Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Molecular mechanisms in the regulation of adult neurogenesis during stress

Key Points

  • There is reciprocal regulation between adult neurogenesis and stress: adult neurogenesis can affect the stress response, and stress can modulate levels of adult neurogenesis.

  • One potential mechanism by which adult neurogenesis could regulate the stress response is through the neurogenesis-dependent modulation of perception of novel events, which would then influence whether events are perceived as stressful.

  • Many pathways that affect adult neurogenesis are also modulated by stress, including the cytokine, neurotrophic factor and morphogen signalling pathways. However, glucocorticoid hormones are undoubtedly the most important group of molecules in this context.

  • The glucocorticoid receptor signalling pathway can be modulated through several mechanisms, both upstream and downstream of the glucocorticoid receptor; all of these mechanisms can potentially modulate the effects of stress on neurogenesis.

  • Glucocorticoid receptor signalling pathways may be modified during stress through crosstalk with other stress-regulated pathways, indicating that the dynamics of the regulation of adult neurogenesis by stress are highly complex.


Coping with stress is fundamental for mental health, but understanding of the molecular neurobiology of stress is still in its infancy. Adult neurogenesis is well known to be regulated by stress, and conversely adult neurogenesis regulates stress responses. Recent studies in neurogenic cells indicate that molecular pathways activated by glucocorticoids, the main stress hormones, are modulated by crosstalk with other stress-relevant mechanisms, including inflammatory mediators, neurotrophic factors and morphogen signalling pathways. This Review discusses the pathways that are involved in this crosstalk and thus regulate this complex relationship between adult neurogenesis and stress.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Theory of contextual emotional processing in stress perception.
Figure 2: Expression of glucocorticoid receptors and mineralocorticoid receptors during hippocampal neurogenesis in mice.
Figure 3: Modulation of glucocorticoid and glucocorticoid receptor activity.
Figure 4: Potential crosstalk mechanisms relevant to stress and neurogenesis.


  1. 1

    Spalding, K. L. et al. Dynamics of hippocampal neurogenesis in adult humans. Cell 153, 1219–1227 (2013). The authors take advantage of known fluctuations in atmospheric 14C to quantify the rate of adult hippocampal neurogenesis in humans.

    CAS  PubMed  PubMed Central  Google Scholar 

  2. 2

    Welberg, L. A bombshell of a finding. Nature Rev. Neurosci. 14, 522 (2013).

    CAS  Google Scholar 

  3. 3

    Kempermann, G. New neurons for 'survival of the fittest'. Nature Rev. Neurosci. 13, 727–736 (2012).

    CAS  Google Scholar 

  4. 4

    Cameron, H. A. & Gould, E. Adult neurogenesis is regulated by adrenal steroids in the dentate gyrus. Neuroscience 61, 203–209 (1994). The first paper to investigate the possible link between stress and neurogenesis.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. 5

    Gould, E., McEwen, B. S., Tanapat, P., Galea, L. A. & Fuchs, E. Neurogenesis in the dentate gyrus of the adult tree shrew is regulated by psychosocial stress and NMDA receptor activation. J. Neurosci. 17, 2492–2498 (1997).

    CAS  PubMed  Google Scholar 

  6. 6

    Gould, E., Tanapat, P., McEwen, B. S., Flügge, G. & Fuchs, E. Proliferation of granule cell precursors in the dentate gyrus of adult monkeys is diminished by stress. Proc. Natl Acad. Sci. USA 95, 3168–3171 (1998).

    CAS  PubMed  Google Scholar 

  7. 7

    Schoenfeld, T. J. & Gould, E. Stress, stress hormones, and adult neurogenesis. Exp. Neurol. 233, 12–21 (2012).

    CAS  PubMed  Google Scholar 

  8. 8

    Tanapat, P., Hastings, N. B., Rydel, T. A., Galea, L. A. M. & Gould, E. Exposure to fox odor inhibits cell proliferation in the hippocampus of adult rats via an adrenal hormone-dependent mechanism. J. Comp. Neurol. 437, 496–504 (2001).

    CAS  PubMed  Google Scholar 

  9. 9

    Czéh, B. et al. Stress-induced changes in cerebral metabolites, hippocampal volume, and cell proliferation are prevented by antidepressant treatment with tianeptine. Proc. Natl Acad. Sci. USA 98, 12796–12801 (2001).

    PubMed  Google Scholar 

  10. 10

    Czéh, B. & Lucassen, P. J. What causes the hippocampal volume decrease in depression? Are neurogenesis, glial changes and apoptosis implicated? Eur. Arch. Psychiatry Clin. Neurosci. 257, 250–260 (2007).

    PubMed  Google Scholar 

  11. 11

    Ferragud, A. et al. Enhanced habit-based learning and decreased neurogenesis in the adult hippocampus in a murine model of chronic social stress. Behav. Brain Res. 210, 134–139 (2010).

    CAS  PubMed  Google Scholar 

  12. 12

    Pham, K., Nacher, J., Hof, P. R. & McEwen, B. S. Repeated restraint stress suppresses neurogenesis and induces biphasic PSA-NCAM expression in the adult rat dentate gyrus. Eur. J. Neurosci. 17, 879–886 (2003).

    PubMed  Google Scholar 

  13. 13

    Wong, E. Y. H. & Herbert, J. The corticoid environment: a determining factor for neural progenitors' survival in the adult hippocampus. Eur. J. Neurosci. 20, 2491–2498 (2004).

    PubMed  PubMed Central  Google Scholar 

  14. 14

    Mirescu, C. & Gould, E. Stress and adult neurogenesis. Hippocampus 16, 233–238 (2006).

    CAS  PubMed  Google Scholar 

  15. 15

    Mineur, Y. S., Belzung, C. & Crusio, W. E. Functional implications of decreases in neurogenesis following chronic mild stress in mice. Neuroscience 150, 251–259 (2007).

    CAS  PubMed  Google Scholar 

  16. 16

    Petrik, D., Lagace, D. C. & Eisch, A. J. The neurogenesis hypothesis of affective and anxiety disorders: are we mistaking the scaffolding for the building? Neuropharmacology 62, 21–34 (2011). A critical but balanced review of the correlations between neurogenesis, stress and depression; it summarizes the major findings up to the time of publication.

    PubMed  PubMed Central  Google Scholar 

  17. 17

    Snyder, J. S., Soumier, A., Brewer, M., Pickel, J. & Cameron, H. A. Adult hippocampal neurogenesis buffers stress responses and depressive behaviour. Nature 476, 458–461 (2011). A pivotal paper on the role of adult neurogenesis in the regulation of the stress response.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18

    Surget, A. et al. Antidepressants recruit new neurons to improve stress response regulation. Mol. Psychiatry 16, 1177–1188 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19

    Sahay, A., Wilson, D. A. & Hen, R. Pattern separation: a common function for new neurons in hippocampus and olfactory bulb. Neuron 70, 582–588 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20

    Aimone, J. B., Deng, W. & Gage, F. H. Resolving new memories: a critical look at the dentate gyrus, adult neurogenesis, and pattern separation. Neuron 70, 589–596 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21

    Kheirbek, M. A., Klemenhagen, K. C., Sahay, A. & Hen, R. Neurogenesis and generalization: a new approach to stratify and treat anxiety disorders. Nature Neurosci. 15, 1613–1620 (2012). A review on the role of neurogenesis in hippocampal function, particularly on the role of pattern separation in certain behavioural functions such as overgeneralization.

    CAS  PubMed  Google Scholar 

  22. 22

    Christian, K. M., Song, H. & Ming, G.-L. Functions and dysfunctions of adult hippocampal neurogenesis. Annu. Rev. Neurosci. 37, 243–262 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23

    Temprana, S. G. et al. Delayed coupling to feedback inhibition during a critical period for the integration of adult-born granule cells. Neuron 85, 116–130 (2015). This paper investigates novel properties of newborn neurons and demonstrates how these properties may enable specific functions related to information processing.

    CAS  PubMed  Google Scholar 

  24. 24

    Kirby, E. D. et al. Acute stress enhances adult rat hippocampal neurogenesis and activation of newborn neurons via secreted astrocytic FGF2. eLife 2, e00362 (2013).

    PubMed  PubMed Central  Google Scholar 

  25. 25

    Kronenberg, G. et al. Physical exercise prevents age-related decline in precursor cell activity in the mouse dentate gyrus. Neurobiol. Aging 27, 1505–1513 (2006).

    PubMed  Google Scholar 

  26. 26

    Leuner, B., Glasper, E. R. & Gould, E. Sexual experience promotes adult neurogenesis in the hippocampus despite an initial elevation in stress hormones. PLoS ONE 5, e11597 (2010).

    PubMed  PubMed Central  Google Scholar 

  27. 27

    De Kloet, E. R., Joëls, M. & Holsboer, F. Stress and the brain: from adaptation to disease. Nature Rev. Neurosci. 6, 463–475 (2005).

    CAS  Google Scholar 

  28. 28

    Cameron, H. A., Woolley, C. S. & Gould, E. Adrenal steroid receptor immunoreactivity in cells born in the adult rat dentate gyrus. Brain Res. 611, 342–346 (1993).

    CAS  PubMed  Google Scholar 

  29. 29

    Garcia, A., Steiner, B., Kronenberg, G., Bick-Sander, A. & Kempermann, G. Age-dependent expression of glucocorticoid- and mineralocorticoid receptors on neural precursor cell populations in the adult murine hippocampus. Aging Cell 3, 363–371 (2004).

    CAS  PubMed  Google Scholar 

  30. 30

    Wong, E. Y. H. & Herbert, J. Raised circulating corticosterone inhibits neuronal differentiation of progenitor cells in the adult hippocampus. Neuroscience 137, 83–92 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31

    Hellsten, J. et al. Electroconvulsive seizures increase hippocampal neurogenesis after chronic corticosterone treatment. Eur. J. Neurosci. 16, 283–290 (2002).

    PubMed  Google Scholar 

  32. 32

    Murray, F., Smith, D. W. & Hutson, P. H. Chronic low dose corticosterone exposure decreased hippocampal cell proliferation, volume and induced anxiety and depression like behaviours in mice. Eur. J. Pharmacol. 583, 115–127 (2008).

    CAS  PubMed  Google Scholar 

  33. 33

    Anacker, C. et al. Antidepressants increase human hippocampal neurogenesis by activating the glucocorticoid receptor. Mol. Psychiatry 16, 738–750 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34

    Mayer, J. L. et al. Brief treatment with the glucocorticoid receptor antagonist mifepristone normalises the corticosterone-induced reduction of adult hippocampal neurogenesis. J. Neuroendocrinol. 18, 629–631 (2006).

    CAS  PubMed  Google Scholar 

  35. 35

    Oomen, C. A., Mayer, J. L., de Kloet, E. R., Joëls, M. & Lucassen, P. J. Brief treatment with the glucocorticoid receptor antagonist mifepristone normalizes the reduction in neurogenesis after chronic stress. Eur. J. Neurosci. 26, 3395–3401 (2007).

    PubMed  Google Scholar 

  36. 36

    Wong, E. Y. H. & Herbert, J. Roles of mineralocorticoid and glucocorticoid receptors in the regulation of progenitor proliferation in the adult hippocampus. Eur. J. Neurosci. 22, 785–792 (2005).

    PubMed  PubMed Central  Google Scholar 

  37. 37

    Hu, P. et al. A single-day treatment with mifepristone is sufficient to normalize chronic glucocorticoid induced suppression of hippocampal cell proliferation. PLoS ONE 7, e46224 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38

    Anacker, C. et al. Glucocorticoid-related molecular signaling pathways regulating hippocampal neurogenesis. Neuropsychopharmacology 38, 872–883 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39

    Fitzsimons, C. P. et al. Knockdown of the glucocorticoid receptor alters functional integration of newborn neurons in the adult hippocampus and impairs fear-motivated behavior. Mol. Psychiatry 18, 993–1005 (2013).

    CAS  PubMed  Google Scholar 

  40. 40

    Renault, V. M. et al. FoxO3 regulates neural stem cell homeostasis. Cell Stem Cell 5, 527–539 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41

    Wu, Y. et al. CXCL12 increases human neural progenitor cell proliferation through Akt-1/FOXO3a signaling pathway. J. Neurochem. 109, 1157–1167 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42

    Graciarena, M., Depino, A. M. & Pitossi, F. J. Prenatal inflammation impairs adult neurogenesis and memory related behavior through persistent hippocampal TGFβ1 downregulation. Brain. Behav. Immun. 24, 1301–1309 (2010).

    CAS  PubMed  Google Scholar 

  43. 43

    Ahn, S. & Joyner, A. L. In vivo analysis of quiescent adult neural stem cells responding to Sonic hedgehog. Nature 437, 894–897 (2005).

    CAS  PubMed  Google Scholar 

  44. 44

    He, Y. et al. ALK5-dependent TGF-β signaling is a major determinant of late-stage adult neurogenesis. Nature Neurosci. 17, 943–952 (2014).

    CAS  PubMed  Google Scholar 

  45. 45

    Anacker, C. et al. Role for the kinase SGK1 in stress, depression, and glucocorticoid effects on hippocampal neurogenesis. Proc. Natl Acad. Sci. USA 110, 8708–8713 (2013). This paper (by our group) describes a series of cellular, animal and clinical studies showing that SGK1 is one of the mechanisms by which glucocorticoids affect neurogenesis, with actions both upstream and downstream of the glucocorticoid receptor.

    CAS  PubMed  Google Scholar 

  46. 46

    Datson, N. A. et al. The transcriptional response to chronic stress and glucocorticoid receptor blockade in the hippocampal dentate gyrus. Hippocampus 22, 359–371 (2012).

    CAS  PubMed  Google Scholar 

  47. 47

    Frotscher, M., Haas, C. A. & Förster, E. Reelin controls granule cell migration in the dentate gyrus by acting on the radial glial scaffold. Cereb. Cortex 13, 634–640 (2003).

    PubMed  Google Scholar 

  48. 48

    Beffert, U. et al. Functional dissection of Reelin signaling by site-directed disruption of Disabled-1 adaptor binding to apolipoprotein E receptor 2: distinct roles in development and synaptic plasticity. J. Neurosci. 26, 2041–2052 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49

    Li, Z. et al. Myocyte enhancer factor 2C as a neurogenic and antiapoptotic transcription factor in murine embryonic stem cells. J. Neurosci. 28, 6557–6568 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50

    Koo, J. W. & Duman, R. S. IL-1β is an essential mediator of the antineurogenic and anhedonic effects of stress. Proc. Natl Acad. Sci. USA 105, 751–756 (2008). The first paper to examine the role of inflammation in stress-induced inhibition of neurogenesis.

    CAS  PubMed  Google Scholar 

  51. 51

    Tozuka, Y., Fukuda, S., Namba, T., Seki, T. & Hisatsune, T. GABAergic excitation promotes neuronal differentiation in adult hippocampal progenitor cells. Neuron 47, 803–815 (2005).

    CAS  PubMed  Google Scholar 

  52. 52

    Lightman, S. L. et al. Hypothalamic–pituitary–adrenal function. Arch. Physiol. Biochem. 110, 90–93 (2002).

    CAS  PubMed  Google Scholar 

  53. 53

    Stavreva, D. A. et al. Ultradian hormone stimulation induces glucocorticoid receptor-mediated pulses of gene transcription. Nature Cell Biol. 11, 1093–1102 (2009).

    CAS  PubMed  Google Scholar 

  54. 54

    Sarabdjitsingh, R. A., Joëls, M. & de Kloet, E. R. Glucocorticoid pulsatility and rapid corticosteroid actions in the central stress response. Physiol. Behav. 106, 73–80 (2012).

    CAS  PubMed  Google Scholar 

  55. 55

    Huang, G.-J. & Herbert, J. Stimulation of neurogenesis in the hippocampus of the adult rat by fluoxetine requires rhythmic change in corticosterone. Biol. Psychiatry 59, 619–624 (2006).

    CAS  PubMed  Google Scholar 

  56. 56

    Sarabdjitsingh, R. A. et al. Recovery from disrupted ultradian glucocorticoid rhythmicity reveals a dissociation between hormonal and behavioural stress responsiveness. J. Neuroendocrinol. 22, 862–871 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57

    Scheff, J. D., Calvano, S. E., Lowry, S. F. & Androulakis, I. P. Transcriptional implications of ultradian glucocorticoid secretion in homeostasis and in the acute stress response. Physiol. Genomics 44, 121–129 (2012).

    CAS  PubMed  Google Scholar 

  58. 58

    Rankin, J., Walker, J. J., Windle, R., Lightman, S. L. & Terry, J. R. Characterizing dynamic interactions between ultradian glucocorticoid rhythmicity and acute stress using the phase response curve. PLoS ONE 7, e30978 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. 59

    Noguchi, T. et al. Regulation of glucocorticoid receptor transcription and nuclear translocation during single and repeated immobilization stress. Endocrinology 151, 4344–4355 (2010).

    CAS  PubMed  Google Scholar 

  60. 60

    Guidotti, G. et al. Glucocorticoid receptor and FKBP5 expression is altered following exposure to chronic stress: modulation by antidepressant treatment. Neuropsychopharmacology 38, 616–627 (2013).

    CAS  PubMed  Google Scholar 

  61. 61

    Cheng, L.-C., Pastrana, E., Tavazoie, M. & Doetsch, F. miR-124 regulates adult neurogenesis in the subventricular zone stem cell niche. Nature Neurosci. 12, 399–408 (2009).

    CAS  PubMed  Google Scholar 

  62. 62

    Vreugdenhil, E. et al. MicroRNA 18 and 124a down-regulate the glucocorticoid receptor: implications for glucocorticoid responsiveness in the brain. Endocrinology 150, 2220–2228 (2009).

    CAS  PubMed  Google Scholar 

  63. 63

    Uchida, S. et al. Characterization of the vulnerability to repeated stress in Fischer 344 rats: possible involvement of microRNA-mediated down-regulation of the glucocorticoid receptor. Eur. J. Neurosci. 27, 2250–2261 (2008).

    PubMed  Google Scholar 

  64. 64

    Wallace, A. D. & Cidlowski, J. A. Proteasome-mediated glucocorticoid receptor degradation restricts transcriptional signaling by glucocorticoids. J. Biol. Chem. 276, 42714–42721 (2001).

    CAS  PubMed  Google Scholar 

  65. 65

    Conway-Campbell, B. L. et al. Proteasome-dependent down-regulation of activated nuclear hippocampal glucocorticoid receptors determines dynamic responses to corticosterone. Endocrinology 148, 5470–5477 (2007).

    CAS  PubMed  Google Scholar 

  66. 66

    Mardirossian, S., Rampon, C., Salvert, D., Fort, P. & Sarda, N. Impaired hippocampal plasticity and altered neurogenesis in adult Ube3a maternal deficient mouse model for Angelman syndrome. Exp. Neurol. 220, 341–348 (2009).

    CAS  PubMed  Google Scholar 

  67. 67

    Godavarthi, S. K., Dey, P., Maheshwari, M. & Jana, N. R. Defective glucocorticoid hormone receptor signaling leads to increased stress and anxiety in a mouse model of Angelman syndrome. Hum. Mol. Genet. 21, 1824–1834 (2012).

    CAS  PubMed  Google Scholar 

  68. 68

    Ito, K. et al. Histone deacetylase 2-mediated deacetylation of the glucocorticoid receptor enables NF-κB suppression. J. Exp. Med. 203, 7–13 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. 69

    Koo, J. W., Russo, S. J., Ferguson, D., Nestler, E. J. & Duman, R. S. Nuclear factor-κB is a critical mediator of stress-impaired neurogenesis and depressive behavior. Proc. Natl Acad. Sci. USA 107, 2669–2674 (2010).

    CAS  PubMed  Google Scholar 

  70. 70

    Tian, S., Poukka, H., Palvimo, J. J. & Jänne, O. A. Small ubiquitin-related modifier-1 (SUMO-1) modification of the glucocorticoid receptor. Biochem. J. 367, 907–911 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. 71

    Lin, D.-Y. et al. Role of SUMO-interacting motif in Daxx SUMO modification, subnuclear localization, and repression of sumoylated transcription factors. Mol. Cell 24, 341–354 (2006).

    CAS  PubMed  Google Scholar 

  72. 72

    Holmstrom, S. R., Chupreta, S., So, A. Y.-L. & Iñiguez-Lluhí, J. A. SUMO-mediated inhibition of glucocorticoid receptor synergistic activity depends on stable assembly at the promoter but not on DAXX. Mol. Endocrinol. 22, 2061–2075 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. 73

    Jewell, C. M. Mouse glucocorticoid receptor phosphorylation status influences multiple functions of the receptor protein. J. Biol. Chem. 272, 9287–9293 (1997).

    PubMed  Google Scholar 

  74. 74

    Wang, Z., Frederick, J. & Garabedian, M. J. Deciphering the phosphorylation 'code' of the glucocorticoid receptor in vivo. J. Biol. Chem. 277, 26573–26580 (2002).

    CAS  PubMed  Google Scholar 

  75. 75

    Yang, J., Liu, J. & DeFranco, D. B. Subnuclear trafficking of glucocorticoid receptors in vitro: chromatin recycling and nuclear export. J. Cell Biol. 137, 523–538 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. 76

    Blind, R. D. & Garabedian, M. J. Differential recruitment of glucocorticoid receptor phospho-isoforms to glucocorticoid-induced genes. J. Steroid Biochem. Mol. Biol. 109, 150–157 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. 77

    Ismaili, N. & Garabedian, M. J. Modulation of glucocorticoid receptor function via phosphorylation. Ann. NY Acad. Sci. 1024, 86–101 (2004).

    CAS  PubMed  Google Scholar 

  78. 78

    Rogatsky, I., Waase, C. L. M. & Garabedian, M. J. Phosphorylation and inhibition of rat glucocorticoid receptor transcriptional activation by glycogen synthase kinase-3 (GSK-3). Species-specific differences between human and rat glucocorticoid receptor signaling as revealed through GSK-3 phosphorylation. J. Biol. Chem. 273, 14315–14321 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. 79

    Adzic, M. et al. Acute or chronic stress induce cell compartment-specific phosphorylation of glucocorticoid receptor and alter its transcriptional activity in Wistar rat brain. J. Endocrinol. 202, 87–97 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. 80

    Bledsoe, R. K. et al. Crystal structure of the glucocorticoid receptor ligand binding domain reveals a novel mode of receptor dimerization and coactivator recognition. Cell 110, 93–105 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. 81

    Freeman, B. C. & Yamamoto, K. R. Disassembly of transcriptional regulatory complexes by molecular chaperones. Science 296, 2232–2235 (2002).

    CAS  PubMed  Google Scholar 

  82. 82

    Conway-Campbell, B. L. et al. The HSP90 molecular chaperone cycle regulates cyclical transcriptional dynamics of the glucocorticoid receptor and its coregulatory molecules CBP/p300 during ultradian ligand treatment. Mol. Endocrinol. 25, 944–954 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. 83

    Han, S. J., Lonard, D. M. & O'Malley, B. W. Multi-modulation of nuclear receptor coactivators through posttranslational modifications. Trends Endocrinol. Metab. 20, 8–15 (2009).

    CAS  PubMed  Google Scholar 

  84. 84

    Zalachoras, I., Houtman, R. & Meijer, O. C. Understanding stress-effects in the brain via transcriptional signal transduction pathways. Neuroscience 242, 97–109 (2013).

    CAS  PubMed  Google Scholar 

  85. 85

    Bierhaus, A. et al. A mechanism converting psychosocial stress into mononuclear cell activation. Proc. Natl Acad. Sci. USA 100, 1920–1925 (2003).

    CAS  PubMed  Google Scholar 

  86. 86

    Haroon, E., Raison, C. L. & Miller, A. H. Psychoneuroimmunology meets neuropsychopharmacology: translational implications of the impact of inflammation on behavior. Neuropsychopharmacology 37, 137–162 (2012). This is an extensive and very useful review on the role of inflammation in depression.

    CAS  PubMed  Google Scholar 

  87. 87

    Johnson, J. D. et al. Catecholamines mediate stress-induced increases in peripheral and central inflammatory cytokines. Neuroscience 135, 1295–1307 (2005).

    CAS  PubMed  Google Scholar 

  88. 88

    Horowitz, M., Zunszain, P. A., Anacker, C., Musaelyan, K. & Pariante, C. M. in Inflammation in Psychiatry (eds Halaris, A & Leonard, B. E.) 127–143 (Karger, 2013).

    Google Scholar 

  89. 89

    Miller, G. E. et al. A functional genomic fingerprint of chronic stress in humans: blunted glucocorticoid and increased NF-κB signaling. Biol. Psychiatry 64, 266–272 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. 90

    Grippo, A. J., Francis, J., Beltz, T. G., Felder, R. B. & Johnson, A. K. Neuroendocrine and cytokine profile of chronic mild stress-induced anhedonia. Physiol. Behav. 84, 697–706 (2005).

    CAS  PubMed  Google Scholar 

  91. 91

    Goshen, I. et al. Brain interleukin-1 mediates chronic stress-induced depression in mice via adrenocortical activation and hippocampal neurogenesis suppression. Mol. Psychiatry 13, 717–728 (2008).

    CAS  PubMed  Google Scholar 

  92. 92

    Zunszain, P. A. et al. Interleukin-1β: a new regulator of the kynurenine pathway affecting human hippocampal neurogenesis. Neuropsychopharmacology 37, 939–949 (2011).

    PubMed  PubMed Central  Google Scholar 

  93. 93

    Green, H. F. & Nolan, Y. M. Unlocking mechanisms in interleukin-1β-induced changes in hippocampal neurogenesis — a role for GSK-3β and TLX. Transl. Psychiatry 2, e194 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. 94

    Seguin, J. A., Brennan, J., Mangano, E. & Hayley, S. Proinflammatory cytokines differentially influence adult hippocampal cell proliferation depending upon the route and chronicity of administration. Neuropsychiatr. Dis. Treat. 5, 5–14 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. 95

    Mahar, I., Bambico, F. R., Mechawar, N. & Nobrega, J. N. Stress, serotonin, and hippocampal neurogenesis in relation to depression and antidepressant effects. Neurosci. Biobehav. Rev. 38, 173–192 (2013).

    PubMed  Google Scholar 

  96. 96

    Gray, J. D., Milner, T. A. & McEwen, B. S. Dynamic plasticity: the role of glucocorticoids, brain-derived neurotrophic factor and other trophic factors. Neuroscience 239, 214–227 (2013).

    CAS  PubMed  Google Scholar 

  97. 97

    Donovan, M. H., Yamaguchi, M. & Eisch, A. J. Dynamic expression of TrkB receptor protein on proliferating and maturing cells in the adult mouse dentate gyrus. Hippocampus 18, 435–439 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. 98

    Schmidt, H. D. & Duman, R. S. The role of neurotrophic factors in adult hippocampal neurogenesis, antidepressant treatments and animal models of depressive-like behavior. Behav. Pharmacol. 18, 391–418 (2007).

    CAS  PubMed  Google Scholar 

  99. 99

    Waterhouse, E. G. et al. BDNF promotes differentiation and maturation of adult-born neurons through GABAergic transmission. J. Neurosci. 32, 14318–14330 (2012).

    PubMed  PubMed Central  Google Scholar 

  100. 100

    Nowacka, M. & Obuchowicz, E. BDNF and VEGF in the pathogenesis of stress-induced affective diseases: an insight from experimental studies. Pharmacol. Rep. 65, 535–546 (2013).

    CAS  PubMed  Google Scholar 

  101. 101

    Jin, K. et al. Vascular endothelial growth factor (VEGF) stimulates neurogenesis in vitro and in vivo. Proc. Natl Acad. Sci. USA 99, 11946–11950 (2002).

    CAS  PubMed  Google Scholar 

  102. 102

    Schänzer, A. et al. Direct stimulation of adult neural stem cells in vitro and neurogenesis in vivo by vascular endothelial growth factor. Brain Pathol. 14, 237–248 (2004).

    PubMed  Google Scholar 

  103. 103

    Segi-Nishida, E., Warner-Schmidt, J. L. & Duman, R. S. Electroconvulsive seizure and VEGF increase the proliferation of neural stem-like cells in rat hippocampus. Proc. Natl Acad. Sci. USA 105, 11352–11357 (2008).

    CAS  PubMed  Google Scholar 

  104. 104

    Fournier, N. M., Lee, B., Banasr, M., Elsayed, M. & Duman, R. S. Vascular endothelial growth factor regulates adult hippocampal cell proliferation through MEK/ERK- and PI3K/Akt-dependent signaling. Neuropharmacology 63, 642–652 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. 105

    Taylor, S. B. et al. Disruption of the neuregulin 1 gene in the rat alters HPA axis activity and behavioral responses to environmental stimuli. Physiol. Behav. 104, 205–214 (2011).

    CAS  PubMed  Google Scholar 

  106. 106

    Mahar, I. et al. Subchronic peripheral neuregulin-1 increases ventral hippocampal neurogenesis and induces antidepressant-like effects. PLoS ONE 6, e26610 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. 107

    Faigle, R. & Song, H. Signaling mechanisms regulating adult neural stem cells and neurogenesis. Biochim. Biophys. Acta 1830, 2435–2448 (2013).

    CAS  PubMed  Google Scholar 

  108. 108

    Han, Y.-G. et al. Hedgehog signaling and primary cilia are required for the formation of adult neural stem cells. Nature Neurosci. 11, 277–284 (2008).

    CAS  PubMed  Google Scholar 

  109. 109

    Lai, K., Kaspar, B. K., Gage, F. H. & Schaffer, D. V. Sonic hedgehog regulates adult neural progenitor proliferation in vitro and in vivo. Nature Neurosci. 6, 21–27 (2003).

    CAS  PubMed  Google Scholar 

  110. 110

    Petrova, R., Garcia, A. D. R. & Joyner, A. L. Titration of GLI3 repressor activity by sonic hedgehog signaling is critical for maintaining multiple adult neural stem cell and astrocyte functions. J. Neurosci. 33, 17490–17505 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. 111

    Lie, D.-C. et al. Wnt signalling regulates adult hippocampal neurogenesis. Nature 437, 1370–1375 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. 112

    Matrisciano, F. et al. Induction of the Wnt antagonist Dickkopf-1 is involved in stress-induced hippocampal damage. PLoS ONE 6, e16447 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. 113

    Wang, X. et al. Interleukin-1β mediates proliferation and differentiation of multipotent neural precursor cells through the activation of SAPK/JNK pathway. Mol. Cell. Neurosci. 36, 343–354 (2007).

    PubMed  Google Scholar 

  114. 114

    Hayley, S., Poulter, M. O., Merali, Z. & Anisman, H. The pathogenesis of clinical depression: stressor- and cytokine-induced alterations of neuroplasticity. Neuroscience 135, 659–678 (2005).

    CAS  PubMed  Google Scholar 

  115. 115

    McKay, L. I. & Cidlowski, J. A. CBP (CREB binding protein) integrates NF-κB (nuclear factor-κB) and glucocorticoid receptor physical interactions and antagonism. Mol. Endocrinol. 14, 1222–1234 (2000).

    CAS  PubMed  Google Scholar 

  116. 116

    Galliher-Beckley, A. J., Williams, J. G., Collins, J. B. & Cidlowski, J. A. Glycogen synthase kinase 3β-mediated serine phosphorylation of the human glucocorticoid receptor redirects gene expression profiles. Mol. Cell. Biol. 28, 7309–7322 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. 117

    Suri, D. & Vaidya, V. A. Glucocorticoid regulation of brain-derived neurotrophic factor: relevance to hippocampal structural and functional plasticity. Neuroscience 239, 196–213 (2013).

    CAS  PubMed  Google Scholar 

  118. 118

    Kumamaru, E. et al. Glucocorticoid prevents brain-derived neurotrophic factor-mediated maturation of synaptic function in developing hippocampal neurons through reduction in the activity of mitogen-activated protein kinase. Mol. Endocrinol. 22, 546–558 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. 119

    Jeanneteau, F., Garabedian, M. J. & Chao, M. V. Activation of Trk neurotrophin receptors by glucocorticoids provides a neuroprotective effect. Proc. Natl Acad. Sci. USA 105, 4862–4867 (2008). This paper examines the potential crosstalk between neurotrophin signalling pathways and the glucocorticoid receptor, with potential implications for adult neurogenesis.

    CAS  PubMed  Google Scholar 

  120. 120

    Chen, M. J. & Russo-Neustadt, A. A. Running exercise-induced up-regulation of hippocampal brain-derived neurotrophic factor is CREB-dependent. Hippocampus 19, 962–972 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. 121

    Lambert, W. M. et al. Brain-derived neurotrophic factor signaling rewrites the glucocorticoid transcriptome via glucocorticoid receptor phosphorylation. Mol. Cell. Biol. 33, 3700–3714 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. 122

    Miller, B. R. & Hen, R. The current state of the neurogenic theory of depression and anxiety. Curr. Opin. Neurobiol. 30, 51–58 (2015).

    CAS  PubMed  Google Scholar 

  123. 123

    Santarelli, L. et al. Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science 301, 805–809 (2003).

    CAS  PubMed  Google Scholar 

  124. 124

    Boldrini, M. et al. Antidepressants increase neural progenitor cells in the human hippocampus. Neuropsychopharmacology 34, 2376–2389 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. 125

    Windle, R. J., Wood, S. A., Shanks, N., Lightman, S. L. & Ingram, C. D. Ultradian rhythm of basal corticosterone release in the female rat: dynamic interaction with the response to acute stress. Endocrinology 139, 443–450 (1998).

    CAS  PubMed  Google Scholar 

Download references


C.M.P. and P.A.Z. are supported by the National Institute of Health Research Biomedical Research Centre in Mental Health at South London and Maudsley NHS Foundation Trust and King's College London, and by the Medical Research Council UK (MR/J002739/1 and MR/L014815/1). M.E. is supported by a Marie Curie Fellowship from the European Commission and a grant from the Lundbeck Foundation. The authors thank S. Thuret and T. Murphy for discussions on this Review.

Author information



Corresponding author

Correspondence to Martin Egeland.

Ethics declarations

Competing interests

Patricia A. Zunszain and Carmine M. Pariante have received research funding from pharmaceutical companies interested in depression such as Johnson & Johnson, but this Review is unrelated to this funding.

PowerPoint slides


Subgranular zone

(SGZ). A small region on the inner boundaries of the granular layer in the dentate gyrus of rodents. Cell proliferation of precursors to adult neurogenesis of granular neurons occurs in the SGZ.

Cell proliferation

Among the adult neurogenesis stages, this is an often-quantified stage of the process and is a measure of the number of new cells being formed in the subgranular zone that have the potential to become new neurons or glia.

Unpredictable mild stress

A rodent model of depression in which animals are exposed to repeated stressors that are deemed as mild in an order that cannot be predicted to avoid the development of habituation resilience.

Pattern separation

The process of reducing interference among similar inputs using non-overlapping representations.


In behaviour, this is the use of a few and/or non-representative experiences to make an inference of a current experience that is incorrect.

Contextual emotional processing

The process of putting a novel experience into an emotional context using the emotional valence of similar previous experiences.

Dorsal dentate gyrus

A region that is thought to be associated with spatial memory processing.

Cell differentiation

A quantifiable stage of adult neurogenesis in which the number of cells fated to become neurons can be measured.

Circadian rhythms

In terms of hormone secretion, these rhythms vary throughout the day and comprise a period in which there is generally a high level of hormone secretion and a period in which a generally lower level of hormone is secreted.

Ultradian rhythms

In terms of hormone secretion, these rhythms vary within circadian rhythms and are composed of roughly hourly pulses of hormone release that result in peaks in hormone levels followed by troughs in which the hormone is broken down.

Subventricular zone

(SVZ). A thin strip composed of several layers on the inner walls of the lateral ventricles of the rodent forebrain. Cell proliferation of precursors to adult neurogenesis of mainly olfactory bulb neurons occurs in the SVZ.

Ventral dentate gyrus

A region that is thought to be associated with emotional memory processing.


A group of signalling molecules that govern tissue development. They classically control morphogenesis through cell proliferation and differentiation.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Egeland, M., Zunszain, P. & Pariante, C. Molecular mechanisms in the regulation of adult neurogenesis during stress. Nat Rev Neurosci 16, 189–200 (2015).

Download citation

Further reading


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing