A role for brain glucocorticoid receptors in contextual fear conditioning: dependence upon training intensity

We studied the possible involvement of corticosteroids in the establishment and long-term expression of contextual fear conditioning and questioned whether a corticosteroid action might be dependent upon stimulus intensity at training. Experiments included: (i) the intracerebroventricular administration of specific antagonists for the two types of intracellular corticosteroid receptors to rats trained at either 1 mA or 0.4 mA shock intensity at conditioning; and (ii) the administration of corticosterone after conditioning rats to 0.2 mA shocks. The results showed that the administration of a type II glucocorticoid, but not a type I mineralocorticoid, receptor antagonist before conditioning rats to the intermediate shock condition attenuated long-term expression of contextual fear conditioning. However, treatment with the antagonists before conditioning to the high shock intensity failed to influence the extent of fear conditioning. In addition, an intraperitoneal corticosterone injection, given immediately after training rats at the low shock intensity, enhanced long-term expression of the fear response. The results support the view that post-training levels of circulating corticosterone, through an interaction with central type II glucocorticoid receptors, modulate the strength to which memory for contextual fear conditioning is established and maintained.

Prior exposure to a single stress session facilitates subsequent contextual fear conditioning in rats. Evidence for a role of corticosterone

Maria Isabel Cordero Campana, Maria del Carmen Sandi Perez

Previous studies showed that exposure of rats to chronic restraint stress for 21 days enhances subsequent contextual fear conditioning. Since recent evidence suggest that this effect is not dependent on stress-induced neurodegenerative processes, but to elevated training-elicited glucocorticoid release in chronically stressed animals, we aimed to explore here whether a single exposure to restraint stress, which is not expected to induce neuronal damage, would also affect contextual fear conditioning. We also questioned whether post-training corticosterone levels might be associated with any potential effect of stress on fear conditioning. Adult male Wistar rats were exposed to acute restraint stress for 2 h and, two days later, trained in the contextual fear conditioning task, under training conditions involving either moderate (0.4 mA shock) or high (1 mA shock) stress levels. The results showed that acute stress enhanced conditioned freezing at both training conditions, although data from the 1 mA shock intensity experiment only approached significance. Stressed animals were shown to display higher post-training corticosterone levels. Furthermore, the facilitating effect of prior stress was not evident when animals were trained in the hippocampal-independent auditory-cued conditioning task. Therefore, these findings support the idea that stress experiences preceding exposure to new types of stressors facilitate the development of contextual fear conditioning. They also indicate that not only repeated, but also a single exposure to aversive stimulation is sufficient to facilitate context-dependent fear conditioning, and suggest that increased glucocorticoid release at training might be implicated in the mechanisms mediating the memory facilitating effects induced by prior stress experiences.

2003

Glucocorticoid involvement in memory formation in a rat model for traumatic memory

Maria Isabel Cordero Campana, Maria del Carmen Sandi Perez

Contextual fear conditioning under training conditions involving high stressor intensities has been proposed as an animal model for traumatic memories. The strength of memory for this task has been related to the intensity of the conditioning stressor and post-training corticosterone values. However, administration of a glucocorticoid receptor (GR) antagonist only attenuated memory for this task in rats conditioned at a moderate shock intensity (0.4 mA), but failed to influence conditioning in rats trained at a high shock intensity (1 mA). Here, we further questioned whether interfering with glucocorticoid action at the time of training might be effective in influencing contextual fear conditioning in rats trained under different shock intensities. Rats were subcutaneously injected with the glucocorticoid synthesis inhibitor metyrapone (50, 100 mg/kg) 90 min before being trained in the contextual fear conditioning task, at either 0.4 or 1 mA shock intensities. The results showed that metyrapone, in a dose-dependent manner: (i) attenuated long-term expression of contextual fear conditioning, both in 0.4- and 1 mA-trained rats; and (ii) efficiently prevented increased plasma corticosterone concentration. In addition to further supporting a facilitating role of glucocorticoids in memory consolidation, these findings suggest a critical involvement of these hormones in the formation of traumatic memories.

2002

Post-training administration of a synthetic peptide ligand of the neural cell adhesion molecule, C3d, attenuates long-term expression of contextual fear conditioning

Maria del Carmen Sandi Perez

The neural cell adhesion molecule (NCAM) plays a key role in synaptic plasticity and memory formation. We have recently developed a synthetic peptide, termed C3d, which, through the binding to the first, N-terminal immunoglobulin-like (Ig) module in the extracellular portion of NCAM, has been shown to promote neurite outgrowth and synapse formation in vitro, and to interfere with passive avoidance memory in rats in vivo. In this study, we investigated whether the i.c.v. administration of C3d, either 5.5 h after or 2 days before training, could be effective to modulate the strength at which emotional memory for aversive situations is established into a long-term memory. The effects of the peptide were evaluated in adult male Wistar rats trained in the contextual fear conditioning task. The results indicated that C3d significantly reduced the subsequent long-term retention of the conditioned fear response when administered 5.5 h post-training, as indicated by retention tests performed 2-3 and 7 days post-training. However, this treatment failed to influence conditioning for this task when injected 2 days pre-training. Additional experiments showed that C3d did not influence the emotional or locomotor behaviour of the animals, when tested in the open field task. Furthermore, hippocampal levels of microtubule-associated protein 2 (MAP2), Synaptophysin and NCAM were found unchanged when evaluated by enzyme-linked immunosorbent assay in crude synaptosomal preparations 2 days after peptide i.c.v. injection. Therefore, post-training injection of this synthetic peptide was efficient to attenuate the strength at which memory for contextual fear conditioning was enduringly stored, whilst it did not affect the acquisition of new memories. In addition to further support the view that NCAM is critically involved in memory consolidation, the current findings suggest that the NCAM IgI module is a potential target for the development of therapeutic drugs capable to reduce the cognitive impact induced by exposure to intensive stress experiences.

2003

Post-training administration of a synthetic peptide ligand of the neural cell adhesion molecule, C3d, attenuates long-term expression of contextual fear conditioning

Maria del Carmen Sandi Perez

2003

Prior exposure to a single stress session facilitates subsequent contextual fear conditioning in rats. Evidence for a role of corticosterone

Maria Isabel Cordero Campana, Maria del Carmen Sandi Perez

2003