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Cited by 85Memory and Neural MechanismsNeuroscience and Neuropharmacology ResearchNeurogenesis and neuroplasticity mechanisms

Regulating Critical Period Plasticity: Insight from the Visual System to Fear Circuitry for Therapeutic Interventions

Open access
Nabel, Elisa M., Morishita, Hirofumi·2013·Frontiers in Psychiatry
DOI 10.3389/fpsyt.2013.00146PMC PMC3822369
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Abstract

Early temporary windows of heightened brain plasticity called critical periods developmentally sculpt neural circuits and contribute to adult behavior. Regulatory mechanisms of visual cortex development - the preeminent model of experience-dependent critical period plasticity-actively limit adult plasticity and have proved fruitful therapeutic targets to reopen plasticity and rewire faulty visual system connections later in life. Interestingly, these molecular mechanisms have been implicated in the regulation of plasticity in other functions beyond vision. Applying mechanistic understandings of critical period plasticity in the visual cortex to fear circuitry may provide a conceptual framework for developing novel therapeutic tools to mitigate aberrant fear responses in post traumatic stress disorder. In this review, we turn to the model of experience-dependent visual plasticity to provide novel insights for the mechanisms regulating plasticity in the fear system. Fear circuitry, particularly fear memory erasure, also undergoes age-related changes in experience-dependent plasticity. We consider the contributions of molecular brakes that halt visual critical period plasticity to circuitry underlying fear memory erasure. A major molecular brake in the visual cortex, perineuronal net formation, recently has been identified in the development of fear systems that are resilient to fear memory erasure. The roles of other molecular brakes, myelin-related Nogo receptor signaling and Lynx family proteins - endogenous inhibitors for nicotinic acetylcholine receptor, are explored in the context of fear memory plasticity. Such fear plasticity regulators, including epigenetic effects, provide promising targets for therapeutic interventions.

AI snapshot

Written from the paper’s full text.

TL;DR

This review uses visual cortex critical period plasticity as a model to propose that molecular brakes—perineuronal nets, Nogo receptor signaling, and Lynx proteins—also regulate fear memory erasure and may be therapeutic targets in PTSD. It synthesizes rodent and human evidence that pharmacological and behavioral interventions can reopen juvenile-like plasticity in visual and fear systems.

Key findings

  • The mouse visual cortex has a well-defined 2-week critical period peaking 1 month after birth; monocular deprivation causes amblyopia, which affects 2–5% of the human population, and adult recovery is limited. Molecular brakes include PNNs, myelin-related Nogo receptor/PirB, and Lynx1.
  • Fear erasure is age-dependent: extinction during a preadolescent critical period (P13–17) permanently erases fear, whereas extinction at 24 days or later leads to return of fear; erasure may be specific to early windows 1–3 days after trauma.
  • Amygdala PNNs increase between days 16 and 23 and protect fear memories from erasure; chondroitinase-ABC injected before fear conditioning—but not after—made adult mice extinguish like juveniles and prevented fear renewal weeks later.
  • Chronic fluoxetine (SSRI) reintroduces juvenile-like visual plasticity and facilitates permanent fear erasure via BDNF; AChEIs and HDAC inhibitors reopen visual plasticity, and reconsolidation update prevents fear reinstatement in humans and rodents.

Methods

  • Narrative review; no primary experiments. It synthesizes rodent visual cortex and fear conditioning/extinction studies plus human studies.
  • Main analysis: conceptual parallel between visual critical period plasticity (amblyopia, monocular deprivation) and fear system plasticity (fear erasure, extinction), examining PNNs, Nogo receptor signaling, Lynx family proteins, and interventions including SSRIs, AChEIs, HDAC inhibitors, and behavioral approaches.
  • No systematic search strategy or meta-analysis is described.

Limitations

  • Stated: mechanisms by which PNNs halt plasticity remain elusive; downstream effectors of PNN disruption are unidentified; whether Nogo receptor contributes to fear erasure remains to be examined; the direct role of Lynx family proteins in fear memory erasure is untested; AChEI effects on fear system plasticity are not directly examined; HDAC inhibitor effects on permanent fear erasure are not examined; interactions among brakes and mechanisms of re-closure need further study.
  • Evident from the text: as a narrative review, it provides no quantitative synthesis or risk-of-bias assessment, and many therapeutic proposals extrapolate from visual system findings to fear/PTSD without direct clinical trials in PTSD.

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

Integrity signals

Registry

Crossref · 10.3389/fpsyt.2013.00146

Cites

84 of 84 references verified0 citation errors · 0 not checkable

Statistics

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Claims the paper makes

0 of 130 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    Visually depriving one eye early in life yields loss in visual acuity (amblyopia) by stimulating anatomical remodeling within primary visual cortex.

    “In humans and animals, visually depriving one eye by obstructing it early in life yields loss in visual acuity (amblyopia) by stimulating an anatomical remodeling within primary visual cortex (3).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [3] Wiesel TN Postnatal development of the visual cortex and the influence of environment. Nature (1982) 299: 583– 91 10.1038/299583a0 6811951

      Not checked in the free run.

  • Premisecitation

    Fear acquisition, measured through the ability to develop conditioned context-shock fear responses, does not emerge until 13-14 days.

    “Fear acquisition, measured through the ability to develop conditioned context-shock fear responses, does not emerge until 13–14 days (12).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [12] Akers KG Arruda-Carvalho M Josselyn SA Frankland PW Ontogeny of contextual fear memory formation, specificity, and persistence in mice. Learn Mem (2012) 19: 598– 604 10.1101/lm.027581.112 23161449

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  • Interpretationreasoning

    In the visual system, critical-period but not adult monocular deprivation triggers functional re-adaptation via visual cortex restructuring that reduces input from the visually deprived eye.

    “In the visual system, critical period (but not adulthood) monocular deprivation triggers a functional re-adaptation via visual cortex restructuring that reduces the input from the visually deprived eye.”
    Quote in the paperNot a substantial claim
  • Premisecitation

    Fear extinction during a critical period in preadolescent mice (P13-17) leads to permanent fear erasure.

    “Fear extinction during a critical period in preadolescent mice (P13-17), leads to permanent fear erasure (13, 14).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [13] Kim JH Richardson R A developmental dissociation in reinstatement of an extinguished fear response in rats. Neurobiol Learn Mem (2007) 88: 48– 57 10.1016/j.nlm.2007.03.004 17459734

      Not checked in the free run.

    • cites [14] Kim JH Richardson R A developmental dissociation of context and GABA effects on extinguished fear in rats. Behav Neurosci (2007) 121: 131– 9 10.1037/0735-7044.121.1.131 17324057

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  • Interpretationreasoning

    Pathways underlying fear systems undergo age-related changes in experience-dependent plasticity.

    “Evidence from both animal and human studies suggest that the pathways underlying fear systems also undergo age-related changes in experience-dependent plasticity.”
    Quote in the paperSubstantial claim
  • Classified as probably not a substantial claim. 4
  • May combine two claims. 33
  • The quote only partly states this claim. 1

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

    Premisecitation

    Additional mechanisms likely contribute to the age-related changes described, including fear memory erasure due to increased rates of neurogenesis during development.

    “Although the following discussion focuses on this parallel nature of plasticity between visual and fear system development, it should be noted that additional mechanisms likely contribute to the age-related changes described, including fear memory erasure due to increased rates of neurogenesis during development (20).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [20] Frankland PW Kohler S Josselyn SA Hippocampal neurogenesis and forgetting. Trends Neurosci (2013) 36: 497– 503 10.1016/j.tins.2013.05.002 23768770

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

    Premisecitation

    Untreated monocular deprivation during childhood results in life-long amblyopia, a condition affecting 2-5% of the human population.

    “Due to a lack of sufficient brain plasticity in adulthood, untreated monocular deprivation during childhood results in life-long amblyopia, a condition affecting 2–5% of the human population (4).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [4] Wu C Hunter DG Amblyopia: diagnostic and therapeutic options. Am J Ophthalmol (2006) 141: 175– 84 10.1016/j.ajo.2005.07.060 16386994

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  • May combine two claims.

    Interpretationnone given

    Early development fear extinction modifies behavior by erasing fear memories that are no longer appropriate, and differs from adult extinction that is temporary and slower.

    “Early development fear extinction modifies behavior by erasing fear memories that are no longer appropriate, and differs from adult extinction that is temporary and slower.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Recovery from deprivation amblyopia in adulthood is limited across species and requires therapeutic intervention.

    “Indeed, recovery from deprivation amblyopia in adulthood is limited across species, from higher mammals (3), to rodents (5, 6), and requires therapeutic intervention.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [3] Wiesel TN Postnatal development of the visual cortex and the influence of environment. Nature (1982) 299: 583– 91 10.1038/299583a0 6811951

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    • cites [5] Prusky GT Douglas RM Developmental plasticity of mouse visual acuity. Eur J Neurosci (2003) 17: 167– 73 10.1046/j.1460-9568.2003.02420.x 12534981

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    • cites [6] Prusky GT West PW Douglas RM Experience-dependent plasticity of visual acuity in rats. Eur J Neurosci (2000) 12: 3781– 6 10.1046/j.1460-9568.2000.00236.x 11029648

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  • May combine two claims.

    Interpretationreasoning

    Both the visual and fear systems maintain a developmentally limited ability to rewire connections that are no longer functionally appropriate.

    “Both the visual and fear systems maintain a developmentally limited ability to rewire connections that are no longer functionally appropriate.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The regulatory mechanisms of critical period plasticity in the visual cortex are sufficiently parallel to those in fear circuitry that insights from the visual cortex can be applied to the fear system.

  • May combine two claims.

    Premisecitation

    Chronic fluoxetine treatment for 3 weeks prior to and throughout the duration of fear conditioning does not influence the encoding of a conditioned fear response, but causes faster extinction and permanent erasure compared to mice that undergo extinction training without prior SSRI treatment.

    “Chronic fluoxetine treatment for 3 weeks prior to and throughout the duration of fear conditioning does not influence the encoding of a conditioned fear response, but rather causes faster extinction and permanent erasure compared to mice that undergo extinction training without prior SSRI treatment.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [51] Karpova NN Pickenhagen A Lindholm J Tiraboschi E Kulesskaya N Agustsdottir A Fear erasure in mice requires synergy between antidepressant drugs and extinction training. Science (2011) 334: 1731– 4 10.1126/science.1214592 22194582 PMC3929964

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  • May combine two claims.

    Premisecitation

    Nogo receptor knock-out mice maintain normal levels of plasticity during the critical period, but the plasticity is maintained beyond the critical period for up to 120 days postnatally.

    “Nogo receptor knock-out mice maintain normal levels of plasticity during the critical period, however the plasticity is maintained beyond critical period for up to 120 days postnatally (23).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [23] McGee AW Yang Y Fischer QS Daw NW Strittmatter SM Experience-driven plasticity of visual cortex limited by myelin and Nogo receptor. Science (2005) 309: 2222– 6 10.1126/science.1114362 16195464 PMC2856689

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  • May combine two claims.

    Interpretationcitation

    Removal of a Nogo receptor brake may return high synaptic turnover, which can result in stronger fear extinction learning.

    “Removal of a Nogo receptor brake may return high synaptic turnover which can result in stronger fear extinction learning (37).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [37] Akbik FV Bhagat SM Patel PR Cafferty WB Strittmatter SM Anatomical plasticity of adult brain is titrated by Nogo Receptor 1. Neuron (2013) 77: 859– 66 10.1016/j.neuron.2012.12.027 23473316 PMC3594793

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  • May combine two claims.

    Interpretationreasoning

    Increased BDNF levels in the visual cortex were accompanied by reduced GABAergic inhibition, likely restoring excitatory-inhibitory balance by reopening visual critical period plasticity.

    “Increased BDNF levels in the visual cortex were accompanied by reduced GABAergic inhibition, likely restoring excitatory-inhibitory balance by reopening visual critical period plasticity.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The effect of SSRI on fear erasure is mediated through BDNF pathways: BDNF expression was exaggerated in the basolateral amygdala by SSRI treatment, and the effect of SSRI on fear erasure was absent in mice heterozygous for the BDNF allele.

    “This effect is mediated through BDNF pathways: BDNF expression was exaggerated in the basolateral amygdala by SSRI treatment, and the effect of SSRI on fear erasure was absent in mice heterozygous for BDNF allele.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [51] Karpova NN Pickenhagen A Lindholm J Tiraboschi E Kulesskaya N Agustsdottir A Fear erasure in mice requires synergy between antidepressant drugs and extinction training. Science (2011) 334: 1731– 4 10.1126/science.1214592 22194582 PMC3929964

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    Premisecitation

    Both Lynx1 and Lynx2 knock-out mice express an amplified response to cue fear conditioning, but demonstrate normal contextual fear conditioning in adulthood.

    “Both Lynx1 and Lynx2 knock-out mice express an amplified response to cue fear conditioning, but demonstrate normal contextual fear conditioning in adulthood (42, 43).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [42] Miwa JM Stevens TR King SL Caldarone BJ Ibanez-Tallon I Xiao C The prototoxin lynx1 acts on nicotinic acetylcholine receptors to balance neuronal activity and survival in vivo. Neuron (2006) 51: 587– 600 10.1016/j.neuron.2006.07.025 16950157

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    • cites [43] Tekinay AB Nong Y Miwa JM Lieberam I Ibanez-Tallon I Greengard P A role for LYNX2 in anxiety-related behavior. Proc Natl Acad Sci USA (2009) 106: 4477– 82 10.1073/pnas.0813109106 19246390 PMC2657456

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

    Premisecitation

    Nicotine administration during extinction training over the course of 6 days after fear conditioning is reported to enhance extinction.

    “Indeed, nicotine administration during extinction training over the course of 6 days after fear conditioning is reported to enhance extinction (45), however, the direct role of Lynx family proteins in fear memory erasure remain to be tested.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [45] Elias GA Gulick D Wilkinson DS Gould TJ Nicotine and extinction of fear conditioning. Neuroscience (2010) 165: 1063– 73 10.1016/j.neuroscience.2009.11.022 19931599 PMC2814978

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  • May combine two claims.

    Interpretationreasoning

    CSPG aggregation is likely involved in initial fear memory encoding and plays a role in maintaining the extinction-resistance of the fear memory rather than regulating processes during extinction.

    “Thus, the CPSG aggregation is likely involved in the initial fear memory encoding, and plays a role in maintaining the extinction-resistance of the fear memory rather than regulating the processes which occur during extinction.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Lifting these molecular brakes can induce critical period plasticity in adulthood and re-introduce ocular dominance remodeling following monocular deprivation.

    “Importantly, lifting these brakes can induce critical period plasticity in adulthood and re-introduce ocular dominance remodeling following monocular deprivation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Structural brakes include perineuronal nets, myelin-related inhibitory signaling mediated by Nogo receptor, and paired immunoglobulin-like receptor B expression.

    “Structural brakes include PNNs (22), myelin-related inhibitory signaling mediated by Nogo receptor (23), and paired immunoglobulin-like receptor B expression (PirB) (24).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [22] Pizzorusso T Medini P Berardi N Chierzi S Fawcett JW Maffei L Reactivation of ocular dominance plasticity in the adult visual cortex. Science (2002) 298: 1248– 51 10.1126/science.1072699 12424383

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    • cites [23] McGee AW Yang Y Fischer QS Daw NW Strittmatter SM Experience-driven plasticity of visual cortex limited by myelin and Nogo receptor. Science (2005) 309: 2222– 6 10.1126/science.1114362 16195464 PMC2856689

      Not checked in the free run.

    • cites [24] Syken J Grandpre T Kanold PO Shatz CJ PirB restricts ocular-dominance plasticity in visual cortex. Science (2006) 313: 1795– 800 10.1126/science.1128232 16917027

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    PNNs in the amygdala play a central role in modifying the plasticity of fear memories and may contribute to protection against fear memory lability during acquisition.

    “In the fear system, the PNNs in the amygdala recently have been shown to play a central role in modifying the plasticity of fear memories and may contribute to protection against fear memory lability during acquisition.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [10] Gogolla N Caroni P Luthi A Herry C Perineuronal nets protect fear memories from erasure. Science (2009) 325: 1258– 61 10.1126/science.1174146 19729657

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  • May combine two claims.

    Premisecitation

    The Nogo receptor is involved in determining the rate of synaptic turnover in the adult cerebral cortex, as knock-out mice have increased levels of synaptic turnover.

    “The Nogo receptor was recently shown to be also involved in determining the rate of synaptic turnover in the adult cerebral cortex, as knock-out mice have increased levels of synaptic turnover (37).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [37] Akbik FV Bhagat SM Patel PR Cafferty WB Strittmatter SM Anatomical plasticity of adult brain is titrated by Nogo Receptor 1. Neuron (2013) 77: 859– 66 10.1016/j.neuron.2012.12.027 23473316 PMC3594793

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Chronic fluoxetine treatment in adult rats not only induced visual cortex plasticity after monocular deprivation, but also improved visual acuity in amblyopic animals.

    “Chronic fluoxetine treatment in adult rats not only induced visual cortex plasticity after monocular deprivation, but also improved visual acuity in amblyopic animals (Figure 1C).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [50] Maya Vetencourt JF Sale A Viegi A Baroncelli L De Pasquale R O’Leary OF The antidepressant fluoxetine restores plasticity in the adult visual cortex. Science (2008) 320: 385– 8 10.1126/science.1150516 18420937

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  • May combine two claims.

    Premisecitation

    Chondroitinase-ABC was only effective when injected before fear conditioning; injection prior to extinction but after fear training was ineffective.

    “Interestingly, chondroitinase-ABC was only effective when injected before fear conditioning; injection prior to extinction but after fear training was ineffective.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [10] Gogolla N Caroni P Luthi A Herry C Perineuronal nets protect fear memories from erasure. Science (2009) 325: 1258– 61 10.1126/science.1174146 19729657

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The number of CSPG containing PNNs increases in the murine amygdala between days 16 and 23, coinciding with preadolescence and the functional switch from fear erasure to less effective fear extinction.

    “The number of CSPG containing PNNs increases in the murine amygdala between days 16 and 23 – the time coinciding with preadolescence and the developmentally related functional switch from fear erasure to less effective fear extinction (10) (Figure 1B).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [10] Gogolla N Caroni P Luthi A Herry C Perineuronal nets protect fear memories from erasure. Science (2009) 325: 1258– 61 10.1126/science.1174146 19729657

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Chondroitinase-ABC treatment coupled with reverse lid-suturing in adult rats causes complete recovery of ocular dominance to the originally deprived eye, accompanied by an increase in visual acuity and dendritic spine density.

    “Further, chondroitinase-ABC treatment coupled with reverse lid-suturing in adult rats – opening the sutured lid of the visually deprived eye while suturing the lid of the other, visually active eye – causes a complete recovery of ocular dominance to the originally deprived eye. This shift is accompanied by an increase in visual acuity and dendritic spine density (28).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [28] Pizzorusso T Medini P Landi S Baldini S Berardi N Maffei L Structural and functional recovery from early monocular deprivation in adult rats. Proc Natl Acad Sci U S A (2006) 103: 8517– 22 10.1073/pnas.0602657103 16709670 PMC1482523

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  • May combine two claims.

    Premisecitation

    The end of the visual critical period coincides with the maturation of intracortical myelin, which contains myelin-related inhibitory proteins NogoA, MAG, and OMgp, all of which bind to the neuronal Nogo receptor.

    “The end of the visual critical period coincides with the maturation of intracortical myelin, which contains myelin-related inhibitory proteins such as NogoA, MAG, and OMgp, all of which bind to the neuronal Nogo receptor (36) (Figure 1A).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [36] Akbik F Cafferty WB Strittmatter SM Myelin associated inhibitors: a link between injury-induced and experience-dependent plasticity. Exp Neurol (2012) 235: 43– 52 10.1016/j.expneurol.2011.06.006 21699896 PMC3189418

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    Premisecitation

    Administering d-cycloserine, a partial NMDA agonist, facilitates extinction and prevents the recovery of fear memories in rats, mice, and humans both before and after extinction training.

    “It is well-established that administering d-cycloserine (DCS), a partial NMDA agonist, facilitates extinction, and prevents the recovery of fear memories in rats, mice, and humans both before and after extinction training (46–49).”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [46] Guastella AJ Lovibond PF Dadds MR Mitchell P Richardson R A randomized controlled trial of the effect of D-cycloserine on extinction and fear conditioning in humans. Behav Res Ther (2007) 45: 663– 72 10.1016/j.brat.2006.07.005 16962066

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    • cites [47] Matsuda S Matsuzawa D Nakazawa K Sutoh C Ohtsuka H Ishii D d-serine enhances extinction of auditory cued fear conditioning via ERK1/2 phosphorylation in mice. Prog Neuropsychopharmacol Biol Psychiatry (2010) 34: 895– 902 10.1016/j.pnpbp.2010.04.013 20416352

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    • cites [49] Weber M Hart J Richardson R Effects of D-cycloserine on extinction of learned fear to an olfactory cue. Neurobiol Learn Mem (2007) 87: 476– 82 10.1016/j.nlm.2006.12.010 17275356

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    Premisecitation

    SSRI treatment starting after fear acquisition was sufficient to induce faster extinction and permanent erasure, a salient difference compared to fear erasure induced by PNN disruption, which was only effective when treated before and not after fear conditioning.

    “Interestingly, SSRI treatment starting after the fear acquisition was sufficient to induce faster extinction and permanent erasure, a salient difference compared to fear erasure induced by PNN disruption, which was only effective when treated before and not after fear conditioning.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [51] Karpova NN Pickenhagen A Lindholm J Tiraboschi E Kulesskaya N Agustsdottir A Fear erasure in mice requires synergy between antidepressant drugs and extinction training. Science (2011) 334: 1731– 4 10.1126/science.1214592 22194582 PMC3929964

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Formation of PNNs in fear systems may alter the function of local inhibitory circuits to promote the formation of an extinction-resistant memory trace during fear conditioning, and degradation of these nets may allow for more inhibitory connectivity to protect against fear memory lability.

    “Thus formation of PNNs in fear systems may alter the function of local inhibitory circuits to promote the formation of extinction-resistant memory trace during fear conditioning, and degradation of these nets may allow for more inhibitory connectivity to protect against fear memory lability.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The regulatory mechanisms of critical period plasticity in the visual cortex are sufficiently parallel to those in fear circuitry that insights from the visual cortex can be applied to the fear system.

  • May combine two claims.

    Premisecitation

    Lynx1 expression in adults suppresses functional plasticity into a latent state, as removal of this brake allows the critical period to remain open until nAChR signaling is actively blocked.

    “Lynx1 expression in adults suppresses functional plasticity into a latent state, as removal of this brake allows the critical period remains open until nAChR signaling is actively blocked (25) (Figure 1A).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [25] Morishita H Miwa JM Heintz N Hensch TK Lynx1, a cholinergic brake, limits plasticity in adult visual cortex. Science (2010) 330: 1238– 40 10.1126/science.1195320 21071629 PMC3387538

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  • May combine two claims.

    Premisecitation

    Otx2 signals PV maturation in GABAergic interneurons and contributes to both the opening and closure of the critical period.

    “This homeoprotein signals PV maturation in GABAergic interneurons and contributes to both the opening and closure of the critical period (29–32) (Figure 1A).”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [29] Beurdeley M Spatazza J Lee HH Sugiyama S Bernard C Di Nardo AA Otx2 binding to perineuronal nets persistently regulates plasticity in the mature visual cortex. J Neurosci (2012) 32: 9429– 37 10.1523/JNEUROSCI.0394-12.2012 22764251 PMC3419577

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    • cites [30] Miyata S Komatsu Y Yoshimura Y Taya C Kitagawa H Persistent cortical plasticity by upregulation of chondroitin 6-sulfation. Nat Neurosci (2012) 15(414–422): S411– 2 10.1038/nn.3023 22246436

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    • cites [31] Spatazza J Lee HH Di Nardo AA Tibaldi L Joliot A Hensch TK Choroid-plexus-derived otx2 homeoprotein constrains adult cortical plasticity. Cell Reports (2013) 3: 1815– 23 10.1016/j.celrep.2013.05.014 23770240 PMC4119931

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    • cites [32] Sugiyama S Di Nardo AA Aizawa S Matsuo I Volovitch M Prochiantz A Experience-dependent transfer of Otx2 homeoprotein into the visual cortex activates postnatal plasticity. Cell (2008) 134: 508– 20 10.1016/j.cell.2008.05.054 18692473

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  • May combine two claims.

    Premisecitation

    Lynx1 and closely related Lynx2 are both expressed in the amygdala and change their expression levels across development in both rodent and human.

    “Lynx1 and closed related Lynx2 are both expressed in the amygdala and change its expression levels across development in both rodent and human (41).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [41] Kang HJ Kawasawa YI Cheng F Zhu Y Xu X Li M Spatio-temporal transcriptome of the human brain. Nature (2011) 478: 483– 9 10.1038/nature10523 22031440 PMC3566780

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  • May combine two claims.

    Premisecitation

    Fear erasure is facilitated in adult mice by SSRI treatment and resembles fear erasure in non-treated juvenile mice.

    “Strikingly, fear erasure is facilitated in adult mice by SSRI treatment and resembles fear erasure in non-treated juvenile mice (Figure 1D) (51).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [51] Karpova NN Pickenhagen A Lindholm J Tiraboschi E Kulesskaya N Agustsdottir A Fear erasure in mice requires synergy between antidepressant drugs and extinction training. Science (2011) 334: 1731– 4 10.1126/science.1214592 22194582 PMC3929964

      Not checked in the free run.

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

    Interpretationcitation

    These behavioral interventions may induce plasticity by lifting molecular brakes or by exploiting endogenous permissive factors such as neuromodulators.

    “These interventions may induce plasticity by either lifting molecular brakes through invasive interventions or by exploiting endogenous permissive factors such as neuromodulators (21).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [21] Bavelier D Levi DM Li RW Dan Y Hensch TK Removing brakes on adult brain plasticity: from molecular to behavioral interventions. J Neurosci (2010) 30: 14964– 71 10.1523/JNEUROSCI.4812-10.2010 21068299 PMC2992973

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  • May combine two claims.

    Premisecitation

    Fluoxetine treated mice had a similar number of PNN-positive neurons compared to control but had a reduced percentage of PNN expressing parvalbumin interneurons in the basolateral amygdala.

    “Fluoxetine treated mice had similar number of PNN-positive neurons compared to control but had a reduced percentage of PNN expressing parvalbumin interneurons in the basolateral amygdala.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [51] Karpova NN Pickenhagen A Lindholm J Tiraboschi E Kulesskaya N Agustsdottir A Fear erasure in mice requires synergy between antidepressant drugs and extinction training. Science (2011) 334: 1731– 4 10.1126/science.1214592 22194582 PMC3929964

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Loss of hippocampal synaptic proteins is associated with a PTSD-like syndrome in mice, and is counteracted with SSRI treatment for 4 weeks of chronic fluoxetine treatment prior to fear conditioning.

    “Loss of hippocampal synaptic proteins has been associated with a PTSD-like syndrome in mice, and is counteracted with SSRI treatment for 4 weeks of chronic fluoxetine treatment prior to fear conditioning (53).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [53] Herrmann L Ionescu IA Henes K Golub Y Wang NX Buell DR Long-lasting hippocampal synaptic protein loss in a mouse model of posttraumatic stress disorder. PLoS One (2012) 7: e42603 10.1371/journal.pone.0042603 22900032 PMC3416820

      Not checked in the free run.

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

    Premisecitation

    Nicotine dosing immediately before training enhances extinction training.

    “AchEI treatment has not been directly examined in the context of fear extinction and memory liability, but nicotine dosing immediately before training has been reported to enhance extinction training (45).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [45] Elias GA Gulick D Wilkinson DS Gould TJ Nicotine and extinction of fear conditioning. Neuroscience (2010) 165: 1063– 73 10.1016/j.neuroscience.2009.11.022 19931599 PMC2814978

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Environmental enrichment and dark exposure may reset excitatory-inhibitory balance, re-introducing juvenile-like plasticity in the adult brain.

    “These interventions may reset excitatory – inhibitory balance, thus re-introducing juvenile-like plasticity in the adult brain (8).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [8] Morishita H Hensch TK Critical period revisited: impact on vision. Curr Opin Neurobiol (2008) 18: 101– 7 10.1016/j.conb.2008.05.009 18534841

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The mechanisms of reconsolidation update are localized to the amygdala and exclude the mPFC.

    “It is notable that the mechanisms of this process are localized to the amygdala and exclude the mPFC (75, 76).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [75] Agren T Engman J Frick A Bjorkstrand J Larsson EM Furmark T Disruption of reconsolidation erases a fear memory trace in the human amygdala. Science (2012) 337: 1550– 2 10.1126/science.1223006 22997340

      Not checked in the free run.

    • cites [76] Nader K Schafe GE Le Doux JE Fear memories require protein synthesis in the amygdala for reconsolidation after retrieval. Nature (2000) 406: 722– 6 10.1038/35021052 10963596

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Fluoxetine treatment selectively shifts parvalbumin interneurons toward an immature state, inducing critical period-like plasticity in local inhibitory neurons in the basolateral amygdala.

    “Together, these data suggest that fluoxetine treatment selectively shifts parvalbumin interneurons toward an immature state, inducing critical period-like plasticity in local inhibitory neurons in the basolateral amygdala.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The regulatory mechanisms of critical period plasticity in the visual cortex are sufficiently parallel to those in fear circuitry that insights from the visual cortex can be applied to the fear system.
    • Rests on an assumption: Permanent fear erasure in rodents is a valid analogue for therapeutic reopening of fear plasticity in PTSD.

  • May combine two claims.

    Premisecitation

    Effects of chronic fluoxetine treatment (4-5 weeks) were also seen in CA1 of the hippocampus, where SSRIs have been shown to return mature granule cells to an electrophysiologically immature state, with reduced synaptic facilitation in the mossy fibers.

    “The effects of chronic fluoxetine treatment (4–5 weeks) were also seen in CA1 of the hippocampus, where SSRIs have been shown to return mature granule cells to an electrophysiologically immature state, with reduced synaptic facilitation in the mossy fibers (52).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [52] Kobayashi K Ikeda Y Sakai A Yamasaki N Haneda E Miyakawa T Reversal of hippocampal neuronal maturation by serotonergic antidepressants. Proc Natl Acad Sci U S A (2010) 107(18): 8434– 9 10.1073/pnas.0912690107 20404165 PMC2889553

      Not checked in the free run.

37 of 37

  • The paper relies on this without support.

    The regulatory mechanisms of critical period plasticity in the visual cortex are sufficiently parallel to those in fear circuitry that insights from the visual cortex can be applied to the fear system.

    “To what extent are visual and fear system critical period mechanisms parallel?”
    “In this review, we turn to the visual cortex as a well-developed model of experience-dependent critical period plasticity to provide novel insights for the mechanisms regulating plasticity in the fear system.”

  • The paper relies on this without support.

    Permanent fear erasure in rodents is a valid analogue for therapeutic reopening of fear plasticity in PTSD.

    “we conceptually consider “permanent fear erasure” analogously to “amblyopia,” both of which are only induced during critical period.”

  • The paper relies on this without support.

    Reopening critical period-like plasticity can mitigate aberrant fear responses in PTSD.

    “Applying mechanistic understandings of critical period plasticity in the visual cortex to fear circuitry may provide a conceptual framework for developing novel therapeutic tools to mitigate aberrant fear responses in post traumatic stress disorder.”

  • The paper relies on this without support.

    A memory is rendered labile after it has been recalled.

    “A newly proposed behavioral intervention for treating PTSD, “reconsolidation update,” involves targeting traumatic memories as an individual reconsolidates it because the memory is rendered labile after it has been recalled (Figure 1D).”
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?

  • During a period of time that varies according to the lifespan of species and the sensory modality, neuronal circuits are particularly receptive to different types of perceptual experience, from vision to fear.

    “During a period of time that varies according to the lifespan of species and the sensory modality, neuronal circuits are particularly receptive to different types of perceptual experience, from vision to fear 34 .”

    From Developmental timing and critical windows for the treatment of psychiatric disorders (2016) · cites this paper as [34]

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.

  • PNN degradation is described as both enabling erasure and protecting memories from lability

    Minor

    The paper says removing PNNs makes fear memories susceptible to erasure, but later says degradation of those nets may protect against fear memory lability. Protecting a memory from lability conflicts with the described effect of PNN removal.

1 of 1

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. [18]Carrion VG Kletter H Posttraumatic stress disorder: shifting toward a developmental framework. Child Adolesc Psychiatr Clin N Am (2012) 21: 573– 91 10.1016/j.chc.2012.05.004 22800995 · DOI

Cited by

Sorted by citations

Authors
Nabel, E. M., & Morishita, H.
Affiliations
Icahn School of Medicine at Mount Sinai (US)
Corresponding author
Morishita, Hirofumi
ORCID
Venue
Frontiers in Psychiatry
Publisher
Frontiers Media SA
Published
2013
Volume
4
Pages
146-146
ISSN
1664-0640 (ISSN-L)
DOI
10.3389/fpsyt.2013.00146
PMC
PMC3822369
OpenAlex
W2138457853
Cited by
85
References
84
Citations by year
2026: 3 · 2025: 6 · 2024: 6 · 2023: 6 · 2022: 6 · 2021: 5 · 2020: 10 · 2019: 9 · 2018: 8 · 2017: 8 · 2016: 6 · 2015: 7 · 2014: 5
FWCI
0.51
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Frontiers in Psychiatry (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • March of Dimes Foundation
  • National Alliance for Research on Schizophrenia and Depression
  • Ögonfonden
Topics
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
Keywords
critical period plasticity, experience-dependent plasticity, visual cortex development, fear circuitry, post-traumatic stress disorder, perineuronal nets, myelin, nicotinic acetylcholine receptors, epigenetic regulation, adult plasticity, therapeutic interventions

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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.

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