Beta Switch Program

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Carmen Sandi Abstract

Glucocorticoid hormones, released from the adrenal glands, easily access the brain where they can affect neural structure and function through the binding to two types of intracellular receptors, the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR). Secretion of these steroids is activated by exposure to stressful situations, and growing evidence indicates that they can interact with the neurobiological mechanisms subserving memory formation. After a brief description of these hormones and their receptors, we will review the scientific literature questioning whether glucocorticoid release, during the processing of certain types of information, could play a role on the neural processes involved in long-term memory formation. Emphasis will be made on findings that have shown a differential role of the two corticosteroid receptors on cognitive function, with MRs involved in behavioural reactivity to novel situations, and GRs in the consolidation of the newly acquired information. Which could be the mediating mechanisms involved in glucocorticoid actions is one of the key questions to be addressed when dealing with the capacity of these hormones to modulate memory storage. Recent evidence suggesting that glucocorticoids could induce their memory effects, at least partially, by regulating expression and function of synaptic proteins (in particular, cell adhesion molecules) will be presented. Finally, the behavioural and neural outcomes induced by chronic exposure to hypercortisolemic situations—a field that has received increasing attention over the past decade—will be reviewed.

Glucocorticoid Hormones and Receptors

Glucocorticoids and the Hypothalamic-Pituitary-Adrenal (HPA) Axis

Glucocorticoids are a major subgroup of steroid hormones, which are produced by the adrenal cortex under the regulatory influence of the adrenocorticotropin hormone (ACTH). They are important elements of the hypothalamic-pituitary-adrenal (HPA) axis, a neuroendocrine circuit critically involved in the response to stress and emotions and in the maintenance of homeostasis in the organism (see Fig. 1). The parvocellular neurons of the paraventricular nucleus (PVN) in the hypothalamus are the endpoint that integrates inputs from different neurotransmitter systems throughout the brain, including influences from the prefrontal cortex, hippocampus, amygdala, and septum. These neurons secrete corticotrophin-releasing hormone (CRH) and arginine vasopressin (AVP), which stimulate the pituitary to release ACTH (for discussion of the roles of these peptides, see de Wied and Kovac, this book).

Therefore, glucocorticoids (cortisol being the major naturally occurring glucocorticoid in humans, and corticosterone in several other animal species, including rats, mice and chicks) are the final products of the HPA system which, under basal conditions, shows a pulsatile and circadian secretion of the different hormones involved. Under exposure to physical or psychological stress, the brain structures involved in the regulation of this circuit stimulate the PVN, which then triggers the chain of endocrine responses on the different components of the axis.

From Messengers to Molecules: Memories Are Made of These, edited by Gernot Riedel and Bettina Platt. ©2004 and Kluwer Academic / Plenum Publishers.

Figure 1. Schematic representation of the hypothalamus-pituitary-adrenocortical (HPA) axis. Corticotropin Releasing Hormone (CRH) is released from the hypothalamus and activates the pituitary, where it activates the secretion of Adrenocorticotropin (ACTH). When ACTH stimulates the adrenal cortex, glucocorticoid secretion is activated. Circulating glucocorticoids can then inhibit HPA axis, by inhibiting ACTH secretion at the pituitary and CRH secretion at the hypothalamus. In addition, glucocorticoids can get access to the brain and also inhibiting HPA axis activation through their binding to specific mineralocorticoid (MR) and glucocorticoid (GR) receptors in different brain areas (particularly the hippocampus and the frontal cortex).

As important as this stress response is for adaptation and survival, as important is the termination of its activation, since sustained exposure to elevated levels of these hormones (particularly glucocorticoids) is well known to be highly deleterious — and potentially lethal- for the organism. Thus, glucocorticoids play a key role in the termination of their own release by inhibiting the secretion of ACTH and CRH at the level of the pituitary and hypothalamus, respectively, and also by interacting with other brain structures, among which the hippocampus plays a very important role.30

In addition to displaying a wide number of actions at different levels of the organism — including the regulation of glucose levels, blood pressure, and the immune response-, due to their lipophilic nature, glucocorticoids can readily enter the brain, where they affect neural function and behaviour mainly by interacting with two types of intracellular receptors: the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR). Although increasing evidence indicates that glucocorticoids can also exert rapid, non-genomic actions by interacting with different proteins of the cell membrane (including neurotransmitter receptors and putative non-genomic receptors for glucocorticoids),37 this mechanism of action is still poorly understood. Here, we will focus on the classic corticosteroid genomic actions through the intracellular corticosteroid receptors.

Corticosteroid Receptors in the Brain

The intracellular corticosteroid receptors belong to the superfamily of nuclear hormone receptors. These are part of a cytoplasmic multiprotein complex, which, in addition to a receptor and several other molecules, involves heat shock proteins (hsp). When a corticosteroid hormone binds to a receptor, a conformational change is induced in the receptor molecule, which then leads to a cascade of events, including the dissociation of the receptor from the hsp complex, and the translocation of the receptor-ligand complex to the nucleus, where it can modulate gene transcription. Depending on a number of factors (such as the cellular context or specific physiological conditions), gene expression can either be activated or repressed, either through a direct interaction of the ligand-activated MR or GR with specific DNA sequences, or by the interaction of the activated receptor with other transcription factors, such as the activating protein (AP-1), the nuclear factor kB (NFKB), or the cAMP-response element-binding protein1 (CREB, see Frankland and Josselyn, this book) (see Fig. 2).

Figure 2. Genomic mechanisms of action of mineralocorticoid (MR) and glucocorticoid (GR) receptors. Due to their lipohilic nature, corticosteroids can easily cross cell membranes. When an agonist ligand (i.e., aldosterone or corticosterone) binds to the intracellular corticosteroid receptors, a chain of events is triggered, including the translocation of the hormone-receptor complex to the nucleus. There, they can either directly or indirectly (through the interaction with other transcription factors, such as AP1) modulate gene transcription, eventually facilitating or inhibiting the synthesis of specific proteins. Cort: corticosterone; Aldo: aldosterone; GR: glucocorticoid receptor; MR: mineralocorticoid receptor; 11-HSD: 11beta-Hydroxysteroid dehydrogenase.

Figure 2. Genomic mechanisms of action of mineralocorticoid (MR) and glucocorticoid (GR) receptors. Due to their lipohilic nature, corticosteroids can easily cross cell membranes. When an agonist ligand (i.e., aldosterone or corticosterone) binds to the intracellular corticosteroid receptors, a chain of events is triggered, including the translocation of the hormone-receptor complex to the nucleus. There, they can either directly or indirectly (through the interaction with other transcription factors, such as AP1) modulate gene transcription, eventually facilitating or inhibiting the synthesis of specific proteins. Cort: corticosterone; Aldo: aldosterone; GR: glucocorticoid receptor; MR: mineralocorticoid receptor; 11-HSD: 11beta-Hydroxysteroid dehydrogenase.

MRs and GRs differ in their affinity to bind different ligands. In particular, affinity of MRs to bind corticosterone is approximately 10-fold higher than the affinity of GRs. As a consequence, at physiological conditions when corticosteroid levels are low (i.e., at the circadian trough at rest), whereas MRs are largely occupied (around 70-80%), GRs only show a low occupancy (around 10%). However, under situations of enhanced corticosteroid levels (i.e., under stressful circumstances), activation of GRs is considerably increased.

Both receptor types also differ in their respective distribution throughout the brain. Although they are co-localized in a number of brain structures involved in emotion and cognition, such as hippocampus, septum and amygdala, the GR has a much wider distribution in the brain, with its highest expression being observed in brain areas involved in the regulatory feedback of the HPA axis, including the pituitary, paraventricular nucleus of the hypothalamus, and the hippocampus. In the context of the present chapter, it is important to emphasize that a particularly high density of both MRs and GRs is found in hippocampal neurons.24,25

Hippocampal MRs have been implicated in the control of the inhibitory tone that the hippocampus exerts on the HPA axis,5 as well as in the maintenance of neuronal excitability in the CA1 subfield.26 Imp ortantly, the expression of MRs in the hippocampus has been found to be rapidly upregulated by acute stress exposure, an effect which seems to potentiate the inhibitory tonus of these receptors on the activity of the HPA axis.52 In contrast, GR action appears to be regulated by the hormone level. Thus, when corticosteroid levels are increased, their activation of GRs (in addition to MRs) has been associated with a facilitation of HPA activation and reduced neuronal activity in the hippocampus. A balance in corticosteroid actions mediated via MRs and GRs has been proposed to be critical for the control of homeostasis.12

Role of Glucocorticoids on Memory Consolidation

The idea that stress hormones, released during training experiences, can modulate the storage of information, was proposed after the observation that emotionally arousing experiences generally lead to stronger memories than more ordinary events.20,22 A wide body of data has lead to recognise that peripheral catecholamines (adrenaline and noradrenaline), secreted as part of the stress response by the activation of the sympathetic nervous system, display important modulatory actions on learning and memory processes21 (see also, Gibbs and Summers, this book). In addition, intensive research, involving a great variety of experimental approaches, has also indicated a key role of glucocorticoids in the storage of information.

The interest in glucocorticoid actions on cognitive processes is multiple. First, although glucocorticoids are peripheral hormones, their lipophilic nature allows them to readily cross the blood-brain barrier and to get access to the brain. Second, the high density of corticosteroid receptors expressed in brain areas involved in learning and memory, such as the hippocampus, septum, cerebral cortex and amygdala, denotes their key location to affect cognitive processing. Third, considerable evidence has shown that protein synthesis is required for long-term memory storage (Stork and Welzel, and also Mileusnic in this book for review). Given that the classic mechanism of corticosteroid action is to modulate gene transcription (with immediate effects on the synthesis of a number of proteins), this functional regulation might have important consequences both on the structural and functional characteristics of the nervous system, including the neurobiological processes involved in memory formation. Furthermore, it is nowadays well established that glucocorticoids affect numerous cellular and molecular events in brain cells,12,38 the main substrate of behaviour and cognition.

In order to question whether these hormones could actually affect cognitive function, different approaches have been used to investigate the role of glucocorticoids on memory formation:

Manipulation of the Degree of Stress Involved in the Training Task

Some studies have evaluated to what extent the strength of a long-term memory could be related to the degree of stress involved in the training situation. One way to assess this question is to manipulate the intensity of the stressor used as the unconditioned stimulus (US) in a particular task, and to subsequently evaluate whether any relationship can be observed between posttraining corticosterone levels and the degree of memory displayed by the animals.

In training tasks in which the US is a footshock, it is the intensity of the shock which is generally varied. Thus, experiments performed in the contextual fear conditioning task, involving groups of rats that received different shock intensities (0.2, 0.4 and 1 mA), observed a direct relationship between the stressor intensity experienced at training and the level of freezing displayed by rats at the testing session. Besides, posttraining corticosterone levels showed a positive correlation with the strength at which fear conditioning is established into a long-term memory.8 However, in the passive avoidance task, it has been reported that very high shock intensities, instead of resulting in potentiated memory, might have the opposite, inhibitory, effect on memory formation, an effect which seems to resemble the amnestic phenomenon associated to the experience of traumatic situations.

In the water maze task, a similar phenomenon has been described by manipulating the temperature of the pool water during the acquisition phase. Rats learning the task at a water temperature of19 °C showed a greater retention of the platform location on the second day of training than rats trained at 25 °C. Again, a relationship was found between the strength of memory and corticosterone levels displayed by rats after the first training session, with rats trained on the experimental conditions that led to a stronger and longer-lasting memory (i.e., at 19 °C) showing the highest circulating hormone levels.68

Therefore, these studies suggest the existence of a correlational relationship between corti-costerone secretion during training and the strength at which long-term memory is established. The following experimental approaches are complementary to this one, and were designed to evaluate the possible existence of a causal relationship between these two phenomena.

Inhibition of Glucocorticoid Secretion

A more direct way to question whether training-induced glucocorticoid secretion might play a role in memory formation is to interfere, around the time of training, either with hormone secretion, or with its neural action, and then to evaluate whether that might have any impact on later retention of the task.

Inhibition of hormone secretion can be accomplished through either surgical adrenalec-tomy or by injecting inhibitors of glucocorticoid synthesis, such as metyrapone or aminogluthetimide. In adrenalectomized animals, there is a total absence of circulating corti-costerone levels. Training rats under such conditions has proved to impair memory formation for a number of tasks, including contextual fear conditioning51 and water maze learning.48,58

Corticosteroid synthesis inhibitors induce a partial chemical adrenalectomy, causing a dose-dependent reduction of plasma corticosterone levels. Pretraining injection of glucocorti-coid synthesis inhibitors has also been reported to interfere, in a dose-dependent manner, with the strength and duration of newly formed memories. Among other tasks, this effect has again been reported for the water maze59 and contextual fear conditioning.7 Interestingly, the effect in the fear conditioning paradigm, in addition to being dose-related was also dependent on the stressor intensity used during training. Whereas systemic administration of a metyrapone dose of 100 mg/kg impaired memory in animals trained at either 0.4 or 1.0 mA shock intensity, a lower dose of 50 mg/kg was only effective to decrease memory in the 0.4 mA condition, suggesting an interaction of the drug dose effectiveness with the endogenous corticosterone levels induced by the training experience.

Therefore, these experiments further supported the idea that training-induced corticos-terone release plays an important role in the mechanisms that determine the strength of memories.

Inhibition of Glucocorticoid Action

Given that corticosterone is released from the adrenal glands, the question, then, is whether its effects are mediated via specific brain receptors or attributable to a peripheral action.

Several studies have addressed this question by administering selective MR or GR antagonists directly into the brain. In the water maze task, intracerebral injection of GR antagonists, either before or immediately after the first training session, decreased long-term retention of the platform location.48,56 However, administration of a MR antagonist, although it slightly changed rats' searching pattern at training, failed to affect subsequent retention of the task. As for the contextual fear conditioning task, the intracerebroventricular (icv) pretraining injection of a GR (RU-38486), but not a MR (RU-28316), antagonist diminished subsequent retention of conditioned freezing in rats trained at an intermediate shock condition (0.4 mA), but failed to affect retention levels in rats trained at a high shock intensity (1 mA).6 This could be either due to the fact that neural processes that mediate memory for drastic experiences might be under the influence of several physiological systems operating in a co-ordinated and redundant manner and, therefore, manipulating only one physiological system (such as MRs or GRs) might be insufficient to interfere with such a memory. However, the fact that we also found that a pretraining systemic injection of metyrapone (100 mg/kg) was effective to diminish the level of fear conditioning7 (see above), suggests that the lack of effect observed with the icv administration of the GR antagonist (100 ng) might have also been due to the use of a dose of the compound not high enough to antagonise all the relevant receptors, even though it should be noted that the same dose has been shown to be sufficient to interfere with a number of behavioural processes in other studies.48,28

From these findings and data obtained in other learning tasks and animal species (see Fig. 3), quite different roles have been proposed for each receptor type on cognitive processes.11,53, 2 Thus, activation of MRs seems to be essential for sensory integration and response selection. However, GR activation has been more directly implicated in the mechanisms of memory consolidation.







Pretraining ic injection



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  • kelsie campbell
    Do corticosteroids reduce neurotransmitters?
    2 years ago

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