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

Molecular Psychiatry volume 27, pages 2689–2699 (2022)Cite this article

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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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Fig. 1: Hippocampus anatomy.
Fig. 2: Mechanisms of synaptic plasticity.
Fig. 3: Molecular regulators of neuroplasticity.
Fig. 4: Before and after treatment.

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References

  1. Friedrich MJ. Depression is the leading cause of disability around the world. JAMA. 2017;317:1517.

    PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  3. Mulinari S. Monoamine theories of depression: historical impact on biomedical research. J Hist Neurosci. 2012;21:366–92.

    Article  PubMed  Google Scholar 

  4. Owens MJ. Selectivity of antidepressants: from the monoamine hypothesis of depression to the SSRI revolution and beyond. J Clin Psychiatry. 2004;65 Suppl 4:5–10.

    CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  6. Mikolas P, Tozzi L, Doolin K, Farrell C, O’Keane V, Frodl T. Effects of early life adversity and FKBP5 genotype on hippocampal subfields volume in major depression. J Affect Disord. 2019;252:152–9.

    Article  CAS  PubMed  Google Scholar 

  7. Lambert HK, Peverill M, Sambrook KA, Rosen ML, Sheridan MA, McLaughlin KA. Altered development of hippocampus-dependent associative learning following early-life adversity. Dev Cogn Neurosci. 2019;38:100666.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Pacheco A, Aguayo FI, Aliaga E, Muñoz M, García-Rojo G, Olave FA, et al. Chronic stress triggers expression of immediate early genes and differentially affects the expression of AMPA and NMDA subunits in dorsal and ventral hippocampus of rats. Front Mol Neurosci. 2017;10:244.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Sheline YI, Liston C, McEwen BS. Parsing the hippocampus in depression: chronic stress, hippocampal volume, and major depressive disorder. Biol Psychiatry. 2019;85:436–8.

    Article  PubMed  Google Scholar 

  10. Ruiz NAL, Del Ángel DS, Olguín HJ, Silva ML. Neuroprogression: the hidden mechanism of depression. Neuropsychiatr Dis Treat. 2018;14:2837–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Kvichansky AA, Tret’yakova LV, Volobueva MN, Manolova AO, Stepanichev MY, Onufriev MV, et al. Neonatal proinflammatory stress and expression of neuroinflammation-associated genes in the rat hippocampus. Biochemistry. 2021;86:693–703.

    CAS  PubMed  Google Scholar 

  12. Bienkowski MS, Bowman I, Song MY, Gou L, Ard T, Cotter K, et al. Integration of gene expression and brain-wide connectivity reveals the multiscale organization of mouse hippocampal networks. Nat Neurosci. 2018;21:1628–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Alaerts K, Bernaerts S, Vanaudenaerde B, Daniels N, Wenderoth N. Amygdala-hippocampal connectivity is associated with endogenous levels of oxytocin and can be altered by exogenously administered oxytocin in adults with autism. Biol Psychiatry Cogn Neurosci Neuroimaging. 2019;4:655–63.

    PubMed  Google Scholar 

  14. Liu B, Liu J, Wang M, Zhang Y, Li L. From serotonin to neuroplasticity: evolvement of theories for major depressive disorder. Front Cell Neurosci. 2017;11:305.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Price RB, Duman R. Neuroplasticity in cognitive and psychological mechanisms of depression: an integrative model. Mol Psychiatry. 2020;25:530–43.

    Article  PubMed  Google Scholar 

  16. Sanchez-Mendoza EH, Camblor-Perujo S, Martins Nascentes-Melo L, Dzyubenko E, Fleischer M, Silva de Carvalho T, et al. Compromised hippocampal neuroplasticity in the interferon-α and toll-like receptor-3 activation-induced mouse depression model. Mol Neurobiol. 2020;57:3171–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  19. Eriksson PS, Perfilieva E, Björk-Eriksson T, Alborn AM, Nordborg C, Peterson DA, et al. Neurogenesis in the adult human hippocampus. Nat Med. 1998;4:1313–7.

    Article  CAS  PubMed  Google Scholar 

  20. Boldrini M, Fulmore CA, Tartt AN, Simeon LR, Pavlova I, Poposka V, et al. Human hippocampal neurogenesis persists throughout aging. Cell Stem Cell. 2018;22:589–99.e5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Oquendo MA, Barrera A, Ellis SP, Li S, Burke AK, Grunebaum M, et al. Instability of symptoms in recurrent major depression: a prospective study. Am J Psychiatry. 2004;161:255–61.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  40. Matsuo K, Glahn DC, Peluso MA, Hatch JP, Monkul ES, Najt P, et al. Prefrontal hyperactivation during working memory task in untreated individuals with major depressive disorder. Mol Psychiatry. 2007;12:158–66.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  43. Fox MD, Snyder AZ, Vincent JL, Corbetta M, Van Essen DC, Raichle ME. The human brain is intrinsically organized into dynamic, anticorrelated functional networks. Proc Natl Acad Sci USA. 2005;102:9673–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Zetsche U, D’Avanzato C, Joormann J. Depression and rumination: relation to components of inhibition. Cogn Emot. 2012;26:758–67.

    Article  PubMed  Google Scholar 

  45. Joormann J, Levens SM, Gotlib IH. Sticky thoughts: depression and rumination are associated with difficulties manipulating emotional material in working memory. Psychol Sci. 2011;22:979–83.

    Article  PubMed  Google Scholar 

  46. Lewis EJ, Blanco I, Raila H, Joormann J. Does repetitive negative thinking affect attention? Differential effects of worry and rumination on attention to emotional stimuli. Emotion. 2019;19:1450–62.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  49. Nolen-Hoeksema S, Morrow J, Fredrickson BL. Response styles and the duration of episodes of depressed mood. J Abnorm Psychol. 1993;102:20–8.

    Article  CAS  PubMed  Google Scholar 

  50. Disner SG, Beevers CG, Haigh EA, Beck AT. Neural mechanisms of the cognitive model of depression. Nat Rev Neurosci. 2011;12:467–77.

    Article  CAS  PubMed  Google Scholar 

  51. Hamilton JP, Gotlib IH. Neural substrates of increased memory sensitivity for negative stimuli in major depression. Biol Psychiatry. 2008;63:1155–62.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  55. Rusch BD, Abercrombie HC, Oakes TR, Schaefer SM, Davidson RJ. Hippocampal morphometry in depressed patients and control subjects: relations to anxiety symptoms. Biol Psychiatry. 2001;50:960–4.

    Article  CAS  PubMed  Google Scholar 

  56. Vakili K, Pillay SS, Lafer B, Fava M, Renshaw PF, Bonello-Cintron CM, et al. Hippocampal volume in primary unipolar major depression: a magnetic resonance imaging study. Biol Psychiatry. 2000;47:1087–90.

    Article  CAS  PubMed  Google Scholar 

  57. Ashtari M, Greenwald BS, Kramer-Ginsberg E, Hu J, Wu H, Patel M, et al. Hippocampal/amygdala volumes in geriatric depression. Psychol Med. 1999;29:629–38.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  68. Yuan M, Rubin-Falcone H, Lin X, Rizk MM, Miller JM, Sublette ME, et al. Smaller left hippocampal subfield CA1 volume is associated with reported childhood physical and/or sexual abuse in major depression: a pilot study. J Affect Disord. 2020;272:348–54.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Lopez JP, Mamdani F, Labonte B, Beaulieu MM, Yang JP, Berlim MT, et al. Epigenetic regulation of BDNF expression according to antidepressant response. Mol Psychiatry. 2013;18:398–9.

    Article  CAS  PubMed  Google Scholar 

  74. Tsankova NM, Berton O, Renthal W, Kumar A, Neve RL, Nestler EJ. Sustained hippocampal chromatin regulation in a mouse model of depression and antidepressant action. Nat Neurosci. 2006;9:519–25.

    Article  CAS  PubMed  Google Scholar 

  75. Waterhouse EG, An JJ, Orefice LL, Baydyuk M, Liao GY, Zheng K, et al. BDNF promotes differentiation and maturation of adult-born neurons through GABAergic transmission. J Neurosci. 2012;32:14318–30.

    Article  PubMed  PubMed Central  Google Scholar 

  76. Li H, Lin LY, Zhang Y, Lim Y, Rahman M, Beck A, et al. Pro-BDNF knockout causes abnormal motor behaviours and early death in mice. Neuroscience. 2020;438:145–57.

    Article  CAS  PubMed  Google Scholar 

  77. Takei N, Nawa H. mTOR signaling and its roles in normal and abnormal brain development. Front Mol Neurosci. 2014;7:28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  82. Kosten TA, Galloway MP, Duman RS, Russell DS, D’Sa C. Repeated unpredictable stress and antidepressants differentially regulate expression of the bcl-2 family of apoptotic genes in rat cortical, hippocampal, and limbic brain structures. Neuropsychopharmacology. 2008;33:1545–58.

    Article  CAS  PubMed  Google Scholar 

  83. Luo C, Xu H, Li XM. Post-stress changes in BDNF and Bcl-2 immunoreactivities in hippocampal neurons: effect of chronic administration of olanzapine. Brain Res. 2004;1025:194–202.

    Article  CAS  PubMed  Google Scholar 

  84. Zeng D, He S, Ma C, Wen Y, Song W, Xu Q, et al. Network-based approach to identify molecular signatures in the brains of depressed suicides. Psychiatry Res. 2020;294:113513.

    Article  CAS  PubMed  Google Scholar 

  85. Amidfar M, Kim YK, Scaini G, Quevedo J. Evidence for additionally increased apoptosis in the peripheral blood mononuclear cells of major depressive patients with a high risk for suicide. Am J Med Genet B Neuropsychiatr Genet. 2018;177:388–96.

    Article  CAS  PubMed  Google Scholar 

  86. Zhang H, Wei M, Lu X, Sun Q, Wang C, Zhang J, et al. Aluminum trichloride caused hippocampal neural cells death and subsequent depression-like behavior in rats via the activation of IL-1β/JNK signaling pathway. Sci Total Environ. 2020;715:136942.

    Article  CAS  PubMed  Google Scholar 

  87. Moxon LN, Rose SE, Haseler LJ, Galloway GJ, Brereton IM, Bore P, et al. The visibility of the 1H NMR signal of ethanol in the dog brain. Magn Reson Med. 1991;19:340–8.

    Article  CAS  PubMed  Google Scholar 

  88. Niklison-Chirou MV, Agostini M, Amelio I, Melino G. Regulation of adult neurogenesis in mammalian brain. Int J Mol Sci. 2020;21:2–21

    Article  CAS  Google Scholar 

  89. Urbán N, Guillemot F. Neurogenesis in the embryonic and adult brain: same regulators, different roles. Front Cell Neurosci. 2014;8:396.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  99. Terreros-Roncal J, Moreno-Jiménez EP, Flor-García M, Rodríguez-Moreno CB, Trinchero MF, Cafini F, et al. Impact of neurodegenerative diseases on human adult hippocampal neurogenesis. Science. 2021;374:1106–13.

    Article  CAS  PubMed  Google Scholar 

  100. Tobin MK, Musaraca K, Disouky A, Shetti A, Bheri A, Honer WG, et al. Human hippocampal neurogenesis persists in aged adults and Alzheimer’s disease patients. Cell Stem Cell. 2019;24:974–82.e3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Spalding KL, Bergmann O, Alkass K, Bernard S, Salehpour M, Huttner HB, et al. Dynamics of hippocampal neurogenesis in adult humans. Cell. 2013;153:1219–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  104. Flor-García M, Terreros-Roncal J, Moreno-Jiménez EP, Ávila J, Rábano A, Llorens-Martín M. Unraveling human adult hippocampal neurogenesis. Nat Protoc. 2020;15:668–93.

    Article  PubMed  CAS  Google Scholar 

  105. Duque A, Arellano JI, Rakic P. An assessment of the existence of adult neurogenesis in humans and value of its rodent models for neuropsychiatric diseases. Mol Psychiatry. 2021. https://doi.org/10.1038/s41380-021-01314-8.

  106. Rakic P. Limits of neurogenesis in primates. Science. 1985;227:1054–6.

    Article  CAS  PubMed  Google Scholar 

  107. Garthe A, Behr J, Kempermann G. Adult-generated hippocampal neurons allow the flexible use of spatially precise learning strategies. PLoS ONE. 2009;4:e5464.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  108. Kempermann G. New neurons for ‘survival of the fittest’. Nat Rev Neurosci. 2012;13:727–36.

    Article  CAS  PubMed  Google Scholar 

  109. Kempermann G. Adult neurogenesis: an evolutionary perspective. Cold Spring Harb Perspect Biol. 2015;8:a018986.

    Article  PubMed  Google Scholar 

  110. Sun W, Winseck A, Vinsant S, Park OH, Kim H, Oppenheim RW. Programmed cell death of adult-generated hippocampal neurons is mediated by the proapoptotic gene Bax. J Neurosci. 2004;24:11205–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  113. Burghardt NS, Park EH, Hen R, Fenton AA. Adult-born hippocampal neurons promote cognitive flexibility in mice. Hippocampus. 2012;22:1795–808.

    Article  PubMed  PubMed Central  Google Scholar 

  114. Snyder JS, Hong NS, McDonald RJ, Wojtowicz JM. A role for adult neurogenesis in spatial long-term memory. Neuroscience. 2005;130:843–52.

    Article  CAS  PubMed  Google Scholar 

  115. Clelland CD, Choi M, Romberg C, Clemenson GD, Fragniere A, Tyers P, et al. A functional role for adult hippocampal neurogenesis in spatial pattern separation. Science. 2009;325:210–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Sahay A, Wilson DA, Hen R. Pattern separation: a common function for new neurons in hippocampus and olfactory bulb. Neuron. 2011;70:582–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, Dulawa S, et al. Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science. 2003;301:805–9.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Pereira Dias G, Hollywood R, Bevilaqua MC, da Luz AC, Hindges R, Nardi AE, et al. Consequences of cancer treatments on adult hippocampal neurogenesis: implications for cognitive function and depressive symptoms. Neuro Oncol. 2014;16:476–92.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  131. Egeland M, Guinaudie C, Du Preez A, Musaelyan K, Zunszain PA, Fernandes C, et al. Depletion of adult neurogenesis using the chemotherapy drug temozolomide in mice induces behavioural and biological changes relevant to depression. Transl Psychiatry. 2017;7:e1101.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Bear MF, Malenka RC. Synaptic plasticity: LTP and LTD. Curr Opin Neurobiol. 1994;4:389–99.

    Article  CAS  PubMed  Google Scholar 

  133. Kaminska M, Harris J, Gijsbers K, Dubrovsky B. Dehydroepiandrosterone sulfate (DHEAS) counteracts decremental effects of corticosterone on dentate gyrus LTP. Implications for depression. Brain Res Bull. 2000;52:229–34.

    Article  CAS  PubMed  Google Scholar 

  134. Jay TM, Rocher C, Hotte M, Naudon L, Gurden H, Spedding M. Plasticity at hippocampal to prefrontal cortex synapses is impaired by loss of dopamine and stress: importance for psychiatric diseases. Neurotox Res. 2004;6:233–44.

    Article  PubMed  Google Scholar 

  135. Huganir RL, Nicoll RA. AMPARs and synaptic plasticity: the last 25 years. Neuron. 2013;80:704–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Collingridge GL, Isaac JT, Wang YT. Receptor trafficking and synaptic plasticity. Nat Rev Neurosci. 2004;5:952–62.

    Article  CAS  PubMed  Google Scholar 

  137. Citri A, Malenka RC. Synaptic plasticity: multiple forms, functions, and mechanisms. Neuropsychopharmacology. 2008;33:18–41.

    Article  PubMed  Google Scholar 

  138. Costa-Mattioli M, Sossin WS, Klann E, Sonenberg N. Translational control of long-lasting synaptic plasticity and memory. Neuron. 2009;61:10–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Malenka RC, Bear MF. LTP and LTD: an embarrassment of riches. Neuron. 2004;44:5–21.

    Article  CAS  PubMed  Google Scholar 

  140. Mayford M, Siegelbaum SA, Kandel ER. Synapses and memory storage. Cold Spring Harb Perspect Biol 2012;4:1–18.

    Article  CAS  Google Scholar 

  141. Bourtchuladze R, Frenguelli B, Blendy J, Cioffi D, Schutz G, Silva AJ. Deficient long-term memory in mice with a targeted mutation of the cAMP-responsive element-binding protein. Cell. 1994;79:59–68.

    Article  CAS  PubMed  Google Scholar 

  142. Won J, Silva AJ. Molecular and cellular mechanisms of memory allocation in neuronetworks. Neurobiol Learn Mem. 2008;89:285–92.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  144. Tanaka J, Horiike Y, Matsuzaki M, Miyazaki T, Ellis-Davies GC, Kasai H. Protein synthesis and neurotrophin-dependent structural plasticity of single dendritic spines. Science. 2008;319:1683–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Lu B, Nagappan G, Lu Y. BDNF and synaptic plasticity, cognitive function, and dysfunction. Handb Exp Pharmacol. 2014;220:223–50.

    Article  CAS  PubMed  Google Scholar 

  146. Huang CC, Chu CY, Yeh CM, Hsu KS. Acute hypernatremia dampens stress-induced enhancement of long-term potentiation in the dentate gyrus of rat hippocampus. Psychoneuroendocrinology. 2014;46:129–40.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  153. Moghaddam B. Stress preferentially increases extraneuronal levels of excitatory amino acids in the prefrontal cortex: comparison to hippocampus and basal ganglia. J Neurochem. 1993;60:1650–7.

    Article  CAS  PubMed  Google Scholar 

  154. John CS, Smith KL, Van’t Veer A, Gompf HS, Carlezon WA, Cohen BM, et al. Blockade of astrocytic glutamate uptake in the prefrontal cortex induces anhedonia. Neuropsychopharmacology. 2012;37:2467–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Gleichmann M, Mattson MP. Neuronal calcium homeostasis and dysregulation. Antioxid Redox Signal. 2011;14:1261–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Küçükibrahimoğlu E, Saygin MZ, Calişkan M, Kaplan OK, Unsal C, Gören MZ. The change in plasma GABA, glutamine and glutamate levels in fluoxetine- or S-citalopram-treated female patients with major depression. Eur J Clin Pharmacol. 2009;65:571–7.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  165. Duric V, Banasr M, Stockmeier CA, Simen AA, Newton SS, Overholser JC, et al. Altered expression of synapse and glutamate related genes in post-mortem hippocampus of depressed subjects. Int J Neuropsychopharmacol. 2013;16:69–82.

    Article  CAS  PubMed  Google Scholar 

  166. Lisman J, Raghavachari S. A unified model of the presynaptic and postsynaptic changes during LTP at CA1 synapses. Sci STKE. 2006;2006:re11.

    Article  PubMed  Google Scholar 

  167. Bourne JN, Harris KM. Balancing structure and function at hippocampal dendritic spines. Annu Rev Neurosci. 2008;31:47–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Balu DT, Hoshaw BA, Malberg JE, Rosenzweig-Lipson S, Schechter LE, Lucki I. Differential regulation of central BDNF protein levels by antidepressant and non-antidepressant drug treatments. Brain Res. 2008;1211:37–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  172. Laifenfeld D, Karry R, Grauer E, Klein E, Ben-Shachar D. Antidepressants and prolonged stress in rats modulate CAM-L1, laminin, and pCREB, implicated in neuronal plasticity. Neurobiol Dis. 2005;20:432–41.

    Article  CAS  PubMed  Google Scholar 

  173. Grønli J, Bramham C, Murison R, Kanhema T, Fiske E, Bjorvatn B, et al. Chronic mild stress inhibits BDNF protein expression and CREB activation in the dentate gyrus but not in the hippocampus proper. Pharmacol Biochem Behav. 2006;85:842–9.

    Article  PubMed  CAS  Google Scholar 

  174. Price JL, Drevets WC. Neurocircuitry of mood disorders. Neuropsychopharmacology. 2010;35:192–216.

    Article  PubMed  Google Scholar 

  175. Ho VM, Lee JA, Martin KC. The cell biology of synaptic plasticity. Science. 2011;334:623–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  179. Sullivan CRP, Olsen S, Widge AS. Deep brain stimulation for psychiatric disorders: From focal brain targets to cognitive networks. Neuroimage. 2021;225:117515.

    Article  PubMed  Google Scholar 

  180. Schlaepfer TE, Bewernick BH, Kayser S, Hurlemann R, Coenen VA. Deep brain stimulation of the human reward system for major depression-rationale, outcomes and outlook. Neuropsychopharmacology. 2014;39:1303–14.

    Article  PubMed  PubMed Central  Google Scholar 

  181. McIntyre CC, Hahn PJ. Network perspectives on the mechanisms of deep brain stimulation. Neurobiol Dis. 2010;38:329–37.

    Article  PubMed  Google Scholar 

  182. Wolkenstein L, Plewnia C. Amelioration of cognitive control in depression by transcranial direct current stimulation. Biol Psychiatry. 2013;73:646–51.

    Article  PubMed  Google Scholar 

  183. Smith R, Chen K, Baxter L, Fort C, Lane RD. Antidepressant effects of sertraline associated with volume increases in dorsolateral prefrontal cortex. J Affect Disord. 2013;146:414–9.

    Article  CAS  PubMed  Google Scholar 

  184. Arnone D, McKie S, Elliott R, Juhasz G, Thomas EJ, Downey D, et al. State-dependent changes in hippocampal grey matter in depression. Mol Psychiatry. 2013;18:1265–72.

    Article  CAS  PubMed  Google Scholar 

  185. Samann PG, Hohn D, Chechko N, Kloiber S, Lucae S, Ising M, et al. Prediction of antidepressant treatment response from gray matter volume across diagnostic categories. Eur Neuropsychopharmacol. 2013;23:1503–15.

    Article  PubMed  CAS  Google Scholar 

  186. Mitani H, Shirayama Y, Yamada T, Maeda K, Ashby CR, Kawahara R. Correlation between plasma levels of glutamate, alanine and serine with severity of depression. Prog Neuropsychopharmacol Biol Psychiatry. 2006;30:1155–8.

    Article  CAS  PubMed  Google Scholar 

  187. Locher C, Koechlin H, Zion SR, Werner C, Pine DS, Kirsch I, et al. Efficacy and safety of selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, and placebo for common psychiatric disorders among children and adolescents: a systematic review and meta-analysis. JAMA Psychiatry. 2017;74:1011–20.

    Article  PubMed  PubMed Central  Google Scholar 

  188. Wang SM, Han C, Lee SJ, Jun TY, Patkar AA, Masand PS, et al. Efficacy of antidepressants: bias in randomized clinical trials and related issues. Expert Rev Clin Pharmacol. 2018;11:15–25.

    Article  CAS  PubMed  Google Scholar 

  189. Zhang G, Stackman RW. The role of serotonin 5-HT2A receptors in memory and cognition. Front Pharmacol. 2015;6:225.

    Article  PubMed  PubMed Central  Google Scholar 

  190. Bouso JC, Dos Santos RG, Alcázar-Córcoles M, Hallak JEC. Serotonergic psychedelics and personality: A systematic review of contemporary research. Neurosci Biobehav Rev. 2018;87:118–32.

    Article  CAS  PubMed  Google Scholar 

  191. Zanos P, Gould TD. Mechanisms of ketamine action as an antidepressant. Mol Psychiatry. 2018;23:801–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Kadriu B, Greenwald M, Henter ID, Gilbert JR, Kraus C, Park LT, et al. Ketamine and serotonergic psychedelics: common mechanisms underlying the effects of rapid-acting antidepressants. Int J Neuropsychopharmacol. 2021;24:8–21.

    Article  CAS  PubMed  Google Scholar 

  193. Anis NA, Berry SC, Burton NR, Lodge D. The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N-methyl-aspartate. Br J Pharmacol. 1983;79:565–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Dravid SM, Erreger K, Yuan H, Nicholson K, Le P, Lyuboslavsky P, et al. Subunit-specific mechanisms and proton sensitivity of NMDA receptor channel block. J Physiol. 2007;581:107–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Liu FF, Zhao S, Liu P, Huo SP. Influence of mTOR signaling pathway on ketamine-induced injuries in the hippocampal neurons of rats. Neurol Res. 2019;41:77–86.

    Article  CAS  PubMed  Google Scholar 

  196. Zorumski CF, Izumi Y, Mennerick S. Ketamine: NMDA receptors and beyond. J Neurosci. 2016;36:11158–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Sattar Y, Wilson J, Khan AM, Adnan M, Azzopardi Larios D, Shrestha S, et al. A review of the mechanism of antagonism of N-methyl-D-aspartate receptor by ketamine in treatment-resistant depression. Cureus. 2018;10:e2652.

    PubMed  PubMed Central  Google Scholar 

  198. Aleksandrova LR, Phillips AG, Wang YT. Antidepressant effects of ketamine and the roles of AMPA glutamate receptors and other mechanisms beyond NMDA receptor antagonism. J Psychiatry Neurosci. 2017;42:222–9.

    Article  PubMed  PubMed Central  Google Scholar 

  199. Duman RS, Aghajanian GK. Synaptic dysfunction in depression: potential therapeutic targets. Science. 2012;338:68–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. Treccani G, Ardalan M, Chen F, Musazzi L, Popoli M, Wegener G, et al. S-Ketamine reverses hippocampal dendritic spine deficits in flinders sensitive line rats within 1 h of administration. Mol Neurobiol. 2019;56:7368–79.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  203. Shelton RC, Parikh SV, Law RA, Rothschild AJ, Thase ME, Dunlop BW, et al. Combinatorial pharmacogenomic algorithm is predictive of citalopram and escitalopram metabolism in patients with major depressive disorder. Psychiatry Res. 2020;290:113017.

    Article  CAS  PubMed  Google Scholar 

  204. Islam F, Gorbovskaya I, Müller DJ. Pharmacogenetic/pharmacogenomic tests for treatment prediction in depression. Adv Exp Med Biol. 2021;1305:231–55.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  207. Gheibihayat SM, Cabezas R, Nikiforov NG, Jamialahmadi T, Johnston TP, Sahebkar A. CD47 in the brain and neurodegeneration: an update on the role in neuroinflammatory pathways. Molecules. 2021;26:1–15.

    Article  CAS  Google Scholar 

  208. Roman M, Irwin MR. Novel neuroimmunologic therapeutics in depression: a clinical perspective on what we know so far. Brain Behav Immun. 2020;83:7–21.

    Article  CAS  PubMed  Google Scholar 

  209. Howren MB, Lamkin DM, Suls J. Associations of depression with C-reactive protein, IL-1, and IL-6: a meta-analysis. Psychosom Med. 2009;71:171–86.

    Article  CAS  PubMed  Google Scholar 

  210. Zunszain PA, Anacker C, Cattaneo A, Choudhury S, Musaelyan K, Myint AM, et al. Interleukin-1β: a new regulator of the kynurenine pathway affecting human hippocampal neurogenesis. Neuropsychopharmacology. 2012;37:939–49.

    Article  CAS  PubMed  Google Scholar 

  211. Le-Niculescu H, Roseberry K, Gill SS, Levey DF, Phalen PL, Mullen J, et al. Precision medicine for mood disorders: objective assessment, risk prediction, pharmacogenomics, and repurposed drugs. Mol Psychiatry. 2021;26:2776–804.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  212. Scangos KW, Makhoul GS, Sugrue LP, Chang EF, Krystal AD. State-dependent responses to intracranial brain stimulation in a patient with depression. Nat Med. 2021;27:229–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  213. Modak A, Fitzgerald PB. Personalising transcranial magnetic stimulation for depression using neuroimaging: a systematic review. World J Biol Psychiatry. 2021;22:647–69.

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Stanford University School of Medicine, Stanford, CA, USA

    Alexandria N. Tartt

  2. Departments of Psychiatry, Columbia University, New York, NY, USA

    Madeline B. Mariani, Rene Hen, J. John Mann & Maura Boldrini

  3. Neuroscience, Columbia University, New York, NY, USA

    Rene Hen

  4. Pharmacology, Columbia University, New York, NY, USA

    Rene Hen

  5. Integrative Neuroscience, NYS Psychiatric Institute, New York, NY, USA

    Rene Hen

  6. Molecular Imaging and Neuropathology, NYS Psychiatric Institute, New York, NY, USA

    J. John Mann & Maura Boldrini

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Conception: AT and MB. Original draft—AT, MM, and MB. Clinical insights—JJM and MB. Editing: JJM and RH. All authors revised the literature, reviewed, edited, and approved the final version.

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Correspondence to Maura Boldrini.

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RH receives compensation as a consultant for Roche and Lundbeck; and JJM receives royalties for commercial use of the C-SSRS from the Research Foundation for Mental Hygiene.

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Tartt, A.N., Mariani, M.B., Hen, R. et al. Dysregulation of adult hippocampal neuroplasticity in major depression: pathogenesis and therapeutic implications. Mol Psychiatry 27, 2689–2699 (2022). https://doi.org/10.1038/s41380-022-01520-y

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