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Cited by 408Treatment of Major DepressionNeurogenesis and neuroplasticity mechanismsStress Responses and Cortisol

Dysregulation of adult hippocampal neuroplasticity in major depression: Pathogenesis and therapeutic implications

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Tartt, Alexandria N., Mariani, Madeline B., Hen, Rene, Mann, J. John, Boldrini, Maura·2022·Molecular Psychiatry
DOI 10.1038/s41380-022-01520-yPMC PMC9167750
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Abstract

Major depressive disorder (MDD) was previously hypothesized to be a disease of monoamine deficiency in which low levels of monoamines in the synaptic cleft were believed to underlie depressive symptoms. More recently, however, there has been a paradigm shift toward a neuroplasticity hypothesis of depression in which downstream effects of antidepressants, such as increased neurogenesis, contribute to improvements in cognition and mood. This review takes a top-down approach to assess how changes in behavior and hippocampal-dependent circuits may be attributed to abnormalities at the molecular, structural, and synaptic level. We conclude with a discussion of how antidepressant treatments share a common effect in modulating neuroplasticity and consider outstanding questions and future perspectives.

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Crossref · 10.1038/s41380-022-01520-y

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  • Findingcitation

    In postmortem human hippocampus, dentate gyrus granule neuron number and dentate gyrus volume were smaller in anterior and mid, but not posterior hippocampus in unmedicated major depressive disorder subjects.

    “We have shown that DG granule neuron number and DG volume were smaller in anterior and mid, but not posterior hippocampus in unmedicated MDD postmortem62.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [62] Boldrini M, Santiago AN, Hen R, Dwork AJ, Rosoklija GB, Tamir H, et al. Hippocampal granule neuron number and dentate gyrus volume in antidepressant-treated and untreated major depression. Neuropsychopharmacology. 2013;38:1068–77. source

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  • Findingcitation

    Resilient subjects exposed to childhood adversity but with no lifetime psychiatric diagnosis and natural death had more granule neurons and a larger dentate gyrus.

    “Additionally, we found more granule neurons and a larger DG in resilient subjects who were exposed to childhood adversity but had no lifetime psychiatric diagnosis and died from natural causes63.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [63] Boldrini M, Galfalvy H, Dwork AJ, Rosoklija GB, Trencevska-Ivanovska I, Pavlovski G, et al. Resilience is associated with larger dentate gyrus, while suicide decedents with major depressive disorder have fewer granule neurons. Biol Psychiatry. 2019;85:850–62. source

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  • Findingcitation

    The authors' group and others have shown evidence of neurogenesis throughout adulthood using double immunofluorescence, in situ hybridization, and 14C decay-defined neuronal age.

    “However, our group and others have shown evidence of neurogenesis throughout adulthood using double immunofluorescence98-101, in situ hybridization102 and 14C decay-defined neuronal age103.”
    Quote in the paperSubstantial claim0 of 6 sources checked
    • cites [98] Moreno-Jiménez EP, Flor-García M, Terreros-Roncal J, Rábano A, Cafini F, Pallas-Bazarra N, et al. Adult hippocampal neurogenesis is abundant in neurologically healthy subjects and drops sharply in patients with Alzheimer’s disease. Nat Med. 2019;25:554–60. source

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    • cites [101] Tartt AN, Fulmore CA, Liu Y, Rosoklija GB, Dwork AJ, Arango V, et al. Considerations for assessing the extent of hippocampal neurogenesis in the adult and aging human brain. Cell Stem Cell. 2018;23:782–3. source

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  • Findingcitation

    In postmortem human brain, unmedicated depressed subjects had fewer neural progenitor cells and mature granular neurons selectively in anterior dentate gyrus compared with non-psychiatric sudden death controls.

    “In postmortem human brain, we found fewer neural progenitor cells and mature granular neurons in unmedicated depressed subjects, selectively in anterior DG, compared with non-psychiatric sudden death controls, suggesting that neurogenesis may be blunted in MDD62, 63.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [62] Boldrini M, Santiago AN, Hen R, Dwork AJ, Rosoklija GB, Tamir H, et al. Hippocampal granule neuron number and dentate gyrus volume in antidepressant-treated and untreated major depression. Neuropsychopharmacology. 2013;38:1068–77. source

      Not checked in the free run.

    • cites [63] Boldrini M, Galfalvy H, Dwork AJ, Rosoklija GB, Trencevska-Ivanovska I, Pavlovski G, et al. Resilience is associated with larger dentate gyrus, while suicide decedents with major depressive disorder have fewer granule neurons. Biol Psychiatry. 2019;85:850–62. source

      Not checked in the free run.

  • Findingown data

    Antidepressant treatment is associated with more neural progenitor cells and granule neurons in the postmortem human dentate gyrus in major depressive disorder than in non-MDD sudden death controls.

    “We found that antidepressant treatment is associated with more neural progenitor cells and granule neurons in postmortem human DG in MDD compared with non-MDD sudden death controls.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [62] Boldrini M, Santiago AN, Hen R, Dwork AJ, Rosoklija GB, Tamir H, et al. Hippocampal granule neuron number and dentate gyrus volume in antidepressant-treated and untreated major depression. Neuropsychopharmacology. 2013;38:1068–77. source

      Not checked in the free run.

    • cites [121] Duman RS, Nakagawa S, Malberg J. Regulation of adult neurogenesis by antidepressant treatment. Neuropsychopharmacology. 2001;25:836–44. source

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  • May combine two claims. 50
  • Classified as probably not a substantial claim. 10

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    Interpretationreasoning

    Different study populations may contain different proportions of mood or cognitive subgroups of depression, which explains conflicting findings and the wide range in incidence of cognitive deficits.

    “Therefore, different study populations may have different proportions of certain mood or cognitive subgroups of depression, explaining conflicting findings and the wide range in incidence of cognitive deficits.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Cognitive deficits affect an estimated 20-90% of patients with major depressive disorder.

    “it has been estimated that cognitive deficits affect 20-90% of MDD patients22-27.”
    Quote in the paperNot a substantial claim0 of 6 sources checked
    • cites [22] McIntyre RS, Cha DS, Soczynska JK, Woldeyohannes HO, Gallaugher LA, Kudlow P, et al. Cognitive deficits and functional outcomes in major depressive disorder: determinants, substrates, and treatment interventions. Depress Anxiety. 2013;30:515–27. source

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    • cites [23] Conradi HJ, Ormel J, de Jonge P. Presence of individual (residual) symptoms during depressive episodes and periods of remission: a 3-year prospective study. Psychol Med. 2011;41:1165–74. source

      Not checked in the free run.

    • cites [24] Jaeger J, Berns S, Uzelac S, Davis-Conway S. Neurocognitive deficits and disability in major depressive disorder. Psychiatry Res. 2006;145:39–48. source

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    • cites [25] Kaser M, Zaman R, Sahakian BJ. Cognition as a treatment target in depression. Psychol Med. 2017;47:987–9. source

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    • cites [26] Siddarth P, Funes CM, Laird KT, Ercoli L, Lavretsky H. Predictors of cognitive improvement following treatment for late-life depression. J Geriatr Psychiatry Neurol. 2021;34:162–8. source

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    • cites [27] McAllister-Williams RH, Bones K, Goodwin GM, Harrison J, Katona C, Rasmussen J, et al. Analysing UK clinicians’ understanding of cognitive symptoms in major depression: a survey of primary care physicians and psychiatrists. J Affect Disord. 2017;207:346–52. source

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    Premisecitation

    Allostatic load is elevated in depression and is associated with a prolonged stress response, including elevated cortisol in melancholia.

    “Allostatic load is elevated in depression, which is associated with prolonged stress response, including elevated levels of cortisol associated with melancholia5, 21.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [5] Dahmen B, Puetz VB, Scharke W, von Polier GG, Herpertz-Dahlmann B, Konrad K. Effects of early-life adversity on hippocampal structures and associated HPA axis functions. Dev Neurosci. 2018;40:13–22. source

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    • cites [21] Wang Q, Van Heerikhuize J, Aronica E, Kawata M, Seress L, Joels M, et al. Glucocorticoid receptor protein expression in human hippocampus; stability with age. Neurobiol Aging. 2013;34:1662–73. source

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    Premisecitation

    The hippocampus regulates mood partly through its connections with the amygdala and anterior cingulate cortex and through feedback regulation of the hypothalamic-pituitary-adrenal axis.

    “First, the hippocampus plays a critical role in mood regulation, in part, due to its connections with emotion-related brain regions such as amygdala and anterior cingulate cortex (ACC)17, 18 as well as its feedback role in regulating the hypothalamus-pituitary-adrenal (HPA) axis.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [17] Ruiz S, Buyukturkoglu K, Rana M, Birbaumer N, Sitaram R. Real-time fMRI brain computer interfaces: self-regulation of single brain regions to networks. Biol Psychol. 2014;95:4–20. source

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    • cites [18] Schumacher A, Villaruel FR, Ussling A, Riaz S, Lee ACH, Ito R. Ventral hippocampal CA1 and CA3 differentially mediate learned approach-avoidance conflict processing. Curr Biol. 2018;28:1318–24.e4. source

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  • May combine two claims.

    Interpretationreasoning

    Hippocampal neuroplasticity is implicated in the etiology of major depressive disorder and in antidepressant action.

    “As such, hippocampal neuroplasticity has been implicated in MDD etiology and antidepressant action.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: High concentrations of hippocampal glucocorticoid receptors make the hippocampus particularly vulnerable to allostatic load.

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    Premisecitation

    Deficits in memory, attention and executive functioning occur in major depressive disorder even without a current depressive episode and in individuals responding well to antidepressants, indicating that cognitive deficits are only partly state-dependent.

    “Furthermore, deficits in memory, attention and executive functioning have been observed in the absence of a current depressive episode28-31 and even in individuals responding well to antidepressant treatment for affective symptoms23, suggesting that cognitive deficits are only partly a state-dependent phenotype in MDD.”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [28] Pu S, Noda T, Setoyama S, Nakagome K. Empirical evidence for discrete neurocognitive subgroups in patients with non-psychotic major depressive disorder: clinical implications. Psychol Med. 2018;48:2717–29. source

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    • cites [29] Hammar A, Sørensen L, Ardal G, Oedegaard KJ, Kroken R, Roness A, et al. Enduring cognitive dysfunction in unipolar major depression: a test-retest study using the Stroop paradigm. Scand J Psychol. 2010;51:304–8.

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    • cites [30] Semkovska M, Quinlivan L, O’Grady T, Johnson R, Collins A, O’Connor J, et al. Cognitive function following a major depressive episode: a systematic review and meta-analysis. Lancet Psychiatry. 2019;6:851–61. source

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    • cites [31] Perini G, Cotta Ramusino M, Sinforiani E, Bernini S, Petrachi R, Costa A. Cognitive impairment in depression: recent advances and novel treatments. Neuropsychiatr Dis Treat. 2019;15:1249–58. source

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    • cites [23] Conradi HJ, Ormel J, de Jonge P. Presence of individual (residual) symptoms during depressive episodes and periods of remission: a 3-year prospective study. Psychol Med. 2011;41:1165–74. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The dominant explanation of antidepressant action has shifted from a synaptic monoamine-deficiency model to a delayed downstream neuroplasticity model in which correcting deficits in neurons, processes and synapses contributes to depression pathogenesis.

    “Consequently, there has been a paradigm shift from a synaptic effect derived from the monoamine hypothesis to a more complex delayed downstream neuroplasticity hypothesis of antidepressant action that involves correcting a deficiency in neurons, processes and synapses that comprise the pathogenesis of depression.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Antidepressant medications are pharmacologically active within hours, but their antidepressant effects are not apparent for weeks after starting treatment.
    • Rests on an assumption: Even when antidepressants have meaningful pharmacologic effects, many patients do not improve.
    • The authors state this as an assumption: The effects of antidepressants depend on downstream processes, such as increased neurogenesis, that take time to appear and are robust only in medication responders.

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    Premisecitation

    In healthy controls, downregulating emotional responses to aversive stimuli hyperactivates the prefrontal cortex and anterior cingulate cortex and hypoactivates the amygdala; upregulating negative emotions activates both the prefrontal cortex and amygdala, suggesting a prefrontal-dependent cognitive component in emotional regulation.

    “In healthy controls, when asked to downregulate emotional responses in the presence of an aversive stimuli, the PFC and ACC were hyperactivated and the amygdala was hypoactivated. When participants were asked to upregulate negative emotions in response to aversive stimuli, both the PFC and amygdala were activated47, suggesting a PFC-dependent cognitive component in emotional regulation in healthy”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [47] Ochsner KN, Ray RD, Cooper JC, Robertson ER, Chopra S, Gabrieli JD, et al. For better or for worse: neural systems supporting the cognitive down- and up-regulation of negative emotion. Neuroimage. 2004;23:483–99. source

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    Premisecitation

    The association between dorsolateral prefrontal cortex activity, memory and major depressive disorder is inconsistent, with some studies reporting hypoactivity together with decreased working memory performance.

    “The association between DLPFC activity, memory and MDD has not been consistent, as others have reported DLPFC hypoactivity in conjunction with decreased working memory performance41, 42.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [41] Elliott R, Baker SC, Rogers RD, O’Leary DA, Paykel ES, Frith CD, et al. Prefrontal dysfunction in depressed patients performing a complex planning task: a study using positron emission tomography. Psychol Med. 1997;27:931–42. source

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    • cites [42] Okada G, Okamoto Y, Morinobu S, Yamawaki S, Yokota N. Attenuated left prefrontal activation during a verbal fluency task in patients with depression. Neuropsychobiology. 2003;47:21–6. source

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    Premisecitation

    In major depressive disorder, the extent of hippocampal gray matter volume loss is related to time spent depressed, and smaller hippocampal volume is associated with worse depression scores.

    “Moreover, in MDD, the extent of hippocampal gray matter volume loss is related to time spent depressed58, 61 and smaller hippocampal volume is associated with worse depression scores.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [58] Sheline YI, Wang PW, Gado MH, Csernansky JG, Vannier MW. Hippocampal atrophy in recurrent major depression. Proc Natl Acad Sci USA. 1996;93:3908–13. source

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    • cites [61] Roddy DW, Farrell C, Doolin K, Roman E, Tozzi L, Frodl T, et al. The hippocampus in depression: more than the sum of its parts? Advanced hippocampal substructure segmentation in depression. Biol Psychiatry. 2019;85:487–97. source

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    Premisecitation

    BDNF binds the TrkB receptor, activating mTOR signaling that promotes neuronal growth, proliferation and migration.

    “This is because BDNF can bind to tropomyosin kinase B (TrkB) receptor which activates the mechanistic target of rapamycin (mTOR) signaling pathway which promotes neuronal growth, proliferation and migration77.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [77] Takei N, Nawa H. mTOR signaling and its roles in normal and abnormal brain development. Front Mol Neurosci. 2014;7:28. source

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    Premisecitation

    Neuroimaging studies consistently report dorsolateral prefrontal cortex hypoactivity at rest in unmedicated major depressive disorder but hyperactivity during working memory tasks.

    “Neuroimaging studies have consistently reported DLPFC hypoactivity at rest in unmedicated MDDs37, 38 but DLPFC hyperactivity during working memory tasks39.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [37] Baxter LR, Schwartz JM, Phelps ME, Mazziotta JC, Guze BH, Selin CE, et al. Reduction of prefrontal cortex glucose metabolism common to three types of depression. Arch Gen Psychiatry. 1989;46:243–50. source

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    • cites [38] Soares JC, Mann JJ. The functional neuroanatomy of mood disorders. J Psychiatr Res. 1997;31:393–432. source

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    • cites [39] Harvey PO, Fossati P, Pochon JB, Levy R, Lebastard G, Lehéricy S, et al. Cognitive control and brain resources in major depression: an fMRI study using the n-back task. Neuroimage. 2005;26:860–9. source

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    Premisecitation

    Decreased brain-derived neurotrophic factor via histone modifications to the promoter region is associated with downregulation of BDNF transcripts and is one potential process involved in neuronal loss.

    “One potential process involved in neuronal loss is decreased brain-derived neurotrophic factor (BDNF) via histone modifications to the promoter region associated with downregulation of BDNF transcripts73, 74.”
    Quote in the paperSubstantial claim0 of 2 sources checked
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  • May combine two claims.

    Interpretationreasoning

    Focus on negative internal stimuli can lead to stronger encoding of negative experiences and sustain negative thoughts and expectations, underlying biased recall of negative relative to other memories in depressed patients.

    “Additionally, focus on negative internal stimuli can result in more strongly encoding negative experiences and sustain negative thoughts and expectations, and underly a biased recall of negative relative to other memories in depressed patients.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Hippocampal-amygdala connectivity varies between resting state and emotional or cognitive tasks, indicating that the network is context-dependent and modulated by environmental stimuli and individual emotional state.

    “Variations between hippocampal-amygdala connectivity during resting state and emotional and cognitive tasks suggests that this network is context-dependent and modulated by environmental stimuli and individual emotional state.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Most studies find that untreated depressed patients have smaller hippocampal volume, neuronal and glial number, and cell size compared with non-psychiatric controls.

    “Most studies find that untreated depressed patients have smaller hippocampal volume58, 59, neuronal and glial number, and cell size60 compared with non-psychiatric controls.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [58] Sheline YI, Wang PW, Gado MH, Csernansky JG, Vannier MW. Hippocampal atrophy in recurrent major depression. Proc Natl Acad Sci USA. 1996;93:3908–13. source

      Not checked in the free run.

    • cites [59] Luo Y, Cao Z, Wang D, Wu L, Li Y, Sun W, et al. Dynamic study of the hippocampal volume by structural MRI in a rat model of depression. Neurol Sci. 2014;35:1777–83. source

      Not checked in the free run.

    • cites [60] Czéh B, Simon M, Schmelting B, Hiemke C, Fuchs E. Astroglial plasticity in the hippocampus is affected by chronic psychosocial stress and concomitant fluoxetine treatment. Neuropsychopharmacology. 2006;31:1616–26. source

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    Premisecitation

    In the absence of familial risk, early childhood trauma severity correlates with amygdala responsiveness and hippocampal volume loss in healthy volunteers, and these associations are not influenced by recent life stress, depression or anxiety scores.

    “For example, in the absence of familial risk, early childhood trauma severity (operationalized via the Childhood Trauma Questionnaire) correlated with amygdala responsiveness and hippocampal volume loss in a group of healthy volunteers, and these associations were not influenced by recent life stress, depression or anxiety scores70.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [70] Dannlowski U, Stuhrmann A, Beutelmann V, Zwanzger P, Lenzen T, Grotegerd D, et al. Limbic scars: long-term consequences of childhood maltreatment revealed by functional and structural magnetic resonance imaging. Biol Psychiatry. 2012;71:286–93. source

      Not checked in the free run.

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    Premisecitation

    In an MRI study of PTSD, smaller hippocampal volume predicted risk of PTSD and did not result from the trauma that triggered PTSD.

    “This concept has been demonstrated in an MRI study of PTSD which showed how smaller hippocampal volume predicted risk of PTSD and did not result from the trauma that triggered PTSD71.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [71] Xie H, Claycomb Erwin M, Elhai JD, Wall JT, Tamburrino MB, Brickman KR, et al. Relationship of hippocampal volumes and posttraumatic stress disorder symptoms over early posttrauma periods. Biol Psychiatry Cogn Neurosci Neuroimaging. 2018;3:968–75.

      Not checked in the free run.

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    Premisecitation

    There is disagreement over which hippocampal regions are smaller in depression, with some studies finding volumetric sparing of CA1 and others CA1 volume loss, and some reporting volume loss selectively in the hippocampal head versus body.

    “Interestingly, there is disagreement over which regions of the hippocampus are smaller in depression. Some find volumetric sparing of CA164 while others report CA1 volume loss61, 65, 66. Some report volume loss selectively in the hippocampal head and others observed volume loss in the hippocampal body67.”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [64] Liu MN, Pantouw JG, Yang KC, Hu LY, Liou YJ, Lirng JF, et al. Sub-regional hippocampal volumes in first-episode drug-naïve major depression disorder. Neurosci Lett. 2021;763:136178. source

      Not checked in the free run.

    • cites [61] Roddy DW, Farrell C, Doolin K, Roman E, Tozzi L, Frodl T, et al. The hippocampus in depression: more than the sum of its parts? Advanced hippocampal substructure segmentation in depression. Biol Psychiatry. 2019;85:487–97. source

      Not checked in the free run.

    • cites [65] Frodl T, Carballedo A, Frey EM, O’Keane V, Skokauskas N, Morris D, et al. Expression of glucocorticoid inducible genes is associated with reductions in cornu ammonis and dentate gyrus volumes in patients with major depressive disorder. Dev Psychopathol. 2014;26:1209–17. source

      Not checked in the free run.

    • cites [66] Huang Y, Coupland NJ, Lebel RM, Carter R, Seres P, Wilman AH, et al. Structural changes in hippocampal subfields in major depressive disorder: a high-field magnetic resonance imaging study. Biol Psychiatry. 2013;74:62–8. source

      Not checked in the free run.

    • cites [67] Travis S, Coupland NJ, Silversone PH, Huang Y, Fujiwara E, Carter R, et al. Dentate gyrus volume and memory performance in major depressive disorder. J Affect Disord. 2015;172:159–64. source

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    Premisecitation

    Unmedicated adolescents with major depressive disorder show less resting-state fMRI connectivity between hippocampus and amygdala than healthy controls, and this lack of connectivity correlates with depression severity.

    “Interestingly, unmedicated adolescents with MDD showed less resting state fMRI (rsfMRI) connectivity between hippocampus and amygdala compared with healthy controls52. This lack of connectivity between hippocampus and amygdala correlated with severity of depression52.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [52] Cullen KR, Westlund MK, Klimes-Dougan B, Mueller BA, Houri A, Eberly LE, et al. Abnormal amygdala resting-state functional connectivity in adolescent depression. JAMA Psychiatry. 2014;71:1138–47. source

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    Premisecitation

    In human and rodent studies, changes to hippocampal circuitry are associated with early life adversity, suggesting an epigenetic mechanism for these changes and for major depressive disorder pathogenesis.

    “Furthermore, in human and rodent studies, changes to hippocampal circuitry have been associated with early life adversity which suggests an epigenetic mechanism for these changes and MDD pathogenesis53, 54.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [53] Turecki G, Meaney MJ. Effects of the social environment and stress on glucocorticoid receptor gene methylation: a systematic review. Biol Psychiatry. 2016;79:87–96. source

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    • cites [54] Smith KE, Pollak SD. Early life stress and development: potential mechanisms for adverse outcomes. J Neurodev Disord. 2020;12:34. source

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  • May combine two claims.

    Interpretationcitation

    The pathogenesis of cognitive and affective deficits in untreated major depressive disorder is not fully elucidated but likely involves abnormalities across multiple brain regions, including changes in functional and/or structural connectivity.

    “The pathogenesis of cognitive and affective deficits in untreated MDD is not fully elucidated but likely involves abnormalities across multiple brain regions33-35, and includes but is not limited to changes in functional and/or structural connectivity.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [33] Cao X, Liu Z, Xu C, Li J, Gao Q, Sun N, et al. Disrupted resting-state functional connectivity of the hippocampus in medication-naïve patients with major depressive disorder. J Affect Disord. 2012;141:194–203. source

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    • cites [34] de Kwaasteniet B, Ruhe E, Caan M, Rive M, Olabarriaga S, Groefsema M, et al. Relation between structural and functional connectivity in major depressive disorder. Biol Psychiatry. 2013;74:40–7. source

      Not checked in the free run.

    • cites [35] Hao ZY, Zhong Y, Ma ZJ, Xu HZ, Kong JY, Wu Z, et al. Abnormal resting-state functional connectivity of hippocampal subfields in patients with major depressive disorder. BMC Psychiatry. 2020;20:71. source

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    Premisecitation

    Reported mechanisms potentially underlying cell loss include glutamate/glutamine cycling, blunted neurogenesis, decreased neurotrophic factor expression, and upregulation of pro-apoptotic pathways.

    “Currently, reported mechanisms potentially underlying cell loss include, but are not limited to, glutamate/glutamine cycling (see section on Molecular and Cellular Mechanisms of Neuroplasticity), blunted neurogenesis, decreased neurotrophic factor expression and upregulation of pro-apoptotic pathways72.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [72] Banasr M, Dwyer JM, Duman RS. Cell atrophy and loss in depression: reversal by antidepressant treatment. Curr Opin Cell Biol. 2011;23:730–7. source

      Not checked in the free run.

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    Premisecitation

    Non-depressed individuals with a familial history of depression exposed to emotional neglect had smaller anterior cingulate cortex, dorsolateral prefrontal cortex, medial prefrontal cortex and hippocampus than non-depressed individuals with no familial risk but exposed to emotional neglect, suggesting a gene-environment interaction affecting cell viability.

    “Smaller ACC, DLPFC, medial prefrontal cortex (MPFC) and hippocampus were shown in non-depressed individuals with a familial history of depression (first degree relative with MDD diagnosis) exposed to emotional neglect when compared to non-depressed individuals with no familial risk factors but who had been exposed to emotional neglect, suggesting a gene-environment interaction affecting cell”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [69] Carballedo A, Lisiecka D, Fagan A, Saleh K, Ferguson Y, Connolly G, et al. Early life adversity is associated with brain changes in subjects at family risk for depression. World J Biol Psychiatry. 2012;13:569–78. source

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  • May combine two claims.

    Premisecitation

    When patients with major depressive disorder are asked to ignore negative stimuli, they fail to recruit the dorsolateral prefrontal cortex, which is correlated with amygdala hyperactivity.

    “Conversely, when patients with MDD were asked to ignore negative stimuli, they failed to recruit the DLPFC which was correlated with amygdala hyperactivity48.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [48] Fales CL, Barch DM, Rundle MM, Mintun MA, Snyder AZ, Cohen JD, et al. Altered emotional interference processing in affective and cognitive-control brain circuitry in major depression. Biol Psychiatry. 2008;63:377–84. source

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

    Premisecitation

    The dorsolateral prefrontal cortex is responsible for attention, working memory and executive function, and its activity is positively correlated with working memory load in healthy controls.

    “The dorsolateral prefrontal cortex (DLPFC) is responsible for attention, working memory and executive function and is positively correlated with working memory load in healthy controls36.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [36] Braver TS, Cohen JD, Nystrom LE, Jonides J, Smith EE, Noll DC. A parametric study of prefrontal cortex involvement in human working memory. Neuroimage. 1997;5:49–62. source

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

    Premisecitation

    In rodents, primitive dentate progenitors migrate along the dentate migratory stream to establish the primitive dentate gyrus during embryonic development, and most dentate granule neurons are generated during the first postnatal week.

    “During embryonic development in rodents, primitive dentate progenitors from dentate neuroepithelium migrate along the dentate migratory stream to establish the primitive dentate gyrus89, 90. The majority of dentate granule neurons are generated during the first postnatal week90.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [89] Urbán N, Guillemot F. Neurogenesis in the embryonic and adult brain: same regulators, different roles. Front Cell Neurosci. 2014;8:396. source

      Not checked in the free run.

    • cites [90] Bayer SA, Altman J. Hippocampal development in the rat: cytogenesis and morphogenesis examined with autoradiography and low-level X-irradiation. J Comp Neurol. 1974;158:55–79. source

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  • May combine two claims.

    Premisecitation

    A few studies provide evidence that absence of neurogenesis elicits depressive-like symptoms in rodents, but most studies find that absent neurogenesis is not sufficient to induce a depressive phenotype, although it is required in mice for the behavioral effects of antidepressants.

    “A few studies provide evidence that the absence of neurogenesis elicits depressive like symptoms in rodents123, 124, but most studies find that absent neurogenesis is not sufficient to induce a depressive phenotype125 although it is required in mice for the behavioral effects of antidepressants118, 126.”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [123] Revest JM, Dupret D, Koehl M, Funk-Reiter C, Grosjean N, Piazza PV, et al. Adult hippocampal neurogenesis is involved in anxiety-related behaviors. Mol Psychiatry. 2009;14:959–67. source

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    • cites [124] Petrik D, Lagace DC, Eisch AJ. The neurogenesis hypothesis of affective and anxiety disorders: are we mistaking the scaffolding for the building? Neuropharmacology. 2012;62:21–34. source

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    • cites [125] Hill AS, Sahay A, Hen R. Increasing Adult Hippocampal Neurogenesis is Sufficient to Reduce Anxiety and Depression-Like Behaviors. Neuropsychopharmacology. 2015;40:2368–78. source

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    • cites [118] David DJ, Samuels BA, Rainer Q, Wang JW, Marsteller D, Mendez I, et al. Neurogenesis-dependent and -independent effects of fluoxetine in an animal model of anxiety/depression. Neuron. 2009;62:479–93. source

      Not checked in the free run.

    • cites [126] Anacker C, Luna VM, Stevens GS, Millette A, Shores R, Jimenez JC, et al. Hippocampal neurogenesis confers stress resilience by inhibiting the ventral dentate gyrus. Nature. 2018;559:98–102. source

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

    Premisecitation

    14C decay-defined neuronal age estimates that the human brain adds up to 700 new neurons each day, approximately 0.004% of total dentate gyrus neurons, resulting in 1.7% cell turnover annually.

    “While 14C decay-defined neuronal age estimates that the human brain adds up to 700 new neurons each day (approx. 0.004% of total DG neurons), resulting in a 1.7% cell turnover annually103”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [103] Moreno-Jiménez EP, Terreros-Roncal J, Flor-García M, Rábano A, Llorens-Martín M. Evidences for adult hippocampal neurogenesis in humans. J Neurosci. 2021;41:2541–53. source

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  • May combine two claims.

    Premisecitation

    Humans receiving chemotherapy, which kills proliferating cells and blunts neurogenesis, experience cognitive deficits and are more likely to develop depression than cancer patients treated with other therapies.

    “Humans receiving chemotherapy, which kills proliferating cells (thus blunting neurogenesis), experience cognitive deficits and are more likely to develop depression than cancer patients treated with other therapies128-130.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [128] Wen S, Xiao H, Yang Y. The risk factors for depression in cancer patients undergoing chemotherapy: a systematic review. Support Care Cancer. 2019;27:57–67. source

      Not checked in the free run.

    • cites [129] Wigmore P. The effect of systemic chemotherapy on neurogenesis, plasticity and memory. Curr Top Behav Neurosci. 2013;15:211–40. source

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    • cites [130] Christie LA, Acharya MM, Parihar VK, Nguyen A, Martirosian V, Limoli CL. Impaired cognitive function and hippocampal neurogenesis following cancer chemotherapy. Clin Cancer Res. 2012;18:1954–65. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Some studies suggest overlap in developmental timing and molecular signatures between rodent and human brain, and sequencing studies show that developmental neurogenesis and adult hippocampal neurogenesis share highly similar transcriptional trajectories.

    “Although less is known about embryonic hippocampal neurogenesis in humans, some studies suggest overlap in developmental timing and molecular signatures between the rodent and human brain91. The switch between developmental neurogenesis and AHN is gradual, and some sequencing studies have demonstrated these two processes share highly similar transcriptional trajectories91.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [91] Hochgerner H, Zeisel A, Lönnerberg P, Linnarsson S. Conserved properties of dentate gyrus neurogenesis across postnatal development revealed by single-cell RNA sequencing. Nat Neurosci. 2018;21:290–9. source

      Not checked in the free run.

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

    Premisecitation

    Some groups report absent or minimal hippocampal neurogenesis in the mature brain using double immunofluorescence and single nucleus transcriptomics.

    “Some groups have reported absent or minimal hippocampal neurogenesis in the mature brain using double immunofluorescence targeting markers expressed by neuronal cells at different maturational stages95, 96 and single nucleus transcriptomics97.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [95] Sorrells SF, Paredes MF, Cebrian-Silla A, Sandoval K, Qi D, Kelley KW, et al. Human hippocampal neurogenesis drops sharply in children to undetectable levels in adults. Nature. 2018;555:377–81. source

      Not checked in the free run.

    • cites [96] Cipriani S, Ferrer I, Aronica E, Kovacs GG, Verney C, Nardelli J, et al. Hippocampal radial glial subtypes and their neurogenic potential in human fetuses and healthy and Alzheimer’s disease adults. Cereb Cortex. 2018;28:2458–78. source

      Not checked in the free run.

    • cites [97] Franjic D, Skarica M, Ma S, Arellano JI, Tebbenkamp ATN, Choi J, et al. Transcriptomic taxonomy and neurogenic trajectories of adult human, macaque, and pig hippocampal and entorhinal cells. Neuron. 2021;110:452–69.e14. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing).

    Premisecitation

    Others argue that these stem cells originated in the ventral hippocampus and migrated dorsally.

    “Others have argued that these stem cells originated in the ventral hippocampus and migrated dorsally94.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [94] Li G, Fang L, Fernández G, Pleasure SJ. The ventral hippocampus is the embryonic origin for adult neural stem cells in the dentate gyrus. Neuron. 2013;78:658–72. source

      Not checked in the free run.

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

    Premisecitation

    Some studies demonstrate that neural stem cells in the adult subgranular zone niche are remnants of dentate neuroepithelium and that this same progenitor population exclusively contributes to hippocampal neurogenesis throughout development and into adulthood, shifting out of quiescence at different time points.

    “Some have demonstrated that neural stem cells in the adult hippocampal subgranular zone (SGZ) niche are remnants of dentate neuroepithelium92 and this same population of progenitors exclusively contributes to hippocampal neurogenesis throughout development and into adulthood, shifting out of quiescence at different time points93.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [92] Seki T, Sato T, Toda K, Osumi N, Imura T, Shioda S. Distinctive population of Gfap-expressing neural progenitors arising around the dentate notch migrate and form the granule cell layer in the developing hippocampus. J Comp Neurol. 2014;522:261–83. source

      Not checked in the free run.

    • cites [93] Berg DA, Su Y, Jimenez-Cyrus D, Patel A, Huang N, Morizet D, et al. A common embryonic origin of stem cells drives developmental and adult neurogenesis. Cell. 2019;177:654–68.e15. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Deficits in adult hippocampal neurogenesis may explain learning and memory deficits in major depressive disorder and may play a role in selective engagement with negative valence memories, mood regulation, and antidepressant response.

    “Deficits in AHN may not only explain the learning and memory deficits in MDD, but also play a role in the selective engagement with negative valence memories, mood regulation and antidepressant response118-122.”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [118] David DJ, Samuels BA, Rainer Q, Wang JW, Marsteller D, Mendez I, et al. Neurogenesis-dependent and -independent effects of fluoxetine in an animal model of anxiety/depression. Neuron. 2009;62:479–93. source

      Not checked in the free run.

    • cites [119] Malberg JE, Eisch AJ, Nestler EJ, Duman RS. Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. J Neurosci. 2000;20:9104–10. source

      Not checked in the free run.

    • cites [120] Boldrini M, Underwood MD, Hen R, Rosoklija GB, Dwork AJ, John Mann J, et al. Antidepressants increase neural progenitor cells in the human hippocampus. Neuropsychopharmacology. 2009;34:2376–89. source

      Not checked in the free run.

    • cites [121] Duman RS, Nakagawa S, Malberg J. Regulation of adult neurogenesis by antidepressant treatment. Neuropsychopharmacology. 2001;25:836–44. source

      Not checked in the free run.

    • cites [122] Wang H, Warner-Schmidt J, Varela S, Enikolopov G, Greengard P, Flajolet M. Norbin ablation results in defective adult hippocampal neurogenesis and depressive-like behavior in mice. Proc Natl Acad Sci USA. 2015;112:9745–50. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In rodents, up to 30-70% of newborn neurons die in the first month and 1300 neurons are eliminated daily from the rodent hippocampus.

    “in rodents, it has been estimated that up to 30-70% of newborn neurons die in the first month and that 1300 neurons are eliminated daily from the rodent hippocampus111, 112.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [111] Dayer AG, Ford AA, Cleaver KM, Yassaee M, Cameron HA. Short-term and long-term survival of new neurons in the rat dentate gyrus. J Comp Neurol. 2003;460:563–72. source

      Not checked in the free run.

    • cites [112] Shors TJ, Townsend DA, Zhao M, Kozorovitskiy Y, Gould E. Neurogenesis may relate to some but not all types of hippocampal-dependent learning. Hippocampus. 2002;12:578–84. source

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  • May combine two claims.

    Premisecitation

    BDNF expression is decreased in postmortem hippocampus in untreated major depressive disorder subjects but not in antidepressant-treated depressed individuals.

    “Additionally, BDNF expression was decreased in postmortem hippocampus in untreated MDDs but not in antidepressant-treated depressed individuals79.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [79] Chen B, Dowlatshahi D, MacQueen GM, Wang JF, Young LT. Increased hippocampal BDNF immunoreactivity in subjects treated with antidepressant medication. Biol Psychiatry. 2001;50:260–5. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In humans, paired associative stimulation-induced increases in motor-evoked potential amplitudes are attenuated during major depressive episodes compared with healthy controls and normalize during remission.

    “However, proxy measurements such as paired associative stimulation (PAS) using a transcranial magnetic stimulation protocol have shown that PAS-induced increases in motor-evoked potential amplitudes were attenuated during major depressive episodes compared with healthy controls and normalized during remission151, 152.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [151] Player MJ, Taylor JL, Weickert CS, Alonzo A, Sachdev P, Martin D, et al. Neuroplasticity in depressed individuals compared with healthy controls. Neuropsychopharmacology. 2013;38:2101–8. source

      Not checked in the free run.

    • cites [152] Moghaddam B, Bolinao ML, Stein-Behrens B, Sapolsky R. Glucocorticoids mediate the stress-induced extracellular accumulation of glutamate. Brain Res. 1994;655:251–4. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Some studies report increased glutamate levels in plasma of untreated major depressive disorder patients, high CSF glutamate concentrations in severely depressed hospitalized major depressive disorder patients, and in untreated elderly major depressive disorder patients compared with healthy controls.

    “Some have reported increased glutamate levels in the plasma of untreated MDD patients157, 158 in line with reports of high CSF glutamate concentrations in severely depressed, hospitalized MDD patients159 and in untreated elderly MDD patients when compared to healthy controls160.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [157] Altamura CA, Mauri MC, Ferrara A, Moro AR, D’Andrea G, Zamberlan F. Plasma and platelet excitatory amino acids in psychiatric disorders. Am J Psychiatry. 1993;150:1731–3. source

      Not checked in the free run.

    • cites [158] Levine J, Panchalingam K, Rapoport A, Gershon S, McClure RJ, Pettegrew JW. Increased cerebrospinal fluid glutamine levels in depressed patients. Biol Psychiatry. 2000;47:586–93. source

      Not checked in the free run.

    • cites [159] Hashimoto K, Bruno D, Nierenberg J, Marmar CR, Zetterberg H, Blennow K, et al. Abnormality in glutamine-glutamate cycle in the cerebrospinal fluid of cognitively intact elderly individuals with major depressive disorder: a 3-year follow-up study. Transl Psychiatry. 2016;6:e744. source

      Not checked in the free run.

    • cites [160] Kantrowitz JT, Dong Z, Milak MS, Rashid R, Kegeles LS, Javitt DC, et al. Ventromedial prefrontal cortex/anterior cingulate cortex Glx, glutamate, and GABA levels in medication-free major depressive disorder. Transl Psychiatry. 2021;11:419. source

      Not checked in the free run.

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

    Premisecitation

    Synaptic strength moderates neural signaling between cells over an extended period, underlying circuit functionality.

    “Synaptic strength moderates neural signaling between cells over an extended period175, 176, underlying circuit functionality.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [175] Ho VM, Lee JA, Martin KC. The cell biology of synaptic plasticity. Science. 2011;334:623–8. source

      Not checked in the free run.

    • cites [176] Harmer CJ, Duman RS, Cowen PJ. How do antidepressants work? New perspectives for refining future treatment approaches. Lancet Psychiatry. 2017;4:409–18. source

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  • May combine two claims.

    Premisecitation

    In vivo proton magnetic resonance spectroscopy detected elevated glutamate levels in ventromedial prefrontal cortex/anterior cingulate cortex in untreated major depressive disorder, consistent with a meta-analysis finding higher glutamate/glutamine concentrations in medial frontal cortex of unmedicated major depressive disorder but not antidepressant-treated patients.

    “In vivo proton magnetic resonance spectroscopy (1H MRS) detected elevated glutamate levels in ventromedial prefrontal cortex/anterior cingulate cortex in untreated MDD161 consistent with a recent meta-analysis of MRS imaging studies that found higher glutamate/glutamine concentrations in medial frontal cortex of unmedicated MDD but not in antidepressant-treated patients162.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [161] Moriguchi S, Takamiya A, Noda Y, Horita N, Wada M, Tsugawa S, et al. Glutamatergic neurometabolite levels in major depressive disorder: a systematic review and meta-analysis of proton magnetic resonance spectroscopy studies. Mol Psychiatry. 2019;24:952–64. source

      Not checked in the free run.

    • cites [162] Yuen EY, Wei J, Liu W, Zhong P, Li X, Yan Z. Repeated stress causes cognitive impairment by suppressing glutamate receptor expression and function in prefrontal cortex. Neuron. 2012;73:962–77. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    It is possible that in humans, as in rodents, newborn neurons predominantly confer resilience on hippocampal circuitry and may facilitate circuit rewiring for antidepressant response.

    “Thus, it is possible that, like in rodents, the role of newborn neurons in humans is predominately for conferring resilience on the hippocampal circuitry, and possibly facilitating circuit rewiring for the antidepressant response.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Stress-induced rodent models generally show increases in dentate gyrus long-term potentiation and reductions in long-term potentiation at Schaffer collaterals-CA1 synapses in response to acute and chronic stress.

    “These studies have generally observed increases in DG LTP147 and reductions in LTP at Schaffer collaterals-CA1 synapses148, 149 in response to acute and chronic stress.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [147] Alfarez DN, Joëls M, Krugers HJ. Chronic unpredictable stress impairs long-term potentiation in rat hippocampal CA1 area and dentate gyrus in vitro. Eur J Neurosci. 2003;17:1928–34. source

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    • cites [148] Chaouloff F, Hémar A, Manzoni O. Acute stress facilitates hippocampal CA1 metabotropic glutamate receptor-dependent long-term depression. J Neurosci. 2007;27:7130–5. source

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    • cites [149] Maggio N, Segal M. Striking variations in corticosteroid modulation of long-term potentiation along the septotemporal axis of the hippocampus. J Neurosci. 2007;27:5757–65. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    BDNF transcription depends on activation of CREB, which plays a critical role in long-term potentiation and synaptic plasticity.

    “The transcription of BDNF is dependent upon activation of the cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) protein which plays a critical role in LTP and synaptic plasticity142, 143.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [142] Won J, Silva AJ. Molecular and cellular mechanisms of memory allocation in neuronetworks. Neurobiol Learn Mem. 2008;89:285–92. source

      Not checked in the free run.

    • cites [143] Tejeda GS, Díaz-Guerra M. Integral Characterization of defective BDNF/TrkB signalling in neurological and psychiatric disorders leads the way to new therapies. Int J Mol Sci. 2017;18:1–24. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    BDNF+/- mice show less dendritic branching and dendritic retraction and simplification in CA3 and dentate gyrus, and dysregulation of BDNF/TrkB pathways has been reported in major depressive disorder and animal models of depression.

    “BDNF+/− mice show less dendritic branching as well as dendritic retraction and simplification in CA381 and DG80 and dysregulation of BDNF/TrkB pathways has been reported in MDD and animal models of depression78, 169-171.”
    Quote in the paperSubstantial claim0 of 6 sources checked
    • cites [81] Magariños AM, Li CJ, Gal Toth J, Bath KG, Jing D, Lee FS, et al. Effect of brain-derived neurotrophic factor haploinsufficiency on stress-induced remodeling of hippocampal neurons. Hippocampus. 2011;21:253–64. source

      Not checked in the free run.

    • cites [80] Chen ZY, Jing D, Bath KG, Ieraci A, Khan T, Siao CJ, et al. Genetic variant BDNF (Val66Met) polymorphism alters anxiety-related behavior. Science. 2006;314:140–3. source

      Not checked in the free run.

    • cites [78] Strauss J, Barr CL, George CJ, Ryan CM, King N, Shaikh S, et al. BDNF and COMT polymorphisms: relation to memory phenotypes in young adults with childhood-onset mood disorder. Neuromolecular Med. 2004;5:181–92. source

      Not checked in the free run.

    • cites [169] Martinowich K, Lu B. Interaction between BDNF and serotonin: role in mood disorders. Neuropsychopharmacology. 2008;33:73–83. source

      Not checked in the free run.

    • cites [170] Kim YK, Lee HP, Won SD, Park EY, Lee HY, Lee BH, et al. Low plasma BDNF is associated with suicidal behavior in major depression. Prog Neuropsychopharmacol Biol Psychiatry. 2007;31:78–85. source

      Not checked in the free run.

    • cites [171] Xu Y, Ku B, Tie L, Yao H, Jiang W, Ma X, et al. Curcumin reverses the effects of chronic stress on behavior, the HPA axis, BDNF expression and phosphorylation of CREB. Brain Res. 2006;1122:56–64. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Normal stress responses involve glutamate release that downregulates AMPA and NMDA receptor expression, glutamate clearance by glia, and less dendritic spine and process complexity.

    “Normal stress responses involve glutamate release which downregulates AMPA and NMDA receptor expression, glutamate clearance by glia, and less dendritic spine and process complexity163, 164.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [163] Floriou-Servou A, von Ziegler L, Waag R, Schläppi C, Germain PL, Bohacek J. The acute stress response in the multiomic era. Biol Psychiatry. 2021;89:1116–26. source

      Not checked in the free run.

    • cites [164] Bernard R, Kerman IA, Thompson RC, Jones EG, Bunney WE, Barchas JD, et al. Altered expression of glutamate signaling, growth factor, and glia genes in the locus coeruleus of patients with major depression. Mol Psychiatry. 2011;16:634–46. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Lower glutamate may be an antidepressant effect and not part of major depressive disorder pathogenesis.

    “As such, lower glutamate may be an antidepressant effect and not part of MDD pathogenesis.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    Antidepressant-induced upregulation of LTP and downregulation of LTD may improve network activity, cognition, and behavior.

    “This may upregulate LTP pathways, and downregulate LTD177, 178, having benefits on network activity and consequently cognition and behavior.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [177] Kraus C, Castrén E, Kasper S, Lanzenberger R. Serotonin and neuroplasticity - Links between molecular, functional and structural pathophysiology in depression. Neurosci Biobehav Rev. 2017;77:317–26. source

      Not checked in the free run.

    • cites [178] Fales CL, Barch DM, Rundle MM, Mintun MA, Mathews J, Snyder AZ, et al. Antidepressant treatment normalizes hypoactivity in dorsolateral prefrontal cortex during emotional interference processing in major depression. J Affect Disord. 2009;112:206–11. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Interpretationreasoning

    Dendritic retraction may be an adaptive way to protect neurons from high glutamate transmission, resulting in less long-term potentiation and cognitive decline.

    “Dendritic retraction may be an adaptive way to protect neurons from high glutamate transmission, resulting in less LTP and cognitive decline.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Exposure to stress attenuates long-term potentiation in dorsal hippocampus but augments it in ventral hippocampus of rodents, which may explain memory deficits in the presence of strong emotional responses.

    “Exposure to stress attenuates LTP in dorsal hippocampus but augments LTP in ventral hippocampus of rodents150, which may explain memory deficits in the presence of strong emotional responses.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [150] Kuhn M, Mainberger F, Feige B, Maier JG, Mall V, Jung NH, et al. State-dependent partial occlusion of cortical LTP-like plasticity in major depression. Neuropsychopharmacology. 2016;41:2794. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Rodent hippocampal neuron infusion with ketamine causes dose-dependent apoptosis that rapamycin rescues.

    “In fact, rodent studies have shown that infusion of ketamine onto hippocampal neurons caused dose-dependent apoptosis, which was rescued by incubation with rapamycin (an inhibitor of mTOR), suggesting context-dependent benefits of ketamine196.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [196] Zorumski CF, Izumi Y, Mennerick S. Ketamine: NMDA receptors and beyond. J Neurosci. 2016;36:11158–64. source

      Not checked in the free run.

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

    Premisecitation

    Psychedelic drugs likely act through 5-HT2A receptors.

    “Psychedelic drugs likely work via 5-HT2A receptors but require more research to elucidate their antidepressant effects202.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [202] Lenze EJ, Nicol GE, Barbour DL, Kannampallil T, Wong AWK, Piccirillo J, et al. Precision clinical trials: a framework for getting to precision medicine for neurobehavioural disorders. J Psychiatry Neurosci. 2021;46:E97–110. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Antidepressant treatment increases neurogenesis above normal levels, allowing mature granule neurons in major depressive disorder to regain control levels.

    “This suggests an increase in neurogenesis over normal levels that allows a catchup in mature granule neurons in MDD to regain levels seen in controls62, 121.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [62] Boldrini M, Santiago AN, Hen R, Dwork AJ, Rosoklija GB, Tamir H, et al. Hippocampal granule neuron number and dentate gyrus volume in antidepressant-treated and untreated major depression. Neuropsychopharmacology. 2013;38:1068–77. source

      Not checked in the free run.

    • cites [121] Duman RS, Nakagawa S, Malberg J. Regulation of adult neurogenesis by antidepressant treatment. Neuropsychopharmacology. 2001;25:836–44. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In rodent models of depression, ketamine administration increases dendritic spine density, length, arborization, and morphological complexity in CA1 pyramidal neurons.

    “Rodent models of depression show that ketamine administration increases dendritic spine density, length, arborization and morphology in CA1 pyramidal neurons201.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [201] Artin H, Zisook S, Ramanathan D. How do serotonergic psychedelics treat depression: the potential role of neuroplasticity. World J Psychiatry. 2021;11:201–14. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Blood levels of sertraline can be predicted by analyzing genes involved in sertraline metabolism, which indicates drug effectiveness.

    “Recent studies suggest that blood levels of sertraline, a common first-line antidepressant, can successfully be predicted through analysis of genes involved in sertraline metabolism and thus, giving an indication of drug effectiveness204-206.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [204] Islam F, Gorbovskaya I, Müller DJ. Pharmacogenetic/pharmacogenomic tests for treatment prediction in depression. Adv Exp Med Biol. 2021;1305:231–55. source

      Not checked in the free run.

    • cites [205] Claudio-Campos K, Padrón A, Jerkins G, Nainaparampil J, Nelson R, Martin A, et al. Acceptability, feasibility, and utility of integrating pharmacogenetic testing into a child psychiatry clinic. Clin Transl Sci. 2021;14:589–98. source

      Not checked in the free run.

    • cites [206] Barrenschee M, Lange C, Cossais F, Egberts JH, Becker T, Wedel T, et al. Expression and function of Neuregulin 1 and its signaling system ERBB2/3 in the enteric nervous system. Front Cell Neurosci. 2015;9:360. source

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55 of 55

  • The paper relies on this without support.

    Antidepressant medications are pharmacologically active within hours, but their antidepressant effects are not apparent for weeks after starting treatment.

    “First, although these medications are pharmacologically active within hours, their antidepressant effects are not apparent for weeks after starting treatment.”

  • The paper relies on this without support.

    Even when antidepressants have meaningful pharmacologic effects, many patients do not improve.

    “Second, even when the medications are having meaningful pharmacologic effects, many patients do not improve.”

  • The authors state this as an assumption.

    The effects of antidepressants depend on downstream processes, such as increased neurogenesis, that take time to appear and are robust only in medication responders.

    “The most widely accepted response to both questions is to assume that the effects of antidepressants are dependent on downstream processes, such as an increase in neurogenesis, that take time to appear and are only robust in medication responders.”

  • The paper relies on this without support.

    High concentrations of hippocampal glucocorticoid receptors make the hippocampus particularly vulnerable to allostatic load.

    “Third, given its role in HPA axis regulation, the high concentrations of hippocampal glucocorticoid receptors make it particularly vulnerable to allostatic load.”

  • The paper relies on this without support.

    Hippocampal volume loss is not pathognomonic for depression and can occur in the presence of environmental stressors, other psychiatric conditions, and neurodegenerative diseases.

    “Hippocampal volume loss is not pathognomonic for depression and can occur in the presence of environmental stressors, other psychiatric conditions, and neurodegenerative diseases.”

  • The paper relies on this without support.

    Traditional antidepressants act on the monoaminergic system to increase synaptic monoamine neurotransmitter levels.

    “As previously discussed, traditional antidepressants target the monoaminergic system to increase levels of monoaminergic neurotransmitters in the synapse.”

  • The paper relies on this without support.

    To increase LTP, some NMDA receptors must remain available.

    “The dosage and affinity are important because, to increase LTP, some NMDA receptors must be available.”

  • The paper relies on this without support.

    Neuroplasticity is integral to healthy cognitive and affective functioning.

    “Neuroplasticity is integral to healthy cognitive and affective functioning.”

  • The paper relies on this without support.

    Major depressive disorder clinical heterogeneity remains poorly understood, particularly how it relates to pathogenesis and treatment choices.

    “MDD clinical heterogeneity remains poorly understood, particularly in terms of how it relates to pathogenesis and implications for treatment choices.”

  • The paper relies on this without support.

    The duration or presence of major depression correlates with declines in neuroplasticity.

    “While duration or presence of major depression correlates with declines in neuroplasticity, administration of antidepressants may reverse some of the neurobiological changes observed in MDD (Figure 4).”
10 of 10

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?

  • Glutamate serves as the principal excitatory neurotransmitter and the primary molecular interface between acute cellular activation and longer-term synaptic remodeling.

    “Within this framework, glutamate serves as the principal excitatory neurotransmitter and the primary molecular interface between acute cellular activation and longer-term synaptic remodeling [38,39].”

    From Synaptic Plasticity—Intrinsic Excitability and Antidepressant Discovery (2026) · cites this paper as [39]

    The Molecular and Cellular Mechanisms of Neuroplasticity section (page not provided) says glutamatergic signaling affects excitatory postsynaptic potentials and LTP, and describes receptor activation leading to enduring synaptic changes. It does not establish glutamate as the principal excitatory neurotransmitter or the primary molecular interface between acute activation and longer-term remodeling; those superlatives go beyond the passage. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • Adult dentate gyrus neurogenesis occurs at least in nonhuman animals, and new granule cells may contribute to depression and antidepressant actions.

    “The dentate gyrus is a unique source of ongoing neurogenesis in the adult brain, at least in nonhuman animals, and there is preclinical evidence that the birth and maturation of new granule cells may play a role in depression and antidepressant drug actions [89].”

    From Plasticity of synapses and reward circuit function in the genesis and treatment of depression (2023) · cites this paper as [89]

Cites

Flagged first, then by citations

10 of the 227 references couldn’t be matched to a known paper.

Research works printed but not linked: 1

  1. Delgado PL. Depression: the case for a monoamine deficiency. J Clin Psychiatry. 2000;61 Suppl 6:7–11.

Cited by

Sorted by citations

Related

Authors
Tartt, A. N., Mariani, M. B., Hen, R., Mann, J. J., & Boldrini, M.
Affiliations
  • Stanford Medicine (US)
  • Columbia University (US)
  • New York State Psychiatric Institute (US)
  • Columbia University Irving Medical Center (US)
Corresponding author
Boldrini, Maura
ORCID
Venue
Molecular Psychiatry
Publisher
Springer Science and Business Media LLC
Published
2022-03-30
Volume
27
Issue
6
Pages
2689-2699
ISSN
  • 1359-4184 (ISSN-L)
  • 1476-5578
DOI
10.1038/s41380-022-01520-y
PMC
PMC9167750
OpenAlex
W4221105875
Cited by
408
References
227
Citations by year
2026: 94 · 2025: 127 · 2024: 115 · 2023: 54 · 2022: 18
FWCI
11.28
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Psychiatry (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institute on Aging (R56AG063372, R01AG076949)
  • National Institute of Mental Health (R01MH083862, R21MH094888)
  • National Institute of Allergy and Infectious Diseases (R21AI164769)
Topics
  • Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
  • Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
Keywords
major depressive disorder, hippocampal plasticity, adult hippocampal neurogenesis, antidepressant mechanism, synaptic plasticity, depression pathogenesis, depression treatment
MeSH terms
Adult, Antidepressive Agents, Depression, Depressive Disorder, Major, Major Depressive Disorder, Hippocampus, Humans, Neuronal Plasticity

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Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-05.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-05.

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