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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.

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

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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.

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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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