Stress, glucocorticoids and memory: implications for treating fear-related disorders

Key Points

  • Strong aversive memories lie at the core of several fear-related disorders. Therefore, the memory-modulating properties of glucocorticoids have become of considerable translational interest.

  • Glucocorticoids affect distinct memory processes that can synergistically contribute to a reduction of fear-related symptoms, for example, by both reducing aversive-memory retrieval and enhancing the consolidation of fear-extinction memory.

  • Stress promotes a shift from a hippocampus-dependent, 'cognitive' memory system to a dorsal striatum-dependent, 'habitual' memory system, which also plays an important part in fear-related disorders. Importantly, glucocorticoids have similar effects on memory processes in both cognitive and habitual forms of memory.

  • Clinical trials have provided the first evidence that glucocorticoid-based pharmacotherapies aimed at attenuating aversive memories might be helpful in the treatment of fear-related disorders. In particular, the strategy to enhance extinction processes by combining exposure-based psychotherapy with timed glucocorticoid administration seems to be a promising approach to treat fear-related disorders.

  • Evidence indicates that the effects of glucocorticoids on both the consolidation and the retrieval of memory depend on interactions with the endocannabinoid system, which may open novel therapeutic avenues.

  • The evidence that genetic and epigenetic variations in the glucocorticoid system are related to traumatic memory, as well as to post-traumatic stress disorder (PTSD) risk and treatment, adds to the understanding of individual risk and resilience factors for PTSD.

Abstract

Glucocorticoid stress hormones are crucially involved in modulating mnemonic processing of emotionally arousing experiences. They enhance the consolidation of new memories, including those that extinguish older memories, but impair the retrieval of information stored in long-term memory. As strong aversive memories lie at the core of several fear-related disorders, including post-traumatic stress disorder and phobias, the memory-modulating properties of glucocorticoids have recently become of considerable translational interest. Clinical trials have provided the first evidence that glucocorticoid-based pharmacotherapies aimed at attenuating aversive memories might be helpful in the treatment of fear-related disorders. Here, we review important advances in the understanding of how glucocorticoids mediate stress effects on memory processes, and discuss the translational potential of these new conceptual insights.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Glucocorticoid effects on different memory systems under stress.
Figure 2: Glucocorticoid signalling-based intervention strategies.

References

  1. 1

    Joels, M. & Baram, T. Z. The neuro-symphony of stress. Nat. Rev. Neurosci. 10, 459–466 (2009). This review explains why stress requires activation of many different stress mediators and how the effects of individual mediators on neuronal function and plasticity are integrated.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  2. 2

    Roozendaal, B. & McGaugh, J. L. Memory modulation. Behav. Neurosci. 125, 797–824 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  3. 3

    McGaugh, J. L. Memory and Emotion. The Making of Lasting Memories (Weidenfeld and Nicolson, 2003).

    Google Scholar 

  4. 4

    de Quervain, D. J., Aerni, A., Schelling, G. & Roozendaal, B. Glucocorticoids and the regulation of memory in health and disease. Front. Neuroendocrinol. 30, 358–370 (2009).

    CAS  Article  Google Scholar 

  5. 5

    Roozendaal, B., McEwen, B. S. & Chattarji, S. Stress, memory and the amygdala. Nat. Rev. Neurosci. 10, 423–433 (2009).

    CAS  Article  Google Scholar 

  6. 6

    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).

    CAS  Article  Google Scholar 

  7. 7

    de Quervain, D. J., Roozendaal, B. & McGaugh, J. L. Stress and glucocorticoids impair retrieval of long-term spatial memory. Nature 394, 787–790 (1998). This study provided the first evidence that stress, via release of glucocorticoids, has a specific impairing effect on the retrieval of previously stored information.

    CAS  Article  Google Scholar 

  8. 8

    Schwabe, L., Joels, M., Roozendaal, B., Wolf, O. T. & Oitzl, M. S. Stress effects on memory: an update and integration. Neurosci. Biobehav. Rev. 36, 1740–1749 (2012).

    Article  Google Scholar 

  9. 9

    Wolf, O. T. Stress and memory in humans: twelve years of progress? Brain Res. 1293, 142–154 (2009).

    CAS  Article  Google Scholar 

  10. 10

    Bandelow, B., Seidler-Brandler, U., Becker, A., Wedekind, D. & Ruther, E. Meta-analysis of randomized controlled comparisons of psychopharmacological and psychological treatments for anxiety disorders. World J. Biol. Psychiatry 8, 175–187 (2007).

    Article  Google Scholar 

  11. 11

    Bandelow, B. et al. Guidelines for the pharmacological treatment of anxiety disorders, obsessive-compulsive disorder and posttraumatic stress disorder in primary care. Int. J. Psychiatry Clin. Pract. 16, 77–84 (2012).

    CAS  Article  Google Scholar 

  12. 12

    Barton, S., Karner, C., Salih, F., Baldwin, D. S. & Edwards, S. J. Clinical effectiveness of interventions for treatment-resistant anxiety in older people: a systematic review. Health Technol. Assess. 18, 1–59 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  13. 13

    Ipser, J., Seedat, S. & Stein, D. J. Pharmacotherapy for post-traumatic stress disorder — a systematic review and meta-analysis. S. Afr. Med. J. 96, 1088–1096 (2006).

    CAS  PubMed  Google Scholar 

  14. 14

    Lin, C. C., Tung, C. S. & Liu, Y. P. Escitalopram reversed the traumatic stress-induced depressed and anxiety-like symptoms but not the deficits of fear memory. Psychopharmacology (Berl.) 233, 1135–1146 (2016).

    CAS  Article  Google Scholar 

  15. 15

    Parsons, R. G. & Ressler, K. J. Implications of memory modulation for post-traumatic stress and fear disorders. Nat. Neurosci. 16, 146–153 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. 16

    Holbrook, T. L., Galarneau, M. R., Dye, J. L., Quinn, K. & Dougherty, A. L. Morphine use after combat injury in Iraq and post-traumatic stress disorder. N. Engl. J. Med. 362, 110–117 (2010).

    CAS  Article  Google Scholar 

  17. 17

    Pitman, R. K. et al. Pilot study of secondary prevention of posttraumatic stress disorder with propranolol. Biol. Psychiatry 51, 189–192 (2002).

    CAS  Article  Google Scholar 

  18. 18

    Wessa, M. & Flor, H. Failure of extinction of fear responses in posttraumatic stress disorder: evidence from second-order conditioning. Am. J. Psychiatry 164, 1684–1692 (2007).

    Article  Google Scholar 

  19. 19

    Ressler, K. J. et al. Cognitive enhancers as adjuncts to psychotherapy. Use of D-cycloserine in phobic individuals to facilitate extinction of fear. Arch. Gen. Psychiatry 61, 1136–1144 (2004).

    Article  Google Scholar 

  20. 20

    Soeter, M. & Kindt, M. An abrupt transformation of phobic behavior after a post-retrieval amnesic agent. Biol. Psychiatry 78, 880–886 (2015).

    Article  Google Scholar 

  21. 21

    McEwen, B. S., Gray, J. D. & Nasca, C. 60 years of neuroendocrinology: redefining neuroendocrinology: stress, sex and cognitive and emotional regulation. J. Endocrinol. 226, T67–T83 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  22. 22

    Joels, M., Pu, Z., Wiegert, O., Oitzl, M. S. & Krugers, H. J. Learning under stress: how does it work? Trends Cogn. Sci. 10, 152–158 (2006). This influential opinion paper laid the theoretical basis for a number of studies on timing-dependent stress effects in the past 10 years.

    Article  Google Scholar 

  23. 23

    de Kloet, E. R., Karst, H. & Joels, M. Corticosteroid hormones in the central stress response: quick-and-slow. Front. Neuroendocrinol. 29, 268–272 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  24. 24

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

    CAS  Article  Google Scholar 

  25. 25

    Coluccia, D. et al. Glucocorticoid therapy-induced memory deficits: acute versus chronic effects. J. Neurosci. 28, 3474–3478 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  26. 26

    McGaugh, J. L. Memory — a century of consolidation. Science 287, 248–251 (2000). This comprehensive review of memory consolidation research focuses on the role of the amygdala and of the noradrenergic system in the basolateral amygdala in modulating long-term memory consolidation in other brain regions.

    CAS  Article  Google Scholar 

  27. 27

    McGaugh, J. L. & Roozendaal, B. Role of adrenal stress hormones in forming lasting memories in the brain. Curr. Opin. Neurobiol. 12, 205–210 (2002).

    CAS  Article  Google Scholar 

  28. 28

    Roozendaal, B., Bohus, B. & McGaugh, J. L. Dose-dependent suppression of adrenocortical activity with metyrapone: effects on emotion and memory. Psychoneuroendocrinology 21, 681–693 (1996).

    CAS  Article  Google Scholar 

  29. 29

    Maheu, F. S., Joober, R., Beaulieu, S. & Lupien, S. J. Differential effects of adrenergic and corticosteroid hormonal systems on human short- and long-term declarative memory for emotionally arousing material. Behav. Neurosci. 118, 420–428 (2004).

    CAS  Article  Google Scholar 

  30. 30

    Oitzl, M. S. & De Kloet, E. R. Selective corticosteroid antagonists modulate specific aspects of spatial orientation learning. Behav. Neurosci. 106, 62–71 (1992).

    CAS  Article  Google Scholar 

  31. 31

    Roozendaal, B. & McGaugh, J. L. Glucocorticoid receptor agonist and antagonist administration into the basolateral but not central amygdala modulates memory storage. Neurobiol. Learn. Mem. 67, 176–179 (1997).

    CAS  Article  Google Scholar 

  32. 32

    Roozendaal, B., Williams, C. L. & McGaugh, J. L. Glucocorticoid receptor activation in the rat nucleus of the solitary tract facilitates memory consolidation: involvement of the basolateral amygdala. Eur. J. Neurosci. 11, 1317–1323 (1999).

    CAS  Article  Google Scholar 

  33. 33

    Andreano, J. M. & Cahill, L. Glucocorticoid release and memory consolidation in men and women. Psychol. Sci. 17, 466–470 (2006).

    Article  Google Scholar 

  34. 34

    Preuss, D. & Wolf, O. T. Post-learning psychosocial stress enhances consolidation of neutral stimuli. Neurobiol. Learn. Mem. 92, 318–326 (2009).

    Article  Google Scholar 

  35. 35

    Cornelisse, S., van Stegeren, A. H. & Joels, M. Implications of psychosocial stress on memory formation in a typical male versus female student sample. Psychoneuroendocrinology 36, 569–578 (2011).

    Article  Google Scholar 

  36. 36

    Buchanan, T. W. & Lovallo, W. R. Enhanced memory for emotional material following stress-level cortisol treatment in humans. Psychoneuroendocrinology 26, 307–317 (2001).

    CAS  Article  Google Scholar 

  37. 37

    Roozendaal, B., Okuda, S., van der Zee, E. A. & McGaugh, J. L. Glucocorticoid enhancement of memory requires arousal-induced noradrenergic activation in the basolateral amygdala. Proc. Natl Acad. Sci. USA 103, 6741–6746 (2006). This study shows that glucocorticoids require emotional arousal-induced noradrenergic activation in the basolateral amygdalato influence memory consolidation.

    CAS  Article  Google Scholar 

  38. 38

    Segal, S. K. et al. Glucocorticoids interact with noradrenergic activation at encoding to enhance long-term memory for emotional material in women. Neuroscience 277, 267–272 (2014).

    CAS  Article  Google Scholar 

  39. 39

    Kuhlmann, S. & Wolf, O. T. Arousal and cortisol interact in modulating memory consolidation in healthy young men. Behav. Neurosci. 120, 217–223 (2006).

    CAS  Article  Google Scholar 

  40. 40

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

    Article  Google Scholar 

  41. 41

    Revest, J. M. et al. The MAPK pathway and Egr-1 mediate stress-related behavioral effects of glucocorticoids. Nat. Neurosci. 8, 664–672 (2005).

    CAS  Article  Google Scholar 

  42. 42

    Bisaz, R., Conboy, L. & Sandi, C. Learning under stress: a role for the neural cell adhesion molecule NCAM. Neurobiol. Learn. Mem. 91, 333–342 (2009).

    CAS  Article  Google Scholar 

  43. 43

    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).

    CAS  Article  Google Scholar 

  44. 44

    Riedemann, T., Patchev, A. V., Cho, K. & Almeida, O. F. Corticosteroids: way upstream. Mol. Brain 3, 2 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. 45

    Johnson, L. R., Farb, C., Morrison, J. H., McEwen, B. S. & LeDoux, J. E. Localization of glucocorticoid receptors at postsynaptic membranes in the lateral amygdala. Neuroscience 136, 289–299 (2005).

    CAS  Article  Google Scholar 

  46. 46

    Barsegyan, A., Mackenzie, S. M., Kurose, B. D., McGaugh, J. L. & Roozendaal, B. Glucocorticoids in the prefrontal cortex enhance memory consolidation and impair working memory by a common neural mechanism. Proc. Natl Acad. Sci. USA 107, 16655–16660 (2010).

    CAS  Article  Google Scholar 

  47. 47

    Roozendaal, B. et al. Membrane-associated glucocorticoid activity is necessary for modulation of long-term memory via chromatin modification. J. Neurosci. 30, 5037–5046 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  48. 48

    Lee, E. J. et al. Impairment of fear memory consolidation in maternally stressed male mouse offspring: evidence for nongenomic glucocorticoid action on the amygdala. J. Neurosci. 31, 7131–7140 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  49. 49

    Karst, H. et al. Mineralocorticoid receptors are indispensable for nongenomic modulation of hippocampal glutamate transmission by corticosterone. Proc. Natl Acad. Sci. USA 102, 19204–19207 (2005).

    CAS  Article  Google Scholar 

  50. 50

    Krugers, H. J., Hoogenraad, C. C. & Groc, L. Stress hormones and AMPA receptor trafficking in synaptic plasticity and memory. Nat. Rev. Neurosci. 11, 675–681 (2010).

    CAS  Article  Google Scholar 

  51. 51

    Conboy, L. & Sandi, C. Stress at learning facilitates memory formation by regulating AMPA receptor trafficking through a glucocorticoid action. Neuropsychopharmacology 35, 674–685 (2010).

    CAS  Article  Google Scholar 

  52. 52

    Zhou, M., Hoogenraad, C. C., Joels, M. & Krugers, H. J. Combined β-adrenergic and corticosteroid receptor activation regulates AMPA receptor function in hippocampal neurons. J. Psychopharmacol. 26, 516–524 (2012).

    CAS  Article  Google Scholar 

  53. 53

    Chen, D. Y., Bambah-Mukku, D., Pollonini, G. & Alberini, C. M. Glucocorticoid receptors recruit the CaMKIIα–BDNF–CREB pathways to mediate memory consolidation. Nat. Neurosci. 15, 1707–1714 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  54. 54

    Campolongo, P. et al. Endocannabinoids in the rat basolateral amygdala enhance memory consolidation and enable glucocorticoid modulation of memory. Proc. Natl Acad. Sci. USA 106, 4888–4893 (2009). This article shows that activation of cannabinoid type 1 receptorsin the basolateral amygdalaenhances memory consolidation and provides the first in vivo demonstration in mammals that endocannabinoid activity is required to enable the memory-enhancing effects of glucocorticoids.

    CAS  Article  Google Scholar 

  55. 55

    Chauveau, F. et al. Rapid stress-induced corticosterone rise in the hippocampus reverses serial memory retrieval pattern. Hippocampus 20, 196–207 (2010).

    CAS  PubMed  Google Scholar 

  56. 56

    Roozendaal, B., Hahn, E. L., Nathan, S. V., de Quervain, D. J. & McGaugh, J. L. Glucocorticoid effects on memory retrieval require concurrent noradrenergic activity in the hippocampus and basolateral amygdala. J. Neurosci. 24, 8161–8169 (2004).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  57. 57

    de Quervain, D. J., Roozendaal, B., Nitsch, R. M., McGaugh, J. L. & Hock, C. Acute cortisone administration impairs retrieval of long-term declarative memory in humans. Nat. Neurosci. 3, 313–314 (2000).

    CAS  Article  Google Scholar 

  58. 58

    de Quervain, D. J., Aerni, A. & Roozendaal, B. Preventive effect of β-adrenoceptor blockade on glucocorticoid-induced memory retrieval deficits. Am. J. Psychiatry 164, 967–969 (2007).

    Article  Google Scholar 

  59. 59

    Kuhlmann, S., Piel, M. & Wolf, O. T. Impaired memory retrieval after psychosocial stress in healthy young men. J. Neurosci. 25, 2977–2982 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  60. 60

    Schwabe, L. et al. Stress effects on declarative memory retrieval are blocked by a β-adrenoceptor antagonist in humans. Psychoneuroendocrinology 34, 446–454 (2009).

    CAS  Article  Google Scholar 

  61. 61

    Atsak, P. et al. Glucocorticoids interact with the hippocampal endocannabinoid system in impairing retrieval of contextual fear memory. Proc. Natl Acad. Sci. USA 109, 3504–3509 (2012).

    CAS  Article  Google Scholar 

  62. 62

    Kuhlmann, S. & Wolf, O. T. Cortisol and memory retrieval in women: influence of menstrual cycle and oral contraceptives. Psychopharmacology (Berl.) 183, 65–71 (2005).

    CAS  Article  Google Scholar 

  63. 63

    Quirk, G. J. & Mueller, D. Neural mechanisms of extinction learning and retrieval. Neuropsychopharmacology 33, 56–72 (2008).

    PubMed  Google Scholar 

  64. 64

    Milad, M. R. & Quirk, G. J. Fear extinction as a model for translational neuroscience: ten years of progress. Annu. Rev. Psychol. 63, 129–151 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  65. 65

    Barrett, D. & Gonzalez-Lima, F. Behavioral effects of metyrapone on Pavlovian extinction. Neurosci. Lett. 371, 91–96 (2004).

    CAS  Article  Google Scholar 

  66. 66

    Cai, W. H., Blundell, J., Han, J., Greene, R. W. & Powell, C. M. Postreactivation glucocorticoids impair recall of established fear memory. J. Neurosci. 26, 9560–9566 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  67. 67

    Yang, Y. L., Chao, P. K. & Lu, K. T. Systemic and intra-amygdala administration of glucocorticoid agonist and antagonist modulate extinction of conditioned fear. Neuropsychopharmacology 31, 912–924 (2006).

    CAS  Article  Google Scholar 

  68. 68

    Blundell, J., Blaiss, C. A., Lagace, D. C., Eisch, A. J. & Powell, C. M. Block of glucocorticoid synthesis during re-activation inhibits extinction of an established fear memory. Neurobiol. Learn. Mem. 95, 453–460 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  69. 69

    Bohus, B. & Lissak, K. Adrenocortical hormones and avoidance behaviour of rats. Int. J. Neuropharmacol. 7, 301–306 (1968).

    CAS  Article  Google Scholar 

  70. 70

    Clay, R. et al. Glucocorticoids are required for extinction of predator stress-induced hyperarousal. Neurobiol. Learn. Mem. 96, 367–377 (2011).

    CAS  Article  Google Scholar 

  71. 71

    Nader, K. & Hardt, O. A single standard for memory: the case for reconsolidation. Nat. Rev. Neurosci. 10, 224–234 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  72. 72

    Nader, K., Schafe, G. E. & LeDoux, J. E. Fear memories require protein synthesis in the amygdala for reconsolidation after retrieval. Nature 406, 722–726 (2000).

    CAS  Article  Google Scholar 

  73. 73

    Schwabe, L., Nader, K. & Pruessner, J. C. Reconsolidation of human memory: brain mechanisms and clinical relevance. Biol. Psychiatry 76, 274–280 (2014).

    Article  Google Scholar 

  74. 74

    Alberini, C. M. Mechanisms of memory stabilization: are consolidation and reconsolidation similar or distinct processes? Trends Neurosci. 28, 51–56 (2005).

    CAS  Article  Google Scholar 

  75. 75

    Schwabe, L. & Wolf, O. T. Stress impairs the reconsolidation of autobiographical memories. Neurobiol. Learn. Mem. 94, 153–157 (2010).

    Article  Google Scholar 

  76. 76

    Coccoz, V., Maldonado, H. & Delorenzi, A. The enhancement of reconsolidation with a naturalistic mild stressor improves the expression of a declarative memory in humans. Neuroscience 185, 61–72 (2011).

    CAS  Article  Google Scholar 

  77. 77

    Bos, M. G., Schuijer, J., Lodestijn, F., Beckers, T. & Kindt, M. Stress enhances reconsolidation of declarative memory. Psychoneuroendocrinology 46, 102–113 (2014).

    Article  Google Scholar 

  78. 78

    Nikzad, S., Vafaei, A. A., Rashidy-Pour, A. & Haghighi, S. Systemic and intrahippocampal administrations of the glucocorticoid receptor antagonist RU38486 impairs fear memory reconsolidation in rats. Stress 14, 459–464 (2011).

    CAS  Article  Google Scholar 

  79. 79

    Pitman, R. K. et al. Systemic mifepristone blocks reconsolidation of cue-conditioned fear; propranolol prevents this effect. Behav. Neurosci. 125, 632–638 (2011).

    Article  Google Scholar 

  80. 80

    Abrari, K., Rashidy-Pour, A., Semnanian, S. & Fathollahi, Y. Administration of corticosterone after memory reactivation disrupts subsequent retrieval of a contextual conditioned fear memory: dependence upon training intensity. Neurobiol. Learn. Mem. 89, 178–184 (2008).

    CAS  Article  Google Scholar 

  81. 81

    Drexler, S. M., Merz, C. J., Hamacher-Dang, T. C., Tegenthoff, M. & Wolf, O. T. Effects of cortisol on reconsolidation of reactivated fear memories. Neuropsychopharmacology 40, 3036–3043 (2015).

    Article  CAS  Google Scholar 

  82. 82

    Meir Drexler, S., Merz, C. J., Hamacher-Dang, T. C. & Wolf, O. T. Cortisol effects on fear memory reconsolidation in women. Psychopharmacology (Berl.) 233, 2687–2697 (2016).

    CAS  Article  Google Scholar 

  83. 83

    Joels, M., Fernandez, G. & Roozendaal, B. Stress and emotional memory: a matter of timing. Trends Cogn. Sci. 15, 280–288 (2011).

    Article  Google Scholar 

  84. 84

    Hermans, E. J. et al. Stress-related noradrenergic activity prompts large-scale neural network reconfiguration. Science 334, 1151–1153 (2011).

    CAS  Article  Google Scholar 

  85. 85

    Katsuki, H., Izumi, Y. & Zorumski, C. F. Noradrenergic regulation of synaptic plasticity in the hippocampal CA1 region. J. Neurophysiol. 77, 3013–3020 (1997).

    CAS  Article  Google Scholar 

  86. 86

    Vogel, S. & Schwabe, L. Stress in the zoo: tracking the impact of stress on memory formation over time. Psychoneuroendocrinology 71, 64–72 (2016).

    Article  Google Scholar 

  87. 87

    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).

    CAS  Article  Google Scholar 

  88. 88

    Schönfeld, P., Ackermann, K. & Schwabe, L. Remembering under stress: different roles of autonomic arousal and glucocorticoids in memory retrieval. Psychoneuroendocrinology 39, 249–256 (2014).

    Article  CAS  Google Scholar 

  89. 89

    Zoladz, P. R. et al. Pre-learning stress differentially affects long-term memory for emotional words, depending on temporal proximity to the learning experience. Physiol. Behav. 103, 467–476 (2011).

    CAS  Article  Google Scholar 

  90. 90

    Schwabe, L. & Wolf, O. T. Timing matters: temporal dynamics of stress effects on memory retrieval. Cogn. Affect. Behav. Neurosci. 14, 1041–1048 (2014).

    Article  Google Scholar 

  91. 91

    Wiegert, O., Joels, M. & Krugers, H. J. Timing is essential for rapid effects of corticosterone on synaptic potentiation in the mouse hippocampus. Learn. Mem. 13, 110–113 (2006).

    CAS  Article  Google Scholar 

  92. 92

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

    CAS  Article  Google Scholar 

  93. 93

    Henckens, M. J. A. G. et al. Dynamically changing effects of corticosteroids on human hippocampal and prefrontal processing. Hum. Brain Mapp. 33, 2885–2897 (2012).

    Article  Google Scholar 

  94. 94

    Henckens, M. J. A. G., van Wingen, G. A., Joels, M. & Fernandez, G. Time-dependent effects of corticosteroids on human amygdala processing. J. Neurosci. 30, 12725–12732 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  95. 95

    Miranda, M. I., Quirarte, G. L., Rodriguez-Garcia, G., McGaugh, J. L. & Roozendaal, B. Glucocorticoids enhance taste aversion memory via actions in the insular cortex and basolateral amygdala. Learn. Mem. 15, 468–476 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  96. 96

    Fornari, R. V. et al. Involvement of the insular cortex in regulating glucocorticoid effects on memory consolidation of inhibitory avoidance training. Front. Behav. Neurosci. 6, 10 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  97. 97

    Packard, M. G. & Knowlton, B. J. Learning and memory functions of the basal ganglia. Annu. Rev. Neurosci. 25, 563–593 (2002).

    CAS  Article  Google Scholar 

  98. 98

    Hermans, E. J. et al. How the amygdala affects emotional memory by altering brain network properties. Neurobiol. Learn. Mem. 112, 2–16 (2014).

    Article  Google Scholar 

  99. 99

    McDonald, R. & White, N. Parallel information processing in the water maze: evidence for independent memory systems involving dorsal striatum and hippocampus. Behav. Neural Biol. 61, 260–270 (1994).

    CAS  Article  Google Scholar 

  100. 100

    Poldrack, R. A. & Packard, M. Competition among multiple memory systems: converging evidence from animal and human brain studies. Neuropsychologia 41, 245–251 (2003).

    Article  Google Scholar 

  101. 101

    Goodman, J., Leong, K. C. & Packard, M. G. Emotional modulation of multiple memory systems: implications for the neurobiology of post-traumatic stress disorder. Rev. Neurosci. 23, 627–643 (2012).

    CAS  Article  Google Scholar 

  102. 102

    Schwabe, L. Stress and the engagement of multiple memory systems: integration of animal and human studies. Hippocampus 23, 1035–1043 (2013).

    Article  Google Scholar 

  103. 103

    Schwabe, L., Wolf, O. T. & Oitzl, M. S. Memory formation under stress: quantity and quality. Neurosci. Biobehav. Rev. 34, 584–591 (2010).

    Article  Google Scholar 

  104. 104

    Kim, J., Lee, H., Han, J. & Packard, M. Amygdala is critical for stress-induced modulation of hippocampal long-term potentiation and learning. J. Neurosci. 21, 5222–5228 (2001). This study provided the first evidence that stress may lead to a shift from hippocampus-dependent to dorsal striatum-dependent spatial memory.

    CAS  Article  Google Scholar 

  105. 105

    Schwabe, L. et al. Stress modulates the use of spatial and stimulus-response learning strategies in humans. Learn. Mem. 14, 109–116 (2007). This study showed for the first time in humans that stress may promote simple S–R learning at the expense of cognitively more-demanding spatial learning.

    Article  PubMed  PubMed Central  Google Scholar 

  106. 106

    Schwabe, L., Schächinger, H., de Kloet, E. R. & Oitzl, M. S. Corticosteroids operate as switch between memory systems. J. Cogn. Neurosci. 22, 1362–1372 (2010).

    Article  Google Scholar 

  107. 107

    Schwabe, L., Tegenthoff, M., Höffken, O. & Wolf, O. T. Mineralocorticoid receptor blockade prevents stress-induced modulation of multiple memory systems in the human brain. Biol. Psychiatry 74, 801–808 (2013).

    CAS  Article  Google Scholar 

  108. 108

    Vogel, S., Fernandez, G., Joëls, M. & Schwabe, L. Cognitive adaptation under stress: a case for the mineralocorticoid receptor. Trends Cogn. Sci. 20, 192–203 (2016). This paper provides a state-of-the-art review of how stress biases the engagement of multiple memory systems and of the neuroendocrine mechanisms that are involved in these effects.

    Article  Google Scholar 

  109. 109

    Schwabe, L. & Wolf, O. T. Stress prompts habit behavior in humans. J. Neurosci. 29, 7191–7198 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  110. 110

    Braun, S. & Hauber, W. Acute stressor effects on goal-directed action in rats. Learn. Mem. 20, 700–709 (2013).

    Article  Google Scholar 

  111. 111

    Schwabe, L., Tegenthoff, M., Höffken, O. & Wolf, O. T. Concurrent glucocorticoid and noradrenergic activity shifts instrumental behavior from goal-directed to habitual control. J. Neurosci. 30, 8190–8196 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  112. 112

    Schwabe, L., Höffken, O., Tegenthoff, M. & Wolf, O. T. Preventing the stress-induced shift from goal-directed to habit action with a β-adrenergic antagonist. J. Neurosci. 31, 17317–17325 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  113. 113

    Schwabe, L., Tegenthoff, M., Höffken, O. & Wolf, O. T. Simultaneous glucocorticoid and noradrenergic activity disrupts the neural basis of goal-directed action in the human brain. J. Neurosci. 32, 10146–10155 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  114. 114

    Paquette, V. et al. “Change the mind and you change the brain”: effects of cognitive-behavioral therapy on the neural correlates of spider phobia. Neuroimage 18, 401–409 (2003).

    Article  Google Scholar 

  115. 115

    Mickleborough, M. J. et al. Effects of trauma-related cues on pain processing in posttraumatic stress disorder: an fMRI investigation. J. Psychiatry Neurosci. 36, 6–14 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  116. 116

    Quirarte, G. L. et al. Corticosterone infused into the dorsal striatum selectively enhances memory consolidation of cued water-maze training. Learn. Mem. 16, 586–589 (2009).

    CAS  Article  Google Scholar 

  117. 117

    Medina, A. C. et al. Glucocorticoid administration into the dorsal striatum facilitates memory consolidation of inhibitory avoidance training but not of the context or footshock components. Learn. Mem. 14, 673–677 (2007).

    CAS  Article  Google Scholar 

  118. 118

    Guenzel, F. M., Wolf, O. T. & Schwabe, L. Glucocorticoids boost stimulus–response memory formation in humans. Psychoneuroendocrinology 45, 21–30 (2014).

    CAS  Article  Google Scholar 

  119. 119

    Atsak, P. et al. Glucocorticoids mediate stress-induced impairment of retrieval of stimulus–response memory. Psychoneuroendocrinology 67, 207–215 (2016).

    CAS  Article  Google Scholar 

  120. 120

    Burguiere, E., Monteiro, P., Mallet, L., Feng, G. & Graybiel, A. M. Striatal circuits, habits, and implications for obsessive–compulsive disorder. Curr. Opin. Neurobiol. 30, 59–65 (2015).

    CAS  Article  Google Scholar 

  121. 121

    Meewisse, M. L., Reitsma, J. B., de Vries, G. J., Gersons, B. P. & Olff, M. Cortisol and post-traumatic stress disorder in adults: systematic review and meta-analysis. Br. J. Psychiatry 191, 387–392 (2007).

    Article  Google Scholar 

  122. 122

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

    CAS  Article  Google Scholar 

  123. 123

    Pitman, R. K. et al. Biological studies of post-traumatic stress disorder. Nat. Rev. Neurosci. 13, 769–787 (2012). This is a comprehensive review about the neurobiology of PTSD.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  124. 124

    Yehuda, R. Status of glucocorticoid alterations in post-traumatic stress disorder. Ann. NY Acad. Sci. 1179, 56–69 (2009).

    CAS  Article  Google Scholar 

  125. 125

    van Zuiden, M. et al. Pre-existing high glucocorticoid receptor number predicting development of posttraumatic stress symptoms after military deployment. Am. J. Psychiatry 168, 89–96 (2011).

    Article  Google Scholar 

  126. 126

    van Zuiden, M., Kavelaars, A., Geuze, E., Olff, M. & Heijnen, C. J. Predicting PTSD: pre-existing vulnerabilities in glucocorticoid-signaling and implications for preventive interventions. Brain Behav. Immun. 30, 12–21 (2013).

    CAS  Article  Google Scholar 

  127. 127

    Castro-Vale, I., van Rossum, E. F., Machado, J. C., Mota-Cardoso, R. & Carvalho, D. Genetics of glucocorticoid regulation and posttraumatic stress disorder — what do we know? Neurosci. Biobehav. Rev. 63, 143–157 (2016).

    CAS  Article  Google Scholar 

  128. 128

    Zohar, J. et al. High dose hydrocortisone immediately after trauma may alter the trajectory of PTSD: interplay between clinical and animal studies. Eur. Neuropsychopharmacol. 21, 796–809 (2011).

    CAS  Article  Google Scholar 

  129. 129

    Kok, L. et al. The effect of dexamethasone on symptoms of posttraumatic stress disorder and depression after cardiac surgery and intensive care admission: longitudinal follow-up of a randomized controlled trial. Crit. Care Med. 44, 512–520 (2016).

    CAS  Article  Google Scholar 

  130. 130

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

    Article  Google Scholar 

  131. 131

    Ludascher, P. et al. No evidence for differential dose effects of hydrocortisone on intrusive memories in female patients with complex post-traumatic stress disorder — a randomized, double-blind, placebo-controlled, crossover study. J. Psychopharmacol. 29, 1077–1084 (2015).

    Article  CAS  Google Scholar 

  132. 132

    Suris, A., North, C., Adinoff, B., Powell, C. M. & Greene, R. Effects of exogenous glucocorticoid on combat-related PTSD symptoms. Ann. Clin. Psychiatry 22, 274–279 (2010).

    PubMed  PubMed Central  Google Scholar 

  133. 133

    Yehuda, R., Bierer, L. M., Pratchett, L. & Malowney, M. Glucocorticoid augmentation of prolonged exposure therapy: rationale and case report. Eur. J. Psychotraumatol. http://dx.doi.org/10.3402/ejpt.v1i0.5643 (2010).

  134. 134

    Yehuda, R. et al. Cortisol augmentation of a psychological treatment for warfighters with posttraumatic stress disorder: randomized trial showing improved treatment retention and outcome. Psychoneuroendocrinology 51, 589–597 (2015).

    CAS  Article  Google Scholar 

  135. 135

    Wood, N. E. et al. Pharmacological blockade of memory reconsolidation in posttraumatic stress disorder: three negative psychophysiological studies. Psychiatry Res. 225, 31–39 (2015).

    Article  Google Scholar 

  136. 136

    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).

    CAS  Article  Google Scholar 

  137. 137

    Schelling, G. et al. The effect of stress doses of hydrocortisone during septic shock on posttraumatic stress disorder in survivors. Biol. Psychiatry 50, 978–985 (2001).

    CAS  Article  Google Scholar 

  138. 138

    Weis, F. et al. Stress doses of hydrocortisone reduce chronic stress symptoms and improve health-related quality of life in high-risk patients after cardiac surgery: a randomized study. J. Thorac. Cardiovasc. Surg. 131, 277–282 (2006).

    CAS  Article  Google Scholar 

  139. 139

    Delahanty, D. L. et al. The efficacy of initial hydrocortisone administration at preventing posttraumatic distress in adult trauma patients: a randomized trial. CNS Spectr. 18, 103–111 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  140. 140

    Delahanty, D. L., Raimonde, A. J. & Spoonster, E. Initial posttraumatic urinary cortisol levels predict subsequent PTSD symptoms in motor vehicle accident victims. Biol. Psychiatry 48, 940–947 (2000).

    CAS  Article  Google Scholar 

  141. 141

    McFarlane, A. C., Atchison, M. & Yehuda, R. The acute stress response following motor vehicle accidents and its relation to PTSD. Ann. NY Acad. Sci. 821, 437–441 (1997).

    CAS  Article  Google Scholar 

  142. 142

    Yehuda, R., McFarlane, A. C. & Shalev, A. Y. Predicting the development of posttraumatic stress disorder from the acute response to a traumatic event. Biol. Psychiatry 44, 1305–1313 (1998).

    CAS  Article  Google Scholar 

  143. 143

    Sijbrandij, M., Kleiboer, A., Bisson, J. I., Barbui, C. & Cuijpers, P. Pharmacological prevention of post-traumatic stress disorder and acute stress disorder: a systematic review and meta-analysis. Lancet Psychiatry 2, 413–421 (2015).

    Article  Google Scholar 

  144. 144

    Amos, T., Stein, D. J. & Ipser, J. C. Pharmacological interventions for preventing post-traumatic stress disorder (PTSD). Cochrane Database Syst. Rev. 7, CD006239 (2014).

    Google Scholar 

  145. 145

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT00855270?term=NCT00855270&rank=1 (2016).

  146. 146

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02402114?term=NCT02402114&rank=1 (2015).

  147. 147

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT00674570?term=NCT00674570&rank=1 (2016).

  148. 148

    Elnazer, H. Y. & Baldwin, D. S. Investigation of cortisol levels in patients with anxiety disorders: a structured review. Curr. Top. Behav. Neurosci. 18, 191–216 (2014).

    CAS  Article  Google Scholar 

  149. 149

    Soravia, L. M. et al. Glucocorticoids reduce phobic fear in humans. Proc. Natl Acad. Sci. USA 103, 5585–5590 (2006).

    CAS  Article  Google Scholar 

  150. 150

    de Quervain, D. J. et al. Glucocorticoids enhance extinction-based psychotherapy. Proc. Natl Acad. Sci. USA 108, 6621–6625 (2011). This study provided the first evidence that glucocorticoid effects on memory can be used to enhance the outcome of extinction-based psychotherapy.

    CAS  Article  Google Scholar 

  151. 151

    Soravia, L. M. et al. Glucocorticoids enhance in vivo exposure-based therapy of spider phobia. Depress. Anxiety 31, 429–435 (2014).

    CAS  Article  Google Scholar 

  152. 152

    Lass-Hennemann, J. & Michael, T. Endogenous cortisol levels influence exposure therapy in spider phobia. Behav. Res. Ther. 60, 39–45 (2014).

    Article  Google Scholar 

  153. 153

    Tiffany, S. T. & Wray, J. M. The clinical significance of drug craving. Ann. NY Acad. Sci. 1248, 1–17 (2012).

    CAS  Article  Google Scholar 

  154. 154

    Preller, K. H. et al. Sustained incentive value of heroin-related cues in short- and long-term abstinent heroin users. Eur. Neuropsychopharmacol. 23, 1270–1279 (2013).

    CAS  Article  Google Scholar 

  155. 155

    Robinson, T. E. & Berridge, K. C. The psychology and neurobiology of addiction: an incentive–sensitization view. Addiction 95 (Suppl. 2), 91–117 (2000).

    Google Scholar 

  156. 156

    Kelley, A. E. Memory and addiction: shared neural circuitry and molecular mechanisms. Neuron 44, 161–179 (2004).

    CAS  Article  Google Scholar 

  157. 157

    Walter, M. et al. Effects of cortisol administration on craving in heroin addicts. Transl Psychiatry 5, e610 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  158. 158

    Milad, M. R. et al. Deficits in conditioned fear extinction in obsessive-compulsive disorder and neurobiological changes in the fear circuit. JAMA Psychiatry 70, 608–618 (2013).

    Article  Google Scholar 

  159. 159

    Mineka, S. & Oehlberg, K. The relevance of recent developments in classical conditioning to understanding the etiology and maintenance of anxiety disorders. Acta Psychol. (Amst.) 127, 567–580 (2008).

    Article  Google Scholar 

  160. 160

    Pitman, R. K. Post-traumatic stress disorder, hormones, and memory. Biol. Psychiatry 26, 221–223 (1989).

    CAS  Article  Google Scholar 

  161. 161

    LeDoux, J. The emotional brain, fear, and the amygdala. Cell. Mol. Neurobiol. 23, 727–738 (2003).

    Article  Google Scholar 

  162. 162

    Phelps, E. A. & LeDoux, J. E. Contributions of the amygdala to emotion processing: from animal models to human behavior. Neuron 48, 175–187 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  163. 163

    Yehuda, R. & LeDoux, J. Response variation following trauma: a translational neuroscience approach to understanding PTSD. Neuron 56, 19–32 (2007).

    CAS  Article  Google Scholar 

  164. 164

    Brewin, C. R. & Holmes, E. A. Psychological theories of posttraumatic stress disorder. Clin. Psychol. Rev. 23, 339–376 (2003).

    Article  Google Scholar 

  165. 165

    Cahill, L., Babinsky, R., Markowitsch, H. J. & McGaugh, J. L. The amygdala and emotional memory. Nature 377, 295–296 (1995).

    CAS  Article  Google Scholar 

  166. 166

    Francati, V., Vermetten, E. & Bremner, J. D. Functional neuroimaging studies in posttraumatic stress disorder: review of current methods and findings. Depress. Anxiety 24, 202–218 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  167. 167

    Armony, J. L., Corbo, V., Clement, M. H. & Brunet, A. Amygdala response in patients with acute PTSD to masked and unmasked emotional facial expressions. Am. J. Psychiatry 162, 1961–1963 (2005).

    Article  Google Scholar 

  168. 168

    Dickie, E. W., Brunet, A., Akerib, V. & Armony, J. L. An fMRI investigation of memory encoding in PTSD: influence of symptom severity. Neuropsychologia 46, 1522–1531 (2008).

    Article  Google Scholar 

  169. 169

    Shin, L. M. et al. A functional magnetic resonance imaging study of amygdala and medial prefrontal cortex responses to overtly presented fearful faces in posttraumatic stress disorder. Arch. Gen. Psychiatry 62, 273–281 (2005).

    Article  Google Scholar 

  170. 170

    Heim, C. & Nemeroff, C. B. Neurobiology of posttraumatic stress disorder. CNS Spectr. 14, 13–24 (2009).

    Article  Google Scholar 

  171. 171

    Ipser, J. C., Singh, L. & Stein, D. J. Meta-analysis of functional brain imaging in specific phobia. Psychiatry Clin. Neurosci. 67, 311–322 (2013).

    Article  Google Scholar 

  172. 172

    Barlow, D. H. & Liebowitz, M. R. in Comprehensive Textbook of Psychiatry/VI 6th edn (eds Kaplan, H. I. & Sadock, B. J.) 1204–1218 (Williams and Wilkins, 1995).

    Google Scholar 

  173. 173

    Marks, I. Fears, Phobias and Rituals: Panic, Anxiety, and their Disorders (Oxford Univ. Press, 1987).

    Google Scholar 

  174. 174

    Bentz, D., Michael, T., de Quervain, D. J. & Wilhelm, F. H. Enhancing exposure therapy for anxiety disorders with glucocorticoids: from basic mechanisms of emotional learning to clinical applications. J. Anxiety Disord. 24, 223–230 (2010).

    Article  Google Scholar 

  175. 175

    McNally, R. J. Mechanisms of exposure therapy: how neuroscience can improve psychological treatments for anxiety disorders. Clin. Psychol. Rev. 27, 750–759 (2007).

    Article  Google Scholar 

  176. 176

    Hermans, D., Craske, M. G., Mineka, S. & Lovibond, P. F. Extinction in human fear conditioning. Biol. Psychiatry 60, 361–368 (2006).

    Article  Google Scholar 

  177. 177

    Hamm, A. O. Specific phobias. Psychiatr. Clin. North Am. 32, 577–591 (2009).

    Article  Google Scholar 

  178. 178

    Nader, K. Reconsolidation and the dynamic nature of memory. Cold Spring Harb. Perspect. Biol. 7, a021782 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. 179

    Kandel, E. R. The molecular biology of memory storage: a dialogue between genes and synapses. Science 294, 1030–1038 (2001).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  180. 180

    Schwabe, L. & Wolf, O. T. Stress and multiple memory systems: from 'thinking' to 'doing'. Trends Cogn. Sci. 17, 60–68 (2013).

    Article  Google Scholar 

  181. 181

    Bouton, M. E. Context, ambiguity, and unlearning: sources of relapse after behavioral extinction. Biol. Psychiatry 52, 976–986 (2002).

    Article  Google Scholar 

  182. 182

    Ohno-Shosaku, T. & Kano, M. Endocannabinoid-mediated retrograde modulation of synaptic transmission. Curr. Opin. Neurobiol. 29, 1–8 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  183. 183

    Di, S., Malcher-Lopes, R., Marcheselli, V. L., Bazan, N. G. & Tasker, J. G. Rapid glucocorticoid-mediated endocannabinoid release and opposing regulation of glutamate and γ-aminobutyric acid inputs to hypothalamic magnocellular neurons. Endocrinology 146, 4292–4301 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  184. 184

    Evanson, N. K., Tasker, J. G., Hill, M. N., Hillard, C. J. & Herman, J. P. Fast feedback inhibition of the HPA axis by glucocorticoids is mediated by endocannabinoid signaling. Endocrinology 151, 4811–4819 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  185. 185

    Marco, E. M. & Laviola, G. The endocannabinoid system in the regulation of emotions throughout lifespan: a discussion on therapeutic perspectives. J. Psychopharmacol. 26, 150–163 (2012).

    CAS  Article  Google Scholar 

  186. 186

    Marsicano, G. et al. The endogenous cannabinoid system controls extinction of aversive memories. Nature 418, 530–534 (2002).

    CAS  Article  Google Scholar 

  187. 187

    Hill, M. N., Karatsoreos, I. N., Hillard, C. J. & McEwen, B. S. Rapid elevations in limbic endocannabinoid content by glucocorticoid hormones in vivo. Psychoneuroendocrinology 35, 1333–1338 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  188. 188

    Atsak, P. et al. Endocannabinoid signaling within the basolateral amygdala integrates multiple stress hormone effects on memory consolidation. Neuropsychopharmacology 40, 1485–1494 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  189. 189

    de Oliveira Alvares, L. et al. Stress response recruits the hippocampal endocannabinoid system for the modulation of fear memory. Learn. Mem. 17, 202–209 (2010).

    Article  CAS  Google Scholar 

  190. 190

    Katona, I. et al. Distribution of CB1 cannabinoid receptors in the amygdala and their role in the control of GABAergic transmission. J. Neurosci. 21, 9506–9518 (2001).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  191. 191

    Ohno-Shosaku, T., Maejima, T. & Kano, M. Endogenous cannabinoids mediate retrograde signals from depolarized postsynaptic neurons to presynaptic terminals. Neuron 29, 729–738 (2001).

    CAS  Article  Google Scholar 

  192. 192

    Di, S. et al. Acute stress suppresses synaptic inhibition and increases anxiety via endocannabinoid release in the basolateral amygdala. J. Neurosci. 36, 8461–8470 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  193. 193

    Lu, A. T. et al. Association of the cannabinoid receptor gene (CNR1) with ADHD and post-traumatic stress disorder. Am. J. Med. Genet. B Neuropsychiatr. Genet. 147B, 1488–1494 (2008).

    CAS  Article  Google Scholar 

  194. 194

    Mota, N. et al. The rs1049353 polymorphism in the CNR1 gene interacts with childhood abuse to predict posttraumatic threat symptoms. J. Clin. Psychiatry 76, e1622–e1623 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  195. 195

    de Bitencourt, R. M., Pamplona, F. A. & Takahashi, R. N. A current overview of cannabinoids and glucocorticoids in facilitating extinction of aversive memories: potential extinction enhancers. Neuropharmacology 64, 389–395 (2013).

    CAS  Article  Google Scholar 

  196. 196

    Jetly, R., Heber, A., Fraser, G. & Boisvert, D. The efficacy of nabilone, a synthetic cannabinoid, in the treatment of PTSD-associated nightmares: a preliminary randomized, double-blind, placebo-controlled cross-over design study. Psychoneuroendocrinology 51, 585–588 (2015).

    CAS  Article  Google Scholar 

  197. 197

    Roitman, P., Mechoulam, R., Cooper-Kazaz, R. & Shalev, A. Preliminary, open-label, pilot study of add-on oral Δ9-tetrahydrocannabinol in chronic post-traumatic stress disorder. Clin. Drug Investig. 34, 587–591 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  198. 198

    Neumeister, A. et al. Elevated brain cannabinoid CB1 receptor availability in post-traumatic stress disorder: a positron emission tomography study. Mol. Psychiatry 18, 1034–1040 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  199. 199

    van Rossum, E. F. et al. Identification of the BclI polymorphism in the glucocorticoid receptor gene: association with sensitivity to glucocorticoids in vivo and body mass index. Clin. Endocrinol. (Oxf.) 59, 585–592 (2003).

    CAS  Article  Google Scholar 

  200. 200

    Ackermann, S., Heck, A., Rasch, B., Papassotiropoulos, A. & de Quervain, D. J. The BclI polymorphism of the glucocorticoid receptor gene is associated with emotional memory performance in healthy individuals. Psychoneuroendocrinology 38, 1203–1207 (2013).

    CAS  Article  Google Scholar 

  201. 201

    Hauer, D. et al. Relationship of a common polymorphism of the glucocorticoid receptor gene to traumatic memories and posttraumatic stress disorder in patients after intensive care therapy. Crit. Care Med. 39, 643–650 (2011).

    CAS  Article  Google Scholar 

  202. 202

    Labonte, B., Azoulay, N., Yerko, V., Turecki, G. & Brunet, A. Epigenetic modulation of glucocorticoid receptors in posttraumatic stress disorder. Transl Psychiatry 4, e368 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  203. 203

    Yehuda, R. et al. Lower methylation of glucocorticoid receptor gene promoter 1F in peripheral blood of veterans with posttraumatic stress disorder. Biol. Psychiatry 77, 356–364 (2015).

    CAS  Article  Google Scholar 

  204. 204

    Vukojevic, V. et al. Epigenetic modification of the glucocorticoid receptor gene is linked to traumatic memory and post-traumatic stress disorder risk in genocide survivors. J. Neurosci. 34, 10274–10284 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  205. 205

    Zannas, A. S., Wiechmann, T., Gassen, N. C. & Binder, E. B. Gene–stress–epigenetic regulation of FKBP5: clinical and translational implications. Neuropsychopharmacology 41, 261–274 (2016).

    CAS  Article  Google Scholar 

  206. 206

    Cheung, J. & Bryant, R. A. FKBP5 risk alleles and the development of intrusive memories. Neurobiol. Learn. Mem. 125, 258–264 (2015).

    CAS  Article  Google Scholar 

  207. 207

    Mehta, D. et al. Using polymorphisms in FKBP5 to define biologically distinct subtypes of posttraumatic stress disorder: evidence from endocrine and gene expression studies. Arch. Gen. Psychiatry 68, 901–910 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  208. 208

    Klengel, T. et al. Allele-specific FKBP5 DNA demethylation mediates gene–childhood trauma interactions. Nat. Neurosci. 16, 33–41 (2013).

    CAS  Article  Google Scholar 

  209. 209

    Wilker, S. et al. The role of FKBP5 genotype in moderating long-term effectiveness of exposure-based psychotherapy for posttraumatic stress disorder. Transl Psychiatry 4, e403 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  210. 210

    Roberts, S. et al. HPA axis related genes and response to psychological therapies: genetics and epigenetics. Depress. Anxiety 32, 861–870 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to Dominique de Quervain.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Glossary

Post-traumatic stress disorder

(PTSD). A disorder that can occur after the exposure to a traumatic event; it includes symptoms of intrusion, avoidance, negative alterations in cognition and mood, and alterations in arousal and reactivity.

Phobias

Anxiety disorders that are characterized by intense fear or anxiety that is circumscribed to the presence or anticipation of a particular object or situation.

Retrograde messenger

A chemical substance that is released from postsynaptic neurons and acts on presynaptic neurons to regulate neurotransmitter release.

Anisomycin

An antibiotic that prevents the synthesis of proteins.

Spontaneous recovery

The reappearance of a previously extinguished conditioned response after a delay.

Stimulus–response (S–R) associations

A type of learning that links single stimuli to responses. This type of learning is considered to be cognitively less demanding than, for example, spatial memory and relies on the dorsal striatum.

Inhibitory avoidance task

A learning and memory task in which animals learn to avoid the place in an apparatus where they received a single footshock during the training.

Trier Social Stress Test

A test that is designed to trigger social stress; participants must prepare and give a presentation and perform an arithmetic task in front of an audience.

Behavioural approach test

A test that is used to measure approach behaviour in the context of a feared stimulus.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

de Quervain, D., Schwabe, L. & Roozendaal, B. Stress, glucocorticoids and memory: implications for treating fear-related disorders. Nat Rev Neurosci 18, 7–19 (2017). https://doi.org/10.1038/nrn.2016.155

Download citation

Further reading