Review
Glucocorticoids and the regulation of memory in health and disease

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Abstract

Over the last decades considerable evidence has accumulated indicating that glucocorticoids – stress hormones released from the adrenal cortex – are crucially involved in the regulation of memory. Specifically, glucocorticoids have been shown to enhance memory consolidation of emotionally arousing experiences, but impair memory retrieval and working memory during emotionally arousing test situations. Furthermore, growing evidence indicates that these different glucocorticoid effects all depend on emotional arousal-induced activation of noradrenergic transmission within the basolateral complex of the amygdala (BLA) and on interactions of the BLA with other brain regions, such as the hippocampus and neocortical regions. Here we review findings from both animal and human experiments and present an integrated perspective of how these opposite glucocorticoid effects might act together to serve adaptive processing of emotionally significant information. Furthermore, as intense emotional memories also play a crucial role in the pathogenesis and symptomatology of anxiety disorders, such as posttraumatic stress disorder (PTSD) or phobias, we discuss to what extent the basic findings on glucocorticoid effects on emotional memory might have implications for the understanding and treatment of these clinical conditions. In this context, we review data suggesting that the administration of glucocorticoids might ameliorate chronic anxiety by reducing retrieval of aversive memories and enhancing fear extinction.

Introduction

Stress activates the hypothalamus–pituitary–adrenal axis, which results in the release of glucocorticoid hormones (cortisol in humans, corticosterone in rodents) from the adrenal cortex. It has long been recognized that glucocorticoids readily enter the brain and affect cognition. Early reports on both enhancing and impairing properties of glucocorticoids on memory [9], [16], [21], [63], [91] have indicated that these hormones have complex effects on cognitive functions. More recent studies investigating glucocorticoid effects on distinct memory phases and studies discerning acute from chronic effects helped to disentangle the multifaceted actions of these stress hormones. For example, acute elevations of glucocorticoids are known to enhance the consolidation of memory of new information, but to impair the retrieval of already stored information [51], [146], [156]. Conditions with chronically elevated glucocorticoid levels are usually associated with impaired cognitive performance and these deficits are thought to result from a cumulative and long-lasting burden on hippocampal function and morphology [102], [172]. Recently, however, it became clear that memory deficits observed under such chronic conditions can also result, at least in part, from acute and reversible glucocorticoid actions on memory retrieval processes [39].

In the present review, we will summarize and discuss how glucocorticoids affect memory consolidation, retrieval and working memory and why these stress hormones specifically modulate memory of emotionally arousing experiences. Furthermore, because emotional memory plays a crucial role in the pathogenesis and symptomatology of anxiety disorders, such as posttraumatic stress disorder (PTSD) or phobias, we will discuss to what extent the basic findings on glucocorticoid effects on emotional memory might have clinical implications.

Section snippets

Glucocorticoid effects on memory consolidation

Memory consolidation is the process by which a fragile short-term memory trace is transferred into stable long-term memory. However, not all information is equally well transferred into long-term storage. In fact, it is well recognized that especially emotionally arousing experiences are well remembered, even after decades [107]. Successful memory consolidation depends on de-novo protein synthesis and on long-term changes in synaptic plasticity [76]. There is extensive evidence that

Glucocorticoid effects on memory retrieval

Studies showing that stress induces memory impairment when retention is tested shortly after learning (before memory consolidation took place) and glucocorticoid levels are still elevated [54], [81], indicated that glucocorticoids possibly interfere with memory retrieval processes. In the first study investigating the specific effects of stress and glucocorticoids on memory retrieval [51], we reported that 30 min after exposure to footshock stress, rats had impaired retrieval of spatial memory

Glucocorticoid effects on working memory

Working memory is a dynamic process whereby information is updated continuously, providing a temporary storage of information [12], [75]. Evidence from lesion, pharmacological, imaging and clinical studies indicates that working memory depends on the integrity of the prefrontal cortex [23], [66], [126]. Stress exposure is known to impair performance of rats on a delayed alternation task, a task commonly used to assess working memory in rodents [11]. Basal levels of endogenous glucocorticoids

Modulatory effects of glucocorticoids on emotional memory: implications for anxiety disorders

From the findings reviewed above we have learned that glucocorticoids enhance memory consolidation but impair memory retrieval and working memory in emotionally arousing situations (Fig. 4). Enhanced memory for emotional events is a well-recognized phenomenon, which helps us to remember important information. Although glucocorticoid-induced temporary impairments of memory retrieval and working memory are certainly unwanted in exam situations, these effects should not a priori be regarded as

Conclusion

In the present paper we have reviewed evidence from both animal and human studies, which indicated that glucocorticoids enhance memory consolidation but impair memory retrieval and working memory (Fig. 4). Importantly, these hormone effects depend on emotional arousal-induced activation of noradrenergic transmission within the BLA and on interactions of the BLA with other brain regions, such as the hippocampus and neocortical regions. Therefore, glucocorticoids, via BLA activation, can modulate

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