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MR antagonist altered pecking pattern diminished avoidance GR antagonist no effect diminished avoidance

Figure 3. Schematic representation of the one-trial passive avoidance task in the day-old chick and the effects of the administration of mineralocorticoid (MR) and glucocorticoid (GR) receptor antagonists on memory for this task. On the training session, due to their innate tendency to peak salient objects in their environment, chicks peck at a bright bead which has been coated in an aversive substance. As a consequence, they display a disgust response and, when subsequently submitted to a retention test, they generally avoid pecking at a similar dry bead. Therefore, avoidance of the bead at test is an index of memory for the task. When chicks are intracerebrally (ic) injected with a MR antagonist prior to training, in addition to a reduction on avoidance at retention, they show an altered reactivity response during the training situation. However, when a GR antagonist is administered, only retrieval for the task is affected. Therefore, MRs are suggested to influence response activation at training, whereas GRs have been proposed to participate in the memory-facilitating mechanisms induced by glucocorticoids in the consolidation period. Based on data taken from refs. 66 and 67.

More recently, genetic tools developed to interfere with GR function have also provided further support for the role of GRs in memory formation as suggested by psychopharmacologi-cal studies. Thus, memory was impaired in experiments in which antisense oligonucleotides that prevented the synthesis of GR were injected in rats28 and in 'knock out' mice of the genes encoding for the GR.49

Potentiation of Glucocorticoid Action

Another way to explore whether posttraining glucocorticoid levels could have an impact on the consolidation of newly acquired information is to assess whether the strength of a memory could be potentiated by increasing corticosterone levels during the posttraining period. This idea has been validated under experimental conditions inducing low to moderate levels of both learning and corticosterone release. Posttraining injections (systemic or central) of either corti-costerone or synthetic corticosteroid agonists have proved to facilitate subsequent retention for a number of tasks, including passive avoidance,18,5 brightness discrimination42 contextual fear conditioning,6 and water maze learning.68

Figure 4. Memory or synaptic strength and corti-costeroid activation. A wide body of data has suggested that conditions in which either very low (as found, for example, in adrenalectomized animals) or very high (as it happens, for example, under strong stressful circumstances) circulating levels of glucocorticoids impair memory formation or syn-aptic potentiation (such as LTP). However, both memory storage and synaptic strength seem to be facilitated under mild stressful conditions involving glucocorticoid levels able to partially activate GRs, in addition to most MRs.

Figure 4. Memory or synaptic strength and corti-costeroid activation. A wide body of data has suggested that conditions in which either very low (as found, for example, in adrenalectomized animals) or very high (as it happens, for example, under strong stressful circumstances) circulating levels of glucocorticoids impair memory formation or syn-aptic potentiation (such as LTP). However, both memory storage and synaptic strength seem to be facilitated under mild stressful conditions involving glucocorticoid levels able to partially activate GRs, in addition to most MRs.

However, a different picture can be observed when animals display high circulating levels of corticosteroids during the posttraining period, either due to the injection of high doses of the steroid, or to the interaction of moderate dose injections with considerably stressful training situations. Thus, in one-day old chicks, the same corticosterone dose that facilitated memory for weak training conditions on the passive avoidance task, impaired memory in chicks trained in a strong learning version of the task.64 Similarly, whereas posttraining corticosterone injections enhanced consolidation processes in rats trained under water maze conditions involving intermediate stress levels (i.e., warm temperature),68 administration of dexamethasone impaired memory under more stressful conditions of the same task.58

Therefore, although there is considerable evidence to propose that endogenously released glucocorticoids potentiate memory consolidation processes by acting through brain GRs during the posttraining period, the whole range of modulatory actions induced by these steroids on cognitive processes requires to be described by an inverted-U shape relationship (Fig. 4). Thus, whereas intermediate glucocorticoid levels leading to the partial activation of GRs (in addition to MRs occupancy) facilitate consolidation, impaired retention is generally observed in animals trained under conditions of either absence (lack of MR and GR occupancy) or excess (high occupancy of MRs and GRs) of circulating corticosteroid hormone.

It is interesting to note that electrophysiological studies have shown similar biphasic modu-latory actions of glucocorticoids on synaptic plasticity. Expression of hippocampal long-term potentiation (LTP)—a long-lasting increase of synaptic efficacy induced by high-frequency electrical stimulation which appears to be relevant to memory—is dependent upon glucocorti-coid levels. Whereas adrenalectomy and elevated glucocorticoid levels interfere with synaptic potentiation, both in vivo and in vitro,13,50 intermediate glucocorticoid levels leading to partial occupation of GRs (in addition to MRs) lead to optimal expression of this phenomenon.76 Therefore, it seems that whereas MR's activation facilitates LTP, GR-induced effects depend upon their degree of occupation. Thus, while facilitating effects would follow their weak or partial occupancy, their extensive occupation would inhibit the induction of this type of synap-tic plasticity. Interestingly, inverted-U shape relationships have also been described for a number of cellular effecs of glucocorticoids, including calcium influx and responsiveness to transmitters.12 In addition, it is interesting to mention that GR activation has been implicated in the facilitation of long-term depression (LTD), a physiological phenomenon opposite to LTP that consists on a weakening of synaptic efficacy.5 ,81

Neural Mechanisms Involved in Glucocorticoid Actions on Memory Consolidation

Increasing attention is being devoted to the study of the neurobiological mechanisms by which glucocorticoids affect the processes of memory consolidation. Here, we will address this question at two different levels of analysis, by firstly dealing with the brain structures that have been implicated in glucocorticoid actions and, then, reviewing the cellular and molecular mechanisms that might mediate their effects.

Brain Regions Implicated in Glucocorticoid Effects on Memory Consolidation

The hippocampus is one of the brain structures implicated in the facilitating effects of GR activation on consolidation. Whereas intra-hippocampal administration of corticosterone or synthetic GR agonists enhanced memory consolidation for different tasks, infusions of a GR antagonist induced the opposite, impairing, effect on the storage of spatial orientation learning in the water maze.42,57 Although glucocorticoids could induce these facilitating effects by direct binding to hippocampal GRs, a regulatory influence of the amygdala has been proposed to be required for glucocorticoids to influence memory consolidation. In particular, the basolateral nucleus of the amygdala (BLA) has been implicated in the glucocorticoid-induced memory consolidation processes involving the hippocampus (Fig. 5).

In fact, studies involving a combination of amygdala lesions and systemic injections of glucocorticoids have led to the view that the BLA, but not the adjacent central nucleus of the amygdala (CEA), is critically involved in the memory-enhancing effects of posttraining glucocorticoids.54,55 This critical participation of the BLA in mediating glucocorticoid effects in memory consolidation involve binding of corticosterone to GRs in this brain area, as shown in experiments in which (i) local administration of a selective GR agonist enhanced retention for the passive avoidance task when administered into the BLA, but was ineffective when infused into the CEA; (ii) administration of a GR antagonist into the BLA interfered with memory for spatial orientation in the water maze.56

In addition, the integrity of the amygdala P-adrenergic system seems to be required for these facilitating actions of glucocorticoid on cognition.53

Cellular and Molecular Mechanisms Involved on Glucocorticoid Effects on Memory Consolidation

Protein synthesis mechanisms have been reported to be required for the transfer of information into a long-term memory storage in a variety of learning tasks. Given that glucocorticoids can regulate (either facilitating or inhibiting) the synthesis of a large number of proteins, including several which have been critically implicated in neural plasticity10,14 the possible involvement of a protein regulatory action on the modulatory actions of glucocorticoids on cognition is receiving increasing attention.62

Using the one-trial passive avoidance task in day-old chicks, a set of experiments was performed to evaluate whether the memory-facilitating effect that induces corticosterone in a weak training version of this learning model is dependent upon protein synthesis.65 By injecting the protein synthesis inhibitor anisomicyn at different times with regards to training, it was found that this inhibitor was effective to reverse the facilitatory effect of the steroid on retention when injected up to 4-5 h after training, but not at later time points. Therefore, these results suggested that receptor-mediated changes in gene expression were involved in the facilitating effect of corticosterone on consolidation. One important question to address from these findings was, therefore, which type/s of proteins could be relevant in this context.

Evidence obtained in the same chick learning model suggested that a family of fucosylated glycoproteins could play a major role, not only in the mechanisms of memory formation, as previously described, 0 but also in the memory enhancement induced by glucocorticoids. Firstly,

AMYGDALA NUCLEI

AMYGDALA NUCLEI

PRE TRAINING PASSIVE AVOIDANCE GLUCOCORTICOID TEST

LESION TRAINING INJECTION

PRE TRAINING PASSIVE AVOIDANCE GLUCOCORTICOID TEST

LESION TRAINING INJECTION

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