Review
Corticosteroid hormones in the central stress response: Quick-and-slow

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Abstract

Recent evidence shows that corticosteroid hormones exert rapid non-genomic effects on neurons in the hypothalamus and the hippocampal CA1 region. The latter depend on classical mineralocorticoid receptors which are accessible from the outside of the plasma membrane and display a 10-fold lower affinity for corticosterone than the nuclear version involved in neuroprotection. Consequently, this ‘membrane’ receptor could play an important role while corticosteroid levels are high, i.e. during the initial phase of the stress response. We propose that during this phase corticosterone promotes hippocampal excitability and amplifies the effect of other stress hormones. These permissive non-genomic effects may contribute to fast behavioral effects and encoding of stress-related information. The fast effects are complemented by slower glucocorticoid receptor-mediated effects which facilitate suppression of temporary raised excitability, recovery from the stressful experience and storage of information for future use.

Introduction

Glucocorticoids are secreted from the adrenal in hourly pulses which are thought to synchronize and coordinate sleep related and daily events [42]. At any time a glucocorticoid response can be triggered by a stressor. In concert with other stress mediators, the stress-induced rise in glucocorticoid concentration facilitates adaptation to stress and restores homeostasis, (among other things) by enhancing emotional arousal and promoting motivational and cognitive processes [6], [17], [26]. A glucocorticoid response that is excessive, prolonged or inadequate impairs adaptation to stress and is considered a risk factor for stress-related diseases. The hormones have profound effects on brain development and are a significant factor in the aging process.

The key towards understanding these fundamental processes underlying homeostasis and health is in the receptors that mediate the action of the corticosteroids. These are the classical glucocorticoid receptors (GR), selective for naturally occurring and synthetic glucocorticoids; and the mineralocorticoid receptors (MR), which retain corticosterone and aldosterone with a very high affinity, i.e. about 10-fold higher than to the GR [6]. The MR also binds progesterone and deoxycorticosterone with relatively high affinity [3] and hence this receptor is considered promiscuous in non-epithelial cells. In epithelial cells the MR is aldosterone-selective because the naturally occurring glucocorticoids are metabolized by the 11β-steroid-dehydrogenase type 1 [13]. The MR and GR are nuclear receptors that mediate genomic actions of the naturally occurring glucocorticoids corticosterone in rodents and cortisol in man [32], [43].

Our contribution to this special issue of Frontiers will focus on the MR and GR. These receptors are abundantly expressed in the limbic brain where they mediate distinct and complementary actions. While most emphasis in the past decades was on their genomic action there obviously was a problem. Thus, over the years findings were reported that showed fast effects of corticosteroids on feedback operation in the HPA axis [4]. Fast effects within minutes were also described for violent behavior propagated by a fast feedforward mechanism [21] which were not genomic, but obeyed the pharmacology dictated by the classical nuclear receptors. Moreover, corticosteroid effects were observed on cognitive operations in appraisal of novel situations [29], [30], extinction processes [2] and more recently on retrieval processes [7], [35]. Recent discoveries using an electrophysiological approach have supplied a mechanistic basis to these fast behavioral and neuroendocrine effects. We first will review these fast cellular effects, and next examine the fast effects in the chain of events that take place from the first encounter with a real or imagined stressor to its long-term outcome on cognitive performance.

Section snippets

Fast effects of corticosteroid hormones on neuronal function

Parvocellular neurons in the PVN are critically involved in the production and release of CRH. These processes are under fast and delayed negative control of corticosterone [4]. Insight in the putative neurobiological substrate of the fast negative feedback was recently provided by Tasker and co-workers [38]. They showed that glucocorticoids rapidly and non-genomically suppress the frequency (but not amplitude) of miniature excitatory postsynaptic currents (mEPSCs), which reflect the

Corticosteroid hormones in the stress response

How can these rapid cellular effects of corticosterone contribute to the central stress response?

With respect to the HPA regulation, it has been known already for a long time that rising levels of corticosterone can exert a fast negative control over the release of CRH and ACTH [4]. This effect may be short-lived, because as soon as corticosteroid levels plateau the negative influence is lost, only to re-appear some time later when gene-mediated effects kick in. This transient character of fast

Perspectives

While electrophysiological studies over the past years have firmly established the existence of rapid non-genomic corticosteroid effects in brain, numerous questions are still unanswered. First and foremost it will be important to link the presently described cellular effects to the sets of behavioral and neuroendocrine observations: the cellular non-genomic effects are likely to underlie fast changes in memory formation and HPA activity, but causative evidence has not yet been provided. In

Acknowledgments

The support by the Netherlands Organisation for Scientific Research and the Royal Netherlands Academy of Arts and Sciences is gratefully acknowledged.

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