Review Article | Published:

Stress and the brain: from adaptation to disease


In response to stress, the brain activates several neuropeptide-secreting systems. This eventually leads to the release of adrenal corticosteroid hormones, which subsequently feed back on the brain and bind to two types of nuclear receptor that act as transcriptional regulators. By targeting many genes, corticosteroids function in a binary fashion, and serve as a master switch in the control of neuronal and network responses that underlie behavioural adaptation. In genetically predisposed individuals, an imbalance in this binary control mechanism can introduce a bias towards stress-related brain disease after adverse experiences. New candidate susceptibility genes that serve as markers for the prediction of vulnerable phenotypes are now being identified.

Key Points

  • This review summarizes the evidence that chronic or repeated stressors can cause neuronal disturbances that resemble the changes that are observed in the brain during depression. We focus on the stress hormones that are secreted by the adrenal gland (that is, primarily, cortisol in humans and corticosterone in rodents), which are secreted after stimulation by peptides that are released from the brain (corticotropin-releasing hormone or CRH) and pituitary gland (corticotropin or ACTH). The corticosteroids act together with the neuropeptides to facilitate adaptation to stress, but if dysregulated, they fail to do so during depression. The goal of the review is to identify mechanisms that are driven by the hormones that might explain why maladaptive changes produce stress-related disorders, such as depression, in some individuals, whereas others remain in excellent health under similar adverse conditions.

  • In the first part of the review, we highlight the adaptive stress-related processes in the limbic brain, which is an area that is involved in the appraisal of new experiences, learning and memory processes. The corticosteroid actions are mediated by nuclear receptors, which are abundantly expressed in these limbic neurons. Two receptor types have been identified: one receptor system (mineralocorticoid receptors or MRs) has a role in the appraisal process and, therefore, in the onset of the stress response; the other system (glucocorticoid receptors or GRs) facilitates recovery from stress. We postulate that MRs and GRs function in a binary fashion.

  • In the second part of the review, we discuss how an inappropriate stress response might lead to a vulnerable phenotype. One model of such an inappropriate response is the chronically stressed animal that shows structural and functional changes in the limbic brain. These changes include aspects of neurogenesis, structural remodelling and synaptic plasticity that might be related to behavioural impairments. Other animal models focus on the role of genetic background and early experience in shaping stress reactivity. Conditions are discussed that programme adaptation to stress depending on mother–infant interactions.

  • In the third and final part of the review, we address how, in genetically predisposed humans, stressful situations might precipitate hypercortisolaemia, as seen in depression, or hypocortisolaemia, as found in post-traumatic stress disorder (PTSD). In the most extreme cases of hypercortisolaemia, psychotic symptoms occur (steroid psychosis). This research has proceeded to the point that genetic factors can be identified in, for example, MR- and GR-related genes, which render individuals either resilient or vulnerable to developing affective disorders.

  • The review concludes with the statement that, together with other stress-system mediators, a binary response system that is operated by corticosteroids preserves health and homeostasis. Their proper function determines the capacity of the organism to contain stress reactions in the acute phase and in the management of the late recovery phase. Imbalance might cause a vulnerable phenotype for mental illness to evolve.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  1. 1

    Selye, H. Syndrome produced by diverse nocuous agents. Nature 138, 32 (1936).

  2. 2

    Levine, S. & Ursin, H. in Stress Neurobiology and Neuroendocrinology (eds Brown, M. R. & Koob, G. F.) 3–21 (Rivier Marcel Dekker, Inc., New York, 1991).

  3. 3

    Chrousos, G. P. & Gold, P. W. The concepts of stress and stress system disorders. Overview of physical and behavioral homeostasis. JAMA 267, 1244–1252 (1992).

  4. 4

    De Kloet, E. R., Vreugdenhil, E., Oitzl, M. S. & Joëls, M. Brain corticosteroid receptor balance in health and disease. Endocr. Rev. 19, 269–301 (1998).

  5. 5

    McEwen, B. in Encyclopedia of Stress Vol. 3 (ed. Fink, G.) 508–509 (Academic, San Diego, USA, 2000).

  6. 6

    Sapolsky, R. M., Romero, L. M. & Munck, A. U. How do glucocorticoids influence stress responses? Integrating permissive, suppressive, stimulatory, and preparative actions. Endocr. Rev. 21, 55–89 (2000).

  7. 7

    Tausk, M. Das Hormon: Hat die Nebennierrinde tatsächlich eine Verteidigungsfunktion? Vol. 3 (Organon International BV, Oss, The Netherlands, 1952).

  8. 8

    McEwen, B. S. Mood disorders and allostatic load. Biol. Psychiatry 54, 200–207 (2003).

  9. 9

    Holsboer, F. The corticosteroid receptor hypothesis of depression. Neuropsychopharmacology 23, 477–501 (2000).

  10. 10

    Van Praag, H. M., de Kloet, E. R. & van Os, J. Stress, the Brain and Depression (Cambridge Univ. Press, 2004).

  11. 11

    Yehuda, R. Post-traumatic stress disorder. N. Engl. J. Med. 346, 108–114 (2002).

  12. 12

    Reul, J. M. & de Kloet, E. R. Two receptor systems for corticosterone in rat brain: microdistribution and differential occupation. Endocrinology 117, 2505–2511 (1985). The first account of two distinct nuclear receptor systems that bind naturally occurring glucocorticoids with a tenfold difference in affinity.

  13. 13

    Arriza, J. L., Simerly, R. B., Swanson, L. W. & Evans, R. M. The neuronal mineralocorticoid receptor as a mediator of glucocorticoid response. Neuron 1, 887–900 (1988).

  14. 14

    Young, E. A., Abelson, J. & Lightman, S. L. Cortisol pulsatility and its role in stress regulation and health. Front. Neuroendocrinol. 25, 69–76 (2004).

  15. 15

    Kitchener, P., Di Blasi, F., Borrelli, E. & Piazza, P. V. Differences between brain structures in nuclear translocation and DNA binding of the glucocorticoid receptor during stress and the circadian cycle. Eur. J. Neurosci. 19, 1837–1846 (2004).

  16. 16

    Miklos, I. H. & Kovacs, K. J. GABAergic innervation of corticotropin-releasing hormone (CRH)-secreting parvocellular neurons and its plasticity as demonstrated by quantitative immunoelectron microscopy. Neuroscience 113, 581–592 (2002).

  17. 17

    Herman, J. P. et al. Central mechanisms of stress integration: hierarchical circuitry controlling hypothalamo–pituitary–adrenocortical responsiveness. Front. Neuroendocrinol. 24, 151–180 (2003).

  18. 18

    Patel, P. D. et al. Glucocorticoid and mineralocorticoid receptor mRNA expression in squirrel monkey brain. J. Psychiatr. Res. 34, 383–392 (2000).

  19. 19

    Trapp, T., Rupprecht, R., Castren, M., Reul, J. M. & Holsboer, F. Heterodimerization between mineralocorticoid and glucocorticoid receptor: a new principle of glucocorticoid action in the CNS. Neuron 13, 1457–1462 (1994).

  20. 20

    Nishi, M., Ogawa, H., Ito, T., Matsuda, K. I. & Kawata, M. Dynamic changes in subcellular localization of mineralocorticoid receptor in living cells: in comparison with glucocorticoid receptor using dual-color labeling with green fluorescent protein spectral variants. Mol. Endocrinol. 15, 1077–1092 (2001).

  21. 21

    Gesing, A. et al. Psychological stress increases hippocampal mineralocorticoid receptor levels: involvement of corticotropin-releasing hormone. J. Neurosci. 21, 4822–4829 (2001).

  22. 22

    Datson, N. A., van der Perk, J., de Kloet, E. R. & Vreugdenhil, E. Identification of corticosteroid-responsive genes in rat hippocampus using serial analysis of gene expression. Eur. J. Neurosci. 14, 675–689 (2001). This paper describes a comprehensive database of MR- and GR-responsive gene patterns in the hippocampus.

  23. 23

    Sabban, E. L. & Kvetnansky, R. Stress-triggered activation of gene expression in catecholaminergic systems: dynamics of transcriptional events. Trends Neurosci. 24, 91–98 (2001).

  24. 24

    Schaaf, M. J., Hoetelmans, R. W., de Kloet, E. R. & Vreugdenhil, E. Corticosterone regulates expression of BDNF and trkB but not NT-3 and trkC mRNA in the rat hippocampus. J. Neurosci. Res. 48, 334–341 (1997).

  25. 25

    Hansson, A. C. et al. Gluco- and mineralocorticoid receptor-mediated regulation of neurotrophic factor gene expression in the dorsal hippocampus and the neocortex of the rat. Eur. J. Neurosci. 12, 2918–2934 (2000).

  26. 26

    Sandi, C. Stress, cognitive impairment and cell adhesion molecules. Nature Rev. Neurosci. 5, 917–930 (2004).

  27. 27

    Kole, M. H., Costoli, T., Koolhaas, J. M. & Fuchs, E. Bidirectional shift in the cornu ammonis 3 pyramidal dendritic organization following brief stress. Neuroscience 125, 337–347 (2004).

  28. 28

    Wossink, J., Karst, H., Mayboroda, O. & Joëls, M. Morphological and functional properties of rat dentate granule cells after adrenalectomy. Neuroscience 108, 263–272 (2001).

  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).

  30. 30

    Woolley, C. S., Gould, E., Sakai, R. R., Spencer, R. L. & McEwen, B. S. Effects of aldosterone or RU28362 treatment on adrenalectomy-induced cell death in the dentate gyrus of the adult rat. Brain Res. 554, 312–315 (1991).

  31. 31

    Hu, Z., Yuri, K., Ozawa, H., Lu, H. & Kawata, M. The in vivo time course for elimination of adrenalectomy-induced apoptotic profiles from the granule cell layer of the rat hippocampus. J. Neurosci. 17, 3981–3989 (1997).

  32. 32

    Nair, S. M. et al. Gene expression profiles associated with survival of individual rat dentate cells after endogenous corticosteroid deprivation. Eur. J. Neurosci. 20, 3233–3243 (2004).

  33. 33

    Almeida, O. F. et al. Subtle shifts in the ratio between pro- and antiapoptotic molecules after activation of corticosteroid receptors decide neuronal fate. FASEB J. 14, 779–790 (2000).

  34. 34

    Tanapat, P., Hastings, N. B., Rydel, T. A., Galea, L. A. & 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). This report describes how stressful experiences rapidly diminish cell proliferation by increasing adrenal hormone levels, which results in a transient decrease in the number of adult-generated immature granule neurons.

  35. 35

    Crochemore, C., Michaelidis, T. M., Fischer, D., Loeffler, J. P. & Almeida, O. F. Enhancement of p53 activity and inhibition of neural cell proliferation by glucocorticoid receptor activation. FASEB J. 16, 761–770 (2002).

  36. 36

    Heine, V. M., Maslam, S., Zareno, J., Joëls, M. & Lucassen, P. J. Suppressed proliferation and apoptotic changes in the rat dentate gyrus after acute and chronic stress are reversible. Eur. J. Neurosci. 19, 131–144 (2004).

  37. 37

    Joëls, M. Steroid hormones and excitability in the mammalian brain. Front. Neuroendocrinol. 18, 2–48 (1997).

  38. 38

    Joëls, M. & de Kloet, E. R. Effects of glucocorticoids and norepinephrine on the excitability in the hippocampus. Science 245, 1502–1505 (1989). This paper shows that glucocorticoids can reduce transmitter-evoked excitability in the hippocampus, presumably through receptor-mediated genomic actions.

  39. 39

    Joëls, M., Hesen, W. & de Kloet, E. R. Mineralocorticoid hormones suppress serotonin-induced hyperpolarization of rat hippocampal CA1 neurons. J. Neurosci. 11, 2288–2294 (1991).

  40. 40

    Beck, S. G., Choi, K. C., List, T. J., Okuhara, D. Y. & Birnsteil, S. Corticosterone alters 5-HT1A receptor-mediated hyperpolarization in area CA1 hippocampal pyramidal neurons. Neuropsychopharmacology 14, 27–33 (1996).

  41. 41

    Kerr, D. S., Campbell, L. W., Thibault, O. & Landfield, P. W. Hippocampal glucocorticoid receptor activation enhances voltage-dependent Ca2+ conductances: relevance to brain aging. Proc. Natl Acad. Sci. USA 89, 8527–8531 (1992).

  42. 42

    Karst, H. et al. Corticosteroid actions in hippocampus require DNA binding of glucocorticoid receptor homodimers. Nature Neurosci. 3, 977–978 (2000).

  43. 43

    Venero, C. & Borrell, J. Rapid glucocorticoid effects on excitatory amino acid levels in the hippocampus: a microdialysis study in freely moving rats. Eur. J. Neurosci. 11, 2465–2473 (1999).

  44. 44

    Di, S., Malcher-Lopes, R., Halmos, K. C. & Tasker, J. G. Nongenomic glucocorticoid inhibition via endocannabinoid release in the hypothalamus: a fast feedback mechanism. J. Neurosci. 23, 4850–4857 (2003). This study presents evidence for rapid glucocorticoid feedback inhibition of hypothalamic hormone secretion by endocannabinoid release in the PVN.

  45. 45

    Dong, Y. et al. Cocaine-induced potentiation of synaptic strength in dopamine neurons: Behavioral correlates in GluRA (−/−) mice. Proc. Natl Acad. Sci. USA 101, 14282–14287 (2004).

  46. 46

    Diamond, D. M., Bennett, M. C., Fleshner, M. & Rose, G. M. Inverted-U relationship between the level of peripheral corticosterone and the magnitude of hippocampal primed burst potentiation. Hippocampus 2, 421–430 (1992). This research shows that corticosterone exerts a concentration-dependent biphasic influence on the expression of hippocampal plasticity.

  47. 47

    Martin, S. J., Grimwood, P. D. & Morris, R. G. Synaptic plasticity and memory: an evaluation of the hypothesis. Annu. Rev. Neurosci. 23, 649–711 (2000).

  48. 48

    Kim, J. J. & Diamond, D. The stressed hippocampus, synaptic plasticity and lost memories. Nature Rev. Neurosci. 3, 453–462 (2002).

  49. 49

    Pavlides, C., Ogawa, S., Kimura, A. & McEwen, B. S. Role of adrenal steroid mineralocorticoid and glucocorticoid receptors in long-term potentiation in the CA1 field of hippocampal slices. Brain Res. 738, 229–235 (1996).

  50. 50

    Xu, L., Anwyl, R. & Rowan, M. J. Spatial exploration induces a persistent reversal of long-term potentiation in rat hippocampus. Nature 394, 891–894 (1998).

  51. 51

    Kim, J. J., Foy, M. R. & Thompson. Behavioral stress modifies hippocampal plasticity through N-methyl-D-aspartate receptor activation. Proc. Natl Acad. Sci. USA 93, 4750–4753 (1996).

  52. 52

    Blank, T., Nijholt, I., Eckart, K. & Spiess, J. Priming of long-term potentiation in mouse hippocampus by corticotropin-releasing factor and acute stress: implications for hippocampus-dependent learning. J. Neurosci. 22, 3788–3794 (2002).

  53. 53

    Rupprecht, R. et al. Progesterone receptor-mediated effects of neuroactive steroids. Neuron 11, 523–530 (1993).

  54. 54

    Korz, V. & Frey, J. U. Stress-related modulation of hippocampal long-term potentiation in rats: involvement of adrenal steroid receptors. J. Neurosci. 23, 7281–7287 (2003).

  55. 55

    Diamond, D. M., Park, C. R. & Woodson, J. C. Stress generates emotional memories and retrograde amnesia by inducing an endogenous form of hippocampal LTP. Hippocampus 14, 281–291 (2004).

  56. 56

    Oitzl, M. S. & de Kloet, E. R. Selective corticosteroid antagonists modulate specific aspects of spatial orientation learning. Behav. Neurosci. 106, 62–71 (1992). This paper shows that corticosteroids affect behavioural strategies and the storage of spatial information through MR and GR in a differential and coordinated manner.

  57. 57

    Oitzl, M. S., Reichardt, H. M., Joëls, M. & de Kloet, E. R. Point mutation in the mouse glucocorticoid receptor preventing DNA binding impairs spatial memory. Proc. Natl Acad. Sci. USA 98, 12790–12795 (2001).

  58. 58

    Sandi, C., Loscertales, M. & Guaza, C. Experience-dependent facilitating effect of corticosterone on spatial memory formation in the water maze. Eur. J. Neurosci. 9, 637–642 (1997).

  59. 59

    Quirarte, G. L., Roozendaal, B. & McGaugh, J. L. Glucocorticoid enhancement of memory storage involves noradrenergic activation in the basolateral amygdala. Proc. Natl Acad. Sci. USA 94, 14048–14053 (1997). This study shows that β-adrenergic activation seems to be an essential step in mediating glucocorticoid effects on memory storage and that the BLA is a locus of interaction for these two systems.

  60. 60

    De Quervain, D. J., Roozendaal, B. & McGaugh, J. L. Stress and glucocorticoids impair retrieval of long-term spatial memory. Nature 394, 787–790 (1998).

  61. 61

    Myers, K. M. & Davis, M. Behavioral and neural analysis of extinction. Neuron 36, 567–584 (2002).

  62. 62

    Cordero, M. I., Merino, J. J. & Sandi, C. Correlational relationship between shock intensity and corticosterone secretion on the establishment and subsequent expression of contextual fear conditioning. Behav. Neurosci. 112, 885–891 (1998).

  63. 63

    Karst, H. et al. Glucocorticoids alter calcium conductances and calcium channel subunit expression in basolateral amygdala neurons. Eur. J. Neurosci. 16, 1083–1089 (2002).

  64. 64

    Vouimba, R. M., Yaniv, D., Diamond, D. & Richter-Levin, G. Effects of inescapable stress on LTP in the amygdala versus the dentate gyrus of freely behaving rats. Eur. J. Neurosci. 19, 1887–1894 (2004).

  65. 65

    Kim, J. J., Lee, H. J., Han, J. S. & Packard, M. G. Amygdala is critical for stress-induced modulation of hippocampal long-term potentiation and learning. J. Neurosci. 21, 5222–5228 (2001).

  66. 66

    Akirav, I. & Richter-Levin, G. Mechanisms of amygdala modulation of hippocampal plasticity. J. Neurosci. 22, 912–921 (2002).

  67. 67

    Maroun, M. & Richter-Levin, G. Exposure to acute stress blocks the induction of long-term potentiation of the amygdala-prefrontal cortex pathway in vivo. J. Neurosci. 23, 4406–4409 (2003).

  68. 68

    Amat, J. et al. Medial prefrontal cortex determines how stressor controllability affects behavior and dorsal raphe nucleus. Nature Neurosci. 8, 365–371 (2005).

  69. 69

    Conrad, C. D., LeDoux, J. E., Magarinos, A. M. & McEwen, B. S. Repeated restraint stress facilitates fear conditioning independently of causing hippocampal CA3 dendritic atrophy. Behav. Neurosci. 113, 902–913 (1999).

  70. 70

    Bowman, R. E., Beck, K. D. & Luine, V. N. Chronic stress effects on memory: sex differences in performance and monoaminergic activity. Horm. Behav. 43, 48–59 (2003).

  71. 71

    Woolley, C. S., Gould, E. & McEwen, B. S. Exposure to excess glucocorticoids alters dendritic morphology of adult hippocampal pyramidal neurons. Brain Res. 531, 225–231 (1990). In this study, changes in dendritic morphology were observed that might have been indicative of neurons in the early stages of degeneration

  72. 72

    Magarinos, A. M., McEwen, B. S., Flugge, G. & Fuchs, E. Chronic psychosocial stress causes apical dendritic atrophy of hippocampal CA3 pyramidal neurons in subordinate tree shrews. J. Neurosci. 16, 3534–3540 (1996). These results indicate that a naturalistic psychosocial stressor induces specific structural changes in the hippocampal neurons of subordinate male tree shrews.

  73. 73

    Sandi, C. et al. Rapid reversal of stress induced loss of synapses in CA3 of rat hippocampus following water maze training. Eur. J. Neurosci. 17, 2447–2456 (2003).

  74. 74

    Wellman, C. L. Dendritic reorganization in pyramidal neurons in medial prefrontal cortex after chronic corticosterone administration. J. Neurobiol. 49, 245–253 (2001).

  75. 75

    Vyas, A., Mitra, R., Shankaranarayana Rao, B. S. & Chattarji, S. Chronic stress induces contrasting patterns of dendritic remodeling in hippocampal and amygdaloid neurons. J. Neurosci. 22, 6810–6818 (2002). The data presented here indicate that chronic stress can cause contrasting patterns of dendritic remodelling in neurons of the amygdala and hippocampus.

  76. 76

    Magarinos, A. M., Verdugo, J. M. & McEwen, B. S. Chronic stress alters synaptic terminal structure in hippocampus. Proc. Natl Acad. Sci. USA 94, 14002–14008 (1997).

  77. 77

    Kole, M. H., Swan, L. & Fuchs, E. The antidepressant tianeptine persistently modulates glutamate receptor currents of the hippocampal CA3 commissural associational synapse in chronically stressed rats. Eur. J. Neurosci. 16, 807–816 (2002).

  78. 78

    Karst, H. & Joëls, M. Effect of chronic stress on synaptic currents in rat hippocampal dentate gyrus neurons. J. Neurophysiol. 89, 625–633 (2003).

  79. 79

    Alfarez, D. N., Joëls, M. & Krugers, H. J. Chronic unpredictable stress impairs long-term potentiation in rat hippocampal CA1 area and dentate gyrus in vitro. Eur. J. Neurosci. 17, 1928–1934 (2003).

  80. 80

    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).

  81. 81

    Czeh, 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).

  82. 82

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

  83. 83

    Malberg, J. E., Eisch, A. J., Nestler, E. J. & Duman, R. S. Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. J. Neurosci. 20, 9104–9110 (2000).

  84. 84

    Alonso, R. et al. Blockade of CRF(1) or V(1b) receptors reverses stress-induced suppression of neurogenesis in a mouse model of depression. Mol. Psychiatry 9, 278–286 (2004).

  85. 85

    Santarelli, L. et al. Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science 301, 805–809 (2003). The authors show that the behavioural effects of chronic antidepressant use might be mediated by the stimulation of neurogenesis in the hippocampus.

  86. 86

    Saravia, F. E. et al. Increased astrocyte reactivity in the hippocampus of murine models of type 1 diabetes: the nonobese diabetic (NOD) and streptozotocin-treated mice. Brain Res. 957, 345–353 (2002).

  87. 87

    De Kloet, E. R. Brain corticosteroid balance and homeostatic control. Front. Neuroendocrinol. 12, 95–164 (1991).

  88. 88

    Herman, J. P., Watson, S. J. & Spencer, R. L. Defense of adrenocorticosteroid receptor expression in rat hippocampus: effects of stress and strain. Endocrinology 140, 3981–3991 (1999).

  89. 89

    Obradovic, D. et al. DAXX, FLASH, and FAF-1 modulate mineralocorticoid and glucocorticoid receptor mediated transcription in hippocampal cells: toward a basis for the opposite actions elicited by two nuclear receptors? Mol. Pharmacol. 65, 761–769 (2004).

  90. 90

    Meijer, O. C. et al. Steroid receptor coactivator-1 splice variants differentially affect corticosteroid receptor signaling. Endocrinology 146, 1438–1448 (2005).

  91. 91

    Karten, Y. J., Nair, S. M., van Essen, L., Sibug, R. & Joëls, M. Long-term exposure to high corticosterone levels attenuates serotonin responses in rat hippocampal CA1 neurons. Proc. Natl Acad. Sci. USA 96, 13456–13461 (1999). This study shows that prolonged elevation of the corticosteroid concentration, which is a possible causative factor for depression in humans, gradually attenuates responsiveness to serotonin without necessarily decreasing serotonin-1A receptor mRNA levels in pyramidal neurons.

  92. 92

    Froger, N. et al. Neurochemical and behavioral alterations in glucocorticoid receptor-impaired transgenic mice after chronic mild stress. J. Neurosci. 24, 2787–2796 (2004).

  93. 93

    Lopez, J. F., Chalmers, D. T., Little, K. Y. & Watson, S. J. A. E. Bennett Research Award. Regulation of serotonin1A, glucocorticoid, and mineralocorticoid receptor in rat and human hippocampus: implications for the neurobiology of depression. Biol. Psychol. 43, 547–573 (1998).

  94. 94

    Dunn, A. J., Swiergiel, A. H. & Palamarchouk, V. Brain circuits involved in corticotropin-releasing factor-norepinephrine interactions during stress. Ann. NY Acad. Sci. 1018, 25–34 (2004).

  95. 95

    Cabib, S. & Puglisi-Allegra, S. Opposite responses of mesolimbic dopamine system to controllable and uncontrollable aversive experiences. J. Neurosci. 14, 3333–3340 (1994).

  96. 96

    Yau, J. L., Kelly, P. A. & Seckl, J. R. Increased glucocorticoid receptor gene expression in the rat hippocampus following combined serotonergic and medial septal cholinergic lesions. Brain Res. Mol. Brain Res. 27, 174–178 (1994).

  97. 97

    Maccari, S. et al. Hippocampal type I and type II corticosteroid receptors are modulated by central noradrenergic systems. Psychoneuroendocrinology 17, 103–112 (1992).

  98. 98

    Reul, J. M., Stec, I., Soder, M. & Holsboer, F. Chronic treatment of rats with the antidepressant amitriptyline attenuates the activity of the hypothalamic-pituitary-adrenocortical system. Endocrinology 133, 312–320 (1993). This paper indicates that during amitriptyline treatment, a rise in limbic MR might be the initial phenomenon in a successively adjusting HPA system, as evidenced by the decreasing plasma hormone concentrations, declining adrenal size and upregulation of GR in particular brain regions.

  99. 99

    Lai, M. et al. Differential regulation of corticosteroid receptors by monoamine neurotransmitters and antidepressant drugs in primary hippocampal culture. Neuroscience 118, 975–984 (2003).

  100. 100

    Hugin-Flores, M. E., Steimer, T., Aubert, M. L. & Schulz, P. Mineralo- and glucocorticoid receptor mRNAs are differently regulated by corticosterone in the rat hippocampus and anterior pituitary. Neuroendocrinology 79, 174–184 (2004).

  101. 101

    Gass, P. et al. Genetic disruption of mineralocorticoid receptor leads to impaired neurogenesis and granule cell degeneration in the hippocampus of adult mice. EMBO Rep. 1, 447–451 (2000).

  102. 102

    Edwards, E., King, J. A. & Fray, J. C. Increased basal activity of the HPA axis and renin angiotensin system in congenital learned helpless rats exposed to stress early in development. Int. J. Dev. Neurosci. 17, 805–812 (1999).

  103. 103

    Degen, S. B., Verheij, M. M. & Cools, A. R. Genetic background, nature of event, and time of exposure to event direct the phenotypic expression of a particular genotype. A study with apomorphine-(un)susceptible Wistar rats. Behav. Brain Res. 154, 107–112 (2004).

  104. 104

    Keck, M. E. et al. Vasopressin mediates the response of the combined dexamethasone/CRH test in hyper-anxious rats: implications for pathogenesis of affective disorders. Neuropsychopharmacology 26, 94–105 (2002).

  105. 105

    Landgraf, R. & Wigger, A. Born to be anxious: neuroendocrine and genetic correlates of trait anxiety in HAB rats. Stress 6, 111–119 (2003).

  106. 106

    Murgatroyd, C. et al. Impaired repression at a vasopressin promoter polymorphism underlies overexpression of vasopressin in a rat model of trait anxiety. J. Neurosci. 24, 7762–7770 (2004).

  107. 107

    Bohus, B. et al. Neuroendocrine states and behavioral and physiological stress responses. Prog. Brain Res. 72, 57–70 (1987).

  108. 108

    Korte, S. M., Koolhaas, J. M., Wingfield, J. C. & McEwen, B. S. The Darwinian concept of stress: benefits of allostasis and costs of allostatic load and the trade-offs in health and disease. Neurosci. Biobehav. Rev. 29, 3–38 (2005).

  109. 109

    Veenema, A. H., Meijer, O. C., de Kloet, E. R. & Koolhaas, J. M. Genetic selection for coping style predicts stressor susceptibility. J. Neuroendocrinol. 15, 256–267 (2003).

  110. 110

    Feldker, D. E. et al. Serial analysis of gene expression predicts structural differences in hippocampus of long attack latency and short attack latency mice. Eur. J. Neurosci. 17, 379–387 (2003).

  111. 111

    Seckl, J. R. & Meaney, M. J. Glucocorticoid programming. Ann. NY Acad. Sci. 1032, 63–84 (2004).

  112. 112

    Francis, D., Diorio, J., Liu, D. & Meaney, M. J. Nongenomic transmission across generations of maternal behavior and stress responses in the rat. Science 286, 1155–1158 (1999).

  113. 113

    Levine, S. Infantile experience and resistance to physiological stress. Science 126, 405 (1957).

  114. 114

    Levine, S., Dent, G. W. & de Kloet, E. R. in Encyclopedia of Stress 518–526 (Academic, San Diego, USA, 2000).

  115. 115

    Meaney, M. J., Aitken, D. H., van Berkel, C., Bhatnagar, S. & Sapolsky, R. M. Effect of neonatal handling on age-related impairments associated with the hippocampus. Science 239, 766–768 (1988).

  116. 116

    Liu, D. et al. Maternal care, hippocampal glucocorticoid receptors, and hypothalamic-pituitary-adrenal responses to stress. Science 277, 1659–1662 (1997).

  117. 117

    Weaver, I. C. G. et al. Epigenetic programming by maternal behavior. Nature Neurosci. 7, 847–854 (2004). These data indicate that a potentially reversible epigenomic state of a gene can be established through behavioural programming.

  118. 118

    Ladd, C. O., Huot, R. L., Thrivikraman, K. V., Nemeroff, C. B. & Plotsky, P. M. Long-term adaptations in glucocorticoid receptor and mineralocorticoid receptor mRNA and negative feedback on the hypothalamo–pituitary–adrenal axis following neonatal maternal separation. Biol. Psychiatry 55, 367–375 (2004).

  119. 119

    Oitzl, M. S., Workel, J. O., Fluttert, M., Frosch, F. & de Kloet, E. R. Maternal deprivation affects behaviour from youth to senescence: amplification of individual differences in spatial learning and memory in senescent Brown Norway rats. Eur. J. Neurosci. 12, 3771–3780 (2000).

  120. 120

    Van Riel, E., van Gemert, N. G., Meijer, O. C. & Joëls, M. Effect of early life stress on serotonin responses in the hippocampus of young adult rats. Synapse 53, 11–19 (2004).

  121. 121

    Coplan, J. D. et al. Persistent elevations of cerebrospinal fluid concentrations of corticotrophin releasing factor in adult nonhuman primates exposed to early-life stressors: implications for the pathophysiology of mood and anxiety disorders. Proc. Natl Acad. Sci. USA 93, 1619–1623 (1996). These data indicate a potential neurobiological mechanism in non-human primates by which early-life stressors might contribute to adult psychopathology.

  122. 122

    Kendler, K. S. et al. Stressful life events, genetic liability, and onset of an episode of major depression in women. Am. J. Psychiatry 152, 833–842 (1995).

  123. 123

    Brown, E. S., Varghese, F. P. & McEwen, B. S. Association of depression with medical illness: does cortisol play a role? Biol. Psychiatry 55, 1–9 (2004).

  124. 124

    Lupien, S. J. et al. Cortisol levels during human aging predict hippocampal atrophy and memory deficits. Nature Neurosci. 1, 69–73 (1998). This study presents evidence that basal cortisol elevation might cause hippocampal damage and impair hippocampus-dependent learning and memory in humans.

  125. 125

    Sheline, Y. I., Sanghavi, M., Mintun, M. A. & Gado, M. H. Depression duration but not age predicts hippocampal volume loss in medically healthy women with recurrent major depression. J. Neurosci. 19, 5034–5043 (1999).

  126. 126

    Müller, M. B. et al. Neither major depression nor glucocorticoid treatment affects the cellular integrity of the human hippocampus. Eur. J. Neurosci. 14, 1603–1612 (2001).

  127. 127

    Tronche, F. et al. Disruption of the glucocorticoid receptor gene in the nervous system results in reduced anxiety. Nature Genet. 23, 99–103 (1999). The authors show that conditional mutagenesis of GR in the nervous system provides genetic evidence for the importance of GR signalling in emotional behaviour

  128. 128

    Boyle, M. P. et al. Acquired deficit of forebrain glucocorticoid receptor produces depression-like changes in adrenal axis regulation and behavior. Proc. Natl Acad. Sci. USA 102, 473–478 (2005).

  129. 129

    Wei, Q. et al. Glucocorticoid receptor overexpression in forebrain: a mouse model of increased emotional lability. Proc. Natl Acad. Sci. USA 101, 11851–11856 (2004).

  130. 130

    Smith, G. W. et al. Corticotropin releasing factor receptor 1-deficient mice display decreased anxiety, impaired stress response, and aberrant neuroendocrine development. Neuron 20, 1093–1102 (1998).

  131. 131

    Timpl, P. et al. Impaired stress response and reduced anxiety in mice lacking a functional corticotropin-releasing hormone receptor 1. Nature Genet. 19, 162–166 (1998).

  132. 132

    Müller, M. B. et al. Limbic corticotropin-releasing hormone receptor 1 mediates anxiety-related behavior and hormonal adaptation to stress. Nature Neurosci. 6, 1100–1107 (2003). This study presents evidence that limbic CRHR1 modulates anxiety-related behaviour independent of HPA-axis function.

  133. 133

    Pepin, M. C., Pothier, F. & Barden, N. Antidepressant drug action in a transgenic mouse model of the endocrine changes seen in depression. Mol. Pharmacol. 42, 991–995 (1992).

  134. 134

    Heuser, I., Yassouridis, A. & Holsboer, F. The combined dexamethasone/CRH test: a refined laboratory test for psychiatric disorders. J. Psychiatr. Res. 28, 341–356 (1994).

  135. 135

    Meijer, O. C. et al. Penetration of dexamethasone into brain glucocorticoid targets is enhanced in mdr1A P-glycoprotein knockout mice. Endocrinology 139, 1789–1793 (1998).

  136. 136

    Purba, J. S., Hoogendijk, W. J., Hofman, M. A. & Swaab, D. F. Increased number of vasopressin- and oxytocin-expressing neurons in the paraventricular nucleus of the hypothalamus in depression. Arch. Gen. Psychiatry 53, 137–143 (1996).

  137. 137

    Zobel, A. W. et al. Cortisol response in the combined dexamethasone/CRH test as predictor of relapse in patients with remitted depression. A prospective study. J. Psychiatr. Res. 35, 83–94 (2001).

  138. 138

    Modell, S. et al. Hormonal response pattern in the combined DEX-CRH test is stable over time in subjects at high familial risk for affective disorders. Neuropsychopharmacology 18, 253–262 (1998).

  139. 139

    Pariante, C. M. et al. Antidepressants enhance glucocorticoid receptor function in vitro by modulating the membrane steroid transporters. Br. J. Pharmacol. 134, 1335–1343 (2001).

  140. 140

    Sullivan, P. F., Neale, M. C. & Kendler, K. S. Genetic epidemiology of major depression: review and meta-analysis. Am. J. Psychiatry 157, 1552–1562 (2000).

  141. 141

    Heim, C. & Nemeroff, C. B. The role of childhood trauma in the neurobiology of mood and anxiety disorders: preclinical and clinical studies. Biol. Psychiatry 49, 1023–1039 (2001).

  142. 142

    Rinne, T. et al. Hyperresponsiveness of hypothalamic–pituitary–adrenal axis to combined dexamethasone/corticotropin-releasing hormone challenge in female borderline personality disorder subjects with a history of sustained childhood abuse. Biol. Psychiatry 52, 1102–1112 (2002).

  143. 143

    Davidson, J. R., Stein, D. J., Shalev, A. Y. & Yehuda, R. Posttraumatic stress disorder: acquisition, recognition, course, and treatment. J. Neuropsychiatry Clin. Neurosci. 16, 135–147 (2004).

  144. 144

    Lindley, S. E., Carlson, E. B. & Benoit, M. Basal and dexamethasone suppressed salivary cortisol concentrations in a community sample of patients with posttraumatic stress disorder. Biol. Psychiatry 55, 940–945 (2004).

  145. 145

    Binder, E. B. et al. Polymorphisms in FKBP5 are associated with increased recurrence of depressive episodes and rapid response to antidepressant treatment. Nature Genet. 36, 1319–1325 (2004). Individuals carrying a polymorphism in FKBP5, a GR-regulating co-chaperone, showed less HPA axis hyperactivity and a significant association with the response to antidepressants.

  146. 146

    Wochnik, G. M. et al. FKBP51 and FKBP52 differentially regulate dynein interaction and nuclear translocation of the glucocorticoid receptor in mammalian cells. J. Biol. Chem. (in the press).

  147. 147

    van Rossum, E. F. & Lamberts, S. W. Polymorphisms in the glucocorticoid receptor gene and their associations with metabolic parameters and body composition. Recent Prog. Horm. Res. 59, 333–357 (2004).

  148. 148

    Stevens, A. et al. Glucocorticoid sensitivity is determined by a specific glucocorticoid receptor haplotype. J. Clin. Endocrinol. Metab. 89, 892–897 (2004).

  149. 149

    Wüst, S. et al. Common polymorphisms in the glucocorticoid receptor gene are associated with adrenocortical responses to psychosocial stress. J. Clin. Endocrinol. Metab. 89, 565–573 (2004). This was the first report to document an effect of GR gene polymorphisms on cortisol responses to psychosocial stress that might contribute to individual vulnerability to HPA-related disorders.

  150. 150

    Caspi, A. et al. Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science 301, 386–389 (2003). An epidemiological study that provides evidence of a gene-by-environment interaction, in which the response of an individual to environmental insults is moderated by genetic makeup.

  151. 151

    Kaufer, D. et al. Restructuring the neuronal stress response with anti-glucocorticoid gene delivery. Nature Neurosci. 7, 947–953 (2004). In this study, a genetic strategy diminished the neurological damage inflicted by glucocorticoids in the hippocampus. In particular, a chimeric receptor combining the ligand-binding domain of the glucocorticoid receptor and the DNA-binding domain of the oestrogen receptor seemed effective.

  152. 152

    Seckl, J. R. & Walker, B. R. 11β-hydroxysteroid dehydrogenase type 1 as a modulator of glucocorticoid action: from metabolism to memory. Trends Endocrinol. Metab. 15, 418–424 (2004).

  153. 153

    Young, A. H. et al. Improvements in neurocognitive function and mood following adjunctive treatment with mifepristone (RU-486) in bipolar disorder. Neuropsychopharmacology 29, 1538–1545 (2004).

  154. 154

    Zobel, A. W. et al. Effects of the high-affinity corticotropin-releasing hormone receptor 1 antagonist R121919 in major depression: the first 20 patients treated. J. Psychiatr. Res. 34, 171–181 (2000).

  155. 155

    Schatzberg, A. F., Rothschild, A. J., Langlais, P. J., Bird, E. D. & Cole, J. O. A corticosteroid/dopamine hypothesis for psychotic depression and related states. Psychiatr. Res. 19, 57–64 (1985).

  156. 156

    Belanoff, J. K. et al. An open label trial of C-1073 (mifepristone) for psychotic major depression. Biol. Psychiatry 52, 386–392 (2002).

  157. 157

    van der Lely, A. J., Foeken, K., van der Mast, R. C. & Lamberts, S. W. Rapid reversal of acute psychosis in the Cushing syndrome with the cortisol-receptor antagonist mifepristone (RU 486). Ann. Intern. Med. 114, 143–144 (1991).

  158. 158

    Oitzl, M. S., Fluttert, M., Sutanto, W. & de Kloet, E. R. Continuous blockade of brain glucocorticoid receptors facilitates spatial learning and memory in rats. Eur. J. Neurosci. 10, 3759–3766 (1998).

  159. 159

    Bachmann, C. G., Linthorst, A. C., Holsboer, F. & Reul, J. M. Effect of chronic administration of selective glucocorticoid receptor antagonists on the rat hypothalamic–pituitary–adrenocortical axis. Neuropsychopharmacology 28, 1056–1067 (2003).

  160. 160

    Holsboer, F. The rationale for corticotropin-releasing hormone receptor (CRH-R) antagonists to treat depression and anxiety. J. Psychiatr. Res. 33, 181–214 (1999).

  161. 161

    Aerni, A. et al. Low-dose cortisol for symptoms of posttraumatic stress disorder. Am. J. Psychiatry 161, 1488–1490 (2004).

  162. 162

    Schelling, G. et al. Stress doses of hydrocortisone, traumatic memories, and symptoms of posttraumatic stress disorder in patients after cardiac surgery: a randomized study. Biol. Psychiatry 55, 627–633 (2004).

  163. 163

    Hsu, S. Y. & Hsueh, A. J. Human stresscopin and stresscopin-related peptide are selective ligands for the type corticotropin-releasing hormone receptor. Nature Med. 7, 605–611 (2001).

  164. 164

    Reyes, T. M. et al. Urocortin II: a member of the corticotropin-releasing factor (CRF) neuropeptide family that is selectively bound by type 2 CRF receptors. Proc. Natl Acad. Sci. USA 98, 2843–2848 (2001).

  165. 165

    Heinrichs, S. C. & Koob, G. F. Corticotropin-releasing factor in brain: a role in activation, arousal, and affect regulation. J. Pharmacol. Exp. Ther. 311, 427–440 (2004).

  166. 166

    De Bosscher, K., Vanden Berghe, W. & Haegeman, G. The interplay between the glucocorticoid receptor and nuclear factor-κB or activator protein-1: molecular mechanisms for gene repression. Endocr. Rev. 24, 488–522 (2003).

Download references


The authors gratefully acknowledge support by the Netherlands Organization for Scientific Research (NWO) and the Royal Netherlands Academy for Arts and Sciences.

Author information

Correspondence to E. Ron de Kloet.

Ethics declarations

Competing interests

E.R.d.K. and F.H. are on the scientific advisory board of Corcept Therapeutics Inc., and F.H. is on the board of directors of Affectis Pharmaceuticals AG.

Related links

Related links


Entrez Gene





Cushing disease


Leiden/Amsterdam Centre for Drug Research



Excess levels of circulating cortisol.


(PTSD). The symptoms of PTSD consist of re-experiencing an extreme stressor or traumatic event, avoidance of reminders of the event and hyperarousal.


(HPA axis). The HPA axis is the endocrine core of the stress system, which involves hypothalamic corticotropin-releasing hormone, pituitary corticotropin and adrenal cortisol.


The regular recurrence of cycles of less than 24 h from one stated point to another.


Systems that involve serotonin or catecholamines.


(SAGE). This method allows the analysis of overall gene-expression patterns. SAGE does not require a pre-existing clone, so it can be used to identify and quantify new as well as known genes.


Technology that can simultaneously measure the expression patterns of thousands of genes on a single chip.


The prolonged strengthening of synaptic communication, which is induced by patterned input and is thought to be involved in learning and memory formation.


A hormonal disorder that is caused by prolonged exposure of the body tissues to high levels of cortisol, owing to a tumour in the adrenal or anterior pituitary.

Rights and permissions

Reprints and Permissions

About this article

Further reading

Figure 1: Time course of cellular responses to stress hormones.
Figure 2: Gene–environment interactions produce a vulnerable phenotype.