Non-competitive NMDA antagonist MK-801 prevents memory reconsolidation impairment caused by protein synthesis inhibitors in young chicks.

Introduction: Reactivation of already consolidated memory can initiate its destabilization, making the memory trace labile. Normally, this destabilization is followed by reconsolidation of the memory trace, enriched by newly acquired experience. Disrupting the reconsolidation process, for example, by inhibiting protein synthesis, impairs subsequent memory retrieval, leading to reminder-related amnesia. Previous studies in various species have shown that this impairment can be prevented by using NMDA receptor antagonists, which interfere with memory destabilization. Methods: In the present study we examined this phenomenon using a one-trial passive avoidance learning model in newborn chicks, the hypothesis being that inactivation of the NMDA-mediated transmission during memory reactivation would inhibit the memory trace labilization and thus prevent the reminder-related amnesia. Results: We found that reminder-associated administration of the NMDA receptor antagonist MK-801 or one of the protein synthesis inhibitors (anisomycin, cycloheximide, 2-deoxygalactose) each alone produced amnesia. However, when combined, injection of MK-801 before the reminder prevented amnesia induced by protein synthesis inhibitors. Discussion: We suggest that the observed paradoxical effect implicates the involvement of NMDA receptors in both protein synthesis-independent engram destabilization upon its retrieval and protein synthesismediated engram stabilization after its updating. This puzzling dual role of NMDA receptors in memory destabilization/restabilization requires further investigation.

Recovery of Impaired Memory: Expression of c-Fos and Egr-1 Transcription Factors during Restoration of Damaged Engram in the Chick Brain.

Impairment of protein synthesis in the brain during learning prevents memory consolidation and results in amnesia, which until recently has been regarded irreversible. However, in some cases impaired memory could be restored by various "reminder" stimuli. The present study is based on the hypothesis that even in behaviorally profound amnesia, some disintegrated fragments of the engram are preserved in the brain and could be re-integrated into the whole system by specific types of stimuli. The aim of the present study was to test this hypothesis in an experimental model of pharmacologically induced memory impairment in young chicks and to reveal the brain areas involved in this process by mapping of reminder-induced expression of transcriptional factors c-Fos and Egr-1. We show that reminder treatment results in the recovery of memory impaired by protein synthesis inhibition during learning and induces c-Fos and Egr-1 expression in the brain regions involved in learning in this behavioral model. The patterns of c-Fos and Egr-1 induced expression in animals with impaired memory differed from the patterns of animals with unimpaired memory and as well as naïve animals with no memory. Thus, analysis of activity-induced c-Fos and Egr-1 expression revealed the brain regions that were specifically activated by the reminder treatment. At the behavioral level, this treatment led to memory recovery. Altogether, these results suggest that the reminder-induced transcriptional activity in the brain of amnestic animals occurs in regions maintaining the engram fragments that reintegrate to recover the impaired memory.

[Possibility of memory reparation: conditioned freezing disrupted by protein synthesis inhibition can be restored by reminder stimulation in mice].

Memory consolidation is a term used to describe the process of memory stabilization from labile, easily disrupted state into disruption-resistant long-term form. Protein synthesis inhibitors injected before or immediately after learning episode, produce significant amnesia. However in a limited number of studies the possibility of memory recovery after such pharmacologically-produced amnesia was shown. The aim of present study was to investigate the possibility of memory recovery in single-session fear conditioning paradigm in mice. Mice were injected with protein synthesis inhibitor cycloheximide twenty minutes prior learning to induce amnesia. Twenty four hours after training mice were subjected to reminder shock, similar to one used during training. Amnestic animals have demonstrated complete recovery of cued fear memory to the level of normal animals when tested 24h after reminder presentation. Thus our data indicate that specific type of memory might be restored using nonspecific stimulus as a reminder. Possible mechanisms of memory reparation after PSI injection during learning are discussed.

[The effect of a caudal hippocampus lesion on learning in a Morris water maze in bank voles (Clethrionomys glareolus)].

A bilateral cytotoxic lesion of the caudal hippocampus (about 1/3 of the whole hippocampus, which is insufficiently studied) influences learning of bank voles (Clethrionomys glareolus) in the Morris water maze. This effect has been estimated in this paper. A version of the test intended to measure long-term spatial memory was used. The lesion was shown to exert an influence on the learning dynamics by slowing it down, as well as to reduce the accuracy of platform location memorizing at early stages of training. The data obtained indicate the involvement of this area in control of spatial learning in rodents.

Increased 5-bromo-2'-deoxyuridine incorporation in various brain structures following passive avoidance training in mice.

We studied the effects of training on DNA synthesis intensity in mouse brain. Brain cells where DNA synthesis-associated processes took place under the influence of training were detected by immunohistochemical labeling of DNA molecules with synthetic thymine analogue 5-bromo-2'-deoxyuridine. The number of 5-bromo-2'-deoxyuridine-positive cell increased in various structures of the brain under the influence of training.

Recovery of impaired memory and c-fos gene expression in brains of amnestic animals in response to reminder stimulation.

Possible mechanisms of recovery of the memory impaired during consolidation process were investigated. In mice, amnesia was induced by intraperitoneal cycloheximide (100 mg/kg) administration 20 min before exposure to tone signal combined with footshock (2 sec, 0.5 mA). Reminder by the footshock (2 sec, 0.5 mA) 24 h after the learning procedure resulted in recovery of impaired memory in amnestic animals up to the level of control animals. Analysis of c-Fos expression in response to reminder indicated increased number of c-Fos-positive cells in prelimbic cortex in the animals with unaffected memory in comparison with corresponding parameter in amnestic animals. These findings are indicative of impairment in prelimbic cortex activity in experimental amnesia as well as for reminder ability to recover the memory impaired in that way.

Increased 5-bromo-2'-deoxyuridine incorporation in various brain structures following passive avoidance training in mice.

We studied the effects of training on DNA synthesis intensity in mouse brain. Brain cells where DNA synthesis-associated processes took place under the influence of training were detected by immunohistochemical labeling of DNA molecules with synthetic thymine analogue 5-bromo-2'-deoxyuridine. The number of 5-bromo-2'-deoxyuridine-positive cell increased in various structures of the brain under the influence of training.

Immunohistochemical detection of two neuronal populations involved in two different episodes of animal cognitive activity.

We developed a method to detect and superimpose neuronal populations involved in two different episodes of activity in the brain of single animal. This method is based on usage of two transcriptional factors with different accumulation curves, c-Fos and pCREB, as the markers. The overlap of neuronal populations involved in performance of spatial and nonspatial tasks in Morris water maze has been shown to occur at "chance" level.