Claude Destrade

Time-dependent reorganization of brain circuitry underlying long-term memory storage

Retrograde amnesia observed following hippocampal lesions in humans and animals is typically temporally graded,, with recent memory being impaired while remote memories remain intact, indicating that the hippocampal formation has a time-limited role in memory storage,. However, this claim remains controversial because studies involving hippocampal lesions tell us nothing about the contribution of the hippocampus to memory storage if this region was present at the time of memory retrieval,. We therefore used non-invasive functional brain imaging using (14C)2-deoxyglucose uptake to examine how the brain circuitry underlying long-term memory storage is reorganized over time in an intact brain. Regional metabolic activity in the brain was mapped in mice tested at different times for retention of a spatial discrimination task. Here we report that increasing the retention interval from 5 days to 25 days resulted in both decreased hippocampal metabolic activity during retention testing and a loss of correlation between hippocampal metabolic activity and memory performance. Concomitantly, a recruitment of certain cortical areas was observed. These results indicate that there is a time-dependent reorganization of the neuronal circuitry underlying long-term memory storage, in which a transitory interaction between the hippocampal formation and the neocortex would mediate the establishment of long-lived cortical memory representations.

Memory-improving action of glucose: indirect evidence for a facilitation of hippocampal acetylcholine synthesis

The effect of a 3 g/kg glucose injection on the velocity of the sodium-dependent high-affinity choline uptake mechanism in the hippocampus was both measured in quiet control mice and in mice immediately after training in an operant bar pressing task. Glucose did not significantly change high-affinity choline uptake in resting animals. High-affinity choline uptake in the hippocampus was increased by training in the operant bar pressing task. Glucose significantly reduced the amplitude of the increase in high-affinity choline uptake observed in the trained animals. Similarly, a 3 g/kg glucose injection also attenuated the increase in high-affinity choline uptake observed in animals injected with 1 mg/kg scopolamine. Finally, a 3 g/kg glucose injection significantly attenuated the amnesia produced by a post-training 1 mg/kg scopolamine injection in mice trained for an operant bar pressing task. These results provide additional evidence for an action of glucose on hippocampal cholinergic activity under conditions of high acetylcholine demand. This action may be mediated via an increase in acetyl coenzyme A availability, one of the precursors of acetylcholine. This facilitative effect of glucose on hippocampal acetylcholine synthesis may constitute the physiological basis for its facilitative action on memory and its attenuation of scopolamine amnesia.

Effects of posttrial hippocampal stimulation on acquisition of operant behavior in the mouse

One-hundred male mice were used of which 70 were bilaterally implanted in dorsal hippocampus. Three experiments were performed: (1) The threshold of electrical seizure was measured by bilateral stimulation of hippocampus. (2) The animals were introduced in a Skinner box and allowed to press 8 times on a lever. Each press was reinforced by a food pellet. Thirty seconds after the eighth press, the two hippocampi were stimulated for 80 sec. The intensity of current was half of the threshold determined in the first experiment. Mice receiving hippocampal stimulation showed better retention of learning than not implanted and nonstimulated mice. (3) In the third experiment the temporal gradient of hippocampal stimulation was estimated; after a 600-sec delayed stimulation no improvement of performances was observed.

Time-dependent improvement of performance on appetitive tasks in mice

Three experiments were carried out to study improvement of performance with time on appetitive tasks in BALB/c mice. Experiments 1 and 2 showed that a 24-hr interval between learning sessions significantly improves performance. It seems that there was a curvilinear relationship between this improvement and the 1st learning session duration. Experiment 3 showed that improvement is time-dependent and occured between 1 and 12 hr after the end of the learning session. These results confirm the hypothesis according to which the consolidation phase should be more an elaborative process than a simple fixing.

Improvement of memory for an operant response by post-training glucose in mice

Previous experiments have shown that a post-training glucose injection can retroactively and non-contingently improve the retention of a previously learned association. To date, the memory-improving action of glucose has only been demonstrated in rats for negatively-motivated tasks. The present experiment sought to generalize these previous results by examining the effects in mice of post-training glucose injections on the retention of an operant bar-pressing response. The results show that post-training glucose can retroactively and non-contingently improve the retention of an appetitively motivated task in mice. There was a U-shaped relationship between the dose of glucose and the effect on memory similar to the ones already observed in rats using negatively motivated training. The implications of these results for an endogenous memory modulation mechanism are discussed.

Differential learning-stage dependent patterns of c-Fos protein expression in brain regions during the acquisition and memory consolidation of an operant task in mice

The present study analysed the effects of the stage of learning of an appetitive operant conditioning task on the spatial and temporal patterns of c‐Fos protein levels in the brain of BALB/c mice. c‐Fos levels were assessed by immunohistochemistry at either 60, 120 or 180 min after either the first, the second or the fifth daily training session and compared to sham animals. The results show an increase of c‐Fos‐positive nuclei in several subcortical and cortical brain regions, 60‐min post‐acquisition. Because these activations were a function of task mastery, the data indicate that they were specifically related to learning. Following the first acquisition session, significant increases in c‐Fos‐positive neurons were observed in the dorsal hippocampus (CA3), anterior cingulate, occipital and parietal cortices. Following the second daily training session, c‐Fos was highly expressed in some subcortical regions, the hippocampus, the subiculum, the entorhinal, and posterior cingulate areas. Moreover, a significant correlation was found between the progression of performance from day 1 to day 2 and c‐Fos expression on the hippocampal CA1 subfield. Following complete acquisition, no further task‐dependent increases in c‐Fos‐labelled nuclei was observed in any brain region sampled, suggesting that the intervention of c‐Fos‐induced mechanisms in the consolidation process were terminated. The training stage‐dependent changes in regional post‐training c‐Fos expression in the hippocampus and the connected limbic regions suggest that this neuronal network is actively engaged in memory consolidation processes.

Effects of hippocampal electrical stimulation on long-term memory and on cholinergic mechanisms in three inbred strains of mice.

Two sets of experiments have been carried out in an attempt to determine the role of hippocampal cholinergic mechanisms in a long-term memory storage. Three inbred strains of mice were presented with two different learning tasks in order to estimate their long-term retention abilities as well as changes in this ability after a post-trial hippocampal stimulation. In parallel experiments the enzymes involved in acetylcholine metabolism were studied under different experimental conditions. Our results indicate: (a) The capacity for long-term memory of the BALB/c line is much greater than that of either the C57BL/6 or C57BR strain. (b) Hippocampal post-trial electrical stimulation leads to an improvement of this capacity in the BALB/c strain. This phenomenon is less pronounced in C57BL/6 and non-existent in C57BR mice. (c) Choline acetyltransferase activity in the hippocampus is significantly higher in BALB/c than in the other two strains. In BALB/c this enzyme activity is greatly changed by the post-trial stimulation whereas in the C57BL/L strain only a slight variation of enzyme activity is observed. No modification occurs in C57BR. The results suggest that the more active acetylcholine synthesizing enzyme in the hippocampus of BALB/c may be related to a greater acetylcholine availability, thus favoring the establishment of a long-term memory, perhaps by releasing greater amounts of acetylcholine in the hippocampus immmediately after the learning session. The electrical stimulation of the hippocampus acts to magnify or accelerate this phenomenon. It is suggested that the efficiency of the stimulation would be related to the genetically determined higher cholinergic activity of the hippocampus.

Memory processing and apamin induce immediate early gene expression in mouse brain

The present study analyses the effects of learning on the spatial pattern and the time-course of changes of immediate early gene messenger RNAs (c-fos and c-jun) in mouse brain produced by training in an appetitive bar-pressing task. Activation of c-fos and c-jun after training is strictly located in the hippocampal formation and is learning-dependent. Levels of both proto-oncogene mRNAs in the trained group were 4 to 5 times higher than in the sham-conditioned group. Injections of apamin, a bee venom neurotoxin that selectively blocks a class of Ca(2+)-activated K+ channels and improves learning and memory retention, produced as compared to untrained animals a 3- to 5-fold increase of expression of c-fos and c-jun with the same pattern as that observed in the trained animals. Post-training injection of 0.2 mg/kg apamin enhanced 1.4-fold the expression of both immediate early genes in CA1, CA3 and dentate gyrus as compared to trained saline-injected mice. All these results suggest that apamin-induced increase of immediate early gene expression might be related to the apamin-induced facilitation of learning.

Memory formation as related to genotypic or experimental variations of hippocampal cholinergic activity in mice.

Abstract Two successive experiments were designed to compare learning and retention and the post-training effect of hippocampal electrical stimulation on retention of a lever-press conditioning among several groups of mice. In parallel experiments, we studied the enzymes involved in acetylcholine metabolism in the dorsal hippocampus. Results showed that either a genotypic or an experimentally induced decrease of choline acetyltransferase activity weakened both long-term retention and the facilitatory effect of post-trial stimulation but improved short-term retention. The role of hippocampal cholinergic synapses in response execution and memory consolidation is discussed.

Post-trial hippocampal and lateral hypothalamic electrical stimulation. Facilitation on long-term memory of appetitive and avoidance learning tasks.

Mice of the BALB/c strain were bilaterally implanted with bipolar platinum electrodes either in the CA1 field of the dorsal hippocampus (HPC) or in the dorsolateral hypothalamus (HL) in order to compare the effects of postsession electrical stimulation on learning and memory. Two learning tasks were used, a discriminative food-reinforced conditioning task and a one-trial passive avoidance conditioning task. In the first two experiments, 30 sec after the end of the first learning session, subjects were stimulated during 80 sec. HPC stimulation intensity was half of afterdischarge threshold values; at HL stimulation intensity (10 μA per electrode) self-stimulation behavior (I.C.S.S.) was effective. Control groups constituted by nonoperated (n.i.) or operated nonstimulated animals (n.ST.HL and n.ST.HPC) were used. In the third experiment the HL stimulation intensities were lowered under the I.C.S.S. threshold values and their post-trial applications were tested on discriminative operant conditioning. Results from experiments I and II showed that HL as well as HPC stimulation improved performances registered during 24-hr delayed retention sessions. However, differences were observed between HL and HPC stimulation. First, HL appeared to be less effective than HPC stimulation on passive avoidance conditioning; second, compared to HPC-stimulated animals, HL-stimulated animals had over all the sessions significantly higher response rates during the food-reinforced sequences and during the nonreinforced sequences. In addition, the small lesions (200 μ m in diameter) due to HL- and HPC-implanted electrodes disturbed in n.ST animals the pattern of retention, but this disruptive effect was task dependent and appears only in the discriminative operant conditioning. In the third experiment, subthreshold I.C.S.S. behavior intensities were found to have a significant facilitative effect. These data indicate (i) that post-trial HL as well as HPC stimulations have similar facilitative effects on retention of learning tasks whether controlled by positive or negative reinforcement; and (ii) that these effects are not dependent on a reward component. It was concluded that the facilitatory effects of these stimulations can be ascribed to their common ability to induce an arousal state during the post-training period.