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.
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.
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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.
Roozendaal, B. & McGaugh, J. L. Memory modulation. Behav. Neurosci. 125, 797–824 (2011).
McGaugh, J. L. Memory and Emotion. The Making of Lasting Memories (Weidenfeld and Nicolson, 2003).
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).
Roozendaal, B., McEwen, B. S. & Chattarji, S. Stress, memory and the amygdala. Nat. Rev. Neurosci. 10, 423–433 (2009).
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).
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.
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).
Wolf, O. T. Stress and memory in humans: twelve years of progress? Brain Res. 1293, 142–154 (2009).
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).
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).
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).
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).
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).
Parsons, R. G. & Ressler, K. J. Implications of memory modulation for post-traumatic stress and fear disorders. Nat. Neurosci. 16, 146–153 (2013).
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).
Pitman, R. K. et al. Pilot study of secondary prevention of posttraumatic stress disorder with propranolol. Biol. Psychiatry 51, 189–192 (2002).
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).
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).
Soeter, M. & Kindt, M. An abrupt transformation of phobic behavior after a post-retrieval amnesic agent. Biol. Psychiatry 78, 880–886 (2015).
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).
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.
de Kloet, E. R., Karst, H. & Joels, M. Corticosteroid hormones in the central stress response: quick-and-slow. Front. Neuroendocrinol. 29, 268–272 (2008).
de Kloet, E. R., Joels, M. & Holsboer, F. Stress and the brain: from adaptation to disease. Nat. Rev. Neurosci. 6, 463–475 (2005).
Coluccia, D. et al. Glucocorticoid therapy-induced memory deficits: acute versus chronic effects. J. Neurosci. 28, 3474–3478 (2008).
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.
McGaugh, J. L. & Roozendaal, B. Role of adrenal stress hormones in forming lasting memories in the brain. Curr. Opin. Neurobiol. 12, 205–210 (2002).
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).
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).
Oitzl, M. S. & De Kloet, E. R. Selective corticosteroid antagonists modulate specific aspects of spatial orientation learning. Behav. Neurosci. 106, 62–71 (1992).
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).
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).
Andreano, J. M. & Cahill, L. Glucocorticoid release and memory consolidation in men and women. Psychol. Sci. 17, 466–470 (2006).
Preuss, D. & Wolf, O. T. Post-learning psychosocial stress enhances consolidation of neutral stimuli. Neurobiol. Learn. Mem. 92, 318–326 (2009).
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).
Buchanan, T. W. & Lovallo, W. R. Enhanced memory for emotional material following stress-level cortisol treatment in humans. Psychoneuroendocrinology 26, 307–317 (2001).
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.
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).
Kuhlmann, S. & Wolf, O. T. Arousal and cortisol interact in modulating memory consolidation in healthy young men. Behav. Neurosci. 120, 217–223 (2006).
Karst, H. et al. Glucocorticoids alter calcium conductances and calcium channel subunit expression in basolateral amygdala neurons. Eur. J. Neurosci. 16, 1083–1089 (2002).
Revest, J. M. et al. The MAPK pathway and Egr-1 mediate stress-related behavioral effects of glucocorticoids. Nat. Neurosci. 8, 664–672 (2005).
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).
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).
Riedemann, T., Patchev, A. V., Cho, K. & Almeida, O. F. Corticosteroids: way upstream. Mol. Brain 3, 2 (2010).
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).
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).
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).
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).
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).
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).
Conboy, L. & Sandi, C. Stress at learning facilitates memory formation by regulating AMPA receptor trafficking through a glucocorticoid action. Neuropsychopharmacology 35, 674–685 (2010).
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).
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).
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.
Chauveau, F. et al. Rapid stress-induced corticosterone rise in the hippocampus reverses serial memory retrieval pattern. Hippocampus 20, 196–207 (2010).
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).
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).
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).
Kuhlmann, S., Piel, M. & Wolf, O. T. Impaired memory retrieval after psychosocial stress in healthy young men. J. Neurosci. 25, 2977–2982 (2005).
Schwabe, L. et al. Stress effects on declarative memory retrieval are blocked by a β-adrenoceptor antagonist in humans. Psychoneuroendocrinology 34, 446–454 (2009).
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).
Kuhlmann, S. & Wolf, O. T. Cortisol and memory retrieval in women: influence of menstrual cycle and oral contraceptives. Psychopharmacology (Berl.) 183, 65–71 (2005).
Quirk, G. J. & Mueller, D. Neural mechanisms of extinction learning and retrieval. Neuropsychopharmacology 33, 56–72 (2008).
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).
Barrett, D. & Gonzalez-Lima, F. Behavioral effects of metyrapone on Pavlovian extinction. Neurosci. Lett. 371, 91–96 (2004).
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).
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).
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).
Bohus, B. & Lissak, K. Adrenocortical hormones and avoidance behaviour of rats. Int. J. Neuropharmacol. 7, 301–306 (1968).
Clay, R. et al. Glucocorticoids are required for extinction of predator stress-induced hyperarousal. Neurobiol. Learn. Mem. 96, 367–377 (2011).
Nader, K. & Hardt, O. A single standard for memory: the case for reconsolidation. Nat. Rev. Neurosci. 10, 224–234 (2009).
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).
Schwabe, L., Nader, K. & Pruessner, J. C. Reconsolidation of human memory: brain mechanisms and clinical relevance. Biol. Psychiatry 76, 274–280 (2014).
Alberini, C. M. Mechanisms of memory stabilization: are consolidation and reconsolidation similar or distinct processes? Trends Neurosci. 28, 51–56 (2005).
Schwabe, L. & Wolf, O. T. Stress impairs the reconsolidation of autobiographical memories. Neurobiol. Learn. Mem. 94, 153–157 (2010).
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).
Bos, M. G., Schuijer, J., Lodestijn, F., Beckers, T. & Kindt, M. Stress enhances reconsolidation of declarative memory. Psychoneuroendocrinology 46, 102–113 (2014).
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).
Pitman, R. K. et al. Systemic mifepristone blocks reconsolidation of cue-conditioned fear; propranolol prevents this effect. Behav. Neurosci. 125, 632–638 (2011).
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).
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).
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).
Joels, M., Fernandez, G. & Roozendaal, B. Stress and emotional memory: a matter of timing. Trends Cogn. Sci. 15, 280–288 (2011).
Hermans, E. J. et al. Stress-related noradrenergic activity prompts large-scale neural network reconfiguration. Science 334, 1151–1153 (2011).
Katsuki, H., Izumi, Y. & Zorumski, C. F. Noradrenergic regulation of synaptic plasticity in the hippocampal CA1 region. J. Neurophysiol. 77, 3013–3020 (1997).
Vogel, S. & Schwabe, L. Stress in the zoo: tracking the impact of stress on memory formation over time. Psychoneuroendocrinology 71, 64–72 (2016).
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).
Schönfeld, P., Ackermann, K. & Schwabe, L. Remembering under stress: different roles of autonomic arousal and glucocorticoids in memory retrieval. Psychoneuroendocrinology 39, 249–256 (2014).
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).
Schwabe, L. & Wolf, O. T. Timing matters: temporal dynamics of stress effects on memory retrieval. Cogn. Affect. Behav. Neurosci. 14, 1041–1048 (2014).
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).
Kim, J. J. & Diamond, D. M. The stressed hippocampus, synaptic plasticity and lost memories. Nat. Rev. Neurosci. 3, 453–462 (2002).
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).
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).
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).
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).
Packard, M. G. & Knowlton, B. J. Learning and memory functions of the basal ganglia. Annu. Rev. Neurosci. 25, 563–593 (2002).
Hermans, E. J. et al. How the amygdala affects emotional memory by altering brain network properties. Neurobiol. Learn. Mem. 112, 2–16 (2014).
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).
Poldrack, R. A. & Packard, M. Competition among multiple memory systems: converging evidence from animal and human brain studies. Neuropsychologia 41, 245–251 (2003).
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).
Schwabe, L. Stress and the engagement of multiple memory systems: integration of animal and human studies. Hippocampus 23, 1035–1043 (2013).
Schwabe, L., Wolf, O. T. & Oitzl, M. S. Memory formation under stress: quantity and quality. Neurosci. Biobehav. Rev. 34, 584–591 (2010).
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.
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.
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).
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).
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.
Schwabe, L. & Wolf, O. T. Stress prompts habit behavior in humans. J. Neurosci. 29, 7191–7198 (2009).
Braun, S. & Hauber, W. Acute stressor effects on goal-directed action in rats. Learn. Mem. 20, 700–709 (2013).
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).
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).
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).
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).
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).
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).
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).
Guenzel, F. M., Wolf, O. T. & Schwabe, L. Glucocorticoids boost stimulus–response memory formation in humans. Psychoneuroendocrinology 45, 21–30 (2014).
Atsak, P. et al. Glucocorticoids mediate stress-induced impairment of retrieval of stimulus–response memory. Psychoneuroendocrinology 67, 207–215 (2016).
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).
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).
Yehuda, R. Post-traumatic stress disorder. N. Engl. J. Med. 346, 108–114 (2002).
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.
Yehuda, R. Status of glucocorticoid alterations in post-traumatic stress disorder. Ann. NY Acad. Sci. 1179, 56–69 (2009).
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).
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).
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).
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).
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).
Aerni, A. et al. Low-dose cortisol for symptoms of posttraumatic stress disorder. Am. J. Psychiatry 161, 1488–1490 (2004).
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).
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).
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).
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).
Wood, N. E. et al. Pharmacological blockade of memory reconsolidation in posttraumatic stress disorder: three negative psychophysiological studies. Psychiatry Res. 225, 31–39 (2015).
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).
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).
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).
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).
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).
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).
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).
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).
Amos, T., Stein, D. J. & Ipser, J. C. Pharmacological interventions for preventing post-traumatic stress disorder (PTSD). Cochrane Database Syst. Rev. 7, CD006239 (2014).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT00855270?term=NCT00855270&rank=1 (2016).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02402114?term=NCT02402114&rank=1 (2015).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT00674570?term=NCT00674570&rank=1 (2016).
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).
Soravia, L. M. et al. Glucocorticoids reduce phobic fear in humans. Proc. Natl Acad. Sci. USA 103, 5585–5590 (2006).
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.
Soravia, L. M. et al. Glucocorticoids enhance in vivo exposure-based therapy of spider phobia. Depress. Anxiety 31, 429–435 (2014).
Lass-Hennemann, J. & Michael, T. Endogenous cortisol levels influence exposure therapy in spider phobia. Behav. Res. Ther. 60, 39–45 (2014).
Tiffany, S. T. & Wray, J. M. The clinical significance of drug craving. Ann. NY Acad. Sci. 1248, 1–17 (2012).
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).
Robinson, T. E. & Berridge, K. C. The psychology and neurobiology of addiction: an incentive–sensitization view. Addiction 95 (Suppl. 2), 91–117 (2000).
Kelley, A. E. Memory and addiction: shared neural circuitry and molecular mechanisms. Neuron 44, 161–179 (2004).
Walter, M. et al. Effects of cortisol administration on craving in heroin addicts. Transl Psychiatry 5, e610 (2015).
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).
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).
Pitman, R. K. Post-traumatic stress disorder, hormones, and memory. Biol. Psychiatry 26, 221–223 (1989).
LeDoux, J. The emotional brain, fear, and the amygdala. Cell. Mol. Neurobiol. 23, 727–738 (2003).
Phelps, E. A. & LeDoux, J. E. Contributions of the amygdala to emotion processing: from animal models to human behavior. Neuron 48, 175–187 (2005).
Yehuda, R. & LeDoux, J. Response variation following trauma: a translational neuroscience approach to understanding PTSD. Neuron 56, 19–32 (2007).
Brewin, C. R. & Holmes, E. A. Psychological theories of posttraumatic stress disorder. Clin. Psychol. Rev. 23, 339–376 (2003).
Cahill, L., Babinsky, R., Markowitsch, H. J. & McGaugh, J. L. The amygdala and emotional memory. Nature 377, 295–296 (1995).
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).
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).
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).
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).
Heim, C. & Nemeroff, C. B. Neurobiology of posttraumatic stress disorder. CNS Spectr. 14, 13–24 (2009).
Ipser, J. C., Singh, L. & Stein, D. J. Meta-analysis of functional brain imaging in specific phobia. Psychiatry Clin. Neurosci. 67, 311–322 (2013).
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).
Marks, I. Fears, Phobias and Rituals: Panic, Anxiety, and their Disorders (Oxford Univ. Press, 1987).
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).
McNally, R. J. Mechanisms of exposure therapy: how neuroscience can improve psychological treatments for anxiety disorders. Clin. Psychol. Rev. 27, 750–759 (2007).
Hermans, D., Craske, M. G., Mineka, S. & Lovibond, P. F. Extinction in human fear conditioning. Biol. Psychiatry 60, 361–368 (2006).
Hamm, A. O. Specific phobias. Psychiatr. Clin. North Am. 32, 577–591 (2009).
Nader, K. Reconsolidation and the dynamic nature of memory. Cold Spring Harb. Perspect. Biol. 7, a021782 (2015).
Kandel, E. R. The molecular biology of memory storage: a dialogue between genes and synapses. Science 294, 1030–1038 (2001).
Schwabe, L. & Wolf, O. T. Stress and multiple memory systems: from 'thinking' to 'doing'. Trends Cogn. Sci. 17, 60–68 (2013).
Bouton, M. E. Context, ambiguity, and unlearning: sources of relapse after behavioral extinction. Biol. Psychiatry 52, 976–986 (2002).
Ohno-Shosaku, T. & Kano, M. Endocannabinoid-mediated retrograde modulation of synaptic transmission. Curr. Opin. Neurobiol. 29, 1–8 (2014).
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).
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).
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).
Marsicano, G. et al. The endogenous cannabinoid system controls extinction of aversive memories. Nature 418, 530–534 (2002).
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).
Atsak, P. et al. Endocannabinoid signaling within the basolateral amygdala integrates multiple stress hormone effects on memory consolidation. Neuropsychopharmacology 40, 1485–1494 (2015).
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).
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).
Ohno-Shosaku, T., Maejima, T. & Kano, M. Endogenous cannabinoids mediate retrograde signals from depolarized postsynaptic neurons to presynaptic terminals. Neuron 29, 729–738 (2001).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
Labonte, B., Azoulay, N., Yerko, V., Turecki, G. & Brunet, A. Epigenetic modulation of glucocorticoid receptors in posttraumatic stress disorder. Transl Psychiatry 4, e368 (2014).
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).
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).
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).
Cheung, J. & Bryant, R. A. FKBP5 risk alleles and the development of intrusive memories. Neurobiol. Learn. Mem. 125, 258–264 (2015).
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).
Klengel, T. et al. Allele-specific FKBP5 DNA demethylation mediates gene–childhood trauma interactions. Nat. Neurosci. 16, 33–41 (2013).
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).
Roberts, S. et al. HPA axis related genes and response to psychological therapies: genetics and epigenetics. Depress. Anxiety 32, 861–870 (2015).
The authors declare no competing financial interests.
- 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.
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.
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.
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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
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