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Cited by 87Memory and Neural MechanismsChild Abuse and TraumaNeuroscience and Neuropharmacology Research

Early life trauma increases threat response of peri-weaning rats, reduction of axo-somatic synapses formed by parvalbumin cells and perineuronal net in the basolateral nucleus of amygdala

Open access
Santiago, Adrienne N., Lim, Kayla Y., Opendak, Maya, Sullivan, Regina M., Aoki, Chiye·2018·Journal of Comparative Neurology
DOI 10.1002/cne.24522PMC PMC6319912
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Abstract

Early life trauma is a risk factor for life‐long disorders related to emotional processing, but knowledge underlying its enduring effect is incomplete. This study was motivated by the hypothesis that early life trauma increases amygdala‐dependent threat responses via reduction in inhibition by parvalbumin (PV) interneurons and perineuronal nets (PNN) supporting PV cells, thus increasing excitability of the basolateral amygdala (BLA). From postnatal day (PN) 8–12, rat pups of both sexes were reared under normal bedding or under insufficient nest‐building materials to induce maternal‐to‐infant maltreatment trauma (Scarcity‐Adversity Model, SAM). At weaning age of PN23, the SAM group exhibited increased threat responses to predator odor. The SAM‐induced increase in threat response was recapitulated in normally reared PN22–23 rats that were unilaterally depleted of PNN in the BLA by the enzymes, chondroitinase‐ABC plus hyaluronidase at PN19–20. Light and electron microscopic analysis of the BLA revealed that anterior‐to‐mid levels of SAM group's BLAs exhibited decreased PNN intensity and decreased axo‐somatic synapses between PV‐to‐principal pyramidal‐like neurons and PV‐to‐PV. PV and PNN densities (cells/mm 2) in the BLA of both control (CON) and SAM groups were still low at PN12 and SAM delayed the ontogenetic rise of PV intensity and PNN density. Moreover, PV cell density in the anterior‐to‐mid BLA correlated negatively with threat response of CON animals, but not for SAM animals. Thus, reduction of PNN‐supported, PV‐mediated somatic inhibition of pyramidal cells provides a mechanistic support for the enduring effect of early life maltreatment manifested as increasing innate threat response at weaning.

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Written from the paper’s full text.

TL;DR

Early-life scarcity-adversity maltreatment in rats reduced perineuronal nets (PNN) and parvalbumin (PV)-mediated axo-somatic inhibition in the anterior-to-mid basolateral amygdala (BLA) at weaning, and unilateral PNN dissolution in normally reared pups increased threat avoidance. These changes provide an anatomical mechanism linking early-life trauma to heightened amygdala-dependent threat responses.

Key findings

  • SAM-reared PN23 rats showed decreased PNN intensity in anterior-to-mid BLA versus controls (p=0.0114), with no significant PNN density difference; PV density and PV intensity were not significantly different at PN23.
  • In controls, anterior-to-mid BLA PV cell density correlated negatively with threat response (N=8, R=−0.87, p<0.0052), but this correlation was absent in SAM rats (N=8, R=−0.08, p=0.84).
  • EM at PN23 showed SAM reduced PV-to-pyramidal axo-somatic input: 27% less plasma membrane contact (p=0.0487), 24% lower contact frequency (p=0.0458), and 13% shorter PV terminal contacts (p=0.0293); PV-to-PV input was reduced by 54% membrane contact (p<0.0001) and 51% frequency (p<0.001).
  • Unilateral BLA PNN dissolution in control pups increased predator-odor avoidance: CON-E made fewer male-odor choices (1.750 ± 0.31) than CON-S (2.625 ± 0.31; p=0.011), resembling SAM-S (2.125 ± 0.31).

Methods

  • Long-Evans rat pups of both sexes were reared under normal bedding (CON) or Scarcity-Adversity Model (SAM; 100 ml bedding) from PN8–12; threat response was tested at PN23 with fox-urine open field and/or Y-maze novel male odor.
  • Histology used PV immunohistochemistry and WFA labeling for PNNs across BLA anterior-to-mid and posterior levels at PN12, 15, 18, and 23; EM at PN23 sampled 10 PV and 10 pyramidal cell bodies per animal from 6 SAM and 6 CON brains to quantify axo-somatic synapses.
  • PNN dissolution used unilateral BLA injections of chondroitinase ABC + hyaluronidase at PN19–20 in CON-S, CON-E, and SAM-S groups (4 males/4 females each), followed by Y-maze testing; analyses used two-way ANOVA, Fisher post hoc, t-tests/Mann-Whitney, and Pearson correlations, with sexes combined because no main effect of sex was found.

Limitations

  • Stated: the causal link between reduced PV-mediated inhibition and heightened innate threat response requires future experimental reduction of PV inhibition during threat testing; whether BLA cellular changes persist through adolescence/adulthood is unknown; SAM was a moderate maltreatment model without weight loss or limbic seizures, and possible secondary social behavioral abnormalities remain untested.
  • Evident: sample sizes were small (EM n=6/group; histology n=8/group; PNN dissolution n=8/group), PNN dissolution was unilateral and partial in 4 of 8 CON-E brains, and the PV-density/threat-response relationship in controls is correlational.
  • Evident: although the abstract states SAM increased threat responses, the open-field group mean distance to predator odor did not differ significantly between CON and SAM (28.98 ± 2.24 cm vs 32.09 ± 3.21 cm, p=0.4406).

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

Integrity signals

Registry

Crossref · 10.1002/cne.24522

Cites

83 of 83 references verified0 citation errors · 0 not checkable

Statistics

38 tests recomputed · 2 with the reported and recomputed p on opposite sides of .05

Claims the paper makes

0 of 75 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    The elevated avoidance of predator odor exhibited by CON-E was mimicked in SAM-S weanlings (2.125 ± 0.31) (p=0.24, t(21)=1.197, comparing CON-E versus SAM-S).

    “The elevated avoidance of predator odor exhibited by animals of the CON-E group was mimicked in SAM-S weanlings (2.125 ± 0.31) (p=0.24, t(21)=1.197, comparing CON-E versus SAM-S).”
    Quote in the paperSubstantial claim
  • Findingown data

    There was no significant change in PNN density across the two groups for any level of the BLA (p=0.5660 for anterior-to-mid; p=0.1923 for posterior).

    “In contrast, there was no significant change in PNN density across the two groups for any level of the BLA (p=0.5660, t(10)=0.5935 for anterior-to-mid BLA; p=0.1923, t(7)=1.443 for posterior BLA; Fig. 4c, upper).”
    Quote in the paperNot a substantial claim
  • Findingown data

    The percentage of PNNs surrounding PV+ cells was not significantly different between anterior-to-mid (90% ± 8%) and posterior (80 ± 16%) BLA in CON.

    “The percentage of PNNs surrounding PV+ cells was not significantly different for the anterior-to-mid level (90% ± 8%) vs posterior level (80 ± 16%) BLA by two-tailed unpaired t-test (p=0.603; t(6)=0.550).”
    Quote in the paperNot a substantial claim
  • Findingown data

    Enzymatic treatment rendered the density of PNNs to be 0 per mm2 within the BLA.

    “The enzymatic treatment also rendered the density of PNNs to be 0 per mm2 within the BLA (Fig. 3a).”
    Quote in the paperSubstantial claim
  • Findingown data

    In CON rats, there was a robust negative correlation between PV density in the anterior-to-mid level of BLA and innate threat response (R=-0.87, p<0.0052).

    “Indeed, Pearson correlation analysis revealed a robust correlation for CON rats (N=8), specifically at the ant-to-mid level of the BLA (p<0.0052; R=−0.87, Fig 2d, left panel)”
    Quote in the paperSubstantial claim
  • May combine two claims. 46
  • Classified as probably not a substantial claim. 45
  • The quote only partly states this claim. 1

  • May combine two claims.

    Findingown data

    In the SAM group, there was no correlation between threat responsivity to predator odor and PV density in the anterior-to-mid level of BLA (p=0.84, R=-0.08) or in the posterior BLA (p=0.30, R=0.51).

    “However, unlike the CON group, analysis of tissue from the SAM group (N=8) revealed no correlation between threat responsivity to the predator odor and PV density in the anterior-to-mid level of BLA (p=0.84, R= - 0.08 Fig. 2d, right panel) or in the posterior BLA (p=0.30, R=0.51 (Fig 2e, right panel).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    At PN15, half of the SAM pups had PNN density similar to CON's, while half displayed an immature phenotype with very sparse PV labeling in the BLA.

    “PN15 represented a transitional time-point for abused litters: while half of the SAM pups had PNN density that was similar to CON’s (Fig 6a and 6b), half of the pups displayed an immature phenotype with very sparse PV labeling in the BLA (Fig. 6c).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The difference among SAM pups at PN15 yielded a trend for a SAM-vs-CON group difference, but did not reach statistical significance (p=0.293 for PV density across all levels; p=0.1953 for anterior-to-mid; p=0.4214 for posterior).

    “Although this difference among the SAM pups yielded a trend for a SAM-vs-CON group difference at this age, the difference did not reach statistical significance (t (42)=1.063 and p=0.293 for PV density across all levels of BLA; p=0.1953 and t(42)=1.316 for the anterior-to-mid level; p=0.4214 and t(28)=0.8160 for posterior level of BLA).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Comparison of PNN labeling in BLA between PN23 CON and PN23 SAM revealed a significant decrease of PNN intensity within anterior-to-mid level BLA of SAM animals (p=0.0114, t(10)=3.093) but only marginally different at the posterior level (p=0.1208, t(7)=1.766).

    “This comparison revealed a significant decrease of PNN intensity within anterior-to-mid level BLA of PN23 SAM animals, relative to the corresponding region of PN23 CON animals (p=0.0114 by two-tailed t-test, t(10)=3.093) but only marginally different at the posterior level (p=0.1208, t(7)=1.766) (Fig. 4c, lower).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Four out of 8 CON-E brains exhibited complete unilateral dissolution of PNN, while four other CON-E brains exhibited partial unilateral dissolution of PNN.

    “Four out of the 8 CON-E brains exhibited complete unilateral dissolution of PNN, such as that shown in Fig. 3a, while four other CON-E brains exhibited partial unilateral dissolution of PNN.”
    Quote in the paperSubstantial claim

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

    Findingown data

    The intensity resulting from enzymatic dissolution of PNN was defined as background labeling and was <16% of average BLA intensity and <9% of average PNN intensity at PN23.

    “The intensity resulting from enzymatic dissolution of PNN was defined to be background labeling and was <16% of the average BLA intensity value (at PN23) and <9% of the average PNN intensity value at PN23.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    One-way ANOVA indicated significant impact of enzyme treatment upon PNN intensity of BLA of CON tissue (p<0.001, F=12.89), due to significant decrease within BLA of CON-E relative to CON-S (13% reduction in normalized PNN intensity, p<0.001, meanCON-S=1.205 ± 0.031; meanCON-E=1.048 ± 0.031, t(21)=4.999).

    “One-way ANOVA indicated significant impact of enzyme treatment upon PNN intensity of BLA of CON tissue (p<0.001, F=12.89), due to significant decrease within the BLA of CON-E, relative to CON-S’s (13% reduction in normalized PNN intensity, p<0.001, meanCON-S=1.205 ± 0.031; meanCON-E=1.048 ± 0.031, t(21)=4.999).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    SAM group exhibited large individual differences in innate threat response at PN23, with distances varying from 19 to 45 cm, and no significant difference in group mean value compared to CON (meanCON=28.98±2.24 cm; meanSAM=32.09±3.21, p=0.4406).

    “SAM group also exhibited large individual differences in this innate threat response at PN23, with distances to the predator odor varying from 19 to 45 cm and no significant difference in the group mean value, compared to CON’s (meanCON ± SEM = 28.98 ± 2.24 cm; meanSAM ± SEM = 32.09 ± 3.21, p = 0.4406 and t(14) = 0.7938 by two-tailed unpaired t-test).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In PN23 SAM BLA, PNNs surrounded the greater majority of PV+ neuronal cell bodies, with no significant difference between anterior-to-mid (99% ± 0.4%) and posterior (99% ± 0.6%) levels.

    “PNNs surrounded the greater majority of neuronal cell bodies immunopositive for PV in PN23 SAM BLA as well, with no significant difference between anterior-to-mid level (99% ± 0.4%) and posterior level (99% ± 0.6%) percentage of PNN surrounding PV cells (p>0.999; t(6)<.001).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The posterior levels of BLA showed a main effect of age (F(2,28)=16.03, p<0.001), but not of treatment (F(1,28)=0.339, p=0.565) and no interaction (F(2,28)=0.202, p=0.818).

    “The posterior levels of the BLA also showed a main effect of age F(2,28)=16.03, p<0.001, but not of treatment [F(1,28)=0.339, p=0.565] and no interaction between age and treatment [F(2,28)=0.202, p=0.818].”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    There was no difference between SAM and CON groups in nursing or mother's proportion of time in the nest.

    “Also notable was the lack of difference between the groups with regard to nursing or mother’s proportion of time in the nest.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The greyscale value for BLA with dissolved proteoglycan was 29.3 AU lighter than average BLA of age-matched CON without enzyme infusion and 11.8 AU darker than average greyscale of a slide containing no tissue.

    “The greyscale value for BLA with dissolved proteoglycan, measured at a point central to the cannula tip on PN23 was 29.3 arbitrary units of intensity (AU) lighter than the average BLA of age-matched CON BLA without enzyme infusion and 11.8 AU darker than the average greyscale value of a slide containing no tissue.”
    Quote in the paperSubstantial claim

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

    Findingreasoning

    There was no effect of SAM upon pups' body weight gains.

    “This fits with the absence of effect of SAM upon pups’ body weight gains.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Two-way ANOVA of PV density in anterior-to-mid levels of BLA revealed age as a significant factor (F(2,42)=24.04, p<0.001) but not rearing condition (F(1,42)=0.1443, p=0.706), with no interaction (F(2,42)=1.190, p=0.314).

    “Two-way ANOVA of PV density in the anterior-to-mid levels of BLA revealed age to be a significant factor [F(2,42)=24.04, p<0.001] but not the rearing condition [F(1,42)=0.1443, p=0.706], with no interaction between age and the rearing conditions [F(2,42) = 1.190, p=0.314.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Two-way ANOVA of PV density across all anterior-to-posterior levels revealed a significant effect of age (F(2,42)=25.21, p<0.001), but not rearing condition (F(1,42)=25.21, p=0.853).

    “Two-way ANOVA of PV density across all anterior-to-posterior (AP) levels revealed a significant effect of age (F(2,42)=25.21, p<0.001), but not rearing condition (F(1,42)=25.21, p=0.853).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    SAM rearing from PN8-12 exhibited more rough handling of pups and were more active in the nest compared to control nests.

    “mother-pup interactions during the SAM rearing from PN 8–12 exhibited more rough handling of pups and were more active in the nest, compared to control nests (CON; p=0.025; Fig 1b).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Fisher's post hoc analysis revealed a robust increase in anterior-to-mid level BLA of CON pups from PN12 to PN15 (10 fold; t(42)=3.763, p<0.001), with no further significant increase from PN15 to PN18 (p=0.617) or from PN18 to PN23 (p=0.84).

    “Fisher’s post hoc analysis revealed a robust increase in the anterior-to-mid level BLA of pups reared under the control condition from PN12 to PN15 (10 fold; t(42)=3.763, p<0.001), with no further significant increase from PN15 to PN18 (t(42)=0.504, p=0.617) or from PN18 to PN23 (p=0.84, t(56)=0.3744).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In anterior-to-mid level BLA of SAM group, PV cell density increased with a delay compared to CON, as plateau was attained by PN15 for CON but not until PN18 for SAM.

    “In the anterior-to-mid level BLA of the SAM group, PV cell density increased but with a delay, compared to the CON group, as the plateau was attained by PN15 for the CON group but was not attained until PN18 for the SAM group (Fig. 6d).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    While there was no CON vs SAM difference in percentage of PV cell bodies' plasma membrane receiving excitatory input from ATs (p=0.96), there was a significant 25% increase in average AT lengths onto PV cells in BLA of SAM group (p=0.0323, t(87)=2.175) and a trend for a 20% decrease in frequency of ATs forming excitatory synapses onto cell bodies of PV cells (p=0.18).

    “While there was no CON vs SAM difference in the percentage of PV cell bodies’ plasma membrane receiving excitatory input from ATs (p=0.96; Fig. 9d), there was a significant 25% increase in average AT lengths onto PV cells in the BLA of the SAM group (p=0.0323, t(87)=2.175, Fig. 9f) and a trend for a 20% decrease in the frequency of ATs forming excitatory synapses onto the cell bodies of PV cells (”
    Quote in the paperNot a substantial claim
    • The authors state this as an assumption: Each neuron is an independent unit that could respond to alterations in levels of afferent activity from a variety of neurons within and outside of the BLA.

  • May combine two claims.

    Findingown data

    Two-way ANOVA of PNN density revealed a strong age-effect (F(2,30)=7.029, p=0.003 for all levels; F(2,30)=7.741, p<0.002 for anterior-to-mid; F(1,17)=0.592, p=0.028 for posterior), as well as a rearing effect in anterior/mid and combined anterior-to-posterior levels, but only marginally in posterior levels (F(1,30)=4.226, p=0.049 for all; F(1,30)=5.084, p=0.032 for anterior-to-mid; F(1,20)=0.1118,

    “Two-way ANOVA of PNN density (Fig. 7b) revealed a strong age-effect (effect of age for all anterior-to-posterior levels F(2,30)=7.029, p=0.003; effect of age for anterior-to-mid level F(2,30)=7.741, p<0.002; effect of age for the posterior level F(1,17)=0.592, p=0.028), as well as a rearing effect in anterior/mid and combined anterior-to-posterior levels, but only marginally in posterior levels (”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Post hoc analyses of the rearing effect in anterior-to-mid level BLA and anterior-to-posterior levels did not yield significance, although there was a strong trend towards reduction of PNN density within SAM brains at PN15 (t(30)=1.981, p=0.0568 for anterior-to-mid; t(30)=1.907, p=0.066 in all levels).

    “Post hoc analyses of the rearing effect in anterior-to-mid level BLA and anterior-to-posterior levels did not yield significance, although we did observe a strong trend towards reduction of PNN density within SAM brains at a single time point of PN15 (t(30)=1.981, p=0.0568 for anterior-to-mid level and t(30)=1.907, p=0.066 in all anterior-to-posterior levels).”
    Quote in the paperNot a substantial claim

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

    Findingnone given

    These SAM-related cellular events occur within the context of profound ontogenetic changes that take place normally during the pre-weaning period, whereby PV and PNN cell densities increase four to ten-fold.

    “These SAM-related cellular events occur within the context of profound ontogenetic changes that take place normally during the pre-weaning period, whereby PV and PNN cell densities increase four to ten-fold.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    This was due primarily to a 24% reduction in frequency of contacts formed by PV terminals onto pyramidal cell bodies per μm of plasma membrane sampled (p=0.0458, t(118)=2.018) but also a significant reduction in average length of synaptic contacts formed by PV terminals (13% reduction, p=0.0293, t(106)=2.209).

    “This was due primarily to a 24% reduction in the frequency of contacts formed by PV terminals onto pyramidal cell bodies, per µm of plasma membrane sampled (Fig 8e; p=0.0458, t(118)=2.018, comparing SAM versus CON) but also a significant reduction in the average length of synaptic contacts formed by PV terminals (Fig 8f; 13% reduction, p=0.0293, t(106)=2.209).”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: Each neuron is an independent unit that could respond to alterations in levels of afferent activity from a variety of neurons within and outside of the BLA.

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

    Findingown data

    There was also diffuse proteoglycan labeling that did not cluster around individual somata, categorized as labeling in the neuropil surrounding the PNN.

    “There was also diffuse proteoglycan labeling that did not cluster around individual somata, which were categorized as labeling in the neuropil surrounding the PNN.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    SAM induced a reduction of PV intensity in the posterior BLA but only transiently at PN12.

    “SAM induced a reduction of PV intensity in the posterior BLA but only transiently at PN12.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Two-way ANOVA of intensity of PNN labeling revealed no significant effect of rearing condition (F(1,27)<.001, p=0.983 for all; etc.) and no significant effect of age (F(2,27)=.265, p=0.769 for all; etc.) and no interaction.

    “Two-way ANOVA of the intensity of PNN labeling (Fig. 6c) revealed no significant effect of rearing condition (all anterior-to-posterior levels: F(1,27)<.001, p=0.983; anterior-to-mid level BLA; F(1,27)<.001, p=0.977; posterior level BLA: F(1,15)= .005, p=.945) and no significant effect of age (all anterior-to-posterior levels: F(2,27)= .265, p=0.769); anterior-to-mid level BLA; F(2,27)= .528, p=0.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    PV-immunolabeling was also readily apparent within perikaryal cytoplasm of cell bodies with deep indentations of the nuclear envelope.

    “PV-immunolabeling was also readily apparent within perikaryal cytoplasm of cell bodies with deep indentations of the nuclear envelope (Fig. 9).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    PV cells were absent in 5 out of 8 CON animals at PN12, increased 19-fold by PN15 and by 250% more by PN18 (t(28)=2.594, p=0.015).

    “PV cells, absent in 5 out of the 8 CON animals at PN12, increased 19-fold by PN15 and by 250% more by PN18 (t(28)=2.594, p=0.015).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The SAM group showed an 8-fold increase from PN12 to PN15 (t(42)=2.664, p=0.029) and another 90% increase from PN15 to PN18 (t(42)=2.79, p=0.021).

    “The SAM group showed an 8-fold increase from PN12 to PN15 (t(42)=2.664, p=0.029) and another 90% increase from PN15 to PN18 (t(42)= 2.79, p=0.021).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    This was due primarily to a 51% reduction in frequency of PV terminal contacts onto cell bodies of PV cells (p<0.001, t(118)=3.549), rather than changes in PV terminal lengths (p=0.35).

    “This was due primarily to a 51% reduction in the frequency of PV terminal contacts onto the cell bodies of PV cells (p<0.001, t(118)=3.549; Fig 9e), rather than changes in PV terminal lengths (p=0.35, Fig 9f).”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: Each neuron is an independent unit that could respond to alterations in levels of afferent activity from a variety of neurons within and outside of the BLA.

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

    Findingnone given

    The great majority of PNNs surround PV neurons in the BLA of PN23 rats.

    “Since the great majority of PNNs surround PV neurons in the BLA of PN23 rats”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The reduction of PNN intensity at weaning was evident for the anterior-to-mid level BLA but not for the posterior BLA.

    “The reduction of PNN intensity at weaning was evident for the anterior-to-mid level BLA but not for the posterior BLA.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    PV, together with PNN, modulate experience-dependent synaptic plasticity in neocortex.

    “Our investigation of PNN was prompted by the finding that postnatal experience influences the ontogeny of PV/PNN in the sensory cortex (Pizzorusso et al., 2002) and that PV, together with PNN, in turn, modulate experience-dependent synaptic plasticity in neocortex (Pizzorusso et al., 2002).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Pizzorusso et al., 2002

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The Scarcity-Adversity Model (SAM) manipulation results in weanlings' exhibition of enhanced fear responses to predator odor and enhanced response of the BLA, with behavioral modifications enduring into adulthood.

    “This manipulation results in weanlings’ exhibition of enhanced fear responses to predator odor and enhanced response of the basolateral nucleus of the amygdala (BLA; Perry et al., in revision), with behavioral modifications enduring into adulthood (Perry and Sullivan, 2014).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Perry et al., in revision

      Not checked in the free run.

    • cites Perry and Sullivan, 2014

      Not checked in the free run.

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

    Premisecitation

    PNNs can encapsulate some PV cells.

    “Moreover, perineuronal nets (PNNs), comprised of chondroitin sulfate proteoglycans, can encapsulate (Pantazopoulos et al., 2008, Baker et al., 2017) and enhance excitability of some PV cells (Balmer, 2016), especially in the anterior and mid-levels of the BLA (Morikawa et al., 2017).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Pantazopoulos et al., 2008

      Not checked in the free run.

    • cites Baker et al., 2017

      Not checked in the free run.

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

    Premisecitation

    PNNs enhance excitability of some PV cells, especially in the anterior and mid-levels of the BLA.

    “Moreover, perineuronal nets (PNNs), comprised of chondroitin sulfate proteoglycans, can encapsulate (Pantazopoulos et al., 2008, Baker et al., 2017) and enhance excitability of some PV cells (Balmer, 2016), especially in the anterior and mid-levels of the BLA (Morikawa et al., 2017).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Balmer, 2016

      Not checked in the free run.

    • cites Morikawa et al., 2017

      Not checked in the free run.

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

    Premisecitation

    The BLA of older pups and adults is active during both learned and innate threat responses and anxiety-like behavior.

    “The BLA of older pups and adults are well-recognized to be active during both learned and innate threat responses (Takahashi et al., 2007; Parkes and Westbrook, 2010; Perry et al., 2016) and anxiety-like behavior (Tye et al., 2011; Janak and Tye, 2015).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Takahashi et al., 2007

      Not checked in the free run.

    • cites Parkes and Westbrook, 2010

      Not checked in the free run.

    • cites Perry et al., 2016

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Postnatal experience influences the ontogeny of PV/PNN in the sensory cortex.

    “Our investigation of PNN was prompted by the finding that postnatal experience influences the ontogeny of PV/PNN in the sensory cortex (Pizzorusso et al., 2002) and that PV, together with PNN, in turn, modulate experience-dependent synaptic plasticity in neocortex (Pizzorusso et al., 2002).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Pizzorusso et al., 2002

      Not checked in the free run.

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

    Premisecitation

    PV cells produce synchronous firing in the BLA.

    “We chose to focus on PV cells, which control excitability of principle excitatory neurons that are commonly referred to as pyramidal cells (McDonald et al., 2005) and produce synchronous firing in the BLA (Ryan et al., 2012).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Ryan et al., 2012

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    PNN in the BLA protects fear memories from erasure.

    “Moreover, PNN in the BLA protects fear memories from erasure (Gogolla et al., 2009), indicating BLA PNN’s importance in threat response.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Gogolla et al., 2009

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Fear conditioning is impaired after unilateral temporal lobectomy in humans.

    “Human neurobiology has also shown that fear conditioning is impaired after unilateral temporal lobectomy (LaBar et al., 1995).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites LaBar et al., 1995

      Not checked in the free run.

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

    Study design and conductown data

    PV immunolabeling was successful in all subjects, confirmed by positive perikarya in the hippocampus and reticular thalamic nuclei.

    “Success of immunocytochemical detection of PV was confirmed through verification of immunopositive perikarya in the hippocampus and reticular thalamic nuclei. Using this measure, brains of all subjects were considered successfully immunolabeled, even when no positive staining was visible in the amygdala.”
    Quote in the paperSubstantial claim

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

    Study design and conductreasoning

    Cell profiles were only image-captured close to the EPON-tissue interface where immunolabeling could be expected to be optimal.

    “To ensure full DAB immunoreactivity of PV cells and terminals, cell profiles were only image-captured close to the EPON-tissue interface carved by the vibratome blade, where immunolabeling could be expected to be optimal.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    Staining of sections from the ontogeny set was conducted on a single day, in parallel, to maintain homogeneity of reagents.

    “Staining of the sections from the ontogeny set, ranging from PN12 to PN23 was conducted on a single day, in parallel, so as to maintain homogeneity of all reagents.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    All EM image acquisitions and quantifications were performed by persons blind to experimental condition.

    “All EM image acquisitions and quantifications were performed by persons blind to experimental condition.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Together, this indicates that any detectable differences in PNN, especially in the SAM group, are likely to affect the PV population specifically, and not the population of PNN surrounded Pyr cells identified by Morikawa et al 2016, which are likely to emerge later in development (Baker et al 2017).

    “Together, this indicates that any detectable differences in PNN, especially in the SAM group, are likely to affect the PV population specifically, and not the population of PNN surrounded Pyr cells identified by Morikawa et al 2016, which are likely to emerge later in development (Baker et al 2017).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Morikawa et al 2016

      Not checked in the free run.

    • cites Baker et al 2017

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    DAB labeling was only considered positive if the soma or terminal was darker than the relatively electron-dense mitochondria in the imaged region.

    “DAB labeling was only considered positive if the soma or terminal was darker than the relatively electron-dense mitochondria in the imaged region.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    In spite of SAM maltreatments, pups gain weight normally.

    “In spite of these maltreatments, pups gain weight normally (Raineki et al., 2012; Raineki et al., 2015; Rincón-Cortés and Sullivan, 2016).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Raineki et al., 2012

      Not checked in the free run.

    • cites Raineki et al., 2015

      Not checked in the free run.

    • cites Rincón-Cortés and Sullivan, 2016

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    All PV and PNN quantifications were performed by persons blind to experimental condition.

    “All PV and PNN quantifications were performed by persons blind to experimental condition.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    Intactness of the BLA that received ChABC-hyaluronidase injection was verified by Nissl staining.

    “To verify intactness of the BLA that received ChABC-hyaluronidase injection, PNN-labeled sections were stained with Nissl.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Interpretationown data

    Assuming BLA excitability is related to threat response, increased density of PV cells could reflect increased efficacy by PV cells to suppress BLA excitability and threat response.

    “Assuming BLA excitability is related to threat response, the increased density of PV cells could be a reflection of the increased efficacy by the PV cells to suppress BLA excitability and with it, threat response.”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: BLA excitability is related to threat response.

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

    Study design and conductnone given

    Images of different ultrathin sections were aligned after image acquisition to ensure that the same cell was never re-analyzed from another grid.

    “Images of different ultrathin sections were aligned after image acquisition to ensure that the same cell was never re-analyzed from another grid.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Human neurobiology has shown that unilateral damage to the amygdala is sufficient to impair fear/threat conditioning.

    “Human neurobiology has shown that unilateral damage to the amygdala is sufficient to impair fear/threat conditioning (LaBar et al., 1995).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites LaBar et al., 1995

      Not checked in the free run.

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

    Study design and conductreasoning

    Staining of sections from the ontogeny set and from PNN-dissolution animals was performed in parallel to minimize inter-animal differences.

    “Staining of the sections from the ontogeny set was conducted in parallel, so as to maintain homogeneity of all reagents. Similarly, staining of the sections of brains from the animals that underwent PNN-dissolution, then the Y-maze test were performed in parallel, so as to minimize inter-animal differences resulting from differences in the reagents.”
    Quote in the paperNot a substantial claim

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

    Interpretationcitation

    The behavioral patterns observed during SAM rearing replicate those published previously by the Sullivan lab.

    “All of these findings replicate the behavioral patterns published previously by the Sullivan lab (Raineki et al., 2012; Perry and Sullivan, 2014; Rincón-Cortés and Sullivan, 2016).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Raineki et al., 2012

      Not checked in the free run.

    • cites Perry and Sullivan, 2014

      Not checked in the free run.

    • cites Rincón-Cortés and Sullivan, 2016

      Not checked in the free run.

  • May combine two claims.

    Study design and conductcitation

    The anti-PV antibody used is specific for PV and exclusively labels fast-spiking cells.

    “Specificity has been determined by preadsorption controls, which eliminate labeling in western blot and histology (Celio and Heizmann, 1981; Hackney et al., 2005). This antibody has been used previously for both light and electron microscopic studies (Rainnie et al., 2006; Fitzgerald et al., 2012), and electrophysiological studies confirm that the antibody exclusively labels fast-spiking cells (Za”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Celio and Heizmann, 1981

      Not checked in the free run.

    • cites Zaitsev et al., 2005

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    In summary, these EM data indicate that SAM reduces synaptic inhibition exerted by PV neurons in the BLA without a significant change in the excitatory drive onto PV neurons.

    “In summary, these EM data indicate that SAM reduces synaptic inhibition exerted by PV neurons in the BLA without a significant change in the excitatory drive onto PV neurons.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    As previously observed, intense PV-immunolabeling was detected within a subpopulation of axon terminals forming axo-somatic axon terminals.

    “As was previously observed (Smith et al., 1998; 2000), intense PV-immunolabeling was detected within a subpopulation of axon terminals forming axo-somatic axon terminals (Figs. 8 and 9).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Smith et al., 1998

      Not checked in the free run.

    • cites Smith et al., 2000

      Not checked in the free run.

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

    Premisecitation

    In the hippocampus of adult mice, Donato et al describe a transient reduction in PV intensity that promotes increased plasticity via reduced inhibition of pyramidal cells.

    “In the hippocampus of adult mice, Donato et al (Donato et al., 2015) describe a transient reduction in PV intensity that promotes increased plasticity via reduced inhibition of pyramidal cells.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Donato et al., 2015

      Not checked in the free run.

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

    Premisecitation

    In agreement with previous studies, PNN labeling around somata ranged from more diffuse to darker and more defined around both somata and proximal dendrites.

    “In agreement with previous studies (Horii-Hayashi et al., 2015), PNN labeling around somata ranged from more diffuse to darker and more defined around both somata and proximal dendrites (Fig 7a).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Horii-Hayashi et al., 2015

      Not checked in the free run.

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

    Premisecitation

    Large PV+ terminals (>1μm2) are associated with PV+ projections from the basal forebrain.

    “Of them, large PV+ terminals (>1µm2) are associated with PV+ projections from the basal forebrain (Muller et al., 2005).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Muller et al., 2005

      Not checked in the free run.

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

    Premisecitation

    Disinhibition via PV innervation of somatostatin+ cells, which contact dendrites of pyramidal cells, drives BLA fear/threat learning.

    “Disinhibition via PV innervation of somatostatin+ cells which, in turn, contact dendrites of pyramidal cells, drive BLA fear/threat learning (Wolff et al., 2014).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Wolff et al., 2014

      Not checked in the free run.

  • The quote only partly states this claim.

    Interpretationreasoning

    Reduction of PV inhibition in the BLA contributes to the heightened innate threat response observed.

    “and heightened innate threat response that we observed.”
    Quote in the paperSubstantial claim

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

    Interpretationreasoning

    A similar mechanism may be at play in the developing BLA for individuals recovering from early life trauma, transiently extending the period of postnatal plasticity.

    “A similar mechanism may be at play in the developing BLA for individuals recovering from early life trauma, transiently extending the period of postnatal plasticity.”
    Quote in the paperNot a substantial claim

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

    Interpretationcitation

    These new findings complement recent results showing continued maturation of PV and PNN in normative development from PN24 to adulthood and the potential for continued impact of developmental insults and recovery from them.

    “These new findings complement recent results showing continued maturation of PV and PNN in normative development from PN24 to adulthood (Baker et al., 2017) and the potential for continued impact of developmental insults and recovery from them.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Baker et al., 2017

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Hyperexcitability of pyramidal cells in the BLA likely contributes to heightened anxiety-like behavior that reduces social behavior.

    “Hyperexcitability of the pyramidal cells in the BLA is likely to also contribute to heightened anxiety-like behavior that reduces social behavior (Felix-Ortiz and Tye, 2014).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Felix-Ortiz and Tye, 2014

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductown data

    This was verified by Nissl staining of the enzymatically treated BLA.

    “This was verified by Nissl staining of the enzymatically treated BLA.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Unilateral PNN depletion within the BLA converts the threat response of normally reared animals to become abnormally high, as shown among weanlings with a history of early life maltreatment.

    “We also show that unilateral PNN depletion within the BLA converts the threat response of normally reared animals to become abnormally high, as we’ve shown among weanlings with a history of early life maltreatment.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    Since PNN dissolution reduces excitability of PV cells, this third finding strengthens a causal link between reduction of PV-mediated synaptic inhibition in the BLA and heightened innate threat response.

    “Since PNN dissolution reduces excitability of PV cells (Balmer, 2016), this third finding strengthens a causal link between reduction of PV-mediated synaptic inhibition in the BLA and heightened innate threat response.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Balmer, 2016

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    This, together with the reduction of PV-innervation onto pyramidal cells, provides anatomical support for the idea that reduction of PV/PNN-mediated inhibition in the anterior-to-mid level BLA causes hyperexcitability of the BLA, which, in turn, elevates innate threat responsiveness of weanlings.

    “This, together with the reduction of PV-innervation onto pyramidal cells, provides anatomical support for the idea that reduction of PV/PNN-mediated inhibition in the anterior-to-mid level BLA causes hyperexcitability of the BLA, which, in turn, elevates innate threat responsiveness of weanlings (Fig. 10).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Since animals receiving enzymatic treatment to dissolve PNN did not exhibit reduction of threat response but instead heightened threat responses, it is likely that the enzymatic treatment with the micropipette left the BLA intact.

    “Since the animals receiving the enzymatic treatment to dissolve PNN did not exhibit reduction of threat response but, instead, heightened threat responses, it is likely that the enzymatic treatment with the micropipette left the BLA intact.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Optogenetic stimulation of axon terminals of pyramidal cells within the CeA generates anxiolysis.

    “when axon terminals of pyramidal cells within the CeA are optogenetically stimulated, anxiolysis is generated.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Tye et al., 2011

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Disruption of GABAergic development broadens tuning curves responsible for adaptive response to stimuli.

    “Since disruption of GABAergic development broadens tuning curves responsible for adaptive response to stimuli (Isaacson and Scanziani, 2011)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Isaacson and Scanziani, 2011

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The BLA of SAM brains is driven more strongly but by fewer sources.

    “this would indicate that BLA of SAM brains are driven more strongly but by fewer sources.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    PV cells coordinate spike timing of pyramidal cells to entrain high frequency oscillations in the BLA.

    “Specifically, PV cells coordinate spike timing of Pyr cells, to entrain high frequency oscillations in the BLA (Ryan et al., 2012).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Ryan et al., 2012

      Not checked in the free run.

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

    Interpretationreasoning

    BLA tuning to threat may also be broadened for SAM rats, as animals develop heightened awareness of potential threats under conditions of resource scarcity.

    “BLA tuning to threat may also be broadened for SAM rats, as animals develop heightened awareness of potential threats under conditions of resource scarcity.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Hippocampal PNNs regulate plasticity at axo-somatic excitatory inputs to PV cells by increasing AMPA receptor localization at the synapse via expression of brevican.

    “Hippocampal PNNs regulate plasticity at axo-somatic excitatory inputs to PV cells by increasing AMPA receptor localization at the synapse via expression of brevican (Favuzzi et al., 2017).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Favuzzi et al., 2017

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Gamma activity may be a critical component to functional theta-gamma coupling between prefrontal cortex and BLA, which is necessary for processing safety signals.

    “and may be a critical component to functional theta-gamma coupling between prefrontal cortex and BLA, which has been shown to be necessary for processing safety signals (Stujenske et al., 2014).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Stujenske et al., 2014

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    PNN intensity is frequently used as a proxy for maturity.

    “PNN intensity is frequently used as a proxy for maturity (Foscarin et al., 2011; Carulli et al., 2013; Chen et al., 2015; Slaker et al., 2015; Happel and Frischknecht, 2016; Vazquez-Sanroman et al., 2016).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Foscarin et al., 2011

      Not checked in the free run.

    • cites Carulli et al., 2013

      Not checked in the free run.

    • cites Chen et al., 2015

      Not checked in the free run.

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

    Premisecitation

    PNNs protect the cells that they enwrap from oxidative stress.

    “In addition, PNNs have been shown to protect the cells that they enwrap from oxidative stress (Cabungcal et al., 2013; Suttkus et al., 2014).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Cabungcal et al., 2013

      Not checked in the free run.

    • cites Suttkus et al., 2014

      Not checked in the free run.

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

    Premisecitation

    Gamma activity increases with PV cell development.

    “Gamma activity increases with PV cell development (Yang et al., 2015)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Yang et al., 2015

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The SAM effects observed at PN23 are the delayed manifestation of SAM, presumably resulting from perturbations in BLA circuitry that exist during SAM, which alter the developmental trajectory of the activity-dependent emergence of PV-synapses and PNNs during the pre-weaning ages that follow SAM.

    “Rather, the SAM effects we observe at PN23 are the delayed manifestation of SAM, presumably resulting from perturbations in BLA circuitry that exist during SAM, which alter the developmental trajectory of the activity-dependent emergence of PV-synapses and PNNs during the pre-weaning ages that follow SAM.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    In the BLA of postnatal week 5-10 male mice, PNNs encapsulate PV neurons in the anterior BLA but more of the excitatory neurons in the posterior BLA.

    “It has recently become evident that PNN in the BLA of postnatal week 5–10 male mice encapsulate PV neurons in the anterior BLA but more of the excitatory neurons in the posterior BLA (Morikawa et al., 2017).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Morikawa et al., 2017

      Not checked in the free run.

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

    Interpretationreasoning

    Peri-weaning PV cells in the BLA of SAM weanlings may also be more prone to oxidative stress and exhibit reduced plasticity at excitatory synaptic inputs.

    “Peri-weaning PV cells in the BLA of SAM weanlings may also be more prone to oxidative stress, and exhibit reduced plasticity at excitatory synaptic inputs.”
    Quote in the paperNot a substantial claim
84 of 84

  • The authors state this as an assumption.

    Knowledge underlying the enduring effect of early life trauma is incomplete; relatively less is known about the effects of this trauma on BLA synaptic circuitry and its involvement in aberrant threat responses at weaning and pre-weaning ages.

    “but knowledge underlying its enduring effect is incomplete.”
    “However, relatively less is known about the effects of this trauma on BLA synaptic circuitry and of its involvement in aberrant threat responses at weaning and pre-weaning ages.”

  • The authors state this as an assumption.

    BLA excitability is related to threat response.

    “Assuming BLA excitability is related to threat response, the increased density of PV cells could be a reflection of the increased efficacy by the PV cells to suppress BLA excitability and with it, threat response.”

  • The authors state this as an assumption.

    Each neuron is an independent unit that could respond to alterations in levels of afferent activity from a variety of neurons within and outside of the BLA.

    “Each neuron was considered an independent unit that could respond to alterations in levels of afferent activity from a variety of neurons within and outside of the BLA (i.e., N= cell).”

  • The paper relies on this without support.

    In normal ontogeny, BLA cells begin to express PV and PNN at PN12.

    “SAM treatment ends just as BLA cells are beginning to express PV and PNN in normal ontogeny (PN12).”
4 of 4

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?

Statistics that don’t add up

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

  • Inconsistent p-value across alpha = .05: F(1,17)=0.592, p = .028

    Major

    The paper reports p = .028 here; recomputing from the test statistic and its degrees of freedom gives p = .452. The two fall on opposite sides of alpha = .05. The check cannot tell whether the statistic or the p-value is the misprint.

    Reported p = .028 · recomputed p = .452

  • Inconsistent p-value across alpha = .05: F(1,42)=25.21, p = .853

    Major

    The paper reports p = .853 here; recomputing from the test statistic and its degrees of freedom gives p < .001. The two fall on opposite sides of alpha = .05. The check cannot tell whether the statistic or the p-value is the misprint.

    Reported p = .853 · recomputed p < .001

  • Inconsistent p-value: F(1,17)=0.592, p = .075

    Minor

    The paper reports p = .075 here; recomputing from the test statistic and its degrees of freedom gives p = .452. The check cannot tell whether the statistic or the p-value is the misprint.

    Reported p = .075 · recomputed p = .452

  • Inconsistent p-value: F(2,27)= .528, p = .977

    Minor

    The paper reports p = .977 here; recomputing from the test statistic and its degrees of freedom gives p = .596. The check cannot tell whether the statistic or the p-value is the misprint.

    Reported p = .977 · recomputed p = .596

4 of 4

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, 42) = 25.21reported p = .853 · recomputed p < .001The two fall on opposite sides of .05

    “F(1,42)=25.21, p = .853”

  • Doesn’t add upF(1, 17) = 0.592reported p = .028 · recomputed p = .452The two fall on opposite sides of .05

    “F(1,17)=0.592, p = .028”

  • Doesn’t add upF(1, 17) = 0.592reported p = .075 · recomputed p = .452

    “F(1,17)=0.592, p = .075”

  • Doesn’t add upF(2, 27) = 0.528reported p = .977 · recomputed p = .596

    “F(2,27)= .528, p = .977”

  • Not confirmedt(42) = 2.664reported p = .029 · recomputed p = .011

    “t(42)=2.664, p = .029”

  • Not confirmedt(42) = 2.79reported p = .021 · recomputed p = .008

    “t(42)= 2.79, p = .021”

  • Not confirmedF(1, 27) < 0.001reported p = .977 · recomputed p = .975

    “F(1,27)<.001, p = .977”

  • ConsistentF(2, 42) = 25.21reported p < .001 · recomputed p < .001

    “F(2,42)=25.21, p < .001”

  • ConsistentF(2, 42) = 24.04reported p < .001 · recomputed p < .001

    “F(2,42)=24.04, p < .001”

  • ConsistentF(1, 42) = 0.1443reported p = .706 · recomputed p = .706

    “F(1,42)=0.1443, p = .706”

  • ConsistentF(2, 42) = 1.19reported p = .314 · recomputed p = .314

    “F(2,42) = 1.190, p = .314”

  • Consistentt(42) = 3.763reported p < .001 · recomputed p < .001

    “t(42)=3.763, p < .001”

  • Consistentt(42) = 0.504reported p = .617 · recomputed p = .617

    “t(42)=0.504, p = .617”

  • ConsistentF(2, 28) = 16.03reported p < .001 · recomputed p < .001

    “F(2,28)=16.03, p < .001”

  • ConsistentF(1, 28) = 0.339reported p = .565 · recomputed p = .565

    “F(1,28)=0.339, p = .565”

  • ConsistentF(2, 28) = 0.202reported p = .818 · recomputed p = .818

    “F(2,28)=0.202, p = .818”

  • Consistentt(28) = 2.594reported p = .015 · recomputed p = .015

    “t(28)=2.594, p = .015”

  • ConsistentF(2, 34) = 1.404reported p < .26 · recomputed p = .259

    “F(2,34)=1.404, p < .260”

  • ConsistentF(2, 34) = 1.379reported p < .266 · recomputed p = .266

    “F(2,34)=1.379, p < .266”

  • ConsistentF(2, 17) = 0.383reported p = .688 · recomputed p = .688

    “F(2,17)=0.383, p = .688”

  • ConsistentF(1, 34) = 2.257reported p = .142 · recomputed p = .142

    “F(1,34)=2.257, p = .142”

  • ConsistentF(1, 34) = 1.631reported p = .21 · recomputed p = .210

    “F(1,34)=1.631, p = .210”

  • Consistentt(17) = 2.672reported p = .016 · recomputed p = .016

    “t(17)=2.672, p = .016”

  • ConsistentF(2, 30) = 7.029reported p = .003 · recomputed p = .003

    “F(2,30)=7.029, p = .003”

  • ConsistentF(2, 30) = 7.741reported p < .002 · recomputed p = .002

    “F(2,30)=7.741, p < .002”

  • ConsistentF(1, 30) = 4.226reported p = .049 · recomputed p = .049

    “F(1,30)=4.226, p = .049”

  • ConsistentF(1, 30) = 5.084reported p = .032 · recomputed p = .032

    “F(1,30)=5.084, p = .032”

  • ConsistentF(1, 20) = 0.1118reported p = .742 · recomputed p = .742

    “F(1,20)=0.1118, p = .742”

  • Consistentt(30) = 1.981reported p = .0568 · recomputed p = .057

    “t(30)=1.981, p = .0568”

  • Consistentt(30) = 1.907reported p = .066 · recomputed p = .066

    “t(30)=1.907, p = .066”

  • Consistentt(30) = 2.965reported p = .006 · recomputed p = .006

    “t(30)=2.965, p = .006”

  • Consistentt(30) = 2.501reported p = .018 · recomputed p = .018

    “t(30)=2.501, p = .018”

  • ConsistentF(1, 27) < 0.001reported p = .983 · recomputed p = .975

    “F(1,27)<.001, p = .983”

  • ConsistentF(1, 15) = 0.005reported p = .945 · recomputed p = .945

    “F(1,15)= .005, p = .945”

  • ConsistentF(2, 27) = 0.265reported p = .769 · recomputed p = .769

    “F(2,27)= .265, p = .769”

  • ConsistentF(2, 15) = 2.394reported p = .125 · recomputed p = .125

    “F(2,15)= 2.394, p = .125”

  • Consistentt(37) = 2.291reported p = .0278 · recomputed p = .028

    “t(37)=2.291, p = .0278”

  • Consistentt(37) = 3.208reported p = .0028 · recomputed p = .003

    “t(37)=3.208, p = .0028”

38 of 38

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.

  • Different injection ages given for the PNN-labeling specificity test

    Minor

    The methods say the specificity-test enzymes were injected at PN23 and the rats euthanized the following day. The results describe that test as injection at PN22 followed by measurement at PN23.

  • Different ages given for the PNN-dissolution Y-maze test

    Minor

    The abstract places the tested, enzyme-treated rats at PN22-23, whereas the methods place their Y-maze test at PN21/22.

  • Identical F statistic and degrees of freedom have conflicting p-values

    Minor

    The two reported tests both give F(1,17)=0.592, but assign it p=0.075 and p=0.028. The same F statistic with the same degrees of freedom cannot have both p-values.

3 of 3

Cites

Flagged first, then by citations

Cited by

Sorted by citations

Related

Authors
Santiago, A. N., Lim, K. Y., Opendak, M., Sullivan, R. M., & Aoki, C.
Affiliations
  • NYU Langone Health (US)
  • New York University (US)
Corresponding author
Aoki, Chiye
ORCID
Venue
Journal of Comparative Neurology
Publisher
Wiley
Published
2018-10-18
Volume
526
Issue
16
Pages
2647-2664
ISSN
  • 0021-9967 (ISSN-L)
  • 1096-9861
DOI
10.1002/cne.24522
PMC
PMC6319912
OpenAlex
W2888639071
Semantic Scholar
c9eb0e34a5ea36f6878aa5297bed772a7c2f7c61
Cited by
87
References
83
Citations by year
2026: 6 · 2025: 9 · 2024: 6 · 2023: 11 · 2022: 11 · 2021: 10 · 2020: 26 · 2019: 7 · 2018: 1
FWCI
6.55
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations
  • The Journal of Comparative Neurology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institute of Mental Health (R21MH105846)
  • National Institutes of Health (F31 MH112372, F32MH112232, R37HD083217)
Topics
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
  • Social Sciences › Psychology › Clinical Psychology › Child Abuse and Trauma
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
early trauma, maternal deprivation, threat response, basolateral amygdala, parvalbumin interneurons, perineuronal nets, axosomatic synapses, somatic inhibition, predator odor, chondroitinase ABC, hyaluronidase, ontogeny, emotional processing
MeSH terms
Animals, Animals, Newborn, Axons, Behavior, Animal, Female, Male, Nerve Net, Stress, Psychological, Synapses, Rats, Long-Evans, Rats, Basolateral Nuclear Complex

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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