Elsevier

Behavioural Brain Research

Volume 183, Issue 1, 1 October 2007, Pages 101-110
Behavioural Brain Research

Research report
Contribution of corticosterone to cued versus contextual fear in rats

https://doi.org/10.1016/j.bbr.2007.05.034Get rights and content

Abstract

Several studies have suggested a positive relationship between circulating corticosterone levels and contextual conditioning. However, a positive relationship between circulating corticosterone levels and cued conditioning has also been reported. This study further investigates the relationship between corticosterone and fear conditioning by modulating the predictive value of contextual and discrete tone cues in separate groups of rats. In a first experiment in which training parameters were chosen to induce strong conditioning (five foot-shocks), we used a correlational approach and investigated whether post-training corticosterone levels were related to subsequent expression of contextual and/or tone fear. In a second experiment, in which training parameters were chosen to induce lower conditioning (one and two foot-shocks), we investigated whether a post-training corticosterone injection enhanced the consolidation of contextual and/or tone conditioning.

In the first experiment, the highest post-training corticosterone levels were obtained in rats trained with paired tones and shocks. Post-training corticosterone levels tended to be positively correlated with freezing scores during the tone-fear test and were negatively correlated with freezing scores during training although not during the context-fear test. In the second experiment, a post-training injection of corticosterone (3 mg/kg) had no effect on subsequent freezing to contextual cues and to a tone that did not predict shock, whereas it was efficient in increasing fear conditioned to a predictive tone. Globally, these results suggest that the predictive value of the conditioned stimulus may be the main determinant of the facilitatory action of acutely enhanced corticosterone in fear conditioning.

Introduction

An extensive literature indicates that cognitive and emotional processes interact in determining a subject's behaviour. In particular, emotional arousal can impair the retrieval of stored information, but usually facilitates memory consolidation in animal and human [38]. This effect of real or anticipated emotionally arousing events is at least partly attributable to an increase in glucocorticoid circulating levels through the activation of the hypothalamo–pituitary–adrenal (HPA) axis. In the brain, glucocorticoids bind to two intracellular receptors, the high-affinity mineralocorticoid receptor (MR) activated under basal conditions and the low-affinity glucocorticoid receptor (GR) activated when glucocorticoids circulating levels are higher [36]. GR activation occurs during the circadian peak of glucocorticoids release or during activation of the HPA-axis [5] and these receptors have been implicated in memory consolidation processes [28], [37], [45].

There are indications that glucocorticoids can modulate the consolidation of memory in appetitively motivated tasks [51] but most of the evidence comes from aversely motivated tasks, and moreover from tasks involving a large contextual or spatial component. For instance, in the rodent, reductions in glucocorticoid receptor activation by adrenalectomy or pretraining systemic or intracerebroventricular injection of GRs antagonists produce memory impairments in water maze [28], [43] and fear conditioning [10], [32], [33], whereas systemic corticosterone or GRs agonist administration shortly after training has been shown to facilitate memory in the same tasks [10], [46] as well as to enhance retention of passive avoidance [40].

Evidence for a role of glucocorticoids in memory consolidation is also provided by studies showing a positive relationship between long-term memory and training-induced corticosterone release [9], [46].

The question however arises as to whether glucocorticoids can bias memory in specific ways, influencing the type of information that is consolidated. Indeed, it has been suggested that glucocorticoids selectively modulate consolidation of contextual information assessed using a Pavlovian fear conditioning paradigm. In such a paradigm, subjects are exposed to inescapable footshocks (unconditioned stimulus, US) signalled by a discrete conditioned stimulus (CS) that precedes each US in a paired manner, in a conditioning chamber which constitutes the learning context. When later re-exposed to this context, animals exhibit species-specific fear responses (conditioned responses, CRs) to both the CS (cued fear) and the context (contextual fear). Contextual and cued fear can be measured using the same behavioural index, freezing behaviour, that is the suppression of all visible movements except from those needed for respiration [4], [16]. In this task, reducing corticosterone below normal physiological levels by adrenalectomy has been shown to prevent contextual but not cued fear conditioning [33]. Contextual but not cued fear is also reduced by GRs antagonists administered either pretraining or post-training [32]. Additionally, Pugh et al. [33] have shown that the impairing effects of adrenalectomy on contextual fear conditioning are prevented by corticosterone administration either before or after conditioning but also by a context preexposure before conditioning. Based on these data, these authors have suggested that corticosterone may contribute to the consolidation of contextual memory. Nevertheless, recent findings have shown that post-training administration of glucocorticoids enhances cued fear [20], [39], [51] suggesting that enhanced corticosterone levels can play a role in the consolidation of cued-fear memory. Taken together, these results suggest that corticosterone may facilitate both contextual and cued fear conditioning but, to date, this hypothesis has not been so far definitely tested.

The aim of this study was to further investigate the interaction between circulating corticosterone levels and fear conditioning to discrete and contextual cues under normal physiological conditions. Our hypothesis was that a selective effect of corticosterone on memory consolidation might depend upon the predictive value of the to-be conditioned cues rather upon their nature, i.e. contextual cues versus discrete cues. Therefore, we used training procedures in which the contextual cues could compete with a discrete cue [27], [35] and modulated the predictive value of these cues in separate groups of rats by training them with either a paired or an unpaired procedure [13], [23], [31]. In the paired procedure, the CS immediately precedes each US delivery. Rats later exhibit strong conditioned freezing to the CS and low conditioned freezing to the context, indicating that the CS is a better predictor of the US than the context when USs are signalled. In the unpaired procedure, the CSs and USs are presented at different instants. Rats later exhibit strong conditioned freezing to the context and low conditioned freezing to the CS, indicating that the context is a better predictor of the US than the CS when USs are unsignalled. In both situations, however, the context remains an imperfect predictor of shocks, because it is present throughout the inter-trial intervals.

Two approaches were used to assess the relationship between corticosterone levels and conditioned fear. In a first experiment in which training parameters were chosen to induce strong conditioning (five US deliveries), we used a correlational approach and investigated whether post-training corticosterone levels were related to subsequent expression of contextual and/or cued fear. In a second experiment, in which training parameters were chosen to induce lower conditioning (one and two US deliveries), we investigated whether a post-training corticosterone injection enhanced contextual and/or cued conditioning.

Section snippets

Subjects

Naïve Long-Evans male rats were obtained from a commercial supplier (Centre d’Elevage et de Recherche Janvier, le Genest-St-Isle, France) at about 8 weeks of age. They were housed in pairs in standard rat cages throughout the experiment with ad lib food and water and a 12-h light:12-h dark cycle (light on at 07:00 a.m.). Conditioning and testing took place in the morning, during the light phase of the cycle. The rats were weighted and handled for 2 min on each of 3 consecutive days before

Experiment 1

The first experiment aimed at testing the effect of the training procedure on post-conditioning plasmatic corticosterone levels, and attempted to correlate this physiological variable with subsequent contextual and/or cued fear expression measured as freezing behaviour. It was expected that individual and group differences in corticosterone levels during conditioning might modulate the level of fear to either the context or the explicit auditory cue. Freezing behaviour and corticosterone were

Experiment 2

The previous experiment indicated that high corticosterone levels were not predictive of subsequent fear to the context. However, rats trained with the paired procedure and strongly conditioned to the tone CS showed the highest corticosterone levels. It is therefore possible that increased corticosterone levels could selectively modulate the consolidation of fear to the predictive CS. This experiment aimed at testing this issue. A paired and an unpaired group were used in order to manipulate

Discussion

The present study provides three types of data to evaluate the role of glucocorticoids in cued and contextual conditioning: the post-conditioning corticosterone levels following different conditioning procedures, the predictive value of these levels with respect to the subsequent expression of fear, and finally the effect of a post-conditioning increase in corticosterone on these same tests. The results showed (i) that conditioning to a predictive tone cue tended to increase corticosterone

Acknowledgements

The authors are grateful to G. Crema for her help, to D. Beracochea and E. Coutureau for valuable discussions and to O. Bildstein, G. Edomwonyi and D. Egesi for animal care.

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