CoChat
Sign Up
Cited by 79Neurogenesis and neuroplasticity mechanismsTreatment of Major DepressionStress Responses and Cortisol

Adult hippocampal neuroplasticity triggers susceptibility to recurrent depression

Open access
Alves, N D, Correia, J S, Patrício, P, Mateus-Pinheiro, A, Machado-Santos, A R, Loureiro-Campos, E, Morais, M, Bessa, J M +2 more·2017·Translational Psychiatry
DOI 10.1038/tp.2017.29PMC PMC5416672
Open this paper in CoChat — free accountOpen PDF

Abstract

Depression is a highly prevalent and recurrent neuropsychiatric disorder associated with alterations in emotional and cognitive domains. Neuroplastic phenomena are increasingly considered central to the etiopathogenesis of and recovery from depression. Nevertheless, a high number of remitted patients experience recurrent episodes of depression, remaining unclear how previous episodes impact on behavior and neuroplasticity and/or whether modulation of neuroplasticity is important to prevent recurrent depression. Through re-exposure to an unpredictable chronic mild stress protocol in rats, we observed the re-appearance of emotional and cognitive deficits. Furthermore, treatment with the antidepressants fluoxetine and imipramine was effective to promote sustained reversion of a depressive-like phenotype; however, their differential impact on adult hippocampal neuroplasticity triggered a distinct response to stress re-exposure: while imipramine re-established hippocampal neurogenesis and neuronal dendritic arborization contributing to resilience to recurrent depressive-like behavior, stress re-exposure in fluoxetine-treated animals resulted in an overproduction of adult-born neurons along with neuronal atrophy of granule neurons, accounting for an increased susceptibility to recurrent behavioral changes typical of depression. Strikingly, cell proliferation arrest compromised the behavior resilience induced by imipramine and buffered the susceptibility to recurrent behavioral changes promoted by fluoxetine. This study shows that previous exposure to a depressive-like episode impacts on the behavioral and neuroanatomical changes triggered by subsequent re-exposure to similar experimental conditions and reveals that the proper control of adult hippocampal neuroplasticity triggered by antidepressants is essential to counteract recurrent depressive-like episodes.

AI snapshot

Written from the paper’s full text.

TL;DR

In rats re-exposed to unpredictable chronic mild stress (uCMS), prior fluoxetine treatment increased susceptibility to recurrent depressive-like behavior and was linked to excessive adult hippocampal neurogenesis plus granule-neuron atrophy, whereas imipramine promoted resilience with normalized neurogenesis and increased dendritic arborization. Arresting cell proliferation with methylazoxymethanol (MAM) blocked imipramine-induced resilience and buffered fluoxetine-induced susceptibility, indicating adult hippocampal neuroplasticity must be finely tuned to prevent recurrence.

Key findings

  • After a 4-week stress-free period, uCMS re-exposure decreased sucrose preference in non-treated and fluoxetine-treated animals (F2,14=16.11, P=0.0002; FLX post hoc P=0.0003; IMIP post hoc P>0.1), while imipramine prevented the re-appearance of depressive-like behavior in the forced-swimming test (IMIP post hoc P=0.0112).
  • Fluoxetine-treated animals showed a significant increase in BrdU+NeuN+ newborn neurons after re-exposure (FLX post hoc P=0.0319), a significant decrease in Ki-67+Sox-2+ progenitor cells (F2,7=9.642, P=0.0097; FLX post hoc P=0.0106), and significant dendritic atrophy of granule neurons; imipramine-treated animals showed increased dendritic arborization (F2,8=19.70, P=0.0008; IMIP post hoc P=0.0286).
  • MAM co-treatment reduced BrdU+NeuN+ cells in both fluoxetine- and imipramine-treated groups (FLX vs FLX+MAM P=0.0303; IMIP vs IMIP+MAM P=0.0153), prevented anhedonic-like signs in fluoxetine-treated animals (FLX+MAM post hoc P>0.1), and led to anhedonic-like behavior in imipramine-treated animals (IMIP+MAM post hoc P<0.001).
  • Recurrent uCMS re-exposure also re-emerged anxiety-like behavior and cognitive deficits in non-treated and fluoxetine-treated animals, while imipramine protected most behavioral domains; fluoxetine uniquely prevented deficits in spatial behavioral flexibility (FLX post hoc P=0.0264).

Methods

  • Adult male Wistar Han rats (2 months old) were used; n=6–8 for behavioral analysis, with 3–4 per group for gene expression, immunofluorescence, and neuromorphologic studies. Rats underwent 6 weeks of uCMS, with the last 2 weeks including saline, fluoxetine (10 mg kg−1), or imipramine (10 mg kg−1), with subgroups co-administered MAM (7 mg kg−1); BrdU (50 mg kg−1) labeled newborn cells. After 4 weeks without stress, animals were re-exposed to a modified uCMS protocol.
  • Behavior was assessed at weeks 6, 10, and 16 using sucrose preference, sweet-drive, novel object recognition, elevated-plus maze, novelty-suppressed feeding, forced-swimming, and Morris water maze tests. Neurogenesis was quantified by BrdU/NeuN/GFAP/Ki-67/Sox-2/DCX immunostaining, dendritic morphology by Golgi-Cox, and neuroplasticity-related gene expression by qRT-PCR. Statistical analysis used GraphPad Prism 6.0 with ANOVA, repeated-measures ANOVA, Bonferroni post hoc tests, and P<0.05.

Limitations

  • Stated in the paper: the contribution of other brain regions, such as the nucleus accumbens, to anhedonic resilience cannot be excluded; the distinct effects of fluoxetine and imipramine could be linked to differential impact on neural cell types and/or receptor selectivity, with future studies proposed to block the noradrenergic component of imipramine.
  • Evident from the text: only adult male rats were studied, with no female or sex comparison; sample sizes were small (n=6–8 behavioral, 3–4 molecular); MAM itself affected anxiety-like behavior in non-stressed animals (Supplementary Figure 3), a potential confound; and no data points were excluded from analyses.

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

Integrity signals

Registry

Crossref · 10.1038/tp.2017.29

Cites

47 of 47 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 47 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    uCMS re-exposure promoted the re-emergence of an anxious-like phenotype in non-treated animals.

    “uCMS re-exposure promoted the re-emergence of an anxious-like phenotype in non-treated (tp3: P<0.001)”
    Quote in the paperSubstantial claim
  • Findingown data

    Quantification of progenitor cells revealed no alterations in the number of Ki-67+ proliferating cells among groups.

    “quantification of the number of progenitor cells revealed no alterations in the number of Ki-67+ proliferating cells among groups (Figure 3g)”
    Quote in the paperNot a substantial claim
  • Findingown data

    Immobility time in the forced-swimming test was significantly increased after repeated uCMS exposure in non-treated animals, suggesting the re-appearance of depressive-like behavior.

    “immobility time in the forced-swimming test, a typical surrogate measure of depressive-like behavior, was significantly increased after repeated uCMS exposure (Figure 1e), suggesting the re-appearance of depressive-like behavior in non-treated animals (P<0.01)”
    Quote in the paperSubstantial claim
  • Findingown data

    uCMS re-exposure to non-treated animals did not promote the re-appearance of anhedonic-like behavior.

    “uCMS re-exposure to non-treated animals did not promote the re-appearance of anhedonic-like behavior (tp3: P>0.1, Figure 1d)”
    Quote in the paperSubstantial claim
  • Findingown data

    The reversion of anhedonic behavior by fluoxetine and imipramine was preserved after a 4-week stress-free period.

    “This effect was preserved after a 4-week stress-free period (tp2).”
    Quote in the paperSubstantial claim
  • May combine two claims. 21
  • Classified as probably not a substantial claim. 24

  • May combine two claims.

    Findingown data

    Fluoxetine-treated animals presented a marked decrease in the number of neuroblasts, contrarily to imipramine-treated animals.

    “Fluoxetine-treated animals also presented a marked decrease in the number of neuroblasts, contrarily to those treated with imipramine (Figure 3j).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    uCMS exposure increased anxiety-like behavior in the elevated-plus maze, which was partially rescued by both antidepressants.

    “uCMS exposure increased anxiety-like behavior in the elevated-plus maze as previously described,9, 20 which was partially rescued by both ADs (tp1: P=0.0071; F2,14=3.264, P=0.0686; FLX: post hoc P=0.0981; IMIP: post hoc P>0.1, Figure 1f)”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The effect of fluoxetine on newborn cells was neuronal-specific, with no alterations in newborn astroglial cells or expression of astroglial differentiation promoting factors STAT3 and BMP4.

    “this effect was neuronal-specific, as no alterations were found in the number of newborn astroglial cells (identified as BrdU+GFAP+ cells; Figures 3d and e) and in the expression analysis of astroglial differentiation promoting factors, STAT3 and BMP4 (Figure 3f)”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Impairments in spatial behavioral flexibility promoted by uCMS re-exposure in non-treated animals were prevented by fluoxetine but not by imipramine.

    “impairments in spatial behavioral flexibility promoted by uCMS re-exposure in non-treated animals (P=0.0018, Figure 2f) were only prevented by fluoxetine, but not by imipramine (F2,13=7.521, P=0.0068; FLX: post hoc P=0.0264; IMIP: post hoc P>0.1, Figure 2f)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    These animals present intact DG dendritic length and no alterations in the survival of newborn neurons.

    “These animals present intact DG dendritic length and no alterations in the survival of newborn neurons, which may account for the observed resilience to anhedonic-like deficits.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Recurrent uCMS exposure potentiated the re-appearance of depressive- and anxiety-like behaviors as well as cognitive deficits.

    “Noticeably, we showed that recurrent uCMS exposure potentiated the re-appearance of depressive- and anxiety-like behaviors as well as cognitive deficits.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The uCMS protocol in animals is a valid model of recurrent depression in humans.

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

    Findingcitation

    Cell proliferation arrestment by MAM impacts anxiety-like behavior of non-stressed animals.

    “Of notice, as previously observed,20, 22, 27 cell proliferation arrestment by MAM impacts anxiety-like behavior of non-stressed animals (Supplementary Figure 3).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [20] Mateus-Pinheiro A, Pinto L, Bessa JM, Morais M, Alves ND, Monteiro S et al. Sustained remission from depressive-like behavior depends on hippocampal neurogenesis. Transl Psychiatry 2013; 3: e210. source

      Not checked in the free run.

    • cites [22] Li YF, Huang Y, Amsdell SL, Xiao L, O'Donnell JM, Zhang HT . Antidepressant- and anxiolytic-like effects of the phosphodiesterase-4 inhibitor rolipram on behavior depend on cyclic AMP response element binding protein-mediated neurogenesis in the hippocampus. Neuropsychopharmacology 2009; 34: 2404–2419. source

      Not checked in the free run.

    • cites [27] Hsiao YH, Hung HC, Chen SH, Gean PW . Social interaction rescues memory deficit in an animal model of Alzheimer's disease by increasing BDNF-dependent hippocampal neurogenesis. J Neurosci 2014; 34: 16207–16219. source

      Not checked in the free run.

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

    Findingcitation

    Treatment with fluoxetine and imipramine promoted a sustained remission of an initial depressive-like state.

    “In accordance to previous reports, we observed that treatment with fluoxetine and imipramine promoted a sustained remission of an initial depressive-like state and a re-establishment of the hippocampal neurogenic process.20”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [20] Mateus-Pinheiro A, Pinto L, Bessa JM, Morais M, Alves ND, Monteiro S et al. Sustained remission from depressive-like behavior depends on hippocampal neurogenesis. Transl Psychiatry 2013; 3: e210. source

      Not checked in the free run.

    • Rests on an assumption: The effects of fluoxetine and imipramine in the uCMS animal model predict their effects in human recurrent depression.

  • May combine two claims.

    Findingown data

    Animals treated with fluoxetine during the initial uCMS exposure presented an increased susceptibility to anhedonic-like behavior once re-exposed to uCMS, in contrast to non-treated animals, which did not present an anhedonic phenotype.

    “Results revealed that animals treated with fluoxetine during the initial uCMS exposure presented an increased susceptibility to anhedonic-like behavior once re-exposed to uCMS, in contrast to non-treated animals, which did not present an anhedonic phenotype.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The uCMS protocol in animals is a valid model of recurrent depression in humans.
    • Rests on an assumption: The effects of fluoxetine and imipramine in the uCMS animal model predict their effects in human recurrent depression.

  • May combine two claims.

    Findingcitation

    This behavioral resilience to repeated uCMS was associated with a normalization of the hippocampal neurogenic process and with a robust increase in the dendritic arborization of DG granule neurons.

    “This behavioral resilience to repeated uCMS was associated with a normalization of the hippocampal neurogenic process,20 but also with a robust increase in the dendritic arborization of DG granule neurons (Figure 5g).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [20] Mateus-Pinheiro A, Pinto L, Bessa JM, Morais M, Alves ND, Monteiro S et al. Sustained remission from depressive-like behavior depends on hippocampal neurogenesis. Transl Psychiatry 2013; 3: e210. source

      Not checked in the free run.

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

    Findingcitation

    Treatment with fluoxetine and imipramine promoted a re-establishment of the hippocampal neurogenic process.

    “In accordance to previous reports, we observed that treatment with fluoxetine and imipramine promoted a sustained remission of an initial depressive-like state and a re-establishment of the hippocampal neurogenic process.20”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [20] Mateus-Pinheiro A, Pinto L, Bessa JM, Morais M, Alves ND, Monteiro S et al. Sustained remission from depressive-like behavior depends on hippocampal neurogenesis. Transl Psychiatry 2013; 3: e210. source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    Treatment with fluoxetine was inefficient in preventing the detrimental behavioral consequences induced by stress re-exposure, including depressive- and anxiety-like behavior as well as cognitive deficits (long-term memory), with the exception of a specific cognitive task (behavioral flexibility).

    “Moreover, treatment with fluoxetine was inefficient in preventing the detrimental behavioral consequences induced by stress re-exposure, including depressive- and anxiety-like behavior as well as cognitive deficits (long-term memory) with the exception of a specific cognitive task (behavioral flexibility).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The uCMS protocol in animals is a valid model of recurrent depression in humans.
    • Rests on an assumption: The effects of fluoxetine and imipramine in the uCMS animal model predict their effects in human recurrent depression.

  • May combine two claims.

    Findingown data

    MAM administration in animals re-exposed to uCMS and co-treated with fluoxetine induced a significant reduction in the number of BrdU+NeuN+ cells, preventing the increased neurogenesis promoted by fluoxetine.

    “As expected, MAM administration in animals re-exposed to uCMS and co-treated with fluoxetine induced a significant reduction in the number of BrdU+NeuN+ cells, preventing the increased neurogenesis promoted by fluoxetine (FLX vs FLX+MAM: P=0.0303, Figure 5b).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    These behavioral alterations were correlated with normal levels of survival of newborn neurons, with the exception of synaptic plasticity that showed persistent impairments after recurrent stress exposure.

    “Moreover, these behavioral alterations were correlated with normal levels of survival of newborn neurons with exception of synaptic plasticity that showed persistent impairments after recurrent stress exposure.”
    Quote in the paperSubstantial claim

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

    Study design and conductcitation

    Sample sizes were based on previous published studies.

    “The sample sizes were based on previous published studies.9, 20”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [9] Bessa JM, Ferreira D, Melo I, Marques F, Cerqueira JJ, Palha JA et al. The mood-improving actions of antidepressants do not depend on neurogenesis but are associated with neuronal remodeling. Mol Psychiatry 2009; 14: 764–773, 739. source

      Not checked in the free run.

    • cites [20] Mateus-Pinheiro A, Pinto L, Bessa JM, Morais M, Alves ND, Monteiro S et al. Sustained remission from depressive-like behavior depends on hippocampal neurogenesis. Transl Psychiatry 2013; 3: e210. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Adult cytogenesis (neurogenesis and gliogenesis) and morphological changes in the hippocampus are altered by chronic stress and reverted by antidepressants.

    “neuroplastic events, including adult cytogenesis (neurogenesis9, 10, 11 and gliogenesis12) and morphological changes, are described to be altered by chronic stress and reverted by antidepressants (ADs).13, 14”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [13] Surget A, Tanti A, Leonardo ED, Laugeray A, Rainer Q, Touma C et al. Antidepressants recruit new neurons to improve stress response regulation. Mol Psychiatry 2011; 16: 1177–1188. source

      Not checked in the free run.

    • cites [14] Patricio P, Mateus-Pinheiro A, Irmler M, Alves ND, Machado-Santos AR, Morais M et al. Differential and converging molecular mechanisms of antidepressants' action in the hippocampal dentate gyrus. Neuropsychopharmacology 2014; 40: 338–349. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Imipramine re-established hippocampal neurogenesis and neuronal dendritic arborization, contributing to resilience to recurrent depressive-like behavior.

    “while imipramine re-established hippocampal neurogenesis and neuronal dendritic arborization contributing to resilience to recurrent depressive-like behavior”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The unpredictable chronic mild stress (uCMS) protocol in rats models recurrent depression in humans.

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

    Premisecitation

    Animals subjected to stress during adolescence are resilient to depressive- and anxiety-like behavior on chronic stress re-exposure in adulthood.

    “animals subjected to stress during adolescence were resilient to depressive- and anxiety-like behavior on chronic stress re-exposure in adulthood7”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [7] Suo L, Zhao L, Si J, Liu J, Zhu W, Chai B et al. Predictable chronic mild stress in adolescence increases resilience in adulthood. Neuropsychopharmacology 2013; 38: 1387–1400. source

      Not checked in the free run.

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

    Premisecitation

    Re-exposure to stress is associated with altered expression of cytoskeletal proteins.

    “the deleterious effects evoked by re-exposure to stress were associated to altered expression of cytoskeletal proteins.6”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [6] Yang C, Wang G, Wang H, Liu Z, Wang X . Cytoskeletal alterations in rat hippocampus following chronic unpredictable mild stress and re-exposure to acute and chronic unpredictable mild stress. Behav Brain Res 2009; 205: 518–524. source

      Not checked in the free run.

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

    Study design and conductnone given

    Rats were randomly divided into six experimental groups.

    “Rats (n=6–8 for behavioral analysis, of which three to four were considered for gene expression quantification, immunofluorescence and neuromorphologic studies) from two independent sets were randomly divided into six groups”
    Quote in the paperNot a substantial claim

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

    Study design and conductcitation

    The uCMS protocol used was validated and previously described.

    “Rats were subjected to a validated uCMS protocol for 6 weeks, as previously described9, 20, 23”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [9] Bessa JM, Ferreira D, Melo I, Marques F, Cerqueira JJ, Palha JA et al. The mood-improving actions of antidepressants do not depend on neurogenesis but are associated with neuronal remodeling. Mol Psychiatry 2009; 14: 764–773, 739. source

      Not checked in the free run.

    • cites [20] Mateus-Pinheiro A, Pinto L, Bessa JM, Morais M, Alves ND, Monteiro S et al. Sustained remission from depressive-like behavior depends on hippocampal neurogenesis. Transl Psychiatry 2013; 3: e210. source

      Not checked in the free run.

    • cites [23] Willner P . Chronic mild stress (CMS) revisited: consistency and behavioural-neurobiological concordance in the effects of CMS. Neuropsychobiology 2005; 52: 90–110. source

      Not checked in the free run.

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

    Premisecitation

    At short-term, behavioral improvements induced by antidepressants rely on hippocampal neuronal remodeling.

    “at short-term, behavioral improvements induced by ADs rely on hippocampal neuronal remodeling,9”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [9] Bessa JM, Ferreira D, Melo I, Marques F, Cerqueira JJ, Palha JA et al. The mood-improving actions of antidepressants do not depend on neurogenesis but are associated with neuronal remodeling. Mol Psychiatry 2009; 14: 764–773, 739. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Stress re-exposure in fluoxetine-treated animals resulted in an overproduction of adult-born neurons along with neuronal atrophy of granule neurons, accounting for an increased susceptibility to recurrent behavioral changes typical of depression.

    “stress re-exposure in fluoxetine-treated animals resulted in an overproduction of adult-born neurons along with neuronal atrophy of granule neurons, accounting for an increased susceptibility to recurrent behavioral changes typical of depression.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The unpredictable chronic mild stress (uCMS) protocol in rats models recurrent depression in humans.

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

    Premisecitation

    Over 85% of remitted patients suffer recurrent episodes of depression within 15 years after an initial event.

    “over 85% of remitted patients suffer recurrent episodes of depression, within 15 years after an initial event.2, 3”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [2] Mueller TI, Leon AC, Keller MB, Solomon DA, Endicott J, Coryell W et al. Recurrence after recovery from major depressive disorder during 15 years of observational follow-up. Am J Psychiatry 1999; 156: 1000–1006. source

      Not checked in the free run.

    • cites [3] Baldessarini RJ, Lau WK, Sim J, Sum MY, Sim K . Duration of initial antidepressant treatment and subsequent relapse of major depression. J Clin Psychopharmacol 2015; 35: 75–76. source

      Not checked in the free run.

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

    Premisecitation

    Recurrent depression has been associated with the persistence of subclinical residual symptoms and the number of previous episodes.

    “recurrent depression has also been associated to the persistence of subclinical residual symptoms and the number of previous episodes.5”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [5] Hardeveld F, Spijker J, De Graaf R, Nolen WA, Beekman AT . Prevalence and predictors of recurrence of major depressive disorder in the adult population. Acta Psychiatr Scand 2010; 122: 184–191. source

      Not checked in the free run.

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

    Premisecitation

    Neuroplastic processes and their disturbances have behavioral repercussions in cognitive and emotional dimensions in both physiological and pathological conditions including schizophrenia and depressive disorders.

    “Neuroplastic processes, and particularly its disturbances, have behavioral repercussions in cognitive and emotional dimensions in both physiological15 and pathological conditions including schizophrenia16 and depressive disorders.17, 18, 19”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [17] Mateus-Pinheiro A, Patricio P, Bessa JM, Sousa N, Pinto L . Cell genesis and dendritic plasticity: a neuroplastic pas de deux in the onset and remission from depression. Mol Psychiatry 2013; 8: 748–750. source

      Not checked in the free run.

    • cites [18] Bessa JM, Mesquita AR, Oliveira M, Pego JM, Cerqueira JJ, Palha JA et al. A trans-dimensional approach to the behavioral aspects of depression. Front Behav Neurosci 2009; 3: 1. source

      Not checked in the free run.

    • cites [19] Sahay A, Hen R . Adult hippocampal neurogenesis in depression. Nat Neurosci 2007; 10: 1110–1115. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Previous stressful events may have short-term detrimental effects on cortico-limbic plasticity but also confer protection against certain behavioral and neuroplastic deficits after recurrent stressful situations.

    “Our findings put forward the understanding how previous stressful events may have short-term detrimental effects on cortico-limbic plasticity but also highlight their importance in conferring protection against certain behavioral and neuroplastic deficits after recurrent stressful situations.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    An aberrant increase in the generation of newborn neurons enhances plasticity and excitability.

    “In fact, an aberrant increase in the generation of newborn neurons was shown to enhance plasticity and excitability,32”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [32] Schmidt-Hieber C, Jonas P, Bischofberger J . Enhanced synaptic plasticity in newly generated granule cells of the adult hippocampus. Nature 2004; 429: 184–187. source

      Not checked in the free run.

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

    Premisecitation

    Animal studies report behavioral deficits in fluoxetine-treated animals re-exposed to stress.

    “these results seem to be in accordance with animal studies reporting behavioral deficits in fluoxetine-treated animals re-exposed to stress6”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [6] Yang C, Wang G, Wang H, Liu Z, Wang X . Cytoskeletal alterations in rat hippocampus following chronic unpredictable mild stress and re-exposure to acute and chronic unpredictable mild stress. Behav Brain Res 2009; 205: 518–524. source

      Not checked in the free run.

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

    Premisecitation

    Spatial reversal learning is not exclusively associated with hippocampal function but also with the prefrontal cortex, namely the prelimbic and infralimbic, and orbitalfrontal regions.

    “This particular cognitive task is not exclusively associated with hippocampal function but also the prefrontal cortex,42 namely the prelimbic and infralimbic, and orbitalfrontal regions;43”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [42] Clark L, Cools R, Robbins TW . The neuropsychology of ventral prefrontal cortex: decision-making and reversal learning. Brain Cogn 2004; 55: 41–53. source

      Not checked in the free run.

    • cites [43] McAlonan K, Brown VJ . Orbital prefrontal cortex mediates reversal learning and not attentional set shifting in the rat. Behav Brain Res 2003; 146: 97–103. source

      Not checked in the free run.

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

    Interpretationcitation

    The contribution of other brain regions, such as the nucleus accumbens, cannot be excluded from this anhedonic resilience.

    “However, the contribution of other brain regions, such as the nucleus accumbens, cannot be excluded of this anhedonic resilience, given the previous association between stress-induced anhedonia and medium spiny neurons”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [25] Bessa JM, Morais M, Marques F, Pinto L, Palha JA, Almeida OF et al. Stress-induced anhedonia is associated with hypertrophy of medium spiny neurons of the nucleus accumbens. Transl Psychiatry 2013; 3: e266. source

      Not checked in the free run.

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

    Study design and conductnone given

    No data points were excluded from the different analyses.

    “No data points were excluded from the different analyses.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    ADs, including imipramine, reverse the shrinkage in dendritic branching induced by stress and allow the re-establishment of the normal neuronal network.

    “in line with previous studies demonstrating that ADs, including imipramine, reverse the shrinkage in dendritic branching induced by stress and allows the re-establishment of the normal neuronal network,9”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [9] Bessa JM, Ferreira D, Melo I, Marques F, Cerqueira JJ, Palha JA et al. The mood-improving actions of antidepressants do not depend on neurogenesis but are associated with neuronal remodeling. Mol Psychiatry 2009; 14: 764–773, 739. source

      Not checked in the free run.

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

    Premisecitation

    Imipramine is known to confer protection to depressive-like behavior through an increase in the dendritic arborization of immature neurons.

    “Likewise, imipramine is also known to confer protection to depressive-like behavior through an increase in the dendritic arborization of immature neurons.46”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [46] Fenton EY, Fournier NM, Lussier AL, Romay-Tallon R, Caruncho HJ, Kalynchuk LE . Imipramine protects against the deleterious effects of chronic corticosterone on depression-like behavior, hippocampal reelin expression, and neuronal maturation. Prog Neuropsychopharmacol Biol Psychiatry 2015; 60: 52–59. source

      Not checked in the free run.

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

    Premisecitation

    Previous studies suggest a strong impact of hippocampal structural alterations in the susceptibility to depression and an important contribution for recurrent episodes.

    “Importantly, previous studies also suggested a strong impact of hippocampal structural alterations in the susceptibility to depression40 and an important contribution for recurrent episodes.41”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [40] Chan SW, Harmer CJ, Norbury R, O'Sullivan U, Goodwin GM, Portella MJ . Hippocampal volume in vulnerability and resilience to depression. J Affect Disord 2016; 189: 199–202. source

      Not checked in the free run.

    • cites [41] Sheline YI, Wang PW, Gado MH, Csernansky JG, Vannier MW . Hippocampal atrophy in recurrent major depression. Proc Natl Acad Sci USA 1996; 93: 3908–3913. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Previous studies have shown an increased anxiety-like phenotype in consequence of increased neurogenesis induced by voluntary wheel running.

    “Moreover, previous studies have shown an increased anxiety-like phenotype in consequence of increased neurogenesis induced by voluntary wheel running.37, 38, 39”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [37] Fuss J, Ben Abdallah NM, Vogt MA, Touma C, Pacifici PG, Palme R et al. Voluntary exercise induces anxiety-like behavior in adult C57BL/6J mice correlating with hippocampal neurogenesis. Hippocampus 2010; 20: 364–376. source

      Not checked in the free run.

    • cites [38] Fuss J, Ben Abdallah NM, Hensley FW, Weber KJ, Hellweg R, Gass P . Deletion of running-induced hippocampal neurogenesis by irradiation prevents development of an anxious phenotype in mice. PLoS ONE 2010; 5: pii: e12769. source

      Not checked in the free run.

    • cites [39] Onksen JL, Briand LA, Galante RJ, Pack AI, Blendy JA . Running-induced anxiety is dependent on increases in hippocampal neurogenesis. Genes Brain Behav 2012; 11: 529–538. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductown data

    All presented data satisfied normal distribution in Kolmogorov-Smirnov testing.

    “All presented data satisfied normal distribution in Kolmogorov–Smirnov testing.”
    Quote in the paperSubstantial claim

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

    Interpretationreasoning

    There is the possibility that fluoxetine treatment may positively affect these prefrontal regions accounting for the observed resilience of reversal learning deficits.

    “thus, there is the possibility that fluoxetine treatment may positively affect these prefrontal regions accounting to the observed resilience of reversal learning deficits.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    Data were subjected to appropriate statistical tests after confirmation of homogeneity of group variances between the groups.

    “After confirmation of homogeneity of group variances between the groups, data were subjected to appropriate statistical tests.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    Adult neuroplasticity changes induced by stress and ADs must be finely tuned to prevent recurrence in depression.

    “In essence, these findings reflect how adult neuroplasticity changes induced by stress and ADs must be finely tuned to prevent recurrence in depression.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The uCMS protocol in animals is a valid model of recurrent depression in humans.
    • Rests on an assumption: The effects of fluoxetine and imipramine in the uCMS animal model predict their effects in human recurrent depression.

  • May combine two claims.

    Interpretationcitation

    Such alterations promote an increased participation of these cells during learning and memory tasks and a reconfiguration of DG-CA3 circuits that degrade stored memories.

    “Consequently, such alterations promote an increased participation of these cells during learning and memory tasks35 and a reconfiguration of DG-CA3 circuits that degrade stored memories.36”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [35] Kee N, Teixeira CM, Wang AH, Frankland PW . Preferential incorporation of adult-generated granule cells into spatial memory networks in the dentate gyrus. Nat Neurosci 2007; 10: 355–362. source

      Not checked in the free run.

    • cites [36] Akers KG, Martinez-Canabal A, Restivo L, Yiu AP, De Cristofaro A, Hsiang HL et al. Hippocampal neurogenesis regulates forgetting during adulthood and infancy. Science 2014; 344: 598–602. source

      Not checked in the free run.

41 of 41

  • The paper relies on this without support.

    The unpredictable chronic mild stress (uCMS) protocol in rats models recurrent depression in humans.

    “Through re-exposure to an unpredictable chronic mild stress protocol in rats, we observed the re-appearance of emotional and cognitive deficits.”

  • The paper relies on this without support.

    The behavioral tests used (sucrose preference, forced-swimming, elevated-plus maze, novelty-suppressed feeding, novel object recognition, Morris water maze) measure the intended emotional and cognitive domains in rats.

    “behavior was continuously monitored for depressive- and anhedonic-like behavior, anxiety and cognition (Figure 1a).”

  • The paper relies on this without support.

    A 4-week stress-free period is sufficient to model remission from a depressive-like episode.

    “For the following 4 weeks after uCMS, animals were not subjected to any stressor.”

  • The paper relies on this without support.

    The uCMS protocol in animals is a valid model of recurrent depression in humans.

    “using a well-established animal model of depression”

  • The paper relies on this without support.

    The effects of fluoxetine and imipramine in the uCMS animal model predict their effects in human recurrent depression.

    “in agreement with clinical studies showing that remitted patients treated with fluoxetine present higher rates of relapse, in comparison with other ADs.30, 31”
5 of 5

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?

  • Treatment with the antidepressant fluoxetine results in an overproduction of new neurons in the adult hippocampus, associated with cognitive decline, increased susceptibility to stress-induced depression, and excessive anxiety.

    “Treatment with the antidepressant fluoxetine resulted in an overproduction of new neurons in the adult hippocampus (Alves et al., 2017) (Table 1). This effect, which at first glance appeared to be beneficial, was surprisingly associated with cognitive decline, as well as increased susceptibility to stress-induced depression and excessive anxiety (Alves et al., 2017).”

    From Adult neurogenesis, glia, and the extracellular matrix (2019) · cites this paper as Alves et al., 2017

  • Pharmacological blockade of adult neurogenesis rescues the deleterious behavioral effects induced by antidepressant treatment, strongly suggesting that in this case the new neurons impaired hippocampal function.

    “Pharmacological blockade of adult neurogenesis rescued the deleterious behavioral effects induced by antidepressant treatment strongly suggesting that in this case, the new neurons impaired hippocampal function (Alves et al., 2017).”

    From Adult neurogenesis, glia, and the extracellular matrix (2019) · cites this paper as Alves et al., 2017

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.

  • Novel-object test F statistic contradicts its reported P value

    Major

    An F statistic of 1.482 with 2 and 29 degrees of freedom has a P value of approximately 0.244, not less than 0.0001. This discrepancy affects the reported significance of the treatment-group comparison at tp3.

1 of 1

Cites

Flagged first, then by citations

Cited by

Sorted by citations

Related

Authors
Alves, N. D., Correia, J. S., Patrício, P., Mateus-Pinheiro, A., Machado-Santos, A. R., Loureiro-Campos, E., Morais, M., Bessa, J. M., Sousa, N., & Pinto, L.
Affiliations
University of Minho (PT)
Corresponding author
Pinto, L
ORCID
Venue
Translational Psychiatry
Publisher
Springer Science and Business Media LLC
Published
2017-03-14
Volume
7
Issue
3
Pages
e1058-e1058
ISSN
2158-3188 (ISSN-L)
DOI
10.1038/tp.2017.29
PMC
PMC5416672
OpenAlex
W2614795543
Semantic Scholar
b3ac803527d9fdb61d7c9cb2286512e891dd682a
Cited by
79
References
47
Citations by year
2026: 2 · 2025: 7 · 2024: 6 · 2023: 8 · 2022: 11 · 2021: 15 · 2020: 9 · 2019: 7 · 2018: 11 · 2017: 2
FWCI
3.36
Type
journal article
Language
en
Open access
Licence
Locations
  • Translational Psychiatry (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Portuguese National Funding Agency for Science, Research and Technology (RCAAP Project by FCT) (submittedVersion, other-oa)
  • Portuguese National Funding Agency for Science, Research and Technology (RCAAP Project by FCT) (submittedVersion, cc-by-nc-nd)
Funders
  • Fundação para a Ciência e a Tecnologia (IF/01079/2014, 01-0145, COMPETE, POCI-01-0145, NORTE-01–0145-FEDER-000013, PORTUGAL 2020, POCI‐01‐0145‐FEDER‐007038, POCI-01-0145-FEDER-, NORTE2020, POCI-01-, NORTE-01-0145)
  • European Regional Development Fund (COMPETE, POCI-01, 01-0145-FEDER-000013, 01-0145, NORTE-01-0145-FEDER-000013, POCI-01-0145, POCI-01-0145-FEDER-007038, POCI-01-0145- FEDER, NORTE-2020)
Topics
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
  • Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
  • Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
Keywords
recurrent depression, adult hippocampal neurogenesis, neuroplasticity, chronic mild stress, fluoxetine, imipramine, antidepressant response, behavioral resilience, dendritic atrophy, granule neurons, cell proliferation, emotional deficits, cognitive impairment
MeSH terms
Animals, Antidepressive Agents, Behavior, Animal, Depressive Disorder, Disease Models, Animal, Disease Susceptibility, Fluoxetine, Hippocampus, Imipramine, Male, Neuronal Plasticity, Recurrence, Stress, Psychological, Rats, Wistar, Rats

About these checks

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

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

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

Statistics and arithmetic are recomputed, not judged.

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

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

Are you an author, or do you see a problem with this page? Request a review