increases olfactory bulb NE that would typically support preference learning.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    The survival rate of the surgery was 91%, including recovery from anesthesia and cannibalism from the mother.

    “The survival rate of the surgery was 91%, including recovery from anesthesia and cannibalism from the mother.”
    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

    Y-maze testing was done blind to the conditioning groups and no drugs were infused during testing.

    “The testing was done blind to the conditioning groups and no drugs were infused during testing.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    The attachment odor learning combined with stress produces dual activation of the attachment circuit (LC-olfactory bulb) together with the fear circuit (amygdala), which results in behavioral aversion to an odor rather than the age appropriate approach.

    “the attachment odor learning combined with stress produces dual activation of the attachment circuit (LC-olfactory bulb) together with the fear circuit (amygdala), which results in behavioral aversion to an odor, rather than the age appropriate approach.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductown data

    Drug diffusion was limited: most amygdala drug diffusion was limited to the amygdala with some spread approximately 1 mm outside, and LC drug diffused less than 1 mm from the LC.

    “most of the drug diffusion was limited to the amygdala, most notably the lateral and central nuclei. However, some drug spread was found approximately 1mm outside the amygdala.”
    • Also stated in: § CORT infusion into the amygdaloid complex and CRH infusion into the LC permits odor aversion learning · plain
      “the volume of drugs infused into the LC diffused less than 1 mm from the LC.”
    Quote in the paperSubstantial claim

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

    Study design and conductown data

    No more than one male and one female from a litter were used in each experimental condition and no difference in behaviors or neural activity between male and female was found.

    “No more than one male and one female from a litter were used in each experimental condition and no difference in behaviors or neural activity between male and female was found.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premiseown data

    Early life stress increases NE but also CORT.

    “Early life stress increases NE but also CORT”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Smith et al., 1997

      Not checked in the free run.

    • cites Hatalski et al., 1998

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    • cites Koob, 1999

      Not checked in the free run.

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

    Study design and conductown data

    Cannula tip placements were verified; all amygdala tip placements were less than 1 mm from the basolateral complex and all LC placements were less than 1 mm from the LC.

    “All tip placements were less than 1 mm from the basolateral complex of the amygdala.”
    • Also stated in: § CORT infusion into the amygdaloid complex and CRH infusion into the LC permits odor aversion learning · plain
      “Cannula tip placements directed at the LC, which were all less than 1 mm from the LC, are shown in Figure 4B.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    Analyses of 2-DG uptake in the olfactory bulb and amygdala were made blind to conditioning groups.

    “Analyses were made blind to conditioning groups.”
    • Also stated in: § Assessing neural correlates within the olfactory bulb and the amygdala · plain
      “Analyses were made blind to conditioning groups.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    No significant difference in weight between conditioning group and rearing condition was found.

    “No significant difference in weight between conditioning group and rearing condition was found (F(3.46) = 0.236, p < 0.8707)”
    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

    The RIA sensitivity was 5 ng/ml and the intraassay coefficient of variation was 1-9%.

    “The sensitivity of the assay was 5 ng/ml. The intraassay coefficient of variation was 1-9%.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    Two paired pups that received 100ng CRH had misplaced cannula and they did not show the aversive behaviors.

    “Among our cannulated animals, 2 paired pups that received 100ng CRH had misplaced cannula and they did not show the aversive behaviors.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In older animals, CORT increase produces a cascade of events beginning with CORT activation of the amygdala increasing the expression of CRH mRNA into the central amygdala, then CRH release exciting the LC to increase the release of NE.

    “in older animals, CORT increase produces a cascade of events beginning with CORT activation of the amygdala increasing the expression of CRH mRNA into the central amygdala”
    • Also stated in: § Introduction · plain
      “then CRH release exciting the LC to increase the release of NE”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Makino et al., 1994

      Not checked in the free run.

    • cites Butler et al., 1990

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    • cites Curtis et al., 1997

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  • May combine two claims.

    Premisecitation

    Early life prolonged stress produces an exaggerated corticosterone (CORT) response, increased corticotropin releasing hormone (CRH) expression and heightened norepinephrine (NE) levels.

    “early life prolonged stress produces an exaggerated corticosterone (CORT) response, increased corticotropin releasing hormone (CRH) expression and heightened norepinephrine (NE) levels”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Smith et al., 1997

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    • cites Hatalski et al., 1998

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    • cites Koob, 1999

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  • May combine two claims.

    Premisecitation

    CORT injection permitted precocious odor aversion learning concurrently with increased amygdala 2-DG uptake.

    “However, CORT injection permitted precocious odor aversion learning concurrently with increase amygdala 2-DG uptake (Moriceau and Sullivan, 2006; Moriceau et al., 2006).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Moriceau and Sullivan, 2006

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    • cites Moriceau et al., 2006

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  • May combine two claims.

    Premisecitation

    Moderate levels of olfactory bulb NE support preference learning, while higher NE levels support aversion learning in rat pups.

    “moderate levels of olfactory bulb NE support preference learning, while higher NE levels support aversion learning in rat pups”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Sullivan et al., 1989

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    • cites Sullivan et al., 1991

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    • cites Yuan et al., 2000

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  • May combine two claims.

    Premisecitation

    During the sensitive period, pups exhibit attenuated odor aversion learning supported by the failure of the amygdala to participate in learning.

    “During the sensitive period, pups exhibit attenuated odor aversion learning supported by the failure of the amygdala to participate in learning (Sullivan et al., 2000a; Moriceau and Sullivan, 2006; Moriceau et al., 2006).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Sullivan et al., 2000a

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    • cites Moriceau and Sullivan, 2006

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    • cites Moriceau et al., 2006

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  • May combine two claims.

    Premisecitation

    The attachment learning circuit enables myriad stimuli (milk, stroking, 0.5mA shock) to support odor learning required for pup survival and is characterized by robust odor approach learning and attenuated aversion learning even when the reinforcer is painful, such as 0.5mA shock, tailpinch, or abusive mother.

    “This circuit also enables myriad stimuli (milk, stroking, 0.5mA shock) to support this odor learning required for pup survival and is characterized by robust odor approach learning and attenuated aversion learning even when the reinforcer is painful, such as 0.5mA shock, tailpinch”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Haroutunian and Campbell, 1979

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    • cites Sullivan and Leon, 1986

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    • cites Camp and Rudy, 1988

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  • May combine two claims.

    Premisecitation

    Early life stress appears to disrupt the programming of the hypothalamus-pituitary-adrenal axis (HPA), the limbic system (hippocampus, amygdala, prefrontal cortex, etc.) and the locus coeruleus (LC).

    “Early life stress appears to disrupt the programming of the hypothalamus-pituitary-adrenal axis (HPA), the limbic system (hippocampus, amygdala, prefrontal cortex, etc.) and the locus coeruleus (LC)”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Caldji et al., 1998

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    • cites Glaser, 2000

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    • cites Dent et al., 2001

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  • May combine two claims.

    Premisecitation

    Systemic CORT injection, direct administration of CORT into the amygdala, or exposure to a psychological stressor increases the expression of CRH mRNA in the central amygdala in both adult and developing rats.

    “Furthermore, systemic CORT injection, direct administration of CORT into the amygdala or exposure to a psychological stressor increases the expression of CRH mRNA into the central amygdala in both adult and developing rats and increases the fear conditioned response in adult (Grino et al., 1989; Makino et al., 1994; Hatalski et al., 1998; Hsu et al., 1998; Merali et al., 1998; Shepard et al., 2000”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Grino et al., 1989

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    • cites Makino et al., 1994

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    • cites Hatalski et al., 1998

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  • May combine two claims.

    Premisecitation

    The attenuated odor avoidance learning is supported by suppression of amygdala due to pups' naturally low CORT and CORT is critical for early life amygdala plasticity.

    “The attenuated odor avoidance learning is supported by suppression of amygdala due to pups' naturally low CORT and CORT is critical for early life amygdala plasticity”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Sullivan et al., 2000a

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    • cites Moriceau and Sullivan, 2006

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    • cites Moriceau et al., 2006

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

    Premisecitation

    CRH is a neuropeptide displaying a broad extrahypothalamic distribution.

    “While CRH is a neuropeptide displaying a broad extrahypothalamic distribution (Bittencourt and Sawchenko, 2000) and CRH interacts with noradrenergic mechanisms in the basolateral complex of the amygdala (Roozendaal et al., 2008), a CRH connection also exists between the amygdala and the LC as shown by CRH neurons from the central nucleus of the amygdala projecting directly to the rostrolateral”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Bittencourt and Sawchenko, 2000

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  • May combine two claims.

    Premisecitation

    Systemic CORT injection, direct administration of CORT into the amygdala, or exposure to a psychological stressor increases the fear conditioned response in adult rats.

    “Furthermore, systemic CORT injection, direct administration of CORT into the amygdala or exposure to a psychological stressor increases the expression of CRH mRNA into the central amygdala in both adult and developing rats and increases the fear conditioned response in adult (Grino et al., 1989; Makino et al., 1994; Hatalski et al., 1998; Hsu et al., 1998; Merali et al., 1998; Shepard et al., 2000”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Grino et al., 1989

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    • cites Makino et al., 1994

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    • cites Hatalski et al., 1998

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

    Premisecitation

    CRH interacts with noradrenergic mechanisms in the basolateral complex of the amygdala.

    “While CRH is a neuropeptide displaying a broad extrahypothalamic distribution (Bittencourt and Sawchenko, 2000) and CRH interacts with noradrenergic mechanisms in the basolateral complex of the amygdala (Roozendaal et al., 2008), a CRH connection also exists between the amygdala and the LC as shown by CRH neurons from the central nucleus of the amygdala projecting directly to the rostrolateral”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Roozendaal et al., 2008

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  • May combine two claims.

    Premisecitation

    Developmental differences in LC activity are reflected during both noxious (electric shock) and nonnoxious (stroking) stimulus-evoked NE release in the olfactory bulb, with neonatal pups releasing significantly more NE than older pups/adult.

    “Indeed, developmental differences in LC activity are reflected during both noxious (electric shock) and nonnoxious (stroking) stimulus-evoked NE release in the olfactory bulb, with neonatal pups releasing significantly more NE than older pups/adult (Kimura and Nakamura, 1987; Nakamura et al., 1987; Nakamura and Sakaguchi, 1990; McLean and Shipley, 1991; Sullivan et al., 1992; Sullivan and Wilson,”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Kimura and Nakamura, 1987

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    • cites Nakamura et al., 1987 source

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    • cites Nakamura and Sakaguchi, 1990

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  • May combine two claims.

    Interpretationcitation

    Elevation of CORT on pups' behavior leads to disruption of social interactions with the mother, as well as learning about the mother.

    “The present results, together with results from the Baram lab (Gilles et al., 1996; Avishai-Eliner et al., 2001), suggest that elevation of CORT on pups' behavior leads to disruption of social interactions with the mother, as well as learning about the mother.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Gilles et al., 1996

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    • cites Avishai-Eliner et al., 2001

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  • May combine two claims.

    Premisecitation

    Early life stress alters the developmental trajectory of myriad brain areas, including the amygdala and LC, with elevated CORT implicated as a causal factor.

    “As demonstrated previously, early life stress alters the developmental trajectory of myriad brain areas, including the amygdala and LC, with elevated CORT implicated as a causal factor (Caldji et al., 1998; Dent et al., 2001; Sanchez et al., 2001; Plotsky et al., 2005; Champagne et al., 2008; McEwen, 2008; Cirulli et al., 2009; Lupien et al., 2009).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Caldji et al., 1998

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    • cites Dent et al., 2001

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    • cites Sanchez et al., 2001

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  • May combine two claims.

    Interpretationcitation

    There is remarkable convergence between this new early life stress paradigm and other paradigms and species, as well as the clinical literature.

    “Overall, there is remarkable convergence between this new early life stress paradigm and other paradigms and species, as well as the clinical literature (Kaufman, 1991; Kaufman et al., 1997; Caldji et al., 1998; Lehnert et al., 1998; Glaser, 2000; Dent et al., 2001; Kaufman and Charney, 2001; Sanchez et al., 2001; Grossman et al., 2003; Teicher et al., 2003; Plotsky et al., 2005; Gunnar and Queved”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Kaufman, 1991

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    • cites Kaufman et al., 1997

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    • cites Caldji et al., 1998

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  • May combine two claims.

    Interpretationreasoning

    These data may suggest a very specific route of activation during early life pain, which is blocked without stress.

    “Since early life activation of LC-CRH has been linked with later life behavioral and neural deficits, these data may suggest a very specific route of activation during early life pain, which is blocked without stress.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Early life activation of LC-CRH is linked with later life behavioral and neural deficits.
38 of 38

  • The paper relies on this without support.

    Early life activation of LC-CRH is linked with later life behavioral and neural deficits.

    “Since early life activation of LC-CRH has been linked with later life behavioral and neural deficits, these data may suggest a very specific route of activation during early life pain, which is blocked without stress.”
1 of 1

Claims other papers make about this one

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

  • The amygdala is mature enough to support threat learning in pups as young as PN6, provided sufficient corticosterone within the amygdala.

    “Indeed, the amygdala is mature enough to support threat learning in pups as young as PN6, provided sufficient levels of corticosterone are available within the amygdala (Debiec and Sullivan, 2014, Moriceau et al., 2004, Moriceau et al., 2009, Moriceau and Sullivan, 2004, Moriceau and Sullivan, 2006).”

    From Early life adversity during the infant sensitive period for attachment: Programming of behavioral neurobiology of threat processing and social behavior (2017) · cites this paper as Moriceau et al., 2009

  • Early life adversity may accelerate maturation of fear extinction/recovery behavior, attachment and avoidance learning, reversal learning, and maturation of frontal-amygdala connectivity.

    “maturation of fear extinction/recovery behavior (Callaghan and Richardson, 2011), attachment and avoidance learning (Moriceau et al., 2009), reversal learning (Thomas et al., 2015), and maturation of frontal-amygdala connectivity (Gee et al., 2013).”

    From Does puberty mark a transition in sensitive periods for plasticity in the associative neocortex? (2017) · cites this paper as Moriceau et al., 2009

Statistics that don’t add up

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

  • Inconsistent p-value: F(3,32) = 9.484, p < .0001

    Minor

    The paper reports p < .0001 here; recomputing from the test statistic and its degrees of freedom gives p < .001. The check cannot tell whether the statistic or the p-value is the misprint.

    Reported p < .0001 · recomputed p < .001

  • p-value fits an unstated one-tailed test: F(1,22) =4.298, p < .05

    Minor

    The paper reports p < .05 here; recomputing from the test statistic and its degrees of freedom gives p = .050. The reported value is what a one-tailed test gives, but the paper does not say near this result that a one-tailed test was used.

    Reported p < .05 · recomputed p = .050

  • Inconsistent p-value: F(2,23) = 12.304, p = .0005

    Minor

    The paper reports p = .0005 here; recomputing from the test statistic and its degrees of freedom gives p < .001. The check cannot tell whether the statistic or the p-value is the misprint.

    Reported p = .0005 · recomputed p < .001

3 of 3

Statistics recomputed

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

  • Doesn’t add upF(1, 22) = 4.298reported p < .05 · recomputed p = .050

    “F(1,22) =4.298, p < .05”

  • Doesn’t add upF(3, 32) = 9.484reported p < .0001 · recomputed p < .001

    “F(3,32) = 9.484, p < .0001”

  • Doesn’t add upF(2, 23) = 12.304reported p = .0005 · recomputed p < .001

    “F(2,23) = 12.304, p = .0005”

  • ConsistentF(1, 22) = 54.06reported p < .0005 · recomputed p < .001

    “F(1,22) =54.060, p < .0005”

  • ConsistentF(3, 32) = 22.171reported p < .0001 · recomputed p < .001

    “F(3,32) = 22.171, p < .0001”

  • ConsistentF(3, 32) = 11.156reported p < .0001 · recomputed p < .001

    “F(3,32) = 11.156, p < .0001”

  • ConsistentF(1, 32) = 6.243reported p < .05 · recomputed p = .018

    “F(1,32) = 6.243, p < .05”

  • ConsistentF(3, 32) = 8.547reported p < .0005 · recomputed p < .001

    “F(3,32) = 8.547, p < .0005”

  • ConsistentF(3, 32) = 7.975reported p < .0005 · recomputed p < .001

    “F(3,32) = 7.975, p < .0005”

  • ConsistentF(1, 32) = 10.215reported p < .005 · recomputed p = .003

    “F(1,32) = 10.215, p < .005”

  • ConsistentF(3, 32) = 8.358reported p < .0005 · recomputed p < .001

    “F(3,32) = 8.358, p < .0005”

  • ConsistentF(3, 32) = 8.827reported p < .0005 · recomputed p < .001

    “F(3,32) = 8.827, p < .0005”

  • ConsistentF(1, 32) = 9.375reported p < .005 · recomputed p = .004

    “F(1,32) = 9.375, p < .005”

  • ConsistentF(5, 22) = 23.507reported p < .0001 · recomputed p < .001

    “F(5,22) = 23.507, p < .0001”

  • ConsistentF(2, 23) = 12.597reported p = .0005 · recomputed p < .001

    “F(2,23) = 12.597, p = .0005”

    The paper states a correction for multiple tests

  • ConsistentF(1, 23) = 9.086reported p < .05 · recomputed p = .006

    “F(1,23) = 9.086, p < .05”

  • ConsistentF(2, 23) = 6.287reported p < .05 · recomputed p = .007

    “F(2,23) = 6.287, p < .05”

  • ConsistentF(1, 23) = 7.039reported p < .05 · recomputed p = .014

    “F(1,23) = 7.039, p < .05”

  • ConsistentF(2, 23) = 3.927reported p < .05 · recomputed p = .034

    “F(2,23) = 3.927, p < .05”

  • ConsistentF(6, 76) = 10.537reported p < .001 · recomputed p < .001

    “F(6,76)=10.537, p < .001”

  • ConsistentF(1, 42) = 96.956reported p < .0001 · recomputed p < .001

    “F(1,42) = 96.956, p < .0001”

  • ConsistentF(7, 42) = 50.938reported p < .0001 · recomputed p < .001

    “F(7,42) = 50.938, p < .0001”

  • ConsistentF(7, 42) = 41.414reported p < .0001 · recomputed p < .001

    “F(7,42) = 41.414, p < .0001”

23 of 23

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

  • CORT analysis gives the conditioning-group effect the wrong degrees of freedom

    Minor

    The paper specifies three conditioning groups: paired, unpaired, and odor only. A main effect across three groups has 2 numerator degrees of freedom, not the reported 1; the reported interaction also uses 2.

    Reported 1 · recomputed 2

1 of 1

Cites

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Related

Authors
Moriceau, S., Shionoya, K., Jakubs, K., & Sullivan, R. M.
Affiliations
  • Centre National de la Recherche Scientifique (FR)
  • National Institutes of Health (US)
  • Nathan Kline Institute for Psychiatric Research (US)
ORCID
Venue
The Journal of Neuroscience
Publisher
Society for Neuroscience
Published
2009-12-16
Volume
29
Issue
50
Pages
15745-15755
ISSN
  • 0270-6474 (ISSN-L)
  • 1529-2401
DOI
10.1523/jneurosci.4106-09.2009
PMC
PMC3345266
OpenAlex
W2049753768
Semantic Scholar
91a7a7919de336b5f80d4d370cffb4c0e7a12dff
Cited by
214
References
122
Citations by year
2026: 7 · 2025: 12 · 2024: 15 · 2023: 16 · 2022: 12 · 2021: 13 · 2020: 33 · 2019: 20 · 2018: 11 · 2017: 13 · 2016: 11 · 2015: 12 · 2014: 9 · 2013: 7 · 2012: 7
FWCI
2.81
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Science Foundation (0850527)
  • Leon Levy Foundation
  • National Institutes of Health (DC009910)
  • National Institute on Deafness and Other Communication Disorders (DC-009910, DC-003906, R01DC009910, R01DC003906)
Topics
  • Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
  • Social Sciences › Psychology › Social Psychology › Neuroendocrine regulation and behavior
Keywords
early life stress, attachment behavior, locus coeruleus, amygdala, corticosterone, corticotropin-releasing factor, odor aversion, nest building, infant rats, 2-deoxyglucose autoradiography, microdialysis
MeSH terms
Age Factors, Amygdala, Animals, Animals, Newborn, Association Learning, Corticosterone, Corticotropin-Releasing Hormone, Female, Locus Coeruleus, Male, Maternal Behavior, Norepinephrine, Olfactory Bulb, Stress, Psychological, Rats, Long-Evans, Rats

About these checks

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

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

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

Statistics and arithmetic are recomputed, not judged.

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

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

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