T t t t t t t t

weeks months

TIME OF EXPOSURE TO ELEVATED GLUCOCORTICOIDS

Figure 7. Schematic representation of the effect of sustained exposure to elevated levels of glucocorticoids on hippocampal CA3 neurons. Animal studies have shown that pyramidal CA3 neurons undergo a time-dependent neurodegeneration process when expossed to excessive glucocorticoids or to sustained stress. When these conditions are mantained for 3-4 weeks, a reversible atrophy of apical dendrites is observed. However, if they last for longer time periods or occur in association with other neural challenges, an irreversible cell death could happen. Based on references cited by ref. 38.

In addition to glycoprotein regulation, evidence suggests that glucocorticoids could also exert their effects on learning and memory processes by their reported modulatory actions on other cellular and molecular factors implicated in cell function and survival, such as growth and neurotrophic factors.4,74

Furthermore, glucocorticoids can increase glutamate concentrations in the hippocampus as well as in other brain regions,31,44 and given that glutamate has been largely involved in the mechanisms of memory formation (see Riedel et al., this book), a regulatory action of corticos-terone through glutamatergic mechanisms has also been proposed.78

Effects of Chronic Exposure to Elevated Glucocorticoid Levels on Cognitive and Neural Function

Although the physiological responses to stress trigger a chain of reactions in the body to promote adaptation to the changing circumstances, it is certainly critical for the system to have an efficient mechanism to restrain these defense reactions to stress. However, when this machinery is damaged (which could happen, for example, when the activation of stress systems is either excessive or maintained chronically), the individual become more prone to develop different psychological and psychiatric disturbances. Conversely, such disturbances are generally associated with an inability to develop adaptive responses under challenging circumstances which, in turn, can potentiate the stress responses of the individual.

Neural Consequences of Chronic Glucocorticoid Exposure

Chronic exposure to either exogenous or stress-induced endogenous glucocorticoids has been associated with deficits in learning, memory and retrieval. These effects have mainly been related to the finding that chronic exposure to high levels of glucocorticoids can lead to atrophy of the hippocampus, both in animals and humans.38,33 In animals, vulnerability of hip-

Figure 8. Effects of chronic exposure to high glucocorticoid levels on spatial orientation learning and reversal learning. The results show that animals submitted to a corticosterone (Cort) treatment for 21 days did not differ from controls in their spatial learning abilities in the Morris water maze. However, when they were subsequently trained to find the platform in other locations of the pool, a consistent deficit was observed in corticosteroid-treated animals, which indicates a detrimental effect of the treatment on reversal learning abilities.

Figure 8. Effects of chronic exposure to high glucocorticoid levels on spatial orientation learning and reversal learning. The results show that animals submitted to a corticosterone (Cort) treatment for 21 days did not differ from controls in their spatial learning abilities in the Morris water maze. However, when they were subsequently trained to find the platform in other locations of the pool, a consistent deficit was observed in corticosteroid-treated animals, which indicates a detrimental effect of the treatment on reversal learning abilities.

pocampal neurons to a number of different insults was shown to be increased under chronic hypercortisolemia.72 Besides, although there has been some controversy as to whether prolonged exposure to stress or to high glucocorticoids levels could eventually result in neuronal loss, there is a general agreement that these treatments can result in more subtle structural changes in hippocampal neurons and, particularly, in the CA3 subregion. Thus, an atrophy of apical dendrites of CA3 pyramidal neurons —the site of mossy fiber projection- has been consistently found after 3-4 weeks of chronic stress or corticosterone treatments, both in rats35,77,80 and primitive primates.36 In addition, atrophy has also been found in granule and CA1 pyramidal cells77,80 (see Fig. 7).

This glucocorticoid-induced neural damage has attracted considerable attention for the critical role of the hippocampus in cognitive function and evidence which supports, in humans, the same type of interactions between chronic glucocorticoid exposure and hippocampal morphology.34,7 In addition, high levels of glucocorticoids have been hypothesised to accelerate brain ageing,29,73 which is frequently associated with learning and memory impairments.40 However, it should be noted that besides these changes in hippocampal structure, the possibility that other brain areas can be functionally altered by chronic stress and/or glucocorticoid administration has been suggested by several neurochemical and biochemical studies.23,43,63,79

Cognitive Consequences of Chronic Glucocorticoid Exposure

Although the initial reports suggested that sustained exposure to stress or high glucocorti-coid levels would result in cognitive impairments, the current picture suggest that the outcome depends on a number of factors, including the duration of the temporal exposure to these treatments, the type of demands involved in the cognitive tasks and individual differences in the vulnerability to develop alterations in hippocampal structure and function. Thus, whereas exposure to these treatments for around 3 months or longer seems to impair the acquisition of spatial learning in a variety of mazes,3,9,39 shorter exposure (for 3 weeks) of rats to stress or corticosterone regimes (which have been shown to induce reversible atrophy of pyramidal CA3 neurons as described above), hardly affected this type of learning.1'3'32 However, a cognitive deficit for these 3-week treatments is detected when rats are evaluated in tasks that require to develop a plastic strategy, such as in reversal learning paradigms (Fig. 8).

A surprising effect has been reported for the effect of a 3-week restraint stress regime on another hippocampus-dependent paradigm, the contextual fear conditioning task. Given that the hippocampus has been implicated to play a significant role in this learning task,27 a decreased conditioning was expected as the outcome of chronic stress. However, chronically stressed rats developed enhanced conditioning, not only when trained at an intermediate shock condition (0.4 mA),5 but also when trained at a high shock intensity (1 mA), an experimental condition that, by itself, leads to considerably high levels of conditioned freezing.69 Since morphological experiments showed that the potentiation of fear conditioning was also observed in stressed rats treated with daily injections of tianeptine (a tricyclic antidepressant that facilitates serotonin reuptake and prevents the development of hippocampal atrophy), the hippocampal alterations induced by chronic stress do not seem to be involved in the conditioning enhancement. It is quite possible that other brain regions, known to be neurochemically affected by this type of chronic regimes (particularly the amygdala, but also the prefrontal cortex or other cortical areas), are implicated in the observed potentiation of fear conditioning.

Therefore, chronic exposure to high glucocorticoid levels predispose individuals to develop enhanced fear conditioning responses, impaired acquisition of spatial learning and reduced behavioural flexibility, a variety of behavioural alterations that accompany and/or underlie many psychopathological disorders. However, it is also important to mention that recent findings indicate that individuals differ in their vulnerability to develop stress-induced cognitive alterations, a phenomenon that in rats seems to be related to the behavioural trait of reactivity to novelty, as well as to the type of demand involved in the stressful situation. Thus, whereas rats characterised by a hightened locomotor response (HR) in a novel environment show learning impairments after exposure to a social stress regime, the low reactive rats (LR) appear to be more affected when submitted to a restraint stress regime (Touyarot, Venero and Sandi, unpublished observations).

Conclusion

Evidence available to date indicates that glucocorticoids can exert profound effects on cognitive and neural function. However, these effects are varied and complex and, therefore, it is not possible to simplify their outcome. In general terms, the evidence discussed favors the hypothesis that GR activation induced by corticosterone released during the processing of information can contribute to the strength of newly formed memories. However, although we cannot conclude that exposure to chronic glucocorticoid elevations impairs performance in all tasks that require the integrity of the hippocampus, the behavioural alterations observed after chronic stress treatments suggest that their constellation of effects could be related to a number of psychopathological disorders. The recent observations of individual differences in the vulnerability to this type of disturbances after chronic stress supports the interest to develop future investigations addressed to find possible behavioural and physiological markers efficient to predict vulnerability of particular individuals to show cognitive alterations after sustained exposure to stressful situations.

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